[House Hearing, 105 Congress]
[From the U.S. Government Publishing Office]



 
                 DEPARTMENTS OF LABOR, HEALTH AND HUMAN
               SERVICES, EDUCATION, AND RELATED AGENCIES
                        APPROPRIATIONS FOR 1999

========================================================================

                                HEARINGS

                                BEFORE A

                           SUBCOMMITTEE OF THE

                       COMMITTEE ON APPROPRIATIONS

                         HOUSE OF REPRESENTATIVES

                       ONE HUNDRED FIFTH CONGRESS

                             SECOND SESSION
                                ________

  SUBCOMMITTEE ON THE DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, 
                    EDUCATION, AND RELATED AGENCIES

                 JOHN EDWARD PORTER, Illinois, Chairman

C. W. BILL YOUNG, Florida        DAVID R. OBEY, Wisconsin
HENRY BONILLA, Texas             LOUIS STOKES, Ohio
ERNEST J. ISTOOK, Jr., Oklahoma  STENY H. HOYER, Maryland
DAN MILLER, Florida              NANCY PELOSI, California
JAY DICKEY, Arkansas             NITA M. LOWEY, New York
ROGER F. WICKER, Mississippi     ROSA L. DeLAURO, Connecticut
ANNE M. NORTHUP, Kentucky        

NOTE: Under Committee Rules, Mr. Livingston, as Chairman of the Full 
Committee, and Mr. Obey, as Ranking Minority Member of the Full 
Committee, are authorized to sit as Members of all Subcommittees.

  S. Anthony McCann, Robert L. Knisely, Carol Murphy, Michael K. Myers,
                and Francine Salvador, Subcommittee Staff
                                ________

                                 PART 4A
                             (Pages 1-1682)

                      NATIONAL INSTITUTES OF HEALTH

                              

                                ________

         Printed for the use of the Committee on Appropriations
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                       COMMITTEE ON APPROPRIATIONS                      

                   BOB LIVINGSTON, Louisiana, Chairman                  

JOSEPH M. McDADE, Pennsylvania         DAVID R. OBEY, Wisconsin            
C. W. BILL YOUNG, Florida              SIDNEY R. YATES, Illinois           
RALPH REGULA, Ohio                     LOUIS STOKES, Ohio                  
JERRY LEWIS, California                JOHN P. MURTHA, Pennsylvania        
JOHN EDWARD PORTER, Illinois           NORMAN D. DICKS, Washington         
HAROLD ROGERS, Kentucky                MARTIN OLAV SABO, Minnesota         
JOE SKEEN, New Mexico                  JULIAN C. DIXON, California         
FRANK R. WOLF, Virginia                VIC FAZIO, California               
TOM DeLAY, Texas                       W. G. (BILL) HEFNER, North Carolina 
JIM KOLBE, Arizona                     STENY H. HOYER, Maryland            
RON PACKARD, California                ALAN B. MOLLOHAN, West Virginia     
SONNY CALLAHAN, Alabama                MARCY KAPTUR, Ohio                  
JAMES T. WALSH, New York               DAVID E. SKAGGS, Colorado           
CHARLES H. TAYLOR, North Carolina      NANCY PELOSI, California            
DAVID L. HOBSON, Ohio                  PETER J. VISCLOSKY, Indiana         
ERNEST J. ISTOOK, Jr., Oklahoma        ESTEBAN EDWARD TORRES, California   
HENRY BONILLA, Texas                   NITA M. LOWEY, New York             
JOE KNOLLENBERG, Michigan              JOSE E. SERRANO, New York           
DAN MILLER, Florida                    ROSA L. DeLAURO, Connecticut        
JAY DICKEY, Arkansas                   JAMES P. MORAN, Virginia            
JACK KINGSTON, Georgia                 JOHN W. OLVER, Massachusetts        
MIKE PARKER, Mississippi               ED PASTOR, Arizona                  
RODNEY P. FRELINGHUYSEN, New Jersey    CARRIE P. MEEK, Florida             
ROGER F. WICKER, Mississippi           DAVID E. PRICE, North Carolina      
MICHAEL P. FORBES, New York            CHET EDWARDS, Texas                 
GEORGE R. NETHERCUTT, Jr., Washington  ROBERT E. (BUD) CRAMER, Jr., Alabama
MARK W. NEUMANN, Wisconsin             
RANDY ``DUKE'' CUNNINGHAM, California  
TODD TIAHRT, Kansas                    
ZACH WAMP, Tennessee                   
TOM LATHAM, Iowa                       
ANNE M. NORTHUP, Kentucky              
ROBERT B. ADERHOLT, Alabama            

                 James W. Dyer, Clerk and Staff Director













                            C O N T E N T S

                              ----------                              

                     NATIONAL INSTITUTES OF HEALTH

                           VOLUMES 4A AND 4B

                                                                   Page

National Institutes of Health Overview...........................     1

National Cancer Institute........................................   333

National Eye Institute...........................................   627

National Human Genome Research Institute.........................   695

National Institute of Allergy and Infectious Diseases............   801

National Institute of Environmental Health Sciences..............   947

National Institute on Deafness and Other Communication Disorders.  1053

National Heart, Lung, and Blood Institute........................  1131

National Institute on Drug Abuse.................................  1277

National Institute on Alcohol Abuse and Alcoholism...............  1377

National Institute of Diabetes, Digestive and Kidney Diseases....  1481

National Library of Medicine.....................................  1619

National Institute of Nursing Research...........................  1683

Fogarty International Center.....................................  1753

National Institute of Arthritis and Musculoskeletal and Skin 
  Diseases.......................................................  1807

National Center for Research Resources...........................  1913

National Institute of Child Health and Human Development.........  1975

National Institute of Dental Research............................  2151

National Institute Mental Health.................................  2235

National Institute on Aging......................................  2355

National Institute of Neurological Disorders and Strokes.........  2445

National Institute of General Medical Sciences...................  2549

Office of the Director and National Institutes of Health 
  Buildings and Facilities.......................................  2619

Office of AIDS Research..........................................  2855

Noble Prize Recipients...........................................  2943

Child Health Hearing.............................................  3019















DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, EDUCATION, AND RELATED 
                    AGENCIES APPROPRIATIONS FOR 1999

                              ----------                              

                                           Tuesday, March 10, 1998.

                     NATIONAL INSTITUTES OF HEALTH

                               WITNESSES

HAROLD E. VARMUS, M.D., DIRECTOR
RUTH L. KIRSCHSTEIN, M.D., DEPUTY DIRECTOR
WENDY BALDWIN, PH.D., DEPUTY DIRECTOR FOR EXTRAMURAL RESEARCH
MICHAEL GOTTESMAN, M.D., DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH
ANTHONY L. ITTEILAG, DEPUTY DIRECTOR FOR MANAGEMENT
FRANCINE V. LITTLE, DIRECTOR, OFFICE OF FINANCIAL MANAGEMENT
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY FOR THE BUDGET, 
    DEPARTMENT OF HEALTH AND HUMAN SERVICES
    Mr. Porter. The subcommittee will come to order. We 
continue our hearings for the Department of Health and Human 
Services with the National Institutes of Health overview of the 
budget for the fiscal year 1999. We are delighted to welcome 
Dr. Harold Varmus, the Director of the National Institutes of 
Health; Dr. Ruth Kirschstein, the Deputy Director, and the 
other representatives of NIH here with us today.
    Dr. Varmus, this is your fifth appearance before the 
subcommittee. You have had many more appearances, but this is 
your fifth formal appearance on behalf of NIH before the 
subcommittee and as you know we place the funding for the 
National Institutes of Health at a very high priority in this 
subcommittee.
    I have to give you my short sermonette and that is that the 
President's budget is very encouraging to me in that he has 
offered an 8.4 percent increase for the next fiscal year and 
said that his goal is to increase funding for NIH by 50 percent 
over five years. The difficulty, the immediate difficulty, is 
that his spending increases, not only in this but in other 
areas, is supported by revenues that are very unlikely in my 
judgment to materialize, at least in this fiscal year.
    That will provide some difficulty for us in respect to our 
302(b) allocation and in reaching the kinds of levels that we 
feel NIH should receive, but we will do our very best both with 
the allocation and with the markup of our bill because, as I 
say, the NIH is a very high priority for all Members, on a 
bipartisan basis, of this subcommittee.
    My second concern with the President's budget has to do 
with the cancer initiative and while I certainly support the 
importance of research in this area, I think that while it may 
be good politics, it is very bad policy to earmark any disease 
as being politically important and to take away from science 
the right to decide where scientific opportunity and progress 
lay.
    So I am very skeptical of the earmark for cancer, but very 
supportive of providing all the funds we possibly can for 
cancer research and research with respect to all the work that 
NIH does and funds.
    We look forward this afternoon to hearing about the 
remarkable scientific advances that your fine institution makes 
possible and I would ask that you introduce the people who are 
with you and then proceed with your statement.

                       Introduction of Witnesses

    Dr. Varmus. Thank you, Mr. Chairman.
    Let me introduce the members that you did not introduce. 
Dr. Michael Gottesman, Deputy Director For Intramural Research, 
on my far left, Dr. Wendy Baldwin, Deputy Director for 
Extramural Research, and Mr. Tony Itteilag, who is the Deputy 
Director for Management. You have introduced Dr. Kirschstein, 
whom you know well. On my right is Ms. Francine Little, 
Director of the Office of Financial Management, and the long-
suffering and ever-present Mr. Dennis Williams, who is the 
Deputy Assistant Secretary for Budget and Management from the 
Department of Health and Human Services. I would also like to 
point out that arrayed behind me in a spectacular show of 
support are the directors of the various institutes and centers 
which hope to receive the good wishes of this committee.
     As you point out, Mr. Chairman, I am here for the fifth 
time and very pleased on this occasion to be presenting the 
President's Fiscal Year 1999 budget request for the National 
Institutes of Health.

                       Appreciation of Mr. Stokes

    Before I begin my formal comments, I would like very 
briefly to make a statement about Mr. Stokes, whose presence 
here I warmly welcome--I only regret that this is going to be 
for the last time. Mr. Stokes, you have been an enormous friend 
to the NIH even at moments when you have been most critical of 
us. I am appreciative of the support you have given and of your 
dedication to the health of all Americans but, particularly, of 
those in minority populations who, as you have pointed out 
repeatedly to us, suffer from disparities in health status that 
it is the task of the NIH to try to reduce. You have drawn 
special attention to many problems that especially afflict 
African-Americanpopulations--including sickle cell disease, 
asthma, eye and oral diseases. I hope that you can take some comfort 
from the fact that during your stewardship here we have made 
considerable advances in some of those areas, particularly the use of 
hydroxyurea in the treatment of sickle cell disease.
    I also appreciate the attention you have paid to the 
training of minority scientists, including your support for the 
undergraduate scholars program on the NIH campus and for our 
clinical research loan repayment program. You have made a big 
difference in those regards. Thank you very much.

                           Opening Statement

    Now, as part of his Research Fund for America, the 
President, strongly supported by Vice President Gore and 
Secretary Shalala, is asking for, first of all, $14.98 billion 
for the NIH for the coming year--an increase of $1.15 billion, 
which, as the Chairman has already pointed out, is 8.4 percent 
above our current 1998 appropriation level.
    Furthermore, the President has outlined a five-year budget 
projection that will allow us to anticipate a stable pattern of 
growth over the next several years to a level of over $20 
billion--approximately 50 percent above our current 
appropriations--by the year 2003.
    Needless to say, we are enthusiastic--indeed, jubilant--
about the prospect of building vigorously on the handsome 
increases that NIH has received over the last few years, when 
budgetary prospects were more problematic. We believe that this 
generous request has come at an especially opportune time, and 
that this is true for two reasons.

                    biomedical research discoveries

    First, as I think this subcommittee is particularly aware, 
discoveries in biomedical research are occurring at an 
unprecedented pace, and those discoveries presage revolutionary 
changes in the practice of medicine. At the same time, we 
recognize that the improved methods of care that we expect to 
result from these discoveries will improve care at a time when 
the nation is confronting some very serious public health 
needs. There are at least three that we need to think about. 
One is the aging of the human population, both here and abroad. 
Second, the disproportionate growth of groups in the United 
States that have historically experienced poor health. And 
third the persistence of many serious diseases that we have 
been unable to conquer, not only in this country but in all 
parts of the world.
    I would like to speak for a moment about the promise of 
science based on accomplishments. As has been the case over the 
last several years, we come to you with a rich harvest of 
recent results, and those results come from both the laboratory 
and the clinic. My colleagues will give you testimony over the 
next three weeks that will describe in great detail some of 
this productivity, and some of the specific accomplishments are 
listed in my written statement. I will not spend the time going 
over them now.
    I would simply point out two things. First, that they 
represent an array of laboratory findings which last year I 
referred to as ``inspirations'' for further work to achieve our 
ultimate mission of improving the nation's health. Those 
inspirations range from the isolation of new genes and our 
progress on a variety of genomes--the collection of genes--to 
discoveries about the brain and the rest of the nervous system, 
new insights into functions of cells, and the molecular basis 
of disease.

                        research accomplishments

    We also will be reporting a large number of what I called 
here last year ``culminations'', the work that actually takes 
those results and puts them to use in the clinic. You will hear 
over the course of the next few weeks about a number of 
vaccines, new drugs, the use of devices to reduce morbidity and 
mortality, new important epidemiological findings, and 
diagnostic tools.
    But beyond these inspirations and culminations, I want to 
remind the committee of a few advances that have occurred over 
the last few years that have had dramatic objective effects on 
the health of this nation, indeed, the health of the world. In 
these several areas, NIH science over many years has had 
dramatic and important contributions to make.
    For example:
          --the virtual elimination of hemophilus influenza B 
        meningitis, which previously occurred at the rate of 
        20,000 cases per year and was one of the major causes 
        of mental retardation in this country;
          --declining cancer mortality rates, that have gone 
        down nearly 5 percent over the last six years;
          --a nearly two-thirds reduction in the transmission 
        of HIV from mothers to infants, and now a reduction in 
        rates that is almost as significant now with the short 
        course of AZT abroad;
          --a decline in AIDS mortality rates of 44 percent for 
        the first half of 1997 compared to 1996;
          --a marked decline in infant mortality that in recent 
        years has been particularly ascribable to a decline in 
        sudden infant death syndrome of 40 percent due to our 
        Back To Sleep program that you will hear more about 
        later;
          --the safety of the blood supply, further secured by 
        definitive tests for HIV, hepatitis B and hepatitis C 
        viruses;
          --and a decrease in disability rates for the elderly, 
        to the tune of as many as 1.4 million fewer disabled in 
        recent years than would have been anticipated from 1982 
        rates.

                            future prospects

    In proposing a very substantial increase in the NIH budget, 
I believe it is appropriate to emphasize our future prospects. 
In the main what we expect to see, of course, are many new ways 
to prevent and treat illnesses, using methods that we expect to 
be based largely on theextraordinary discoveries and 
technologies that are currently being delivered in many fields of work, 
especially neuroscience, genetics, cell biology, bio-engineering, 
computer science and others.

                           molecular medicine

    One way in which we can see this change most vividly is by 
observing a passage that science is currently making from 
molecular biology to molecular medicine using our knowledge of 
the large molecules of life to prevent and to treat disease. We 
discussed here last year the marked improvement in the 
treatment of AIDS that serves as an incredible example of this 
approach and also serves as a harbinger of the rational 
mechanism-based approach to medicine that will be, I believe, 
the major legacy of current molecular and genetic science.
    You will recall that the new therapies for HIV infection 
are built on an understanding of the relatively few genes and 
few proteins of the virus. We are beginning to see this pattern 
now for much more complex illnesses that arise from our own 
much larger genome.
    The next venue in which I believe the impact of molecular 
medicine is going to be most dramatically perceived is the 
application of genetics and molecular biology in the study of 
cancer. This is true for a number of reasons. First, cancer is 
intrinsically a disease caused by mutations. Secondly, some of 
the genes affected by those mutations are among the first to 
have been isolated from animals of the vertebrate class. 
Thirdly, because the functions of many of those genes are now 
intimately understood through work in cell biology and 
biochemistry in the last couple of decades. Because of all of 
these things, it is now already possible to begin to predict an 
individual's genetic predisposition to several forms of cancer, 
to assess the specific genetic damage in individual cancers, to 
design novel ways to do the traditional things that we do in 
cancer therapy--destroy cancer cells--and also to take 
advantage of new knowledge to think about entirely novel 
approaches to cancer therapy.
    In the very near future our ability to think about new ways 
to prevent and treat cancer and many other diseases is going to 
be based on a much more detailed and much more refined view of 
normal biology and disease. I want to illustrate this important 
point today by showing you a single new technique among the 
many recent technologies that have currently become available. 
[See figure 1]


[Page 6--The official Committee record contains additional material here.]



                            expression array

    This method is sometimes called the expression array. It 
takes advantage of the fact that the scientific community has 
already accumulated large collections of pieces of genes made 
available by the technologies used in molecular biology and 
genomics. If one takes hundreds or, indeed, thousands of such 
individual gene pieces and places them, by using a highly 
refined technology--based in part on the use of laser jet 
printers--one can put onto a little slide the size of the one 
that I am holding in my hand as many as several thousands of 
genes in an orderly array and then use this chip or array to 
ask about the activity in each of those thousands of genes in a 
single cell; to ask whether each gene is turned on or turned 
off, or to compare the activity of the gene in one cell or 
another.
    I would like to illustrate this with an example that comes 
from an actual case of a patient who had a T-cell lymphoma that 
was being treated at the University of Pennsylvania Hospital. 
During the course of this patient's disease, the tumor that was 
initially indolent, growing extremely slowly, turned into a 
much more malignant or aggressive form of the disease. By 
taking material from the tumor at both stages of development, 
it has been possible to look at 10,000 genes--10,000 of the 
available 80,000 to 100,000 in the human genome--and to examine 
the activity of each of those genes in the two phases of the 
disease. [See figure 1]
    Now, the colors here indicate what is going on. If a gene 
is active, it turns up as a colored dot. If the color is red, 
then that gene is more active in the aggressive form of the 
disease. If the color is green, then the gene is more active in 
the indolent form. If the color is yellow, there is no 
difference. And that, of course, is the case for the vast 
majority of genes.
    As you can see in the blow-up of one small segment of this 
chip on the right, these results could in the future have 
direct bearing on the choice of treatment. For example, there 
is one gene, bleomycin hydrolase, that destroys a drug that is 
commonly used in chemotherapy for certain--not this one--but 
certain kinds of cancers. Some of the other genes that are 
turned on or turned off, such as the ATM gene, are genes that 
have been implicated in other kinds of cancer and could provide 
the kind of fingerprint of the cancer that would be useful for 
instructing the patient about the prognosis, or about the 
appropriate choice of therapy at that stage. [See figure 1]

                      impact of technical advances

    In presenting this single technical advance, which is going 
to have very wide ramifications in medical science, I want to 
make four additional points.
    First, this kind of technology, using modern molecular and 
genetic methods to look at the disease in the most precise 
terms, is going to have major applications not only to 
treatment of disease but also to prevention.
    Second, the method that I am illustrating will have an 
impact not only on cancer but on a large number of other 
diseases. We are already using these techniques for AIDS, and 
they will be used in many other contexts.
    Third, this method is only one among many kinds 
ofinnovations that I could have illustrated to you today. Innovations 
that are on the horizon are going to be applicable to visualization of 
the disease process, to bio-engineering, to repair of disease, to 
development of devices that will measure brain functions and so forth.
    The fourth point is a subtle one. This experiment is the 
result of a collaboration between Government scientists, 
university scientists, and industrial scientists, illustrating 
the kind of interaction that is going to be essential if we are 
going to control disease in the long run.

                fiscal and administrative responsibility

    We believe that increased funding for the NIH would produce 
better science and better health. But we also believe that 
increased fiscal responsibility demands close administrative 
attention. I would like to describe, very briefly, five areas 
in which the NIH is paying attention to the increased 
responsibility placed upon us by this budget increase.

                            research grants

    The first area is research grants. I have argued here 
before that the most important instrument that we use to 
achieve our goals is the individual investigator research 
grant. In Fiscal Year 1999 we plan to increase the number of 
grants substantially, to an all time record of over 30,000 
grants. We will also set a record for our so-called new and 
competing grants--the grants awarded in this year of nearly 
8,300. That will allow us to achieve an overall success rate 
for our grant applicants of close to one-third.
    In addition, we are going to be increasing the average size 
of new grants by about 10 percent. I can describe later on some 
of the reasons why we feel that it is appropriate to do so.
    What are these grants for? The topics, of course, will not 
be precisely known until the proposals have been written and 
they have been judged. But we have identified, in priority 
setting discussions with the Institute Directors, many 
important research topics to which we expect to devote enhanced 
resources.
    As in recent years, we have approved most of these new 
initiatives within six broad areas of NIH research emphasis. 
And initiatives within each of these broad domains would 
address a wide spectrum of diseases: cancer, diabetes, heart 
disease, central nervous system disease, and many others. We 
expect that this expanded grant portfolio to accelerate our 
discovery and our approach to applications to health across a 
very large frontier of medical science.

                            instrumentation

    The second area is instruments. As medical science becomes 
more complex, it also becomes more dependent on innovation in 
instrumentation and multi-disciplinary work. There are many 
areas of science that have received the benefit of this 
expanded effort to improve the way in which we measure the 
performance of biological systems in health and disease. With 
the resources requested in the President's budget, we will 
develop new and more powerful instruments. We are going to 
attract trainees and scientists in many fields to problems 
posed by technology development in biology and medicine. We 
will allow more groups of investigators to share instruments 
through a shared instrumentation program and will expand the 
use of computers for storage, analysis and exchange of data.

                                training

    The third area is talent. We all know that recruiting and 
training and retaining our most talented individuals is crucial 
to the success of biomedical research. Attracting people into 
our field has a long-range impact. Someone recruited this year 
may not make his most important discoveries until the year 
2020; therefore, this is a particularly important 
responsibility for us.
    With this year's budget we plan several strategies to 
encourage young people to enter these incredibly exciting 
fields. We will have innovative research training programs that 
emphasize trans-disciplinary work. We are going to increase our 
stipends by 25 percent--both for graduate students and for 
post-doctoral fellows--to come close to the levels previously 
recommended by the National Research Council. By increasing our 
general support for research over many years, we will create a 
stable environment that induces our young and talented 
individuals in this country to enter medical research areas.

                           clinical research

    The fourth general area I would like to comment on is 
clinical research. We all know that the promises of biomedical 
research cannot be achieved unless we strengthen the nation's 
commitment and capacity to perform clinical research. To do 
this, we have been putting into practice most if not all of the 
recommendations made by my distinguished Panel on Clinical 
Research.
    We discussed some of these last year but I want to mention 
a few new ones that are currently going into the implementation 
phase. Most recently we announced new programs to enhance the 
training and support of clinical investigators, a program that 
will provide a supervised five-year apprenticeship for over 400 
additional young clinical investigators; A program that will 
provide salary support for the clinical research activities of 
nearly 400 mid-career scientists who have distinguished 
themselves already and can serve as mentors for new clinical 
trainees; and a didactic training program that will bring 
organized programs in training of clinical research to over 20 
institutions.
    In addition, we will be strengthening our programs at 
clinical research centers including the General Clinical 
Research Centers, and expanding new programs on the NIH campus 
that introduce medical and dental students to the joys and 
tribulations of clinical research. And we will continue our 
construction of the Mark Hatfield Clinical Research Center.
    We also have a variety of plans to increase our capacity to 
do clinical trials that are outlined in the written statement.

                             administration

    Finally, I would like to address four issues concerning our 
administrative functions at the NIH, because we know that our 
ability to use money effectively is dependent upon strong 
administrative practices. First, in the area of grant review. 
We are renowned for our expert review of grant applications 
but, nevertheless, we feel that more needs to be done to ensure 
that we are appropriately reviewing proposals from our 
grantees. So the Center for Scientific Review has undertaken a 
thorough reexamination and restructuring of our peer review 
panels.
    Second, in response to a suggestion from this committee, we 
last year commissioned from the Arthur Andersen Company a 
large-scale review of our administrative practices. While this 
review was generally complimentary, it did include roughly 80 
recommendations for improvement and many of these we hope will 
be implemented in the coming year.
    Third, this committee and others have been interested in 
the way in which we identify priorities for research funding 
and we have just signed a contract with the Institute of 
Medicine to carry out a study of our practices in addition to 
many other activities we have undertaken in this area.
    Finally, as mandated by the Government Performance and 
Results Act, we have incorporated our first annual performance 
plan with goals and measures into this budget request.
    Mr. Chairman, committee members, we are in the midst of a 
remarkable phase in the history of biomedical research. We have 
an opportunity before us to create a stable environment for 
continued discovery that will benefit the citizens of this 
country and people throughout the world for decades to come.
    I hope we can work together to seize this opportunity and 
to realize its benefits.
    Mr. Chairman, thank you for the opportunity to speak at 
such length, and I am pleased to respond to any questions that 
you and your colleagues may have.
    [The prepared statement follows:]


[Pages 11 - 19--The official Committee record contains additional material here.]



     Mr. Porter. Dr. Varmus, thank you for your opening 
statement. Let me advise members of the subcommittee that we 
will operate under the seven-minute rule considering how many 
Members are at our hearing. We will call on Members who are 
present at the opening of the hearing, by party, back and forth 
then to those who arrived in order of arrival with the 
exception that I will call on Mr. Obey for questions 
immediately following my own.

                           disease earmarking

    Dr. Varmus, I expressed in my welcome to you a concern 
about the President's budget in respect to the cancer 
initiative. I have expressed very frequently a concern about 
the politicalization of science. And I wonder if you had any 
opportunity during the formulation of the President's budget to 
raise the question or issue of disease earmarking before the 
budget or State of the Union message or both were offered?
    Dr. Varmus. Mr. Porter, naturally we have had discussions 
with the Administration about budget formulation. Just as we 
discuss with members of this committee their interests, we have 
discussed the interests of the Administration in various 
diseases. But the budget was put together in our traditional 
manner--that is, in response to scientific opportunity and our 
sense of what is needed.
     Mr. Porter. Did the cancer initiative idea come from NIH 
or from the White House?
    Dr. Varmus. Well, I think you would have to--it is, as the 
Secretary commented--it is a chicken and an egg problem in a 
sense. The budget as formulated afforded major increases to 
many cancer-related activities for reasons which I think I 
spelled out in my testimony--the remarkable opportunities that 
are available in cancer research, the fact that cancer is going 
to be a major area in which the fruits of molecular and genetic 
technology are first applied.
    There is the additional fact that many of the 
infrastructural issues in medical science--clinical trials 
development, training of clinical investigators--are going to 
be exercised. So the budget for cancer was large. The 
identification of a cancer initiative that the President and 
Vice President have emphasized is a decision made by the 
Administration but it is completely consistent with the budget 
numbers that we developed.
    There are other diseases that receive increases in the 
budget equal to or even greater than cancer. But in view of the 
magnitude of the cancer problem, the public's concern about 
cancer, and the remarkable advances that we believe have come 
and are in the immediate future, it has been featured in the 
President's display of the budget.
     Mr. Porter. In other words, you are saying that the 
President did not necessarily vault cancer ahead of 
otherdiseases, he simply emphasized cancer in the increases that were 
being provided, and he could have emphasized other diseases in the same 
way?
    Dr. Varmus. In fact, as I think the budget proposal makes 
clear, there is a very handsome increase for every disease 
area. I do not believe that the modest increase in advance of 
the average for cancer research is discriminatory to other 
disease areas.

                            mind and health

     Mr. Porter. Thank you. We will treat it that way.
    Last fall we had some special briefings on the role of the 
mind in health and healing. Is there any important role of the 
mind in molecular medicine or does it simply become irrelevant? 
And if there is an important role, what is NIH doing in terms 
of its own work in grant funding in this area and what 
Institutes are involved?
    Dr. Varmus. Well, Mr. Porter, I chose to speak about 
molecular medicine because it is at the verge of having a 
tremendous impact on changes in medical practice. But I hope 
that I made clear that it was only one of many profound changes 
that are occurring and represents only one area of our science.
    We believe that the mind is a manifestation of a physical 
entity, the brain. What is occurring in neuro-science and the 
understanding of how activities of the brain affect health are 
germane to a wide variety of activities carried out by at least 
a dozen institutes--I could name them if you would like, 
starting with the Institutes for Mental Health for Neurological 
Disorders and Stroke, and many others.
    The connections between mind and health are being explored 
by a variety of technologies, ranging from neuro-imaging to 
classical behavioral work, to attempts to understand 
connections, for example, between the nervous system and the 
immune system.
    There is a coordinating function here that is carried out 
largely by the Office of Behavioral Science and Social Research 
that attempts to overview the activities of many institutes in 
understanding the relationship between mental attitude, 
behavior and health outcomes.
     Mr. Porter. Is there any way that the brain, like other 
organs, can simply be reduced to dealing with it in respect to 
molecular biology and not worry about behavior or anything 
outside of the physical work of the brain?
    Dr. Varmus. Well, I do not think that any of us are 
interested in learning about molecular interactions without 
knowing about their consequences. For example, to talk about 
one fairly simple thing, we know that when a patient uses a 
psychotropic drug, or uses a drug for the treatment of mental 
illness, or uses a drug in an illicit way, that there is an 
engagement between a molecule, namely that drug, and a receptor 
on the surface of nerve cells. We also know that there is a 
change in behavior and we can see the places in the brain that 
respond to the drug. They may even respond to the possibility 
of obtaining that drug.
    The changes that we can see by neuro-imaging combined with 
our understanding of the molecular events that transpire 
between the interactions of the drug with the nerve cell and 
the actual change in behavior, are things that we are trying to 
understand in order to intervene to prevent the events that 
produce ill consequences for health.
    So I think it is very difficult to separate the molecular 
components of your question from the behavioral, because what 
we are trying to effect are the behavioral changes that are 
desired, using molecular tools for understanding.

                          100 percent increase

     Mr. Porter. You mentioned, in a general way at least, how 
you would use the increases that the President has proposed in 
his budget, a 50 percent increase over five years. Many are 
proposing a 100 percent increase for NIH over five years and 
other research components within the Federal Government. Can 
you tell us whether you could reasonably absorb an increase of 
100 percent over five years and how, if it is different, you 
might use funding at an increased rate of that magnitude?
    Dr. Varmus. Mr. Porter, I believe that what is going on in 
medical science at the moment is truly extraordinary, and that 
the capacity of our research community to make good use of 
funds is at an all time high.
    It is very difficult for me to calibrate exactly where the 
limit is reached. But we do know that there are many excellent 
grant proposals that go unfunded, many investigators who have 
been well-trained and are able to do work who are currently not 
working at peak capacity. We know that there are areas of 
research that we under-explore.
    And we also recognize--and I give malaria as one example--
certain diseases that have greater impact abroad than they do 
in our own country.
    We also know that as we make this transition from a 
molecular-based science to molecular-based medical practice, 
there is going to be an expanded need for clinical trials, for 
general clinical research, both of which are more expensive 
than some of the laboratory work we do. Animal experimentation 
has become very important in the last few years as a result of 
our ability to build truly informative and accurate models of 
disease in experimental animals. And that kind of research, 
too, requires additional resources.
    We know that science moves faster with good 
instrumentation. We have seen many of the programs to 
understand the full genetic blueprint of organisms moving at a 
pace that is slower than could be achieved simply because there 
is a limitation on methodology and on the number of machines 
available to advance research.
    We are entering into a whole new era, that I illustrated 
with that chip experiment, in which the talents of people who 
are currently in other fields will be required, mathematicians 
to help us to understand the dynamics of how a single cell 
works, or physicists and computer scientists to help us manage 
the information that has become available and to cope with a 
new way of thinking about normal and diseased tissues.
    So I believe the opportunities are extraordinary and that 
even as much as twice the current level of funding could be 
extremely well used.

                              success rate

     Mr. Porter. I think you said we are funding about a third 
of the good science that is offered, is that correct?
    Dr. Varmus. This year we will achieve an overall success 
rate of about 31 percent. But I would point out a couple of 
things about that number. First of all, that number is not 
uniform among all the institutes. And secondly, the number is 
higher for those who are competing for their renewal than it is 
for our new investigators.
    On average, between 22 and 24 percent of our new 
investigators receive their first grant. And we know that, 
first of all, we believe that a higher number of those who went 
through NIH training programs should have a chance to show 
their mettle.
    We also have recently decided that new investigators should 
be better supported than they have been in the past. In the 
past, as you know, over half of our new investigators were 
receiving an award known as the FIRST award or the R29 award, 
which gave investigators only $70,000 a year for five years.
    In my view, this was not a fair start. A study carried out 
this year at the NIH strongly confirmed that perception. The 
Institute Directors voted to end the R29 award and instead 
ensure that at least the number of new investigators we had 
supported before would now be supported in our traditional R01 
manner.
    That is going to cost us roughly $50 million this year and 
perhaps as much as $500 million over the next several years. 
But I feel it is very important that our newly trained 
individuals show what they can do with adequate support.

                          new proposals funded

     Mr. Porter. Is there any way of investigating if anything 
of that magnitude were possible; is there any way of estimating 
what percentage of the new proposals would be funded? Have you 
done anything like that?
    Dr. Varmus. I am not sure I quite understand what you are 
asking.
     Mr. Porter. Well, we are at 22 to 24 percent, I think you 
said.
    Dr. Varmus. Right. That is for new investigators. And that 
is the number we anticipate for 1999.
     Mr. Porter. If funding were increased at the rate we are 
talking about, would that number increase appreciably? Would 
the 31 percent increase appreciably as well?
    Dr. Varmus. Well, this is a difficult question to answer, 
Mr. Porter.
     Mr. Porter. I know that it is.
    Dr. Varmus. I have actually asked that we start to do some 
modeling to try to make some estimates. One of the things I 
have encouraged this year is that we increase the size of our 
competing awards as well.
    Over the last several years with tight funding it has been 
practice for most institutions not to allow a significant 
increase between the first award--that is the initial R01 
award--that an investigator might obtain and the level of the 
competing renewal. The consequence has been that when an 
investigator is successful, in order to increase the size of 
the laboratory group it is necessary to apply for a second 
grant. And, indeed, there are several thousand of our 
investigators who carry two and sometimes even three awards 
rather than just one. I would like to move us back in the other 
direction. It simplifies administrative practices and review 
and program management, and that needs to be figured into the 
modeling of the system.
    We are not intending to increase the pool of investigators 
by expanding the number of training slots. I think I have made 
it clear in the budget rationale that we expect to increase our 
stipend levels to bring the stipends up to a more humane level. 
But we do not expect to increase the number of trainees because 
we do not believe that it is appropriate to expand this 
universe forever. We want to make the universe a better one.
     Mr. Porter. My concern is that we have young investigators 
who get discouraged and leave the field and obviously we want 
to keep them in if they have good science and good talent.
    Dr. Varmus. If they are doing well, I agree. We have, of 
course, always had an exit rate. That has been roughly 9 
percent per year. And that is a biphasic rate of departure. But 
we would like to ensure that everyone gets a very good chance 
to be in the system. If they do not succeed, then someone else 
is given their place, but I think we agree on this point.
     Mr. Porter. Thank you, Dr. Varmus.
    Mr. Obey.

                        rate of budget increase

    Mr. Obey. Thank you, Mr. Chairman.
    Doctor, I have 31 questions which I will submit to you for 
the record of the Office the Director hearing and I would 
appreciate a response to them as soon as possible.
    Let me begin by going in the other direction from the 
chair. I, frankly, am skeptical that NIH--and I would 
appreciate it if you would keep your answers to about a minute 
apiece, so, I can get at least five questions in--I am very 
skeptical about whether or not NIH, in fact, has the capacity 
to absorb the kind of money which is being talked about in the 
President's budget, particularly in the last two years.
    I will ask you to expand for the record, but can you 
explain to me in one minute or less, why I should believe that 
that kind of huge expansion will be wisely spent without waste, 
especially in the last two years?
    Dr. Varmus. Well, Mr. Obey, I think that it helps to 
recognize that not all the money would be going into grants. We 
are not simply trying to increase the grant pool and increase 
the success rate. What we are imagining are new kinds of 
initiatives and more involvement in clinical research, which 
is, as you know, expensive. We are interested in developing new 
aspects of the research portfolio. We see ourselves expanding 
into areas ofinstrumentation and bio-engineering that will 
bring the talents of people in other disciplines to medical research. 
As we cost out these programs and think about what is possible over the 
next several years, we do believe that certainly the President's 
request can be used very well throughout the next five years.

                          50 percent increase

    Mr. Obey. Well, let me ask you if you would outline for the 
record how a 50 percent increase will be used for grants for 
clinical trials, for training, for intramural programs, for 
construction et cetera. I would like to know if you could use 
it. I would like to see how, in fact, you plan to use it right 
now. If you are still betting we can put a plan together 
sometime down the road?
    I would like to know what decisions have been made now as 
to where the money will go in the next five years.
    Secondly, if you take a look at the stability and the 
mechanism distribution over the years and you could take this 
year and last year, for instance, how much change between those 
categories? Is that a sign that the budget has become too 
stagnant and locked in, and how much do you expect that 
distribution to change if we allocate what you have asked us to 
provide?
    Dr. Varmus. Actually, Mr. Obey, there are some significant 
changes in the mechanism for this year. One, of course, 
reflects the change in stipends for trainees. The dollar value 
is not enormous compared to our dollars invested in grants but, 
nevertheless, is a very substantial percentage of----
    Mr. Obey. If you look at the percentage changes in your 
budget----
    Dr. Varmus. It is a very large percentage change actually. 
And it is about 20 percent change in the training category--or 
18 percent.
    Mr. Obey. I am talking about as a share of your, I am 
talking about----
    Dr. Varmus. As a share, of course. Because that is, of 
course--because we have a very large commitment base, as you 
know. So, I think the important----
    Mr. Obey. Right, but I prefer that we not change terms when 
I am asking you a question.
    Dr. Varmus. Okay. I was just pointing out that the way we 
can make changes is by looking at the----
    Mr. Obey. All I am saying is that if you look at what is 
happening from 1987 through 1996, you may have a 1 or 2 percent 
change for any of these categories, at most. I would say that 
is fairly stable.
    Dr. Varmus. Yes, it has been very stable. I agree with 
that.
    Mr. Obey. And I am simply asking whether that also means it 
is very stale.
    Dr. Varmus. Well, I think there are two answers to that. 
First of all, it is only with this year's budget request that 
we have been able to forecast the kinds of increases that would 
make some differences in the way the money is divided up.
    I would also point out that what is probably more important 
is to look within each of those categories at how we are 
spending our money--for example, on grants and intramural 
programs, and to ask: What is the quality of research? At this 
point, to envision an NIH that is fundamentally different in 
character--that it spends 20 percent of its money on grants and 
80 percent on intramural programs, for instance--it would seem 
to me an arguable possibility for an abstract discussion but I 
do not think it would be terribly consonant with the reality of 
where our scientists are and where the buildings are.

                           clinical research

    Mr. Obey. Well, let me ask you with respect to clinical 
research, I confess that my bias over the years has been that 
given limited resources we should focus most of our resources 
on basic research and basic cell biology, et cetera, et cetera. 
But it seems to me that as the nature of health delivery has 
changed and as the HMO movement is driving out the ability of 
physicians to actually do research--they damn near do not have 
time to see patients.
    My question is are you confident that NIH is responding to 
that change by making a sufficient reallocation of resources to 
really strengthen what we provide for clinical research? What 
do you intend to do in the next five years?
    Dr. Varmus. As I mentioned in my opening statement, we 
think part of the problem requires attention to recruitment and 
training and the sustenance of clinical investigators.
    And that is why in the last few months the Institute 
Directors and I have put together a program of new training 
initiatives and stipends for early- and mid-career clinical 
investigators which, if they prove successful, could be further 
expanded.
    We are also aware of concerns that clinical research 
applications may not be getting a fair shake in the peer review 
process. The Director of the Center for Scientific Review, Dr. 
Ellie Ehrenfeld, has made special efforts to improve the 
oversight of that review process.
    Thirdly, we have done an evaluation of where our money is 
going. The numbers of our dollars that go into clinical 
research activities, as we define them, has been found to be 
over 30 percent--nearly 40 percent in terms of dollars, nearly 
30 percent in terms of grants. And we feel this is a pretty 
substantial investment, although we expect to see it increase 
for some of the reasons I outlined a moment ago to Mr. Porter.

                           reasonable pricing

    Mr. Obey. Let me make this point to follow-up on that, 
because I am concerned that NIH may be providing someresponse 
but frankly not sufficient response to that concern.
    Let me ask another question. I have a letter here that has 
been circulated by Congressman Rohrabacher, Congressman 
Campbell, Congressman Sanders and Congressman Patrick Kennedy, 
and it says, among other things, ``that President Bush 
instituted reasonable pricing costs for drug development 
largely with government resources at NIH.''
    ``Unfortunately, under pressure from pharmaceutical 
companies NIH cancelled the clause in 1995,'' and then they 
assert that NIH spent 15 years and $32 million of the 
taxpayers' money to develop Taxol and then they go on to say 
that following the successful development of Taxol, the company 
involved was awarded exclusive marketing rights and extensive 
government information on the drug. They charge roughly 20 
times what Taxol cost them to produce. So, the cancer patients 
will pay $10,000 a year while it cost the manufacturer only 
$500.
    I guess my question is simply, what do you think we ought 
to do about this? Is there some happy middle ground that we can 
find between the original proposition that was in effect under 
President Bush and the zero protection which we have now?
    Dr. Varmus. It's probably best to dissociate the Taxol case 
which has been a very contentious one, from the general 
principle underlying our withdrawal from the reasonable pricing 
clause. The reasonable pricing clause was subject to a number 
of workshops early in my term here, and it became clear that 
the ability of NIH to interact with industry especially in the 
development of the so-called CRADAs--the cooperative research 
and development agreements--was being impeded by the existence 
of this clause, which we had not exercised. We really did not 
know how to exercise it; we are not a regulatory agency, and it 
is very difficult to do that. In fact, the interactions between 
our government scientists and industry have improved 
significantly with respect to exchanges, material agreements, 
and formation of CRADAs since then.
    I think we have made the right decision and individual 
cases like the Taxol case simply need to be looked at one by 
one. I think it is probably too complex to get into here.
    Mr. Obey. Well, I guess I would ask you to expand further 
on that for the record because it would seem to me that 
certainly I want drug companies to recover a reasonable cost 
and have enough incentive to get into the field, but I also do 
not want us to have no protection for patients under those 
circumstances.
    It seems to me we are stuck between the two poles right 
now. Mr. Chairman, let me simply submit the rest of my 
questions for the record.
    Mr. Porter. Thank you, Mr. Obey.
    Mr. Bonilla.

                           diabetes research

    Mr. Bonilla. Thank you, Mr. Chairman.
    Dr. Varmus, nice to see you again. You said five years. 
This is my sixth year so we are almost to the line and I can 
remember when you first started. You used to have those flip 
cards you used every time.
    Dr. Varmus. I still have them. I just do not need them any 
more.
    Mr. Bonilla. I would like to start out by thanking you for 
the comments that you made last fall while you were visiting 
the University of Texas Health Science Center with Dr. Howe 
down in San Antonio. We got feedback from some of the doctors 
there about the nice things you said about the work we are 
doing on this subcommittee and I appreciate that very much.
    I also would like to get into specifics on diabetes in just 
a second but I would like a comment as well, I have some 
concerns not directly related to what Mr. Obey said, but sort 
of, the President's proposed budget has a great reliance on the 
tobacco settlement which is very, very tenuous at this point. 
And I think that, realistically, on this subcommittee we are 
going to have to assume that that is not going to happen unless 
we get some indication in the next few weeks or days that that 
is likely to happen.
    But at least it is a nice change to hear that the 
Administration is interested in giving you more dollars 
because, historically, this subcommittee has had to carry the 
water after the proposed budget that we felt was inadequate. 
So, it is nice to hear that he is finally listening to the need 
for biomedical research dollars out in the heartland. What I am 
getting to is diabetes because I am concerned that diabetes has 
a huge impact on each of these factors, yet it continues to be 
a low priority for NIH research. I will run through the numbers 
quickly.
    Close to 16 million Americans have diabetes. Diabetes costs 
this Nation $98 billion each year. Diabetes kills 187,000 
Americans annually. Yet your budget request only calls for 
spending $388 million on diabetes research spending.
    The Speaker has noted, saying in speeches around the 
country, that almost one-third of every dollar we spend on 
Medicare in this day and age is directly related to problems 
with diabetes. The question is: Why does diabetes research 
continue to have a relatively low priority at NIH?
    Dr. Varmus. Well, Mr. Bonilla, I don't believe it does have 
a low priority. You will recall last year we had discussions of 
this topic at the hearings, and in response to some of the 
concerns that we received here and some of the concerns 
expressed to us by advocacy groups for patients with diabetes, 
the NIH underwent a very rigorous review of its entire program. 
We had a major meeting in September to look for unexplored 
opportunities in diabetes research, and to try to recruit new 
talent into the field. We have a very substantial increase for 
diabetes funding in the 1999 budget request--I believe it is a 
little over an 11 percent increase overall, which is, among the 
disease areas, one of the highest.
    As you are aware, under last year's Balanced Budget Act, 
there was a $30 million allocation per year for 5 years to 
diabetes, 90 percent of which is being used by the NIH through 
our trans-NIH diabetes research group, and there are many 
initiatives not only in the NIDDK but in several other 
institutes that address the problems of diabetics.
    So I would submit that we are paying special attention to 
diabetes at the present time and that it is difficult, in my 
view, to try to develop any simple one-to-one metric that 
relates what we spend to what is being spent on care. There are 
many other issues involved, including the number of years that 
we have been working on this problem, the scientific 
opportunities that are available for pursuing it and the number 
of other activities--for example, studies of the eye or of the 
vascular system or of the nervous system--that have profound 
effects upon our approach to the problems posed by diabetes but 
may not be counted as diabetes research. Those factors are 
extremely important.
    Mr. Bonilla. When I arrived here, just one year before you 
did, I was a big crusader back then for trying to give diabetes 
research a bump in funding because it was non-existent for 
several years prior to my arrival here in 1993. What about the 
factor, Dr. Varmus, of the country's aging population? And down 
the road--11 percent, maybe it is a good number right now, but 
as we escalate into the years, it is going to be even more of a 
problem than even the figures that I cited to your earlier.
    Dr. Varmus. We agree entirely that the problem posed by 
diabetes is one that will increase as the population ages, but 
that is also true of many other diseases, including cancer and 
nervous system disorders such as Alzheimer's disease and 
Parkinson's disease. So we have to consider the effects not 
just on diabetes but on other diseases as well.
    Mr. Bonilla. Well, rest assured we are supportive of the 
research dollars in those areas as well, so it is not a matter 
of picking the ones you mentioned over another.
    Dr. Varmus. But I would like to point out, Mr. Bonilla, 
that I do believe, especially with the increased scrutiny that 
we are giving to diabetes at present, that there isn't a stone 
that people believe should be turned that is not being turned.

                    diabetes research working group

    Mr. Bonilla. The Diabetes Research Working Group, Dr. 
Varmus, what are your expectations of this group? And does the 
budget request include the resources necessary to begin 
implementation of their plan?
    Dr. Varmus. The plan that the working group has endorsed is 
already being followed, through the appropriations in the 1998 
budget and through appropriations made available through the 
Balanced Budget Act. So they are already in gear. They have had 
a successful first meeting. I was pleased that Representative 
Nethercutt was able to come to that meeting. That they are 
already working is a consequence of our having developed a 
workshop in September that was intended to set out goals for 
doing research in relatively unexplored areas. There was a 
blueprint made quite quickly available to this group. Many NIH 
institutes participate as well as advocacy groups and outside 
scientists. The group is chaired by Ron Kahn, a distinguished 
diabetologist from Boston. The group is doing extremely well 
and has the funding necessary to carry out its plan.
    Mr. Bonilla. I hear the beeper. That says my time is up, 
Dr. Varmus. I have some questions for the record that I would 
appreciate you getting back to me promptly on, if you could 
answer, and I am glad you mentioned Mr. Nethercutt. He is, as 
you know, a champion in this area as well and has done a lot of 
good work over the last couple of years in this area.
    Thank you.
    Mr. Porter. Thank you, Mr. Bonilla.
    Mr. Stokes.

                           health disparities

    Mr. Stokes. Thank you, Mr. Chairman.
    Dr. Varmus, welcome. Let me at the outset thank you for 
your very kind and warm remarks at the beginning of this 
hearing. Let me also say that it has been a pleasure for me to 
work with you, Dr. Kirschstein, and so many others at NIH over 
the years. I appreciate, in particular, the responsiveness and 
the sensitivity that you have had in many of the areas of 
concern that I have discussed with you, not only in the 
hearings but also in my office, at NIH and on other occasions 
we have had to meet.
    To remain constant relative to these concerns, let me start 
off with my first question in that area.
    Recently, the President of the United States utilized his 
Saturday broadcast to speak to and address the very same 
concerns that I have discussed with you and your associates for 
many, many years. And, I guess that as I get ready to close out 
my career, I leave with some very real concerns in that area.
    Seated next to you and behind you are the finest scientists 
and doctors in the world, and it seems to me that I have to 
utilize whatever I can in order to try and impress upon all of 
you the absolute necessity for us to try to make some type of a 
dent in the disparity between white and minority health in this 
country.
    Obviously, the President is also concerned because he has 
included in this budget $80 million for a special race 
initiative. I think for the record it would be important to me 
if you could tell us where we have come since 1985 when we had 
our first report. That report told us about the excess deaths 
and other disparities, where we are today and whether our 
budget today really addresses our being able to seriously 
reduce, to cease, or terminate the disparate gap between white 
and minority health.
    If you could just tell us where we are, I would appreciate 
it.
    Dr. Varmus. Well, as you know, Mr. Stokes, we have not 
narrowed the gaps as much as you and I would like. The 
President has selected six emphasis areas for the coming few 
years, and we have major investments in all those areas. We 
feel it is particularly important that we use our resources for 
communication of medical information.
    For example, in the area of sudden infant death syndrome, 
we know that the reduction in death from that syndrome has been 
much more appreciable in the majority community than it has 
been in the minority communities. We believe that part of the 
problem is not using the right tools to reach the minority 
households where sudden infant death syndrome is still 
occurring at too high a frequency.
    I believe this is also true with respect to 
bringingindividuals into screening for breast and cervical cancer and 
for making an early diagnosis of diabetes.
    In all the major areas in which the discrepancies exist, 
there is a deep investment in clinical and basic research, and, 
of course, that investment will improve outcomes for all 
Americans. But as you know, in the last several years in 
particular, we have focused our attention on the minority 
issues specifically and insisted on minority representation in 
those studies in the hopes that we will begin to level the 
playing field. But it hasn't been entirely successful.
    I would be happy to provide some numbers for incidence and 
mortality rates in the areas that you have highlighted in your 
Black Caucus meetings and provide those, as I mentioned, for 
the record.

               president's initiative on minority health

    Mr. Stokes. Will this new initiative that the President has 
put in his budget help?
    Dr. Varmus. It has focused our thinking, and I believe it 
has been beneficial for us to have this initiative. As you 
know, we have ourselves been very concerned about these 
differences, both as a result of your drawing attention to them 
and our own perception of morbidity and mortality data that we 
collect and look at very closely as we think about the problems 
we are trying to solve.
    But I do feel heightened attention to some of the six 
specific problems that he has outlined as worthy of special 
attention will energize us.

                              role of ormh

    Mr. Stokes. How about the Office of Research in Minority 
Health? Do you see that office playing a larger role in this 
whole picture?
    Dr. Varmus. Well, as you know, Dr. Ruffin, who runs the 
office, has been coordinating minority health efforts. His 
budget is slated for a very substantial increase in the 1999 
budget. We have been working very closely with him and are 
about to meet with his advisory council to ensure that we are 
encouraging the institutes to follow all the appropriate leads 
on research that will benefit minority health.
    He is an integral player in the process, and his office has 
performed very well.

                  hiv/aids in the minority communities

    Mr. Stokes. Let me ask you about another area. The Centers 
for Disease Control testified here a few days ago, and one of 
the most stark facts that they brought out to us at that time 
was that the HIV/AIDS problem in the black community is now 
seven times that of the white community. This, of course, is a 
reason for great alarm.
    Can you tell us what NIH is doing relative to this problem?
    Dr. Varmus. Well, we have been aware, of course, for some 
years that particularly in the inner cities and in minority 
communities--Hispanic as well as black--AIDS is having a 
disproportionate effect.
    The general approach that we have been taking, of course, 
is to understand the basic damage that HIV does to individuals, 
find therapies, seek leads that might allow us to make an AIDS 
vaccine, and do behavioral research that attempts to seek ways 
to better prevent the transmission of HIV infection.
    In response to the President's initiative, which includes, 
as you know, HIV/AIDS among the targets, we have some plans for 
improved efforts to communicate preventive strategies to 
minority communities, and we hope those will be successful. But 
the amount of additional investment in HIV/AIDS as a 
consequence of the initiative is relatively modest.
    Mr. Stokes. Thank you very much, Dr. Varmus.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Stokes.
    Mr. Dickey.

                         success of nih funding

    Mr. Dickey. Hi, Dr. Varmus. I want you to know that in some 
parts of my rural district we have people who are rather 
elderly now who don't know that after the Depression hit in 
1929 things improved for the rest of the country. It has all 
been the same to them. As I watch the number of dollars that 
have been put into your agency increase every year, I just 
wonder if you know that there have been hard times for other 
agencies around here in Washington.
    Dr. Varmus. I do know that.
    Mr. Dickey. You are living in kind of an embryo of some 
sort, some type of protection, and I don't understand quite how 
we are going to justify it, but I guess we are going to. We 
have for the last three times I voted on this appropriation 
bill. I want to congratulate you on what you have done.
    Dr. Varmus. I appreciate it.

                      diabetes research investment

    Mr. Dickey. I understand that over the past year NIH has 
undertaken a number of critical initiatives related to diabetes 
and its complications. The budget for NIH has increased 101 
percent, and diabetes over the past 10 years has only increased 
by 35 percent. If we were to find more money for diabetes, how 
would you put that money to use? What else could be done?
    Dr. Varmus. Well, Mr. Dickey, we in a sense faced that 
problem last year, and, you know, we are only as good as our 
ideas. It is not as though there is a cure out there to be 
purchased. When faced with this question last year, we pulled 
together the best minds in the country to think about the 
various components of diabetes research--genetics, clinical 
research, metabolism--and asked them, what are the things that 
are underserved? What should we be doing more work on? And we 
came up with a series of important initiatives. At least four 
major initiatives thatemerged from that workshop and are being 
funded by the Balanced Budget Act funds, and there are several other 
intiatives that the NIDDK has put together.
    There may be others we ought to be initiating. Right now 
there are exploratory grants in certain areas. There is a very 
extensive interest on the part of several institutes to 
understand the genetic basis of diabetes. There are new drugs. 
We believe that there is reason to make an investment in the 
bioengineering devices that might allow us to sense glucose 
levels better.
    I don't think that there are totally unexplored areas. I 
think we could expand some of the areas that we are looking at. 
Right now I think, reasonably appropriate investments are being 
made in the current fiscal year and projected for the next 
fiscal year. Those could be strengthened, but I think in 
balance with our obligations and opportunities in other areas, 
we are making a reasonable set of decisions.
    Mr. Dickey. Well, you say there is no stone being unturned 
and no one would complain, but I have a friend named Duke Roos 
and his wife, Barbara, who lost a 32-year-old daughter, Debby.
    Dr. Varmus. You mentioned that last year, yes.
    Mr. Dickey. They would think that there is some stone that 
has not been unturned.
    Now, what I want to ask you is, you are saying that you are 
satisfied and everything is fine, but there are people out 
there who are not agreeing with you. How do we reconcile that?
    Dr. Varmus. Let me draw a distinction, Mr. Dickey, between 
pursuing scientific possibilities and achieving the ideal 
outcome.
    We are very far from having a perfect treatment for 
diabetes. People suffer and die from the complications of both 
Type I and Type II diabetes every day.
    When I referred to stones turned and unturned, I was 
referring to identifiable areas of research in which we are 
investing in the hopes of finding better ways to control and 
revert the complications of diabetes and the metabolic 
manifestations.
    So I understand that we have not achieved the goal that we 
have set for ourselves in this area, but I do believe that all 
the identifiable research activities that we could undertake 
are in general being undertaken.
    Now, could we do more in those areas? Very likely. Could we 
attract more talent? Yes, very likely.

                         Obesity and Nutrition

    Mr. Dickey. Okay. To stay within my time, let me change the 
subject. My developing interest in preventive health care leads 
me to ask questions of you related to obesity and nutrition. 
Can you tell us how obesity is defined?
    Dr. Varmus. It is defined in relation to norms established, 
I believe by the National Center for Health Statistics, and it 
represents a certain percentage above the average. I would like 
to submit that for the record. I am aware of the definition, 
but I don't have the precise numbers.
    [The information follows:]

                         Obesity and Nutrition

    Mr. Dickey. Can you tell us--could you help me with how 
obesity is defined?
    Dr. Varmus. A recent publication of the latest data from 
the full National Health and Nutrition Examination Survey III 
(1988-94) divides the U.S. population into several categories 
delineated by Body Mass Index, or BMI, which is a measure of 
weight compared to height. The categories used to describe 
overweight are: pre-obese (BMI 25.0 to 29.9), class I obesity 
(BMI 30.0-34.9), class II obesity (BMI 35.0 to 39.9) and class 
III obesity (BMI equal to or greater than 40.0). Thus, overall, 
a BMI equal to or greater than 25.0 is defined as overweight. 
By these measures, for the U.S. population age 20 years and 
older, the prevalence of overweight is now almost 55%. In the 
various categories, the prevalence is approximately: 33% for 
pre-obese, 14% for class I obesity, 5% for class II obesity, 
and 3% for class III obesity. I'd like to clarify one point 
about these definitions. They are used for overall 
classification of populations, not for diagnosis of an 
individual's degree of obesity. Because individuals vary in 
their body composition and their body frame, someone who is 
very muscular might not be overweight even at a BMI 
substantially greater than 25.0. On the other hand, someone 
with a very slight frame who has little muscle might be 
overweight at a much lower BMI.

    Mr. Dickey. What do you perceive to be the extent of 
obesity in the United States?
    Dr. Varmus. It is the only risk factor for cardiovascular 
disease that is actually increasing. The other major risk 
factors--blood pressure, smoking, and cholesterol levels--are 
all declining. So it is a very appreciable problem, and the NIH 
has a trans-Institute obesity study group that is coordinating 
efforts to combat obesity. We believe it is one of the most 
significant health problems we face as a Nation, with many 
possible approaches. There have been tremendous advances in the 
last few years in our understanding of how appetite is 
controlled. We also understand the important component that is 
played by behavioral research and efforts to increase exercise 
activity and control diet by methods other than medication. And 
we understand that it affects a very large number of body 
systems.
    Mr. Dickey. How much are you allocating to the research of 
obesity?
    Dr. Varmus. I don't know if we collect that number. I don't 
believe we do. But I can tell you that it is a very large 
figure if we put together the behavioral and the metabolic--
diabetes-related--and, of course, many kinds of studies of 
heart disease and cancer that deal with the problem of obesity. 
It may be rather difficult tosort out a totally accurate number 
for you.
    Mr. Dickey. I will ask another question that might be 
difficult. What is the estimated cost to our society of 
obesity?
    Dr. Varmus. I would be hesitant--it would depend a great 
deal on how you decided to measure it, whether that would 
include the cost of trying to treat it, the cost of the 
illnesses that are influenced by it. Certainly many billions, 
but I would prefer to defer to my economic advisers before 
giving you a number for the record.
    Mr. Dickey. Thank you. My time has expired.
    Mr. Porter. Thank you, Mr. Dickey.
    Mrs. Lowey.

                 recommendation of diabetes conference

    Mrs. Lowey. Thank you, Mr. Chairman.
    Dr. Varmus, I want to thank you for your testimony and 
welcome you and the other doctors who have joined you here to 
our committee this year. I am pleased that Dr. Kirschstein and 
Dr. Varmus as New Yorkers are here and that you understand the 
importance of medical research. He was originally born in New 
York. [Laughter.]
    Mr. Hoyer. So many of us were.
    Mrs. Lowey. I mention that, Dr. Varmus, you know, the 
incredibly importance of the National Institutes of Health to 
the medical community in New York, and we appreciate all the 
important work you are doing.
    Before I move on to my questions, there have been several 
comments or questions about diabetes, and I just want to thank 
you for your comments, and if you could submit for the record 
or to my office the implementation that you feel will result 
from the conference findings. At the conference there were 
recommendations, and I would be most appreciative, because 
there are many of us on the committee who represent 
constituencies who passionately care about research in 
diabetes, and I would be most appreciative.
    Dr. Varmus. We can send that to you very promptly.

                        clinical research awards

    Mrs. Lowey. With regard to clinical research, I appreciate 
your comments today. As you know, I have again introduced the 
Clinical Research Enhancement Act that was originally inspired 
by the 1994 IOM recommendations addressing the clinical 
research crisis. The lack of research resources and the 
financial barriers to attracting and maintaining a pool of 
talented M.D.'s to research careers as detailed by the IOM in 
their report unfortunately still exist today.
    I am very pleased, Dr. Varmus, that the NIH is proposing 
new clinical research awards. These awards, however, are very 
similar to those recommended by the IOM and echoed by the NIH 
clinical research panel led by Dr. Nathan.
    However, my concern is that in the 4 years since the IOM 
report was issued, the crisis facing clinical research has 
worsened, and there is concern that these awards may simply not 
be sufficient. In addition, my understanding is that at least 
one of these new awards is replacing a current clinical 
research award program.
    I want to understand these awards, and, therefore, I would 
like to ask a few clarifying questions.

                              k-23 awards

    The NIH is proposing K-23 awards to young investigators. It 
is my understanding that this new program will replace the 140 
clinical associate position, or CAP, awards that are currently 
funded--it feels like alphabet soup here--through the GCRC. Is 
that the case?
    Dr. Varmus. I am glad for the opportunity to clarify that. 
The award has been confused both the K08 and with the CAP 
award. But, indeed, what we are proposing here is in addition 
to those.
    Now, it is possible for individuals who currently receive 
these other awards, like the K08 or the CAP award to be 
converted to this new award, the K23. But we are committed to 
at least 80 new K23 awards each year over the next 5 years, and 
the number could indeed be larger as a result both of 
conversion of individuals from one of the others--but these are 
not substitute awards. They are in addition to the current 
level of clinical research training.

                          k-24 and k-30 awards

    Mrs. Lowey. It's confusing and I have been trying to 
understand this. What number of K24 and K30 awards are you 
proposing in FY99?
    Dr. Varmus. Well, in '99 we are talking about roughly at 
least 80 new K23s. Those are the awards to clinical trainees 
who will have a mentor, who will be undergoing training over 
five years.
    The K24 awards are for more senior people who already have 
faculty positions--are at junior or intermediate or even 
possibly in some cases senior levels on faculties. Those 
individuals have already demonstrated their capacity to do 
clinical research and serve as mentors. There will be in the 
range of 60 to 80 new awards in that category in 1999. It is a 
five-year award and renewable once. We expect to build up to a 
cohort of roughly 350 to 400.
    The third award is a didactic award to institutions and we 
expect to make that award to at least 20 institutions that now 
have or will soon develop a significant number of clinical 
trainees. These may be sponsored by us or by other 
organizations, because, as you know, we are not alone in 
training clinical investigators. The didactic award is intended 
to develop a course program specific for clinical research 
training at those institutions that qualify.

                   status of clinical research awards

    Mrs. Lowey. Just for the record if I could request the 
total number of new clinical research awards that you 
areproposing for FY99 and the number of clinical research awards you 
are proposing to phase out. What are the new ones you are proposing and 
what are the numbers you are going to phase out?
    Dr. Varmus. We are not proposing to phase out anything. The 
other award categories still exist, but the Institutes may 
decide to support those awards to convert them to K23s. That 
would be in addition. There is no simple conversion. The point 
is that the number of trainees is going to go up by a very 
substantial amount.
    Mrs. Lowey. Could we have for the record the total number 
of new clinical research awards you are proposing in FY99?
    Dr. Varmus. I think I just gave you those numbers.
    Mrs. Lowey. What is the total number?
    Dr. Varmus. Of new ones?
    Mrs. Lowey. Yes.
    Dr. Varmus. It will be 80 new trainees, at least, in 
addition to the existing trainees.
    Mrs. Lowey. Okay. So you are saying there will be 80 new 
ones but some of the old categories just may not be funded.
    Dr. Varmus. No. If those categories are retained by the 
institutes, then they will continue to pay new individuals in 
those programs. There is no simple conversion of an old program 
to a new one. It is all additive. So whatever the base was 
before would be built on. This is not a hat trick. This is not 
a substitution. It is an increment.
    Mrs. Lowey. Is my time up? Oh, my goodness. Let me just 
conclude, then.
    If we could clarify for the record, I would be most 
appreciative because there seems to be some confusion or 
misunderstanding in the community as to the actual increase in 
clinical research positions.
    Thank you, Mr. Chairman, for your indulgence.
    Mr. Porter. I don't know why, but seven minutes does seem a 
lot shorter than eight minutes. Thank you, Mrs. Lowey.
    Mrs. Northup.
    Mrs. Northup. Thank you, Mr. Chairman and thank you, Dr. 
Varmus. I have really learned so much in the last year about 
what NIH means to this country and to so many people and how 
many challenges are unmet in so many different ways in terms of 
health itself and quality of life. And I really thank you for 
what you all wrestle with.
    Every day those of us on this committee meet people that 
represent organizations or actually constituents in our 
districts that are affected or afflicted and depend on NIH 
research for their future. I say it is the closest to trying to 
be Solomon that probably any of us have ever been.
    One of the things that I have most appreciated and learned 
from our committee chair, quite frankly, is how important it is 
not to let politics make decisions that science should make.
    I would just like to ask you whether you agree. First of 
all, I feel like we are challenged not to let a political base 
divide up research dollars, and I wonder how effectively NIH 
itself is able to do this. For example, do you experience what 
many of us experience every day, where organizations that 
represent people with like afflictions come to see you and ask 
for increases in research dollars?
    Dr. Varmus. I think in the aggregate that probably is true 
every day, that we do have our advocacy groups come to the NIH 
to describe their interest in our activities and to give us a 
hand. Frankly, what I find most useful about those interactions 
is not the concern for funding but the offer of help. Patients 
can provide a special perspective on the diseases we are trying 
to combat. Many of our advocacy groups are extremely well 
informed about the issues, understand the grant portfolio, know 
investigators, and are very helpful in our decision-making 
processes.

                   co-funding of meritorious science

    Mrs. Northup. Let me ask you, do you find that there are 
projects that are joint funded and does NIH agree with that, 
and do you ever find that a group might offer to joint-fund a 
project that might actually have a vested interest in what the 
research would come out? How do you make sure that the research 
is uncorrupted, I guess, uncorrupted in a broad sense?
    Dr. Varmus. We do have such collaborations. We have quite a 
few of them. Sometimes they occur directly through our offices. 
Most investigators in this country are funded by more than one 
source, so we know that, in a sense, we are collaborating with 
many advocacy groups and professional societies because we are 
supporting the same investigators.
    There are, however, a number of examples of actual 
cofunding. One of the most prominent is the cofunding that goes 
on between the Juvenile Diabetes Foundation and NIH of certain 
diabetes initiatives and centers. That is carried out, 
actually, with as many as four different institutes.
    The advantage to the outside organization is that we 
provide the peer review, and the advantage to us, of course, is 
that it allows us to extend the use of our monies.

                   funding of peer reviewed research

    Mrs. Northup. But is there any worry that, for example, if 
you know you have a million dollars and somebody is going to 
offer a $2 million match for that million if it is spent in a 
certain way compared to another disease or challenge that has 
no match out there for it, that you would be more likely to 
say, ``Well, we get $3 of research for every dollar here?''
    Dr. Varmus. Well, I wouldn't deny the possibility of that 
happening. But among the many responsibilities with which my 
Institute Directors are entrusted, one of them is to evaluate 
such proposals, to bring those proposals to their councils, and 
to ask for an informed opinion about whether this is a good 
idea.

                       politicization of research

    Mrs. Northup. I think one of the concerns I have is if 
those of us on this committee agree that there should not be a 
politicization of research and we try hard to resist that and 
depend on the most promising and emerging science to make those 
determinations, I would want to know that that didn't go on in 
any other area of government, too in the executive branch or in 
any of the Cabinet departments that may benefit from your 
research.
    I wonder what reassurance you could give me that there is 
not this relationship, especially now that we see the cancer 
initiative. Maybe we would resist that sort of politicization, 
but that there would be forces equally unscientifically based 
that might succumb to it.
    Dr. Varmus. Well, Mrs. Northup, I understand your anxiety 
on this topic and I share it. On the other hand, I would point 
out that the distribution of funds that is eventually achieved 
by looking at public health problems and scientific 
opportunities is not going to result in a budget in which 
everyone gets exactly the same level of increase or exactly the 
same number of dollars.
    I do think that it is appropriate for us, as we develop our 
budget based on scientific opportunities and new areas of 
emphasis, to say to the public, ``Here are some diseases that 
are going to be benefitted by the investment we are making 
across these scientific frontiers.''
    Mrs. Northup. Yes, but it is only if you have one of those 
and your life depends upon that research that that really is 
very meaningful to you and there are some of those groups in my 
district and they are very concerned and they are very 
desperate. I would hate to think that I was depending on the 
purity of reasoning where not everybody else is playing by the 
same rules.

                            disease funding

    I would like to ask you another question. That is about the 
relative amounts of money that are spent for diseases. I think 
on this committee in particular we are constantly bombarded 
with organizations who tell us how little relative money is 
spent on the addressing of treating or investigation of their 
diseases and I wondered if those figures come actually from NIH 
and if they don't, how correctly independent organizations 
would be able to total up the dollars that are spent to 
investigate----
    Dr. Varmus. I appreciate that question, Mrs. Northup. As I 
have said here before, it is difficult to come up with a number 
for a specific disease.
    The numbers that we determine are largely numbers that 
respond to requests from Congress--perhaps even five or ten 
years ago--and the numbers are developed with a definition that 
was provided at that time.
    As you can well appreciate, the way in which we ascribe 
research dollars to a certain disease can vary dramatically 
based on the definition. I think we have discussed before the 
difficulty of saying, for example, what constitutes research 
on, say, Alzheimer's disease or on diabetes. How do you tote 
up, for example, the dollars that go into the basic research 
that leads to discoveries about a specific disease?
    Now in the diabetes arena, for example, we are faced with 
enormous opportunities to intervene in the basic metabolic 
defect because of basic research on the way in which a cell 
senses a signal and responds by changing patterns of gene 
expression, as I was illustrating earlier. Such research was 
not classifiable as diabetes research in the past but its 
impact on our understanding of diabetes is profound.
    Mrs. Northup. Thank you.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mrs. Northup.
    Mr. Hoyer.

                          political influences

    Mr. Hoyer. Mr. Chairman, thank you very much. I do not 
think I will pursue the purity of peer group procedures and the 
total lack of politics with peer group review committees, but I 
have talked to a lot of my friends in the academic community 
and sometimes find that even they are somewhat involved with 
political influences.
    Indeed, we have a system of political influences and we are 
dealing with their dollars. And when they talk to us about how 
they would like to have their dollars spent, it seems to me it 
is not unreasonable for those of us who listen to them, who 
were sent here to represent them, to express their preferences.
    But that notwithstanding, let me talk a little bit about--
--
    Dr. Varmus. I hope I didn't seem to say that those 
influences didn't exist. Of course they do and we are 
responsive to them, as you know.
    Mr. Hoyer. Doctor, there are a lot of people in the room to 
communicate with. I know exactly.
    Doctor, I want to thank you and Dr. Kirschstein in 
particular and all of you. Mr. Stokes and I were commenting and 
he referenced it, the incredible intellect and integrity that 
exists in this room at this very moment. It is always 
impressive to me, the quality of people that we have serving 
the American public and indeed all the people of the world, 
because obviously NIH has an impact worldwide as the premiere 
biomedical research organization.
    Mr. Dickey. Which side of the table are you talking about? 
This side?
    Mr. Hoyer. I am still praying for you. I want you to know 
that. [Laughter.]
    And there is an extra chair over here any time you want. We 
have, however, studying the neurological disorders that lead 
one to be a Republican but we have not come up with an answer 
yet. [Laughter.]
    Mr. Dickey. Is his time over? [Laughter.]

                    definition of clinical research

    Mr. Hoyer. We are the break in the monotony.
    Doctor, going back to clinical research that Congresswoman 
Lowey was talking about, would you comment perhaps a little 
more broadly about the definition of clinical research because 
we are all hearing about 15 percent, 30 percent. The problem is 
how you define clinical research. Can PhDs do clinical 
research? Do MDs do clinical research? Would you comment on 
that? My office has received a number of inquiries on that.
    Dr. Varmus. Let me just say, without going into boring 
detail on this topic, first of all, the definition used by the 
IOM--the Institute of Medicine--report a few years ago was much 
narrower than ours. Ours, however, encompasses many kinds of 
interactions, all of which involve patients. Thatis, it is not 
clinical research to simply work on a sample that comes from a human 
being. There has to be some need to interact specifically with certain 
patient groups. That does include certain kinds of behavioral research. 
It does include epidemiology.
    The definition that we use now includes a collection of 
clinical research activities that range from clinical trials to 
what is sometimes called translational research, in which the 
individual patient is under study with respect to the 
development of the disease or response to certain kinds of 
interventions.

                          Food-borne Illnesses

    Mr. Hoyer. Okay. Well obviously, you deal with that daily.
    Food-borne illnesses. Doctor, can you tell me briefly what 
kind of resources we are dedicating to NIDDK or other 
institutes as relates to food-borne illnesses, obviously a 
growing concern in this country?
    Dr. Varmus. We don't seem to have a number but I know that 
it is in the range of $53 million for NIAID for next year, and 
the number for NIDDK, I believe, is just slightly less than 
that. But both Institutes are aware of the increasing toll that 
food-borne illnesses are taking in this country.
    There was an interesting article in today's New York Times, 
in fact, about the impact of improved eating habits on food-
borne disease, in the sense that we are importing a lot of 
fruits and vegetables. It is a little bit like being in a 
developing country every day and exposed to some of the things 
that a meat-eater and someone who eats stewed turnips is 
unlikely to be exposed to, as opposed to someone who is eating 
fresh strawberries and raspberries that have recently come off 
the fields in Central America.
    Mr. Hoyer. One of the frustrations, I suppose, of us all is 
that today we are told that item A is bad for us and that item 
B is good for us.
    Dr. Varmus. The food is still good. It is just that you 
don't want it contaminated with bacteria.

                                 Autism

    Mr. Hoyer. It is a moving target sometimes, of course but I 
am glad to hear that food is good for us.
    I will not ask you a specific question but I will at some 
point in time have a question about Rett syndrome. As you know, 
I am very interested in that. There is no reason that you 
should know about it particularly. It is a very small program.
    Let me ask you about this. You have referenced and some 
others have, also, some compelling testimony from Dr. Rothman, 
Congressman Rothman's brother who has an autistic child. And we 
get this argument that you spend X here but there is a bigger 
problem over here that you do not spend as much on. Obviously 
you have to deal with that and we have to deal with it.
    But can you tell me where we are on autism, what your 
thought is on the relative contribution we are making to deal 
with autism?
    Dr. Varmus. Well, in the several years that I have been at 
the NIH, the attention being given to autism by at least four 
of our Institutes has increased by leaps and bounds. We had a 
very important workshop about three years ago at which a number 
of scientific opportunities were identified in neuroimaging and 
genetics, molecular biology, and behavioral approaches to 
autism.
    It is now recognized that autism is actually a spectrum of 
disorders with very different characteristics, and the four 
institutes that are involved have increased their financial 
commitment to autism research by large percentages.
    Now, the current funding level is roughly $20 million but I 
could get the more precise numbers for you for the record.
    Mr. Hoyer. If you would. I know Congressman Rothman in 
particular, is interested but obviously a broad spectrum of 
people are interested, as I am and everyone on the committee. 
Thank you.
    I want to say also that Dr. Penn was very kind to come 
visit in my office and spend some time with me and bring me up 
to date. She gave me, I don't know whether it was a book or a 
report on the autism meeting. I don't know whether it was that 
meeting to which Dr. Varmus referred.
    Dr. Varmus. It probably was. That was the large meeting we 
had.
    Mr. Hoyer. I provided a copy of that to Steve Rothman and I 
appreciate, Dr. Penn, your coming by.
    Mr. Porter. Thank you, Mr. Hoyer.
    Mr. Hoyer. My time is up.
    Mr. Porter. Despite your partisan comments I am going to 
call on two Democrats in a row. Ms. Pelosi.
    Mr. Hoyer. Said in jest, Mr. Chairman, as you know.

                           behavioral changes

    Ms. Pelosi. Maybe three, Mr. Chairman. Congresswoman 
DeLauro is here.
    Thank you, Mr. Chairman. I want to join my colleagues in 
welcoming Dr. Varmus and Dr. Kirschstein to the committee 
today, as well as the array of excellent leaders of the NIH 
that are with you today. Although born in New York, you made a 
very valuable contribution to the University of California at 
San Francisco and any chance I get I like to talk about that 
great institution. And it was UCSF that Dr. Varmus attended.
    One of the advantages of coming late in the game here in 
terms of asking questions is that so many of the questions that 
I had have been addressed and I want to associate myself with 
the concerns of Mr. Dickey and his discussion of behavioral 
change, whether it is obesity or smoking, whatever those issues 
are. That is a very important issue in prevention and I will 
submit a question on that for the record.

                                diabetes

    As far as diabetes in concerned--and I am sorry Mr. Bonilla 
left because I would like him and others to know that tomorrow 
my Medical Research Caucus is having the subject of diabetes as 
our focus. I think the Speaker is even coming to that and, of 
course, you know that our scientific leader of the caucus is 
Dr. Michael Bishop, chancellor-designate of the University of--
--
    [Laughter.]
    Ms. Pelosi. I don't know if he will still be able to help 
us on this caucus once he takes his full responsibilities as 
chancellor, but he is the co-laureate with Dr. Varmus. 
[Laughter.]
    Mr. Hoyer. You are pleased to bask in the glow.
    Mr. Dickey. Are you all just having a regular conversation? 
Would you like to share with us what in the world you are 
talking about?
    Ms. Pelosi. I just said great things about you. I 
associated myself with your remarks.
    Mr. Porter. And you are going to be charged for the time, 
also. [Laughter.]
    Ms. Pelosi. Enough of that.
    Mr. Hoyer. She is in a safe district or she wouldn't 
overcome it.
    Ms. Pelosi. Well, I will skip over the stuff about our 
distinguished leader, Mr. Chairman.
    Mr. Porter. Well, I will give you extra time.

                 outreach in clinical research centers

    Ms. Pelosi. I have to go really fast because I do have some 
questions. I would like to submit my specific question about 
clinical research centers for the record in terms of the budget 
priorities and ask a little different question.
    In your testimony, Dr. Varmus, you said that in relation to 
the GCRC you will continue the loan repayment programs for 
clinical trainees from disadvantaged backgrounds. I wondered 
what else you were doing in terms of outreach for research 
patients at every step of the way in these clinical research 
centers to ensure that the position the President has about 
removing the disparities of race in terms of illness, using 
those centers as one place where we could implement an outreach 
into the communities.
    Dr. Varmus. I am not sure of the focus of your question, 
Ms. Pelosi, but I would point out that----
    Ms. Pelosi. What are you doing other than loan forgiveness?
    Dr. Varmus. Loan forgiveness, unfortunately at this point, 
only applies to clinical trainees at the NIH intramural 
program. We would be interested in trying to develop a loan 
repayment program extramurally but that requires additional 
authorization to NIH.
    Ms. Pelosi. But what are you doing at the clinical research 
centers?
    Dr. Varmus. Well, a number of things. I point out that the 
``general clinical research centers''--GCRCs--comprise roughly 
25 percent of our clinical center activity. Much of the other 
is, of course, disease-specific--cancer, diabetes, Parkinson's.

                         decline of gcrc budget

    Ms. Pelosi. If I may, is it so, and recognizing that large 
percentage, it is my understanding that your GCRC budget has 
declined as a portion of the NIH budget from 3 percent to 1 
percent?
    Dr. Varmus. Well, in the current proposal we are going to 
be increasing the number by, I believe, roughly 12 percent over 
the '98 level.
    The results of the deliberations of Dr. Nathan's clinical 
research panel suggested that the GCRCs ought to take on a more 
central role in clinical research training and coordination at 
the campuses at which they are located. We are trying to 
identify those that show the promise to carry out those 
extended activities and proposing to give them a larger stipend 
with which to operate.

                president's initiative and gcrc outreach

    Ms. Pelosi. I would hope that they would be reflective of 
the problems of women in what they are set up to do in 
relationship to the President's initiative.
    Dr. Varmus. Well, certainly all clinical research 
activities--all clinical trials proposals--now must include 
explicit descriptions of how women and minorities will receive 
equal treatment. That has been true for several years and that 
will still be true.

                           cancer initiative

    Ms. Pelosi. I appreciate your emphasizing that point. I am 
sorry to intervene.
    You note in your statement that the next dramatic 
transformation of medicine in molecular biology is likely to 
occur in the study of cancer and I draw from that that that is 
why this initiative on cancer is being set forth, because of 
the opportunity that you describe.
    Dr. Varmus. Yes. And I don't mean to say that there are not 
similar opportunities for other diseases, but this is closest 
to the clinical interface, in my view.
    Ms. Pelosi. That is very good news.
    NIH's Office of Research on Women's Health. I will submit 
for the record some questions about what actions are currently 
being taken by NIH to meet the Office of Women's Research 
mandate because I want to put a couple of other questions on 
the record.

                          international health

    When Secretary Shalala was here she talked about an 
international cast to some of what was happening and said you 
might elaborate on some of that when you were here. Some of us 
serve on the Foreign Ops Committee that does the appropriating 
and sometimes even on health issues.
    Dr. Varmus. Well, I am pleased to have that opportunity. My 
own view is that it is in the interest of this country to pay 
attention to health problems of countries abroad, not simply 
for altruistic reasons but also because the economic and 
political stability of those countries is strongly influenced 
by health.
    Moreover, health is an arena in which we can improve the 
cultural, and scientific, and educational infrastructures of 
those countries. I have seen this most clearly in my own 
activities on malaria, a disease which is clearly very uncommon 
in this country. It is largely imported when it occurs here. It 
is a tremendous global problem, causing as many as 3 million 
deaths a year and infecting 300 to 500 million people around 
the world.
    We are carrying out a strengthened program on malaria 
research. We think that genetics and immunology have taken us 
to the point where there are remarkable new opportunities to 
combat the disease, both through research carried out in this 
country and through strengthened our collaborative interactions 
with research partners in Africa, Asia and South America.
    Ms. Pelosi. Thank you very much, Dr. Varmus.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Ms. Pelosi.
    Ms. DeLauro.

                             ovarian cancer

    Ms. DeLauro. Thank you very much, Mr. Chairman.
    Thank you and I apologize to you, Dr. Varmus and Dr. 
Kirschstein and the directors of the NIH for not being here at 
the outset.
    We had a wonderful visit from the President to the State of 
Connecticut at a meeting today in Bridgeport, Connecticut 
talking about child care and also talking about doing about the 
tobacco legislation, so we are very excited about that visit.
    Don't you have, Dr. Varmus, some connection to Yale 
University?
    Dr. Varmus. I have spoken there. I am a friend of Dr. 
Kessler's.
    Ms. DeLauro. Let me ask a couple of questions. I know you 
all know this but two-thirds of those diagnosed with ovarian 
cancer die within five years of diagnosis, yet we still do not 
have a simple diagnostic test that detects the disease in the 
early stages.
    Last year the NIH devoted $41 million out of an overall 
budget of $13 billion for ovarian cancer research. If I could 
ask you how much you plan to spend this year on ovarian cancer 
research and what progress has been made toward developing a 
diagnostic test that could detect the disease and help save 
lives.
    Dr. Varmus. The anticipated number is $46 million for FY99. 
But I would emphasize that that number probably does not 
encompass all the things that are going on that will affect our 
approach to ovarian cancer--for example, to understand some of 
the genes that we know to be involved in ovarian cancer: The 
large attack that is being made through the cancer genome 
anatomy project, which you will hear more about from Dr. 
Klausner, has chosen ovarian cancer as one of its targets for 
development.

                       nih and nasa collaboration

    Ms. DeLauro. I look forward to talking with Dr. Klausner 
when he comes up to talk about a whole range of activities with 
regard to this disease.
    Also I might ask you to talk a little bit about--I know 
NASA is doing some work in cancer research. I attended a 
luncheon last year where NASA talked about some of the work 
that they are doing in basic biology of cancer cells and how 
they grow, how they don't grow, how we can stop them from 
growing and, with regard to ovarian cancer, tumors using 
something that they have called the NASA rotating vessel in 
order to grow the tumors and monitor their progress.
    I would like to know about the collaboration between the 
NIH and NASA and what you are doing on this issue and other 
areas.
    Dr. Varmus. We have quite a number of interactions with 
NASA, most focussed on neurological disorders. We are involved 
in some of the Neurolab projects. We have been studying balance 
and hearing and we also have a component of our research that 
is addressed to similarities between aging and time and space. 
But Dr. Klausner informs me that we are working with them to 
develop what is called a bioreactor, in which various types of 
cells are grown to extremely large numbers for a variety of 
purposes.

                       nih and doe collaborations

    Ms. DeLauro. I am again interested in those kinds of 
collaborative efforts because last year I asked about some of 
the discoveries that were being made with regard to children's 
brains and when our children learn and what that process is 
about and how to make some of the leaps to education and Head 
Start and Early Head Start in the year 2003. Can you talk about 
that collaborative effort with the Department of Education? Are 
you working with them on this?
    Dr. Varmus. We do work with them and you will hear from Dr. 
Alexander from the National Institute of Child Health and Human 
Development who will testify about some of those things.
    We have had some remarkable discoveries just in the last 
few weeks about the way in which the use of brain imaging can 
influence our understanding of reading disorders. You may have 
seen in the paper the pictures of brain images that show the 
different components of the brain illuminated in normal as 
opposed to dyslexic children. That gives us a very important 
focus for further studies of this disorder. And whatever 
understanding is achieved is, of course, shared with the 
Department of Education. I think you can get more details of 
that collaborative arrangement from Dr. Alexander.
    Ms. DeLauro. I am aware of Dr. Shaywitz's work.
    Dr. Varmus. Yes. I omitted the fact that that work did come 
from Yale University. My oversight.
    Ms. DeLauro. I have had the opportunity to hear her speak. 
What we are going to try to do in the next several weeks is to 
bring together people from the education field in the district, 
from superintendents of schools, parents and others to get the 
benefit of this research, to understand it in some way again, 
in the effort to take the knowledge that is being developed and 
move it into an arena for learning and for kids to be able to 
take advantage or for our teachers to be able to take advantage 
of research. It is real but to make it real in the classroom or 
real in doctors' offices, with the work that you are doing.

                 collaborations among federal agenices

    Dr. Varmus. I might just make one more general point about 
collaboration among federal agencies. Mr. Bonilla referred 
earlier to my flip cards. Well, I have a couple of flip cards 
that are full of the interactions that occur between individual 
NIH Institutes and a wide variety of federal agencies, both 
within the PublicHealth Service and outside it. I believe those 
are extremely useful interactions, and I think in all fields, including 
education, we are working very productively with other agencies.
    Ms. DeLauro. I think that that kind of information is very 
important to us because the work you do and its applicability, 
as I said earlier, to doctors' offices, to the classroom, to a 
practical setting, if you will, is important for us to know 
that, to make those connections, that this work does not exist 
for the sake of research alone, which is critically important--
don't misunderstand me. I think you know what my sentiments 
are.
    But I think we need to be able to leave this committee and 
to take these collaborations and be able to explain that to 
other colleagues, to talk about these efforts.

                                earmarks

    Dr. Varmus. We are especially proud this year of the very 
productive interactions we have had with the National Science 
Foundation, which led in part, among other things, to the 
development of a new training program in which NSF-sponsored 
physicists, engineers, and mathematicians will come to the NIH 
campus to become more involved in biological research.
    Ms. DeLauro. Thank you very, very much.
    Mr. Porter. Thank you, Ms. DeLauro.
    Dr. Varmus, am I correct that you will also be present when 
each of the other directors of the institutes testify?
    Dr. Varmus. I am looking forward to it, Mr. Chairman.
    Mr. Porter. Well, we have had a request for a second round, 
but I think Members will have ample opportunity to ask further 
questions of Dr. Varmus, if they wish, when he appears during 
the coming two plus weeks.
    While the gentleman from Maryland is here, let me agree 
that all of us have matters within the bioresearch activities 
that we feel very strongly about and we not only express that; 
we encourage, cajole, pressure, for our viewpoints. But what we 
don't do is direct or earmark. In the final analysis, we 
believe very strongly that the decisions must be the decisions 
of NIH and not the decisions of the Congress, and I think that 
is the right policy and I think the gentleman agrees very 
strongly with me.
    Dr. Varmus, let me thank you for your excellent testimony 
and your direct answer to all of our questions. We believe that 
NIH is truly one of the great treasures of this country. We 
believe in what you do. We want to do our very best to provide 
you with the resources you need to do your vital work. The 
existence of NIH, the wonderful people that it brings to it and 
the entire biomedical research enterprise of this country makes 
all of us very proud to be Americans.
    Thank you very much for your appearance here today.
    Dr. Varmus. Thank you, Mr. Chairman.
    Mr. Porter. The subcommittee will stand in recess until 10 
a.m. tomorrow.
    [The following questions were submitted to be answered for 
the record:]


[Pages 47 - 331--The official Committee record contains additional material here.]



                                         Wednesday, March 25, 1998.

                       NATIONAL CANCER INSTITUTE

                               WITNESSES

DR. RICHARD D. KLAUSNER, DIRECTOR, NATIONAL CANCER INSTITUTE
DR. ALAN RABSON, DEPUTY DIRECTOR, NATIONAL CANCER INSTITUTE
DR. HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS

    Mr. Porter. The subcommittee will come to order. We 
continue our hearings for the National Institutes of Health 
with the National Cancer Institute, and we are very pleased to 
welcome Dr. Richard Klausner, the Director.
    I apologize to you, Dr. Klausner, for being a little late. 
We will be able to spend the next two hours with you, though, 
and we will, I hope, cover a lot of ground. So why don't you 
proceed with your statement, and then we will go to questions.

                           progress in cancer

    Dr. Klausner. Thank you, Mr. Chairman and members of the 
committee. I am pleased to appear before you for the third time 
as Director of the NCI.
    The President in his 1999 budget has proposed that the 
Institute receive $2,776,267,000, including the estimated 
allocation for AIDS, which is an increase of $228,953,000, or a 
little less than 9 percent over the current appropriation. This 
increase will allow us to accelerate the progress that I 
believe we are making against cancer.

                annual report card on cancer statistics

    Last year, as you will recall, we reported for the first 
time the first sustained significant decrease in cancer 
mortality rates since such statistics were first collected in 
the 1930s. At that time we said that we would have an annual 
report card on how we were doing by reporting cancer 
statistics, which we did 2 weeks ago. Those positive trends 
continue. Overall death rates continue to decrease by 0.5 
percent per year after a prolonged rise of 0.4 percent per 
year.
    For the first time, this year we reported what is happening 
to cancer incidence rates. From 1973 to 1990, overall cancer 
incidence rates were rising by 1.2 percent per year. That 
increase has changed. It is now going down by about 0.7 percent 
per year.
    Decreased cancer incidence reaffirms that cancer can be 
prevented. Multiple strategies will be required to prevent 
cancer. The development and testing of new drugs to prevent 
cancer is a relatively new and growing aspect of our work. The 
NCI is currently sponsoring over 85 chemoprevention clinical 
trials for breast, colorectal, lung, prostate, and other 
cancers, and a growing number of these are based upon a real 
understanding of what these interventions are supposed to do. 
Twenty-five new prevention trials will be initiated this year.

                            clinical trials

    This past year, we completed accrual for one of the major 
prevention trials that we are engaged in, the accrual of 13,000 
women at increased risk of developing breast cancer to a 
critical clinical trial to determine whether an anti-estrogen, 
Tamoxifen, can actually prevent this disease, and we anxiously 
await the results of that trial.
    New possibilities for very selective hormonal manipulation 
for cancer prevention are emerging with thedevelopment of so-
called designer estrogens, and we are actively evaluating clinical 
trials to examine their utility.
    Unfortunately, advances in treatment are often only 
incremental, and they take time to have an effect on cancer 
mortality. However, it is this incremental progress that, in 
part, explains the mortality trends for numerous cancer sites.
    Over the past 2 years, we have completed clinical trials 
that have established new standards for optimal therapy for 
women with node-negative and locally advanced breast cancer, 
for women with ovarian cancer, for patients with nasopharyngeal 
cancer, melanoma, childhood renal cancer, and others.

                 CLINICAL TRIALS--PROGRESS IN TREATMENT

    A major explanation for the incremental nature of progress 
in treatment is that our therapies generally to date have not 
been designed to target the machinery of cancer, and that 
brings me to focus on what I think is the most dramatic change 
in the National Cancer Program.
    Thirty years ago, Peyton Rous, in receiving his Nobel 
Prize, in his lecture said, and I quote, ``Tumors destroy man 
in a unique and appalling way, as flesh of his own flesh, which 
has somehow been rendered proliferative, rampant, predatory and 
ungovernable * * * yet despite more than 70 years of 
experimental study, they remain the least understood.'' He 
finished by saying, ``What can be the why for these 
happenings?''
    Three decades later, Dr. Rous would be amazed. With 
dizzying speed and growing precision, we are mapping the inner 
workings of the tumor cell. In the poster we see what Dr. Rous 
was looking at 30 years ago: basically a cell that we knew very 
little about. Now that has been replaced by a cell in which we 
see the intricate circuitries of cancer. The cancer genes so 
frequently reported in the news are altered relays in this 
circuitry. Viruses, carcinogens, radiation--all act by altering 
one or more of these specific pathways.

                CLINICAL TRIALS--PREVENTION AND THERAPY

    Now, what is important about this and what is remarkable 
about this difference is that each circuit is now suggesting a 
rational target for prevention or therapy of cancer. This is 
shown in the next poster. Dozens of these are now being 
developed. This will be the new approach to prevention and 
therapy for the future.
    Ten years ago, 60 drugs were entering clinical trials for 
cancer. Today that number has increased to about 320. Let me 
briefly illustrate one.
    Thirty-five percent of breast cancers overexpress a 
particular protein called HER-2. These cancers tend to be more 
aggressive, and clinical trials have shown that women with such 
cancers require more intensive therapy to achieve the same 
outcome as women who do not activate one of those circuits, the 
HER-2 circuit.
    Last December, Genentech announced the results of the first 
clinical trial using an agent targeted against that specific 
cancer circuit relay. That agent, when added to taxol, showed a 
clinical response rate three times greater than taxol alone in 
women with advanced metastatic breast cancer--a cancer for 
which we desperately need new therapies. New clinical trials 
have already begun to rapidly build on this result for breast 
cancer but also for other cancers that overexpress HER-2, such 
as ovarian cancer and a fraction of lung cancers.

                              ANGIOGENESIS

    In one of the more exciting new tests of our new knowledge 
of cancer biology, we now know that altered circuits in cancer 
cells result in the production of molecules that stimulate the 
growth of blood vessels that nourish growing tumors, a process 
called angiogenesis. Without angiogenesis, the tumor will die 
or never grow beyond a microscopic size.
    Over the next year, we plan to have the first potent anti-
angiogenesis agents into clinical trials for cancer. There are 
few new ideas in cancer therapy that have generated as much 
hope and excitement as anti-angiogenesis therapy.
    So what is the challenge? With the increased proposed in 
the President's budget, we can drive progress by increasing the 
success rate for the funding of individual investigator-
initiated research. We will continue to build on and expand the 
infrastructure of the Cancer Genome Anatomy Project, which I 
introduced to you last year, to speed the discovery of the 
pieces of the machinery of cancer and especially to give us new 
molecular tools for early detection. This proposed budget will 
allow us to support a number of new initiatives. Among these 
are:

                         DRUGS AND SMART ASSAYS

    The development of new chemistry-biology centers to capture 
revolutionary new approaches to the production of millions of 
small molecules and to couple this with so-called smart assays 
in order to find those drugs that interact with each of those 
circuitries;

               RAPID ACCESS TO INTERVENTIONAL DEVELOPMENT

    To build a new program for the Rapid Access to 
Interventional Development, which we call RAID, designed to 
accelerate the movement from the lab to the clinic of the best 
new ideas for cancer intervention from investigators throughout 
the country;

                      CLINICAL TRIALS--INFORMATICS

    To build a redesigned, informatics-based clinical trials 
system to expand access to prevention, detection, and treatment 
trials, to improve the speed and value of those trials, and to 
allow what is clearly a growing number of compelling new ideas 
to actually be tested in people;
    To build a new imaging research network to rapidly evaluate 
emerging technologies in tumor imaging, both for early 
detection and for the new field of image-guided therapy;
    To fund new behavioral and health communications research, 
particularly to reduce tobacco use;
    And to enhance our cancer surveillance system so that we 
have a better understanding of the burden of cancer and where 
we need special efforts in cancer control so how we respond to 
some really remarkable changes that these cancer statistics are 
pointing out to us as well as others.
    These new programs were designed through extensive planning 
and priority-setting processes. They are aimed at bridging the 
gap between the explosion of discoveries in basic science and 
our ultimate goal of reducing the burden of cancer for people. 
Many of these illustrate the transition from molecular biology 
to molecular medicine that Dr. Varmus spoke of in his opening 
statement at the beginning of these hearings.
    As always, I appreciate the opportunity to appear before 
you, and I am happy to attempt to answer any questions you 
might have.
    [The prepared statement follows:]


[Pages 337 - 351--The official Committee record contains additional material here.]



                     INCIDENCES OF VARIOUS CANCERS

    Mr. Porter. Dr. Klausner, thank you very much for that 
excellent opening statement.
    You said the incidence of cancer, its rate, is going down, 
but you did not really say why. Is that for all cancers? Is it 
lifestyle changes? What is causing the rate to be less than it 
has been in the past?
    Dr. Klausner. Well, of course, cancer is many diseases, and 
the answer we have to look at is disease by disease. The 
overall rate gives an aggregate report, but, in fact, to 
understand it we have to look at each.
    For lung cancer, it is overwhelmingly the drop in smoking 
causing lung cancer rates to go down.
    For colorectal cancer, the rates are going down, and 
frankly, we are not sure why. Some of it may be detection of 
precancerous lesions such as polyps, and some of it may relate 
to changes in diet, the use of, for example, nonsteroidal anti-
inflammatories. We actually do not know.
    For breast cancer, the rates had been going up for years by 
about 1.8 percent per year, and now they are flat.
    The reality is most of the incidence numbers, with the 
exception of tobacco-related cancers, remain mysterious. These 
numbers, as I said when we presented this, actually sound like 
they are exclamation points or periods, and they are not. They 
are question marks. They actually tell us what is happening in 
sub-populations--men, women, different ethnic groups. That then 
allows us to do research to try to answer some of the 
questions.
    Mr. Porter. Will you permit a non-scientist to ask you for 
an explanation of the science?
    Dr. Klausner. Yes.

                      CIRCUITRY OF CANCEROUS CELLS

    Mr. Porter. If you looked at the first poster, it basically 
showed a nucleus and the cytoplasm. Now, the second poster 
showed a great deal of detail. Can you tell us whether 10 years 
from now we will see a third poster that will show detail of 
the detail, or are we down to the smallest parts?
    Dr. Klausner. No. In fact, we had to edit that so that we 
can even see it. We already know many more components of the 
circuitry. We have a lot more that we need to unravel.
    What is different now is actually we know how to get to 
those circuits. We know how to get at them much more rapidly, 
much more systematically, because of new concepts and new 
technologies. It will look much more complicated, and that is 
only part of the circuitry. That is simply the circuitry within 
the cancer cell.
    We know that there is an equally complex circuitry of how 
the cancer cells talk to other cells in places where the cancer 
may metastasize or not, the blood vessel cells, immune system 
cells. All of that is modified by the circuitries of what we 
are exposed to and how we deal with those exposures, which 
again relate to, for example, variations in genes.
    How these circuits might be affected by exposure, for 
example, to environmental carcinogens we know itself can only 
be interpreted by understanding the nature of each individual's 
filter. That determines why one person may respond, for 
example, to alcohol ingestion with an increased risk of oral 
cancer and another person does not.
    So the answer is we all need to be prepared. These diagrams 
are going to get much more complicated.

                   GENETIC PREDISPOSITIONS TO CANCER

    Mr. Porter. Is it fair to say that we could have a genetic 
predisposition or a weakness to some type of cancer and that 
the probable causes are either lifestyle matters or 
environmental matters, that there are not outside agents that 
pass the disease?
    Dr. Klausner. Absolutely. The whole area of predisposition 
to cancer is a very complicated area. One thing that is very 
important is few of these genetic changes guarantee that a 
person is going to get cancer. This idea that a gene determines 
your absolute fate is a misconception. It changes the 
probability that many of the same external factors--tobacco, 
reproductive behavior, exposure to infectious agents, et 
cetera--change the probability thatthose exposures will result 
in the development of first precancerous and then cancerous changes.

                     gene-environment interactions

    So, in fact, it is not an either/or: Do we study genes or 
do we study the environment? In fact, what the genes are doing 
for us is allowing us in many ways an entirely new way to look 
at and interpret the environment--the environment defined as 
diet, environmental carcinogens, reproductive behavior, 
infectious agents, sunlight, et cetera.

                   stress and the incidence of cancer

    Mr. Porter. There is one other thing I would like to ask 
about in that regard. We seem, anecdotally, to find people 
being afflicted at times of great mental stress. Is this a 
factor? And what are you doing to study that situation?
    Dr. Klausner. We have been studying the relationship 
between attitudes, stress, a variety of psychological factors, 
and the incidence of cancer and the nature of the cancer that 
is diagnosed. And, in fact, we have been unable in multiple 
studies to actually find evidence that stress or psychological 
factors predispose people to cancer.
    There are some studies, however, that have looked at how 
well people do with cancer based upon what we might call 
psychological factors, specifically support groups or 
psychotherapy.
    There are a number of studies looking at breast cancer, 
melanoma, and a few other cancers that suggest a beneficial 
effect for individuals that enter, for example, group therapy. 
We are pursuing those studies through our community clinical 
oncology program to try to follow up to see whether those 
approaches can be generalizable beyond the institutions where 
they were developed and whether the positive results hold up.

                           nci reorganization

    Mr. Porter. When you came to NCI, you undertook a rather 
thorough reorganization of your Institute. Is that correct?
    Dr. Klausner. That is.
    Mr. Porter. Can you tell us how all that has turned out? 
There was some talk that others have looked at your Institute 
as a model and have made changes in their Institutes based upon 
what you were able to accomplish at NCI. Can you describe any 
of that as well?
    Dr. Klausner. Well, we made a large number of changes. Not 
only did we reorganize, but we examined many of our processes 
that relate to advisory structures, planning processes, how the 
different components of the Institute interact, as well as how 
we functioned administratively.
    Personally, I think that we are doing okay. I think it has 
been very beneficial. And one of the major measures of the 
benefit has been a remarkable change, an increase in our 
ability to recruit superb people from many different fields to 
actually come and be part of the NCI.

                    evaluation of business practices

    Mr. Porter. As far as the other Institutes, has there been 
any changes that others have done based upon what you did?
    Dr. Klausner. Well, maybe I would ask Dr. Varmus to 
comment.
    Mr. Porter. Dr. Varmus might answer that, yes.
    Dr. Varmus. Well, I think that the success that Dr. 
Klausner has had in obtaining opinions about how to develop 
scientific initiatives through use of outside consultants has 
been very effective. Many institutes, of course, have had other 
kinds of planning processes that use outside advisers, but I 
think some of those institutes that have been lagging in that 
regard may have taken a positive signal from what has gone on 
at the NCI and what has gone on at other institutes that 
effectively use outside consultants.
    Mr. Porter. Dr. Varmus, are you satisfied that each of the 
Institutes has really looked at how they do things over the 
last few years and have made changes similar to the kinds of 
changes that NCI has made to do things better? In other words, 
has there been kind of a mini-revolution going on?
    Dr. Varmus. I think that there has been much more 
engagement with outside advisers, and that is something that I 
think I would have to say does not emanate only from the Cancer 
Institute. It has been something that has actually been 
encouraged by this committee. When I came to the NIH in 1993, 
we had already received the direct advice from this committee 
to evaluate our intramural program with an outside advisory 
committee.
    Mr. Porter. Are these non-scientists?
    Dr. Varmus. No, no, no. These are scientists. But that is 
only emblematic of the kind of activity that brings people from 
outside the NIH, whether it is managerial as in the case of the 
Andersen report that we did in response to your suggestion last 
year, or the Marks-Cassel report that was done to evaluate the 
intramural program several years ago, or the Bishop Calabresi 
committee that provided advice to the Cancer Institute before 
Dr. Klausner came on board. It was addressed to the structural 
organization of the NCI. All those things have been highly 
successful and have been validations of the idea that NIH 
should not try to answer all its own problems with its own 
personnel, that it should depend more heavily on outside 
opinion.
    That has been my own creed since I have been there; Dr. 
Klausner has certainly espoused it very forcefully, and I think 
many other institutes have.
    There is always room for further improvement. As you know, 
the Center for Scientific Review is currently undergoing a re-
evaluation of its study sections, and that isbeing undertaken 
by a panel of distinguished outside scientists. That might not have 
been the case some years ago, and I think the ethos has been 
established by these many activities in which the Cancer Institute has 
figured importantly. It has been very beneficial.
    Mr. Porter. Well, I would certainly commend both you and 
Dr. Klausner and others who have really made this a very 
dynamic process, and have not allowed things simply to be 
continued because we have done it that way in the past so we 
will do it that way in the future. I think that makes any 
organization, any enterprise, work much better, and I think you 
have done an excellent job of stirring up the pot and making 
things work better.
    Dr. Varmus. Well, you have helped us with that, and I 
appreciate it.
    Mr. Porter. Mr. Hoyer.
    Mr. Hoyer. Thank you very much, Mr. Chairman, and welcome, 
Dr. Klausner.

                   cancer funding--effects on society

    Dr. Klausner, it is difficult for any of us to extricate 
ourselves from the personal involvement with cancer. I imagine 
there is no one in this room who has not been personally 
affected in a very real way by this disease.
    I was at a funeral yesterday for a very close friend of my 
daughter's mother. It was difficult for my daughter, as you can 
imagine. She went to high school with Andrea Vespoint whose 
mother died of breast cancer, fought it for 6 years. And as I 
went through the viewing and talked to Sal, her husband, he 
looked at me and he said, with real pain, as you can imagine, 
``The right woman has not yet died of breast cancer.'' He was 
angry.
    And what he meant by that, of course, was that from his 
perspective, having gone through this 6 years, Rosemary's 
doctor saying she had had more chemotherapy and other extrinsic 
treatment than any other patient he had ever had, Sal's 
frustration and anger that those of us in power--anger at me, 
although he knew my wife very well, as well. But he was angry 
with us. He was angry with us because we are not spending 
enough money and we are not solving this problem, because he 
believes scientists like you, with the incredible capability 
that you have, can somehow save his wife and others.
    I told him, I said, Sal, I understand what you are saying, 
and obviously he knew I understood his feelings. But we are 
spending a lot of money, and we have some very good minds.
    You will also be interested in a comment of my daughter 
after we left and I took her to dinner. She was up from Florida 
to go to the funeral. She said, ``Dad, you know, I understand 
Mr. Vespoint,'' she said, ``but it is in the scheme of things 
that we will die.'' And, of course, that is true, but at a 
young age we do not expect that to happen. We do not want it to 
happen. That is why we spend this money.

                           funding for cancer

    Let me ask you first--and if you do not know the answer 
then for the record, how much money have we spent since 1971 or 
1972 when we declared a major effort under the Nixon 
administration to try to eradicate or intervene or cure? How 
much money have we spent? Your budget this year is 
$2,300,000,000, not an insignificant sum of money. And, Dr. 
Varmus, perhaps with all the institute directors, we know that 
it is not just the $2,300,000,000, just as the $2,300,000,000 
impacts on other institutes and other diseases and the research 
that is done, the research that is done in other institutes 
impacts and assists and moves us forward with respect to yours.
    But if you could do that, because I would like to be able 
to respond to Sal, and to all our constituents, and to 
everybody here, on how much we have dedicated to this effort. 
You may want to respond to that. But then I will ask you the 
question: Are we making sufficient effort? And the Chairman has 
asked this. Although we do not want to direct it by disease, 
quite obviously, we do want to assure our public that we are 
dedicating sufficient resources to do everything that we 
possibly can to eradicate or at least intervene more 
successfully than we have been doing.
    Dr. Klausner. Mr. Hoyer, all of us who come before you hear 
and experience the burden and frustration about all of the 
diseases that we feel responsible for. Since the National 
Cancer Act was passed, about $36,000,000,000 in total has been 
expended. Of course, the dollars alone do not express the 
effort and commitment of countless thousands of people who are 
committed to doing as much as they can. Can we do more? Yes.
    Have we invested that money well? I actually think we have, 
and I think we are beginning to see the impact of those 
investments. We want it to go faster. We are trying all 
possible approaches, I believe, and, in fact, as Mr. Porter 
pointed out, specifically in breast cancer, we have brought 
together hundreds of people over this past year in something 
called the Progress Review Group to advise us. For the first 
time, we are looking at what are all the things that we could 
do, and at the same time looking at everything the NCI and the 
NIH is doing, trying to match that and prioritize what are we 
missing, where are the gaps?

                        breast cancer detection

    We are learning better to early detect breast cancer and to 
treat it more effectively. The significant drops--not 
experienced by all women, but especially younger women and 
especially white women, that is, drops of over 3 percent per 
year for women in mortality rates for under the age of 50--per 
year for the last 5 or 6 years. That is really quite 
significant. Overwhelmingly, I believe that is due toadvances 
in treatment.
    I think we see progress. I think we all feel that it is not 
enough, it is frustrating, and every time that we are 
confronted with the suffering and the failure of our ability to 
prevent the suffering and prevent the death from these 
diseases, it affects us deeply.
    I think not only have we invested a lot, I think we can 
actually point to the fruits of that investment. And we are 
seeing that, especially in breast cancer, in some very 
significant changes not only in incidence but, more 
importantly, in mortality rates.

                          cancer effort at nih

    Dr. Varmus. Mr. Hoyer, I wanted to respond to your points 
that were addressed to me.
    First, as you properly point out, it is very difficult to 
say that money in one place is going to affect one disease. As 
we do our calculations, a little less than 90 percent of the 
overall cancer effort is in the NCI, and a little more than 10 
percent is elsewhere in the NIH.
    With respect to whether could we do more: yes, we could 
always do more. We could do more in cancer. We could do more in 
many things. We have to balance that desire against other 
demands on the Federal budget.
    Mr. Hoyer. Doctor, the reason for the question is--and the 
frustration that everybody has, including yourself; this is not 
accusatory. This is how do we deal with this and talk to the 
people we all represent. And, Dr. Klausner, there are tens of 
millions of people, obviously, who are relying on you, which is 
an incredible burden and an unfair burden, because there are 
thousands of you, around the country in and out of Government, 
in and out of the private sector.

                         progress toward a cure

    Doctor, when I ask that question, it seems to me we have 
spent a lot of money, and it is slow. And I am not so sure that 
Dr. Salk was successful, or others, Sabin and others who were 
successful, were successful just because of money. Maybe they 
were lucky. But now when we have the Internet and every little 
piece of information that everybody is gathering so you can 
decide, well, that is not a useful road to go down, it ought to 
make us so much more efficient in this process.
    Dr. Klausner. And I think that is happening, and the cross-
communication that you point to is very important. I do not 
know if I have a minute to illustrate that.
    Mr. Hoyer. That light was for me, not for you, Doctor. I am 
out of time. You are not.

                           thiozolidinediones

    Dr. Klausner. In those examples in the upper right of the 
poster, is this long name called Thiozolidinediones. These were 
approved by the FDA for the treatment of diabetes last year. It 
reduces the insulin dependence on diabetes.
    I raise this because what this drug does, with very little 
toxicity, is interacts with a molecule that sits in the nucleus 
of a cell and tells the cell to turn into a fat cell--
irreversibly, it seems.
    The investigators that discovered this and discovered the 
target, up in Boston as well as UCSD, have recently reported 
that a significant fraction of breast cancer cells express that 
target, and when treated with this anti-diabetes agent, seems 
to irreversibly turn into nonproliferating fat cells.

                 clinical trials--breast and colorectal

    Over the past year, we have helped them begin a clinical 
trial, first in a rarer cancer of sarcomas, liposarcomas, but 
we will be moving into clinical trials for both colorectal 
cancer--where almost every cancer expresses the target for this 
drug--and a significant fraction of breast cancers.
    This is one of these examples where research in one area, 
coupled with the ability to discover these circuitries and ask 
where they are, gives us new areas. There was no way we would 
have predicted that that would be a new approach potentially. 
We do not know if it is going to work, but we will be testing 
it for, in this case, breast and colorectal cancer.

                       limits on medical science

    Dr. Varmus. Mr. Hoyer, if I could comment just briefly on 
your bringing up the founders of the polio vaccine, I think the 
success that medical science has had with infectious disease 
and the prolongation of average life expectancy in this country 
has given people a sense that medical science can do more than 
we probably can do with respect to some of these much more 
difficult conditions. Cancer arises from within our own genes 
and our own cells. The pathways, as you have seen, are 
incredibly complicated contrasted with invasion from an 
outside, very simple virus. And the difference between those 
two kinds of problems is really immense.
    We all feel frustrated, but I think it is not simply a 
matter of luck that we were able to conquer polio long before 
we were able to deal with some of these chronic and much more 
complex diseases.
    Mr. Hoyer. Thank you, Doctor. And, again, I do not want 
this to be taken in any way accusatory. It is to try to better 
focus us on how we can meet one of the world's great problems.
    Mr. Chairman, I have other questions. I will submit them 
for the record.
    Mr. Porter. We will have a second round. I should tell 
members we are operating under the 8-minute rule.
    Mr. Hoyer. Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Hoyer.
    Mr. Miller.

                            emerging trends

    Mr. Miller. Dr. Varmus, the NIH and the Cancer Institute, 
certainly we all can be very proud of it, but following up 
along with Mr. Hoyer's comments, one of the frustrations I have 
is people do not appreciate or understand what is going on at 
the NIH, and that includes the Members of Congress. We have a 
small number of members of the 435 of us that sit in this room, 
and we do have this appreciation. But it is a frustration when 
you go home to my district in Florida or wherever you go that 
people do not understand what all we do. So we have a real 
marketing job that we need to keep working on. We have talked 
about it before, and we will try to help get staff members to 
visit out at NIH and things like that to organize it. We just 
need to have a better grasp of what that is and a recognition 
of what a great asset this is, something to be very proud of in 
our country.
    You talked with Mr. Porter about what it has been like over 
the past years and 10 years in the future. You mentioned it 
will be much more complicated. If you are the head of the 
National Cancer Institute 10 years from today, what would you 
be testifying about? We see trends developing. What will that 
trend be like? If you are still there, what do you think?
    Dr. Klausner. Well, I think hopefully the numbers will all 
be much lower and we will be talking about some real successes.

                       therapy and interventions

    What I think is that the difference between that black box, 
which led to us using relative toxic, non-specific approaches 
to therapy, where we often did not know the cause and so we had 
these vague associations about what we might do--to prevent 
cancer, to what we are going to be seeing is a very new world 
where--the interventions that we will be using will be based 
upon knowing exactly what we are going after, analogous to the 
protease inhibitors for HIV, that is a very good model. They 
will be chosen and designed for the machinery that 
characterizes each cancer, that actually distinguishes one 
cancer from another.
    One of the problems with the black box is that we did not 
know whether all breast cancers were the same or all brain 
cancers were the same. We know that they are not. But how are 
they different? It is the different circuits that one breast 
cancer uses versus another, one prostate cancer versus another 
that makes them different.
    I think we will be talking about our much less toxic and I 
assume much more specific and hopefully much more effective 
interventions.

                           cancer prevention

    I suspect that we are going to be talking much more about 
prevention, not because we are going to switch our policies 
from paying attention to therapy to paying attention to 
prevention. But what we are learning about cancer is that it is 
not an event, it is a process. It takes years, even decades. 
And we will learn how to detect the earliest changes in these 
circuits and begin to, I believe, treat--which we now call 
prevent--a set of states--we may not call them diseases--of 
precancer rather than cancer.
    So I suspect 10 years from now that is what I or my 
successor will be talking about.

                              tobacco use

    Mr. Miller. Will the trend continue like it has been over 
the past couple years as far as going down?
    Dr. Klausner. From everything that we can see, we suspect 
this trend will continue over the next several years. Beyond 
that, I would be loath to make predictions. We certainly hope 
so.
    We are concerned with certain troubling trends, and that is 
the drop in lung cancer is a perfect measure of the drop of use 
of tobacco, primarily cigarettes. But we are now seeing in our 
young people a significant upturn in the use and the addiction 
to cigarettes. If that continues, then we will go back to this 
epidemic of lung cancer, and it has been an epidemic--an 
epidemic that tracks with the use of tobacco. So there is some 
uncertainty there.

                           youth and tobacco

    Mr. Miller. You mentioned tobacco. This committee does not 
expect to get involved in the tobacco settlement. But what is 
the solution to keep kids from smoking?
    Dr. Klausner. Well, from all the studies that have been 
done--and we need to do more--the evidence suggests that 
decreasing tobacco use among kids probably relates to three 
types of areas:
    One is the price, and there is good evidence to believe 
that the higher the price, the less kids will take up tobacco, 
and that has been shown in different places.
    The second relates to decreasing access. Kids that have 
ready access to tobacco will use it.
    And the third is to decrease the appeal, and that is to 
make sure that kids are not assaulted with things that make it 
look attractive and sexy and good to take up tobacco.

                     smoking and behavior in youth

    In addition, we need to do more research, which we are and 
will be doing, into the behavior of kids, both social behavior 
and individual behavior. We see tremendous differences in the 
rate of tobacco use among kids, adolescents, in different 
groups, different ethnic groups, for example, different racial 
groups. We need to examine that. We need to understand that. We 
need to learn from that.
    And, of course, if kids and when kids take up tobacco, 
there is this problem of adolescent addiction. It is an 
addiction problem. It is every much as addictive for many 
people as cocaine. We need to understand it from theviewpoint 
of addiction, who is susceptible to addiction, what are the best 
approaches to dealing with the addiction once it happens.

               recruitment of scientists and researchers

    Mr. Miller. Let me change the subject. You mentioned how 
you were able to recruit outstanding people. How are you able 
to compete salary-wise and benefit-wise for the top scientific 
minds and researchers? Are you able to?
    Dr. Klausner. I believe that we are. Over the last few 
years, there has been some real changes in the flexibility we 
have in terms of mechanisms of hiring and in terms of some of 
what had been dramatic salary differentials, especially for 
clinicians. With a variety of new mechanisms, that gap has been 
closed, but more than just the gap, it is the flexibility of 
having a range of new opportunities.
    I must say that still we have to struggle with what are 
often cumbersome rules and regulations of a personnel system 
that is not necessarily designed and built to deal with the 
flexibility needs of science and clinicians, epidemiologists, 
et cetera. We are working on that, and I am sure Dr. Varmus may 
have more to say about that.
    Dr. Varmus. Well, I think Rick has summarized what our 
situation is quite well. We are competing much more effectively 
in the clinical arena than we could before. We can pay up to 
$200,000 a year. We do have problems when we are competing for 
individuals in the highest paid specialties, especially when 
they are at the top of their fields.
    Mr. Miller. What is the flexibility you have? Is it just 
salary, or are there other----
    Dr. Varmus. Well, we have a number of personnel mechanisms 
now. One is the Senior Biomedical Research Series that allows 
us to pay Ph.D. investigators up to as much as $151,000 now, 
and that has improved tremendously our ability to recruit Ph.D. 
scientists. We now have two other mechanisms--one called Title 
42, one called Title 38--that allow us to pay a variety of 
individuals up to $200,000 a year. And those mechanisms 
markedly increase our ability to recruit.
    Mr. Miller. You do not have endowed chairs like 
universities?
    Dr. Varmus. No, we do not.
    Mr. Miller. Did you ever look into that?
    Dr. Varmus. It was actually proposed when the National 
Foundation of Biomedical Research was put into our 
reauthorization bill in 1993, but it seems to me that that is 
not really the primary charge to the Foundation, that what 
really matters is how much we pay our scientists and we are 
going to pay them with Government pay mechanisms. So I do not 
see any real benefit to endowed chairs. Perhaps when the 
foundation is better endowed, we might consider that 
possibility again. But right now I do not think it is the most 
effective use of the Foundation's time or money.
    Mr. Miller. Thank you.
    Mr. Porter. Thank you, Mr. Miller.
    Mrs. Lowey.
    Mrs. Lowey. Thank you, Mr. Chairman.
    Dr. Klausner, again, I welcome you with great pride. In 
addition to Dr. Varmus, whom many of us share as a native New 
Yorker, you are from Yonkers, New York. I just want to 
congratulate you again for your extraordinary leadership and 
for your enthusiastic approach to directing the National Cancer 
Institute. It is your enthusiasm and your great intelligence 
and this list of honors that makes me indeed feel fortunate 
that we have you there. We are doing something right in this 
country if we can attract the likes of Dr. Varmus and you and 
all the other outstanding scientists who appear before us. So I 
thank you.

                          lung cancer in women

    I would like to follow up with a question that was just 
asked specifically with regard to the report card on cancer 
which you issued. Generally, the news was heartening as you 
reported to us, the incidence of cancer and rate of deaths from 
cancer declined between 1990 and 1995. However, there were some 
very troubling trends.
    For example, as you mentioned, among the four major 
cancers--lung, breast, prostate, and colorectal--the most 
negative news was that lung cancer is still rising among women. 
So when we talk about the decrease in lung cancer, it is still 
rising in women even though it is declining in men.
    We know so much more about how to prevent lung cancer than 
we do any of the other major cancers. We know that 80 percent 
of lung cancers are related to tobacco. So my question is: 
Number one, what is the NCI doing to stop this killer of women? 
And is more public education or more research needed?
    Dr. Klausner. I suspect it is both, but primarily we need 
more public education because we know--we have done the 
research--we know that the issue is cessation of smoking.
    Now, the difference between what is happening with women 
exactly tracks the pattern of tobacco use. Women started 
smoking later, and they stopped smoking later.
    Now, smoking rates have declined in women, but lag the 
decline in men. In fact, while lung cancer rates are continuing 
to rise over the last few years in women, what we are seeing is 
that it is beginning to flatten, and we can be pretty confident 
because we can look back and see the tobacco use rates--that we 
will very soon reach the plateau of that epidemic in women, and 
it should start coming down. That actually is a relatively 
straightforward prediction because it tracks withsmoking. I 
think that is the difference.
    Mrs. Lowey. Although I hear that as we target decrease in 
advertising to children, we can increase advertising to women, 
as the NRA did with those ads that were specifically targeted 
to women, put a gun on every kitchen table for safety. So I 
think we have to watch what happens carefully. I would also be 
very interested in knowing whether there is any research in 
addition to just usage patterns, that clearly defines the 
difference between men and women, or is it all public 
education.

                          smoking and behavior

    Dr. Klausner. I think there is a need for a lot of research 
in a variety of areas related to the behavioral issues of 
smoking, which we are doing and need to do more. We had a 
recent review of that, and it does specifically point us to 
ways that we can attempt to intervene in groups that are 
dropping smoking less, such as women.
    There are other things, because it does not just end with 
the success of getting people to quit smoking. Unfortunately, 
after people have smoked, they continue to be, often, depending 
upon the disease, for decades, at an increased risk of 
developing disease, including cancer.
    And so one of the things we need to do is not assume that 
our job is done just by convincing people to stop smoking, 
which is hard enough. We are doing a lot of research in terms 
of new methods of early detection of precancerous lesions in 
the lung and new methods of prevention, for individuals, 
especially former smokers, who clearly are at increased risk.

                        lung, cancer prevention

    In a recent study, when you look at former smokers, you 
look in their lungs and the cells in their lungs, almost all of 
them have significant genetic damage to those cells, and it 
persists for years. This is very important. We can use that as 
a marker for individuals to attempt new prevention strategies, 
and that is what some of those chemoprevention trials are 
actually aimed at. I think that is very important.
    There is a lot of research to do.

                          breast cancer grants

    Mrs. Lowey. And with regard to breast cancer, I personally 
appreciate the extraordinary leadership you have shown in your 
commitment to fighting breast cancer. And I am particularly 
enthusiastic about the progress that you have been talking 
about and the progress that will be coming. Yet, as you know, 
this year alone we see 180,000 new cases of breast cancer, 
40,000 women will die of the disease.
    If the NCI had more money to spend on breast cancer 
research, my first question is: Could you continue to fund 
high-quality research? or Have we reached the point where we 
have saturated the research community with breast cancer 
grants? And, in addition to answering this question generally, 
could you also tell us the pay line for breast cancer grants; 
that is, what percentage of breast cancer grants that make it 
through peer review receive funding?
    Dr. Klausner. Let me start with the last. We do not have a 
separate pay line for breast cancer. The general success rate 
for grants now, for NCI grants, is between 25 and 30 percent, 
and that is about the success rate for breast cancer grants as 
well. I must say I do not have the exact numbers, but we do not 
attempt to separate them.
    There is much that we are doing. There is no question that 
while there is a 25 to 30 percent success rate, that means that 
there is a 70 to 75 percent failure rate of getting that grant 
funded.
    Mrs. Lowey. These are the ones that have gone through the 
peer review process successfully.
    Dr. Klausner. Well, these are the ones that have actually 
been submitted. What does it mean to go through it 
successfully? Of course, what we pay are the ones that do most 
successfully in peer review. There is a gradient. The way we 
determine pay lines is we ask the peer reviewers to rank them. 
It does not mean we would not very much like to pay very good 
ideas that are beyond our pay line, but certainly we attempt to 
follow peer review and we do follow peer review to fund that 25 
to 30 percent that the peer review says are the most 
outstanding.
    Mrs. Lowey. Right. So that there are 70 to 75 percent--is 
my math right?
    Dr. Klausner. Yes.
    Mrs. Lowey [continuing]. That could be funded if there were 
additional funds.
    Dr. Klausner. Yes.

                      colorectal cancer--screening

    Mrs. Lowey. On colorectal cancer, we know that colorectal 
cancer is the Nation's second leading cancer killer, and each 
year in this country 131,000 new cases are diagnosed and 55,000 
people die from this dreaded disease.
    Can you update this committee on the research agenda with 
respect to colorectal cancer?
    Dr. Klausner. Sure. There are several things about 
colorectal cancer. We do know that screening can reduce 
mortality. We also know that a very small fraction of the 
population avail themselves of screening. There are many 
reasons for this, and we have a number of research studies, and 
we are participating in a roundtable with the CDC and the 
American Cancer Society specifically aimed at trying to 
increase the use of screening, which has been demonstrated to 
reduce mortality rates, by looking at blood in the stool reduce 
the mortality rates by about 33 percent.
    We do not have as good data for other screening techniques. 
From a type of study called case control studies, there is a 
suggestion that sigmoidoscopy may reduce mortality by 60 to 80 
percent in the region that the test canactually see.
    We are funding a variety of new ways to screen. There are 
different problems with the screening for colorectal cancer. 
One is the hesitancy of individuals to avail themselves of 
screening because of sigmoidoscopy or colonoscopy. It does not 
have a great reputation.
    One of the things that we are trying to develop is a new 
approach called virtual colonoscopy.
    Mrs. Lowey. Can I put on the record that the test is not so 
bad?
    Dr. Klausner. Yes, you should put on the record it is not 
so bad.
    Mrs. Lowey. I will not be any more cryptic.

              colorectal cancer--therapeutic interventions

    Dr. Klausner. So a very important thing is our research 
agenda aimed at new detection technologies and trying to make 
sure that the detections that we have are used.
    Another very important thing in colorectal cancer is that 
it is one of the cancers where therapeutic interventions, at 
least for moderately advanced disease where much of the 
mortality is, seems to work. Recent studies from our 
cooperative groups have demonstrated up to a 35 percent 
reduction in mortality from the use of adjuvant therapy.
    Now, we need to improve on that. There are new trials going 
on. But we also need to make sure we understand whether those 
advances are being disseminated, whether they are being used, 
and if not, why not. There is much we need to do.

                     colorectal cancer--prevention

    There have been tremendous advances in understanding the 
circuitry and the genetic bases of colorectal cancer which has 
given us some new hints at prevention. Included are some new 
drugs that we are testing that we think may prevent the 
development of colorectal cancer, may prevent the progression 
from polyps to colorectal cancer. These have been established 
by a variety of studies, epidemiologic studies, and animal 
models which can mimic colorectal cancer. These are called COX-
2 inhibitors. They are like nonsteroidal anti-inflammatory 
drugs. There are intervention studies looking at diet to 
prevent, again, the progression of polyps, which are 
precancerous lesions, to cancer.
    It is an extensive research portfolio. I think it is an 
area where we are making progress and can certainly make more.
    Mrs. Lowey. Thank you. I would love you to continue 
educating us----
    Mr. Porter. We will have a second round. Thank you, Mrs. 
Lowey.
    Mrs. Northup.
    Mrs. Northup. Thank you, Doctor. I have to echo what Mr. 
Hoyer said earlier, that probably there is nobody in this room 
that does not have close relatives that have been through 
cancer. And when it is your family, I remember my feeling was I 
cannot believe there are thousands of people that are going 
through this at the same time. And so, you know, I think that 
there is great cheer that we seem to be making progress.

                            drug development

    I have a couple of questions to follow up some of the 
earlier ones. The first one is, as you talk about the drugs 
that we may develop that will be very specific to the 
communications part of the cell, are there similarities in the 
base of those drugs? There are all sorts of antibiotics, say, 
but there are similarities between them, too.
    Is that the case with the drugs that we are developing for 
cancer, or do we have to sort of start from ground zero with 
every single cancer and is it an entirely different compound?
    Dr. Klausner. I suspect we are going to be looking at a 
very large range of compounds. But I mentioned something in the 
beginning, in my opening statement about these new chemistry-
biology centers. Let me describe a bit about that.
    There is an entirely new technology of ways to discover 
drugs, to create not one drug at a time and then modify it, but 
literally billions of potential drugs at a time. It is called 
combinatorial chemistry. It is actually very interesting 
because it takes the principles of biology, the generation of 
diversity, and then selecting them. It is the principles of 
evolution, but now applies them to chemistry.
    What we are now funding is a series of centers where we are 
asking individuals to generate literally millions to billions 
of potential drugs and to then use new technologies that will 
couple the discovery of those new compounds that may look like 
almost anything. They are sort of randomly generated, but then 
we select them by linking them directly to those pathways. We 
call them smart assays. I hope I am not misheard with that.
    My feeling is that while I do not think there is going to 
be any single principle of drug structure that will answer all 
of these circuits, we actually have in front of us an actually 
quite revolutionary new paradigm that will potentially really 
change drug discovery from searching in soil, from searching in 
marine animals for one drug at a time, to being able to sample 
millions or billions of compounds.
    So I think at the same time where we see this, as you are 
worried about, this proliferation of how we are going to 
discover all these drugs, we have an entirely new way to sample 
many more possible drugs.
    Mrs. Northup. I think actually, now that you mention that, 
there is a place in Louisville where one of those companies 
exists. It was very interesting. They canmultiply it with high-
tech.
    Dr. Klausner. That is right.

                        pharmaceutical industry

    Mrs. Northup. The tests that you perform simultaneously.
    Can you give me some idea how much of the money that is 
spent and how many of those efforts are National Cancer 
Institute-initiated and how much are initiated by 
pharmaceutical companies, and what role the pharmaceuticals 
play in that?
    Dr. Klausner. Well, the pharmaceutical industry plays a 
huge role in this, and, in fact, we have a very long history, 
the whole NIH and certainly the NCI, of working very closely 
with the pharmaceutical industry, which we are doing with this 
as well.
    Much of the development of this technology has been in the 
pharmaceutical industry. Some of it is in academia. The 
pharmaceutical industry has been very supportive of the 
expansion of this into academic research labs, which is what we 
are trying to accomplish with these chemistry-biology centers.
    There is no question that ultimately what we hope to 
discover are lead compounds which will feed into the industry, 
which will be transferred through technology transfer to 
industry, so that actually products for people can be 
developed.

               effects of tobacco use on various cancers

    Mrs. Northup. I would like to ask you about tobacco use, 
too. You know, people think of it with lung cancer. In reality, 
I know that there are a number of cancers that are increased, 
even though you cannot exactly see the physical connection of 
where the smoke actually is taken in and affects the cell. I 
just wondered if you could give me some idea of the extent of 
the numbers of cancers that actually show higher increases 
based on smoking.
    Dr. Klausner. Yes. It is, as you say, extensive. It is not 
only lung cancer. It is oral cancer, laryngeal cancer, 
esophageal cancer, interestingly kidney cancer and bladder 
cancer. There also is some evidence that colorectal cancer is 
increased among smokers.
    Recently, there have been some studies suggesting the 
possibility that breast cancer may be associated with smoking, 
and we are pursuing that now. That evidence is weak, but 
intriguing.
    So there is no question there is a whole variety of cancers 
that are associated. Pancreatic cancer is another one.
    Mrs. Northup. Is my time up?
    Mr. Porter. No.

                      funding for specific cancers

    Mrs. Northup. Oh, okay.
    As you work through the grant process, do you allocate 
money specifically for some cancers, like this is what we are 
going to spend on colorectal, this is going to be what we spend 
on breast? And how do you divide that up? Do you feel like 
there are some cancers that are underfunded? Does it help to 
have the specific cancer groups come and argue on behalf of 
theirs?
    What is the best way and do you feel like we are at the 
best way of appropriating money for specific cancers?
    Dr. Klausner. Well, this is a complicated and dynamic 
process. We do not sit down and decide how much money we are 
going to spend on individual cancers. In fact, our approach has 
been to bring individuals into the NCI and make them feel at 
home with our planning process that may begin by asking what 
are the critical things we need to do for prostate cancer or 
for breast cancer.
    And the incredible thing that we all see when we do that is 
we tend to get--not entirely--very similar answers. Then we can 
step back and say that we need to develop better animal models 
for each of those cancers and do that in a way that may or may 
not be specifically targeted to the cancers.
    The interesting thing is that while we do not distribute 
our money specifically or plan to distribute our money 
specifically by different cancers, when we look at the 
distribution it is intriguing that, by and large, there is some 
relationship between the incidence or death rates of cancers, 
of major cancers--it is not one to one--and the level of money 
that is expended. But interestingly, that seems to be emerging 
from the research community that recognizes those needs, 
recognizes the frequency, couples that with scientific 
opportunity, and then proposes the research they are going to 
do.

                       grant application process

    Mr. Porter. Can I interject here and ask Dr. Varmus or Dr. 
Klausner something? It is because of a question that Mrs. Lowey 
asked and now one that Mrs. Northup asked. If you could 
describe when you decide where the research is on a specific 
disease. In other words, my understanding is you do not go out 
and say this research is breast cancer research. You have a 
proposal and only later when you see where it leads do you code 
it. Can you expand on that for the Members of the subcommittee 
so that they understand the process?
    Dr. Varmus. Well, there are several phases to the process. 
When a grant comes in, of course, it is evaluated by the study 
section, it is given a score, and then a decision is made by 
Dr. Klausner's team, at the NCI, or by other institutes, 
wherever it has been assigned about whether that grant is going 
to be funded.
    Now, that decision is made based, in very large part on the 
score that the application receives from the study section, but 
the decision is also based on some general sense of what the 
research portfolio ought to look like. So when you get to a 
certain level as you go down the list, you may say, ``Well, we 
will fund this but not that one; the scores are very close, but 
we need more activity in a certain area.''
    Before that decision is made, there has been a planning 
process, and the Institute, using a variety of techniques, will 
have evaluated its research portfolio, looked at public health 
needs, looked at the distribution of scientific activity, and 
made some prior decision that in this year's grant funding it 
ought to pay more attention to developing stronger initiatives 
in certain areas.
    That planning process can be linked to the award of grants 
by incentives to encourage applications in certain areas. Those 
incentives may be as mechanical as saying we are going to set 
aside a certain number of dollars to encourage research in a 
certain area, or we are going to develop a new program, like 
the biology-chemistry program that we just talked about. Or it 
may inspire the Institute or a group of Institutes to say 
``Let's have a workshop and bring new people into the field so 
we are more likely to get applications, or let's have a program 
announcement.''
    All those things tend to move the science in that new 
direction.
    Mr. Porter. Thank you, Mrs. Northup. Your time was over 
right as I asked the question. [Laughter.]
    Ms. Pelosi.
    Ms. Pelosi. Thank you, Mr. Chairman.

                          virtual examinations

    Dr. Klausner, welcome. Thank you for your leadership. Many 
people have their hopes pinned on you. You carry a heavy 
burden.
    Dr. Varmus, once again, welcome. Thank you for providing 
such great leadership at NIH to attract the likes of Dr. 
Klausner and the other heads of your institutes and all the 
others there. It is just remarkable.
    Having said that, I want to follow up on a couple of points 
my colleagues have made and then ask my own question.
    You were in the middle of talking about a virtual 
examination--and then I think the time was up--to detect 
colorectal cancer. Virtual?
    Dr. Klausner. Yes, virtual.
    Ms. Pelosi. Cyberspace?
    Dr. Klausner. It is through photons and electrons. It is by 
using x-ray technology. These x-ray technologies may be 
computerized tomography. Some of our technologies may fuse 
those images between standard x-rays, CT, and even magnetic 
resonance in order to actually allow the computer to generate a 
virtual trip through the entire colon. I can actually at some 
point show you a movie of it, what it looks like. It is 
actually quite extraordinary.
    It is being developed in a variety of places, and we are 
now testing it. It has a long way to go, but it is moving ahead 
both for bronchoscopy and colonoscopy because you can get the 
contrast between the tissue and the air, and actually with 
tremendous precision be able to, without any insertion of 
anything, be able to reconstruct a tour through the bowel or 
the bronchial tree. Through computers it very much looks like--
if you saw the movie ``Contact,'' the travel that the person 
went through. You are going through these tubes, and you can 
stop and look and amplify it.
    We are very optimistic about this type of technology 
developing to make these sorts of detection approaches more 
usable, more useful, easier to transmit the information 
electronically and have experts see it as a type of 
telemedicine, as well as, being much more acceptable to 
patients.

              improved instrumentation and early detection

    Ms. Pelosi. That is very interesting. As part of Dr. 
Varmus' presentation--a couple of weeks ago, I guess--he talked 
about improved instrumentation as part of one of the 
initiatives at the NIH. Would this fall into that category?
    Dr. Varmus. Yes.
    Ms. Pelosi. I did not know if it was just about research, 
or about detection as well.
    Dr. Varmus. In the NCI plan for next year, there is 
increasing emphasis on using instrumentation for early 
detection, and they are linking their clinical trials networks 
to the use of more advanced instrumentation for early 
detection. You can see how that would interface very nicely 
with clinical trials.
    Ms. Pelosi. I am glad it is about detection as well as 
research. Along that line----
    Dr. Varmus. They are really inextricably linked.
    Ms. Pelosi. Yes.
    Dr. Varmus. We have to do research to learn how to do 
better detection, just as we were doing research to learn about 
more accurate diagnosis and better therapies.

                 screening alternatives to mammography

    Ms. Pelosi. Along that line, how much emphasis is being 
given to funding research into screening methods that can be 
used as an alternative to mammography, methods that do not 
involve radiation exposure and that are effective in women of 
all ages?
    Dr. Klausner. We have actually a very extensive portfolio, 
looking at non-mammographic ways of visualizing--this is for 
visualizing--breast lesions. These include optical imaging 
techniques, some new ways of migrating photons through tissue, 
a near-infrared approach that now can penetrate up to 10 
centimeters, which would be adequate for mammography, MRI, and 
magnetic resonance spectroscopy, which has the potential to 
look not only at whether there is an anatomic change, but 
whether there is a molecular change.

                         imaging working group

    We have an imaging working group, and we have challenged 
them with the challenge: Can we create imaging tools that will 
allow us to read in the intact body these networks so that we 
can actually see in small numbers of cells when genes are 
turned on or turned off? We think that is possible.
    Ms. Pelosi. How soon is that possible?
    Dr. Klausner. I have no idea, but we are beginning to move 
towards that. This is a whole new area. It is going to take a 
while to develop. But we are doing a fair amount of research in 
it.
    There are other possibilities besides ionizing radiation.
    Ms. Pelosi. I have the privilege of serving on the 
Intelligence Committee, and when I am up there, I ask some of 
the representatives of that community about detection and some 
of the technology that is available there. Are they part of 
your imaging working group?

                   collaborations with dod and darpa

    Dr. Klausner. Yes. in fact, even with mammography, digital 
mammography was developed through a consortium that the NCI put 
together in 1993 that resulted in four different companies 
developing digital mammography. We are working with the DOD. In 
fact, I am going to meet tomorrow with DARPA, the Defense 
Advanced Research Projects Agency, about a memorandum of 
understanding between the two agencies specifically for what we 
are talking about is revolutionary technologies in detection, 
using different models of funding and different models of 
collaboration.
    Ms. Pelosi. Wonderful. Thank you. I look forward to hearing 
more about that.
    I just want to make a point about lung cancer. You can 
hardly pick up a magazine without reading about--a woman's 
magazine, which you probably do not pick up too frequently, but 
maybe the next time you are at the beauty parlor. You can 
hardly pick up----
    Dr. Klausner. Is this a suggestion? [Laughter.]
    Ms. Pelosi. No.
    Dr. Klausner. It will not help.

                              lung cancer

    Ms. Pelosi. It was silliness. You can hardly pick up a 
woman's magazine without reading an article about breast 
cancer, somebody's experience or what women are doing 
themselves to organize, et cetera. And you never read about 
lung cancer. You never read about lung cancer in a woman's 
magazine. You do read about cigarette ads; you do see lots of 
cigarette ads. And I hope that when we are talking about 
getting the message out, somehow this message penetrates that 
world, as you said in your comments, the increasing rate of 
death among women from lung cancer. Education on that has to 
break through to that audience.
    Dr. Klausner. You are absolutely right. There are some real 
myths about frequencies of different cancers. The number one 
cause of cancer death among women is not breast cancer. It is 
lung cancer.
    Ms. Pelosi. And so this audience must be susceptible to a 
message because if they were not, the cigarette companies would 
not advertise in these magazines.
    Dr. Klausner. I think that is right.
    Ms. Pelosi. So, by the same token, there has to be some way 
that we, the public, we, the Federal Government, or somebody 
says to them you have a responsibility, even if you are going 
to take the cigarette ads, to write about lung cancer as well. 
So there is equal time devoted to staying alive.
    Dr. Klausner. Yes, and we have been over the past year 
working with a developing advocacy organization for lung 
cancer, and we cannot allow it to be a forgotten disease. There 
is no question one of the differences is that survival from 
lung cancer is much less than survival from breast cancer. So 
you have a large population of survivors who are very active in 
getting the word out.
    We all need to be advocates about lung cancer.
    Ms. Pelosi. That is very interesting.
    Dr. Klausner--oh. I was just going to ask a quick question.
    Mr. Porter. You may continue.

                  breast cancer rates in san francisco

    Ms. Pelosi. Okay. I have a little beachhead here on this 
question, so I am going to continue. Thank you, Mr. Chairman.
    Last year, as you know, you had visited our community, and 
you noted the concerns that people have, and I thank you again 
for visiting the Bayview Hunter's Point area as well as meeting 
with people in our community who are concerned about the 
environmental aspects of--the impact of the environment on 
women. Many of us are concerned about the higher incidence of 
breast cancer in the area.
    Last year in your testimony before the subcommittee, we 
talked about high breast cancer rates in San Francisco. You 
noted the study was being done to try to determine the possible 
cause of these higher rates of cancer, and to see if you could 
tie that to the environment.
    Dr. Klausner. Yes. That study I talked about from Stanford 
was published, and we were expecting it, and the results were 
very interesting. It asked the question whether the rates of 
breast cancer in the San Francisco area could be explained by 
the distribution of known risk factors. Most of these relate 
not to the environment as far as we know, but to the hormonal 
pathway, the estrogen pathway, reproductive patterns as well as 
they also included alcohol consumption, which seems to be a 
risk factor of breast cancer.
    In that study, the authors concluded that essentially 100 
percent of the difference in the rates can be explained by the 
known risk factors: differences in age at first birth, 
differences in number of children, what we call the standard 
risk factors. Not that we necessarily understand the meaning of 
those risk factors, but it did suggest that it is going to be 
very difficult to find on top of that a specific environmental 
cause to explain the particular breast cancer rate in San 
Francisco.

                       breast cancer risk factors

    I must say that over the last few years numerous studies 
have pointed out that it is the unequal distribution of risk 
factors in different cultures, in different cities, in 
different parts of the country. There are different rates of 
early pregnancy, of age at first pregnancy, of when one begins 
menstruating, when one enters menopause, et cetera. So that was 
an important conclusion.
    We continue to look and we continue to fund studies, 
including new studies, to examine the environmental causes or 
potential environmental causes of breast cancer. There were 
numerous reports suggesting that PCBs and DDT and a metabolite 
that is called DDE may be associated with increased risk of 
breast cancer. We still do not know, but this year a study was 
published from Harvard, I think the nurses health study, the 
largest study looking at whether exposure to DDT correlated 
with breast cancer, and in fact, it did not. This is the 
largest and I think the best study so far on that.
    We continue to look. We continue to fund studies. It 
isgoing to be hard to find.
    Ms. Pelosi. I thank you for your answer and for the 
initiative you are taking on it. It is still a question that 
many people find----
    Dr. Klausner. It is.
    Ms. Pelosi. It seems obvious, but obviously we do not have 
the science to support the link.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Ms. Pelosi.
    Ms. DeLauro.
    Ms. DeLauro. Thank you very much, Mr. Chairman.
    Good morning, Dr. Klausner.
    Dr. Klausner. Good morning.

             genetic testing as a screen for breast cancer

    Ms. DeLauro. It is wonderful to have you all here again 
today, and I thank you very, very much for your incredible 
contributions.
    Let me just pick up on a question on breast cancer, because 
I read in this morning's Washington Post--there was a small 
piece that talked about ``Gene testing questioned as a breast 
cancer screen.'' It says it is a new study which found that the 
genes BRCA1 and 2 were not as linked to breast cancer as was 
once thought.
    I just wanted to get your view and your thoughts on the 
study.
    Dr. Klausner. There are some other studies--these are 
recently published studies in JAMA, I believe, Journal of the 
American Medical Association--that continue what we sort of 
expected, and that is, these genes that do, in fact, predispose 
to breast and ovarian cancer, and that link is clearly there. 
The issue is how frequently are those genes altered in the 
general population.
    This is important in terms of whether screening would be 
valuable or not. If it is very rare, it would be very hard to 
imagine screening the entire population.
    So since these genes were discovered, many studies have 
attempted to answer a number of questions. What is the 
frequency in different populations of these inherited 
alterations in these genes to explain the breast cancer that 
you see? And even when you find alterations, what actually is 
the age-dependent risk of developing breast cancer? Because, of 
course, that is very important.
    It is very different in terms of decisions women might make 
in terms of prophylaxis, in terms of monitoring, in terms of 
being tested, to know what is the meaning of the test. Numerous 
studies over the last year have demonstrated that a very small 
percentage of women with breast cancer, even with early onset 
breast cancer, actually have detectable, inherited alterations 
in the BRCA1 and BRCA2 gene. I believe it was in this study for 
all women below--that have breast cancer even below 35, only 
about 7 percent--I am sorry, about 12 percent--between 7 and 12 
percent in different studies actually will be found to have 
these alternations. These are important.
    Another important study that was done at the NCI was to ask 
the question: If you find in individuals these inherited 
alterations, what is their ultimate risk of developing ovarian 
or breast cancer? The original studies began by looking at 
families where many individuals had cancer. That is how they 
came to our attention. But if you started the other way and you 
identified the gene and then you did not know the family 
history and tried to figure out what is the probability of 
getting cancer, what we found in those studies, the risk of 
developing cancer was much lower, significantly lower than we 
initially thought. Instead of 80 percent risk of lifetime risk 
of breast cancer, we calculate it is more like 50 percent. That 
is still very high, but less. Ovarian cancer had been quoted as 
high 60 percent. And what we found in that study is that it was 
16 percent.
    These are very important pieces of information in terms of 
helping people make decisions about whether to be tested and, 
if to be tested, what to do about it.
    Ms. DeLauro. It is just that the headline is--you do not 
write, I do not write, but someone sits there and decides to 
talk about gene testing questioned, and, you know, it just sets 
people off in thinking about what is happening.
    Dr. Klausner. Sure.

                      screening for ovarian cancer

    Ms. DeLauro. I would like to ask, because I know you know 
that I was going to ask the questions about ovarian cancer. Let 
me just move forward on that.
    There is no simple diagnostic test to detect ovarian 
cancer, and I understand that what you are doing is running 
clinical trials to evaluate new tools to identify women with 
early-stage ovarian cancer. I just want to be updated on the 
trials, how they are progressing.
    This is an unfair question, but I have to ask it. What do 
we believe is the time frame on finding something that is a 
reliable screen that will be available to women?
    Dr. Klausner. I wish I knew the time frame, but I can tell 
you what we are doing to try to move it along, and I think 
significantly speed it up. This is one of the goals of this 
Cancer Genome Anatomy Project, to try to look at cancers, such 
as ovarian, which is one of the first that we have been 
studying. Now there are in our database about 30,000 sequences 
from ovarian cells or ovarian cancer cells. In the database 
there are now possibilities of 500 that are listed as 
potentially specific. We can now start working through these 
very quickly over this year to find out if there are. I do not 
know if any of those 500 will turn outto be true, but suddenly 
we have a menu of possibilities that we never had before.
    There is one particular marker that many people are 
interested in. That is something called the folate receptor. 
Ninety percent of ovarian cancers quite significantly 
overexpress a receptor for folate, which is a vitamin, on their 
surface. There are some agents that have been developed where 
you can link a molecule that can sense the folate receptor to a 
radioactive marker to see whether this would be a new 
diagnostic to detect early ovarian cancer.
    You have pointed this out, and it is absolutely true. The 
single most important thing we need for ovarian cancer are 
better early detections because only 20 to 30 percent are 
diagnosed when they are localized, and that is the major 
challenge.
    But we have set up an infrastructure to try to discover 
possible tags in a way that we never have before that will be 
used--if you remember Dr. Varmus' poster, with those thousands 
of genes, these gene chips. That is exactly what we will be 
doing over the next year for these ovarian genes.

                             ovarian spore

    Ms. DeLauro. And is the SPORE part of what you are talking 
about as well? Is that going to be an effective way to deal 
with ovarian cancer in the way it was with breast cancer?
    Dr. Klausner. Well, that may be. We certainly are 
considering this year an ovarian SPORE. Our advisers are 
evaluating the SPORE program. We will have that evaluation by, 
I believe, June. I think it is going to be very positive, and 
our plan, assuming that is positive, is actually to move ahead 
with an ovarian SPORE.
    There have been advances this year again with ovarian 
cancer, and mortality rates are falling. There are a number of 
things, including some very new therapeutic ideas, for ovarian 
cancer that are being tried out. The virus that is being 
developed by the Onyx Pharmaceutical Company is being looked at 
for ovarian cancer. We are interested in local therapies within 
the peritoneum, where even if it has spread it is usually 
there, such as photodynamic therapy, which are compounds that 
are specifically taken up by tumor cells, and you shine light 
on them and they kill the tumor cells.
    This year the FDA approved that for early lung cancer as a 
treatment as opposed to a palliation. It has been approved 
before for esophageal. This is going to be looked at for 
ovarian cancer. There are ideas. It is still a huge challenge.

                 ovarian cancer collaboration with dod

    Ms. DeLauro. Let me ask you, because I know the Department 
of Defense is doing research on ovarian cancer, and they have 
applications out for grants to look at this. What kind of 
collaboration are you doing with DOD on this effort?
    Dr. Klausner. We have a very good relationship with them 
and are coordinating all of their cancer activities. One of the 
things that we have been providing for them is a newly 
organized portfolio analysis that organizes all of our research 
on certain cancers, not just where there is an endless list 
called breast cancer, but it is actually divided into questions 
about breast cancer. And so we have had the community organize 
our portfolio, conceptually. Now we can say to anyone this is 
what we are funding in all these areas.
    Recently, the California breast cancer funding agency came, 
used this portfolio, feel that it is really useful for them, 
and we're working with the DOD so that they can use this 
portfolio analysis so they can see what we are doing, where 
there are gaps that they may be able to fill.
    Ms. DeLauro. They recently have put out this RFP, and it 
was to take a look at screening, et cetera. Do you review those 
applications as well as the DOD?
    Dr. Klausner. No.

                      coordinating review with dod

    Ms. DeLauro. I just do not know if we are going--you know, 
it is hard to say reinventing the wheel. Do not misunderstand 
me. But I just want to know that we have got a pot of money 
here and we have one here that, in fact, what we are doing is 
making the most of the money we have.
    Dr. Klausner. You are right, and we are concerned about 
that. We all are, the DOD and the NCI are working very well 
together. They do their own review. NCI individuals often 
participate in that. They participate in their oversight 
committees, and we meet with them to basically compare what we 
are doing versus what they might do.
    Ms. DeLauro. That is great. Thank you.
    Mr. Porter. Thank you, Ms. DeLauro. We will have a second 
round. At this point, Bill Natcher would say, ``Now, then, Dr. 
Klausner.'' I can hear him saying it.

                   incidence rates of various cancers

    If you took the statistics regarding incidence for lung 
cancer out of the overall incidence, what would it then show 
for all other cancers? Is the incidence going up or down? And 
if so, by how much?
    Dr. Klausner. Yes, the incidence is still dropping when you 
take lung out. Mortality rates then drop even more when you 
take lung out. And that has been true for some time.
    The other thing, of course, that is different with these 
statistics is how it affects, as I said, different populations 
and different ages. So the mortality drop is much more dramatic 
below the age of 65. It is just flattening and beginning to 
come down below the age of 65. So there is, again, a lot of 
details here.
    Mr. Porter. Well, we seem to know that the lung 
cancerstatistics come from lesser use of tobacco. If we took lung out, 
though, the incidence rates for other cancers we really do not know 
why. Is that correct?
    Dr. Klausner. That is right. We have ideas, but we do not 
know for sure.
    Mr. Porter. What are, again, the ideas regarding all the 
other types?
    Dr. Klausner. Well, prostate, Dr. Varmus mentioned 
prostate.
    Dr. Varmus. Well, by way of talking about the incidence 
rates and what that might mean.
    Dr. Klausner. Yes, that is an example. Prostate is a good 
example of the complexity of these numbers. Prostate cancer 
incidence has been going up over decades, but then in the mid 
to late 1980s, they started shooting up. And this was not a 
real increase in the incidence. What was happening, it was the 
introduction of a new test, PSA, that led to the increase of 
diagnosis of cases that would have probably been diagnosed the 
following year or 3 years or even 5 years--we do not know--or 
maybe never have been diagnosed.
    Now what is happening is, as PSA use is saturated, we are 
seeing, quote, the incidence rate dropping, but really what is 
happening is the real incidence rate is not dropping. What we 
have done is we have found what we call all the prevalent 
detectable cancers, and now we are getting presumably back to 
either the incidence rate that we saw before, or it may drop 
below. We will have to see. We are not sure.
    As I said, colorectal cancer, where the incidence is 
dropping quite significantly, especially among white women, we 
are not sure what that is.

                      residual effects of smoking

    Mr. Porter. Okay. Let me get some free medical advice here. 
If you had been a smoker but stopped 30 years ago, would there 
still be residual effects in your lungs?
    Dr. Klausner. Yes.
    Mr. Porter. In other words, how long does it take to clear, 
or is there such a thing?
    Dr. Klausner. Well, we are not sure if the lungs, 
especially at a detailed molecular level, ever entirely go 
back. We are just not sure. We do know that the risk of lung 
cancer does fall gradually, and it certainly is down very 
significantly by 20 to 30 years.
    Interestingly, for other cancers that are associated with 
smoking, such as esophageal and colorectal cancer, it looks 
like there is very little significant drop in the persistent 
risk over decades. That is very surprising. We are not sure why 
that is.
    Mr. Porter. So your risk in those areas is raised 
permanently, it looks like, from having smoked?
    Dr. Klausner. At least from recent studies over 30 years.

                     president's cancer initiative

    Mr. Porter. We talked earlier--and I believe that you were 
present then--about the President's emphasis on cancer, his 
initiative on cancer mentioned in his State of the Union 
address. My recollection is that Dr. Varmus said that this is 
not putting cancer ahead of other diseases politically. It is 
simply an emphasis on one of the increases in NIH's budget. Do 
you see it exactly the same way or do you see it differently?
    Dr. Klausner. I see it exactly the same way as Dr. Varmus 
does.
    Mr. Porter. Maybe I should have asked this question when 
Dr. Varmus was not here. [Laughter.]
    Dr. Varmus. Dr. Varmus is always here.
    Dr. Klausner. For exactly that reason.

                      increases in cancer funding

    Mr. Porter. You are now spending about $2.5 billion in the 
Cancer Institute. That is more than the budget of many 
countries in this world. We are talking now about doubling the 
research expenditure over a 5-year period.
    If we were able to do that, 6 years or 7 years from now you 
would be dealing with a $5 billion budget. And this follows on 
the question that was asked in reference to, I think, breast 
cancer. Can you really reasonably handle that amount of money 
and get good results from it?
    Dr. Klausner. I believe that we can, and I believe that we 
can handle it well. I actually think, if I can elaborate on 
that, there are four ways that we would deal with that.
    First of all, we know cancer is a complicated puzzle, but I 
actually believe we know what we need to do to push us much 
further to knowing what the puzzle looks like. I do not know 
how long it would take to finish, and I do not know what we 
will find. But we really do know what to do. That is coupled 
with something quite extraordinary. I think for really the 
first time in history not only do we know that, but we have the 
technology to actually do it, and do it in a way that is much 
faster, more efficient, and more complete than was ever 
imaginable, even a few years ago. So we need to do that so that 
we can actually really get answers to the nature of cancer, to 
how it develops, and new answers to what causes it. That is one 
thing. I think we can do that. I think we have laid out the 
types of investment--and they are significant--that we can very 
productively spend in order to achieve that.

                      development of interventions

    The second thing is all of that information is going to 
have to be coupled, as Mrs. Northup asked, to the development 
of successful interventions, and so I think we need a 
significant new investment in new types of chemistry, chemistry 
that is built on biology, the new immunology, etcetera, to 
bring in those areas and target them to the molecular opportunities for 
prevention and treatment that we are going to have. And I think we have 
begun that, but we have begun it on a very small scale. It is the type 
of thing that is very scalable and, in fact, can utilize well a fair 
number of resources.

                        clinical research system

    But all of that then leads to a real significant demand on 
our clinical research system. We are going to need a much 
better, much larger, much more rapidly responsive clinical 
trials system than we have now in order to answer the types of 
questions we are going to have and to test what we know is 
going to be a dramatic increase in number of good ideas for 
interventions, whether it is prevention, for detection, for new 
diagnosis, and for treatment.
    As I said in the opening, we see just over the last 10 
years going from 60 cancer drugs to well over 300. This is 
actually just going to increase based upon the science. We need 
to be prepared for it, and we have laid out a plan for 
expanding that system, which is, again, especially with the 
changes of the health care system, we are going to need to step 
in to support our clinical trial system.

                       application of discoveries

    And then the fourth area, just very quickly, is that we are 
going to need to make sure that once we have those trials done 
that we have effective ways to apply what we learn across the 
entire population, to all of our communities, changing 
behavior, making sure that not only do we know what to do, but 
we act on it.
    I think in those four areas, and we have laid out in great 
detail what we would do, I think we can accommodate such 
increases and I believe accommodate it well.

             partnerships between NIH and private industry

    Mr. Porter. Let me ask one final question. You have raised 
this, but this is a matter of education for myself and for the 
subcommittee.
    Especially in reference, I think, to your Institute, there 
is a great deal of pressure to find the cure, and questions 
were asked about the amount of money spent and where we are in 
the process. But we often talk about NIH being primarily a 
basic research institution and that the concepts developed 
through NIH research are then applied in private industry. Can 
you describe the nature of this process as it applies to the 
Cancer Institute? What interface is there, if any, with private 
industry in these matters? How far do you go in developing the 
drugs that may be used after you find the mechanism? Is this 
typical of all our Institutes? Can you kind of give us an 
education on that? Maybe Dr. Varmus would want to comment on 
this.
    Dr. Klausner. The NIH and the NCI is a research 
institution. Is it uniquely what we might call a basic research 
institution? No. It does clinical research. It does population-
based behavior, epidemiologic research, as well as--often, 
basic research often means cellular or molecular research. It 
is all those things, but it is research.
    Now, the NCI certainly for a very long time--and this will 
continue--is involved with the interface. That interface is 
getting much more extensive. It is an interface with industry 
at the level of basic research in terms of genomics and genomic 
technology, in terms of detection and detection technology, et 
cetera. It is an interface at the level of drug development. We 
have long had our own process, as academia does, of discovering 
agents, of developing them.
    We actually believe that the changes in research, in 
scientific research, even basic research in the types of 
laboratories that Dr. Varmus and I are from, are laboratories 
that can now discover potential drugs. They may be gene 
products. They may be actual small molecules.
    I think this is going to be a real change and increase the 
range of interface between basic research, between research 
laboratories and industry.

                rapid access to intervention development

    We will continue to be involved in drug development. This 
program we call RAID is a program that will allow us to provide 
to researchers, wherever they are, when they have new ideas for 
a new antibody, a new vaccine, a new small molecule, access to 
any of the steps of development that they cannot access 
themselves through their interaction with either small or large 
industry, but our hope certainly is--it is not to compete with 
industry, just the opposite, to create more attractive 
possibilities for industry to then come in, work with us, and 
develop things.
    In fact, I believe there are 70-some-odd drugs that the FDA 
has approved for cancer. All of them have been essentially 
involved with industry. But the NCI has held the IND for over 
50 of those 73.
    Mr. Porter. For the record, could you also describe 
whether--and I assume the answer is no--you are picking winners 
in the competition out there for treatments or other ways of 
addressing cancer? In other words, are you able to determine by 
whom you work with what company benefits as opposed to another 
and how you control this mechanism if it is a factor at all?
    Mr. Stokes, I was planning on calling on Ms. Pelosi next 
unless you have a need to be at another hearing.
    Ms. Pelosi. Please, call on Mr. Stokes.
    Mr. Porter. All right. Mr. Stokes.
    Mr. Stokes. I am in hearings next door, and I just had a 
few questions and go right back to where I am the rankingmember 
over there. I appreciate your accommodation very much, Ms. Pelosi.
    Ms. Pelosi. My pleasure.
    Mr. Stokes. Dr. Klausner, nice to see you. Always a 
pleasure.
    Dr. Klausner. Good to see you.

               effects of cancer on minority populations

    Mr. Stokes. Doctor, over the years, you and I have had some 
discussions regarding the disparity in minority health and, in 
particular, the disparate situation as it relates to minorities 
as it relates to cancer.
    Is the situation still the same? Or do we note any changes 
taking place?
    Dr. Klausner. Well, before I answer, may I just add to what 
Dr. Varmus said at the beginning of these hearings, how much we 
appreciate the consciousness that you have raised in all of us 
and how much we will miss interacting with you that way.
    Mr. Stokes. Thank you very much.
    Dr. Klausner. The disparity in terms of cancer burden, 
first of all, overwhelmingly is disparity not between all 
minority communities, but in this case very much in the African 
American community. Overall cancer burden in Hispanics and 
Asian Americans, Native American men overall is lower than in 
the majority community. We need to learn from that.
    However, in the African American community, we are and have 
been very concerned and are very disturbed about the disparate 
burden of cancer, both for incidence and mortality.
    Once again, as with anything in cancer, it varies from 
cancer to cancer. It is not all cancers. There are some cancers 
where mortality rates are lower among the African American 
community. But, unfortunately, for many cancers and some of the 
most common, incidence rates are high and mortality rates are 
way too high.

                       mortality among black men

    Are we making progress? In the overall statistics, the 
group in whom the percentage fall in overall mortality is 
highest is in black men. So in our statistics this year, there 
is about a 1.4 percent per year drop in mortality among black 
men. The next group is white men, which is about 0.9 percent. 
We hope, if that continues, that can eventually reduce what is 
a significant gap between mortality rates in African American 
men in particular and majority men.
    What is really very important is that we look at each of 
these cancers, that we have good statistics so that we can 
begin to understand the whys, and for you to know that we are 
committed to having those numbers and then to acting on them to 
try to understand why they are different.

                     breast cancer mortality rates

    Maybe I can use one cancer as an example. Breast cancer 
rates, mortality rates are about 20 percent higher overall for 
African American women than for Caucasian women. That disparity 
is even higher for younger women.
    Why is that? First of all, mortality rates are falling for 
all white women under the age of 80. Actually, mortality rates 
are either flat or falling now for all black women under the 
age of 70, but above 70 and above 80, it continues to rise.
    What is the explanation? Well, it is correlated with two 
facts. One, the percentage of women diagnosed with breast 
cancer at later stages remains higher for African American 
women than for white women; 51 percent of white women are 
diagnosed with localized disease versus only 35 percent of 
black women. For distant disease, about 22 percent of black 
women diagnosed with distant disease versus only about 11 
percent for white women.
    In addition to that, even within every stage, the tumors 
tend to be more aggressive and the outcome tends to be poorer. 
So why is this?

                     screening and early detection

    Well, we certainly are concerned that the use of screening, 
the use of early detection is not as high, and historically 
that has been true, and that could certainly in part explain 
the difference in the stage of diagnosis.
    However, by 1992, our numbers show that for the first time 
African American women are using mammographic screening at the 
same rate as white women.
    Now, we do not expect to see the benefit of mortality for 
that for 7 or 8 years. That is what the studies have shown. 
Once you reach 60 percent, which we are over that we believe 
now, of mammographic screening, you should see that. So we 
should see the effective screening in the African American 
community now begin to fall.
    There had been disparities in the delay between symptoms 
and diagnosis, and in terms of the aggressiveness of treatment 
for African American women and white women. Our latest data 
suggests that those differences are being reduced. We will be 
following that carefully.

                  biological characteristics--obesity

    The final thing is that the biologic characteristics may be 
different. Now, what does that mean? Does that mean that it is 
genetic differences? I suspect not, although there may be some 
of those, and let me just point out one issue.
    We know that obesity is associated with later diagnosis, 
with poorer outcome at any stage, and with a greater risk of 
recurrence. And we know that there is a significantly different 
rate of being overweight or obese among the African American 
community women than men. Quite a significant--52 percent 
versus 34 percent. We have several studies specifically aimed 
at understanding dietary patterns and attempting to produce 
educational materials aimed at the individuals, schools, 
workplace, and the community to deal with this issue.
    I do not know if it is obesity, but that is one example 
where there may be a biologic difference that relates to 
cultural differences in behavior such as diet. So that just 
gives you a flavor of how we are analyzing it and what we are 
doing.
    We do know, for example--and I will just finish--that when 
black women and white women with breast cancer are in the same 
clinical trial and we look for a particular stage and 
characteristic of their tumors, when they receive the same 
treatment, they do equally well. We know that from NCI clinical 
trials. That is very important. What we need is to figure out 
why the tumors are being diagnosed at a later stage and why 
they appear to be larger or more aggressive even within stage.

                prostate cancer in african-american men

    Mr. Stokes. Very interesting data. How about prostate 
cancer? When you last testified here, I think you told us that 
African American men have the highest rate of prostate cancer 
in the world.
    Dr. Klausner. They do.
    Mr. Stokes. And is that still the prevalent situation?
    Dr. Klausner. That is still the case. Prostate cancer 
incidence rates, because of the PSA phenomenon, is now dropping 
in African American men as fast as it had been dropping in 
whites, although the drop is delayed by about 2 years.
    There are real changes going on in prostate cancer. 
Actually, probably the most dramatic changes we see in cancer 
in terms of these numbers are in prostate cancer. One of the 
most significant things is over the last 3 to 4 years there has 
been a 50 to 60 percent drop in the diagnosis and the detection 
of distant disease--not percentage but absolute numbers. And 
that drop is the same--and this is one example we are finally 
seeing it the same in both the African American and the 
majority community. We are very anxiously watching those 
numbers to see if they, as we hope they will, translate over 
the next few years to a significant drop in mortality. But that 
is a very dramatic drop, 50 to 60 percent of distance disease. 
But this is an example where we are seeing it in both.
    One of the things is that there is still a disparity 
between the nature of treatment in the African American 
community and the white community. We are working very hard to 
understand that through, for example, the prostate cancer 
outcome study. We are working with black organizations and a 
variety of organizations to get the word out both to physicians 
and to individuals about treatment options to make sure that 
everyone is being treated optimally.

                           cancer and poverty

    Underneath all this, I must say, however, is an issue not 
of race but of poverty. Poverty rates are significantly higher 
among the African American community, and issues that relate to 
access to care and quality care that relate to poverty is not 
something we are going to solve by our studies, and this is 
something we need to continue to talk about.
    Mr. Stokes. My time has expired, but I just want to take a 
moment and thank you for your excellent response to my 
questions. I wish I could stay longer and pose some more 
questions, but you have been very helpful and I will submit the 
balance of my questions for the record. Ms. Pelosi, thank you 
very much for your accommodation, also.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Stokes.
    Ms. Pelosi.

                     access to quality health care

    Ms. Pelosi. Thank you. I thank Mr. Stokes for his questions 
because they are questions that we are all interested in. I was 
very pleased that in Dr. Varmus' opening remarks those many 
weeks ago he said that one of the priorities was to reduce the 
discrepancy in health status between different segments of 
society, and that would apply in incidence of disease but also 
in access to quality health care, which, as you mentioned, is 
not something we will solve here. But whatever the NIH is doing 
on that, I know they are doing more because of you, Mr. Stokes. 
So thank you.
    Mr. Stokes. Thank you.
    Ms. Pelosi. We will have more time to praise and be sad 
about Mr. Stokes' leaving us, but every chance I get, I like to 
thank him for his leadership.
    Mr. Stokes. Thank you very much. You are very kind. I 
appreciate that.
    Ms. Pelosi. Now, see, I do not have to ask my question 
about the incidence of breast cancer in African American women.
    When we started a couple of weeks ago, our chairman said we 
did not have as much time as we would all have liked with Dr. 
Varmus because we would have at him along the way. And I guess 
along the way is sort of coming to an end. I may not even be 
here Friday afternoon, so I have a couple questions for Dr. 
Klausner and a couple for Dr. Varmus. And, of course, each of 
them is welcome to weigh in on the other.

                              nci funding

    Dr. Klausner, just quickly, you mentioned to Mr. Hoyer that 
$30,000,000,000 had been spent on breast cancer research.
    Dr. Klausner. No. That is the total----
    Ms. Pelosi. What does that include?
    Dr. Klausner. That is the total dollars spent, and it is 
not a precise number but approximately $36 billion.
    Ms. Pelosi. But what does it capture? What is happening 
that the Federal Government has spent?
    Dr. Klausner. Yes. That is the research budget for cancer 
research to----
    Dr. Varmus. Real dollars.
    Dr. Klausner. In real dollars, that is right, to the NIH 
over the years in cancer research. It is somewhat over 
$36,000,000,000.

                                nci pdq

    Ms. Pelosi. Thank you. And while we are on the budget, I 
wanted to ask a budget question. Dr. Klausner, the FDA reform 
legislation provides for a consumer-friendly, one-stop shopping 
database of clinical trials for all life-threatening diseases. 
How much money would it take to establish the cancer section of 
the database and how quickly will theinformation be available 
to cancer patients? Is this funding in this 1999 budget?
    Dr. Klausner. Well, of course, we actually feel that we 
have at least the basis of an accessible database about 
clinical trials. It is called PDQ. We are in the process of a 
redesign of PDQ. We had a meeting, a three-day meeting, I 
believe it was, in February where we invited all the 
institutes--and Dr. Varmus helped sponsor that--to actually 
look at just this issue, to build on the relatively long 
tradition now that we have of developing accessible databases. 
We brought in people from many different fields, cancer 
researchers, advocates--in fact, it was cosponsored and co-run 
by a breast cancer advocate--in order to define first what are 
the parameters that we want in a clinical trials database that 
would be accessible and useful and understandable to all the 
users.
    We are now getting the recommendations through the steering 
committee from that. We should have that over the next few 
weeks. And our plan is to undergo, one, a PDQ redesign that 
would be much more user-friendly, that would be available to a 
much larger array of clinical trials, including industry 
clinical trials. We have already worked out some through 
negotiations with industry, with the pharmaceutical industry 
and the FDA about simpler ways to put in industry information 
of clinical trials into this database. And we will be working 
through Dr. Varmus' office with all of the institutes to 
provide this infomatics system available through both 
telephone, through the Internet, the Web, faxes, et cetera, for 
this type of database.
    I do not know yet what it will cost. The reality is, as I 
think you know, with databases it could probably cost almost 
anything, depending upon what you put in, what you demand of 
it. We are going to have to look at what the community told us 
they are looking for and they need, figure out what is 
technologically and resource possible, and then we will be 
working on designing that system. But we are committed to 
moving into a redesign that will make such an access point 
available.
    Ms. Pelosi. So in a few weeks, you will have the 
recommendations.
    Dr. Klausner. From the steering committee, yes.
    Ms. Pelosi. From that point you will establish your 
priorities.
    Dr. Klausner. Yes.

                       clinical trials databases

    Dr. Varmus. I would just comment briefly about this, Ms. 
Pelosi. We think that the meeting that Dr. Klausner referred to 
was extremely useful for those institutes that have clinical 
trials programs to get their databases up and running. In fact, 
some of them already have some databases. The difficulties we 
face are several-fold. One is getting an actual budget estimate 
of what this is going to cost. Secondly, knowing what to do 
with those clinical trials that are not sponsored by the NIH, 
gathering up all that information from industry and from other 
private sources may be difficult.
    The third problem we are concerned about is the one phone 
line; manning that line could be an extremely expensive 
process, and we are a little concerned about that. Doing it 
through the computer will be not a problem.
    Ms. Pelosi. Thank you. Dr. Varmus, if I may--forgive me, 
Dr. Klausner, for a moment--I have another question.
    Dr. Varmus. He is enjoying it.

                        needle exchange program

    Ms. Pelosi. As you know, Dr. Varmus, last year the NIH 
convened a panel of individuals to review the scientific 
research to tell us about the prevention of HIV, and one of the 
issues they addressed is the question of whether needle 
exchange programs promote drug use. The panel concluded a 
preponderance of evidence shows either no change or decreased 
drug use. In addition, the panel found that individuals in the 
areas with needle exchange programs have an increased the 
likelihood of entering drug treatment programs.
    As you know, in our legislation last year, we established 
some criteria that a needle exchange program should reduce the 
spread of HIV-AIDS and draw people into a drug treatment 
program.
    Last year you gave us your opinion about the efficacy of a 
needle exchange program. Would you like to----
    Dr. Varmus. Well, my opinion has not changed. As you know, 
the Secretary will be in a position to make a determination 
about whether or not we have met the criteria--which, as you 
know, apply differently to CDC and NIH as opposed to SAMSHA 
with regard to needle exchange program support. The criteria 
that need to be met for NIH and CDC is that these programs--
have health benefits that decrease the spread of infection, and 
that they do not increase the use of drugs.
    From our review of the literature through the conference 
that you mention, we believe those criteria can be met.
    Ms. Pelosi. Thank you, Doctor.
    I know that the OAR was supposed to be here yesterday, but 
that hearing date was changed.
    Did the bell go off? I did not hear it. No? Okay. I was so 
engrossed.

                         oar--levine commission

    Dr. Varmus. The OAR discussion will be on Friday.
    Ms. Pelosi. Yes. I would like to know if we have talked 
before about the Levine Commission--or do we call it the 
``Levine'' Commission?--the Levine Commission report.
    Dr. Varmus. He calls it the ``Levine'' Commission.
    Ms. Pelosi. Well, that is what we call it, then, theLevine 
Commission.
    Can you tell us what the success has been of the Office of 
AIDS Research and the success you have had in following through 
on the Levine Commission Report?
    Dr. Varmus. Yes. I think we did have a brief discussion of 
this somewhere along the line--perhaps you were not in the 
room, Ms. Pelosi--about the 14 recommendations the Levine 
Committee report made.
    Ms. Pelosi. Well, I did, but I wanted you to be more 
specific about the Office of AIDS Research.
    Dr. Varmus. Right. We believe that the OAR is carrying out 
its function in a very admirable way. As you know, Dr. Paul has 
left the OAR to return full time to his laboratory. Dr. Jack 
Whitescarver has been overseeing the office very effectively. 
He will be here to testify on Friday, and we are in the final 
phases of a search for a new director. I hope to be able to 
deliver the name of a new director sometime in the next month.
    The office continues to carry out its major mandates, which 
is to coordinate and oversee AIDS research across all the 
Institutes, to help in budget formulation, to do program 
planning with the Institutes.

                              oar funding

    Ms. Pelosi. How do they plan their budget working with the 
other Institutes?
    Dr. Varmus. First of all, there is a very extensive 
planning process that the OAR coordinates itself. That is a 
very important aspect of this. They have identified five broad 
areas of research activity that are addressed by working groups 
that come from both the extramural research community and from 
the NIH staff. Those groups develop a series of initiatives and 
work with the Institute directors to develop a research plan 
appropriate for each Institute.
    The budget for the AIDS effort across the NIH is developed 
through conversations between the OAR director and the director 
of each Institute. As you know, each Institute has an AIDS 
budget, and that process has been working extremely well.
    Through a few conversations with Mr. Porter and others, we 
have developed the means to award the money for AIDS research 
to the Institutes in a way that is acceptable to everybody.

                          transmission of hiv

    I think you have seen, especially when Dr. Fauci was here, 
that we have made some extremely dramatic progress in 
countering the transmission of HIV from mother to child and in 
reducing mortality from AIDS. We have reduced transmission 
between adults in some groups and not others. There are some 
tremendous challenges ahead as a result of the increase in HIV 
transmission in certain groups in our population and as a 
result of the rampant spread of HIV abroad, especially in Asia 
and Africa. Although we have hand in hand with industry 
produced drugs for the treatment of AIDS, we still are 
encountering very significant failure rates, and we think that 
many more drugs are going to be required if we are going to 
very effectively treat HIV infections.

                             aids vaccines

    We need a vaccine. We have many initiatives, as you know, 
that are being coordinated by the OAR to develop a much more 
effective vaccine research program, both within the NIH and 
through our innovation awards in the extramural community. The 
OAR plays a very, very significant role in developing and 
coordinating those programs.
    Ms. Pelosi. Well, I appreciate your laying out the 
challenge as you answered the question, the challenge that 
remains.
    My time now really has expired. Dr. Klausner, I am going to 
have to submit for the record my question on vinyl chloride 
vapors, which I will do.
    Once again, Mr. Chairman, I wanted to thank Dr. Varmus and 
Dr. Klausner today and all the others for this dazzling 
presentation of the last several weeks. I think we are very 
blessed on this committee to have the benefit of this 
testimony.
    Thank you for your leadership, Dr. Varmus, for attracting 
all of these great people to the NIH. Thank you for what you 
do.
    Mr. Chairman, I will submit my questions for the record and 
yield back the balance of my time.
    Mr. Porter. We certainly are blessed. We have not asked Dr. 
Varmus yet, but I wonder whether we would benefit by having the 
Nobel Laureates come up after we finish our regular hearing 
schedule, say, in mid-May.
    Ms. Pelosi. I think that is an excellent idea. We have 
benefitted in the past when we have brought them here.
    Mr. Porter. Yes.
    Ms. Pelosi. It is a wonderful day.
    Mr. Porter. It is the highlight of our hearing year. We are 
considering that right now.
    Ms. Pelosi. With stiff competition, mind you.
    Mr. Porter. Dr. Klausner, let me thank you on behalf of the 
subcommittee. We not only appreciate your statement and your 
answering all our questions, but we will have additional ones 
for the record.
    You give us great confidence that with someone of your 
intellect, energy, and your enthusiasm for your work that we 
really will have breakthroughs and some day soon have control 
over this terrible disease that you cope with every day. So 
thank you very much for all that you do there and for the fine 
job you do for our country.
    Dr. Klausner. Thank you, Mr. Porter.
    Mr. Porter. The subcommittee will stand in recess until 
2:00 p.m.
    [The following questions were submitted to be answered for 
the record:]


[Pages 387 - 626--The official Committee record contains additional material here.]



                                         Wednesday, March 18, 1998.

                         NATIONAL EYE INSTITUTE

                               WITNESSES

DR. CARL KUPFER, M.D., DIRECTOR, NEI
DR. JACK A. McLAUGHLIN, Ph.D., DEPUTY DIRECTOR, NEI
JUDITH DUFF, ACTING EXECUTIVE OFFICER, NEI
CAROL LIPSON FIVOZINSKY, BUDGET OFFICER, NEI
DR. HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF 
    HEALTH AND HUMAN SERVICES

    Mr. Porter. The subcommittee will come to order.
    We continue our hearings on the National Institutes of 
Health and welcome Dr. Kupfer, the Director of the National Eye 
Institute for his testimony and questions. Dr. Kupfer, if you 
would introduce the people who have come with you and then 
proceed with your statement.

                       Introduction of Witnesses

    Dr. Kupfer. Thank you, Mr. Chairman.
    To my far left is Ms. Judith Duff, who is the Acting 
Executive Officer; on her right is Ms. Carol Fivozinsky, who is 
the Budget Officer; to my immediate left is Dr. Jack 
McLaughlin, who is the Deputy Director; and of course, you know 
the gentlemen to my right.

                           Opening Statement

    Mr. Chairman, as in each year, we are continuing to be 
involved in many, many different areas of problems of the 
visual system, I'd like to highlight some of the more immediate 
developments that have taken place since last we met.
    The first area has to do with how well the interaction 
between the NIH and the private sector operates. Two new drugs 
were developed in the last year or two, both of which were 
supported initially by NIH funding through the National Eye 
Institute, for, in one case, 10 years and in another case, 15 
years. Once the basic science was done, these two drugs were 
taken up by the pharmaceutical industries. We have two new 
drugs for the treatment of glaucoma--one called lantanoprost, 
which has the trade name, Xalatan and the other dorzolamide, 
which is known as Trusopt.
    These two new drugs have further made it possible to bring 
high levels of intraocular pressure under control and to 
ameliorate the progress of glaucoma, especially in those areas 
of the population at high risk for glaucoma.
    A second area that has recently developed in a very 
interesting way has been the first breakthrough in trying to 
understand the genetic basis for diseases of the macula. We've 
talked many, many times about age-related macular degeneration, 
but there are a number of macular degenerations that occur in 
very young people. One of them is called Stargardt's macular 
degeneration.
    A group of cancer researchers were looking for genes that 
control the entry of molecules into cells to see how they can 
overcome the resistance that cancer cells sometimes develop to 
therapy. In doing this, they came across a family of genes, and 
looking through the genes that had already been identified, 
came across a gene that had been expressed only in the retina.
    To make a long story short, they quickly identified that 
this gene is present in almost all the cases Stargardt's 
macular degeneration.
    What has been particularly exciting has been the fact that 
in about 16 percent of patients with the age-related macular 
degeneration, which as you know is reaching epidemic 
proportions in our country, this gene also appears to manifest 
itself.
    We were very fortunate when this relationship became known 
that Dr. Varmus, dipping into his director's discretionary 
fund, gave us some additional funds to immediately jumpstart a 
collaboration between the Cancer Institute and the Eye 
Institute. We are now trying to confirm these findings in a 
very large population of age-related macular degeneration 
patients that we have in our clinical trial, the Age-Related 
Eye Diseases Study.
    That was a very interesting example where cancer 
researchers were looking for a way to improve the treatment of 
cancer and came upon a gene that had implications in a serious 
eye disease.
    There is another reverse example which I think is 
particularly interesting also. That is, we had a vision 
researcher who was looking for small molecules that were under 
genetic control to regulate the growth of nerve fibers and 
nerve cells in the central nervous system in an effort to learn 
more about regenerative possibilities.
    In the course of doing this, it was found that this gene 
also affected the growth of cancer cells in the brain, so-
called gliomas. Again, it turned out that when this gene was 
producing quite a bit of protein, these gliomas were able to 
grow very, very rapidly and if the glioma did not have this 
gene producing this stimulus, then the glioma would not grow 
very rapidly and would be more like secondary metastases.
    Again, here is a project that begins as a vision research 
project and ends having some very important implications in 
cancer.
    The area of diabetes research is moving very, very rapidly. 
Underlying the complications of diabetes in the eye is the 
proliferation of new vessels and there are now a host of 
inhibitors that are being developed, primarily by private 
industry, pharmaceutical companies, that inhibit the growth 
factors that stimulate the growth of new vessels.
    These are now being tested extensively in animal models and 
will soon begin in clinical trials. In fact, we're going to 
begin a clinical trial probably within the next three or four 
months looking at one of these inhibitors.
    The area of myopia is moving very, very rapidly. Much of 
the animal work has pointed to environmental factors as having 
a major role and we're now beginning to try to apply those 
environmental factors in clinical trials.
    We have three clinical trials ongoing, trying to slow down 
the progression of myopia in children who are just beginningto 
develop near-sightedness.
    The retinal degenerations offer another challenge and there 
are a whole host of small molecules called neurotrophins that 
seem to be able to support degenerating cells so that they 
degenerate much more slowly or not at all, or allow 
regeneration to take the place of degenerating cells.
    Again, this entire group is in animal model experimentation 
and I think within the next two or three years, we'll be having 
clinical trials.
    Finally, the National Eye Health Education Program, in 
addition to its work in glaucoma education and diabetes 
education, has now entered the field of education in low vision 
in an effort to address that large segment of the population 
for which treatment has not been beneficial and who have lost 
vision and still want to maintain a high quality of life.
    Perhaps I'll stop at this point and be happy to answer any 
questions.
    [The prepared statement follows:]


[Pages 630 - 634--The official Committee record contains additional material here.]



                        laser surgery for myopia

    Mr. Porter. Thank you, Dr. Kupfer.
    Often we read in the media of advances in certain areas and 
want you to give us the insights as to what the real facts are. 
Most recently, we read about the professional golfer, Tom Kite, 
having a laser surgery of some type on his eyes. His vision 
started at 20/100 the press said, and after surgery, is now 20/
15. The operation cost around $4,600, but has completely 
changed his myopia from wearing ``coke bottle'' glasses to 
wearing no glasses at all after 40 years of struggling with 
poor eyesight.
    Can you tell us what this surgery was and is it applicable, 
without looking at the cost, to broad populations who suffer 
from simple myopia? Do you expect this to become a procedure of 
choice in the future?
    Dr. Kupfer. Mr. Chairman, I'm not familiar with the 
specific example but from what you said, I imagine he has had a 
laser treatment to reshape his cornea so that he would not have 
to wear thick glasses, which probably are correcting 
nearsightedness, and can perform hopefully better on the golf 
links.
    As I mentioned, we are very much interested in myopia. Our 
approach to myopia is to try to understand what the basis for 
the elongation of the eye is, which is really the major 
phenomenon and to prevent this elongation. We do know that 
signals from the retina go to the white coat of the eye and 
cause that coat to stretch. The signals are triggered by the 
fact that the image that a child is looking at is not in good 
focus on the retina.
    We have the system to study myopia and we are now very 
aggressively going after looking at the sequence of signals 
between the retina and the white of the eye, the so-called 
sclera, to see what causes this elongation.
    What is happening in the community, of course, is that 
there are ways of reshaping the curvature of the cornea and if 
one makes the cornea less steep, flatter, then the nearsighted 
eye will be able to focus objects right on the retina. It will 
no longer be nearsighted because the cornea will not be able to 
refract the light as much if it can be flattened.
    If you remember, we talked about radial keratotomy which 
was a technique introduced about 15 years ago to flatten the 
cornea by making incisions in the cornea. This has now given 
way to what is called excimer laser treatment, which is a 
special laser that can peel off layer by layer of the cornea 
until you have the right shape.
    In the case of radial keratotomy, a group of 
ophthalmologists and health care professionals came to the Eye 
Institute and said, we don't know if this is safe and 
effective, let's do a clinical trial, which we did. We had ten-
year data on what the results were, so a patient coming in 
wanting radial keratotomy could be told pretty much what they 
could expect in terms of results.
    We don't have that degree of information on the excimer 
laser, so it is very difficult to predict precisely what is 
going to happen. It has become very popular, it's very highly 
advertised. I would say thousands of people are going to be 
having this done every year and eventually, we will learn how 
beneficial it is in the long run.
    I think it would have been very nice if we had better 
clinical data to be able to advise patients as to whether they 
should seek this treatment or not.
    Mr. Porter. Was this treatment developed through research 
or is this laser treatment simply a different way of doing the 
same thing--another way to flatten the cornea?
    Dr. Kupfer. Yes, it really came from development of a new 
type of laser, the so-called excimer laser where literally you 
could take off the cornea several microns at a time.
    Mr. Porter. Am I correct that there is some risk with this 
procedure, where you could make a mistake as to how much you 
took off?
    Dr. Kupfer. Yes. We know there are some side effects. We 
don't know what will happen after many years. There is 
scarring, there is haze, there are problems with glare at night 
when one drives. We really haven't a good handle on this.
    Mr. Porter. Is any research underway in this area so you 
can follow people who have been operated on?
    Dr. Kupfer. We have supported animal work in trying to 
improve the healing of the cornea after the surgery is done, 
but our National Advisory Eye Council, and I think wisely, said 
unless there is going to be a clinical trial that will really 
look at this critically, we, the National Eye Institute, should 
not be involved in supporting any of the clinical studies 
unless they are done very, very well, and that did not come 
about.

                             myopia causes

    Mr. Porter. Is there evidence that myopia is genetically 
based? In other words, if a parent has it, is it likely that a 
child also has it?
    Dr. Kupfer. There certainly is evidence that there's a 
genetic component. As a matter of fact, we're going to begin 
several genetic studies of myopia looking at populations that 
have a very, very high prevalence and incidence of myopia 
versus those that do not, and then comparing what the potential 
risk factors may be that separate these two groups.
    On the other hand, there is also strong evidence that 
perhaps if we could control the environmental factors, this 
defocusing of the image, that we could provide some interim 
treatment and that's what we're doing. We're moving on both the 
epidemiological side and the clinical trials.
    Mr. Porter. Is there any possibility that the muscles of 
the eyes can have anything to do with elongating the eyeball 
and putting the image out of focus?
    Dr. Kupfer. Yes. As a matter of fact, when one looks very 
close at an object, the muscles inside the eye, the ciliary 
muscle, must contract to allow the focus to be on the retina. 
If that muscle doesn't do it precisely, the image will not be 
focused on the retina. So there is an involvement of the muscle 
in the eye, not the muscles that move the eyes externally.

                            PROGRAM PLANNING

    Mr. Porter. To get input from the public, you posed two 
questions on the NEI home page requesting respondents to 
identify the most significant accomplishments or advances in 
vision research over the last five years and the most important 
vision research questions that should be addressed during the 
next five years. How many responded to this request and what 
were the consensus answers? Do you know?
    Dr. Kupfer. Dr. McLaughlin, who was in charge of that, says 
there were several hundred responses over the period of time 
that this appeared on the Web.
    Mr. Porter. Was there a consensus as to what they were and 
what they should be?
    Dr. McLaughlin. I would say, first off, the responses were 
gathered as input to the expert panels which we then convened. 
I would say that most of the responses, as you might imagine, 
of course some of them were self-serving kinds of things--I'm 
doing research in x area, the area I know best--but I think in 
general, the program staff at the Institute and the people 
involved on the panels thought it was a very worthwhile 
exercise and something we might expand in the next go around.

                            ASTHMA INHALANTS

    Mr. Porter. Dr. Kupfer, there was a study published in the 
Journal of the American Medical Association last March which 
concluded that older persons may be at higher risk of 
developing glaucoma if they take high doses of asthma inhalants 
that contain steroids for months at a time.
    There was some concern that this particular study was 
flawed and that more research was needed to confirm the link 
between glaucoma and steroids and inhalants.
    Then four months later, the results of a different study, 
also conducted on older people, was published which found that 
using asthma inhalants doubled the risk of one developing 
cataracts. Are you familiar with both of these studies and are 
there any followup studies being conducted?
    Dr. Kupfer. Yes, sir, I'm very familiar with both studies. 
These studies were a form of study called a case control, where 
one takes cases and compares them with controls. In both of the 
studies, people with and without cataracts were identified and 
then they were asked in questionnaires whether they took 
inhalants with steroids, how often, and that sort of thing.
    These sorts of studies are very important to do because 
they raise questions, as these two studies do, but they cannot 
do more than suggest an association, not a cause and effect. I 
think amongst the people who are in the glaucoma field, the 
jury is still out on whether this is a serious concern upon the 
part of patients with glaucoma using these inhalants.
    I think what probably is going to be done is a third study 
that will be constructed specifically to answer this question. 
The first two studies really weren't specifically looking at 
this but a whole host of risk factors. So I think if we design 
a study that will specifically look at this, we could perhaps 
get a better answer.
    Mr. Porter. Thank you, Dr. Kupfer.
    Ms. Lowey.

                        LASER SURGERY FOR MYOPIA

    Ms. Lowey. Thank you, Mr. Chairman, and thank you, Dr. 
Kupfer.
    If I may follow up on the question of our Chairman because 
I'm puzzled and I, as many of us, have been hearing about the 
benefits of the surgery.
    You said the NIH is not doing a clinical study. I'm puzzled 
because there are thousands of these occurring, I believe you 
said. What assurance do we have that they are performed in the 
best professional manner?
    Dr. Kupfer. Ms. Lowey, the development of these lasers, and 
there are basically two companies, came about strictly on the 
basis of a small number of lasers being made available and 
ophthalmologists beginning to use them to learn more about how 
well they function.
    The FDA tried to bring into some working order a clinical 
trial but at the time, which now goes back seven or eight years 
ago, devices did not have to undergo clinical trials to be 
accepted by the FDA as opposed to drugs which did. Now devices 
are being brought under the umbrella of clinical trials.
    So we were confronted with a situation where no one else 
wanted to do a clinical trial. We can't do a clinical trial 
unless there are people who are anxious to do this and to then 
study very, very carefully and follow up the patients, as we 
did with the radial keratotomy study. Unless we can do these 
trials, the free market is going to operate and individuals 
wanting this surgery will be able to seek it out.
    I would say that more than 90 percent of the insurance 
companies do not reimburse this procedure. It's considered 
cosmetic and I wish we would have been approached by a group of 
investigators saying we really should mount a clinical trial.
    We cannot really play a role when the companies themselves 
fund these trials. They are done in a way where they may or may 
not give us a good, clean answer and therefore, we're left not 
being able to say to a patient whether they are a good 
candidate or not for this particular procedure and what the 
long-term complications may be.
    Ms. Lowey. Obviously, I'm puzzled by the response because I 
would think that we're almost caught up with the current laws 
that exist, but don't we have a responsibility in protecting 
the public and to what extent would this be the responsibility 
of NIH because it concerns the health of the eye or the FDA 
which may have responsibility for the devices? Maybe I'm not 
asking the right question, but I'm very puzzled.
    For example, my ophthalmologist, a very respected 
ophthalmologist, discussed it with me and I said, are you 
kidding, what are the risks, what are the studies? Forget it, 
I'll wear my contacts and my glasses.
    Dr. Kupfer. You're absolutely right and there are 
individuals who approach it that way. There are others who say, 
I will do anything, anything to be able to get rid of my 
glasses. This is a personal preference sort of thing. I don't 
see any role that the Federal Government can play through NIH 
in trying to restrict this.
    There are many, many procedures out there in the medical 
world that have never been tested that are being done every day 
and it's a personal preference on the part of the publicas to 
whether they wish to have this performed. I would love to be able to 
give them answers. With the radial keratotomy, we did it the right way.
    Ms. Lowey. I just want to say that I share the concern of 
my Chairman. Should FDA have a greater responsibility? It seems 
to me that if thousands and thousands of these procedures are 
being done, some place in our government, if it's not the NIH, 
there should be some responsibility for validating either the 
justification for it or recommending that it's not justified.
    I would think there are enough ophthalmologists that would 
want, forgetting the two manufacturers of the product, to see 
some clinical trials done. Maybe I'm missing something.
    Dr. Kupfer. No, you're not missing anything, Ms. Lowey. 
It's just that once the horse is out of the barn, it's very 
hard to say let's back off and do a clinical trial on a 
procedure which, as I said, is probably being done on several 
thousands of people or more. That's the facts of the real 
world, I guess one would have to say.
    Mr. Porter. Would the gentlelady yield?
    Ms. Lowey. Yes.

                         LASER SURGERY FOLLOWUP

    Mr. Porter. I don't think we need to do a clinical trial, 
what we need to do is a followup on those people who had the 
procedure to see what problems there have been. Wouldn't that 
be sufficient?
    Dr. Kupfer. Yes, and FDA is doing that.
    Mr. Porter. They're doing that?
    Dr. Kupfer. Yes. This is post-approval surveillance and 
they are doing that. It will take some time before we see.
    Mr. Porter. So there's no sense in doing a clinical trial 
after the fact?
    Dr. Kupfer. No. It should have been done seven years ago at 
the beginning.
    [The information follows:]

                             Laser Surgery

    The NEI has not itself conducted or supported clinical 
trials on the safety and efficacy of this procedure. This is 
due to the fact that the manufacturers of these devices 
conducted independent clinical studies which the FDA found 
acceptable in approving the devices as safe and effective for 
treating moderate myopia. The devices were not available for 
NEI use prior to this FDA decision. It is our understanding 
that the manufacturers have agreed to submit post-approval 
studies to the FDA on the long-term safety and efficacy of 
these devices. In addition, the FDA has placed a number of 
restrictions on the use, labeling, and promotion and 
advertising of the lasers.

                          CATARACT OPERATIONS

    Ms. Lowey. Thank you and I hope we can follow up with you 
on this since I know there is interest.
    Another area that I've been concerned about is the number 
of cataract operations that have been performed. If you go down 
to Florida, where members of my family reside, they are done by 
the tens of thousands. Can you update us on the status of 
surgical techniques to treat patients with cataracts? Ten years 
ago when laser surgery became available, patients could be 
treated for cataracts in a doctor's office and that was thought 
to be the cutting edge.
    Is the latest treatment an improvement on the original 
treatment, and again, what kind of consistency is there in the 
cataract operations that are being performed?
    Dr. Kupfer. First of all, Ms. Lowey, I can make the 
statement that cataract is probably one of the most successful 
operations that's ever been devised. You're quite correct, it's 
being done as an outpatient procedure, very often done in the 
morning and the patient goes home in the afternoon. There have 
been many modifications in the type of artificial lens that is 
used, in the surgical procedure to reduce the time it takes for 
the wound to heal and things like that.
    I think that the operation is probably as good as it's 
going to be developed, unless there is some very, very unusual 
breakthrough.
    The number of cases being done is increasing, partly 
because I think that as people are getting into the age where 
they develop cataracts, they still want to be able to drive, 
they still want to be able to play golf and tennis, they still 
want to participate in all the activities and to do this, you 
need very good vision.
    So 20 or 30 years ago, an individual might not have 
cataract surgery until their vision was really interfering with 
their being able to function, but today, the cataract surgery 
can be done at an earlier time in the development of the 
cataract so that the individual's vision can be restored.
    Of course in Florida, there are many, many people who are 
retired and they do want to maintain a very high quality of 
life, and I think that's what we're seeing.
    Ms. Lowey. Have there been consistent reports of success 
with this operation or have you had some other responses?
    Dr. Kupfer. I think in general the perception is that it's 
been very successful. The American Academy of Ophthalmology is 
beginning to look at the results of cataract surgery by 
ophthalmologists who are willing to turn in the results of 
their surgery every month and then as the number increases, 
they will be able to come up with some indications. Perhaps by 
next year, I'll be able to report to you on that.
    Ms. Lowey. Thank you.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Ms. Lowey. Mr. Stokes.

                    age-related macular degeneration

    Mr. Stokes. Thank you, Mr. Chairman.
    Dr. Kupfer, welcome to our subcommittee. It's nice to see 
you again.
    In your formal testimony under the category ``Age-Related 
Macular Degeneration,'' I'm struck by a statement that you make 
when you say, ``As the baby boom generation ages and in the 
absence of further prevention and treatment advances, the 
prevalence of AMD is estimated to reach epidemic proportions of 
6.3 million Americans by the year 2030.''
    Dr. Kupfer. Yes, sir.
    Mr. Stokes. That seems to create quite a problem, I would 
think, for us futuristically and it's something we ought to be 
thinking very carefully about. I'm sure in your Institute, you 
are thinking about it?
    Dr. Kupfer. Yes, sir. I would say that this is probably at 
the top of our priorities in terms of where we're trying to put 
our research efforts. As I mentioned, we had a very good 
development in terms of identifying a gene that occurs in a 
macular degeneration occurring in the first 10 to 20 years of 
life, Stargardt's macular degeneration, and the gene that is 
causing that condition apparently has been found in some of the 
patients with the age-related macular degeneration.
    We are moving very, very rapidly forward with the help of 
Dr. Varmus, from the funding he has available, to begin to 
collaborate with the Cancer Institute, where the original work 
was done, in looking at whether this gene is present in a very 
well defined population of patients that we have enrolled in 
clinical trials.
    We are moving very rapidly in the area of the laboratory 
with a number of animal models. We can begin to see in the two 
types of macular degeneration, where the one type of cell, the 
so-called photoreceptor, undergoes degeneration, whether 
there's some way to slow that down or even after it has begun, 
to rescue the cells and restore and regenerate these cells.
    This is a very high priority. We're doing genetic studies, 
population-based studies to see what the genetic basis is. 
Again, it's probably a multigenetic disease. This is really at 
the top of our priority list, Mr. Stokes. There is no doubt 
about that.

                              neuroscience

    Mr. Stokes. I note that brain disorders in neuroscience are 
topics that the National Institutes of Health is emphasizing in 
its fiscal year 1999 budget. Tell us, what research is NEI 
doing in this area?
    Dr. Kupfer. There are three areas that we are concerned 
with and I might say these concerns are also shared by the 
Neurology Institute, the Mental Health Institute, those 
institutes that are looking at the brain as we are.
    We're interested in slowing down the degeneration of cells 
in the brain. In our case, it would be the retina or the 
different way stations between the retina and the visual parts 
of the brain. This is done by finding that there are a group of 
molecules called neurotrophins that can actually slow down the 
degeneration of these cells. A lot of work is going on in that 
direction.
    There is work going on in regeneration on two fronts. One, 
why is the central nervous system not able to regenerate when 
the peripheral nervous system can regenerate? We want to see 
why the central nervous system shuts down its capability in 
terms of not being able to continue to be able to regenerate 
when the infant is just several weeks or a month or two old.
    There is also research going on what it is that directs 
nerve fibers to the places they're supposed to go, because if 
we're ever going to get regeneration, whether in the optic 
nerve or the spinal cord, we've got to be sure that the nerve 
fibers go to the right places in the brain.
    There now have been found small molecules that attract or 
repel growing nerve fibers and sort of direct them to where 
they should go. That research is growing very considerably.
    So I think we are moving ahead along with the other 
Institutes learning more and more about what is involved in the 
functioning of the central nervous system, farther into 
rescuing cells undergoing degeneration or maintaining the cells 
or allowing regeneration of nerve tracts.
    We have a particular problem in ophthalmology because, as 
you well know, the cells in the retina in glaucoma die and we 
are very actively involved in trying to understand what the 
mechanism of that is and to develop neuroprotective drugs that 
will prevent those cells from dying.

                            minority health

    Mr. Stokes. Dr. Kupfer, over the last several years, you 
and I have had some discussions about certain eye diseases, 
visual impairments and so forth that are more prevalent in 
African Americans than in White Americans. We've talked about 
diabetes, we've talked about glaucoma and things of that sort.
    Can you give me some type of an update on where we are in 
terms of that discussion?
    Dr. Kupfer. There is no doubt now that the National Eye 
Health Education Program is beginning to have an impact by 
dissemination of information to African-Americans in terms of 
having a dilated eye examination after the age of 40 every year 
by an eye care professional. I think we are seeing that the 
knowledge is getting out there. We've done some demonstration 
projects to show that this can work.
    As discussed by Dr. Fauci earlier, the health care system 
sometimes does not accommodate an individual to have an eye 
examination every year, so we are trying to work with the 
health care maintenance organizations and convey to them this 
is a very important thing.
    It's been done successfully with diabetes. Most HMOs will 
now build in a dilated eye exam for every diabetic. I think 
that's been a major step forward. We'd like to be able to do 
the same thing while they're dilating the eye to look at 
diabetics, they certainly could do it to look for changes in 
the optic nerve. I think we're slowly making an impact.
    The diabetes story is a more complicated one and it appears 
that just informing the diabetic of the need for an eye 
examination is not enough. There's got to be the entire medical 
team of the diabetologist, the general physician, the family 
physician, to keep pushing the individual to see 
theophthalmologist, to see the eye care professional to determine 
whether they are at risk for going blind and should receive laser 
treatment, which is very effective.
    We are now beginning to change our approach to try to bring 
these various groups together to present a united front to the 
patient.
    Mr. Stokes. Do we know why we have this type of 
disproportionate disease in the African-American community?
    Dr. Kupfer. I think there are some suggestions that there 
certainly, probably, is a genetic--in the case of glaucoma, I'm 
almost certain there's a genetic predisposition. I think that 
would be my main concern as far as glaucoma is concerned.
    In the case of diabetic eye disease, I think it has more to 
do with the need for the diabetic to really keep blood sugar 
under control, to be concerned with diet and be concerned with 
continual monitoring of the eye complications. This is not an 
easy thing to do.

                          vision research plan

    Mr. Stokes. NEI has recently formulated a sixth vision 
research plan for fiscal years 1999-2003. Can you tell us how 
this plan, was developed and how do documents like this enhance 
the Institute's research?
    Dr. Kupfer. Yes, Mr. Stokes. For the last 20 years, the 
staff of the National Eye Institute has been collaborating with 
a subcommittee of the National Advisory Eye Council to have 
five year plans. As you point out, this is our sixth plan.
    We began by putting on the Web the two questions that Mr. 
Porter mentioned earlier to the research community and to 
anyone else who wanted to respond, what has been done in the 
last five years, what successful steps have been taken, and 
what do you think are the most important questions to answer in 
the next five years.
    Following that, we convened seven panels to look at the 
different areas of research that we are involved in and each 
panel consisted of a dozen members and each of the members 
called upon up to 10, 20 or 30 colleagues in the field. So in 
the development of these priorities for the next five years, 
there's probably an input of 300 or 400 scientists in the 
vision research community that entered these ideas.
    This was presented to the Council, trimmed down, targeted 
so that we really were looking at the most important areas to 
focus on, especially in terms of where we could match not only 
the needs but the opportunities to solve those needs. We have 
many, many needs, but we have to look at opportunities.
    When we had a draft of the plan, we sent it out to all the 
organizations that were involved in vision research, public-
private organizations, some 60 organizations, foundations and 
asked for their input because they are very important players 
in this entire field. We incorporated their ideas.
    Finally, just recently in January, the final plan was 
submitted to the Council, approved and hopefully we will have 
it published and more important, on the Web probably in the 
next two or three months.

                          high blood pressure

    Mr. Stokes. How about hypertension? Does that create 
additional problems in persons who have hypertension?
    Dr. Kupfer. You mean elevation of blood pressure?
    Mr. Stokes. Yes, sir.
    Dr. Kupfer. Yes. Hypertension, for instance, is an 
additional risk factor for the development of diabetic 
retinopathy, diabetic eye disease. That's been very well shown 
in several studies.
    It does not seem to play a role in glaucoma, although you 
might think it would but it doesn't. In other words, there is 
not a close association between high blood pressure and 
glaucoma.
    There is an interesting association of high blood pressure 
and high intra-ocular pressure but these people do not go on to 
get glaucoma, so there are some very interesting phenomena 
going on there.
    The other aspect is that when the individual has diabetic 
retinopathy and has high blood pressure, they probably do not 
respond as well to treatment with the laser as if we could get 
the blood pressure under control.
    So I think elevated blood pressure of course is a risk 
factor for many, many diseases and diabetic retinopathy is 
certainly one of them.
    Mr. Stokes. Thank you, Dr. Kupfer.
    Thank you, Mr. Chairman.
    Dr. Kupfer. Before I move on, I'd just like to say, Mr. 
Stokes, I've been coming to these hearings since 1970 and 
you've been here since 1971, so I really appreciate all the 
efforts you've put in on behalf of the National Institutes of 
Health.
    Mr. Stokes. Thank you very much, Dr. Kupfer.

               wine consumption and macular degeneration

    Mr. Porter. Dr. Kupfer, thank you for your testimony and 
answering our questions today. I have to ask you one final 
question. Both the New York Times and Time Magazine reported in 
January that as little as one glass of wine a month, red or 
white, may cut in half the risk of macular degeneration. Is 
there any truth to this statement?
    Dr. Kupfer. We'd all like to believe so. [Laughter.]
    I don't think the definitive study has been done yet, sir, 
but I think there is circumstantial evidence to suggest that 
this would be the case because some of the risk factors in 
macular degeneration such as elevated cholesterol might be 
ameliorated by a glass of wine.
    Mr. Porter. So while the research is going on, maybe a 
little protective glass of wine will help us all, right?
    Dr. Kupfer. Exactly. I think we should keep a baseline 
level.
    Mr. Porter. Dr. Kupfer, thank you. You've been wonderful at 
NEI all these years and we very much appreciate your fine 
testimony, your direct answers to our questions, and the 
wonderful job that you're doing there.
    Thank you very much.
    Dr. Kupfer. Thank you very much.
    Mr. Porter. The subcommittee will stand in recess until 
10:00 a.m. tomorrow.
    [The following questions were submitted to be answered for 
the record:]


[Pages 645 - 694--The official Committee record contains additional material here.]



                                          Thursday, March 12, 1998.

                NATIONAL HUMAN GENOME RESEARCH INSTITUTE

                               WITNESSES

DR. FRANCIS S. COLLINS, M.D., Ph.D., DIRECTOR
DR. ELKE JORDAN, Ph.D., DEPUTY DIRECTOR
CHARLES E. LEASURE, JR., ASSOCIATE DIRECTOR FOR MANAGEMENT
ERIN S. BURGESS, BUDGET OFFICER
DR. HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF 
    HEALTH AND HUMAN SERVICES

    Mr. Porter. The subcommittee will come to order.
    We continue our hearings on the National Institutes of 
Health and are pleased to welcome Dr. Francis Collins, the 
Director of the National Human Genome Research Institute. Dr. 
Collins, it's wonderful to see you and if you would introduce 
the people who are at the table and proceed with your 
statement, please.
    Dr. Collins. Thank you very much, Mr. Chairman.
    At the table we have Mr. Charles Leasure, who is our new 
Executive Officer. Mr. Leasure has moved over from the NIEHS to 
us in the last month. We are quite happy and they are quite 
sad.
    Mr. Porter. Yes, yesterday he was with them.
    Dr. Collins. One foot in both camps, but rapidly moving in 
our direction.
    Dr. Elke Jordan, the Deputy Director. Ms. Erin Burgess, 
who's our Budget Officer. Dr. Varmus, who you've been 
conversing with for several days already and Mr. Williams, from 
the Department.
    I want to say how pleased I am that Mrs. Miller is here to 
listen to the proceedings this morning.

                            opening remarks

    I appear before you at a particularly interesting time for 
the Human Genome Project. In its short history, we are now just 
about at the halfway mark. Two weeks from now, we will hit the 
halfway point in the 15-year effort to map and sequence all the 
human DNA.
    I would say there is much to celebrate in the first half of 
the Human Genome Project. All of the original goals which were 
set in 1990 and then revised in 1993 have been achieved on or 
ahead of schedule, despite a budget which has been 
substantially less than originally predicted.
    Having completed or exceeded the mapping goals which were 
expected to occupy this first half, we are now turning in a big 
way to large scale human DNA sequencing. But why does this 
matter? Many people had assumed that we'd have to wait until 
2005 when that sequence is in hand before the information would 
be of much use to medical research.
    That has certainly proved not to be the case. Beginning 
almost immediately after the Human Genome Project started, and 
now dramatically accelerating, we see a remarkable harvest of 
gene discoveries, diagnostic abilities, and the beginning 
emergence of ideas about rational genetic medicine therapies 
that we have hoped for for many years.
    Probably every institute director who appears before you in 
these two weeks will talk about advances in genetics which have 
arisen in some part because of the tools and technologies and 
resources the Human Genome Project has produced. Every 
pharmaceutical company now has a genomics division, recognizing 
the power of this for their future.

                      story of parkinson's disease

    But I want to put a human face on this effort for this 
morning's hearing and tell you about Thalia. Thalia is 65 years 
old and is of Greek origin. She has Parkinson's disease, a disease 
which is usually sporadic. But in her family, others have been affected 
as well. Her brother is affected and her mother died of Parkinson's 
disease.
    To her great distress, one of her five children, only in 
her mid-40s, is now showing early signs of the disease.
    Decades of research on Parkinson's disease have taught us 
something about the ``what'' of the disease, that there is 
something awry in certain neurons in a part of the brain which 
seem to be dying prematurely. But we know very little about the 
``why''. Thalia's family was part of a research study which was 
inspired by a workshop which came out of the National Institute 
of Neurological Disorders and Stroke interest in new 
opportunities in Parkinson's research. That interest in turn 
was somewhat inspired by the Congress, proposing that some new 
innovations would be appropriate.
    Out of that workshop came a project to investigate families 
like Thalia's, which has in the course of the last year led us 
to a very surprising and interesting result. If I could see the 
first poster, please, Meg.
    [The information follows:]


[Page 697--The official Committee record contains additional material here.]



                          finding the pd gene

    What was done with families, including hers, was to collect 
DNA samples and, using the genetic maps that the Human Genome 
Project has produced in the last seven and a half years, in the 
space of exactly nine days it was possible to map the gene to 
chromosome 4. This is an activity which used to take us two or 
three years, but can now be done in just days.
    Knowing where the gene was on chromosome 4, Drs. Mihael 
Polymeropoulos and Robert Nussbaum, who are with the 
institute's intramural program, then went to the worldwide web 
and looked at a physical map, determined that investigators at 
the Whitehead/MIT Genome Center had already mapped this 
interval, so they didn't have to map the region, it was already 
done. Then they went to a different map, a gene map, which was 
put up by the National Center for Biotechnology Information 
about a year and a half ago, to see what genes were already 
known to lie in this candidate interval.
    The genes are the arrows that you see there on the chart. 
It's important to know that only about 5 percent of the human 
genome is actually coding, actually part of genes, and the rest 
is of unknown significance. If you're looking for the cause of 
Parkinson's disease, you want to see where the genes are 
located. Having them already mapped there for you helps a lot.
    Dr. Polymeropoulos and Dr. Nussbaum identified an 
interesting candidate in that interval, simply from a computer 
search, and then set about sequencing that gene in the affected 
individuals. On the left what you can see is the gene in the 
healthy situation, there is a G in a particular position, 
whereas, all the affected individuals with Parkinson's disease 
had an A.
    This is a gene called alpha-synuclein, about which very 
little had been known prior to this time. By most people's 
recognition, this represents the most major advance in 
Parkinson's disease in 30 years. Here is an answer to ``why'', 
at least in these families. That very subtle change, one single 
letter out of 3 billion, is capable of causing this terrible 
disease in this circumstance.
    Pharmaceutical companies are intensely interested now in 
this molecule called alpha-synuclein. It appears that while 
having it mutated in this way is a very uncommon cause of 
Parkinson's disease, that the same protein participates in the 
common varieties of Parkinson's. So here we have a pathway 
that's ripe for exploration. That is a very exciting 
development.
    Now, you see that set of arrows in the gene map. At the 
time these investigators used this gene map, about 20 percent 
of the genes had been mapped. I'm happy to tell you something 
that's not yet published, but will be coming out in the very 
near future, is that a new version of the gene map will double 
the number of human genes that have been placed into precise 
locations on chromosomes, from 16,000 a year and a half ago to 
30,000 in the next month or so.
    [The information follows:]


[Page 699--The official Committee record contains additional material here.]



    This means that close to half of the estimated 70,000 or 
80,000 that exist in the genome will at that point be of known 
location. And that will greatly aid this process of hunting 
down disease genes for conditions like Parkinson's disease.

                             dna sequencing

    Of the original goals for the Human Genome Project, the one 
that still mostly lies ahead is getting the DNA sequence 
itself. Three billion base pairs is a lot of information. We 
had expected to be starting about now on that part, figuring 
that you have to walk before you can run, you have to build 
maps and develop technologies before you can do that kind of 
high through put sequencing.
    We have been practicing very productively on other model 
organisms. Yeast is finished, the bacterial organism E. coli 
was finished in this last year, a very useful model. The round 
worm C. elegans will be completed before this year is over, 
also a very important milestone.
    Human sequencing of those 3 billion base pairs is already 
being piloted. And we are at the point now of having done a 
hundred million base pairs of human sequencing. While we're 
sitting here in this hearing today, 64,000 base pairs will be 
completed. We need to increase that through put by about a 
factor of six to get the job done by 2005.
    [The information follows:]


[Page 701--The official Committee record contains additional material here.]



    This next diagram shows you that in fact the effort is 
vigorously underway. This is a diagram of human chromosomes. 
Shown in black on each one are regions ofchromosomes where 
sequencing has been begun. It's not completed in these regions since 
only about 3 percent of the total has been completed.
    But for each area that you see blackened in there is an 
active effort underway in a sequencing center somewhere in the 
world to get that part done. And it seems very likely, Mr. 
Porter, that by the end of this calendar year, the first human 
chromosome, chromosome 22, will be completed. That will be a 
very exciting milestone.
    Sequencing needs to be done right. We have put a lot of 
effort in the last couple of years in these pilot projects to 
establishing standards. We are insisting on accuracy of no more 
than one error in 10,000 base pairs. In a recent exercise where 
we had centers check on each other, we are now achieving that 
accuracy target. We're insisting the sequence be assembled into 
large blocks, not little islands here and there, and it has to 
be affordable. Right now, sequencing costs about 40 to 50 cents 
a base pair, and we need to continue to drive that down.
    Perhaps most importantly, it needs to be accessible. If the 
scientific community can't use it, it doesn't exist as far as 
we're concerned. So we have instituted a principle where 
sequencing information is put into a public data base within 24 
hours of the time a laboratory has determined it. That is now 
the international standard.

                     understanding complex diseases

    All of this has already led to a great deal of advance in 
the medical arena. I want to tell you about a new goal of the 
Human Genome Project which has arisen since last we met and 
which I think has profound significance for understanding the 
genetic basis of common illnesses.
    We have done a pretty good job in finding genes like BRCA-1 
or some of the strongly hereditary colon cancer syndrome genes 
using this process we call positional cloning. But what of the 
common diseases? What about diabetes, which you talked about 
yesterday? What about finding the rest of the Alzheimer's 
genes? What about hypertension, the major mental illnesses, 
conditions that don't follow simple inheritance rules? How are 
we going to figure those out?
    Most scientists believe that those conditions come about 
because of an unfortunate combination of relatively common 
variants, variants which may be benign most of the time, but in 
a certain circumstance may not be. What we propose to do, and 
this is an initiative which is now supported by NHGRI and 17 
other institutes of NIH, is to build the catalog of human 
variation. Basically we will look at as many of those 80,000 
genes as we can, over the course of the next three years, and 
characterize the different spellings that occur at a reasonable 
frequency. Within that catalog will be the answers to the 
genetics of common disease.
    The next poster shows you how this might work.
    [The information follows:]


[Page 703--The official Committee record contains additional material here.]



    I'm drawing as labels on particular people here, variants 
that would occur in a particular gene. Look at gene A, for 
instance. Now, here's a circumstance where 10 people who are 
affected with the disease--those are the 10 purple and green 
people on the top--have a certain frequency of purple or green 
versions of this gene. And the unaffected individuals have 
about the same frequency.
    So that would be a negative result. In that circumstance, 
there's no indication that gene A is involved in the disease 
being studied.
    But look at gene B. Here's a circumstance where when you 
look at that gene, there's a very different ratio of orange to 
blue, with the affected people primarily having the orange 
version, and the unaffecteds primarily having the blue, 
implying that this gene may very well be involved in this 
disease.
    This kind of an analysis, which we can only do once we 
build this catalog, should short-circuit what would otherwise 
take many years and many millions of dollars to try to 
understand the genetics of common diseases like diabetes. I 
think it is an extremely exciting opportunity.
    It's come about in part because of technologies like the 
one I have in my hand here, which is a DNA chip. To do this 
kind of catalog generation and then to be able to use the 
catalog, you need technologies that will allow you to look at 
very large amounts of DNA information in a short period of 
time. This chip is made by Affymetrix, a company which was 
founded, I'm happy to say, with support from an NIH grant about 
seven years ago, and which was featured this morning on NPR. 
This is the kind of technology that we've been waiting for.
    This kind of analysis can now be applied to a wide variety 
of disorders, including those that affect certain populations. 
We have a new initiative with Howard University, a 
collaborative effort to try to study why it is that diabetes 
and prostate cancer are particularly common in African-
Americans. I'm very excited about that partnership between our 
institutions, because I think minority genetic initiatives have 
been relatively few and far between. There has been a lot of 
concern about exactly how those initiatives would be organized 
and we're quite pleased to see this coming together.

                 ethical, legal and social implications

    Coming back to Thalia, the woman with Parkinson's disease 
at 65: she is, of course, excited about the research, glad that 
somebody's working on her problem, hoping that it will help 
her, and if not her, her children, and worried about the other 
four children who are not yet symptomatic. We are now in the 
situation, since we know precisely what's wrong in that family, 
to offer her children the chance to find out whether they have 
inherited this alteration or not. Such a protocol has recently 
gotten underway.
    Her children, upon hearing about this, all expressed an 
interest in being tested. But after hearing the risks to them 
of having this information potentially misused, most have 
pretty much decided that they don't want to know. The final 
poster again brings me back to an issue which we discuss every 
year, where I'm happy to say there also has been substantial 
progress, and where the motivation to continue that effort is 
higher than ever. Because more and more conditions are becoming 
possible to test for.
    [The information follows:]


[Page 706--The official Committee record contains additional material here.]



    As you can see from this cartoon here, I believe there are 
two things that we have to do. We have to build two pillars of 
a building if we expect the public to feel reassured about the 
ways that genetic information will be used to help them and not 
hurt them. One is the ``fair use'' pillar, to prevent genetic 
discrimination in health insurance, in the workplace, and in 
other places as well. And the other is the privacy pillar.
    And if we don't build both of those, I don't think people 
will be reassured that it's safe for them to find out this 
information, which many of them desperately want. We already 
know that this is having a dampening effect on research. People 
are afraid to find out this information.
    With the passage of HIPAA, we have achieved a major step 
forward for health insurance, since that legislation does say 
if you're in a group plan, this information can't be used 
against you. But we still have loopholes in the individual 
market which need to be filled.
    I was very gratified last July by the President making a 
major statement about the importance of plugging those 
loopholes. The Vice President in January said the same thing 
about employment discrimination. We have to get this job done. 
Thomas Jefferson said, ``Our Laws and institutions must keep 
progress with advances of the human mind. And we clearly need 
to do that on both fronts.
    Our ELSI program has provided wonderful scholarship on this 
issue. We know what needs to be done. In a partnership between 
those of us on this side of the table and those of you on that 
side, I think we need to push this over the finish line, so 
that people can feel safe in finding out this critical 
information.
    In summary, Mr. Chairman, in just two weeks we will stand 
at the halfway mark of this 15-year project. Many people have 
called this the most important scientific undertaking of our 
time, or perhaps of all time--perhaps surpassing going to the 
moon or splitting the atom, an investigation into ourselves.
    As Director of NHGRI, I am very gratified at the stunning 
progress of our investigators, which allows me to come before 
you once again this year and indicate that we are ahead of 
schedule and under budget, words which I know are often welcome 
in this room. Our goals for the coming years are truly 
ambitious. But I believe they are achievable.
    The full benefits of this effort for transforming the 
practice of medicine still largely lie ahead, but not very far 
ahead. The research engine that will produce those 
breakthroughs is revved up and is roaring forward. We are 
gratified with the President's budget this year of 
$236,996,000, an increase of 10.4 percent.
    I'd be happy to answer your questions.
    [The prepared statement follows:]


[Pages 708 - 713--The official Committee record contains additional material here.]



                     Congressional Role in Research

    Mr. Porter. Dr. Collins, thank you very much for your 
excellent statement.
    You mentioned Congress' role in looking at Parkinson's 
disease. I want to tell you that I think a great deal of the 
pressure from within Congress came from members of Congress who 
have suffered or are suffering the disease, beginning with Mo 
Udall and continuing with Joe Skeen and Joe McDade. Outside 
pressure comes within my knowledge, most strongly from Morton 
Kondracke whose wife suffers from Parkinson's disease.
    Dr. Collins. Yes, I understand.
    Mr. Porter. It shows that the feelings of people can be 
reflected into initiatives and ultimately work out into policy 
and then into results. Sometimes the people in this country 
don't know how much power they have to change things and to 
direct things. The pressure comes, I imagine each one of them 
would tell you, from the people that have come to them because 
they knew they had the disease or in Morton's case, his wife 
had the disease and pressed him on it, or them on it.
    Dr. Varmus. Mr. Porter, could I comment just briefly on 
this topic?
    Mr. Porter. Yes.
    Dr. Varmus. This is a favorite example of mine with respect 
to advocacy and its good effects. Because what brought about 
the consequences that Dr. Collins justdescribed is not money, 
per se, but instead, a response from NIH that include a workshop 
organized by Dr. Zach Hall, who was then Director of NINDS, that put 
into the same room geneticists and physicians taking care of patients 
with Parkinson's disease, and allowed the collaborative work that 
produced the genetic advances you've heard described.
    Now of course, there is money being poured into the follow-
up. That to my mind is the right way in which to move the field 
forward.
    Dr. Collins. The consequence of that follow-up is already 
apparent. This month's issue of Nature Genetics reports the 
second Parkinson's gene mapped to chromosome 2. So we're on a 
roll.

                       dna sequencing on schedule

    Mr. Porter. I read a blurb, it wasn't very much, but I 
thought it had said that the Human Genome Project is only 5 
percent complete, and that it's way behind schedule. I know 
that not to be the case, didn't I read this somewhere recently?
    Dr. Collins. The New York Times had a science piece on 
Tuesday, a long article about the Human Genome Project. I'd 
like to address that.
    Mr. Porter. Please.
    Dr. Collins. It is true when it comes to the sequencing 
part of the project that we have done only about 3 percent of 
the total sequence. So in a somewhat simplistic view, which is 
I think the source of that statement, you might say, well, come 
on here, you're halfway through 15 years and you've only done 3 
percent of the work.
    Well, that's not the correct analysis, because the original 
plan was to have less than 1 percent of the sequence done at 
this point. The first half of the project was to be devoted, 
and has been, to the development of genetic maps and physical 
maps. The attention to sequencing model organisms, which are 
smaller and more gene-rich, and the improvement of the 
technology, to bring down the cost of sequencing was done 
first, so that it would be feasible to do the human at an 
affordable price.
    So if you look at the milestones that were set for this 
project in the initial five year plan in 1990, and then revised 
in 1993, in every instance we have exceeded those, including 
the sequencing goals.
    The prediction was that at the end of 1998, we would be 
sequencing at a rate of about 50 million base pairs per year. 
We're already at twice that. So once you step beyond the 
superficial level about what's been accomplished and how much 
time has gone by, it's clear that in fact the goals are being 
met very handily.
    Now, is it going to be a stretch to get the sequence done 
by 2005? You bet it is. I don't think this Congress would be 
enthusiastic about a project that set such limited goals that 
everybody said, well, of course, that's easy. We are going to 
have to work very hard. Our genome sequencing centers are ready 
for the challenge. We're going to have to bring the cost down 
about another factor of two over the next seven or eight years 
to be able to do this for the budget that's available.
    But I'm quite confident with the talent that's being 
applied to this and given the track record in the past that we 
will achieve this goal. Can I tell you that 100 percent for 
sure? Again, if I could tell you that for sure, I think you'd 
tell me, Dr. Collins, you don't have very ambitious goals.

                         cost of dna sequencing

    Mr. Porter. I don't think we'd tell you that.
    Let's talk about cost for a minute. You said it was 
something like 50 cents per sequence.
    Dr. Collins. Per base.
    Mr. Porter. Yes, per base. Looking ahead, and looking back, 
do you have an idea of the total cost of the project, and can 
you relate that to the estimates that were originally made for 
it? And give us some understanding of the overall cost 
involved.
    Dr. Collins. Sure. The original prediction was that the 
Human Genome Project would cost $200 million a year for 15 
years. So adding that up, that's a total of $3 billion in 1990 
dollar equivalents.
    Up to the present time, between our effort and the 
Department of Energy's effort, which as you know is the co-
supporter in the U.S. of the Human Genome Project, and spends 
about half what NIH does, a total of $1.5 billion in 1990 
dollars has been spent in nine years. I'm including the 1999 
budget in that.
    You would have predicted at that point, if we were spending 
at the original plan, that we would be at $1.8 billion. 
Instead, it's at $1.5 billion. So we are significantly under 
the predicted budget.
    I think it is a little hard to predict how things will go 
in the last six or seven years. I would hope the Human Genome 
Project will be judged by the total budget that was required to 
get the job done. If it's possible to get the job done earlier, 
by having the budget go up faster, well, that would be all 
right. But I think it's fair to say, when you look at the 
predictions, in most instances the tasks that have needed to be 
done, have been done for somewhat less than expected.
    Now, it's a very critical question, what happens to the 
cost. The difference between 50 cents a base and 49 cents a 
base is $30 million worth of cost. That's how the numbers work 
out. So we are critically interested in driving that cost down 
in every way we know.
    We have instituted a new method of bringing together our 
genome sequencing centers, which will come into play in about a 
year and a half. They will form a cooperative agreement to 
share their technology ideas and to figure out who is saving 
money in this step and who's saving money in that step, and 
together let's see if we can move those costs downward even 
more quickly.
    Mr. Porter. So it might cost us as much as $3 billion?
    Dr. Collins. It might. At the current rate, you could say 
it's going to come in a little under that. But we have seven or 
eight years to----
    Mr. Porter. Four B-2 bombers to map the entire human 
genome. [Laughter.]
    Dr. Collins. You could look at it that way.
    Mr. Porter. Well, I think it's probably going to go down, 
as you've said, as the best money we've ever spent. I'm 
extremely pleased to hear that you are continuing under budget 
and ahead of schedule and that great progress is being made.
    I have to admit that I saw the front page blurb in the New 
York Times and thought, there's something wrong with this, and 
didn't read the rest of it, so I'm glad you could explain that 
to us.
    Dr. Collins. I appreciate the question.

                       genetic testing--why do it

    Mr. Porter. Dr. Collins, we know that genetic testing isn't 
perfect. For example, cystic fibrosis can be caused bymore than 
600 different mutations in a particular gene. Because it's too 
expensive to test for all of them, labs usually test for the most 
common 70. So a negative genetic test doesn't necessarily mean you 
don't have a cystic fibrosis mutation.
    Dr. Collins. Correct.
    Mr. Porter. In another example, studies have shown that 
people with any genetic makeup can get Alzheimer's. They don't 
have to carry the gene that has been identified with the 
disease. So why should we spend billions of dollars to identify 
gene mutations, and why should anyone be tested?
    Dr. Collins. It's an appropriate question. Mutation 
testing, genetic testing, like most forms of diagnostic 
testing, is not perfect. False negatives and false positives 
will occur, not because of laboratory errors, but because 
disease is heterogenous. That's not a surprise. We've known 
that for most diseases for a long time.
    Cystic fibrosis is an interesting case in point. If you are 
tested to see if you're a CF carrier, and you test negative and 
if you're of northern European background, there is still about 
1 chance in 250 that you might be a carrier because the test 
misses about 10 percent of the changes.
    Nonetheless, many people find that information quite 
useful. It is a challenge to offer that information in a way 
that truly explains the limitations of the test. That challenge 
is going to be one of the major issues for medicine in the 
coming decades. We are likely to see, five or ten years from 
now, the opportunity for any of us who wish to know our genetic 
risks of illness, to have testing done for perhaps 15, 20, or 
30 different conditions.
    Most of those tests will move your risk up or down. But 
they will not be all or none. It will be necessary to convey 
that information about risk in a statistically sophisticated 
way, so that people don't get the wrong idea about what this 
information tells you.
    It's still incredibly useful. If I knew that I was at 
three-fold increased risk for colon cancer, I'd be a lot more 
likely to go in and get that screening every year to see if 
I've developed a polyp that needs to be removed. For many 
circumstances, if we could individualize our preventive 
medicine efforts based on genetic testing, we could do a much 
better job of keeping people healthy and saving costs. That 
doesn't mean the test has to be perfect, it means it has to 
provide useful information.
    Mr. Porter. I'll ask one more question. You're quoted as 
saying all of us are walking around with 5 to 50 flawed genes 
that place us at risk for some illness. If that's the case, how 
does an individual know which flaws to be tested for?
    Dr. Collins. Another good question. At the present time, 
very few conditions are in the circumstance where you would 
propose to offer testing to somebody without a family history. 
For cystic fibrosis, relatively soon testing will be offered to 
all couples who are contemplating a pregnancy, because it's 
such a common alteration. Sickle cell testing is now offered to 
African-American couples in many situations for the same 
reasons.
    But in most circumstances right now, being tested for 
susceptibility is preceded by the recognition that that person 
has a particular vulnerability because of their family history. 
Women are not tested in general for BRCA 1 alterations unless 
they have a family history, although some are suggesting that 
testing might be appropriate for Ashkenazi Jewish individuals. 
That proposal is still quite controversial, and I think most of 
us think that would be premature.
    So at the present time, testing, if it's to be offered, 
depends upon the individual circumstances and particularly 
their family history. That may change over time. In another 15 
or 20 years, when tests are more easily available and better 
understood in terms of their value, it is quite possible that a 
panel of tests would be offered to virtually anybody who's 
interested in having the information. Let me hasten to say that 
nobody should have such a test without deciding they want to 
know.
    Mr. Porter. Thank you, Dr. Collins.
    Mr. Bonilla.

                          food genome projects

    Mr. Bonilla. Good morning, Dr. Collins. The work you're 
doing is fascinating. I can recall when I visited the NIH we 
got a nice briefing at your facility, and were very impressed.
    One thing that I'd like to ask is, I'm also on the 
Agriculture Subcommittee on Appropriations. Recently their 
research, education and economics division testified about the 
efforts there researching food and animal genes.
    My question is, do other agencies such as the Department of 
Agriculture play a role in your Institute's work and in what 
you're doing? For instance, does your Institute share 
technology with USDA's food genome strategy?
    Dr. Collins. Yes. In fact, it's a very timely question. You 
may know that about a year ago, there was a great deal of 
enthusiasm, inspired by the Corn Grower's Association, to begin 
an initiative on the genome of corn.
    That is not the first interest in plants, however. Plants 
have the same DNA animals do, and already, for the past two or 
three years, there's been a significant effort underway, 
primarily led by the National Science Foundation, to determine 
the sequence of Arabidopsis, which is a simple plant with a 
manageable genome size. That research is going quite well. A 
number of our grantees are also working on that project. And we 
have contributed a lot of technology to that same effort.
    Out of this interest in plant genomes, a working group was 
formed last year and Dr. Elke Jordan of the National Human 
Genome Research Institute has been part of that group, to try 
to plan a plant genome initiative. A report has now come 
forward from that group which suggests that some $400 million, 
over the course of the next five years, ought to be identified 
to support plant genome analysis. This would include finishing 
Arabidopsis and putting a lot more effort into rice, a very 
important model with a relatively modest-sized genome compared 
to some of the other cereals.
    That effort will also collect mapping information and gene 
sequence information from other plants of agricultural value, 
particularly corn and wheat. USDA has been intimately involved 
in that working group, and will be very much involved in the 
implementation of this plant genome initiative, although the 
original allocation of funds has been primarily to the NSF.
    So I think there is a lot of interaction. NIH's role in 
this will be to contribute technology as vigorously as we can, 
because the methods that we use to map and sequence a plant 
genome are the same as what you would use to map a mouse or a 
human.

             similarity between humans, animals and plants

    Mr. Bonilla. This is fascinating to a layperson like 
myself, I'm not a doctor and I don't have a health background, 
health care background, to think that there canbe a link 
between plants and animals. I think the average person would be shocked 
to hear that there is a link and that they can be helpful to one 
another.
    Dr. Collins. It is remarkable.
    Mr. Bonilla. Do you find that when you talk about it?
    Dr. Collins. Yes. I think most people who haven't been 
exposed to this concept are surprised to hear that the same 
information molecule, DNA, with the same chemical structure, is 
at the root of the information content of all living organisms, 
from bacteria to plants to animals, and that the methods that 
we use to try to read that blueprint are generalizable.

                       collaborations within nih

    Mr. Bonilla. You learn something every day.
    In your testimony, Dr. Collins, you discuss the tremendous 
progress you've made in identifying the genetic components in 
some forms of cancer. Along the same line as my previous 
question, please tell us about the coordination between various 
NIH institutes and the genome research project. For example, 
what role did the National Cancer Institute plan in these 
discoveries regarding the genetics of cancer?
    Dr. Collins. I think that's a very appropriate question, 
and given the current climate at the NIH, the number of 
collaborations between institutes has grown quite large. Cancer 
research is a very strong example of NIH collaborations.
    As Dr. Varmus said in his testimony day before yesterday, 
cancer is at a particularly exciting point, where uncovering 
the genes involved in this disease has been quite successful. 
We're now trying to move into the phase of using that genetic 
information to characterize at the most detailed level the 
difference between a cancer cell and a normal cell.
    The collaborations between the National Human Genome 
Research Institute and the National Cancer Institute have 
occurred on many levels. In our intramural program, for 
instance, we have a Laboratory of Cancer Genetics which 
interacts heavily with the NCI's intramural program in a 
variety of methods for genetic analysis. One method, 
development of expression arrays, was featured on this 
morning's NPR program. Dr. Varmus showed an example on Tuesday 
in a poster. That's been a very tight collaborative effort 
between the two institutes.
    In the extramural program, our ELSI program, which looks at 
ethical, legal and social issues, has been very interested in 
the question about genetic testing, and who wants to get tested 
and what happens after you've had that result. Out of that 
interest has come a Cancer Genetic Studies Consortium, which is 
co-funded by the NCI, ourselves, and of the National Institute 
of Nursing Research.
    That Cancer Genetic Studies Consortium is the precursor for 
the National Cancer Genetics Network, which is about to get 
underway, and which the NCI has set up with a great deal of 
cross collaboration and coordination with NHGRI. So I think, 
and Dr. Klausner would probably echo this same statement, that 
this is a very appropriate area for a lot of cross-talk. I 
think it's been quite useful for both of our institutes to work 
together in this way.
    Dr. Varmus. If I could just add one other example, Mr. 
Bonilla. You'll be hearing in more detail about the Cancer 
Genome Anatomy Project, which represents a coalition among the 
NCI, the National Human Genome Research Institute, and the 
Library of Medicine, which supplies the so-called bioinfomatics 
computer structure that absorbs the information and analyzes 
it, compares the genes discovered in cancer to genes that are 
isolated from other organisms, like the worm and the yeast. 
That three-way partnership has been very instrumental in 
expanding the number of genes available for mapping this year.
    Dr. Collins. That's another very good example.

                        predisposition to cancer

    Mr. Bonilla. Well, what's the difference, when a person is 
predisposed to getting a certain kind of cancer, for example, 
because of their genetic makeup, because there's a family 
history and, let's say for example, a brain tumor or some other 
form of cancer that's generally not caused by bad habits like 
smoking or laying out in the sun too often, where you get skin 
cancer, or get lung cancer from smoking, is there a genetic 
predisposal to getting a skin cancer or lung cancer already in 
situations where people choose to take on those bad habits?
    Dr. Collins. Yes, there does appear to be.
    Mr. Bonilla. Does that mean, for example, that a person who 
does have the bad habits of lying in the sun too much or 
smoking too much could also have a predisposal to not getting 
cancer because of their genetic makeup?
    Dr. Collins. That's correct, too. I think it's fair to 
think of all diseases, and cancer is a particular example, as 
an interaction between genetic susceptibility and environmental 
influences. Lots of people smoke two packs of cigarettes a day 
for 40 years, yet don't get lung cancer and others do. It's 
been carefully looked at, and it appears that there are 
familial factors involved in that susceptibility. There is 
recent evidence, in fact, of a couple of specific genes that 
are involved in detoxifying the carcinogens in smoke, which may 
play a role in that susceptibility.
    So if you have a particularly vigorous detoxifying system, 
you may get away with exposure to tobacco smoke, whereas 
someone else with a less extreme exposure may develop cancer 
just the same. This is a very fertile area for investigation, 
and I'm glad you brought it up. Because I think sometimes 
people make the assumption that if you're interested in 
genetics, you're saying environment's not important.
    That is not the case at all. Another institute we have a 
lot of interaction with is NIEHS. Clearly, where we're going to 
really get the answers to diseases, is figuring out which 
people are particularly vulnerable to which environment 
factors, on the basis of their genetic susceptibilities. With a 
few systems, like tobacco smoke, for instance, we're beginning 
to make inroads into that.
    Mr. Bonilla. Thank you so much again for appearing here 
this morning, and keep up the great work.
    Dr. Collins. Thank you, Congressman.
    Mr. Porter. The chair would advise members we're operating 
under the 10 minute rule. You actually have a couple more 
minutes.
    Mr. Bonilla. I'm finished, thank you.
    Mr. Porter. Mrs. Lowey.
    Mrs. Lowey. Thank you, Mr. Chairman.
    I want to join my colleagues in congratulating you on the 
extraordinary work that you've been doing and the progress that 
you are making. It's certainly a scientific feat of enormous 
importance, and I also want to thank you for your tremendous 
leadership in addressing the serious social and ethical issues 
that arise from this research.
    In fact, you've presided over several task forces dealing 
with discrimination, both insurance and employment-
relatedgenetic discrimination. These task forces have reported out 
meaningful recommendations that both Louise Slaughter and I have used 
as the basis for legislation. Your involvement in the ELSI working 
groups and related activities is critical. I personally appreciate it, 
and I wanted to just thank you.
    Dr. Collins. Thank you.

                         risk of breast cancer

    Mrs. Lowey. First of all, can you please update us on the 
status of research regarding the BRCA1 and BRCA2 breast cancer 
genes? The genes, as we know them, are common in Jewish women 
of European descent, and at present, mean a greatly increased 
risk of developing breast cancer.
    Can you tell us what we have learned about these genes 
since our hearing last year? Are there any available results 
from the large Washington area study of Jewish families? What 
are the questions that we need to answer next?
    Dr. Collins. It's obviously a very important area, and one 
which is now in the midst of a frenzy of activity. Researchers 
are trying to get the answers to some of these questions, and 
appropriately so.
    Just by way of defining terms, BRCA1 and BRCA2 are two 
genes, which if misspelled, carry a high risk of breast and 
ovarian cancer. The original studies were based upon families 
that had many cases of breast and ovarian cancer already 
occurring and that's how they came to the attention of 
researchers.
    The estimates were that a woman with a BRCA1 or a BRCA2 
mutation had about an 80 to 90 percent chance of breast cancer, 
and perhaps a 50 percent chance of ovarian cancer. Very high 
numbers, indeed.
    The Washington study, which you referred to and which was 
published since we met here last, looked at a much larger group 
of individuals, over 5,000 volunteers, who came in to be 
studied. They gave a blood sample and they gave a very detailed 
medical history of themselves and their family members.
    The individuals understood in that study that they would 
not receive specific results about themselves. That was part of 
the informed consent procedure, in part because of the 
uncertainty about what to do in this circumstance if they had 
the misspelling. Other studies are now available that will 
allow people who want to know to find out the results. But in 
this particular study, these volunteers were providing this 
information, but they understood they would not get results 
back.
    From that study, it was confirmed that about 1 in 40 Jewish 
Ashkenazi women have, one of three possible misspellings in the 
BRCA1 or BRCA2 genes. This is a surprisingly high number, given 
that the estimates in other populations had previously been 
something like 1 in 500.
    But I think the answer people were particularly looking for 
is, what was the consequence to people in this group. The 
lifelong risk of breast cancer in that study came out at about 
55 percent. This is still way too high and dramatically higher 
than the lifetime risk of 12 percent which all women face. But 
not the 80 to 90 percent that had previously been estimated.
    The risk of ovarian cancer came out at about 15 percent, 
again, substantially lower than previous predictions, but still 
much higher than the 1 or 2 percent baseline in the entire 
population.
    Men, it turns out, who have one of these three alterations, 
faced an increased risk of prostate cancer. This had also been 
suspected previously, but this study seemed to confirm that 
rather strongly. That risk is not nearly as dramatic, however, 
as the ovarian and breast cancer risk in women.
    We have learned as a consequence of that study, that yes, 
these particular alterations are of great significance. The 
actual absolute risk is perhaps not as high, at least in this 
group of people, most of whom didn't have dramatic family 
histories, as we had previously thought.
    It still leaves us, though, in a quandary about how to use 
this information clinically. Many women who have a strong 
family history have chosen to find if they have one of these 
three alterations, and testing is available through either 
research protocols, which many of us believe is the ideal way 
at the present time to get this information, or through a non-
research based clinical testing.
    There was a very compelling story about this in the New 
Yorker, about a month ago, by Jerry Groopman, which I would 
recommend to anybody who wants to look at the human side of 
going through this testing experience. It's quite powerful.
    The dilemma, of course, which we still don't have a good 
answer to, is what should a woman do who has one of these 
alterations. Is going through regular mammography sufficient to 
pick up a breast cancer while it's still small enough to cure? 
Or should more drastic measures, like prophylactic mastectomy 
and removal of the ovaries be strongly considered also?
    The NCI is moving swiftly to try to get answers to those 
questions. But those are complicated studies to do. At the 
present time, we still don't have good guidance to know what to 
tell women in that circumstance. I wish we did.
    Finally, in the basic science area, we are learning a whole 
lot of information about what these genes are normally doing. 
They're not there just to get misspelled and cause cancer. 
They're doing something important.
    It appears that both BRCA1 and BRCA2 are involved in a 
similar pathway, a process of protecting DNA against damage. 
They're part of the early warning system that says, ``Something 
has happened here to DNA, we need to fix this, or if we can't 
fix it, we need this cell to die before something like a cancer 
cell arises.''
    BRCA1 and BRCA2, are involved in this pathway, although 
their exact roles are not entirely clear, and which other 
proteins in the cell they hold hands with is not yet worked 
out. But that research is going to shed light on a whole host 
of important issues, including, probably, the effects of 
radiation exposure.
    Mrs. Lowey. Just to pursue that, women are living longer. 
And if this gene has been identified as damaged, and the 1 in 
40, as you said, has this gene, is there any indication of at 
what age the woman would be at risk for breast cancer?
    Dr. Collins. Yes. The Washington study also provided the 
best data yet to look at that curve of the age of onset. It is 
clear that the breast cancers that do arise in this 
circumstance tend to occur somewhat earlier than breast cancer 
does in general.
    As you know, most breast cancer in the general population 
occurs post-menopausally. And yet, in women with BRCA1 or BRCA2 
mutations, the risk of breast cancer is already significantly 
elevated in the 30s and 40s. So it comes up somewhat more 
steeply than it does in the normal circumstance.
    Again, we now have that information. That's good. Wedidn't 
have it before. But it still leaves a woman in that circumstance in a 
dilemma about what to do.

                    genetic counseling and education

    Mrs. Lowey. And are you satisfied with the work you've been 
doing that the counseling and advice that is being given to 
women is adequate in the situations where the gene has been 
identified?
    Dr. Collins. I think most cancer centers that are staffed 
by qualified genetic counselors have been doing a good job of 
informing women. It's very challenging. We have a research 
protocol at NHGRI that is going through this. It takes a great 
deal of time and attention and sensitivity to help people think 
these issues through before being tested.
    I worry that as this becomes more commonplace, and the 
counseling is done by people who have had less training, that 
some of that sensitivity may not be as carefully sustained. 
This is a serious issue for the future, for genetic medicine of 
all sorts, not just for breast cancer testing. It will also 
apply to testing for diabetes, hypertension, or whatever the 
disease is that somebody's interested in.
    We have to figure out how to move genetic medicine into the 
mainstream, how to have every primary care physician and nurse 
able to handle the kinds of questions that people will ask 
about this area. We have catalyzed a new National Coalition for 
Health Professional Education in Genetics, jointly with the 
American Medical Association and the American Nurses 
Association. This group will take this challenge on and try to 
achieve the kind of literacy about genetics amongst health care 
professionals. We need to move swiftly to do that.

           disseminating information to health professionals

    Mrs. Lowey. I'm aware that the medical profession is 
beginning to disseminate information to their members about the 
ethical and social issues related to genetic testing, such as 
the recommendations made by your ELSI task force. Do you feel 
that there is sufficient work and sufficient interaction, as 
you mentioned, with the medical groups around these issues?
    Dr. Collins. I think it could be better. I think there's a 
great deal of interest and quite a vigorous discussion is going 
on in many instances. I will spend this weekend at a meeting 
organized by the American Medical Association for their members 
on genetics for the practicing physician. This meeting which 
has attracted several hundred primary care physicians who are 
interested in being leaders on this topic, many of them being 
presidents of their local medical societies.
    The American Medical Association has identified this as 
their number one priority for educating their members, 
comparing this challenge to the advances in antibiotics that 
occurred several decades ago. They see this as a very urgent 
matter, and they are interested in participating in a very 
constructive way.
    I see that as a good sign. It's one thing if the 
geneticists are up there saying, you guys need to learn about 
this. It's another thing if the front line physicians are 
themselves saying, tell us about this, we're ready to hear it.
    Mrs. Lowey. I think my time has expired, thank you.
    Mr. Porter. Thank you, Mrs. Lowey.
    I will tell Mr. Stokes that there's a vote, so he's not 
going to have time for the full 10 minutes. We will save the 
time when we recess for the votes and come back.

                          year 2000 compliant

    Mr. Stokes. What steps of your technology based research 
have you taken to ensure that your operations are year 2000 
compliant?
    Dr. Collins. Perhaps you could define the term year 2000 
compliant. You're talking about the computer problem?
    Mr. Stokes. The computer problem.
    Dr. Collins. Okay, now I've got you. We, as many other 
parts of the NIH, are concerned about this issue. There is a 
master plan already well underway to make sure that when the 
year 2000 comes, we don't find ourselves with a particularly 
difficult crunch.
    I think actually this will have little affect on the Human 
Genome Project. Our computer operations are pretty new, for the 
most part. We are not, like the Social Security Administration, 
working with programs that were written 30 years ago. We didn't 
even know we were going to exist 30 years ago.
    In fact, the data bases upon which the Human Genome Project 
depend are all, for the most part, of construction within the 
last five or six years. And while I don't think one ought to be 
dismissive of this as a serious issue, the information I have 
at the present time is that the few areas that need attention 
can be dealt with relatively straightforwardly, more so perhaps 
that in other parts of the Government.

                    howard university collaboration

    Mr. Stokes. I understand that you have a collaborative 
project with one of the Historically Black Colleges and 
Universities, Howard University. Can you tell us what you're 
studying there and what you anticipate to gain from it?
    Dr. Collins. Yes, I appreciate the question. And by the 
way, Mr. Stokes, like others who have come here to this table, 
I would certainly like to thank you for raising the visibility 
of issues about disparities between minority and majority 
health care.
    That is a major factor in this new initiative with Howard 
University about which I'm quite excited, and which I'm 
spending a good deal of my own personal time on. I met with 
President Swygert of Howard University the day before 
yesterday. We talked about this initiative, which has now been 
underway for a couple of years. We both concluded that this is 
a truly exciting opportunity for joining together an NIH 
institute and an institution, Howard University, with a great 
deal of credibility and capability which is hungry for a 
presence in genetics and genomics as applied to minority 
illnesses.
    We already have two very ambitious pilot projects underway. 
One is an effort to study diabetes, obviously a disorder which 
is disproportionately present in African-Americans. We are 
collecting affected siblings with diabetes in Ghana and 
Nigeria. This is a very challenging way to do genetic research, 
but it has many arguments going for it in terms of the 
likelihood of success because of the nature of the population 
structure.
    We have recently initiated, in the last few months, a 
second project on prostate cancer. This project will collect, 
in the course of the next three years, a hundred families with 
multiple affected males who are African-American, affected with 
prostate cancer.
    Our investigators, about a year ago, mapped the first 
prostate cancer gene to chromosome 1. The gene itself is still 
being searched for. But it appears that this gene is 
particularly important in African-Americans. And yet very few 
families have been studied.
    That effort, for which Howard University serves as the 
coordinating center, now involves seveninstitutions around the 
country, most of whom are led by African-American physician scientists. 
I think this is a very exciting opportunity to move genetics into this 
arena.
    I think the relationship with Howard University is an 
extremely gratifying one. We are making every effort to have 
investigators go back and forth between our institutions, to 
achieve some training opportunities which have not previously 
been as vigorous as they could be. At the highest levels of the 
Howard University administration this is being seen as a very 
high priority for their own program building.
    Dr. John Ruffin, the Director of the Office of Research on 
Minority Health, has been a very enthusiastic supporter of this 
concept as well, and he and I have worked together I think very 
productively in trying to set this up.
    So for me right now, of the things we are doing in our 
intramural program, this is one of the most exciting.

                breast cancer in african-american women

    Mr. Stokes. I personally appreciate your kind remarks. Let 
me say, I also appreciate your sensitivity to these areas of 
concern that I've discussed with you and Dr. Varmus and others. 
I also appreciate the sensitivity that Dr. Varmus has displayed 
for these concerns over the years.
    What about African-American women? They also have a higher 
death rate for breast cancer than the white population.
    Dr. Collins. Yes.
    Mr. Stokes. Are you doing anything to address that?
    Dr. Collins. Dr. Georgia Dunston, who's an investigator at 
Howard University, did a sabbatical in my laboratory two years 
ago, studying breast cancer in African-American women. It does 
appear that BRCA1 and BRCA2 play a role, but they don't 
completely explain what's going on. There are probably other 
genetic influences, and undoubtedly environmental ones, as 
well.
    What I dream of is a center at Howard University to look at 
diseases that disproportionately affect African-Americans, 
which could expand beyond diabetes and prostate cancer, which 
we've already started on. The center could expand to breast 
cancer, to asthma, to Alzheimer's disease, which we have 
learned in the last day seems to be at a higher risk in 
African-Americans, a rather surprising observation that needs 
an explanation.
    Mr. Stokes. Thank you.
    Mr. Porter. Thank you, Mr. Stokes. You'll have additional 
time when we return.
    The subcommittee will stand in recess briefly for two 
votes.
    [Recess.]
    Mr. Porter. The subcommittee will come to order.
    Mr. Stokes.

                 ethical legal and social implications

    Mr. Stokes. Okay. Dr. Collins, as you know, over the years, 
we've discussed the ethical, legal and social implications of 
genome research, with a focus on the possible discrimination 
implications that could stem from increased genome research 
findings. The Administration recently released a report 
entitled Genetic Information in the Work Place, and is urging 
employers not to discriminate against workers because of their 
genetic makeup.
    What protections currently exist to address and prevent 
this form of discrimination?
    Dr. Collins. I appreciate the question. Clearly, when you 
ask the public about their concerns about misuse of genetic 
information, health insurance and the work place are the number 
one and number two answers you get. In a telephone survey of a 
thousand people done last year, 85 percent of the respondents 
said they did not believe that employers should have access to 
genetic information.
    So what are we doing about it? At the present time, the 
protections against this largely stem from a ruling of the EEOC 
based upon the Americans with Disabilities Act. Three years 
ago, the EEOC ruled that an employer who uses predictive 
genetic information about an individual to deny them a job is 
actually violating the ADA. Because that employer is regarding 
them as disabled, even though that person is healthy at the 
time.
    That was very gratifying. It was a strong statement that 
this is not something that should happen. And yet many people 
looked at that and said, well, it's a gratifying statement, but 
its ability to actually prevent mischief may be somewhat 
limited.
    The EEOC ruling has not yet been tested in the courts. And 
of course, it seems only to apply to a hiring decision. There 
are other decisions, like promotions, for instance, which 
remain vulnerable to this type of discrimination.
    Furthermore, there was nothing in that ruling that dealt 
with whether an employer could insist upon having someone 
tested. We sponsored a workshop on this issue which then led to 
a published statement jointly between the ELSI working group 
and the National Action Plan on Breast Cancer. This published 
statement, issued a year ago, outlined what needs to be done at 
the Federal level to provide legislative protections against 
the misuse of genetic information in the workplace.
    I'm delighted to see a great deal of interest in that 
issue. And Congresswoman Lowey, who just entered the room, has 
played a major role by introducing a bill in the House. The 
companion bill has been introduced by Senator Daschle in the 
Senate. Both bills build on the recommendations from that joint 
effort of the ELSI Working Group and the National Action Plan 
on Breast Cancer. These two bills, I think, do exactly what 
needs to be done to prevent that kind of discriminatory 
practice.
    They are also careful to do it in a way that I don't 
believe damages the employer's situation. I think employers 
looking at these would be quite comfortable with what's 
recommended.
    There was recently a case in the Ninth Circuit, a 
California case, where a number of individuals who had been 
tested without their knowledge for sickle cell disease, for 
syphilis and for pregnancy, actually, by a Government agency, 
brought suit, because they felt their privacy had been invaded.
    After an initial lower court threw that out, the higher 
court said this is a serious issue. That's actually quite 
gratifying. It indicates a judicial opinion of a fairly 
significant sort that testing without the knowledge and consent 
of the individual ought not be done. So I would see that also 
as a positive step.
    Once again, we have a circumstance now where I think the 
scholarship that's come out of the ELSI program has outlined 
what needs to be done. There's a lot of enthusiasm in both 
parties and in both Houses. The Vice President of the United 
States on January 20th made a strong statement in this regard. 
There is this report which you've referred to. The Department 
of Labor has played a very significant role in this, and have 
been a wonderful ally in this enterprise.
    So it's pretty clear what needs to be done, now we just 
need to do it. We need to get Mrs. Lowey's bill passed. 
[Laughter.]

                     health professional education

    Mr. Stokes. You've got me.
    Let me give you a real quick question. What's being done to 
ensure that academic medical centers, other medical schools and 
continuing medical education programs include your recent 
Centers research findings in their curriculum and to ensure 
that the practicing health care community are aware of these 
advances as well?
    Dr. Collins. This is a very critical issue, both in terms 
of physicians and other health care professionals who are 
already out in practice, and those who are in the next 
generation, who are currently being trained. This National 
Coalition for Health Professional Education in Genetics, which 
I briefly mentioned a moment ago, is taking on a lot of 
interest and responsibility for both of those arenas.
    The Coalition has a working group which is developing an 
effort on curriculum development for medical schools and 
nursing schools. It also includes an effort to put together a 
clearinghouse for valid genetic information to be available 
through electronic means, through the web, but also as hard 
copies for those who need it.
    And the Coalition has a vigorous effort to influence 
licensure and certification, so that there is both a carrot and 
a stick here in terms of getting this information integrated 
into medical training. I think we've got a lot of work to do, 
but I think those are the right ideas, and we just need to roll 
up our sleeves and get it done.
    Mr. Stokes. Good.
    Dr. Varmus. Can I make one addition? This is the second 
time the Coalition has come up, and I wanted to point out that 
the Coalition is being managed and financed through the 
activities of the National Foundation for Biomedical Research, 
or the Foundation of the NIH to which you very kindly have 
appropriated a half a million dollars in 1998, and we're asking 
for $300,000 in 1999.
    This is one of the several activities of the Foundation and 
it's an important illustration of how the Foundation can work 
to achieve NIH's goals through mechanisms that wouldn't be very 
simple for us to carry out through the normal appropriation 
process, affecting both the intramural and the extramural 
activities of the NIH. I thank you for the support of the 
Foundation.
    Dr. Collins. I agree.
    Mr. Stokes. Thank you very much.
    Thank you, Mr. Chairman.

                    complexity of biological systems

    Mr. Porter. Thank you, Mr. Stokes.
    Dr. Collins, and Dr. Varmus may want to comment on this as 
well, when a scientific investigator undertakes a research 
project, he or she has certain expectations as to what they 
might find. I wonder if you could tell us, looking back seven 
and a half years, whether you find a greater complexity, a 
greater feeling about the complexity and interrelationships 
within the human body than you expected to find. In other 
words, have you gained greater respect for the difficulty of 
this organism to be understood?
    Dr. Collins. That's an interesting question to think back 
on, and try to reconstruct what we all imagined we would find 
back in 1990. I think the answer is also a complicated one, and 
it is that in some instances, things have turned out to be 
simpler than we expected. In others, vastly more complicated.
    The simpler ones more immediately come to mind, because 
they are so gratifying, when you uncover something that you 
thought was going to be impenetrably difficult. Last week's New 
England Journal of Medicine had a really interesting example of 
that, if I can take 30 seconds to tell you. It also evidences 
that we've been on the right track in our approaches to 
disease.
    Tuberculosis, a disease that's obviously very prevalent in 
some parts of the world, is clearly an infectious disease. Who 
would have thought that genetics would have had much to offer 
this one, right?
    Yet it's clear that the same exposure doesn't always give 
the same results. Some people fight off the infection very 
quickly and never even know they were exposed. Others may go on 
to severe lung disease.
    People studying mice seven or eight years ago developed a 
mouse model for this disease, and discovered that some mouse 
strains are more sensitive to tuberculosis than others. Using 
the tools of the Human Genome Project in 1993, they were able 
to identify a specific gene that seems to confer that 
resistance, a gene called N RAMP-1. This is a gene you could 
never have guessed, people still don't quite understand what it 
does. But it clearly is the major gene involved in TB 
susceptibility in mice.
    Well, so what? What about humans? Last week's New England 
Journal reports a study from Gambia where they looked at 
individuals with severe TB lung disease and compared them to 
others who'd been exposed but fought off the infection. This 
same gene, N RAMP-1, only the human homologue of it, seems to 
be the major contributor to that difference in host 
susceptibility.
    Seven or eight years ago, I would never have dreamed we 
could get to that point by now, that something as complicated 
as host factors that determine response to an infectious 
disease could get sorted out in this time period. The same, of 
course, has been done for AIDS, with a variety of different 
genetic alterations being discovered that confer resistance to 
that disease. And of course, there's the paradigm of malaria 
and sickle cell trait, which we've known about for decades, but 
which many people thought would be an exception.
    So in those instances, where we've gotten insights into the 
genetic basis of diseases that seemed impossibly muddy, I would 
say, wow, research has really moved more swiftly than I could 
have imagined.
    When it comes to the work of the Human Genome Project, to 
building the infrastructure, getting maps and sequences and the 
technologies, it's hard work. Three billion base pairs is easy 
to say. When you have to actually contemplate doing it, there's 
no question that's enormously challenging. I think we're right 
now in the throes of absorbing just how hard this is going to 
be.
    I don't know that it's caught us off guard, but you 
certainly, when you get up to it, as opposed to talking about 
it, you perceive just how complicated it is. In that regard, it 
is wonderful that this is an international effort. We had a 
meeting two weeks ago of all the international groups. There 
are serious efforts underway, particularly in the United 
Kingdom, but also in France and Germany and Japan, as partners 
to try to make this happen.
    I think that partnership is going to be critical. The 
genome belongs to all of us.
    Dr. Varmus. Could I comment just briefly, Mr. Porter?
    I think we always knew that understanding life systems 
would be a complicated process. I think what's impressed usis 
in the last year or so, as we've acquired so many tools for 
investigating how life works, either through the genome or through 
analysis of proteins made by the genes that have been identified, and 
by studying, very importantly, the way in which signals are transmitted 
within cells.
    All of us who are trying to understand how cells are 
controlled have been excited but also mystified by the number 
of interactions between individual proteins. At this point, 
when you draw out a map--and you actually see an example of 
such a map when Dr. Klausner comes--of what is interacting 
within the cell to transmit the message, we are at the limits 
of the ability of biochemists and biologists to understand 
these systems.
    There's tremendous interest in bringing mathematics and 
physics and engineering to bear on the interpretation of these 
problems. I believe Dr. Cassman actually will tell you about 
some initiatives he's undertaken to bring new communities into 
the investigation of biological systems.
    For some organisms, like yeast and many bacteria, we have 
all the genes already, and we soon will have them, as you 
heard, for one complex organism, C. elegans, a round worm. I 
think now is the time to expand our efforts to broaden the 
community of scientists trying to understand the dynamics that 
control the life of any single organism.

                    beyond the human genome project

    Mr. Porter. And this would be the next step beyond the 
completion of the human genome project?
    Dr. Varmus. It's actually a step that's coming now, because 
we do have genomes already fully understood. Even in the case 
of mammals, we have enough components of the signaling pathways 
that govern aging, cell death, and growth control, to be able 
to develop some much more interesting models--based on chaos 
theory or on the way in which homeostasis is maintained in an 
engineering system, in a machine.
    I was at Cal Tech this weekend, and met mathematicians who 
were invited to a workshop that Dr. Cassman organized and who 
were truly energized about the possibility of using their 
methodology, in this case pure mathematics, to try to 
understand how these systems work. It actually brings us back 
to the original question that got many people interested in 
biology, Schrodinger's question of how does life operate, what 
are the thermodynamic principles that allow life to go on, such 
a complex event, with what seems to be such a small energy 
source.
    Mr. Porter. Did we contemplate that we would find these 
kinds of further complications in understanding when we began 
the project of mapping?
    Dr. Varmus. I think you don't have to say we're going to do 
a mapping project to realize that we'd eventually have most of 
the components that allow cells to function. I think what's 
been incredibly exciting is that epiphany that occurs when we 
actually have so many of the elements that control the cell 
behavior in our hands and now it's up to us to decide how these 
things fit together.
    Of course, knowing how these things fit together normally 
is the other side of the coin of understanding what happens 
when things go wrong and cells die or disease occurs.
    Dr. Collins. I think it's a very important question, just 
to follow up. I think computational biology is going to be an 
area that flowers enormously in the next few years. At our 
Council meeting last month we talked about this and initiated 
two new programs to try to bring more people into this field 
who are really capable at handling both sophisticated 
computational approaches and understanding the biology. Because 
we're going to have this wealth of data about genes and 
proteins and a challenge to see how it all works.
    The Human Genome Project is building the periodic table for 
biology, and now we have to figure out how that table puts 
things together.
    Mr. Porter. What I read from both of you is that you have 
no doubt that we will, in time, figure it all out. Is that 
correct or not?
    Dr. Collins. I don't know what ``all'' is.
    Dr. Varmus. Remember the display I showed you? I showed you 
a display on Tuesday comparing a tumor at different stages of 
growth and the number of genes turned on and off. You can do 
the same kind of experiment with single cells exposed to 
different environmental conditions. That's been done now for 
yeast. You put yeast in one growth condition, then transfer it 
to a different growth condition or expose it to a toxin or add 
a mutant gene.
    You can look at every gene in yeast and ask whether it's 
being turned off or turned on as you change conditions. How 
does an organism respond to altered conditions of life? We're 
now accumulating that information. There are bioinformatic 
specialists who are showing us how to group the genes that are 
affected in different ways, and try to relate them to the 
functional properties of the genes, most of which we have some 
understanding of in the case of yeast.
    And now the next step will be figuring out, what does that 
all mean? Why are these controls organized the way they are?
    I think we have a couple of decades of work before we 
understand that.
    Dr. Collins. And all is of course----
    Mr. Porter. I didn't mean in anyone's lifetime here, but at 
some point.
    Dr. Collins. Even if we knew all of those wiring patterns, 
would we understand some of the unique aspects of human nature, 
would we understand what love is, would we understand what 
personality is about, I'm somewhat reserved on that.
    Mr. Porter. That's beyond the all I was trying to capture. 
[Laughter.]
    Dr. Collins. Good, then I don't need to go on. [Laughter.]

                        clinical trials in nhgri

    Mr. Porter. All right, let's see. When the genome project 
reaches the point where clinical trials are appropriate, do you 
envision your Institute actually conducting the trials or 
relying on the clinical trial expertise of other institutes?
    Dr. Collins. We do have some clinical trials already 
underway. In our intramural program, which is heavily involved 
in the applications of genome research to an understanding of 
disease, there is quite a long list of protocols. Each of these 
are trying to understand the biologic basis of certain genetic 
conditions and increasingly, also, gene therapy trials. There 
are some five or six of those actively underway through our 
intramural program, which has a rather different flavor than 
the extramural program.
    In the extramural program, we have had a series of clinical 
trials on genetic testing. For cystic fibrosis, we funded a 
whole series of such projects, and a great deal ofuseful 
information came out of that in terms of people's interests and how 
they adapted to the information. We are also still funding the Cancer 
Genetic Studies Consortium, which is looking at testing for breast 
cancer and colon cancer in a clinical setting.
    But it is clear that our primary goals are not going to be 
such that our extramural program becomes heavily involved in 
clinical trials. We would like to be participants in such 
efforts. We're about to see in the near future a set of 
programs in hemochromatosis, where we join with the National 
Heart, Lung and Blood Institute and the National Institute of 
Diabetes, Digestive and Kidney Diseases to issue an RFA to 
study this disease.
    This is a fascinating disease, Mr. Chairman, which 1 in 300 
people are walking around with, most of them unaware of it. 
It's a completely treatable disease if you know you have it. 
You build up too much iron. The treatment is, you go to the Red 
Cross and give your blood more often than other people. If you 
do this, you should prevent all of the consequences of heart 
failure, liver failure, and endocrine failure, which otherwise 
come about. So it's a really good example of the kind of 
genetic disease where population screening might be very 
sensible to initiate.
    But you don't want to launch into that until you've studied 
this on a research basis. And we're about to do that. But the 
major funding from that will come from the National Heart, Lung 
and Blood Institute. We will contribute something to the 
effort.
    But I think you're correct, that clinical trials are not 
likely to be a major focus of our extramural program.

                            pharmacogenetics

    Mr. Porter. Pharmacogenetics is a growing field of science 
which studies the genetic reasons why drugs affect people 
differently. It is thought that knowing the genotype of an 
individual will permit more effective prescription of drugs and 
more precise testing in clinical trials. If this goal were 
realized, would it force difficult choices between more precise 
medical care and the added costs of genetic testing for each 
patient?
    Dr. Collins. That's a very interesting question. Certainly 
the pharmaceutical industry is voting with their feet that they 
believe that this is going to be a very significant part of the 
future of medicine. Why is it that if you take 10 people with a 
particular disease, whether it's cancer or diabetes, or 
whatever, and you try out the standard therapy, some fraction 
of them respond very well and some don't. Some occasional 
uncommon side effects pop up in some people and not in others.
    Presumably, in many instances, that is because of an 
interaction between the therapy and that individual's genetic 
makeup. The possibility, therefore, of using genetic testing to 
more individually prescribe the most effective therapy is 
something that has a lot of people excited. Dr. Klausner will 
certainly talk about this, I'm sure, when he comes before the 
subcommittee because of the hope that individualizing therapy 
will turn out to be more effective than using a standard 
therapy, just based on the pathological type in treating 
tumors.
    But I think it will generalize beyond cancer to virtually 
all diseases, once we have that kind of information. You're 
correct to raise the concern, is this just going to make 
everything more expensive. In order to avoid that, we have to 
drive the technology forward to do genetic testing at a much 
less expensive rate. Things like this chip, for instance, will 
potentially bring that cost down by orders of magnitude.
    I think the timing is likely to be about right there, as we 
gain enough information to figure out what kind of testing is 
appropriate in designing therapy, the cost of technology for 
doing that testing will be coming down quite substantially. I 
think it's a very exciting set of developments. I think it is a 
major chapter to this book about the future of medicine that 
we're trying to anticipate right now.
    Mr. Porter. I would tell my colleague from New York that I 
plan to call on her at 10 minutes of 12:00 and give her the 
last 10 minutes. Will that work? I didn't charge myself with 
the macro question. I figured we'd all learn from it. 
[Laughter.]

                 having genomic data publicly available

    We've talked in the past about private industry withholding 
genomic data out of a proprietary interest. Some reports 
indicate that the situation is improving with more data bases 
entering the public domain. But there still seem to be 
instances where refusal to share data is creating needless 
duplication. How serious a problem do you consider data 
hoarding at the present time?
    Dr. Collins. I think your statement is correct, that things 
have improved in this regard. But they're not perfect. 
Certainly from our perspective as a granting agency, which is 
distributing public funds, we feel that accessibility to the 
mapping and sequence information is just absolutely essential.
    So we have moved from a stance a few years ago where we 
said people had to put their data in the public domain in six 
months to a stance now where we say they have to do it in 24 
hours, and in fact our genome centers are compliant with that. 
We regularly check on those things.
    That standard has also been adopted by the international 
community that has been meeting every year. There is still a 
concern in other areas other than sequence, however, 
particularly this business of building the human catalog of 
variation that I mentioned. We're in the throes right now of 
trying to figure out how to optimize the deposit of that 
information into the public domain as well.
    Mr. Porter. We've just changed our sequencing here.
    Ms. Pelosi.
    Ms. Pelosi. Having nothing to do with the Human Genome 
Project.

                      privacy and confidentiality

    Thank you, Mr. Chairman. Thank you, Dr. Collins.
    Again, forgive me if these questions have been asked in my 
absence, because of my other responsibilities. And if they're 
on the record, I'll just read the record.
    But I wondered, my colleague, Congresswoman Lowey, has been 
a leader in addressing the potential for discrimination. I 
heard her question, and I just wondered if perhaps you could 
just elaborate, and if you have, I'll read it, regarding what 
work you're doing regarding the maintenance of confidentiality 
of genetic records, and what you envision in terms of how a 
patient chart is kept. Would it still be in the same manner as 
now?
    Dr. Collins. I appreciate the question. I put up that 
poster of the two pillars of what we need to give people 
protection so that they're safe in getting genetic information, 
and one of the pillars was privacy and confidentiality.
    When you think of the medical record, and try to imagine 
whether you could provide protections that are specific for the 
genetic information, that are different from the rest of the 
record, it gets very difficult to do that. I can't take a 
patient chart and decide which part is which, they're all 
intertwined together.
    So genetic privacy basically becomes medical privacy in 
general. There have been many developments in this area. As you 
know, HIPAA charged the Secretary of HHS to put forward 
recommendations about medical records privacy. That was done 
last September. The recommendations do not apply to information 
that has been obtained solely on the basis of research. They 
apply only to information that's part of the clinical record.
    The Congress is supposed to act in the next two years, or 
those regulations will become law. There's a lot of interest in 
the Congress, as you know, in this issue, with a number of 
bills, some introduced, some waiting to be dropped, on this 
topic. It's clearly very complicated.
    Ms. Pelosi. Do you have any recommendations in that area?
    Dr. Collins. Well, we've been very involved in the process. 
The National Bioethics Advisory Commission has been 
deliberating, particularly about things such as archived tissue 
samples, and when can you use them, and is that an appropriate 
part of this package.
    Dr. Varmus has set up a trans-NIH group to look at 
bioethics issues. This committee, has also now gotten very 
involved in questions about privacy, as they relate to genetics 
and other non-genetic information, particularly in the research 
arena. And they have come up with a white paper, which is being 
circulated amongst the institutes right now for comment.
    I could not at the present time tell you that I would have 
a strong recommendation about one piece of legislation or 
another. I'm not sure it would be proper for me to, anyway. But 
there's clearly a lot of overlap in the various proposals, but 
some significant differences. The balance, of course, is trying 
to protect people against misuse, without so ensnarling the 
medical care system that you can't actually deliver care, which 
could be a serious issue if you make a written approval 
necessary for every possible transaction.
    If I could add one other thing, in the research arena, I 
think it's also really critical that we don't write legislation 
that is so onerous that it prevents the possibility of doing 
epidemiological research. We have learned a lot from medical 
record review, trying to figure out a common thread to some new 
illness.
    If you have to get individual permission for that kind of 
research, it will be very difficult for many studies to be 
carried out. That's something to think about very carefully. 
Even with the best of intentions, sometimes, people have 
notions about very rigorous forms of consent being required for 
every transaction, which could be quite damaging to research.
    Ms. Pelosi. Well, I recall just the other day, the Acting 
Director of the CDC said to us, am I correct, Mr. Chairman, she 
said, if it isn't counted, it isn't done, in terms of 
prevention, in any event.
    Dr. Collins. Counting is important.
    Ms. Pelosi. Dr. Varmus, did you have something?
    Dr. Varmus. I just wanted to endorse Francis' comments on 
this topic, especially with respect to research. It's important 
to remember that the computer can be your friend in this 
circumstance, that while the computer tends to be criticized, 
in fact there are ways to set up security systems that allow us 
to use information and not go back to identifiers that would 
connect the information with individual patients.
    If we can learn to stratify the experiments that need to be 
done--especially with things like stored tissue samples or 
stored DNA samples that will be of major benefit--and provide 
the kinds of protections that would allow us to not have to go 
back and get informed consent from everyone who may have been 
the donor of a tissue sample 20 years ago, we'll be able to 
make much better use of the resources that are available, while 
still providing the protections against misuse of the 
information that represents the dangerous aspect of what we 
appropriately look at.

                      gene therapy for hemophilia

    Ms. Pelosi. I appreciate your statement, because obviously 
science and technology have taken us to new places in basic 
biomedical research and instrumentation as well as in access to 
information that some could view as a problem. But your putting 
it in perspective that way is very helpful.
    I understand that gene therapy is a promising area of 
research in the area of hemophilia. Can you tell us more about 
your work with the Heart, Lung and Blood Institute to pursue 
vectors for gene expression in immunity needed to make gene 
therapy technology available to individuals with hemophilia?
    Dr. Collins. Hemophilia is a common blood disorder which 
affects primarily males, because it's a genetic disease where 
the alteration is on the X chromosome. Females who have two X 
chromosomes can carry the illness, but are usually not 
affected.
    There are two different types of hemophilia, types A and B, 
due to two different genes. Clearly, this is a disorder where 
gene therapy is an appealing idea, because you only need about 
5 percent of normal levels of this clotting factor to be 
normal. It's when you drop below 5 percent the disease begins 
to appear.
    The genes for hemophilia A and B have been cloned for some 
time. The notion of putting one of those genes into a viral 
vector or some other delivery system, and then transferring it 
to a boy who's affected with this disease is a very appealing 
one. And yet, as with all efforts in gene therapy, this has 
been a real challenge to reduce to practice.
    We have a number of vectors that we know can do this. But 
the delivery efficiency is usually not as high as you'd like. 
And when the gene is transferred and expressed, sometimes it 
doesn't last very long, because the immune system comes along 
and says, ``what's this,'' and gets rid of it.
    Nonetheless, I think there has been steady progress in gene 
therapy for this disease in animal models. And in fact, our 
intramural investigators are planning, in the near future, in 
collaboration with the National Heart, Lung and Blood 
Institute, to initiate a trial of gene therapy for hemophilia. 
The notion here is to put the normal gene into cells from 
individuals with this condition, so you can do this in a less 
invasive way. Do a skin biopsy, grow the cells up, put the 
normal gene in there, and then reimplant those as sort of a 
patch under the skin.
    And the hope is, and this has to be tested, that 
thosecorrected cells will make enough of this factor, which will find 
its way into the bloodstream, to provide that correction.
    These are very early days for gene therapy. There are many 
diseases for which gene therapy might be applied. But 
hemophilia is probably near the top of the list of ones that 
are realistic targets in the not too distant future. Yet there 
are many hurdles ahead.
    Dr. Varmus organized a very useful review of gene therapy a 
couple of years ago by a number of experts to provide some 
advice about what we should be doing about this field. Out of 
that has come a very rigorous set of questions: are we going in 
the right direction, are we using the right vectors, are there 
new ideas out there that haven't been tested. And my sense is, 
that has provided a real impetus to move us in the direction we 
want to be going.
    Ms. Pelosi. You mentioned the immune system. I wondered if 
you could tell us about the potential import of the genome 
project for knowledge about the human immune system in general, 
and HIV in particular.
    Dr. Collins. Sure. The Human Genome Project is very 
democratic. We care about all the genes, no matter what 
diseases they're involved in. We're determined to find them 
all. And certainly, the immune system is an extremely important 
part of this goal.
    Dr. Varmus was talking earlier about getting to the point 
where it's hard to even put all the pathways into your head. 
Well, the immune system has a lot of pathways that are being 
worked out, which are clearly complex and which the Human 
Genome Project is contributing additional complexities to, 
challenging us to figure out how it works.
    There are many disorders of the immune system, some 
inherited, a few of which are actually the first targets of 
gene therapy, and some acquired, as in AIDS, for instance. We 
have a gene therapy trial in the intramural program on AIDS, 
which is looking very interesting. This is a very challenging 
strategy.
    Dr. Rick Morgan and Dr. Michael Blaese have identified 
about 150 identical twins where one of the twins has AIDS and 
the other does not. The idea is to take cells from the 
unaffected twin, put into those cells a gene therapy vector, 
and then infuse them back into the affected twin. There will be 
no problem with compatibility, since they're identical twins.
    It gives you a very elegant system to see whether your 
therapy is working. If it does, the cells that you've put the 
gene therapy vector into should survive longer than the 
patient's own cells.
    There is some hint that this is beginning to show promise. 
These vectors have already shown promise in a monkey model, 
published this past month in Nature Medicine. So all of these 
tools certainly can be applied to that very challenging 
problem. And again, I think the Human Genome Project is in the 
happy circumstance of being able to say almost everything we do 
has the potential to help some disease.
    Ms. Pelosi. Thank you, I appreciate that.
    Is my time up, Mr. Chairman?
    Mr. Porter. Yes, I'm afraid so. We were operating on the 
10-minute rule.
    Ms. Pelosi. Thank you, Mr. Chairman.
    Mr. Porter. The Chair has just spotted Craig Higgins in our 
audience this morning, the former clerk of our Senate 
subcommittee counterpart. Craig, we are delighted to see you. 
We welcome you, we wish you well in your new position, and we 
know that you are intellectually challenged in it with the 
Institute. [Laughter.]
    Dr. Collins. He's intellectually challenging us, too.
    Mr. Porter. I imagine he is.
    Mrs. Lowey, you have five minutes.

                        pharmaceutical companies

    Mrs. Lowey. I'll be very brief, I just have two questions. 
I appreciate the time you've taken with us this morning.
    One is a puzzle to me. We spent some time talking about the 
bill that Louise Slaughter has and the one I have prohibiting 
the genetic discrimination. The pharmaceutical companies have 
not embraced these issues. You talked a little bit before about 
working with the private sector. It would seem to me that it 
would be in their best interests to embrace these bills, 
because of the important research they are doing, that they 
should be concerned about the public's concern about 
discrimination and stigmatizing.
    Do you have any recommendations? I wonder how we can work 
that out with the pharmaceutical industry and the biomedical 
research community in helping us move these bills along, which 
also would help them move their research along even more 
quickly.
    Dr. Collins. Well, I think statements like the one you just 
made are very important. Because I think in fact the 
pharmaceutical industry is quite concerned about these issues. 
Clearly, their future depends on the public feeling comfortable 
with genetics as part of medicine. If the public is afraid to 
use this information, then all the investments that are being 
made now in gene-based therapies, and pharmacogenetics may fall 
on an unreceptive public, and that would be pretty bad for 
their business.
    So in that regard, I think they are actually very 
supportive of solving these problems of discrimination in 
health insurance and employment.
    Mrs. Lowey. Quietly.
    Dr. Collins. Quietly. Traditionally, large industries do 
not take positions that are seen to be in opposition to other 
large industries' positions. And in this regard, I think 
pharmaceutical companies are reluctant to take a strong visible 
stance on a topic which the health insurance industry is not so 
happy about.
    I think that has led to some reticence to be as vocally 
supportive as might otherwise have happened. I think statements 
from people like yourself would be very helpful in that regard, 
because I think you have stated it correctly, that they have a 
lot at stake here, too.

                 solving problems--relieving suffering

    Mrs. Lowey. I thank you. And lastly, and this is probably a 
larger philosophical question, but I had a lunch meeting with a 
group of really outstanding scientists at Harvard just a couple 
of weeks ago. We got into quite a long conversation about why 
scientists spend hours and hours in the lab finding answers to 
challenging problems. And the scientists said to me, no names, 
in fact, quite a well-known scientist, that, we spend all 
weekend, and night after night working in the lab to find 
solutions to challenges, not because there is an application to 
human problems or to solve human problems, but for the joy and 
the gratification of solving the problem--Dr. Varmus is shaking 
his head.
    And I as a Congresswoman kept saying, I don't believe this. 
How could you just be working on solving a problem unless you 
know it can relieve human suffering such as cancer or can solve 
a problem directly connected to human life? I gather this is a 
larger problem and a larger question.
    But my direct question, which follows up on my colleague 
Ms. Pelosi's question, because I don't want to wait decades and 
decades and decades, and I wonder, what new therapies do you 
envision resulting from our mapping of the human genome and 
perhaps this will be a longer conversation, but I know that 
people in your institute are directly focused on solving the 
pain and suffering that results from human illness.
    So if you want to touch briefly on the first, or maybe go 
to the second.
    Dr. Collins. I can't resist touching on the first. I think 
scientists involved in an exciting mystery get caught up in 
that situation. You can glimpse that an answer is coming, but 
you don't quite have it, and then you do the right experiment 
and you get a clear result. Suddenly you realize you know 
something that nobody knew before. That in itself is an 
enormously gratifying experience.
    But on the other hand, I think, the majority of people who 
went into biomedical research had alarger reason to do that. 
They wanted to do something for humanity. That's certainly true of 
myself.
    You can do both of those things. You can have this large 
goal, but also, to be realistic, it's hard to perceive that 
your little effort is making a major impact on humanity week by 
week. You can still get pretty jazzed about the experiment that 
gave a new result, gave you insight into something that's a 
purely intellectual problem. I think a scientist needs both of 
those features to be effective in biomedical research.
    So I think you did get a fairly accurate description. But I 
wouldn't lose heart that the scientific community out there is 
solely driven by intellectual academic interests, and that they 
don't care about finding cures for disease. I think they do.
    Mrs. Lowey. Maybe at Harvard.
    Dr. Collins. Oh, yes, right, it was Harvard, after all.
    Now, to come to your specific question about the future 
that we could hope to see come out of the Human Genome Project, 
and I do feel pretty passionate about this, I think the reason 
we're doing this project is to cure illness and alleviate 
suffering. It may be wonderful basic science, and it is, and it 
may be exciting to see that latest revelation of a basic 
science, and that is true. It's good for biotechnology and it's 
probably good for the economy.
    But the real reason we're doing this is your reason, to try 
to, as quickly as possible, get answers to unanswered questions 
that will lead us towards cures. Now, how are we going to see 
that happen? In some instances, the gene discovery itself will 
provide you with an idea. We talked about hemophilia as an 
example, where the normal gene becomes the drug.
    And after I think a number of years of really struggling to 
find out how to do this, gene therapy is beginning to provide 
new insights. And I think it will find a place for many 
diseases. But probably not all.
    Perhaps even more generalizable will be this notion that by 
understanding at the most precise molecular level what's wrong, 
which we haven't been able to do for most diseases, that you 
could then design a therapy that goes right to the heart of the 
problem, that really takes care of the issue, the way we have 
seen happen with protease inhibitors and HIV, for instance. But 
we need to apply that to diabetes or to hypertension or to 
coronary artery disease or to schizophrenia--not just treating 
the symptoms, not just relying on empirical good guesses to 
find the best drug, but really knowing at the molecular level 
what the problem is you have to solve. That's the hope for 
cancer right now that's leading to so much enthusiasm. Because 
that particular molecular puzzle is really beginning to reveal 
its secrets.
    To make that happen, though, we need this cadre of partly 
basic science, partly clinical investigators, to come up with 
those insights and then to try them out. I am delighted that at 
this very opportune moment, the NIH is enjoying this kind of 
enthusiastic support from this Congress and from the 
Administration as reflected by the budget that we're here 
talking about during these two weeks. There could not be a 
better time to have that happen.
    Mrs. Lowey. I thank you. And as you well know, our Chairman 
and this committee are all very strong supporters. We're even 
sorry to take you away from your important work. [Laughter.]
    Dr. Varmus. I would just caution you, Mrs. Lowey, not to be 
disheartened by the attitude you heard expressed. Because while 
it is important to know that there are many of us who are 
focused on the applications of knowledge, we need to have a 
cohort that is simply excited about the solutions they're 
trying to come up with.
    Much of the great work that Francis Collins and his 
colleagues are trying to do now is only possible because 30 
years ago there were people trying to solve this problem of why 
certain bacterial viruses couldn't infect certain bacterial 
cells. That is the basis for the whole recombinant DNA 
revolution. It was a problem as removed from disease as any you 
can imagine.
    Mrs. Lowey. I thank you.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mrs. Lowey.
    Dr. Collins and Dr. Varmus, thank you very much.
    Ms. Pelosi. Is the hearing over, Mr. Chairman?
    Mr. Porter. Yes.
    Ms. Pelosi. Don't I get another chance? [Laughter.]
    Mr. Porter. Well, I'm reluctant to hold them past 12:00.
    Ms. Pelosi. All right.
    Mr. Porter. You can if you wish and if they're willing.
    Ms. Pelosi. Just for a minute, if I may. I won't do my 
basic questions, but I'll just follow up on the theoretical 
questions that Mrs. Lowey posed.
    Dr. Collins. That's fine.
    Ms. Pelosi. First of all, I just want to make a statement, 
and I'll be very brief, Mr. Chairman, it is exciting that, what 
you're doing is exciting, and we're all so delighted to be so 
supportive of it, and it's no accident. It's about the talent 
that is at the NIH, of course, the distinguished leadership of 
Dr. Varmus, being a Nobel laureate himself, with his own 
scientific credentials, as well as the ability to have these 
collaborative efforts scientifically across the board, and then 
with universities, with business, as well as the imagination 
that we see there. And that takes me to my question.
    Once a distinguished scientist brought some other 
scientists to my office to talk about worms. Do you remember 
that, Dr. Varmus?
    Dr. Varmus. I do, very well.

                        discoverers and creators

    Ms. Pelosi. Before Dr. Varmus was on the national scene, 
well, he was on the international scene. And I appreciate what 
you were saying about that excitement, of course, that a person 
would devote her life to studying these worms. And the outcome, 
of course, would be beneficial to all of us. But she had to be 
encouraged every day to go back into that lab.
    And what you're doing now with all these breakthroughs in 
science that we see, are we still in the discovery mode or is 
there a creative mode at work as well? Are we discoverers or 
are we creators? Or both?
    Dr. Varmus. Both.
    Dr. Collins. Yes, I think you wouldn't want to have a sort 
of dividing line where you said, okay, right now we're just 
discovering, don't create yet.
    Ms. Pelosi. No, but I just wondered if we still need to 
discover so much more or----
    Dr. Collins. That's true, too. But we have a sufficient 
collection of fascinating data and observations. I'm glad you 
mentioned the worm. The worm will have its completesequence 
known by the end of this year. We will have it, the encyclopedia of how 
the C. elegans worm works.
    That represents a lot of discovery, and creativity has 
already started to be applied in a big way. We've learned 
insights from the worm about aging, about diabetes, about 
development, about cancer, a whole host of issues. So it's a 
very good example of how these two things are intertwined. You 
do the discovery, but you do the creativity as early as you 
can.
    Ms. Pelosi. Dr. Borenstein, you know, has written about 
discoverers and creators. We're all finding out something new, 
it's just a question of if it's something that was there that 
we found, or it's something we created, and also where we go 
from there. Last year, Dr. Varmus divided his testimony, what 
was it, Dr. Varmus, illumination and--
    Dr. Varmus. Inspirations and culminations.
    Ms. Pelosi. Inspirations and culminations. So following his 
lead of placing these things in categories, I just wondered.
    Dr. Varmus. It's possible the distinction that Dan 
Boorstein makes may be more appropriate to the arts than to the 
sciences. We could pursue that.
    Ms. Pelosi. Well, he also talks about discovering things 
that aren't. You discover things that aren't, and that's 
knowledge as well. You discover places that aren't there.
    Dr. Collins. Right. Little harder to publish, but very 
important. [Laughter.]
    Ms. Pelosi. Well, eliminating possibilities is a gain in 
knowledge.
    Dr. Varmus. Published in different journals. [Laughter.]
    Ms. Pelosi. In any event, I want to join my Chairman, I 
told him I would be brief, I don't know if I was, but in any 
event, thank you very much for your work, Dr. Collins, and your 
leadership. Thank you, too, Dr. Varmus, and everyone here.
    Mr. Porter. And let me add my thanks. You're doing 
wonderful work. I always like to hear under budget and ahead of 
schedule. That's wonderful as well.
    We're always fascinated to sit down with you and Dr. Varmus 
and we learn a great deal every time we do. So thank you very 
much for the fine job you're doing there, and for your 
testimony.
    Dr. Collins. Thank you, Mr. Chairman, for your leadership. 
Thank you for giving us a whole morning. That's a really 
wonderful luxury for the National Human Genome Research 
Institute to have that opportunity.
    Mr. Porter. It's a luxury for us as well.
    The subcommittee will stand in recess until 2:00 p.m.
    [The following questions were submitted to be answered for 
the record.]


[Pages 741 - 800--The official Committee record contains additional material here.]



                                         Wednesday, March 18, 1998.

         NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

                               WITNESSES

ANTHONY S. FAUCI, M.D., DIRECTOR
JOHN LA MONTAGNE, DEPUTY DIRECTOR
THOMAS WILLIAMS, FINANCIAL MANAGEMENT OFFICER
MILTON HERNANDEZ, ACTING DIRECTOR, OFFICE OF RESEARCH ON MINORITY AND 
    WOMEN'S HEALTH
HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS

    Mr. Porter. The subcommittee will come to order.
    We continue our hearings on the budget of the National 
Institutes of Health and are pleased to welcome Dr. Anthony 
Fauci, the Director of the National Institute of Allergy and 
Infectious Diseases.
    Dr. Fauci, would introduce the people that you brought with 
you, and then proceed with your statement.
    Dr. Fauci. Thank you very much, Mr. Chairman. I'd like to 
introduce, on my far left, Dr. Milton Hernandez, who is the 
Acting Director of the Office of Research on Minority and 
Women's Health in our Institute; Dr. John La Montagne, who is 
the Deputy Director of the Institute; Mr. Thomas Williams, who 
is the Director of our Financial Management Office; and you 
know Dr. Varmus and Mr. Dennis Williams.
    I've submitted my written statement for the record, Mr. 
Chairman. I would like to take just a few minutes with some 
visuals to highlight some of the features of that if I could.
    One of the very impressive advances that has occurred in 
HIV/AIDS research and health care delivery over the last year 
has been the rather remarkable decrease in the number of deaths 
due to HIV/AIDS. [See figure 1]
    [The information follows:]


[Page 802--The official Committee record contains additional material here.]



    This is associated with the use of the agents that I 
testified about before this committee for several years in a 
row; namely, the triple combination therapies, including the 
protease inhibitors. However, we cannot become complacent 
because, although this trend is remarkably downward, there are 
still a considerable number of individuals who actually have a 
microorganism resistant to the drugs involved or who cannot 
tolerate the drugs. So the idea of drug development is very 
important and needs to continue.
    But notwithstanding that, a very important effort on the 
part of the NIH over the past couple of years, intensified over 
this year, is the accelerated effort for an HIV vaccine. 
[Figure 2] This has taken the form of a selective increase in 
our research resources relative to other aspects of HIV 
research. It includes a number of innovative programs, such as 
our innovative grant and targeted programs, as well as the 
creation of an NIH Vaccine Research Center, the director of 
which is being actively recruited at the present time.


[Page 804--The official Committee record contains additional material here.]



    HIV/AIDS, as we've mentioned before to this committee, is 
just a very dramatic example of an emerging and reemerging 
microbe. One of the themes of the Institute over this past year 
and into the future as we enter the 21st century is global 
health and the importance of emerging and reemerging diseases 
in our research endeavors with regard to global health. [Figure 
3] This map is just a partial list of some of the important 
diseases that have emerged or reemerged recently. Some of them 
are very familiar to us, such as the E. coli 0157, causing the 
terrible epidemics of E. coli-induced systemic disease related 
to the contamination of certain foods; antibiotic resistance; 
tuberculosis; et cetera; and we could go on and on.




[Page 806--The official Committee record contains additional material here.]



    One of the very dramatic emerging and reemerging microbes 
has been malaria, something that is very under-appreciated in 
the developed world. [Figure 4] The statistics for malaria are 
staggering. Three hundred to five hundred million people are 
infected, with up to three million deaths per year. And the 
most dramatic figure of all is that every 20 seconds a child 
dies of malaria in this world, which is just absolutely tragic. 
What we've done at the NIH, under the leadership of Dr. Varmus, 
has played a major role in a multinational multilateral 
initiative on malaria, where we are lending our research and 
other efforts to a global effort regarding malaria research and 
the development of drugs and vaccines.
    The importance of this is that we've involved host 
countries, particularly sub-Saharan and African countries, as 
well as selectively putting additional research resources, and, 
in addition to that, accelerate the development of a malaria 
vaccine program, including both the intramural program at NIH 
as well as the extramural program through our grants.
    Another example of an emerging and reemerging disease is 
the experience we had this winter with the H5N1 avian 
influenza. [Figure 5] This was an excellent example of the 
collaborative capabilities and efforts among Public Health 
Service and nongovernmental organizations, particularly with 
regard to the CDC who did an absolutely terrific job in their 
response to H5N1 in Hong Kong.


[Pages 808 - 809--The official Committee record contains additional material here.]



    The NIH's role, being a research institution, was to use 
our capabilities, particularly the fact that we had already 
made an antibody to H5N1 that was in our repository. We gave 
the antibody to the CDC, and they used it in the development of 
their diagnostic kits. These kits were so important in the 
screening and surveillance in the Hong Kong area as well as to 
the State and local health authorities right here in this 
country. We moved very rapidly on this. In fact, this was a 
good example. Dr. Varmus utilized his Director's reserve and 
gave us money in the middle of the fiscal year to supplement 
grants for NIH grantees to actually go to Hong Kong and play a 
major role in this effort. And, as you know, it turned out very 
well, but we need to keep our guard up because this may not be 
the end of H5N1.
    Vaccines, as I've said to this committee several times in 
the past, are really the fundamental foundation of how you 
attack global diseases and have a major impact on public 
health. [Figure 6] Over the past several years, I have 
testified regarding each and every one of these vaccines to 
this committee. I just want to point out that the global impact 
of each of these has been most extraordinary. A very cogent 
example of the application of fundamental research all the way 
through to the delivery of health care.


[Page 811--The official Committee record contains additional material here.]



    H. influenza type B is a very good example of this. When I 
first testified before this committee a few years ago, I told 
you that this had the potential to essentially wipe out the 
leading cause of mental retardation and deafness in children. 
If you look at the statistics in the United States, this 
disease is actually disappearing due to the vaccination 
programs. The impact is very impressive even in developing 
countries. There was a recent study from The Gambia in Africa 
in which there was equally as impressive results from 
vaccinating the children against H. influenza.
    Finally, one of the things I'd like to mention to you 
that--I see Ms. Pelosi walk in and she keeps asking me to talk 
about breakthroughs--I'm not going to say breakthrough, Ms. 
Pelosi, but I'm going to say this I think is going to 
revolutionize how we look at transplantation in immunology----
    Ms. Pelosi. Is it a culmination? [Laughter.]
    Mr. Porter. Thank you, Ms. Pelosi.
    Dr. Fauci. Close,--and that is the concept of immunological 
tolerance. [Figure 7] Again, another example of taking 
fundamental basic research discoveries of how the immune system 
works and literally tricking it into not responding to 
something you don't want it to respond to. The most cogent 
example of that is a solid organ transplant. But it also has 
impact on autoimmune diseases as well as allergic diseases.


[Page 813--The official Committee record contains additional material here.]



    Let me give you a very brief example of what I'm talking 
about. The entire immune system when it recognizes something 
like an organ transplant, does so in the context of the cell 
that responds, which we call a T-cell, seeing the antigen in 
question. [Figure 8] If this were a transplantation antigen in 
the context of another cell that presents it, in order for this 
cell to respond and ultimately get rid of the graft, there has 
to be two signals. There has to be the recognition signal and 
what we call the co-stimulatory signal. When that happens, this 
cell responds and all the progeny cells from this cell will 
forever try to eliminate that transplant.
    However, researchers have discovered if, at the time that 
this cell sees that antigen, you block the second signal, not 
only does this cell not destroy the graft, but its progenies 
will never recognize the graft. If this works, and it has 
worked in animals, if this is successful, then we will not have 
to immunosuppress people who have organ transplants. And, as 
you well know, one of the major causes of morbidity and 
mortality in transplant patients is the immunosuppressive 
therapy that you give to people.
    I'd like to close with a slide, a version of which I show 
every year [Figure 9], and that is to reemphasize to you the 
importantmarriage and dependency back and forth between basic 
research--with regard to our Institute it's immunology and 
microbiology, but for other Institutes it can be any of the other 
disciplines--feeding into the practicalities, in our case drug 
development, vaccines, and diagnostics, and then the practical 
applications ultimately feeding back into the basic research. That's 
exactly how the progress has been. The examples that I have shown you 
in this testimony are good examples of just that.


[Pages 815 - 816--The official Committee record contains additional material here.]



    I'd be happy to answer any questions.
    [The prepared statement follows:]


[Pages 818 - 835--The official Committee record contains additional material here.]



    Mr. Porter. Dr. Fauci----
    Mr. Hoyer. We're just going to cheer.

                        future cost of research

    Mr. Porter. Well, we should all cheer. The successes that 
have occurred particularly with reference to HIV/AIDS has just 
been one of the great success stories of all biomedical 
research. AIDS deaths have dropped 44 percent when comparing 
the first six months of 1996 to the first six months of 1997. 
New AIDS diagnoses are also declining. The NIH and the 
researchers within NIH and the researchers that it has funded 
have done an absolutely magnificent job in addressing a real 
threat to humankind and have put it on the defensive, although 
we have not, as you've very carefully pointed out, yet 
conquered it.
    Dr. Fauci, you mentioned that HIV was only one of the 
infectious agents that you have to deal with; there are so many 
others, many causing more deaths around the world even than 
this. Today, if you look at your budget, AIDS research consumes 
about 52 percent of your entire spending on research 
activities. If you looked out five years to the outyears, where 
do you see that percentage number headed? Is there any way of 
telling where we might be five years from now in terms of how 
much you have to spend in that particular area as opposed to 
others?
    Dr. Fauci. Well, Mr. Porter, there are two components to my 
answer. The first is that it's very difficult to predict, 
particularly given the fact that we're still having an evolving 
epidemic. Although the numbers in our own country are going 
down, we cannot slack off on drug development and clinical 
trials. We have a very, very important goal that we need to 
fulfill with regard to vaccine.
    But in NIAID, and with Dr. Varmus and NIH as a whole, we're 
starting to look at the idea of emerging and reemerging 
microbes and to encompass HIV as one of them. So when you think 
in terms of where we'll be with HIV, I think that needs to be 
balanced with where we might be regarding our opportunities in 
malaria and tuberculosis and others. So I tend to like to look 
at the entire effort as global health and emerging diseases of 
which, as you conquer one, then you can accelerate an effort on 
the other. That's exactly the point that I try to make.

                         aids vaccine liability

    Mr. Porter. I don't need to tell you that, as the success 
in dealing with HIV/AIDS has shown itself, there is increased 
pressure on the Congress and this subcommittee to deal with 
other diseases that might, had we had no HIV/AIDS epidemic, 
have received more funding and a chance perhaps to make the 
same kinds of--and I know you don't use the word breakthrough, 
but I'll use it--that same kinds of breakthrough that we've had 
in reference to HIV/AIDS. So, obviously, we are vitally 
interested that we not only continue the progress on AIDS, but 
that we look at the other diseases that are plaguing humankind 
and attempt to reach the same level of success in dealing with 
them.
    What about the liability issues regarding an AIDS vaccine, 
are you dealing with that subject?
    Dr. Fauci. I do not think that with regard to a vaccine 
trial, Mr. Porter, that this is going to be a major issue. It 
always comes up as a potential disincentive for industry to get 
involved. But if one looks at the way a trial is conducted, you 
actually have the types of informed consent that I think would 
be satisfactory, as we do in any vaccine trial.
    If we develop an HIV vaccine and we do have a successful 
safe and effective vaccine, then I think the liability issues 
associated with them would fall under the same category of the 
liability issues that we have with virtually every vaccine. A 
few years ago, that was kind of circling around as a potential 
disincentive. In the interactions that we've had with the 
companies that have been involved or potentially involved in 
the development of a vaccine, I don't see that as a very 
prohibitive issue right now.
    Mr. Porter. Dr. Fauci, we have a vote that has been called. 
As I understand it, it is the last vote of the day. We will 
have to take a short recess. The subcommittee will stand in 
recess briefly.
    [Recess.]

                        office of aids research

    Mr. Porter. The subcommittee will come to order. Dr. Fauci, 
we've made a change in the way OAR is funded, as you know. Have 
you noticed any change in the way the funding mechanism now 
works from the way it did before? And, if so, is the change of 
substance as far as the funding for OAR and your Institute is 
concerned?
    Dr. Fauci. No. Actually, quite frankly, Mr. Chairman, in 
the interactions between OAR and the Institutes over the past 
few years really, there has been no noticeable difference with 
regard to the change in funding. The planning function, the 
coordination, and the interaction has been really quite good. 
Where the funding lands and evolves from really has not had a 
substantial impact, certainly not on NIAID and I don't think 
from my sister Institutes. It has worked well.
    Mr. Porter. This is a question for Dr. Varmus, although you 
both may want to comment. At last year's hearing, you mentioned 
that the Office of AIDS Research had carried out a review of 
the entire AIDS portfolio and came up with a number of 
recommendations. They did not ask for more money; instead, they 
asked for better use of the money.
    My question is twofold. One, what were the recommendations 
from the OAR to make better use of the AIDS portfolio and what 
changes did you make to implement these recommendations? 
Secondly, why, since they didn't ask for more money, are we 
seeing an increase in the AIDS budget request?
    Dr. Varmus. As far as the first question is concerned, 
among the many recommendations, a few were of special 
importance. One was a suggestion that more money go into 
tradition RO1s--that is, more investigator-initiated research. 
Indeed, there has been a major shift, I don't remember the 
exact percentages, but the shift is very substantial, nearly a 
doubling of the amount of money that goes to investigator-
initiated research in the AIDS program.
    The second major recommendation that has a budgetary impact 
was for increased attention to development of an AIDS vaccine 
and to work on human immunology. As you know, in both of those 
areas there has been a very substantial realignment of the 
budget.
    There were a number of other minor recommendations, 
virtually all of which have been carried out--I think very much 
to the benefit of the program--including increasing efforts to 
cope with the spread of infection through behavioral strategies 
and epidemiology.
    The budget increase requested for AIDS this year is 
substantial, of course, but it is below the NIH average and 
only slightly above the smallest increase that we were asking 
for any of the Institutes. We believe that there are very 
significant opportunities in the AIDS portfolio for further 
work. As Dr. Fauci has outlined to you, the problem is far from 
over. We are quite concerned that the 44 percent drop in 
mortality that we have seen is a drop that is caused by 
effectiveness of the drugs in those patients for whom drugs are 
going to work. We still don't know what's going to happen over 
the next few years. That graph may not continue to plummet, but 
may, instead, plateau because we know there is a very high 
frequency of drug resistance and a high frequency of a failure 
to tolerate the protease inhibitors.
    Moreover, we know that the drugs we're currently using are 
not usable in the parts of the world where AIDS is most 
prevalent, and we want to be able to develop drugs that will 
work in those situations.

                             aids treatment

    Mr. Porter. Why is that? Why aren't they usable in other 
parts of the world?
    Dr. Varmus. Because they're too expensive.
    Mr. Porter. So it has to do with the cost of them?
    Dr. Varmus. Yes, the cost is prohibitory. Of course, it is 
not just the cost of the drugs. It's the cost of the entire 
care system required to use these drugs. The monitoring of 
efficacy is based on monitoring of what we call viral load, 
which at this point is still a sophisticated analysis that 
depends upon DNA and RNA hybridization. So the care is simply 
too elaborate for what can be performed in most developing 
countries where most of the AIDS cases reside.

                          aids clinical trials

    Mr. Porter. Dr. Fauci, how do you view the long-term role 
of the pediatric AIDS clinical trials? Will the success of AZT 
and limiting prenatal transmission continue? Will it be 
difficult to find enough infected infants to test combination 
therapies and other therapeutics?
    Dr. Fauci. I think ultimately that's our goal, that there 
will not be enough infants to be able to do that. But 
currently, at the present time, there are still enough infected 
infants that require the kind of clinical trial apparatus that 
we have. We will of course, as these mechanisms come up for 
recompetition, examine, as we've done with the adult ACTG and 
the CPCRA, the size, the scope, and the need for a particular 
approach that we would have. We constantly monitor that. 
Actually, our goal would be that we would not need that 
ultimately, but the goal has not been attained yet.
    Mr. Porter. Thank you, Dr. Fauci.
    Mr. Stokes.

                           aids in minorities

    Mr. Stokes. Thank you, Mr. Chairman.
    Dr. Fauci, it's a pleasure to welcome you back before our 
subcommittee. As Mr. Hoyer said when you finished your 
presentation, rather than ask you questions, we wanted to 
cheer. I think all of us are proud of your preeminence in the 
field of medicine, and it's a pleasure always to have you 
before us.
    You started your presentation with a chart on AIDS and 
talking about the fact that we're now seeing some decrease in 
AIDS. However, you were present in the hearing room a few days 
ago when Dr. Brule, of the Centers for Disease Control, and I 
discussed the fact that AIDS in the black community is seven 
times that of the rate in the white community and three times 
the white rate for hispanics. In fact, I cited the fact that 
within the next hour seven persons will contract HIV/AIDS, and 
that of them, three will be minorities.
    So while you give us some good news in terms of the 
decrease in the number of aids deaths, we're dealing with these 
type of statistics. Is the news as good as it relates to 
minority communities?
    Dr. Fauci. No. The answer is, no, it is not as good. In 
fact, if you look at the decrease in deaths and the decrease in 
new cases, it is skewed with much less of a decrease among 
minorities and actually an increase among women and 
heterosexuals. Among the heterosexuals, particularly in the 
inner-city areas, there is a skewing of the curve towards 
African-American and Hispanics in those situations. So although 
the total numbers are getting better, at best they're holding 
steady, and in some cases actually not doing very well at all.
    At the NIH, we have tried to address that because, as you 
might imagine, it's a very complicated situation that's really 
very integrally related to the inadequacies of health care 
delivery to inner-city and disenfranchised populations. What 
we've tried to do is several things.
    One is, we have tried to keep the enrollment of minorities 
in our clinical trial program at least to the level, and even a 
greater proportion than the percentage of minorities that are 
infected with HIV and have AIDS. As I've told the committee 
over the past few years, we started off at what we all 
considered was an unacceptable number. But right now 35 percent 
of the AIDS cases are among African-Americans and 37 percent of 
the enrollment in our clinical trials is of that group. So we 
are keeping up with that.
    We also have other mechanisms that are fundamentally aimed 
at trying to bring minority populations into our research 
efforts: our HIV Network on preparatives and prevention, our 
Women's Interagency Health Study, and our Women and Infant 
Transmission Study. We've been relatively successful.
    We're not doing enough, but we're doing a lot. There are 
things that are beyond our control, and that's the health care 
delivery components that I have mentioned to you. But I share 
with you the concern you have that the numbers, if we broke 
them down for minorities and non-minorities, we would see 
something that wasn't as encouraging in the minorities.

                          outreach activities

    Mr. Stokes. I appreciate very much your response.
    Let me ask you this. In terms of trying to engage in 
outreach, and I suppose your Institute does have some outreach 
aspect.
    Dr. Fauci. Yes.
    Mr. Stokes. I'm concerned, for instance, about the fact 
that up at the Harvard AIDS Institute, with which I'm sure 
you're familiar, I sit on that advisory board up there, just 
recently reported that they fear that while the appropriations 
may be satisfactory, a lot of the money is not filtrating down 
to community groups, where outreach is prevalent, in order to 
try and attack this overall problem.
    To what degree are you engaged in outreach in this area?
    Dr. Fauci. We have a significant engagement in outreach in 
our clinical trials and in our prevention efforts. A good 
example of that is our community groups that are associated 
directly as an integral part of our AIDS Clinical Trial Group. 
For every clinical trial group unit that we have, we have a 
community program that actually outreaches into the community.
    So, unlike what it was years ago, before we even begin to 
think about executing a clinical trial in a community, we have 
community representatives that are actually an up front part of 
the process of discussing the feasibility of it and whether or 
not it's going to fit with the community. That's something that 
we instituted several years ago and it's working very well. 
I've actually been personally involved in it and meet at least 
once and sometimes twice a year with the community groups.

                     development of an aids vaccine

    Mr. Stokes. Good. You mentioned in your presentation an HIV 
vaccine. How far are we away from achieving a vaccine for AIDS?
    Dr. Fauci. I can't tell you in terms of years, but I can 
tell you that we have mounted an accelerated effort to try and 
iron out some of the unknowns about it. Namely, what we call 
the correlates of immunity, to take some new innovative 
approaches to dissecting out some of the mysteries of how the 
body responds to HIV and contains it. It would not be 
appropriate for me to say it's going to be two years, or three 
years, or five years. But suffice it to say, that over the past 
two years, and as we go into the millennium, we are selectively 
having more activity and resources towards the HIV vaccine.
    We have a candidate approach right now that is in Phase II 
trials in many of our vaccine evaluation groups. It is 
predicated on the concept of priming someone with an HIV 
antigen that's incorporated into a vector, in this case a pox 
virus, a Canary pox or a vaccinia pox, and then boosting the 
person on multiple subsequent times. In that approach, we have 
what we did not have with the simple GP120 protein that we 
discussed here I believe three or four years ago. In addition 
to having antibody response, we have a cytolytic T cell or 
cell-mediated immune response. We're going to be evaluating 
that data in mid to late summer to make some sort of a decision 
of where we go with that; do we expand it or do we incorporate 
other limbs. So there is some promise in that regard.

                             global health

    Mr. Stokes. I was interested in your presentation this 
morning relative to emerging microbes where you talked about 
malaria and the fact that every 20 seconds a child dies from 
malaria. What part of the world are we talking about?
    Dr. Fauci. About 90 percent of the malaria deaths that 
you're talking about are in sub-Saharan and Africa. So it's a 
very heavy burden in sub-Saharan and African countries.
    Mr. Stokes. Thank you, Dr. Fauci.
    Dr. Fauci. Before you leave, Mr. Stokes, I just want to 
make mention of something that other institute directors have 
said. This is my 14th year that I've appeared before you now 
and I just want to say that we're going to miss you very, very 
much. You've been wonderful with us and we truly, sincerely 
appreciate it and thank you for everything you've done.
    Mr. Stokes. Thank you very much, Dr. Fauci. Thank you, Mr. 
Chairman.
    Mr. Porter. Thank you, Mr. Stokes.
    Mr. Hoyer.
    Mr. Hoyer. Dr. Fauci, again, all of us welcome you. I think 
the dramatic success that your chart and the work reflects is a 
powerful support of the support this committee has given in 
terms of some of the priorities. We needed to look at AIDS 
which, in terms of numbers is outranked by some in the United 
States in gross numbers, perhaps not in fatalities per 
infected, it may be the highest disease still?
    Dr. Fauci. Yes.

                   microbial association with cancer

    Mr. Hoyer. But from Presidents Reagan and Bush to President 
Clinton and this committee, the support that has been given to 
AIDS research has been very substantial. I think this is 
something we can point to and say, look, if you dedicate 
resources to it, it can have a pay-off. Quite obviously, I 
think we all look forward to the day when we will have similar 
statistics for cancer, a dramatic turnaround. That will be a 
great day for all of us.
    I wanted to ask you a question I obviously have a personal 
interest in. You have been quoted as saying, or you've 
mentioned at least, that some cancers are virus related, 
stomach cancer perhaps being one of those. Could you comment on 
that a little further? Obviously, that's thecancer which Judy 
died of and I have a real interest in that.
    Dr. Fauci. Right. In the case of stomach cancer, it is not 
a virus, it's a bacteria, Helicobacter pylori. As we learn more 
and more about microbes, and as we have the capability of 
identifying microbial associations with cancers by molecular 
probes, as the years go by, we see more and more. We know 
there's an association of human papilloma virus with cervical 
carcinoma, a B virus with certain types of lymphoma, of 
Helicobacter pylori with gastric carcinoma, of hepatitis B and 
hepatitis C with carcinoma of the liver. The list goes on and 
on.
    There's a very important amount of information that needs 
to be learned, because all of us in the field believe that we 
will probably continue to see more associations, either direct 
or indirect, as cofactors that are involved in cancer. That's 
the reason why we're seeing a sort of crossroads of infectious 
disease and microbiology with cancer research. A very, very 
important area of research.
    Mr. Hoyer. One of the things that struck us as we faced 
that was the few number of instances of stomach cancer in women 
in the United States versus the Far East where there apparently 
is a very high incidence and, therefore, a much greater 
inclination for early diagnosis. One of the things in Judy's 
case that we were so taken aback by was that it took so long to 
find out, even after going the first three visits to Hopkins. 
They did not find it until the fourth visit when they finally 
diagnosed the cancer. It, of course, grew in the lining of the 
stomach and did not tumor. They thought it was an ulcer.
    What are we speculating? Is this diet related?
    Dr. Fauci. It is probably, as is the case with many 
cancers, multifactorial, a combination when you think of it, a 
microorganism that contributes to people who have some sort of 
predisposition. Just because you have Helicobacter pylori 
doesn't mean that you're inevitably going to wind up with 
gastric cancer. Also, genetic makeup and genetic background, 
I'm certain that there is some genetic component to it that has 
not yet been deciphered out. Then you add on that dietary 
component and you have what we call the multifactorial nature 
of cancer.
    All the things have to be in the right situation for you to 
get a cancer, which is the reason why very rarely, if ever, do 
you see an absolute one-to-one relationship between a cancer 
and a particular factor, be that a microbe or a genetic factor. 
In some, there are very, very strong relationships, such as 
some of the breast cancer genes that have been delineated and 
shown to have in certain populations an extraordinarily high 
incidence. But it is usually a combination of multiple factors 
that just have to hit it right for you to get a cancer.

                            asthma research

    Mr. Hoyer. Let me shift. I think it was on your last chart 
as you went around, you had the only malady, if I could use 
that term probably imprecisely, was asthma and other allergies 
in that chart.
    Dr. Fauci. Right.
    Mr. Hoyer. That interested me because you did not have any 
other specifics. I suffered from asthma. Why was that? And what 
are you doing in your Institute as it relates to the other 
Institutes that focus on asthma?
    Dr. Fauci. The reason I put asthma there is because it's 
particularly amenable to the approach of immunological 
tolerance that I mentioned to you in the previous poster. There 
are two ways, well, there are multiple ways, but there are two 
major ways that we at the NIAID, and the National Heart, Lung, 
and Blood Institute also has a major effort on that, are 
looking at asthma.
    One way is from the concept of more of a health care 
delivery component, where our inner-city asthma program has 
identified certain factors, such as cockroach allergen and the 
proper way to take medications. So that when you have a 
counsellor or an outreach person who is there making sure the 
medications are being taken properly, they are also making sure 
that children who have an asthma diathesis are not in an 
apartment that has cockroach antigens all over it. The 
hospitalizations have decreased by a considerable amount over 
the couple of years that we've been doing it. That's the more 
practical approach to health care delivery.
    On the more basic approach, the immunological tolerance and 
trying to tolerize the system when it sees the antigen that 
would normally trigger an asthma attack on you, would have the 
same sort of refractor as I was referring to regarding the 
organ transplants. I think that's in the foreseeable future.
    Mr. Hoyer. Obviously, an allergy triggers a reaction and 
the mucus is formed. Did you see the movie ``As Good As It 
Gets''?
    Dr. Fauci. No. No, I didn't.
    Mr. Hoyer. It is a pretty neat movie. You'd like it. Part 
of the story is about a waitress who has Jack Nicholson as sort 
of a kooky client or customer. But ultimately he interfaces and 
becomes----
    Ms. DeLauro. Don't tell the end. [Laughter.]
    Mr. Hoyer. I'm not going to tell the end. But he becomes 
someone who helps her get her child treatment for asthma. Her 
child suffers from asthma. But in the course of that, of course 
they excoriate HMOs because the HMO has not funded all of the 
processes that are necessary to find out what allergens the 
child is responding to or what's causing this problem. And, the 
bottom line is he gets better and that's great.
    How prevalent do you think that is? In terms of the 
children who do not have access to private health care but are 
getting clinic care or some other lower cost care, how 
prevalent do you think it is that a lot of children in America 
are suffering who otherwise could through intervention be 
relieved of suffering because they are not getting proper 
health care?
    Dr. Fauci. It's very prevalent.
    Mr. Hoyer. Very prevalent.
    Dr. Fauci. In fact, that's one of the targets of our inner-
city asthma program. We were seeing that children in the inner-
cities were not properly instructed on how to take their 
medications and there were many more hospitalizations and even 
some deaths among those children, merely because what is 
available to someone who has a physician, who on a consistent 
basis tends to them. The difference between that and someone 
who does not have that access is extraordinary.
    Mr. Hoyer. Doctor, this may sound off the wall and you'll 
wonder why is Hoyer mentioning this. I am a big proponent of 
what I'm now calling full service schools. Full service schools 
would have a very strong health component to them, mainly in 
the elementary school. One of the reasons is in these 
communities where children don't have access to goodhealth 
care, particularly when it is a relatively simple intervention and a 
relatively inexpensive intervention, it is criminal that in a country 
as wealthy as the United States of America is we are allowing children 
to go undiagnosed and unserved in terms of health care.
    In any event, Mr. Chairman, this is another reason why I'm 
going to hound all of you on the full-service school concept 
when we have markup.
    Thank you, Doctor.
    Mr. Porter. We like it, Mr. Hoyer. Thank you.
    Would Mr. Miller take the Chair, please.
    Mr. Miller [assuming chair]. Ms. DeLauro.
    Ms. DeLauro. Thank you, Mr. Chairman.
    Dr. Fauci, as I came in during your presentation and was 
listening to you, and having listened to you in the past, my 
colleague, Ms. Pelosi, yesterday said to Dr. Alexander that he 
must have one of the best jobs in the world. I was just sitting 
here thinking as I was listening to the questions that I think 
we've got the best job in the world. We have the opportunity to 
listen and, hopefully, to learn something of what you, 
specifically, with the other directors in NIH are doing.
    It really is a remarkable opportunity that we all have. I 
don't mean to be hokey, I truly don't. I am so delighted that I 
have the opportunity to be in this institution and to serve on 
this committee and listen to the incredible kinds of research 
that is being done and what it means in terms of lives of 
people in this country. I just wanted to say thank you for all 
of that.
    Dr. Fauci. Thank you.

                     Sexually Transmitted Diseases

    Ms. DeLauro. The whole issue of sexually transmitted 
diseases continue to affect a large number of Americans, 
particularly women and minorities. Studies show that if we can 
reduce the number of new infections of diseases like syphilis 
we can also reduce the number of people who contract the HIV 
virus. My interest is in getting some update on your work that 
helps us to prevent and control the sexually transmitted 
diseases.
    Dr. Fauci. We have an effort that we have been accelerating 
over the past couple of years that is centered around our 
sexually transmitted diseases centers, which have not only a 
fundamental basic research base looking at the biology and the 
microbiology of STDs, but also that have a behavioral component 
in it. In other words, a biologically based behavioral 
component.
    The point that you made about the relationship between 
sexually transmitted diseases and, for example, HIV 
transmission cannot be underestimated because there are 
definitive studies in other environments that show that. For 
example, a study in sub-Saharan and African countries showed 
that if you go into a village and treat just the sexually 
transmitted diseases and do not have anything else to do with 
HIV, you can markedly cut down the transmissibility of HIV 
merely by getting rid of those infections that leave genital 
ulcerations which markedly increase the efficiency of 
transmission.
    Another thing about sexually transmitted diseases that came 
out this year that I didn't have the opportunity to talk about 
last year because it happened just a few months after last 
year's hearing, is the importance of early diagnosis of 
chlamydia infection in women. Look at the relationship between 
chronic pelvic inflammatory diseases and chlamydia. If you go 
in and diagnose chlamydia in asymptomatic women and treat them, 
even though they don't have symptoms, as compared to waiting 
until the woman comes into the office with symptomatic 
chlamydia, the decrease in chronic pelvic inflammatory disease 
is extraordinary. It goes down by about 30 or 40 percent just 
by having the diagnostic capability and the health care 
delivery capability of bringing women in and diagnosing it even 
when they don't have symptoms.
    Close to the majority of the chlamydia infections are 
essentially asymptomatic. Women do not know they have it until 
they wind up either having symptomatic pelvic inflammatory 
disease or they find out when they're trying to have children 
and they have tubes that are scarred. That's really a tragedy 
because the diagnosis can be made beforehand. You have just got 
to get them into the clinic and make the diagnosis. That, I 
think, has been an important advance over the last year.
    Ms. DeLauro. And getting them into the clinic, what's your 
sense of your advances in doing that? It's a little bit like 
what my colleague, Congressman Hoyer, was talking about with 
youngsters in school-based clinics.
    Dr. Fauci. It's the same problem. Congressman Hoyer 
mentioned about asthma, Mr. Stokes mentioned it about the 
access to care among the minorities with HIV, and it's the same 
point you're making about getting women into clinics, it really 
relates to the adequacy of the access to health care delivery.
    Ms. DeLauro. Continuing on that just a bit, I'm interested 
in your work regarding HPV, and you made reference to it 
before. How has that research progressed? Are you continuing in 
your work with NCI on that?
    Dr. Fauci. Yes. Actually, we have a very nice collaboration 
with the National Cancer Institute, ourselves fundamentally 
from the microbiological standpoint, the Cancer Institute from 
a oncologic and epidemiological standpoint. It is really 
working very well. It is again an example of needing to develop 
better diagnostic capabilities, the same sort of early 
detection that I mentioned with regard to chlamydia, as well 
prevention, certain types of outreach and education, in 
addition to ultimately therapies and vaccines which are always 
the bottom line of eliminating a public health threat like 
this.
    Ms. DeLauro. Clinics with regard to breast and cervical 
cancer, if we can have these clinics in every State and so 
forth rather than just at random.
    Dr. Fauci. Right.
    Ms. DeLauro. Or it takes us I don't know how many years to 
get there. I'm just sharing a frustration. I guess it's by 
virtue of your geography that could determine whether you live 
or die.
    Dr. Fauci. Or your economy.

                           Hepatitis C virus

    Ms. DeLauro. Given the kind of work that's being done, 
given the rapid pace at which we're moving to understand some 
of these illnesses and the connections, it would just seem to 
me that that's the harder job. I just think that the easier 
part of the job is the outreach and the education portion of 
it. That is something that we should know how to do and we're 
being delinquent in getting what research and what information 
that we have that can save people's lives out to them in some 
way.
    Hepatitis C has emerged as a major cause of chronic liver 
disease. As you know, a large number of people may 
haveunknowingly contracted the virus through blood transfusions and 
most likely will develop complications of the disease in coming years. 
Last year's committee report encouraged NIAID to develop an HCV 
vaccine, to conduct clinical trials research in order to find the best 
treatment for the disease. How have we progressed on the research and 
the carrying out of the clinical trials?
    Dr. Fauci. There has been some important advances that I 
think are going to lead to something that probably I'll be able 
to talk in more concrete terms about next year. But the 
research discovery is important; namely, that there has been a 
successful isolation of what we call an infectious cDNA clone 
of hepatitis C, which means that we have the molecular 
microorganism in our hands now so we can (a) use it in animal 
models to look at pathogenesis; and (b) that's the next step 
towards tailoring some more efficient and more effective 
antiviral therapies.
    Right now, the riboviren and the interferon alpha are the 
fundamental tools that we have for the treatment, but that is 
not a very effective treatment. The ultimate goal will be 
vaccination, obviously. Having the microorganism in its 
molecular form in our hands is the first major step towards 
developing a vaccine. If we could have the same sort of success 
that we've had with hepatitis A and hepatitis B and apply that 
to hepatitis C, I think we're going to have a major impact. As 
you well know, about 80 percent or more of the people who have 
hepatitis C go on to chronicity of infection. That's a very, 
very large percentage, whereas in, for example, hepatitis B, it 
is about 25 percent of adults and about 70 to 75 percent of 
children. But 80 to 85 percent is a lot. As you know, it is the 
leading reason for liver transplants today in this country.
    Ms. DeLauro. Thank you very, very much.
    Dr. Fauci. You're quite welcome.
    Mr. Miller. Ms. Pelosi.
    Ms. Pelosi. Excuse me. I'm waiting for Dr. Varmus to bring 
in a picture of somebody with a chocolate addiction to see what 
their brain looks like. [Laughter.]
    Mr. Varmus. It looks good, Ms. Pelosi, I hope. I suffer, 
too.

            HIV Treatment Guidelines and the Ryan White Act

    Ms. Pelosi. I'm very happy. Sorry to do that. I was 
watching those charts before and I just had to go get some 
chocolate.
    Dr. Fauci, thank you and Dr. Varmus, all of you, for being 
here today. We've commended Dr. Varmus over and over again for 
his great leadership at the NIH. And you know what a hero you 
are to so many of us in the work that you do. We're just always 
happy each year that you're still there. That's my worry is 
that you won't be there one of these times.
    You co-chaired the HHS advisory panel which developed 
treatment guidelines for people with HIV. These guidelines have 
been critically important to health providers and policymakers 
as we work to maximize the benefits of the powerful new drugs 
in fighting HIV. In your opinion, how do the new treatments 
affect the scope of services that should be provided under the 
Ryan White Care Act?
    Dr. Fauci. I think they're going to be very important in 
how we look at the various components of Ryan White, because we 
now have, as you know, looked very, very carefully at all the 
data and made strong recommendations that if an individual 
comes in with a certain level of virus and a certain degree of 
immunosuppression, that they need to be treated and they need 
to be treated with at least a triple combination of drugs. The 
other thing that we decided strongly on is that adherence to 
the regimens is critical, not only for the individual patient, 
but in order to avoid the emergence of resistance. So there are 
really two components of the Ryan White that are affected by 
that.
    One is the Title II ADAP program. So there is no excuse 
right now for anyone to say that you can't give anything other 
than optimal therapy, which in this case would be triple 
therapy including a protease inhibitor. Now some of the 
recommendations are even going to be updated and might even 
include four drugs under certain circumstances. But, certainly, 
one or two drugs has clearly been said to be inadequate.
    With regard to the other aspect of the Ryan White; namely, 
the services component, the Title I, I think if we don't have 
that kind of case management, we're in danger of having people 
not have adherence to the regimen. To me, our recommendations 
do nothing but strongly fortify what is going on vis a vis the 
Ryan White provisions.
    Ms. Pelosi. I appreciate that and I thank you for your 
leadership in working to put out the treatment guidelines 
because they have been very important. I also appreciate your 
talking about the challenges that people face in complying with 
the complex drug regimens. Just doing sufficient outreach to 
people is difficult even in an area as sophisticated about this 
issue as my own. The physicians there tell me that we would be 
lucky if we can get 50 percent penetration into the market of 
people who should be availing themselves of these drugs.
    Dr. Fauci. Right.
    Ms. Pelosi. And, of course, the other obstacle is the same 
old one, and that is sufficient resources for those who cannot 
afford the therapies.
    But the guidelines, of course, went a long way in making it 
clear to the private sector as well as the public sector what 
needed to be done, and I thank you for that valuable 
contribution.

       Intergovernmental Cooperation in International Initiatives

    I've asked Dr. Varmus and I've asked in my other committee, 
Foreign Operations, of the USAID director, what kind of 
intergovernmental cooperation you have on the international 
initiatives. I heard you when I came in earlier talking about 
malaria and AIDS as two initiatives. Can you talk about any 
interaction.
    Dr. Fauci. Actually, it has been very good, Ms. Pelosi. One 
of the examples is the Multilateral Initiative on Malaria that 
has been led very nicely by Dr. Varmus himself taking a special 
interest in that. We have interactions with USAID, with the 
Department of Defense, with the FDA, with the CDC, and others, 
as well as international organizations. All of our AIDS efforts 
are grounded not only in national agency collaboration, but 
international collaboration.
    A very, very good example of the Public Health Service 
interactions and non-Public Health Service Government agencies, 
like the Department of Defense and others, was what went on in 
Hong Kong with the H5N1 flu. That was really quite remarkable. 
We have a flu pandemic plan in the Public Health Service that 
emanates out of Secretary Shalala's office. Right from the very 
beginning we all met, and each had a job to do; the FDA had a 
job, the CDC had a job, if necessary the DoD would have a job, 
and we had interactions with them.The NIH's role was to provide 
some of the science that was associated with developing the diagnostic 
kits that the CDC very, very efficiently got put together and 
distributed to do the surveillance that was necessary to see what the 
scope of the epidemic was.
    You might recall that it was unclear whether or not there 
was efficient human-to-human transmissibility or whether it was 
just bird-to-human. The decision that it was only tangential 
evidence of human-to-human--namely, one or two health care 
workers had antibodies that they probably had through exposure 
to a sick child but they didn't get sick--was a spur to try and 
put an end to the chicken-to-human transmission as rapidly as 
possible. Based on that, the decision to slaughter the chickens 
in Hong Kong was made, which clearly the proof of the pudding 
is that it shut the epidemic right down. That was a good 
example of the interagency collaboration.
    Ms. Pelosi. Congratulations.
    Dr. Fauci. Thank you.

                              aids funding

    Ms. Pelosi. That could have been a terrible thing. In some 
of my time that I have remaining, I wanted to ask you if you 
would just for a moment talk about the percentage of AIDS 
funding, because earlier it was mentioned that now that we've 
spent all this money on AIDS, too bad we didn't have it to 
spend on other things if AIDS had never appeared. I happen to 
think that the issue of AIDS increased the NIH funding and the 
whole pie was increased at the same time. So AIDS wasn't taking 
up any other money.
    But I do know, because I've heard you say in the past and I 
want you to say again, what percentage of AIDS funding goes for 
basic research which is applicable to discoveries for a wide 
range of diseases, particularly what it has contributed to our 
understanding of the immune system, and some of the things 
we've learned--it's really a repetition of my first question--
that would benefit us with other diseases.
    Dr. Fauci. If you look at the various aspects of what we 
call the functional categories--pathogenesis, drug development, 
vaccine--at least 50 percent, and probably much more than that, 
closer to 60 percent is involved in doing things that have 
rather striking extrapolation to other disciplines. I've given 
you examples in the past and I'll repeat some of them.
    For example, the whole question of diagnostics with 
molecular probes, although we had it before, it's been brought 
to a new level of sophistication. What we learned from the 
diagnostic capabilities with PCR and other techniques for HIV 
has played a major impact in the use of those, for example, in 
our diagnostic capability for chlamydia.
    When you talk about targeted drug design, there's an 
example that's more than a practical example. The development 
of Livimudine 3TC for HIV is now used very successfully in 
hepatitis B. So you have a drug that was developed for one 
virus that is now effective against another. But it really goes 
beyond that. It goes to the whole concept of targeted drug 
design, crystallization, tailor made components of drugs that 
are then used. That's the reason why I brought in the idea that 
when you think in terms of emerging diseases and what we're 
interested very much in is global health. The spin-offs from 
HIV research are almost going to be nonseparable from our 
approach towards other diseases. So it's a very strong 
component of positive spin-offs.
    Dr. Varmus. Ms. Pelosi, I have one comment here. I'm going 
to endorse everything Dr. Fauci has said, and I want to add one 
further comment. I think it would be a mistake to take away 
from the decline in mortality the idea that if the money 
invested in AIDS had been invested in something else we would 
see the same decline in mortality.
    One of the reasons that money was devoted to the AIDS fight 
in very substantial amounts is because we knew what the cause 
was. It was an infectious agent. It was like having an invader 
arrive on your shores, putting at risk of death as many as a 
million people, and knowing what that invader is, having some 
of the tools available that we thought could combat it. We 
haven't succeeded on all fronts yet--we don't have a vaccine, 
we don't have the ideal therapeutic armamentarium--but it is a 
very different matter to attempt to reverse the mortality rates 
in an infectious disease than it is in some of the other more 
chronic, difficult conditions that we also think we can make 
progress on, but where progress is going to be more difficult.
    Ms. Pelosi. I appreciate that addition, Dr. Varmus. Thank 
you very much, both Dr. Fauci and Dr. Varmus, and you, Mr. 
Chairman.
    Mr. Miller. Mrs. Lowey.
    Mrs. Lowey. Thank you, Mr. Chairman.
    I, too, want to join my colleagues in admiration of you, 
Dr. Fauci. In fact, as I look through your biography, I really 
wonder if maybe you can give us some answers to the secrets of 
life and success, and when do you sleep and when do you eat. 
[Laughter.]
    Dr. Varmus. He won't even tell me, Mrs. Lowey.
    Mrs. Lowey. Well, you're doing pretty well yourself. 
[Laughter.]
    On this committee we manage to get some free medical advice 
as well. Since we don't watch ER, we depend upon this 
committee. [Laughter.]

                      public-private partnerships

    But I do join my colleagues in amazement at how you have 
enough hours in your day. I won't ask you to testify on that 
today, but before I ask a question, I just want to associate 
myself with the question of my colleague, Congresswoman Pelosi, 
and the response of both Dr. Fauci and Dr. Varmus. I do wish my 
colleagues were here to hear that because I think this is so 
very important that the investment in AIDS research and the 
paths that your answers are taking us on are really providing 
cures for so many other diseases. I think it's important that 
we understand that and mention it again. I'm so glad that my 
colleague, who has been a leader in this committee in 
investment in AIDS research, brought that up. I, too, 
appreciate your responses.
    I was very pleased, Dr. Fauci, to see in your budget 
justification that the Institute is participating in the public 
awareness and physician education activities of the Jeffrey 
Modell Foundation. Many of us on this subcommittee have met 
with the Modells and have been following their very important 
work. If you could either now or for the record tell us how 
much money the Institute has actually contributed to the 
Interactive Physicians Symposium that was cosponsored by the 
Foundation and several NIH Institutes in collaboration with the 
American Red Cross on October 31st of last year, that would be 
helpful.
    Many of us on both sides of the aisle have beeninterested 
in public-private partnerships and the Modell Foundation is certainly 
an excellent example of that.
    Dr. Fauci. The exact figure I'll supply for the record. But 
I can tell you that it has been a most fruitful collaboration. 
We've had very good interactions and I believe the product of 
the outreach that we've been able to accomplish has been 
productive.
    [The information follows:]

         Education Program on Primary Immunodeficiency Diseases

    The NIAID was involved in several aspects of the Continuing 
Education Program on Primary Immunodeficiency Diseases, 
cosponsored by the Jeffery Modell Foundation, the American Red 
Cross, and three NIH Institutes. We actively participated in 
the planning process by providing recommendations of panelists 
and topics for discussion, developing appropriate materials, 
and disseminating information of the program to sites 
throughout the United States. As part of our support, the NIAID 
initially agreed to support the attendance of three scientific 
panelists. In an effort to provide a wide breadth of experience 
and thorough consideration of the issues, we ultimately 
provided additional support that allowed four scientific 
panelists to attend. Total costs for the activity were $6,400.

    Mrs. Lowey. Have you had other examples of this type of 
collaboration, or is this rather unique?
    Dr. Fauci. Actually, it's not unique. We have 
collaboration, for example, with the Juvenile Diabetes 
Foundation, with the Arthritis Foundation, a variety of others, 
and some of the infectious disease groups. We put a strong 
stock on reaching out to our constituency groups. We believe 
that they have a lot to offer to give us a really good feel for 
what is going on in the trenches and the directions that we 
need to go. That is one of the things that the Jeffrey Modell 
Foundation provided, because they took a very keen interest in 
childhood immunodeficiencies which, obviously, are an important 
component of what we do from an immunological standpoint.

                  centers of excellence in immunology

    Mrs. Lowey. I thank you. I also see in the justification 
that in fiscal year 1999 you will be launching Centers of 
Excellence in immunology. I have a couple of questions related 
to these centers.
    First of all, how many centers do you expect will be funded 
in fiscal year 1999 and beyond?
    Dr. Fauci. Four to five in 1999. Depending on how they do, 
which I believe they'll be successful because the pool of 
investigators that we hope will respond to that initiative are 
of the highest quality, so if we have a good response, then we 
will likely expand that in the future. That's part of our plan 
for expanding our efforts in that regard, depending on the 
budget.
    Mrs. Lowey. You mentioned several immunology issues that 
will be addressed. Will one or more of these centers do 
research into inherited genetic disorders?
    Dr. Fauci. Yes. As a matter of fact, particularly the 
genetics of the immune response. I believe a question came up, 
in fact, it was Mr. Stokes who asked, of the different 
components that go into the development of cancer--
environmental, genetic, infectious, et cetera. The same thing 
holds true with the body's capability of responding 
immunologically to a particular stimulus; that is, 
understanding the fundamental genetic makeup that allows me to 
respond in a certain way to a particular disease. Why does 
someone get Lupus and someone does not? Why does someone get an 
inflammatory vascular disease and someone does not? Why do 
women get takayasu arteritis and men hardly ever do? All of 
that is going to be studied in that component of the 
immunological response.
    Mrs. Lowey. I won't even ask you to explain what that last 
one was. But you could for the record because others may be 
interested. I was going to ask as if I knew.
    Dr. Fauci. It's a very interesting form of inflammatory 
vasculitis that I have actually studied prior to my life in 
AIDS when I was doing fundamentally rheumatologic disease. It's 
an inflammation of the large blood vessels around the aorta and 
around the valve that leads from the heart to the aorta. It is 
seen almost exclusively in women and it can be a very 
devastating disease leading to stroke and congestive heart 
failure and death.
    Mrs. Lowey. Another question regarding the centers. Do you 
expect them to begin by themselves, or will they be connected 
to other centers?
    Dr. Fauci. What they will be is a conglomerate of 
investigators, almost all of which have been RO1 or PO1 
grantees of the Institute. The purpose of the centers, as we 
have done, for example, with the Centers for AIDS Research, are 
to bring them together with an infrastructure approach that 
would allow them to synergize better, as opposed to having 
individual components of the grantees.
    Mrs. Lowey. So existing immunology centers would be able to 
apply?
    Dr. Fauci. Without a doubt. There are no limitations on who 
can apply to that.

                           diabetes research

    Mrs. Lowey. Another area that we've had a lot of interest 
in in the committee, certainly with the Institute of NIDDK, is 
the area of diabetes. I know that there is cooperative effort 
in that regard, certainly with regard to the successful 
transplantation of insulin-producing cells.
    Dr. Fauci. Right.
    Mrs. Lowey. Could you give us some idea of the contribution 
your Institute is making with regard to that?
    Dr. Fauci. Yes. Actually, that plays very nicely into the 
slide that I had put up about immunological tolerance. In fact, 
we presented to Dr. Varmus several months ago because this was 
such a hot area of immunological tolerance, and we had a 
proposal for trying to tolerize in islet cell transfusions for 
the treatment of people with established diabetes. Dr. Varmus 
actually used his 1 percent transfer authority to give the 
Institute $4.5 million to jump start that program which we are 
now in 1999, the budget that we're addressing here, going to 
try and accelerate that.
    Our role in that, in close collaboration with NIDDK, is to 
provide the immunological component towards the approach in 
diabetes. In this case, it fits in perfectly with immunological 
tolerance.

                          topical microbicides

    Mrs. Lowey. On another area, could you give us an update on 
the status of clinical trials for over-the-counter spermicides 
as microbicides and for new topical microbicide products?
    Dr. Fauci. Yes. We have several clinical studies that are 
ongoing right now. There is one going on with nonoxinol-9 and 
its effect on the prevention of HIV transmissibility. The 
definitive data is not in, but the study is off the ground and 
is doing very well.
    We also have some animal model studies that are being 
employed. One of the difficulties with using topical 
microbicides, that we haven't completely gotten over the hurdle 
yet, is the inflammatory component, the double-edged sword of 
killing a microbe but causing vaginal or cervical inflammation 
that might then propagate transmission of HIV. There's an 
animal model now of transplanting vaginal tissue and looking at 
what the components are of the inflammatory component, so that 
we can get the microbicidal effect without the inflammatory 
effect.
    So we have an actual clinical trial that's ongoing and we 
have a basic research animal model trial going. So I'm 
optimistic that it is going in the right direction.
    Mrs. Lowey. Thank you. I think my time is up.
    Mr. Porter [resuming chair]. Thank you, Mrs. Lowey.
    Mr. Miller.

              articulating the importance of nih research

    Mr. Miller. To start off with, I'm on the Budget Committee 
also and I have a great frustration, and Dr. Varmus and I 
talked about it the other day. In fact, we're going back into a 
meeting at 4:30 this afternoon, working to make sure that we 
have the maximum amount that we can work through our budget for 
biomedical research. We've been going through this debate in 
the Budget Committee of what do we do with our surplus issue, 
too. And it's always good to see when the Speaker of the House 
comes in and testifies that research has to be one of those 
priorities for any surplus revenue.
    But I feel we still have an educational issue that we need 
to work on for all 435 Members. As Ms. DeLauro said, it's 
exciting for the few of us who get to sit on this committee, 
but there's 400-some other Members and we need to do whatever 
we can to help educate them on the benefits of biomedical 
research. I think we're trying to work out a trip for the 
Budget Committee members. So we need to get some ideas of how 
we can excite other Members. This is one of the things we all 
should feel very proud about in the Federal Government. One of 
the crown jewels of the Federal Government is NIH.
    We need ideas of whether it's getting Members to go visit 
medical institutions in their communities and have them express 
that appreciation. But I don't have a medical research facility 
in my district. But we need some help along those lines to 
promote the overall need of NIH. Any comments about that? When 
people hear you speak about what's happening, you get excited 
about it.
    Dr. Fauci. Well, we've actually discussed this, Dr. Varmus 
and the Institute directors, about the need of getting the 
message out of what we do in the biomedical research capacity 
at NIH. Obviously, individuals going out, like the Institute 
directors, we do that, but that's only going to be a small dent 
in it. It has to be a much more general effort of getting out.
    What we do is we try to encourage, for example, our 
councils and our advisory groups to take the message back to 
their communities. We have noted a considerable amount of 
enthusiasm on their part. For example, our own council put 
together a program of actually providing slides and information 
for council members and the individuals in their respective 
institution to go out and talk about what NIH does and what the 
role of biomedical research is in public health. That's a small 
amount, but I think it is a good start.
    Harold.
    Dr. Varmus. I think there is a very powerful effect upon 
any Member who hears about the work of any investigator who is 
NIH-supported. I know Ms. Pelosi frequently refers to a visit I 
made to her office about seven years ago in the company of a 
young, very enthusiastic worm geneticist, and the effect of 
that visit is still apparent, even in the questioning this 
year.

                    improved drugs for hiv treatment

    Mr. Miller. I will work on my end of it to try to encourage 
my colleagues, whether it is to go visit a nearby medical 
research institution, to spend some time shadowing a 
researcher, or whatever it is. I think we need to come up with 
some ideas because I think we have an education effort to the 
country. It's nice when a Mohammed Ali comes here and testifies 
about Parkinson's disease. And I think as long as that supports 
the overall goal of NIH, that's good.
    Let me switch to something more specific. There's been a 
lot of success, obviously, with HIV and we have a lot of pride 
in having seen it progress to the stage we are today. Where are 
we going as far as longevity efforts, studies with this 
combination therapy? In the past you've said you're not ready 
to say that we've really conquered it. Are we moving towards a 
chronic disease yet?
    Dr. Fauci. I can give you some of the numbers. If you look 
at the clinical trials, which is much more pristine than in the 
trenches, as we say, when you have someone who is in a clinic 
in an inner-city area, about 85 percent of the people have 
responded, their virus goes to below detectable levels, and 
about 65 percent total after a period of two years are still 
doing well. If you look at the people in the clinic who are not 
pristine, in the sense that they've had prior treatment of one 
or other drug which lessens the impact of when you come in de 
novo in an untreated person, the response rate there is about 
60 to 65 percent, and it may go back down to 50 percent of 
breakthroughs.
    The thing that we're struggling with, and it really relates 
to the questions of several Members, is why we need to keep up 
the pressure of drug development. Becausealthough the people 
who are responding are responding well, and by well, I mean no 
detectable or very little detectable virus and leading relatively 
healthy lives, those people are going out now two, three years, some of 
them, and the concern is will they be able to tolerate the drugs 
chronically over ten or fifteen years; and secondly, will there be 
breakthrough with resistant micro-organisms.
    There's two ways to approach that, and we're doing both. 
One is to develop newer drugs at the same target, or drugs at 
different targets of the virus; the virus has multiple targets 
that we aim at. The second is to make drugs that are more user 
friendly, and we've seen a lot of activity in that regard over 
the past year. Instead of having to take 35 tablets or 
capsules, which is the average amount that someone with 
advanced disease takes, to try and have, for example, a form of 
a drug that you only need to take once a day in the morning. 
That would be very important for what we call compliance. It is 
very difficult in the disruption of a lifestyle to tell 
somebody that they have to take a pill every hour or two.
    If we can get that component of it, then I think the answer 
to your question is we're going to see long range survival with 
good quality of life. Whether that's going to last a normal 
lifetime, we can't say. That's going to depend on whether or 
not we're able to eradicate the virus. Thus far, it looks like 
the virus is rather stubborn. And even in people who we 
suppress virus so that you can't detect the virus in the 
plasma, there is still persistence of virus in the tissue.

                               hemophilia

    Mr. Miller. One area I've been interested in is hemophilia. 
I guess the incidence of new hemophiliacs doesn't happen 
anymore because of blood control.
    Dr. Fauci. Right.
    Mr. Miller. The complications of hemophilia, does that make 
it any more difficult than other treatment? And then I'm going 
to ask you about the hepatitis issue with hemophilia, too, 
what's going on there.
    Dr. Fauci. Actually, you put your finger on it, the 
complications. The the non-hematologic complications of 
hemophilia, the joint problems, the blood loss problems, 
generally are not made better or worse with regard to HIV. It 
doesn't impact negatively on the survival of a well-treated 
hemophiliac who is on appropriate antiretroviral therapy.
    Since the incidence of hepatitides, because of the 
transfusions that they may need to receive because of bleeding 
episodes, is understandably higher in hemophiliacs, the 
negative aspects of the impact of HIV on hepatitis is seen more 
predominantly in hemophiliacs. So the secondary negative 
consequences of hepatitis as a co-infection with HIV by pure 
numbers alone segregates more heavily in the hemophiliac 
population.
    Mr. Miller. I see my time is about to expire and I was 
going to ask a longer question.

                           aids in minorities

    Mr. Porter. You can ask the question.
    Mr. Miller. Mr. Stokes had asked a question about the 
statistics for minorities with HIV being much greater. I guess 
the statistics for hemophiliacs is very much distorted, too, 
but it is different causes. Are we fractionizing our approach 
to treatment? I see Dr. Hernandez over here. Is drug use a 
better determinant of who gets AIDS than race? I get concerned 
whether we're trying to say, well, let's just look at it as a 
black disease. It's not a black disease.
    Dr. Fauci. No. Not at all. Absolutely, not at all. In fact, 
if you look at the disproportionately higher percentage of, for 
example, African-Americans and Hispanics who are HIV infected 
and get AIDS, that's purely reflective of the conditions 
associated with transmissibility. If you live in an inner-city 
area where there's a high degree of IV drug use, the 
heterosexual transmissibility by definition will be higher in 
that environment.
    Unfortunately, it happens that it is much more heavily 
weighed that that group is going to be a minority group. So 
they are going to be physically in an environment where 
exposure and transmissibility is greater than it would be if 
you had a middle class white person living, for example, in a 
place where there isn't a high density of either infection or 
IV drug use.
    Mr. Miller. So, statistically then for African-Americans 
and whites under the same conditions of environment?
    Dr. Fauci. Right. There is no difference whatsoever. If you 
have an African-American, a Hispanic, a man or woman in the 
same environment with the same degree of exposure, there is no 
segregation towards race or gender or what have you with 
infection.
    Mr. Miller. But do you divide research separately?
    Dr. Fauci. No, we don't. In fact, the vast majority, the 
bulk of the research is pathogenically related, drug 
development related, and vaccine related. That does not take 
into account race or gender. When we do either epidemiological 
studies or when we look at our clinical trial apparatus, since 
we have a disproportionate number of minorities that are 
infected, we make sure that in the entry into our clinical 
trials, that they are represented appropriately in the clinical 
trial. But the fundamental basic research impacts all races and 
genders equally.
    Dr. Varmus. I hope it's also clear, Mr. Miller, that we 
keep track of AIDS cases or cases of HIV infection with respect 
to the probable mode of transmission. So we have data on the 
percentage of cases in any one year that areattributable or 
likely to be attributable to intravenous drug use, to men having sex 
with men, heterosexual sex, maternal to infant transmission, and so 
forth.
    Mr. Miller. Okay. Thank you.
    Dr. Fauci. Thank you.
    Mr. Porter. Thank you, Mr. Miller.
    Dr. Fauci, we apologize to you and Dr. Kupfer for the 
interruptions we've had this afternoon and the delays in our 
schedule. We all do applaud you, the NIH, and all of the 
Institutes for the wonderful work that you do. We can't be more 
proud of the Institution and of the scientists who are there or 
funded through NIH grants. We think you're doing wonderful work 
and we want to give you the resources you need to do it even 
better and faster.
    Dr. Fauci. Thank you very much.
    Mr. Porter. Thank you for appearing today.
    Dr. Fauci. Thank you. It's a pleasure to be here.
    Mr. Porter. The subcommittee will stand briefly in recess.
    [The following questions were submitted to be answered for 
the record:]


[Pages 857 - 946--The official Committee record contains additional material here.]



                                         Wednesday, March 11, 1998.

          NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

                               WITNESSES

DR. KENNETH OLDEN, DIRECTOR, NIEHS
DR. SAMUEL H. WILSON, DEPUTY DIRECTOR
LAURIE JOHNSON, BUDGET OFFICER
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT 
    HEALTH AND HUMAN SERVICES
CHARLES E. LEASURE, JR., ASSOCIATE DIRECTOR FOR MANAGEMENT
DR. HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH

    Mr. Porter. The subcommittee will come to order. We 
continue our hearings with the National Institutes of Health. 
We are pleased to welcome this morning Dr. Kenneth Olden, the 
Director of the National Institute of Environmental Health 
Sciences.
    Dr. Olden. Thank you.
    Mr. Porter. Dr. Olden, you and the other Institute 
Directors were all arrayed behind Dr. Varmus yesterday. It is 
good to see you again today. We thank you for coming to 
testify.
    Why don't you proceed with your statement and then we will 
go to questions.

                       Introduction of Witnesses

    Dr. Olden. Thank you very much.
    Let me just introduce the people to my left. Mr. Charles 
Leasure is the former Associate Director for Management for the 
Institute. Mr. Leasure recently left our institute to join Dr. 
Collins at the National Institute for Human Genome Research.
    And we have a national search to find a replacement for Mr. 
Leasure.
    The Deputy Director, Dr. Sam Wilson; and the Budget 
Officer, Ms. Laurie Johnson; and you know Dr. Varmus and Mr. 
Williams.

                           Opening Statement

    Mr. Chairman and members of the committee, I welcome the 
opportunity to appear before you today to discuss the important 
work of the National Institute for Environmental Health 
Sciences. Today I want to accomplish just two goals.
    First, I want to direct your attention to a list of 
strategic investments which will have the potential to change 
the face of environmental health policy decisions. And second, 
I want to showcase an example of what can happen if such 
investments are indeed made.

                         strategic investments

    If I could have the first exhibit, please.
    I have listed seven issues here that we have talked about 
before this committee in previous appearances. First, I think 
we should make an investment to develop high throughput 
approaches for carcinogenicity and toxicity testing.
    And in fact, I will devote most of my remarks to this 
issue.
    Second, we need to determine the basis for the wide 
variation and individual responsiveness to exposure to 
environmental toxicants. Third, we need to develop analytical 
techniques for direct assessment of human exposure.
    Fourth, we need to define the health effects of exposures 
to mixtures. Fifth, we need to elucidate environmental health 
and safety threats to children. Sixth, we need to investigate 
the possible complex interaction between poverty, environmental 
pollution and health disparities.
    And lastly, elucidate carcinogenic and toxic mechanisms.

                         carcinogenicity tests

    Now I will discuss the impact of alternative test systems 
that we have developed to respond to issue number one. And let 
me say at the outset, our ability to develop these test systems 
has been based on recent developments in our understanding of 
cancer genetics.
    We now know that all cancers involve a disruption of the 
normal restraint in cell proliferation. For each cell type, 
there is a finite number of ways in which such disruptions can 
occur. In fact, changes in a relatively small number of genes 
appear to be responsible for much of the deep disregulation of 
proliferation in cancer.
    The identification of many of these genes has been one of 
the great triumphs of molecular biology over the past 20 years. 
These genes can either stimulate cell proliferation or they can 
inhibit it.
    Scientists at the NIH have used both kind of genes, that is 
stimulatory genes and inhibitory or suppressor genes, to create 
animals, mice, that are more responsive when exposed to 
environmental carcinogens.
    In the next exhibit, they have created four such animals, 
and I will describe three of those today. They have created 
animals that we call TgAC mouse and Hras2 mouse. Both of these 
are genetically engineered so that they contain a tumor 
stimulatory gene.
    The p53 mouse contains an inactivated tumor suppressor 
gene. So we have created mice that have stimulatory genes 
andmice that have inactivated inhibitory or suppressor genes.
    Such animals that are so genetically modified in this way 
are referred to as transgenics. To date, we have tested 32 
chemicals in this system. In other words, 32 chemicals have 
been screened using the transgenic animal models.
    The results shown here are typical of the results that we 
have obtained. In most cases, shown in the red bars and gold 
bars, the same result was obtained in both the conventional and 
transgenic models.
    If you will look at the first quadrant, conventional all 
red, p53 all red, TgAC and Hras2 are also all red. The question 
mark simply represents the fact that we have not tested that 
specific chemical in that transgenic animal model.
    If you move down to the next quadrant, again those 
chemicals that tested negative in the conventional model were 
also negative in the transgenic animal models as shown by the 
gold bars.
    And as you move across the three transgenic lines, you see 
again, in every case in which it has been tested, they also 
were negative. Now if you move to the last quadrant of the 
exhibit, you will see that we obtain mixed results.
    That is, the result obtained in the conventional model was 
not always repeated in all three of the transgenics. But you 
will note that the result obtained in the conventional model 
was repeated in at least two of the transgenic animal models.
    So today, we can conclude that if we use a screen of three 
transgenic animal models, we may be able to substitute for the 
conventional rodent bioassay.

                    advantages of transgenic models

    Now the advantages of the transgenic model over the 
conventional is shown in the next exhibit. First of all, you 
will see that for the transgenic animal model, it costs us 
$110,000 per chemical versus two to six million dollars per 
chemical in the conventional.
    It takes 150 animals to perform the experiment in the 
transgenic animal model, and it takes 800 animals to perform 
the experiment in the conventional model. And most importantly, 
it takes six months in the transgenic model and two years in 
the conventional model. So we save time, money and animals.
    Now I am not yet prepared to declare victory, so today I 
cannot recommend the use of transgenics in lieu of the 
conventional rodent bioassay. Clearly more studies are needed. 
Nevertheless, these results are very exciting.
    And I am optimistic that within the next one to two years, 
we will have adequate experience with the new test systems so 
that a firm recommendation can be made with respect to their 
use in carcinogenicity testing.
    Now the potential impact that transgenic models will have 
on hazard identification is just one example of how the 
strategic investments that I outlined in Exhibit Number 2 can 
impact and modernize risk assessment.
    I indicated to you about four to five years ago that NIEHS 
would make the investment to develop these transgenic animal 
models. So today, this is the progress report. These models can 
provide you as policy makers with the information needed to 
make important public health decisions in a timely manner.
    The President's budget request for NIEHS is $348,100,000, 
and I would be very pleased to answer any questions that you 
might have.
    [The prepared statement follows:]


[Pages 950 - 961--The official Committee record contains additional material here.]



    Mr. Porter. Dr. Olden, thank you for that fine opening 
statement. You already answered my first question, which was 
how long is it going to take to actually achieve the use of 
transgenics in lieu of conventional rodent assays and one to 
two years is what your answer was, I thought.
    Dr. Olden. Yes. But I can add that the Food and Drug 
Administration will already accept an alternative model. The 
model has to be an animal, though; it is not an in vitro model. 
And in most cases, it is the transgenic animal models that they 
will accept.
    So it is already being used. In other words, FDA will 
accept one test in a conventional animal model, and then one in 
a transgenic. And that, in itself, is a major advance.

                               pesticides

    Mr. Porter. All right, let me change the subject and ask 
you a question that arose at a forum I had last Monday night. 
This may be a little out of your field, but it relates to the 
idea that we are creating cancers and negative health effects 
by spraying pesticides that are used for insect control. I 
assume that the EPA has jurisdiction over pesticide chemicals?
    Dr. Olden. They do over the regulation of pesticide 
chemicals.
    Mr. Porter. Do you have responsibility for testing those 
chemicals?
    Dr. Olden. We have responsibility for probably more than 
50% of the research on pesticides. And as Dr. Klausner will 
testify when he comes here, we have a collaboration with NCI 
and EPA. We have what we call an agricultural health study that 
we have been conducting now for over five years.
    And what we are doing for the first time in the case of 
non-cancer end points is to look at--determine--what the health 
effects of exposures to agricultural chemicals really are. And 
the emphasis is on developmental issues, immune issues and 
respiratory issues.
    This is a ten year study that is being supported by all 
three of us. And for cancer, this will be a definitive study. 
We have a number of other studies ongoing to investigate the 
health effects of pesticides.
    For example, the National Academy reported to us about 
three years ago now that the impact of pesticides on children 
was a serious public health issue. So we initiated studies in 
the National Toxicology Program to look at the effects of 
pesticides on the developing embryo and the early pups of mice 
once they are born.
    We look at the effects of pesticides throughout the life 
history of the animal. We have a number of studiesgoing on on 
the health effects of pesticides.
    Mr. Porter. Would it be a fair statement to say that for 
many of the pesticides in common use in the United States 
today, we do not know whether they are carcinogens or not?
    Dr. Olden. Some of the ingredients in pesticides we know 
are carcinogens at high levels. We do not know about low 
levels, the level at which most of us are exposed. But the 
truth is, we do not know anything about the toxicity or 
carcinogenicity of most of the components of pesticides.
    So your statement is a fair statement.
    Mr. Porter. Then at the close of the ten year study, 
presumably we are going to know a lot more?
    Dr. Olden. Absolutely.
    Mr. Porter. And that would then, presumably, be a basis for 
regulation by the EPA of these substances?
    Dr. Olden. In the case of cancer, I think that the studies 
will be fairly definitive in terms of whether there are 
increased cancer risks from exposures to pesticides. We are 
looking at pesticide applicators on farms. We are looking at 
the farmers themselves, the male, the female and the children, 
the offspring.
    In a case of end points other than cancer, however, this 
represents the first major study. So what we are doing mostly 
in the case of non-cancer end points is hypothesis building 
rather than really testing hypotheses because we just do not 
have adequate information.
    So in the case of non-cancer end points, additional studies 
will clearly be required before we can make any recommendations 
to you or to the regulatory agencies such as EPA and FDA about 
the health effects of pesticides.
    Mr. Porter. Well, to get a little more specific, my home 
State of Illinois, in anomaly of constitutional law created 
mosquito abatement districts years ago. They spray larvacides 
and they also spray pesticides, and they spray the pesticides 
directly into the foliage in cities.
    Dr. Olden. Yes.
    Mr. Porter. Is it a fair statement to say that they may be 
spraying chemicals that may be carcinogenic and may be a threat 
to children?
    Dr. Olden. That is a fair statement.

                     potentially harmful chemicals

    Mr. Porter. Why do we allow the use of chemicals that we do 
not know whether they are harmful or not?
    Dr. Olden. Well----
    Mr. Porter. I know this is a little bit out of your 
bailiwick.
    Dr. Olden. Yes, my opening statement was a bit long, so I 
cut it down a little bit last night, and I would have said that 
the Environmental Defense Fund and the National Research 
Council of the National Academy of Sciences have both reported 
that, of the high use, high volume chemicals in use in the 
United States, toxicity and carcinogenicity testing has not 
been performed--none--on more than 75 to 78% of those 
chemicals.
    So, in most cases, we simply do not have the toxicity data 
in place to tell you whether those components of pesticides 
cause harm or not. Now we know that many of them do. We have 
tested many of them.
    As a matter of fact, we have tested over 500 chemicals in 
all in the National Toxicology Program. And of the 500 tested, 
68, or 14 to 15% of those are listed in the report on 
carcinogens. So we know something about many of them.
    Mr. Porter. But we also know that there are a number of 
chemicals that are not carcinogenic.
    Dr. Olden. Absolutely, but they could affect development, 
and we know that some do. A number of chemicals affect 
development. As a matter of fact, the major concerns about 
children are asthma, lead exposure, and number three would be 
pesticide exposure because of the impact on development.
    I indicated that we are doing studies in the National 
Toxicology Program where we are looking at the effect on 
developing embryos in mouse model systems. And indeed, we are 
detecting problems in development.
    Mr. Porter. Well, this again is outside of your 
responsibility, but why couldn't your Institute recommend to 
EPA the chemicals that appear most benign at this point in 
time, and why couldn't we limit the spraying of those chemicals 
even though we do not know for sure that they are benign and 
not allow the spraying of those we do not know anything about?
    Dr. Olden. Well----
    Mr. Porter. Or do we already do that?
    Dr. Olden [continuing]. The strategic investments that I 
outlined, Mr. Chairman, would allow us to provide you and 
regulatory agencies with that kind of information. One of the 
investments that I identified was the need to determine exactly 
what it is that the American people are exposed to.
    What body burdens do all of us have? That investment would 
allow us to know whether to prioritize. In fact, that is what 
it would do, would allow us to set some priorities as to which 
chemicals are likely to be harmful to humans based on actual 
uptake into our bodies and into cells and tissues.
    Without the kind of data that I outlined in the strategic 
investments, we simply do not have the information.
    Mr. Porter. So what you're saying is our knowledge base is 
just not strong enough yet, but we are working on it. We will 
have some answers as a result of this survey?
    Dr. Olden. The first exhibit talks about the gap. It 
indicates there is a major gap between public policy and 
science. Public policy is, in almost all cases, out in front of 
the science.
    And that simply is a reflection of the fact that we have 
not made the investment to answer some of the fundamental 
questions and issues that ought to be answered about the 
environment.
    Mr. Porter. If we doubled the resources at your disposal 
over the next five years, presumably you would be able to speed 
up the process of discovering the answers to these questions.
    Dr. Olden. Absolutely. We have had this discussion with Dr. 
Varmus. And with the budget increases that the President 
proposes, we plan to invest in those issues that we have 
outlined in the strategic investments.
    Mr. Porter. Thank you, Dr. Olden.
    Mr. Stokes.
    Mr. Stokes. Thank you, Mr. Chairman.
    Dr. Olden, nice to see you and your colleagues.
    Dr. Olden. Thank you.

                            lung hemorrhage

    Mr. Stokes. Let me start by asking you about lung 
hemorrhage in infants. Is that a matter of which your institute 
has become aware? As you may know, about one-third of the 
cases, nationally, are in the Cleveland area, and about one-
half of them are around the Great Lakes area. Can you tell us 
whether or not this is a matter that you haveinquired into or 
conducted any research?
    Dr. Olden. Yes, we are aware of it. We know that it is 
caused by a mold due to dampness, damp conditions. And we have 
provided some support to a physician in the Cleveland area to 
look into this issue and mostly to generate case reports.
    Dr. Fauci probably would be the person who is doing the 
most because it is a biological, although we certainly are 
making some investments. We are providing one physician in the 
Cleveland area with some resources to build a database.
    Mr. Stokes. Has any part of your budget been directed to 
support this operation?
    Dr. Olden. Yes, a very small portion. And I do not know how 
many dollars we are providing the physician, but that would be 
the only portion of our budget that is going into this effort.
    But we looked into it about two years ago when it first 
appeared.

                           children's health

    Mr. Stokes. Okay. We will probably pursue this further with 
Dr. Fauci when he comes up.
    Dr. Olden, as you are keenly aware, environmental justice 
remains a primary concern, especially as it relates to 
children's health. Environmental hazards must be clearly 
defined. What type of projects are needed to provide the 
database to facilitate the identification of environmental 
hazards that threaten children's lives, or rather, their 
health?
    Dr. Olden. As I indicated in part to my answer to 
Congressman Porter, the major threat to children is lead 
poisoning. And we have a number of research efforts to address 
that, and let me come back to it.
    Asthma would probably be second. Exposures to pesticides 
would be third. There we are concerned about cognitive 
development and embryonic development. And the fourth would be 
susceptibility, and we are addressing all of those--
susceptibility in terms of behavior, susceptibility because of 
differences in metabolism.
    And we have research programs to address all of them, 
Congressman Stokes. With 15 other institutes in the National 
Institutes of Health, we initiated a study to look at the 
genetic basis for susceptibility.
    We are supporting research grants to look at the effect of 
behavior on exposure and, in other words, uptake due to 
children's behavior is very different. We have a number of 
projects on asthma.
    We are collaborating with the National Institute of Allergy 
and Infectious Diseases on the Inner City Asthma Study and two 
asthma research centers. For example, we have three centers in 
New York.
    They are in the Manhattan area at Columbia University, 
Harlem Hospital, Albert Einstein College of Medicine, and one 
is in the Bronx at Mt. Sinai. And they are looking at the 
health effects of asthma.
    Air pollution is another major problem in children with 
asthma, and so we have a number of research efforts, as you 
know, to look at the health effects of particulates and ozone 
and acid aerosols on respiration and pulmonary dysfunctions.
    So we have a substantial program, and I think we are 
addressing the four or five major health threats to children.

                socioeconomically disadvantaged children

    Mr. Stokes. How about those children who are classified as 
being socioeconomically disadvantaged? Is there any emphasis on 
that category?
    Dr. Olden. Yes we have one special asthma project called 
The Five-Cities Study that focuses exclusively on children that 
are socioeconomically disadvantaged. But I would say the 
overall thrust of our inner-city asthma project is focused on 
socioeconomically disadvantaged children.
    The lead studies focus on socioeconomically disadvantaged 
children because that is where the problem is today. It is not 
a problem of middle class families as a rule. It is in the 
inner city--it is an urban problem.
    Asthma the same way; it is thought to be mainly associated 
with indoor household allergens, such as cockroach allergens. 
Such allergens may not be a major problem that we have in 
middle class communities.
    Well, many years ago, we felt that there was a connection 
between the fact that poor people, socioeconomically 
disadvantaged people, live and work in the most hazardous 
environments and surely those exposures are at least in part 
responsible for the disparities in health outcomes.
    And so we created three to four programs to address that 
issue. One, we created a developmental Centers Program to 
encourage academic health science centers to go into low income 
communities to address some of the health problems encountered 
there.
    We have three such centers--the center at Harlem--
collaboration between Harlem and Columbia University is one 
such center. We also have a center in New Orleans that is also 
of that type. We also created a grants program to encourage 
partnerships between academic health science centers and 
communities.
    One example, we have such a grant in upstate New York that 
is looking at the effects of PCB's in pregnant women on 
development of the fetus. And that is funded by us through the 
partnership. We have a partnership in California at the 
University of California at Davis that is focusing on the 
health effects of pesticides on farm workers, which are about 
90% minority and poor and Hispanic.
    That center has developed a test to improve or 
standardize--a test called acetylcholine esterase which is a 
biomarker for exposure to pesticides. So the University of 
California at Davis scientists have developed a test that is 
now used by the state to--that is more reliable than the 
previous test to estimate exposure to pesticides.

                   biomedical research opportunities

    Mr. Stokes. Dr. Olden, as the Nation prepares for the new 
millennium and Congress debates the need to nearly double the 
NIH budget, what is the condition of the basic and clinical 
biomedical researcher's pipeline as it relates to the 
researchers under the purview of your institute?
    Well, I guess what we would like to examine what your 
institute is doing to promote increased biomedical research 
opportunities?
    Dr. Olden. Well, first of all, we are participating in all 
of the programs that are sponsored by the NIH--for example, the 
MARC and MBRS programs. We are also supporting a program that I 
think is unique and very promising called the Meyerhoff Program 
at the University of Maryland--Baltimore.
    We are providing support for that program. And that program 
has been very successful. I think it is a national model as to 
how to get minority children into biomedical research.
    We also are creating a new program called the ARCH Program. 
And that program is created to form a partnership between a 
research intensive university and a minority serving 
institution.
    For example, we expect organizations like the institution 
Morehouse in the Atlanta area to form partnerships with an 
institution like Emory, or Meharry to form partnerships with 
organizations like Vanderbilt.
    But the objective of the ARCH Program is threefold. And one 
is to increase quality teaching and research at the minority 
serving institution. It is to provide a larger pool of 
qualified applicants for the research intensive university.
    And in the end, we hope we will establish an 
infrastructure, a partnership, between a research intensive 
university and a minority serving institution that will be long 
lasting. And think, if every state just provided training to 
two nationally competitive minority scientists per year, we 
would not be having the problem that we are talking about 
today--just two.
    So we hope that after our grants programs are no longer in 
place, that these partnerships between institutions, let us say 
between like Meharry and Vanderbilt, will be long lasting.
    Mr. Stokes. Thank you.
    Mr. Porter. Thank you, Mr. Stokes.
    Mr. Stokes. Thank you, Mr. Chairman.
    Mr. Porter. The Chair would like to exercise a prerogative 
and recognize some students over in the corner who are here 
under the Close Up Program from the 10th congressional district 
of Illinois. We welcome you.
    Mr. Hoyer.
    Mr. Hoyer. Who represents the 10th district of Illinois?
     Mr. Porter. I cannot imagine. (Laughter.)
    Mr. Hoyer. They are well represented, the 10th district of 
Illinois, I can tell them that.
    Mr. Porter. Thank you, sir.

                               pfiesteria

    Mr. Hoyer. Mr. Chairman, thank you.
    Dr. Olden, I apologize for being late. I was chairing the 
Caucus which ran a little over time.
    You mention Pfiesteria in your statement, and you mention 
the eastern shores of our country, the Atlantic coast. 
Obviously the Eastern Shore for a Marylander is the Maryland 
Eastern Shore; for Virginia, the Virginia Eastern Shore.
    But North Carolina, Virginia, Maryland in particular, as 
you point out in your statements, had a real problem. We have 
tried to get some additional funds made available to CDC and to 
other agencies.
    Could you bring me up to date on where you think we are on 
Pfiesteria?
    Dr. Olden. We started working on Pfiesteria in 1993, I 
believe, when there was an outbreak in North Carolina. We 
joined forces with Dr. Joanne Burkholder, who is the scientist 
who first identified this organism.
    Mr. Hoyer. Right.
    Dr. Olden. And we have to date succeeded in isolating at 
least two fractions. There is a dermonecrotic fraction, and 
then there is a neurotoxic fraction. And so we have those two 
fractions isolated.
    We have with other institutes in the National Institutes of 
Health--and there are at least four of us involved in these 
efforts--initiated studies. The bottleneck had been having the 
isolated, purified fractions in large enough quantity that we 
could do toxicity studies.
    And we now have those fractions and we have them in large 
enough quantities to do toxicity studies. We are now doing 
studies in sheep--inhalation studies, for example. We are also 
doing studies in mice and rats--memory studies using skin 
paint.
    Some clinical studies using PET scans have been done at 
University of Maryland-Baltimore and Johns Hopkins, and these 
studies were supported by a number of institutes and not just 
NIEHS.
    So the problem is the following: Pfiesteria has 24 life 
stages, and we can only recognize one of them. So what we need 
to do is develop a biomarker to identify all 24 life stages. So 
there needs to be an effort to maybe clone the genome of 
Pfiesteria.
    And so that is one thing that is being proposed, and 
obviously all 24 different life cycles will have the same 
genome. Whereas, any other biomarker may not work.
    The other issue that needs to be worked out is what are the 
growth conditions. Exactly what conditions promote the growth 
and proliferation of the infectious form? And we do not know 
what that is. But now we are beginning to grow the organism 
under laboratory conditions where we can control the nutrients 
and we can figure out what the growth conditions are 
accurately.
    Mr. Hoyer. Doctor, obviously this is a very timely issue in 
terms of the nutrients and what is causing it as it impacts 
farmers----
    Dr. Olden. Yes.
    Mr. Hoyer [continuing]. Who raise livestock or have 
livestock, whether it is chickens or pigs or other farm animals 
on their property and the nutrients that flow into the 
Chesapeake Bay or to other tributaries or other waterways.
    Dr. Olden. Yes.
    Mr. Hoyer. How soon do you think we are going to have 
answers which can be relied upon by policy makers as definitive 
enough to make policy?
    In other words, I know you will not be sure 100%, but 
policy makers will be making judgements at the Federal level 
and certainly in our state, and I know in North Carolina, 
Virginia and other states as well.
    Dr. Olden. Well, this is a guess and I probably should not 
do that. My guess is in one to two years we will understand the 
health effects of the isolated chemicals and we will know what 
the growth conditions are.
    Mr. Hoyer. Okay.
    Dr. Olden. And if we choose to go after the genome, we can 
also isolate that.
    Mr. Hoyer. Okay. Well, I think that is helpful in terms of 
policy makers knowing what time frame they are dealing with. 
And maybe they are going to have to act sooner than that 
without full knowledge acting safe--I frankly think Governor 
Glendenning, for instance, acted correctly.
    We do not have all the facts, but if the worst case 
scenario turned out----
    Dr. Olden. Right.

                                 asthma

    Mr. Hoyer [continuing]. Then we would be lamenting the fact 
that we did not act waiting for definitive answers. So I thank 
youfor that, Dr. Olden.
    Doctor, let me follow up. Obviously asthma is of great 
concern to you. I have asthma. Vic Fazio, one of my closest 
friends in the Congress who is leaving, is also a asthma 
sufferer. Both of us came from, I would presume, relatively 
middle class homes. Not advantaged homes by any stretch of the 
imagination, but middle class homes.
    I lived in New York City until I was nine. I lived in 
Greenwich Village in housing that was decent housing, not bad 
housing. One of the things that interests me and I talked to 
doctors about it is the extent to which you believe there is a 
psychological component of asthma.
    I have found the more traumatic environment in which I am 
living at a given time, the more likely I am to have an 
asthmatic problem. And I do not know whether that is 
psychosomatic or whether it is in fact a causation.
    Dr. Olden. Well, I am not the person to comment on that. 
But let me just say----
    Mr. Hoyer. You mean personally diagnose me? No, I was not 
looking for that. [Laughter.]
    And I thank you for your forbearance.
    Dr. Olden. Having a child who is asthmatic, it does appear 
to be a stress related issue. But asthma is not an illness that 
is limited to one socioeconomic class versus another.
    Now it is a fact, however, that in urban, inner city areas, 
that asthma is in crisis proportion. For example, in some parts 
of New York City. And that is probably environmentally related. 
The New York Times has been running a series of articles 
recently about the conditions in New York.
    And in some parts, it is two or more times higher than the 
national average. However, the incidence of asthma is very high 
in regions of New York that are mixed use--where there is 
housing, there is industry, there are waste facilities.
    And so it is probably related to diesel exhaust, soot, 
particulates, acid aerosols, as well as kids having the 
predisposition, as many of us might have. And if we are placed 
because of socioeconomic reasons in environments in inner city, 
we might have an allergic response.

                         air quality and asthma

    Mr. Hoyer. Doctor, last question because, as you know, the 
EPA has recommended tighter standards for air quality. In the 
course of that consideration, one of the things that the 
opponents of the tightening of regulations have argued is that 
as the air has gotten cleaner, more particulate free, asthma 
statistics have gone up.
    Now, I do not know that you can. Obviously, I do not 
necessarily believe you can have a correlate between the two, 
but how would one view those statistics, as unrelated and 
irrelevant to one another?
    Dr. Olden. Well, it is a fact that nationwide the air 
quality has greatly improved, and nobody can deny that. But in 
some inner cities automobile use, diesel buses, dilapidated 
housing, and poverty are also risk factors.
    And that may be what is occurring now. I mean, if you look 
in the parts of New York City where asthma is in epidemic 
proportions, all of those factors are involved. If cockroach 
allergens are important, and our studies demonstrate that 
indeed they are, that is a major problem in upper Manhattan and 
the Bronx.
    Particulates that EPA wants to regulate are certainly a 
huge problem because of use of diesel buses and automobiles, 
incineration and other issues. So it is not clear why asthma 
rates are increasing because the air is indeed getting cleaner.
    Mr. Hoyer. Thank you, Doctor.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Hoyer.
    We will have a second round. Are each of you going to stay 
for the second round? I understand Mr. Stokes will.
    Mr. Hoyer. I have to go in ten minutes.
    Mr. Porter. Pardon me?
    Mr. Hoyer. I have to go in ten minutes, but I do not have 
any additional questions.
    Mr. Porter. All right. We will then divide the remaining 
time.
    Mr. Stokes, do you have another place where you are 
expected?
    Mr. Stokes. I am going across the hall to another hearing.
    Mr. Porter. Then why don't you proceed right now for seven 
or eight minutes.

                     institute for the environment

    Mr. Stokes. Fine. Thank you, Mr. Chairman.
    Dr. Olden, recently, there has been a growing effort by 
some persons in the environmental community to have Congress 
establish a National Institute for the Environment, 
particularly over on VA/HUD appropriations subcommittee on 
which I sit.
    Are you aware of this?
    Dr. Olden. Yes, I am.
    Mr. Stokes. This issue continues to be brought before 
Congress, particularly those of us who serve on that 
subcommittee.
    I just wondered if, in your professional judgement, you can 
give us some insight as to whether you see a need for both a 
National Institute for Environmental Health Research and a 
National Institute for the Environment, separate from the 
NIEHS; and if so, why?
    Dr. Olden. Let me comment on the need for the science and 
limit my remarks to that.
    There is a need for additional research in the Federal 
Government on ecological issues. That is an area of research in 
the environment that is indeed under funded. It is presently 
supported, to the extent that it is supported, by the EPA and 
NSF.
    It appears to me that infusion of resources to either one 
or both of those agencies could get the science that is needed 
done. There is a need for the science. Do we need another 
agency? There are two agencies that are already in place.
    And certainly the NSF has an excellent track record of 
supporting peer reviewed research like the NIH, and so that 
would be, in my estimation, a reasonable place to put such a 
program.

                     water chlorination byproducts

    Mr. Stokes. Okay, thank you.
    Let me ask you this. There have been some recent articles 
noting an association between miscarriages and the byproduct of 
water chlorination. Tell us what research is underway at the 
NIEHS to help address this public health problem.
    Dr. Olden. Yes, there is a report out of California thatwas 
conducted by the State Department of Health demonstrating that 
increases in trihalomethane levels in the drinking water has increased 
miscarriages by about twofold.
    Now, that is a preliminary result and it needs to be 
confirmed. However, in our National Toxicology Program, we have 
for a long time been looking at chlorination and other 
disinfectant by-products.
    At the present time, we have about 14 such products under 
study in the National Toxicology Program. We are looking at 
carcinogenicity, as well as reproductive health problems.
    So it is a major effort underway in NIEHS, and we have 
asked NTP to look at these disinfection by-products. And some 
of them have indeed been demonstrated to be toxic. 
Trihalomethanes, for example, at very high doses, are certainly 
carcinogenic, as are other by-products.
    But the point is that the levels at which we are exposed 
are important. The real issue is dose-response relationships 
and the NTP is studying this.

                             SUCCESS RATES

    Mr. Stokes. I notice, Dr. Olden, that the highest reduction 
in research grant award success rates over the last ten years 
occurred in NIEHS. The rate reduced by half from 28% in 1990 to 
an estimated 14% in 1999.
    Tell us what has caused this decrease and whether it is a 
reflection of a reduced priority in environmental health 
research project grants.
    Dr. Olden. No, it is not the latter.
    In 1991, about 300 plus grants were referred to the 
institute through the NIH review mechanism for funding 
decisions. Now about 900 grants are referred to our institute 
for funding decisions. So the number of grants referred to the 
institute have gone up about threefold.
    Now the budget has gone up significantly during the same 
period of time, but obviously I think it reflects that the 
institute has attracted many more outstanding investigators. We 
have expanded our mission in sense of our priorities. I would 
say in '91, '90 we mainly focused on cancer as the disease end 
point.
    And I promised you five or six years ago in 1992 that we 
were going to begin to emphasize other disease end points such 
as asthma, reproductive health, and immune toxicity. And we 
have done that.
    And as we have done that, we have begun to attract 
scientists who are also co-funded or funded by other institutes 
in the National Institutes of Health. For example, we have 
attracted a number of new grantees who are funded by Child 
Health, for example, as we broaden our interest to 
developmental problems.
    So I think it is a reflection mostly of increased interest 
on the part of the scientific community in the research 
objectives and mission of NIEHS.
    Dr. Varmus. May I comment briefly, Mr. Stokes, about this?
    Mr. Stokes. Sure, Dr. Varmus.
    Dr. Varmus. The NIH is acutely aware of the problem faced 
by an investigator whose grant is assigned by our Center for 
Scientific Review to an institute whose success rate may not be 
as high as another institute which might legitimately also fund 
a grant in that area--for example, a grant on the effect of 
environmental agents on development.
    At last year's leadership retreat, the Institute directors 
discussed this problem. We have agreed that, in addition to the 
existing mechanisms for possible co-funding of grants and for 
sharing of grants, we would find some way to make completely 
transparent to all Institutes those grants that are falling 
below the pay line in other Institutes so that there can be an 
easier mode of access for investigators to have access to the 
resources of an Institute to which their grant was not 
initially assigned.
    Mr. Stokes. Thank you, Dr. Varmus.
    Thank you, Dr. Olden.
    Thank you, Mr. Chairman. I have a number of other questions 
which I will submit for the record.
    Mr. Porter. Thank you, Mr. Stokes.

                               PFIESTERIA

    Mr. Hoyer. Mr. Chairman, could I ask one question before I 
go?
    Mr. Porter. Absolutely, Mr. Hoyer.
    Mr. Hoyer. Doctor, I did not follow up on the question I 
should have. On the Pfiesteria issue, would it be useful, would 
it accelerate, would it in any way enhance the dealing with 
Pfiesteria if you had additional resources? In other words, 
could they be applied to some meaningful objective that you 
cannot now----
    Dr. Olden. Well, I think the NIH and the department--and 
that case needs to be made--have made a substantial 
contribution to our understanding of the Pfiesteria outbreak. 
And I think the issues that need to be addressed in this area 
are being pursued by agencies in the department.
    Mr. Hoyer. So could the department use more resources?
    Dr. Varmus. You can say yes. [Laughter.]
    Dr. Olden. Yes, and I think the department has an 
outstanding record of performance on this issue, and we have 
done well.
    Mr. Hoyer. Thank you, Doctor.

                             DEFORMED FROGS

    Mr. Porter. Thank you, Mr. Hoyer.
    Dr. Olden, several years ago we talked about the mutations 
of animals that had been found. One was a frog mutation 
discovered by Minnesota school children in 1995, and then there 
was a book that came out that described other mutations that 
had been discovered.
    What can you tell us about our knowledge base in reference 
to that issue or question?
    Dr. Olden. Well, this has been an interesting year in that 
regard. We, as I indicated to you a year ago, I believe, had 
developed a partnership with the State of Minnesota.
    That is not the only state where deformed frogs have 
appeared. I think 32 such states have reported frogs that are 
deformed or have extra limbs.
    But we tested the water from various sites in the state in 
the region where deformed frogs were found and, under 
laboratory conditions, we were able to demonstrate that the 
water indeed would cause deformities.
    We do not know what the causative agent is, however. 
Studies are underway now in collaboration with the 
Environmental Protection Agency and CDC to figure out what the 
causative agent is.
    Turns out that very slight manipulations, for example, of 
the salt balance, can create deformities so it is not going to 
be easy to figure out, but I think it will be resolved in a 
cooperative fashion in a very short period of time.
    Mr. Porter. So when I ask the question next year, you will 
have the answer?
    Dr. Olden. I should hope so.
    Mr. Porter. If there is an answer.
    Dr. Olden. I should hope so.

                 GOVERNMENT PERFORMANCE AND RESULTS ACT

    Mr. Porter. In your budget justification, your institute, 
the EPA and CDC are spearheading a large children's program in 
response to the President's Executive Order on Children's 
Health and the Environment.
    Centers will be established which will focus on 
environmental influences on asthma and other respiratory 
diseases, childhood learning, and growth development. Planning 
a new program provides you with a prime opportunity to 
implement the Government Performance and Results Act. What 
performance standards and outcomes measurements are being 
established to comply with GPRA in this new program?
    Dr. Olden. Mr. Porter, NIEHS, like all the other 
institutes, has a planning process and we have documents that 
are developed in response to that. However, we have not set 
specific goals because we have gone in with the other 
institutes, all 24 units of the NIH, to establish aggregate 
targets and goals.
    And I think that is appropriate given that the three 
activities that NIH is involved in--research, training and 
support facilities--is not something that is limited to the 
boundaries of institutes.
    So we are required to contribute to the NIH goals and 
priorities. And so I think it is appropriate that our goals and 
priorities be folded into the NIH aggregate goals and 
priorities.
    Mr. Porter. But if you have a new program that you are 
jointly sponsoring with several other institutions, could not 
that program and should not that program have performance 
measures and standards written into it at the time the 
initiative is set up?
    Dr. Olden. Yes, sir; and we do.
    Dr. Varmus. Perhaps I should comment briefly about this.
    Mr. Porter. Please.
    Dr. Varmus. We did not talk about GPRA yesterday.
    One of the things that we have done is to establish what we 
call ``means goals''. That is, goals for those components of 
our activities that are required to achieve the goals of 
understanding, preventing, treating disease.
    Among those might be, for example, the means goals of 
establishing a certain number of centers under this program, 
reviewing a certain number of projects, establishing 
activities. We think those are very useful indicators of how 
well the agencies are functioning.
    In that case, NIEHS would obviously be a component of the 
mechanism used to achieve those means for achieving our long 
term goals.
    Mr. Porter. And I suppose outcome measures would be much 
more difficult or impossible to----
    Dr. Varmus. They are more difficult.
    We have some cases where we believe the quantitation is 
appropriate, but those are a limited number of circumstances, 
to find those.
    For example, in the context of genomic work--where it is 
possible to say, as the Genome Institute has said, that we 
would like to establish the complete sequence of the human 
genome, all three million base pairs, by 2005--we can set up 
some milestones.
    The difficulty there is, of course, as you know, the GPRA 
plan calls for annual goals. But we can try to establish some 
milestones and we have done that in some cases. Or, in Dr. 
Olden's case, a similar kind of goal might be to say that we 
will have a certain number of newly developed transgenic models 
for more rapid environmental testing.
    Now that is a little different from saying we will have the 
new tests in place, but we will at least have the tools. And 
those kinds of measures in very limited circumstances, we 
think, are useful indicators for how well our scientists are 
doing.
    But we are much more reluctant to try to develop specific 
quantitative goals for achieving our long range objectives for 
improving health. It actually provides a very dangerous 
precedent for making our science conform to the regulatory 
process or to the oversight process rather than having the 
oversight process look at how well we do in----
    Mr. Porter. Discovery cannot be programmed according to a 
schedule, obviously.
    Dr. Varmus. And we do not want it to end up being the tail 
that wags the dog.

                            EXTERNAL REVIEWS

    Mr. Porter. Dr. Olden, you instituted two major external 
reviews of your institute this past year. One group is 
assessing the institute's research programs with special 
emphasis on the appropriate balance between extramural and 
intramural research. The other one is evaluating the 
epidemiology program to determine if the current resources and 
staff are appropriate to meet the challenges and opportunities 
developing in environmental epidemiology.
    When do you expect to have the results of these reviews? Do 
you plan to expand this concept to look at other management or 
scientific issues? What is the reason for undertaking this 
review? And are you aware of any other institutes undertaking 
similar reviews?
    I can go back through those one by one if you want.
    Dr. Olden. No, these two reviews represented the end of a 
long process. We started this process in 1991-92. We have had 
every single entity with one exception reviewed. The one entity 
that is yet to be reviewed, but we have been advised to have 
that group reviewed, is our extramural program, our grants 
program.
    We will have that done. The epidemiology review is 
complete. It is in hand. And it was an excellent review. The 
overall review of the institute by the institute's advisory 
council--working group of the advisory council--is also in 
hand.
    And we just received it, and I forwarded it to Dr. Varmus 
about two weeks ago. We are preparing a response to that 
review. It was an outstanding review. It was good. It was 
thorough. It was comprehensive.
    And it was by an outstanding group of people, and they 
recommended things that we can do to make NIEHS the very best 
institute that it can be. And that is exactly what we asked. It 
was one of the charges that we gave to the committee. So we do 
not plan to have any other reviews because this was the end. 
Remember we had the National Toxicology Program reviewed. We 
reorganized the institute. We had the report on carcinogens 
reviewed.
    And so we think, with the final review, which is an over 
arching review, that we now have a blueprint to really move the 
institute forward in the year 2000 and beyond.

                  NIH MANAGEMENT AND STRUCTURE REVIEW

    Mr. Porter. NIH also had a management and structure review 
by an outside consulting firm, did it not?
    Dr. Olden. Yes, it did.
    Mr. Porter. Presumably this management review gave advice 
not only to NIH generally, but to each of the institutes, is 
that correct?
    Dr. Olden. Yes.
    Mr. Porter. Have you seen what advice they have given you?
    Dr. Olden. Yes.
    Well, one of the recommendations was that we use more 
service group units. In other words, the institutes come 
together, and rather than duplicating, we share services--
centers.
    And we were already doing that. But I think we were already 
doing that in response to previous reviews. We have subjected 
our institute to an awful lot of reviews over the years. And we 
were already using service centers. We were servicing the human 
genome. We were using ones in Heart, Lung and Blood.
    So I think we had already had service centers. Over the 
years, I have been trying to find resources to do the important 
things that I talked about. In order to do that, we have taken 
a look at management to make sure that we are managing the 
organization as efficiently as possible.
    We are close to it. I think the final review made some 
recommendations, and we will follow them, absolutely. So we are 
using service centers.
    Mr. Porter. Dr. Varmus, are you satisfied with what NIEHS 
is doing in this area?
    Dr. Varmus. They have been very active in review processes.
    I have mandated only a few kinds of reviews for all 
institutes to take part in, and one is review of their 
intramural program by experts in addition to those 
investigators who normally are serving as boards of scientific 
counselors and review of institute directors every five years.
    The other reviews are made in response to specific problems 
posed by certain institutes. For example, you may recall that 
four years ago we asked the Cancer Institute to carry out a 
review of the way in which it was organized and the way in 
which the intramural and extramural components were built into 
divisions.
    But Dr. Olden is to be congratulated for carrying out very 
vigorous reviews of many aspects of his program.
    Mr. Porter. I think Dr. Olden thinks he is over reviewed. 
[Laughter.]
    Dr. Olden. I do not, but some people in the Institute think 
so. We are never over reviewed. [Laughter.]

                          predicting toxicity

    Mr. Porter. Dr. Olden, one final question. There are 
thousands and thousands of chemicals in use in America today.
    Dr. Olden. Right.
    Mr. Porter. When you discover a chemical that is a 
carcinogen, can't industry simply create another one? And if 
this is the case, can you ever catch up with this game, or can 
you isolate chemicals by groups and say that if, for example, 
they contain chlorine--the whole group is likely carcinogen and 
should not be used?
    How do you address that?
    Dr. Olden. That is exactly what is occurring. Industry 
clearly--it is not in their best interest from a profit point 
of view to create products that have to be removed from the 
market or products that harm people.
    And that is not their intent. So now there is close 
collaboration discussions between Government and industry, and 
we are using the same resources, and we are trying to identify 
those chemical groups that are problems.
    And although I did not talk about them here today, we are 
developing tests to predict toxicity in advance of synthesizing 
and making a chemical. Industry is in partnership with us, EPA 
and FDA to do that work.
    So we will be able to predict and know in advance so that 
industry will not, in the future, create as many harmful 
products as we have in the past.
    Mr. Porter. Is there any way to give us a time line as to 
when we will be at that point?
    Dr. Olden. Well, our predictive capabilities are very 
sophisticated already. When we will be able to never make a 
product that is harmful, that we can never guarantee down to 
every single chemical because the capacity of industry to make 
chemicals now is unbelievable.
    I heard a number, something like seventy to eighty thousand 
new chemicals can be made now by industry pharmaceuticals in 
one year because, you know, they just make slight permutations 
of a chemical and they have a way of doing that that we did not 
have a few years back.
    So we must be more sophisticated in predicting toxicity 
because otherwise we are just going to be swamped with a 
mountain of things that we do not know anything about the 
toxicity of.
    But I am optimistic that we are going to do the science 
that I outlined on that board. It is going to get us through 
testing for all the things that have been made in the past, and 
there are seventy-five or eighty thousand chemicals out there 
that we know very little about.
    Mr. Porter. Well, Dr. Olden, I think you have made an 
excellent presentation of your Institute this morning. I think 
that if people look at the responsibilities you have, your 
Institute can make an excellent argument that more resources 
will bring more results. And obviously there is a lot of risk 
out there that if we can understand it better, we can protect 
people and their health in the future. So, Dr. Varmus, I think 
you should use Dr. Olden and his Institute, as a prime example 
of why more resources will mean more results.
    Thank you very much.
    Dr. Olden. Thank you very much.
    [The following questions were submitted to be answered for 
the record:]


[Pages 978 - 1051--The official Committee record contains additional material here.]



                                         Wednesday, March 11, 1998.

    NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

                               WITNESSES

DR. JAMES F. BATTEY, DIRECTOR, NIDCD
DR. DONALD H. LUECKE, DEPUTY DIRECTOR
WILLIAM DAVID KERR, EXECUTIVE OFFICER
PATIENCE T. SPARKS, BUDGET OFFICER
DURWOOD O'QUINN, INTERPRETER, NIDCD
DR. HAROLD VARMUS, DIRECTOR, NIH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS

    Mr. Porter. We are pleased to welcome the new Director of 
the National Institute on Deafness and Other Communication 
Disorders, Dr. James F. Battey. This is his first appearance 
before the subcommittee. Dr. Battey, we are delighted to see 
you. Would you introduce the people who are with you and then 
proceed with your statement, please?

                       Introduction of Witnesses

    Dr. Battey. Thank you very much, Mr. Porter.
    It is indeed a pleasure to be here and have an opportunity 
to present our research to the subcommittee. On my far left is 
Ms. Patience Sparks, who is our budget officer of the NIDCD; 
Mr. David Kerr, who is our Executive Officer; Dr. Donald 
Luecke, who is the Deputy Director of NIDCD. And of course you 
know Dr. Varmus and Mr. Williams on my right.
    I am really honored to have an opportunity to appear before 
you today as the newly appointed Director of the National 
Institute on Deafness and Other Communication Disorders.

                           Opening Statement

    And I am pleased to be able to present the President's 
budget request for the NIDCD for fiscal year 1999 representing 
the sum of $213.8 million dollars which is an increase of 
roughly $15 million above the FY 1998 appropriation.
    Communication skills will be central to a successful and 
fulfilling life in the new century for all Americans. For the 
46 million Americans with communication disabilities, however, 
facing each day can be a challenge. The simple acts of 
speaking, listening or making their wants and needs known are 
often impossible for these individuals.
    For those who cannot speak without stuttering, or for those 
who are unable to express ideas clearly after suffering a 
stroke, or those who cannot use their voices to talk with a 
friend on the phone due to a voice disorder, or the devastation 
of throat cancer, each day poses a challenge.
    Similar challenges are faced by children who have autism 
and consequent language disabilities, as well as for their 
families who must care for these children. For an older person, 
loss of their sense of balance can result in falls and 
fractured bones, and a loss of hearing can result in isolation.
    For the young child who begins a struggle with language 
acquisition that without proper intervention will be a lifelong 
struggle, communication disabilities pose a constant challenge.
    The NIDCD has made important progress in understanding and 
helping to develop better treatments for these disorders of 
human communication this year, and we have identified new 
targets, new tools and new teams to accelerate discovery in 
fiscal year 1999.
    For example, we now are using the advanced neuroimaging 
tools to image the brain at work during normal and disordered 
human communication. These studies have taught us that much of 
the brain is used for hearing, balance, voice and speech, and 
the manipulation and production of language, as well as the 
ability to smell and taste.
    Having the ability to image brain activity patterns during 
various communication events or disorders such as stuttering, 
or aphasia, or ringing in the ear or tinnitus, or imaging the 
use of Americans using American sign language is 
revolutionizing our understanding of normal and disordered 
processes of human communication.
    In one of many remarkable advances this year, NIDCD 
scientists have been able to visualize brain activity that is 
correlated with tinnitus or ringing in the ear.
    In another remarkable study, an intramural investigator 
showed that individuals who stutter have a completely different 
brain activity pattern associated with speech production 
whether or not they are fluent or dysfluent.
    NIDCD supported scientists are determining the properties 
of remarkable and unique sensory cells of the inner ears that 
we call hair cells that are shown on the electron micrograph to 
my left. And I think if you look at the cell, which is really 
very unique, you can understand why biological scientists call 
it a hair cell.
    It is that hairy structure or cluster of sterocilias that 
is absolutely critical for auditory signal transduction. When 
the tips of those stereocilia get deflected, that results in an 
electrical stimulation of the cell which sends the electrical 
information into the brain, and that is in fact how we hear and 
how we maintain balance.
    Very often, it is the loss of these unique hair cells in 
the inner ear that lead to hearing impairment and balance 
disorders. And our scientists are working hard to try to 
understand what the molecular mechanisms might be that would 
allow these cells to regenerate.
    We know that in birds, these cells can regenerate. And 
within the last year, even in some mammals, scientists have 
been able to effect regeneration of hair cells after they have 
been damaged. And we think this is a very exciting new area of 
research.
    Now in a very different way, NIDCD scientists are also 
trying to restore hearing through support and development of 
the cochlear implant, and this has been research that has been 
ongoing for the last several decades.
    The cochlear implant is a sensory neural auditory 
prosthesis that we now know improves the economic and social 
outcomes for postlingual hearing impaired individuals. And I 
direct your attention to the second exhibit on my left.
    Let me tell you a little bit about how the cochlear implant 
works. If you look at item number one, you have a microfilm 
that detects the sound. The sound is then sent to item number 
two, which is a speech processor.
    And that speech processor converts the sound into 
electrical energy; which is then sent to number three, which is 
a radio transmitter; which transmits the information across the 
skin into a receiver, which is item number four; then sends the 
information to an array of electrodes, sometimes as many as 22 
electrodes, which a surgeon has inserted into the cochlea, 
which is the structure in the inner ear where the hair cells 
are where the hearing happens.
    And these electrical impulses are changed with a time--with 
a doubling time of less than a millisecond so that the 
information is now being delivered to the cochlear structure in 
a way very similar to the way that information was delivered 
before the hair cells were lost.
    This device is truly remarkable. And individuals who lose 
their hearing, suddenly, they are able to stay in their jobs. 
And in fact, over 60% of them are still able to use the 
telephone after they have had the cochlear implant installed 
and had proper training in its use.
    NIDCD continues to investigate the development of language 
in children who are deaf or hard of hearing. We now know that, 
within the first six months of life, there is a critical window 
of opportunity for language acquisition,either spoken or 
signed.
    As I am sure you are well aware, a number of states are 
currently implementing universal newborn hearing screening 
which begins with a test for auditory function very soon after 
birth.
    In 1998, NIDCD supported scientists will complete a five 
year study showing that two methods, measurement of otacoustic 
omissions, which are sounds that those hair cells make 
themselves, or auditory brain stem responses, which is the 
electrical activity moving through the brain stem associated 
with hearing--we can use these tools to accurately identify 
infants in the newborn nursery who have hearing impairment.
    And this, we believe, will stimulate clinical research into 
what the proper intervention strategies might be to help these 
infants get the greatest language acquisition ability that they 
can have as they progress through life.
    Our institute has also made progress in studying specific 
language impairment. Specific language impairment is a deficit 
in language acquisition that is present in about eight percent 
of American school age children.
    And what it is, is a deficit in language acquisition that 
is independent of any other cognitive defect. It is very 
frustrating for these children. They often get turned off to 
schools or maybe leave school earlier than they would have 
because they struggle with these language disabilities.
    What we have learned is that specific language impairment 
is often caused not by any sort of language problem per se, but 
it is an inability of these individuals to process rapidly 
changing auditory information which occurs during normal human 
speech.
    What that suggests is maybe, by slowing down the rate at 
which the auditory information comes in, we may be able to 
train these individuals to improve their language acquisition 
skills and hopefully restore a language acquisition in these 
children.
    I am sure every one of us who is a parent in this room is 
aware that otitis media, or middle ear infection, is the most 
frequent reason why a sick child visits either an emergency 
room or a pediatrician's office.
    The estimated total cost for otitis media is about five 
billion dollars a year. And the organisms that cause it are 
proving to be increasingly resistent to the conventional 
antibiotic therapy that has been used to manage this disorder.
    We continue our research efforts to try to develop vaccines 
against the organisms that cause otitis media. And we have 
observed that one of the most difficult aspects of treating 
otitis media is it so often relapses within days or weeks of 
when the antibiotics are taken off some of the children who 
develop otitis media. And we are currently investigating why 
these infections are both recurrent and resistent to treatment.
    In addition to new targets and new tools, new teams of 
scientists are providing collaborations to help us progress.
    Molecular genetics is now revealing the identity of genes 
involved in many disorders of human communication. The search 
for hearing impairment genes has been enormously facilitated by 
timely collaboration and information exchange among many of the 
NIH institutes and both our intramural and extramural 
laboratories.
    We see an opportunity to support teams who will work 
together now to understand the biology and genetics of voice, 
speech and language disorders and translate this into improved 
diagnostic and better intervention strategies in such disorders 
as velocardiofacial syndrome and autism.
    New tools, new targets and, most importantly, new teams 
will be needed to rapidly and effectively seize the remarkable 
opportunity before us. We look forward to expanding our 
understanding of the biology and genetics of human 
communication disorders and to translate that knowledge into 
better strategies for diagnosis, early intervention and 
treatment.
    And I would like to thank you for your kind attention. And 
I, with my colleagues, would be happy to try to answer any 
questions you might have. And I would also bring to your 
attention this little box that I brought with me.
    Inside it has a metal cast of a human cochlea so you can 
see what it looks like and how small it is, as well as the 
electrode array from the cochlear implant that is actually 
inserted into the cochleas and the radio receiver that is 
implanted in the skull immediately behind the ear.
    So if you are curious to see it, I would be delighted to 
let you have a look.
    [The prepared statement follows:]


[Pages 1058 - 1063--The official Committee record contains additional material here.]



    Mr. Porter. Dr. Battey, thank you for your very fine 
statement. How long have you been with the institute?
    Dr. Battey. I have been at the NIH since 1983 and have been 
in a number of institutes. I arrived at NIDCD in 1995 when I 
was appointed by Dr. James Snow, my predecessor, as the 
institute's Director of Intramural Research or Scientific 
Director.

                           research progress

    Mr. Porter. When we met yesterday I said that you have 
great enthusiasm for your new job, and I think that is evident 
in what you told us this morning. You were in the room when Dr. 
Olden was testifying. I am struck by the fact that Dr. Olden's 
responsibilities seem more at the beginning of discovery, and 
your institute has come a long way toward reaching solutions to 
many of the problems of deafness and communication disorders. 
Do you see it that way also?
    Dr. Battey. I believe that there has been great progress. 
And the cochlear implant, I think, is one such manifestation of 
that progress. But I would be wrong in telling you that we have 
licked the problem.
    As I am sure you are aware, 20 million Americans or more 
have hearing impairment. Many of them would benefit from the 
use of a hearing aid. Only about five million of those 
individuals actually use the hearing aids.
    And the reason is that they do not like them. And they do 
not like them because they do not do what--they do not restore 
what is missing in these hearing impaired individuals. What has 
happened in the hearing impaired individuals is that the 
dynamic range of their ability to hear has shrunk.
    What do I mean by that? I mean that the difference in sound 
intensity between a sound that can barely be heard and one that 
is intolerably or painfully loud is teeny compared to the size 
in a normal individual.
    So if you just put a device and a hearing aid that linearly 
amplifies everything--in order to hear the sounds you need to 
hear to communicate, you are going to amplify the louder sounds 
so much that they are painful and disturbing to the user.
    So clearly a lot of work needs to be done to design devices 
that more accurately replace the hearing loss that is missing.
    In the area of the genetics of hereditary hearing 
impairment, we are making progress, but we have a long way to 
go. As I am sure you are aware, roughly one child in a thousand 
is born with profound hearing impairment at birth.
    And all together too often, the cause is a genetic cause.
    Roughly 30 genetic loci have been identified by gene 
mapping studies to have hearing impairment genes. Within the 
last year, we have gone from locating to identifying about a 
half dozen of these genes.
    And there are a remarkably diverse group of proteins that 
do many different sorts of things within the cell that we can 
talk about in detail if you are interested, but I am just 
struck by how diverse they are.
    We need to find the rest of the genes. We need to determine 
what their importance is in auditory function. We need to 
determine why it is that they clinically manifest their genetic 
problem only in the inner ear and not elsewhere in the body; 
the same mutant genes are everywhere else.
    Is it because they are only expressed there, or is it 
because their expression or function is somehow rate limiting 
in the inner ear? We then need to use this information 
ultimately when gene therapy moves from being really a 
laboratory exercise to reality towards the long term goal of 
maybe someday replacing these broken genes with functional 
genes and hopefully restoring the ability to hear in these 
individuals, assuming we do not get to them too late and the 
hair cells are not already gone and we cannot bring them back.

                            genetic research

    Mr. Porter. Where at NIH were these sites discovered? Were 
they discovered through Dr. Collins' work or your institute's 
work or a collaborative way?
    Dr. Battey. All of the above.
    It would have been impossible to discover any of these 
genes without the infrastructure laid down by the Human Genome 
Project. The nearly million expressed sequence tags in gene 
databases make the search in a large megabase interval of DNA 
for genes now possible simply by sampling DNA sequence within 
the interval.
    The mapping that I talked about of the 30 genes is only 
possible because we have evenly spaced markers or sign posts 
throughout all the chromosomes which allow us to determine a 
linkage or association between that sign post that we know 
where it is and the hearing impairment gene.
    Now having said that, let me tell you a story about one of 
these genes called the DFNB4. The B stands for--it means it is 
an autosomal recessive which means you need to inherit a bad 
gene from both your mom and your dad to get the disorder.
    DFNB4, it turned out, our intramural scientists discovered, 
but only after Eric Green in the National Human Genome Research 
Institute cloned the gene for Pendred's Syndrome, which is a 
disorder of the thyroid abnormality that sometimes has hearing 
impairment.
    When we heard of Eric's discovery, we noted that the 
Pendred's gene was located in essentially the same place as 
DFNB4. And in advance of publication, Eric provided us with the 
sequence information of the gene that allowed us to determine 
that different mutations in that same gene caused non-syndromic 
hereditary hearing impairment.
    So in the genetic arena, there really are no institute 
boundaries. The scientists move very freely. And progress in 
one institute almost inevitably will lead down the road to 
progress in another.
    That is part of the excitement of doing that work.
    Mr. Porter. Thank you.

                        genetic research ethics

    I have a question for Dr. Varmus that I do not want him to 
answer right now, but let me ask it right now.
    In listening to Dr. Battey, it seems to me that, as a 
result of the mapping of the human genome, a couple that might 
be contemplating marriage will be able, at some point in time 
in the future, to determine whether they contain in their 
genome, defects that can lead with some degree of probability 
to an outcome that a child would be hearing impaired or have a 
particular disease or be susceptible to that disease.
    I wonder what the implications are for policy. I don't want 
you to answer it now because it is a rather long question, but 
sometime I would like to discuss it with you further. There are 
already bills introduced on genetic discrimination and the 
like, but I wonder what the implication of this might be in the 
future.
    Dr. Varmus. It is not in the future, Mr. Porter; it is 
already here----
    Mr. Porter. It is already here.
    Dr. Varmus [continuing]. In some cases.

                         hair cell regeneration

    Mr. Porter. Yes, we will have to talk about it.
    Dr. Battey, you mentioned hair cell regeneration and it 
seems to me that I recall three years ago, maybe it was two 
years ago, when there was great criticism of a study that was 
being made of birds--I think it was canaries--in regeneration 
of hair cells. This was one of the issues that was highlighted 
on PrimeTime Live by Sam Donaldson as being charged with 
wasting of public money. Do you want to comment on that a 
little bit?
    Dr. Battey. Yes, I would like to comment on that specific 
example, but then I would like to comment, if I could, on the 
use of animal models in biomedical research in general.
    First of all, I think that it is--hopefully it is obvious 
from my earlier comments that often animal models provide us 
with the means to discover important new ways to deal with 
human disorders that cannot be appreciated in human 
populations.
    And I think the hair cell regeneration in birds is a great 
example. Not only do we know that hair cells can be regenerated 
based on these studies done in birds, but the more important 
fact is that once the hair cells come back, they rewire and 
send their information into the central nervous system in a way 
that results in restoration of normal auditory function.
    And that is what is absolutely astounding to me is that 
either the cells can find a way to not only grow back, but to 
send the information in right; or the brain is sufficiently 
plastic, that it can readjust to this new set of regenerated 
hair cells and restore auditory function.
    Mr. Porter. So the criticism that this was a waste of money 
may, in the end, prove to be one of the most important 
expenditures of money for science because this may lead to a 
discovery to regenerate hair cells and restore hearing in 
humans?
    Dr. Battey. That is absolutely true.
    And let me cite another example because I think it is very 
important for our understanding of the genetics of hereditary 
hearing impairment. It turns out that, although much smaller 
than us, the ears of mice work pretty much the same way as the 
ears of humans.
    Now they can hear at somewhat higher frequencies, and that 
is an interesting question all unto itself. But other than 
that, structurally and functionally, they are really very 
similar. What does this mean?
    This means that we can use mice to help us identify the 
genes for human hereditary hearing impairment. And in fact, we 
are currently supporting a contract to screen all of the mice 
in the largest mouse repository in the world, the Jackson Labs, 
to identify strains of mice that have hereditary hearing 
impairment.
    And lo and behold, it is the same loci that we are mapping 
in humans, are mapping to their syntenic or similar locus in 
the mouse. In the mouse, as Dr. Olden showed you earlier, with 
much less expense, we can rapidly zero in on the location of 
the gene, enormously facilitating the time and the expense 
otherwise required to positionally clone those genes.
    The other thing we can do in the mouse which we will 
probably never be able to do in the human is we can prove it is 
the right gene and we can do that--I am sure you have heard of 
gene knock outs. Well, I am going to tell you about a gene 
``knock in.''
    We can knock the functional gene back into the mouse genome 
and restore hearing. And in fact, one of our intramural 
scientists did that with another hereditary hearing impairment 
gene just within the last two months.
    Mr. Porter. That is truly exciting.
    Thank you, Dr. Battey.
    Mrs. Northup.

                      specific language impairment

    Ms. Northup. Thank you, Doctor. I have a couple of 
questions. First of all, I did notice that you all have done 
some work on SLI, the specific language impairment?
    Dr. Battey. Yes.
    Ms. Northup. It affects three to six percent of our 
children that are in school. I was wondering, first of all, at 
what age can we diagnose that a child has that specific 
problem?
    Dr. Battey. I'm not a speech pathologist, so I'll merely 
speculate, and give you my--the best understanding that I have. 
But I think that problem can be diagnosed pretty much at the 
same time as language acquisition begins to come on board, 
which would be around two to three years of age.
    Ms. Northup. I have a number of questions to follow up. For 
example, should schools be making this diagnosis? Should we 
screen every child? Is there an affordable test that would make 
it possible to efficiently screen every child for this type of 
disability?
    It's clear to me that many of the children that have this, 
that are diagnosed with dyslexia, and we know that dyslexia 
often isn't diagnosed when it needs to be, at five years old, 
and so forth. It's much later. And that's very troubling to 
many children who don't read. Because they pick up bad eye 
patterns, and so forth.
    And unlearning is as hard as it is to learn the correct way 
to read. I wondered if you're communicating your findings on 
SLI to those whose primary role it is to educate our children. 
And if you're developing or testing strategies for remediation 
of these children, how do we apply that understanding of their 
difficulty in distinguishing phononyms, to how we teach them, 
then, in first grade, how to read.
    And if you were working at all with the panel that was 
established between the Department of Education and NICHD last 
year, to communicate on what the emerging science is regarding 
children that have learning disabilities, and what we do in our 
schools, in practice, you know?
    How do we connect what we learn with how we apply it?
    Dr. Battey. That is a large number of very important 
questions. I guess I'll answer the ones which I feel I'm best 
able to respond to directly.
    One of the exciting things about our determining, that in 
fact, it's an auditory processing defect that's behind specific 
language impairment offers an opportunity for us to more 
accurately make the diagnosis, and distinguish it from other 
things that can cause language delay.
    So, I think that the recent break-throughs in research will 
provide a more accurate diagnosis. And were it appropriate to 
do screening, would provide a more accurate way to do the 
screening.
    As to who ought to do the screening, my understanding of 
the testing, and given the fact that it is an auditory problem, 
I would think that speech language pathologists and 
audiologists would be the appropriate group to be involved in 
doing such a screening.
    And as far as translating results into the public domain, 
we do that--scientists do that by virtue of publishing their 
results in peer review journals, thereby making the information 
available to health care professionals in other arenas. And 
that's been the traditional way that information has moved from 
the research arena, and into the--hopefully development of 
better treatment strategies.
    One investigator in particular, Paula Tallal, feels that a 
strategy for improving the language abilities of these children 
involves a strategy she calls fast forward. And what happens in 
that strategy is, the speed at which the language phonemes come 
in are slowed down with a computer.
    And in some of the studies she's done, and these are 
preliminary, and they have not yet been replicated by another 
investigator, so I hasten to place too much weight on them just 
yet. But if her results are right, they're very exciting.
    She is able to improve the language acquisition skills, by 
doing exactly that, by slowing down the rate at which the 
phonemes are introduced into the auditory system. And I think 
that if that holds up, that's pretty exciting, for either six 
or eight percent, depending on how, I guess, you diagnose them, 
of school age children with specific language impairment.
    Ms. Northup. When you have children that are dyslexic, what 
you find out is that there is an array of signs. And not all--
all of them have a different collection of those signs. They 
are visual, you know? They're reversal. Everybody think 
dyslexics reverse--reverse letters.
    And actually, some do. But they don't all. Some are 
dysgraphic. And some, actually, you say, go to bed, and they 
think you said, the goat is dead. And you can understand why a 
child that works through this has reading problems.
    And you know, what we found last year is, that the 
Department of Education really was largely unaware of the 
research that was being done by NICHD.
    And that was the reason that this committee set up that 
panel, to make sure emerging research joined with the people 
that--whose real dedication in life is helping children all be 
successful.

               early identification of hearing impairment

    Do I have time for one more question? I have several 
friends that have been very involved in the Louisville Deaf 
Oral School, in Louisville, Kentucky.
    And one of the complaints that a number of those parents 
have is that the screening that is supposed to go on at birth, 
a very preliminary screening, was not picked up. Children that 
were really pretty severely deaf.
    And so, they lost those very early years, when 
communication skills, and developing language patterns are so 
important. And they were at the Louisville Deaf Oral School for 
a longer time, due to that, and had some developmental problems 
that early diagnosis could have helped with.
    I just wondered what sort of confidence you have in the 
national effort to screen children, babies, newborn, in the 
hospital, before they go home. And if there is anything we 
should do to improve that screening?
    Dr. Battey. A number of states are already implementing 
universal newborn hearing screening. I think New York is one of 
them. I believe Colorado is one of them. And the State of Rhode 
Island would represent a third.
    In hearing the presentations by individuals that are 
associated with these screening efforts, they feel that the 
screening methodology is there, that it works. It's 
satisfactory.
    So, technologically, we can do it. The big issues are 
implementing it across all of the states, who will pay for it. 
The test costs $30-$35 an infant to do the screening, with the 
current technology.
    But most importantly is follow-up. In that it does no good 
to screen if you don't get the child back for appropriate 
intervention. And that then brings us to the final area, where 
I think NIDCD has a big responsibility, and that's proper early 
intervention.
    We're going to be finding children that have mild to 
moderate hearing impairment at birth. And we do not know today 
what the optimal intervention strategy is. There are ideas out 
there, and many things in practice. But none of them have been 
validated by really well controlled clinical trials.
    And we feel that a big responsibility of our institute is 
to stimulate that clinical research, and to support it. And I 
think we're actually playing catch-up on that, because those 
infants are going to be found within the next couple of years.
    Ms. Northup. Okay. Thank you. Thank you, Mr. Chairman
    Mr. Porter. Thank you, Mrs. Northup. Mr. Stokes.

                     hereditary hearing impairment

    Mr. Stokes. Thank you, Mr. Chairman, Dr. Battey. You may 
have gotten intothis. I've had to be between two subcommittees 
this morning, and you may have gotten into this. If you have, just tell 
me, and we'll skip on to something else.
    But have we talked about whether or not we're getting 
closer to unraveling the cause of hereditary hearing 
impairments?
    Dr. Battey. There has been remarkable progress in the last 
year. And we talked a little bit about it, but maybe I can 
quickly summarize it for you.
    Mr. Stokes. I'd appreciate it if you would.
    Dr. Battey. I'd be happy to do that. Last year, when Dr. 
Snow appeared before you, we knew the map location of maybe 15 
or 20 genes involved in so-called non-syndromic hereditary 
hearing impairment. That's hearing impairment without any other 
obvious clinical manifestation.
    We now know the location of over 30 genes that cause non-
syndromic hereditary hearing impairment. But more importantly, 
within the last year, we not only know where a half dozen of 
them are, we know what they are. We have cloned the genes.
    Much of this is through NIDCD supported efforts, or 
collaborations between NIDCD investigators, and investigators 
supported by other mechanisms.

                            autism research

    Mr. Stokes. My next question is, what major activities are 
under way in autism research? And what is the size of our 
investment there?
    Let me share this with you, before you try to answer my 
question. Cleveland newspapers have just recently had a very 
interesting story about a young African-American kid who is 
eleven years old, in middle school, who is described as being a 
spelling wizard.
    He recently competed in the school spelling bee, and would 
have proceeded on to the next stage of competition, at 
Cleveland State University. But, in the final questions put 
between he and one other young person who was competing with 
him, he was asked the question, to spell sachet.
    And he did not think to ask for a description of the word, 
which he was entitled to do. And so, he thought of sachet 
meaning to walk casually. He spelled it S-H-A-Y. And they were 
really referring to sachet, the French word for small bag, S-A-
C-H-E-T. And so, they disqualified him on the basis of it.
    Since then, it has been determined that he should have been 
permitted to ask for a description. If he didn't, he should 
have been told, when two words fall into the same category of 
that sort.
    So, they reinstated him in. And he is now back in the 
competition at Cleveland State University. And of course, the 
newspapers had another big article about the fact that he had 
now sacheted back into the competition. [Laughter.]
    But I'd appreciate it if you would talk about autism 
research, and what we're doing.
    Dr. Battey. I'm very excited about the NIH's efforts in 
autism. And I say NIH, because NIDCD is one of four institutes, 
including NIDCD, NINDS, NICHD, the Child Health Institute, and 
NIMH, the Mental Health Institute, which are collaborating on 
funding a series of centers to take a comprehensive approach to 
autism.
    Understanding the genetics of autism. If you look at 
identical twins, the concordance for autism is 70 percent in 
identical twins. Whereas in non-identical twins, it's three 
percent. What does that tell us about the importance of 
genetics in autism? Got to be pretty important.
    They're looking into the diagnosis. Is it one disorder, or 
is it a spectrum of disorders? And how can we more precisely 
classify these individuals to optimize the proper intervention 
and treatment?
    We are very close, I believe, to identifying the map 
location for at least one major locus involved in autism, based 
on discussions I've had with investigators working in these 
centers. And I think it's one of the more important areas of 
research that NIDCD supports.
    If autism is anything, it is a communication disorder. And 
that is the fundamental sine qua non of autism. So, I view it 
as very important. And if I'm remembering correctly, the 
aggregate support from the four institutes for these centers is 
about $23 million.

               collaboration with department of education

    Mr. Stokes. Okay. To what degree, Dr. Battey, does your 
institute collaborate with the Department of Education? It 
seemed to me that there should be some type of collaborative 
effort here.
    Dr. Battey. One recent example of our collaboration with 
the Department of Education, as well as the Department of 
Labor, is a workshop that we co-sponsored on the economic and 
social realities, for individuals with communication 
differences and disorders.
    I learned at that workshop that, in the early part of this 
century, most individuals were in jobs that involved physical 
labor, and very little communication and information processing 
skills.
    But as we move into the next millennium, 90 percent or more 
of the jobs, jobs that give--put money in people's hands, that 
make them feel satisfied with their lives, involve 
communication and information processing and exchange.
    Clearly, communication disorders are going to be a more 
important problem in the next millennium, than they were in 
this millennium. And they're already a pretty severe 
limitation. If you look at how difficult it is for an 
individual with hearing impairment to keep a job, or to get 
another job after they've lost their job.
    So, yes. We are very interested in working with people in 
the Department of Education, and Labor. And they help provide a 
very important perspective on the importance of our research.

                         otitis media research

    Mr. Stokes. Dr. Battey, one of the areas that I've 
maintained interest in over the years are ear infections. And 
as we know, doctor's offices, emergency rooms, are filled 
constantly with children with ear infections.
    Is this an area in which we're making any progress in terms 
of research?
    Dr. Battey. Mr. Stokes, my background is in pediatrics. So, 
I am very much very aware of ear infections. And in fact, my 
eleven year old son was treated over 40 times with antibiotics 
for otitis media during the first eight years of his life.
    So, I know what a problem it is. And it's a big problem. 
Because antibiotics, in the case of my son, were not a very 
satisfactory way to manage the problem. It's a big problem, 
because the organisms, strep pneumoniae, non-typable 
haemophilus influenza, and Moraxella, that caused the disorder, 
are appearing in antibiotic resistant forms, which will require 
the use of more expensive and sophisticated antibiotics to 
treat these organisms.
    And it's a problem because, even when you treat them 
withantibiotics, the infection comes back. Some of the progress that's 
been made by NIDCD investigators in this area, involve a better 
understanding of why the infection occurs.
    An investigator at the University of Pittsburgh, Dr. Garth 
Erlich, has shown, using molecular biology assay, called the 
polymerase chain reaction, that organisms are--remain in the 
middle ear after treatment, and that these organisms are in 
relatively indolent, slowly dividing forms. Which explains why 
they're resistant to antibiotics, because most antibiotics kill 
bacteria only when they divide.
    And these--these little sort of niches hiding away in the 
middle ear are called bacterial bio-films. Bio-films is an 
emerging area of importance in the infectious disease arena. 
And I think that as we better understand how these organisms 
can hide, and evade our abilities to treat inner ear 
infections, we will be able to develop better treatments, maybe 
antimicrobials that don't require cell division to kill the 
bacteria.
    But the ultimate solution is a vaccine. And our institute, 
both intramurally and extramurally, supports research to 
develop vaccines against otitis media. And the intramural 
research program, it's a lipooligosaccharide, which is a sugar 
molecule on the outside of the bacteria, of the non-typable 
haemophilus, that we couple to a protein called tetanus toxoid.
    And this antigen has provided protective immunity in a 
variety of animal--systems, including direct bacterial 
challenge to the middle ear, in the chinchilla, within the last 
year. And we are moving this forward, into a phase one clinical 
trial, in the NIH's clinical center, hopefully before the 
conclusion of this fiscal year.
    Extramurally, individuals are looking at the fimbrin 
protein, which is a protein on the outside of the bacteria, 
that allows it to stick to surfaces. And that's, in fact, how 
we think the middle ear gets seeded with bacteria.
    These investigators are exploring whether or not developing 
vaccines using the fimbrin antigen might not be effective in 
treating, or excuse me, vaccinating, and providing protection 
against otitis media.

          social and economic costs of communication disorder

    Mr. Stokes. I was just thinking as you were speaking, about 
your previous comments to my question about, what's going to 
happen in the new millennium, the year 2000 and beyond. We talk 
about 90 percent of the jobs requiring communications skills, 
as opposed to what it has been in the past.
    Obviously what we're talking about is social and economic 
costs that attaches, then, to communications disorders, is that 
right?
    Dr. Battey. Yes. I think if you look at it carefully, you 
will conclude, as I have, that the cost to do the research 
today, to alleviate the communication disorders of tomorrow, 
will more than pay us back, both in the economic contributions, 
and the employability of the individuals with these 
communication disorders.
    Going beyond the fact that you provide these people with 
good self-esteem, and the satisfaction that comes from being a 
productive, full player in the American work force.
    Mr. Stokes. Mr. Chairman, I guess my time is expired.
    Mr. Porter. Thank you, Mr. Stokes.
    Mr. Stokes. Thank you very much.
    Mr. Porter. Dr. Battey, I'm very impressed with your broad 
knowledge, and as I said earlier, your enthusiasm for your new 
position. I think you're doing a fine job and we appreciate 
very much your very detailed and direct answers to our 
questions, as well as your fine opening statement.
    I have a lot more questions, and I wish I had more time to 
talk with you, but we'll have to put these in the record, 
because the second bell has rung for the vote. We wish you well 
in your new position and look forward to talking to you again 
soon. Thank you so much.
    Dr. Battey. Thank you, Mr. Porter. And I'd like to thank 
the committee for their support.
    Mr. Porter. Thank you very much. The subcommittee will 
stand in recess until 2:00 p.m.
    [The following questions were submitted to be answered for 
the record:]


[Pages 1074 - 1130--The official Committee record contains additional material here.]



                                          Thursday, March 12, 1998.

               NATIONAL HEART, LUNG, AND BLOOD INSTITUTE

                               WITNESSES

DR. CLAUDE LENFANT, M.D., DIRECTOR
DR. CARL ROTH, PH.D., LL.M ASSOCIATE DIRECTOR FOR SCIENTIFIC PROGRAM 
    OPERATION
JAMES WEHLING, FINANCIAL MANAGEMENT OFFICER
SHEILA MERRITT, EXECUTIVE OFFICER
DR. JOHN WATSON, PH.D., ACTING DEPUTY DIRECTOR
DR. HAROLD VARMUS, M.D., DIRECTOR, NIH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS

    Mr. Porter. The subcommittee will come to order.
    We continue our hearings on the National Institutes of 
Health and the fiscal year 1999 budget request of the National 
Heart, Lung, and Blood Institute. We're pleased to welcome Dr. 
Claude Lenfant, the Director of NHLBI.
    If you would introduce the people who are with you, Dr. 
Lenfant, and then proceed with your statement, please.
    Dr. Lenfant. Thank you, Mr. Chairman. On my far left is Dr. 
John Watson, who is the Acting Deputy Director of the 
Institute; next to him is Ms. Sheila Merritt, who is the 
Executive Officer of the Institute; and then next is Dr. Carl 
Roth, the Associate Director for Scientific Program Operations; 
and here on my immediate left is Jim Wehling, who is the Budget 
Officer of the Institute; and, of course, you have met Dr. 
Varmus and Mr. Williams.

                      increases in life expectancy

    Mr. Chairman, I am really very pleased to be here today and 
this year, I would say. As you know, 1998 is a very special 
year for the Institute. It is the year that we are celebrating 
our golden anniversary.
    In the next few minutes, I would like to highlight some of 
our accomplishments, and then focus on the opportunities for 
further progress--opportunities I should say which would have 
been unthinkable ten or fifteen years ago.
    As you can see on chart 1 here, when theInstitute was 
created in 1948, that the Nation was witnessing an epidemic of heart 
disease which was causing an ever-increasing death rate from this 
condition in men and in women as well. With the support that we 
received from this committee and from the Congress and the 
Administration, plus the work of the scientific community, we have seen 
in the next 50 years the occurrence of many life-saving treatments as 
well as we have learned how to prevent some of these diseases. As a 
result, we have witnessed a very significant decline in the death rate 
from heart disease; see chart 2.
    As a result of that, the life expectancy of the American 
people has increased by approximately six years, as you can see 
here on chart 3, during the years 1965 and 1995. But the thing 
that I would like to underscore is that approximately 60 
percent of this increase in the life expectancy is due to the 
decline in death rate from cardiovascular diseases--coronary 
heart disease, the most important, stroke, and other heart and 
vascular diseases.


[Pages 1133 - 1135--The official Committee record contains additional material here.]



    I should also point out that some of the increasing life 
expectancy can be accounted for by decline in death rates from 
perinatal diseases, some of them being within the purview of 
the National Heart, Lung, and Blood Institute, especially 
neonatal respiratory distress syndrome.

                               thrombosis

    I should say, however, Mr. Chairman, that we must not 
become complacent, as heart disease and disease of the lung and 
of the blood remain the most important public health problem 
that we have in this country in terms of morbidity and 
mortality.
    Fortunately, we have before us opportunities which, if they 
are pursued, will lead to even more improvement in the health 
of the American people. And I would like to spend a moment 
talking about a special case, which is that of thrombosis.
    Thrombosis, or the formation of blood clots, is a very 
important health problem in this country. When blood clots are 
inappropriately formed, as you can see on chart 5, they are 
responsible for a host of life-threatening events--heart 
attack, stroke, pulmonary embolisms, and deep vein thrombosis--
which affect millions of people in this country. However, 
today, the discovery of compounds and molecules in the 
bloodstream, molecules and compounds which promote thrombosis, 
coupled with advances in the genetics of thrombosis, gives us 
the opportunity to learn more about this condition and actually 
to develop some very effective interventions.
    In fact, I would say that the case of thrombosis is truly a 
paradigm of how we can use human genetic and genomic research 
to approach the disease problems which are within the mandate 
of our Institute.
    One of the first things that we can learn to do from this 
research in human genetics is to identify the susceptibility to 
disease. And let me explain what I'm saying by that. Two 
individuals may smoke during their entire life; one of them 
will have all these elements that we know so much about and 
I'll discuss so much today, but one may not get a disease. And 
that is basically because of a difference in susceptibility.
    Knowing more about the susceptibility to disease, we can, 
of course, develop some prevention intervention which would be 
much more effective than the kind of shotgun approach that we 
are using today. As well, we can make early diagnoses and 
develop a prognosis for this condition, we can predict disease 
manifestation, we can, of course, understand the mechanisms of 
disease, and we can tailor our pharmacological interventions 
specific to individuals. Already, we know of a case coming from 
the work of the Institute where we know that some individuals 
with asthma are responsive to a specific medication where other 
individuals may not be responsive to this medication.

                 chronic obstructive pulmonary disease

    Finally, I would like to demonstrate a new avenue of 
research which may have a very remarkable impact on the well-
being of many patients. When I presented to you the 
contributions to a change in life expectancy, I did not say 
anything about chronic obstructive pulmonary disease. As you 
can see on chart 3 here from this chart, chronic obstructive 
pulmonary disease, or emphysema, has a negative impact. 
Basically, what it means is that the morbidity and mortality of 
this condition keeps on increasing in contrast to what we have 
seen in the cardiovascular area.
    Now, chronic obstructive pulmonary disease, or emphysema, 
is responsible for the destruction of the lung tissue and in so 
doing impedes normal breathing. I would like to illustrate that 
on this chart which shows some work from an animal model.
    Here is a normal lung. And as you can see, all these little 
spaces are called air sacs. That is where oxygen goes into the 
blood and the carbon dioxide is eliminated. In the case of 
emphysema, as you can see, all these little air sacs disappear 
and are now replaced by larger spaces, open spaces. That is why 
the breathing and the transfer of oxygen is impeded.
    Recently, it has been found that if a lung with emphysema 
is treated with a certain retinoic acid, you can witness the 
restoration of the air sacs that you find in the normal lung. 
That is quite an interesting new avenue of research which we 
believe offers new prospects for all these patients affected by 
this condition.
    So, Mr. Chairman, during the last few minutes I've recited 
to you some opportunities which certainly will bring to the 
patients hope for a better life and a healthier life as well.


[Pages 1138 - 1140--The official Committee record contains additional material here.]



    I'll be pleased to answer your questions.
    [The prepared statement follows:]


[Pages 1142 - 1153--The official Committee record contains additional material here.]



    Mr. Porter. Thank you, Dr. Lenfant.
    Before I begin questions, let me take just a minute to 
introduce and welcome James Beckman, a student at Glenbrook 
South High School in the tenth congressional district, who is 
here with the Congressional Youth Leadership Conference. He's 
from my district. [Laughter.]

                       impact of budget increases

    Dr. Lenfant, you're asking for a 7.7 percent increase for 
the next fiscal year, including the OAR transfer. Many of us in 
Congress want to see an even greater rate of increase over the 
following five years. A great deal of progress, obviously, has 
been made in reference to diseases of the heart and blood and 
of the lungs. Can you reasonably use a doubling of your budget 
over the following five years after this fiscal year? What 
would you do with the additional money?
    Dr. Lenfant. I believe so, Mr. Chairman. Let me try to 
convey this feeling that we have in the various communities 
which are served by the Institute. Today, the opportunities are 
limitless. When we look back at what has been happening during 
the year past, much progress has been made, there is no doubt, 
but we have failed to understand the mechanisms of many of the 
conditions which are before us. In certain other instances, we 
have uncovered in great part these mechanisms but we haven't 
been able to develop therapies and cures to address these 
problems.
    The case of thrombosis that I just mentioned to you is one 
example. We're putting together all that we have learned, plus 
bringing into the areas which are of interest to our Institute 
molecular medicine. And I could say that heart, lung, and blood 
medicine are now moving to the forefront of molecular medicine. 
By bringing these techniques, we can make immense progress and 
I believe reduce the morbidity and the mortality of these 
conditions as well as finding cures. I would like to underscore 
the word ``cures'' as opposed to treatments. Often a treatment 
is something that you have to do forever because, in fact, you 
haven't cured the condition.
    I think that today there are a number of conditions which 
eventually can be cured as a result of the research that we can 
do using these new approaches and combining that with what we 
have learned about the physiology and pathophysiology of the 
organs in which we are interested.

                           age adjusted data

    Mr. Porter. Could you explain what age-adjusted is in 
reference to the charts. How do you adjust for age to get the 
data?
    Dr. Lenfant. Well, to adjust for the age means that we make 
the data that you see today comparable; you can compare the 
data that you had seen 10 or 15 years ago or even that you 
would see 10 or 15 years from now.
    Mr. Porter. Why does the data require adjustment?
    Dr. Lenfant. Because the size of the population for 
different age brackets changes. Today, we have many more people 
above 60 years old than we had 30 years ago. The adjustment 
allows you to make that comparison in spite of the shift in the 
demographics of the population.

                              hepatitis c

    Mr. Porter. I see. Dr. Lenfant, you state in your testimony 
that a highly sensitive anti-hepatitis C test implemented in 
1992 is estimated to have prevented 33,000 cases of hepatitis 
annually, resulting in savings of $323 million in health care 
costs. Dr. Satcher, our new Surgeon General, testified last 
week that many Americans infected with hepatitis C are unaware 
that they have the disease. The recommendation is that anyone 
who had a blood transfusion prior to 1990 should be tested for 
the disease.
    In light of your testimony, shouldn't the recommendation be 
for anyone who received a blood transfusion prior to 1992?
    Dr. Lenfant. Yes, Mr. Chairman. Attached to my testimony is 
a graph which shows the declining risk of post-transfusion 
hepatitis. I should say that all the steps that you have seen 
here between 1960 and now are, in fact, the result of some of 
the research that has been supported by the Institute.
    As you can see, in 1980, we estimated that approximately 7 
or 8 percent of the transfused population might have been at 
risk of hepatitis. And so, therefore, there is no question that 
if we want to ascertain the situation of these transfused 
people in the year past, we have really to go back past 1990 
and even 1992.


[Page 1156--The official Committee record contains additional material here.]



                         noninvasive screening

    Mr. Porter. Through your studies several less invasive 
imagining techniques have emerged as potential screening 
techniques for coronary arterial blockages. One of these 
techniques is retinal scanning which detects early signs of 
systemic vascular damage in the blood vessels of the eye. Do 
you expect that someday a test like this will be used as a 
component of a routine physical exam?
    Dr. Lenfant. Yes. Yes. I think that will become possible. 
But I think that the technique at this time needs to be 
considerably improved, first of all, to make it better, more 
reliable, and, perhaps more importantly, so that the cost of 
the equipment which is necessary decreases in order to make it 
available to a greater population.

                          treatment guidelines

    Mr. Porter. After two decades of decline in deaths from 
stroke and heart disease, we are seeing a small increase in 
stroke deaths and a leveling off of mortality from heart 
disease. In addition, congestive heart failure in end-stage 
kidney disease is on the rise. This has caused the Institute to 
update the 1993 guidelines and, for the first time, provide 
recommendations about which drugs should be used to treat which 
patients. The new guidelines will also recommend for the first 
time ways to control blood pressure using diet.
    Do you think this is a trend for the future? Will we be 
seeing new guidelines making specific recommendations for other 
diseases?
    Dr. Lenfant. Yes. If I may, Mr. Chairman, I'd like to say a 
few words about the findings in the research that dietary 
intervention may be quite effective for the treatment of, say, 
a condition like high blood pressure. Indeed, we have conducted 
a fairly large study of hypertensive subjects treating them 
only with a dietary intervention which included a diet low in 
fats, rich in fruits and vegetables. And, indeed, after I think 
it was five years, we saw a very significant decline in the 
hypertension in the blood pressure of these patients. My 
recollection is that it was in the order of 5 or 6 percent of 
the number, the blood pressure, which is a fairly significant 
decline.
    Your question, as I understand it, was whether such dietary 
intervention can be applied to other conditions as well. And I 
think that the answer is certainly true. We do know, for 
example, that coronary heart disease can be prevented or 
certainly reduced in severity by way of dietary intervention 
which requires limitation of saturated fat. We know also that 
in many cases of cancer, dietary interventions are very 
important to prevent the occurrence of this cancer. So I think 
the answer to that is yes.
    Admittedly, there are some conflicting signals which are 
coming from various studies. In fact, at the request of Dr. 
Varmus, we are looking at these conflicting signals to see how 
we can reconcile all the information that is coming from 
different sources.

                           healthy lifestyles

    Mr. Porter. Although this isn't your direct responsibility, 
it seems to me that more than any other disease, coronary heart 
disease tends to be a disease of lifestyle. We seem to know a 
great deal about the positive effects of exercise, of a diet 
low in fat and rich, as you say, in fruits and vegetables. And 
we know a great deal about the effects of tobacco use over a 
long period of time on the heart.
    What do you do to interface with the CDC and others who are 
attempting to influence people in choosing a healthy lifestyle? 
And what should we be doing that we aren't doing in that 
regard?
    Dr. Lenfant. Well, let me first say, Mr. Chairman, that as 
we look at the things which we believe we can do to improve the 
cardiovascular health of the American people, we do include 
exercise as one of the issues that we are interested in. Now 
having said that, we do work fairly closely with the CDC, the 
Centers for Disease Control and Prevention and we cooperate on 
many activities to basically make sure that the outcome of our 
research programs is communicated to the people and, more 
specifically, to the communities, because we do believe that 
programs which are at the community levels are often much more 
effective than a program that results from a centralized 
intervention.
    The other aspect of your question, what should we do, I 
think the answer to that is simple. We should intensify that 
because we believe that lifestyle is a key aspect, a key thing 
that we can do to prevent the development of many conditions 
which are within our mandate, certainly heart disease, blood 
pressure elevation, the complications of which may be heart 
disease, or stroke. And dietary intervention, I think the 
American people have got to be ``educated'' or informed about 
these things. But I have to tell you it is very, very difficult 
to do.
    Mr. Porter. I think it's obvious that it's very difficult 
to do because, although tobacco use has been curtailed a great 
deal in our country, we now seem to be on the problem of over-
weight and out of shape even to our young children. Somehow 
we've got to get a handle on that because, if we could turn 
those kinds of things around, we could save a huge number of 
lives and a great deal of health care costs that are reflected 
now in our system.
    Dr. Lenfant. On Tuesday when Dr. Varmus appeared before you 
the issue of obesity was brought up. I can only underscore 
again what he said, that obesity is the only risk factor for 
cardiovascular diseases on which we not only have made no 
progress, but the issue and the problem has worsened over the 
years. It is an issue of tremendous concern that, as you heard 
Dr. Varmus say, is addressed by several Institutes and we are 
one of them. In fact, we have now a task force which is just 
about to report on some guidelines for the prevention and the 
approach to obesity.
    Mr. Porter. Thank you, Dr. Lenfant.
    Ms. DeLauro.
    Ms. DeLauro. Thank you very much, Mr. Chairman.

                            cooley's anemia

    Thank you, Dr. Lenfant, for your testimony. It's good to 
see you back here. Last year, I asked you about Cooley's anemia 
and I would like to talk a little bit about the disease again. 
As you know, Cooley's anemia disproportionately affects people 
of the mediterranean heritage, particularly Italian-Americans. 
Twenty years ago the average life expectancy of someone with 
Cooley's anemia was mid-teens. Now, most of those patients live 
to their thirties. I applaud the progress and want to continue 
to do better.
    In the conference report last year for Labor, HHS, the 
report endorsed a recommendation of a September 1996 special 
emphasis panel that the National Heart, Lung, and Blood 
Institute create a network, if you will, of collaborative 
clinical centers to address the special research related 
toCooley's anemia. As I understand it, another special emphasis panel 
which met last September endorsed the creation of that same kind of a 
network. What action has been taken to establish the network of 
clinical centers?
    It is also my understanding that people who suffer from 
Sickle Cell anemia can benefit from the same kinds of treatment 
that Cooley's anemia patients use. Have you expanded the 
research or undertaken any new efforts toward improving 
treatment of those patients?
    Dr. Lenfant. Let me first answer the second part of your 
question, which is whether we have expanded the research 
portfolio on this condition. The answer to that is, yes, yes, 
yes; a big yes, actually. We have initiated a new research 
program on the clinical aspect of Cooley's anemia. A 
solicitation was issued by the Institute shortly after the 
hearing last year, I would say, in part, in response to your 
comments and your interest, and looking again at the report of 
these panels which you mentioned. We did issue that 
solicitation. The applications have been received and they are 
in the process of being reviewed. I think that review is going 
to be completed within a couple of weeks or something like 
that.
    I can tell you that the applications that we have received, 
there are I think a dozen or so, all are extremely interesting. 
If they are judged meritorious by the review process that we 
have, I think that will contribute greatly to move the research 
several steps ahead.
    The applications focus on the induction of fetal 
hemoglobin, as you know, which is a possible treatment for this 
condition, on the assessment of iron deposits especially in the 
heart, there are also some projects on the development of new 
cheleators, which are the compounds that can help remove excess 
iron, and then also there is some work which is quite 
interesting and concerns the feasibility of exchange 
transfusion in these patients. So that's the answer to the 
second part of your question.
    Ms. DeLauro. You said you received a dozen or so 
applications?
    Dr. Lenfant. We have a dozen applications. I don't know how 
many will be funded because it depends on the quality of the 
applications.
    Ms. DeLauro. And you expect the results or the applications 
within the next couple of weeks to be determined what will be 
accepted or not.
    Dr. Lenfant. Yes. And then it has to go to our national 
advisory council, the next meeting of which is in May. But 
after May, the applicants will be advised. From what I've 
heard, I hope I'm not speaking too fast and out of turn, but 
I'm fairly confident that we will end up with a very reasonable 
program.
    Ms. DeLauro. Terrific.
    Dr. Lenfant. Now the first part to your question was have 
we initiated or given further thought to the clinical network. 
We haven't initiated it but we have given much more thought to 
it. In fact, we have budgeted in the 1999 budget an allocation 
for the development of this clinical network. The details of it 
are not developed as yet. Most likely, it will be a clinical 
network which will be joint for Cooley's anemia and Sickle Cell 
disease because there are so many similarities between these 
two conditions.
    Ms. DeLauro. What is your sense of timing on the 
development of the centers? And is it a question of resources? 
What has held up you're doing that?
    Dr. Lenfant. Well, let me tell you, Ms. DeLauro, the issue 
is not one of resources, because the Institute is, and has 
always been, very committed to this condition. The issue was 
the practicality and the feasibility of developing these 
centers. It is the support of an infrastructure. It's like 
buying a building, if you will, but if nobody goes and works in 
the building, what's the point of having the building? And the 
question that we had is whether there would be enough patients 
in some sites, whether there would be enough interest for the 
comparisons between the different sites to support this 
infrastructure. After looking into it and making the decision 
that we would combine that with Sickle Cell disease, we have 
come to the conclusion that that was a reasonable thing to do.
    You asked me the time frame for that. I would think that in 
one year from now I could give you some reasonably good news 
about it; in other words, the process would be on its way in 
one year from now. Whether they would be awarded or not, we 
would be approximately six months into fiscal year 1999 in one 
year from now, we could have made the award or we would be very 
close to making the awards.
    Ms. DeLauro. I'm sure I'll ask the question again the next 
time.
    Dr. Lenfant. I am confident.

                           designer estrogens

    Ms. DeLauro. Again as you know, heart disease is the number 
one killer of women. Can you tell us about the progress that 
you have made in the last year in the study of so-called 
designer estrogens which appear to protect women from heart 
disease. Are you doing any research toward developing a similar 
drug or therapy that would protect from heart disease without 
the side effects of estrogen in terms of breast cancer, blood 
clot formation?
    Dr. Lenfant. That's a very difficult question. One thing I 
can say is, yes, the Institute's tests supported for years the 
development of designer estrogen, actually a specific one, one 
which would be derived from plants. In fact, last night I was 
watching the national news and heard that the FDA has just 
approved a designer estrogen which is derived from soybeans. I 
don't know if that's a result of our own research, but we have 
done research on that for a number of years.
    The second part of your question was whether that has 
modified prescriptions and what happens in the real world and 
in the practice of medicine. I don't know. Within the studies 
that the Institute is supporting, especially I would say the 
Women's Health Initiative, which, you may know, has been 
transferred to our Institute, we are not using a designer 
estrogen because that would affect the continuity of the study. 
We cannot just change the estrogen which is being used for the 
simple reason that, as yet, there is very little data on the 
effectiveness and the use of these new medications and, 
therefore, we cannot replace something with which we have 
considerable experience with something else with which we have 
much less because we don't know what impact it might have on 
the study.
    But there is another issue. The advent of all these new 
compounds and new hormonal products is of some concern. The 
Institute actually is in the process of working with the other 
Institutes at NIH which are interested in this issue to develop 
a group to monitor the effectiveness of these new designer 
estrogen compounds and see whether they could eventually be 
used to replace what we are using now. So it's kind of a long 
winded answer to your question because so far nothing has 
clearly been done at least within the purview of the Institute. 
But we are looking at it and are getting prepared to take 
action if warranted and appropriate.
    Ms. DeLauro. Just a quick comment, Mr. Chairman, I know my 
time is up.
    Again, with the eye toward looking at how we deal with the 
side effects of estrogen, which is a scare with regard to 
breast cancer and blood clots, we're trying to figure out how 
we lessen those side effects as well with what we're doing 
here; is that part of----
    Dr. Lenfant. The issue is that we don't know as yet. What 
we have learned about the estrogens which are being used now is 
the result of years of observation and research. With regard to 
the designer estrogens, we do not have these years of research 
and observation.
    Ms. DeLauro. Thank you very much, Mr. Chairman.
    Mr. Porter. Thank you, Ms. DeLauro.
    Mrs. Northup.
    Mrs. Northup. Thank you.

                             bioengineering

    Thank you, Doctor. I would like to ask you about a couple 
of things. First, I know that more and more people that are 
suffering from heart disease and heart problems are depending 
increasingly on sensors and artificial valves and pacemakers. I 
just wondered what the Institute was doing interms of 
interdisciplinary studies to look at micro fabrication and engineering 
sensors in order to make sure that the medical community and the 
engineering community put these things together, and whether your 
Institute is engaged heavily in that.
    Dr. Lenfant. Our Institute is, indeed, very much engaged in 
bioengineering research. In fact, Dr. Watson, whom I introduced 
earlier as the Acting Deputy Director of the Institute, is a 
bioengineer of very long experience and has driven the 
Institute down the path of bioengineering research for 20 or 
some years. So all that is to say that we are very much abreast 
and informed of what's going on in the bioengineering world.
    In fact, the Institute does a number of studies which use 
some devices which are either for the sake of support or 
substitutions when there is failing, say, of the heart. The 
Institute has been really the agency of the department which is 
developing the artificial heart, the total replacement heart 
now, but also what is called the assist device which is, as its 
name says, to assist the failing heart. We also have been very 
much involved with the development of pacemakers and 
defibrillators, devices which now are implanted in a number of 
patients who have conditions which warrant the implantation.
    Dr. Varmus. Could I make just one additional comment?
    Mrs. Northup. Yes.
    Dr. Varmus. Dr. Watson just last week co-chaired a large 
bioengineering symposium at the NIH, organized by a group 
called BECON, for Bioengineering Consortium, that the Office of 
the Director at NIH recently developed to involve virtually all 
of the Institutes in bioengineering. Senator Frist came out to 
give the keynote address. Bioengineering is a very lively 
activity at the moment at the NIH.
    Mrs. Northup. That's reassuring. We talked about diabetes 
yesterday and we know that there are assist devices. It is of 
concern that medicine is talking about genes, and what you eat, 
and how you exercise, and the body, and it's important that we 
also make sure that we advance and marry, if you will, the 
artificial supports besides just drugs and medicines.
    Dr. Lenfant. I may add, Mrs. Northup, that relative to 
Cooley's anemia, which we were discussing just a moment ago, 
that, as, in diabetes there is need to have a pump that infuses 
drugs called the chelators, and that is also the result of 
bioengineering development. These patients with that condition 
have benefitted from that for years.

                            genetic research

    Mrs. Northup. Okay. I'm sorry that I had another hearing 
and was not here for the genome testimony. But, in particular, 
I have a strong interest in what your Institute does in terms 
of genetics and heart disease, heart problems. I assume that 
there is quite a bit of coordination between other genome 
research, in particular heart disease.
    Dr. Lenfant. Yes. We do work very closely with the Genome 
Research Institute. And, yes, the Institute is moving in a big 
way into applying the molecular genetic approaches to our 
problems. Already, quite a bit of progress is being made. I 
believe I heard Dr. Varmus on Tuesday mention the gene for the 
long QT syndrome, which is a heart disease with an irregular 
heart beat, and that now hopefully will be treated much more 
effectively in the future.
    There are a number of cardiovascular conditions which are 
due to one gene which is an alteration or a mutation. One of 
them is hypertrophic cardiomyopathy, for example. That one is 
fairly well known by the public because one of its 
manifestations is sudden death, and when that occurs in 
athletes, basketball players, in particular, everybody 
recognizes the problem.
    But here there is an extensive amount of work which is 
being done in some of the institutions that we support and I 
would say in our Institute as well. In fact, our Institute, in 
our internal programs, has been at the forefront of these 
conditions for I believe 40 years. Now, we are bringing 
molecular genetics into it in association with the Genome 
Research Institute.
    Mrs. Northup. Certainly, the genetic side of heart problems 
often does result in sudden deaths, sort of maybe unpredictable 
sudden deaths; certainly, athletes are one of those groups. And 
prevention would be connected to testing ahead or something 
that's predictive, so I'm interested in that.
    Dr. Varmus. Can I make one additional comment, Mrs. 
Northup. I don't want to suggest that Dr. Lenfant is being 
unduly modest, but he should take credit for the fact that his 
Institute has been in the leadership on the rat genome project, 
which is very important for the study of many physiological 
problems including cardiovascular disease.
    Mrs. Northup. Thank you.
    Dr. Lenfant. I just wanted to add one thing. I gave as a 
couple of examples diseases which are determined, if you will, 
by one gene and its function. But, by and large, most 
cardiovascular diseases are polygenic; that is, there are an 
array of genes which intervene in these conditions. That's why 
they are called complex diseases from the genetic viewpoint. 
Lots of work is needed to understand these conditions and be 
able to address them. I am saying that because that was, in 
fact, what the Chairman was asking me at the beginning, do we 
have anything else to do? The answer is, yes, indeed.
    Mrs. Northup. Thank you. Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mrs. Northup.
    Mr. Stokes.

                          sickle cell disease

    Mr. Stokes. Thank you very much, Mr. Chairman.
    Dr. Lenfant, as Dr. Varmus just commented about how modest 
you were, I'm reminded that a few days ago when Dr. Varmus was 
testifying I made the comment to him that seated next to him 
and behind him were some of the finest scientists and doctors 
in the world. I was uniquely aware of the fact that you were 
one of those seated immediately behind him. I think that all of 
us are very proud of what you represent in the medical 
profession, and I've enjoyed the opportunity over the years to 
sit across the table and have various discussions with you 
regarding medical problems that confront this country.
    Let me start out by making reference to a disease that you 
and I have discussed often. When Ms. DeLauro was talking about 
Cooley's anemia, which uniquely affects persons of Italian 
extraction and Middle East origin, I thought about Sickle Cell 
disease which we know affects African Americans in the same 
manner. You and I have talked about it for many, many years 
right here in this hearing room. Are we anywhere near reaching 
a cure for this devastating disease?
    Dr. Lenfant. I think we are getting closer to it. When it 
will be at hand, I don't know. I wish I could tell you next 
year or five years from now, but I cannot tell you that. But 
one thing I can tell you is that each year when I come and 
appear before you I have some new advances to report to you 
which I think are of immense benefit to this population.
    Mr. Stokes, before you came, I was showing what has 
happened to cardiovascular diseases the 50 years before the 
Institute was created and the 50 years since the Institute has 
been created. If you would look at Sickle Cell disease 50 years 
ago, patients with severe Sickle Cell disease were dying in 
their teens or in the sub-decades of their life. Today, these 
patients are living to their 50s and 60s, living a productive 
life. Undoubtedly, the quality of that life is often affected 
by their condition, but they are alive. That is a result of the 
research that we have supported, and I should say in great part 
because of your support. And for that, in fact, when we 
celebrated the 25th anniversary of the National Sickle Cell 
Disease Research Program last fall the entire audience stood up 
and saluted you for the support that you have given for that 
research.
    Mr. Stokes. I'm the first to acknowledge that we have 
obviously made great progress, particularly over the last ten 
years. Yet, one just has to wonder will we ever find a cure for 
this disease. That's what's so troubling to me.
    Dr. Lenfant. A cure for this disease I am confident will 
happen but I just cannot tell you when. There are lots of 
people and the best minds in this country working on 
genetherapy which would produce if you will the ultimate cure for this 
condition, but, as my colleagues have said during the last couple of 
days and as you will hear more during these hearings for the NIH, it is 
a very difficult problem, very difficult problem.
    But meanwhile, I do have some good things to tell you that 
I didn't tell you last year.
    Mr. Stokes. I want to get into that. And since you're 
suggesting it, why don't you just do it right now? [Laughter.]
    Dr. Lenfant. Okay. Well, the first good thing that I want 
to tell you is that infants and children who have Sickle Cell 
disease have the risk of two very major complications. One is 
infection, and you may recall that three or four years ago I 
came here and I told you how we could prevent this infection. 
The second one was the development of stroke. We talk a lot 
about strokes here in this room, but here we are talking about 
strokes in kids who are in their teens, which is, of course, a 
terrible human problem.
    This year we have reported the result of a study that has 
shown that we can, in effect, prevent the occurrence of stroke 
in these children because now we are able to detect how the 
blood flow is in their brain and, if some abnormal blood flow 
is detected, we can initiate a therapy that will prevent the 
occurrence of a stroke because the abnormal blood flow is 
actually a precursor sign of a stroke to come.
    The treatment in question is blood transfusion, to initiate 
blood transfusion very early. That, indeed, prevents the 
occurrence of a stroke. Approximately 90 percent of the kids 
who have been treated did not develop a stroke compared to a 
group which was not treated. There are problems with that 
treatment that need to be addressed. Now, we have put into 
place a research program to address these problems. But at 
least these children do not have a stroke. So that's one thing 
that's happened since last year.
    As you may recall, Mr. Stokes, you asked me over the years 
about bone marrow transplantation and I told you that it was 
emerging in Europe as an approach but coming along very slowly 
in this country because I suppose physicians in this country 
are perhaps more conservative than those in Europe.
    Today, I can tell you about an experience of 37 children 
who have been bone marrow transplanted here in this country, 
and the good thing is that 95 percent of them are still alive 
and that 80 percent of those appear to be free of their 
condition. So here is an approach which I believe opened the 
door on opportunities. Bone marrow transplantation is not a 
benign procedure. It's not like injecting blood or injecting a 
medication; it has its own risk. That is under study and I 
believe that in the years to come a larger population study 
will be reported and we will see a continuation of the success 
that we have in this small population.
    The third thing that I would like to mention is that two 
years ago I came here and told you about a result that we had 
with hydroxyurea in adults. You may be interested to know that 
two or three weeks ago the Food and Drug Administration 
approved that drug for use in adults. Meanwhile, we have 
initiated a study in children giving them hydroxyurea and so 
far, so far, the results are quite satisfactory.
    So here are three examples of progress which I can report 
to you and that I did not mention to you the year before.
    Mr. Stokes. Obviously, we are making significant progress, 
as you've stated. Let me ask you, Dr. Lenfant, with respect to 
medical schools at Historically Black Colleges and 
Universities, to what extent are they directly involved in the 
basic applied and clinical Sickle Cell disease research that is 
under the purview of your Institute? Tell us what is the size 
of the investment in this area.
    Dr. Lenfant. Three of these colleges have a medical 
school--Howard University, Meharry, and Morehouse. Two that I 
know of have at the present time support from the Institute for 
Sickle Cell disease research. Unfortunately, this support will 
not continue past a few months from now because the competition 
was not favorable to permit this continuation.
    Having said that, we are working with these institutions in 
the hope of fostering some other activities in Sickle Cell 
disease research.
    Mr. Stokes. Okay. I heard the bell, but let me just make 
this comment, Mr. Chairman, if I may. That's an area in which I 
hope that the Institute will work with those particular schools 
to try and help them be able to qualify. I think it's extremely 
important that the Historically Black Colleges and Universities 
be involved in research and the things that are necessary 
relative to diseases that particularly and uniquely affects 
African Americans. That is imperative. Thank you.
    Mr. Porter. Thank you, Mr. Stokes.
    Ms. Pelosi.

                  transdisciplinary research training

    Ms. Pelosi. Thank you, Mr. Chairman.
    Dr. Lenfant, thank you very much for your testimony and for 
your leadership at the National Heart, Lung, and Blood 
Institute.
    Following up on Mr. Stoke's questions about involving our 
institutions of higher learning and training across the board, 
I wanted to ask you about behavior change and research 
training. To seriously address many of the leading causes of 
death in this country, we need to improve our understanding of 
the factors involved in initiating and sustaining positive 
changes in behavior. In addition, and this is my point, it is 
essential that increased attention and resources be given to 
training a new generation of behavioral scientists to focus on 
these questions especially in the prevention area.
    Can you tell me more about your prevention research efforts 
and your involvement in professional training of investigators?
    Dr. Lenfant. The Institute pursues several avenues to 
foster prevention research including, of course, behavioral 
research for the purpose of adopting different lifestyles and 
so forth. First of all, we support a number of training 
programs in I believe three or four institutions in the 
country. We have a number of research projects in more 
institutions which combine biomedical as well as behavioral 
approaches, seeking some new regimens and interventions to 
develop preventive regimens. And then, thirdly, I should tell 
you that just a few months ago the Institute released a 
blueprint of behavioral research as adapted to the needs of the 
Institute in heart, lung, and blood research basically with the 
expectation that that will stimulate further work from the 
interested community.
    Ms. Pelosi. I appreciate that. Dr. Varmus, the other day 
when you were presenting your initial testimony, the flagship 
testimony, you mentioned in the category of talent--you said, 
``We will fund innovative research training programs that 
emphasize transdisciplinary work. We propose to increase by 25 
percent the stipends that we provide to graduate students and 
post-doctoral fellows, and we will create a research 
environment that offers improved stability and the likelihood 
of research funding that was true in the early years of this 
decade.'' Bravo.
    Do you have the resources to do that?
    Dr. Varmus. We will under the President's budget. As a 
result of the healthy increases we received this year, we have 
already started to do some of these things, particularly create 
the healthy research environment. The decision to increase 
stipends would not apply until fiscal year 1999.
    Ms. Pelosi. And then, hopefully, all the things that Mr. 
Stokes talked about might be captured by that into the 
communities that are----
    Dr. Varmus. Certainly, some of the new training programs 
we're envisioning would be directed toward our continuing 
concern about the number of biomedical investigators who come 
from minority populations.
    Ms. Pelosi. You will have outreach in that group?
    Dr. Varmus. Absolutely.
    Ms. Pelosi. Could you just tell me, is the term of artnow 
transdisciplinary?
    Dr. Varmus. I don't know the subtlety that might 
distinguish interdisciplinary from transdisciplinary.
    Ms. Pelosi. Okay. I just didn't know if I was missing 
something.
    Dr. Varmus. We can send this as a letter to Mr. Safire and 
he can help us with it. [Laughter.]
    Ms. Pelosi. Yes, he's good at that.
    Dr. Lenfant. Although I may say that when it comes to 
prevention research, multidisciplinary rather than 
transdisciplinary is quite an important, I would say necessary, 
way to approach the problem. Because as you pointed out in your 
question actually, to achieve prevention takes change in 
lifestyles but also some change in what you eat. Basically, the 
biology of it needs to be known as well as the behavioral 
approaches to achieving that. So here is an example I suppose 
of a multidisciplinary approach combining biology with 
behavioral.
    Ms. Pelosi. Well, as I said when I was invited to UCSF when 
they were announcing an interdisciplinary multi or 
transdisciplinary approach to their cancer project, I said at 
that time, Mr. Chairman, that I found it fascinating because 
knowing the coordination that it would take among the 
departments. I commended the chancellor for a level of 
political skill that was a game we were not familiar with here. 
I imagine that that would be a challenge. But you seem to have 
a comfort level with it and I'm encouraged by that.
    Dr. Varmus. You know my lineage, Ms. Pelosi, so you can see 
where I developed those instincts.
    Ms. Pelosi. Yes, indeed.

                     applicability of aids research

    I applaud all of your work, Dr. Lenfant, and successes with 
securing a safe blood supply for all of us. Thank you. I 
understand that your budget request for your efforts on AIDS 
research is contained in the Office of AIDS Research budget 
proposal. But I wonder if you can tell us about the recent work 
by your Institute in the area of AIDS and the potential this 
work has to expand our ability to address other serious 
illnesses. Can you give me an example of how broader 
understanding of HIV disease has improved our ability to fight 
a broad range of diseases affecting the circulatory system?
    Dr. Lenfant. The AIDS program of the Institute is basically 
related to the heart, to the lung, and to the blood, with the 
bulk of it making sure that we keep a safe blood supply. The 
research that we do is really to develop better and further 
tests to detect the presence of antibodies which are the result 
of a viremic infection, AIDS or any virus.
    In fact, the Institute is now initiating some new programs 
where we hope to be able to detect the nucleic acid which is 
part of the DNA of the virus which would allow us to reduce the 
window between the infection and when the antibodies occur. Our 
expectation is that if we are successful, we may reduce that 
window to only a few days, where now, depending on the virus 
that has infected the subject, it may be several weeks. So that 
would be a tremendous advance in safety, if you will, from that 
viewpoint.
    Now with regard to, say, the heart, now that patients with 
AIDS are surviving much longer, many of these patients are 
developing some heart complications. Our research program is to 
assess the extent of these complications, to understand them 
and see how we can develop some therapies which are independent 
of the therapy that is given for the AIDS infection.
    With regard to the lung, it's also the same kind of 
approach. Many of these patients with AIDS in the terminal 
phase of their disease die from pulmonary infection. We are 
studying the defense mechanisms of the lung against these 
infections.
    Ms. Pelosi. I really appreciate your very thorough response 
and all that is implied by it. Thank you for your attention to 
this, Doctor.
    Mr. Chairman, next week I'll probably ask Dr. Varmus to 
tell us more about the active collaboration among universities, 
government, industry, and how such interactions are vital to 
our efforts to control disease. But I probably don't have time 
to do that today.
    Mr. Porter. You have 36 seconds.
    Ms. Pelosi. Would you like to comment on that, Dr. Varmus?
    Dr. Varmus. I think we could do that in a little more 
leisurely way.
    Ms. Pelosi. Okay. Thank you very much, all of you. Thank 
you, Mr. Chairman.
    Mr. Porter. We're going to have a second round, also.

                             retinoic acid

    Dr. Lenfant, on retinoic acid, if I understand it 
correctly, the tests have occurred only in animals. Is that 
correct?
    Dr. Lenfant. That's correct.
    Mr. Porter. We haven't yet done it with human beings. How 
far are we from doing that?
    Dr. Lenfant. Well, if I may expand on that. It has been 
done only on animals, rats and mice. It is now being done on 
nonhuman primates. But the results have been so spectacular, so 
spectacular in the rats, in particular, that I know that some 
investigators in the country are in the process of initiating a 
clinical study that is to give retinoic acid to patients who 
have those conditions.
    Mr. Porter. Since retinoic acid is a derivative of Vitamin 
A, what does this mean for people who are at risk for chronic 
lung disease, like smokers? If they take Vitamin A they might 
reduce the risk? Does it have any meaning that way?
    Dr. Lenfant. Well, if they are still smokers, I think it 
wouldn't do too much good. If they had been smokers and have 
developed a lung disease like, say, emphysema, whether it will 
work or not, I don't know. But that is what is going to be 
tested by these investigators who are interested in doing it.
    Mr. Porter. But could Vitamin A then be considered a means 
of protecting against the damage of smoking perhaps?
    Dr. Lenfant. I think it requires that it be retinoic acid 
because the retinoic acid, my biochemistry here is going to be 
challenged, but I think it is a precursor of the development of 
Vitamin A, and it is that precursor which is the active 
compound and not the Vitamin A itself.
    Mr. Porter. I see.
    Dr. Lenfant. Was that the correct answer?
    Dr. Varmus. That's correct.

                               melatonin

    Mr. Porter. Dr. Varmus agrees. I've read that several 
school districts in Minnesota have delayed the start of the 
school day for high school students and have seen a remarkable 
change in student attitudes, test scores, and discipline 
problems. It is believed that melatonin which induces 
sleepiness is secreted later in the evening in older teens. The 
result is that high school students are starting class in the 
morning before their body's biological clocks have woken them 
up. Have you studied this phenomenon in your Sleep Disorders 
Center? Do you agree with this theory? And would delaying the 
start of the school day for high school students give them a 
better chance to succeed?
    Dr. Lenfant. I cannot agree with that. I think the only 
thing that I know about that is from having read about this 
report. I have to admit that it is fairly impressive. Now the 
issue of melatonin is a very interesting one. We are discussing 
within the Institute whether a carefully controlled study 
should be done. In fact, we are discussing that with the Office 
of Alternative Medicine. As yet, I am not personally aware of 
any controlled study using melatonin. But the statements which 
are made that you reported are making a good deal of sense.

                          alternative medicine

    Mr. Porter. Dr. Varmus, from time to time there are hot 
drugs, for want of a better term, that are sold in health food 
stores and other places. Do we have any kind of program within 
NIH to quickly look at the efficacy and safety of these kinds 
of things, or is that something that the FDA--well, the FDA 
doesn't do that.
    Dr. Varmus. No, they don't. As I think you and I may have 
discussed once or twice in the last year, we have decided to 
give a more vigorous role to the Office ofAlternative Medicine 
in sorting out some of these claims.
    The most prominent study of that sort is one that is now 
being carried out in a collaboration of the Office of 
Alternative Medicine with the National Institute of Mental 
Health to support a clinical trial at Duke to study St. John's 
Wort in depression. Several other similar studies are actually 
in formulation, including one to look at chondroitin sulphate 
in osteoarthritis.
    We are giving very careful attention, as Dr. Lenfant 
mentioned, to some studies of melatonin, both in sleep cycling 
and in treatment of jet lag. A number of other medications that 
are fashionable and used without FDA imprimaturs are going to 
be the subject of rigorous clinical trials through the OAM and 
other Institutes.
    Mr. Porter. The OAM, it seems to me, could perform a great 
service to American society by taking these matters up very 
quickly when they begin to break and give some guidance to 
people as to whether these things are worth anything.
    Dr. Varmus. I agree entirely. This represents a bit of a 
change in tactics. While we are still supporting some centers 
to develop scientific expertise among those people who are 
interested in alternative therapies, we also feel that it is 
important to use the money that goes to the Office of 
Alternative Medicine to allow traditional clinical trialists to 
do definitive trials of some of these medications.
    I also should draw to your attention, Mr. Porter, to the 
fact that in the last several months I have developed a 
transagency group that includes representatives from the FDA, 
from AHCPR, from CDC, and from many of the NIH institutes to 
identify candidate therapies for such trials. That group has 
met. We have quite a dossier of recommendations, and Dr. 
William Harlan, who runs our Office of Disease Prevention and 
has immediate oversight over the Office of Alternative 
Medicine--OAM--is working with the OAM to try to develop the 
appropriate set of trials in conjunction with the categorical 
institutes.
    Mr. Porter. A lot of the medical newsletters take these 
matters up and get them to what I would judge to be a fairly 
educated audience. But the vast majority of people, it seems to 
me, aren't reading those kinds of things and don't know what 
they really ought to do.
    Dr. Varmus. The fact is that although there may be 
discussions in such newsletters, in the vast majority of cases, 
there have not been well-designed definitive trials.
    Mr. Porter. No, but they can raise issues and give people 
caution. I agree with you that they don't have any definitive 
answers necessarily, but they sometimes will say this hasn't 
been tested, you ought to----
    Dr. Varmus. I agree, a more balanced presentation than you 
might find in an advertisement.
    Dr. Lenfant. If I might say something here with regard to 
retinoic acid, which is actually available over the counter. 
When the initial study was published, which was maybe a year 
ago or so, it was picked up by many of these information 
publications just mentioned. As a consequence, the Institute 
must have received maybe 200 or 300 letters from patients with 
emphysema asking if they should start taking retinoic acid. Of 
course, our response was we don't know and we don't think you 
should do it, certainly without consulting your physician. But 
it is sometimes a real problem because everything jumps ahead 
of the scientific knowledge.

                            arrhythmia study

    Mr. Porter. Dr. Lenfant, a three-year study comparing the 
two most popular approaches to treating abnormal heart rhythms 
was halted because of overwhelming results. The study was 
comparing commonly prescribed heart drugs to an implantable 
device that corrects abnormal heart rhythms. An early analysis 
of the data showed significantly better survival rates in those 
who had the devices. In addition, the drugs can have serious 
side effects.
    It has been almost a year now since you announced the 
findings of the study. Has the medical community used the 
results? Have you seen a trend toward the use of more implants?
    Dr. Lenfant. Yes. Maybe to a fault. We are concerned with 
that because the study was not to establish that all patients 
with heart beat disorder should be implanted with one of these 
devices. And so now we are in the process of having further 
studies to really clarify or specify more precisely which 
patients should be receiving these devices.
    I can understand why the reaction has been what it is 
because the results have been quite spectacular. There were two 
groups, as you may know, one treated with medication, and one 
with these devices. And 98 percent of the patients having a 
device were free of further problems, whereas it was not the 
case in the medication treated group. Incidentally, I should 
say that this study has since been corroborated by a similar 
study conducted in Canada. So we think that these are pretty 
good results. But we need to become more specific as to which 
patients are eligible.
    Mr. Porter. When we're talking about the drugs, are we 
talking about beta blockers and similar type drugs?
    Dr. Lenfant. Yes. Yes, that's what it is.

                            hemochromatosis

    Mr. Porter. Dr. Lenfant, I asked Dr. Collins this morning 
the question, ``When the genome project reaches the point where 
clinical trials are appropriate, do you envision your Institute 
actually conducting the trials or relying on the clinical trial 
expertise of other Institutes?'' In Dr. Collins' response, he 
described some promising work his Institute was collaborating 
on with your Institute on hemochromatosis. Maybe you could give 
us your views on this question as well.
    Dr. Lenfant. I think, first of all, that's a condition 
which is around but it's not terribly common. You may know also 
that it is more prevalent in men than in women. It is, indeed, 
an inherited condition. The gene has been uncovered, and the 
issue today, and that's what Dr. Collins and I are discussing, 
is to develop a study to assess the effectiveness of screening 
for this condition.
    Dr. Collins asked our Institute to conduct the study, and 
we are now in the process of developing the protocol in 
consultation with him, I should say. But we will be conducting 
the study which is actually an epidemiological study, it is not 
a clinical trial at this time, it's an epidemiological study. 
Our Institute has a very significant portfolio and expertise I 
would say in epidemiology. So we think, and I personally think 
that this collaboration between the Genome Institute and 
NHLBI--where basically something that he knows best, which is 
the genetics of this condition, is capitalized on with what we 
also know best--is quite a very fruitful marriage.

                            mri angiography

    Mr. Porter. Last year we also discussed a new noninvasive 
technology, the magnetic resonance imaging angiogram which can 
be repeated without any danger to the patient and cost five to 
six times less than conventional angiograms. Has this technique 
developed to a point of widespread use?
    Dr. Lenfant. No, not yet. But it is getting closer to it. 
In fact, I don't know if you heard about it, but our Institute, 
where we are doing lots of work in this area, is now in the 
process of developing a collaboration with the hospital which 
is just across the street from the NIH in order to have access 
to a larger number of patients and to assess the effectiveness 
of this technique. So that's one thing that we are going to do 
in our Institute. And I would anticipate that within some 
period of time, I'm not prepared to say how long that's going 
to be, it will become a routine way to assess patients.
    Mr. Porter. The Bethesda Naval Hospital?
    Dr. Lenfant. No, no. It is Suburban Hospital.
    Mr. Porter. Suburban Hospital.
    Dr. Lenfant. It's a community hospital where there is a 
continuous flow of patients with coronary heart disease and 
stroke. The National Institute of Neurological Disease and 
Stroke is also involved in this project. I think it is a very 
exciting thing.

                                aspirin

    Mr. Porter. We're seeing more and more evidence that a 
daily dose of aspirin reduces the risk of heart attacks, 
especially in men. Do you think enough evidence exists 
torecommend that everyone take a low dosage and topically coated 
aspirin a day, or, at the very least, all those who are at higher risk 
of heart attacks?
    Dr. Lenfant. Well, I take it. [Laughter.]
    I think that, yes, people should do that. The issue is how 
much they take. There have been some problems reported. Aspirin 
is a drug, so you have to know what you are doing. Some people 
think that taking 300 milligrams a day is better than taking 80 
milligrams a day. The fact of the matter is that for this 
purpose that is not correct. It should be a low dose. What is 
usually advocated is 80 milligrams a day, which is what I'm 
taking, that does not make it necessarily right, but I think it 
certainly puts me out of the kinds of possible complications 
with taking too much aspirin.
    Mr. Porter. When I talked to another of your Institute 
directors, that director said that you should only take it five 
days a week and not seven because of the effect on your 
stomach. Do you agree with that?
    Dr. Lenfant. Oh, 80 milligrams won't cause any stomach 
problems. I feel very strongly about that.
    Dr. Varmus. Some advise every other day.
    Mr. Porter. He advised five days a week, not on weekends.
    Dr. Lenfant. But when it's every other day, it is usually 
150 milligrams. I am talking about 80 milligrams a day.
    Mr. Porter. You're saying it is too low a dosage to have 
any effect on your system?
    Dr. Lenfant. Yes. I have been taking it for ten years. I am 
still looking for any bad effects. But my heart is okay.
    Mr. Porter. Is there any problem with skipping a day now 
and then?
    Dr. Lenfant. Oh, no. Of course not.
    Dr. Varmus. The clinical trial in which I was a subject 
personally, the Physicians' Health Study carried out by Dr. 
Hennekens at Harvard, involved the use of aspirin every other 
day.
    Mr. Porter. Okay. We're getting free medical advice here. 
[Laughter.]

                      cholesterol lowering therapy

    Mr. Porter. It was reported for the first time in 
November--and this is my last question, then Mr. Stokes will 
have the second round as well--that cholesterol-lowering drugs 
could help even healthy middle-aged people with ordinary 
cholesterol levels reduce their risk of heart trouble by more 
than one-third. This announcement came from a study paid for by 
a drug manufacturer and could impact an additional 8 million 
Americans. Do you agree with the findings of this study? Are 
there other scientific studies to support this recommendation?
    Dr. Lenfant. Yes. Certainly, I agree with it. I think it 
was a wonderful study. Let me give you just a little bit of 
background on the cholesterol debate. Ever since these drugs 
appeared on the market there have been debates as to who should 
take it, should people take it at all, and so forth. Little by 
little, I think all specialists in the field would tell you 
that if you have had a coronary event, it does not have to be a 
heart attack, but angina or whatever, you should take it. That 
is pretty much accepted in medical practice.
    If it is after a coronary event, it's called secondary 
prevention. That is, you know you have the disease, some 
manifestation of the disease and you want to limit further 
development of that condition.
    The study you are talking about was looking at primary 
prevention. That is, it was a study that was done on military 
personnel, I think that is the one that you are talking about 
that was reported in November, and they took healthy, normal 
men with normal cholesterol and they gave them this 
cholesterol-lowering medication and then they observed them as 
well as observing a group of similar kinds of individuals for I 
think it was five years. At the end of it, the ones who had 
taken the medication for five years, with no evidence of 
coronary heart disease, had something like 60 percent fewer 
heart events than those who had not taken the drug.
    Mr. Porter. Thank you.
    Mr. Stokes.
    Mr. Stokes. Thank you, Mr. Chairman.

              cardiovascular disease in african americans

    Dr. Lenfant, despite the progress that has been made, 
claiming a life every 33 seconds, cardiovascular diseases now 
account for about 42 percent of all deaths in the United 
States. More than one in five Americans suffer from 
cardiovascular diseases, at an estimated cost of $274 billion 
in 1998 in medical expenses and lost productivity. I understand 
further that from ages 35 to 74 the age-adjusted death rate 
from coronary heart disease for African American women is more 
than 71 percent higher than that of their white female 
counterparts. What major research is underway to address this 
enormous health disparity gap, and what is the size of that 
investment?
    Dr. Lenfant. The specific amount of money on this 
particular problem, I think I would like to provide that later.
    Mr. Stokes. If you could provide that for the record.
    Dr. Lenfant. Yes. How much we are spending on heart disease 
in the African American population, specifically in women; is 
that the question?
    Mr. Stokes. Particularly in African American women for that 
particular problem.
    [The information follows:]

      Clinical Research on Heart Disease in African-American Women

    The Institute's investment in clinical research to address 
the health disparity in African American women was about $25 
million in FY 1997, an estimate based on the representation of 
African American women as research subjects in its portfolio of 
human-subject-based studies.

    Dr. Lenfant. The amount of money I don't know, but I do 
know that there are many, many programs which are involving and 
studying this cardiovascular condition in African American 
women, men and women, I should say.
    Mr. Stokes, I wish I could come here and tell you we are 
making progress. We are making some but certainly not as fast 
as we could or should. Now, what are the barriers to that? I 
think, as has been discussed here before, many of the issues 
about cardiovascular diseases involve what you do for yourself. 
Therefore, we have to be able to communicate to the population 
where you want a change to occur, what needs to be done. That 
is very, very difficult. But it is possible. In fact, just 
yesterday, and not in preparation for this hearing, but because 
we were talking about these things, I heard about some data 
which I would like to share with you which will show you that 
it is not a hopeless situation.
    You know about the stroke belt, the 11 Southeast States 
where there is a very high prevalence of stroke. I have 
discussed that here year after year. Well, yesterday I was 
informed of the impact of the program that we have had there, 
which is a program of building coalitions to work with the 
people, with the cities, the communities, and church leaders to 
really help people to do something about this condition. That's 
what we have been doing for better than 12 years. Theresult 
that I heard yesterday is that we have seen a decline of stroke in that 
population which was 17 percent in the white population in these 11 
States. That compares with 18 percent for the Nation as a whole.
    Now, in the black population there, the decline of death 
rate from stroke was 31 percent--31 percent, about twice as 
much as what we saw in the white population, and that compared 
with a decline for the U.S. black population as a whole of 26 
percent.
    So the meaning of all that is that by having some very 
active intensive programs of getting the community involved and 
the patients involved, outreach, you can succeed and you can do 
something. Here, again, we have a decline of stroke mortality 
in these 11 States which is higher than the U.S. population as 
a whole, and also higher than the white population which was 
not specially targeted in this project.
    Mr. Stokes. So, there's a direct relationship or ratio in 
terms of saving lives and education?
    Dr. Lenfant. I think there is no question that the issue of 
communication and getting the people or the patients to be to 
participate is absolutely critical to be successful.

                    high blood pressure in children

    Mr. Stokes. Very good. Let me ask you this question, Dr. 
Lenfant. About 50 million Americans age 6 and older suffer from 
high blood pressure which also disproportionately affects 
African Americans. What is the extent of high blood pressure in 
children ages 6 to 19, and what do we know about the early 
onset of this health condition? Is it a condition that is more 
concentrated within this specific age group of children?
    Dr. Lenfant. It is known to be higher in the African 
American children than it is in the Americans from European 
descent. The prevalence in children is not as high as it is in 
adults. Indeed, in adults, especially African American adults, 
the prevalence of high blood pressure is much higher.
    Last November, we issued some new guidelines on the 
diagnosis, treatment, and prevention of high blood pressure. On 
that occasion, we noted that we have seen a decline in the rate 
of awareness and control of high blood pressure in the American 
population, black and white. We are exceedingly concerned to 
see that because for years we had seen a continuous decline in 
the prevalence of high blood pressure and all of a sudden 
during the last few years we are beginning to see an increase 
again. The Institute is talking a lot about what to do next to 
address this problem. But here, again, is an issue of the 
patients themselves participating in this effort.

                    dietary interventions in schools

    Mr. Stokes. Let me ask you this also with regard to 
children. In light now of findings that there are strong 
relationships between poor diet and exercise and high blood 
pressure, what is being done to encourage healthy eating in 
school lunch programs, in WIC services, and physical education 
activities in our schools?
    Dr. Lenfant. A lot, actually. For years the Institute 
supported a study which involved several school districts in 
several States, there were four or five States, to see if we 
could make these schools adopt a dietary pattern which was 
different from what they had, and whether these kids would 
continue to accept these new dietary habits that they did not 
have before.
    That has been very, very successful, so much so that all 
the approaches and methods which have been developed in that 
study have been widely distributed and now are adopted, as I 
understand it, by school districts in States which were not 
even involved in the initial study. We hope that will have an 
impact. But, again, here is an issue of education which must be 
fostered and encouraged as much as we can.
    Mr. Stokes. Mr. Chairman, I have a number of other 
questions which I will submit for the record. Dr. Lenfant, 
thank you very much.
    Dr. Lenfant. Thank you, sir.
    Mr. Porter. Thank you, Mr. Stokes.
    I also have a number of other questions for the record.
    Dr. Lenfant, thank you for your excellent testimony, your 
direct answers to our questions, and the fine job you're 
continuing to do at NHLBI.
    The subcommittee will stand in recess until 10:00 a.m. 
Tuesday next.
    [The following questions were submitted to be answered for 
the record:]


[Pages 1177 - 1276--The official Committee record contains additional material here.]



                                          Thursday, March 19, 1998.

                    NATIONAL INSTITUTE ON DRUG ABUSE

                               WITNESSES

ALAN I. LESHNER, PH. D., DIRECTOR
RICHARD A. MILLSTEIN, DEPUTY DIRECTOR
LAURA S. ROSENTHAL, EXECUTIVE OFFICER
DONNA M. JONES, BUDGET OFFICER
HAROLD VARMUS, DIRECTOR, NIH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY FOR BUDGET, DEPARTMENT 
    OF HEALTH AND HUMAN SERVICES

    Mr. Porter. The subcommittee will come to order. We 
continue our hearings with the National Institutes of Health 
and the budget of the National Institute on Drug Abuse. We are 
very pleased to welcome Dr. Alan Leshner, who always has 
interesting things to tell us. Dr. Leshner, it is very good to 
see you, sir.
    Dr. Leshner. Very nice to be here.
    Mr. Porter. Would you introduce the two people who are with 
you and then proceed with your statement, please.

                       Introduction of Witnesses

    Dr. Leshner. Sure. I would like to introduce Donna Jones, 
who is the NIDA Budget Officer; Laura Rosenthal, who is the 
Executive Officer. You know Dr. Varmus, Mr. Millstein, the 
Deputy Director of NIDA, and you know Dennis Williams. I think 
you have met.

                           opening statement

    I am very pleased to report that the National Institute on 
Drug Abuse has had another outstanding year. NIDA-supported 
researchers continue to make enormous strides toward improved 
understanding, prevention, and treatment of one of our 
country's most serious public health problems-- drug abuse and 
addiction.
    As just one example, we have moved this year beyond the 
single snapshots of a brain high on drugs that I have shown you 
in past years to now being able to actually look at the dynamic 
changes that occur in the brain as an individual has a drug 
experience.
    We can observe the different brain changes that occur as a 
person experiences the rush, the high, and, finally, the 
craving of a commonly abused drug like cocaine.
    In addition to that, we are continuing to use brain-imaging 
techniques to understand the neurochemical changes that are 
occurring during the process of addiction. This first poster 
shows you your brain on tobacco smoke.
    These PET scans show, for a cigarette smoker on the top and 
a nonsmoker on the bottom, the levels of an enzyme known to be 
important in the breakdown of the neurotransmitter dopamine. 
This enzyme is called Monoamine Oxidase A. Red and yellow on 
the chart is more MAO-A, green is less.
    Here you see that being a heavy smoker results in lower 
levels of MAO-A, which means higher levels of dopamine, because 
it is not there in order to break the dopamine down. People 
very much like having higher dopamine levels, and they do not 
like it when dopamine levels fall.
    So, actually, maintaining these higher brain dopamine 
levels which occur via these changes in MAO-A may be one of the 
mechanisms that keep smokers smoking. They may be trying to 
keep their dopamine levels up by reducing their MAO-A levels.
    As you know, brain dopamine also plays a key role in 
another of our country's most serious emerging drug problems, 
the spread of methamphetamine abuse.
    As you can see from the second poster, which I hope you can 
see, the use of methamphetamine, this highly addictive 
substance, first was a major problem in limited, isolated 
cities like Philadelphia in the early 1980s.
    In the 1990s it became predominant in the Southwest, and it 
is now spreading rapidly eastward across the country and 
becoming a major problem in previously untouched cities. This 
is particularly disturbing in light of recent research that 
shows the drug's actual neurotoxic effects.
    Now, NIDA has mounted a major science-based initiative to 
help avert a greater national methamphetamine crisis. We are 
working on methamphetamine-focused public education and 
prevention campaigns. We are working aggressively to develop 
more effective behavioral treatments and new medications to 
treat both methamphetamine addiction and methamphetamine 
overdose.
    We are confident that we will be able to develop more 
effective treatments for methamphetamine abuse, just as we have 
for other addictions like heroin and nicotine.
    I can also tell you that we are beginning to see some real 
progress in our search for an anti-cocaine medication that we 
have talked about in years before. This remains one of our 
country's greatest needs and one of NIDA's highest priorities.
    The good news this year is that we are now about to begin 
our first ever large-scale, multi-center clinical trial of a 
very promising anti-cocaine addiction compound called 
selegeline. I have learned in the last couple of weeks that we 
actually have five or six other compounds that are waiting in 
line for additional trials.
    We are optimistic that this trial will not only lead to an 
effective cocaine medication, but will also serve as a first 
step in launching what, ultimately, will become a national drug 
treatment clinical trial network.
    This network will take new behavioral and pharmacological 
therapies that have been shown to be effective in small-scale, 
academic studies and evaluate them in large-scale, multi-site 
clinical trials conducted in real-life treatment settings.
    Through this network, we hope to more rapidly and 
systematically bring science-based treatments into actual 
practice.
    We have learned that in the drug addiction arena, we cannot 
just disseminate findings through traditional routes like 
journal articles. This is one of the reasons we will be holding 
the National Conference on Drug Addiction Treatment next month, 
for which we already have over 650 registrations.
    We will be bringing together treatment researchers, 
practitioners, and policy-makers to discuss the best that 
science has to offer in drug treatment.
    We are also continuing to take our science to the American 
public. We are about to have our seventh town meeting on April 
2nd with the citizens of Boston. This is going to follow 
closely on, and be coordinated with, a March 29th premiere of a 
five-part series on addiction that Bill Moyers of National 
Public Television has produced using, I might say, NIDA 
technical assistance.
    We are also providing communities with the tools they need 
to prevent drug use in their own neighborhoods. Last year we 
debuted here what has now become one of our most popular 
publications, ``Preventing Drug Use Among Children and 
Adolescents.'' Over 150,000 copies of this document have been 
sent to communities across the country to use as they develop 
and evaluate their own prevention programs.
    All of these exciting research efforts are moving us closer 
to truly understanding drug abuse and addiction and what to do 
about it. NIDA will continue to bring multi-disciplinary 
strategies to bear on these issues, will continue to build on 
our past accomplishments and to exploit the many new scientific 
opportunities we now have to help this country gain control 
over one of the most complex and pressing issues we all face.
    I will be happy to answer any other questions you might 
have.
    [The prepared statement follows:]


[Pages 1280 - 1289--The official Committee record contains additional material here.]



                             reaching youth

    Mr. Porter. Dr. Leshner, obviously, your responsibilities 
are primarily in the research area, but you have been doing, as 
you mentioned, a great deal to spread the word on the effects 
that use of drugs have on health and particularly using very 
graphic demonstrations as to the effect on the brain.
    It seems to me that this problem is probably the most 
important one to address of all and that somehow we have got to 
get to the young people of this country with a real message 
that this is not something they want to do.
    I think it is great that Bill Moyers is going on National 
Public TV, but I will bet you the audience that watches that 
show will not be the audience that we want to really reach. The 
watchers will be people who already understand the dangers of 
the use of drugs. While they may be opinion leaders and help 
put pressure on the system to raise this to a higher priority, 
somehow we have got to get to young people.
    TV seems to me to be the most important way. Town meetings 
are good, but how many people can you reach at a town meeting. 
Unless the message goes on TV, how many young people can you 
reach? We have to set the message on the kind of TV that young 
people really watch.
    So how do we get these brain pictures on MTV? How do we get 
them on the shows that are watched by our youth in this 
country? How do we get the message from your brain into their 
brain that this is something that is just not for them to do.
    Dr. Leshner. Well, we actually have been very fortunate to 
have a number of very effective collaborators, mostly in the 
private sector, who have been working with us to spread that 
information.
    In October, we released a set of science-based materials 
for middle school kids at the National Association of Biology 
Teachers meeting. Because the response to those materials was 
so tremendous we are now placing those materials, which are 
very graphic and very descriptive, into every middle school in 
the United States.
    In addition to that, as you may recall, two years ago we 
put out a brochure made specifically for young people--
``Marijuana: Facts for Teens''--and 1,500,000 copies have been 
distributed. I notice that the Partnership for A Drug Free 
America in its print ads uses that brochure as the focal point.
    I will not go into others in great detail, but your point 
about the need is unquestionably true. We are working hard at 
it. I think working with some of the anti-drug coalitions 
around the country has been another vehicle that we have been 
using. But the core issue has got to be, obviously, to get the 
science into the hands of the people and to kids in particular.

                          media collaboration

    Mr. Porter. If you were to identify an agency of Government 
that ought to take the lead on this, who would you identify?
    Dr. Leshner. We have had an interesting collaboration. As 
you know, we collaborate with many other NIH Institutes. We 
have tremendous relationships with both the Department of 
Education, through their Drug-Free Schools program, and with 
multiple parts of the Department of Justice. We have been 
working heavily with SAMHSA to help and inform some of their 
prevention activities and some of their media activities.
    The other obvious arm of Government that has taken major 
leadership in this area is the Office of National Drug Control 
Policy (ONDCP), which has its media campaign. We work very 
closely with them to make sure that the messages that are 
conveyed through that media campaign are scientifically 
accurate.
    We do not pretend to be advertising experts, but we are 
science experts. We do, in fact, review the content--not the 
concept--for all of the ads the Partnership for a Drug Free 
America--all of their ads--and for this ONDCP campaign.

                               education

    Mr. Porter. How much of your budget is spent on education? 
I am sure it is not a very large portion.
    Dr. Leshner. Sadly, it is not.
    Mr. Porter. Because it is not your primary responsibility.
    Dr. Leshner. It is hard to give you a precise number. Our 
best estimate is about $8.5 million out of our total of $527 
million, but it is distributed across public education 
campaigns, where we take science to the public, and our science 
education program, which is, again, drug-specific, which has 
produced a number of materials that are used widely. So about 
$8.5 million.
    Mr. Porter. If you take a look at the total that we spend--
what is spent by General McCaffrey, what is spent by you, what 
is spent by numerous agencies--in fact, I think there is some 
drug money in every department of Government. It seems to me 
though, that funding is tilted toward prosecution, 
interdiction, and treatment and not much, relatively speaking, 
for education.
    It seems to this observer that we can spend all of the 
money we want to try to interdict or stamp out the growing of 
the sources of drugs, we can prosecute all we want, we can 
treat all we want, but if the demand remains in the United 
States, somehow the drugs are going to get in and somehow they 
are going to be used. So it seems to me that the real effort 
ought to be to teach our young people that they do not want 
them and dry up the demand, and then you will dry up all of the 
rest.
    I wonder what the results would be if the Federal 
Government was to give one of our agencies a large sum of 
money, probably small relative to what is being spent on this 
entire effort, and we said, go out and buy some time on MTV, go 
out and buy some time on the major shows that young people 
watch and put on Alan Leshner's information in a graphic way 
that will hit people between the eyes as to what they are doing 
to themselves when they use drugs. Do you think that would be 
money well spent or not?
    Dr. Leshner. Well, I am a big supporter, as you may know, 
of ONDCP's public media campaign, which is literally doing that 
with $195 million; that is to say, they are taking ads from the 
Partnership for a Drug-Free America and trying to adhere to the 
science as much as possible in the production of those ads, and 
we are all very hopeful that they will be productive.
    I think there is no question that educating people about 
drugs is ultimately the best tool we are going to have in 
combatting the problem. I also believe that it is a complex 
issue that requires complex strategies. Sadly, no matter how 
good a job I do, I will never come up with a magic bullet. We 
are going to need multiple strategies.

                           drug user profile

    Mr. Porter. Can you give us a profile of a marijuana user 
and a profile of a hard drug user? Who is using these drugs or 
does it go all of the way across all kinds of different strata 
of society?
    Dr. Leshner. The bad news is that drug use in this country 
is an equal opportunity destroyer. Drug use among young people 
is actually as high or higher in affluent communities than it 
is in poor communities. People have trouble remembering that 
fact.
    In addition to that, the majority of even hard-core drug 
users are white, people who may have begun in the middle class. 
The truth is minority and ethnic groups are over-represented 
among hard-core drug users as adults, as a percentage of the 
society, but, in fact, again, even for adults, drug use, 
including addiction, is an equal opportunity destroyer and 
affects people of all varieties.
    Mr. Porter. Some of those teachers who might be given the 
materials might, in fact, be drug users themselves; is that 
possible?
    Dr. Leshner. Absolutely. Yes, sir.

                                progress

    Mr. Porter. It seems to me that we spend a great deal of 
resources on this problem. Let me put this in the form of a 
question. Can you tell me whether you see a lot of progress 
being made and whether you are encouraged or discouraged? Are 
we doing things better now than we did them five years ago and 
ten years ago? Obviously, we know more, but are we doing a 
better job get the message across to people?
    Dr. Leshner. I am fond of saying that advances in science 
over the course of the last decade have totally revolutionized 
our fundamental understanding of the nature of the phenomenon. 
When I came to NIDA, I had a sort of slogan: Science must 
replace ideology. I have now changed that slogan; that is, that 
science can replace ideology, and I think we have a science 
base on which to base what we do in this country.
    Having said that, I also have been committed to trying to 
change public understanding, and I hope I am not deceiving 
myself that we are beginning to see more and more people feed 
back to us information about what the science has taught about 
drug abuse and addiction. It is a slow process.
    But I do believe, and I do take heart in the thought that 
we are starting to make some progress, and I think that 
certainly the way in which the Administration has structured 
changes in the budget this year, not necessarily at all 
absolute levels, clearly reflects an understanding among Dr. 
Shalala, General McCaffrey, and others about what some of the 
science is teaching us.
    Mr. Porter. Thank you, Dr. Leshner.
    Mr. Hoyer.

                                strategy

    Mr. Hoyer. Thank you very much, Mr. Chairman.
    Dr. Leshner, welcome. We are pleased to have you here.
    I sit on the Treasury Postal Committee which oversees the 
budget of the ONDCP.
    We now have a strategy which is a ten-year long-term, five-
year short-term strategy. Would you tell me your view of that 
strategy and of the probability or the appropriateness of the 
objectives that are set forth in that strategy and the 
probability of success that you foresee for that strategy.
    Dr. Leshner. One of the things that I particularly like 
about this strategy is that it uses science very heavily, 
probably for the first time in our history of developing such 
strategy. Science is a core element of each of the major goals, 
and it is a core element of each of the major objectives that 
lie under them.
    I am very supportive of each of the goals. I am 
particularly enthusiastic about Goal No. 1, which relates to 
Mr. Porter's question about work with our youth. We have been 
working closely with ONDCP and other agencies on that goal.
    The second has to do with public health consequences, both 
for the individual and for society, of drug use. My own view is 
that it is a rational strategy that attempts to take a 
rational, focused approach to the problem. I am, of course, 
very pleased that there is a heavy science complement to it.
    Mr. Hoyer. Doctor, the strategy, as you know, has been 
characterized as a timid, weak, defeatist policy. Would you 
tell me whether or not you agree with that characterization 
and, if not, why not?
    Dr. Leshner. My own view is that this is the most complex 
problem facing humankind. It is a social issue. It is a health 
issue. It affects parents. It affects children. It affects 
everybody in the society. I believe the only way we will 
ultimately get a handle on it is when our strategies are as 
complex as the problem that we are trying to address.
    Having said that, I think, A, there will never be a magic 
bullet and, B, the solutions will not come very quickly.
    My own view of the strategy--which, again, we have had a 
part in the production of--is that it is a rational, systematic 
approach to getting a handle on the problem. It is complex, and 
it does use multiple elements. My own view is that it is a good 
strategy.
    Mr. Hoyer. Would I be correct, then, Doctor, that you do 
not think it is a timid strategy?
    Dr. Leshner. No, sir, I do not.
    Mr. Hoyer. And you do not think it is a weak strategy?
    Dr. Leshner. No, sir.
    Mr. Hoyer. And you do not think it is a defeatist strategy?
    Dr. Leshner. No, sir. I see it as a positive strategy.
    Mr. Hoyer. I do not want to get you in an argument with the 
Speaker of the House of Representatives----
    Dr. Leshner. Thank you. [Laughter.]

                                 goals

    Mr. Hoyer [continuing]. But, frankly, I agree with the 
Chairman's views that has expressed, as opposed to the 
Speaker's view, which I think was simplistic and wrong and not 
helpful to the fight against drugs, to which this 
administration and this budget has applied $17.1 billion.
    Chairman Porter observed that perhaps too much of that is 
for enforcement and interdiction, which is critically 
important, in my opinion.
    If we do not get people off drugs, particularly hard-core 
users, who are the biggest consumers and, therefore, the 
biggest buyers, and, therefore, the biggest drive of demand 
and, therefore, the biggest drive for people to create supply, 
we are not going to win and winning is not, obviously, 100 
percent.
    But do you think the goals are reasonable goals then? I ask 
that in this context: We had a long discussion with General 
McCaffrey on this issue. One of the criticisms is that the 
goals are not high enough. In other words, the reductions are 
not high enough. Notwithstanding the fact that they are 
substantially lower by a point, point-and-a-half, two points, 
than the lowest use rates that have been recorded over the last 
15 years.
    Do you think the goals are sufficiently low or high, 
depending upon what we are looking for, to be, in effect, 
worthwhile goals and achievable goals?
    Dr. Leshner. Again, I think that the strategy, as it is 
laid out, is as realistic as we can be, given what we know and 
what we know how to do at this point.
    I hope that by the time those five years are up I will have 
provided you, through the research that we support, new tools 
and techniques that we have not even thought of today, that we 
will be able to use to speed up the pace.
    Mr. Hoyer. That is a good point. On an annual basis we will 
look at these goals as it relates to our capabilities to see 
whether or not, we ought to raise the bar as to what we want to 
accomplish. I think that makes a lot of sense.
    Doctor, I want to say that I know General McCaffrey 
believes you are a critically important component.
    It is a complex problem, and one of the great things I 
think about President Clinton's appointment of General 
McCaffrey, who is a nonpolitician, not involved with any 
parties, the most decorated soldier in America, and clearly 
somebody who has been given some of the highest 
responsibilities when the United States was at risk in terms of 
a military perspective, has come into this and has applied a 
very rational, considered, long-term view, while at the same 
time wanting to reach short-term objectives.
    But I know that he believes you are a critically important 
component of this because without the medical intervention, 
without getting people off drugs and having effective 
rehabilitation strategies, we are just not going to win this 
thing.
    I talk to police officers in Prince George's County, and 
they say--and, Mr. Chairman, I am sure you have talked to 
police officers that say the same thing--you could be in the 
corner of the room over here arresting somebody for a 15-year 
penalty for selling crack and in that corner you will have 
somebody else selling crack, because the profits are so high.
    So we are not stopping people because of incarceration. 
What we need to do is make sure that we stop the buyers 
because, as the Chairman points out, if we educate them on how 
dangerous this activity is, we can find a way to get the ones 
who have already gotten hooked off.
    I have three daughters who smoke. One has now stopped 
because she had a child and, in the process, obviously, stopped 
smoking and continued not to smoke. But I have two other 
daughters who continue to smoke and I bring home all of this 
information that you folks give me. I show them these pictures 
and all of that and I have a 26-year-old daughter who looks me 
in the eye and she says, Dad, I do not want to stop smoking. It 
is the toughest thing I have ever tried to do, and she says it 
with tears in her eyes. She is hooked on those cigarettes, and 
she cannot get off. I have never smoked. Judy never smoked.
    So God bless you.
    I do not know whether my time is up. Is my time up?
    Mr. Porter. You have 20 seconds.
    Mr. Hoyer. Let me try one question then.
    Mr. Leshner. I will answer quickly.

                       prenatal cocaine exposure

    Mr. Hoyer. Obviously, we are having a major medical cost 
impact with prenatal cocaine exposure on the development of a 
child. Can you discuss that in 20 seconds.
    Dr. Leshner. Let me give you the quick answer, if I may, 
but it is an issue, I think, of tremendous importance.
    One of the problems, by the way, that we have had is that 
we have had an unusual pendulum swing in this country that is 
making me, at least, extremely uncomfortable. We began with 
abject hysteria about crack babies in the late 1980s when we 
first saw that they were born with low birth weight and a 
number of other problems.
    Now we have had a pendulum swing in the other direction of 
what I call excess sanguine feelings about crack babies; that 
is, everybody thinks they are just fine.
    What we have discovered, and I might tell you that in 
September of this year the New York Academy of Sciences, with 
our support, held the first-ever meeting bringing together 
basic and clinical scientists to address this problem.
    What we are seeing is some very important latent and subtle 
effects, so that some children, not all children, but some 
children prenatally exposed to cocaine develop attentional 
problems that are not expressed until ages five to six.
    They develop learning and cognitive disabilities that do 
not emerge until they are 10 to 12 years old. Now, these are 
subtle changes. They are not very dramatic. But a study was 
done at Brown University that showed in the aggregate the mean 
IQ of the prenatally exposed kids, opposed to the general 
population was three IQ points, lower which for any individual 
child is in the noise. It is a testing error.
    But when you look at moving the mean three IQ points, it is 
14 thousand kids who need intervention because of their 
prenatal cocaine experience. Therefore, we have increased our 
efforts looking at the 12 cohorts that we are now studying who 
were prenatally exposed to cocaine; to figure out first the 
nature of the problem, obviously, and, secondly, what we can 
actually do about it without stigmatizing those many thousands 
of babies who were born prenatally exposed who might not be 
affected.
    So it is a very complex problem, both from a scientific and 
from a public health point of view.
    Mr. Hoyer. Thank you, Doctor, and thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Hoyer.
    Mrs. Northup.

                               prevention

    Mrs. Northup. Doctor, I agree that we have to reduce the 
demand. We also have to reduce the supply. I think it is sort 
of interesting that we would ever diminish either one of those. 
We are certainly not doing that in tobacco.
    I notice that we are not just educating kids not to smoke. 
We are also going after the people that make it attractive and 
make it available as aggressively as we can,and that is what a 
two-pronged approach is. I agree that we have to do both of those well.
    Since you are talking about the medical side of it and not 
the enforcement side of it, I will keep my point structured to 
that, but I would not want it at all to be assumed that I did 
not think that reducing the supply was very important, too.
    Reducing the demand has got to be done at every level, and 
I think that education is important. We could put ads on 
television. It is not the only way of approaching it, and I 
just wondered how closely you work with those agencies that are 
both involved in prevention and in education, particularly 
SAMHSA, and whether or not you have ongoing conversations about 
your work and what might be applicable to their work in 
prevention.
    Dr. Leshner. Let me mention, first, that we have a very 
close relationship with the Department of Education, since you 
mentioned education. The Drug-Free Schools Unit within the 
Department of Education, which has been distributing our 
prevention brochures everywhere around the country trying to 
make sure that it, in fact, gets used.
    We have a number of interactions with various elements 
within SAMHSA, and you may know that the new SAMHSA CSAP 
director is a NIDA grantee, Karol Kumpfer, and so we are very 
hopeful that we will actually have even more relationships 
developing over time, where we would, of course, be looking at 
ways to implement that which has been discovered in the 
scientific research that we produce.

                          workplace prevention

    Mrs. Northup. I think that the Chairman had a real point 
when he said the demand is created at sort of every level, 
every strata of society, and every age. I have talked to a 
couple of organizations, businesses, that have put in very 
effective no-use policies, and I wondered if you have done any 
studies that would show what the best practices are that exist 
in drug-free workplaces that would help other companies and 
other communities that are trying to implement a no-use policy.
    Dr. Leshner. Let me say two things, if I may, about that; 
one, we do have some research going on now about workplace drug 
prevention. I would not want to create the impression that we 
have a formula that could be used. However, first, just to have 
the presence of drug testing, to have the presence of drug 
prevention programs in workplace environments is very 
important.
    The second thing I would mention is drug treatment. Many 
employed individuals are, in fact, addicted--and it is hard for 
people to remember that something like 70 percent of the 
addicts in this country are, in fact, employed. Employee 
Assistance Programs within work environments have been 
developing more, and better, and more effective treatment 
programs to help people return to functionality.
    A finding I think was just published--it may be about to be 
published--showed that in the Employee Assistance modality you 
can, in fact, literally match the service needs of a particular 
individual to the services being offered. This may sound 
obvious, but it is actually a change from historic practice--
and increase the efficacy of the intervention by 20 percent.

                        grassroots organizations

    Mrs. Northup. It is a tough issue because we know that to 
overcome whatever challenges each of us face, there has to be a 
strong inner motivation, too. I think the threat of losing your 
job is part of making sure there is some intervention, but 
there is the opportunity for treatment, the opportunity for 
survival in your job, even if you fail the first time.
    I also happen to know of a number of people that have been 
young adults, they used drugs, but the opportunity to have a 
really good job and know that they were going to have to take a 
drug test and then be tested at random after that was just 
enough to stop use. I do not think we would classify them as 
addicted, but they are part of the reduced use, reduced demand 
that helps eliminate the market that we are trying to 
eliminate.
    Those type of best practices, I think, are very important 
and very important that we make them available.
    I am also interested in what goes on in schools and what 
type of grassroots efforts are being used. If you believe that 
it has to be a multifaceted campaign as I do, then you agree 
that maybe some mass media is important.
    I also believe that what we have done in communities 
regarding smoking is a pretty good model, and that is the 
grants that exist in every state for grassroots planning. They 
compete for them. I think half of them come through HHS and 
half of them come through CDC.
    But they are a grassroots organization, a coalition to 
reduce smoking. They are the coalitions, in most States, that 
have pressed for strong public policy, that have pressed for 
strong education programs, that have met youth where youth are, 
in terms of both physically and mentally. I wondered if there 
is any effort that you see going on to create that same sort of 
grassroots organization in all of our states regarding the 
drugs.
    Dr. Leshner. Actually, there is a phenomenon that has been 
going on for the last five years in this country. Just to give 
you a very large number, there are now 4,000 anti-drug 
coalitions in communities around this country. They are 
organized collectively in something called the Community Anti-
Drug Coalitions of America, and you may know that Mr. Portman 
was influential in a bill to provide support for those 
communities.
    Mrs. Northup. Right.
    Dr. Leshner. Well, one of the nice things that has been 
happening is we have been working very closely with CADCA, and 
they have developed a program called, ``The Practical 
Theorist,'' where they take our scientific findings and 
actually translate them, with our participation, into a format 
that then is circulated to these 4,000 coalitions and then gets 
diffused out into the community setting.
    The first issue they did was on our prevention activities, 
and they are co-sponsors in our Treatment Conference next 
month, and we are very hopeful that that will be another 
vehicle, whereby communities can get their hands on the best of 
what we have. Again, I do not want to create the impression we 
know everything, but we do have a lot to offer.
    Mrs. Northup. Well, I think you do. The advantage, though, 
of the State grants, and I am searching for the name of those 
two--ASSIST, one of them is ASSIST, and I cannot think of what 
the other one is. The advantage is that they provide not that 
much money, but enough to bring together a lot of coalitions, 
the PTA and so forth, to have sort of an organized approach, 
and I just have wondered if that would not be valuable.
    It is very hard. I was very involved in the tobacco one in 
Kentucky. There are a lot of diverse groups, a lot of 
volunteers, a lot of people that already have other 
responsibilities, and the planning grant actually helped move 
them from Point A to further down the line very fast. I would 
just be interested in whether that model would help give us an 
impetus.
    Dr. Leshner. I do think that these coalitions have been 
tremendously effective.
    Mr. Porter. Thank you, Mrs. Northup.
    Mrs. Lowey.
    Mrs. Lowey. Thank you, Mr. Chairman.
    Again, I would like to welcome you, Dr. Leshner, Dr. 
Varmus.
    Dr. Leshner. Thank you.
    Mrs. Lowey. Because time is limited I will submit some 
questions for the record.

                            biological basis

    Mrs. Lowey. I am particularly interested in discussing your 
statements in your initiative called Genetics of Addiction 
Initiative, and your comments regarding the complexity of 
addiction.
    When you think about this, and the interaction, the 
interrelationships between food addiction, and alcohol 
addiction, and drug addiction, and the cost to society today in 
health, in criminal activity, I think it is probably one of the 
most important things we can do.
    When you look at our prisons, you see that 90 percent of 
the people are there as a result of drug addiction and related 
crimes.
    So I am very interested in the results of that initiative, 
which I will ask you to discuss at another time.
    My colleague, Mr. Hoyer, talks about his daughters. I do 
not smoke. My husband never smoked. Neither of us ever smoked, 
and we have the same situation, they all got off cigarettes, 
but they also said to me it was the hardest thing they ever did 
in their life.
    The reason your research concerning the biological basis 
for drug addiction is so interesting to me, there has been a 
longstanding perception that drug addiction, for example, is 
more prevalent in low-income communities. You say it is an 
equal opportunity addiction, which is true. We see it at all 
levels.
    If this is the case and if there is a biological basis for 
addiction, then it is a very important message to us here and 
that how do you deal with it? What is the interaction between 
the socioeconomic forces and the biological basis? Do we treat 
everyone who is arrested for drug addiction as a sick person? 
And considering the cost to society, as someone who has been so 
involved with DARE and peer assistance programs, why can we not 
do something that is successful?
    Steny Hoyer has talked for years, and I have been very 
involved with him as well, in comprehensive programs in the 
school. We have loads of these programs, although not the ones 
he is talking about, and I support that. But the numbers of 
users may dip a little bit, but basically it is rising.
    So my question is, perhaps, briefly, where is this study 
going? Is the interaction based upon information now between 
the biological basis for addiction and the socioeconomic 
forces, and what are we learning about it? What are we doing 
about it?
    Dr. Leshner. I may have to sort those two parts; what we 
are learning and what we are doing.
    Vulnerability to addiction is, obviously, a tremendously 
complex phenomenon, but there is no question in 1998 that it is 
the result of the intersection between genetics and 
environmental influence; that is, that every twin study or 
adoption study that has been done shows amazingly high levels 
of heritability of the vulnerability to being addicted.
    The numbers that I have been given recently approximate 50 
to 70 percent of the vulnerability as contributed by genetic 
factors. Now, we have not studied that in enough depth for me 
to be confident that that will prove to be the number forever, 
but it is showing us a tremendous influence.
    Having said that, obviously, not everyone who carries the 
genetic load becomes addicted and, therefore, we have to look 
at the intersection between genetic vulnerability and the 
expression of that genetic vulnerability and actually being 
addicted.
    Therefore, our own work--apropos what are we learning about 
it--is trying to look at this area; and we are about to mount a 
major initiative looking at the genetics of vulnerability. We 
will look at that as an element, then look at the environmental 
determinants, and then look at the intersection between the two 
of them.
    I think among the things that we all need to address, 
obviously, is the issue of what do we do with that information 
once we have it, given that not everyone who is vulnerable will 
actually become addicted. Therefore, we will need to have, as 
our markers for vulnerability get better over time, just as we 
have new strategies for dealing with social environmental 
markers, we will need to have new strategies for knowing whom 
to interview with and how to intervene with those people once 
we understand the nature of the relationship.
    Mrs. Lowey. We have to go vote, but I am very much 
interested in this, and I would like to have a further 
discussion because knowing that people have a predisposition 
towards depression, predisposition towards many other mental 
illnesses, and the interrelationship between the biological 
basis, certainly, for drug addiction and the other mental 
illnesses certainly leads me to say we have to just do a better 
job of detecting this in our young people today, not only to 
ensure that they have a successful, healthy life, but because 
the cost to society is enormous. We know that once a youngster 
is addicted, the numbers are not very good.
    I have worked with Phoenix House and so many of the 
programs within my district, and it all leads to you having to 
figure it out early, detect those youngsters early because once 
they are addicted, the recurrence rate, as you know, is 
extraordinarily high.
    We are out of time, and so I will save the rest of my 
questions, but I just want to----
    Mr. Porter. Mrs. Lowey, I am sorry we are not going to be 
able to save questions because we have Dr. Gordis to testify 
yet.
    Mrs. Lowey. No, no. I mean I will just submit them for the 
record. I just wanted to emphasize this is an area that I, 
personally, am very interested in because I think it is so 
important as a public health issue, as a cost issue and, 
although, we have done so much, and I think you have heard the 
frustration of so much of us, there are so many successful 
programs yet we cannot replicate them on a large enough scale 
to really be successful.
    I want to thank you for the very important work you are 
doing, and I look forward to hearing more about your success.
    Dr. Leshner. Thank you.
    Mrs. Lowey. Thank you.
    Mr. Porter. The Chair would like to also say that you are 
doing a superb job at NIDA, Dr. Leshner, and all of us 
appreciate that and want to give you the resources that you 
need to do it even better.
    Dr. Leshner. Thank you, sir.
    Mr. Porter. We will do our best. I am very sorry we do not 
have enough time. It is a scheduling problem for us. We are 
attempting to move our hearings along a little bit faster than 
last year and it sometimes simply is too compact, for which we 
apologize.
    Thank you very much for appearing and testifying.
    Dr. Leshner. Thank you, sir.
    Mr. Porter. The subcommittee will briefly stand in recess.
    [The following questions were submitted to be answered for 
the record:]


[Pages 1301 - 1375--The official Committee record contains additional material here.]



                                          Thursday, March 19, 1998.

           NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

                               WITNESSES

ENOCH GORDIS, DIRECTOR
MARY DUFOUR, DEPUTY DIRECTOR
MARTIN K. TRUSTY, EXECUTIVE OFFICER
STEPHEN LONG, DIRECTOR, OFFICE OF POLICY ANALYSIS
CARMEN M. RICHARDSON, BUDGET OFFICER
HAROLD VARMUS, DIRECTOR, NIH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS

                            Opening Remarks

    Mr. Porter. The subcommittee will come to order.
    We continue our hearings on the National Institutes of 
Health with the National Institute on Alcohol Abuse and 
Alcoholism. We are pleased to welcome Dr. Enoch Gordis, the 
Director.
    Dr. Gordis, it is good to see you and if you will introduce 
the people that you brought with you and then proceed with your 
statement, please.
    Dr. Gordis. Thank you, Mr. Porter.
    Starting from that end of the table is Mr. Steve Long who 
is head of our Office of Policy Analysis; Mr. Martin Trusty, 
our Executive Officer; Ms. Carmen Richardson, our Budget 
Officer; Dr. Mary Dufour, our Deputy Director of the Institute 
and I think you know everybody else at this table.
    Before I begin on my remarks about Institute activities, I 
would like to join the other colleagues at NIH who, over the 
last few days, have had an opportunity to congratulate Mr. 
Stokes on his distinguished career and to wish him all the best 
in the years to come.
    Mr. Stokes. Thank you very much, Dr. Gordis.
    Dr. Gordis. The Fiscal Year 1999 President's budget request 
for our institute is $230,243,000, an increase of $17.5 million 
over the 1998 appropriation. Including the estimated allocation 
for AIDS, total support proposed for our Institute is 
$245,000,000, an increase of $18.6 million over the 1998 
appropriation. Funds for NIAAA AIDS research are included in 
the Office of AIDS Research budget request.
    The problem of alcohol is immense in this country, Mr. 
Chairman. Fourteen million Americans have been diagnosed as 
having alcohol abuse or alcoholism. It is by far the leading 
drug of abuse in this country, especially among the youth. One-
quarter to one-half of all hospital beds in urban hospitals are 
occupied by people being treated for the medical consequences 
of their drinking. It causes 100,000 deaths annually and in 
1992 the estimated cost to society was over $100,000,000,000.

                       early onset of alcohol use

    As a result of our extensive epidemiological work, an 
important addition to our knowledge appeared this year. The 
first poster shows that when we analyzed the relationship 
between the age of onset of drinking and the odds of becoming a 
diagnosable clinical alcoholic as an adult, each year that the 
age of onset was delayed decreased the risk 14 percent compared 
to the year before. Forty percent of the people who start 
drinking below the age of 15 will have a diagnosis of 
alcoholism some time in their adult life, while starting later 
reduces that risk to about 10 percent.
    Now, of course, the appearance of alcoholism in adulthood 
is only one reason for being concerned about adolescent 
drinking. Adolescent drinking causes highway deaths, 
destruction of school activities, date rape in colleges, binge 
drinking and all of the things that I think we are familiar 
with. But this is yet another reason to be very concerned about 
the onset of drinking in the young.
    The range of our research is from molecular biology through 
treatment, toxicology to organs including the fetus, prevention 
activities of all sorts and also a portion of work on the 
health benefits of drinking because, as a scientific agency, we 
have a responsibility to look at all aspects of the use of this 
substance.

                      research to bedside--timing

    In the second poster, I am going to make the point in 
response to a question which is frequently asked and that is, 
how long does it take to get from the science to its useful 
application in treating patients? And what this shows here is 
that it depends on what kind of science you are talking about. 
The distance from science to clinical application is relatively 
short if we are talking about clinical trials. If we talk about 
neuroscience it is a bit longer. Exciting new approaches of 
medications development are just beginning to be seen and, in 
the case of alcoholism, the route from the genetic work, which 
I will tell you about shortly, to its applicability in the 
clinic is probably even longer still.
    Clinical trials, of course, include Project MATCH which is 
a randomized control trial of 1,700 patients that was just 
completed. Other work has shown that naltrexone, an opiate 
antagonist, is useful for the treatment of alcoholism--which 
led to the FDA approval of this drug three or four years ago.
    A new drug in Europe called acamprosate is being widely 
looked at now in the United States and has become the subject 
of one of our new cooperative studies. And new drugs, such as 
amperozide and many others, which I will not take the time to 
go over, are on the horizon.
    But the important point is that these clinical trials have 
already been able to exploit the fruits of basic science in 
treating patients.
    When we get to neuroscience, we are learning what happens 
in the brain which will then provide us with the tools to 
provide new medications. Unlike the drugs of abuse, which Dr. 
Leshner discussed with you in the previous hour, alcohol 
affects virtually every receptor system in the brain which is 
studied. And one of the main issues in our research is to 
understand the common principles by which alcohol reacts with 
these receptors
    There are, in general, two ways we can look at the 
neuroscience of alcohol abuse. One is to look at what is called 
positive reinforcement. That is, what is there about drinking 
which is enjoyable? That involves one set of neurocircuits and 
one set of neurotransmitters.
    The other side of the coin is what is there about the 
discomfort of not having alcohol when one is dependent which 
leads to relapse? That involves other neurocircuits and other 
kinds of neurotransmitters. Both of these approaches have 
helped explain why the drugs that we have introduced are useful 
and promise a route to the discovery of new ones.
    Of course, we use all the high-tech approaches in 
neuroscience--imaging, using transgenics, and knock-outs, and 
site-directed mutagenesis, which is a technical method for 
changing the structure of receptors and seeing exactly where 
alcohol acts upon them. And if there is any interest in that I 
will be happy to respond.
    The third one, new approaches to medication development is 
the following idea. In general new medications have been found 
in many areas of medicine by a combination of luck and accident 
on the one hand, by exploring off-the-shelf what is available 
as well as finding new uses for medications which are used for 
other purposes, and our field has benefitted from that as well.
    What is happening now in medication development is our 
ability to understand the three dimensional structure of body 
molecules such as proteins and enzymes which permit us to 
design beforehand which kind of medications would suit the fit 
of those molecules.
    A very exciting piece of work by a group of our grantees 
was the unraveling of, the crystalline structure of the 
molecule of aldehyde dehydrogenase, a key enzyme in 
themetabolism of alcohol.

                       flushing response mutation

    What it has helped explain is why the mutation, which had 
been previously identified in Asian people who often have a 
flush after drinking and, therefore, are in some ways protected 
against developing alcohol dependence, happens?
    Time does not permit me to go into this now but because of 
this particular structure which gives the shape, the coiling, 
the chains, the linking of the various parts of this molecule, 
we can now explain why that mutation causes the activity which 
it does, and it is a prototype of what is coming in the future 
of how this kind of approach will permit us to devise new 
medications.

                                genetics

    The final arrow on the poster previous to this was about 
genetics. And I know that the Committee is interested in this, 
judging by the questions in the previous session. Our 
collaborative study on the genetics of alcoholism now is in its 
eighth or ninth year. And we are happy to report what will be 
in the press shortly, that we have found four chromosomal loci, 
so-called ``hot spots,'' for alcoholism in the genome, as well 
as other loci which relate to various electroencephalographic 
abnormalities which are risk markers for alcoholism.
    In the next few years we hope to identify the genes and get 
the rewards of this effort. The rewards of efforts in genetics 
really are to understand the function of the proteins which are 
abnormal and develop new medications, based on that 
understanding, to have more targeted prevention and finally to 
understand the relation between gene and environment more 
precisely.
    Our research includes a wide range of other activities in 
prevention, studying FAS and toxicity to other organs, youth 
drinking, public education both to the lay public and to 
physicians and other professionals and also to clarify the 
health effects of moderate drinking.
    I will be very pleased to answer any questions that you may 
have.
    [The prepared statement follows:]


[Pages 1381 - 1387--The official Committee record contains additional material here.]



               government expenditures for alcohol abuse

    Mr. Porter. Dr. Gordis, thank you very much for your 
excellent testimony. You were in the room when we were 
discussing with Dr. Leshner the problem of the substances under 
his jurisdiction that are abused and we talked about how much 
money is spent by the government in that area. I recall it 
being around $20 billion. Do you know how much does the 
government spend on alcohol abuse overall?
    Dr. Gordis. No. I do not have that figure in front of me 
right now, Mr. Porter. I am sure, however, that it is 
considerably less despite the fact that alcohol is the number 
one drug problem in our country, especially among youth.

                      resources and opportunities

    Mr. Porter. It seems to me that the problems that hard 
drugs cause in our society are severe, but the problems that 
alcoholism cause are much more severe as you just stated. We do 
not put nearly enough of our resources toward aiming at 
solutions that affect a much larger population in our country.
    Alcohol abuse and alcoholism are serious problems for our 
economy, for families, for addicted individuals and has a lot 
of deleterious effects on society.
    Let me I ask you, if we were to double your funding over 
five years, could you use those funds in a meaningful way to 
advance your research goals or would we simply be putting money 
out there that really would not do much?
    Dr. Gordis. I think we could use this kind of money in a 
very meaningful way. In view of the budget discussions which we 
have all been party to in the last months we have, obviously, 
like our sister institutes given a lot of thought to that kind 
of a question. And I believe there are many areas, greatly 
exciting, some of them novel, some of them elaborate 
continuations of what we are doing, where we could make some 
very meaningful advances in the field.
    I would be very happy to discuss some of them with you but 
the answer to your question is, yes.

                   alcohol use and neurotransmitters

    Mr. Porter. In your opening remarks you mentioned two 
different types of, I think you called them, receptors. One had 
to do with the pleasure that people derive from drinking 
alcoholic beverages and the second had to do with the addiction 
to them. Is that correct?
    Dr. Gordis. Well, the feeling of deprivation when it is not 
present.
    Mr. Porter. Can you describe the research you are doing in 
both areas a little bit more? Do you ever see a situation where 
the pleasures that people associate with using alcoholic 
beverages could be cut after their use so that you do not get 
the effects of the alcohol and you do not get the dependence 
that often follows?
    In other words, can you get part of the whole, the good 
part and not the bad part?
    Dr. Gordis. This is a dream which man has had for a long 
time. [Laughter.]
    Mr. Porter. Woman, too. [Laughter.]
    Dr. Gordis. Just a short answer to the second part of your 
question because the first, I think, is more directly related 
to what we are doing now. Agents which reverse the intoxication 
from alcohol have been called amethystic agents. I think it 
comes from the Greek, amethyst which is a stone which in Greek 
mythology had the capacity of undoing drunkenness.
    So, these have been called amethystic agents. And there are 
none available right now. Whether it will be valuable to have 
one, I think, is a matter of some dispute because it involves 
certain aspects of social policy such as violence at home and 
highway deaths and so on. And it is a complicated issue.
    But for all practical purposes, there is no such agent now 
which undoes intoxication. Whether there will be an agent which 
permits one to enjoy the legitimate pleasures of alcohol 
without going on to addiction, I think in the future that is 
conceivable as we get to understand more of the mechanisms to 
which you alluded.
    Let me just take a moment to clarify a little bit about 
these two kinds of circuits. I said pleasure but I was using a 
commonly used word. What I am talking about are circuits having 
to do with reward and reinforcement, that is those brain 
circuits which once a behavior has happened make it highly 
probable that it will be repeated.
    And this kind of activity can be studied both in people and 
especially in animals. The circuits which have been largely 
involved in that are the so-called mesolimbic systems involving 
circuits of the brain where dopamine is a key player but not 
the only one. Especially with alcohol we know that the opiate 
system, the GABA system, and the serotonin system are all 
involved in this. I could go into this in much greater detail; 
this is a very active area of work in understanding which 
receptors are involved in the nerve connections in the circuits 
that have to do with reward.
    In the last few years, the other side of the coin is 
becoming increasingly prominent as well. That is the so-called 
alcohol deprivation effect. That means that after an animal, 
for example, is permitted to get alcohol at will for a period 
of weeks or months sometimes, if it is terminated the drinking 
resumes at a very high amount. And this seems to involve 
somewhat different circuits than thereward circuits I just 
described. It is a circuit which produces the discomfort that the 
animal feels in the absence of alcohol which human patients also feel 
even when they are sober for many months. This feeling or ``craving'' 
is one of the things which antedates relapse.
    Here we know that different neurotransmitters are probably 
involved in part. Certainly, the NMDA receptor which is an 
excitatory neurotransmitter is involved because we know that 
acamprosate, which is a drug that is undergoing clinical trials 
now, as a matter of fact, does act at that receptor. In Europe 
acamprosate has had important effects in curbing the rate of 
relapse. I hope it will in America, too, when the clinical 
trial is over.
    So, the answer to your question is we are actively engaged 
in research in both these aspects of neural control of alcohol-
related behavior.

                         alcohol use and abuse

    Mr. Porter. There are a lot of reasons why we have a 
separate Institute for Dr. Leshner and a separate Institute for 
you. One reason is historical and that is alcoholism and 
alcohol abuse was a problem in this country before the use of 
harder drugs.
    But there are several others and one is that alcohol is 
legal in this country, whereas the use of other drugs under Dr. 
Leshner's jurisdiction are not. And finally, and this is my own 
view of it, alcohol has been used throughout history as a 
social lubricant and, I think, in practically every society.
    In fact, if alcohol is used moderately and with some 
reasonableness it is viewed in a benign or even a positive way. 
There is also research saying that moderate use of alcohol can 
be healthful, but there are not such studies about the use of 
drugs that are illegal.
    Somehow, it seems to me, there has to be a separation 
between that benign or even positive use of alcohol and the 
over-use or misuse of alcohol and it seems to me that your 
research is terribly important in defining some way of drawing 
that line and preventing the negative effects of people who do 
not use alcohol in a reasonable way. That is why I am 
interested to know what kind of progress you are making.
    If you look at your research, Dr. Gordis, are you 
optimistic that we are going to find some of these ways that 
will really make the use of this drug a more benign substance 
or the misuse of it less possible?
    Dr. Gordis. Yes. I am optimistic about it. I think the work 
of the last 10 years has exploded in many fields, all of which 
contribute the kind of information which will lead to the 
answers to the questions you are asking.
    Our main goal is to understand why some people never get 
into trouble with alcohol while a minority do. Our genetics 
research is contributing to that; when we find the genes we 
will understand something about that. Our neuroscience is 
already trying to do that because even now we know that within 
the brain there are different regions where the 
neurotransmitters vary in their shape and their form and we are 
studying that.
    And the more we understand that I think we will be in a 
better position to be able to intervene early. Now, having said 
this--and I mentioned before why genetics is going to reveal 
the abnormalities in proteins in those who become addicted 
compared to those who do not and we will be able to develop 
medications based on that knowledge, too--I do not want to 
minimize the important side of the environmental influences 
here.
    There are many such influences in this country as we know. 
The parents' attitudes towards alcohol right from the start, 
including how the parents handled it, and whether they drink 
abusively or not is one. Friends and peer pressure are another 
influence. We have the issue of many young people having a 
misconception of how much drinking is really being done by 
their friends. We know that they all think their friends are 
drinking more than they are in many situations.
    We have the immense power, of course, of the commercial 
interests and advertising--the industry and its advertising in 
all media. So, there are tremendous social influences which 
determine the use of alcohol and the question you are asking is 
really profound. One of the reasons why I believe our country 
has not come to grips with the alcohol question in a very 
serious way is because of these various aspects which you have 
pointed out in your question. It is legal, it has a legitimate 
use, it has been used throughout history and, therefore, it is 
harder for people to come to grips with the complexities of 
this issue.
    Nevertheless, I think one of these days the country is 
going to have to do that because as I said, it is the number 
one cost and killer among drugs of abuse.
    Mr. Porter. Thank you very much, Dr. Gordis.
    Mr. Stokes.

                  alcohol advertising on the internet

    Mr. Stokes. Thank you, Mr. Chairman.
    Dr. Gordis, it is a pleasure to welcome you back before our 
subcommittee and thank you for your very kind remarks.
    When we left for this last vote, as we got into the 
elevator, we ran into one of our colleagues who had on her 
lapel a campaign button that said, ``Stop Cyber Booze.''
    Some of us inquired as to what the button was about and she 
told us the story about how a minor had ordered a case of 
liquor on the Internet. When the case of liquor was delivered, 
the minor used his parent's credit card and paid for it. So, 
she has introduced some legislation to address that issue.
    And, so, the question I have for you is have we learned 
what impact the advertising of alcohol products and the 
drinking of alcohol in television shows and in movies and on 
references of alcohol in music impacts adolescent alcohol 
consumption?
    Dr. Gordis. Thank you, Mr. Stokes.
    Let me lay out the main controversy that exists in this 
field because I think it gives shape to what I will tell you.
    Mr. Stokes. Sure.
    Dr. Gordis. On one hand are many advocacy groups which 
believe that the industry is intentionally trying to advertise 
to cause young people to begin drinking when they have not been 
drinking before. That is one extreme. The other extreme is the 
industry's response which is that that is not their intention 
at all. Their intention is only to maintain brand loyalty and 
make sure people keep using the brand they happen to be 
manufacturing.
    Where does the truth lie in all of this? I think that is 
really the heart of the question you are asking.
    Mr. Stokes. Sure.
    Dr. Gordis. The fact is that we have hints there but we do 
not know the full answer. Let me give you a reasonable sequence 
by which advertising could have an effect and I will tell you 
what is missing in our ability to know the answer for sure.
    You have to see the ad, you have to be exposed to it, you 
have to understand it, you have got to remember it, and then 
following that, you have to have an attitude change toward 
alcohol as a result of it. That has to lead to an intention to 
drink and then you have to start drinking.
    In order to know the answer to your question ideally we 
would like to know the whole sequence and to be able to say 
that advertising has such and such a role in marching a young 
person through that sequence. We have pieces of it. The idea 
that expectancy is related to future drinking, that the 
expectancy of the good effects has been documented, I think, 
very persuasively.
    Also, there are studies which show that alcohol advertising 
does lead to expectancies and to a better attitude towards 
alcohol itself. And we know that very young children know a lot 
about the difference between brands and about beverages.
    So, why is the answer incomplete? The answer is incomplete 
for a couple of reasons. First of all, the same populations 
have, in general, not been followed longitudinally over a 
period of time so we know for sure that that is what is 
happening. We have chunks of information for one age group, we 
have chunks of other kinds of information for another and, 
therefore, we do not have the answer convincingly.
    From what we do know it is not likely that advertising 
accounts for more than a minority of the variance in drinking. 
Although that is a good plausible answer, we are not absolutely 
sure of it.
    We will now be studying this in great detail. We have a 
request for applications out on this very topic in which the 
issue that you have just raised, Mr. Stokes, is going to be 
looked at extensively with longitudinal studies to finally sort 
of put the nail in this coffin, that is, to find out what is 
the role of advertising in the initiation of drinking in the 
young.

                      age of onset of alcohol use

    Mr. Stokes. Now, I noted, Dr. Gordis, that in your 
congressional justifications the examination of data from the 
National Longitudinal Alcohol Epidemiologic Survey found that 
the age of onset of alcohol use is a strong predictor of future 
alcohol problems. The younger age of onset is associated with 
an increased likelihood of future alcohol and related problems. 
And you have already made some reference to that in your 
remarks here this morning.
    These findings indicate that there is an increased need for 
family-centered prevention programs. To what extent do these 
programs exist and how effective are they?
    Dr. Gordis. To many people--not to you nor this committee--
the idea that prevention can be actually researched so you can 
find what works has been a novel idea. But the fact of the 
matter is that just as a new medication can be researched, 
prevention can be researched also. It is possible to try 
interventions in one community with one group of kids and see 
if they have an effect compared to another group of kids or 
other communities which are not given that intervention.
    And we have done that and we have had some positive results 
for several interventions in which the family plays a role. For 
example, in Project Northland in Minnesota, which examined the 
issue of drinking in an age group roughly from about 11 to 14, 
we found that a combination of family work, parents and 
children working together with assignments on this problem, 
school-based activities and several other details led to a 
reduction in the initiation of drinking in that group by about 
25 percent. For any kind of a social effect this is really 
quite large.
    Those kids are actually being followed for the next three 
years and within about a year or so we expect to have the data. 
The interventions that one needs with somewhat older kids are 
less of the homework kind of stuff, these interventions tend to 
involve more community interventions. And we know from some of 
our other prevention trials that community interventions which 
involve many aspects of enforcement, of public activities about 
drinking and driving and so on, all have a role. For the 
record, I will be glad to give you the results of some of those 
other trials.
    But I want to just conclude this answer by pointing out 
that the cyber booze you are talking about--selling booze over 
the Internet is a minor issue but an important one because of 
the fact that there are many places in this country where an 
under-age kid can still go into a liquor store and buy it.
    This is where the rubber hits the road, as a matter of 
fact. And every single one of the community-based interventions 
which does not address this problem is not going to work.
    Mr. Stokes. Well, in light of what you have just told us, 
Dr. Gordis, do you have some ongoing collaborative efforts with 
the Department of Education relative to the schools? What type 
of programs currently exist in the schools?
    Dr. Gordis. Yes. We have several things going on that way. 
And we also are working with the Department of Justice, by the 
way, on the advertising issue that you spoke to us about. Mary, 
did you want to comment on the education efforts any further?
    Dr. Dufour. Just to say that most of the things are related 
to the issue of alcohol and adolescence and going from middle 
school through high school. We are especially interested in 
college issues because that has been a very difficult one.

               physicians screening for alcohol problems

    Mr. Stokes. Okay. Dr. Gordis, let me ask you this, the rise 
of managed care has increased the importance of primary care 
providers over the years. The Institute has emphasized that 
primary care providers could be a valuable and effective tool 
in talking to patients about alcohol consumption.
    With the restraints placed on physicians in terms of time 
spent with patients in many managed care arrangements, how 
likely is it that physicians will have the time for this type 
of discussion or that managed care administrators will provide 
physicians with additional time? Can you tell us what is being 
done to educate managed care plans about the benefits of this 
kind of dialogue?
    Dr. Gordis. You are absolutely correct that the primary 
care physician is the gatekeeper on making sure that a patient 
who has an alcohol problem is going to be identified and 
handled right. We have been very active in that. We have just 
published a physicians' guide to helping patients with alcohol 
problems and a similar booklet of training for primary care 
physicians. And I must say that the managed care firm, as well 
as ONDCP, has been very helpful to us in distributing this to 
almost 300,000 doctors across the country.
    Managed care, even when you consider that they do have 
bottom line interests, obviously are also interested in making 
sure that the patients who are being seen are not going to cost 
them more in the future. And one good way of doing that is 
intervening in alcohol problems early before they end up as a 
costly hospital admission.
    So, I would not be pessimistic that managed care 
organizations would want to deprive doctors who are working for 
them of the opportunity to do this kind of intervention you are 
talking about especially since the kind of interventions that 
we are talking about, of which this booklet is only one 
example, are designed to be rapid and efficient.
    Obviously, if you have 40 minutes to see a patient or half 
an hour, you are not going to devote 20 minutes to talking 
about alcohol when you have got many other things to talk about 
as well. So, you have to get into the topic in a way that is 
going to give you a high yield quickly. And we know two things 
about this from research on primary care.
    First of all, that it is very cost efficient in the sense 
that it is possible to have a non-physician do some of the 
counseling once the problem has been identified. This leads to 
a diminution in the rates of hospitalization which Dr. 
Fleming's study has shown in a very extensive study in 
Michigan. And secondly, Dr. Israel in Pennsylvania has shown 
that if you use the history of trauma as one of your first 
questions, you can identify about 60 or 70 percent of the 
expected number of alcoholics in your population without even 
mentioning alcohol first.
    The point of all this is that with efficient interrogation 
methods there is no reason to assume that managed care folks 
would not be very happy to cut down the costs of the 
complications of alcoholism by giving the primary care doctors 
a chance to do it right.
    In line with your question, I just am reminded that the 
parity issue which is, of course, very much related to that is 
whether health care plans of all sorts are going to be required 
to take care of alcohol and drug questions to the same extent 
that they are now required to take care of mental health 
problems and in parallel to what they do for medical and 
surgical complaints.
    And certainly the science would support the wisdom of going 
that route for the reasons I have talked about; by preventing 
complications, the costs spent in treating these folks is saved 
many-fold over.
    Mr. Stokes. My time has expired.
    Thank you, Dr. Gordis.
    Dr. Gordis. Thank you, Mr. Stokes.
    Mr. Stokes. Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Stokes.

                         genetics of alcoholism

    Mrs. Lowey.
    Mrs. Lowey. Thank you, Mr. Chairman.
    And welcome, Dr. Gordis.
    Dr. Gordis. Thank you.
    Mrs. Lowey. I thank you for your excellent presentation. I 
apologize that we are pulled in so many different directions. 
This morning we have been talking about the genetic basis of 
drug abuse and I am particularly interested in the growing 
evidence that alcoholism is genetic in nature, as well.
    And I was interested in your comments regarding the promise 
of research in that area. Perhaps you can update us on what 
progress has been made--and I know you feel they are at the 
beginning and there is a lot more that has to be done--what 
progress has been made on identifying genes that do influence 
behavior? And, in fact, I would be interested in the 
interaction between the genetic basis and the socioeconomic 
basis, as well.
    Dr. Gordis. Sure.
    Mrs. Lowey. And before you give that comment, I just have 
to react to the conversation before and your response in terms 
of under-age youth buying alcohol. What I think is truly 
unfortunate in this country is that you have bartenders who do 
not have to be 21 and it is very common, certainly in New York, 
for the local bars to have guest bartenders and bring your 
friend that night.
    Now, if the bartender is 18 and he fills the bar up with 
his friends, I just wonder about the enforcement of the 21-year 
old drinking age.
    Dr. Gordis. Well, I share that point of view.
    Mrs. Lowey. And perhaps you can respond then to my question 
regarding genetics.
    Dr. Gordis. Yes. Okay. The wisdom of Congress had led to 
the funding of a collaborative study on the genetics of 
alcoholism which is now in its eighth year. This is taking 
place at six centers across the country where diagnostic 
instruments for defining alcoholism were designed and arrived 
at. They have been found so useful they have been translated 
into eight or nine languages and used all over the world now.
    Thousands of potential probands, that is the initial case 
who has alcoholism in their families, have been interviewed and 
over the course of this time, this has been honed down to about 
320 informative families, that is, families where you have 
multi-generational alcoholism, some with and some without, 
where the genetics studies can be done.
    The studies have progressed very well, indeed. And the 
first publications actually are appearing this spring. Four 
sites on the human genome that are so-called ``hot spots,'' 
locations within the chromosomes where the genes for the 
vulnerability to alcoholism have been found have been 
identified, chromosomes 1, 7, 8, and 16 for alcoholism itself.
    In addition two other ``hot spots'' have been identified 
for certain kinds of brain wave abnormalities which are found 
in kids known to be high-risk who have never even used alcohol. 
These ``hot spots'' predict this as a high-risk group.
    And, so, the next five or 10 years, and I think that is 
part of what Mr. Porter was asking about regarding how we would 
spend more money, the goal is to actually find the genes, 
themselves, because now we only have their locations. We have 
other clues from animal work in genetics where some of these 
genes might be. But in the interest of time, if you are 
interested in that I will be happy to supply that for the 
record.
    So, we are very confident that over the next five or 10 
years we are going to find genes that have to do with the 
vulnerability to alcoholism. And as has been said before and I 
will say it again, alcoholism is not only a genetic disease but 
the role that genes and environment have in any individual will 
vary from person to person. With a heavy genetic load it will 
not take much of an environmental push, with a lighter one you 
will need more of an environmental influence to shape that.
    So, clearly by knowing the genes, we are going to be able 
to define the environmental pressures even more accurately.
    Now, having said that I will give you one example of where 
we have a beautiful example of the question you are asking of 
the environment and the genes.

                   flushing response and environment

    One of the striking triumphs of molecular biology and 
alcoholism is the identification of the mutation in the gene 
for an enzyme which, because of that mutation, leads to 
inadequate metabolism of alcohol and a very uncomfortable 
reaction from drinking.
    It is almost like you took antabuse, except you have a gene 
for it instead of taking the medicine. About half the Asian 
population has this mutation, which leads them to avoid 
alcohol. Among alcoholics in Japan, for example, this mutation 
while it is 40 to 50 percent through the whole population, you 
hardly ever find it in alcoholics because it seems to be 
protective, not because it protects against alcoholism, but 
because the initial experience with alcohol is so unpleasant 
you do not go further.
    Now, the interesting wrinkle about this is there is a mild 
form of this where you have one copy of the normal gene and one 
copy of the mutant gene but you do not have such a severe 
reaction. So, what has been looked at is how has the presence 
of this mild form of this genetic mutation changed over the 15 
years that it has been looked at in Japan?
    That is the enzyme but it is not related really to the 
present discussion as I am answering Ms. Lowey's question.
    The fact of the matter is that the mild form of this 
mutation has been less and less effective in protecting people 
in Japan from drinking because it is mild enough that you can 
tolerate it and as the environmental and as the social 
pressures for westernization of drinking habits has increased 
since the late 1970s to now, you find more and more of the 
alcoholic population who have this mild form of the flushing 
reaction.
    This is a beautiful example of how social pressures can 
overcome a mild genetic protective effect. And I am sure that 
when it comes to the vulnerability to alcoholism we are going 
to find very interesting interactions of this sort as well.

                          drinking and driving

    Mrs. Lowey. I really appreciate that and I am very 
interested in your statement as well, where you are pursuing 
research on reducing drunk driving, understanding the effects 
of alcohol advertising on our nation's youth, improving 
adolescent alcohol treatment and clarifying the health effects 
of moderate drinking.
    I guess I have been the villain today. There is a full-page 
ad taken by the liquor industry, the beer industry specifically 
against me. I feel so strongly that the alcohol abuse is such a 
cost to our nation but if people are going to drink they should 
just get their hands off the wheel of a car.
    And they are going to have to do what they want about their 
own alcohol problems and hopefully we can get some additional 
research to help them, but at least they should get their hands 
off the wheel of the car and I, frankly, feel that the 
government that acts in so many ways to move legislation 
forward should take positive action in that direction.

                           clinical research

    Another totally unrelated question. I have been very 
interested in what we can do to stimulate more clinical 
research, certainly in this area and reverse the steep decline 
in MDs seeking research careers. There is concern that has been 
brought to our attention that psychiatrists are not being 
trained as researchers, specifically as clinical researchers. 
Could you just share with us what your institute is doing to 
encourage more psychiatrists to go into research?
    Dr. Gordis. Sure.
    We are very interested in this and, of course, we have 
participated with the American Psychiatric Association by 
bringing research to the meetings annually and meeting with 
young residents in psychiatry to interest them in research 
careers. Dr. Varmus, in his introductory remarks at his hearing 
a couple of weeks ago, of course, spoke about the newK 
mechanisms which are designed to increase the amount of clinical 
researchers who need the opportunity and support to learn how to do it 
right. And we are participating in that.
    Of course, we are a small institute so that we do not have 
large numbers of grants but we will be increasing the number of 
the new mechanisms, both the one that succeeds the K08 where 
several psychiatrists already have them with us as well as the 
middle level K24s for the mid-career people.
    And to the degree that it fits proportionally in the size 
of our institute, we will be very much going in that direction 
as well.

           informing physicians and health care professionals

    Mrs. Lowey. In a related question how do you provide 
physicians and other health professionals with the latest 
research findings? I often wonder what kind of delay there is 
from science to the bedside, from research science to the 
bedside?
    Dr. Gordis. Well, there are various avenues for doing this. 
And the physicians and the health professionals are not the 
same folks, as you know. The physicians, generally read medical 
literature. So, that is certainly one route.
    Most of them do not read the research literature. So, even 
there, there is a translation step from the research to the 
clinical literature, the standard medical journals. And for the 
people who are other health professionals, for example, 
counselors, social workers, or psychologists who are working in 
treatment programs, their literature has to be somewhat 
different. And for that reason we have a wide variety of 
publications.
    I mentioned before our physicians' guide, and we have 
publications for patients, both in English and Spanish about 
drinking and about drinking in pregnancy. For the counselors we 
have a variety of publications, for example, Alcohol Alert, 
which is a pamphlet circulated to about 100,000 people all over 
the country four times a year. It is designed to translate for 
the lay person or the educated lay person the findings of 
research in relatively non-technical ways.
    And, of course, we meet with a variety of constituency 
groups representing the various people throughout the year 
where people from the research community as well as from the 
Institute present the latest fruits of research.
    One interesting thing which we have afoot now are 
discussions in New York with the State authorities on alcohol 
and drugs about an interesting thing we would like to do. The 
commissioner came to us and asked for some help to see how the 
fruits of the research could be translated more effectively 
into treatment not only because it is a good idea but because 
it is a cost saving idea.
    We have been working on setting up a conference which we 
believe we will have next fall mostly for senior people who 
determine policy in their treatment programs. They are the ones 
who decide whether naltrexone or acamprosate is going to be 
used in the program and bring in new methods instead of the 
traditional old ones.
    In addition to that discussion--that is coming along fine--
are discussions to choose two or three programs who have 
volunteered to be demo programs in which we, with the help of 
some of our experts in clinical research, would actually go 
into the treatment programs and see if we can help them 
incorporate some of the new ideas and treatments into their 
programs.
    And we are very much looking forward to seeing that this 
comes to fruition.

                      stopping unhealthy behaviors

    Mrs. Lowey. Mr. Chairman, I just wanted to make one, brief 
comment apropos our conversation before about our children and 
smoking. We tend to personalize so many of these issues. The 
pamphlets concerning alcohol abuse and the damage to one's 
health are very clear and they have been out there a long time.
    And, speaking for my daughter who recently had a child, 
boy, she didn't have a drink for about a year-and-a-half when 
she became pregnant and also now that she is nursing. There was 
no question. And yet, these kids know or they should know that 
alcohol abuse can cause them bodily harm in so many other ways. 
If not, are we doing something wrong?
    And, so, for another time, I think it would be interesting 
to pursue the fact that when there is a powerful incentive, 
boy, they stop. But otherwise, we are not curbing drug and 
alcohol use as effectively as we should.
    I thank you for your indulgence.
    And thank you, Dr. Gordis.
    Mr. Porter. Thank you, Mrs. Lowey.
    Ms. Pelosi.
    Ms. Pelosi. Thank you very much, Mr. Chairman. Before I 
commend Dr. Gordis for his work, I want to commend my colleague 
for her leadership on this issue. Villain she may be to some, 
but heroine to most of us for her leadership on this issue. I 
am very proud of that attack they made on you this morning in 
the paper. [Laughter.]
    It demonstrates how effective you are on this issue and how 
necessary your initiatives are on it. Thank you. And as we 
compare photographs of our grandchildren, we all have a 
different perspective on some of these issues, and it is 
interesting to see what the responsibility is from a mother to 
a child in terms of carrying a baby and being responsible, 
knowing what we know today about the price that would be paid 
by a mother drinking excessively while pregnant.
    Dr. Gordis, thank you for your leadership. I am sorry I 
missed Dr. Leshner's presentation from National Institute on 
Drug Abuse, because his work is a priority for our office and 
always has been, and I commend him for his leadership.
    I would like to submit some questions for the record to 
him, Mr. Chairman.

               alcoholism: disease or voluntary behavior?

    Welcome, Dr. Varmus, again. And, Dr. Gordis, for your work. 
I wondered if any of you saw Nightline last night, because on 
the show it opens up by policemen banging in the door of 
someone's home. And the point is, as they said, police don't 
break into the homes of people who have cancer and they don't 
break into the homes of people who have heart disease or have a 
heart attack, but they break into the homes of people who have 
an addiction, whether it is a drug addiction--and then they go 
on further into the discussion about alcohol addiction.
    Perhaps you saw the show. If I mischaracterize it, please 
stop me. The point was that this is a health problem that 
America is facing, not that people are not responsible for 
their behavior, but nonetheless it is a health problem that 
they are facing. Even one of our colleagues was on the show as 
a person who had had a problem with alcohol, and from his own 
firsthand experience was talking about how the insurance 
industry, and how we as a society treat and regard people with 
an alcohol or a drug addiction.
    And I was thinking at the time what the Congress had done 
about the disabilities issue as relating to people with 
addiction with alcohol, which we have discussed here before, 
and I wondered, I know that we are each of us responsible, but 
then you have talked about the genetics of some of this. But do 
you think that as a society we should be addressingthis issue 
completely differently as an affliction that people have? How much is 
behavior, how much is preordained?
    Dr. Gordis. You have asked a question, one of the 
profoundest issues in our fields, not only ours but the field 
that Dr. Leshner deals with, and that has to do with what kind 
of an affliction is it, since there is obviously some sort of 
volitional component to the behavior? After all, the muscles 
that you lift a drink to your mouth with are the same ones that 
you swing a baseball bat with, so they are called voluntary 
muscles.
    And I don't want to take too long at this, except perhaps 
to make two points briefly, and if you would like me to enlarge 
on that some other time I would be very happy to do so, either 
in writing or personally.
    At what point does alcohol use become involuntary? I think 
there is a trajectory in life where the initial exposure and 
the initial choice of using it is really a voluntary event. And 
so to what degree are you responsible for becoming alcoholic if 
you start drinking?
    Well, if you know nothing about anything, then probably you 
are not responsible at all. If you have a strong family history 
of alcoholism, I would say that it is the job of society or the 
parents, or yourself if you are 17 or 18, to realize that you 
are at risk. Therefore even at that point, drinking should be 
considered very seriously and maybe reflected on carefully if 
it begins to escalate.
    But as we move from this initial voluntary stage into the 
area of affliction or disease or disorder or whatever you want 
to call it, we are talking about voluntary behavior in a very 
narrow sense, but voluntary behavior determined by a 
motivational state which is so severe that it displaces the 
normal judgment that we have with voluntary behavior.

                               addiction

    Now several of you mentioned the smoking issue and how 
difficult it was for your own offspring to stop, and we have 
all seen that in our families. It always surprises me to see 
how often the public can understand how difficult it is to stop 
smoking, and yet they cannot translate that into addictions 
which are equally strong and understand how difficult it is to 
stop using cocaine or alcohol.
    So we have a bit of a problem there in which the smoking is 
understood to be a hard habit to kick and the other ones are 
not, which is interesting, but nevertheless it is the same 
thing. We have seen people who are perfectly responsible, 
intelligent, competent, respected people, who can't give up 
smoking because there is a motivation here to use tobacco which 
defies their own judgment and knowledge, and that is what 
addiction is really all about.
    That is what we are trying to explain with the science, the 
kind of questions that I have been asked before by Mr. Porter: 
these various brain circuits which determine the state of 
desire for the substance or a feeling of deprivation when it is 
not there, which are so overwhelming to the people who are 
afflicted that even though there is a voluntary component to 
obtaining it and buying and so on, we are dealing with a very 
disordered motivational state, and I think that is the issue 
which you are trying to understand.
    Ms. Pelosi. I am glad you brought up the smoking issue, 
because I believe this is one of the points that they made last 
night, and that is, people smoke and then some get lung cancer, 
there is never any question that their insurance is going to 
cover their lung cancer if they have, you know, a comprehensive 
health insurance policy, even though smoking which was a so-
called voluntary action caused their lung cancer.
    So if we treat, if the insurance covers that, then why 
wouldn't there be some transfer over to treating addiction or 
the consequences of addiction, as well?
    Dr. Gordis. Well, the consequences of addiction are being 
treated. You see, the analogy----
    Ms. Pelosi. By insurance, by private insurance?
    Dr. Gordis. Sure. I mean, if you get cirrhosis of the 
liver, or you fall off a fifth floor story from drinking, you 
are still going to get covered by your insurance.
    Ms. Pelosi. Yes. Okay.
    Dr. Gordis. The issue comes up with the treatment of the 
behavior itself, the drinking or the smoking or the drug 
addiction.
    Ms. Pelosi. Right, exactly.
    Dr. Gordis. The complications are not the issue. The 
complications are being treated, whether they are lung cancer 
from smoking, cirrhosis of the liver from alcohol, or maybe a 
stroke from a cocaine use, those complications are not where 
the issue is. The issue is the behavioral treatment itself, and 
that is where the difficulties lie.
    Ms. Pelosi. Yes, you are exactly right. Right. So do you 
have an answer for that?
    Dr. Gordis. Yes. I think that science should dictate public 
policy, and science says that treatment for the addictions 
ought to be covered like any other illness.

                          health services plan

    Ms. Pelosi. I completely agree with you. I thank you for 
that answer.
    Some other more specific questions, and forgive me, if 
these have been asked I will just read the record.
    I understand that the NIAAA National Advisory Council has 
just published an excellent document called ``A National Plan 
for Alcohol Health Services Research.'' Can you tell us about 
the major recommendations included in the plan and how you 
intend to respond to those recommendations?
    Dr. Gordis. Yes. Well, the document you are referring to is 
here in the executive summary, but actually the committee which 
created this was created by our Advisory Council in order to 
guide us in how we should study the issues related to health 
services research: access, financing, managed care, and so on.
    And this document does provide an extensive list of 
recommendations of which topics would be best to spend the 
Institute's money on, and they are a guide to some of the 
research which is already going on now. I think it is a very 
extensive document. I would be very happy to give you more 
details of that for the record, in fact, supply you with an 
executive summary of the proposal itself.

                            college drinking

    Ms. Pelosi. Oh, I would love to see that. Thank you. Thank 
you.
    What does your Institute-supported research tell us about 
changing campus drinking culture? And perhaps you did address 
this earlier.
    Dr. Gordis. The college drinking issue is a very big one. 
We have studies showing the various potential interventions 
that have been suggested to be useful on college campuses, both 
as far as changing the environment to a certain degree, but 
largely individual-based ones with college students to teach 
them what normal patterns are, to relieve them of 
misapprehensions as to how much their buddies are drinking, to 
explain to them what the effects of drinking on their risk for 
auto accidents and bad school work is, and so on.
    The fact of the matter is, we don't have a good research 
answer to a potent intervention on college now, in my view, and 
for that reason we are doing several things. The first thing 
is, we have a Request for Applications on this very topic.
    The second thing is, we are creating a subcommittee of our 
council, very much analogous to the one you just asked about in 
relation to health services research, on the issue of college 
drinking. This subcommittee will be chaired by Father Malloy, 
the president of Notre Dame, who was the head of the committee 
from CASA, Mr. Califano's unit in New York which published a 
study on college drinking, not terribly research-based but very 
reasonable. Father Malloy is going to be co-chairing our 
Council subcommittee, he is a member of our council--together 
with Dr. Mark Goldman, who is professor of psychology in 
Florida.
    And we are going to be devoting the next couple of years to 
having a thorough analysis of what the research needs and 
opportunities are on this issue. Following that, we will embark 
in a major program of research in this area.
    I think we have bits and pieces of it, but frankly, judging 
by what we read about what is happening on college campuses, I 
cannot give you a totally convincing, plausible answer of what 
we ought to be doing. And partly that isbecause of the 
heterogeneity of college campuses: some are rural, some are urban, some 
are church-run, some are not, some are private and have a different 
ethnic group, and so on. I think as a result of these deliberations we 
will be in a much better position to create a program of research which 
will give us much-needed answers.
    Ms. Pelosi. I think it is so very, very important, and I am 
pleased that you are going down that path.
    I did have some more questions about how many of your 
trainees or young researchers are psychologists. I know a third 
of your grantees are psychologists, which I will submit for the 
record, also.

                       alcohol research spending

    Mr. Porter. Ms. Pelosi, let me ask a question of Dr. Varmus 
at this point, because we have been here for the last hour 
talking about the effects on individuals, the huge burden on 
society, how it affects young people, and yet we spend in NIAAA 
less than half of what we are spending in NIDA, where the 
effects are narrower and not nearly as great on society.
    Why are we spending so little on alcohol abuse and so much 
on hard drug abuse, and shouldn't we at least be spending the 
same amount, considering that alcohol is a much more abused 
subject with much greater burdens on society?
    Dr. Varmus. Dr. Gordis welcomes that question. [Laughter.]
    I think you are raising a legitimate issue. On the other 
hand, we have to recognize that the problems that the NIDA is 
facing are more numerous--there are a number of drugs of abuse 
that NIDA is studying, ranging from heroin to cocaine to 
tobacco. Moreover what happens over the course of the history 
of an institute is the development of a cohort of investigators 
who may be doing things that have very wide applications to 
research across many domains. Certainly Dr. Gordis and Dr. 
Hyman and others depend a great deal on some of the 
neuroimaging and extramural activities that are being carried 
out through NIDA, and we see certainly a tremendous collection 
of exciting neuroscience going on within the Institute.
    Some would argue that understanding tobacco addiction in 
particular has enormous effects on health, that I think it very 
hard to compare the effects of drug or tobacco to alcohol. If 
one looks at the toll that any single behavior exerts on 
health, tobacco is the lead. There are of course other kinds of 
effects that alcohol has on our society. These things are very 
hard to compare, and I would rather try to evaluate the budget 
in relation to the quality of the science that is being done.
    Mr. Porter. Well, I am sure there are explanations and 
reasons, but it seems to me that--and this predates your 
stewardship by a great deal----
    Dr. Varmus. But I would agree with you, Mr. Porter, that 
there is a great more to be done focusing particularly on the 
kinds of results that Dr. Gordis brings to us today, and that 
public advocacy of the kind we talked about earlier with Dr. 
Leshner is particularly important in getting the message out 
about alcohol abuse in adolescent years.
    Mr. Porter. Yes, I think perhaps we ought to really look at 
what we can do in this area, because the effects on the economy 
and society are very large under the jurisdiction of Dr. 
Gordis, and I think we probably have not given the kind of 
attention overall within the government or the kinds of 
resources that we ought to place on this very, very serious 
problem for our country, and we ought to look at it again.
    Dr. Gordis, thank you for the fine job you are doing. We 
thank you for your testimony this morning.
    Ms. Pelosi. Mr. Chairman?
    Mr. Porter. Ms. Pelosi.
    Ms. Pelosi. Would the gentleman yield?
    Mr. Porter. Yes, of course.
    Ms. Pelosi. Just one point. I didn't think the point was 
that there would be less for NIDA----
    Mr. Porter. No, no, no.
    Ms. Pelosi [continuing]. But more for NIAAA.
    Mr. Porter. Exactly, exactly.
    Ms. Pelosi. So we thank you, Mr. Chairman.
    Mr. Porter. Thank you, Dr. Gordis.
    Dr. Gordis. Thank you, Ms. Pelosi.
    Mr. Porter. The subcommittee will stand in recess until 
2:00 p.m.
    [The following questions were submitted to be answered for 
the record:]


[Pages 1404 - 1480--The official Committee record contains additional material here.]



                                         Wednesday, March 11, 1998.

    NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

                               WITNESSES

DR. PHILLIP GORDEN, DIRECTOR
L. EARL LAURENCE, DEPUTY DIRECTOR
CHARLES ZELLERS, FINANCIAL MANAGEMENT OFFICER
DR. HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF 
    HEALTH AND HUMAN SERVICES

    Mr. Porter. The subcommittee will come to order. We 
continue our hearings regarding the budgets of the National 
Institutes of Health and are pleased to welcome Dr. Phillip 
Gorden, the Director of the National Institute for Diabetes and 
Digestive and Kidney Diseases at NIH.
    Dr. Gorden, it's wonderful to see you.
    Dr. Gorden. Thank you, sir.
    Mr. Porter. Will you introduce the people who are with you 
and then proceed with your statement, please?
    Dr. Gorden. Yes, Mr. Porter. To my far left is Mr. Charlie 
Zellers, our Budget Officer; to my immediate left is Mr. Earl 
Laurence, the Deputy Director; and of course, you know Dr. 
Varmus and Mr. Williams.
    Mr. Chairman and Members of the Committee, I am pleased to 
testify before the Committee on behalf of the National 
Institute of Diabetes and Digestive and Kidney Diseases. The 
President in his FY 1999 budget has proposed that the NIDDK 
receive $927.5 million, an increase of $69 million over the 
comparable figure of 1998. Including the estimated allocation 
for AIDS, total support proposed for NIDDK is $944.3 million, 
an increase of $70.5 million over the FY 1998 appropriation. 
Funds for NIDDK efforts in AIDS research are included within 
the Office of the AIDS Research budget request.
    A major goal of the NIDDK is to make investments in 
innovative technologies and discoveries that can be directly 
applied to patients in clinical trials. These advances then 
have immediate application to patient care and to public 
health. This general process can be illustrated by examples in 
diabetes that clearly point to research advances and help chart 
our further progress.
    One of the most important objectives of our current 
research investment is to reduce the intensity and the duration 
of an individual's exposure to high levels of blood glucose and 
develop other risk reducing therapies. I'd like to give you one 
example of this approach taken from our diabetes research 
agenda. First, I must point out that diabetes is the most 
common cause of end stage renal disease, comprising one third 
of end stage renal disease in diabetic patients.
    I'd like to call your attention to the chart that you see 
on my left. This chart plots on the vertical axis the percent 
risk of developing renal failure in a type 1 diabetic patient 
as a function, on the horizontal axis, of years of exposure to 
diabetes risk. Please note the top blue line. This represents 
the cumulative risk of developing renal failure for a diabetic 
patient on general maintenance treatment. You note that this 
risk approaches almost 40 percent.
    Now, if you will focus on the purple line just below, you 
will see the result of one of our recently completed clinical 
trials. A drug that was first introduced for the treatment of 
hypertension, called an ACE inhibitor, was found in 
experimental animals to interdict the course of diabetic renal 
disease independent of any effect that it had on blood pressure 
or the blood glucose concentration. Here you see the results of 
administering this drug at the earliest stages of renal 
disease. You see that it markedly decreases the risk of renal 
failure in these patients.
    Incidentally, a very recent analysis of this study has 
indicated that this maneuver alone saves over $189 million per 
year. This we call a form of tertiary prevention. Tertiary 
prevention means that the agent affects the end organ per se, 
that is, the kidney, independent of any systemic effect, that 
is, an effect on the blood glucose concentration or of the 
blood pressure. It's a major goal of our further technology 
development.
    Now, if you'll focus on the green line, you will see the 
results of adding to this study the results of our Diabetes 
Control and Complications Trial (DCCT). The DCCT was a form of 
secondary prevention in that it addressed the question of blood 
glucose control and demonstrated clearly that rigid control of 
the blood glucose concentration markedly ameliorates the 
complications of diabetes, not only with respect to the kidney, 
but also with respect to the eye and the nervous system.
    You see the results of these two trials are additive. 
Further, it is important to note that these trials are 
completed and their findings have been introduced into medical 
practice, but we must certainly continue to make them 
applicable to all patients with either type 1 or type 2 
diabetes.
    Now, I'd like to call your attention to the dashed red line 
at the bottom. This represents an ongoing trial of primary 
prevention. Primary prevention means that we have discovered 
ways to recognize the pre-diabetic state and can act to 
interdict the development of diabetes per se. I must be clear. 
We have no actual results from this study and the data shown 
are drawn from a model based on the statistical characteristics 
of the study. If we were to achieve the statistical result that 
would give us a positive study, then you would see the results 
shown here. To reiterate, in each of these three trials it was 
essential that we establish the technology for the intervention 
and the knowledge base required and that we demonstrate the 
efficacy of the approach directly in patients.
    This general approach is basically something that we can 
use for a number of other examples, but we wanted to illustrate 
it for type 1 diabetes. We could do exactly the same for type 
2, except we would refer to our Diabetes Prevention Program 
which is a separate study of primary prevention in type 2 
diabetes.
    Now with these studies that are completed and the one 
ongoing, we must improve on these successes. Patients and their 
families want better technologies that will produce easier and 
more effective treatments. To expand our therapeutic tools, we 
will pursue innovative strategies for achieving the diabetes 
research results and advances of the future.
    Let me give you just a few examples of these approaches and 
goals. We will continue to exploit the mechanism of 
interdicting immune destruction of the beta cell in Type 1 
diabetes. We're using transgenic technology to create animal 
models to pinpoint mechanisms that will modulate the immune 
system, first in animals and then in patients who are at high 
risk for developing Type 1 diabetes.
    We will attempt to identify viral or other environmental 
factors that may cause Type 1 diabetes including retroviruses.
    We will attempt to find factors that regulate the tissue-
specific generation of insulin-producing cells including the 
possibility of stimulating a progenitor cell to produce insulin 
after mature cells have been destroyed.
    We will attempt to engineer insulin-producing cells using 
constructs that will confer specific properties on the cell, 
such as glucose-sensing or glucose recognition or other similar 
regulatory steps.
    To close the gap in the difficulty of administering 
insulin, we will foster research on a variety of glucose-
sensing technologies. Further approaches to understand the 
cause of diabetes and its complication will be pursued by 
genetic techniques. Six known genes are involved in several 
forms of Type 2 diabetes. And several large-scale studies using 
``high through-put genomics'' are attempting to find new genes 
and more conventional forms of Type 1 and Type 2 diabetes.
    We are also looking for diseases that relate to the 
complications of the disease such as diabetic renal disease. We 
will disseminate important research findings through the 
National Diabetes Education Program, which is making special 
efforts to reach minority populations disproportionately 
affected by Type 2 diabetes.
    For support of this program and for all of our activities 
to improve the health of minorities through NIDDK research, I 
would like to extend our sincere appreciation to Congressman 
Stokes. On a personal note, Mr. Stokes, I would like to thank 
you for your persistence and your patience and I'd like to 
assure you that the very high goals that you've set for us will 
be met.
    Mr. Stokes. Thank you very much.
    Dr. Gorden. Let me just give you a few other examples of 
important research needs and investments that we plan to 
pursue. Obesity is a major risk factor for Type 2 diabetes, 
lipid disorders, hypertension, cardiovascular disease and 
cancer. Through basic research, we've discovered multiple 
genetic loci for obesity in animals--with human parallels. The 
most dramatic discovery in the field of energy regulation was 
the identification of the first obesity gene and its protein 
product leptin.
    In Fiscal 1999, we will continue to expand our programs to 
explore the discovery of obesity genes and the complex 
neuroendocrine system that regulates both food intake and 
energy utilization. Most importantly, we are making plans to 
initiate a major clinical trial which we hope will show that 
the numerous health risks posed by obesity can be reduced by 
voluntary weight loss.
    Other diseases within the NIDDK mission on which we will 
intensify research include diseases such as hepatitis C, food-
borne illnesses such as hemolytic uremic syndrome, and urologic 
diseases. We're promoting enhanced efforts to understand the 
biology of the bladder and the pelvic floor, and susceptibility 
to infection and inflammation--research that is very relevant 
to interstitial cystitis, urinary tract infections and urinary 
incontinence.
    Concomitantly, we are intensifying research on the biology 
of the prostate, which includes studies of benign prostatic 
hyperplasia, prostatitis, and prostate cancer, which we're 
conducting in collaboration with the National Cancer Institute.
    In cystic fibrosis, we'll be exploiting newly discovered 
concepts about how chronic infection is initiated and 
perpetuated. In hematology, we have dramatic advances in our 
understanding of the iron-overload diseases, such as 
hemochromatosis, and new opportunities for treating these 
diseases.
    Underpinning these and other NIDDK programs to combat 
disease will be our continued strong support of basic research, 
which is the wellspring for clinical and medical advances.
    Mr. Chairman, I'd be very pleased to answer any questions 
that you and the committee may have.
    [The prepared statement follows:]


[Pages 1485 - 1491--The official Committee record contains additional material here.]



                       kidney disease of diabetes

    Mr. Porter. Dr. Gorden, thank you very much for your 
opening statement.
    Could we go back to your chart for just a second? I have a 
related question. If you continued the chart out to the right, 
it looks as if, in Type 1 diabetes even with no interventions 
at all that the chart would indicate less than a 50 percent 
chance of developing kidney disease. Is that correct?
    Dr. Gorden. That's exactly correct, Mr. Porter.
    Mr. Porter. Is that the same for Type 2 diabetes?
    Dr. Gorden. It is the same for Type 2 if we take a very 
high-risk population. If we take the usual population of the 
entire mixture of the country, the risk is even lower.
    Mr. Porter. It's a bell shaped curve in other words.
    Dr. Gorden. It's a bell shaped curve in the sense that if 
you don't develop diabetric renal disease within 20 to 30 
years, you essentially don't develop it. This a very 
interesting problem: how we distinguish an individual who will 
develop renal disease from one who will not is unknown to us at 
the present time and that's a major subject that we're taking 
up.
    Mr. Porter. Does this chart represent seven years and does 
each line mark a year?
    Dr. Gorden. No. The chart, the reason I've actually taken 
the numbers off this chart is because it's an attempt to 
compress all four data sets onto the same scale, so that 
patients enter this model at different times.
    If you take, for reference, the blue line, which is the 
untreated group, the usual way that that's portrayed is over 
about a 20 to 30 year exposure to diabetes. That is the period 
in which people develop all the complications including renal 
disease.
    Mr. Porter. Am I correct that you could look at half that 
length of time and if you hadn't developed diabetes by that 
time your risk begins to decline? Or does it begin to decline 
after the full length of time you're describing?
    Dr. Gorden. It is likely that, if you're looking at the 
population at large, you would not know which individual would 
develop risk until you got out to approximately 20 years.
    In other words, you have markers that will begin to show up 
earlier, well before deterioration in kidney function and they 
are important markers for therapeutic intervention. In fact, in 
the second line the therapeutic intervention only started when 
patients had obvious renal disease and that's very late in the 
course of diabetes.
    Mr. Porter. And the tertiary treatment is aimed not at 
diabetes, but at the effect of diabetes on the kidneys?
    Dr. Gorden. Exactly. And this is exactly the approach we're 
taking in the eye. There are new agents that are being tested 
now to try to interdict the complication at the tissue level 
itself, independent of what we can do for overall metabolic 
control. That is a very powerful way to add to your therapeutic 
efficacy.

                     eye complications of diabetes

     Mr. Porter. You can do the same thing for the eye?
    Dr. Gorden. You can do the same thing for the eye but not 
with this particular therapy--with a different therapy.
    Mr. Porter. Different therapy.
    Dr. Gorden. Exactly.
    Mr. Porter. When you go to secondary treatment, you're 
adding glucose control?
    Dr. Gorden. Exactly.
    Mr. Porter. And at the primary treatment level you have 
those two plus----
    Dr. Gorden. Plus the prevention of hyperglycemia itself. In 
other words, you find an individual that you know will develop 
diabetes within three to five years. That person has normal 
blood glucose concentration. You do an interdiction of some 
kind and you prevent hyperglycemia from occurring. The line is 
drawn indicating the expected success rate based on the 
statistics of the study. So you can see that what you achieve 
by all three of these means of prevention is really quite 
dramatic. This is really a major goal because to reduce the 
fundamental risk of complications is our primary goal in 
diabetes research at the present time. If we can interdict 
onset of the entire disease, that of course is the major goal, 
but this is something that we don't have evidence for at the 
moment.
    Mr. Porter. Well, aren't there other risks as well? Kidneys 
and eye complications are certainly two of the most prevalent 
ones, but what about heart disease, stroke?

                    diabetic heart and nerve diease

    Dr. Gorden. Yes.
    Mr. Porter. How are we going to interdict those 
complications?
    Dr. Gorden. The health issues with respect to the 
complications that I've described are what we call 
``microvascular.'' Those are diabetes-specific complications. 
They do not occur in the absence of hyperglycemia at all. The 
risk for those begins when hyperglycemia begins.
    ``Macrovascular'' complications include vascular disease, 
myocardial infarction, stroke, and peripheral vascular disease. 
Fundamentally all of us are incurring some risk for these over 
a lifetime; diabetes imposes a greater risk.
    Now the idea here is to use all of the strategies that 
we've already learned, such as lipid control and hypertension 
control which have a dramatic effect, even more dramatic in 
diabetics, and to add glycemic control to that. That strategy 
is the subject of a major study that we're planning to do in 
collaboration with the Heart Institute and the subject of other 
studies that are on-going, either of a relatively short nature 
or studies that we're actually supporting in England right now 
to try to get a bit of a handle on how to approachthis. This is 
a major area that we plan to attack now, to see if we can't reduce the 
cardiovascular mortality and morbidity of diabetes.
    Mr. Porter. Dr. Gorden, how long has NIDDK been in 
existence?

                     progress in diabetes research

    Dr. Gorden. We will be celebrating our 50th anniversary in 
the Year 2000. The bill creating the NIDDK was signed into law 
by President Truman in 1950.
    Mr. Porter. Given that we have been doing diabetes research 
for a long time, where are you on the scale of optimism about 
real breakthroughs? Are we making any real progress? Is this 
still as elusive as it was 50 years ago? Are we close to where 
we are really going to see some progress made? Why don't you 
give us a greater description regarding diabetes.
    Dr. Gorden. Mr. Porter, I think I could illustrate that to 
some extent by the chart again. I think what you see is a 
measure of the progress we've made. We know that with careful 
glucose control, as was achieved in the Diabetes Control and 
Complication Trial, we can markedly change the Complications 
rate. And if we could reduce blood glucose levels just a little 
bit more, if we could do just a little bit better, we would be 
approaching this primary prevention line. You see the 
difference between the green and the dashed line is not all 
that great. That's where we're trying to get to.
    I think we've made a considerable amount of progress. What 
we've got to do now is we've got to close the gap in the 
difficulty of achieving that. We know what can be achieved. We 
have achieved it. But we've got to close that gap in 
technology. For instance, we've got to have better ways to 
administer insulin or we've got to close some sort of glucose-
senor loop, or we've got to have a cell-based therapy. We've 
got to now use these sorts of technology which I think are 
things that we've only been able to do for the last several 
years. So I think we know what can be achieved and I think we 
have all of the ingredients ready to go to accomplish the 
closing of that loop.
    Mr. Porter. In talking about glucose control, are you 
talking only about pharmaceuticals or are you talking about 
diet, exercise, control of weight? Is that all that's in that 
picture?
    Dr. Gorden. If I were to have used a Type 2 diabetes model 
rather than the Type 1, I would have emphasized much more the 
issue of diet, exercise, and drugs. We do have a lot of 
evidence for the effect of diet, a lot of evidence for the 
effect of exercise, and we have at least four classes of drugs, 
including one very new one that's been introduced in the past 
year, that are quite efficacious.
    Mr. Porter. Is that Rezulin?
    Dr. Gorden. this is the troglitazone class--yes, Rezulin is 
the brand name. It has been introduced just in the past year. 
It's the first of the so-called insulin sensitizing drugs. That 
is, it decreases insulin resistance and it's the first time 
we've had a pharmacologic agent that we could use for that 
purpose, which is very, very important.
    So we have the ability to achieve these things or at least 
we know what will happen if we can achieve them. Now what we've 
got to do is to show that we can decrease that exposure to 
hyperglycemia further and we're attempting this prevention 
strategy. In other words, rather than to try a variety of other 
therapeutic strategies, we're going directly to an attempt at a 
prevention strategy for both Type 1 and Type 2 diabetes. That 
is the on-going program at the present time.

                          genetics of diabetes

    Mr. Porter. Is there a lot of evidence that diabetes is 
genetically based?
    Dr. Gorden. Yes, genetically based in the sense that it's a 
complex genetic disease. What we mean by that is that it is not 
a disease caused by a single gene, except in rare forms of the 
disease--that's where I mentioned we know what six of those 
genes are. Those reare forms represent maybe 5 percent of all 
of diabetes. Those are specific syndromes that are related to 
diabetes, but the vast majority of people with so-called Type 1 
and Type 2 diabetes have presumably a number of genes that are 
interacting with each other and we're attempting to learn how 
this system works. It's a major issue for multiple diseases 
such as hypertension, dyslipideima, Alzheimer's disease and a 
whole variety of complex diseases. So this is an approach, and 
in diabetes, we're making a considerable amount of progress 
vis-a-vis all of the other complex genetic diseases, but it's a 
very difficult and complex problem.
    Mr. Porter. Thank you, Dr. Gorden. Mr. Stokes?
    Mr. Stokes. Mr. Chairman, I think Mr. Hoyer was here ahead 
of me.
    Mr. Hoyer. No, no, go ahead.
    Mr. Porter. I think you were both here at the start of the 
hearing.

                            type 2 diabetes

    Mr. Stokes. Thank you very much, Mr. Chairman. Dr. Gorden, 
nice to see you and thank you for your very kind remarks. I 
appreciate that.
    Let me start with the Type 2 diabetes where you mentioned 
the clinical trials. Can you tell us a little bit about your 
interventions there, where the trial stands, and when we can 
expect the results?
    Dr. Gorden. What we refer to as the Diabetes Prevention 
Program is a study that is underway that will include 4,000 
Type 2 diabetics, at least 50 percent being minority. This is 
an example in which minorities are clearly over-represented as 
patients with Type 2 diabetes, and so, they are over-
represented in the trial. We have to be certain that our 
strategies are going to be applicable to each particular group 
that participates.
    This study has four arms. It has a control arm. It has an 
arm related to intense diet and exercise that Mr. Porter just 
mentioned. It has two drug arms. One is using this new insulin-
sensitizing drug Troglitazone and another drug that's been 
around for a little bit longer, called Metformin. We want to 
see if a strategy using the best diet and exercise program 
possible will achieve our goals of interdicting the conversion 
of so-called ``impaired glucose tolerance'' to overt diabetes, 
or whether a pharmacological approach will be required. So 
we've covered essentially all of those bases in this trial and 
it's moving forward. The recruitment has gone extremely well 
and we think that it will take about another four years before 
we will actually have enough definitive results to present.

                    african-americans with diabetes

    Mr. Stokes. Both in your formal statement this morning and 
in your presentation here, you've mentioned the serious 
situation regarding African-Americans. According to your 
opening statement, between 1980 and 1994, the number of 
African-Americans with diabetes rose 33 percent, which is three 
times the rate of increase for all other Americans. In terms of 
trying to reach that target group, tell us what you're doing to 
address that type of national situation.
    Dr. Gorden. I think there are three kinds of approaches, 
Mr. Stokes. First of all, we're very hopeful that the 
fundamental basic research that we're doing to try to 
understand insulin resistance and insulin secretion and the 
broad aspects of Type 2 diabetes will be even more applicable 
because of the higher risk in the African-American population.
    The second major tool that we're using is this prevention 
trial I've just described and the information that we will gain 
from it.
    The third is our newly inaugurated National Diabetes 
Education Program which will have a specific minority component 
that actually is going to be added this summer, to disseminate 
the information that we have and everything that we know about 
controlling moderate to mild diabetes, which we think we can do 
very well. We must be certain that the information base is out 
there where it really counts. We believe that those combined 
strategies will have a major impact on this issue. That is our 
goal and that's what we're trying to achieve.

                    hypertension and kidney diseases

    Mr. Stokes. Dr. Gorden, let me ask you about hypertension 
related kidney disease. That obviously is another extremely 
tragic problem in the African-American community and I 
understand that you have a clinical trial underway relative to 
that.
    Dr. Gorden. Yes.
    Mr. Stokes. Can you tell us about it?
    Dr. Gorden. Yes. It was the recognition through United 
States Renal Data System that led us to understand that 
African-Americans who had hypertension developed renal failure 
at a rate that was markedly greater than any other population. 
We felt that we must find some way to interdict the course of 
this rapidly deteriorating renal disease. We inaugurated a 
clinical trial that basically has two different modalities of 
therapy. One modality is to try to understand what is the most 
optimal blood pressure for an African-American hypertensive 
patient. Is it what we call conventional normal or is it 
something that might actually be lower than that? That's one 
goal of this study.
    The second goal is to see if a different class of drugs may 
have a special effect, such as this so-called ``ACE inhibitor'' 
that I've described here, or other agents known as calcium 
channel blockers, or other types of drugs. There are at least 
three different types of drugs being tested and two different 
levels of blood pressure. We believe because we already have 
preliminary evidence in other situations that at least one of 
those two modalities is going to have an important effect, but 
we don't know which one. We really believe that this study will 
have a very important effect in ameliorating this incredible 
deterioration in kidney function that occurs once someone 
develops hypertension. We're very optimistic about this study 
giving us the kind of tool we need to interdict this problem.

                            obesity research

    Mr. Stokes. Let me ask you a little bit about obesity and 
diet pills. Can you tell us what type of research is being done 
on diet pills as it relates to persons trying to fight obesity, 
and diseases of that sort?
    Dr. Gorden. Well, Mr. Stokes, obesity is a major problem in 
this country, and there have been a number of attempts to 
develop pharmacologic agents that will interdict the course of 
obesity or that will ameliorate it, and will help people lose 
weight.
    Thus far there's been only very limited success and there 
have been some very difficult problems in terms of drug 
toxicity. We believe that we are beginning to focus on the 
technology that will allow us to move ahead with this long-term 
risk-reduction trial that I was discussing in the opening 
statement.
    But the fundamental issue in obesity is our lack of a good 
technology, and that distinguishes obesity research from what 
we've done in hypertension, what we've done in 
hypercholesterolemia, and what we're doing in diabetes. This 
lack of a technology to treat obesity has really been the major 
obstacle, but we're beginning to close ranks. The success in 
basic science in the last three or four years in obesity has 
been absolutely phenomenal. We're hoping that we can capture 
that exciting science and apply it to things that are going to 
be clinically relevant. We must do that because if we don't do 
something clinically relevant, we're not going to be able to 
get ahead of this problem. We're really working very hard to 
make this true. We believe that we're getting closer, but we've 
still got a way to go.
    Mr. Stokes. What about the relationship of genetics to 
obesity? Are we doing much there?
    Dr. Gorden. We are doing a considerable amount of research. 
The real breakthrough in genetics has come from animal genetic 
studies from which we've had some extraordinarily exciting 
findings. It turns out that we're beginning to find that a 
certain number of the genes that affect the animals also 
produce specific syndromes in patients, and that's the first 
clue that this approach may be a useful approach.
    In addition, we're beginning to apply what we call the 
``genomic approach,'' the ``whole genome search.'' This the 
sort of thing we're doing in diabetes, and that's being done in 
hypertension and a number of other diseases. We're getting to 
the point where we can actually do this kind of research in 
obesity, but obesity is a more difficult problem to attack 
genetically. We're really gratified about this analogy with the 
animal research that has been such a positive and useful thing. 
This gives us a lot of encouragement that we're moving in the 
right direction.
    Mr. Stokes. Thank you. Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Stokes. Mr. Hoyer.

                           Nutrition research

    Mr. Hoyer. Thank you very much, Mr. Chairman. Dr. Gorden, 
again, welcome to the committee.
    I am not going to have some questions on diabetes, but I do 
want to congratulate you and the Institute on the work that you 
are doing. Many of my colleagues will ask those questions. It 
is obviously one of the critical problems that confronts all of 
our constituents in our country.
    Doctor, the question occurs to me and I want to ask you 
some questions on nutrition, but one of the challenges that 
confronted us in Judy's illness was her inability to eat which 
is common, obviously, to cancer patients. I'm wondering if you 
do any work because one of the things that we tried to get was 
things to allow Judy to eat. She wanted to eat. She knew she 
had to remain strong, but it was incredibly difficult for her. 
Do you do any work on that issue? Obviously, it's not a 
digestive disease. It is, however, an inability to have any 
psychological inclination, I suppose, for intake and then an 
inability to digest and use the food that is taken to remain 
strong. I'm wondering do you do any work in this Institute on 
that issue?
    Dr. Gorden. Yes. This is an extremely important issue, Mr. 
Hoyer. There are really two fundamental issues here. One is the 
purely mechanical issue and that, of course, is a very 
difficult one. There are a variety of maneuvers that can be of 
some help. But the other one you refer to is really not 
mechanical, it is the simple situation of anorexia or simply 
not having any desire to eat.
    We're beginning, I believe, to understand something about 
what we call satiety or the regulation of why one wants to eat 
or when one feels satiated. Of course you could look at it the 
other way and say that one has no desire to eat.
    It is likely that a similar set of control mechanisms is 
involved in both of those directions, and we're beginning to 
understand control sites in the brain that appear to regulate 
that. For instance, just in the past few weeks, there have been 
some important papers published about new peptides that have 
been found or receptors for those peptides that have been found 
in an isolated, very small area of the brain. When applied in 
animal studies, these peptides can cause feeding behavior. We 
already know of a number of so-called ``neuro peptides,'' 
meaning these hormone-like products that can be isolated from 
nervous tissue, that will stimulate appetite or will inhibit 
appetite. It is very likely that this kind of research, which 
is partly related to eating disorders, partly related to 
obesity, and partly related to the kinds of problems that you 
refer to will be extremely important in helping us overcome 
these problems.
    It's a terribly important area that we see in cancer and in 
a whole variety of other diseases that will certainly yield, I 
believe, to this kind of research.
    Mr. Hoyer. Thank you. It was evident as we dealt with it 
that this was a very common problem and one which frustrated 
the doctors with whom we dealt very greatly.
    Dr. Gorden. Yes.
    Mr. Hoyer. I know how tough it was for Judy because she 
knew she had to eat and she couldn't eat.
    Dr. Gorden. Absolutely. That nutritional support is so 
terribly important for maintenance and it is almost impossible 
to provide in some cases other than through parenteral 
nutrition, which is another issue.

                          food-borne illnesses

    Mr. Hoyer. We ultimately went to that. Doctor, we mention 
in our report last year on E. coli, everybody is very concerned 
about E. coli, as well as other food-borne--obviously in our 
state, Pfeisteria, the fish, we worried about that.
    You were asked to report to us with recommendations for 
additional research that could be pursued. Can you tell us the 
status of that?
    Dr. Gorden. Yes, this report has actually, I was just 
informed this morning, been sent to the Congress. You should be 
receiving the report very soon. It is through clearance.
    This is a rather large issue. The real focus from the point 
of view of NIDDK was on an outbreak of food-borne illness 
caused by a special type of E. coli that particularly 
contaminates meat. It turns out that it causes a rather severe 
form of diarrhea, but in children, particularly young children, 
it also causes a renal disease called a hemolytic uremic 
syndrome, which can cause acute renal failure in children and 
can actually lead to end stage renal disease and tragically in 
some instances, to death.
    That's been the focus for NIDDK research. The National 
Institute of Allergy and Infectious Diseases has a larger 
program with respect to a whole variety of bacteria that are 
involved in food-borne illnesses, but both the Allergy 
Institute and NIDDK and NICHD have a focus on this particular 
E. coli. We have a series of grants that we've awarded to 
address this problem specifically. We are augmenting those 
grants through our research centers mechanism. We are 
establishing a core in one of Digestive Diseases Research 
Centers to address this problem. We plan to add to this by an 
initiative that we're going to be talking to several other 
institutes about in FY 1999. It's an area that we feel is very 
important, and we feel that our role is to deal with the 
disease per se in ways of trying to both treat, interdict or 
prevent the actual disease. And of course there are multiple 
other parts of the government--the Department of Agriculture 
and others--that are involved in the whole food safety program, 
and we actually are coordinated with them through the 
Department and through the Department of Agriculture.

                        nutritional assessments

    Mr. Hoyer. That uses my time up. You reference this as an 
aside and obviously a lot of others deal with this. Do you deal 
with preventive nutrition? We talk a lot about diet in terms of 
what's bad and also obviously what's good in terms of being 
healthful, in terms of practice, behavioral, we talked about 
that yesterday.
    Do you deal with that in nutritional assessment of 
populations. Have you been making such assessments as well?
    Dr. Gorden. Well, this is a trans-NIH issue and the NIDDK 
is the home of Dr. Varmus's Nutrition Coordinating Committee. 
So, although we're the lead institute for nutrition research, 
we actually coordinate this in a broader sense. Some of those 
things relate to NIDDK and some relate to more trans-NIH 
issues. The National Cancer Institute has a major interest in 
this area, as does the National Heart, Lung and Blood 
Institute. The National Institute of Child Health and Human 
Development addresses issues including folic acid and neural 
tube defects. All of these things come under this general 
purview of nutrition. We've been very much involved in 
developing, through the National Academy of Sciences the so-
called RDAs, the Recommended Dietary Allowances for 
micronutrients such as vitamins. Of course, there's a broader 
aspect in terms of food composition, and all of these things 
from a purely research point of view are in the purview of this 
coordinating function at NIH and the purview of individual 
institutes. We are also very much involved in trying to develop 
strategies that will help us understand how food might be used 
as a disease preventive. There's been a lot of interest in the 
antioxidant agents such as vitamin E, vitamin C and vitamin A. 
We're trying to learn more about how these agents, these 
naturally occurring agents would not only prevent their own 
deficiency diseases, which have been a major focus, but would 
also at some level be preventive. This is a major area of 
research and I think that we will hopefully make some progress 
in this area, just as we have clearly made progress in 
understanding folic acid, and we've clearly made progress in 
understanding the need for enhanced levels of calcium. These 
are examples where we clearly have evidence that these agents, 
used in larger amounts, are preventive for diseases such as 
osteoporosis, neural tube defects, and perhaps cardiovascular 
disease.
    Those are the examples.
    Mr. Hoyer. Thank you, Doctor. Thank you, Mr. Chairman.
    Mr. Porter. Ms. Northup.

                     capacity for diabetes research

    Ms. Northup. Thank you, Doctor. I'd like to just ask, about 
the capacity that we have for diabetes research and for 
progress and in particular. It seems to me like diabetes is 
something that we treat and research in a variety of areas. We 
talked about that yesterday with Dr. Varmus, but I assume that 
your institute coordinates and watches what goes on in the 
other institutes and that there's good communication.
    In the last year, I believe that Medicare has expanded 
considerably the treatment that's available or the monitoring 
treatment for people with diabetes. Have you seen any 
differences, any improvements? Are there recommendations you 
would make to the Congress regarding extensions or obvious lack 
of coverage?
    Dr. Gorden. Let me just address several points, Ms. 
Northup, first, in terms of coordination, one of the really 
important things that happened last year was that--with Dr. 
Varmus's help--we organized a trans-NIH conference to bring in 
people who had an interest that related to diabetes research in 
a number of different NIH institutes. Each institute has a 
special kind of expertise that actually strengthens the field 
as a whole. It's important to coordinate it, but it's important 
also to capture the strength that's across the NIH We've 
mentioned the issue of vascular complications in the National 
Heart, Lung and Blood Institute. We mentioned the issue in the 
immunology of the disease in NIAID. There's a lot of strength 
around NIH. And Dr. Varmus really helped us very much to 
capture and develop an enlarged focus. I think in that sense 
that we're moving in the right direction.
    Your other question was related to Medicare and part of the 
Budget Reconciliation Act in which there were at least three 
important things that were related to diabetes. One was the new 
Medicare benefits that were allowed for diabetic patients, 
particularly Type 2 diabetic patients who were permitted to buy 
diagnostic strips and other types of materials that are 
important for their care, and a certain amount of educational 
support was given through Medicare. That was a major thing for 
Type 2 diabetics.
    There was a also a portion of the law related to Native 
Americans, and Native Americans have the highest rate of 
diabetes in the country. That portion of the law will largely 
be dealt with through the Indian Health Service in terms of 
community action, and things of that nature that deal with the 
Indian Health Service. And of course, the third part was 
related to Type 1 diabetes and that was put under the purview 
of NIH through Dr. Varmus by way of the Secretary. The NIDDK, 
as the lead institute, coordinates for Dr. Varmus the efforts 
in Type I diabetes. So there was a whole group of things that 
happened vis-a-vis the Budget Reconciliation Act that ranged 
all the way from Medicare changes to more direct kinds of NIH 
research. So I think that there's been a lot happening. Now the 
question. We have a lot of evidence, but not the kind of 
evidence that I feel comfortable in telling you about, about 
improvements--of course, these things are very new. We can't 
talk about what effect they have had, but we have evidence that 
things are actually getting better for patients. Because we've 
been instituting some of the things I mentioned over a period 
of at least a few years and even before that, we think that 
things are already getting somewhat better. We can point to 
certain studies, but they're not the kind of studies that I 
think would convince you. That's what I want to be able to do. 
I want to be able to present the kinds of studies that clearly 
can convince you that things really are getting better.

                          dietary supplements

    Ms. Northup. We've touched on obesity drugs some, but 
there's obesity and then there are, all the vitamins and herbal 
remedies that are out in the market. I just wondered how 
involved you all are in looking at those particularly related 
to obesity and the fact that they don't have to be tested 
before they actually are on the market. And then you can extend 
that beyond that point. I sort of feel like everybody I know 
that's my age started with C and E and B complex and now it's 
Ginkgo and they all have a little bag they take on trips. I 
just sort have wondered what the recommendations is for those 
things, both the weight control drugs, in particular and 
others--what is the effect they have on the systems.
    Dr. Gorden. Well, you're absolutely correct. Severalyears 
ago we established the National Task Force on the Prevention and 
Treatment of Obesity, which operates within NIDDK. It's a trans-NIH 
group, in order to be able to at least address some of these issues. 
It's impossible to address them all. They keep cropping up literally 
every minute. Each time you think you've put one in the basket, another 
one comes up.
    This task force has put out a number of papers that speak 
to some of these issues. They have to do with so called yo-yo 
dieting, the issue of weight going down and up, and they speak 
to----
    Mr. Dickey. You just called my name.
    Dr. Gorden. We have a publication for you, Mr. Dickey. And 
the papers speak to drugs, the use of pharmacologic agents. 
That was why we wanted a cross section of people who are not 
specifically coming from NIH or government representatives, but 
a variety of scientists to give us their best opinions. One of 
the real problems is that we've got to come up with alternative 
treatments, because every time we say these things don't 
matter, then we have to come up with an alternative for it, and 
that's what we're so much striving to do. Because what people 
grasp onto is whatever straw there is when there isn't 
something more substantial available. That's what so many of 
these things really are.
    Of course, there's a tremendous advertisement for diet 
aids. There's a tremendous market for a variety of these 
agents. This is just the way our system is right now, and until 
we can really develop a rational approach that's easy for 
people to use, I'm afraid we're not going to be able to do very 
much about this overall problem. But we're going to try, and 
we're going to try, to educate people as best we can.
    Ms. Northup. And you do look at the drugs we're talking 
about and the effects. You know, somebody might lose weight 
with chromium picolinate, but they might also ruin their 
kidneys.
    Dr. Gorden. Exactly. In fact, it was because of this 
surveillance that we were able to address this so-called Fen-
Phen issue, which causes this rather tragic situation with 
heart valves. We actually had surveillance mechanisms in place 
and we had the only control groups. One of the issues that 
comes up is what happens in the native state? That is, what 
does obesity per se do to heart valve thickening? If you don't 
know that, you can't know that the drug is really having some 
sort of an adverse effect.
    We had a mechanism in place through one of our Clinical 
Nutrition Research Centers to answer that question, and we 
answered it very quickly, so there was a very rapid response 
through the NIH and through the FDA that actually recognized 
this problem rather quickly and stopped the marketing of the 
drugs.
    We're proud of the fact we were able to do that. We would, 
of course, be prouder if we were able to do something positive, 
but that's the kind of surveillance that we're involved in.
    Ms. Northup. Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Ms. Northup. Ms. Lowey.

                         women's health issues

    Ms. Lowey. Thank you, Mr. Chairman, and it's a pleasure to 
see you again, Dr. Gorden. I won't pursue Ms. Northup's line of 
questioning, but I've had some individual conversations with 
you and I think I said at one of the hearings that it's my 
understanding that a survey was done and most Americans get 
their health information from ER. This was actually a poll that 
was done and I have very similar questions to yours and I'm 
delighted that you are doing some work on, I believe it's St. 
John's wort and chondroitin glucosamine sulfate, you can 
correct the spelling for the record, but I think it is really a 
concern because we all know people who are getting this 
information, going around with a dozen pills and I often wonder 
about the interaction between a chromium picolinate and a 
ginkgo and a St. John's wort, etcetera. So perhaps we can--I 
know so many of us are interested in this. Perhaps we can have 
an informal conversation some time in the future about the 
scientific base of some of this alternative mediation and the 
current investigation that's going on, but to the issue today I 
want to just tell you that I'm very pleased to see the 
continued collaboration between your institute and the Office 
of Research on Women's Health focusing on cardiovascular 
disease in women with Type 1 diabetes and I understand that 
this is a long-term study. But can you share with us the 
progress that's been made thus far, and what you hope to 
accomplish in the coming year?
    Dr. Gorden. There are really two aspects. We have a very 
active collaboration with the Office of Research on Women's 
Health. One collaboration is what we call the EDIC study, which 
is the long-term follow-up of the Diabetes Control and 
Complications Trial. That is, this group that I showed you on 
the chart under secondary prevention. We're continuing to 
follow all 1400 of those patients. Mr. Porter asked about 
macrovascular, or in other words, large vessel disease. One of 
the first things that this collaboration allowed us to do was 
to do a cross sectional measurement of blood vessels by a 
certain type of ultrasound technique so that we can get some 
idea about the progress of macrovascular disease in that 
population.
    In addition to that, we have a number of other projects, 
including gestational diabetes, obesity control and several 
other projects that are ongoing with the Office of Research on 
Women's Health. It's been both of these types of projects, one 
on the vascular disease and the other on diseases related to 
pregnancy and other diabetes-related concerns that we continue 
to work with the Office on.

                         islet transplantation

    Ms. Lowey. I'm also aware that islet transplantation holds 
promise for the treatment of diabetes, particularly Type 1 or 
insulin-dependent diabetes. How would you assess the current 
state of research in this area?
    Dr. Gorden. Well, it's an extremely exciting form of 
therapy. It would essentially take cells from the pancreas, 
isolate them, exploit their insulin-producing capacity and 
their glucose-sensing capacity, so that they can be then 
infused into a recipient individual. Then essentially these 
cells can take over for the cells that have been destroyed.
    The problems have been related to two things. One is that 
we really don't understand the requirements for growth and 
maintenance of isolated cells when they're transplanted, and 
we've not completely been able to deal with the immunologic 
issue. We know that when you transplant a whole organ, such as 
the pancreas, it works and it's fine. But when you isolate the 
cells out of that organ and transplant them, it's been very 
difficult. But this is something that we're continuing to work 
with. We have new technologies now that allow us to actually 
construct those cells out of cells that were never insulin-
producing cells. We're hopeful that we can create a more rugged 
cell, so to speak, that will allow us to get around some of 
these growth properties. We have a lot of different 
opportunities now that we haven't had before.
    The approach is an extremely valid approach, but it's 
clearly going to require further development in order to make 
it clinically useful. We're continuing to pursue that quite 
vigorously.
    Ms. Lowey. I thank you and in another area, last year we 
learned of some promising advances in the fight against Crohn's 
disease. Could you briefly update us and give us an idea of 
your future research agenda with respect to this disease?

                       inflammatory bowel disease

    Dr. Gorden. This has been really a disease that is really 
quite severe. It's part of the so-called inflammatory bowel 
diseases. Crohn's disease is a disease of the small bowel. 
Ulcerative colitis is the disease of the large bowel. There 
have been some exciting therapeutic advances in the last year 
or two. One of the more exciting ones is the development of an 
antibody to something called tumor necrosis factor, which is a 
kind of a cytokine. It's a protein product of a cell that 
occurs during an inflammatory situation that can have a very 
negative effect on tissues. It turns out that infusing these 
antibodies has a major effect in people who are refractory to 
other treatments in Crohn's, so that helps us get a better 
understanding about thenature of the disease and also offers us 
other therapeutic options.
    There have been a number of other advances such as 
corticosteroid preparations that work locally or are not 
absorbed into the systemic circulation so that you can get the 
advantage of them. There have been drugs developed that have an 
aspirin-like quality to them that can be given, and they're 
used in a format that's not absorbed, so you can get the 
reaction to occur in the gastrointestinal tract.
    We've made some progress in understanding some aspects of 
the genetics of the disease. There's no question that there's 
been a marked decrease in the actual morbidity and certainly 
the mortality, a tremendous reduction in mortality. It's really 
one area in which we've made great progress. We have a way to 
go. People who do have the refractory forms of the disease 
suffer a great deal, so there's still a lot to be done. I think 
that a lot has been done to help a larger and larger subset of 
people.
    Ms. Lowey. Thank you very much and I thank you Mr. 
Chairman.

                        obesity as a risk factor

    Mr. Porter. Thank you, Ms. Lowey. Mr. Dickey.
    Mr. Dickey. Dr. Gorden, how are you doing? What I'd like to 
do is have short questions and short answers. I'll try to live 
up to my side of it. Some of the things we talked about 
yesterday, but I'd like to know within a reasonable medical 
certainty how many diseases are related and caused by or are 
increased by obesity?
    Dr. Gorden. There are at least eight, maybe ten.
    Mr. Dickey. Can you name some of them, please?
    Dr. Gorden. Certainly obesity is a risk factor for 
diabetes, heart attacks, stroke, the lipid disorders, the 
arteriosclerosis, in general, and certain forms of cancer, 
gallstones and at least two or three other things that 
certainly are related, such as osteoarthritis, and in other 
words, any kind of condition involving pressure on joints. 
There would be a variety of those related conditions.
    Mr. Dickey. Cancer?
    Dr. Gorden. Cancer, yes, at least certain forms of cancer.

                            costs of obesity

    Mr. Dickey. Do you know the economic costs to our society 
of obesity?
    Dr. Gorden. We don't really know exactly. There are numbers 
that have been actually produced that are in the range of just 
under $50 billion in direct costs; an estimate of $47 billion 
is a number that one could produce some evidence to support. 
And there's another number for indirect costs, so that the 
numbers that are out there are in the range of about 68 or just 
under $70 billion with respect to direct and indirect costs of 
obesity.
    Mr. Dickey. Now if we're looking at avoiding obesity as our 
target, controlled nutrition and activity are two cures for 
obesity. Is that a fair statement?
    Dr. Gorden. Yes.
    Mr. Dickey. Which affects obesity more?
    Dr. Gorden. Nutrition.

                     funding of nutrition research

    Mr. Dickey. Okay, now I notice the increase of funding at 
least between 1995 and 1996 of the nutrition research amount 
went up only 2.5 percent.
    Dr. Gorden. I don't actually have the percentage. We do 
have the actual nutrition numbers. The 1997 total NIH nutrition 
number is $452.8 million.
    Mr. Dickey. What was it in 1996?
    Dr. Gorden. The 1996 comparable figure is $438,812,000.
    Mr. Dickey. Okay, so there was an increase, but not a great 
deal of increase.
    Dr. Varmus. The number projected for 1999 is $507 million.
    Mr. Dickey. What percent increase is that, Dr. Varmus?
    Dr. Varmus. Seven percent over 1998.
    Mr. Dickey. Okay, so that's in keeping with the overall NIH 
increase.
    Dr. Varmus. That's correct. Actually, the numbers overall 
are not out of sync with the overall increase.
    Dr. Gorden. These increases are pretty much keeping pace 
with the average.
    Mr. Dickey. Is part of that money going to the research of 
what causes food addiction?
     Dr. Gorden. Well, this is a total NIH nutrition research 
figure and included in that would be the kind of research that 
relates to issues such as food addiction or terms that we've 
talked about, that relate to craving for food. So a subset of 
that research would relate to what you asked, yes.
     Mr. Dickey. Is there any other agency that you know of 
that's doing the same thing, studying nutrition from the 
standpoint of an addiction or why we eat so much?
    Dr. Gorden. Yes, the Department of Agriculture has a rather 
substantial research program related to this. There are also 
programs in the Veterans Administration. There are programs in 
the Department of Defense that relate to this general area of 
energy utilization and obesity, the broad term that we're 
discussing.
    Mr. Dickey. Does the CDC have anything going in that 
relationship?
    Dr. Gorden. The CDC's Work is more related to translational 
issues, not so much related to research per se.
    Mr. Dickey. What is translational?
    Dr. Gorden. Translational issues have to do with taking 
information and trying to use state health departments or other 
kinds of community action to disseminate it and to get some 
sort of community effect. That is the area that they work in 
mostly.
    Mr. Dickey. All right, now do you think we have too much 
duplication?
    Dr. Gorden. I don't really think so, in terms of 
duplication. I think the agenda here is quite different. As I 
mentioned, the CDC's and the NIH's agendas are quite different. 
We have, I think, very good coordination in terms of the two 
major Federal components, the Department of Agriculture and the 
HHS. I think we have excellent coordination, and that also 
works through Dr. Varmus' Nutrition Coordinating Committee 
where we're represented in this broader context within the 
Department and with Agriculture. And we have contacts with the 
other agencies, such as the VA and the DOD.

                           combating disease

    Mr. Dickey. We've done a good job of explaining obesity, 
and informing people of the potential dangers to their health. 
Then we have a lot of companies and efforts being made at least 
on TV to get us to exercise more and to eat less. Now there's 
something missing here and I'm going to suggest that it's the 
incentives that we're missing. In other words, we know why we 
need to lose weight and we know how to do it, and yet we're not 
doing it. Isn't obesity on the rise in America?
    Dr. Gorden. Yes.
    Mr. Dickey. Okay, now what is the problem and what can we 
do through the funds that we give to you to try to solve it? 
Can you be brief on that one?
    Dr. Gorden. I think honestly, Mr. Dickey, we're going to 
have to have a technology, a drug, something like that. That's 
where our success has come in other areas. Until we develop 
this kind of intervention, we're not going to be totally 
successful. We're going to try prevention strategies; we're 
going to do everything we can, because once the obese state 
occurs, it's very difficult to reverse it. But prevention is 
also very difficult. We can talk about it but it's very 
difficult to achieve.
    We've got a number of pilot things that we're trying to do 
to see if we can't at least get that approach moving in a 
better way. If we're going to be as successful as in 
hypertension or in the lipid disorders or as we are now 
becoming more successful in diabetes, we've got to have a new 
technology. That's why we want to begin to try to test some of 
this now to see if we could demonstrate to you that we can 
decrease these morbidities, in other words, all these health 
risks that I've said. That would have an enormous effect and 
that would give us something to build on. That's the general 
approach that we're taking to do.
    Mr. Dickey. But the reduction is completely up to us and as 
a nation, we're deciding to be obese.
    Dr. Gorden. Well, I guess that's true in one sense, but 
it's very complex in another because----
    Mr. Dickey. I know that for a fact.
    Dr. Gorden. We know, for instance, from our research that 
there are individual people who are more fuel efficient than 
others. What I mean by that is the same as an automobile that's 
more fuel efficient. If you want to use gas, you don't want to 
have a fuel inefficient automobile. We're built like that too. 
Why exactly we're like that, we don't know. We suspect that 
some of that is genetic, but we can measure that, and we know 
that an individual that falls into this more fuel efficient 
category is prone to gain weight. We've done those kinds of 
studies and we know at least seven or eight risk factors for 
gaining weight. We can measure a number of those things. Each 
time we understand one of them it gives us a potential point of 
interdicting in a more specific way.
    These are the ways that I think this problem is going to be 
solved, and I think our basic approach is still the best one, 
because we simply can't make an absolute overreaching step 
right now and make the problem go away.
    Mr. Dickey. Can I ask one more question? Dr. Gorden, 
there's a company in Dallas, it's a health clinic actually, 
that uses financial incentives. They gave out $33,000 in one 
year of incentives, with individual employees receiving all the 
way up to $300, depending on what their baseline health 
statistics were and what they did as far as improvement. They 
saved $117,000 in health claims in that one year. Now what I'm 
saying is this problem, as I can see it, has a lot to do with 
economics. The incentives that were given for that clinic could 
reduce health premiums in the national work force level, the 
federal work force level or it could be just outright cash or 
vacations or whatever. Obviously, we've got to have something 
to dynamite the logjam and get people to take what they know 
and what's available and do something about it.
    Now is there anything, can you put any faith in financial 
incentives working in this area?
    Dr. Gorden. I can only point to the analogies that have 
been done in research and various forms of behavior 
modification. Certain types of rewards and types of approaches 
as you indicate are used and they're used with some success.
    Now, how to do that on a national or global basis from a 
reward point of view, I don't know. Scientists have suggested 
that perhaps, rather than a cigarette tax, we need a tax on 
some sort of fast food restaurants or things of that nature, 
and these have been suggested. I don't honestly know myself. 
I'm just----
    Mr. Dickey. That's a negative. I'm talking about positive 
incentives such as giving money to people.
    Mr. Porter. Would the gentleman yield on this?
    Mr. Dickey. Sure.

                          obesity in childhood

    Mr. Porter. Perhaps this is a suggestion. A lot of our 
obesity problems that are not related to disease or related to 
genetics would be better addressed by teaching good eating 
habits at a very young age.
    Dr. Gorden. Yes.
    Mr. Porter. Maybe we should put money into a children's 
health initiative that educates parents and kids on good eating 
habits and gets them started early and on the right path, so 
they don't develop the kinds of habits that lead to health 
problems. Actually, the most recent statistics show all of our 
young kids are already overweight.
    Dr. Gorden. That's correct.
    Mr. Porter. So bad eating habits seem to start very early 
in life and carry through the rest of life. If we can catch 
them before they start, then I think we've got a good chance of 
reducing them.
    Mr. Dickey. That's an excellent point because we learned 
that in cigarettes. The cigarette industry made the decision 
that if they got someone under 18 they would get them for life. 
Now I don't think there's any food conspiracy here. Maybe there 
is. But I'm just saying you've got an excellent point in that 
we may be losing the battle if people haven't been reached by 
the time they get out of college.
    Dr. Gorden. Yes, there have been studies, Mr. Porter, to 
suggest that the vast majority of adults who are overweight 
were not overweight as children. On the other hand, if you're 
overweight as a child, you have double the chance of being 
overweight as an adult. So what you say is absolutely true. We 
know in certain studies that the problem begins in childhood. 
We know in others that it begins in adolescence. If you look at 
the incremental weight that these individuals gain after 
they're 20, they're not different from a control. All of that 
happens while they're adolescents. So we know that there are 
different factions, but it clearly happens at a young age and 
then there are a multiple other things that happen when one is 
older. So it's a very complex issue. There are multiple 
different things at play here and I'm quite sure that some of 
these strategies are going to work for some people. No 
question.
    Dr. Varmus. May I make one brief comment about this? I 
noticed when you asked Dr. Gorden about the relative importance 
of exercise and diet he said diet and this is probably 
accurate. But the importance of exercise should not be 
underestimated. In my readings of this literature, the most 
successful attempts to gain control of weight in children have 
occurred when family units have learned exercise patterns that 
are sustained over years; they are much more important than 
either drug use or temporal changes.
    Mr. Dickey. Does that suppress appetite?
    Dr. Varmus. It probably has an effect on the amount of food 
that's taken in proportion to caloric intake and in proportion 
to how much exercise is undertaken, but I just want to stress 
this because in addition to teaching proper nutrition in 
school, it seems to me it's important that we perhaps place 
less emphasis on winning teams and more emphasis on being sure 
that all children who go to school acquire exercise patterns 
that will last them throughout their lifetime.
    Mr. Dickey. Excellent.
    Mr. Porter. Thank you, Mr. Dickey.
    Mr. Dickey. Thank you, sir.

                        genetic basis of disease

    Mr. Porter. Dr. Varmus, a question for you, if I may. You 
have decided, more or less, that all disease has some genetic 
base that can be ultimately discovered. Is that a fair 
statement or not?
    Dr. Varmus. We believe that, possibly excepting certain 
forms of trauma, there probably is a genetic contribution to 
all disease.
    Mr. Porter. Then the question is, are we putting all other 
research approaches on hold and telling the Institutes, until 
we can unlock the genetic keys you should be looking at what 
the diseases do to us and what can be done to prevent the 
damage that they cause us? Is that happening?
    Dr. Varmus. Absolutely no.
    Mr. Porter. I knew you were going to say no. I want to know 
why.
    Dr. Varmus. In fact, as you probably will hear from Dr. 
Collins tomorrow when you hear testimony from the National 
Human Genome Institute, we are actually worried about the 
difficulty of identifying the genetic contributions made to 
complex diseases. That's going to be difficult in the case Type 
II diabetes, I believe. It's going to be difficult in the case 
of hypertension and many other disorders. We're just beginning 
now to have a look at that by identifying the so-called 
polymorphisms that are scattered around human chromosomes, but 
this is going to be a 20 or 30 year struggle, in my mind, to 
identify those markers. And even then it may be difficult to 
know how to act on that information to carry out gene-based 
diagnostic, or preventive, or therapeutic maneuvers. So there's 
very much to be gained by looking at kinds of interdictions 
that are being thought about in the context of obesity and 
behavioral changes. In short, we are trying to understand the 
genetic basis of disease and it's going to make a very 
important contribution, especially to those so-called unigene 
diseases, but other things must continue in parallel.

                        urinary tract infections

    Mr. Porter. Thank you. Dr. Gorden, it was reported 
inScience Magazine that researchers had developed a genetically 
engineered injectable vaccine that prevents urinary tract infections in 
mice. The vaccine must still be tested in humans, but holds promise for 
the 8.5 million people in the U.S. alone that suffer from urinary tract 
infections. How long do you think it will be before we will know if 
this discovery is effective in humans?
    Dr. Gorden. I can't give you an exact time frame, Mr. 
Porter, but I would like to elaborate on the problem. 
Antibiotics have certainly been extremely helpful for the 
treatment of urinary tract infections, but there are a number 
of individuals who are really plagued with recurring urinary 
tract infections. This is an intriguing observation that was 
made by a group of our scientists. The bacteria have a 
particular kind of protein that's involved in attaching to a 
particular part of the bladder wall and the isolation of this 
protein has permitted this vaccine attempt. If the vaccine is 
given, at least in experimental animals, then this protein that 
is necessary for attachment to the bladder wall to produce the 
infection can't take place. This is an extremely promising 
approach and it uses concepts that have been built on basic 
science that comes from plant biology: a product of plants 
known as lectins have to do with the binding to particular 
kinds of carbohydrate components of proteins. It is really one 
of those phenomenal things coming out of very basic research, 
now used in the experimental animal model for a very important 
disease. Now scientists will be moving towards the human 
application of that finding, but I can't tell you exactly when. 
Usually it takes several years before clinical application 
would be possible.

                         interstitial cystitis

    Mr. Porter. Can you tell me where we are with respect to 
research on interstitial cystitis? Have we made a lot of 
progress in that disease?
    Dr. Gorden. I think that the real progress that's been made 
is in terms of categorizing a variety of disorders that cause 
extreme pain that are related to the bladder. One of the ways 
we've gone about this is to deal with it directly, clinically, 
by establishing a group of clinical centers that recruit 
individuals who have the characteristics that are associated 
with interstitial cystitis and attempting to assess each one of 
them. We now have a battery of biopsied material and material 
from cultures to put together. We've just recompeted this group 
of centers because we thought this was an extremely valuable 
program. We've just recompeted it to try to see if we can 
develop therapeutic strategies to treat some of these 
individuals. We have some ideas about how to go about that. 
This has been a really debilitating disorder for many people. 
We are working with the community and we just had our second 
international conference sponsored with the Interstitial 
Cystitis Society. Our program director, Dr. Lee Nyberg, was 
very much involved in this, and we think we both developed a 
tremendous rapport with the community. We have addressed their 
problems and we're trying very hard to make this something that 
could be therapeutically important.

                 liaison with diabetes voluntary groups

    Mr. Porter. Since you raised rapport with the interstitial 
cystitis community, how about your rapport with the diabetes 
community? I'm talking about the Juvenile Diabetes Foundation, 
the American Diabetes Association and others. Where are you 
with them? Is it a good, close relationship?
    Dr. Gorden. Well, this year has been a phenomenal year for 
diabetes, for patients, for researchers and for all of us at 
NIH and so I really wanted to do exactly what you say. I wanted 
to try to test the water as much as I could in terms of our 
relationshis with the organizations. About a month ago I went 
to New Orleans to meet and address the Juvenile Diabetes 
Foundation's Board. About 50 or 100 people made up of their 
national leadership there and I spoke to them and we had a 
general discussion. I hope I was able to impart something to 
them, and I certainly came away with the feeling that they had 
a very positive feeling about what was going on and about the 
approach that was being taken, and a renewed sense of what they 
really want to achieve, which is a cure and a treatment. Some 
of the things that we put into motion now address some of their 
concerns directly. For example, the particular initiatives that 
we put into place, that address issues such as treatment, and 
trying to close the loop on insulin, therapy, which has been 
such a plague to the patients and their families. I came away 
with a very positive view of their feeling towards the research 
establishment, certainly of their enormous appreciation to the 
Administration and the Congress for what has taken place. So it 
was very positive. In addition, I met with the leadership of 
the American Diabetes Association in a slightly different 
format, but again I came away with the same kind of feeling. I 
think they are very pleased about progress on Medicare issues 
that has been achieved. That was one of their major objectives. 
They're very happy about the Type 1 initiative and they're very 
happy about the appropriations increases that have occurred in 
the area, particularly with respect to NIDDK, but also in 
trans-NIH research diabetes. My own sense is that these 
organizations that do represent patients at a national level 
have a very special kind of new feeling and this is really 
something that's happened in the last year in a very augmented 
way. I perhaps am just speaking from a biased point of view, 
but that is the sense that I got in my interactions. I've 
really tried, through our National Advisory Council, through 
this trans-NIH network, through communicating directly with 
scientists and speaking to as many people in the public as I 
can, to make the community aware of what's going on. I think 
it's had an enormous impact and I really again cannot express 
my appreciation to you and the committee enough for what has 
happened. I also have appreciation for Dr. Varmus for giving us 
a very special boost and supporting us in terms of getting the 
ball rolling. I think that we're moving in the right direction 
and I'm very encouraged.

                            kidney diseases

    Mr. Porter. Thank you. Dr. Gorden, NIDDK supported research 
on kidney diseases focuses or seem to focus mainly on 
preventing or delaying the progression of the disease to end 
stage and on improving the quality of life of individuals who 
do have end stage renal disease. Is there also a focus on 
research that prevents the onset of kidney diseases in the 
first place?
    Dr. Gorden. Well, certainly there are at least two or three 
areas that are extremely important in that regard. First is 
diabetes, because as I mentioned, diabetes is the most common 
cause of end stage renal disease or renal deterioration. The 
kinds of studies that I've outlined here are terribly 
important. That would be something that will be very important 
for ameliorating or interdicting the course of renal disease.
    Hypertension is another area, particularly in populations 
such as African Americans, as we've discussed with Mr. Stokes. 
Hypertension has a very specific effect in the generation of 
kidney disease in African Americans and the progression of that 
disease.
    A third area is in something we're beginning to explore, 
and it's something that is important for us to address. That is 
things like drugs, and what effect drugs might have on the 
kidney, particularly common analgesic drugs. A number of years 
ago there was a common drug that many people took called 
phenacetin. There were many brand names for it. It was 
ultimately removed from the market, but we still have a concern 
about people who ingest large amounts of analgesic drugs of a 
particular class. We're beginning to look at that. We're 
looking for diagnostic criteria that would give us an idea 
about how to diagnose drug--induced or analgesic--induced 
nephropathy.
    Those are examples of areas where we would hope to 
interdict the kidney disease per se, and improve the treatments 
after they occur.
    Mr. Porter. Phenacetin sounds familiar. Do you know the 
brand names?
    Dr. Gorden. Anacin.
    Mr. Porter. Anacin is phenacetin.
    Dr. Gorden. And drugs like Stand Back and those kinds 
ofthings. Those analgesics were usually combinations of drugs. They 
contained some aspirin, but they contained phenacetin, which was one of 
the major ingredients.
    Mr. Porter. Is Anacin off the market today?
    Dr. Gorden. Yes. APC, there were a variety of these so-
called drugs: aspirin/phenacetin/caffeine. Those were drugs 
that were proprietary drugs at the time.
    Mr. Porter. I have to say that Anacin was the regular 
choice for most things when I was in the Army, APC.
    Mr. Stokes.

                            minority health

    Mr. Stokes. Thank you, Mr. Chairman. Dr. Gorden, as you 
know, over the years, I have been involved in the development 
of the collaboration between the NIH, Office of Research on 
Minority Health and your institute. Over the past several years 
you've had some joint initiatives, I think, between the two 
Offices. Can you provide us with an update on any major joint 
initiatives that are currently underway?
    Dr. Gorden. Yes, we have again with Dr. Ruffin's Office a 
very active collaborative program on the order of about $8.5 
million. There are two different things that we do. One is that 
we are the administrative support for the MOTTEP, the program 
that's involved in trying to recruit more African Americans and 
other minorities to become organ donors. This is a program 
that's a national program that the Office funds and we actually 
administer for them through NIDDK.
    We also have a high school student program that we have 
used at each of these same sites. We bring, these students to 
work in laboratories in the cities in which these sites happen 
to be. We have a very nice meeting once a year and bring these 
students in,trying to interest them in biomedical research. 
That's been a very active program.
    We have another effort related to a program, a clinical 
research program, that's being inaugurated at Drew University. 
We have a whole variety of individual projects. One has to do 
with genetics of diabetes. Another has to do with support of 
our Diabetes Prevention Program clinical trial, and also a 
series of individual research grants that cut across everything 
from H. pylori infections to hepatitis C, to obesity, to 
diabetes--the diseases that are of major concern. Of course, 
the Office also plays a major role in our African American 
hypertension study. In all of the diseases that represent major 
disparities in minority health, the Office has been involved in 
collaborating with us to enhance our own resource base to build 
on these programs. We found it to be a very productive 
interaction.

                              hepatitis c

    Mr. Stokes. I'm pleased to hear that because, as you know, 
over the years I've seen this sort of improve and grow and the 
collaboration take on much more meaningful aspect in terms of 
not only your institute, but several of the other institutes. 
So, I'm glad to hear that.
    You mentioned hepatitis C a moment ago. And I notice in 
your formal statement you say that to combat chronic liver 
disease, you will launch a major natural history study on 
hepatitis C based on a consensus development conference 
response with NIAID. Can you tell us a little bit about that?
    Dr. Gorden. This first consensus conference on Hepatitis C 
is another example of the real utility of these conferences. 
This one was extremely successful in allowing us to catalyze 
some major objectives and major concerns in a broad community.
    What we've done first is to bring on Dr. Leonard Seeff, who 
is a major national expert in hepatitis C, to work with us on 
this problem. We are also inaugurating a multi-center program 
of multiple clinical centers and a central coordinating center 
to begin to collect natural history data on the course of 
hepatitis C.
    It is a disease in which approximately 70 percent of 
patients who are infected with hepatitis C develop chronic 
liver disease. And of that 70 percent, approximately 20 percent 
develop cirrhosis. Once they develop cirrhosis, there is about 
a one to two percent per year risk of liver cancer.
    We are developing a program that will allow us to 
understand the difference in the course of one patient versus 
another and to try to find ways to interdict the course of this 
disease. We think this will be a major collaborative effort. 
And we are further going to, in Fiscal 99, begin to augment 
this effort by an additional group of research grants.
    This is an area that we feel is very important and one that 
we, along with several other institutes, including the National 
Institute of Allergy and Infectious Diseases, are going to play 
a major role in the future.

                            prostate disease

    Mr. Stokes. Very good. Another important item, I noticed, 
in your formal statement. Let me refer to it. You say we are 
intensifying research on the biology of the prostate which 
includes studies of benign, prostatic, hyperplasia, prostatis 
and prostate cancer in collaboration with the NCI. I note this 
particularly because we talk about minorities, we know that 
African Americans have the highest rate of prostate cancer then 
any males in the world. Obviously this is going to be very 
important in terms of making some impact upon that situation. 
Will you please comment on this?
    Dr. Gorden. Yes. Actually this is a very active area of 
collaboration with the NCI. We sponsor five George O'Brien 
Urology Research Centers, three of those we co-fund with the 
NCI with the specific objective of studying both benign and 
malignant prostate disease. We, along with the NCI, want to 
develop a very interactive program because so many of the 
issues, the technologies, and the influences on the prostate 
are similar and the kinds of approaches that one takes are 
similar.
    Along those lines, we are having the second International 
Conference on Prostate Growth starting this weekend. Just to 
emphasize the importance of that, our plenary scientific 
speaker is Dr. Varmus. I think this illustrates his broad 
interest and expertise, particularly in cancer research and 
issues of cell growth and related issues.
    Prostate research has been an enormously important area of 
growth within NIDDK. We really are excited about the prospects 
of increased understanding. We have a multi-center clinical 
trial involved in the medical treatment of BPH, benign 
prostatic hyperplasia, that has a very substantial number of 
minority participants. We think that trial will also be 
important to the issue of cancer research, because we are 
collecting information--PSAs and a lot of other information--
that we think is going to be very useful in understanding 
cancer. But the real issue here is to treat benign prostatic 
hyperplasia.
    We think this is an excellent example of where two NIH 
institutes have many common objectives. The Cancer Anatomy 
Genome Project is of enormous importance, and prostate is one 
of the major areas of concern. There will be a major importance 
to this particular process.
    We think that prostate research is an area in which we are 
making some real progress in terms of medical therapy. We bring 
our expertise in endocrinology to this, because some of the 
major treatments for cancer of the prostate have been 
endocrinologic treatments because the prostate is an 
endocrine--responsive organ. Testosterone, anti-testosterone 
therapies, all of these things that have been brought to bear, 
help us in the fight against prostate cancer.
    Mr. Stokes. Thank you. Dr. Varmus, did you care to comment 
in this area, also?
    Dr. Varmus. Well, Dr. Gorden has covered it very well, and 
I think that those topics will definitely come up when we have 
the NCI here. Those are the two institutes that are most 
heavily involved. There is some less minor involvement by one 
or two other institutes.
    But there is clearly a great deal more research and 
emphasis, on prostatic cancer.
    Mr. Stokes. I thank you both. I appreciate your testimony. 
Thank you Mr. Chairman.
    Mr. Porter. Thank you Mr. Stokes. Mr. Dickey.

                                obesity

    Mr. Dickey. Yes sir. Dr. Gorden, again let's go short 
questions, short answers. Where is the center of the National 
Obesity Task Force?
    Dr. Gorden. It is operated within NIDDK. We are the 
administrator----
    Mr. Dickey. They are in the same location?
    Dr. Gorden. Yes sir.
    Mr. Dickey. Who is head of that?
    Dr. Gorden. It is operated within the Division of 
Nutrition, Digestive Disease and Nutrition, by Dr. Susan 
Yanousky, who is an expert at eating disorders, as an executive 
secretary of that group. She is the person who is responsible 
for coordinating and for disseminating the activity of that 
group.
    Mr. Dickey. Okay, now I want to go into this 
$45,000,000,000 a year that obesity costs our society. What are 
the reasons that we know of that inspire people to lose weight 
or to fight obesity?
    Dr. Gorden. Well I think that is multi-faceted. I think 
that one important issue, and perhaps the most prevalent one 
that one hears about, has to do with a certain cosmetic reason. 
That is people have a certain desire to be----
    Mr. Dickey. To look better.
    Dr. Gorden [continuing]. Thin. In other words, it has to do 
with your looks.
    Mr. Dickey. What else?
    Dr. Gorden. Well, I would hope that it is the health aspect 
of it. It is the realization that there is a particular set 
point of weight. If you exceed that set point of weight, you 
markedly begin to increase your risk of all those health 
problems that we mentioned earlier, and those things are not 
necessarily independent. That is, you could increase your risk 
of all of them, or one of them, or a subset.
    I believe that those two things are the driving force.
    Mr. Dickey. But it seems to me that we have more peer 
pressure on the cosmetic look than we do on the health side. In 
listening to you and thinking about this problem, I see that we 
have more of a concern nationally than we do individually. 
Would you agree with that?
    Dr. Gorden. Well, it seems to me that almost every 
individual you talk to wants to lose weight. And so----
    Mr. Dickey. But they do not do it.
    Dr. Gorden. Well, they do not do it, but they sure seem to 
want to do it. I think it's kind of part and parcel the same 
thing. It is very unusual to hear someone talking about their 
desire to gain weight.
    Sometimes you do because there are certain individuals that 
want to gain up to this normal set point, that is true. But for 
people of normal weight, it is very unusual to hear someone say 
that.
    On the other hand, to hear someone talk about wanting to 
lose weight is a very common thing.
    Mr. Dickey. But what I am really saying is that nationally, 
health care costs are going to consume us by increasing. Even 
as we bring the increase down we have the tragedy you might say 
of HMOs and what they are doing to us in that regard.
    But if we could ever convince our populace that health care 
is a national patriotic duty, then we are putting a national 
concern above our individual concerns, in a way. It is like if 
we go to war.
    Dr. Gorden. Sure.
    Mr. Dickey. We forget about overtime. We forget about who 
is working where or how many hours you have done this or that. 
When you are at war, it is expedient to keep moving.
    Now what I am saying is we do not have that attitude yet. I 
do not know what it is going to take. But I can--I didn't know 
it was going to come down to just to two reasons, cosmetic or 
the way you look and your health. But obviously those two 
things are not winning the battle. We have got to do something 
else. And that is what I am trying to bear down on.
    But let us move away from that right now because I think we 
have talked enough about behavioral control.
    Is obesity related to poverty in any way?
    Dr. Gorden. I think that there is a relationship of weight 
to socio-economic status. In general, there tends to be more 
obesity in lower socio-economic strata.
    Mr. Dickey. Why is that? Do they have less concern about 
the way they look?
    Dr. Gorden. I do not honestly know exactly what the answer 
is. I suppose that it would be, just coming back in a simple 
way to the things I said before, less concern about cosmetics. 
Perhaps also, cultural issues that relate to the fact that 
different cultures have a different view of weight and they do 
not have the same concern. There are a whole variety of 
things----
    Mr. Dickey. How about to live for? If you feel hopelessly 
lost in poverty, you have less to live for, maybe.
    Dr. Gorden. Perhaps that is certainly another element.
    Mr. Dickey. Okay, now what I'm saying, go back to the 
incentives. We are now being informed by the marketplace as to 
how to do something about it, with all of these diets and 
everything else. The connection has to be some kind of 
incentive. Do you offer any other ideas?
    Dr. Gorden. Well as I say, Mr. Dickey, I think our best 
hope is to develop a technology that people can use in a 
relatively easy way. I think people want----
    Mr. Dickey. You are thinking of drugs now.
    Dr. Gorden. Yes. I think people really do not want to be 
overweight. And I think if they are overweight, they want to 
get back to a normal weight. But they want a way that allows 
them to do it. And so many people have found dieting very 
difficult to do. I think we need to----
    Mr. Dickey. It is stressful.
    Dr. Gorden. Very stressful.
    Mr. Dickey. And that causes overeating.
    Dr. Gorden. That may cause it; certainly in some people it 
causes overeating. It is a kind of boomerang. You are 
absolutely right. And I think that the ease in which we can 
introduce things for people to do would help. If we could 
simply do as Dr. Varmus has suggested--through education, just 
have everyone simply balance their nutrition with a really 
active life--that would be a wonderful thing. It is probably 
the healthiest thing we could do.
    Mr. Dickey. But it is not happening.
    Dr. Gorden. But it is not happening, and we need to keep 
pushing at that. Because the fact it is not happening does not 
mean it is not important. It is very important.
    And when you ask me which is most important, diet or 
exercise, I answer diet only in the sense of what we know about 
weight gain. About 75 percent of it relates to the intake of 
energy. And about 25 percent to the utilization of energy, 
which is exercise.
    But the interplay between these two things are enormous. 
And so we cannot really----
    Mr. Dickey. Excuse me. There is something we are not 
talking about and that is productivity. I mean we are talking 
about good health and not having as many health care claims, 
but you know productivity on the job, is improved if the 
employee is in good health, I do not think this is measurable, 
but it has got to be one of the dividends of such an effort.
    And I wanted to say that, but that still does not have 
anything to do with what you are doing yet. Is that right?
    Dr. Gorden. Well, we have to stick to what we know best. I 
think that is to try to do the research that is going to 
develop the technologies, that is going to permit weight 
control to be easier for people. That is where I think we have 
to be.
    All these things that you mention are obviously very 
important. It is just that I am not quite sure I have any great 
insight into how to accomplish them.
    Mr. Dickey. Well I am not--my effort comes partly because 
my state, I think, the latest statistic is the second highest 
percentage increase of obesity in the last five years, or 
something like that. Now this is Arkansas, a rural state.
    And I am being driven a lot by that. But there is a lot of 
things I am going to be doing, but they are notscientific. They 
are more or less what wins ball games, wins wars, wins battles and 
things like that. It is--I just hope you will be tolerant as we move 
into this area of us ground level folks, and not you ivory tower 
people.
    Dr. Gorden. Mr. Dickey, I know exactly where Arkansas is 
and I understand the problem. I think all of these things may 
be important for us to do until we can really reach a kind of 
utopia. I think we are all on the same track there.
    Mr. Dickey. I am looking forward to working with you and 
thank you for your testimony. And Dr. Varmus, you have 
something to say.
    Dr. Varmus. Well, my only concern, Mr. Dickey, is I do not 
think we have any evidence that argues conclusively that 
overweight contributes to a lack of productivity. I think there 
would be a concern that----
    Mr. Dickey. Absenteeism.
    Dr. Varmus. Well, again, I do not--if it is due to illness 
yes, but I think there is a concern about a prejudice against 
and discrimination against people because they are overweight. 
And concern about the further deterioration of self image. So I 
think one has to be cautious in that area. That is all I would 
argue.
    Mr. Dickey. Okay, I do not have any more time. Thank you, 
Mr. Chairman.
    Mr. Porter. Thank you Mr. Dickey. Ms. Pelosi.

                      laser treatment in diabetes

    Ms. Pelosi. Thank you very much, Mr. Chairman, Dr. Gorden, 
& Dr. Varmus. I do thank you for your testimony today. Forgive 
me for coming in late here, but my responsibilities as ranking 
on foreign ops prevented me from being here for the entire 
time.
    We did at lunch have our biomedical research caucus 
presentation and we heard some very exciting things. And among 
those was that there are new breakthroughs in diagnosing vision 
impairments which can result from diabetes. Two doctors, a son-
in-law and father-in-law, came up with this. Forgive me for not 
knowing their names. Is that something that has sustained the 
test of time?
    Dr. Gorden. Certainly laser photocoagulation has been an 
extremely important therapeutic tool in treating the eye 
disease of diabetes. The National Eye Institute has conducted 
some really important clinical trials and has shown clearly 
that that laser treatment will markedly interdict the 
deteriorating course of eye disease. Laser treatment has had 
enormous effect in diabetic eye disease, no question about it.

                     regeneration of blood vessels

    Ms. Pelosi. That is encouraging. And then, again, a number 
of major newspapers reported a few weeks ago, as you know, that 
a major dent in the use of growth factors for the regeneration 
of blood vessels in the heart. How do you think this research 
will help persons with diabetes who are much more likely to 
suffer from heart problems?
    Dr. Gorden. This technology has not been specifically 
applied to diabetics. There are some differences in the type of 
atherosclerotic or arteriosclerotic lesions that diabetics get, 
as opposed to non-diabetics. By and large, any technique that 
is going to permit the growth of new blood vessels in 
particular areas would be helpful. The growth of new blood 
vessels is a real problem in the eye. But in the leg, around 
arteries and the heart, there is no particular reason why this 
approach should not have efficacy in diabetics. But at this 
point, to my knowledge, it has not been tried in diabetics.
    Ms. Pelosi. In our state of California, there is a great 
deal of interest in the work of your institute. We are home to 
over 1,000,000 adults with diagnosed diabetes. Of course, it is 
the largest number of any state in the country.
    But we are also very concerned about the issues of juvenile 
diabetes and I had hoped that this breakthrough in terms of 
regeneration of blood vessels in the heart would give us some 
reason to be hopeful on the juvenile diabetes front. Dr. 
Varmus, did you want to add something to that?
    Dr. Varmus. I just think that, the result reports that I 
have seen have been in the limb vessels.
    Dr. Gorden. There actually have been some very preliminary 
studies.

                         diabetes in minorities

    Ms. Pelosi. I am certain that my colleague Mr. Stokes asked 
you about the disproportionately high rate of diabetes in the 
African American community, as well as in other minority 
populations. According to what I hear, diabetes is 70 percent 
higher among African Americans than among whites.
    I wondered if you could tell us what your institute is 
doing to ensure that the benefits of research and prevention in 
treatment of diabetes are shared equally and by largest number 
of people. If you answered this already, I will just see it in 
the record, Dr. Gorden. Refer to what your successes have been 
in making this prevention available.
    Dr. Gorden. We have commented on it as we talked about our 
major Diabetes Prevention Program. That clinical trial over-
represents minorities, both Hispanics, who have a higher 
prevalence, and African Americans and Native Americans, who 
have a higher prevalence of diabetes. They are over-represented 
in the trial and will also be a major focus for education 
programs. We will have a special emphasis for these populations 
that are disproportionately affected. These are all ongoing 
projects at the present time.
    Ms. Pelosi. Thank you, Dr. Gorden. Listening to your 
responses to Mr. Dickey about obesity, I wondered--I always 
think the answer to all of these questions is the same. It is 
not the only answer, but it is one of the answers to all these 
questions, and that is access to quality and affordable health 
care.
    We tell people that obesity is not good for their health, 
but then again we do not enable them easily to have access to 
quality health care.
    So if that is a value, if it is something that is important 
that people should not engage in smoking, or use of drugs. We 
are saying that these things are important for their health, 
but at the same time, we do not place a value on every American 
having access to that health care. Then our message, I believe, 
is a mixed one.
    And so every day we hear about this issue of obesity here 
and now I know why, because there is something going on in 
Arkansas about obesity. But in any event, I would think that if 
those people that we were talking about, the lower end of the 
economic scale, had access to quality health care, they might 
be told more often than not about appropriate prevention and 
care. And also the importance of maintaining weight.
    I am not particularly interested in the cosmetic aspects of 
it, but I was interested in the side effects of obesity that 
are so costly in terms of personal well being and the obvious 
loss to productivity in our country.
    Unless you wanted to comment on access to quality health 
care and if you thought that would help people at the low end 
of the scale avoid some of the problems of obesity?

                         behavioral approaches

    Dr. Varmus. That is an important issue, Ms. Pelosi, and 
people I think forget that a crucial part of the whole 
behavioral treatment of obesity is having a doctor tell you, 
the patient, not the entire society, that you need to lose 
weight to be optimally healthy.
    Ms. Pelosi. It is the same thing that we do with education. 
We tell children that education is the key to success in their 
lives and it is important to the competitiveness of our 
country, and yet we send them to schools in tumble down 
buildings, they are leaking and have environmental hazards, and 
are not equipped electronically with technology for the next 
couple of years. You say the next century, it is right around 
the corner.
    And I keep thinking if we would only send a consistent 
message, children would learn--would take us seriously about 
smoking in this case, and studying in the case of education 
which is another jurisdiction that our subcommittee has.
    If I may, Mr. Chairman, I just want to ask one quick 
question, but I cannot find the reference in Dr. Varmus' 
testimony from the other day, and it may have been in theQ&A. 
Dr. Varmus, you talked about interdisciplinary research and approaches 
to what you were doing, you presented it so eloquently, but I cannot 
seem to find it here now. Can you, just taking the word 
interdisciplinary into your computer tell me----
    Dr. Varmus. Well we talked about that in several contexts, 
Ms. Pelosi. We talked about it in the context of developing new 
instrumentation. We talked about it with respect to developing 
new ways to analyze the avalanche of data that we are now 
generating in medical science. We talked about it in relation 
to developing new therapies. So I am not sure about the context 
because interdisciplinary work was such a broad theme in 
yesterday's discussion.
    Ms. Pelosi. And the collaborative efforts being so----
    Dr. Varmus. With other agencies, yes.
    Ms. Pelosi. Do you believe that the NIH, that you have the 
resources, administratively, to deal with the politics as well 
as the rest of the interdisciplinary approach?
    Dr. Varmus. Well, I think that is one area in which the 
limits that have been placed on our support of our research 
management and the RMS budget has begun to pay a toll. The kind 
of outreach that is required by our program managers to 
maintain those collaborative interactions and to develop new 
programs that would be more interdisciplinary in nature will 
require, especially as our grant portfolio enlarges, some 
significant increase in the amount of money that we make 
available for research management and support.
    We are asking for a three percent increase for RMS, but 
then an eight and a half percent increase overall. And I am 
not, myself, completely confident that that is an adequate 
increase in RMS for optimal management of our research 
portfolio.
    Ms. Pelosi. Well then, I'm glad I asked.
    Mr. Porter. Ms. Pelosi, why don't you continue with your 
first and second rounds combined until the next bell rings.
    Ms. Pelosi. Thank you very much, doctors one and all. Thank 
you, Mr. Chairman. I thought you were serious.
    Mr. Porter. I am serious.
    Ms. Pelosi. I thought we had to go vote.
    Mr. Porter. We have five more minutes until the second 
bell, so why don't you take the remainder of the time and ask 
whatever questions you would like.
    Ms. Pelosi. I do not want to put our guests through some 
questions that they have already been through. So let me just 
take one, if you will bear with me for a moment, Mr. Chairman, 
because I think that----
    Dr. Varmus. Mr. Chairman, could I make one brief statement 
while Ms. Pelosi is looking?
    Mr. Porter. Yes.
    Dr. Varmus. I wanted to at some point mention to you and to 
people who were listening, that this year we are going to make 
special use of our NIH web sites to make available to the 
scientific and advocacy communities the opening statements of 
our institute directors as soon as they are delivered here. So 
already, my presentation from yesterday, the presentations you 
heard this morning, are up on our web sites and we hope this 
will allow those that follow our activities almost 
instantaneous access to our opening statements.

                          accessible databases

    Mr. Porter. Let me ask you a question? The Speaker at 
today's luncheon which was focused on diabetes research, said 
that he wanted to ensure that the country had, in the future, a 
system where practicing physicians could immediately know the 
state-of-the-art procedures when dealing with specific 
diseases. Don't we already have that in place in the sense of 
the National Library of Medicine or am I jumping the gun?
    Dr. Varmus. It is not in place at this point. There are two 
problems. One is developing the right kind of accessible 
database for all diseases. It is in place for some things. For 
example, if you wanted to ask what is the current therapy for 
ovarian cancer, you could get that very quickly because the NCI 
has developed a very sophisticated database.
    The other problem is the problem of making our physicians 
more computer literate and developing the habit of using the 
computer as a resource. Many of them have neither the expertise 
nor the time to do what the Speaker is asking them to do. But I 
am sure that when Dr. Lindberg comes here, he will tell you 
about efforts to do for other diseases what has already been 
done for some.
    Mr. Porter. So when I saw the National Library of Medicine 
on the monitor in the community health center I visited in the 
inner city of Chicago, that system has some of the data that 
they would need, but not in reference to all diseases.
    Dr. Varmus. That is correct.
    Ms. Pelosi. I was pleased to hear that, Mr. Chairman, 
because of one of the efforts that we fund in our bill, the 
centers, which are started at the University of California, San 
Francisco, to get information out to the rest of the country on 
therapies for treating people with AIDS and HIV. I mean, this 
was even before the very sophisticated protease inhibitors. 
Because so many people did not have knowledge of this.
    Dr. Varmus. I should make clear Mr. Porter that the entire 
literature database is available. The problem is making the 
information digestible for someone who doesn't have the time to 
look through all the articles.
    Mr. Porter. Exactly. If I could say one thing to the 
gentlelady from California. I believe, I am not certain I am 
right in this, but I believe that we have just passed 
legislation that is now taking effect where we are collecting a 
special tax to hook up all libraries and all schools in the 
United States to the Internet. So I think we are already doing 
a part of what you were referring to that we should be doing.
    Ms. Pelosi. Oh yes. Well, my problem was that some of the 
schools do not even have the electrical wiring to accommodate.
    Mr. Porter. Oh, okay.
    Ms. Pelosi. I think that with the technology the way it is, 
lots of this information will be available, as Dr. Varmus said, 
people have to know what is there and how to avail themselves 
of it.
    Mr. Porter. I think we are now going to have to thank Dr. 
Gorden and go vote.
    Ms. Pelosi. Okay, thank you.
    Mr. Porter. The second bell has rung. Dr. Gorden thank you 
very much for the job you are doing at NIDDK and I think all 
members of the Committee appreciate your very good opening 
statement and your very good detail and candid answers to our 
questions. We thank you very much.
    Dr. Gorden. Thank you very much, Mr. Chairman.
    Mr. Porter. I just wish we had more than two hours because 
there are so many questions left unanswered. We will have to 
ask you to answer some for the record.
    Dr. Gorden. Thank you, sir.
    Mr. Porter. The Subcommittee will stand in recess until 
10:00 a.m. tomorrow.
    [The following questions were submitted to be answered for 
the record:]


[Pages 1523 - 1617--The official Committee record contains additional material here.]



                                         Wednesday, March 18, 1998.

                      NATIONAL LIBRARY OF MEDICINE

                               WITNESSES

DONALD A.B. LINDBERG, DIRECTOR, NATIONAL LIBRARY OF MEDICINE
KENT A. SMITH, DEPUTY DIRECTOR
DAVID J. LIPMAN, DIRECTOR, NATIONAL CENTER FOR BIOTECHNOLOGY 
    INFORMATION
DONALD C. POPPKE, EXECUTIVE DIRECTOR, NATIONAL LIBRARY OF MEDICINE
SUSAN U. LEVINE, BUDGET OFFICER, NATIONAL LIBRARY OF MEDICINE
HAROLD E. VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF 
    HEALTH AND HUMAN SERVICES

    Mr. Porter. The subcommittee will come to order.
    We continue our hearings this morning and are pleased to 
welcome Dr. Donald Lindberg, the Director of the National 
Library of Medicine.
    Dr. Lindberg, it's good to see you. I understand you have a 
demonstration and we're going to turn the lights down for you.
    Dr. Lindberg. I appreciate your indulging us in that 
respect, Mr. Porter. It's going to take another moment.
    [Pause in proceedings.]

                           Opening Statement

    Dr. Lindberg. Thank you very much. I very much appreciate 
your kindness, and I apologize for the delay.
    I wanted to report to you, give a progress report on the 
work of the Library in this brief statement, particularly with 
respect to three areas in which the committee had inquired last 
year, and to some extent given us some very helpful guidance.

                              free medline

    Firstly, free public access to the MEDLINE data base of the 
scientific literature. The committee heard last year testimony 
from Dr. DeBakey. Dr. DeBakey drew attention to the importance 
of getting access to the scientific literature, both for 
patients and for physicians.
    The committee then told us, very helpfully and clearly, 
that we should continue our outreach efforts directed toward 
health care professionals and the public, that we should use 
the new technology. And specifically, the committee endorsed 
and supported our decision to extend free MEDLINE access. This 
was tremendously helpful.
    By the late summer, we were ready to start that experiment. 
And Senator Specter called a press conference.
    [Video presentation.]
    Dr. Lindberg. Happily, Senator Harkin was on hand also to 
encourage us.
    [Video presentation.]
    Dr. Lindberg. The video shows the Senate, but today we are 
in the House. Everybody had a good time that day, it was a 
happy event. Mr. Gore showed up to do the first free MEDLINE 
search, and with the help of Dr. Varmus and Dr. Lipman, it was 
a successful search.
    [Video presentation.]
    Dr. Lindberg. Of course, that event got very good press 
coverage, print and electronic. The Post, for example, said 
quite well in the headline, ``medical research is made 
available to all.'' That's what the Congress wants, what the 
committee wants, and it's what NLM wants.
    The Chicago Tribune covered it well, the Wall Street 
Journal gave it their own slant, but good coverage. And the 
Times of New York and of Los Angeles reported it.
    Probably partly as a result of this good coverage, the use 
of MEDLINE searching has increased in the last six months by 
tenfold, a thousand percent, going from a rate of 7 million 
searches a year to a rate of 70 million searches a year. And 
more remarkable to us, the percentage of those searches that 
come from the general public has increased from virtually zero 
to 30 percent. So the experiment clearly is working, if we can 
keep the computers pumping along and keeping up with it, we'll 
be certain of it.
    Speaking of ER, here's a clip.
    [Video presentation.]
    Dr. Lindberg. While we of course do try to make the systems 
understand ordinary speech such as numb chin and to make the 
equivalents to the Greco-Roman expressions that medical people 
and librarians favor, we wanted to be understood by the public, 
and we wanted to be easily used by the health care 
professionals as well.

                              telemedicine

    The next area I should report on, telemedicine, as I 
indicated before, is the strongest strategy for getting good 
biomedical applications on Internet and also the Next 
Generation Internet. So I wanted to show you very briefly a few 
examples of those applications. And I agree with Dr. Patricia 
Grady's high appraisal of them.
    [Video presentation.]
    Dr. Lindberg. This also is a home health care application 
in which the nurse with her back to us is making an electronic 
call on an old person at home. She can do six or eight home 
visits before noon.
    This is working quite well. The primary funding in this 
case was HRSA, and we're involved more in the evaluations. That 
used a lot of bandwidth, because you have live television both 
ways between the patient and the nurse.
    [Video presentation.]
    Dr. Lindberg. This is the opposite. This is a good medical 
application. It's teledermatology. It's in eastern and southern 
Oregon, remote areas. This is a clinic, general practice 
clinic, probably good doctors, but they're not dermatologists. 
And here comes a patient with a dermatological problem. He's 
been almost unable to work for five years because of this 
eruption, for which he's seen four doctors and gotten no 
suitable treatment.
    The application here is to use digital cameras, which make 
a photograph in that clinic office, and a computer to transmit 
it to the expert, in this case, the Oregon Health Sciences 
University. You can see the pictures are quite detailed and 
good, even though they go over an ordinary phone line with 
ordinary modems.
    It took actually 20 seconds for the dermatologist to make a 
diagnosis, which is eczema herpeticum, and to come up with a 
treatment, probably Acyclovir, which can be taken by mouth, and 
in 48 hours, this disease that had lasted five years is cured.
    Again, you have a computer based patient record, so that we 
can get evaluation of the ultimate worth and contribution and 
cost of these systems. There are many others in the 
telemedicine area.

                 molecular biology information services

    The third area I want to bring attention to is progress in 
genome infomatics. Dr. Lipman is here to take us into any 
details that we might wish. He and I have selected two 
examples, sort of at opposite ends of the spectrum, to bring to 
your attention.
    Firstly, there is now a new version of the gene map. About 
a year ago, his group, with collaborators from all over the 
world, produced a map of 16,000 human genes. They now have 
32,000 which is perhaps half of all that will ever be known. 
And it's presented in these colorful codings for the gene 
pairs.
    But the text, which obviously I wouldn't ask you to try to 
read, is expressed in terms that are suitable for students and 
for the public, and is oriented around diseases. Nonetheless, 
the same data base, exactly the same, is used by and accessible 
by molecular biologists and physicians. One can go as far into 
the data base as he or she wishes simply by clicking. So that's 
one extreme.
    The second is a whole experiment which NCBI is doing with 
National Cancer Institute. It's called Cancer Genome 
AnatomyProject, and probably has been reviewed by NCI or perhaps will 
be. I know they got rescheduled.
    What we're showing here is the traditional histology. I'm a 
pathologist, so I'm used to looking at thousands of these. And 
this is a dilemma. Patient number two will get well with 
treatment. Their lymphoma will respond. Patient number one will 
die, because the drugs won't work. And yet the histology is 
identical. We just can't learn any more by looking at those 
haemotoxylin and eosin pictures.
    A new way to look at that problem is presented by these 
gene matrices. This scheme allows the examination for the 
activation or non-activation, the state, I guess you'd say, of 
10,000 genes. The representation here is that if there's a 
little red dot, it means that the gene is expressed strongly, 
and only in the patient on the left, in the case of the first 
one I gave you, the one that's a non-responder. If it's green, 
it means that the gene, which is coded by position, is strong 
only in the cases that do respond to the therapy.
    So this still doesn't tell you the answer to cure that 
patient today. But it is a clue to the persons doing basic 
research in oncology, which the traditional histology has 
simply denied us.
    So again, I thank you very much for putting up with the 
technology. But I did want to show you that we live by the 
sword and die by the sword after, lean on the computers.
    Thank you.
    [The prepared statement follows:]


[Pages 1623 - 1629--The official Committee record contains additional material here.]



    Mr. Porter. Dr. Lindberg, do you have an additional 
statement beyond the demonstration?
    Dr. Lindberg. No, I thought I'd just respond to your 
questions. I guess I should give you the President's budget 
request, which is, as you probably know, $171.3 million, plus 
an estimated contribution from AIDS to a total of $174.7 
million.

                             internet users

    Mr. Porter. What do you make of the 30 percent increase in, 
I guess you'd call them hits, on your site coming from the 
general public?
    Dr. Lindberg. I think it indicates that there's been a 
tremendous thirst for information about health and disease on 
the part of the public. I'm impressed myself, every day, by the 
extent to which patients are educated and anxious to 
participate in their own health care, as contrasted with when I 
was a beginning student, when I think they really were neither.
    Mr. Porter. Someone commented on the incredible amount of 
medical information the population gets from the show ER. 
[Laughter.]
    Have you heard this?
    Dr. Lindberg. It's pretty popular.
    Mr. Porter. If you want to get something in the minds of 
the public, you have to get it on ER and it will get there. 
Obviously, you did a very good job of showing what can be done 
with information through the media.
    Dr. Lindberg. I probably should say that that story they 
showed is a true story. That is a real search, it really was 
done. I don't know where they think their hospital is, but this 
particular hospital was in Atlanta where the search was 
actually done.
    Mr. Porter. So you can now look up numb chin and get the 
same result that they got?
    Dr. Lindberg. You can, unfortunately, it's not a happy 
sign. In the case where it was reported to us, it was actually 
a first sign of a malignancy. But at least they could get 
treated right away.
    Mr. Porter. You mentioned Lake County in your statement, it 
just happened to be in Oregon. Part of my district is in Lake 
County, Illinois, so it was close. [Laughter.]
    I was beginning to wonder whether that was part of my 
district.

                              telemedicine

    Dr. Lindberg. Well, as you know, the telemedicine works in 
cities just as well as it works in the remote rural areas. And 
there are telemedicine applications in Chicago. And in fact, 
there are telemedicine applications in Washington, D.C., an 
ambulatory renal dialysis clinic that Georgetown runs. It has 
an NLM telemedicine experiment.
    The actual clinic is sort of around the corner from Union 
Station. But the nephrologists, of course, are all back at 
Georgetown, and can't be everywhere. First, we thought it was 
rather stretching to apply, but we now see the wisdom of it. I 
mean, it actually allows them to look at the status of those AV 
shunts, which is the major reason for renal dialysis failing 
and the major reason for hospitalization.
    So even in a city, telemedicine has really quite a lot to 
offer.
    Mr. Porter. I may have mentioned this to you, but if I 
didn't I want to. I was visting a community health center in 
the inner city of Chicago. They were showing me the various 
things they do, and as I walked past a television, or a 
computer monitor, there was the National Library of Medicine on 
the screen.
    Dr. Lindberg. Oh, good.

                 molecular biology information services

    Mr. Porter. So they were hooked right into you, and were 
using your resources for their work very directly.
    At last year's hearing, we discussed the problem of not 
having enough Ph.D.'s trained in computer science information 
technology and genetics to help manage the overwhelming 
quantities of data being produced from genetic sequencing. We 
also discussed the possibility that private industry would lure 
these specialists away from academic, thus depleting the talent 
needed to train the next generation.
    At this time last year, this wasn't a problem. With the 
Human Genome Project coming on line ahead of schedule and other 
technological advances happening at a rapid pace, where do we 
stand on all this today? Has the picture changed over the last 
year?
    Dr. Lindberg. Oh, I think there will be a severe shortage 
of people who understand informatics and molecular biology. 
There's no question at all about that. I think we have foreseen 
it to some extent. NLM can only do what a small institute can 
do.
    But we support 12 training grants in medical informatics 
and have for some 25 years. All of those currently train people 
in molecular biology. Only one of them, Rice-Baylor, focuses 
exclusively on molecular biology. We suspect that it would 
probably be a good idea, if we could, to support a few 
additional ones.
    There are a lot of other parts of the question to support 
people and entice them into that field. Creation of information 
resources I think is part of it, to make it so that researchers 
can get at the information no matter where they are, and no 
matter where the information is. There are a number of such 
knowledge sources that I could mention that NLM does support.
    Beyond that, there are the medical schools. Medical 
schools, by and large, at the moment, don't spend--there are 
many things they don't teach us enough about, but one of them 
is computing. Probably molecular biology is in that category as 
well. Because all of these things are new, with respect to the 
old curriculum, and there's not space enough for all of them.
    In this Next Generation Internet scheme, many people are 
enthusiastic about remote learning, adult learning, teaching at 
a distance. It may be that that will be one of the answers in 
recruitment of persons into that field. Dave Lipman tells me 
that on the NCBI home page, the one I showed you about diseases 
and the gene maps even, that students use it quite a lot.
    They think they are actually recruiting middle school and 
high school students into this field, because they actually do 
experiments in such classes, I think even in this city, to 
determine short sequences of nucleotide sequences out of gene 
parts, and then submit those and find out if it's a new 
discovery or add it to what's already there. I can hardly 
imagine that a student wouldn't be enormously excited by that 
opportunity.

                        next generation internet

    Mr. Porter. You're requesting a study by the National 
Research Council at the National Academy of Sciences to look at 
the elements that will be required in order for the Next 
Generation Internet to be of maximum service to health care and 
medical research. Do you expect to have the 
Council'srecommendation in time to proceed full scale with the 
initiative?
    Dr. Lindberg. Yes, sir. They actually did quite a good job 
in other studies they've done for us, the Computer Science and 
Telecommunications Board did a study on medical data privacy 
and what would be involved in assuring such to the patients. 
We're quite pleased with that study.
    Now we're asking them essentially to look at the Next 
Generation Internet project and tell us what would it have to 
look like in order to be maximally useful to health care 
applications and to biomedical research. I'm confident they 
will be able to do that.
    They'll focus, no doubt, on certain features of the Next 
Generation Internet that will be from an applications point of 
view. For example, the capacity of the Internet, the quality of 
the communication, the reliability and the security. Those are 
terms that I think are meaningful to both you and me. But in 
order for it all to work, that has to be translated in a kind 
of engineering terms, such as jitter and latency and meantime 
to failure, and addressing schemes and recovery schemes, the 
technical parts.
    So I hope that this will help us, since the Computer 
Science and Telecommunications Board has plenty of computer 
science capability and engineering. I'm hoping that that will 
short-circuit some of the troubles which the biomedical people 
would otherwise be enmeshed in, and allow us, our people, to 
deal from an applications point of view, to tell us what is 
required in order to do mammography, what is required in order 
to do teledermatology, what is required to do these other 
health care applications that we so much need.

                          internet advertising

    Mr. Porter. This is a policy question that Dr. Varmus may 
want to comment on as well. The pharmaceutical industry spent 
about $600 million advertising prescription drugs directly to 
patients on the Internet last year. FDA regulates prescription 
drugs, but what about advertising on the Internet? Who's 
monitoring what's being advertised there, and do you think this 
is a problem?
    Dr. Lindberg. Are you asking Dr. Varmus?
    Mr. Porter. I was asking both of you, so whoever would like 
to comment.
    Dr. Varmus. Actually, I think I would have to consult on 
that. We don't have any oversight of what they're doing. And I 
was unaware of the number, or that the cost was that large. I'd 
rather consult on that.
    Mr. Porter. I think they also advertise prescription drugs 
on television, if I'm not mistaken.
    Dr. Varmus. Yes.
    Mr. Porter. That puts a certain amount of pressure on 
professionals. But I don't know whether that's----
    Dr. Varmus. They're advertising in the newspaper as well. 
They are obviously free to do that. I would rather reserve 
judgment.
    Mr. Porter. So we haven't studied the implications of this?
    Dr. Varmus. No, we certainly haven't, and I'd rather 
consult with my colleagues at the FDA and get their views 
before I comment publicly.
    Mr. Porter. I assume, Dr. Lindberg, you want to do the 
same.
    Dr. Lindberg. Sounds right.
    Dr. Varmus. Very wise. [Laughter.]
    Mr. Porter. Mr. Stokes?
    Mr. Stokes. Thank you very much, Mr. Chairman.
    Dr. Lindberg, nice to see you again.
    Dr. Lindberg. Thank you, sir.

                                outreach

    Mr. Stokes. Dr. Lindberg, to what extent has the Library of 
Medicine been able to conduct effective outreach efforts with 
respect to environmental hazards and pollutants, and 
particularly as it relates to disadvantaged and minority 
populations?
    Dr. Lindberg. I understand the question. We've been 
interested in and concerned about the problem for quite a long 
while. Again, as a small agency, we do what we can.
    But our basic job is to acquire, organize and disseminate 
information for the benefit of the public health. We do this 
through a couple of dozen data bases that relate to toxicology 
and environmental health. Very often, data comes from other 
agencies, NIOSH, CDC, ATSDR, etc., and sometimes funding comes 
along with those as well.
    There are two persistent problems in this field. One, the 
data bases have on several occasions been examined by experts, 
let me just say, including the National Academy. They're always 
given very high grades for quality. And yet I think they're 
under-used by the health care fraternity in general.
    And we actually started eight years ago to look into the 
question what could be done to improve and increase the use of 
it. We paid particular attention to minority populations, 
because we had heard that in fact, such populations are more at 
risk for environmental hazards at home and work.
    So we thought we would look in on the HBCU group of 
schools, particularly those that had health components, 
medicine and dentistry or pharmacy. And it turned out that they 
were under-users also. So we started a program aimed at that 
group of schools that's been really very, very helpful. A lot 
of guidance has been given by the deans and chairmen of those 
schools. We started with them, and then we started with 
faculty, and then we've worked with students and graduate 
students and equipment, connections to Internet as that came 
along, that whole business.
    There was enough enthusiasm from ATSDR that they actually 
contributed money such that we could go from our original set 
of 9 schools to 42 schools. I think a lot of headway has been 
made in that respect.
    In the end, there was a great difficulty in understanding 
chemical problems if one isn't trained in chemistry. So we 
found that it has been helpful to provide special training to 
groups that might take an interest in environmental health. 
That's been done both at the community level and also at the 
level of medical librarians and the toxicology meetings and the 
pharmacy departments.
    So I would say in general we're doing a reasonable job with 
it. Now, there are several uncompleted pieces we haven't had 
time or money to get to. We started one recent one that I think 
you might find encouraging. There's a project called SPRY, 
which I have to always look up what it means, oh, yes, Setting 
Priorities for Retirement Years. I mean, actually they put a 
high priority on having a cute name. [Laughter.]
    Mr. Stokes. I'd be interested in that.
    Dr. Lindberg. Essentially, that group wishes to get older 
people, senior citizens and also particularly minority, and 
particularly urban groups, informed about how to use Internet 
for their own purposes, basically. But in our case, we're 
particularly interested in this environmental health issue.
    So we've started a train the trainers program. And this is 
operating now in 20 cities, 20 cities and 14 States. That seems 
to be encouraging. My colleague, Mr. Smith, points out that 
Cleveland, Ohio, happens to be one of those. And that's not a 
surprise.
    Mr. Stokes. I'm pleased to hear that.
    Dr. Lindberg. They're on the ball.
    So that's going to put sort of power to the people, I 
suppose, is the principle behind this. This will give the 
people, in this case the elderly, the ability to make their own 
searches, find out how their own communities are doing.

                              free medline

    Mr. Stokes. Your answer sort of leads me into my next 
question, and that's with reference to the fact, as you know, 
this past June, Vice President Al Gore came to Capitol Hill and 
introduced Congresspersons and staff to the new free Web-based 
access to MEDLINE. This approach, of course, offers the public 
wider access to up-to-date information on state of the art 
treatment, diagnoses and prevention health information.
    Such information is of course becoming more and more 
critical in our ever-changing health care system, especially in 
this managed care era. Today, a patient has to play a more 
direct and active role in his or her treatment.

                      health information resources

    What major efforts do you have in mind for extending the 
availability of health information?
    Dr. Lindberg. We have big plans. I don't know how fast 
we'll get them all achieved. But we agree with exactly what you 
indicated, particularly the new health care reform, that the 
best protection that a patient and a family have is direct 
access to the best information, which is of course in the peer 
reviewed public literature.
    We're really taking three approaches to this. Firstly, we 
think that we probably can and should enhance the content of 
the library data bases, if they're going to be aimed at the 
public. So we have already added a string of consumer 
newsletters and journals about consumer health, and taken the 
pains to be sure that the index and terminology is something 
that we think is suitable. We hope it's suitable.
    I think I indicated that the genome map frankly caters to 
the public. I mean, it's got a tremendously good readership of 
students and the public, and we want to do more of that. 
Actually, Dr. Varmus has spoken about that to Dr. Lipman. We 
were originally afraid we would talk down to people. When we 
found that someone with the background of the Director could 
take an interest in it, it's encouraged us to go further.
    Clinical practice guidelines is another area that I know 
the committee has had an interest in as well as we. We have 
arrangements with the Agency for Health Care Policy and 
Research to, let's just say for the moment, integrate our 
efforts, so that the patient would benefit.
    I think, Mr. Stokes, I should also say, in a way it's 
repeating the obvious, but the last 10 or 15 years have brought 
a whole lot of new areas, therefore a whole lot of new data and 
a whole lot of new collections for us. Women's health is one of 
the areas, AIDS is one of the areas that didn't exist before. 
And we've added those.
    Now the Congress has taken an interest, and this committee, 
even, in complementary and alternative medicine. That is an 
intellectual area that is represented by journals and 
terminology. We've addressed that as well, and we think we know 
that that's of interest to consumers.
    So those are the steps that we're taking. And we have a 
long way to go. But the one last step that needs to be taken, I 
would say, for not only this question but for the whole 
country, is to be sure that everybody, to the extent we're 
capable of that, certainly every town and every school, every 
hospital, has access to the Internet. That isn't the case in 
this country yet. And where there is access, it often isn't 
wonderful.
    So we are participating in Next Generation Internet. We're 
also ourselves doing a string of surveys to try to make sure 
that things continue to improve in that respect, to monitor, to 
push it, to give connection grants to those that are having 
trouble getting connected. I think that's the general domain 
that we have to work in.

                              telemedicine

    Mr. Stokes. I was very impressed by the presentation that 
you gave us here this morning with reference to telemedicine 
and technology. When we talk about telemedicine in terms of 
being user friendly, how is this reflected in access by inner 
cities and, remote, rural areas of the country?
    Dr. Lindberg. Yes, I think the main thing, I do understand 
your question, and I think the answer clearly is, yes, it's 
important. But I think we can't lose sight of effectiveness. I 
mean, the doctors that saw one of the patients I showed you had 
this terrible eruption for five years. Well, he probably saw 
lots of nice people and they smeared stuff on or wiped stuff 
off or gave him antibiotics and were kind to him. But it was 
all the wrong thing. It wasn't the right diagnosis. I mean, 
isn't it so much better if you just take the time and, all 
right, it takes 15 minutes for the things to be transmitted. 
But you waited five years, so 15 minutes doesn't matter.
    I mean, the technology has to be effective. It has to be 
high quality. It has to work. And I think in rural areas or 
urban areas or anywhere, we all appreciate that most.
    Mr. Stokes. Thank you very much, Doctor, my time has 
expired.

                      health information resources

    Mr. Porter. Mr. Stokes, we'll have a quick second round 
here.
    Let me ask you Dr. Lindberg, about the volume of published 
or available information that is growing hugely. It's already 
huge and it's getting larger all the time. I think people who 
look on the Internet often find too much information. Is there 
any way to give qualitative direction through what you've put 
on the web to direct people to the best information and what 
they might want more easily?
    Dr. Lindberg. Yes, it's a very, very important question. 
And I can't say that we know exactly what to do about it. We 
worry about it a lot.
    We definitely are very, very careful to whom NLM links. 
Because it is a heavily-used page; it may be one of the most 
heavily used. And legalisms aside, we don't want it to be an 
implied endorsement when we switch somebody to a source that 
isn't really good.
    So we in general don't do that. We switch to other parts of 
our institution, of NIH, sometimes within HHS. Or labeling the 
nature of the link, we will switch to universities that have 
been given grants by us and then the connection is very 
obvious. So all those telemedicine projects, for instance, have 
home pages.
    But I don't think that's a good ultimate answer to you. 
There is another level of implication, of course, in the 
literature that we embrace, if you will. We subscribe to 
something like 25,000 journals of one sort or another. We 
index, in round numbers, 4,000. So we've already sort of 
skimmed the cream off the top. And this is done by a peer 
review process: NIH and HHS actually chartered committees, and 
with great care. But still, that is the cream.
    Beyond that, everyone is a bit confused, to be frank. There 
are a number of places that purport to give you a list of URLs, 
as they say, the addresses of what's cool and what's new and 
what's fun. That doesn't seem relevant to any of the questions 
that this committee would ask, because you want to ask what's 
medically important and relevant.
    Our answer is that we switch to institutions we know to be 
good. We switch to research grants that we know got a very high 
priority and are done by sincere and hard-working people. As I 
say, we now are bringing into the main MEDLINE materials that 
are created by consumer groups. So for instance, some of the 
new additions that we've just made this month are FDA Consumer, 
then of course, Harvard Health Letter and Men's Healthwatch. 
The Harvard and the Hopkins ones are well known.
    There are other journals such as the Mayo Clinic Health 
Letter and Health News from the New England Journal of 
Medicine. There's one we put in on breast feeding review which 
actually comes from Australia. That was picked by the 
biomedical library reviews, by our own reviewers; our chartered 
group. And MedScape Women's Health also that went through a 
peer review.
    So we're bringing different voices, I suppose, more than 
any orchestration, but selected voices carefully. I don't know 
how to go further, I truly don't.
    Mr. Porter. Is there a need, and maybe Dr. Varmus wants to 
comment on this, is there a need to look at this even more 
broadly and pull together some others, even outside the 
Institute, that might have thoughts on all this?
    Dr. Varmus. There is a cohort of computer-savvy people, not 
necessarily within the NIH, that happen to know something about 
this. One of my former post-doctoral fellows is heavily 
involved in evaluating Internet sites for information on health 
and information on science. The average scientist going to get 
more information about technology or about allied fields, there 
is a plethora of available sites, but not all of them are up to 
date or highly reliable.
    Some of the journals--Science, the Journal of the American 
Medical Association and others--now have technology and web-
oriented sections of their journals that allow their readers to 
be guided to particularly effective web sitesafter someone who 
is knowledgeable has reviewed a large number of sites.
    Mr. Porter. Mr. Stokes.

                              free medline

    Mr. Stokes. Thank you.
    You mentioned earlier that on the MEDLINE services there's 
a category known as Women's Health. Is that correct?
    Dr. Lindberg. Yes. Well, it's an intellectual domain, 
anyway, that's represented.
    Mr. Stokes. Can I also go on MEDLINE and find a category in 
terms of minority health?
    Dr. Lindberg. Oh, sure, absolutely.
    Mr. Stokes. Tell us what we'll find there.
    Dr. Lindberg. You'll probably find a great deal written 
about it. Now, it has that same issue. In this case, what 
you'll find is all peer reviewed articles in the traditional 
journals. And no doubt, there will be many different aspects. 
I'm sure that you'd get so many that you'd want to say narrow 
your search to say, tuberculosis and hypertension and whatever. 
There would be many, many such articles.

              historically black colleges and universities

    Mr. Stokes. I'm pleased to hear that.
    You mentioned earlier Historically Black Colleges and 
Universities. If I understood you correctly, they are not quite 
up to par in terms of the new technology, is that correct?
    Dr. Lindberg. Well, I hope they are now. I think they 
weren't at the time we started our study. But I mean, the nine 
HBCUs that we worked with initially are Drew, Florida A&M, 
Howard, Meharry, Morehouse, Texas Southern, Tuskeegee, 
University of Arkansas (Pine Bluff) and Xavier.
    So you know, that covers quite a big range. Obviously 
Howard is looked upon by the others as being rather fortunate 
and in rather good shape. But I think in the confidence of the 
group that formed, they essentially said, well, look, it isn't 
a matter of equipment alone. Some of us need to get better 
equipment. But we all need to get a better understanding. And 
they joined hands to start a program which, as I said, has 
lasted eight years now, to be certain that the leadership of 
the school and the senior faculty had a good understanding of 
what we at NLM have and others had in the way of data bases and 
support, and also a way to keep current.
    So I think we've plugged the holes as far as those schools 
being behind. I'm not sure they aren't ahead right now, to be 
truthful. They certainly had a very sincere, good effort.

                          science recruitment

    Mr. Stokes. I'm also very pleased to hear that. The fact 
that you have been so sensitive and responsive to that area is 
commendable.
    Recently, the media has been reporting on a possible 
shortage of highly skilled, highly technical personnel, 
especially in the computer field. Is the Library experiencing 
this type of thing in recruiting or in being able to retain 
persons in this area?
    Dr. Lindberg. I think what you say is true generally, 
particularly in cities like Washington, where the unemployment 
rate for those kind of people is very close to zero. They're 
greatly sought after.
    I think we're doing okay in the Library and at NIH. But I 
think we are concerned about the role that we and NIH need to 
play in, first of all, recruiting new people to science, to 
recruiting minorities to science, and making sure that there is 
technical training made available. We have only 12 programs, 
but those are quite good. They deal by and large with pre-doc 
and post-doc education, I shouldn't say training, really, it's 
education.
    We've had a little bit of contact with the high school 
level, Coolidge High School. At NIH, each of the institutes has 
a kind of a little brother school, if you will. So ours has 
helped us a great deal to understand what it would take to 
inspire boys and girls at that age to science.
    As I say, I think NCBI is doing a very, very fine job with 
the Entrez and the home page that draws high school students 
into science. Maybe you'd want to ask Dr. Lipman to comment on 
that.
    Mr. Stokes. Dr. Lipman, would you like to comment?
    Dr. Lipman. Thank you. I agree with everything Dr. Lindberg 
has said.
    Dr. Lindberg. That's good. [Laughter.]
    Dr. Lipman. I would point out that since we're an 
intramural group, one of the best things we can do beyond the 
outreach that we're doing with the web site to intrigue high 
school and college students in the area and educate them is 
that we obviously train post-docs and graduate students 
ourselves. We also have high school students coming through and 
so forth.
    And although that's just a drop in the bucket in terms of 
the number of people, sometimes these individuals can make a 
big impact. So that's a great opportunity that we have to work 
with young students and we would look forward to increasing 
that.
    Mr. Stokes. Thank you, Dr. Lipman. Thank you, Dr. Lindberg.
    Thank you, Mr. Chairman.
    Mr. Porter. Mr. Stokes, thank you.
    Dr. Lindberg, thank you so much. You're doing a wonderful 
job there and we appreciate your coming to testify today. It's 
always fascinating to listen to all the developments that are 
occurring and thank you for the fine job you are doing.
    Dr. Lindberg. Thank you.
    Mr. Porter. We have two votes on at this time and I must be 
at a meeting with the Speaker at noon. I'm going to attempt to 
find another person to chair in my absence. We may be able to 
get started, at least, and see how we go. If not, we're going 
to have to reschedule, because we're going to run up against a 
time limit, but let's see what we can do.
    We'll stand in recess for the votes.
    [Recess.]
    [The following questions were submitted to be answered for 
the record:]



[Pages 1640 - 1682--The official Committee record contains additional material here.]















                               I N D E X

                              ----------                              

                 National Institutes of Health Overview

                                                                   Page
AIDS.............................................................   219
Alzheimer's Disease..............................................   235
Appreciation of Mr. Stokes.......................................     2
Asthma...........................................................   218
Autism...........................................................    40
Behavioral Changes...............................................    41
Behavioral Research.............................................86, 236
Bioethics........................................................   232
Budget:
    Allocation of Additional Resources...........................    47
    Budget Consultation Process..................................   188
    Chronology of Budget.........................................    55
    Director's Discretionary Fund................................    57
    Transfer Authority...........................................    72
Cancer:
    Breast Cancer Funding........................................   244
    Cancer Initiative............................................    43
    Ovarian Cancer...............................................    44
    Prostate Cancer.............................................99, 110
Clinical Research:
    Clinical Research......................................25, 118, 233
    Clinical Research Awards....................................34, 242
    Definition of Clinical Research..............................    39
    NIH Director's Panel on Clinical Research....................    87
    Outreach in Clinical Research Centers........................    42
    Status of Clinical Research Awards...........................    36
Cloning Research.................................................    54
Co-Funding of Meritorious Science................................    37
Consensus Conference on Health Centers...........................   100
Creutzfeldt-Jakob Disease (CJD)..................................    92
Decline in Physician Scientists..................................   243
Diabetes:
    Diabetes Conference.........................................34, 244
    Diabetes Research.......................................27, 85, 102
    Diabetes Research Investment.................................    32
    Diabetes Research Working Group..............................    29
    Funding for Diabetes.........................................    97
    National Diabetes Education Program..........................    97
Disease Areas:
    Earmarking...................................................    20
    Fifty Percent Increase.......................................    48
    Funding......................................................    38
    Research on Special Diseases.................................    62
    Research Spending per Death for Selected Diseases............    98
Drug Development.................................................   195
    Reasonable Pricing...........................................    26
Earmarks.........................................................    46
Earmarks for Biomedical Research.................................    95
Extramural Construction..........................................   194
Extramural Infrastructure........................................    98
Five Year Review of Institute Directors..........................    52
Food-borne illnesses.............................................    40
Food Safety......................................................    74
Foreign Research.................................................    65
Funding of Peer Reviewed Research................................    37
Full Time Equivalent.............................................    58
FY 1997 Emergency Supplemental Funds.............................    73
General Clinical Research Centers................................   237
    Decline of GCRC Budget.......................................    42
    President's Initiative and GCRC Outreach.....................    43
Genome Projects..................................................    75
Global Health Activities.......................................206, 239
Grants:
    Grantee Compliance...........................................    72
    K-23, K-24 and K-30 Awards..................................35, 245
    Number of Activities.........................................    62
    Success Rates................................................22, 64
GRPA Performance Measures.......................................50, 122
Health Disparities...............................................    29
Hepatitis C......................................................   226
Historic Opportunity.............................................   224
How Children Learn...............................................   121
Indirect Costs...................................................   195
Infant Mortality.................................................   231
Information Dissemination........................................   203
Infrastructure:
    Critical Research Infrastructure.............................   217
    Need for Infrastructure Investment...........................   218
    Research Infrastructure......................................   225
Imaging Services/Technology......................................   113
International Health.............................................    43
Introduction of Witnesses........................................     2
IOM Priority Setting Study.......................................    50
Investigator-Initiated Projects..................................   114
Involvement of Outside Entities..................................   188
Managed Care Costs...............................................   196
Measures of Success..............................................   185
Mind and Health..................................................    21
Minority Health:
    Closing the Health Disparity Gap.............................   210
    Coronary Artery Disease and Stroke...........................   216
    Diabetes.....................................................   215
    HIV/AIDS in the Minority Communities.........................    31
    IOM report on Cancer Research in Minorities..................   214
    Minority Health Investments..................................   209
    President's Initiative on Minority Health....................    30
National Institute of Environmental Health Sciences Success Rates   187
National Institute for the Environment...........................   224
NIH Overview FY 1999 Budget......................................   247
NIH Research Opportunities.......................................   146
NIH Collaborations:
    NIH and NASA Collaboration...................................    44
    NIH and DOE Collaborations...................................    45
    Collaborations Among Federal Agencies........................    45
New Proposals Funded.............................................    23
New Research.....................................................   118
Number of Committees.............................................    82
Nutrition:
    Obesity and Nutrition.......................................33, 103
    Cancer and Nutrition.........................................   106
        Trials...................................................   106
        Dietary Changes..........................................   106
Office of Research on Minority Health (ORMH).....................   223
    Joint ORMH/Institute Projects................................   228
    ORMH Accomplishments.........................................   230
    ORMH Funding.................................................   230
    Role of ORMH.................................................    31
Office of Research on Women's Health.............................   237
Partnerships:
    Collaboration of Resources...................................   119
    Investment in Biomedical Research and Private Industry.......   189
    Public and Private Partnerships..............................    81
Peer Review Process.............................................53, 116
Political Influences.............................................    39
Politicization of Research.......................................    37
Public Education Activities......................................    61
Quality Control of Study Sections................................   205
Rate of Budget Increase..........................................    24
    100 Percent Increase.........................................    22
    50 Percent Increase..........................................    24
Rates of Inflation...............................................    64
Recommendations: Review of NIH Administrative Structure..........   145
Research Based Science...........................................   116
Research Management and Support.................................60, 124
Rett Syndrome....................................................   234
Scleroderma......................................................   227
Statement of Harold E. Varmus, M.D., Director, NIH...............     3
Success of NIH Funding...........................................    31
Third Party Payment..............................................   208
Witnesses........................................................     1
Women's Health Initiative........................................   246

                       National Cancer Institute

A National Agenda................................................   493
Access to Quality Health Care....................................   382
AIDS:
    Advances in AIDS Research....................................   497
    AIDS Vaccines................................................   385
    AIDS Among Minorities........................................   494
Alternative Treatments...........................................   510
Angiogenesis...................................................335, 397
Annual Report Card on Cancer Statistics..........................   333
Application of Discoveries.......................................   377
Barriers Information on Clinical Trials..........................   404
Biological Characteristics--Obesity..............................   380
Breast Cancer:
    Breast Cancer Detection......................................   356
    Breast Cancer Due to Exposure of Vinyl Chloride..............   511
    Breast Cancer Grants.........................................   363
    Breast Cancer Mortality Rates................................   379
    Breast Cancer Rates in San Francisco.........................   371
    Breast Cancer Risk Factors...................................   371
Budget Justification, Estimates of...............................   515
Budget for FY 2003...............................................   452
Bypass Versus President's Budget.................................   457
Cancer Advocacy..................................................   446
Cancer and Infectious Agents.....................................   505
Cancer and Poverty...............................................   381
Cancer Causes as a Percentage of Cancer Cases....................   459
Cancer Centers Review Group Report...............................   398
Cancer Cube......................................................   405
Cancer Effort at NIH.............................................   357
Cancer Funding--Effects on Society...............................   355
Cancer Genetics:
    Cancer Genetics Network Versus Human Genome Project..........   422
    Cancer Genome Anatomy Project................................   387
Cancer in Minorities.............................................   485
    Effects of Cancer on Minority Populations....................   379
    IOM Study--Cancer Among Minorities...........................   494
    Morality Among Black Men.....................................   379
    Minority Health Offices......................................   421
Cancer Mortality Rates...........................................   479
Cancer Statistics................................................   461
Cancer Survivorship..............................................   416
Causes of Cancer.................................................   480
Cervical Cancer..................................................   499
Children and Cancer..............................................   441
    Children and Cancer Effects..................................   446
    Children and Cancer Treatment................................   442
Circuitry of Cancerous Cells.....................................   352
Clinical Data Update System......................................   391
Clinical Research System.........................................   377
Clinical Trials................................................334, 488
    Clinical Trials--Breast and Colorectal Clinical Trials.......   358
    Clinical Trials By Type of Cancer............................   426
    Clinical Trials Databases....................................   383
    Clinical Trials--Informatics Clinical Trials.................   336
    Clinical Trials--Prevention and Therapy......................   334
    Clinical Trials Program Review Group.........................   418
    Clinical Trials--Progress in Treatment.......................   334
    Major Unfunded Clinical Trials...............................   491
Collaborations with DOD and DARPA................................   370
Collaborations with CDC..........................................   414
Colorectal Cancer:
    Colorectal Cancer--Prevention................................   364
    Colorectal Cancer--Therapeutic Interventions.................   364
Control and Prevention...........................................   339
Coordinating Review with DOD.....................................   374
Coordination Efforts.............................................   430
Coping with a Predisposition to Cancer...........................   436
Development of Interventions.....................................   377
Diet and Cancer..................................................   485
    Diet and Cancer in African American Women....................   486
    Dietary Guidelines...........................................   412
Digital Mammography and Telemammography..........................   420
Director's Consumer Liaison Group................................   396
Drugs:
    Drugs and Smart Assays.......................................   335
    Drug Development.............................................   365
    Drug Resistance..............................................   495
Emerging Trends..................................................   358
Environment and Cancer...........................................   503
Evaluation of Business Practices.................................   354
Fight Against Cancer.............................................   393
Five Year Cancer Survival Rate...................................   487
Funding and Cancer:
    Funding and Cancer...........................................   356
    Funding for Specific Cancers.................................   366
Genetics:
    Gene-Environment Interactions................................   353
    Genetics of Cancer...........................................   498
    Genetic Predisposition to Cancer.............................   353
    Genetic Testing as a Screen for Breast Cancer................   372
Grant Application Process........................................   367
Imaging:
    Imaging Research.............................................   436
    Imaging Working Group........................................   369
Improved Instrumentation and Early Detection.....................   369
Incidence Rates of Various Cancers.............................352, 375
Increase in Cancer Funding.....................................376, 493
Incremental Advances.............................................   339
International Cancer Information Center..........................   409
Investigator-Initiated Research..................................   441
Limits on Medical Science........................................   358
Lung Cancer......................................................   370
    Lung Cancer in Women.........................................   362
    Lung, Cancer Prevention......................................   363
Multi-Valent Vaccine Against Cancer Causing Strains of HPV.......   387
NCI Reorganization...............................................   354
NCI PDQ..........................................................   382
NCI Funding......................................................   382
Needle Exchange Program..........................................   384
OAR:
    OAR Funding..................................................   385
    OAR--Levine Commission.......................................   384
Opening Statement................................................   337
Ovarian Cancer...................................................   508
    Ovarian Cancer Collaboration with DOD........................   374
    Ovarian SPORE................................................   374
Partnerships Between NIH and Private Industry....................   377
Patient Access to Clinical Trials..............................391, 439
PDQ..............................................................   421
Pharmaceutical Industry..........................................   366
President's Cancer Initiative..................................376, 393
Prevention:
    Cancer Prevention............................................   359
    Cancer Primary Prevention....................................   460
    Prevention...................................................   480
    Prevention Activities........................................   461
Progress:
    Progress in Cancer...........................................   333
    Progress Review Groups.......................................   400
    Progress Toward a Cure.......................................   357
Prostate Cancer................................................501, 507
    Prostate and Breast Cancer Progress Review Groups............   402
    Prostate Cancer Among Hispanic Men...........................   432
    Prostate Cancer in African-American Men......................   381
    Prostate Cancer Progress Review Group........................   424
    Translating Prostate Cancer Research into Clinical Trials....   433
PSA Testing as Screening.........................................   389
Psychosocial Interventions.......................................   512
Rapid Access to Intervention Development.......................335, 378
Recruitment of Scientists and Researchers........................   360
Research Project Grant Pool......................................   407
    Specialized-Comprehensive Research Centers...................   412
    SPORE Grants.................................................   399
Screening:
    Screening Alternatives to Mammography........................   369
    Screening and Early Detection................................   380
    Screening for Ovarian Cancer.................................   373
Smoking and Behavior.............................................   362
    Residual Effects of Smoking..................................   376
    Smoking and Behavior in Youth................................   360
Strategic Technology Specialist..................................   419
Stress and the Incidence of Cancer...............................   353
Ten Year Budget Mechanism........................................   482
The Fruits of Research...........................................   340
The Challenge....................................................   340
The Disparity Gap................................................   492
Therapy and Interventions........................................   359
Thiozolidinediones...............................................   357
Tobacco:
    Effects of Tobacco Use on Various Cancers....................   366
    Tobacco Assist Program.......................................   438
    Tobacco Cessation Initiatives................................   402
    Tobacco Use..................................................   360
    Youth and Tobacco............................................   360
Training and Fellowships.........................................   406
Trans-NIH Special Initiatives....................................   409
Transmission of HIV..............................................   385
Vaccine Development..............................................   497
Virtual Examinations.............................................   368

                         National Eye Institute

Age-Related Macular Degeneration.................................   640
Asthma Inhalants.................................................   637
Cataract Operations..............................................   639
Clinical Trials..................................................   657
Diabetes.........................................................   651
Diabetic Retinopathy.............................................   648
Glaucoma.......................................................653, 659
High Blood Pressure..............................................   643
Hispanic Education Program.......................................   651
Identification Technology........................................   653
Infrastructure...................................................   646
Introduction to Witnesses........................................   627
Laser Surgery Follow-up..........................................   639
Laser Surgery for Myopia.......................................635, 638
Macular Degeneration.............................................   655
Minority Health..................................................   642
Minority Health-African Americans................................   659
Myopia Causes....................................................   636
Myopia Clinical Trials...........................................   647
National Eye Health Program......................................   645
Neuroscience...................................................641, 656
New Specialized/Comprehensive Research Center....................   647
Opening Statement...............................................631-634
Plan.............................................................   658
Program Planning.................................................   636
Public Health Education..........................................   649
Research Techniques..............................................   661
Small Business Innovation Grants.................................   653
Spending on Eye Diseases.........................................   646
Vision Impairment and Rehabilitation.............................   658
Vision Research Plan.............................................   643
Wine Consumption and Macular Degeneration........................   644

                National Human Genome Research Institute

Applied Research & Outreach......................................   753
Autism...........................................................   750
Availability of DNA Sequencing DATA..............................   743
Breast Cancer:
    Risk of Breast Cancer........................................   721
    Breast Cancer in African-American Women......................   725
    Discovery of AIB1 Gene.......................................   761
Cancer Genetics Studies Consortium Recommendations...............   747
Center For Inherited Disease Research............................   743
Clinical Trials in NHGRI.........................................   731
Collaborations within NIH........................................   719
Complex Organisms................................................   748
Complexity of Biological Systems.................................   728
Congressional Role in Research...................................   714
Discoverers and Creators.........................................   740
Dissemination Information to Health Professionals................   723
DNA Sequencing:
    DNA Testing in Legal Proceedings.............................   742
    Cost of DNA Sequencing.......................................   715
    DNA Sequencing on Schedule...................................   714
Ethical, Legal, & Social Implications (ELSI).....................   726
Fear of Genetic Discrimination Impact on Clinical Trials.........   757
Food Genome Projects.............................................   718
Gene Based Health Care...........................................   758
Gene Discovery...................................................   708
Gene Therapy For Hemophilia......................................   735
Genetic Testing--Why Do It.......................................   716
Genetic Factors in Diabetes......................................   745
Genetic Counseling and Education.................................   723
Having Genomic Data Publicity Available..........................   733
Health Professional Education....................................   727
Howard University Collaboration..................................   724
Human Genome Project Progress....................................   709
National Human Genome Research Institute FY 1999 Budget..........   762
Opportunities....................................................   755
Ovarian Cancer Research..........................................   757
Parkinson's & Alzheimer's Disease--A Common Mechanism............   760
Patient Knowledge................................................   749
Pharmaceutical Companies.........................................   737
Pharmacogenetics.................................................   732
Predisposition to Cancer.........................................   720
Privacy and Confidentiality......................................   733
Prostate Cancer & Breast Cancer..................................   751
Research Centers.................................................   745
Similarity Between Humans, Animals, & Plants.....................   718
Single Nucleotide Polymorphisms (SNP's)..........................   756
Solving Problems--Relieving Suffering............................   738
Statement of Francis Collins, M.D., Ph.D., Director, NHGRI.......   695
Task Force on Genetic Testing Recommendations....................   744
Technology Development...........................................   746
The Human Genome Project.........................................   730
The Health Disparity GAP.........................................   754
Third Five-Year Plan for Human Genome Project....................   742
Year 2000 Compliant..............................................   724

         National Institute of Allergy and Infectious Diseases

AIDS:AIDS..................................................
    877, 884AIDS Clinical Trials.................................
838AIDS Funding........................................................
848AIDS in Minorities............................................
    839, 855AIDS Treatment.......................................
838AIDS Vaccine Liability..............................................
836Development of an AIDS Vaccine......................................
840HIV Treatment Guidelines and the Ryan White Act.....................
846Improved Drugs for HIV Treatment....................................
853Office of AIDS Research.............................................
837Outreach Activities.................................................
                                                                    840
Applied Research and Outreach....................................   879
Articulating the Importance of NIH Research......................   852
Asthma...........................................................   888
Asthma Research..................................................   842
Autoimmune Diseases............................................861, 867
Centers of Excellence in Immunology..............................   850
Chronic Fatigue Syndrome.........................................   860
Clinical Trials..................................................   881
Diabetes Research................................................   851
Education Program on Primary Immunodeficiency Diseases...........   850
Food Safety......................................................   859
Future Cost of Research..........................................   836
Global Health....................................................   841
Hantavirus.......................................................   860
Hemophilia.....................................................854, 869
Hemophilia Treatment.............................................   870
Hepatitis A Vaccine..............................................   867
Hepatitis C......................................................   891
Hepatitis C Virus................................................   845
Historically Black Colleges and Universities.....................   882
Infectious Diseases..............................................   857
Intergovernmental Cooperation in International Initiatives.......   847
International Vaccine Institute..................................   863
Kentucky Tuberculosis Outbreak...................................   872
Lung Hemorrhage in Infants and SIDS..............................   891
Micorbial Association with Cancer................................   841
Migraine Headaches...............................................   873
Minority Health Disparity Gap....................................   878
New and Reemerging Infectious Diseases...........................   887
New Research Programs on the Immune System.......................   894
Opening Statement................................................   801
Organ Shortages..................................................   875
Organ Transplantation............................................   895
Primary Immune Deficiency........................................   862
Progress in the Development of a Vaccine for Cholera.............   865
Public-Private Partnerships......................................   849
Range of Studies.................................................   876
Research on Hepatitis C Virus....................................   865
Sexually Transmitted Diseases....................................   844
Sinusitis Research...............................................   863
Spread of Tubercolosis...........................................   868
Support for Topical Microbicide Research.........................   894
Tissue Transplant................................................   875
Topical Microbicides.............................................   852
Transplantation..................................................   873
Tuberculosis Research............................................   866
Vaccine Development..............................................   864
Vaccine for Diabetes.............................................   865
Various Spending Levels..........................................   862
Witnesses........................................................   801

          National Institute of Environmental Health Sciences

Agricultural Health Study.....................................989, 1004
Air Quality and Asthma...........................................   970
Asthma...................................................969, 996, 1008
Biomedical Research Opportunities................................   966
Body Burden 2000..............................................980, 1000
Carcinogenicity Tests............................................   948
Chemicals, Potentially Harmful...................................   963
Children:
    Childhood Learning...........................................  1007
    Children's Health............................................   965
    NIEHS Research Affecting Children............................   994
Chronic Beryllium Disease........................................  1010
Community-Based Prevention/Intervention..........................   989
Competing Research Projects......................................   986
Deformed Frogs...................................................   973
Electric and Magnetic Fields..................................992, 1005
Environmental Estrogens..........................................  1006
Environmental Genome Project..................................978, 1005
Environmental Justice..........................................987, 998
External Reviews.................................................   975
Government Performance and Results Act...........................   973
Hormonally Active Compounds and Cancer...........................  1009
Inappropriate Use of Research....................................   995
Individual Susceptibility........................................   994
Institute for the Environment....................................   970
International Projects...........................................   990
Intramural and Extramural Programs...............................   981
Introduction of Witnesses........................................   947
Lung Hemorrhage in Infants.....................................964, 996
Mechanistic Data.................................................   978
Mississippi Delta Project........................................   986
National Allergen Study..........................................   982
National Toxicology Program......................................   984
NIH Management and Structure Review..............................   975
Opening Statement................................................   947
Pesticides.......................................................   962
Pfiesteria...............................................967, 972, 1003
Reimbursable Activities..........................................   984
Research Pipeline................................................  1001
Saccharin........................................................   983
Scientific Review................................................   982
Socioeconomically Disadvantaged Children.........................   966
Statement by Dr. Olden...........................................   954
Strategic Investments............................................   947
Success Rates....................................................   971
Superfund........................................................   983
Toxicity, Predicting.............................................   976
Transgenic Models, Advantages of.................................   949
Type 1 Diabetes..................................................   992
Water Chlorination Byproducts....................................   971
Women and the Environment........................................   985
World Expo '98...................................................   979

    National Institute on Deafness and Other Communication Disorders

Autism Research........................................1070, 1078, 1096
Budget Justification.............................................  1082
Clinical Trials..............................................1083, 1087
Collaboration with:
    Department Education.........................................  1071
    NINDS........................................................  1086
Consumer Advocacy................................................  1085
Deafness and Other Communication Disorders.......................  1092
Dysphonia........................................................  1085
Ear:
    Development in Children......................................  1097
    Infections...................................................  1091
Education and Child Development..................................  1089
Genetic:
    Research.....................................................  1065
Research Ethics..................................................  1065
Hair Cell Regeneration...........................................  1066
Hearing Aid:
    Collabortive Efforts in Technology...........................  1074
    Research and Development.....................................  1080
Hearing Impairment:
    Early Identification.........................................  1069
    Hereditary...................................................  1069
Introduction of Witnesses........................................  1053
Justification of the Budget Estimates............................  1099
Language:
    Impairment in Children.......................................  1098
    Research.....................................................  1076
Noise Induced Hearing Loss and Women.............................  1078
Opening Statement................................................  1053
Otitis Media Research............................................  1071
Partnership Program..............................................  1081
Public Information Activities....................................  1079
Renal and Auditory Systems.......................................  1077
Research:
    Funding......................................................  1078
    Interest.....................................................  1087
    Pipeline.....................................................  1093
    Progress.....................................................  1064
    Project Grants...............................................  1082
Social and Economic Cost of Communication Disorders..............  1072
Speical Research Initiatives.....................................  1082
Specific Language Impairment.....................................  1067
Statement of Director............................................  1058
Tinnitus.........................................................  1075

               National Heart, Lung, and Blood Institute

Age Adjusted Data................................................  1154
Alternative Medicine.............................................  1169
Applicability of AIDS Research...................................  1167
Applied Research and Outreach....................................  1213
Arrhythmia Study.................................................  1170
Aspirin and Heart Attacks........................................  1214
Aspirin..........................................................  1172
Asthma Research..................................................  1224
Asthma.................................................1188, 1217, 1228
Behavioral Research and Prevention...........................1183, 1212
Bioengineering...................................................  1161
Black-White Differences in Cardiovascular Disease................  1215
Blood Transfusion Therapy in Sickle Cell Anemia..................  1200
Budget Estimates, Justification of...............................  1230
Calcium Channel Blocker--A Greater Risk..........................  1210
Cardiovascular Disease in African Americans......................  1173
Cardiovascular Diseases..........................................  1203
Cholesterol Lowering Therapy.....................................  1173
Chronic Obstructive Pulmonary Disease............................  1136
Clinical Research Networks.......................................  1177
Clot-Dissolving Drugs............................................  1192
Congenital Heart Disease.........................................  1190
Congestive Heart Failure.........................................  1190
Constant Dollars.................................................  1205
Cooley's Anemia..................................................  1159
Depression.......................................................  1181
Designer Estrogens...........................................1160, 1187
Diabetes.....................................................1189, 1194
Diet and Blood Pressure..........................................  1207
Dietary Interventions in Schools.................................  1175
Emphysema........................................................  1198
Genetic Research.................................................  1162
Genetic Factors and Cardiovascular Disease.......................  1180
Health Disparity Gap.............................................  1219
Healthy Lifestyles...............................................  1158
Heart Arrhythmias................................................  1195
Hematopoietic Stem Cells: Origin and Development.................  1183
Hemochromatosis..................................................  1171
Hemophilia.......................................................  1198
Hepatitis C......................................................  1155
High Blood Pressure In Children..............................1175, 1206
Hypertension and Kidney Disease..................................  1209
Infrastructure Initiatives.......................................  1185
Impact of Budget Increase........................................  1154
Increase in Life Expectancy......................................  1131
Lung Volume Reduction Surgery....................................  1178
Lung Health Education Program....................................  1226
Melatonin........................................................  1169
MRI Angiography..................................................  1171
National Heart, Lung, and Blood Institute........................  1230
New Asthma Therapies.............................................  1192
NHLBI's Impact...................................................  1142
Noninvasive Screening............................................  1157
Nutrition Academic Award.........................................  1187
Obstructive Pulmonary Disease....................................  1193
Potential Health Care Cost Savings...............................  1222
Primary Pulmonary Hypertension (PPH).............................  1222
Progress.........................................................  1201
Promising Research Areas.........................................  1143
Research Centers.................................................  1183
Retinoic Acid....................................................  1168
Selected Areas of Research.......................................  1182
Sickle Cell Disease..............................................  1163
Sleep Disorders..................................................  1188
Statement of the Director........................................  1142
Stem Cell Supply.................................................  1181
Stroke Belt......................................................  1197
Therapeutic Angiogenesis.........................................  1179
Thrombosis.......................................................  1136
Tissue Engineering, Biomimetics and Implant Science..............  1184
Tobacco and Heart Disease........................................  1227
Training.........................................................  1185
Transdisciplinary Research Training..............................  1166
Treatment Guidelines.............................................  1157
Umbilical Cord Blood Stem Cells..................................  1191
Women In Clinical Trials.........................................  1226
Women's Health Initiative..............................1177, 1186, 1227

                    National Institute on Drug Abuse

Adolescent Drug Use..............................................  1301
AIDS Prevention and Control......................................  1328
AIDS Related Activities..........................................  1311
Behavioral and Cognitive Science.................................  1318
Biological Basis.................................................  1298
Brain, The.......................................................  1325
Children and Adolescents.........................................  1333
Clinical Trials..................................................  1330
Drug Abuse/Use Factors...........................................  1320
Drug Treatment Systems...........................................  1305
Drug User Profile................................................  1292
Education........................................................  1291
Genetics.....................................................1324, 1326
Goals............................................................  1293
Grassroots Organizations.........................................  1297
Introduction of Witnesses........................................  1277
Justification of FY 1999 Budget Estimates........................  1336
Managed Care.....................................................  1303
Marijuana........................................................  1323
Measuring Drug Use...............................................  1308
Media Collaboration..............................................  1290
Medications Development..........................................  1334
Mental Health Disorders..........................................  1326
Methadone Treatment..............................................  1309
Methamphetamine Treatments.......................................  1307
Nervous System...................................................  1317
Nicotine.........................................................  1335
Nicotine Addiction...............................................  1310
Nicotine Replacement Therapies...................................  1316
NIDA Research Findings...........................................  1307
Office of National Drug Control Policy...........................  1301
Opening Statement................................................  1277
Opiate Addiction.................................................  1306
Outreach and Public Education....................................  1321
Parents and Children.............................................  1314
Prenatal Cocaine Exposure........................................  1295
Prevention.......................................................  1296
Progress.........................................................  1292
Public Awareness Programs........................................  1312
Reaching Youth...................................................  1290
Research Pool, The...............................................  1320
Science-Based Prevention Guide...................................  1304
Statement by Dr. Leshner.........................................  1280
Strategy.........................................................  1293
Workplace Prevention.............................................  1296

           National Institute on Alcohol Abuse and Alcoholism

Addiction........................................................  1400
Age of Onset of Alcohol Use............................1378, 1392, 1433
Alcohol:
    Advertising..................................................  1417
    Advertising, Effects on Youth Consumption....................  1410
    Advertising on the Internet..................................  1391
    Brains of Children...........................................  1416
    Induced Hepatitis............................................  1426
    Research Spending............................................  1402
    Use and Abuse................................................  1390
    Use and Neurotransmitters....................................  1388
Alcoholism: Disease or Voluntary Behavior........................  1399
Center's Portfolio, Review of....................................  1410
Clinical Research................................................  1397
Clinical Trials........................................1384, 1418, 1427
Collaborations with Other Federal and State Agencies.............  1411
Collaborations on Genetics.......................................  1424
Collaborative Efforts with the Department of Education...........  1434
College Drinking.................................................  1401
Commercial Availability of Medications...........................  1404
Dissemination of Materials.......................................  1417
Drinking and Driving.............................................  1396
Driving under the Influence......................................  1407
Driving under the Influence, Interventions for...................  1408
Early Onset:
    Alcohol Use..................................................  1378
    Study........................................................  1415
Early Onset Drinking and Alcohol Dependency......................  1416
Emerging Technologies............................................  1433
Family History...................................................  1415
FAS, Reduction of the Incidence..................................  1406
Fetal Alcohol Syndrome.......................................1405, 1422
Fetal Alcohol Syndrome, Vulnerability to.........................  1407
Flushing Response and Environment................................  1396
Flushing Response Mutation.......................................  1379
Gender and Alcohol...............................................  1420
Genetics...............................................1379, 1386, 1423
    Alcoholism...................................................  1394
    Collaborations on............................................  1424
    Environmental, and Psychological Factors.....................  1425
    Influences on Alcohol Drinking Behavior......................  1437
Government Expenditures for Alcohol Abuse........................  1388
Health Services Plan.............................................  1401
Informing Physicians and Health Care Professionals...............  1397
International Comparisons........................................  1430
Justification of the Budget Estimates............................  1440
Korsakoff's Syndrome.............................................  1408
Media Impact.....................................................  1431
Medications..................................................1420, 1438
Medication for Alcohol Dependence................................  1404
Medications, Commercial Availability of..........................  1404
Medications Development, New Approaches to.......................  1385
Moderate Alcohol Consumption, Effects of.........................  1414
National Alcohol Screening Day (Program)...............1405, 1419, 1439
National Clearinghouse for Drug Information......................  1409
Neuroscience.................................................1384, 1426
Opening Statement............................................1377, 1381
Pathways from Research to Application............................  1383
Physicians Screening for Alcohol Problem.....................1393, 1435
Problem of Alcoholism............................................  1382
Promise of Research..............................................  1383
Research to Bedside--Timing......................................  1378
Research Dissemination to Physicians.............................  1409
Resources and Opportunities......................................  1388
Stopping Unhealthy Behaviors.....................................  1398
Success Rates....................................................  1429
Welfare Reform...................................................  1412
Where are We Going...............................................  1386

    National Institute of Diabetes and Digestive and Kidney Diseases

Accessible Databases.............................................  1521
African-Americans with Diabetes..................................  1496
Allocation Decisions.............................................  1529
Antibiotic Therapy for Cystic Fibrosis...........................  1526
Behavioral Approaches............................................  1519
Capacity for Diabetes Research...................................  1500
Children and Obesity.............................................  1551
Clinical Nutrition Research Units................................  1534
Clinical Trials on Diabetes Prevention...........................  1555
Collaboration with ORMH..........................................  1548
Combating Disease................................................  1506
Costs of Obesity.................................................  1505
Current Multicenter Clinical Trials..............................  1537
Cystic Fibrosis..................................................  1525
Diabetes as an Illustration of Research Investment...............  1486
Diabetes in Minorities...........................................  1519
Diabetes Education Program.......................................  1556
Diabetes Research Working Group..............................1523, 1547
Diabetes Funding from Balanced Budget Act........................  1537
Diabetes.........................................1524, 1530, 1543, 1571
Diabetes Research................................................  1540
Diabetes Prevention Program......................................  1547
Diabetes Research Working Group..................................  1523
Diabetic Heart and Nerve Disease.................................  1493
Dietary Supplements..............................................  1501
Digestive Diseases...............................................  1579
Education and Outreach...........................................  1553
Endocrinology....................................................  1576
Eradication of Helicobacter pylori...............................  1569
Eye Complications of Diabetes....................................  1492
Food-Borne Illnesses.............................................  1499
Funding of Nutrition Research....................................  1505
Future Direction for Diabetes Research...........................  1543
Gene Therapy Centers.............................................  1535
Genetic Basis of Disease.........................................  1509
Genetics of Diabetes.............................................  1495
Genetics and Obesity.............................................  1559
Gestational Diabetes.............................................  1525
Glucose Monitoring Devices.......................................  1557
Hematologic Diseases.............................................  1585
Hepatitis C......................................................  1513
Hypertension and Kidney Diseases.................................  1496
Hypertension-Related Kidney Disease..............................  1555
Inflammatory Bowel Disease.......................................  1504
Innovation in Management and Administration......................  1588
Interstitial Cystitis............................................  1510
Islet Transplantation............................................  1503
Kidney Diseases..............................................1511, 1582
Kidney Disease of Diabetes.......................................  1492
Kidney Disease of Diabetes Mellitus..............................  1549
Laser Treatment in Diabetes......................................  1518
Liaison with Diabetes Voluntary Groups...........................  1510
Liver Transplantation Database...................................  1527
Metabolic Diseases...............................................  1577
Minority Health..................................................  1512
National Diabetes Educational Program........................1523, 1545
Neurodegenerative Diseases.......................................  1586
New Diabetes Initiatives.........................................  1524
Nutrition........................................................  1581
Nutrition Research...........................................1498, 1533
Nutritional Assessments..........................................  1499
Obesity......................................................1515, 1558
Obesity Research.................................................  1497
Obesity Nutrition Research Centers...............................  1533
Obesity in Childhood.............................................  1508
Obesity as a Risk Factor.........................................  1504
Office of Research on Minority Health............................  1554
Other Examples of Important Research Needs and Investments.......  1489
Overall Budget Policy............................................  1588
Phoenix Office...................................................  1536
Polycystic Kidney Disease....................................1526, 1542
Professional Judgement Budget....................................  1543
Progress in Diabetes Research....................................  1494
Prostate Disease.................................................  1513
Regeneration of Blood Vessels....................................  1518
Reimbursable Activity............................................  1531
RM&S and Administrative Costs....................................  1529
Special Emphasis Initiatives.....................................  1587
Spending on Specific Diseases....................................  1530
Structural Biology...............................................  1587
The Molecular Basis of Obesity...................................  1567
The Genetics of Polycystic Kidney Disease........................  1570
The Prevention and Treatment of Diabetes and its Complications...  1566
Type 2 Diabetes..................................................  1495
Type-2 Clinical Trials...........................................  1553
Ulcer Disease................................................1527, 1560
Unintended Consequences of Drugs.................................  1552
Urinary and Bladder Diseases.....................................  1551
Urinary Incontinence.............................................  1536
Urinary Tract Infections.........................................  1509
Urologic Diseases................................................  1584
Urology..........................................................  1541
Voluntary Weight Loss Trial......................................  1540
Women's Urological Health........................................  1541
Women's Health Issues............................................  1502

                      National Library of Medicine

Community Libraries..............................................  1640
Computational Molecular Biology..................................  1646
Free MEDLINE...........................................1619, 1634, 1637
Health Information Resources.................................1634, 1636
High Performance Computing Costs.................................  1644
Historically Black Colleges and Universities.....................  1637
Inner City Areas and Remote Rural Areas..........................  1654
International Projects...........................................  1645
Internet Advertising.............................................  1632
Internet Users...................................................  1630
Justification of FY 1999 Budget Estimates........................  1657
Kassebaum-Kennedy Act............................................  1641
Molecular Biology Information Services.......................1621, 1631
Next Generation Internet...............................1632, 1648, 1653
Opening Statement................................................  1619
Outreach...............................................1633, 1647, 1651
Regional Medical Libraries.......................................  1644
Science Recruitment..............................................  1638
Shortage of Highly Skilled Workforce.............................  1656
Statement by Dr. Lindberg........................................  1623
Telemedicine.........................1620, 1630, 1635, 1640, 1642, 1652
Video Taping.....................................................  1656
Visible Human Project............................................  1640
Year 2000 Computer Ready Issue...................................  1653
Aging Research...................................................  1697
AIDS Funding.....................................................  1693
AIDS Risk Reduction..............................................  1696
Applied Nursing Research.........................................  1709
Arthritis Self-Management........................................  1684
Behavioral Research..............................................  1696
Care at the End of Life..........................................  1706
Cognitive Stimulation............................................  1697
Collaborations with HRSA.........................................  1696
Community-Based Interventions....................................  1701
Diabetes Research................................................  1698
Early Hospital Discharge.........................................  1685
End of Life Research.............................................  1685
Genetics Counseling..............................................  1694
Health Care Delivery.............................................  1693
Home Monitoring for Organ Transplants............................  1705
Home Visits by Nurses--A Change in the Delivery of Health Care...  1706
Home Visits by Nurses--A Positive Impact on the Patient Health...  1706
NINR Funding Level...............................................  1709
Nursing:
    Education....................................................  1712
    Home and Family Caregivers...................................  1702
    Research Questions...........................................  1684
    Responsibility Growing.......................................  1694
Opening Statement................................................  1683
Pain:
    Gender Effects...............................................  1684
    Management...................................................  1700
    Relief and Surgery...........................................  1686
Pressure Sores in Spinal Cord Injury.............................  1695
Quality of Care Studies..........................................  1707
Support for Research in Clinical Practice........................  1695
Tele-Health......................................................  1685
Witnesses........................................................  1683
Women's Health...................................................  1711

                      Fogarty International Center

AIDS.............................................................  1778
AIDS in Africa...................................................  1764
Accomplishments..................................................  1765
Biodiversity Program.............................................  1766
Chernobyl........................................................  1763
Contraceptive Vaccine............................................  1772
Demographic Impact of HIV in Africa..............................  1764
Effectiveness of Research on Treatment Regimens..................  1772
Emerging Infectious Diseases.....................................  1763
Environmental Health.............................................  1776
Human Frontier Science Program...................................  1771
International Cooperation........................................  1765
Justification of Budget Estimates................................  1780
Lederberg Panel Recommendations..................................  1769
Medical Informatics Program......................................  1768
Minority International Research Training Program.................  1774
Office of Research on Minority Health............................  1779
Polio............................................................  1762
Tuberculosis.....................................................  1775

 National Institute of Arthritis and Musculoskeletal and Skin Diseases

Alopecia Areata..................................................  1845
Autoimmune Disease...............................................  1809
Benefits of Medical Research in Bones, Joints, Muscles, and Skin.  1811
Biomimetics......................................................  1842
Bone:
    Biology......................................................  1844
    Connective Tissue............................................  1862
    Diseases.....................................................  1808
Budget Estimates, Justification of...............................  1869
Building Bone Mass...........................................1808, 1818
Calcium Intake...................................................  1820
Cartilage Restoration............................................  1831
Clinical Trials..............................................1828, 1864
DNA..............................................................  1842
Epidermolysis Bullosa............................................  1821
Ergonomics.......................................................  1852
Familial Mediterranean Fever.....................................  1809
Fat-Free Diets and Osteoporosis..................................  1820
Funding for Disease Areas....................................1846, 1847
Future Challenges and Plans......................................  1814
Future Research Plans............................................  1809
Gender and Autoimmunity..........................................  1831
Hair Loss........................................................  1832
Historically Black Colleges and Universities.....................  1865
Lupus..................................................1826, 1842, 1857
Lupus and Vulnerable Populations.................................  1827
Lupus in African Americans.......................................  1858
Minority Health Disparity Gap....................................  1859
Musculoskeletal Disorders........................................  1851
NIAMS Opening Statement..........................................  1811
Office of Alternative Medicine, Collaboration....................  1829
Office of Research on Women's Health, Collaboration..............  1830
Osteoarthritis.........................................1808, 1840, 1860
Osteoporosis.....................................1820, 1823, 1841, 1867
Pain Research....................................................  1840
Partnerships with Voluntary and Professional Organizations.......  1814
Psoriasis........................................................  1822
Public Education.................................................  1821
Repetitive Motion Injury.........................................  1850
Research Advances and Initiatives, Additional....................  1812
Research Centers.................................................  1846
Resurging Enthusiasm.............................................  1824
Rheumatic Disease and the FMF Gene...............................  1863
Rheumatoid Arthritis.........................................1809, 1819
Scleroderma..................................................1843, 1867
Skeletal Morphogenesis and Growth................................  1854
Skin Cancer..................................................1809, 1848
Skin Diseases....................................................  1855
Stress and Low Back Pain.........................................  1830
Success Rates....................................................  1832
Tribute To Mr. Stokes........................................1807, 1826
Value of Being a Part of the National Institutes of Health.......  1813

                 National Center for Research Resources

Advanced Instrumentation and Computers.......................1914, 1919
Advanced Technologies............................................  1915
Biology of Brain Disorders...................................1916, 1921
Clinical Research................................................  1933
Clinical Training and Career Development.........................  1930
Collaboration with NCI...........................................  1932
Extramural Construction..........................................  1929
General Clinical Research Centers................................  1935
Genetic Medicine.............................................1916, 1922
HBCU Competitiveness.............................................  1930
Human Genome Project.............................................  1928
Internet.........................................................  1928
National Center for Research Resources...........................  1913
NCRR Request.....................................................  1913
NCRR Resources...................................................  1926
New RCMI Institutions............................................  1931
Rare Diseases....................................................  1932
RCMI Clinical Research Initiative................................  1930
Regional Primate Research Centers................................  1935
Research Capacity............................................1917, 1922
Research Centers in Minority Institutions........................  1929
Research Collaboration...........................................  1933
Research Infrastructure..........................................  1931
Shared Resources.............................................1927, 1931

        National Institute of Child Health and Human Development

1998 Research Center Support.....................................  2016
Adolescent Health................................................  2078
AIDS.............................................................  2082
Animal Models....................................................  2015
Autism.......................................................2000, 2019
Back-to-Sleep Campaign...........................................  2005
Back-to-Sleep Outreach Effort....................................  1999
Birth Defects................................................1978, 1982
Brain Development................................................  2083
Child Care.............................................1988, 2039, 2079
    Concerns.....................................................  1992
    Effects......................................................  1992
    Long Term Effects............................................  1990
    Public Policy................................................  1995
    Studies......................................................  2042
    Study Fact Sheet.............................................  1993
Child Day Care...............................................1980, 1984
Child Development and the Role of the Family.....................  2037
Comprehension of Math and Science................................  2036
Developmental and Genetic Defects of Immunity Research...........  2022
Diabetes.........................................................  2022
Disparity in Minority Health.....................................  2070
Dyslexia.........................................................  1987
E. Coli Vaccine..................................................  2012
Education--Academic Achievement..................................  2069
Family Planning..................................................  1986
Funding for Mental Retardation and Cancer........................  2025
Funding for Selected Research Areas..............................  2016
FY 1999 Budget Justification.....................................  2084
Genetics.........................................................  1978
H. Pylori Screening..............................................  2015
Health Profiles in Children......................................  2004
Home Life and Reading............................................  2035
In-Utero Screening...............................................  2018
Information:
    Based Interventions..........................................  2006
    Dissemination................................................  2004
    Technology...................................................  2018
Intramural Molecular Medicine....................................  2018
Learning Disabilities............................................  2022
Lung Hemorrhage in Infants.......................................  2002
Mental Retardation and Gender....................................  2003
Milk Matters Campaign............................................  2005
Minority Children Health Disparity...............................  2001
Motor Vehicle Issues.............................................  2010
Pediatric:
    AIDS.........................................................  2012
    Environmental Health.........................................  1995
    Pharmacology.......................................1980, 1985, 2076
    Research Initiative..........................................  2011
Pelvic Floor Disorders and Urinary Incontinence..................  1996
Premature Labor..............................................1978, 1983
Preschool........................................................  2033
Reading..........................................................  1979
    Achievement..................................................  2034
    Auditory Processing..........................................  2029
    Development and Disability...............................1978, 1983
    Development--Getting the Word Out............................  1990
    Disabilities--Early Screening................................  1988
    Habits.......................................................  2035
    Instruction..................................................  2032
    Instructional Devices--Technology............................  2029
    National Panel...............................................  2028
    When to Diagnose Disabilities................................  1989
Research Accomplishments.....................................1975, 1981
Rett Syndrome................................................2000, 2021
SIDS.............................................................  2008
SIDS and the Minority Community..................................  1999
SIDS Rate and Sleep Position.....................................  1977
Smoking Prevention for Children..................................  1997
State of Children's Health.......................................  2073
Statement of the Director........................................  1981
Substance Abuse..................................................  2082
Teaching Methods.................................................  2030
Testing Prescription Drugs on Children...........................  1994
The Adolescent Health Study......................................  1991
The NICHD Day Care Study.........................................  1991
The NICHD Study of Early Child Care..............................  2043
Type I Diabetes..................................................  2026
Vaccine Research.............................................1978, 1983
Vaccines.........................................................  2081
Vaginal Immunology & Physiology..................................  2020
Violence.........................................................  2077
Violence and Children............................................  2003
Welfare Reform and Children......................................  1996
Women's Health Research......................................1980, 1984
Women's Reproductive Health Research.............................  2021
Zebrafish........................................................  2013

                 National Institute of Dental Research

AIDS.............................................................  2191
Biomimetics............................................2170, 2193, 2201
Birth Defects....................................................  2177
Bone Grafts......................................................  2202
Budget Increases.................................................  2171
Budget Estimates, Justification of...............................  2205
Centers of Discovery.........................................2174, 2203
Change in Institute's Name.......................................  2167
Clinical Trials..................................................  2195
Diabetes and Oral Health.........................................  2180
Diagnostics......................................................  2170
Early Childhood Caries...........................................  2200
Fluoridation.....................................................  2166
Future Directions................................................  2166
Health Disparity.................................................  2197
Medically Necessary Dental Care..................................  2199
National Oral Health Information Clearinghouse...................  2182
Opening Statement................................................  2151
Oral Health of Disadvantaged Americans...........................  2180
Oral Health......................................................  2191
Oral and Pharyngeal Cancer.......................................  2167
Pain:
    Chronic......................................................  2173
    Differences Between Men and Women............................  2187
    Gender Differences...........................................  2168
    Management...................................................  2194
Periodontal Disease and Low-Birth Weight Babies..................  2168
Periodontal Diseases...................................2178, 2187, 2195
Premature Births.................................................  2201
Professional Training............................................  2171
Public Health Education..........................................  2169
Research Benefits................................................  2184
Taste, Touch, and Smell..........................................  2174
Temporomandibular Joint Disorders............................2175, 2189

                  National Institute of Mental Health

Access to Mental Health Services.................................  2301
Activation of the Amygdala (Figure 2)............................  2239
Accomplishments During the Decade of the Brain...................  2252
Autism...........................................................  2283
Balance between Basic and Clinical Research......................  2278
Behavioral Clinical Trials.......................................  2257
Behavioral Prevention of AIDS....................................  2268
Bipolar Disorder.................................................  2293
Brain Mechanisms Underlying Panic Disorder.......................  2240
Brian Molecular Anatomy Project..................................  2240
Children.........................................................  2286
    Advances and Challenges in Treating Childhood Depression.....  2245
    Children's Mental Health.....................................  2285
    Childhood Mental Health and Disorders........................  2255
    Mental Disorders in Children and Adolescents.................  2294
    Mental Health in Children....................................  2282
    Normal and Abnormal Brain Development........................  2299
    Research to Insure Safety of Medications for Children........  2261
Clincal Trials...................................................  2287
Consensus Conference on the Definition of Attention Deficit 
  Hyperactivity Disorder.........................................  2267
Contribution of Neurobiology to Panic/Anxiety Treatment..........  2262
Co-occurrence of Mental and General Medical Illnesses............  2263
Dissemination of Research Results and Science Education..........  2258
Excessive Disability Stems from Mental Illness...............2235, 2242
Explanation of Functional Magnetic Resonance Imaging (MRI).......  2250
Funding for Specified Disorders..................................  2268
Genetic Link to Mental Disorders.................................  2296
Health Status of Under-privileged Minorities.....................  2263
How NIH Educates the Public About Medical Science................  2259
Justification of Budget Estimation...............................  2302
Leading Causes of Disability, Established Market Economies 
  (Figure 1).....................................................  2236
Learning Disabilities............................................  2270
Linking Clinical Trails to Health Services Research..............  2265
Mechanisms of Cellular Memory................................2237, 2243
Medication and Psychotherapy in Treating Depressive Illness......  2253
Mental Conditions of Patients....................................  2281
Mental Health Research Training and Career Development...........  2275
Mental-Physical Health Line......................................  2285
Multiple Audiences for Science and Health Education..............  2260
Neurobiology of Fear and Anxiety.............................2249, 2262
NIMH Plans for Effective Use of Significant New Funds............  2251
NIMH Research Priorities.........................................  2245
NIMH Efforts to Reduce Stigmatization of Mental Illness..........  2264
Opening Statement of Steven E. Hyman.............................  2242
Opportunities for Expanded Genetics Research and Clinical Trials.  2254
Other Factors....................................................  2286
Progress in Research on Eating Disorders.........................  2256
Protecting Clinical Research in the Evolving Health Care System..  2261
Relocate the Neuroscience Center/Neuropsychiatric Research 
  Hospital.......................................................  2267
Research Career Development......................................  2279
Research Focus on Clinical Interventions.........................  2244
Research on Behavioral Aspects of Gambling.......................  2267
Research Priority................................................  2289
Ritalin and Attention Deficit Disorder...........................  2291
Schizophrenia................................................2272, 2293
Stress...........................................................  2288
Stress and the Bran..............................................  2281
Supply of Researchers........................................2283, 2296
Translational Research.......................................2274, 2277
Treatment and Prevention Interventions...........................  2298
Victims of Torture...............................................  2269

                      National Institute on Aging

Alzheimer's Disease Clinical Trials..............................  2401
Alzheimer's Disease Research........2358, 2365, 2371, 2374, 2377, 2389, 
                                                             2399, 2409
Alzheimer's Disease in Special Populations.......................  2390
Baltimore Longitudinal Study on Aging........................2376, 2391
Behavioral and Social Research...................2364, 2369, 2383, 2420
Biology of Aging.......................................2355, 2367, 2412
Clinical Trials..............................................2376, 2391
Collaborative Research...........................................  2396
Congestive Heart Failure.........................................  2387
Depression.......................................................  2372
Diabetes Research................................................  2386
Diuretic Treatment of Systolic Hypertension Cuts Cardiovascular 
  Risk...........................................................  2363
Estrogen and Vitamin E...........................................  2378
Funding Stability................................................  2380
Genetics of Aging............................................2377, 2394
Health and Retirement Survey.....................................  2384
Information Dissemination....................................2379, 2382
Justification of FY 1999 Budget:
    Conclusion--Meeting New Challenges through Changing Research.  2425
    Developing a Scientific Infrastructure.......................  2424
    Innovations Management and Administration....................  2423
    Overall Budget Policy........................................  2425
NASA Collaboration...............................................  2372
Opening Statement............................................2355, 2365
Parkinson's Disease..............................................  2373
Reducing Disease and Disability..................2362, 2368, 2395, 2416
Relative Risk of Alzheimer's Disease.............................  2361
Selegiline and Vitamin E as Treatment for Alzheimer's Disease....  2359
Sleep Research...................................................  2382
Special Populations..........................................2380, 2397
Telomerase and Cell Division.....................................  2357

        National Institute of Neurological Disorders and Stroke

Alzheimer's Disease..........................................2465, 2498
Amyotrophic Lateral Sclerosis (ALS)..............................  2485
Basic vs. Targeted Research..................................2474, 2475
Batten Disease...................................................  2455
Childhood Diseases...............................................  2467
Children.........................................................  2492
Children and Neurological Disorders..............................  2451
Clinical Research................................................  2469
Clinical Trials..............................................2464, 2496
Congressional Justification......................................  2499
Creutzfeldt-Jakod Disease....................................2474, 2475
Diabetes.........................................................  2473
Dyslexia.........................................................  2462
Dystonia.........................................................  2463
Epilepsy.....................................................2462, 2477
Funding for Specific Diseases....................................  2477
Infant Mortality.................................................  2464
Institute of Radiology...........................................  2455
Lewy Body........................................................  2446
Morehouse Schools of Medicine....................................  2458
Neurological Disorders in Children...............................  2458
Neuroradiology...................................................  2454
New Initiatives..................................................  2451
Niemann Pick Disease.............................................  2467
Pain.............................................................  2484
Parkinson's Disease............2445, 2448, 2453, 2460, 2461, 2462, 2467
Research Participation...........................................  2494
Rett Syndrome....................................................  2459
Secretary's Task Force Report....................................  2489
Spinal Cord Injury.....................................2457, 2461, 2450
Spinal Muscular Atrophy..........................................  2479
Statement of Director............................................  2448
Stroke...............................2449, 2456, 2463, 2472, 2480, 2487
Stroke and Heart Disease in Kentucky.............................  2483

             National Institute of General Medical Sciences

AIDS Research....................................................  2579
Basic Research at NIH............................................  2565
Basic Research on Microbial Biology May Help Fight Bacterial 
  Diseases.......................................................  2590
Budget Policy....................................................  2604
Budget Tables....................................................  2606
Ensuring Effectiveness of Antibiotics............................  2576
Evaluation of National Research Service Award Program............  2567
Fellowships Funded by MORE Division..............................  2570
Funding for Historically Black Colleges and Universities.........  2567
Future Research Directions.......................................  2597
High Risk, High Impact Research..................................  2566
Increases for MARC and MBRS Programs.............................  2579
Innovations in Management and Administration.....................  2603
Interim Funding..................................................  2573
Introduction.....................................................  2584
Introduction of Witnesses........................................  2549
Justification of FY 1999 Budget Estimates........................  2580
Lupus............................................................  2577
MBRS.............................................................  2576
Minority Opportunities in Research...............................  2600
MSTP Evaluation..................................................  2570
New Frontiers in Drug Delivery...................................  2596
New Insights into Biological Processes...........................  2587
NIGMS Organizational Chart.......................................  2581
NRSA Evaluation..................................................  2575
Opening Statement................................................  2549
Other Areas of Interest..........................................  2598
Potential Initiatives Under Budget Increase......................  2571
Research:
    Centers......................................................  2566
    Grants.......................................................  2599
    HIV..........................................................  2569
    Infrastructure...............................................  2602
    Related to Lupus.............................................  2568
    Training.....................................................  2598
    Using Synchrotrons...........................................  2565
Science Advances.................................................  2586
Sharing Research Information.....................................  2565
Stipend Increase.................................................  2574
Story of Discovery: Basic Research Yields Big Reward:
    Possible New Class of Anti-AIDS Drug.........................  2585
Studies of Molecular Structures and Interactions Aid Drug 
  Development....................................................  2592
Support for MARC and MBRS Programs...............................  2569
Training Minority Biomedical Scientists..........................  2578
Underrepresented Minorities in Research Pipeline.................  2566

          Office of the Director and Buildings and Facilities

Administrative Accountability....................................  2680
Administrative Costs Associated with Grants......................  2687
AIDS Programs:
    AIDS in Minority Communities.................................  2748
    AIDS Research............................................2677, 2736
    AIDS Outreach and Public Education Activities............2750, 2761
    Demographics of NIH AIDS Clinical Trials.....................  2756
    Funding for Drug-Resistant HIV...............................  2754
    Funding Levels for AIDS Vaccine Development..................  2763
    HIV/AIDS Behavioral and Social Science Research..............  2739
    HIV AIDS Vaccine.............................................  2762
    Increase in AIDS Among Older Americans.......................  2751
    Minority Organizations Role in the Fight Against AIDS........  2759
    New Drug Regimens............................................  2754
    NIH and CDC Sponsored Clinical Trials........................  2759
    Outreach and Public Educations Conferences...................  2760
    Outreach of AIDS Therapies...................................  2755
    Sickle Cell Disease..........................................  2759
    Transmission of Drug-Resistant HIV...........................  2752
Andersen Recommendations:
    Andersen Budget Proposal Recommendation......................  2667
    Implementation of the Andersen Report........................  2661
    Recommendations From the Andersen Report.....................  2679
Approaches to Disease Prevention and Health Promotion............  2730
Caribbean Primate Center.........................................  2675
Chronic Fatigue Syndrome.........................................  2651
Comprehensive Partnerships for Math and Science..................  2744
Consulting Services..............................................  2684
Cost Sharing.....................................................  2669
Diabetes Research................................................  2730
Dietary Supplements Research:
    Adverse Reactions to Dietary Supplements.....................  2733
    Mixing Dietary Supplements...................................  2732
    Office of Dietary Supplements................................  2732
    Prioritizing Office of Dietary Supplements Research..........  2675
    Studies on Dietary Supplements...............................  2674
Director's Discretionary Fund....................................  2684
Education Activities.............................................  2664
Essential Safety and Health Improvements.........................  2675
Expanding Research into Other Areas..............................  2732
FTE's Associated with HIV/AIDS...................................  2683
Funding Levels for OD Programs...................................  2658
GPRA Compliance..................................................  2662
Heart Disease and Stroke.........................................  2633
Indirect Costs...................................................  2665
Justifications of Budget Estimates--Buildings and Facilities.....  2765
Justifications of Budget Estimates--Office of the Director.......  2785
Minority Programs:
    Advisory Committee on Research on Minority Health............  2747
    Behavioral Research on Minority Health.......................  2734
    Bridges to the Future Program................................  2671
    Closing the Gap in Minority Health...........................  2645
    Differences Between ORMH and MHI.............................  2685
    IOM Study on Cancer Among Minorities.........................  2744
    National Agenda for Research on Minority Health..............  2743
    Office of Research on Minority Health........................  2633
Multiple Grant Awards............................................  2654
Newly Appointed Advisory Committee...............................  2646
Number of FTEs...................................................  2682
Office of Alternative Medicine:
    Efficacies of Alternative Medicine...........................  2671
    Funding for the Office of Alternative Medicine...............  2681
    Integrating OAM with NIH Institutes..........................  2673
    OAM Investigator-Initiated Projects..........................  2654
    OAM Peer-Review Practices....................................  2671
    OAM Studies..................................................  2670
    Published OAM-Funded Research................................  2673
    Role of NIH Institutes in the Study of Alternative Medicine..  2681
Office of Behavioral and Social Sciences:
    Office of Behavioral and Social Sciences.....................  2734
    OBSSR Interdisciplinary Training.............................  2667
    OBSSR Research...............................................  2731
    OBSSR Research Agenda........................................  2763
Opening Statement............................................2619, 2635
Other Personnel Compensation.....................................  2683
Outreach Activities Addressing Violence..........................  2745
Overlapping of OD Programs.......................................  2682
Reimbursable Activities..........................................  2653
Research Leading to Medical Breakthroughs........................  2664
Research on Women's Health:
    Office of Research on Women's Health.....................2633, 2634
    ORWH's New Initiatives.......................................  2657
Salary Costs.....................................................  2682
Scientific Opportunities Available by Institute..................  2689
Scientific Standards to Evaluate Grants..........................  2670
Senior Administrative Leadership Intramural Position.............  2663
Special Personnel Services Payments..............................  2684
Steps to Strengthen the Research Infrastructure..................  2669
Time Cycle of Grant Applications.................................  2663
Tobacco Settlement...............................................  2650
Tran-NIH Offices.................................................  2745
Women and Minority Programs:
    Coordination of IC's with ORMH and ORWH......................  2745
    Women and Minorities in Biomedical Careers...................  2735
    Women and Minority Programs..................................  2644
Violence.........................................................  2646
Violence and Youth...............................................  2648
Ungraded Positions...............................................  2683
Unobligated Carryover Balances...................................  2659
Urology Grant Applications.......................................  2665
Use of Acupuncture...............................................  2653

                        Office of AIDS Research

Analysis of Cost Recovery at the NIH Warren G. Magnuson Clinical 
  Center......................................................2875-2891
Arthur Andersen Study............................................  2871
Behavioral Research...........................................2900-2903
Budget Increase..................................................  2896
Budget Estimates, Justification of............................2904-2941
Clinical Research Capacity.......................................  2863
Complementary and Alternative Medicine...........................  2872
Congressional Justification......................................  2904
Consolidated AIDS Appropriation..................................  2864
Foundation for the National Institutes of Health.................  2893
HIV:
    In Women.....................................................  2868
    Therapies....................................................  2869
    Therapies--Side Effects......................................  2897
HIV/AIDS:
    Affected Populations.........................................  2864
    Child Development............................................  2893
    Origin of the Virus..........................................  2865
Inexpensive Drug Therapies.......................................  2865
Information Technologies.........................................  2892
    Cost Savings.................................................  2892
International AIDS Activities....................................  2868
Long-Term Nonprogressors.........................................  2866
Office of AIDS Research-Discretionary Fund.......................  2896
Opening Statement of Jack Whitescarver, Ph.D..................2855-2862
Pediatric Research...............................................  2894
Third Party Payments.............................................  2874
Vaccine Research Center......................................2863, 2867
Witnesses........................................................  2855
Women's Health Initiative........................................  2893
Year 2000........................................................  2892
Youth and HIV....................................................  2870

                          Child Health Hearing

Challenges in Science............................................  3078
Child Abuse and Neglect..........................................  3180
Dental.......................................................3185, 3187
Dental/Birth Defects.........................................3178, 3187
Diabetes.....................................................3174, 3188
Dissemination of Results.........................................  3081
Health Education.................................................  3073
Healthy Behaviors and Lifestyles.................................  3068
International Travel.............................................  3082
Marijuana and Driving............................................  3074
Prevention.......................................................  3183
Public Private Partnership.......................................  3080
Report Card, 1997 American Health Foundation.....................  3159
Safety and Efficacy of Drugs for Mental Health Problems..........  3078
Sexually Transmitted Diseases....................................  3184
SIDS.........................................................3175, 3185
Statement of Audrey H. Nora, M.D., Director, MCHB................  3102
Statement of Alan I. Leshner, Ph.D., Director, NIDA..............  3052
Statement of Duane Alexander, M.D., Director, NICHD..............  3020
Statement of Ernest L. Wynder, M.D., President, AHF..............  3145
Statement of James S. Marks, M.D., Director, NCCDPHP.............  3120
Statement of Steven E. Hyman, M.D., Director, NIMH...............  3038
Support for Education Policies and Reforms.......................  3098
Witnesses........................................................  3019