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



 
                 DEPARTMENTS OF LABOR, HEALTH AND HUMAN
               SERVICES, EDUCATION, AND RELATED AGENCIES
                        APPROPRIATIONS FOR 1998

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

                                HEARINGS

                                BEFORE A

                           SUBCOMMITTEE OF THE

                       COMMITTEE ON APPROPRIATIONS

                         HOUSE OF REPRESENTATIVES

                       ONE HUNDRED FIFTH CONGRESS

                              FIRST 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, Susan E. Quantius, Michael K. Myers,
                  and Francine Mack, Subcommittee Staff
                                ________

                                 PART 4A

                             (Pages 1-1307)

                      NATIONAL INSTITUTES OF HEALTH

                              

                                ________

                     U.S. GOVERNMENT PRINTING OFFICE

 40-478 O                   WASHINGTON : 1997


------------------------------------------------------------------------

             For sale by the U.S. Government Printing Office            
        Superintendent of Documents, Congressional Sales Office,        
                          Washington, DC 20402                          







                       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        THOMAS M. FOGLIETTA, Pennsylvania   
HENRY BONILLA, Texas                   ESTEBAN EDWARD TORRES, California   
JOE KNOLLENBERG, Michigan              NITA M. LOWEY, New York             
DAN MILLER, Florida                    JOSE E. SERRANO, New York           
JAY DICKEY, Arkansas                   ROSA L. DeLAURO, Connecticut        
JACK KINGSTON, Georgia                 JAMES P. MORAN, Virginia            
MIKE PARKER, Mississippi               JOHN W. OLVER, Massachusetts        
RODNEY P. FRELINGHUYSEN, New Jersey    ED PASTOR, Arizona                  
ROGER F. WICKER, Mississippi           CARRIE P. MEEK, Florida             
MICHAEL P. FORBES, New York            DAVID E. PRICE, North Carolina      
GEORGE R. NETHERCUTT, Jr., Washington  CHET EDWARDS, Texas                 
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

                                VOLUME 4

                                                                   Page

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

National Cancer Institute........................................   199

National Eye Institute...........................................   419

National Center for Human Genome Research........................   495

National Institute of Allergy and Infectious Diseases............   583

National Institute of Environmental Health Sciences..............   711

National Institute on Deafness and Other Communication Disorders.   805

National Heart, Lung, and Blood Institute........................   865

National Institute on Drug Abuse.................................   983

National Institute on Alcohol Abuse and Alcoholism...............  1091

National Institute of Diabetes, Digestive and Kidney Diseases....  1177

National Library of Medicine.....................................  1309

National Institute of Nursing Research...........................  1377

Fogarty International Center.....................................  1443

National Institute of Arthritis and Musculoskeletal and Skin 
  Diseases.......................................................  1491

National Center for Research Resources...........................  1573

National Institute of Child Health and Human Development.........  1635

National Institute of Dental Research............................  1737

National Institute of Mental Health..............................  1809

National Institute on Aging......................................  1915

National Institute of Neurological Disorders and Strokes.........  2001

National Institute of General Medical Sciences...................  2095

Office of AIDS Research..........................................  2155

Office of the Director and National Institutes of Health 
  Buildings and Facilities.......................................  2249









DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, EDUCATION, AND RELATED 
                    AGENCIES APPROPRIATIONS FOR 1998

                              ----------                              

                                      Wednesday, February 26, 1997.

                     NATIONAL INSTITUTES OF HEALTH

                               WITNESSES

HAROLD VARMUS M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH
RUTH KIRSCHSTEIN M.D., DEPUTY DIRECTOR
WENDY BALDWIN Ph.D., DEPUTY DIRECTOR FOR EXTRAMURAL RESEARCH
MICHAEL GOTTESMAN M.D., DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH
ANTHONY ITTEILAG, DEPUTY DIRECTOR FOR MANAGEMENT
FRANCINE LITTLE, DIRECTOR, OFFICE OF FINANCIAL MANAGEMENT
DENNIS WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF 
    HEALTH AND HUMAN SERVICES

    Mr. Porter. The subcommittee will come to order.
    We're very pleased to welcome Dr. Harold Varmus and Dr. 
Kirschstein and the representatives of the National Institutes 
of Health this morning for another round of hearings on the 
NIH. We relish these opportunities to learn about the 
remarkable scientific advances that your fine institution makes 
possible.
    I have high hopes for NIH this year, because I see 
increasing recognition in many quarters of the importance of 
biomedical research, from the designation of the AIDS 
researcher, Dr. David Ho, as Time's man of the year, to news 
that the Washington Post will be sponsoring a public television 
series on biomedical research, to the repeated mention of 
research in the President's speeches.
    I'm also encouraged that the support of NIH seems to be 
broadening in the Congress, particularly in the Senate. I have 
to say, Dr. Varmus, I'm very disappointed, however, that the 
President's NIH budget does not match the rhetoric of his 
speeches. I've already expressed my dismay to Secretary Shalala 
about what I consider to be an inadequate NIH budget request, 
which is below the rate of biomedical inflation and therefore 
amounts to a cut in your budget. I sincerely hope that we can 
do much better.
    I would caution everyone in this room, however, that it 
will not be easy to craft a bill with the kinds of increases 
NIH deserves and that NIH has had for the last two years, given 
the competing demands of education and other priorities. We 
must have a 602(b) allocation with enough room to address all 
of these priorities so that we can produce a bill that can be 
passed by the House of Representatives and signed into law by 
the President.
    Mr. Obey, the ranking minority member on the panel, is at 
another hearing. I will call on him for opening remarks when he 
arrives here. And Dr. Varmus, we'd be pleased to hear from you.

                       Introduction of Witnesses

    Dr. Varmus. Thank you, Mr. Porter.
    Before I begin, let me introduce the colleagues who are 
here at the table with me. Dr. Wendy Baldwin, the Deputy 
Director for Extramural Research; Mr. Tony Itteilag is the 
Deputy Director for Administration; Dr. Ruth Kirschstein, well 
known to you, is my Deputy Director; and Francine Little, who's 
the Director of the Office of Financial Management; and the 
indefatigable Mr. Dennis Williams represents the Department on 
these occasions.
    Mr. Porter, this is the fourth time I've had the pleasure 
and the honor to represent the NIH at appropriations hearings. 
I had not anticipated the press would be so interested in this 
anniversary. [Laughter.]

                           Opening Statement

    Dr. Varmus. As you know, I very much enjoy on these 
occasions relating our recent accomplishments and telling you 
about promising paths our research may take in the immediate 
future. But before we get into these annualized accounts of our 
progress and descriptions of promise, we need to remind 
ourselves of a few stern realities: that the conquest of 
disease is a formidable challenge; that progress is best 
measured over many years or decades; that advances against 
disease require long-term investments in research and training 
and facilities; and that the benefit of most research is in 
fact unpredictable, demanding that we institute a broad range 
of research activities.

                        culminations of research

    Now, over the course of the next ten days, you'll hear from 
the Institute directors who are arrayed behind me about two 
kinds of recent accomplishments, kinds that I will refer to as 
``culminations'' and ``inspirations.'' Culminations are 
practical health benefits built upon many years of research in 
which NIH has had a very significant role. Let me mention just 
a few examples of such culminations.
    The further validation of an effective treatment for stroke 
with tissue plasminogen activator and of cryotherapy for the 
retinopathy of premature infants; the evidence that we can 
reduce disability among the elderly; the first measured real 
declines in cancer mortality for cancers of the lung, colon, 
gynecological cancers, prostate cancer and breast cancer; the 
efficacy of vaccines in nearly eliminating hemophilus influenza 
meningitis among our children, and more recently, an effective 
vaccine against rotavirus, which causes diarrhea worldwide; the 
application of the Visible Human project that you've heard 
about in previous years to the teaching of medicine and the 
practice of surgery; the use of antibiotic combinations to 
treat the common cause of gastric ulcers, H. pylori; and the 
increasing use of recombinant DNA products, growth factors, for 
the treatment of marrow suppression that occurs during cancer 
chemotherapy.

                        inspirations of research

    Inspirations are more common. They are the important 
discoveries in basic science that may, we hope, be the 
foundations for future culminations. They are abundant. Let me 
give you just a few examples from three areas of recent 
research. In genetics, the area that has attracted a great deal 
of press attention, we've all read about the complete 
sequencing of the genomes, the entire collection of genes, from 
a number of organisms, yeast and several bacteria. Other 
genomes have been fully mapped, and some partially mapped, 
including the human, and all this information has been made 
miraculously accessible to all investigators and to the public 
through the GeneBank at the National Library of Medicine.
    Many other disease genes have been isolated--disease genes 
for glaucoma, polycystic kidney disease, for retinitis 
pigmentosa, for a number of forms of diabetes that are 
inherited, for basal cell carcinoma in hereditary form, for 
hemochromatosis. Other disease genes have been identified but 
not yet isolated in pure form. Those include, most importantly 
in the past year, the gene for a familial form of Parkinson's 
disease and one for a familial form of prostate cancer.
    Advances in neuroscience continue at a remarkable pace. 
Imaging technologies are showing us the physiological basis of 
many important neurological phenomenon, including aspects of 
behavior, pain, emotion and drug abuse. Animal models have been 
increasingly useful in the study of neurological disorders, 
clarifying the causes of disease, for example, Alzheimer's 
disease, Huntington's disease and spinal cerebellar atrophy. 
And the animal models are also stimulating new kinds of 
treatment, for example, the use of growth factors in treatment 
of spinal cord injury.
    Finally, in the area of cell biology, the understanding of 
blood vessel growth is signalling new strategies for improving 
blood supply to the heart and the brain; and our understanding 
of how blood clotting occurs is even giving rise to the new 
strategies for treatment of cancers. New information about how 
cells talk to each other is informing research in a wide 
variety of categories, too numerous to mention.

                      culminations in hiv research

    I'd like to give you some sense of how these inspirations 
and culminations actually work in the pace of research, by 
telling you about a couple of events that have occurred in the 
past year in the area of our research on HIV and AIDS.
    First, a culmination. We've referred already to the public 
attention that's been given to recent progress in the treatment 
of HIV through your mention of the man of the year award by 
Time Magazine.
    The demonstrated efficacy of protease inhibitors has been 
seen as a bombshell by the public, but from our perspective, 
this is a culmination that depends upon many years of 
fundamental work. Our work on retroviruses extends back to the 
early days of this century. Work on the enzymes that are 
programmed by retroviruses extends back to the 1970s. 
Identification of one of those enzymes, the protease; and the 
determination of how it works biochemically; its three 
dimensional structure; studies of other proteases made by 
cells; and the development of inhibitors that are used in the 
treatment of hypertension. All this was followed by drug 
development, largely by the pharmaceutical industry, whose 
strengths also depend upon NIH-sponsored training and research.

                      inspiration in hiv research

    Inspiration in HIV research has come from the long-awaited 
discovery of a class of cell proteins that is required to allow 
HIV to enter cells, proteins known as the co-receptors. These 
co-receptors, which are essential for establishing HIV 
infection, turn out to be proteins we already knew, proteins 
that recognize molecules called chemokines, proteins that are 
important in inflammation. We already know, even in the span of 
a few months, that chemokines can block infection with HIV, and 
that some people lack, medically lack, the co-receptors and 
can't be infected, even though they're otherwise healthy. What 
this means is that there is inspiration here for new strategies 
to prevent infection through vaccines and to control infection 
when it occurs.

                oversight and administrative activities

    Well, so much for science. Let me say a few words about 
oversight and administrative activities. Last year in our 
hearings, we focused on problems that beset clinical research 
and the need to build a new clinical research center at the NIH 
and to reorganize the existing clinical center. I'm happy to 
report that due to the generosity of this committee and your 
Senate counterparts, funding for the clinical research center 
has begun.
    The design is underway. We have carried out many of the 
improvements we talked about last year in the functioning of 
the clinical center. A board of governors has been established. 
We've been devising new ways to recruit clinical investigators. 
We've expanded our training in clinical research. We've just 
instituted a new program that brings medical students to the 
NIH campus for training in clinical research--a specific 
response to a recommendation made by my panel on clinical 
research that's staffed by mostly extramural investigators.
    We have responded to a variety of other administrative 
directives and concerns that we discussed last year. We have 
held our research management and support dollars steady, and we 
have initiated a more extensive study of all our administrative 
activities as a result of consultations with you and your 
colleagues in recent months. We have made increased use of our 
competitive service centers at NIH to allow institutes to carry 
out administrative tasks conjointly and to thereby effect some 
reductions in our FTEs. We have developed a search for a chief 
information officer and mounted a number of other strategies to 
improve our information systems, which could represent large 
cost savings over the next several years.
    I have instituted a number of new reviews in conformity 
with earlier patterns of behavior--reviews of institute 
directors, of several intramural programs, and of a variety of 
research areas, including AIDS, clinical research, and gene 
therapy.

                    the president's budget proposal

    Finally, a few comments about the budget. As you know, the 
President is requesting $13.078 billion for the NIH. This is 
$337 million more than was in the 1997 budget, a 2.6 percent 
increase. That request includes $90 million for the Mark O. 
Hatfield Clinical Research Center. That $90 million is not, 
however, part of the increase, because it equals the amount 
that was in the 1997 appropriation. And we should also say that 
we expect to ask for $90 million in 1999, and another $40 
million in the year 2000 to finish the construction project.
    Most of the increased monies will be devoted to research 
project grants, our traditional strength and pride. There is a 
3.9 percent increase in that category. We recognize the 
constraints upon the Federal budget that restrict our ability 
to pursue every inspiration. So we believe that the increase 
requested by the President--built on the very strong 
appropriations we've received due to the generosity of the 
Congress and the Administration the last two years--will allow 
us to maintain our momentum and achieve the largest number of 
grants in the history of NIH, nearly 27,000 grants total.
    We can do this because the rates of inflation in biomedical 
research have been lower in the last couple of years, because 
we are concentrating the increased dollars on our research 
project grant pool, and because we plan to limit increases in 
awards to 2 percent per year.
    In summary, the Institute and center directors and I are 
proud of what has been done with the generous appropriations 
we've received in the past. We are optimistic about our future 
prospects to use science for the advances in human health and 
relief of human suffering. They and I look forward to answering 
any questions you may have over the next ten days.
    [The prepared statement follows:]

[Pages 6 - 10--The official Committee record contains additional material here.]


                            budget estimates

    Mr. Porter. Dr. Varmus, thank you for your opening 
statement.
    Let me spend just a minute looking into the budget figures. 
Because NIH two years ago was increased by 5.7 percent, last 
year by 6.9 percent. At the Democratic convention, the 
President had Christopher Reeve talk to the American people 
about the importance of biomedical research and has mentioned 
it very prominently, both in his acceptance speech and in his 
State of the Union speech this year.
    And yet, the budgetary increase that the President suggests 
is 2.6 percent. I believe that is below the rate of biomedical 
inflation. I would first like to ask you, because there are 
really three filters here, one is your own in preparing your 
budget with your Institute directors, the second is the 
Department's and Secretary Shalala's, and the third of OMB and 
the White House. I would like to ask you first what request you 
made of Secretary Shalala in the beginning of this process. 
What was the budget that you developed within NIH?
    Dr. Varmus. Mr. Porter, we had a professional judgment 
budget that was in the range of $13.88 billion. And what we 
were allowed by the Department was $12.865 billion. The OMB 
returned to----
    Mr. Porter. A billion dollars less than what you asked for 
or would suggest in your professional judgment budget?
    Dr. Varmus. We didn't submit a direct request at that 
stage. The numbers returned to us by OMB were $12.667 billion.
    Mr. Porter. So OMB initially suggested a cut from last 
year's appropriation?
    Dr. Varmus. That's correct.
    Mr. Porter. A cut in nominal terms as well as real terms?
    Dr. Varmus. Correct.
    Mr. Porter. And what happened then?
    Dr. Varmus. There was a series of discussions involving OMB 
and the White House and the Department and NIH. And the final 
agreement was the budget request that you've heard, $13.078 
billion.
    [Clerk's Note.--The following was submitted by Dr. Varmus 
to clarify his remarks:]

    The NIH budget request to the Department for 1998 was for 
$12.865 billion, a 3.9 percent increase over the 1997 
President's budget of $12.377 billion. Prior to final 1997 
Congressional appropriations action, the Department submitted a 
1998 budget request to OMB for NIH of $12.667 billion, 
representing a 2.3 percent increase over the 1997 President's 
budget. The Congress then appropriated $12.741 billion for NIH 
for 1997, which established a new base for discussions of the 
1998 proposals. Finally, the 1998 President's budget request 
for NIH of $13.078 billion was developed, a 2.6 percent 
increase over the 1997 appropriations level.

                      professional judgment budget

    Mr. Porter. I realize that you and NIH have to be good 
soldiers and all this, but our job is to determine priorities 
for the country and where the money can best be spent. And if 
your professional judgment budget is $13.88 billion, that means 
you believe that you can wisely spend that amount of money in 
the next fiscal year. And I would like for you to give us some 
idea of what has to be foregone between the $13.88 billion that 
you've suggested in your professional judgment budget, and the 
$13.1 that is suggested by OMB and the President.
    Dr. Varmus. Let me first point out, Mr. Porter, that we 
make that professional judgment in an intellectual framework in 
which we don't worry about the other demands on the budget 
process.
    Mr. Porter. Yes.
    Dr. Varmus. We recognize that's a number that represents a 
starting point in a dialogue that will lead to some kind of 
compromise with the realities of balancing the budget and 
meeting other important demands upon the economy and upon the 
budget.
    Mr. Porter. Absolutely.
    Dr. Varmus. It's very difficult to say that there is one 
thing we cannot do. Because obviously we're going to continue 
to work on all fronts with the budget that's below our 
professional judgment. But what will happen is that some 
projects will not get funded. And many things that could go 
quickly will go less quickly.
    In some areas, it's possible to say that certain fairly 
predictable milestones will be met less quickly. For example, 
in a process like the sequencing of the human genome, where we 
can say that given a certain amount of money and equipment and 
personnel, we can do the sequencing so much more quickly, we 
can actually make some very clear predictions about how many 
fewer nucleotide sequences will be determined.
    In other areas of less predictable, discovery type science, 
we simply have to say that we will fund fewer grants.

                        establishing priorities

    During the process of putting together the 1998 budget, I 
met individually with every institute director and asked them 
to tell me about areas of priority that they would like to 
receive allocations for in the context of the NIH areas of 
emphasis. These are, as you recall, broad areas of research 
promise that we put together in a way that emphasizes the 
interactions among the institutes, the broad themes of 
biological research that we think are useful in the advancement 
of health.
    And I received, during the course of the several weeks in 
which we deliberated, long lists of research projects, research 
areas that institute directors felt were particularly 
promising, and warranted my assigning to them amounts of money 
that might range from an additional $1 million to an additional 
$10 million. I put together a series of budget possibilities 
based on various levels of increment in our budget that might 
be anticipated. And as I reviewed that list, I can see that the 
institute directors and I worked out a list of priorities that 
now reflects the conviction we have that progress could be made 
with varying limits on our budget.
    So I could give you some sense in detail, if you like, but 
I think it's better to say that some of these initiatives that 
we would like to undertake will not be undertaken, or will be 
undertaken with fewer dollars, instead of putting $2 million 
into a project to work on asthma in the Heart Institute, maybe 
we'll put in $1 million.

                             success rates

    Mr. Porter. Let me raise this in a different way. Isn't it 
true that in most institutes, if not all, the percentage of 
competing grants, that is science that has been peer reviewed 
and thought to be very promising, that we can fund, even with 
the increases we've had recently, is going down rather than up?
    Dr. Varmus. The success rate actually varies among the 
institutes. But of course, in the last two years, because we've 
had good appropriations from the Congress, our success rate is 
currently, we estimate, about 28 percent for 1997. And we 
expect it will be fairly similar in 1998.
    Mr. Porter. So we're funding three out of every ten?
    Dr. Varmus. A little less than that. It's important to 
point out, Mr. Porter, that that number is an aggregate number 
and it is slightly misleading in the sense that there are, 
first of all, lower rates for new grants as opposed to renewal 
grants, lower rates for new investigators. We find it's very 
important to bring new investigators who are just out of 
training into the process early, otherwise they become 
discouraged and leave science. It may be lower in some of the 
most competitive areas, in areas where the demand upon NIH 
monies is particularly tight.
    So it's an aggregate number, it's somewhat misleading about 
the----
    Mr. Porter. Well, we're very concerned that we maintain the 
momentum that NIH has had and that we don't lose a young, 
promising scientist because they can't get their promising 
projects funded and become discouraged. And our job, as you 
know, is to choose priorities. We may end up seeing it a little 
differently than the President.
    I sincerely hope that we do, because I believe that this is 
among the best money that we ever spend, that it pays for 
itself many times over, that there is so much promising science 
there that to delay and put NIH on hold is unwise policy. And I 
believe that this Congress can do that, to put NIH at a high 
priority within the context of bringing the budget into 
balance. That, after all, is our job.

                                cloning

    Let me now raise another question that has come up in the 
news over the weekend, that I think shocked many in the 
scientific community, because they said it couldn't be done. 
But we've read of experiments in Great Britain by Dr. Wilmot 
where they have used adult DNA to clone a sheep. And I would 
like to ask you if you will tell us whether this is valid 
science, whether it would lead to cloning of adult human 
beings, what the implications are, both positive and negative, 
for science itself, and what the ethical implications are for 
all of society.
    Dr. Varmus. How much time do I have, Mr. Porter? 
[Laughter.]
    Mr. Porter. As much as you'd like.
    Dr. Varmus. Let me begin by telling you something about 
these experiments and perhaps describing them slightly more 
precisely and give you some idea of the intellectual context in 
which they arise. These experiments have strong antecedents in 
research that dates back quite a long time, to work by Gurdon 
and his colleagues in England who showed some years ago that it 
was possible to take the nucleus of a frog skin cell that had 
been grown in culture and to transfer that into the egg of a 
frog that had been relieved of its own nucleus.
    By appropriate stimulation, it was possible to allow that 
egg, now supplied with the nucleus from the skin cell, to grow 
to the tadpole stage. Never to the full adult, but 
nevertheless, this was the first indication that one could do 
something that has a deep scientific meaning that I will come 
back to, and that is, you can take a cell which has undergone 
the process of differentiation--the process by which certain 
genes are turned off and others are turned on--to make a cell 
with a defined function and demonstrate that the nucleus of 
that cell--the nucleus being the compartment of the cell 
surrounded by a membrane, containing all the genes of the 
organism--could undergo some kind of still not fully understood 
process that would allow the cell to be able to generate all 
the components of a tadpole.

                     an earlier cloning experiment

    The report you refer to is not the first report that's been 
published from the Roslyn Institute in Edinburgh. About a year 
ago, the same group of investigators, headed by Ian Wilmot, 
published a paper in Nature in which they had done the 
following kind of experiment with sheep. That experiment had 
followed the clue from frogs, starting with an oocyte that had 
been relieved of its own nucleus and adding to that enucleated 
egg the genetic material from a very, very young sheep embryo, 
this actually was an embryo at the 8 to 16 cell stage. And the 
DNA, or the genes of the organism, were introduced by fusing an 
entire cell, including the nucleus after growth of the embryo 
cells in culture into the enucleated egg.
    At this very early stage in embryogenesis, the cells are 
still believed to have all the potential for making all of the 
tissues of the organism. So it wasn't as electrifying as the 
current experiment when it turned out that by fusing cultured 
cells to the enucleated egg and returning the reconstituted egg 
with its nucleus from a cultured cell to a potential surrogate 
mother, that sheep were born. As I said, this work was 
published about a year ago.
    The investigators in Edinburgh then took the next step of 
using other sources of genetic material--namely whole cells at 
other stages of development--and fusing them to the enucleated 
egg. Those additional sources of cells included older embryos, 
embryos that had been allowed to proceed to a much more 
complicated multi-cell stage; cells from a fetus representing a 
partly-developed sheep; and most dramatically, a cell that had 
been taken from the udder, from the mammary gland, of a six 
year old female sheep.
    In each case, the cells were manipulated in an interesting 
way. After they had been grown in culture, the cells were 
returned to a resting state by slowly reducing the nutrients 
supplied to the cells. Normally when cells are grown in a petri 
dish in culture, they are grown in serum obtained from animal 
sources. By reducing the level of serum, it was possible to 
make the cells quiescent, so they weren't undergoing growth. 
That appears to be quite important in the success of these 
experiments.
    In any event, with all three new sources of genetic 
material--that is, older embryos, fetal cells, or, in one case, 
mammary cells--a reconstituted egg, now carrying the nucleus 
from each of those three cell types, was returned to a prepared 
uterus and the investigators waited for a sheep to develop. In 
all three cases, they did. Only one succeeded out of 277 
reconstituted eggs, in the case of the cells derived from the 
adult female sheep. It was inefficient, nevertheless, it was 
successful.
    Now, as you know, public attention has been focused 
initially on the most sensational aspects of this. And that's 
only natural. Because it is quite clear that this experiment 
opens the possibility of being able to do the same experiment 
with virtually any other mammal. And naturally, given the 
imaginations and novelistic inclinations of all of us, the idea 
of generating human clones of mature individuals has been much 
discussed.

                   scientific significance of cloning

    In my view, this makes interesting movies, but poor science 
and poor ethics.
    Let me speak a little bit to the scientific importance of 
the experiments that were described, and then come back to some 
of the ethical issues. The first level of significance of the 
experiments that are described is very much in the tradition of 
agricultural husbandry. Both in the area of agriculture and in 
animal husbandry, there is a strong tradition of trying to 
recapitulate strains that are particularly productive for food 
production.
    So whether it's the selfing of corn, or the generation of 
in-bred strains of animals, or the twinning of cattle, there is 
tremendous interest in trying to enlarge a population that 
appears to be very productive. And in that sense, there are 
practical applications of what we've read about, with respect 
to agriculture.

                        medical uses of cloning

    The second application has to do with the medical research 
uses of animals. There are a number of possible experimental 
routes that are opened by the experiments we've read about. In 
one case, the interest would be in the production of medically 
useful products. Proteins that are produced in animals, for 
example, in milk, could be made in large amounts in a more 
convenient way that is currently possible through recombinant 
DNA technology. Another product that might be possible is to 
make organs for transplantation that have been made more like 
human organs because they are programmed to make antigenic 
proteins on their surface that would lead to less problem with 
rejection in transplantation procedures.
    Equally important is the possibility of using animal models 
other than the mouse or the rat for certain disease states. I'm 
sure you're aware that in recent years scientists have made 
increasing use of our ability to manipulate the genetic 
constitution of mice. We can add genes to the mouse, we can 
change the genes that exist, and we can make use of our 
increasing knowledge of disease genes of humans to attempt to 
generate models for disease that can be used for developing 
novel therapies that may be applicable to man.
    In not all cases, however, have those disease models 
reproduced faithfully and instructively the kinds of pathology 
that are seen in human beings. One good example of that is in 
the case of cystic fibrosis, where we know the human gene and 
the mutations that exist in the gene have been identified. We 
can make the same mutations in the mouse, but the disease is 
different. Using an animal like the sheep might open the way to 
make better disease models that could be instruments for 
developing and testing more useful therapies for some of these 
disorders.

                       how genes turn on and off

    The third area of importance is one that has been neglected 
for the most part in discussions today, but to my mind is the 
most important. And that is that these experiments open the 
door to a much deeper understanding of how genes are turned off 
and turned on. I remind you that we as human beings have 
roughly 80,000 genes, that all of those genes are useful in 
some of our many different kinds of cells. We have perhaps 200 
different types of cells in our bodies. Each expresses a 
different subset of those 80,000 genes.
    During the course of our development to produce an organism 
that has a liver and skin and brain and many other organs, our 
bodies are programmed to turn such genes on and off. And it's 
generally been considered difficult, if not impossible, to 
redirect a cell of one type to behave like a cell of another 
type.
    In the sheep experiments we've been discussing, a cell 
derived from an adult mammary gland has been reprogrammed to 
become a fully potent cell to make every component of a sheep. 
That's a remarkable achievement. We know very little about what 
that process entails, save for the fact that it seems to be 
fostered by moving a growing cell into a quiescent state, as I 
mentioned before, by reducing the serum in the medium used for 
growth of the cell.
    There are many applications that could be imagined for 
greater knowledge of how genes are turned off and on. Let me 
begin with the simplest. We already use such a strategy for the 
treatment of sickle cell disease. In sickle cell disease, one 
of the globin genes is impaired. We know that we can overcome 
that impairment by expressing another form of globin gene 
that's normally expressed only in the fetus. Hydroxyusea is a 
drug therapy that's currently in use and shown to be quite 
effective; it turns on the fetal globin gene in the adult and 
reduces the morbidity of sickle cell disease by about 50 
percent.
    We still have an imperfect notion of how to turn that gene 
back on. So anything further to help in our ability to control 
that process would be very useful.

                     use in bone marrow transplants

    Let me give you some other examples. We know that when 
persons undergo chemotherapy for cancer that their bone marrows 
are frequently severely affected, and it's been increasingly 
common to treat such individuals with bone marrow transplants. 
Those transplants are difficult because of rejection of the 
donated marrow, because of protein incompatibility between the 
donor and the recipient. So one long-term goal has been to use, 
in such transplantation experiments, marrow that's compatible 
with the recipient. Sometimes that's done by using the marrow 
from the individual who's undergoing treatment. But that's 
obviously less than ideal, because those cells may include 
cancer cells.
    The prospect of being able to take the nucleus from a skin 
cell and put it into some other, cell, to produce bone marrow 
cells in culture, and return those to cancer patients is made 
real by the experiments with the sheep--far off, but 
nevertheless possible. One could imagine, and if you'd like an 
inversion of that experiment, where you consider somebody who's 
been incapacitated by massive burns and needs skin 
transplantations, one can imagine taking the nucleus from a 
liver cell, for example, putting it into another enucleated 
cell as a recipient, and making skin cells that could then be 
used for a non-rejectable transplant to the burned individual.
    One could imagine similar kinds of experiments in neuro- 
degenerative diseases. There are instruments for remodeling 
cells to behave as mature nerve cells with the antigenic 
properties, of the recipient. So there are some remarkable 
possibilities here that definitely require exploration and will 
be fired by the sheep experiments.

                          ethical implications

    Let me say a few words about some of the ethical issues. We 
have been aware of the possibility of doing such experiments 
for some time. In 1994, I convened a panel headed by Dr. Steven 
Muller to look at the ethical issues that surround many forms 
of human embryo research, including this form. And in that 
year, that panel brought back to me recommendations about which 
kinds of experiments involving the human embryo would be 
suitable for Federal funding, unsuitable for Federal funding, 
or fall in between.
    And with respect to carrying out experiments of the sort 
described for the sheep in the human being, that is, human 
cloning, the committee designated such experiments as not 
suitable for Federal support, for reasons that I think perhaps 
are worth reading very briefly. The panel said, ``the notion of 
cloning an existing human being or of making carbon copies of 
an existing embryo, appears repugnant to members of the public. 
Many members of the panel share this view, and see no 
justification for Federal funding of research involving nuclei 
transplantation for this purpose.''
    I agree with that point of view. Frankly, as an 
experimental strategy, it doesn't offer anything. We have a 
much better experiment carried out in nature. We have identical 
twins who are sometimes reared together, sometimes reared 
apart. That to my mind, if one wants to look at the effects of 
environment on human development, using genetically identical 
subjects, that experiment has already been done. It occurs done 
very commonly in human populations.
    Secondly, our sense of ourselves as human beings is very 
closely linked to our diversity. And the notion of carrying out 
cloning of the human population, to my mind, is not consistent 
with the traditional ideas of human individuality and 
diversity. This does not mean that cloning strategies should 
not be used in other animals for purposes of agriculture or for 
purposes of medical research. But in the case of human beings, 
the NIH panel rejected it, as it happens, these experiments 
would also be forbidden by the amendment that's attached to our 
appropriation bill, the so-called Dickey-Wicker amendment.
    That's a long speech, Mr. Porter. I'd be happy to answer 
any more questions.
    Mr. Porter. Thank you, Dr. Varmus. I might say to my 
colleagues that I'm not going to charge myself with that 
question or answer, because all of us wanted to ask the 
question. And I also would say, Dr. Varmus, that's probably the 
longest answer ever not interrupted by a member of Congress.
    [Laughter.]
    Dr. Varmus. I appreciate your indulgence.
    Mr. Porter. Mrs. Lowey.

                          legislating cloning

    Mrs. Lowey. Thank you very much, Mr. Chairman.
    And again, Dr. Varmus, it truly is an honor to have you 
here before us. We feel honored to be on this committee to 
somehow have some role in this great Nation's investment in 
biomedical research. So I want to thank you personally for your 
leadership.
    Just briefly, and I guess this will be counted against my 
time, or maybe not, I just wanted to have a few comments about 
your response. Because thus far, the sheep cloning has raised a 
great deal of justifiable anxiety across the Nation. In my own 
State of New York, a bill has already been introduced in the 
State senate to ban scientists from cloning humans. And we are 
clearly at the dawn of a new era in the history of mankind. 
Fifty-two years ago, the world changed forever at Alamagordo, 
New Mexico, when we exploded the first atomic bomb. This past 
week, as we know, and I appreciate your asking this question, 
the world has changed again.
    Cloning raises the most profound questions about man's 
humanity, about God, about religion, about life and death. 
These are sensitive issues, and they must be dealt with 
seriously and thoughtfully. And I want to say, I applaud the 
President's decision this week to appoint a high level panel to 
examine the issue. And I look forward to reading their report.
    As you stated, we have to ensure that science does not 
outrace our values. But we must also recognize that once the 
genie is out of the bottle, it cannot easily be put back in. 
And history demonstrates that if the technology exists, it will 
be applied. So the question before us then is whether or not we 
will be able to harness this scientific advance, this miracle, 
in fact, to work for us and improve the human condition.
    Will advances in cloning be able to cure diseases like 
breast cancer and Alzheimer's? You referred to the great 
possibilities of medical research. Can we utilize this 
technology to provide hope to tens of millions of people with 
genetic disorders across the Nation and around the world? 
Perhaps so. And I certainly hope so. And while I know that 
cloning technology is fraught with peril, it also contains real 
opportunity and promise.
    The future of cloning can look like our worst nightmare, 
like all this Huxley's Brave New World or the Island of Dr. 
Moreau, a world where freakish experiments know no bounds. Or 
cloning technology can cure diseases and improve our lives. And 
it's really up to all of us to decide. And as members of the 
Congressional panel that funds biomedical research, we have a 
special responsibility to engage this issue in all its 
complexity. And I certainly look forward to the discussion.
    There is clearly a need for regulation. But regulation, I 
hope, that is consistent both with our human values and our 
support of biomedical advances.
    I was going to ask you to discuss it, but I think perhaps 
we've taken a good deal of time, and I hope that in a rational, 
reasonable way, we can engage in this discussion if you have 
additional comments.
    Dr. Varmus. I'd like to make one comment, Mrs. Lowey, 
because your point reminds me of something that I was hoping to 
say at some point, which is that I'm concerned about the rush 
to legislation in this arena. We have a new finding. It needs 
to be absorbed and discussed.
    I, too, applaud the President's referral of this matter to 
his National Bioethics Advisory Commission, which as you know 
was established about a year ago to consider questions of just 
this kind. The Commission is very well suited, in the light of 
the personnel who have been appointed to that commission, to 
discuss these issues and to make some recommendations.
    I am worried, as my comments reflected, about the 
possibility that in rejecting the one aspect of these 
experiments that all of us find repugnant--that is, the idea of 
cloning adult human beings--that we end up with legislation, be 
it state or Federal, that restricts the experimental 
possibilities that will be beneficial to all.
    Mrs. Lowey. I thank you.
    I assume I can go on. I'm not sure if I was charged for 
that comment. But I have a little time left.
    Mr. Porter. Yes, you were charged. [Laughter.]

                iom recommendation on clinical research

    Mrs. Lowey. Then I'll ask one of my questions. Thank you.
    Dr. Varmus, this subcommittee supports the construction, as 
you know, of a new clinical research center on the NIH campus 
which you are undertaking. And I'm pleased that the new center 
will surely strengthen the clinical research conducted on the 
NIH campus.
    However, we continue to hear from clinical researchers at 
academic medical centers across the country that they face 
major obstacles in obtaining Federal funding and retaining 
talented researchers. Last year, this committee did urge NIH to 
respond to the recommendations of the 1994 Institute of 
Medicine report on clinical research as well as to accelerate 
the work of the NIH panel formed to deal with the problems 
faced by clinical researchers.
    As you know, last Congress I introduced legislation with 
three colleagues on this subcommittee to implement the IOM 
recommendation. This legislation was included in the Senate NIH 
authorization bill. However, NIH has the authority to implement 
most of the recommendations without legislation. And I need 
your help in responding to the frustrations, frankly, of the 
extramural clinical research community.
    Can you provide to this subcommittee, by perhaps the end of 
March, what specific extramural initiatives NIH will undertake 
in the next six months to reinvigorate clinical research in 
this country? We'd be most appreciative.
    [The information follows:]

    The National Cancer Institute (NCI) and the Department of 
Defense (DoD) signed an agreement to allow DoD medical 
beneficiaries to participate in various NCI sponsored clinical 
trials of new cancer treatments. Participants may receive 
treatment either through the medical treatment facilities that 
have been approved to conduct NCI trials or through medical 
care arrangements reimbursed through TRICARE/CHAMPUS, the DoD's 
health program. This partnership allows DoD beneficiaries 
throughout the country to receive state-of-the-art care through 
NCI sponsored clinical activities by participating in emerging 
new approaches that have significant promise for the successful 
treatment of cancers.
    NCI will continue to provide a user-friendly, active 
information system through an expansion of the Physician Data 
Query. This allows physicians quick access to information about 
open available protocols at the nearest or most appropriate 
institution or to physician participating in the suitable 
protocols.
    In the training area, the NCI has developed a new program, 
the Career Transition Award, to provide support to outstanding 
newly trained basic or clinical investigators to develop their 
independent research skills through a two phase program; an 
initial period involving an intramural appointment at the NIH 
and a final period of support at an extramural institution. The 
award is intended to facilitate the establishment of a record 
of independent research by the clinical investigator in order 
to sustain or promote a successful research career. It is 
anticipated that this new program will be announced in the NIH 
GUIDE in the next few months.
    In addition, the NCI has recently implemented an 
Accelerated Executive Review (AER) that targets new competing 
research grant applications that are within 4 percentile points 
of the payline for basic research or 10 percentile points for 
``patient oriented research''. This AER is designed to 
encourage clinical projects by allowing a broader range of 
eligible applications, 10 percentile beyond the payline for 
funding. In FY 96, the NCI Executive Committee reviewed 51 
applications under the AER (31 basic research and 20 patient 
oriented research). The committee recommended 26 of these for 
awards, for a total cost of $6.7 million. Nine of these were 
for ``patient oriented research''.
    The National Heart, Lung and Blood Institute, in 
collaboration with the Health Care Financing Administration, is 
sponsoring a randomized trial, Lung Volume Reduction Clinical 
Trial, to determine the benefits and risks of this operation to 
patients with end-stage emphysema. Currently, hundreds of 
patients are being subjected to this operation despite the fact 
that its effectiveness had never been established. Furthermore, 
there are no data on long-term outcome, and no evidence is 
available to indicate which patients might benefit from the 
operation. This trial will provide patients with the 
information they need to make informed, intelligent decisions 
about their health care.
    Within the next six months, the National Institute of 
Allergy and Infectious Diseases (NIAID) will fund ten new 
clinical research initiatives in FY 1997 and announce an intent 
to fund 12 additional ones that will be funded in FY 98. These 
initiatives span the range of clinical research activities from 
small pilot studies to large clinical studies and phase II and 
III clinical trials. New career development activities for 
clinical investigators are included in the goals of the 
initiatives on emerging and re-emerging diseases. The clinical 
research needs and opportunities addressed by these 22 new 
clinical research initiatives include AIDS, vaccine development 
and testing, chronic fatigue syndrome, immunological effects of 
aging, women's health issues, sexually transmitted diseases in 
adolescents, transplantation, and emerging and re-emerging 
infectious diseases, including malaria. A list of the titles of 
these initiatives is attached. The NIAID is also conducting a 
review of its infectious diseases research training programs to 
ensure that these programs are producing investigators with the 
capacity to carry out independent research in clinical 
investigation.
    Beyond its specific initiatives and activities, the NIAID 
is also applying newly developed, streamlined grants management 
procedures to expedite the evaluation and funding of clinical 
research grant applications. These streamlined procedures 
consist of selective payment of applications that are 
identified as having important clinical research goals; 
electronic peer review and early Council review to expedite the 
award of grants to clinical investigators.
    In FY 97, The National Center for Research Resources (NCRR) 
will support the network of GCRC and other related activities 
with a total of $157 million. The NCRR funded one new GCRC in 
FY 96 and depending on available funds, may consider funding an 
additional new center in FY 97. The FY 96 award was made to 
Howard University which is particularly significant in that it 
related to research on diseases that affect African Americans 
and for Historically Black Colleges and Universities. In 
addition, NCRR funded a new satellite site at Children's 
Hospital, Seattle, WA.
    The NIH loan repayment program is currently limited to 
scientists in the intramural program and is being implemented. 
The NIH may seek a legislative change to broaden the 
eligibility for the loan repayment program to include clinical 
researchers at academic health centers throughout the country, 
a situation under legislative restrictions now.

    Mrs. Lowey. I know that NIH is currently working with 
certain health plans such as the military's CHAMPUS plans, to 
arrange for their subscribers to participate in NIH research 
protocols. This is an important development. I know you share 
that opinion. Could you explain to us the prospects for similar 
arrangements with private insurers and more broadly speaking, 
can NIH help to encourage managed care companies to support 
academic research?
    Dr. Varmus. Mrs. Lowey, you've given me a large task. I'd 
be happy to provide more written details. We're going to be out 
of time if I don't do that.
    Mrs. Lowey. Right.
    [The information follows:]

               Subscribers Participation in NIH Protocols

    I and my staff recognize the importance of new partnerships 
to enhance clinical research in the coming century. These 
partnerships must include the NIH, academic health centers 
(AHCs), foundations, the pharmaceutical industry, managed care 
organizations (MCOs) and private insurers. I believe NIH can 
help to encourage MCOs to support academic research in the 
context of such partnerships. Heartened by NCI's successes in 
working with the Department of Defense/CHAMPUS and the 
Veteran's Administration to obtain coverage for the routine 
clinical care component of clinical trials, NIH's Institutes 
and Centers, including the Clinical Center, will work with MCOs 
to ensure the nation's clinical research endeavors.
    In November 1996, some Institute Directors and I met with 
representatives of managed care organizations, including Aetna/
US Healthcare, Group Health Cooperative of Puget Sound, Harvard 
Pilgrim Health Plan, HealthPartners, Kaiser Permanente, 
Prudential and the United Healthcare Corporation. Many of these 
organizations already maintain extensive research portfolios 
and receive NIH funding for some of their research projects. We 
agreed to work together to address our mutual interests in 
clinical research and identified significant research areas 
where NIH and others can cooperate.
    This dialogue will be enhanced by a recently-developed NIH 
Fellowship in Managed Care. We have identified a senior MCO 
manager of research to serve as liaison to enhance 
communication among NIH, AHCs and MCOs. NIH's goals are to 
develop proposals to advance clinical research through greater 
involvement of health plans and their patients in peer-reviewed 
research studies; to determine what is known about 
participation of MCO beneficiaries in NIH-approved protocols; 
to assess health plan policies regarding enrollment in NIH 
studies; and to explore models of health plan collaboration 
with AHCs.
    Other NIH initiatives include the convening of an NIH-wide 
Managed Care Workgroup made up of representatives from each 
Institute and Center to serve as a central source for 
discussing and coordinating approaches for collaborating with 
the managed care community. The Workgroup will share strategies 
advanced by individual Institutes and Centers, develop 
proposals for grass-roots experiments, design innovative 
approaches for linking AHCs with managed care partnerships, 
enhance NIH research information dissemination, and communicate 
widely about what has been learned in the process.
    The effects of changes in the financing and delivery of 
health care on the research infrastructure, the nation's 
capacity to sustain medical progress and the quality of health 
care are issues of particular concern to NIH. I remain 
committed to our traditional venues of support for clinical 
research, but at the same time I am ready to explore new 
opportunities for collaborative research partnerships. As 
managed care organizations become responsible for the health 
care of greater numbers of Americans, their support of patient-
oriented studies will be increasingly critical to the NIH as it 
seeks to develop new mechanisms to enhance and stimulate 
clinical research.

               progress in support for clinical research

    Dr. Varmus. But as you know, first of all, we're working 
very closely with the clinical research panel that I 
established about a year and a half ago. Many of their 
recommendations are already being implemented. And I think 
you'll find that clinical researchers around the country are 
appreciative of the changes we've made. In some cases, we're 
limited by authorization, for example, we're attempting to 
develop a loan repayment program for clinical investigators, 
but we simply don't have the authorization to institute it. But 
we do have such a program on the NIH campus.
    We have had very productive conversations with 
representatives of the managed care industry to explore our 
common interest in research, for example, in clinical trials 
and epidemiology, in health services research, we are dealing 
with some of the most enlightened members of what is obviously 
a very heterogeneous group of organizations, but they represent 
many millions of patients.
    We are finding common ground, and I am hopeful we'll be 
able to work very productively with them. But I think in view 
of the time constraints, I'd rather give you a more detailed 
account of the very considerable progress I think we've made in 
the last year in the clinical research arena for your perusal.
    Mrs. Lowey. Given the time, I will close. And I just want 
to thank you again. We're aware of the progress, but I'm sure 
you're aware of the frustrations as well. So I look forward to 
that response and I thank you again.
    Mr. Porter. Thank you, Mrs. Lowey.
    Mr. Wicker.

                     impact of 7.5 percent increase

    Mr. Wicker. Thank you, Mr. Chairman.
    Dr. Varmus, we're always glad to have you before our 
subcommittee. Let me ask you about money. I understand you've 
commented about the funding level briefly in your opening 
statement. But particularly, we have here that Senator Specter 
has suggested a 7.5 percent increase in your budget, as opposed 
to a rather modest 2.6 percent Administration request. I wonder 
if you could comment on the difference in programs that impact 
the health of Americans between those two levels of funding.
    And also, in the out years, are you making plans at NIH for 
the very modest level of growth proposed by the Administration?
    Dr. Varmus. Mr. Wicker, as the numbers you've given me to 
work with in answering this question indicate, we would have 
over $500 million more under the proposal made by Senator 
Specter compared to the President's request. And obviously, 
with that money, we could support a large number of additional 
grants that otherwise might not be funded because of the 
constraints of the budget that's being proposed.
    Mr. Wicker. What would be your priorities there?
    Dr. Varmus. Well, as I mentioned earlier, we've 
established, during a reiterative process during the past year, 
a long list of new efforts we'd like to undertake. And I have 
tried to look at those initiatives in the context of an 
inflationary increase, an increase of perhaps 5 percent, 7 
percent, and 9 percent. And there are some initiatives we 
wouldn't undertake and there are some we would undertake with 
less money if we were to receive a smaller budget.
    So it's not as though we would not do genetics research 
with one budget but would with another. But in general, things 
would go more slowly. And fewer investigators would be working 
on the problem, or certain areas, certain narrowly defined 
initiatives might not be undertaken with the smaller budget 
appropriation.
    So it's difficult to say that there is one thing that we 
will not be working on, because we will continue to work, 
albeit less rapidly than we might be able to with a larger 
budget, on a broad range of research activities.
    As far as the out-years are concerned, I have developed a 
mind set over the last few years of concentrating on the year 
at hand. So right now, I'm concentrating on 1998. The President 
and OMB, in making the out-year projections for NIH, have 
proposed very modest increases. But those modest increases are 
indications that we are a Presidential priority, and we take 
that as a sign that when the budget is formulated for 1999, 
that there will be a solid budget for the NIH. We are planning 
around 1998 and not making specific plans based on the budget 
projections for 1999 and 2000.

                      consensus development panels

    Mr. Wicker. Let me ask you, Dr. Varmus, what is a consensus 
development panel?
    Dr. Varmus. We have a tradition dating back over 20 years 
of bringing together, and we have done so over 100 times, 
groups of speakers who are informed about a certain medical 
topic, for example, a new treatment for a disease, to present 
their findings to a panel of informed but impartial individuals 
who then, after listening to the speakers, puts together a 
statement that hopefully represents consensus in the scientific 
community about the state of the art in a certain area.
    Let me give you one particularly useful example. About two 
years ago, we had a conference on ulcers and an organism known 
as Helicobactor pylori. For many years, it was thought that 
stress and gastric acidity were the major causes of gastric and 
duodenal ulcer. It wasn't appreciated until more recently that 
there was a bacterial cause. And the consensus conference 
allowed a number of investigators to present the findings and 
to have a public airing of this new view about the cause and 
treatment of gastric and duodenal ulcer. The effect of the 
consensus was to diffuse through the medical community these 
new ideas, to establish their credibility, and make anti-
bacterials more widely used.
    Mr. Wicker. The witnesses are people outside.
    Dr. Varmus. They are outside, they are experts brought to 
the NIH to present their findings to a panel, which is also 
from the outside. But the panelists have no declared views on 
this topic. They have not published opinions about that area of 
research. They listen to the experts then come up with a 
statement.
    Mr. Wicker. Let me just ask you, because we are short on 
time, I understand there was recently such a consensus 
development panel focused in part on needle exchange programs.
    Dr. Varmus. That's correct.

                panel on potential research on marijuana

    Mr. Wicker. Perhaps another one on legalization of 
marijuana.
    Dr. Varmus. No, let me correct you on that. The marijuana 
discussion was not a consensus development conference.
    Mr. Wicker. It was a different type of panel?
    Dr. Varmus. Yes. We can discuss that if you like. It had a 
very different intention in mind. If you like, I can expand on 
that.
    Mr. Wicker. Please, yes.
    Dr. Varmus. As you know, due to the passage of referendums 
in Arizona and California, the use of marijuana for medical 
purposes has become an important public health issue. There is 
very limited evidence available on the issue of whether there's 
any appropriate use for marijuana in the treatment of a number 
of conditions, including the anorexia and wasting syndromes 
that occur in AIDS, nausea in cancer chemotherapy, glaucoma, 
multiple sclerosis and so forth. And we felt that it was 
incumbent on us to ask whether there was enough evidence to 
suggest that there should be more clinical trials in this area. 
And equally importantly, whether methodology existed for doing 
a credible clinical trial on a smoked product.
    So we brought experts in clinical trial design, in the 
pharmacology of marijuana, and in the treatment of the various 
conditions for which marijuana has been recommended in the 
past, to come together and discuss these issues. The outcome of 
the meeting, for which a formal report has not yet been 
written, is that there is very limited evidence on the efficacy 
of smoked marijuana in these conditions. There are some 
indications that it may be useful in certain limited contexts 
and that it would be possible to design credible clinical 
trials. And the NIH has been open to applications for clinical 
trials in this area. We've funded very few because we've had 
very few applications that passed peer review. But we are 
prepared to do such studies if they are properly designed and 
pass peer review.

                            needle exchange

    Mr. Wicker. Let me back up then to the needle exchange 
programs. As you are aware, section 505 of our appropriation 
bill specifically states that no such funds should be used for 
needle exchanges. In light of that, why is it appropriate for a 
consensus development panel to be focusing in on this issue, 
and to conclude, among other things, that significant policy 
and legal barriers must be removed in order for this powerful 
weapon to be effective?
    Dr. Varmus. Two points, Mr. Wicker. First of all, the 
consensus conference was not about needle exchange solely. It 
was about behavioral modalities that might be used to restrict 
the spread of HIV, which as you know is the cause of a lethal 
disease. Second, section 505 does not simply prevent the use of 
Federal money for needle exchange. It prevents such use unless 
the Secretary can certify that needle exchange programs would 
reduce the spread of infection without increasing the use of 
intravenous drugs.
    We are continually asking whether those conditions can be 
met, because we are seeking, in the light of the threat posed 
by HIV, any means that can be used to reduce the spread of 
infection.
    Now, we all acknowledge that, first of all, drug abuse is a 
major avenue for the spread of infection. We believe that at 
present, perhaps half of the new infections that occur in the 
U.S. each year, half of between 40,000 and 80,000 new 
infections that occur each year, can be directly attributable 
to drug use or to sexual encounters with drug users, or to 
being the offspring of somebody who uses drugs. Those are 
troubling numbers.
    There have been many studies of the use of needle exchange 
programs in a variety of communities in this country and 
elsewhere. And there is increasing evidence in favor of the 
idea that needle exchange programs can reduce the spread of 
blood-borne infections with hepatitis viruses and with HIV. 
There is also evidence--less compelling because of the nature 
of the evidence, but nevertheless evidence--that the use of 
needle exchange programs does not increase the use of 
intravenous drugs. Therefore, it seemed to those who listened 
to the consensus conference that good could be achieved by 
needle exchange programs--namely, a reduction in transmission 
of these lethal infections--without apparent harm, that is, 
increase in drug use.
    Mr. Wicker. A quick follow-up. Do you believe, based on the 
evidence that you now have, that the Secretary should make a 
finding that the use of needle exchanges is appropriate?
    Dr. Varmus. It is a difficult issue. Because the nature of 
the evidence for the absence of increased use of drugs is less 
compelling than the direct evidence of measuring virus in the 
blood for demonstration of efficacy. Nevertheless, my own 
personal view is that the evidence is supportive of that 
conclusion.
    Mr. Porter. Thank you, Mr. Wicker.
    Our ranking member, who was required to be at his hearing 
on Armed Services, is here and I would like to call Mr. Obey 
for any opening statement that he might wish to make, and then 
he can proceed with his questions.

                           mammography policy

    Mr. Obey. Mr. Chairman, thank you. I don't have any opening 
statement. It's just that I've recently had hernia surgery, so 
I ask you to please don't say anything that makes me laugh or 
sneeze.
    I just want to raise one question. I note that while I was 
at home, the Senate gave its advice and directed its wisdom on 
the subject of mammograms to NIH. And I guess I would simply 
say that I would like to question what appears to be 
conventional wisdom in the Senate that either House or Senate 
ought to start telling NIH exactly what it ought to be 
recommending in these areas.
    That is not a totally accurate characterization of what the 
Senate did. But I can recall in the 1970s, when we used to have 
a lot of pressure to see to it that women were told to have 
mammograms at earlier ages than had been the case in the past. 
And very frankly, at that time, it seemed to me, and certainly 
to a lot of people who knew a lot more about it than I did, 
that given the state of imaging technology it was an open 
question as to whether or not mammographies at an early age 
caused more harm than good.
    We've now had an improvement in the technology. But it 
seems to me that there are still legitimate questions about 
exactly how much emphasis should be given to advising women in 
their 40s that they ought to have mammographies. And so I guess 
I would just say that I would urge you, despite the Senate's 
resolution, to call them as you see them. Because it would seem 
to me that in the end, we would do the most good by seeing to 
it that we have a lot of emphasis on having women above 50 
certainly obtain mammographies, because there is no question 
that you can save a lot of lives if they do. It seems to me 
that the greatest emphasis ought to be there. And that science, 
rather than conventional wisdom in the political field, ought 
to drive what happens with respect to other age groups. I don't 
know if you have a comment or not.
    Dr. Varmus. Well, I appreciate your comment, Mr. Obey. 
Yesterday, I attended the National Cancer Advisory Board 
meeting at which this topic was discussed. And I'm sure it will 
be further aired this afternoon, when Richard Klausner from the 
NCI testifies. In the course of the deliberations of the NCAB, 
the points that you were just making right now were emphasized 
in a very useful way, trying to place into context the much 
greater importance of getting women in the age range of 50 to 
70 in for mammography. Currently less than half take advantage 
of what is clearly an effective means of detecting early cancer 
in that age group. And also, it is important to get those who 
are positive into treatment.
    Also emphasized during the course of the discussion was the 
importance of educating caretakers and patients who are in 
their 40s of the benefits and risks of mammography in the 40s, 
and to teach people that there's nothing magical about turning 
40 or turning 50, that throughout the 40s, the benefits 
increase as one ages. And given one's attitude toward 
screening, given one's apprehension about a false positive 
diagnosis, which is fairly common in the 40s, given one's 
genetic family history and given the changing nature of the 
technology, people may make different decisions at different 
times in their 40s to begin mammographic screening.
    I believe this is a much more sensible approach than 
mandating one or the other. I think much of this is driven by 
concerns about reimbursement and perhaps that might be where 
some of the emphasis is placed in the discussion of this issue.

                           cloning of humans

    Mr. Obey. Thank you. With respect to the marijuana 
question, again, I would hope that NIH would proceed to try to, 
as much as possible, provide the scientific answers. It seems 
to me that what is most important is not the opinion of Arizona 
or California activists, or for that matter, the President's 
drug czar. What's important is what the facts are. And it seems 
to me that we would in the end benefit from having NIH proceed 
to provide as much information as they can by way of whatever 
trials they can put together.
    I understand that you made some comments about the recent 
events in Scotland with respect to animal cloning. I guess I 
just have one question on that score. I am concerned about the 
long-term implications of that in terms of research on human 
beings. But I have a dark Irish soul which has taught me a long 
time ago that if anything bad can happen, it eventually will. 
Where are we in terms of the possibilities with respect to 
human cloning? What is the state of the science on that? And 
how in fact can we discourage going down that road, given the 
fact that as long as possibilities are there, I'm convinced 
that people are going to try to go down that road.
    Dr. Varmus. Well, to answer your question of where we are 
with respect to human cloning experiments, at the moment, the 
evidence that such experiments can be done depends entirely on 
what you've read about the sheep. There are similar efforts 
being made with other organisms, mice, for example, and 
experiments are being done with embryo cells from a variety of 
organisms.
    But nothing is being done with humans for a number of 
reasons. First, there is a prohibition, as you know, on human 
embryo research. As I mentioned earlier, the panel I 
commissioned in 1994 to look at the prospects for Federal 
funding of experiments that involve the human embryo had 
expressly indicated that experiments that would involve nuclear 
transplant for human cloning would not be recommended for 
Federal funding for a variety of reasons that I elaborated on 
earlier.
    Mr. Obey. I understand that. I know there's a prohibition 
on Federal funding. But not everything that happens in the 
world happens with Federal funds.
    Dr. Varmus. If you're asking whether I know that such 
experiments are being done in the private sector, I essentially 
can't comment.
    Mr. Obey. No, I mean, how likely do you think it is that 
over the next 30 or 40 years the scientific community is going 
to be totally dissuaded from trying to go down that road as far 
as the knowledge?
    Dr. Varmus. Well, the scientific community, I think, will 
not find that experiment something worth doing. It doesn't have 
any particular scientific objectives, and it is repugnant to 
the scientific community in general for a variety of reasons 
having to do with our belief in human diversity and 
individuality.
    That is not to say there isn't a renegade who would want to 
do such experiments. As the papers have repeatedly pointed out, 
the experimental design for the work that was done on the sheep 
is surprisingly simple, and doesn't require a cyclotron. It 
requires fairly limited scientific instrumentation. And it 
would be very difficult for anyone to say that there is not 
anybody who is trying to do such an experiment.
    So it's hard for me to answer you in a very direct fashion, 
except to say that such work done in animals has a variety of 
uses. The extrapolations of such work to an understanding of 
how genes are turned off and on, and how we can make different 
kinds of cell types--not whole human beings, but different 
kinds of human tissues--for transplantation and treatment of 
disease. I think it offers tremendous prospects, which is why 
I'm very concerned about a rush to put into place some 
restriction on this whole area of research, which I think could 
severely limit our ability to capitalize on the most 
interesting, important, and medically useful aspects of the 
work.
    Mr. Obey. Thank you.
    Mr. Porter. Thank you, Mr. Obey.
    Ms. Pelosi.

                 national bioethics advisory commission

    Ms. Pelosi. Thank you, Mr. Chairman. Thank you for your 
leadership on this NIH issue.
    And welcome, Dr. Varmus. I was very thrilled, really, to 
hear your explanation of what we are calling an ``experiment,'' 
in Scotland. Mr. Obey, when I had to run out of the room to 
testify in Transportation, I used up my time re-explaining it 
to them. [Laughter.]
    I didn't have as much time as you had, Dr. Varmus. I didn't 
do it justice. [Laughter.]
    I don't know whether I succeeded in my mission of getting 
more money for rapid transit for San Francisco. [Laughter.]
    But I think that the members of the committee are 
scratching their heads, wondering what a sheep in Scotland has 
to do with the price of rapid transit in California.
    But in any event, it was very interesting, and it takes me 
to the question that Mr. Obey was pursuing, are you satisfied 
that in our educational institutions the curriculum is 
inclusive enough of the ethics courses that we need, or the 
leadership in this arena to match the science as it marches 
ahead?
    Dr. Varmus. Are you referring to graduate training in 
science?
    Ms. Pelosi. Yes, graduate training in science, and then 
also just, for example, I'm very pleased, too, that the 
President has this National Bioethics Advisory Commission. I'm 
not completely familiar with it. If you want to say more about 
it.
    Dr. Varmus. Yes, I'd be happy to.
    Ms. Pelosi. What kind of people are they? Mostly 
scientists? Are they philosophers?
    Dr. Varmus. Perhaps I should address that first. The 
National Bioethics Advisory Commission did exist, initially I 
think in 1978. It was in place for a couple of years, and then 
was simply not constituted for many years. The President 
reconvened it under the leadership of Dr. Harold Shapiro, who's 
an economist and the president of Princeton University, about a 
year and a half ago.
    There are 18 members of the Commission. Some are scientists 
who work in the areas of genetics, embryology, and development. 
Others are ethicists. Some are lawyers. They represent a 
diversity of occupations. A very well balanced committee with 
very well-known people who have made significant contributions 
in the areas of the relevant science.
    And their charge is not simply to look at issues that 
surround human development or embryo research. Their mission is 
much broader. Indeed, some of the things they have talked about 
focusing on include a number of issues relating to human 
genetics, including issues of privacy and genetic testing. 
They've also been interested in informed consent and the 
conduct of clinical trials. So there are many issues to which 
they might be assigned.
    The President was very wise in referring this issue to them 
and giving them three months to begin deliberations and to make 
some proposals about things that might be done. As I said 
earlier, I am a little concerned that in the frenzy of the 
excitement about the novelistic possibilities here that 
something more limiting of the research possibilities generated 
by these new findings would be done precipitously. Nothing is 
going to happen immediately in the scientific arena. It's worth 
exploring some of the deeper aspects of these experiments with 
respect to gene regulation before we throw the baby out with 
the bath water.

                            ethics training

    With respect to ethics training, we have made it a part of 
NIH graduate training programs for the last several years that 
there be a component devoted to the conduct of science. That 
encompasses a large number of topics ranging from issues of how 
you work with your colleagues to scientific misconduct, to how 
you apply for grants, and what to consider as career 
possibilities after training in these fields.
    But it would also include ethical issues of the sort that 
we're describing today. We don't prescribe a program narrowly, 
but we do require that all of our training programs have such a 
component.
    Ms. Pelosi. And do you think that in the educational 
institutions, the institutions of higher learning in our 
country, that there is sufficient attention paid to the ethical 
challenges that we will be facing?
    Dr. Varmus. Well, Ms. Pelosi, I actually think that these 
issues grab such attention that they should be used as vehicles 
for interesting people in science. All too few folks are able 
to appreciate the deeper significance of the purported 
experiments, because they know too little about genes and 
nuclei and eggs and how fertilization normally occurs, and how 
a human being or any other animal develops from a single 
fertilized egg.
    What I'd like to see is institutions at all levels, from 
the grade school level on up, take this news account and use it 
as a lasso to bring people into thinking about biology. We have 
tremendous opportunities generated by the genome project or by 
use of recombinant DNA products in generating food to attract 
the attention of young folks who frequently see science as 
tedious, because their textbooks are full of terms they have to 
memorize instead of being brought into the scientific arena 
through public issues such as the one we're discussing today, 
that could be the vehicles for driving people to a greater 
appreciation of science and how its principles underlie many 
public issues that we have to worry about.

                              hiv vaccine

    Ms. Pelosi. Thank you. I was pleased with what you had to 
say earlier about your work being to promote human health and 
reduce human suffering. If this research is in furtherance of 
that, the research that you said, that you don't want to cut 
off because of the possibility of developing the tissue for 
transplantation, etc.
    You talked also about culminations and inspiration. And I 
was pleased that the new AIDS therapies were part of the 
culmination. I guess they're part of the inspiration as well.
    I wanted to ask you about, I don't know if Dr. Fauci would 
call it a breakthrough----
    Dr. Varmus. He never calls anything a breakthrough. He's 
very conservative. [Laughter.]
    Ms. Pelosi. But I wanted to ask you about the possibility 
of an HIV vaccine that the President referenced in his State of 
the Union speech. Under your leadership, NIH has made a 
commitment to give a higher priority to developing a vaccine. 
As we all know, a vaccine is needed to end the global threat 
and domestic threat of HIV/AIDS. What is the status of that 
research?
    Dr. Varmus. Ms. Pelosi, as you know, about a year ago, a 
very broad review of all our AIDS research programs was carried 
out under the leadership of Arnold Levine from Princeton 
University, joined by 100 colleagues. One of the major 
recommendations of that review was that we devote greater 
attention to the possibility of developing a vaccine against 
HIV. HIV has been a difficult combatant in the development of 
vaccines for a variety of reasons I won't go into here. But 
it's been increasingly appreciated that we have not understood 
our failures, nor have we exploited all the potential for 
developing a vaccine.
    We are excited about protease inhibitors as treatment 
devices, but we know they're terribly expensive. They don't 
work for everybody in this country. And they're really not 
accessible to the parts of the world where HIV infection has 
its most devastating and widespread effects, because of the 
cost of the drugs and because of the difficulty in 
administering them and monitoring the response to the drugs.
    So we need something more decisive to control the epidemic 
that's occurring worldwide. A vaccine is that answer.
    In response to the recommendations of the Levine Committee, 
we have increased the amount of money that's available in our 
AIDS program for vaccines. We have put together an AIDS 
advisory group headed by David Baltimore of MIT, one of the 
world's leading immunologists and virologists, who with the 
advice of a number of people who have already met, are putting 
together an important program to move our vaccine program 
forward on a variety of fronts.
    Ms. Pelosi. I appreciate that. Thank you.
    I have some other questions about brain research and child 
abuse, etc., but my time is up, and I'll submit those for the 
record if we don't have another round.
    Mr. Porter. Thank you, Ms. Pelosi.
    Mr. Hoyer.
    Mr. Hoyer. I'll pass.
    Mr. Porter. Mr. Bonilla.

                    commitment to diabetes research

    Mr. Bonilla. Thank you, Chairman.
    Good morning, Dr. Varmus. It's always good to see you, and 
I apologize for not being here for the beginning of your 
testimony. We were in the midst of a hearing questioning the 
Secretary of Defense this morning on the Defense Appropriations 
Subcommittee and it ran a little long. But again, welcome. I 
appreciate any time you call me or visit with me, because I 
hope you always remember that I've got that open door policy, 
that if you ever want to talk about anything, just pick up the 
phone, like you always have.
    I'd like to start, Dr. Varmus, by talking about why you 
concur with others on this committee who believe strongly that 
science and not politics are the direct medical research funds 
in this country, and you've done a great job at the NIH since 
day one. Example, last December, scientists at the University 
of Chicago were conducting research unrelated to diabetes, and 
made a new discovery of two genes linked to causing the 
disease. And prior to this surprise discovery, neither gene had 
been a suspect in diabetes. But this now opens the door for 
more research and understanding of the disease. It was a big 
breakthrough.
    Obviously, in this case, a broad approach to research 
served diabetes well. But with significant momentum, it 
concerns me that NIH has assigned a low 2.23 percent increase 
at NIDDK, a percentage which does not keep pace with biomedical 
inflation which is expected to be at 3 percent for the next two 
years.
    As you know, diabetes is extremely prevalent in Texas, and 
a major concern to me and other members of this committee. I 
especially have worked closely with Mr. Stokes on this issue. 
One in every 15 Texans has been diagnosed with this disease. In 
light of the fact that 27 percent of the entire Medicare budget 
is spent on caring for persons with diabetes, my concern is 
that if it's not given a high priority, we will lose the 
momentum needed to prevent and cure this disease.
    So if you would, Dr. Varmus, explain the NIDDK's low 
priority at NIH, especially when it is truly on the brink of 
pivotal breakthroughs in this area.
    Dr. Varmus. Mr. Bonilla, I agree entirely with your 
assessment of the discovery of the two genes that are involved 
in maturity onset diabetes of the young. But I would take issue 
with you about our lack of commitment to diabetes research. I 
don't believe that the NIDDK is unfairly penalized. Secondly, 
it's not the only venue in which diabetes research is 
conducted. Thirdly, that institute of course conducts research 
on a wide variety of topics.
    Let's look at the example you provided. Much of the work, 
that you described, of course, emerges from a study of gene 
regulation and from the genome project, as well as from 
initiatives in diabetes. What we're dealing with here is a 
problem in the coding of disease and the numbers which we look 
at, which tend to differ by fairly small percentage points, are 
the result of a frankly imperfect attempt to assign dollars to 
various categories. They are very inaccurate assignments.
    What really counts here is the way in which we exploit 
discoveries of the sort that you mentioned. And I will 
guarantee you that those discoveries will be very vigorously 
pursued, because they represent very important avenues of new 
discovery. Having new genes that clearly are involved in the 
pathogenesis of diabetes offers that most miraculous of things, 
a scientific opportunity that people are going to leap to. 
People who didn't work on diabetes before are going to be 
jumping on these topics, and we will be pursuing them as 
vigorously as possible.

                   diagnois and detection of diabetes

    Mr. Bonilla. I'm sensing a lot more attention being paid to 
the prevention and education among those who have not yet been 
affected by diabetes but are in a high risk category. Are you 
feeling that as well? When I'm visiting with researchers and 
even the Speaker talks about it all the time now. He thinks it 
would be a great way to combat the higher projected Medicare 
costs in the future. Are you sensing that as well, that we 
really need to get on the horse here?
    Dr. Varmus. Yes. I think we have a responsibility in three 
areas. One, the area we just discussed, doing more research to 
advance our ability to diagnose and treat diabetes, secondly, 
better methods of detection. Very importantly, as was 
demonstrated by a long-term study of the treatment of diabetes 
by the NIDDK, we have a major responsibility to take those 
findings which show that careful control of metabolism in 
patients affected with diabetes has an important outcome on the 
complications of diabetes, reducing heart disease, renal 
disease, and neurological disease.
    And the careful control has to be instituted. The Eye 
Institute, which has a major role in diabetes research, has 
shown conclusively that early detection of the retinopathy of 
diabetes is incredibly important, because we can treat the 
retinopathy and prevent blindness. And yet, all too many 
individuals with diabetes fail to see an ophthalmologist 
regularly.
    So we have initiatives for discovery, initiatives to 
identify those who are at risk, and very importantly, 
initiatives to develop a sense in the physician community and 
among patients of the need for careful surveillance of their 
disorder. Because the complications in very large measure can 
be prevented.
    Mr. Bonilla. So just to sum up this area of questioning, 
even though I mentioned this 2.23 percent, you're not concerned 
that we're neglecting diabetes research at this time?
    Dr. Varmus. I do not believe we're neglecting diabetes 
research.

                            imaging research

    Mr. Bonilla. I want to turn now to the subject of imaging, 
which we've discussed before. I'm interested in knowing how 
much of a priority imaging research is at the NIH. And as you 
know, some people would like to see an imaging institute 
created at the NIH. They suggest that current funding which is 
dispersed throughout NIH for imaging should be combined to 
create this institute.
    Tell us specifically how you intend to address imaging 
research, Dr. Varmus.
    Dr. Varmus. Well, as I mentioned in my introductory 
remarks, imaging is playing an increasingly important role in 
the study of neurological disorders and in the study of many 
other disorders as well, for example, in cardiology and in the 
study of the vascular system. Imaging is fundamental to both 
research and to clinical practice. Virtually every institute 
has some involvement in imaging technology and the use of new 
imaging devices, be it advanced x-ray procedures or magnetic 
resonance imaging or PET scanning to further their 
understanding of the body and the diseases that afflict it.
    I know there is an interest in an imaging institute. My 
personal attitude is, this will not occur on my watch. That's 
true for many reasons. Administrative expenses will be 
increased if we do that, it will remove from the place where 
imaging should be practiced, namely the institutes looking at 
various diseases, the incentive to advance instrumentation in 
the areas of special interest to that institute.
    And right now, we coordinate our activities in imaging 
extremely well. We've had a recent review of our imaging 
activities in the intramural program. And we are developing new 
programs that are well coordinated among the institutes. We 
have the existing mechanisms for coordinating our efforts in 
imaging. We don't need another administrative structure.
    Mr. Bonilla. Thank you, Dr. Varmus.
    Mr. Porter. Thank you, Mr. Bonilla.
    Ms. DeLauro.
    Ms. DeLauro. Thank you for being here, Dr. Varmus. I'm 
sorry I won't be in New Haven to listen to your lecture. I 
would be delighted to do it, but I know the city will treat you 
well while you're there.
    I think the questions of this morning have shown that the 
experiment in Edinburgh really was truly the ``baa'' that was 
heard around the world. [Laughter.]
    Ms. DeLauro. So I think we have covered the topic, so I'm 
not going to ask a question in this area, and, at the risk of 
my colleagues throwing something at me, I feel a little 
sheepish about doing one. [Laughter.]

                             ovarian cancer

    Ms. DeLauro. But I did want to ask a couple questions. 
First, in 1997, the NIH spent $41 million out of the $12.7 
billion budget on ovarian cancer research. And over the past 
few years, increases in ovarian cancer research funding have 
been extremely incremental. We know through the studies that if 
it's properly diagnosed, treated early, that the survival rate 
for women is 92 percent. But to date, we have no simple 
diagnostic test to detect ovarian cancer.
    My questions are, how much does the NIH plan to spend this 
year on ovarian cancer research? What types of initiatives does 
this include? And will the research be done primarily through 
the extramural or the intramural programs?
    Dr. Varmus. While my valued colleagues are digging up the 
exact number for 1998--it will be in the range of $40 million--
let me say a few things about what's going on. First of all, 
there is activity in ovarian cancer research, both intramurally 
and extramurally. We have clinical activities and basic science 
activities within the intramural program and of course, many 
activities outside. I agree with you that we have yet to 
achieve the ideal diagnostic procedure in the case of ovarian 
cancer. And that actually is true for many internal cancers, 
unfortunately.
    The number for 1998, I'm told, is going to be $41 million.
    But there are at least a couple of things that are being 
explored in a large scale study attempting to evaluate both 
trans-vaginal ultrasound and an existing immunological marker, 
CA-125, that I'm sure you're familiar with, that attempts to 
evaluate their usefulness.
    One major source of activity in ovarian cancer research in 
the last year that's given us a lot of optimism is the large 
number of clinical trials, approximately 60. Importantly, 
almost half of those are phase one trials that involve new 
drugs. We're also extremely encouraged by the efficacy of 
certain combination therapies, particularly those that use 
taxol and cis-platin, often in combination with a third agent. 
And as you know, that has had a dramatic effect on our ability 
to control mortality from this disease.

                  advances in ovarian cancer research

    I'm also pleased to say that one of the initiatives that 
I'm sure Dr. Klausner will discuss this afternoon, involving 
our efforts to understand the genetic anatomy of cancers, 
includes ovarian cancer as one of the five target sites for 
initial investigation. As you know, one of the major 
discoveries of the last few years, the isolation of the BRCA-1 
and BRCA-2 genes, which was initially an initiative mainly seen 
in the context of breast cancer, has had dividends in the area 
of ovarian cancer. Because individuals who are born with 
mutations in either of these two genes are at higher risk for 
ovarian cancer. It's also possible to predict from the nature 
of the mutation the likelihood the individual will have ovarian 
cancer.
    So there have been advances. They're not as far along as I 
would like. When you were here three years ago, we discussed 
the role of telomerase in the treatment of ovarian cancer. That 
has not yielded the benefits that some anticipated at the time. 
But you can be assured that we recognize the great significance 
of ovarian cancer and are pursuing it as actively as possible.
    Ms. DeLauro. I would call on you, and I will say the same 
thing to Dr. Klausner this afternoon, that 27,000 women will be 
diagnosed with ovarian cancer, 15,000 will die. When we can 
find this in the early stages, and when it's treated, it's 92 
percent survival.
    Dr. Varmus. This year, two of those diagnosed individuals 
are friends of mine. So I'm with you on this one.

                    child development and the brain

    Ms. DeLauro. Thank you. Can you please discuss the NIH's 
research in the area of child development and the work that's 
being done on the brain, how children learn? How has the NIH 
coordinated or are you coordinating with the Department of 
Education programs like Head Start and others that ensure that 
the results that you are uncovering in a brilliant way, this 
research, is applicable to public policy and the classroom?
    Dr. Varmus. Well, there is a great deal of activity in this 
arena. And I'm sure you'll be hearing a great deal more about 
it, both from Duane Alexander, when he speaks to you about the 
activities of the NICHD, and from Steve Hyman, when he talks 
about NIMH. And of course, a lot of this is yet further 
inspired by the President's interest in studying early brain 
development to ensure that all Americans can read by the third 
grade.
    One important development has been our deeper understanding 
of the mental processes that go on during the efforts to learn 
how to read, the ability to recognize phonemes, the components 
of words that represent a special kind of thinking that we are 
beginning to understand, using imaging devices and tools of 
behavioral research. Investigators supported by NICHD have 
developed methods for diagnosing difficulties in appreciating 
phonemes, and have developed interventions that are useful in 
being able to correct the reading abilities of individuals, if 
they are detected early.
    We are working closely with the Department of Education, 
trying to put some of these principles into effect. The 
evidence to date shows that the interventions are effective, 
and we hope that through the White House initiatives in early 
development and the emphasis being placed on education in the 
current Administration that some of the principles that we're 
uncovering by these studies in fundamental neurobiology will 
have outcomes of the most practical kind, namely a public that 
consists only of those who can read.

                     impact of third party payments

    Ms. DeLauro. The point, and the wonder of this committee 
is, that the work that you do is under our purview, at the same 
time the work that's done with Head Start is, too. Now we're 
uncovering information that says, we have a successful model in 
Head Start, and we will continue to work to make it better. We 
now understand that if you can have an impact with children in 
the zero to three years, which also is part of the work of this 
committee, that we need to really work those together among 
departments in order for us to get the best of both worlds.
    In your budget, Dr. Varmus, there's a request for $15 
million in savings through third party payments for the cost of 
patient care at the NIH clinical center. Can you explain the 
proposal, and what it would mean for those who are receiving 
the care at the clinical center, and would these payments 
affect NIH's ability to attract patients for clinical trials?
    Dr. Varmus. Well, I thank you for the question. We 
obviously are concerned about the possibility that requesting 
third party payment might impede referral of patients to the 
clinical center or the ability of, or the willingness of, our 
patients to come there. So we've been working with potential 
third party payors to gauge what the impact would be. We 
recognize our fiscal responsibility to collect for medical care 
delivered in the course of research, in view of the 
stringencies in our budget. And yet we are also sensitive to 
the possibility that we would impede access to the kind of 
research that we do.
    So, at the moment, we have no third party payment 
procedures in place. We have never collected, and we are 
obviously being urged by many to do so. We're moving toward 
that in a cautious manner. And we hope to have some payment 
processes that don't impede patient access.
    Ms. DeLauro. That would defeat our purposes. So I really do 
ask you to proceed cautiously.
    Dr. Varmus. We are doing so.
    Ms. DeLauro. Finally, I'd like to associate myself with the 
comments of my colleague Mrs. Lowey on clinical research. We're 
always in awe of the discoveries, and what happens with regard 
to patients in doctors' offices. So I look forward to seeing 
your response.
    Thank you. And thank you, Mr. Chairman.
    Mr. Porter. Thank you, Ms. DeLauro.
    Mr. Istook.

        comparison of medicare costs and disease research costs

    Mr. Istook. Thank you, Mr. Chairman.
    Dr. Varmus, good morning. We spoke yesterday and also some 
last year, of course, about allocation of research dollars 
within NIH. And you're well aware of my concerns of whether we 
are putting the resources where they can be most significantly 
used.
    I don't know if you've had a chance to look at the graph.
    [See figures 1 and 2.]

[Pages 37 - 38--The official Committee record contains additional material here.]


    Dr. Varmus. Just out of the corner of my eye.
    Mr. Istook. Of course. Let me tell you, the document 
provided to you and committee members, we've spoken before 
about the ratio of funding of different diseases compared to 
the frequency of their occurrence in a population and the 
national cost of it.
    We obtained from HCFA the report of how much it is costing 
taxpayers through Medicare to treat patients with certain 
diseases. Now we were told they were not able to give us a 
breakdown on Medicaid. But this chart is to represent the ratio 
at which the taxpayers are paying for treatment of different 
diseases. And because it's Medicare it includes not only an 
aged population but also those that are disabled by their 
disease. Certainly there are a number of debilitating diseases, 
AIDS, we've talked about, is certainly one of them. So you will 
have people, regardless of their age, that are reflected in 
this chart if they're disabled.
    The point that I'd like to focus on is the difference in 
the amounts that Medicare is paying and the proportion of 
Medicare payments compared to the proportion of disease-
specific funding by NIH. For example, if you look at cancer, 
you see that 9 percent of the taxpayers' money that's going for 
Medicare treatment is going to care for cancer patients. But 
only 5 percent of the NIH research is going to cancer patients. 
That's of the disease-specific research.
    [Clerk's note.--Later corrected to ``49.7%''.]
    Mr. Istook. If you also look through, you'll find, for 
example, chronic obstructive pulmonary disease, again, 
Medicare, 2.6 percent of its payments are to take care of 
patients with that difficulty. Whereas 1 percent of the 
disease-specific research is going to it.
    [Clerk's note.--Later specified at ``1.2%''.]
    Mr. Istook. Diabetes, if you look there, type 1 and type 2 
diabetes, 2.6 percent of Medicare outlays compared to 6 percent 
of disease-specific NIH. However, if you drop down to the 
bottom of the chart and you look at the complications of 
diabetes, the complications are more than one-fourth of the 
total Medicare payments for those treatments. And again, this 
compares to a research allocation of about 6 percent.
    [Clerk's note.--Later specified at ``5.8%''.]
    Mr. Istook. Again, just finishing up on a couple of other 
examples, pneumonia and influenza is 4.3 percent of the cost to 
taxpayers through Medicare, whereas it's 1 percent of the 
disease-specific NIH research. AIDS is two-tenths of 1 percent 
of the outlay for Medicare. But it's 27 percent of the NIH 
research dollars. So that AIDS has 100 percent greater 
proportion of research dollars than what it's costing taxpayers 
through Medicare.
    [Clerk's note.--Later specified at ``1.2%''.]
    [Clerk's note.--Later specified at ``27.5%''.]
    Mr. Istook. I might mention also that the figure of the 
number of AIDS patients of some 46,000 that are being, having 
their expenses paid through Medicare, compares to the CDC 
report of just over 80,000 AIDS patients in 1994. It's a very 
significant proportion of the AIDS patients. In fact, the 
Government outlays, unique on AIDS, $1.5 billion for research, 
$270 million for treatment. No other disease has anywhere near 
that ratio, where the research outstrips the cost of care.
    [Clerk's note.--``New AIDS patients'' later added.]

                     allocation of research dollars

    Mr. Istook. Now, this is part of the concern that I've 
expressed to you before about the priorities, are we putting 
our research dollar where it benefits a greater amount of the 
population, where it benefits the taxpayers and links up with 
the extraordinary expense to the taxpayers of providing health 
care. I would appreciate your comments on that, especially if 
there is any formal consultation process in allocating the 
funding for NIH disease research, any formal consultation 
process with HCFA, which administers the Government Medicare 
and Medicaid outlays, Centers for Disease Control, private 
insurance companies and hospital administrators, and anyone 
else that may be in the private sector as well.
    Is there any formal process for them to have input on how 
we are allocating our research dollars?
    Dr. Varmus. Mr. Istook, there are a number of ways in which 
I would like to respond to your comments.
    Mr. Istook. Sure.
    Dr. Varmus. As far as the formal consultation process is 
concerned, there isn't any formal process that we go through. 
However, the data of the sort that you're presenting--I haven't 
seen this table before--but other kinds of information, of 
course, is not only accessible to us, but we look at it quite 
closely. As you know, in the past we provided to the Congress 
cost of illness reports, and we're of course following the 
epidemiology of disease throughout the Nation very, very 
closely, because we are concerned about these figures. They do 
feed into the overall priority setting process.
    I haven't seen this table before, and I'd have to question 
some of the numbers that you're quoting. Because----
    Mr. Istook. These are from HCFA, by the way.
    Dr. Varmus. The HCFA numbers, I'm sure are correct, but the 
numbers that relate to percentage of disease spending are 
somewhat perplexing to me, and I'm sure perplexing to Dr. 
Klausner, since he previously was receiving almost 20 percent 
of the NIH budget and is now only receiving 5 percent.
    Mr. Istook. Certainly any errors we want to rectify.
    Dr. Varmus. There may be some corrective----

                    criteria for funding allocations

    Mr. Istook. Sure, we may correct information. But the 
ratios, of course, still indicate that a significant question 
of at least $1.5 billion of the application.
    Dr. Varmus. I think we would be remiss if we were 
allocating our dollars solely on the basis of Medicare payment. 
Obviously, the economic burden of disease is one of the things 
that we take into consideration when we think about how our 
appropriations are spent. If there were a major disease we were 
not studying, we'd be quite troubled.
    But as you know, there are many other criteria that we have 
to consider in putting together our budget. One is the other 
kinds of burdens posed by the disease, because they're not all 
financial. The age at which the disease occurs--disease of 
children, disease of middle age, disease of adults, of aged 
adults--makes a difference. The degree of morbidity, the 
longevity of the illness.
    But then we have to consider many things other than the 
illness itself, because, of course, much of our money is spent 
in research that's very difficult to categorize as belonging to 
one disease or another. And one of the places we always run 
into trouble in these discussions, and it's a trouble that's 
inherent in the process of setting priorities and explaining 
what we do, is that much of our research is an effort to 
understand the workings of cells and organisms that may not 
apply to any single disease, yet of course, the public has a 
right to expect us to be able to categorize what we spend in 
understandable terms.
    Mr. Istook. Which calls into question why even allocate 
among any disease at all if research is just going to be of 
such general application?
    Dr. Varmus. Well, because some research is, classifable. If 
we do a clinical trial to treat a certain condition, we can say 
we're spending money on that disease in that case without 
appreciable ambiguity, even though as you know, sometimes such 
clinical trials do lead to developments that affect other 
illnesses as well. But that's a by-product.
    I think we end up with the difficulty we've been in before: 
that, for us, scientific opportunity and the submission of 
applications to study certain questions end up being a very 
significant driver of where our money is spent. We don't expect 
there to be a one to one relationship between any cost 
accounting and the place where we spend our monies. I find 
myself more responsive to a complaint that there is a promising 
opportunity that we're not seizing than I am to the notion that 
there is a less than uniform correspondence of one component of 
our priority making to the way we spend our money.

                       reducing health care costs

    Mr. Istook. Of course when you have, it's hard to find any 
other disease that has a one to one ratio. And yet you've got 
one disease that has a 100 to 1 percentage or priority ratio. 
I'm concerned, especially, we're spending tremendous amounts, 
of course, through NIH on research.
    But it doesn't seem to me that one of the purposes is to 
try to reduce not only the burdens, but the cost of health 
care, to patients, to their families, to citizens, to 
taxpayers, to all the people that are being hit with tremendous 
health care costs. And our research doesn't seem to take into 
account that national priority of trying to reduce the burden 
of health care costs by making sure that research is focused on 
the diseases that are costing so many people so much. Instead 
it is grossly focused on a disease that, although terrible, is 
not more terrible than many other diseases, and certainly does 
not represent the same degree of threat to nearly as many 
people in this country as other diseases, such as cancer and 
diabetes.
    Dr. Varmus. Well, let me take issue with a couple of things 
you've said. One is that the goal of our research is not solely 
to reduce health care costs. In fact, sometimes the outcome of 
our research is to increase costs. In some areas that does 
happen. We like to point to advances that in fact do save 
money, but they don't all save money. Sometimes we have an 
advance that decreases human suffering, but does so at the cost 
of increased medical expenses.
    Secondly, I would take issue with the question of the 
populations at risk. And let's talk specifically about AIDS, 
because that's obviously what's on your mind. AIDS is currently 
the leading cause of death for individuals between the age of 
25 and 44. It's a disease which has tremendous impact 
worldwide. Every child growing up in America, every parent is 
concerned about HIV. Peoples' attitude toward life is affected 
by it. It's a new disease. It's a disease which continues to 
spread in certain populations here, even though the infection 
rate has begun to stabilize.
    We do have some therapies for it. It represents an enormous 
challenge, which we have already seen pays dividends in 
thinking about other ailments. We discussed this before, and I 
understand that money we spent on other diseases also has 
ramifications beyond the narrow disease confines to which the 
monies are classified.
    But I think the pervasive nature of infection with HIV, its 
involvement of every organ system, has produced for us 
challenges that have had particularly broad ramifications in 
all of medical science.
    Mr. Istook. Thank you, Dr. Varmus. I will work with you and 
try to get more information from you on how many people and how 
much input actually goes into deciding the allocation of the 
research dollars within NIH, and whether we need a much broader 
and more inclusive process to make those determinations.

                      nih priority setting process

    Dr. Varmus. I would like to make just one very brief 
comment if I can.
    Mr. Istook. Sure.
    Dr. Varmus. We are preparing, for the public and for the 
Congress, a booklet that describes how we go about the priority 
setting process. As you'll see, many, many constituencies are 
involved in that process, and my response to your request for 
information about formal interactions was accurate. But those 
influences are felt, just not through a formal process----
    Mr. Istook. Sure. You'll give us the information on the 
informal part.
    Mr. Porter. I might say to my colleagues that everyone, 
except Mr. Stokes, who had to leave, has had an opportunity to 
ask questions this morning. Dr. Varmus will be here with each 
of the Institute directors for seven full days of additional 
hearings. And would be available to answer any questions, as 
well as the directors themselves.
    Dr. Varmus, we'd like to thank you very much for your 
testimony this morning. You've enlightened us a great deal. We 
appreciate the wonderful job you do at NIH. You and the 
Institutes are truly national treasures, and we appreciate your 
strong leadership there.
    The subcommittee will stand in recess until 1:30 p.m.
    [The following questions were submitted to be answered for 
the record.]

[Pages 43 - 197--The official Committee record contains additional material here.]


                                      Wednesday, February 26, 1997.

                       NATIONAL CANCER INSTITUTE

                               WITNESSES

RICHARD D. KLAUSNER, DIRECTOR, NATIONAL CANCER INSTITUTE
ALAN RABSON, DEPUTY DIRECTOR
HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH
DENNIS WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF 
    HEALTH AND HUMAN SERVICES

    Mr. Porter. The subcommittee will come to order.
    We're pleased to welcome Dr. Richard Klausner, the Director 
of the National Cancer Institute, this afternoon. And Dr. 
Klausner, I'm going to forego an opening statement and so are 
my colleagues on this side. And why don't you simply proceed.

                       Introduction of Witnesses

    Dr. Klausner. Thank you, Mr. Porter, members of the 
committee. It's a pleasure to have the opportunity to speak to 
you.
    Before I start, let me introduce, you know the people on my 
right, but on my left is Dr. Alan Rabson, the Deputy Director 
of the National Cancer Institute.

                           Opening Statement

    This past year, we recognized the 25th anniversary of the 
1971 National Cancer Act. And it's been for us an historical 
year as we sought to evaluate this Nation's investment in 
cancer research and assess the fruits of that investment. This 
fall, we were able to announce that for the first time since we 
began to track the constant rise in cancer mortality over 60 
years ago, we had encouraging news. Sometime around 1990, we 
appeared to have reached the peak in the mortality rate and for 
the past five years, the overall age-adjusted mortality rates 
have fallen for all cancers. And that's shown here, you can see 
what we've been able to observe for the last few years.
    [See figure 1.]

[Page 200--The official Committee record contains additional material here.]


    Dr. Klausner. Every 2 percent drop represents 10,000 to 
15,000 lives that would have been lost. These include for the 
first time the most common causes of cancer death, including 
lung, colorectal, breast, prostate, bladder, head and neck and 
others. We believe that these encouraging results are the 
results of the investment we have all made. They are probably 
the result of multiple factors, including prevention, 
especially declining tobacco use among American adults, early 
detection and better therapy.
    The burden of cancer, as you all know, is not shared 
equally among all in our society. African-Americans, for 
example, experience a 20 to 30 percent excess rate of cancer 
death compared to white Americans. However, the latest 
mortality data included again for the first time a significant 
drop in the cancer death rate in African-Americans. We can see 
that here. In fact, you can see from looking at this that the 
percentage drop appears to be larger over the past five years 
in the African-American community than among all Americans, 
suggesting if those hold up that this terrible gap in survival 
may be closing.
    [See figure 2.]

[Page 202--The official Committee record contains additional material here.]


    Dr. Klausner. Today over 10 million Americans are cancer 
survivors. The majority of these were diagnosed over five years 
ago. In recognition of the many unanswered questions that long-
term survivors face, there is a need to do research to answer 
questions about medical and psychological consequences, of 
delayed recurrences, second cancers, and long-term effects of 
treatment. As I announced last year, we're initiating several 
funding initiatives, in this area. Our fundamental goal is to 
develop effective interventions to reduce the incidence, 
mortality and morbidity of cancer.
    There is probably not going to be any one intervention or 
even any one type of intervention that will successfully 
conquer cancer, or the many diseases, in fact, that we call 
cancer. Our approach must be and is open and broad-based, 
identifying those at risk and modifiable risk factors, for 
developing sensitive and predictive means of early detection, 
and learning to finally correctly diagnose each cancer so that 
the diagnosis predicts the course of the disease and dictates 
the choice of therapy. Cancer is a disease in which one of the 
trillions of cells in our body gradually changes over time. 
That cell is a crucible in which the interacting players of 
genes and environment meet and produce the alterations that 
drive the behavior, in this case the misbehavior, of each 
cancer.
    The ability to look at genetic changes in cancer cells 
offers us an interesting twist to the search for external 
causes of cancer, a type of reverse epidemiology. Scientists 
are now exploring whether the fingerprint of particular types 
of carcinogens can be found within the DNA of the cancer cell, 
much like the thief that leaves incriminating evidence at the 
crime scene. And to help us use the effects of environmental 
carcinogens to identify the culprits.
    Such an approach has recently been demonstrated for one of 
the carcinogens, benzopyrene, found in tobacco smoke, as well 
as a carcinogen that causes liver cancer, and is found 
contaminating certain foods, for sunlight and for vinyl 
chloride.

                           cancer prevention

    Prevention in part explains the drop in cancer mortality 
rates, and prevention will play an increasingly important role 
in our approach to cancer in the future. Prevention studies 
range from evaluating behavioral intervention against tobacco 
use, and for healthful diets to pharmacologic interventions 
that include drugs that block the interaction of hormones for 
breast and prostate cancer, to anti-inflammatory drugs and 
their ability to prevent the development of colon and other GI 
cancers, to vitamin derivatives to prevent aerodigestive and 
other cancers.
    In fact, now we're testing 24 agents in over 78 clinical 
trials aimed at preventing cancer, in approaching cancer not as 
a single event, which it's not, but as a long and potentially 
stoppable process. The identification of infectious causes of 
cancer provides another type of prevention opportunity. Based 
on major recent breakthroughs at the NCI, we have made a 
commitment to proceed with the development and testing of a 
multi-valent vaccine against cancer-causing strains of human 
papilloma virus. These are the viruses that cause cervical 
cancer. This is the first such effort to vaccinate against an 
agent solely for the purpose of preventing cancer.
    Early detection remains a critical part of increasing 
cancer survival and enhancing the possibility of a cure. And I 
expect we'll be discussing this issue in the question period.

                            clinical trials

    The final component of the decreasing cancer mortality is 
improved treatment. Clinical trials are the means by which we 
test and establish the best treatment for cancer. We have 
continued to work with partners to assure that patients have 
access to clinical trials by strengthening our cancer clinical 
trials agreement with the Department of Defense, and conducting 
a new agreement with the Veterans Administration to integrate 
the entire VA medical system into the NCI clinical trials and 
cancer centers network.
    We have embarked on a strategic plan to restructure our 
clinical trials information system, to create a modern 
informatics base developed in conjunction with the FDA and the 
International Committee on Harmonization, to develop electronic 
systems for data on adverse events and the use of common 
toxicity criteria. A single entry clinical data reporting 
system will greatly facilitate these trials, and pilot testing 
for the system will be completed by April. These efforts will 
improve the speed and accuracy of reporting, produce resource 
savings, and remove impediments of burdensome and cumbersome 
paperwork.
    Critical to enhancing access to clinical trials is 
available and useful information. We're currently working with 
patient and consumer groups to rewrite the NCI PDQ information 
system to be more inclusive of all trials, to be more user 
friendly and comprehensible and accessible. The NCI clinical 
trials evaluation program is currently sponsoring over 750 
active clinical trials, including almost 260 phase one trials 
this year to test new drugs and new therapeutics. Such new 
approaches include viruses engineered specifically to kill 
cancer cells, gene therapy, immunologic approaches to cancer, 
photon based therapy, and new small compound drugs directed 
against the cancer cells or the blood vessels that nourish 
those cancers.
    In addition, hundreds of other trials are conducted at NCI 
cancer centers and through other funding mechanisms. This past 
year, 12 new drugs were approved by the FDA for use in cancer. 
And we anticipate over 30 new investigational drug applications 
in 1997.
    In the biotechnology industry, over 40 new agents are in 
clinical trials for cancer. And cancer is the largest 
beneficiary of this burgeoning industry. Notable results of 
clinical trials of the past year include the demonstration of a 
30 percent reduction in mortality for adjuvant therapy in stage 
C colon cancer, translating into approximately 4,000 lives 
saved a year. And as these benefits may also translate, extend 
to stage B patients, the mortality reduction may prove to be 
even greater.
    Interferon has been demonstrated to be of benefit in at 
least a subset of patients with advanced melanoma. Remarkably 
improved survival from combination chemotherapy with radiation 
for nasopharyngeal cancer resulted in a cooperative trial being 
stopped early because of the positive results. Other examples 
illustrate the incremental advances being made, each adding to 
improved survival for patients with multiple types of cancers.
    These trials examine new agents, new combinations of 
therapy, new ways of delivering therapy such as neo-adjuvant 
treatment where chemotherapy, for example, is given before 
rather than after surgery, in order to improve surgical success 
and even allow less extensive surgery.
    One recent therapeutic advance, let me just illustrate, how 
cancer therapy is being altered by our new understanding of the 
molecular characteristics of cancer. Recently, investigators at 
the National Cancer Institute have been studying a particularly 
aggressive form of lymphoma. And with the previous treatment, 
using five drugs, we see that about 50 percent of the patients 
were cured. Those that were not cured relapsed within about the 
first year.
    [See figure 4.]

[Page 206--The official Committee record contains additional material here.]


    Dr. Klausner. The question was, why 50 percent? What did 
those other patients have? Well, it turns out virtually all 
those other patients had a mutation and alteration in one 
particular gene, p53, whose loss of function is involved in 
over 50 percent of human cancer. So it was actually two 
different diseases. Now, they developed a new drug regimen, and 
now we're seeing that for this type of cancer, over 90 percent 
of patients, including this other category, which we had 
previously lumped together, are either being cured or at least 
look like they have long-term remission.

                    breast cancer--molecular markers

    This illustrates a principle that's guiding a fundamental 
transformation in oncology. We can begin to identify the 
defining characteristics of any cancer, leading us to precise 
and informative diagnoses. Let me give you one example. Breast 
cancer. One of the most difficult therapeutic decisions we have 
to make now is an early stage breast cancer without node 
involvement. Who needs chemotherapy? Who needs adjuvant 
therapy? Some fraction of these women will relapse or develop 
evidence that their cancer has spread. And it's very important 
that we learn to look at these cancers that we've been lumping 
together and recognize that there will be molecular signatures 
that will distinguish a cancer that needs a particular therapy 
from one that doesn't.
    This has recently been published, and this shows using two 
molecular markers that were discovered through studies on 
understanding the basic properties of moving through the cell 
cycle, something called cyclin-E and an inhibitor called p27. 
And notice these differences. This is the outcome for women 
with early stage breast cancer, and these are those cancers 
that have high levels of one of these and low levels of the 
other. And you see what happens. It's clear that these women 
are the women we need to focus on for adjuvant therapy.
    [See figure 5.]

[Page 208--The official Committee record contains additional material here.]


    Dr. Klausner. Whereas, look at the outcome for that subset 
of women which have low E levels and high p27 levels. Again, 
getting a feeling for how this is going to change in the 
future.
    The molecular profile of the cancer cell will define the 
actual targets for therapy, therapy that will be designed 
rather than arrived at empirically as we have done for the past 
20 years. It is this molecular distinction between cancers that 
will allow us to tailor the correct therapy to the correct 
diagnosis. Because we've made great strides in beginning to 
understand how we look at the molecular fingerprint of cancer, 
we've recognized in addition that we can actually accelerate 
this process. We can do much better.
    For that reason, the NCI has embarked on an ambitious 
project to identify all or almost all the genes expressed in 
cancer versus normal cells. We call this the Cancer Genome 
Anatomy Project, and its goals are two-fold: to produce a full 
index of expressed genes for normal, pre-malignant and 
malignant cells, to help support the development, dissemination 
and application of a whole new generation of technologies that 
will alter our approach to detection, to diagnoses and to 
choosing therapy.
    This project, which we call CGAP, both builds on and is 
complementary to the Human Genome Project, and is being done 
jointly through collaboration between the intramural and 
extramural programs. CGAP has been developed with explicit 
annual milestones, and will be, and already, we believe, is, 
building a national resource that everyone can tap into via the 
World Wide Web, and this is the Web page for this new CGAP, you 
can go to it, click on any particular cancer, and what we hope 
eventually to fill this with is a description of all possible 
genes, how one would approach asking diagnostic detection and 
therapeutic questions.
    [See figure 7.]

[Page 210--The official Committee record contains additional material here.]


    Dr. Klausner. This will be the way that we will learn to 
detect cryptic cancers, such as ovarian, pancreatic, stomach 
and others. Again, CGAP involves a collaborative effort with 
the National Library of Medicine, the Department of Energy and 
with a series of industrial partners who are co-funding this.
    There of course are many other initiatives that I would be 
delighted to share with you. But the challenges and 
opportunities clearly before us are great. To address these, 
Mr. Chairman, the budget request for the NCI for fiscal year 
1998 totals $2,217,482,000, an increase of over $61 million. I 
am pleased to be able to appear before the committee, and look 
forward to answering any questions.
    [The prepared statement follows:]

[Pages 212 - 220--The official Committee record contains additional material here.]


                              mammography

    Mr. Porter. Dr. Klausner, let me first say that we believe 
you're doing a wonderful job at NCI in providing leadership not 
only for your own institute but for many of the other 
institutes in how you approach the research that you fund.
    Let me also apologize for being late. I was in a meeting 
with the full committee Chairman and had every intention of 
starting us off at 1:30 and was unable to do so. So I apologize 
to you and Dr. Varmus and everyone in the room.
    The topic was raised briefly this morning with Dr. Varmus, 
but I want to begin by discussing the ongoing controversy about 
mammography guidelines for women in their 40s. NCI initially 
recommended mammography for this age group, and your 
predecessor later withdrew the guidelines. You convened a 
consensus development conference on the subject in light of 
recent research findings. That group concluded that the 
evidence was not strong enough to recommend guidelines, and 
that it should be the individual choice of a woman and her 
doctor.
    The press reports that the conference was acrimonious and 
even raucous. The impression given in the popular press was 
that you disagreed with the findings of the consensus 
conference. Some groups charge that you are now changing your 
mind and supporting the findings.
    Dr. Klausner, I'd like to know not only your own personal 
views on this, but the course of events in the recent past and 
what plans there are for the future to address this very, very 
serious issue.
    Dr. Klausner. Absolutely. I think this is a very important, 
very confusing and, as we've seen, very contentious issue. I 
think it's the NCI's responsibility to speak clearly about the 
evidence that we have, to provide guidance to women and their 
physicians about decision making, guidance that's based upon a 
clear and balanced description of evidence. And as Dr. Varmus 
said this morning, the National Cancer Advisory Board, I will 
be working very closely with them, they have a subcommittee 
now, we will be working with all due speed in order to provide 
just that, to provide guidance for us, so that we will, as 
quickly as possible, communicate a very clear message about 
what information women and their physicians should use in terms 
of making decisions about when to begin screening mammography.
    The question is not whether to do regular mammography 
screening, the question and the controversy is about when. We 
will be coming out with what we believe will be very clear 
statements that will provide guidance so that individuals and 
physicians can make decisions about this difficult issue.
    Let me just clarify by simply repeating the things that 
I've said over the past month, including what I said at the 
time of the consensus conference. The consensus panel, in 
looking at all of the latest data, said that in their opinion, 
they did not think a single uniform recommendation to begin 
screening mammography for all women in their 40s, was warranted 
by the data.
    I think that is not an unreasonable position to take. And 
what I said is that I agreed with the sentiment of that 
conclusion. My concern that I said at the time was simply with, 
and this is important, the wording, the balance and the tone in 
the draft report. Because I want to make sure, if we are to say 
that women and their physicians need to be informed to make an 
educated decision, I want to make sure that we provide the most 
balanced and clear and least confusing answer to the questions 
of evidence, to the questions of the evidence for benefit, to 
the questions about limitations, and the question of risk.
    And that was where I think some of the confusion comes 
about who was agreeing and disagreeing. I thought their 
conclusion was defensible. I was concerned that the draft 
report, and it is still a draft report, that the draft report 
did not have the clarity and the balance about the evidence 
versus the limitations to actually allow women and physicians 
to make the decisions that they were recommending.
    Perhaps I can try to spend a few minutes trying to clarify 
why this is such a complicated, contentious and difficult 
problem. Let me just say that whatever guidance the NCI 
provides, I believe, as I've said all along, must be based upon 
available evidence. I think the National Cancer Institute must 
base its statements in science and what we know. And as I said 
at the time and continue to say, while many of us want 
extremely clear-cut, yes or no, black and white answers to 
often difficult problems, we cannot nor should not produce 
certainty or say that there is certainty where there is not.
    So where are we? Why is this so complicated? There is 
complete agreement from the data that's available that women 50 
and above should have regular screening mammography. There is 
wide agreement that women below the age of 40 should probably 
not be recommended to having regular mammography. So we're left 
with 40 to 49. What happens? How do we know?
    But why don't we look for data. There have been 8 
randomized clinical trials from around the world over the past 
30 years that have looked at over 180,000 women who were 
invited to the trials to begin screening--and this is very 
important--at some time during their 40s. The average age of 
women receiving mammograms during those 8 studies is 48. But at 
some time during the 40s.
    None of those studies alone have convincing statistically 
significant data, have enough deaths from breast cancer to 
reach a conclusion. So all the data, all the studies have been 
put together through a process called metanalysis to try to 
see, do they all say something together. When one does that 
metanalysis, which is fraught with some uncertainties and 
difficulties, one, and I think there's general agreement on 
this, that there is approximately a 15 to 17 percent reduction 
in mortality for beginning screening mammography at some time 
in the 40s. The data does not address 40, or 40 and 3 months or 
45.
    And of course, one of the problems with the controversy is 
the way we frame the question. Nothing sudden happens to a 
woman when she turns 50. And certainly, nothing sudden happens 
to all women when they turn either 40 or 45 or 50. By asking 
for a yes/no, black/white question that at this birthday, 
suddenly there is benefit, we get into this very confusing and 
contentious argument that evidence and data could not directly 
address, because in fact it does not fit anything we know about 
the biology of risk of breast cancer, or breast cancer or the 
performance of mammography.
    So there is going to be uncertainty. There will always be 
some period in which you move and move gradually from when 
there does not seem to be a benefit that outweighs the 
limitations and the risks to a period where it clearly does. I 
think to argue overly about trying to come up with a precise 
age for all women will keep us in an argument that does not 
move us beyond an unanswerable question to one that provides 
useful guidance to women. One size won't fit all. And I think 
the guidance we will come up with will be based upon the 
evidence and hopefully will be very useful and clear. I think 
we can strive for clarity, even when there's not certainty. I 
think that's what we will be doing over the next month.

                               screening

    Mr. Porter. Dr. Klausner, correct me if I'm wrong in this, 
and I may well be, but if this consensus panel had said, and 
you had agreed, that women should all be screened beginning at 
the age of 40, have mammographies, then wouldn't that become a 
guideline that would be widely adopted, particularly in the 
Medicaid program, for example, and when you say that this is an 
issue that has to be determined on a case by case basis, aren't 
you really saying, though, that poor women won't necessarily 
get screening that might detect cancer early and perhaps save 
their lives?
    Dr. Klausner. Well, remember, the difference between a 
technique being capable of detecting cancer, even detecting it 
early, and that translating into a benefit, is something we try 
to determine by doing studies so that we actually make our 
decisions based on evidence. My feeling is, if there is 
evidence that supports benefit in the 40s and we don't have 
anything more precise than that, but that that evidence would 
support the decision, for some women it may make sense earlier 
in their 40s, for some women it may make sense later in their 
40s. I think that then we can provide that guidance to make 
sure that those decisions are supportable.
    This is the type of issue that we will be grappling with 
over the next couple of weeks to months. I hope, and I think it 
will be very soon, we will work very quickly, so that the 
position of the NCI is clear, but does not go beyond what we 
are comfortable that the evidence actually tells us.
    Mr. Porter. But if I understand correctly, you're giving a 
scientific view, and this issue has tremendous public health 
consequences. For example, women over 50, I believe, the 
guidelines show that they will get regular mammography. And 
those under 50 in public programs probably will get nothing. 
And what you're saying is that at some point, perhaps in their 
40s, they need this additional prevention. But if the 
guidelines don't provide for it, you can be sure that the 
funding won't be forthcoming, for poor people. Now, for rich, 
for a wealthy individual, they can go to their individual 
doctor and the doctor may well say, well, sure, you're 40, but 
we think you need this.
    Dr. Klausner. Well, again, I wouldn't want to prejudge what 
the guidance will be. I think that's unfair to the NCAB process 
that we're doing now. We're very aware of all these issues. We 
want to make, we want to provide guidance that will be clear 
and will be helpful. Right now, I believe it's 40 states 
require insurance companies, now we're talking about insurance 
companies, to pay for mammography, I believe it's over the age 
of 40 or over the age even of 35. And four more states are 
considering such legislation.

                           ncab subcommittee

    Mr. Porter. You say you're going back now to develop this. 
How long will it take and are additional studies needed to 
develop the responsive guidelines?
    Dr. Klausner. There is a question whether there's need for 
more studies. And I believe there certainly is a need for more 
studies in the early detection of breast cancer and new 
technologies. And perhaps we can talking about that.
    But for the process that we started yesterday with the 
National Cancer Advisory Board, no, we are not looking for new 
studies. We will be working, there is a subcommittee that has 
been announced, announced this morning. And they will be 
working with all due speed. And their expectation is certainly 
within one or two months to have completed their 
recommendations to the National Cancer Institute about what 
message the NCI should communicate to women and providers about 
this important issue.
    Mr. Porter. Thank you, Dr. Klausner.
    Mrs. Lowey.
    Mrs. Lowey. Thank you, Mr. Chairman.
    And welcome, Dr. Klausner. I want to express to you my 
personal appreciation for the outstanding leadership you have 
provided at the National Cancer Institute. I can assure you, as 
former Chair of the Women's Caucus, as the daughter of a victim 
of breast cancer, as the mother of two daughters in their 30s, 
I share the anxiety of women across America about the issue of 
mammography screeing guidelines and we appreciate that this 
advisory board is meeting. And we are hopeful that there can be 
clear guidelines.
    But most importantly, I would hope that in the absence of a 
consensus, that the whole issue of insurance can be resolved 
and that insurance must cover mammograms. I think we're all 
agreed on that.
    Dr. Klausner. Yes.

             other detection technologies for breast cancer

    Mrs. Lowey. It seems to me that we've got to provide women 
in their 40s with clear guidance. I'm hoping that this panel 
can do just that.
    However, I'm concerned, that when you look at the 
statistics, in women under 40, 25 percent of the cases of 
breast cancer are not detected by mammograms. So I would like 
to follow up on my colleague's comments to talk about the 
possibilities of additional research on other techniques. 
Improvements in mammography quality, greater access to 
mammograms, certainly have contributed to the decrease in 
breast cancer mortality. And there's no question that 
mammograms save lives. And it's the most important screening 
tool for cancer that we have.
    However, as you have explained to me and to others, there 
are fundamental reasons why mammogram technology would never be 
as accurate as we would like it to be. And mammograms are 
limited in their ability to pick up aggressive tumors.
    My concern is, what are we doing about it? Where do we go 
from here? What alternate technologies is NCI working on that 
may allow us to detect an aggressive tumor in its earliest 
stages? Is a blood test for breast cancer, such as the PSA test 
for prostate cancer, a viable goal? Are there other 
technologies that hold promise?
    Even in women above 50, I believe that 10 percent of those 
tumors are not detected. And again, as a woman, it's very 
frustrating to many of us to get a mammogram and speak to a 
friend who then, because of self-examination a week or two 
later, discovers a tumor. So perhaps you can enlighten us on 
where we're going from here.
    Dr. Klausner. Sure. Let me just say, the statistics that we 
have suggest that it's women under 50, where about 25 percent 
of cancers are missed. And then in older women, it drops to 
about 15 to 10 percent that are missed.
    And as you point out, while mammography is clearly capable 
of being and is a life saving technology, let me emphasize two 
things. First of all, in the age groups where we know that 
regular mammography results in a 30 percent reduction in 
mortality, still not all women, far from all women, are using, 
or are availing themselves of access to mammography. And we 
need to make sure that all women do have access to mammography. 
Only about 50 percent of women above the age of 50 are having 
regular mammography. So we need to do much better with that.
    We also realize the limitation, a 30 percent reduction in 
mortality, which is very important that we can ascribe to 
regular mammographic screening. We can turn it around and 
recognize that 70 percent of breast cancer deaths in women that 
never have mammograms will still happen in women that have 
regular mammograms. So mammography is not perfect. It's the 
best we have right now. But we need to do much better.

                detection technologies for breast cancer

    This year, the NCI will be investing over $40 million in 
studies related to imaging, imaging, as an approach to 
detection in breast cancer. And I'll come back to molecular 
approaches like a PSA. These include improving mammography. And 
we all believe that the most important avenue for improving 
mammography now is a technology called digital mammography, 
where instead of using film, you create the image directly 
through a computer through a variety of sensors, of electronic 
sensors. And then you can use very sophisticated new techniques 
of image analysis, can also have telemammography, where you 
send the images to Centers of Excellence. And we believe that 
that's a very important area. And much of our investment in 
mammography development is in this new area of digital 
mammography.
    There are lots of other areas of detection technologies for 
breast cancer. They include technologies that don't include 
radiation, such as magnetic resonance, both magnetic resonance 
imaging and something called magnetic resonance spectroscopy, 
to look at the characteristics of any possible lesions. There 
are other techniques, such as PET, SPECT, optical imaging, 
ultrasound, microwave, photon migration. There's really a 
proliferation of new ideas.
    And in fact, as I think I've mentioned to you, we've just 
constituted a new think tank, headed by Dr. David Bragg, to 
advise us on new opportunities in technology detection. We are 
also proposing for the first time to establish a standing 
clinical trials group for diagnostic imaging. So we have 
available to us an infrastructure that will allow us to test 
clinically new ideas and new approaches in detection technology 
for breast cancer and other cancers. And we are actually 
bringing that to our board next week. So there is a lot that we 
are doing.
    But as you said, there are other possibilities for 
detecting cancer besides just imaging. What do we do when we 
detect something is important. One of the problems with 
mammography is most of what we detect is not cancer. And even 
when we detect something, we're not always sure what to do 
about it.
    The answer there I believe is going to come from what I 
began with, the sort of approach of the cancer genome anatomy 
project, that will allow us to look at all of the products of 
cancer cells, and of different types of cancer cells, so that 
we can learn as quickly as possible, are there PSAs for breast 
cancer. And when we detect a lesion, will that lesion be able 
to be ignored? Because while we call it cancer by looking under 
the microscope, it may not ever do anything. Such as in Ductal 
Carcinoma In Situ, we don't know which fraction we need to do 
something about.
    These are the important ways that we need to look at the 
future, move forward, so we can improve this limited but 
important technology.

                      funding allocation decisions

    Mrs. Lowey. If I may, Mr. Chairman, just following up on 
that briefly, you mentioned that $40 million was currently 
being spent on various techniques, mammography, improvements in 
mammography, etc. Grants are currently reviewed, there's peer 
review of all grants. However, there are thousands and 
thousands of grants that are rejected.
    One of the questions I've had is, how do you determine what 
percent of the dollars are put in mammography technology or in 
other forms of technology or in prevention, or in cures? There 
are many eager scientists out there working in all of these 
areas. How do you make these determinations? We all know, and 
perhaps Dr. Varmus knows one, who recently joined the Strang 
Clinic. He was doing work on brain research, and now is at the 
Strang Clinic because of a particular grant, and has made major 
advances in that direction.
    Often, the scientist will be enticed to pursue a certain 
field because of the availability of dollars. Most of us, 
including our Chairman, wish we could double and triple the 
amount of money, if it could prove productive. So perhaps you 
can shed some light on that.
    Dr. Klausner. Well, you're asking an important but, of 
course, very difficult question. We need to make sure that 
we're covering in essence all of the bases. We can't choose 
between prevention or detection and treatment and understanding 
the basic biology. It's a constant juggling, a constant balance 
that relates to opportunities, as Dr. Varmus has talked about. 
When we have a new opportunity, researchers rush in. And that 
is a very good use of dollars. Because we know there's an idea, 
there's an opportunity, there's an inspiration. We're closing 
in on an opportunity to get a definitive answer.
    It is a very dynamic process. And coupled with that is that 
we depend upon the larger community to come up with their 
ideas, they're thinking about this all the time. They produce 
proposals that then are reviewed for their quality and for 
their importance, for what they can achieve. And our approach 
is to allow the distributed wisdom of the entire scientific 
community to, in essence, interact with us, so that we maintain 
a balanced portfolio. Because we need to approach this and all 
of these problems from all possible angles. And often we don't 
know, as you know very well, we don't know exactly where a new 
advance is going to come. I know you hear that again and again 
from us. But it is, it has to be a very dynamic process.
    Mrs. Lowey. Thank you, Dr. Klausner, and thank you, Mr. 
Chairman.
    Mr. Porter. I want to apologize to my colleague, Lou 
Stokes. We started the year by saying that we would recognize 
the members in the order in which they arrive at the hearing. 
But we also said that where you are a ranking member on another 
subcommittee and have other responsibilities, we would give 
that member preference. And Mr. Stokes, in VA-HUD, has had a 
very busy day and had to leave this morning and didn't get a 
chance to ask his questions. And I'd like to call on him next 
for that reason.

                      advances in minority health

    Mr. Stokes. Thank you, Mr. Chairman.
    Since I didn't get a chance to pose any questions to Dr. 
Varmus, may I also pose some to him?
    Mr. Porter. Sure.
    Mr. Stokes. Dr. Varmus, let me welcome you once again 
before our subcommittee. It's always a pleasure to have the 
chance to talk with you.
    The NIH programs funded by this Subcommittee are absolutely 
essential to improving, prolonging and protecting the health 
and well-being of the American people. As you are keenly aware, 
the health of African-Americans and other minorities lags 
dramatically behind that of the general population.
    What major advances in diseases and disorders that 
disproportionately impact African-Americans and other 
disadvantaged minorities can you report to the Subcommittee 
this year?
    Dr. Varmus. Mr. Stokes, that's an important question and 
one to which I've given a lot of thought. Because you know we 
share this concern, that even when we make advances, we still 
are failing to close the gap between the health of minorities 
and the health of majority populations.
    But what I don't want to give you a list of the things that 
we're trying to do. Because that's not satisfactory. But I 
think this year I can point to a number of advances that affect 
minority populations in particular, or have special meaning for 
minority populations. Because the diseases are common in those 
populations.
    Let's start with sickle cell disease. You heard a couple of 
years ago that we were making significant progress there, 
because of the drug I mentioned this morning, hydroxyurea, 
which has a very positive effect on the outcome of the disease, 
and reduces the episodes of sickle crisis by about 50 percent. 
In the past year, there's been evidence that bone marrow 
transplantation can also have a very beneficial effect in quite 
a significant number of patients. It's a more laborious 
procedure, but it has been done both in children and in some 
cases, in fetuses, and had remarkable effect.
    The experiments with fetuses, I should say, were not done 
with sickle cell disease, but the same procedure could be 
applied in sickle cell.
    And the second area I want to draw to your attention is the 
area of stroke and hypertension. There has been progress in 
hypertensive medication over the last several years that has a 
definite effects on the minority population. Because as you 
know, African-Americans in particular have a very incidence of 
hypertensive disease. The advances in treatment of stroke that 
you'll hear about from Dr. Hall again will have particularly 
beneficial effects on the minority population because of the 
high incidence of stroke in that population.
    You would be right to point out to me that one of the 
deficiencies thus far in the application of the new treatment 
of stroke, with tissue plasminogen as an activator, is the need 
to educate physicians and patients of the urgency of treating 
stroke. And in many cases, the disparity in health of minority 
populations can be traced to less aggressive care. And this is 
one of those situations where it will be particularly important 
for physicians in rural areas, and physicians treating minority 
populations to become aware of the advances that have been made 
in the treatment of stroke.
    There have been advances in diabetes, another disease which 
disproportionately affects the minority populations. 
Understanding some new genes that are involved in the 
generation of the diabetic state, and continued advances in the 
long-term management of diabetes. Again, as you would be quick 
to point out to me, it's important that we get that message out 
to the provider community and to the patient community, so that 
we can adapt readily.

                            funding for nih

    Mr. Stokes. How important, Dr. Varmus, is the research 
that's done in these various areas throughout the National 
Institutes of Health?
    Dr. Varmus. Crucial. Every advance that I've described to 
you is dependent upon NIH sponsored research.
    Mr. Stokes. That then brings me to my next question. To my 
understanding, last year NIH received a percentage increase 
across the board, did it not?
    Dr. Varmus. Yes, it did. The NIH increase was 6.9 percent, 
6.5 percent in program.
    Mr. Stokes. Now, did offices such as the Office of Research 
on Minority Health also receive correspondingly an increase, or 
percentage increase?
    Dr. Varmus. Let me point out to you, Mr. Stokes, that that 
office is not the primary source of funding for minority 
programs. That office is intended to coordinate the activities, 
provide stimulus to activities in the institutes. We spend well 
over a billion dollars a year on projects that we can identify 
as being highly oriented toward minority health. A very, very 
small fraction of that goes to the Minority Health Office. Dr. 
Ruffin's job is to provide a stimulus to those programs. And I 
believe he does that very effectively.
    So the increase in spending for minority programs has gone 
up.

                         minorities and cancer

    Mr. Stokes. Let me switch to Dr. Klausner for a couple of 
questions before my time expires.
    Dr. Klausner, it's always a pleasure to see you. Your 
cancer mortality by race and gender chart indicates a 
significant decline in cancer among black men as compared to 
the rest of the population. Can you elaborate for us on this, 
that is, which cancers accounted for this decline, what role 
did prevention play--that is access to health care, early 
detection and so forth?
    Dr. Klausner. That's a very good question. These new 
numbers, in fact, this is figure 2, which shows the difference 
between men and women, black and white, you can see the 
enormous increase in the previous 20 years in the mortality 
rate, especially black men, from cancer, and then what's 
happened over the past five years. We've just gotten these 
numbers. We're very encouraged by them. And we have gotten 
groups of people together to try to analyze exactly what are 
the components. We see the drop in mortality across a number of 
cancers, colorectal, lung, bladder, prostate.
    We're trying to understand these. Because I think that's 
going to be very important. Here we have an opportunity to see 
a change in the direction we want to go. We need to understand 
what we're doing right, if indeed it's something that we're 
doing right, so that we can stimulate that. And we have groups 
of people now working on the different sites, as well as the 
different changes among different racial and ethnic groups, so 
that we can try to understand this data. And that's the first 
thing that happens, once you get surveillance and epidemiologic 
data. We now know this, and we need now to try to understand 
what's behind it.

                     office of special populations

    Mr. Stokes. How is that reflected in the budget before us? 
Is there built into your budget some means for us to be able to 
detect how you want to build upon this type of progress?
    Dr. Klausner. Well, as I think I mentioned last year, last 
year in the spring, I was about to receive a report from what's 
called a Special Actions Committee specifically about what the 
NCI should do in terms of its research programs vis-a-vis 
special populations. And over this past year, we've acted on 
many of those things. We've established a new Office of Special 
Populations. I think you know Dr. Otis Brawley, I think he's 
doing a spectacular job. And what he's doing is systematically 
going through all of our programs. He has an Advisory Committee 
as well.
    He in fact this spring will be making a series of priority 
recommendations to me. One of the first things that we never 
had that we're now doing is to create an information base so we 
know exactly what is going on, what the needs are. It will be 
setting up a special what we call Progress Review Group of 
experts to come in and advise us on what are the areas of need 
coupled with what we're doing. This year, our programs directed 
at minority programs have increased. There are over 110 
projects and programs specifically oriented towards minority 
populations. And in fiscal year 1998, the budget for that will 
increase to about $115 million, that is specifically looking 
only at issues in minority populations. I can go through many 
of these.
    But I think the major point is that now we have this office 
to coordinate these activities. It is a real priority for us. 
And I think the recommendations, considerations and activities 
in that office are going to be very important.

                            cancer survivors

    Mr. Stokes. You mentioned, Dr. Klausner, that over 10 
million Americans are cancer survivors. What is the racial and 
ethnic percentage distribution of these survivors?
    Dr. Klausner. I do not know the answer to that, but I will 
get that.
    [The information follows:]

   The Racial and Ethnic Percentage Distribution of Cancer Survivors

    Of the approximately 10 million Americans who are cancer 
survivors, approximately 91% are white, 7% are black and 
Hispanic and 2% are other minorities: Asian, Hawaiian, American 
Indian, etc.

                        five-year survival rates

    Mr. Stokes. What is the current five-year survival rate for 
the five leading cancers in African-Americans?
    Dr. Klausner. The five leading cancers for African-
Americans include, lung cancer is the number one, prostate 
cancer, colon cancer, breast cancer, and I believe pancreatic 
cancer is the fifth. The five-year survival rates for lung and 
pancreatic cancer are and have been and remain dismal. The 
five-year survival rates are increasing for the other cancers. 
I may misquote if I try from memory to give you the exact five-
year survival rates. But what I will say, we still continue to 
see a significant disparity between the five-year survival 
rates between African-Americans and white Americans. We see a 
disparity in almost all these cancers in terms of the stage of 
diagnosis and in terms of the outcome.
    For example, breast cancer incidence among women over the 
age of 50 is lower among African-American women than among 
white women. That's the corrected incidence. And yet mortality 
rates are about the same. So again, we've seen in each of these 
cancers, there's now for the first time an improvement. So 
we're seeing it move in the right direction. Mortality rates 
are higher. Survival rates are lower for each of those, for 
colorectal, for breast and for prostate. For lung and pancreas, 
again, I don't think there's a significant difference in 
survival, as far as I know.
    Mr. Stokes. I see that I am out of time, Mr. Chairman.
    Mr. Porter. Yes, actually you are.
    Mr. Stokes. All right, thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Stokes.
    Mr. Miller.

                          nih reauthorization

    Mr. Miller. I'm sorry I missed this morning with Dr. 
Varmus. In my area of Florida, the Sarasota, Florida area, I 
don't have a center in my area or district, but Moffitt is not 
too far away. So I was there this past fall when they 
celebrated their anniversary, along with Congressman Young of 
our committee, who is very involved with it because of this 
committee and because of Defense money that flows into cancer 
research, and also Congressman Bilirakis who is from that area. 
So we are all there together, which makes me want to ask the 
question, where do we stand on reauthorization of NIH? NIH is 
not authorized right now, is that correct?
    Dr. Varmus. Well, we still have authorization under the 
original Public Service Act.
    Mr. Miller. Right.
    Dr. Varmus. Last year, a bill was passed by the Senate, 
after being written by Senator Nancy Kassebaum's committee, but 
it wasn't taken up by the House, by the corresponding House 
committee. This year, we are hoping to go through the 
authorization process. We're working at the staff level to try 
to make that happen.
    Mr. Miller. Is there a sense that it may be taken up?
    Dr. Varmus. Yes, I think it's very likely.
    Mr. Miller. It's Congressman Bilirakis' committee?
    Dr. Varmus. Yes, that's correct. In the House.

                              angiogenesis

    Mr. Miller. But at any rate, I've always been impressed 
with what they've been doing at Moffitt. I have visited often. 
They've come a long way.
    I happened to see you on ABC news Monday evening, and it 
raises questions and level of interest about you, you have a 
very difficult job. You have to cover all the bases of 
prevention and treatment and detection, and where you allocate 
your resources. Then all of a sudden, in this case, ABC news 
picked out one area. And I wonder, what impact does national 
media has in program selection? You have hundreds of programs. 
And this one on that special that you were commenting about 
Monday evening, is this----
    Dr. Klausner. I believe this was on angiogenesis?
    Mr. Miller. Yes.
    Dr. Klausner. Yes. I didn't see it, but----
    Mr. Miller. You came across very positive and very focused.
    Dr. Klausner. Oh, thank you.
    Mr. Miller. And very photogenic on television.
    Dr. Klausner. Well, I think the media has tended to pick up 
things that the scientific community views as interesting or 
hot. And this is clearly one of those examples. If I can say 
something about angiogenesis. While we talk about how each 
cancer is different, one of the things we've realized about all 
cancers is that in order for them to grow beyond a certain 
point and to spread, and that's what kills people, that they 
spread, is that they need to make sure that they establish 
their own blood supply. The blood supply isn't there for them.
    And so cancers, in order to kill people, have to be able to 
create a new blood supply, which is really pretty 
extraordinary. And that has led many investigators to recognize 
a blood supply specific for tumors. It's called angiogenesis 
for birth of vessel, and is a remarkably attractive target for 
anti-cancer therapy. Some have even claimed that if all these 
tumor vessels are the same, maybe all we'd have to do is 
develop a therapy targeted against the blood vessels. Others 
say that there will likely never be a single treatment for 
cancer may not be so accurate.
    I think we need to be cautious about that, as I think I was 
on that show, because there may be many types of blood vessels 
for different types of cancer. But the point is, this is a 
whole new approach to the treatment of cancer. And the early 
studies which are in animals look extremely promising. Right 
now, the NCI is supporting I think somewhere between 10 and 20 
new agents that are being developed that are directed either at 
killing the blood vessel cells or at clotting the blood vessel, 
or at preventing the blood vessel cells from growing, or at 
stimulating those cells to kill themselves. There's a whole 
bunch of different approaches.
    We are in fact very excited about this area. Being excited 
is wonderful. It helps us keep going. And we'll just have to 
see how well this looks. But we are putting this new approach 
on a fast track for development. And in fact, I've just 
recently asked for there to be a special meeting at the NCI so 
that we can talk with the investigators, with people who are 
excited, as well as skeptical about this, to come together and 
help advise us along with the industry, how we push forward 
developing these new agents into clinical trials.
    Dr. Varmus. May I comment just briefly about this?
    Mr. Miller. Yes.
    Dr. Varmus. This is a good illustration of an area in which 
research toward one remedy, that is cutting off the blood 
supply to a cancer, is also research on other kinds of 
therapies. Those therapies that are designed to increase the 
blood supply to organs like the brain and the heart and the 
kidney and peripheral muscles, because the same principles that 
are involved in trying to interfere with blood vessel growth to 
tumors are being exploited to enhance blood vessel growth to 
the heart, to the brain and to other organs affected by 
diminished blood supply that frequently accompanies aging.

                       areas impacting on cancer

    Mr. Miller. On that line of thought for just a minute, I 
know Mr. Istook was talking about it this morning, the question 
of how much money goes to different diseases. Some people 
question what AIDS gets on a per capita basis to the persons 
exposed to AIDS, they think it's far too much money compared to 
cancer. Part of the explanation that Dr. Varmus has made, and I 
agree, is that, as you just made here, research applies over 
all areas, it's not just targeted.
    Can you, Dr. Klausner, identify areas that research outside 
of NCI have had a direct impact on types of research? For 
example, AIDS research, immune system, that has been able to 
draw from that to be beneficial in the cancer area?
    Dr. Klausner. Oh, absolutely. We wouldn't be able to make 
the progress we think are making in terms of cancer, in any 
sort of vacuum. And we rely totally on the entire enterprise.
    Let me just give you one example that was just published 
last month that I'm particularly intrigued about, coming from 
work looking at diabetes and at the development of fat cells. 
It turns out that there's a critical gene, and this gene is 
like the gate that determines, as primarily a single gene, 
whether a cell becomes a fat cell. It's called PPAR gamma. And 
this is work that's been worked on by Ron Evans and Spiegelman. 
And what they found is that, they found this particular 
receptor, and have found drugs that stimulate this receptor. 
And in fact, some of these drugs have recently been approved by 
the FDA for treatment of adult onset diabetes.
    Now, what does this have to do with cancer? It turns out, 
the most common type of sarcoma in adults are liposarcomas, 
that relates to the lineage that relates to fat cells. It turns 
out what's been recently published, just a month ago, is that 
all of these sorts of tumor cells have this receptor. And when 
you give this very non-toxic drug, the tumor cells stop 
growing, differentiate to just be fat cells.
    Now, this is just an experiment in the lab. But in fact, 
they are now moving and we're talking with them to move very 
quickly to clinical trials for this currently relatively 
untreatable form of cancer, these sarcomas. And this is just 
one example. It goes on and on.
    The fact is, we are a very integrated community, and that's 
very good.
    Mr. Miller. You sound very optimistic about the direction 
of cancer research, more optimistic than ever, through so many 
different areas. We see a light at the end of the tunnel, 
maybe.
    Dr. Klausner. We certainly see a lot of light.
    Mr. Miller. Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Miller.
    Ms. Pelosi.

                  environmental links to breast cancer

    Ms. Pelosi. Thank you, Mr. Chairman.
    I too want to join with my colleagues in welcoming you, Dr. 
Klausner, and thanking you for your leadership. I personally 
want to thank you for the time you took to come to the Bay area 
last summer to meet with researchers and breast cancer 
activists in our community about our high rate of breast 
cancer. We were all very appreciative of the opportunity to 
have you come out and speak with our group, but also for you to 
listen to our concerns regarding the possible environmental 
links to breast cancer. As you know, that has been one of the 
questions I keep posing to our distinguished scientists who 
come before us, is the answer in the lab? Yes. Is part of the 
answer outside? Let's see.
    Dr. Varmus, in fact, testified this morning that the 
precise changes that occur in genes during our lifetimes are 
telling us how environmental agents like tobacco and sunlight 
cause cancer by inducing mutations, and how normal mechanisms 
for correction of DNA can fail, allowing harmful mistakes to 
persist in our genetic material. Is that correct, Dr. Varmus?
    Dr. Varmus. Correct.
    Ms. Pelosi. I did better than I think I did with my 
Transportation Committee and the cloning story.
    As you hopefully both know, and I know Dr. Klausner does, 
the San Francisco Bay area has one of the highest breast cancer 
rates in the world. You're aware of the great concern.
    Dr. Klausner. Yes.

                         san francisco bay area

    Ms. Pelosi. And that there is a concern we have that this 
high rate is linked to environmental factors. Report language 
in the fiscal year 1997 bill urges the NCI to work with 
community groups and the National Institute on Environmental 
Health Sciences on this concern.
    I have a question about the NCI's report to this language 
in the budget justification. You cite the Long Island breast 
cancer study project as an example, and I commend my colleague, 
Congresswoman Lowey, for her success with that project. The 
studies from the Bay Area cited in the response are not studies 
of breast cancer in the Bay Area. And only one, which is not 
funded by the Government, looks at the epidemiology of breast 
cancer.
    Does the NCI intend to study the San Francisco Bay Area 
with regard to the possible environmental link to breast 
cancer? I would just, as you answer, also consider in our area 
possible exposure sources to radiation are plentiful. If you 
would answer that with a current assessment of the possible 
role of radiation as an environmental factor in causing breast 
cancer.
    Dr. Klausner. Yes. We've made it very clear that we're 
interested in supporting studies in areas where there appears 
to be an excess of any cancer, but certainly breast cancer, 
that cannot be explained by known risk factors. And in fact, I 
have met, subsequent to coming out to San Francisco, with 
researchers from that area who came to the NCI to talk to them 
about grants that they could put in and our interest in funding 
such studies. But they have to put in the grants, and we'll see 
what happens.
    What is going on now in the San Francisco area is to 
analyze the data to actually try to understand whether there 
is, in fact, an excess and how much of an excess, when one 
takes into consideration known risk factors. All of the 
evidence that we have suggests that modifiable factors, whether 
it's diet or environment, change the risk of breast cancer. We 
see that from migration studies, we see that from the 
differences in incidence of breast cancer in different areas of 
the world, and especially, as I said, when people move.
    It's been extremely difficult, despite many, many studies, 
to pin down specific risks from the environment. It doesn't 
mean we should stop, we should keep going. I happen to think, 
as I said in my opening statement, that we need a new approach, 
such as this reverse epidemiology, where we can look at the 
breast cells themselves to try to see whether breast cancers in 
particular areas have a different pattern of DNA damage that 
might tell us that there's a type of carcinogen that those 
women are being exposed to.
    Certainly, as we've learned over the past year, when we 
reanalyze the data of local or regional variation in breast 
cancer incidence, when we correct for known risk factors, and 
there are, as we know, multiple known risk factors, even though 
we don't understand all of them, then those regional 
differences, not entirely, but largely, go away. Seventy 
percent or more of those differences no longer exist. And this 
was published last year from researchers at the NCI.
    Currently, there are studies at Stanford University 
specifically to do the same thing in the San Francisco Bay 
Area. We really need to know that. We need to be able to 
subtract out known risk factors in order to really get hints 
that there may be regions that would be amenable to the type of 
epidemiologic study that would be hopefully useful in tracking 
down environmental culprits.
    Ms. Pelosi. So the status of the study would be, there's an 
opportunity for a grant, should the grant application be made. 
But if this Stanford----
    Dr. Klausner. This is actually already going on, and we're 
actually just waiting for the result of this now.
    Ms. Pelosi. I understand. But is that a preface to what----
    Dr. Klausner. No, absolutely not.
    Ms. Pelosi. You said--what I heard, and I might have 
misunderstood, was that this would decide whether this would 
be----
    Dr. Klausner. I think in order to interpret and understand 
epidemiologic studies, we need to make sure that we understand 
the full range of risk factors, so that when we're trying to 
correlate, the way epidemiologic studies go, you observe peaks 
of disease and try to correlate that with something you can 
measure, an environmental exposure, radiation, diet, etc. So 
you really need to make sure you have a full data set to make 
sure those correlations are going to be informative.
    Ms. Pelosi. I see, okay. So I should tell our folks back 
home to get their pencils out and----
    Dr. Klausner. I think they've already heard that message 
and are doing that.
    Ms. Pelosi [continuing]. That the ball is in their court, 
and that's where the initiative will come from now.
    Dr. Klausner. Yes, ma'am.

                         breast cancer survival

    Ms. Pelosi. I appreciate your response. Thank you, Dr. 
Klausner.
    With relation to the continued funding of mammography and 
the question that has been before the committee this afternoon, 
in the interest of time, I won't go into that, but to associate 
myself with the concerns expressed by our Chairman and others, 
and the statements of Mr. Obey when he said that whatever the 
decision is about what age, etc., that it should be science-
based. But I would add to that, when it is a question that it 
should come down certainly in favor of women's health. Because 
it is so that although there's a lower rate of incidence of 
breast cancer among younger women, there's a lower survival 
rate, as well, is that not so?
    Dr. Klausner. Yes, there is a somewhat lower survival rate 
for women who are diagnosed with cancer at a younger age. There 
is some, it's either a subset, and probably is a subset that 
changes those statistics of what appears to be more aggressive 
cancer in younger women.

                           clinical treatment

    Ms. Pelosi. In the past year, dividing the world now since 
this morning into culminations and inspirations, and I just 
wondered if there were any culminations in the clinical 
treatment of breast cancer, is culmination too high a standard 
to put on that, in the past year?
    Dr. Klausner. We'd have to ask Dr. Varmus for exactly his 
definition. We can get a reading from the Office of General 
Counsel, I guess, about the exact definition of a culmination.
    Ms. Pelosi. Last year we went through this on the word 
breakthrough.
    Dr. Varmus. I've never felt so influential, Ms. Pelosi.
    Ms. Pelosi. Well, you are a man of words, is that not your 
original training, Dr. Varmus?
    Dr. Klausner. There have been advances in the clinical 
treatment. And we are anticipating the results of some 
important studies in treatment, just over the next few months.
    But I will hasten to add that these advances are 
incremental. They are not the dramatic changes that we would 
like to see.

                            prostate cancer

    Ms. Pelosi. The same thing for prostate cancer as well?
    Dr. Klausner. I think for new therapies for prostate 
cancer, we have not seen any results in the past year that 
suggest that we are learning to improve mortality through new 
therapies, therapies that we hadn't had before. Whereas, in 
breast cancer, we do have upcoming results of, as I said, neo-
adjuvant therapy, the value of giving chemotherapy before 
surgery, with the idea that you can reduce the size of the 
tumor, perhaps even then significantly reducing the type of 
surgery that needs to be done.

                          breast cancer--abmt

    We are finishing accrual, finally, for the first study to 
look at autologous bone marrow transplantation in advanced 
breast cancer. And we expect early results by August of 1998. 
We have a series of results that will be coming out soon, or 
that have come out, that all suggest that more intensified 
chemotherapy or combinations of anti-hormonal and chemotherapy 
improve disease-free survival in different subgroups or 
survival in different subgroups of women with breast cancer.
    What this adds to is unfortunately a slow but a clear 
incremental set of advances in our understanding of how to 
approach each woman with breast cancer in terms of making 
therapeutic decisions.

                             access to care

    Ms. Pelosi. Thank you, Dr. Klausner.
    In closing, Mr. Chairman, I just want to associate myself 
with the concerns also expressed by Congressman Stokes. I see a 
big change in what we're hearing presented by the NIH and the 
NCI from several years ago before this committee. And I truly 
believe that what you do there shouldn't be a trickle-down so 
that minorities and women, for example, eventually reap the 
benefit of research that you do on white males as concerned as 
I am about white males as well.
    But all that I hear tells me over and over again for the 
need for universal access to quality health care. Because 
prevention, I keep saying it, early detection and prevention 
are so essential. Access to quality health care, if that were 
increased in the minority community, I'm sure it would reduce 
the incidence of some of this disease, as well as not only 
enriching personal lives, but costs to our economy as well.
    Thank you, Mr. Chairman.
    Dr. Klausner. Can I make one quick comment?
    Mr. Porter. Yes, surely.
    Dr. Klausner. About that issue of access to care that 
relates to what Mr. Stokes asked me. The NCI and the Department 
of Defense completed a study looking at the outcome of prostate 
cancer in African-Americans versus whites, where the outcome in 
general is quite different, as we've said. But now within a 
system of equal access and equal care, and the outcomes were 
the same. I think that's a very, very important thing that 
we've recently learned. And it reinforces that.
    I also want to thank you for hosting me in San Francisco 
and introducing me to a restaurant that I've gone back to many 
times. [Laughter.]
    Mr. Porter. Thank you, Ms. Pelosi.
    Mr. Istook.
    Mr. Istook. Well, if you come to Oklahoma, we'll give you 
good barbecue. [Laughter.]
    I was going to inquire, Dr. Klausner, Mr. Stokes beat me to 
it, you had in your testimony of course the reference to the 
significantly larger, higher incidence of cancer and cancer 
mortality in blacks. I share his interest in getting further 
information from you, not only on the situation, but on the 
allocation of resources to that. Because that's a very, very 
major differential that I know you'll want to reflect in your 
research allocations.
    I did want to inquire, I'm also, as Mr. Bonilla is, on the 
Defense subcommittee. And there are certainly certain aspects 
of medical research that get significant funding from that. One 
major one is breast cancer. Where women in the armed forces 
certainly supply a, base is not the right word, but a 
population that can be utilized in those studies, for that 
matter, they could also utilize men in the armed services for 
prostate cancer research.
    Dr. Klausner. Right.

                         coordination with dod

    Mr. Istook. My question on that is, can you describe to me 
what level of coordination there is or is not, where you think 
it's sufficient, where you think it may be deficient, in the 
coordination of cancer research with the significant monies 
that are being spent on that through the Defense budget?
    Dr. Klausner. I think that's an excellent question, and I 
am very pleased with the level of interaction and communication 
that we have with the Department of Defense, especially under 
the leadership of Dr. Joseph. As you know, we established last 
year a model system, which is an integration of the DOD health 
care system with the NCI clinical trials system, so that all 
phase two and three therapeutic trials for the NCI, that there 
is access to those trials for anyone within the 8.3 million 
member. It's not just uniformed individuals, 8.3 million member 
health care system.
    We are going to have a day or day and a half retreat I 
believe beginning March 18th with the Department of Defense 
specifically to look at how to extend that program and to 
further coordinate and integrate our research efforts and 
planning efforts in cancer. So I think the interactions have 
been really excellent. And we're learning a tremendous amount 
from this new interaction we have in terms of clinical trials 
in cancer.
    Mr. Istook. I would appreciate, I'm sure there's some 
documents that describe the relationship, that there's always 
concerns about overlap in grant application process and 
research. And you may decide you want to fund a particular 
program, but they may be interested in funding the same one. 
There's a lot of elements in coordination.
    Dr. Klausner. I'd be happy to provide that.
    Mr. Istook. That would be much appreciated.
    [The information follows:]

                     Coordination Efforts With DOD

    NCI staff has maintained close contact with the DOD staff 
of the Breast Cancer Research Program (BCRP) since its 
inception in 1993. An NCI representative is a member of the 
BCRP Integration Panel, which is responsible for advising the 
DOD on the overall direction of the Program and its investment 
strategy, and provides a second-level review for grants, much 
as does NCI's National Cancer Advisory Board (NCAB). Other NCI 
scientists have served as members of many of the scientific 
review panels convened to review grant applications to the 
Program and as ad hoc consultants to the Integration Panel at 
several programmatic meetings. Using the NCI data base 
resources NCI has performed a portfolio analysis of all its 
grants and contracts with a breast cancer component. This 
information includes number of active grants and contracts and 
level of funding in each of the tracking categories in use by 
the DOD's grants administration unit. This information is also 
provided to members of the Integration Panel at the yearly 
meetings when grant funding recommendations are made to the 
DOD. The purpose of this information sharing is to avoid 
unnecessary scientific overlap and duplication and to maximize 
resources for breast cancer research for both NCI and the DOD 
Breast Cancer Research Program.
    Further coordination is provided through the NIH Inter-
Agency Breast and Gynecologic Cancer Working Group, which was 
established by NCI in 1993. This group, which is chaired by an 
NCI staff member, serves to coordinate the research of numerous 
agencies in breast and gynecologic cancer. Representatives from 
all NIH Institutes with an interest in this area, as well as 
representatives from DOD, DHHS-Office on Women's Health, 
Uniformed Services University of Health Sciences, EPA, FDA, and 
NIOSH attend monthly meetings of this group, which serves as a 
clearinghouse for information dissemination and scientific 
exchange.
    The NCI has recently established a Breast Cancer Progress 
Review Group. The Review Group will examine the field of breast 
cancer research and the current NCI efforts in this field. The 
results of this analysis will be made available to the DOD 
Integration Panel.

                      professional judgment budget

    Mr. Istook. I also, I recognize of course that each 
institute, as you indicated before, receives benefit from the 
research in other institutes. And there is a lot of crossover 
in that. Nevertheless, everybody is jealous of their own 
funding and wanting to maximize that, that they know they can 
focus on areas most likely to benefit their particular focal 
area.
    I wanted to inquire, and you've probably got this in some 
documents that you can get to me as well, if the NCI funding 
were at a higher level, what are the areas in which you would 
want to increase the cancer research funding? And that could be 
by type of cancer, that could be by some other descriptive 
term, but what would those be?
    Dr. Klausner. Well, we're asked to provide an annual, 
essentially professional judgment budget, the so-called bypass 
budget. And I'd be happy to provide this to you.
    But actually, the way we wrote this bypass budget last 
year, and now we're working on a new one this year, is exactly 
in terms of delineating new priority opportunities that if 
there was a sufficient increase of funds, what we would be able 
to fund. We described them in terms of fairly exact budgets, 
milestones, accomplishments, explanations, and where the 
opportunity is. I'm happy to provide you with a copy of this 
bypass budget, and I think it does explain that process.
    Mr. Istook. If you would, and I'll certainly look at it. If 
there's some very summary fashion overview of what funding is, 
since it's getting near the NCAA tournament, we ought to say 
what funding is on the bubble.
    [Clerk's note.--Information submitted was too voluminous to 
be printed and is available in Committee files.]
    Dr. Klausner. I'd be happy to actually give that to you in 
terms of the types of priorities that we identify.

                             opportunities

    Mr. Istook. Right. There's nothing you'd want to give a 
quick overview on?
    Dr. Klausner. Oh, yes. The way we did it, we first stepped 
back and established a set of criteria for what was what we 
call an extraordinary opportunity. And we had a very extensive 
process of asking the community at large to feed in what are 
extraordinary opportunities, what we could say reasonably if we 
had an unexpected increase in available resources, what we 
might be able to accomplish, that would push forward cancer 
research.
    So we went through that process. And these were clinicians, 
epidemiologists, basic scientists. And overwhelmingly, there 
was a confluence on five areas that met those criteria, that we 
were ready to go if we had the new investment. There wasn't 
just a fantasy, we were ready to go. And they were areas such 
as a new approach to developmental diagnostics, how to actually 
make real this new possibility of molecular diagnostics for 
cancer, new detection technology, so that we actually can 
detect things very sensitively and know what we were detecting.
    Cancer genetics, an important problem. And in cancer 
genetics, how to develop the field of the interface between 
genetics and the environment and diet. And a fourth area was 
the need for animal models. Or for what we call pre-clinical 
models, from some of the advances that Dr. Varmus talked about, 
there's a whole new way that we can look at organisms, very 
simple organisms to fairly complex organisms, such as the 
mouse, to create real understandings of the processes of 
cancer. So those were some of the examples. They were really 
infrastructure needs that in fact we feel would advance all 
cancer.
    Mr. Istook. Sure, I appreciate that. And I guess Dr. 
Varmus, this probably is best for you, the same process that he 
described of saying where the next steps would be with funding, 
is that something that each institute does in the same fashion, 
essentially?
    Dr. Varmus. Not exactly the same fashion. One difference is 
that the Cancer Institute always has a bypass budget, which 
provides them with a chance to think about what they would do 
with a great deal more money than they're likely to get, given 
the current constraints.
    But as I mentioned this morning, I don't believe you were 
in the room, I was talking about how we put together the 
request for new money in what I call the areas of NIH research 
emphasis. That's done by having each institute spend some time 
with its constituents, its scientists on the outside and the 
inside, coming then to me with a list of things they would like 
to emphasize as new research priorities, and reevaluate those 
together. And we build a series of budgets at different levels 
of increase, at which we would spend different amounts of money 
on longer lists of those projects as the amount of money gets 
greater.
    So we are trying to prioritize within those available new 
opportunities.
    Mr. Istook. Okay. And whatever the most parallel document 
might be from the other institutes, I would appreciate getting 
a copy of that from the others, too. That would be helpful.
    Dr. Varmus. All right.
    [Clerk's note.--Information submitted was too voluminous to 
be printed and is available in Committee files.]
    Mr. Istook. Thank you very much.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Istook.
    Ms. DeLauro.

                             ovarian cancer

    Ms. DeLauro. Thank you, Mr. Chairman.
    Welcome, Dr. Klausner.
    Just three or four questions. First of all, I'm very 
excited when we have the opportunity to talk about what you are 
doing with the genome anatomy project and the focus on ovarian 
cancer. In last year's report language, the committee asked NCI 
to provide funding for ovarian cancer research under SPORE. 
Just a question on whether or not that's been done.
    Dr. Klausner. Let me go back and talk a little bit about 
our advances in ovarian cancer. I think Dr. Varmus did an 
excellent job of describing what we're doing. I just want to 
reemphasize what he said, that almost half of 60 clinical 
trials are looking at new therapies, new agents, from gene 
therapy to immunologic therapies. And as he said, for the first 
time, we have agents, that are far from perfect, that are 
showing responsiveness in advanced ovarian cancer. We have just 
opened what we think will be an important trial in looking at 
bone marrow transplantation and stem cell replacement with much 
more intensified chemotherapy for ovarian cancer.
    But as you pointed out, the problem with ovarian cancer is 
that it's a secret cancer. It's hidden. And the majority of 
cases are not diagnosed until they are advanced, when our 
ability to cure is much more limited, as you pointed out. 
That's one of the reasons we put ovarian cancer in the first 
year of the cancer genome anatomy project. We've already begun 
to make what we call the libraries from ovarian cancer cells, 
so that we can in a systematic way search for tags, molecules, 
that can act as flags for us, that will provide us with better 
detection, hopefully earlier detection, as well as new insight 
into how to intervene in ovarian cancer. I think that's really 
going to be a very important investment.
    Let me also say that there was another advance that I think 
is going to be important for ovarian cancer recently reported, 
and that is the first evidence that one can observe pre-
malignant changes in ovaries. Now, for a long time, that's 
never been seen. These are in individuals at high risk. That is 
going to be very important, because it's going to give us the 
opportunity to ask the questions, what are the cells and what 
are the events that initiate or move forward the progress of 
the changes that result in ovarian cancer. I think that's an 
important research advance.
    Now, in terms of the SPORE, we did not fund a new SPORE in 
ovarian cancer. The reason is, the SPORE, or the Specialized 
Program in Research Excellence program is a new one. As a 
program, it's experimental. And our advisors have advised us 
that the program should be reviewed. And we plan to review it. 
There's much to say that these programs can work very well. So 
this is not any idea that we're not going to continue this. But 
we really felt that this specific mechanism required a careful 
review so we would learn from the first several years what is 
the best way to organize and fund a SPORE, and whether the 
SPORE mechanism is the best mechanism for this type of 
transitional research.
    Ms. DeLauro. What's the timing on this?
    Dr. Klausner. I think our plan to do that is either next 
year or the year after. One of the reasons is that we've just 
completed a very extensive complete review of our whole cancer 
centers program. I'd be happy to talk about that. And most of 
the SPOREs are within NCI cancer centers.

                          human papillomavirus

    Ms. DeLauro. Also with regard to last year's report 
language, it encouraged NCI and the NIAID to collaborate in 
sponsoring basic and clinical research on HPV diagnosis and 
prevention. Can you tell me if this has been done?
    Dr. Klausner. Yes. A lot has happened with HPV--there's 
several things. First of all, there are at least, I think, six 
clinical trials going on now or about to go on, on therapeutic 
vaccines aimed against HPV or HPV gene products. These are 
vaccines attempting to mobilize the immune system for patients 
with cervical cancer. Ninety percent of cervical cancer is 
caused by a series of subtypes of HPV.
    As I mentioned in my opening statement, there have been 
some recent advances in moving towards what may well be an 
effective vaccine against oncogenic or cancer-causing forms of 
HPV. And we are working closely with NIAID, and in fact, 
researchers from multiple institutes. This is another example 
where researchers are involved in vaccines from the Child 
Health Institute and others. And we have made a commitment that 
we will move forward to develop a multi-valent vaccine aimed at 
attempting to vaccinate against the subtypes that are 
responsible for 80 percent of cervical cancer.

                     office of cancer survivorship

    Ms. DeLauro. NCI has established, you said, a new office 
for cancer survivorship?
    Dr. Klausner. Yes.
    Ms. DeLauro. What kinds of activities will be performed 
there?
    Dr. Klausner. That office is to coordinate a whole range of 
activities related to the long-term medical, psychological, 
psychosocial and biologic consequences of cancer, including 
looking at second cancers, late recurrences, the effects of the 
current therapies that we use, psychological aspects of being a 
cancer survivor, cost and health outcomes issues.
    There are four initiatives already. We had a meeting in 
November, we brought together a large number of people. They 
created within a month a very good report, which I'd be happy 
to provide for you, which laid out what a research agenda would 
look like for long-term survivorship. I then gave the staff 
about a month to act on that, to create a series of 
initiatives.
    We have four types of initiatives, including a proposal for 
an RFA that we'll be bringing to our board next week for a 
whole series of research programs aimed at answering quality of 
life issues, and that whole range of issues I just described, 
as well as providing supplemental funding to cancer centers, to 
cooperative groups, to SEER registry system, and to other 
national and international registries so that we can quickly 
get answers to the issue of long-term effects of cancer and 
survivorship.
    Ms. DeLauro. Let me just say that I'm sure all the members 
on this committee want to work very closely with you on some of 
these issues--the issue of HPV and what that means in terms of 
cutting back, and in terms of cervical cancer. You have such 
good information. I continue to look forward to working very 
closely with you in seeing how we can move the agenda along as 
quickly as we can.
    Thank you very much.
    Dr. Klausner. Thank you.
    Mr. Porter. Thank you, Ms. DeLauro.
    We have myriad questions for the record that we would ask 
that you address for us, Dr. Klausner. By all accounts, you're 
doing an excellent job at NCI, and the obvious intellect and 
enthusiasm and energy you bring to that endeavor is just 
amazing to us. And we very much enjoy working with you and 
seeing the progress that you are making.
    So we thank you for your testimony this afternoon, and 
appreciate your candor and directness in answering all of our 
questions.
    Dr. Klausner. Thank you very much.
    Mr. Porter. Thank you so much, Dr. Klausner.
    The subcommittee will stand in recess briefly.
    [The following questions were submitted to be answered for 
the record.]

[Pages 244 - 418--The official Committee record contains additional material here.]


                                      Wednesday, February 26, 1997.

                         NATIONAL EYE INSTITUTE

                               WITNESSES

CARL KUPFER, M.D., DIRECTOR
EDWARD McMANUS, DEPUTY DIRECTOR
JACK McLAUGHLIN, Ph.D., DIRECTOR, DIVISION OF EXTRAMURAL RESEARCH
CAROL LIPSON FIVOZINSKY, BUDGET OFFICER
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 are pleased this afternoon to welcome Dr. Carl Kupfer, 
the Director of the National Eye Institute.
    Dr. Kupfer, it's very good to see you. I think I'm going to 
have you to myself. But why don't you proceed with your 
statement, and then we'll go into questions.

                       Introduction of Witnesses

    Dr. Kupfer. Thank you, Mr. Chairman.
    Perhaps before I begin I might just introduce those to my 
left who are representing the National Eye Institute also. To 
the far left is Ms. Carol Fivozinsky, who is our budget 
officer. Next to her is Mr. Ed McManus, who is the deputy 
director. And to my immediate left is Dr. Jack McLaughlin, who 
is the associate director for extramural programs.

                           Opening Statement

    Mr. Chairman, the National Eye Institute continues to 
support research on the vast array of blinding eye diseases, 
but today I would like to focus on some of the exciting new 
areas of research that really impact upon the concerns amongst 
our older Americans.
    It's a condition which is the main cause of visual 
disability and blindness. At present, there are 1.7 million 
Americans over the age of 60 who suffer from severe visual 
impairment and blindness, and by the year 2030 this number will 
be increased to about 6.3 million.
    This is a condition called ``age related macular 
degeneration,'' and then the term ``age-related,'' that tells 
you why there's going to be such an increase as our baby 
boomers, who are just reaching age 50, will continue to go into 
the 60 and above age group.
    We are pursuing a number of very exciting areas, and I'd 
like to just very briefly tell you what they are.
    In the laboratory, we are very interested in the evaluation 
of growth factors, and these are factors that can rescue cells 
and allow regeneration to take place in the central nervous 
system and the retina, which is affected by age-related macular 
degeneration. The retina is part of the central nervous system.
    The disease affects the macula, which is that part of the 
retina we use for straight-ahead vision. We use it for reading, 
for driving, for sewing. And, therefore, the individual who has 
age-related macular degeneration is unable to do these 
activities, but fortunately can still get about and ambulate, 
although the impact on quality of life is very severe.
    We are very much interested in an item that Dr. Klausner 
brought up, and that is blood vessel growth. Just as blood 
vessels are important to maintain the integrity of a cancer, 
and if you could reduce the amount of blood vessels, you can 
kill the cancer. There are eye conditions--age-related macular 
degeneration being one and diabetic retinopathy being a 
second--where new blood vessels form. And we are actively 
engaged in looking at factors that prevent proliferation of new 
blood vessels--we, and people in the Cancer Institute, and the 
many other institutes who are interested in preventing abnormal 
blood vessel growth.
    We are pursuing techniques for the introduction of genes 
into the retina, and this has been accomplished in experimental 
animals, and I think in the next two or three or four years we 
will begin to see these experiments done in patients.
    We are very much interested in retinal cell transplants. 
This, again, is going to be primarily done in experimental 
animals for the foreseeable future, because there are many very 
important aspects of this type of work, including graft 
rejection, that must be overcome before we can assure that a 
clinical trial is worth doing.
    And, finally, there is a condition in which the cell seems 
to commit suicide, and a number of diseases, including glaucoma 
and macular degeneration, appear to share this problem. We want 
to know what regulates this activity and how we can turn it 
off.
    From a clinical point of view, we are well into our Age-
Related Eye Disease Study, which involves some 4,700 patients, 
and from this study we will be able to assess the aging process 
of a retina, the potential risk factors that may predispose to 
the development of age-related macular degeneration.
    We're very much interested in measuring the quality of 
life, and we do have an instrument, a questionnaire, that 
enables us to assess this very quantitatively.
    And, finally, there is a clinical trial component to look 
at the effect of certain vitamins and minerals as to whether 
they can be of benefit in slowing down the degenerative 
process.
    We are also beginning two new studies in which we're 
evaluating the genetic factors in macular degeneration. There 
are a number of families in which two or more members do have 
macular degeneration, either in the same generation or in two 
generations, and we're looking very aggressively at what the 
genetic factors might be.
    I don't want to forget to mention that we are also very 
much interested in the infant and the young child. We recently 
announced the results of our retinopathy of prematurity study 
in which freezing the outside of the eye has reduced blindness 
considerably, now that we're able to measure the vision at age 
five-and-a-half and six years.
    As far as young Americans are concerned, we've had a very 
interesting experience with a pilot study in which patients 
with uveitis who are on large amounts of drugs, which do have 
adverse side effects, can have those drugs reduced by the 
introduction of a purified protein derived from the retina is 
actually fed to the patient.
    The National Eye Institute is requesting for 1998 a budget 
figure of $330,955,000.
    Mr. Chairman, I'd be happy to answer any questions.
    [The prepared statement follows:]

[Pages 422 - 425--The official Committee record contains additional material here.]


                      professional judgment budget

    Mr. Porter. Thank you, Dr. Kupfer.
    I'm inclined to want to ask you first about the budget 
number. We understand that the request, including the OAR 
transfer, would be roughly $340.4 million, up about $8 million 
over the fiscal year 1997 appropriation. And I'd like to know 
what, in your professional judgment, your budget should be.
    In other words, what could you reasonably really use? How 
much promising research is there in the area of the eye? And 
won't you, in fact, because of inflation, be actually working 
with less money in the next fiscal year if we were to fund you 
at the $340 million level than you have to work with right now?
    Dr. Kupfer. I did mention in my opening statement those 
areas that are very promising that have to do with age-related 
macular degeneration. And, of course, they impact on other 
retinal diseases, such as retinitis pigmentosa.
    And we would go ahead and take advantage of these research 
opportunities, no matter what. In fact, in the last three or 
four years we have increased the amount of money in age-related 
macular degeneration from $5 to $17 million, and the present 
level of support of retinal research is about $70 to $75 
million.
    [Clerk's note.--later corrected to ``$16'']
    But there are other opportunities. For instance, just in 
the last two weeks a gene for glaucoma was discovered, and the 
exciting thing about this is that usually when we find the 
gene, we aren't quite sure what it does, because we first have 
to find out what the gene produces in the way of a protein and 
determine what the protein does.
    In this case we not only know where the gene is; we can 
identify the gene, we know what protein it produces, and we 
know what the protein does--it clogs up the out-flow channels 
in glaucoma.
    And we can immediately apply this within the year to 
screening families that have this form of juvenile glaucoma--
that is, they develop the blindness within the second and third 
decade of life--and identify quite convincingly those 
individuals who are at high risk of going blind.
    So this is an area that should immediately be followed up 
very aggressively in terms of how does this finding apply to 
open-angle glaucoma, which is the main form of glaucoma 
throughout the United States and the world.
    In particular, that happens to be a very major problem 
amongst African-Americans. It's about six times more common in 
African-Americans than Caucasians.
    [Clerk's note.--``to seven'' later added.]
    So there are other opportunities.
    In cornea research we now have for the first time 
identified channels in the cornea through which water is 
transported. And, of course, the whole trick in keeping the 
cornea clear is to keep it free of fluid, and therefore the 
ability to see the channels where water is continually being 
pumped out of the cornea becomes a very important point in 
preventing the cornea from becoming opaque.
    In cataract there are new findings that should be put to 
hypothesis testing because we want to slow down the development 
of cataract. I mentioned before, if we could just slow down the 
development of cataract by ten years we'd reduce by about 45 
percent the number of people who need surgery.
    [Clerk's note.--``to 50'' later added.]
    Right now we, as taxpayers, support about $5 billion to do 
the 1.6 million cataract surgeries every year, and that's a 
major economic impact. Even though it's one of the most safe 
operations and most effective operations, it still represents a 
major economic impact.
    So there are a number of opportunities, and I would say 
that we would pursue all of them at a slower rate. With 
additional resources, the rate could be increased.

                             glaucoma gene

    Mr. Porter. I always enjoy the interplay between the budget 
you really would like to have and the one the President has 
handed you, so I like to ask these kinds of questions.
    We remember the painful retirement of Kirby Puckett from 
baseball last year because glaucoma had irreversibly damaged 
his right eye before it was detected.
    Now recent scientific findings may result in new tools for 
early diagnosis of glaucoma. Researchers in Iowa have located a 
gene that causes a particularly virulent form of glaucoma which 
strikes young people, as you said. They expect to develop a 
test for the gene within a year.
    This seems to be different from most cases when genes are 
discovered and years of work lie ahead before there is an 
impact on patients. Once tested, glaucoma patients could be 
diagnosed early and treated before any vision loss had 
occurred. Does this test also hold promise for people with more 
common forms of glaucoma?
    Dr. Kupfer. Yes, sir. First, as far as the juvenile type, 
it's going to be a very effective way of really preventing 
blindness from ever occurring, because for this group, the use 
of a straightforward operative procedure before the disease 
really has taken away vision, will basically prevent the 
blindness from ever occurring.
    In the case of open-angle glaucoma, I think we're going to 
have to see what additional genes are involved in addition to 
the one that has just been found, and I think in the next year 
or two or three we will identify those additional genes.
    This finding has really spurred on the researchers. We have 
several groups working very hard in trying to identify 
additional genes.
    So I think there will be a major impact on this disease.
    Mr. Porter. So that most eye diseases that are genetic are 
not single-gene conditions; they're more likely to be multiple?
    Dr. Kupfer. Yes, sir. I think it is very clear that 
glaucoma, age-related macular degeneration, retinitis 
pigmentosa are multiple-gene diseases. We've got to find all 
the genes involved.
    [Clerk's note.--Reference to ``retinitis pigmentosa'' later 
struck and ``diabetic retinopathy'' added.]
    Mr. Porter. And if you had more money, you could presumably 
find them faster?
    Dr. Kupfer. Faster. Yes, sir.

                            neuron survival

    Mr. Porter. Your justification describes a protein found in 
cells that lie behind the retina which encourages neuron 
survival. The therapeutic potential of this protein is being 
explored for a variety of conditions in which neural cells die, 
such as stroke, traumatic brain injury, and Parkinson's 
disease. This seems to highlight the difficulty of ascribing 
research to one disease or another.
    When you're asked to estimate your total expenditures for a 
list of diseases, how would you categorize the research on this 
protein? Would it be research on eye disease or Parkinson's 
disease, or stroke?
    Dr. Kupfer. Well, if we do it on the basis of what seems to 
have the greatest impact, the experiments that have been done 
on the cells which are affected by Parkinson's disease show 
clearly a survival of these cells. They do not degenerate in 
tissue culture.
    So I would say this is probably going to have initially a 
major impact on Parkinson's disease.
    As a matter of fact, this research was done in 
collaboration with the investigators in the Neurology 
Institute.
    We are trying to see what role it plays in cell survival in 
the retina, and, of course, that is being pursued very 
aggressively.

                radial keratotomy versus laser technique

    Mr. Porter. In past years we've talked about RK surgery as 
a method to correct near-sightedness. Now physicians are 
heavily marketing a laser technique that is intended to correct 
myopia. What kind of clinical trials or approvals did this 
procedure undergo before marketing began? Has it been compared 
to RK in terms of safety and effectiveness? And what is your 
scientific opinion of this procedure and its effects, both in 
the long and short term?
    Dr. Kupfer. You may remember, sir, that when radial 
keratotomy, RK, first appeared on the scene--which is now 
perhaps 15 years ago--we were approached by a number of 
investigators in the community that said, ``We are very 
concerned about the safety and efficacy of this procedure, and 
we would like to submit a clinical trial.''
    We expedited the review. It was a very good review, and we 
supported the clinical trial and actually have ten-year data on 
the outcome of radial keratotomy.
    So from both a scientific point of view and from a patient 
information point of view, the surgeon can tell the patient 
what to expect in terms of outcome.
    This research data base does not exist with the laser 
studies to the same extent that it does with RK. These studies 
were done without support from the National Eye Institute. We 
were very interested in supporting animal studies and did so, 
but the clinical studies were supported primarily by the 
manufacturers of the lasers, and it is difficult to assess the 
long-term effects of these procedures because the longest data 
now is about two years.
    So I think we will want to see what the long-term effects 
will be.
    However, I do want to add that FDA has reviewed these 
studies and has given approval for the use of the lasers.

                              fda approval

    Mr. Porter. When FDA has these matters before them, do they 
contact you for data that you might have?
    Dr. Kupfer. Yes, sir. As a matter of fact, we usually have 
a member of the National Eye Institute on their outside review 
panel.
    We have been working with FDA over the past five years and 
working with the private sector, the pharmaceutical companies, 
the device makers, and academia, trying to bring together the 
four components to make the translation from the laboratory to 
the clinic and eventual FDA approval a little more secure in 
terms of designing the very best clinical trial possible and 
then helping to see that it's carried out well.
    And I think gradually we are moving in this direction, and 
I have great hopes that we will see more collaboration between 
FDA, National Eye Institute, the private sector, and academia.

                          macular degeneration

    Mr. Porter. In your testimony you mentioned that 1.7 
million people are affected with macular degeneration today, 
and that you estimate that by--I think you said the year----
    Dr. Kupfer. The year 2030.
    Mr. Porter [continuing]. 2030 it would be something like 
six million.
    Dr. Kupfer. Approximately 6.3 million. Yes, sir.
    Mr. Porter. We're hearing from groups that are very 
concerned about macular degeneration that they say 13 million 
people are affected today.
    Why is there a difference in this estimate?
    Dr. Kupfer. When we quote the figure 1.7 million, we are 
saying that these are individuals who actually have severe 
visual disability or are legally blind. The larger figure are 
those who are at risk of developing age-related macular 
degeneration, and a certain subset of those individuals will go 
on to develop severe visual impairment, but not all of them.
    Mr. Porter. Mr. Stokes?
    Mr. Stokes. Thank you, Mr. Chairman.
    Dr. Kupfer, it is nice to see you again.
    Dr. Kupfer. Yes, sir.

                             glaucoma gene

    Mr. Stokes. It is always a pleasure.
    Doctor, according to your budget justification, 
approximately three million Americans have glaucoma, and at 
least half of those who have glaucoma are unaware of their 
condition. As many as 120,000 people now are blind from the 
disease.
    Recent articles report that the gene associated with 
glaucoma was recently identified by NEI-supported 
investigators.
    What are the major implications of this finding with 
respect to early treatment and detection of glaucoma?
    Dr. Kupfer. The gene that was found and cloned and the 
protein product that it produces and what it does, primarily 
applies to a subgroup of glaucoma that's called juvenile 
glaucoma because they develop during the first two decades of 
life.
    In those individuals who are in families--and this is 
inherited as a dominant characteristic--we can now, within the 
year, test members of the family and determine very clearly 
whether they will go on to develop glaucoma or not.
    The important thing is that when these individuals develop 
glaucoma they develop such high pressures in the eye that they 
can go blind in a matter of months, so early diagnosis is 
absolutely critical.
    And if we can diagnose them early, we can do a surgical 
procedure to produce a new channel through which the fluid can 
leave the eye, and there's every expectation that they will 
then never get into trouble again.
    Now, the real impact is how is this gene related to open-
angle glaucoma, which accounts for about 85 percent of all the 
glaucomas, and that is being very actively pursued.
    I think that it will be found that this gene does play a 
role in open-angle glaucoma, but there are other genes also 
involved, and those are the genes we are looking for now.

                       retinopathy of prematurity

    Mr. Stokes. What major progress do you have to report to 
our committee with respect to research on retinopathy of 
prematurity, the blinding eye disease that affects premature 
babies? What is the extent of this problem?
    Dr. Kupfer. At the present time it has been estimated that 
about 4,000 infants weighing 3.3 pounds or less are born every 
year. And of those, it's estimated about 700 to 750 will become 
blind. We now can probably reduce that figure to about 400 by 
the treatment of freezing the outside of the eye.
    We now have five-and-a-half year data on the first cohort 
of premature infants from a clinical trial begun about seven 
years ago, and we know that to actually prevent blindness, to 
restore good vision and keep vision, we can do that in about 25 
percent of the children. And others may not have good vision 
but have useful vision.
    So I think that we really have made major strides; however, 
we haven't stopped. We are continuing two other trials, one 
that deals with providing oxygen but at a very constant level. 
Technology has now enabled us to monitor the arterial oxygen 
levels continuously in premature infants lying in an incubator, 
so we can be sure that the level of oxygen stays constant.
    There is the hypothesis that it's not just the level of 
oxygen but the changing level of oxygen that may be a risk 
factor in inducing retinopathy of prematurity.
    And then there's another trial that is looking at the 
question whether there are other environmental factors that may 
contribute to the retinopathy of prematurity.
    So we are very actively and aggressively pursuing this in 
conjunction with the Child Health Institute and with the 
Nursing Institute.

                          biology of the brain

    Mr. Stokes. Doctor, as you know, the NIH has included the 
biology of the brain among its special emphasis areas, and, of 
course, you, Doctor, over the years have focused attention on 
the eye as the window to the brain.
    What major research studies are underway at the Institute 
with respect to the biology of the brain? And, tell us--what 
are the implications of this work for furthering advances in 
neuro-degeneration and spinal cord injury.
    Dr. Kupfer. I think that the seeing part of the eye, the 
retina--and perhaps I could just illustrate that with this 
figure. This is a cross-section of the eye, and the light comes 
through the cornea and is focused by the cornea and the lens 
onto the retina, and the retina is actually part of the brain. 
It's part of the central nervous system.
    [The information follows:]

[Page 432--The official Committee record contains additional material here.]


    So that the connection between the retina and the brain, 
which we call the ``optic nerve,'' is quite comparable to the 
spinal cord. In fact, they are the same level of complexity and 
conveying roughly the same sort of information from the 
periphery to the central nervous system.
    The research that is then going on in the optic nerve has a 
bearing on spinal cord injury, and this research is primarily 
looking at what growth factors are necessary to allow cells of 
the central nervous system to regenerate similar to what 
happens when one has an injury to a peripheral nerve. Those 
peripheral nerves usually regenerate.
    We're trying to determine what is the difference between a 
peripheral nerve, which can regenerate, and a central nerve 
track that cannot.
    Growth factors are involved. Genetic control is another. 
These central nerves will regenerate in a very, very young 
infant, but somewhere along the line the genetic control to 
allow regeneration to occur stops. And we want to know how to 
reactivate it.
    We're interested in therapy of various drugs that will 
stimulate the development of central nervous tracks.
    So this is a very major area of work.
    In addition, all the diseases that affect the retina--
retinitis pigmentosa, age-related macular degeneration, the 
juvenile dystrophies, they also need to be studied in terms of 
growth factors, gene replacement, transplantation, all the 
sorts of studies that underlie neuroscience at the present 
time.
    Mr. Stokes. Doctor, considering the importance of this 
area, how much is included in the fiscal year 1998 budget 
request for the work in this area? How much are we currently 
investing?
    Dr. Kupfer. I think in terms of the retinal disease, we're 
investing about $75 million. This will probably increase in 
fiscal year 1998 because we want to take advantage of these 
research opportunities and we will move funds in that 
direction.
    Mr. Stokes. I think I have exceeded my time. Thank you, Mr. 
Chairman.

                       transplanted retinal cells

    Mr. Porter. Thank you, Mr. Stokes.
    Dr. Kupfer, the press has reported that surgeons in Chicago 
have transplanted retinal cells from aborted fetuses in an 
attempt to treat macular degeneration. Is this an approach you 
believe holds promise?
    Dr. Kupfer. Mr. Porter, this technique has been used in 
various parts of the world during the last five to ten years. 
It has been used in Sweden. It has been used in India. I think 
this may be the first report in the United States.
    My feeling is that we have so much more to learn in terms 
of what must be done for a transplanted tissue to survive, that 
perhaps these types of clinical studies may be a bit premature.
    We are pursuing this in the laboratory very aggressively, 
and we will continue to do so. I think that there is a high 
probability in the next five, ten, fifteen years, that we will 
learn the surgical technique of transplantation, how to prevent 
rejection of the transplant, how to maintain the transplant 
long enough to begin to develop connections with the retina and 
the brain, and then how to reorient these transplants so they 
can actually convey information that's going to be meaningful 
to the brain.
    These are very major problems that have to be overcome 
before I think this sort of surgery will be useful.

                              fetal tissue

    Mr. Porter. Is there evidence that fetal tissue is less 
likely to be rejected than adult tissue?
    Dr. Kupfer. Yes, there is, sir, and I think that was the 
reason that the fetal tissue was used. But, nevertheless, I 
think there is still the possibility that fetal tissue may 
remain viable for much longer than if it were adult tissue, but 
eventually I think it is going to either be rejected or it will 
develop into a scar and not be functional. That would be my 
prediction at the present time.

                          macular degeneration

    Mr. Porter. Cigarette smoking has been shown to increase 
the risk of developing macular degeneration. Are you working 
with the CDC and the Cancer Institute to include that warning 
in their cancer control messages about the dangers of smoking?
    Dr. Kupfer. These are results that recently came to our 
attention through three different studies. I think that, given 
the fact that cigarette smoking is a disaster for lung cancer 
and for cardiovascular disease and several other things, adding 
this additional piece of information is desirable, but I think 
it doesn't quite have the same urgency as those other areas.
    But we are in contact with CDC through our National Eye 
Health Education Program, and I know the Cancer Institute is 
aware of these studies.
    Mr. Porter. Was it an NEI study that linked nutritional 
supplements like selenium and vitamins to a slowing of macular 
degeneration?
    Dr. Kupfer. Slowing of macular degeneration--I think that 
the present clinical trial in which we are using some vitamins 
and minerals is the first systematic attempt to see if these 
are of any benefit.

                       marijuana use for glaucoma

    Mr. Porter. This morning we discussed the debate about 
possible medical uses of marijuana. One disease for which 
marijuana is claimed to have a therapeutic affect is glaucoma. 
Is there a scientifically-validated basis for these claims?
    Dr. Kupfer. In the early 1970s it was found that smoking 
marijuana reduces the pressure in the eye in normal 
individuals. Following that, a number of patients with glaucoma 
did report that their pressures did go down when smoking 
marijuana, and this was observed to be the case by eye care 
professionals.
    There were a number of animal experiments done during the 
early 1970s. In 1978 we actually issued a request for 
applications to study this in patients. No applications came 
forth, so we really do not have any strong scientific basis on 
which to make a judgment.
    I hasten to add that we do have a very large armamentaria 
of drugs that have been approved by FDA that do lower intra-
ocular pressure and do not have some of the very serious side 
effects that marijuana does have.
    But we would be prepared to conduct clinical trials if 
there was an interest upon the part of the research community 
and individuals with glaucoma.

                          private foundations

    Mr. Porter. You suggested last August that your Institute 
and the Foundation for Fighting Blindness should jointly plan 
their research agendas to direct research funding more 
effectively. Is this a departure from usual practice at NIH, or 
is it common to coordinate research agendas with private 
foundations?
    Dr. Kupfer. I think it's becoming more and more common, 
sir. As a matter of fact, one of the models that I'm most 
familiar with began with the Diabetes Institute, and that was a 
collaboration between the Diabetes Institute and the Juvenile 
Diabetes Foundation, where they jointly funded research grants.
    We now have that same relationship with the Juvenile 
Diabetes Foundation, and we would like to have that same 
relationship with the Retinitis Pigmentosa Foundation.
    The reason for that is that, although their resources are 
not as extensive, they have much more flexibility than we do, 
and therefore they can do certain things that we cannot do, and 
we want to look for areas where we can complement each other in 
that nature.
    I think we're going to see more of this rather than less.
    I don't know, Harold, if you want to make any comment about 
the----
    Dr. Varmus. I have urged Institute directors to take 
seriously propositions from private organizations.
    We offer one very important component that is often 
difficult for them to provide, and that is an extensive, well-
established peer review system that allows them to make the 
best possible use of the dollars they receive from donations 
and volunteers.
    Mr. Porter. How would you plan to coordinate your research 
portfolio, since you place heavy emphasis on investigator-
initiated research rather than Institute-generated research?
    Dr. Varmus. Well, we would not want to subscribe to a 
program that we didn't think was in our interest, and, through 
discussions that have been held with a number of funding 
organizations, we have been able to agree that there are 
initiatives of mutual benefit we both would agree would be to 
the advantage of both sponsors and that we'd be happy to 
sponsor.
    Dr. Kupfer. One could see at least two occasions. What 
we're doing with the Juvenile Diabetes Foundation is to co-fund 
RO-1s, research grants that we've reviewed but do not fund. 
They're very meritorious, but we do not have adequate funds to 
fully fund them. And the Juvenile Diabetes Foundation looks at 
these, makes their own decision. We notify the grantee that if 
they are going to accept this grant it's going to be co-funded, 
so that they are fully prepared, and then we move ahead.
    The second area is to supplement our fellowship support. 
There are opportunities where to bring individuals into a 
particular area, a supplementation of the NIH fellowship might 
be helpful in an individual, for instance, who has a very large 
debt and would need some additional financial resources. The 
private foundations can do this. We cannot.

            nutritional supplements for retinitis pigmentosa

    Mr. Porter. You're conducting clinical trials of a 
nutritional supplement to halt the progression of retinitis 
pigmentosa. Vitamin A has already been shown to delay the 
progress of RP. Reports suggest that, if successful, this 
treatment could allow patients to retain useful vision for 
their entire lives. How can a nutritional supplement stop the 
progression of an eye disease?
    Dr. Kupfer. Perhaps I could answer that by first going back 
to the first study that you alluded to.
    The first study actually used Vitamin A or Vitamin E or a 
combination of the two or a placebo, and it was felt, on the 
basis of many, many animal studies, that both Vitamin A and 
Vitamin E would be of value, Vitamin A because it is part of 
the molecule in the retina that captures the light, rhodopsin; 
Vitamin E because it's an antioxidant and is supposed to 
stabilize membranes. And the photoreceptor is made up of 
thousands of membranes, so it was felt that this would be very 
valuable.
    As it turned out, the Vitamin A was of benefit, but the 
Vitamin E was not of benefit and actually caused an 
acceleration of the degenerative process.
    So one must be very, very careful in testing these in a 
very well-controlled clinical trial, so the recommendation from 
that first study was that Vitamin A is of benefit, and we have 
an explanation.
    The second trial is additional assessment of nutritional 
ingredients, and we will see how that turns out.
    Mr. Porter. And if this therapy turns out to be successful, 
it would be very low-cost, would it not?
    Dr. Kupfer. Yes, it would be, just as Vitamin A is very low 
cost. Yes, sir.

                        long-range research plan

    Mr. Porter. Your Institute is in the early stages of 
developing your next long-range research plan. What would you 
consider the most significant ways the vision research field 
has changed since your last plan was released?
    Dr. Kupfer. I think the areas of neuroscience, of genomics, 
the tracking down of genes, and the role of immunology are 
probably the three major changes. Automation has played a very 
major role. High-speed computers have allowed us to do things 
we weren't able to do.
    I think we're going to see research done in a very 
different way in the next decade than we have previously.
    I think we're also seeing that collaboration is absolutely 
essential. This article on finding the gene in glaucoma must 
have had 15 authors, and I think this is not unusual. Many of 
these articles require the skills of many, many different 
groups, and I think we're seeing more coordination of research 
activities, and I think we've got to shape our research grant 
support in that direction.

                            cataract surgery

    Mr. Porter. Apparently, many people who have cataract 
surgery must have a second operation because the cataract forms 
again as a response to the residual lens cells remaining after 
the surgery. What share of those undergoing cataract surgery 
face this problem and how much could be saved if drugs or 
better surgical techniques could prevent the formation of the 
second cataract?
    Dr. Kupfer. Yes, sir. It has been estimated that about 25 
percent of the individuals who undergo cataract surgery have 
this proliferation of cells that occlude the vision, and 
therefore a laser treatment is necessary to sort of punch a 
hole in this membrane.
    If we assume that there are about 1.5 million or 1.6 
million cataracts done a year, and about 25 percent of those, 
that's about 300,000 to 400,000 develop this problem, and the 
average cost, with hospitalization and return visits, is about 
$1,000. We're talking about $300 to $400 million.

                             contact lenses

    Mr. Porter. How many Americans are contact lens wearers? Do 
we know that?
    Dr. Kupfer. That's a very good question. The problem with 
the answer is we know how many people purchase contact lenses, 
but we don't know how many people are wearing them. It has once 
been said there are more contact lenses in the top bureau 
drawer than in the eyes of people.
    I would guess--and I could correct this when I look at the 
transcript--somewhere between 5 and 10 million people are 
wearing contact lenses.
    [Clerk's note.--later corrected to ``24.'']
    Mr. Porter. And are there any long-term studies of the 
effects, the possible negative effects of wearing such lenses?
    Dr. Kupfer. Yes, sir, there are. Many of the studies have 
dealt with what was the original type of lens, the hard lens, 
and they have given way almost completely to the soft lens. The 
hard lenses do have some complications after about 15 to 20 
years of wearing, but the soft lenses so far are being watched 
very carefully.
    The main problem with soft lenses is that they are so 
comfortable that people forget to take them out at night and 
will sleep with them--in fact, may keep them in three or four 
days--and then corneal ulcers can develop, and that's a major 
complication.

                vision conditions needing more research

    Mr. Porter. We talked about glaucoma and the tools to 
detect and prevent it. We seem to have a much more limited 
stockpile of weapons against other eye diseases. For which 
vision conditions would you say we know the least about 
treatment and prevention?
    Dr. Kupfer. In terms of the public health impact, it's age-
related macular degeneration. Of the cases, 90 percent are what 
we call ``the dry type.'' That is, there is breakdown of the 
retina very slowly. The wet type is 10 percent. That's where 
new vessels develop. But it's that 10 percent that causes legal 
blindness.
    And we can only treat successfully about 15 percent of 
those patients, so we really do not have an awful lot to 
answer. That's our major concern at the present time.
    Mr. Porter. And that, in a sense, is a result of being 
successful in other fields and having people live longer and 
healthier to later ages and then develop diseases like age-
related macular degeneration.
    Dr. Kupfer. That is it completely.
    Mr. Porter. Or Alzheimer's disease.
    Dr. Kupfer. That's right.
    Mr. Porter. Well, we thank you very much, Dr. Kupfer, for 
your good testimony.
    I'm going to ask Dr. Varmus if he would stay just a moment, 
because I have several questions left over from this morning 
that I'd like to pose to him. But thank you for your good 
testimony. Thank you for your excellent work at the National 
Eye Institute. You do a wonderful job there and we appreciate 
the candid and good testimony that you give us and insights 
into what is being accomplished in your field.
    Thank you very much.
    Dr. Kupfer. Thank you, Mr. Porter.

                        angiogenesis and cancer

    Mr. Porter. Some of these questions probably are for Dr. 
Klausner, but since he's not here----
    Dr. Varmus. We can call him back. He's still in the 
building.
    Mr. Porter. I thought you might be able to answer them.
    We talked earlier about reducing the blood flow to certain 
cancers.
    Dr. Varmus. Right.
    Mr. Porter. And the promise that that has. I wonder if you 
know whether that is NCI-supported research that led us to 
where we are?
    Dr. Varmus. Most of it is. Yes. There are actually two 
approaches that are being taken. One is based on the idea that 
the process of blood vessel formation, like so many things that 
go on in the body, is a ying and yang process. There are 
factors that promote blood vessel development and there are 
factors that inhibit it.
    Dr. Judah Folkman at Harvard, who is one of the pioneers in 
this field and a long-term NCI-supported investigator, has, for 
example, identified at least two or three compounds, natural 
products of the body--indeed, in some cases natural products of 
tumors--that can inhibit blood vessel growth and have been used 
in treatment of tumors in animals, and have, indeed, been 
proposed for clinical trials.
    The other avenue is to make use of clotting mechanisms to 
induce thrombosis, clots, in blood vessels that lead to tumors.
    I'm not sure who sponsored those experiments. There was a 
paper recently published in the journal, ``Cell,'' describing 
the use of this approach in an experimental tumor in an animal, 
in mice. We could find out for you who supported that.

                    consolidated aids appropriation

    Mr. Porter. Dr. Varmus, your budget again proposes a 
consolidated appropriation for the Office of AIDS Research. I 
know you're obligated to support the President's budget 
request, but could you tell me if the approach we used in 
fiscal year 1997 for AIDS funding was workable? Did our 
language prevent you from doing anything that you wanted to do 
in managing AIDS research?
    Dr. Varmus. It did not prevent us from doing anything. The 
budget was, of course, allocated according to the plan worked 
out by the Office of AIDS Research. It was slightly cumbersome 
in its operation, in that the money went to the institutes, 
back to the office, then back out to the institutes, but it was 
a paper transfer and it worked efficiently and everybody was 
happy.

                        aids transfer authority

    Mr. Porter. Do you and Dr. Paul intend to use the transfer 
authority we gave you in this fiscal year to move AIDS funds 
between institutes?
    Dr. Varmus. You're referring to the 3 percent transfer 
authority?
    Mr. Porter. Yes.
    Dr. Varmus. At the moment we don't have any expectations of 
using it. As you probably know or will soon know, we have 
identified a number of projects that will be funded by use of 
my 1 percent transfer authority, assuming that the committee is 
willing to approve that request. None of those are in the AIDS 
area.
    I believe one of the reasons we've had so little need for 
it is that the planning process was carried out right up to the 
time when the allocations were made, and, as a result, I think 
the appropriations were appropriate.
    And, given Dr. Paul's discretionary budget, I think in toto 
we were able to operate effectively without using this transfer 
authority. If there is a need as an emergency later in the 
year, we, of course, would employ the transfer authority.

                         earmarks for diseases

    Mr. Porter. I wish I'd had an opportunity to say this 
earlier, but I want to put it in the record.
    Dr. Varmus, we fight hard to keep our bill and our report 
free of disease earmarks. We've heeded your warnings that this 
is destructive to the scientific enterprise, and I'll continue 
to fight to preserve this principle, despite what is a growing 
rebellion in some quarters of the Congress.
    I have to say the President's pronouncements last year 
pledging specific dollar amounts to spinal cord injury 
research, for example, have the effect of undermining these 
kinds of efforts.
    How can you and the scientific community expect Congress to 
continue ``letting science decide'' when the President of the 
United States seems to be leading a charge in the opposite 
direction?
    That's more of a statement than a question.
    Dr. Varmus. Thank you.
    Mr. Porter. I think that it does us a great deal of harm 
for the White House to work in the direction that takes 
discretion away from science, from you in determining the 
proper allocation of funds, and we would like to give you the 
maximum discretion in doing that.
    While all of us have strong feelings, as does the 
President, we do our very best to try to keep them out of the 
bill and only in the report where they belong.
    Dr. Varmus. I perhaps should say, Mr. Porter, that there 
was a happy confluence of events in that circumstance, because 
there have been some recent developments in the study of 
central nervous system injury that allowed us to make extremely 
good use of those additional allocations.

                            priority setting

    Mr. Porter. In each year that I've been chairman of the 
subcommittee, I've been approached by advocacy groups concerned 
that NIH spending in certain diseases is out of balance with 
its incidence and associated health care costs, and I think 
Representative Istook raised some of those questions earlier.
    Some feel that political pressures are applied to NIH 
spending decisions. Can you lay out for us your response to 
these concerns?
    For example, when the committee provides more funding for 
NIH than was requested by the President and we ask your advice 
in allocating the increase, what guides your decision about 
distributing the funds among the institutes?
    Dr. Varmus. You ask me to do that here or for the record?
    Mr. Porter. No. Here.
    Dr. Varmus. There are several things. I have to say, Mr. 
Porter, as we think through priority setting, it is an 
imperfect process. When we're given money to spend on research, 
we have to depend upon subjective estimates and our judgment, 
and ultimately I suppose we come back to the idea that those of 
us who have been entrusted with positions such as director of 
NIH or director of an institute have the judgment that allows 
us to make the best possible guess about how the money can be 
well spent.
    When we have an increased amount of money, there are two 
kinds of things that can be done. One is simply to fund more 
grants than we could otherwise fund. As you know, we have a 
list of grant applicants with different priority scores.
    Currently, in some institutes, grants that received 
extremely high priority scores, perhaps ranking among the top 
20 percent, but with scores that indicate a very high degree of 
excellence as perceived by the study sections, don't get 
funded, and we are able to fund those.
    That's just a simple lowering of the threshold so that we 
have a higher success rate.
    The other thing that happens is in the programmatic 
allocations by each institute--an allocation that is made 
differently in different institutes. Some institutes will fund 
the top 80 percent of their grant applicants and then look at 
the distribution of grants among programs and decide to reach 
lower in the priority list among grants to make sure that 
there's adequate support in various areas. Others divide the 
grants by program and fund to certain levels within each 
program.
    Regardless of how that's done, when additional money is 
available the director of the institute, in consultation with 
outside experts, with members of his program staff, with his 
National Advisory Council that's composed of both consumers and 
scientists from the outside, will decide whether to go further 
in funding certain programmatic areas.
    Now, when I say ``program,'' I'm referring both to funding 
in certain categories--be it basic research or disease-specific 
research--or sometimes it means providing more funding for 
certain kinds of mechanisms--for training grants, for 
construction.

                         shared instrumentation

    You will recall that we've had discussions here before 
about the amount of money we're able to spend on extramural 
construction or on shared instrumentation. Shared 
instrumentation is a very useful item to talk about, because, 
as you're aware, we cut back on our support for shared 
instrumentation. I, myself, believe that's one of the most 
potent ways we can advance science, especially at centers where 
equipment does get used by a large number of individuals. And 
that's one of the things that tends to get cut when the money 
is tight, because we're not funding an individual investigator; 
we're funding the purchase of equipment that services many 
different investigators. But when we have more money, we're 
liable to say we will support the shared instrumentation grants 
or other endeavors that benefit a group of investigators.

                       areas of special emphasis

    Mr. Porter. I thought I heard you earlier in the day refer 
to budgeting at various levels--in other words, I'm interested 
in at what point you do this.
    Obviously, you've worked out a budgeted 2.4 percent 
increase. Do you also have in place where you might go if the 
funding were at 4.8 percent or 5 percent or----
    Dr. Varmus. Yes, I do.
    Mr. Porter. It's all done in advance?
    Dr. Varmus. This year, in particular, I went through, in 
painstaking detail, with each institute director the kinds of 
projects they would identify as falling within areas of special 
emphasis, areas where they could foresee--as, for example, Dr 
Kupfer could see increased interest in glaucoma as a 
consequence of cloning the glaucoma gene this year. He would 
tell me that there were three or four areas which he would like 
to expand because of new, recent discoveries or because of some 
pressing scientific need or because of a resurgence of a 
disease.
    I have a list of initiatives that the institute directors 
would like to advance. As a result of our discussions, I have, 
by a semi-subjective and semi-informed process, developed my 
sense of what the most urgent items and the most productive 
items on that list are likely to be.
    And I, in order to sustain our commitments and also 
initiate some new endeavors, have tried to put together a 
budget that's fair to the various institutes, fair to our 
existing grantees, and still allow initiatives to be started 
for various budget levels, not knowing where the actual outcome 
will lie. So I have some sense of how much we'll be able to put 
into these new projects if we have various levels of support.
    Obviously, if we had this professional judgment budget, we 
would be able to support virtually all of the initiatives. If 
we have a more modest budget that is constrained by the 
budgetary issues we've agreed exist, we will support fewer of 
those or support them with less money than we might otherwise 
do.

                      royalties for drug products

    Mr. Porter. Dr. Varmus, we've been approached about a 
legislative provision that would extend five additional years 
of market exclusivity to unpatented drug products which are the 
subject of a CRADA with NIH. In return, the pharmaceutical 
companies would pay a royalty to NIH to enhance appropriated 
research funding. What is NIH's view of this proposal?
    Dr. Varmus. Well, we're willing to look at it, but I've 
only heard it described in the kind of detail you just 
provided. And until we see it in further detail, I would be 
hesitant to endorse it. We would be perfectly willing to work 
with whomever is proposing it and look at the details of the 
proposition.

                 government performance and results act

    Mr. Porter. Thank you.
    From Department documents, we understand that NIH has 
determined that it will need to ask OMB for permission to 
develop an alternative approach to the Government Performance 
and Results Act performance measures for its research 
activities. Understanding the difficulty of establishing 
performance measures for investigator-initiated basic research, 
what alternative measures are you considering? And what 
approaches to GPRA are the other Federal science agencies 
contemplating, if you know?
    Dr. Varmus. Yes. Well, I do know something about that.
    As you know, Neal Lane and I chair the Fundamental Science 
Committee of the National Science and Technology Council, and 
about two years ago, in preparation for the implementation of 
GPRA, we gave some thought to how the agencies that do 
fundamental science would be able to evaluate their programs in 
accord with GPRA.
    In thinking through this process on the behalf of NIH, we 
came to the conclusion that we could develop some quantitative 
measures for our activities in support of training and in 
support of facilities and other infrastructure, so we plan to 
do that, to develop a logarithm that will allow us to make some 
judgments about how we're doing in those areas.
    But, as you point out, with respect to fundamental research 
it is a good deal more difficult.
    There are a number of qualitative measures that we can 
imagine. We can imagine descriptions of specific scientific 
advances as a way of portraying what we do. We can talk about 
the impact of our science on industry, on the biotechnology and 
pharmaceutical industries. We can talk about how basic science 
has benefitted clinical practice. We can talk about the impact 
of our research on improved health, on the reduction of 
hospital days or on the development of procedures that have 
been shown to be effective in the treatment of various 
diseases.
    There is the possibility of some more quantitative 
measures. I, myself, find them rather unsatisfactory--for 
example, patent applications, citation indices, and other 
measures which I think are less instructive and less pertinent 
to what we do than actual descriptions of discovery.

                              managed care

    Mr. Porter. This morning you touched on this question. I 
have been concerned for a long time about the changes in our 
health care delivery system that are leaving our teaching 
hospitals without the resources that they need, because in many 
instances managed care plans simply bypass those kinds of 
facilities because of their higher cost.
    I'm also concerned as to what managed care organizations 
will do to contribute to the cost of biomedical research. I 
think you've had some discussion with representatives of the 
managed care industry recently about this. Can you fill us in, 
in a general way, on what you see?
    Dr. Varmus. Sure. We've met twice now with representatives 
of Kaiser Permanente, the Puget Sound Health Care Program, and 
several others.
    Mr. Porter. Did you initiate those meetings or did they?
    Dr. Varmus. Well, I guess we did at one level, but there 
were a couple of preliminary conversations, some of them 
initiated by Dr. David Nathan, who is the head of my clinical 
research panel. But I asked them then to come to NIH.
    But it was clear from our preliminary conversations that 
they were interested in having these conversations.
    As you know, the managed care industry includes a number of 
organizations that have been in existence for a long time, have 
a strong research record, receive NIH money, do interesting 
research, and have connections in many cases to academic health 
centers. And we see those connections strengthening.
    Managed care organizations have much to offer the NIH. They 
have large stable patient populations that are easy to track, 
and particularly useful from the perspective of epidemiology 
and health services or outcomes research, or for the conduct of 
clinical trials.
    I think there's a difference in overall program in that 
managed care organizations, for fairly obvious reasons, are 
less interested in the fundamental research than we might be, 
but we have many areas of shared interest.
    And it's to their advantage, I think, to form partnerships 
with us because they know that their staff appreciates the 
chance to participate in research, they recognize that there 
are benefits to the kinds of research we're describing for 
their planning and for benefitting patients who are enrolled.

              partnerships with managed care organizations

    One of the things that we recognize as a joint concern is 
how they make their contribution to research without being 
penalized in what is currently a fiercely-competitive market.
    Therefore, one of the players that needs to be brought into 
this discussion, but has not yet been brought in as actively as 
I would like be done--the employers who are the ultimate 
purchasers of these health care plans.
    If we were to persuade a managed health care provider to 
join with us and to provide some of the resources necessary to 
carry out more clinical research at our academic health 
centers, it would be necessary to pass on some of those costs 
to those who pay for the health care that's provided.
    We believe that the benefits accrue both to those who are 
in those health care plans and to the Nation at large, and that 
either by force of persuasion of the employers who pay for 
these plans, or perhaps by persuading Congress to help us in 
finding ways to achieve means to ensure that health care plans 
include some allocation for research, that we can achieve the 
benefits that I think are to be gained by the managed health 
care revolution.
    Mr. Porter. Let's say that Congress did that. Let's say 
Congress directed all managed care plans to allocate 1 or 2 
percent of their revenues to research. What effect would that 
have in directing research? And maybe you can talk generally 
about where we are in reference to basic research as opposed to 
research that tends to be more directed toward a specific end.
    Dr. Varmus. Well, I believe that money would be most 
appropriately spent largely on clinical activities, and I 
believe that because that is what the managed care 
organizations are going to be interested in, in part because a 
very significant part of the erosion of support of academic 
health centers has affected clinical research. Not all of it, 
because, as you know, patient care revenues that have 
traditionally gone to academic health centers have frequently 
gone into either a departmental fund or a dean's fund, which 
ends up supporting both basic and clinical research.
    So I want to emphasize that the loss of revenues has 
affected both basic and clinical activities. But I think the 
expectation would be that whatever is provided from the managed 
care industry would go largely to clinical activities.
    What I then imagine happening is that proposals that could 
be jointly funded by the NIH and by managed care would be 
supported through both avenues. I've not thought through in 
great detail exactly how that would be done, whether it would 
achieve the kind of partnership, we just discussed, with some 
of the voluntary organizations--for example, the Diabetes 
Foundation--or whether we would prefer to work with separate 
pots of money with managed care industry picking up some 
proposals and us picking up others.

                         research partnerships

    Mr. Porter. It seems to me that we are--Dr. Kupfer referred 
to this--we are increasingly looking for partnering in one way 
or another with foundations or even with industry, and that at 
some point we end up with a great deal of research that is 
directed to specific ends and less perhaps resources than we 
ought to have on basic research.
    Is that possible?
    Dr. Varmus. I wouldn't jump to that conclusion, Mr. Porter.
    Mr. Porter. Good.
    Dr. Varmus. Because if you look at the research in basic 
sciences these days and look at the acknowledgements in 
research papers, as I frequently do as someone, of course, 
looking for acknowledgement that NIH helped to support the 
research, what you find almost inevitably is support from a 
variety of institutions.
    In fact, since it's frequently the case that NIH is the 
major supporter, it sometimes seems to me that the attribution 
to NIH is somewhat buried among a long list of foundations and 
other organizations that have provided support for post-
doctoral training and for fairly modest amounts of money, but 
we all have supported the research.
    So virtually everything that's done these days is a 
partnership, and the question is whether you allow those 
partnerships to be brokered independently by the investigator 
who has gone out to six places to get the money, or whether the 
investigator can go to one place and get support for a project 
from two organizations at the same time, as we do in the case 
of some of the projects co-supported by the Juvenile Diabetes 
Foundation and certain institutes at NIH.
    Mr. Porter. Dr. Varmus, thank you for your patience and for 
your very candid and direct answers to all of our questions.
    We will now stand in recess until 10:00 a.m. tomorrow.
    Dr. Varmus. Thank you very much. I appreciate your 
interest.
    [The following questions were submitted to be answered for 
the record.]

[Pages 446 - 494--The official Committee record contains additional material here.]


                                       Thursday, February 27, 1997.

                NATIONAL HUMAN GENOME RESEARCH INSTITUTE

                               WITNESSES

FRANCIS S. COLLINS, M.D., Ph.D., DIRECTOR, NATIONAL HUMAN GENOME 
    RESEARCH INSTITUTE
ELKE JORDAN, Ph.D., DEPUTY DIRECTOR
KATHY HUDSON, Ph.D., ASSISTANT DIRECTOR FOR POLICY COORDINATION
JAMES C. VENNETTI, EXECUTIVE OFFICER
ERIN S. BURGESS, BUDGET OFFICER
HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH
DENNIS WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF 
    HEALTH AND HUMAN SERVICES

    Mr. Porter. The subcommittee will come to order.
    We begin our hearings this morning with the National Human 
Genome Research Institute and Dr. Francis Collins. Dr. Collins, 
welcome. Nice to have you here as an institute now. Why don't 
you introduce the people who are with you and then proceed?

                       Introduction of Witnesses

    Dr. Collins. Thank you very much, Mr. Porter.
    Sitting at the table, beginning at my left, Mr. James C. 
Vennetti, who's the Executive Officer; Dr. Kathy Hudson, who is 
the Assistant Director for Policy Coordination; Ms. Erin 
Burgess, Budget Officer; Dr. Elke Jordan, the Deputy Director; 
Dr. Harold Varmus you are familiar with, and Mr. Dennis 
Williams from the Department.

                           Opening Statements

    It is indeed an honor to testify for the fourth time in 
front of this committee, but the first time as the Director of 
the National Human Genome Research Institute. I have to keep 
thinking before I say those words, or I tend to get them wrong.
    In reality, the former NCHGR, the National Center for Human 
Genome Research, is now the NIH's newest research Institute. On 
January 14, after consultation with you and other Congressional 
leaders, Secretary Shalala signed documents that gave the 
National Center for Human Genome Research a new name and new 
status. We are proud the NCHGR has been recognized for its 
successful leadership of the Human Genome Project, the 
accomplishments of its cutting-edge intramural laboratories, 
and its active policy research programs. As an Institute, NHGRI 
looks ahead to completing the Human Genome Project and to 
playing a leading role in 21st century health science based on 
understanding the instructions encoded in our DNA.
    In my statement, I could enumerate milestones and 
accomplishments of this grand adventure called the Human Genome 
Project over the last year and project some of the future ones, 
and don't worry, I will. But I also thought it would be 
appropriate to put this into the context of human health. 
Because as a physician, clearly my excitement about this 
project is what it will do to benefit human beings, to 
alleviate suffering, and to avoid illnesses which currently 
plague so many.

                            prostate cancer

    So I would like to tell the committee about an individual 
named Robert. Robert is currently 64 years old. At the age of 
54, he was diagnosed with prostate cancer. This was for him in 
some ways a surprise, and in other ways not. Both his father 
and his paternal uncle had previously been diagnosed with 
prostate cancer and they had both died of it. So finding his 
own diagnosis at age 54 was perhaps less surprising than it 
would have been to others, although certainly a very young age 
to have that diagnosis.
    Now, Robert was treated at the Johns Hopkins University 
surgically and is currently doing well some 10 years later. 
However, his son was recently diagnosed at the age of 42 with 
prostate cancer.
    Families of this sort are not rare, although they are 
uncommon. In a collaborative effort between Johns Hopkins and 
the National Human Genome Research Institute, an intense effort 
was made to try to figure out what is at the basis of this 
inherited predisposition to prostate cancer. There had been 
indirect evidence for three or four years, based on studies of 
large families, that there was something going on in the way of 
a hereditary factor.
    Last November, we published in the journal Science that in 
fact there is a specific gene on chromosome 1 named HPC-1, for 
hereditary prostate cancer gene number 1, which if misspelled, 
or mutated, carries an estimated 80 percent likelihood of 
conferring prostate cancer on an individual by age 80. And the 
age of onset for such individuals is skewed towards a 
considerably earlier age than the general risk of prostate 
cancer.
    Now, prostate cancer is a terribly common disorder. Three 
hundred and forty thousand men will be diagnosed with that 
disease this year and more than 40,000 will die from it. It is 
this early onset type that is particularly of concern. It is 
estimated that some quarter of a million men have mutations in 
this gene called HPC-1, and that identifying those individuals 
might potentially be of great value by warning them of their 
high risk.
    Now, let me hasten to say, we have not yet identified the 
precise gene involved. We know its neighborhood. We know the 
company that it keeps. And an intense effort is underway now to 
identify the gene itself.
    This same strategy that mapped this gene in Robert's family 
was applied this past year to also map a gene for Parkinson's 
disease in a large Italian family to chromosome 4. A great 
advance, I think, in terms of understanding a disorder which 
has been very frustrating and puzzling. And up until recently, 
there had not been much evidence that genes played a role. And 
now it's very clear that at least in that family, they do.

                       inherited disease research

    Similar advances have been made in mapping genes for 
diabetes and multiple sclerosis. And in fact, in collaboration 
with the Johns Hopkins University, the NIH has now set up a 
Center for Inherited Disease Research with the National Human 
Genome Research Institute acting as the lead agency within NIH 
to facilitate this kind of mapping of genes for complex 
disorders. The NIH recognized that this is at the forefront of 
what we need to accomplish, and that many investigators don't 
have the technology in their own local institutions to do this, 
but would like to be able to. And we're looking forward to this 
being a very important addition to NIH's powerful set of tools 
to further the business of identifying genes that contribute to 
disease.
    I might also say, we have a new initiative within NHGRI 
partnering up with Howard University and with the Office of 
Research on Minority Health to specifically look at the genetic 
underpinnings of diabetes and prostate cancer in African-
Americans. Requests for proposals have been issued for both of 
those and one of those studies on diabetes is now getting 
underway. And I have personally been very pleased to play a 
role in getting those efforts underway, given that those are 
both disorders which disproportionately affect African-
Americans. And clearly, there may be genetic causes for that.

                           finding the genes

    In order to take the situation that Robert's family is now 
in, where we know the general neighborhood of a prostate cancer 
gene, and go to the gene itself, one needs the next step. And 
here is where the Human Genome Project's tools, which are 
already available, and happily you didn't have to wait until 
the project was done, have played a major role. So the area 
around HPC-1, which normally would have taken a matter of a 
couple of years to develop a map of, already has a very 
detailed map, because the Human Genome Project has now mapped 
96 percent of the human chromosomes to a level of specificity 
that we thought would take us until 1998.
    Furthermore, once you have the neighborhood, you not only 
want to know where the milestones are, you want to know where 
the genes are. Because each one of those genes is a potential 
candidate for a gene that's involved in prostate cancer.
    A major step forward occurred last October with the 
publication in Science magazine of the first gene map of human 
DNA. Associated with the article is a very useful Web site with 
16,334 of the estimated 80,000 genes placed in rather precise 
intervals on human chromosomes. So that for the gene hunter, 
there was about a 20 percent chance, as of last October, that 
the gene you're looking for has already been placed in the spot 
you're searching, and that saves you a huge amount of time.
    I think positional cloning, this business of finding genes 
that are responsible for disease, continues to accelerate as a 
consequence of this. Last year some 21 disease genes were 
identified, the best year yet. And I think that number will 
continue to grow in a very gratifying way.

                         complete dna sequence

    But the sequence, all of the DNA, is what we now really 
want. And of course, that is the ultimate goal of the Human 
Genome Project. And I'd like to tell you also that this is 
coming along quite well. This past year saw the completion of 
the complete DNA sequence of yeast, and the completion about a 
month ago of E coli, the bacterial organism which has served as 
the work horse for a very large amount of microbiology research 
over the course of many decades. That particular sequence was 
accomplished by a grantee of the Human Genome Project, is 
already in high demand, and is available on the public data 
base run by the National Library of Medicine.
    Our partnership with the National Library of Medicine in 
all of these databases, including the World Wide Web page I 
cited a moment ago, has been critical to the availability of 
this genomic information. NLM is also, I think very 
appropriately, being sensitive to the possibility of using 
these databases as educational tools. The gene map Web page 
that I mentioned had 500,000 hits on it in the first two 
months. And the estimates are that more than half of those were 
from high school students who were looking to learn something 
about human genetics. And this Web page is set up in a fashion 
that makes it very accessible to them, and a very useful 
educational tool.
    I might add, as the DNA sequencing is now ramping up, and 
we have initiated six pilot projects around the country, which 
by the end of next year should have produced something like 100 
million base pairs of sequence. A great deal of enthusiasm is 
coming forward for this effort from private industry. For 
instance, I was gratified to see that the CEOs of the 
biotechnology industry organization last year chose the maps 
from the Human Genome Project as the thing that they most 
wanted to celebrate as having done the most for their industry, 
an unusual step, because they usually choose some more defined 
effort that's come from a particular company.

                       beyond the first sequence

    Furthermore, we are very much now in the process of 
thinking about what shall we do when this sequence is in hand 
in 2005, or maybe if all goes well, a little sooner than that. 
Many people have compared the determination of the human genome 
sequence as something analogous to deriving the periodic table 
of the elements for chemistry. The periodic table for biology 
might have 80,000 entries, one for each of the human genes, 
instead of the 100 or so elements of the chemical table.
    But the parallel is a useful one to consider, because it 
sort of puts into context what a table of genes does for you. 
It provides you with that basic chart of the elements of the 
human organism, and then a great deal of exciting activity can 
follow in terms of figuring out how these genes talk to each 
other, interact to make a cell or a tissue or a whole organism.

                 ethical, legal and social implications

    So back to Robert. I have tried to sort of outline here 
briefly some of the accomplishments of the last year. What 
about Robert? Well, Robert has another son. I told you he has 
one who has been diagnosed with prostate cancer at 42. He also 
has another son who's just turned 40. And of course, that 
individual is anxious, as is Robert, about the future. I think 
it's fairly likely that in the course of the next year or two, 
the HPC-1 gene will be found and Robert's son will have the 
chance, if he desires to know the information, to learn whether 
he is at similarly high risk or not. And he might not be, of 
course, the transmission of this disease is not 100 percent. 
It's probably in the neighborhood of 50 percent that this son 
would have the same risk as his father.
    But of course that then raises the question, is that a good 
piece of information to know? And this again raises all of the 
ethical, legal and social issues which come out of genome 
research. I ran across a quote recently from Winston Churchill, 
which I'm fond of, because I think some people have argued that 
the ethical considerations are so severe that we should really 
slow down this research. And I completely disagree with that 
logic, because I think this research holds within it the 
promise of curing so many human ills. Churchill said: ``My 
faith is in the high progressive destiny of man. I do not 
believe we are to be flung back into abysmal darkness by those 
fearsome discoveries which human genius has made. Let us make 
sure that they are our servants, but not our masters.''
    Well, our effort to make sure these discoveries are our 
servants, not our masters, is the ethical, legal and social 
implications program, the ELSI program of the Human Genome 
Project. And in the past year, a number of important things 
have happened. The Task Force on Genetic Testing, which has 
been meeting for almost two years, has produced its principles 
and very recently published in the Federal Register a set of 
implementation recommendations, which are being submitted for 
public comment. These recommendations involve a number of new 
initiatives to look at the issue of testing, to make sure that 
it's done accurately, that the results can be trusted, and also 
that there is some oversight about when a test is ready to 
leave research and move into clinical practice.
    In the area of health insurance discrimination, I think we 
all should celebrate the Kassebaum-Kennedy bill, which does on 
its list of issues which health insurers should not use to take 
away coverage or to set exorbitant premiums, list genetic 
information. Just the same, there are areas that are not 
covered by that legislation, particularly for individual policy 
holders. And we are very interested in providing information to 
the degree that we can to assist the process of closing those 
loopholes.
    In the area of employment discrimination, there is some 
optimism that employers would not be at the present time able 
to use genetic information to discriminate. And I think that is 
something to be hoped for, because clearly, your DNA is not 
something you get to choose. And to have your DNA used to deny 
you a job seems inherently unfair. But to really prevent that, 
a legislative approach is needed. And we held a conference last 
October, out of which came a series of very specific guidelines 
which have been submitted for publication, which we hope will 
be looked at. That was a conference organized by the National 
Action Plan on Breast Cancer in collaboration with the ELSI 
working group, and I think produced a very useful document.
    Finally, the area of education, particularly of health 
professionals, continues to be one that we have enormous 
interest in catalyzing. Increasingly, individuals are going to 
their doctors with the latest copy of Time or Newsweek, saying, 
does this refer to me? Should I have this test for breast 
cancer? And soon it will be questions about testing for 
prostate cancer. And most physicians are not well prepared to 
answer those questions.
    In collaboration with the American Medical Association and 
the American Nursing Association, a coalition for health 
professional education in genetics has been started, and will 
have its first full meeting in about 10 days. We're very 
optimistic that that will be an effective way to pull together 
a whole host of primary care provider disciplines, allowing 
them to work together to achieve better literacy for health 
care professionals and genetics on a short turnaround.
    So Mr. Chairman, even without this week's revelations about 
Dolly, we live in exciting times. The Human Genome Project is 
proud to be at the center of a revolution in biomedical 
research. The promise for better health that the Human Genome 
Project provides is beginning to be realized in some quarters, 
although most of that promise lies ahead, and most of what I've 
been talking about are more in the area of inspirations than 
culminations.
    But I'm glad once again to be able to tell you that we are 
ahead of schedule and under budget. The request for the 
National Human Genome Research Institute is $202,197,000. And 
I'd be happy to answer your questions.
    [The prepared statement follows:]

[Pages 501 - 504--The official Committee record contains additional material here.]


               finding the gene--the end of the beginning

    Mr. Porter. Dr. Collins, thank you for that wonderful 
statement.
    The average person reading the newspaper and let's say they 
read about HPC-1 and that you've found it, probably thinks to 
themselves, we now can cure or prevent prostate cancer. And I 
wonder if you could carry the concept of finding HPC-1 further 
and tell us what is required or may be required to get to the 
actual point of being able to change the gene or to cure the 
disease from what you have found.
    Dr. Collins. Thank you for the question. I think there is a 
great concern that many of us have that media reports of gene 
discoveries may sound like cures for disease, when in fact it 
is only a step down that path. Finding the gene is sort of the 
end of the beginning. Without the gene in hand, one is often 
really feeling in the dark, to try to understand the disorder.
    So for HPC-1, when the gene is identified, hopefully in a 
year or two, it will almost immediately, if it seems to be a 
good thing, allow the possibility of diagnostic testing to 
identify the men at highest risk. And that kind of testing 
would not ordinarily be done except for individuals with a 
strong family history of the disease, because applying it 
across the board might pick up many false positives. Basically, 
finding the HPC-1 gene would put prostate cancer in the 
circumstance where breast cancer is now, with BRCA-1 and BRCA-2 
being a few years ahead of HPC-1.
    That testing alone for prostate cancer could be quite a 
valuable advance. This is a disease where early detection is 
the mainstay of cure. And we have a blood test, the PSA test, 
which detects early evidence of tumors. But it's almost too 
sensitive, in that it finds things that you're not quite sure 
what to do about. If you could combine that test with a genetic 
susceptibility test, you might have a more valuable predictor 
about who really needs an intervention.
    But I will not be satisfied, nor should anybody else be, by 
simply having the ability to do diagnosis. The discovery of the 
gene should tell us something fundamental about how is it that 
a prostate epithelial cell becomes malignant. That same gene, 
one would expect, may turn out to be involved in the more 
common variety of sporadic prostate cancers. One can't be sure 
until you get there, but that's a likely outcome. That's 
certainly been the case for many other cancers.
    Learning about how that gene functions, what its biological 
niche is, should provide new insights into therapies. And 
that's where you really want to go, and I think that's the 
nature of your question. Those therapies might come in the form 
of a gene therapy, although that is probably going to be quite 
difficult for an organ like the prostate, and especially if it 
turns out that this is one of those genes where if you don't 
correct it in every single cell, the cells you miss will go on 
and form the cancer anyway.
    On the other hand, understanding how the gene works might 
give you much better ideas about drug therapy, as protease 
inhibitors have arisen out of understanding the HIV genome. 
That sort of designer drug pathway is a very appealing one. But 
it is a pathway whose timetable can never be predicted.
    And so I can tell you these views of what's coming in the 
future, but the one thing I can't tell you is how many years 
between where we are now and where we really want to be. And 
anybody who sort of tries to make those predictions I think is 
speaking beyond the information that they have. There are so 
many things that are unpredictable about this. But it is the 
way to get there. And we're on the road.

                            budget increase

    Mr. Porter. You said, and we applaud the fact that you are 
ahead of schedule and under budget. That's the best news that 
appropriators can hear.
    How would you respond to a question that said, well, if 
you're under budget and if NIH as a whole is only getting a 2.6 
percent increase, why is your Institute scheduled for an 8.3 
percent increase?
    Dr. Collins. One of the reasons I guess is that ramp-up of 
the Human Genome Project to full funding has never quite been 
achieved. And I understand the reasons for that. Starting a new 
program at a time of fiscal restraint has been quite a 
challenge. I think the Congress has been very generous in their 
enthusiasm for this project in appropriating what has come our 
way so far. And we understand those restraints.
    I do think that we are now in a circumstance, having 
succeeded at the mapping phases for the most part of this 
project and now beginning to ramp up the sequencing component, 
where we in many ways are significantly budget limited. We know 
what to do, we know pretty much how to do it. How soon we get 
there will be a function of how much budget we have available. 
We could go faster at this point, in fact, if it were possible 
for the budget to ramp up more than it has.
    In the current proposal, in the President's budget, I think 
we have done well on the basis of the NIH initiatives. Some $14 
million, which is almost all of our increase, comes out of 
those specific initiatives, particularly in the area of genetic 
medicine, which Dr. Varmus and the rest of the NIH leadership 
have identified as being the highest priorities for payoff in 
fiscal year 1998.
    So I think the answer to the question would be, if we're 
going to basically deliver the products that the Congress 
wants, that the public seems to want, we could actually do 
better if this budget continues to ramp up. If we're truncated, 
we can continue to sort of do what we've been doing. But it 
will take us longer to get there.
    Another part of this is we are beginning to spend a small 
fraction of our effort looking at what happens after the human 
genome sequence is done. It would be very unfortunate to sort 
of get there and then realize we should have been planning for 
the next step. So we are doing that planning, and we've issued 
a couple of requests for applications this year for people to 
begin to look at whole genome technology and for developing a 
``genome attitude'' towards biology on a larger scale. And I 
think that's a very important part, but a small one at the 
present time, of our portfolio.

                    finishing faster--finding a cure

    Mr. Porter. Is the real answer then that there is a 
certainty that more money will get more results with respect to 
the mapping project, and that therefore, the likelihood of 
bringing real progress to prevention and curing of disease is 
more likely with the money spent at a higher rate earlier than 
in other places?
    Dr. Collins. You could argue that every year that goes by 
that we don't have the complete human genome sequence we are 
missing out on opportunities to cure disease. You could 
certainly argue that every year that goes by, people are 
wasting a lot of money getting bits of sequence that wasn't 
already available for them. And people have tried to add up 
what that amounts to, and especially if you include the private 
sector, that may be as much as a half a billion dollars every 
year that's spent on activities that won't be necessary when 
the Human Genome Project is done.

                   cloning--scientific opportunities

    Mr. Porter. Dr. Collins, you were present yesterday when 
Dr. Varmus addressed the Dolly question.
    Dr. Collins. Yes.
    Mr. Porter. I wonder if you would like to expand on that 
answer, or add your own viewpoint to it, and see what you think 
about cloning.
    Dr. Collins. Sure. When I came to this job as Director of 
the National Center for Human Genome Research, which is what we 
were called then, I did so with some trepidation. But after I 
had been here a year or so, it occurred to me that many of the 
aspects of my own training had actually prepared me pretty well 
for this position in terms of having a background in physical 
science, being a physician trained in genetics. Only this week 
did I realize another part of my background was appropriate, 
and that is that I grew up on a sheep farm. [Laughter.]
    So from that particular context, and mindful of Mark 
Twain's remarks: ``There is something fascinating about 
science. One gets such wholesale returns of conjecture out of 
such a trifling investment of facts.'' That seems to be 
happening rather broadly this week in the press.
    Nonetheless, I think what was reported and I guess is being 
reported in Nature today, but has already been talked about 
very broadly, is a fundamentally exciting scientific 
achievement. And I completely agree with Dr. Varmus' analysis 
of some of the scientific opportunities that this offers in 
terms of understanding development.
    For me as a geneticist, this notion that the DNA sequence 
of a differentiated cell could be convinced to sort of go back 
and start over again as a fully undifferentiated embryonic 
state is remarkable. I think most of us would not have guessed 
that would happen. It sort of says that the whole array of 
genes are like an orchestra, and in a particular cell maybe 
only some parts of the orchestra are playing. But the whole 
orchestra is there. And if you can figure out how to sort of 
shut off the playing for a little while and then start it back 
up again, you can get the whole orchestra to perform. And that 
is fundamentally really interesting. I think the possibilities, 
some of which Harold mentioned yesterday, about being able to 
use this kind of de-differentiating process medically are very 
intriguing ones. I would also say that in terms of the ethical 
issues, we should make it very clear that the use of this 
technology to clone human beings is unacceptable. Repugnant is 
the word that Dr. Varmus used yesterday and I agree with that.
    On the other hand, to rush in and criminalize a certain 
aspect of scientific research without careful thought would be 
unfortunate. And I applaud the President's decision to involve 
the National Bioethics Advisory Commission, a group that I 
think is very well positioned to look at this issue over the 
next 90 days and come back with some observations about 
possible options of what might be done.
    So I think although in many instances, when you have a 
media event around science, you worry a little bit that it's 
going to scare the public off. This observation has engaged the 
public in conversations that we might not otherwise have had. 
And I think the reverberations of this observation, provided it 
can be duplicated, of course, we will all be interested to see 
the first confirmation of this report. But provided that is so, 
I think something has really changed in science, in the way we 
view biology. And that is something to be welcomed.
    Mr. Porter. So you're expressing some scientific skepticism 
that this is actually good science, or you want to at least 
have it proved that it can be done repetitively?
    Dr. Collins. I think any new observation that is as 
fundamentally revolutionary and unexpected as this ought to be 
confirmed by another investigator. I have read the paper 
reporting this. It looks very solid. I don't see anything wrong 
with it. It seems quite well founded, and I suspect it will be 
possible to reproduce. Although it is clear that this was a 
very difficult thing to do with only 1 lamb actually being born 
out of almost 300 that were attempted. So there must be some 
enormous inefficiency in the process.
    One of the things I'll be very interested in is to see 
whether Dolly ages prematurely. There is a history of arguments 
about the molecular basis of aging and is it in fact something 
that is acquired as a cell divides over and over again and 
acquires mistakes in the DNA? Is that what eventually causes 
the process to run down and the cell to die?
    Now, Dolly's single original cell, typically in the one 
cell stage, had already gone through six years of life. Is it 
going to be the case, therefore, that her longevity is 
affected? That will be a very interesting thing to follow.
    Mr. Porter. With your background on a sheep farm, maybe 
this is where you can----
    Dr. Collins. Go back to my roots here. [Laughter.]
    Mr. Porter [continuing.] Add something to the research.
    Mrs. Lowey.

                     genetic testing--breast cancer

    Mrs. Lowey. Thank you, Mr. Chairman.
    And thank you, Dr. Collins. The possibilities of the work 
of your institute are certainly overwhelming. And it is 
certainly a privilege for us to play some small role in helping 
advance the important research you're doing, and I want to 
thank you.
    And I look forward to working with you on the whole area of 
employment discrimination, and I am delighted that those 
findings will be published. As you know, I have been working on 
that whole issue, and I'm looking forward to your presentations 
on the legislative remedies.
    Because I have to participate in another hearing 
immediately, I just want to, and I know what we'll be 
discussing the areas of employment discrimination with regard 
to genetic testing, etc., I would like to just ask you, since 
we gathered last and you reported to us on your BRCA-1 and 
BRCA-2 findings, have there been any additional findings in 
that regard, any other additional research that you'd like to 
share with us?
    Dr. Collins. I appreciate the question, and I very much 
appreciate your leadership in the area of genetic 
discrimination and legislative initiatives to do something 
about that. I appreciate what you're doing about employment 
this year. I think the opportunities are quite good to solve 
this problem at the Federal level.
    BRCA-1 and 2 research is in sort of an incredible flurry of 
activity, now that the genes have been in hand for a year or 
two, some of the best labs in the country have turned their 
attention to trying to figure out what they do. Mouse models 
have been made for both of those, where the BRCA-1 and BRACA-2 
genes have been knocked out to see what happens. At the present 
time, it's not clear that the mouse models show the same risk 
of cancer, at least not in the first few months. But still, 
those models are likely to be quite useful in understanding the 
mechanisms and how these genes contribute to cancer of the 
breast and ovary.
    In terms of understanding how the protein products of these 
genes work, there have been at least two, and one hears rumors 
of a third, experiments that show other proteins in the cell 
that interact with the BRCA-1 protein and therefore probably 
work together with it to do whatever its normal function is. 
And that is one of those clues that starts you into a pathway 
which might be very useful in understanding how these genes do 
their work and how they don't succeed when they need to in 
somebody who has an alteration.
    In terms of understanding the clinical consequences of 
alterations in this gene, the Washington Area Ashkenazi Jewish 
study has now been going on for a year, and the results of that 
study have been submitted for publication. I'm not at liberty 
to describe them. But this particular study looked at 5,300 men 
and women, collected their family history and obtained a blood 
sample to find out whether or not they are carrying one of 
these genetic alterations. One in 40 of those individuals was 
carrying a mutation in either BRCA-1 or BRCA-2, about the 
expected number, based on previous studies.
    And obviously, the main payoff that we are waiting for from 
that study is to find out what really is the risk to such an 
individual? Is it as high as the 85 percent that has been 
proposed in other studies? This study I think gives a better 
window on that, because it's less likely to be a biased 
estimate, and hopefully those results will come forward very 
soon.
    Mrs. Lowey. I appreciate that. Because I believe you shared 
with us two facts, among many other facts, but number one, it's 
still a very small percent of the cancers.
    Dr. Collins. Yes.
    Mrs. Lowey. And number two, or perhaps I should ask you 
this in the form of a question, when you're saying 1 in 40, are 
you determining at what age that cancer appears, so after a 
certain age, the incidence of cancer increases in every 
population?
    Dr. Collins. Sure.
    Mrs. Lowey. So that if you're identifying that gene to be 1 
in 40, you're not making determinations at this point whether 
that person will get that cancer at the age of 40, 50, 70 or 
80. Or are you?
    Dr. Collins. I may not have been completely clear. The 1 in 
40 is the frequency of finding an alteration in BRCA-1 or 2 in 
a Jewish individual, regardless of their cancer history. What 
the study is trying to determine for those individuals who do 
have those alterations, what is their likelihood of getting 
cancer and at what age. Is it an early age of onset, which some 
of the other studies have suggested, and if so, by how much. We 
don't have the answer, but in the coming months, that should 
come forward.

                genetic testing--counseling and control

    Mrs. Lowey. And has there been any progress made on 
counseling and control of these tests? Because many of us are 
concerned, and we talked about that last year, about the 
commercialization of these tests and what goes with it, and 
what kind of consistency is there in the counseling with those 
tests.
    Dr. Collins. Well, there are a number of answers to that 
question, certainly a number of centers are looking at 
counseling, trying to figure out what is an effective way to 
deliver these services. There is a Cancer Genetics Studies 
Consortium which is funded jointly by the National Human Genome 
Research Institute, the National Cancer Institute, the National 
Institute for Nursing Research and the National Institute of 
Mental Health that has banded together about 11 researchers to 
share their experiences doing genetic counseling for both 
breast cancer and colon cancer. And a lot of useful information 
has come out of that consortium with at least four publications 
in prominent journals to guide the rest of the world in terms 
of how to present this information so that it is absorbed and 
understood and put into practice.
    The other thing you're referring to, though, is really sort 
of the marketing of the tests themselves. There has been, since 
we last met in this room, the marketing announcement of a 
company in Utah of a test for BRCA-1 and 2. It cost $2,400 to 
have a particular sample analyzed to see if there is a mutation 
present. And it is available to individuals outside of research 
protocols, which up until fairly recently was where most of 
this testing was being done.
    So that's raising questions about whether this is premature 
or not. Various statements have been made on that topic, and 
they don't all agree with each other. The National Action Plan 
on Breast Cancer has a published statement saying that it's 
unfortunate to have such testing done outside of research 
protocols when we're not sure yet what the clinical utility is.
    But at present, there is no Federal oversight to prevent 
that. The Task Force on Genetic Testing, which I mentioned in 
my opening statement, has very much been looking at this issue. 
And they have actually made the recommendation that the 
Secretary of Health and Human Services establish an Advisory 
Council on Genetics and Public Policy to review such tests and 
to make such judgments about whether or not they are 
appropriate for taking up a role as part of general clinical 
medicine. It will be very interesting to see how that's 
received.
    Mrs. Lowey. Well, thank you, and I look forward to continue 
working with you in this area. And I thank you, Mr. Chairman. 
And I do apologize.
    Dr. Collins. Thank you, Mrs. Lowey.
    Mr. Porter. Thank you, Mrs. Lowey.
    Mr. Miller.

                   cloning--international cooperation

    Mr. Miller. Thank you, Mr. Chairman.
    Dr. Collins, I always look forward to your presentation, 
you're so excited about it. A couple of questions. The Dolly 
question. Were you caught off guard by that? Was that 
unexpected, or is that type of research being done here in the 
United States?
    Dr. Collins. I was totally caught off guard. This was a 
result that I think was not expected to succeed. There were 
preliminary experiments by the same group published a year or 
so ago, where they were able to take sheep embryo cells and 
take out the nucleus and then put it back into an oocyte and 
produce a lamb. But that was less surprising. An embryo cell is 
sort of programmed to be an embryo cell. The idea that you 
could take a mammary epithelial cell from the udder of a sheep 
and convince it to behave that way, that is the profoundly 
surprising part of this. And I think most people would not have 
expected that to work.
    Clearly, the group that did this work kept it very tightly 
under wraps. A strong effort was made not to have this leak out 
prematurely. So no rumors had been circulating.
    This kind of research is certainly done in this country, 
although it is in sort of the animal husbandry area, which is a 
separate discipline from the folks that are looking at, say, 
mouse models of human disease using molecular biology. But it 
has certainly electrified the community. You cannot walk down 
the hallways of a research building in any university in this 
country, I don't think, without being engaged in a conversation 
about Dolly this week.
    Mr. Miller. Was that in an animal husbandry department?
    Dr. Collins. It's animal science, I guess, it's in an 
institute in Scotland which is privately funded, and involves a 
biotechnology company as well.
    Mr. Miller. Is that an embarrassment, to have this--
[Laughter.]
    Dr. Collins. Oh, I can't be embarrassed. I guess as a 
scientist, I've always been sort of a fan of the notion that 
science is an international activity. Certainly the Human 
Genome Project is. And we tend to celebrate exciting advances 
wherever they come from.

                      future health care delivery

    Mr. Miller. When I get a chance to speak to young people, 
one thing I say is, there are two areas that are so exciting, 
what the future holds. And it's hard to comprehend what it's 
going to hold. One is the whole area of telecommunications and 
computers, which is mind-boggling how far we've come in the 
past 10 years. I'm not sure where we're going.
    But the other area is the area you're in. And it's hard to 
comprehend what medicine is going to be like. I was speaking to 
a group, I was even relating that to a group of employees at a 
hospital last week, health care delivery is going to be very 
different 10, 20 years from now. How could you describe the 
potential of the way health care is being delivered 10 years 
from now? We're on the verge of so much that's happening. 
People will still grow old, parts will wear out, but the ideas 
of cancer and all that, how could you describe what a health 
care delivery system will be like 10 years from now?
    Dr. Collins. I'll give it a shot. As my old professor of 
medicine kept reminding me, the death rate will still be one 
per person. [Laughter.]
    We have to have realistic expectations, but I do think 
there will be stunning advances in the next 20 or 30 years in 
understanding the basis of the common diseases that so 
frequently cut people down prematurely, things like cancer and 
diabetes, hypertension, schizophrenia. This very long list of 
disorders which we currently can describe the symptoms of and 
often treat the symptoms of, but whose underpinnings have not 
really made themselves known.
    Obviously, as the geneticist, I will tell you that a 
significant route to getting to those underpinnings will be our 
understanding of the genetic contribution to those disorders. 
We all are walking around, it's estimated, with 5 to 20 genes 
that are misspelled and that are sort of lurking there, waiting 
to potentially cause us trouble. You may have a different set 
than I do, but we all have some. There are no perfect genetic 
specimens, not even in these hallowed halls of the Congress, 
I'm afraid.
    So the possibility of uncovering those misspellings becomes 
quite real over the course of the next 10 or 15 years, with the 
Human Genome Project producing all of these tools. And with 
that will come the ability to make individualized predictions 
about risk.
    Now, if I knew I was at risk for colon cancer more than the 
average person, that would be something I'd like to find out 
about, as long as I was sure it wasn't going to be the end of 
my health insurance, because I know that colon cancer can be 
cured if it's detected early, while it's still a small, benign 
polyp. So you will see, in I would say the next 10 years, you 
wouldn't have to wait longer than that, the emergence of 
individualized programs of preventive medicine based on this 
kind of genetic susceptibility testing, to allow people to 
design programs for themselves, focused on staying well.
    And not just one size fits all, everybody should do the 
same thing, which is what we often do, but individualized 
programs based on your own susceptibility. Obviously, that 
depends on the kind of testing. It has to be voluntary, and I 
would hasten to say this is the sort of thing that some people 
maybe won't want to know, and shouldn't have to know. But I 
suspect for disorders where interventions are available, a lot 
of people will be interested.
    Now, the therapeutic side of medicine is also going to be 
going through remarkable changes in the next 20 or 30 years. 
Whether those come from gene therapy, a field which is still in 
its infancy and therefore it's hard to tell what kind of kid 
it's going to be when it grows up, or comes from drug therapies 
that are really designed to target the precise problem. We were 
talking about therapies for HPC-1 a minute ago, I'm not sure 
which therapy will develop and I don't care, as long as it 
works. And I think there's a good likelihood that you will see 
many of those things, not tomorrow, not next year, but in the 
next 20 or 30 years.
    Furthermore, medicine will probably become very much 
influenced by the computer revolution that you mentioned. 
Things like telemedicine will become much more familiar parts 
of everyday medical care. I think that's good. I think we have 
to be cautious about how we oversee that, so that we don't lose 
the human touch. As a physician, I will argue very strongly 
that a very important part of medicine is that human touch. And 
if everything we do ends up being robotized, we've lost 
something really important and we should resist that.

                        designer drug strategies

    Mr. Miller. You mentioned, one area that you mentioned is 
protease and how the Genome Project had a relationship to that. 
I see Dr. Fauci is coming up next right behind you.
    Dr. Collins. Yes, he might disagree with that. [Laughter.]
    Mr. Miller. But what areas have we already seen a 
relationship to bring out that's available, the relationship 
for example of protease? What areas are we farthest along as 
far as providing treatments available on diseases? Is protease 
a good illustration of that?
    Dr. Collins. I used it as an example of a designer drug 
strategy, whereby understanding the genome of HIV, and that was 
not the Human Genome Project, but that was AIDS researchers 
working very hard to try to understand this very frustrating, 
difficult virus, learning that it did make this particular 
enzyme, this protease, and then figuring out what kind of small 
molecule could be designed to effect that activity. Then you 
see this revolution that seems to be happening over the course 
of the last year, where potentially the course of the illness 
has been significantly altered. And I'm sure Dr. Fauci will 
talk more about that. That's the model, the designer drug 
strategy.
    Another example that I guess I would give is in the area of 
cholesterol management. We have learned a lot about why it is 
that some individuals have early heart attacks by understanding 
this disease called familial hypercholesterolemia, which turns 
out to be rather common, and it's an alteration in a receptor 
that normally binds to LDL, which is one of the molecules that 
carries lots of cholesterol. Understanding that genetic 
alteration led to insights by the Nobel laureates, Brown and 
Goldstein, which have now put in our hands a whole generation 
of cholesterol controlling drugs, which are actually very 
effective. In situations where individuals in the past really 
didn't have many options other than diet control, which didn't 
work well, these are now very treatable conditions. It's 
another model where gene understanding led to insight about 
pharmacological therapy and then to the control of a disease 
which had really been quite resistant. There are others, but 
that's a particularly attractive one.
    I might say, another area of future medicine will be the 
business of predicting what kind of drug should this person get 
for this disorder, based on their genetic endowment, 
pharmacogenetics, as it's sometimes called. It may be that some 
drugs work particularly well for some people and less well for 
others. It may be that the toxicity of drugs is determined to 
some degree by the genes of the host. If we understood that 
better, and there's a great effort to do so in many 
pharmaceutical companies, then we could individualize 
therapies, to avoid the toxic side effects and maximize the 
benefit.
    Mr. Porter. Thank you, Mr. Miller.
    Mr. Wicker.
    Mr. Wicker. Thank you, Mr. Chairman.
    Dr. Collins, let me ask a question about cloning. And let 
me just observe, Mr. Chairman, that you have figured out a way 
to get the television cameras here, just tell people, as you 
did yesterday, that we're going to talk about cloning, and CNN 
will show up. And I saw Dr. Varmus last night on Headline News 
talking about cloning.
    Mr. Dickey and I have been whispering about these technical 
terms that Mr. Miller's been using. We're very impressed.
    [Laughter.]

                      Cloning--Potential for Hoax

    Mr. Wicker. I want to try to ask a real layman's question. 
The Chairman, asked a question about skepticism. And I believe 
Dr. Varmus used the word science fiction yesterday in talking 
about this very serious subject. First of all, do you think 
there's a chance this Dolly experiment might be a hoax? Are you 
convinced beyond a doubt that it is real?
    Dr. Collins. I think it's unlikely that it's a hoax, 
looking at the data and seeing that this is a paper produced by 
several authors, not just one, certainly the data as presented 
does indicate that Dolly's genes appear to be identical to the 
genes of the sheep that donated that mammary epithelial cell, 
so there wasn't a mix-up of some sort.
    I guess I would say it is never possible to sort of look at 
a published paper and say absolutely for sure this could not be 
a hoax, but it doesn't seem to have that flavor. I guess what I 
was saying a moment ago was that science always should be 
confirmatory. When you have a new result, particularly a 
surprising one, other people should--and believe me will--be 
going out to see whether they can reproduce that result. So I 
think it's very unlikely that it is a hoax.
    Mr. Wicker. I have an article about you from the Chicago 
Tribune. It describes you as a lanky, laconic physician, 
chemist, geneticist, country music singer, and motorcycle buff. 
And we should now add former sheep farmer. [Laughter.]

                          Cloning--Why a Sheep

    Mr. Wicker. Is there anything about a sheep, and you 
wouldn't know this from having been a farmer, but as a 
scientist and geneticist, something about that particular 
mammal that you think made it an easier candidate for this type 
of experiment?
    Dr. Collins. I don't know if there's something unique about 
it. Certainly one of the motivations for using sheep for this 
experiment is there's a great deal of interest in using sheep, 
particularly the ability to put genes into the mammary glands 
in order to make proteins in sheep milk, which could then be 
purified and used as pharmaceuticals. So there was a drive from 
the point of view of the biotechnology industry to try to 
achieve this in a sheep and not in, say, a horse.
    There are a couple of interesting things about sheep. You 
can operate on the sheep uterus without inducing labor. You 
can't do that in most other mammals. So there's been a long 
experience of doing fetal surgery with sheep, which may in some 
way have played into this. There's a lot of veterinary 
experience dealing with the sheep reproductive system, because 
it seems to be more tolerant of interventions during gestation.
    Outside of that, I'm not sure that this could not somehow 
have been done in some other large mammal. It just happened 
that this group that was doing it was most interested in that 
particular mammal.
    Mr. Wicker. Well, you mentioned a horse. And I was thinking 
a race horse, you know. [Laughter.]
    Dr. Collins. Well, you can be sure people in Kentucky are 
talking about that this week.
    Mr. Wicker. Undoubtedly. I appreciate what you and Dr. 
Varmus have said about the ethical considerations. There are 
very profound considerations that go into this. But the human 
is a mammal. And I just want to hear your comments, if you can 
clone a sheep, and if somebody had the money to pour into the 
project, is it totally science fiction to assume that a human 
being could not be cloned?

                             Cloning Humans

    Dr. Collins. Harold, do you want to jump in?
    Dr. Varmus. I just want to clarify my reference to the term 
science fiction yesterday. I did not use that term to say that 
it would not be possible to do similar experiments in humans. 
What I was pointing out was that there was a lot of science 
fiction composed around this idea. And that from the point of 
view of most scientists, this is not where the interesting 
component of the current experiment lies. The interest lies in 
the use of animal models, the or understanding of how genes are 
turned off and on, and the possible exploitation of that for 
benefit.
    Mr. Wicker. Okay, but I really am interested, though, in 
the answer to the question.
    Dr. Varmus. We acknowledge the possibility that it is 
possible. I made that clear yesterday. And with not very 
expensive equipment. However, your question about sheep is 
right on the mark. We don't really know whether this is a 
special case. It's impossible to evaluate how easy it was in 
the sheep, because remember, starting with an adult cell, it 
was only 1 case out of almost 300. Now, in someone else's 
hands, that might have been 1 out of 5,000, in which case it 
probably wouldn't have happened, because it's too difficult to 
do. Perhaps in other species, it will prove to be more 
efficient or less efficient. I think we don't know.
    And when Dr. Collins referred to the importance of 
confirmation of the observation, one of the things that will be 
interesting is not simply confirming the observation with 
sheep, but looking in other agricultural animals or for that 
matter in the mouse. Dr. Collins referred to some interesting 
notions about aging that could come from these experiments. And 
it will be very important to try to do this kind of experiment 
in the mouse.
    I point out to you that what is called a clone is not 
strictly speaking a clone--in fact, less identical than 
identical twins. The reason for that is that when this 
experiment is done, you are putting the cell into an 
environment where there are mitochondria, the small DNA-
containing organelles that exist in the cytoplasm--I'm sorry to 
use the terminology, but----
    Mr. Wicker. I'll get Mr. Miller to explain that later.
    [Laughter.]
    Dr. Varmus. So there is other DNA, there is DNA outside of 
the nucleus, in the cytoplasm of our cells, which is in Dolly, 
but was not in the donor. That's important. So it's not truly a 
clone.
    Moreover, as Dr. Collins mentions, the cells that came from 
the donor have been through many, many duplications. In the 
course of those duplications, there were almost certainly 
mutations introduced into the DNA. We don't know the effect of 
those mutations. But it makes Dolly different from the 
fertilized egg that gave rise to the donor.

                         Human Embryo Research

    Mr. Wicker. Okay. Let me just ask a quick question, for 
either one of you. The case of Dr. Mark Hughes. I wonder if you 
could comment on that. He was forced to leave NIH because it 
turned out he was using Government equipment to conduct human 
embryo research in violation of the so-called Dickey-Wicker 
amendment.
    In that case, I understand it was disputed who alerted NIH. 
And I just wonder, how confident we can be that other 
situations like this don't exist and what steps are being taken 
to make sure of this?
    Dr. Varmus. Perhaps I should answer that, Mr. Wicker. 
Obviously, as in the case of any law, all we can do is look for 
offenders and be sure that people understand the law. There is 
no doubt that Dr. Hughes understood the law. It was explained 
to him by many people, including myself. The intramural NIH 
research program was fully aware of the law. Anyone who had 
applied to the NIH for grants to do work that could involve 
human embryo research not only was informed, but had signed a 
statement saying that they knew that in receiving money from 
the NIH, they were not to use any of that money to do that kind 
of work.
    We have put reminders in light of the evidence about Dr. 
Hughes on our Web site. The Department of HHS has sent to all 
institutions that receive our grants reminders about your 
amendment as well as other restrictions on the use of our 
money. We've made every effort to be sure that our grantee 
institutions and our grantee scientists understand what the law 
is, and we expect them to follow it.
    Mr. Porter. Mr. Dickey.
    Mr. Dickey. Thank you, Mr. Chairman.
    I apologize for not being here yesterday. It wasn't because 
the cameras were here. I know I'm kind of a shy guy and I'm 
sometimes afraid of the cameras, but it wasn't for that reason.
    I'm concerned overall, and I've expressed to you my concern 
about the Dickey-Wicker amendment. And I think I've settled 
that. But I'm concerned overall that we might not be 
progressing toward cures, and we might be distracted by giving 
appropriations to more areas. Can you help me with that? Is 
that question clear?
    Dr. Varmus. No.
    Mr. Dickey. What I'm concerned about, as I look at the 
expenditures, we're taking money away from heart disease, and 
cancer and so forth. Or stated another way, we have money that 
we're sending to other areas of responsibility like diabetes, 
for example; we could be taking that money and bearing down 
more toward a cure.
    Tell me how I'm wrong in that perception.
    Dr. Varmus. Again, I'm not quite sure where you get this 
idea that we're taking money away from those areas. All areas 
of research could be aided by additional funds. There are 
various ways to evaluate whether the amount we're spending in 
different areas is appropriate; it may seem appropriate to some 
and not to others.
    We believe that the money that we spend is all directed 
toward alleviation of human suffering, and that the calculus 
that one uses to determine what is correct may vary from 
calculator to calculator. But it's not the case that there is 
money being taken away from the areas you've mentioned. Every 
area you've mentioned is an area that has received increases 
over the last several years. Not always equal to the increases 
that are received by every component of NIH for example, as we 
discussed earlier, the Genome Center, now Institute, has been 
``ramping up,'' in Francis Collins' words, more rapidly, 
because it began from a very low level. A very similar argument 
could be made for the funding of AIDS research, which for a 
time ``ramped up'' quickly. Now it receives the same increase 
as every other area of NIH. Breast cancer research was ``ramped 
up'' some years ago as were Alzheimer's, and tuberculosis 
research, in response to specific needs. We've been funding 
research on diabetes and heart disease and cancer for many 
years, at quite generous levels. We believe that we respond to 
the scientific opportunities and that great progress is being 
made in all the areas that you mentioned.
    So I would take issue with the general contention that we 
are taking money away from these areas of serious medical 
concern, and I'm not quite sure where you think the money is 
going where it's not deserved. Maybe you could be more explicit 
about that for me.
    Mr. Dickey. I just got the impression, and I just watched 
it, diabetes is one particular thing that I've gotten concerned 
about because of a friend of mine's loss of his daughter, 32 
year old daughter. I think it was heart complications of 
diabetes that caused her to lose her heart functions.
    Now, I get this idea (and I don't think I can support it 
factually) that we are, that some things are old hat and we're 
making progress; however we're not really going to war in 
certain areas. Heart disease, for instance, let's see, $28 
billion was spent out of Medicare for heart disease, covering 
some 17 million, 18 million patients. Now, I don't see an 
intensity of that going at the heart disease, and saying, we're 
closer, we're closer, we're closer. Is that an accurate 
observation?
    Dr. Varmus. I don't believe it is, sir. And I say that for 
a number of reasons. One is that we've made tremendous strides 
in the treatment of heart disease and prevention of heart 
disease over the last 20 or 30 years. So the mortality rates 
have fallen by about 50 percent. That doesn't mean that we're 
there. There's still a very high burden of disease, especially 
with the aging of the population. We have a number of very 
important initiatives, and you'll hear about them next week. We 
spend over $1 billion a year on a variety of research on the 
heart and the vessels. As you know, much of the heart disease 
that we have in our society is due to diseases of the vessels. 
You could read yesterday's testimony about the intensity of 
research on the process we call angiogenesis. That's a word, 
Mr. Miller, that refers to our understanding of how blood 
vessels are generated. [Laughter.]
    It is a very, very important new field of research, because 
if blood supply to an organ like the heart or the brain is 
impaired, obviously what we would like is a way to replenish 
the blood supply by making new blood vessels. And we've learned 
largely from research in cancer new ways to do that.
    Mr. Dickey. Let me interrupt you, because I'm afraid my 
time's run out. From what I understand, NIH over the last 10 
years appropriation has increased 98 percent. Diabetes, from 
that appropriation, diabetes has increased only 32 percent. 
Maybe that is a way of describing what I'm trying to say. In 
other words, just taking diabetes, it hasn't increased, as we 
increased your appropriation, diabetes has gotten a lesser----
    Dr. Varmus. Well, I don't know, I'd have to look at the 
source of those numbers. It probably is the case that if you 
look at the numbers over that long a period, you may see a 
lower than average increase because a number of things have 
expanded in a very major way because of the growth of the 
genetic enterprise or because of the growth of our expenses to 
respond to the AIDS epidemic or in response to Alzheimer's, 
which has become an increasing problem.
    But I think if you look at diabetes research broadly and 
analyze the way in which diabetes research is being affected by 
other disciplines, you will get a different picture. Let me 
give you one very pertinent example. The kind of work that Dr. 
Collins and the Genome Institute have done has allowed in the 
last year the isolation of two genes that have been studied for 
totally different reasons that are responsible for two 
inherited forms of diabetes called maturity onset diabetes of 
the young. These are remarkable opportunities, inspirations, if 
you will, for understanding diabetes at the fundamental level.
    I will also point out to you that we have made tremendous 
progress in diabetes. You can read the transcript of Dr. 
Kupfer's performance yesterday, and you'll see that we now have 
the means to treat diabetic retinopathy very effectively. One 
of the problems in caring for diabetics at the moment is 
persuading patients and physicians to respond to the new 
information that we've accrued over the last several years by 
studying the long-term complications of diabetes. As the death 
of your friend's daughter illustrates, we know that diabetes 
affects blood vessels and nerves and kidneys and eyes. We also 
have learned that careful control of diabetes, which is 
difficult to achieve and requires patience and hard work, has a 
major effect in reducing the morbidity of the complications of 
diabetes. So a large part of the problem in diabetic morbidity 
has to do with taking the discoveries that have been made with 
NIH research and getting them applied in the clinic.
    Mr. Dickey. I really believe that my support of what you're 
doing has a lot to do with the intensity of the commitment. And 
I just don't want you all to let up. I mean, you all are 
scientists and I'm where I am. But I'm just saying, it's the 
intensity, and it's just pushing forward. It's the cure that we 
need to go after. Diabetes is only an example.
    Dr. Varmus. I appreciate your comments. And I hope you'll 
come to hear from Dr. Gordon and Dr. Lenfant, who will address 
some of these issues.
    Mr. Dickey. As long as there aren't any cameras. 
[Laughter.]
    Thank you, Dr. Varmus.
    Mr. Porter. Thank you, Mr. Dickey.
    Before I call on Ms. DeLauro, I want to say that the 
situation is a very unfortunate one that we are running out of 
time. And we have asked Dr. Fauci if he might stay a little bit 
later. The Chair intends to go until 12:30 with Dr. Fauci. And 
Dr. Varmus, I am feeling that we are not allowing sufficient 
time in some instances. And I would ask that we consider 
perhaps bringing back yourself and certain institute directors 
later in the year, if we feel we really haven't had a thorough 
opportunity to look at the situation in each of those 
institutes.
    Dr. Varmus. We would be delighted to do that.
    Mr. Porter. I know how valuable your time is, and I don't 
want to burden you, but I also don't want members of the 
subcommittee to feel they haven't had a real opportunity to 
discuss things that are on their minds with you.
    Ms. DeLauro.

                   Genetic Discrimination and Privacy

    Ms. DeLauro. I'm very supportive of what this project and 
this institute is about, in terms of what it means to our 
ability to identify therapies or cures in the long-term. I 
think it's one of the most important efforts that we have 
taken.
    One of the concerns that I have is there are about 40 
million people today who are not covered by health insurance in 
this country. We've got tremendous advances in medical 
technology like the human genome map. What concerns me is that 
in the future you may have someone who tests positive for a 
mutated gene that could yield breast cancer at some point in 
their lifetime, and they will not be able to get any kind of 
preventive care in order to avoid that disease.
    You have a landscape with insurance coverage today that 
potentially may make it very difficult, once we've got this 
wonderful discovery, she may be left without any recourse, 
unable to deal with it. I mean, the question is, and I'm 
struggling with the question here myself, with what you are 
doing and what you are able to uncover in the Human Genome 
Project, will it help or hurt individuals with little or no 
health care coverage in the future? That may not be 
specifically what you are about, but we're dealing with what 
science is uncovering and what is happening to the people at 
the other end of the process.
    Dr. Collins. It's a very serious matter. We are, among all 
Westernized, civilized countries, the one that seems most 
willing to let the largest fraction of our own population be in 
a circumstance where they can't get access to health care. And 
you really do look at that and wonder, how did this happen.
    I don't think that the genetic aspect of medical care is 
particularly different from the rest of medical care. If you're 
not covered, you're not covered, and that's a serious tragedy, 
and one which I think this Congress seems interested in 
addressing, albeit maybe not in the overarching way that was 
discussed a couple or three years ago.
    Ms. DeLauro. I get scared about pre-existing conditions.
    Dr. Collins. Well, sure. There are two areas that we can 
and should start to fix, even within our existing flawed health 
care system. And I sort of think of these as the two pillars of 
a building. And one of them is privacy and the other is 
avoiding discrimination. The avoiding discrimination pillar, in 
order to really be robustly protective, requires Federal 
legislation to make it illegal for health insurers to use 
genetic information to deny coverage or to set exorbitant 
premiums. And Kassebaum-Kennedy moves in that direction in a 
very gratifying way, if you're in a group policy. For 
individual policies, it's much less protective. Efforts are 
underway in the current Congress to do something about that as 
for instance, Congresswoman Slaughter announced yesterday 
legislation that I think highly appropriate.
    Discrimination comes in other flavors besides health 
insurance. Employment issues need to be addressed as well.
    The other pillar is privacy and confidentiality. Not only 
should third parties not be able to use this genetic 
information against you, they really shouldn't be able to see 
it unless you tell them it's okay. And if you have one of those 
pillars without the other, the building still falls down.
    We really need a way to protect medical records in this 
country. Right now, it's ridiculous. If you start counting up 
the number of people that can look at your medical records, you 
sort of get tired after 100, because it just keeps getting 
bigger and bigger. And there is no meaningful control of that 
process. Clearly that is an area of great concern amongst the 
public and in the Congress. There are at least three bills this 
year that are being introduced or will be shortly.
    My own view is that you can't take the genetics part of the 
medical record and set it in a separate category and say we're 
going to apply protections to that and not worry about the 
rest. Because which part is the genetic part? Every disease has 
a genetic component. Everything in your medical chart, if you 
want to look at it with really a hard, cold eye, you could say 
there is some familial contribution. It's not possible to 
separate the information.
    So to solve the privacy issue for genetics, we have to 
solve it for the whole medical record. And I certainly think 
that ought to be a very high priority, especially as more and 
more of this information becomes electronic, and maybe it gets 
easier therefore to eavesdrop in places that the patient would 
not allow had they known.
    So I think every possible effort ought to be made. I must 
say, I'm very gratified, after four or five years of bringing 
up these topics and not receiving much enthusiasm, now one sees 
in many areas on both sides of the aisle in both houses of the 
Congress, a good deal of interest in doing something about 
this. And in the case of Kassebaum-Kennedy, an actual piece of 
legislation has been passed and signed.
    Ms. DeLauro. Well, I think it's important to have your 
voice engaged in this discussion, because I think it's a very 
important road we're going down.
    Dr. Collins. I couldn't agree more.
    Ms. DeLauro. These are uncharted areas in a whole variety 
of these cases. And we truly do need to make sure we're going 
to continue with discovery part of it, and then how do we 
ensure, that we can protect the individual.
    Dr. Collins. The greatest tragedy would be if this project 
is scientifically successful but socially unacceptable. And you 
have this wonderfully powerful new brand of medicine which has 
promise to save many lives, but nobody wants to have anything 
to do with it, because they're fearful that the information 
will get used against them. What a terrible stillbirth that 
would be. Yet, we can prevent that if we act now.
    Ms. DeLauro. Thank you.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Ms. DeLauro.
    Mr. Hoyer.
    Mr. Hoyer. No questions, Mr. Chairman.
    Mr. Porter. Dr. Collins, thank you for the marvelous work 
that you do at your new institute, and for your always 
fascinating testimony. We very much appreciate that.
    I suspect that the subcommittee may want to ask you to come 
back, perhaps for another hour, sometime later in the year.
    Dr. Collins. I'd be delighted.
    Mr. Porter. If we do, I hope that you would be able to 
respond. We do respect your very, very busy schedule and Dr. 
Varmus'. Sometimes these hearings are just too short to get 
really deeply into this. I have pages of questions I haven't 
been able to ask and I really want to ask them.
    So again, we appreciate your testimony today, and hope you 
remain ready to come back. If we ask you, would you?
    Dr. Collins. I am most ready at your wish, by all means.
    Mr. Porter. Thank you very much.
    The subcommittee will stand in recess briefly.
    [The following questions were submitted to be answered for 
the record.]

[Pages 523 - 581--The official Committee record contains additional material here.]


                                       Thursday, February 27, 1997.

         NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES

                               WITNESSES

ANTHONY S. FAUCI, M.D., DIRECTOR
JOHN J. McGOWAN, M.D., ACTING DEPUTY DIRECTOR
GEORGE W. COUNTS, M.D., DIRECTOR, ORMWH
STEVEN J. BERKOWITZ, ACTING ASSOCIATE DIRECTOR FOR MANAGEMENT AND 
    OPERATIONS
THOMAS D. WILLIAMS, BUDGET OFFICER
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.
    Dr. Fauci, we somehow scheduled both you and Dr. Collins in 
the same two-hour timeframe. I think it's insufficient for 
either one of you, and we will ask you also if you would 
consider coming back later in the year when we can spend a 
little more time. I just think this timeframe is simply too 
short.
    Dr. Fauci. I'd be delighted to do so.
    Mr. Porter. With that, I am going to ask you to introduce 
the people with you, and then proceed. We will see how 
expeditious we can be and perhaps we can save some time at this 
point in the proceedings.

                       introduction of witnesses

    Dr. Fauci. Thank you very much, Mr. Chairman.
    Let me first introduce my colleagues at the table. This is 
Dr. George Counts on my far left, who is the Director of our 
Office on Research on Minority and Women's Health; Dr. John 
McGowan, who is the Deputy Director of the Institute; Mr. 
Steven Berkowitz, who is the Associate Director for Management 
and Operations; Mr. Thomas Williams, who is our Budget Officer; 
and you know Dr. Varmus and Mr. Dennis Williams.
    You have my written statement, Mr. Porter. What I would 
like to do is just take a few minutes and summarize some of the 
salient features of that, with some visual aids.

                           Opening Statement

    The question that I often get asked relates to the cover of 
Newsweek magazine and other popular lay magazines that we've 
seen over the years; are we really approaching or at the cusp 
of the end of HIV/AIDS? And the answer is, although there have 
been substantial and dramatic advances over the past year, the 
answer to this question is no.
    [See figure 1.]

[Page 585--The official Committee record contains additional material here.]


    Dr. Varmus appropriately spoke about culminations and 
inspirations. Certain aspects of AIDS research are almost but 
not quite yet culminations, and there are probably more 
inspirations than there are culminations.
    Since I have testified before this committee about the 
advances in AIDS several times over the past years, what I 
would like to do very briefly is summarize, in a temperate 
fashion, some of the things that I've actually told you in this 
committee regarding the evolution of treatment strategies for 
HIV/AIDS.
    You might recall that in 1987 when I came before the 
committee and told you about the use of AZT as a single drug 
monotherapy, let me put into perspective what this drug and 
other drugs have done, one, to the virus, and two, to the 
patient in question.
    [See figure 2.]

[Page 587--The official Committee record contains additional material here.]


    This is a measurement of level of virus, and this is week 
of study or time upon the antiviral. When we had AZT alone in 
1987, this is what we call a logarithmic scale, so that when 
you go down from 1 to 2, you are actually going down by 10--10 
times the amount, not twice the amount.
    As you can see, there is a substantial drop in the level of 
virus, but that drop is transient, and comes back down with 
mutations that are resistant to the drug. So in the short run, 
AZT was good for people with advanced disease, but proved in 
people with early disease to not be sufficient to have a 
significant clinical impact.
    Then in 1994, just a couple of years ago, I came before the 
committee and told you about the double-drug combination which 
not only brought the virus down further, but it was more 
sustained, and for the first time it was actually a clinical 
benefit in early disease.
    What we are seeing now in 1997 with the combination of 
three drugs, including the protease inhibitor, is the virus 
going, in many cases--and sometimes the majority of cases, 
depending on the study--to below detectable level in the blood. 
But as we know from recent studies, the virus has not been 
eliminated from the body, because you can still isolate it. But 
in the blood it is below detectable level, and that is 
sustained.
    Just a couple of days ago we had a study which compared 
three drugs in late disease, including protease, with two 
drugs, and for the first time a clinical benefit with regard to 
death and adverse events in late disease was shown. What we 
don't know is if there is going to be a clinical benefit if 
given over a long period of time, and whether the cumulative 
toxicities and the emergence of resistance might outweigh some 
of the beneficial effects that everyone seems to be so excited 
about.
    I said this, actually, in an editorial last summer at the 
time of the Vancouver meeting, when I stated--which is really 
summarized right here--that there has been much accomplished in 
AIDS research, but still much to do. What I would like to spend 
the next couple of minutes on is talking to you about some of 
those things that Dr. Varmus referred to as ``inspiration.'' 
Again, going back historically, several years ago, more than 
just a few, I came before the committee and told you about the 
different targets of our antiviral drugs. Looking at the life 
cycle of HIV, very quickly, the virus binds to the cell; enters 
it; uses an enzyme to convert its genetic material--this is the 
target of AZT and ddI and ddC. It integrates into the nucleus, 
and then it has production of additional virions. This is the 
target of the protease inhibitors. But what we just discovered 
this year is very exciting because it's the example of the 
convergence of two areas of research, one that was directly 
AIDS. You've heard several of the members talk about the 
overlap between AIDS and non-AIDS. Investigators were looking 
at the physiology of a cell and the receptors that it uses, and 
investigators were looking at how you block the virus in a 
particular cell, and a co-receptor or a co-factor was found by 
investigators who were looking at why cells, when they get 
infected, fuse with each other. This co-receptor turned out to 
actually be a normal receptor for a protein that the body uses 
to mount an inflammatory response.
    [See figures 3, 4, and 5.]

[Pages 589 - 591--The official Committee record contains additional material here.]


    So investigators have been working on this for years, 
having relatively little interest in AIDS. AIDS investigators 
were looking for the receptor for the virus. You put them 
together, and what you find out is that these natural proteins 
are very, very potent in blocking the ability of the virus to 
bind to the cell because they occupy the same receptor.
    So just on a fundamental basic science observation, we now 
have a brand new target, not only for the development of 
therapeutics, but perhaps for the development of a vaccine. 
This is a classic example of how something came out of basic 
research, and hopefully in future hearings I will be telling 
you about some of these clinical trials.
    We heard yesterday a bit about where we are in AIDS 
vaccine. You know that we have a renewed effort in AIDS 
vaccine. We have Dr. David Baltimore now who is heading our 
Advisory Committee.
    Rather than go into any detail about this, I would say that 
we have a balance of the fundamental basic research approach 
with an empiric approach of looking at candidates that are in 
various stages of development, and you'll be hearing more about 
this over the next year or so.
    [See figure 6.]

[Page 593--The official Committee record contains additional material here.]


    Speaking of basic research, you might also remember one 
thing that hit the newspapers, which is that the Nobel Prize 
for 1996 in medicine was given to two immunologists, Dr. Peter 
Doherty and Rolf Zinkernagel, a current and a former grantee of 
NIAID. And more than 20 years ago, they made a fundamental 
observation that had nothing to do with any particular disease. 
They were able to very clearly demonstrate that when a T cell, 
which is the major guardian cell looking for disease in the 
body, encounters a virus-infected cell, that the molecules that 
form the fit of a lock-and-key account for both the specificity 
and the restriction of that response, opening up an entire new 
avenue of research to explain many immunological phenomena. 
They didn't even fully realize then, when they were dealing 
with an animal virus, that they would open up so many doors in 
immunology.
    [See figure 7.]

[Page 595--The official Committee record contains additional material here.]


    One of the doors that they opened for us has to do with 
vaccines, because the vaccines of the future--again, this has 
been in the newspapers a lot over the last year--is the DNA 
vaccine. You actually take the gene that codes from a protein 
of a microbe, so that it's perfectly safe; you don't take the 
whole microbe. You inject it into the muscle of an individual, 
and that protein presents itself to the body in association 
with the right molecules that Doherty and Zinkernagel spoke 
about over 20 years ago, giving you a very potent immunological 
response of both antibody and cell-mediated response.
    [See figure 8.]

[Page 597--The official Committee record contains additional material here.]


    We already have clinical trials looking at it in influenza. 
We've begun them in HIV, and it's going to open up new 
possibilities for diseases for which we don't have a vaccine: 
malaria. We can get an approved vaccine for measles, hopefully; 
but also, the other emerging microbes that I spoke to this 
committee about, that we haven't even identified yet. But once 
you identify them, once you use the genetic technology that we 
have available, you can go right into this type of vaccine 
work.
    This is another example of basic research leading to very 
important and potentially practical results.
    So let me close on this introduction by getting back to the 
thing that I started with, the fundamental area of basic 
research and how this is the source of the inspirations that 
Dr. Varmus spoke about yesterday. For our Institute, it's 
immunology and infectious disease. But this chart could just as 
well apply to virtually all of the Institutes that you're going 
to be hearing from over the next week or so. And in our case, 
the fundamental research leads to these types of advantage.
    [See figure 9.]

[Page 599--The official Committee record contains additional material here.]


    We would, again, thank you very much for the support that 
you have given us--not only for the practical things, like for 
an identifiable disease, but for the basic research that is the 
source for the inspirations that lead us to those practical 
applications.
    I would be very happy to answer any questions.
    [The prepared statement follows:]

[Pages 601 - 604--The official Committee record contains additional material here.]


                          protease inhibitors

    Mr. Porter. Thank you, Dr. Fauci.
    You may have answered this in part, but let me ask it 
anyway. Viral load testing of the patient's blood is thought to 
be the most accurate measure of the severity of a patient's HIV 
infection. Some reports, however, indicate that even though 
viral load testing may indicate no evidence, which you 
indicated on the chart, of the virus, it may still be present 
in the lymph nodes.
    Dr. Fauci. Right.
    Mr. Porter. How can we be confident that we are correctly 
measuring the impact of the protease inhibitors?
    Dr. Fauci. It is very clear from a number of studies, Mr. 
Chairman, that the level of replication of the virus is 
reflected in the level of the virus in the blood that we 
measure by our sensitive techniques.
    Also of importance is that there have been good 
retrospective and prospective studies that indicate that the 
level of virus in a particular individual accurately predicts 
where that person is going with their disease. So that if you 
have a very high level, you know that the curve of disease is 
like that, and they will deteriorate more rapidly than someone 
who has a low level.
    That doesn't tell you that the virus is completely absent 
if this goes below detectable level. In fact, we know from 
experiments that it isn't. But what it does accurately tell you 
is that there is a correlation between the level of virus and 
the clinical course, so that it is better to bring down the 
virus to below detectable level, even if you haven't gotten rid 
of it.
    I tend to explain this to people by saying that this means 
there's good news; we've gotten the virus to below detectable 
level. How good that news is going to turn out to be over the 
long run, vis-a-vis how long we can keep it suppressed, remains 
to be determined by clinical trials. But just because you can't 
get rid of the virus doesn't mean that bringing the virus down 
is not a very good thing with regard to the clinical course of 
a patient.

                       hiv multiple drug therapy

    Mr. Porter. How long have we been testing the multiple drug 
therapy? How long do we know that it keeps the level down?
    Dr. Fauci. Well, again, it depends--and this is a very 
interesting, complicated situation vis-a-vis the sometimes lack 
of appreciation of the scope of this throughout the country. If 
you look at a very well controlled population of individuals 
who are highly motivated in a clinical trial, with triple 
combinations of drugs, you could bring down the virus to below 
detectable level in about 80 to 85 percent of individuals and 
keep it there for anywhere from 40 to 52 weeks. After a while, 
a certain percentage of them will start to break through with 
resistant viruses.
    If you go into the trenches, as we call it, in people who 
have had a number of different types of antiviral drugs, the 
percentage of getting those people down is somewhere around 40 
or 50 percent. So what we can say, in direct answer to your 
question, is that for at least a year we know that in the 
majority of people we can keep that virus down. But since we 
know that the virus can stay latent for a long period of time, 
it won't be until several years from now that we can say 
confidently that we've been able to keep it down.
    Mr. Porter. You talked about motivated patients. Who would 
be not a motivated patient? An IV drug user maybe? Who would 
fall in the class that aren't highly motivated?
    Mr. Fauci. I don't want to use the word ``motivated'' in a 
pejorative or a laudatory sense. What I'm talking about is that 
when someone is within the confines of a clinical trial and 
they have a clinic and a doctor that's very interested in them, 
encouraging them to stay on the trial despite the fact that 
there are toxic side effects to the drug, encouraging them to 
continue to take their medicine, that's an excellent 
environment. That is much different than a situation where 
someone may not have a doctor that readily follows them or a 
clinic that has an intensive interest in them, gives them some 
drugs, the person feels better, then after three weeks to a 
month they stop taking the drug.
    That's what I mean by motivated, not necessarily in a 
pejorative sense of someone is not motivated. It's 
accessibility of the kind of care and environment that allows 
someone to feel good about staying on this type of regimen.

                          aids clinical trials

    Mr. Porter. It's been reported that three or four trials 
being supported by your AIDS Clinical Trial Group include 
potentially suboptimal treatments because they were designed 
before the new potent drug combinations were available.
    Dr. Fauci. Right.
    Mr. Porter. Do you plan to modify the design of these 
trials?
    Dr. Fauci. Definitely. And that's already underway right 
now. There are a few trials--when you say suboptimal, you have 
to look at both the laboratory and the clinical data. For 
example, literally just a couple of days ago, and I alluded to 
it briefly in my opening statement, a trial called ACTG-320, by 
the number of the trial, was looking at triple combination of 
drugs compared to two nucleoside analogues, either AZT and D4T 
or AZT and 3TC, compared to that same regime together with 
Indinovir or Crixivan, which is one of the several protease 
inhibitors. And before the study was over, as the data and 
safety monitoring board analyzed the data, it became clear that 
there was a distinct advantage to three drugs compared to two 
drugs in late disease, not early disease.
    So we go back now, when we look at all the protocols in 
which there are two drugs in late disease, and since we know 
that that's suboptimum, you must reconsider then adding the 
option of a third drug and a protease inhibitor. However, what 
is still an open question is two drugs versus three drugs in 
very early disease. That's something where, as I alluded to 
before, you have to balance the potential clinically beneficial 
effect with the possibility of cumulative toxicities and the 
emergence of resistance.
    The answer to your question is that they are being 
carefully looked at on a protocol-by-protocol basis.
    Mr. Porter. We've heard that as many as five new types of 
protease inhibitor drugs are in the pipeline. Do you expect 
them to overcome some of the difficulties with the current 
protease inhibitors?
    Dr. Fauci. The answer is yes, some, but not all. Each of 
these drugs are potent drugs and each of them will either have 
similar or different types of toxicity. One of the things we 
would like to see overcome, and we already have some indication 
that this is the case, is that the mutation that is induced by 
one might not lead to a virus that is cross-resistant to the 
other. In other words, you can measure little changes in the 
genetics that lead to amino acid changes in the proteins of the 
virus. Sometimes protease inhibitor No. 1 would lead to a 
mutation at this particular point. If protease inhibitor No. 2, 
even if it leads to mutations, if it's a different mutation, 
you could wind up putting them together and still having the 
virus be susceptible. So that's our hope for developing new 
protease inhibitors in the pipeline.
    Mr. Porter. Do you think it is realistic to ever expect the 
drug companies to invest resources in the development of an 
AIDS vaccine, since its market would be undeveloped countries 
in large part?
    Dr. Fauci. The answer is, I don't think it's going to be 
easy because it will follow the same pattern as we see with any 
vaccine. This is not a field where there are many, many 
pharmaceutical companies which are breaking the doors down to 
try and get into the field. However, as we have consulted 
closely with our colleagues in industry, the limiting factor is 
really the scientific opportunity.
    If we can get a concept that proves to be having at least a 
reasonable chance of working, I think you'll see a larger 
number of drug companies than you see currently involved in the 
field. As part of our renewed effort in vaccine at the NIH vis-
a-vis HIV/AIDS, we are engaging our industrial colleagues in 
discussions and collaborative efforts. So it's not going to be 
a simple problem to overcome, but I don't think it is going to 
be prohibitive if we get a good scientific concept to prove.
    Mr. Porter. Does the need to halt clinical trials due to 
ethical considerations limit your ability to measure the 
emergence of resistance?
    Dr. Fauci. The answer is, from a purely technical 
standpoint, if you stop a trial before you show that there's a 
relationship between a resistant mutant and a clinically 
deleterious course, one can say yes. But that's just part of 
the turf of research. The most important thing that we 
understand and guide ourselves by is to ``do no harm'' to the 
patient. So if a situation arises where there is an ethical 
consideration, that's what we call a non-starter. That's the 
first thing that takes preference. It may take a little longer 
to get to the truth, but we have done it successfully.
    You might recall, in fact, I think we had somewhat of a 
similar conversation several years ago when we had AZT proved 
to be effective and we couldn't have a placebo. There were 
those who threw up their hands and said we'll never show again 
that another drug works if we can't do a placebo trial. And now 
I just showed you three examples of how we did it within the 
realm of having people on drugs that ultimately turned out to 
be not as good as the one we were testing, but we didn't know 
it at the time. So, in the real world, I don't think it is a 
serious negative impact on our ability to answer questions.
    Mr. Porter. Thank you, Dr. Fauci.
    Ms. Pelosi.

                         hiv drugs and vaccines

    Ms. Pelosi. Thank you very much, Mr. Chairman. Welcome, Dr. 
Fauci. It's always an honor when you are here. We are indeed 
blessed to have Dr. Varmus, at the head of NIH, and you in your 
capacity. I just wanted to call to my colleagues' attention the 
fact that Dr. Fauci has over 850 scientific publications, and 
that of the one million scientists in the world who publish 
each year, Dr. Fauci is the second most quoted among those. I 
think that, again, the NIH and our country are indeed blessed 
with your contribution.
    In that spirit, I wanted to follow up on a question asked 
by our Chairman about the involvement of the private sector. My 
question had been what actions can NIH and Congress do to help 
harness pharmaceutical expertise to the challenge of HIV 
vaccine research. You have said scientific opportunity is the 
key. But is there anything else that we could be doing to 
smooth the way?
    Dr. Fauci. I think you made the point. You are in some 
respects inadvertently doing it by supporting us. But a 
specific question that comes up, and I don't think it's a major 
problem, but it does come up and should be considered, and that 
is the question of the concern that drug companies have about 
liability and concern that they have about interference with 
pricing.
    We've come to a good agreement in our CRADAs in discussions 
about fair pricing in the sense that we don't have strict 
regimented controls on that. That has opened up the doors to 
more easy negotiations with them. With regard to the liability, 
that's a very difficult issue. But if it can be discussed with 
them at least that there is an intention of working with them 
to make sure that we can draw people in without that sometimes 
unrealistic concern, but sometimes realistic concern, regarding 
liability, that might be helpful.

                              hiv therapy

    Ms. Pelosi. I think that is a tremendous challenge, 
including that non-interference in the pricing. Although we 
want to be the free market, we also do not want an exploitation 
of the need of these people.
    That brings me to standards of care. It is my understanding 
that the NIH panel to define principles of therapy for HIV 
infection has a draft report under review.
    Dr. Fauci. Right.
    Ms. Pelosi. As a committee co-chair, you expect to issue a 
report on standards of care for HIV disease shortly. Could you 
outline your timeline for these two reports?
    Dr. Fauci. Yes. There are actually two committees that are 
working in synergy; one is the committee that is a 
fundamentally NIH-based committee that is looking at principles 
of care. The other is a departmental committee, of which I'm 
co-chair with Dr. John Bartlett from the Johns Hopkins 
University, and what we're doing in that group is that we're 
actually going to be making recommendations based on the 
principles that were established by the NIH committee.
    We actually have a meeting next week, March 6th, I believe. 
We will be looking at the hopefully next to final, if not 
final, draft of the two committee recommendations. We will 
then, after we fine tune it and get it in a presentable form, 
send it out for public comment. After that, we will publish it 
in the MMWR and hopefully in a standard medical journal. So the 
timeline we're talking about is, if you include a month or so 
period for public comment, would probably be sometime in the 
early spring.
    Ms. Pelosi. Early spring. Mr. Chairman, you have been so 
receptive to our having a full discussion of this issue, and 
even in your own questioning about what the penetration is 
among people with HIV having access to these new therapies, and 
I would hope that in your willingness to pursue more 
information we might have a hearing specifically geared toward 
the new therapies; how they are available, how they meet the 
standards of care. I know you've always been open on these 
subjects.
    Mr. Porter. If I could respond to the gentlelady. I am not 
sure you were here when I said that I felt that we were short-
changing the subcommittee in the sense that we have too much 
scheduled in too narrow a timeframe, and I've already asked Dr. 
Collins and Dr. Fauci as well as Dr. Varmus if they will make 
themselves available later in the year when we might follow up 
with them.

                              hiv vaccines

    Ms. Pelosi. Thank you, Mr. Chairman. I'm sorry, in my 
capacity as ranking member on another committee, I couldn't be 
in the room to hear that, but I am very encouraged by it. I 
would hope at that time we could have people with HIV as well 
as their health care providers and hear directly from HIV-
infected people and their care providers at such a hearing. 
Some of the stories are absolutely, to use Dr. Varmus' word of 
yesterday, ``miraculous'' in that people who were looking for 
help to make out a will now need help getting a job; people who 
were going on disability are now being made partner in their 
law firms. The stories are quite remarkable. But everyone 
doesn't have access to these drugs and everyone doesn't respond 
to them. So I would think that hearing directly from people 
with HIV and their care providers, in addition to our very 
distinguished witnesses, would be useful.
    In terms of the vaccine, I had a very specific question, 
because Dr. Varmus addressed it yesterday, and certainly the 
President did in his State of the Union address. Concerns have 
been raised about at least two structural issues concerning the 
way NIH awards funding to researchers. First, the peer review 
process often rewards proposals that demonstrate innovative 
science at the cost of more practical and less ground-breaking 
research which may be needed in order to develop an HIV 
vaccine. Second, the absence of a study section for vaccines 
has sometimes meant that the vaccine research is underfunded. 
How can these concerns be addressed, and how can Congress be of 
assistance in making NIH the engine of discovery?
    Dr. Fauci. A very important point, Ms. Pelosi, and we're 
aware of that. One of the ways you can do that, and it is short 
of creating a study section, because we've done it in other 
areas, is to create a special emphasis panel of review where 
you make known, as we have already done with the reconstituted 
advisory committee, about certain areas that absolutely need to 
be addressed. In fact, we've even gone so far as to establish a 
new kind of grant mechanism that is very rapid in its 
implementation, called an IDEA Grant, that has to do with the 
basic questions that need to be asked and answered in HIV 
vaccine research. You bring up a very good point. It is a 
problem and we are addressing it. I don't think there's 
anything that Congress could do. I think it is a question of 
being aware that we must look at these applications and the 
questions that they're asking in somewhat of a different light 
than just throwing them in the hopper with everything else.
    Ms. Pelosi. Is that it?
    Mr. Porter. I don't know. No, you've got a couple more 
minutes.
    Ms. Pelosi. Would Mr. Hoyer be able to finish?
    Mr. Hoyer. Mr. Chairman, you're going to have Dr. Fauci 
come back, is that it?
    Mr. Porter. Later in the year, yes, if the subcommittee 
wishes to do so, and I think they will.
    Mr. Hoyer. We have no members here, but I want Dr. Fauci at 
some point in time either to come before the committee or for 
the record to supplement Dr. Varmus' response on what clearly 
is going to be part of the debate when we mark this bill up in 
terms of how we allocate the resources to various diseases or 
Institutes within NIH. I think it is very important for us to 
understand on this committee, first of all, the fungibility of 
the research, if that's an appropriate way to refer to it, and 
secondly, the rationale behind the allocation that has been 
proposed. That was the question I was going to ask. I know we 
have a vote now, and I want Ms. Pelosi, who, in my opinion, is 
probably the expert, along with yourself, on this issue, to 
pursue her questions. But at some point in time, I want that 
question addressed by Dr. Fauci.
    Mr. Porter. Fine. If the gentleman would yield, I think it 
is a question that seems to be on the minds of a number of 
members and I think it might be an appropriate subject for us 
to have a panel from NIH to address together for us.
    Mr. Hoyer. Fine. That's an excellent idea, Mr. Chairman.
    Mr. Porter. Perhaps that's the way we ought to pursue it.
    Mr. Hoyer. I yield back to Ms. Pelosi.

                             new therapies

    Ms. Pelosi. If I could just make one comment in closing, 
and that is when we have Dr. Fauci back, I hope he would be 
prepared to tell us when we would have new therapies that are 
easier to tolerate for many people for whom there's hope of new 
drugs.
    Dr. Fauci. Yes. I would be happy to, Ms. Pelosi.
    Mr. Porter. I've asked Dr. Fauci to stay until 12:30. We do 
have a vote on. Are you going to be able to come back here, Ms. 
DeLauro?
    Ms. DeLauro. I cannot come back.
    Mr. Porter. That's what I was afraid of.
    Ms. DeLauro. I've got several questions but I can submit 
them for the record. There will be opportunity to ask them 
again at a later time. I think Mr. Hoyer has said it, and Ms. 
Pelosi has asked appropriate questions, and we have the kind of 
work that you have been doing that Ms. Pelosi has talked about. 
So I can submit my questions for the record.
    Mr. Porter. Well, we did not expect, at least I did not 
expect to have a vote that we're going to have to address. Mr. 
Dickey, have you voted?
    Mr. Dickey. That's a personal question. [Laughter.]
    Mr. Porter. Yes, I know. I'm going to ask you to take the 
Chair.
    Mr. Dickey. Oh, boy! [Laughter.]
    Mr. Hoyer. Mr. Chairman, I'm going to have to go vote with 
everybody else and will not be back. Obviously, these hearings 
are a little bit difficult for me. But I want to say to Dr. 
Fauci and his colleagues that I know how difficult it is when 
we confront disease. But Dr. Fauci, Dr. Varmus has been with us 
for a long time and I consider myself a good friend of his and 
totally subjective, as is Ms. Pelosi, when dealing with him. We 
have extraordinary people at the Institutes, at NIH. I 
particularly on the record want to say that I was not here for 
the Cancer Institute yesterday purposefully. I didn't think I 
could make that. But Dr. Rosenberg was incredibly supportive at 
a very difficult time for me, and I want to thank you.

                        office of aids research

    Mr. Dickey [assuming chair]. Thanks for sharing that, 
Steny. We've all been thinking about you.
    Dr. Fauci, I don't know if you've answered this question, 
but I would like to ask it of you. It seems redundant to have 
an Office of AIDS Research, OAR, in addition to your Institute 
which spends half its resources on AIDS. Couldn't the functions 
of OAR be handled by NIAID?
    Dr. Fauci. The NIH has a number of components besides 
NIAID. True, the NIAID is the major component of the AIDS 
research effort at the NIH, but it really spans multiple 
Institutes. The OAR, as it is constituted now, has functioned 
very well in the coordination of the research among the 
Institutes. We've had a very good working relationship with the 
OAR. So, I'm sure at any given time you could change the 
configuration, but the OAR actually is performing their 
function of coordinating research among the NIH Institutes.
    Mr. Dickey. Is it wasting money in any fashion by having a 
duplication?
    Dr. Fauci. No, I don't think that it's a money situation at 
all.
    Mr. Dickey. Why is it not a duplication?
    Dr. Fauci. Because the NIAID is an individual Institute. 
Since there are substantial efforts in other Institutes, such 
as the Cancer Institute, the Child Health Institute, and on and 
on, virtually every Institute, an office that is apart from the 
Institute is functioning in a coordinating fashion. There was 
concern about having an individual Institute be coordinating 
efforts of a variety of other Institutes as opposed to having a 
body outside of any Institute to coordinate the work of the 
individual Institutes.
    Mr. Dickey. Did you want to add to that?
    Dr. Varmus. Just that there have been very appreciable 
gains in just the past couple of years that could be 
attributable to the planning and evaluation processes of the 
OAR. The OAR, as you know, does not support research directly--
all of the research is done through the Institutes--but the OAR 
carried out a review of the entire AIDS portfolio that does 
involve, as Dr. Fauci mentioned, every Institute of the NIH and 
came up with a number of important recommendations that I think 
are going to make our expenditures in the AIDS field get more 
productive. It did not ask for more money for AIDS; it asked 
for better use of the money. I believe that attitude is one 
that actually contributes to a savings.

                       aids from other countries

    Mr. Dickey. Dr. Fauci, what are we doing as far as 
preventing AIDS from coming to us through other countries?
    Dr. Fauci. Well, that's not a question that I have any 
responsibility for. But I would not be concerned, as I 
mentioned before, about AIDS coming from other countries when 
you have about 800,000 people in this country already infected 
with HIV. So, if you were dealing with a disease that's 
transmitted by a respiratory route, then you would have a 
different kind of a situation.
    Mr. Dickey. I see.
    Dr. Fauci. Whereas, if you have a disease that's spread by 
a behavioral pattern, be that sexual behavior or intravenous 
drug use, since the pool of infected people in this country is 
substantial, I don't see any public health benefit in trying to 
keep out other people who are infected rather than educating 
the public on how they can avoid infection within this country.

                       aids cure versus treatment

    Mr. Dickey. Are your expenditures divided so that you can 
answer the question, what percent of your expenditures is being 
spent in the AIDS area on research to find a cure, and what 
percent is being spent on trying to cure people who already 
have AIDS?
    Dr. Fauci. If you look at the way we have the breakdown of 
the budget, according to what we call the NIH AIDS Plan, within 
that plan are two major categories that you're referring to. 
One is therapeutics, the other is vaccine, and then there is 
another called behavior that in some respects has to do with 
prevention. With regard to the percent of the total, 35 percent 
of what we do is for the treatment, either the development of 
drugs or the clinical trials of individuals. In our Institute, 
15.7 percent is on vaccines. For the NIH as a whole, it's going 
up each year but it is somewhat less than 10 percent, about 8.9 
or 9 percent. But in the NIAID it is 15.7 percent. And in our 
Institute we have a relatively small amount on behavior 
research. But Institutes such as the Mental Health Institute 
and the Drug Abuse Institute have a substantial amount more on 
behavior.
    Mr. Dickey. I'm not getting enough numbers here. I wanted, 
and I don't mind it being divided three ways, behavioral, 
preventive----
    Dr. Fauci. Behavioral, vaccine, and therapeutics.
    Mr. Dickey. Okay. And therapeutics is after you get it.
    Dr. Fauci. Therapeutics is drug development and clinical 
trials, and that's after you get it; correct.
    Mr. Dickey. Bring me to 100 percent on those.
    Dr. Fauci. Okay. The rest is 14.8 percent in what we call 
the epidemiology or natural history, where we follow cohorts of 
individuals who are infected and follow them and look at the 
transmissibility from mother to infant or among sexual 
partners.
    Mr. Dickey. Isn't that aimed toward curing it or finding a 
cure?
    Dr. Fauci. That overlaps with virtually every aspect, 
because they are cohorts of patients that we study that you can 
examine pathogenesis in them, you can initiate them into 
clinical trials, and even some cohorts of individuals who are 
not yet infected might be put in a vaccine trial.
    Mr. Dickey. Are we spending more money on taking care of 
the patients who have AIDS, or are we spending more money on 
trying to find a cure?
    Dr. Fauci. Right now, percentage-wise, there is more money 
in trying to find a therapy, as I discussed earlier, for the 
treatment of infected people as opposed to preventing it. But 
if you look at the trend of where we're going over the last 
couple of years, the vaccine trend is steadily increasing at a 
time that the therapy has stayed either flat or is coming down 
somewhat. The trends are going now much more towards prevention 
either with a vaccine or with behavior modifications. But if 
you look at the numbers, there's more money going to treatment.
    Dr. Varmus. One comment, Mr. Chairman. It is inherent in 
nature of clinical trials that they are expensive. Therefore, 
it is probably not fair to look at the effort solely in 
monetary terms. The number of answers you can get may be 
equally great with a smaller amount of money in the prevention 
area. You heard that there is hesitancy on the part of 
pharmaceutical industries to enter into the vaccine area 
because of a lack of fundamental ideas about how to approach 
vaccine development. So there may be a large number of small 
projects, any one of which might give the inspiring result that 
would then result in development of a vaccine; whereas, 
probably, simple ideas for testing the various combinations of 
drugs, which Dr. Fauci alluded to, is a very expensive process 
involving hundreds or thousands of patients and many different 
combinations of drugs.
    Mr. Dickey. Do you share talent in those two areas, 
therapeutic and vaccine?
    Dr. Fauci. Definitely.
    Mr. Dickey. You do?
    Dr. Fauci. Yes. Not only do we share it in those two 
distinct categories, but, as Dr. Varmus just alluded to, those 
categories are very heavily fed into by the basic researchers 
that are looking at the pathogenesis, either the viral or the 
immunological pathogenesis, and both of those areas feed 
directly into both therapeutics. In fact, we have trials of 
therapies that are called pathogenesis-based and all of 
pathogenesis, or understanding how the virus works, will 
ultimately feed into vaccine development. That's the reason 
why, as appropriately referred to by Dr. Varmus, it is 
sometimes misleading when you look at strict coding of how you 
spend money because of the overlap and spill-over from one to 
the other.
    Mr. Dickey. I understand that.
    Dr. Varmus. To give you one very straightforward example. 
You've heard a lot about viral mutants. That is a particular 
problem with viruses, especially viruses like HIV, that become 
resistant to therapies and are potentially resistant to 
protection by vaccines. Attempts to understand the source of 
genetic change in these viruses, to categorize the viruses by 
genetic makeup, is fundamental to all the areas you've heard 
about. People who are studying the genetic properties of HIV 
have to be in touch with all the areas you've mentioned.

                          behavioral research

    Mr. Dickey. What are you doing in behavioral?
    Dr. Fauci. In my Institute, the behavioral research that we 
do at NIAID is linked very closely to two components. One is 
the vaccine effort where we are building up cohorts that might 
ultimately serve as the group that we would try a vaccine on. 
Inherently built into that is behavioral modification.
    Mr. Dickey. Does that include abstinence?
    Dr. Fauci. Oh, absolutely.
    Mr. Dickey. How are our Federal dollars encouraging 
abstinence in the AIDS area?
    Dr. Fauci. If you look at the instructions of when you put 
someone in a vaccine trial, there are discussions of doing 
whatever you possibly can to avoid infection, and that's both 
for the people who are going to receive the vaccine as well as 
for the people who are not going to receive the vaccine. It is 
very clear and right up front that the most surefire way of 
avoiding HIV infection is abstinence, number one, and number 
two, if you're going to have sex with a person whose HIV status 
you are not sure of, then you use a condom. That's very clear. 
That's now essentially in every public health discussion that 
you have about prevention.
    Dr. Varmus. In fairness to Dr. Fauci, a number of the 
studies that address the issue of abstinence, that you've 
raised with me before privately and are now raising with him, 
are under study in other Institutes--the Child Health 
Institute, and the Mental Health Institute. There are a number 
of----
    Mr. Dickey. On AIDS?
    Dr. Varmus. Yes, absolutely. Many programs have 
incorporated a consideration of sexual avoidance or abstinence 
in relation to HIV transmission. Obviously, we understand that 
abstinence is very good protection. But how do you get there? 
One of the interesting things that we've learned is that in 
instructing children and young adults about the risks, it is 
very important to be explicit about sexual practices. There is 
early evidence from some of these attempts to understand the 
role of sex education and education about sexual habits that it 
is important to understand that if individuals don't learn 
about the means for protection, when they actually engage in 
sexual activity later that they put themselves at higher risk. 
There is some evidence already that individuals who have simply 
learned that abstinence is important without being similarly 
educated about the need for protection engage in much higher 
levels of risky behavior when they do become sexually active.
    Mr. Dickey. Mr. Miller, do you want to ask some questions?

                          protease inhibitors

    Mr. Miller. Thank you, Mr. Chairman. It is always a 
pleasure to see you. It's always exciting to be going through 
this series of sessions because I learn so much.
    Let me start off with the issue of protease. I remember 
last year talking about the issue of whether there was a 
breakthrough. First of all, when were protease inhibitors made 
available commercially?
    Dr. Fauci. It became available within the last year. The 
initial trials were a year ago last fall. The first licensure 
for it came about six months after that, last spring. So 
they've been out now about a year commercially available.
    Mr. Miller. Just before we had our hearing last year.
    Dr. Fauci. Right. Exactly.
    Mr. Miller. The question was raised then, in our 
discussion, ``is this a breakthrough?'' I forget how you 
qualified it. How do you evaluate that now? And has anything 
else come up more significant than protease since that last 
time?
    Dr. Fauci. In answer to the question, as Dr. Varmus joked 
about yesterday, I rarely, if ever, call anything a 
breakthrough, but I would say that this has now turned out to 
be an extremely important therapeutic advance. No question 
about that. [Laughter.]
    Mr. Miller. ``Therapeutic advance.''
    Dr. Fauci. Yes. The point that I made, I don't believe that 
you were there when I was presenting it in my formal 
presentation, is that there is some confusion about how good 
this will ultimately turn out to be. If it does nothing other 
than what we've already observed it can do--namely, profoundly 
bring down the level of virus in many cases to below detectable 
level, associated with a clear-cut clinical benefit in people 
with advanced disease, and, in my opinion, will likely also be 
shown, as the clinical trials come to fruition, to have a 
clinical benefit in people who get the combinations with 
protease even earlier in the course of the disease--that, we 
know, is a very important advance in and of itself. If you want 
to call that a breakthrough, you can call that a breakthrough.
    The questions that remain open, since we know this is an 
extraordinary illusive virus and these drugs are very potent 
and can have terrible toxic side effects and can be difficult 
to take over a long period of time, are two among several very 
important questions: one, will the cumulative toxicity over a 
period of two, three, four years lead to an imbalance or 
somewhat negating the beneficial effects; and number two, will 
the emergence of resistant mutants in those individuals who 
haven't had complete suppression of the virus' ability to 
replicate, will those mutants now come back with a vengeance, 
as it were, and be refractory to other drugs.
    That gets us to the thing that you alluded to in your 
second question, which is: has anything else come along. What 
has come along have been other protease inhibitors that are 
more than just complementary to the existing ones in that they 
induce a resistant mutant that's a little bit different than 
some of the originals. Which means that if you give them, and 
there are various trials that they are now undergoing, two 
protease inhibitors either alone or together with the AZT class 
of drug, we want to determine if that can actually give you 
even more benefit than having the triple combination with one 
protease inhibitor.
    The other answer to your second question is that we are 
constantly looking for new targets in the life cycle of the 
virus. I gave an example of one, which was serendipitous, as it 
were, with regard to AIDS research, the discovery of a 
particular receptor that the virus absolutely needs to get into 
the cell but which may not necessarily be absolutely essential 
for the survival of the person. So that if you block that 
receptor, you might be able to profoundly interfere with the 
ability of the virus to replicate.
    There's an intensive amount of activity going on in biotech 
firms, et cetera, to try to develop molecules that can be used 
to interfere with that binding side. So there are other things 
going on. We're constantly looking for new targets and/or new 
drugs for the same targets.

                                 media

    Mr. Miller. Yesterday, we had Doctor Klausner from the 
Cancer Institute. I saw him on ABC News earlier in the week and 
it was about a new idea, which you brought up here a few 
minutes ago. The question I asked him is regarding the 
treatment of the media to scientific breakthroughs. Kind of 
like the Newsweek phenomena. The implication is maybe that 
headline is not what you would have written.
    Dr. Fauci. No, definitely not.
    Mr. Miller. How much of a problem is that? I read it, and 
this was Newsweek, and I watch ABC News whenever I get a 
chance, or MacNeil-Lehrer, and Business Week is always 
interesting because they have that material a lot of times 
because of the financial interest. But it is always interesting 
how the media overplays certain areas.
    Dr. Fauci. Right. So how much of that is a problem for me?
    Mr. Miller. Yes. How much of a problem is that with you, 
and then maybe Dr. Varmus would make a comment, too.
    Dr. Fauci. Actually, to be honest with you, none as a 
scientist. The problem, if there is a problem, is trying to 
clarify, and we have to put in more time on that. I have spent 
a considerable amount of time trying to be the moderating force 
in this hype aspect of the drugs. Even though the drugs are 
quite good, I have found that the media has perhaps pushed it 
over in the eyes of the general public to be a little bit more 
than we know it actually is right now. But from a scientific 
standpoint, it doesn't really have any impact on what we do. 
And it involves several of us here in the room; it involves Dr. 
Varmus, who doesn't get impressed with that at all, and, in 
fact, has his areas of emphasis based on scientific 
opportunity, not what's in the newspaper. Quite frankly, I also 
applaud not only the administration for not responding to that, 
but also the appropriations subcommittee--Mr. Porter, yourself, 
and all the other members of the subcommittee--for allowing us 
to make scientific decisions based on the scientific 
opportunity and not what's in Newsweek. So I'll end my answer 
by saying thank you for not making it a problem for me.
    Mr. Miller. I remember reading about Dr. Ho, I believe, 
that won the Nobel Prize. He was very reluctant, at least in 
what I was reading, because why should one person be singled 
out? That is a very legitimate question when there is a wide 
range of people contributing to that.
    Do you have any comment, Dr. Varmus?
    Dr. Varmus. I think Tony has covered many of the important 
aspects. We appreciate the attention that's being paid to 
medical science in these articles. Sometimes they have an 
emphasis that we may not share, but the fact is that Time 
magazine devoted nearly an entire issue to research on AIDS. 
They did endow many of the properties in the field on a single 
individual, but it made the story better reading. Time magazine 
also recently ran a wonderful piece about early development of 
the nervous system, featured on the cover. And there's been a 
tremendous interest in genetics. All of this has had a very 
strong educational influence on the public and has had a role 
in attracting young people to the ferment that exists in 
biomedical research.

                               hemophilia

    Mr. Miller. I guess the point is that it makes the American 
people feel good that there are some good things that 
government is doing, and this is obviously one of the good 
things.
    Let me switch my line of questioning to an area that I'm 
very interested in, which is hemophilia. The statistics have 
levelled off with respect to hemophiliacs. Their exposure was 
way back in the early 1980s or whenever and I assume blood is 
not now a major factor any more.
    Dr. Fauci. No.
    Mr. Miller. And most of it is either drug related or sexual 
transmission. I think the gay community has levelled off too, 
as I understand.
    Dr. Fauci. Yes.
    Mr. Miller. But specifically hemophilia, how does it relate 
to the effectiveness of treatment today versus others? Do drug 
users have a different reaction versus the gay community and 
all for the different protocols available?
    Dr. Fauci. No. We have as a component of our AIDS Clinical 
Trial Group, our ACTG that you hear me refer to frequently, the 
Hemophilia Foundation as a designated AIDS clinical trial unit 
with several subunits. So we have incorporated the treatment of 
hemophiliacs into our AIDS treatment agenda in a totally 
integrated manner. As we can tell thus far, they respond to the 
drugs in the same manner as individuals who have been infected 
from other routes.
    Mr. Miller. There's no difference then?
    Dr. Fauci. No. No.

                              drug issues

    Mr. Miller. Okay, onto the drug issue. The drug companies--
is there any problem about the sharing of information with the 
drug companies between themselves, and the fact of the 
potential amount of money here is enough incentive for a lot of 
them getting into it. In cancer there is a much larger market 
dollar-wise from an investment standpoint.
    Dr. Fauci. Right.
    Mr. Miller. How does that play in this whole issue?
    Dr. Fauci. There are a couple of parts to your question. 
With regard to HIV therapeutics, there certainly is an 
extraordinary market for that. So there's not any constraints 
of companies getting involved because what they don't see as a 
profitable market margin for them. So that's not a question.
    With regard to sharing information, whenever you have 
proprietary rights to something there is always the question of 
companies sharing information. But I must say I was very 
gratified a year-and-a-half, two years ago when some of the 
major drug companies brought themselves together in a 
consortium whereby they shared their Phase I or earliest data 
with each other so that other companies wouldn't go down a 
track that is a non-fruitful track that one of the other 
companies already did. It is the first time to my knowledge 
that I've ever seen that. The reason they did it I think was 
twofold. One, I think there was a bit of altruism in it. But 
also it was good for the companies because it was a give-and-
take, they could learn something from another company about 
what direction they went. As it turned out, that has turned out 
to be very, very fruitful.
    What we're also seeing now is more collaborations among 
companies in donating their drugs for a clinical trial to 
compare them head-to-head. A typical example was the 
Glaxowelcome/Merck collaboration on the study that I referred 
to just a little while ago where AZT and 3TC came from Glaxo 
and Merck gave us the Crixivan and Indinovir. So although you 
have competition, which is good, I think what we're seeing 
right now is a considerable amount of collaboration that you 
would not have predicted if you had thought that the market was 
very secretive. It isn't.
    Mr. Miller. Thank you. Thank you, Mr. Chairman.

                                malaria

    Mr. Porter [resuming Chair]. Thank you, Mr. Miller.
    Dr. Fauci, there seems to be a resurgence of interest in 
the research community in malaria. The disease kills more than 
one million people a year. Efforts to develop a vaccine have 
been unsuccessful, and many anti-malarial drugs are becoming 
ineffective because of resistance. But early reports of a new 
vaccine candidate developed at Walter Reed are encouraging. A 
large malaria genome sequencing project is underway, and a 
major conference in Africa in January brought together 
scientists, including Harold Varmus, to kick off a new 
coordinated plan to attack malaria. With this encouraging news 
on several fronts, do you think it is likely that effective 
therapeutics and perhaps even a vaccine will be developed 
before we lose the battle against drug resistance?
    Dr. Fauci. The answer is that the battle against drug 
resistance is an ongoing battle. It is not a single battle that 
you win or lose. If you go to certain parts of developing 
countries, a substantial fraction of the malaria there will be 
drug resistant. What we're seeing now, and I feel very good 
about it, and there has really been a considerable amount of 
help from Dr. Varmus who has been very interested personally in 
this and has actually, as you mentioned, gone to Africa, is a 
resurgence of interest of combining the new technologies, for 
example, of being able to sequence the genome of microorganisms 
including the malaria microorganism, but also of getting the 
countries involved. We call them ``Host Countries,'' countries 
in which you do clinical trials, to get their scientists 
involved and utilize the resources of their country as well as 
our own country, and, in addition, to train them to really be 
partners with us. That's something that we've seen little bits 
of but never really in a full-blown effort, and we're starting 
to see that now. So, again, it is a convergence of the age of 
molecular technology, the ability to approach the question of 
resistance from that standpoint, as well as the idea of a 
vaccine. So I think things are going to be going in much more 
accelerated fashion with regard to malaria than they have been 
in the past.
    Mr. Porter. Dr. Varmus, do you want to comment on that?
    Dr. Varmus. Just briefly because Tony has covered many of 
the important points. One of the things that you learn when you 
go to Africa to see malaria in its native setting is that--
while there is tremendous need for new research opportunities 
that will come from the malarial genome project and from more 
emphasis on vaccines and drug development and better 
understanding of the life cycle of the organism--there is also 
the need for research at the local level that addresses 
epidemiology, treatment patterns, health services research. One 
of the things that you learn very quickly is that in certain 
parts of Africa drug resistance is not really the problem at 
all. Drug resistance is very sparse in these places, but the 
real problem is getting the right drugs to the right people at 
the right time, and having people be able to recognize disease 
in young children where it is frequently lethal in the cerebral 
malaria form.
    One of the things that I found very heartening was that in 
areas such as Mali--where NIH has established a research 
foothold, building a very excellent research team headed by 
African scientists--that the field stations that are used by 
those laboratories as sites for research on epidemiology and 
pathogenesis become treatment areas. In these places, the 
disease is controlled even though the infection rate is still 
extremely high from the tremendous number of Anopheles 
mosquitoes carrying the organism. But treatment is prompt, 
people don't die of the disease, and people learn about the 
disease. In many parts of Africa it is not understood that the 
mosquito is the transmitting agent, but it becomes very 
apparent when people are being recruited into the studies to 
capture mosquitoes that this is the way it is transmitted. That 
knowledge spreads to other communities, and other kinds of 
health benefits, like digging wells to prevent infantile 
diarrhea, follow from these initiatives on malaria.

                        tuberculosis and cholera

    Mr. Porter. Do you think a similar concentration of effort 
is necessary in the worldwide fight against tuberculosis and 
cholera? What makes these conditions different from malaria?
    Dr. Fauci. The answer to the question is yes. Both of those 
could benefit. You may be aware that we have accelerated 
greatly our tuberculosis effort both on the national and 
international front. Just a few short years ago, the 
tuberculosis effort in the NIH was just a few million dollars. 
We now have it up in my Institute alone to $37 million and 
there is activity in other Institutes as well. Cholera. We're 
testing a new cholera vaccine which we feel has some hope in 
giving us some good results with regard to cholera.
    They're different because of the complexity. Cholera and 
tuberculosis are really spread from person-to-person. Both of 
them are bacteria. Malaria is a parasite, a larger organism 
that has an intermediate vector, the mosquito. The complexity 
of malaria compared to tuberculosis, which is a difficult 
enough problem, as is cholera, is related to the fact that you 
have the vector itself to deal with. So it is a mosquito 
problem, a vector borne disease. The other is essentially a 
person-to-person disease. With cholera, it is because of the 
contamination of water supply. With tuberculosis, it is 
generally respiratory borne.
    Dr. Varmus. But you shouldn't go away with the idea that 
we're spending tremendous amounts of money on malaria. We spend 
only about $20 million at NIH. The NIH is the largest funder 
worldwide of malaria research. So our spending in the area of 
malaria research, despite the new initiatives for 
collaboration, is still, in my view, very small in relation to 
the magnitude of the problem.
    Dr. Fauci. Yes, this falls under the category of something 
that I've said several times before the committee. That is the 
discordance between the scientific opportunity and the 
resources available. You could look at a disease like 
tuberculosis, cholera, malaria, or even several others, 
notwithstanding the extraordinary world burden of it, there are 
scientific opportunities that don't match the resources that 
are in them. I can say that very clearly without any holding 
back. There's no question the opportunities we have in all 
three diseases that you just referred to are far greater than 
the resources that are in them.

                            hansen's disease

    Mr. Porter. Dr. Fauci, you've agreed to support in 1998 the 
Hansen's Disease research formerly funded by the Health 
Resources and Services Administration's Carville appropriation. 
What are your plans for continuing this effort in 1999? And 
will you open up Hansen's Disease research through competition 
to a potentially different set of researchers?
    Dr. Fauci. The answer to the question is yes. The way we 
have it now, we have had $3 million that has been put into our 
appropriation for the Hansen's Disease research that is going 
on now in Carville, in Louisiana, with the instructions that it 
should ultimately be turned over into a competitive grant line. 
In 1998, since it is difficult to so quickly do that, we're 
passing through the money back to them, and then in 1999 we're 
going to recompete and open up the granting process to anyone 
who wants to put in for a grant. So by the year 1999, it will 
be competed at the level that anyone either down in Louisiana 
or elsewhere could compete for that money.
    Mr. Porter. Dr. Fauci, thank you very much for your 
willingness to stay late. I have to say to both you and Dr. 
Varmus, you've seen from the questions today that there's a 
certain amount of concern on the subcommittee about the 
allocation of resources to different areas of health concern. I 
believe that what we probably ought to do, Dr. Varmus, is to 
bring back yourself and Dr. Fauci and the Institutes most 
concerned with cancer, heart, diabetes, and maybe some others 
and have a panel here where we can allow the subcommittee to 
raise these questions and get answers from everyone.
    Dr. Varmus. I think that would be extremely instructive.
    Mr. Porter. Wouldn't that be helpful?
    Dr. Varmus. Yes.
    Mr. Porter. And then we could perhaps raise other issues 
that we have not been able to cover in the abbreviated time 
we've had today. I would ask you to work with us on finding an 
appropriate time when everyone might be free. Perhaps setting 
it early, now, in other words, for sometime in April or May 
might serve everyone's interest best. We will be in touch with 
you about this and see if we can set aside maybe half a day or 
maybe even longer.
    Dr. Fauci. I would be happy to do that.
    Mr. Porter. Dr. Fauci, thank you for the absolutely 
wonderful job you do for humankind; not only for NIAID, and for 
health in general. You're one of our real treasures. Thank you 
so much.
    Dr. Fauci. Thank you very much.
    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 622 - 710--The official Committee record contains additional material here.]


                                       Thursday, February 27, 1997.

          NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

                               WITNESSES

KENNETH OLDEN, PH.D., DIRECTOR
SAMUEL H. WILSON, M.D., DEPUTY DIRECTOR
CHARLES E. LEASURE, JR., ASSOCIATE DIRECTOR FOR MANAGEMENT
LAURIE JOHNSON, BUDGET OFFICER
HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH
BILL BELDON, [DIVISION DIRECTOR, OFFICE OF DEPUTY ASSISTANT SECRETARY] 
    BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES

    Mr. Porter. The subcommittee will come to order.
    We're pleased to welcome Dr. Kenneth Olden, the Director of 
the National Institute of Environmental Health Sciences, for 
his testimony. Dr. Olden, would you introduce the people who 
are with you and then proceed.

                       Introduction of Witnesses

    Dr. Olden. To my far left is Ms. Laurie Johnson. She's 
Director of the Budget Office. The Deputy Director, Dr. Sam 
Wilson; Mr. Charles Leasure, and you know Dr. Varmus, and Mr. 
Bill Beldon is on the end representing the Department.

                           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 of Environmental Health 
Sciences. The development of environmental regulatory policy is 
one of the most problematic areas of Congressional 
responsibility. This is a problem area, because there's too 
little scientifically sound information on which to base 
decisions.
    When there is too little information, there can be no 
satisfactory solution to the complex issues surrounding human 
exposure to environmental pollutants and health outcomes. In my 
testimony today, I want to outline a vision for environmental 
health science research that will transform environmental 
health decision making. A vision based on four critical areas 
of science. Areas where major information gaps exist, areas 
where reasonable research questions can be formulated, areas 
where technologies are available, and areas where understanding 
offers the potential to significantly improve public health and 
regulatory policy.
    First, research is urgently needed to determine the basis 
for the wide variation and individual responsiveness to 
exposures to environmental toxicants. To address this problem, 
NIEHS proposes to expand its molecular genetics research to 
identify susceptibility genes for environmentally induced 
diseases through a new Environmental Genome Project. This 
genome project will be a broad multi-center effort to obtain 
information about DNA sequence diversity for the U.S. 
population on all the environmental susceptibility genes 
identified to date.
    Second, there is an urgent need to develop new approaches 
for toxicological testing, to cut costs and to increase 
timeliness. If we are going to work our way through the 
thousands of chemicals to which humans are exposed, we must 
develop bold new screening strategies. Technologies are now 
available to develop new high through-put technologies to 
screen that are less costly and more relevant to predicting 
human health. And they should be more timely in terms of 
generating the information. Identification of carcinogens and 
other toxicants can be reduced from years to days.
    Third, investigation of the mechanism of the health effects 
of mixtures is another area where lack of scientific 
information is a problem. The current toxicologic data bases 
were developed using single chemicals in animal bioassays. As 
we all know, humans are exposed to a variety of chemicals in 
the form of mixtures. Depending on the assumptions made 
regarding the nature of the interaction between components of 
the mixture, risks may be either seriously over or under 
estimated with dire economic and public health consequences. 
NIEHS proposes to develop high through-put biologically based 
screening procedures to address this problem.
    And lastly, a major challenge is to strengthen the links 
between environmental science, toxicology, epidemiology and 
public health. To achieve this objective, NIEHS proposes to 
monitor human exposure to specific chemicals in our environment 
by measurements in body tissues such as blood and urine. Such 
real world exposure assessment would be far more useful than 
the estimation of exposure based on the EPA toxic release and 
production information as is currently done. Estimation of 
exposure based on toxic release and production information is 
at best only a reflection of the potential for human exposure.
    In conclusion, progress in the four areas of research 
emphasized offers real world answers to the quagmire of 
indecision and discontent as a consequence of having too little 
information. Our vision of a more science-based environmental 
health regulatory decision system is achievable, given today's 
technology. The President's budget request for NIEHS is 
$313,583,000. I would be happy to answer any questions that you 
might have.
    [The prepared statement follows:]

[Pages 713 - 716--The official Committee record contains additional material here.]


                            funding increase

    Mr. Porter. Dr. Olden, thank you for your excellent 
statement.
    I notice that the rate of increase for your institute is 
higher than the rate of increase for NIH generally. I assume 
you think that is a very good sign.
    Dr. Olden. I'm very pleased with that.
    Mr. Porter. My question is, does this reflect expenditures 
on the new screening procedures that you described in your 
testimony, or is this apart from that?
    Dr. Olden. Well, if I may go back a bit, it probably 
reflects a number of things. And certainly the resources that 
we are requesting will at least in part be used to address the 
new issues. And these are new issues for NIEHS. And we think 
they are extremely important. I think we've convinced Dr. 
Varmus that these are important new initiatives and I guess 
that's at least one of the explanations for why we are enjoying 
a good budget increase recommendation.
    But let me say, over the years, the Institute has not fared 
as well as some of the other institutes. So in fact, maybe it's 
at least in part a recognition on Dr. Varmus' part of the 
important public health problems that this Institute must 
address. Other institutes have important problems as well, but 
the point is, to deal with these issues I just mentioned. It 
creates problems for Congress in making decisions about what is 
the appropriate standard. I think we have to do the science in 
order to answer these questions to put risk assessment on a 
solid scientific foundation.
    Mr. Porter. Dr. Varmus, would you like to comment also?
    Dr. Varmus. Just briefly, since we've been talking about 
priority setting. The fact that one institute happens to be a 
half percent or a quarter percent or even 1 percent above some 
of the others, does not represent an evaluation of that 
institute or an attempt to remedy what may be perceived as past 
inequities. Because almost every institute feels it's been 
penalized at some point in the past.
    It represents a decision by me and my colleagues to place 
money on initiatives which are frequently trans-institute in 
nature. And what I try to avoid is getting into a discussion of 
the pecking order of institutes based on hundredths of a 
percentage point difference and instead, look to support new 
initiatives, of which the NIH has many good ones this year. And 
that may account for NIEHS being slightly above the others.
    Mr. Porter. Yes, sir. My question was, does this reflect 
the cost of the new screening procedures? I wasn't suggesting 
anything different at all. And I simply wanted to know whether 
that was included in this budget figure, which obviously is a 
high priority.
    Dr. Olden. Yes, absolutely. The Environmental Genome 
Project is a high priority. And we will make the investment 
with it in 1998.
    Mr. Porter. And you didn't skirt around Dr. Varmus and talk 
to the President directly to get this?
    Dr. Olden. No, we did not. [Laughter.]

                     vitamin d and prostate cancer

    Mr. Porter. Last December, researchers at your Institute 
reported that men with a particular vitamin D receptor appeared 
to have only a third the risk of developing prostate cancer 
requiring surgery. How does vitamin D play a role in prostate 
cancer?
    Dr. Olden. Well, vitamin D is protective. And that's been 
known for some time. And what the investigator at NIEHS 
demonstrated was that, depending on the level of activity, 
whether the receptor was active or inactive, it increased the 
susceptibility to prostate cancer. In other words, if one had 
an inactive receptor, then the protective effect was not 
observed.
    Mr. Porter. No matter how much vitamin D you might absorb 
or take?
    Dr. Olden. Exactly. It could not be metabolized. So this is 
an example of the kind of research that I had in mind when I 
talked about looking at differences in susceptibility. And 
that's just one of them.

                                mixtures

    Mr. Porter. In January, NIEHS scientists reported that 
three existing tests used in combination provide a rapid 
assessment of whether chemicals have estrogen-like qualities. 
This topic of environmental estrogens has been hotly debated in 
the past year. What can these new tests contribute to the 
debate that was unavailable previously?
    Dr. Olden. Well, that gets at the issue of mixtures. And I 
said, we don't know whether agents in mixtures--estrogens or 
otherwise--act additively, synergistically or even 
antagonistically. In the papers that were reported by 
scientists who used to work at NIEHS, but did not at the time 
we reported those studies, it was determined that estrogens, in 
the particular yeast assay systems that they used, acted 
synergistically. In other words, the response together was 
elevated by more than a thousand-fold.
    Potentially, that was very significant. Because of the 
threat that even low level exposures to a mixture of estrogens 
could be a significant health effect. Last year, I testified 
before this committee that my impression was that the low level 
exposures to synthetic or man-made chemicals would probably be 
dwarfed by exposures to natural estrogens, and that my opinion 
was that man-made chemicals probably did not represent a health 
threat.
    But if their observations were found to be correct, then 
that would be a very significant and important finding. 
However, I must point out that a number of other investigators, 
using different yeast systems, have been unable to repeat that 
observation in other systems. We are bringing all of the 
investigators together at our Institute in the near future to 
try to resolve the differences in the observations between the 
one laboratory and many others who were unable to get the same 
results. But admittedly, in different yeast systems.
    So I guess the answer is, we don't know what it means. 
Because that may be simply a unique or artifactual observation 
for that one system.

                          endocrine disruptors

    Mr. Porter. The Environmental Protection Agency by statute 
is required to evaluate the risk of chemicals to the endocrine 
system. In addition, EPA is funding a two-year National Academy 
of Sciences study on the health impact of synthetic and natural 
substances that have estrogen-like effects. Has EPA taken the 
lead role in this area of science, and how does your research 
on endocrine disruptors mesh with their research portfolio?
    Dr. Olden. Well, EPA has not taken the lead role. We've 
been involved in this research area for over 20 years. What EPA 
is doing mainly is two things. Most of their estrogen-related 
research is directed towards ecology, for one. And the other is 
to develop risk assessment methodologies. Our research is 
coordinated at two levels, or at two official and formal 
levels. First is through the Environmental Health Policy 
Committee of the Department of Health and Human Services, which 
is chaired by the Assistant Secretary. In fact, we met on 
Tuesday of this week with the Assistant Secretary, EPA, to 
discuss the Government estrogen-related research.
    So it is coordinated through the Environmental Health 
Policy Committee. It is also coordinated through the CENR, 
which is the Committee for Environment and Natural Resources of 
OSTP. There is a subcommittee of CENR that deals specifically 
with estrogens. And we co-chair that subcommittee with EPA and 
the Department of Interior. And again, the purpose of the 
subcommittee is to coordinate estrogen research across the 
Federal Government. We've done an inventory of the research in 
the Federal Government, so it is closely coordinated formally 
through those two committees.
    Now, when EPA recently funded their estrogen grants, they 
consulted with us to make certain that they were not funding 
research that we were already funding. In some cases we agreed 
that we had not funded adequate research because of limitation 
of resources. And they are co-funding some projects with us as 
a consequence of that consultation.
    So the research is very closely coordinated, not to mention 
that the Health Effects Laboratory is right down the street 
from NIEHS in Research Triangle Park. And so there is also 
informal interaction to make certain that there is synergy 
between the two programs.

                          congressional visit

    Mr. Porter. Speaking of Raleigh-Durham, we are attempting, 
as you are aware, Dr. Olden, to get our subcommittee, as many 
members as can do so, to come down and visit you. Because 
you're off there by yourself and we want to have a chance to 
see what you're doing. And if the other facilities are nearby, 
maybe that would work out very well.
    Dr. Olden. Thank you very much. We are looking forward to 
your visit.
    Mr. Porter. Both of us have to talk to Dr. Varmus about 
this.
    Dr. Olden. Dr. Varmus has been down recently, and we 
enjoyed having him.

                       new testing methodologies

    Mr. Porter. Tell us more about your Beat the Mouse 
experiment in which researchers are testing alternative methods 
to predict whether 30 chemicals cause cancer before the results 
are available from a series of standard rodent tests. Has 
anyone crossed the finish line yet?
    Dr. Olden. No, but they will, the results will be reported 
out soon. In our November meeting of our advisory committee, 
the results will be revealed, and we'll see. We are 
anticipating that we will have at least 30 chemicals that have 
been tested through the traditional classical two-year rodent 
bioassay and have also been tested through our transgenic 
animal models in a period of six months at a reduced cost. And 
we are hopeful that the results will demonstrate that the 
transgenic animal models are just as effective in identifying 
carcinogens, both genotoxic and non-genotoxic, as the two-year 
rodent bioassay.
    Mr. Porter. Assuming that's true, how many increased 
chemicals can you test in, let's say, a year, with this faster 
procedure, if that's factual?
    Dr. Olden. Well, we haven't, I can't tell you what the 
costs for the transgenics are exactly. We are testing about 10 
in the rodent bioassay now. We think with the same dollars, we 
could test about 40 new ones.
    Mr. Porter. Four times as many?
    Dr. Olden. That's what we think. Now, let me say that the 
tests that I just described in my testimony, the high through-
put technologies, we are very excited about those. We've had 
discussions with people in pharmaceutical industries. The 
technologies are available so that we should be able to screen, 
if we make the investment into the technologies, we should be 
able to screen a hundred or more chemicals per year for the 
same dollars. So it's mind-boggling, what the potentials are. 
It is simply the fact that we've never made the commitment to 
develop these new tests. And we are excited about them.
    During my tenure as Director of the Institute, I am 
confident that I can come back here and report exciting results 
about these new tests. And we've consulted people in the 
scientific community, and they are eager and excited, and tell 
us that these things can be done. But for the first time, we 
will be asking them to do them.

                      environmental genome project

    Mr. Porter. Before I call on Mrs. Lowey, I wonder if you 
would explain to us more about the environmental genome project 
that you mentioned in your testimony.
    Dr. Olden. I present it to you somewhat prematurely, let me 
say that. I have had brief preliminary discussions with Dr. 
Varmus. This is in a sense a trans-NIH effort. And what we are 
going to do, as a matter of fact, is we have a date I think 
some time in March, to meet with Dr. Varmus, Dr. Collins and 
Dr. Klausner, and some other staff to talk about this project. 
We are confident that it doesn't overlap activities going on in 
the Human Genome Project or in NCI. But we want to make certain 
of that. We think there is synergy between the two projects.
    The Human Genome Project is identifying disease genes, but 
not the ones that interact and are affected, influenced by, the 
environment. In our case, an individual could inherit an 
environmental susceptibility gene and not have a disease at 
all. In fact, the only way that that person would be at 
increased risk would be in a certain or specific environment, 
that is, when exposed to a specific environmental agent.
    For example, recently one of our investigators demonstrated 
that individuals who have either none or very low levels of a 
detoxifying enzyme called glutathionine-s-transferase, cannot 
detoxify certain toxic chemicals. Those individuals then are at 
increased risk. But they are only at increased risk if they are 
exposed to the chemicals that glutathionine-s-transferase 
detoxifies.
    We also reported that one of our grantees recently reported 
that individuals differ in their susceptibility to 
organophosphate. We were interested in it and reported it to 
you because it's a component of nerve gas, Sarin. It is also a 
component of a lot of pesticides. One of our grantees 
demonstrated that there is an enzyme that detoxifies the lethal 
form of the organophosphate pesticides. And individuals who 
have a defect in that enzyme are more susceptible to nerve gas, 
because the organophosphates nerve gases inhibit choline 
esterase. So they inhibit nerve transmission.
    So these are the kinds of genes, that we will go after. 
There's roughly 200 identified to date. What we will try to do 
is sequence those 200 or so genes and ask what is the 
variability in the population, and can that account for the 
differences in susceptibility.
    Now, when we have that kind of information in hand, then we 
can begin to protect people based on individual differences in 
susceptibility, not on the basis of an average person to an 
average exposure. The absence of that information really 
creates a problem for risk assessment. That information is 
being obtained now at a slower rate. We want to enhance the 
rate at which we do that. And make that a major initiative. I 
would say the four things that I've presented here, even though 
I've presented seven or eight in my written submission, the 
four things that I've presented here will revolutionize 
environmental health decision making. And those are the 
Institute's and my top priorities. And these are things that I 
would like to be the legacy for my tenure as Director of the 
Institute.
    Mr. Porter. Dr. Olden, I can see how you convinced Dr. 
Varmus. [Laughter.]
    Dr. Olden. Thank you.

                 link between science and public health

    Mr. Porter. Mrs. Lowey.
    Mrs. Lowey. Thank you, Mr. Chairman.
    And I do apologize, Dr. Olden, as you know, with our 
schedules, it's hard to be in three places at the same time.
    But I want to assure you that I am extremely interested in 
the work of your Institute. And I think there is rising concern 
and rising interest in almost every area of the country about 
the impacts of the environment on health. And we're all 
struggling to gain additional knowledge about the impact of the 
environment on the health of women, children, families.
    I have had scientists come to me and express concern about 
the research that is being done involving human subjects versus 
research on animal subjects. Research in the lab versus beast 
research on actual populations. Could you discuss this with me 
and your view of this and the dollars that are being spent?
    Dr. Olden. In my opening statement----
    Mrs. Lowey. And I do apologize if I missed it.
    Dr. Olden. I said there are four priorities. And one of 
those is creating the linkage between basic laboratory science, 
epidemiology, toxicology and public health. We're very much 
concerned that the science that we do is linked to public 
health. Now, at least three or maybe all four of the projects I 
talked about are population based studies.
    For example, I talked about exposure assessment. Now, we 
propose to do the exposure assessment with EPA and CDC. And we 
already have a pilot study going now with CDC. And what we 
really need to know is exactly, of all the chemicals in the 
universe, in the U.S., which ones should we really be worried 
about. And the way to make that determination is to decide 
exactly which ones are we taking up in our bodies. Which 
chemicals are humans actually exposed to. Not based on some 
potential. But really exposed to.
    And we can do this by taking samples of blood, of urine. 
And we can find and identify, either by biomarkers or chemical 
markers, and we can come back in a matter of years and say to 
the American people, these are the 40 or so chemicals out of 
the thousands or so that we really should be worried about. 
Because these are the ones that people are indeed being exposed 
to.
    That's a public health initiative. That's why we're 
involving CDC. We already are funding such studies. The money's 
been transferred to CDC to do this for us. Because they have 
the technologies. And we want to expand that effort.
    The Environmental Genome Project is population based. And 
we will sample maybe 10 different populations, maybe 100 
individuals. And again, we will have information that's 
relevant to public health. So we are doing that.
    But in addition, we have some human studies. We have a 
study that I discussed here before, looking at developing a 
treatment for lead poisoning in the range of 20 to 45 
micrograms per deciliter of blood, a project devoted to 
children. We also have a project that we're funding, that is 
being conducted in China, to look to see if we can use the 
biomarker of oltipraz as an agent that we've demonstrated from 
basic research that will prevent aflatoxin-induced liver 
cancer.
    Well, now we have a trial going on in China to see if we 
can indeed prevent the formation of an adduct between aflatoxin 
and albumen in the blood. And what we've demonstrated, at least 
preliminarily, is that if we treat individuals with oltipraz 
that indeed we prevent the formation of aflatoxin albumen 
adducts. And that's an intermediate bit of information to say 
that we can prevent aflatoxin-induced liver cancer. And that's 
the next phase of the study.
    So we are supporting human studies. But I think all of our, 
at least my four priority areas, are oriented toward public 
health.

                          endocrine disruptors

    Mrs. Lowey. Thank you. And I also know that NIEHS has been 
a pioneer in conducting research on the health effects of 
endocrine disruptors.
    Dr. Olden. Yes.
    Mrs. Lowey. And I'd like to know how your agency is 
coordinating its research with other Federal agencies, 
particularly in light of these new directives, and what is your 
best estimate of how long it will be until we have definitive 
answers about the threat to public health posed by endocrine 
disruptors?
    Dr. Olden. Well, I am personally spending a lot of time 
talking with everybody who's concerned and has research 
programs dealing with environmental endocrine disruptors, not 
only estrogens, but other hormone mimics. We have 
collaborations with EPA, I mentioned earlier, we are co-funding 
projects with EPA. Every three months, we meet in the 
Department to talk about the research going on in the Federal 
Government, not just in the Department, because EPA, 
Agriculture and other departments participate, to make sure 
that we are indeed coordinating the research. It's coordinated 
also through the Committee for Environment and Natural 
Resources.
    I have also reached out to industry. I have met with 
chemical manufacturing industries that are responsible for 
making many of these estrogens. And we believe that we are 
going to be able to develop a partnership with the chemical 
manufacturing industry to pursue the research to make certain 
that we leverage our dollars which you provide us to have an 
impact that's much larger than the amount of money that we're 
devoting to this project.
    So we are in touch with and coordinating our research 
efforts with everybody, not only other Federal agencies, but 
with private industry, because private industry, the ones that 
make more than 95 percent of all the estrogenic-like chemicals 
in the United States, are represented through the chemical 
manufacturing industry.

                      collaboration with industry

    Mrs. Lowey. I'm delighted you brought that up. Because 
recently, I attended a conference, and one of the participants 
was a representative from DuPont. And I'm aware of the fact 
that they've invested quite a bit of money and done a good deal 
of research, because they understand it's in their own 
interests.
    Dr. Olden. Right. And we had discussions with them about 
that at the outset. And they are part of the chemical 
manufacturing industry.
    Mrs. Lowey. Actually, if the Chairman would approve, I 
wonder if you can enlighten us as to cooperation from other 
corporations. I mean, they are spending enormous amounts of 
money, making enormous profits, and to what extent are they 
investing in this kind of research, as DuPont seems to be 
doing?
    Dr. Olden. Significantly. The project that I mentioned 
about developing the transgenic animal models, new alternative 
models that are faster and cheaper, well, that project is an 
industry-Government collaboration. There are 35 industry groups 
participating in the partnership. EPA is participating, and FDA 
and the NIH. So this is indeed a Government-industry 
partnership.
    Now, we got everybody to the table because when I first 
became Director, I went around and met with the industry, 
DuPont, Dow Chemical, Proctor and Gamble, and I discovered that 
they have exactly the same problems that we have in the 
National Toxicology Program. They need models that are faster 
and cheaper, because they have to provide information to EPA, 
FDA and regulatory agencies to get their products approved.
    So we then convinced them that it was in their best 
interests for all of us to pool our intellectual and economic 
resources to address these problems collectively. We have now 
had several meetings. We meet regularly in Research Triangle 
Park, around the table just like this, and we discuss these 
issues. We decided together what body of science was necessary 
to convince the American people that indeed, these new models 
are valid. In other words, will they identify a carcinogen? And 
that's what we're focusing on at the present time, just 
carcinogens.
    And they were eager to do this, because if these tests cost 
the Government $2 million to $6 million per chemical, it costs 
them the same amount of money. So they are interested in the 
same issues we are, saving money and saving time and getting 
products to the market sooner. So we have that partnership, and 
we are very proud of that.
    Mrs. Lowey. Well, thank you very much. In light of budget 
realities, I would encourage you to continue to encourage the 
private sector to continue to invest in these areas.
    Dr. Olden. We are.
    Mrs. Lowey. I thank you.
    Dr. Olden. Thank you very much.

                           gulf war syndrome

    Mr. Porter. Thank you, Mrs. Lowey.
    Dr. Olden, has your Institute been involved in any of the 
ongoing evaluations of whether there is a true Gulf War 
Syndrome? We seem to be caught between the President's panel, 
which doubts its existence, and a series of studies published 
in January in the Journal of the American Medical Association, 
which assert that the syndrome is real.
    What's your personal assessment of the available evidence?
    Dr. Olden. Well, Mr. Porter, actually I had it in my 
opening statement, but it would have made it a bit too long, so 
I cut it out. I simply was going to say that the Gulf War 
veterans' illness is a prime example of what I said, of having 
too little information to make a decision. And that's the 
problem. It's a problem for you, it's a problem for the 
American people. And in this case, there's too little 
information about multiple chemical sensitivity, or chronic 
fatigue syndrome, or fibromyalgia, and those three at least 
probably have some similarities in terms of underlying 
mechanism.
    There's too little information about susceptibility. Again, 
from what I read in the newspapers, and it was just in the 
newspapers today, that some of the veterans were indeed exposed 
to Sarin. Sarin is a nerve gas. We know what the components 
are, organophosphates. We know that if you expose 10,000 
people, there are going to be ranges of susceptibility. Some 
are going to be susceptible and others aren't. And we 
understand now why that is the case.
    So there's too little information about susceptibility, and 
there is also too little information about mixtures. Clearly, 
from what I read in the newspaper, indeed the veterans were 
exposed to mixtures. There were pesticides. And pesticides 
often contain as many as 100 different chemical components. 
There was possibly the nerve gas exposures also.
    So I would say, Mr. Porter, there's too little information 
about multiple chemical sensitivity. There is too little 
information about mixtures. And there's too little information 
about differences in susceptibility for us to ever figure out 
what happened. And what we need to do, and my recommendation 
has been, when we've had these discussions on one occasion in 
the Department, is that we do what I've asked be done here, and 
that is, let's focus on doing the science to answer the basic 
fundamental questions that we need to do intelligent human risk 
assessment, irrespective of whether there is a war here or 
there. Because the American people have the same kinds of 
exposure. They are exposed to mixtures. We don't know about 
differences in susceptibility. We have the same kinds of 
problems. If we had solved these problems for civilians, then 
we would not be in this quagmire about what to do about the 
Gulf War.
    So, I don't think we'll have a satisfactory solution, 
because there's inadequate science.
    Mr. Porter. It kind of indicates a problem, perhaps, also 
with our legal system. Because let's assume this was not a 
Government, but a private party, and the burden of proof would 
be on the plaintiff to prove that this was a cause and effect. 
And what you're telling me is, in a situation like this, it's 
probably impossible to prove.
    Dr. Olden. That's what I think.
    Mr. Porter. Yes. And that means that maybe we need some 
method apart from the traditional methods to compensate people 
who are injured, and not worry about the cause of the injury or 
even the causor of the injury. A total aside.
    Dr. Olden. Right.

                         artificial sweeteners

    Mr. Porter. At the time of its initial approval concerns 
were expressed by some about the safety of the artificial 
sweetener, aspartame, and its possible links to brain cancers. 
In the intervening years, has your Institute or anyone else 
supported research providing further answers to this question?
    Dr. Olden. Aspartame has been nominated for testing on 
several occasions. We've discussed the nominations with FDA on 
each occasion, once during my tenure. And we will discuss them 
with FDA officials, tomorrow. I have a 10:00 o'clock meeting 
tomorrow to discuss aspartame again.
    And the reason that we keep coming back to aspartame is, 
first of all, and there are other sweeteners among these----
    Mr. Porter. That's my next question.
    Dr. Olden. There is increased usage in terms of sweeteners 
in sodas, for example. We're very much concerned about 
increased exposure for children, in one example.
    Also, aspartame was tested in the early 1970s when test 
standards and methodologies were very different from what they 
are today. And although we've reviewed that data critically, we 
don't see anything flawed about it. But we have to admit if it 
was tested today, it may test differently, in other words, 
positive.
    But there is a problem, and I understand FDA's reluctance 
to go back and test any chemical that we tested 20 years ago. 
The reluctance is, once you open that can of worms, that's a 
slippery slope. Because there are a lot of chemical agents that 
are in the marketplace that were tested using 1970s 
technologies and standards. So why single out aspartame and 
other sweeteners? Are we going to get petitions to test all the 
others? We believe, the American people are very concerned 
about sweeteners, there is tremendous exposure and increased 
usage in sodas and other things that children are exposed to 
recently.
    So we are concerned about it. We are going to express our 
concerns to FDA tomorrow morning, as we have done in the past. 
And based on that discussion, we will decide whether we want to 
reevaluate aspartame in a two-year rodent bioassay.
    Mr. Porter. Being a major user of the product, I think you 
should do that. [Laughter.]
    Dr. Olden. Well, that's what we hear. NutraSweet, is the 
trade name, commercial name.
    Mr. Porter. A new artificial sweetener already used in 
Canada called Sunett is being considered for approval in this 
country for soft drinks, and again, safety concerns are being 
raised about possible links to tumors. Do you plan to conduct 
studies on this sweetener?
    Dr. Olden. It's included in the discussion tomorrow. 
There's two. And that's the other one. It's been nominated for 
testing and fits into the same category. Both were tested in 
the early 1970s. Same kind of test procedures, same problems. 
And we're going to discuss it with FDA tomorrow morning at 
10:00 o'clock.

                            nanofabrication

    Mr. Porter. Last year, we briefly discussed the technology 
of nanofabrication. Your justification indicates that this 
field has matured to the point of application in environmental 
health. Can you give us some examples of possible uses of 
nanofabrication in your Institute's work, and do you have any 
plans to support this technology?
    Dr. Olden. Well, I must say, thanks to you, I really gave 
it a lot of thought and looked into it. And it is a very 
rapidly developing technology. It developed as a consequence of 
the computer industry, and informatics industry, and it is 
important. And it is being used now for environmental 
monitoring and assessment, mainly in the defense industry.
    Right now, my prediction is that nanoscale tests will be 
developed some time in the future. Right now, the tests that 
I've talked about, the new tests, the fast through-put 
technologies, are going to be done on a microscale, not 
necessarily a whole animal. But we're talking about a 
microscale, much smaller. And I think with time, we will be 
doing tasks that are fast through-put on the nanoscale 
dimension.
    So yes, I am interested. The Institute is very interested 
in new technologies. And we have scheduled, in fact, to bring a 
few people in to talk about this technology and its potential 
for some of these fast through-put screening tests that we want 
to develop. But right now, as we perceive it, we will be 
working at the microscale level. But in a matter of years, we 
will be at the nanoscale level, and the technologies will be 
highly relevant.
    But they could also be very important for exposure 
assessment, individual exposure assessment. They are relevant, 
highly relevant, to what we do in NIEHS. And we are exploring.

                           contract mechanism

    Mr. Porter. Your budget continues to emphasize the use of 
the contract mechanism, 22 percent of the total compared to an 
NIH average of 6 percent. You have testified in previous years 
that you were trying to increase the share of your budget 
allocated to research project grants. Does that continue to be 
an interest for you, or have you found that the nature of your 
work requires you to heavily use the more directed mechanism of 
contracts?
    Dr. Olden. Well, I'm clearly interested in getting more 
money into the grants mechanism, in part because I think we buy 
better science. So that's the motivation.
    During my tenure, we have dramatically decreased the amount 
of money that, dramatically may be an overstatement, sir, but 
we have decreased the amount of money that we spend via the 
contracts mechanism. For example, many of the NTP studies now 
we are doing on a grant mechanism. And I can just cite two.
    There was the National Academy report about two to three 
years ago about the health effects of pesticide exposures on 
children. And it turns out that we just had no studies any 
place to address any of those issues. Most pesticide exposure 
experiments are done with an adult animal.
    We are now doing studies involving in-utero exposure to 
pesticides and to estrogens. It seems that the critical time 
for exposures to estrogens at low levels may not be during 
adulthood, but may be during development. And there's lots of 
studies to suggest that is the case. And those studies are NTP 
studies that are being done via a grant mechanism, R01 grant 
mechanism. We advertised RFAs, we took the very best grant 
applications that we had and we funded those.
    So that is the trend, and we will continue to do that. But 
in the end, for some work that we do through the National 
Toxicology Program we simply have to use the contract 
mechanism. I mean, they are kind of routine kind of screening 
activities that we would not get a scientist to invest time and 
effort to do. And you don't need a university professor to do. 
I mean, these are just studies that are kind of assembly line 
things, same activity day after day after day for two or three 
years.
    So unfortunately, that's where we are. I can get it down, 
and I've gotten it down. But in the end, I won't be able to 
reach the NIH average.
    Mr. Porter. Thank you, Dr. Olden.
    Mrs. Lowey.

                                 asthma

    Mrs. Lowey. Thank you, Mr. Chairman.
    And I just have two follow-up questions. Dr. Olden, you 
talked about your focus on public health problems. In recent 
years, there has been an increased number of children being 
admitted to the emergency room as a result of asthma. Could you 
give us some insight as to the work you are doing in that 
regard? Especially in our cities.
    Dr. Olden. Yes. We created one new program, and it's called 
the Five Cities Study, to specifically address that problem. 
Then we collaborated with the National Institutes of Allergy 
and Infectious Diseases on another project called the Inner 
City Asthma Project that Dr. Fauci may have described to you 
this morning. The Inner City Asthma Project is an effort to 
look at indoor allergens, cockroach dust, and dust mites on 
asthma in inner city children. These are kids who are mostly 
minority and also economically disadvantaged.
    Since the Inner City Asthma Project focused on indoor air, 
and it is at the point now of being an intervention study, we 
created a new project this year called the Five Cities Study, 
to look at the effects of outdoor air pollution on asthma 
admission rates to emergency rooms. And so those are the two 
major projects that we initiated specifically to address those 
issues.
    But let me say, we go way back. We have 24 city studies, 
the 6 city studies, and in fact, the bulk if not all of the 
data that's being used to debate the new EPA-proposed air 
standards for ozone and particulate matter in the air, that 
data was generated through NIEHS grant mechanisms by Doug 
Dockery and collaborators at Harvard. So we've been in this 
business a long time. And I would say have made the major 
contribution to that area.

                         retesting of chemicals

    Mrs. Lowey. Just one last follow-up question to the 
Chairman's question. If I heard correctly, you mentioned that 
you were concerned about retesting aspartame because there 
would be, I don't remember what you said, thousands, many 
petitions to retest other products.
    Dr. Olden. Right.
    Mrs. Lowey. Now, what immediately came to mind were the 
advance in science, with all the new information, how do you 
make determinations on which products, which additives you 
should retest? If something is passed 15 years ago, there's a 
good deal of new information since then. How do you set your 
priorities and how do you make those determinations?
    Dr. Olden. Well, that's going to be very difficult. Because 
even the test, the rodent bioassay that we're using today, I 
hope that that becomes obsolete. That's what we're working for. 
Everything that we're testing today will be obsolete in 20 
years in terms of the test standards. And do you want to go 
back and test the things that we're testing today that we 
believe in?
    So that is what we're faced with. And obviously, I can't 
make that decision alone. I have to have a number of people who 
are more expert than I to give us advice on what we should do. 
And in the end, it's not only a scientific issue, it's a social 
issue. Do we want to make that kind of investment, because 
we've never tested about 80 percent of the agents--chemicals, 
man-made chemicals--that are in use commercially today. About 
80 percent have never, ever been tested in a single assay. 
We've only tested about 20 percent of them.
    Now, do we want to spend our money retesting or do we want 
to go forward and test new things that may pose a health 
hazard. This is a dilemma. And that is FDA's position, or it 
has been, and we'll find out if it still is tomorrow. And I 
don't have a lot to combat that. We'll present it, we have 
advisory councils, and I will take the discussion tomorrow back 
to my advisory council, and it's made up of scientists, 
industry people, and lay people, and we'll present it and get 
their input.
    Mrs. Lowey. I'd be interested in hearing more from you in 
that area. It certainly seems to me roughly, well, I imagine 
there are thousands, of chemicals and additives that are part 
of foods and products. And right now, you're saying that if a 
product's been tested 15 years ago, it's safe, it's off the 
agenda, is that correct?
    Dr. Olden. I'm saying that that is a position. And do we 
want to go back and retest those? Because once you start that, 
there's an awful lot of things that we tested over the last 20 
or 30 years. And the test standards and methodologies were 
different. The things we're testing today, we will have 
sophisticated, better tests 20 years from today. And so it's 
kind of a never-ending issue.
    So I guess what we'll do is present it to our Council and 
we'll get a feel for how comfortable people are with data that 
was generated 20 years ago. The artificial sweeteners are 
obviously of concern, because 60 Minutes featured them in a 20 
minute segment one evening about a month ago. And I get a lot 
of letters, and FDA gets a lot of letters about it. And the 
public is very concerned, as Mr. Porter said. Well, all of my 
friends who saw 60 Minutes immediately the next morning came to 
us and asked us, what are you doing, can you assure us of 
safety.
    So these are the issues. And our council and board of 
advisors will have the same kind of reservation.
    Mrs. Lowey. Well, thank you. I frankly didn't watch the 60 
Minutes, and I'm much more concerned today than I was yesterday 
as a result of your question. [Laughter.]
    Mrs. Lowey. So I certainly look forward to continuing this 
dialogue. Thank you.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mrs. Lowey. I think there's a 
difference between those things that we voluntarily ingest and 
believe are okay and those that we might be exposed to 
involuntarily or unknowingly. And with the volume of use of 
artificial sweeteners like aspartame now in our society, it 
seems to me that looking at children, who would probably be at 
greatest risk on these things, it's probably a wise thing to 
do, if it otherwise seems to point in that direction.
    Dr. Olden. Yes. And that we can do.

                         air quality standards

    Mr. Porter. Speaking of coordination between agencies, 
there is considerable discussion in Congress about whether EPA 
air quality standards are based on sound science. You know 
there are new regulations.
    Dr. Olden. Yes.
    Mr. Porter. Has your Institute provided any data to EPA to 
aid in this debate?
    Dr. Olden. Yes in part. In my answer to Congresswoman 
Lowey, I mentioned that the data that is being used to decide 
what the new standard is, and in fact, the reason it's being 
debated at all, was the result of the 24 city study that was 
done by Doug Dockery at Harvard. He found that particles, and 
he called them particle size ten, which are very small 
particles, he discovered and demonstrated in his epidemiologic 
study that the mortality rate was increased by something like 
23 percent and that translates into a life expectancy decrease 
of 2 years. He found that that was true for the most polluted 
cities compared to the least polluted cities.
    It is exactly that data that EPA is now using to advance a 
new regulatory policy. And in fact, we've been in discussion 
with EPA and Congress, as a matter of fact, in the last week or 
two, about that data. So the data from these studies is being 
used for documentation. And the reason that there is a concern, 
even going way back to the Middle East oil crisis, has to do 
with work that the NIEHS supported.
    Mr. Porter. So you, I can conclude that you believe that 
the science on which EPA based their regulations is sound 
science?
    Dr. Olden. Well, I think, as I understand it out of the 
newspaper, both EPA and industry are not, people aren't 
refuting the science. The question is, EPA and industry both 
agree that more data is needed. I think where they disagree is, 
should you regulate, err on the side of safety now and put in 
place a regulation, or should you wait until the science is in. 
I think that's the debate.
    So it's not about the need for more science. I think EPA 
would like to see more science in place. Industry would like to 
see more science in place. So this again is an example of where 
there's inadequate information. And probably, no matter what 
decision is made, it's going to be problematic. People aren't 
going to be satisfied with the decision without the additional 
information which we do not have today.
    So the data that's been presented is fine, but there are 
gaps. And that's the problem, and that's what the debate is 
about, those gaps. EPA acknowledges those gaps.

                                smoking

    Mr. Porter. Dr. Olden, I thought we had planned our time 
quite well, but Ms. DeLauro just arrived. Ms. DeLauro, would 
you like to ask questions of Dr. Olden? You can proceed if you 
want.
    Ms. DeLauro. One question, because I just came from the 
Agriculture subcommittee where we were talking about tobacco.
    I've been a strong advocate for trying to get at kids to 
stop smoking. We have something called the Kick Butts 
Connecticut campaign, where we're working with middle school 
kids. We've got this army of middle school kids, about 50 or 60 
of them in the district, who are going to the elementary 
schools and talking to their peers about not smoking. It's a 
great effort.
    But what I wanted to ask about is your initiatives in terms 
of dealing with a link between cigarette smoking, disease and 
cancer. That effort in terms of what that body of research is, 
and getting that information out to deal with the issue of 
children and adolescent smoking. If you could just comment on 
that.
    Dr. Olden. Over the years, the National Cancer Institute 
and NIEHS, and I would say more even the years before I got 
there as Director, made long-term commitments and investment in 
basic, fundamental research, on the health effects of chemical 
agents in cigarette smoke. And it's that long-term commitment 
to the basic fundamental research that demonstrated the 
epidemiological association between cigarette smoking and 
cancer. And many of the chemicals were subsequently 
indentified, not only by NTP assays, but also by the bioassay 
program conducted by the National Cancer Institute.
    We played a major role in it, and we continue to look at 
some aspects of lung cancer. I did not say one of our other 
susceptibility gene discoveries in the past few years was one 
that enhances the susceptibility to lung cancer if exposed to 
925 cigarette smoke carcinogens.
    So we continue to do research in that area. But so does the 
National Cancer Institute. And they are clearly much more 
active, I would say, than we are in the outreach component in 
terms of public education.
    Ms. DeLauro. They are more active on the outreach component 
than you?
    Dr. Olden. That's what I would guess. We do have an 
information service. But I would say we probably get no 
questions on that issue. And NCI has, as you know, an 
information service and community outreach that's focused on 
smoking cessation. So I would say that the bulk of that work is 
being sponsored and supported by the NCI, although we certainly 
have played a major role over the years and will continue to.
    Ms. DeLauro. Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Ms. DeLauro.
    Dr. Olden, thank you very much for your good testimony, 
your forthright answers to our questions, and for the fine job 
that you're doing at NIEHS. And we look forward to coming down 
and visiting you and seeing things up close in April.
    Dr. Olden. Thank you. We look forward to your visit.

                                 autism

    Mr. Porter. Thank you.
    Now, as Dr. Snow comes to the table, I want to ask a 
question of Dr. Varmus. I want to keep you a little busy here, 
Dr. Varmus.
    Many of us on the subcommittee have been visited this past 
week by parents of autistic children who are concerned about 
the level of support that NIH research provides with respect to 
this disease. I wonder if you could tell us which institutes 
are involved, do you have an estimate of how much is being 
spent, has the money been constant or has it been rising or 
falling, and what are the prospects for research into autism in 
the years ahead?
    Dr. Varmus. Thank you for the question, Mr. Porter.
    As you may have read, the NIH is taking a dramatically 
increased interest in autism for a number of reasons that I'll 
come to. At the moment, there are roughly four institutes that 
do research in this area: NICHD, NINDS, NIMH and NIDCD, which 
is at the table with me now.
    The level of funding as of 1996 was approximately $14 
million. I can give you the exact number if you like. And there 
was a very substantial increase for 1997 of about $4 million. 
And we expect to have that increased a little further in 1998.
    In addition, we as a result of my request for initiatives 
to support with my 1 percent transfer authority, we have 
decided to put together a package of $4 million that will go 
for the study of the genetics of autism, to be sponsored by the 
Institutes to my left, NIDCD, NIMH and NICHD.
    Now, let me say a word or two about autism. This is 
obviously a devastating illness for the child and for the 
family. And for many years, it was marginalized, in my view. 
But for a number of reasons, it's become more central and more 
accessible to research. And now it's positioned itself in the 
middle of the technological advances that are revolutionizing 
our view of neuroscience. It's approachable by neuroimaging, 
it's approachable by genetics, approachable by neurophysiology.
    It's become recognized as a disease that is likely 
developmental in origin, with subtle anatomical changes. It's 
been changed by the perception that it's not really one 
disease. It's a range of diseases, at least four, possibly 
five, discrete syndromes, that can be fairly well recognized. 
And that is changing our notion of how to go about approaching 
the disorder.
    There is already underway a fairly extensive attempt to 
understand the genetics of autism. In particular, the NIMH has 
assembled a large cohort of families. Recently published work 
suggests that it's possible to exclude a fair amount of the 
genome as the site of genetic lesions that contribute to 
autism. That's helpful to narrowing down this ever-engaging 
search for the loci involved.
    As you might appreciate, since there seem to be several 
syndromes that go under the general term of autism, it's 
important to have clear criteria for deciding what disorder 
you're looking at. And recently, the four institutes that are 
involved in the study of autism have gotten together and agreed 
to try to work out some common defining principles, so that the 
genetic information that we're assembling can be made more 
useful.
    In addition, there have been recent reports that suggest 
that it's possible to develop an animal model for at least one 
sub-form of the disease. And that's based on evidence from a 
small number of autopsy patients who seem to lack what are 
called the nuclei for some of our cranial nerves. What that 
suggests to developmental neurobiologists is that the 
developmental lesions in at least some cases of autism occur 
about the time of the closure of the neural tube during 
development.
    By using known developmental anomaly-inducing agents, one 
in particular called valproic acid, which happens to be a drug 
that's used in the treatment of epilepsy and schizophrenia, 
using that drug in a rat model, it's been possible to reproduce 
some of the anatomical defects that are seen in at least an 
occasional case of autism.
    So all those things combined, I don't want to go on longer, 
it's clear there are a lot of new things to do. I'm sure you're 
aware that about two years ago, we had an important workshop on 
the NIH campus. It was very widely attended, I was there myself 
to hear many of the talks. I think that had the effect that I 
like to see when we think about funding at increased levels in 
an area. That is, people were there from a number of fields 
that had not participated actively before. We were drawing new 
talent to a field instead of simply putting more money into the 
pockets of those who were already working on the problem.
    And the synergy among the neurobiologists, geneticists, and 
clinical and behavioral students of autism, was very obvious. 
One of the reasons that there was a lot of enthusiasm among my 
outside advisors for supporting the work on autism that was 
proposed for the 1 percent transfer authority was the fact that 
in response to the RFA that Dr. Snow and Dr. Alexander put 
together, applications of very high quality were received in 
excess of the ability of those institutes to support them.
    Mr. Porter. Thank you, Dr. Varmus.
    [The following questions were submitted to be answered for 
the record.]

[Pages 734 - 803--The official Committee record contains additional material here.]


                                        Thursday, February 27, 1997

    NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

                               WITNESSES

JAMES B. SNOW, JR., M.D., DIRECTOR
DONALD H. LUECKE, M.D. DEPUTY DIRECTOR
W. DAVID KERR, EXECUTIVE OFFICER
PATIENCE T. SPARKS, BUDGET OFFICER
MARSHALL MOORE, INTERPRETER
HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH
BILL BELDON, DIVISION DIRECTOR, OFFICE OF DEPUTY ASSISTANT SECRETARY, 
    BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES

    Mr. Porter. Now we'd like to welcome Dr. Snow, Director of 
the National Institute on Deafness and Other Communication 
Disorders.
    Dr. Snow, we're anxious to hear from you. And my first 
question will be to ask you whether you want to follow up on 
anything that Dr. Varmus had to say about autism. Why don't you 
proceed to introduce the people at the table and then your 
statement, and then if you'd like to address the autism 
question further, please feel free.

                       Introduction of Witnesses

    Dr. Snow. Thank you very much, Mr. Chairman.
    It's my pleasure to introduce Dr. Donald H. Luecke, the 
Deputy Director of the NIDCD; Mr. David Kerr, the Executive 
Officer of the NIDCD; Ms. Pat Sparks, the Budget Officer of the 
NIDCD. Mr. Marshall Moore is the sign language interpreter. 
You, of course, know Dr. Varmus and Mr. Beldon.

                           Opening Statement

    Mr. Chairman, members of the committee, I am grateful to 
have this opportunity to appear before you to report on the 
research progress of the National Institute on Deafness and 
Other Communication Disorders. That research benefits 46 
million Americans who are challenged by diseases and disorders 
affecting hearing, balance, smell, taste, voice, speech and 
language.
    The NIDCD is seizing opportunities to accelerate discovery 
that will lead to elucidation of the biology of brain disorders 
such as aphasia, finding new approaches to the pathogenesis of 
diseases including laryngeal carcinoma and spasmodic dysphonia; 
new treatment strategies against immune-mediated inner ear 
hearing loss; and applying genetic medicine to hearing 
impairment and the velo-cardio facial syndrome, while 
developing new therapy for disorders of balance and the symptom 
of tinnitus that are critically important in improving the 
quality of life for those faced with communication disorders.
    Progress that we're experiencing within the portfolios of 
the NIDCD is due to careful planning and emerging opportunity. 
In the past several years, with the support of the NIDCD, a 
multitude of genes for syndromic and nonsyndromic forms of 
hearing impairment, including autosomal dominant and recessive, 
X-linked and mitochondrial modes of transmission have been 
located in specific regions of the human genome. And at least 
12 different genes on 10 different chromosomes have been 
located for various forms of autosomal dominant nonsyndromic 
hearing impairment and at least 11 different genes on as many 
chromosomes have been identified for autosomal recessive 
nonsyndromic hearing impairment.
    Recent NIDCD-supported research will further our 
understanding of normative patterns of brain development in all 
children and provide a more detailed understanding of the 
acquisition of sign language in deaf children.
    The Institute has established two clinical trial 
cooperative groups to plan, implement, conduct, analyze and 
disseminate results of priority research in the efficacy of 
treatment of diseases and disorders affecting human 
communication. The Institute is improving technology for 
individuals with communication disorders. A unique 
collaborative effort is fostering partnerships among 
scientists, industry and Federal laboratories to carry out 
research needed for commercialization of promising hearing aid 
technology.
    There is progress in developing a new vaccine against 
otitis media in infants and small children. Plans are underway 
for a Stage I clinical trial in the NIH Clinical Center of a 
conjugate vaccine against the nontypeable hemophilus influenza.
    The chemical senses, smell and taste, greatly influence 
nutrition. Scientists are studying the role of the gustatory 
thalamus in food aversions and food-seeking behavior that will 
help in the effort to understand life-threatening eating 
disorders.
    NIDCD investigators are applying the newest tools and 
strategies to long-misunderstood and often misdiagnosed 
diseases and disorders of human communication.
    Mr. Chairman, the fiscal year 1998 budget request for NIDCD 
is $192,447,000. I will be pleased to try to answer any 
questions you might have.
    [The prepared statement follows:]

[Pages 807 - 810--The official Committee record contains additional material here.]


                            autism research

    Mr. Porter. Thank you, Dr. Snow.
    Would you like to add to what Dr. Varmus said about 
autistic children?
    Dr. Snow. I'd just like to add an experience that I had 
yesterday. The first meeting of the Autism Research 
Coordinating Committee was held. All of the directors of the 
institutes involved were present. Some of the staff of the 
Institute are meeting with the Cure Autism Now group, actually 
right at this time this afternoon in Bethesda.
    I think that the coordination is really enormously 
important and an agreement was made yesterday afternoon to try 
to work towards a common phenotyping clinical description of 
children in autism, so that all the various groups, the 
molecular geneticists supported by the National Institute of 
Mental Health, as well as those that will be supported by the 
NICHD and the NIDCD, will use a common basis for categorizing 
the patients. And that will greatly improve and hasten the 
work.
    Mr. Porter. Just one small question. Is it correct that the 
inability to properly hear sounds of human speech may 
contribute to the disorder of autism?
    Dr. Snow. Well, I don't think there has been any 
satisfactory demonstration of that as far as I know. Certainly 
autism is a disorder of human communication. It's a language 
disorder. It is of particular interest to us because it is at 
times associated with near-normal or even above normal 
intelligence, a situation where the language disorder occurs in 
the presence of normal cognition. And to approach the molecular 
genetics of that leads us directly to an understanding of the 
genetics of language. And that, of course, is an area that we 
have had great trouble breaking into. We have not had the 
success in that area that we have, let's say, in the hearing 
area, where we have literally a multitude of genes that have 
been discovered.
    So we're very interested in trying to get a handle on the 
molecular genetics of language. And we think this may be a very 
fine opportunity to do that.

                         hair cell regeneration

    Mr. Porter. Dr. Snow, last October, researchers in 
Philadelphia found a method to generate the growth of hair 
cells in chickens. This finding was the first to suggest a 
possible method to regenerate hair cells which are often the 
cause of deafness when they die. Is the scientific community 
optimistic that this finding may also work for mammals?
    Dr. Snow. Yes, we are optimistic that it may also work for 
mammals. I believe that you're referring to the work of the 
principal investigator that's supported by the NIDCD, Dr. 
Oberholtzer. And his finding in the chick was that compounds 
that activated cyclic AMP, and that in turn activate the 
protein kinase A system, led to the development of new hair 
cells when there had been no injury present. All of the other 
research on the regeneration of hair cells had been in a 
situation where first the hair cells had been destroyed.
    So this is of enormous importance. This publication, which 
actually appeared in Nature in August, was brought to my 
attention immediately by Dr. James Battey, the Scientific 
Director of the Institute. And we agreed that this was an 
enormously important finding and indeed, in turn, acquainted 
Dr. Varmus with it. And indeed, that has become one of our 
areas of emphasis for 1998.
    And in the development of the budget, $500,000 was 
committed to pursuing research along that line.

                          stochastic resonance

    Mr. Porter. Nature Medicine Magazine reported last August a 
finding that translates a principle of physics into a possible 
aid for the deaf. Stochastic resonance is a process in which 
the addition of the right amount of noise results in an 
improvement in response. Applied to the cochlear implant 
device, it is thought that hearing is improved when noise is 
added to the stimulus. Do you expect random noise to be added 
to commercial cochlear implants to improve hearing for the 
deaf?
    Dr. Snow. Yes, I think that may well be, that in time the 
principles of stochastic resonance may be added to the input to 
cochlear implants. Stochastic resonance is a phenomenon of non-
linear statistical physics, which as you say, introduces noise 
or interference, and in this case, it is truly noise, into a 
system. And this increases the informational content of 
responses when you're dealing with a non-linear system, and the 
auditory system, as well as some other sensory systems, is a 
non-linear system.
    Actually, we benefit from stochastic resonance all the time 
in natural hearing. If we were presented with strictly pure 
tone rather than the ambient noise that exists all around us, 
both in a relatively quiet room like this, as well as in 
nature, it would be more difficult for us to understand and to 
appreciate certain phonemes, particularly those that are 
represented by the vowels. So not only is that helpful in 
normal hearing, but it would also be helpful in cochlear 
implantation.
    For several years, we've recognized that the opposite of a 
stochastic resonance stimulation is a deterministic 
stimulation. And that, when there is electrical stimulation of 
the remaining nerve fibers, they tend to all respond at the 
same time. You might think of it as a military organization 
marching all together, all in step. They are all synchronized.
    Although that tends to happen naturally in the normal 
auditory system, there's a certain amount of phase locking that 
brings that about which is beneficial. But when the system is 
being driven by electrical stimulation, that deterministic or 
phase locking becomes too severe. And as you rise in the 
auditory system from one waystation to another, that becomes 
more severe, and actually interferes with understanding.
    Dr. Terry Hambrecht, who is in charge of our cochlear 
implant program, where we issue requests for proposals for 
directed research through contracts, has been aware of this for 
several years, and has investigators trying to achieve 
stochastic resonance, rather than a deterministic form of 
stimulation. So we've been incorporating this kind of principle 
into our cochlear implant research and development work for the 
last several years.
    Mr. Porter. Thank you, Dr. Snow.
    Ms. DeLauro.

                     consensus conference findings

    Ms. DeLauro. My understanding is that the NIDCD has engaged 
in a number of activities and initiatives regarding kids, 
particularly the consensus conference to evaluate research on 
hearing impairment in children. Were there some findings that 
you might be able to discuss with us and how they are being put 
to use in doctors' offices in this country?
    Dr. Snow. Yes. We've had two consensus development 
conferences that involved hearing impairment in children. The 
first was in 1993. And it dealt with the early identification 
of hearing impairment in infants. And a very important 
recommendation came out of that consensus development 
conference. For the first time, anywhere in the world, there 
was the recommendation that there should be universal screening 
for hearing impairment of all newborn infants.
    Now, that recommendation was made in 1993. And it has 
greatly influenced the field since then.
    Ms. DeLauro. Are we doing that? Are we screening them?
    Dr. Snow. We're making progress in it, but we have a long 
way to go. Maternal and Child Health has recently awarded a 
grant to the University of Colorado to implement as a 
demonstration project, to implement infant screening in 19 
states. And we are currently in conversation with the CDC and 
Maternal and Child Health to extend that screening to a larger 
number of states through Maternal and Child Health.
    Hearing identification of infants is in the Secretary's 
initiatives for this year, under child care. And we're hopeful 
that we'll move forward in a major way this year.
    Ms. DeLauro. Are there any states that are currently doing 
it?
    Dr. Snow. Yes. States that have the very best and most 
complete systems are Colorado and the Hawaiian Islands. Next I 
would probably put Utah.
    The way in which this is developing, though, is to do it 
hospital by hospital. There are two good techniques for 
identifying hearing impairment in the newborn. The measurement 
of oto-acoustic emissions and the use of automated brain stem 
responses. Both are very effective, very efficacious in 
identifying hearing impairment. Once the infant is suspected of 
having hearing impairment on the basis of one or the other of 
these tests, then they are brought to a diagnostic evaluation, 
usually about six weeks later, to determine whether there is 
actually hearing loss that can be confirmed or not.
    Both of these techniques have a very high success rate, 
though, high specificity. And so both are good for that 
purpose.
    Ms. DeLauro. Has there been any evaluation in Colorado or 
the Hawaiian Islands or Utah? Are we able to affect any 
outcomes, finding something early enough to prevent it 
happening in the future? Do we have any results?
    Dr. Snow. Oh, yes. The average age of identification of 
hearing impairment in the United States is now at about two 
years. The latest information from CDC is that in their survey 
in the Atlanta area, it's down to two years. That's down from 
two and a half to two years over the last seven years.
    And then when we identify an infant that has a hearing 
impairment, we begin special education of that infant right 
away. And indeed, we'll put a hearing aid on the infant as 
early as six months of age. Then the family, of course, needs 
to begin to decide what form of education they wish to pursue, 
what form of rehabilitation in the way of special education, 
whether they follow the manual-visual approach through American 
Sign Language, or whether they follow an oral-auditory 
approach, which would make maximum use of any residual hearing, 
either with a hearing aid or with a cochlear implant.
    Ms. DeLauro. Would hospitals hesitate to incorporate 
something like this? You say we need to go hospital by 
hospital. But what would be the hospitals' resistance? I am not 
saying that there is any, but what would be the hospitals' 
resistance?
    Dr. Snow. They have to work out a form of reimbursement for 
it. If this is a service that has not been delivered in that 
community before, both the insurance companies or the health 
maintenance organizations don't know what to do with the bill 
when they get it the first time. So there has to be negotiation 
over how the reimbursement is to take place for these services.
    So that's the principal block.
    Ms. DeLauro. Is this an expensive procedure?
    Dr. Snow. No. As screening procedures go, it is not. It 
costs about $35 per child. About 1 in 1,000 infants are born 
with hearing impairment. And in order to test all 1,000 of 
those, it would cost about $35,000.
    What this says is that in order to identify a deaf child 
early, it costs about $35,000. That's $35,000 per deaf child, 
and $35 for each child screened.
    The other consensus development conference had to do with 
cochlear implantation, both in adults and children. The outcome 
of that as far as adults were concerned is that there was a 
recommendation that individuals who did not get more than 30 
percent of sentences correct on sentence material with the best 
hearing aid arrangement probably would benefit from a cochlear 
implant. This is because it was found that individuals who had 
received a cochlear implant did much better than those 
individuals who got 30 percent or less of their words or the 
sentences correct.
    This was an enormous change in the field. There are 1 
million people in the United States who fit this new 
classification. And so this increased the number of people that 
are now candidates for cochlear implants among adults increased 
by 1 million people.
    As you probably know, cochlear implantation was not done in 
the United States until two years of age. There have been some 
experimental trials at an earlier age in Europe. And one of the 
recommendations of the consensus panel was that more research 
should be done about earlier implantation of children with 
cochlear implants. And of course, more study needs to be done 
on what leads to a successful outcome and what does not.
    Ms. DeLauro. Thank you very much.
    Dr. Snow. Yes.
    Ms. DeLauro. Thank you, Mr. Chairman.

                          sensory regeneration

    Mr. Porter. Thank you, Ms. DeLauro.
    Dr. Snow, your budget justification mentions research 
demonstrating that odor responsive neurons in the brain are 
capable of regenerating and reconnecting in adults, and that 
this regeneration occurs throughout life. Does this finding 
have promise for restoring the sense of smell lost through 
injury or age, and more broadly, does this suggest research 
leads in other fields like spinal cord injury and 
neurodegenerative disease?
    Dr. Snow. Yes, the interneurons in the olfactory system are 
continuously replaced, even if there is no injury. If the 
system is injured, then that activity greatly increases. If the 
first order neurons are injured, those that have connections 
within the nose and extend to the olfactory bulb, if they are 
injured, they are reconstituted, not regenerated from 
themselves, but from other cells in the area. They make central 
connections and the function is restored.
    And this ability throughout the olfactory system for neural 
regeneration or neurogenesis to occur suggests that this might 
be very helpful in bridging across a defect area, either in the 
brain or in the spinal cord. And we are supporting research 
through the grant mechanism that is studying the use of these 
interneurons in the repair of created neural lesion. And that 
could, if it proved to be successful, turn out to be of value 
in spinal cord injury.

                     eating behavior and nutrition

    Mr. Porter. Dr. Snow, variations in eating behavior and 
nutrition among individuals have been linked to genetic 
variation in tasting ability. Is it far-fetched to think that 
genetic manipulation of tasting abilities would be a strategy 
for weight loss for the chronically obese? Or is consumption 
not likely to be altered by taste sensations?
    Dr. Snow. Well, there are many factors that enter into 
obesity. And the influence of smell and taste is only one. 
Characteristically, individuals who are tasters of PROP 
(propylthiouracil), particularly women who are tasters of it, 
tend to be thinner individuals. Some people are tasters of this 
compound, some people aren't; some have a mild reaction to the 
taste, others have a severe reaction to the bitter taste. Those 
that have the more severe reaction, among women, also 
experience more sweetness and more bitterness from the 
additives to food that provide those tastes. And as a group, 
they tend to be thinner, slimmer individuals.
    It is an important consideration, but of course not the 
only one. And there is the genetics that primarily determines 
obesity, for which major discoveries have recently been made.
    But assuming that the person does not have that sort of 
genetic predisposition to obesity, and is more governed by 
simply what the food intake is, this probably plays an 
important role in their body habitus.
    Mr. Porter. And maybe genetic manipulation could therefore 
be of help in those individuals?
    Dr. Snow. Well, what's been found is a good thing. You 
wouldn't want to change, I think, slim women. I don't know 
where the manipulation comes in.
    If we had a finding, which we don't, not one that comes to 
mind, where it led to the obverse situation of obesity, then 
yes. But no, this is a healthy phenomenon.
    Mr. Porter. This is far-fetched, I can tell.
    Dr. Snow. We'll just let it be.

                             sense of smell

    Mr. Porter. Women are thought to have a keener sense of 
smell than men. Is it known why that is the case, and is it 
true with any other senses? Is it true with that sense?
    Dr. Snow. Yes, it is very true with the sense of smell, and 
it goes throughout the lifetime. Young girls have a keener 
sense of smell than young boys of the same age. And that goes 
throughout the life span. There is of course a dropping off of 
the acuity of the sense of smell starting at about age 60, and 
that goes on for the rest of one's life. And all through the 
years, women maintain their sense of smell better than men for 
each comparable age.
    In other sensory systems, I don't know. Of course, the same 
is true in hearing, in terms of the hearing level. Women hear 
better than men in advanced age. But young women don't hear 
better than young men and girls don't hear better than boys of 
a comparable age. And I don't think there is any difference in 
vision or the other sense that come to mind.
    Mr. Porter. Do we know why?
    Dr. Snow. No, I don't know why that is.

                    balance disorders in the elderly

    Mr. Porter. Disorders of balance and vestibular function 
are common among the elderly. Do we have any idea what 
percentage of falls resulting in hip fractures, which often 
seem to be the first step toward assisted living, are 
attributable to balance disorders? Are any treatments or 
compensating rehabilitation techniques available for balance 
disorders?
    Dr. Snow. Yes. It is believed that 50 percent of the falls 
that result in hip fractures are due to a vestibular 
disturbance. The elderly tend to develop vestibular 
disturbances that lead to all sorts of uncertainties about 
their position in space and these can be improved. This 
inability or disability can be improved by physical therapy. 
There are techniques that the NIDCD has supported that lead to 
an improvement in an individual's ability to manage under 
relatively adverse circumstances, of shifting weight, getting 
in and out of a bathtub and other things in the way of daily 
living. And these individuals can be trained to cope with these 
situations and the actual exercise improves their ability to 
deal with them.

                             loss of voice

    Mr. Porter. Your budget mentions that little research has 
been done in the field of voice loss. Is this condition thought 
to be a muscle disorder that may be amenable to therapy, or is 
it the result of cell death or some other degenerative 
condition? How prevalent is voice loss in the population?
    Dr. Snow. Mr. Chairman, I'm not sure what you're asking. 
Voice loss from what cause?
    Mr. Porter. All causes.
    Dr. Snow. Well, let me just say that 6 percent of our 
budget supports research on voice and voice disorders. There 
are a number of causes of voice loss. And we have a fairly 
extensive portfolio of research in that area.
    Mr. Porter. Does any of it relate to muscle disorder that's 
amenable to therapy, or does it relate to cell death?
    Dr. Snow. Yes, there is a lot that relates to muscle 
disorder, if you include both neuromuscular, both the neural 
supply as well as the muscle itself. For example, spasmodic 
dysphonia, a condition that I've discussed with the committee 
before, is an abnormal muscular activity, perhaps mediated 
through the central nervous system, but the end organ being the 
larynx. This is the condition, you know, that we have developed 
the treatment by injection of botulinum toxin into the muscles 
of the voice box. And that research continues, and actually we 
have engaged in that kind of research in the intramural program 
since 1989.
    Current, new research efforts are aimed at developing 
objective clinical procedures for the diagnosis of these 
disorders, generally spoken of as dystonias, which spasmodic 
dysphonia is one part of. And these are patients that have 
generally been misdiagnosed or incorrectly diagnosed. And now 
there is a greater recognition of the problem, and a better 
recognition of what to do about it.
    When it was recognized in the past, the recommendation was 
to cut one of the nerves to one of the vocal cords. And indeed, 
we practiced that for many years. And it was some help, but it 
tended to be a temporary one. Often the condition would return. 
And not only would the patient still have the spasmodic 
dysphonia, but would also have a vocal cord paralysis.
    The botulinum toxin injection, on the other hand, does wear 
off after several months, but gives several months of relief, 
and then the injection can be repeated.
    Mr. Porter. Are there any side effects from that injection?
    Dr. Snow. Well, sometimes, if it's overdone, it can lead to 
an incompetence of the larynx. There can be aspiration of food 
or fluid. This is usually a temporary matter. And there can be 
weakness of the voice if it is overdone. In each patient, there 
has to be a calibration or a titration as to how much should be 
used. We start with a small dose and then gradually work up 
until a satisfactory response is reached. Sometimes there is an 
overshoot of that and it results in one of these complications. 
Fortunately, they're temporary. They wear off, too.
    Mr. Porter. Since I am suffering some voice loss today, I 
am very interested in this subject.
    Did you tell us how prevalent voice loss is in the 
population in general, do you know?
    Dr. Snow. It's difficult to answer that question. We don't 
have good epidemiologic data on voice disorders. Voice 
disorders, of course, are very common. All of us may experience 
an episode of laryngitis in the course of a year, and have 
several days of hoarseness. We see many individuals who use 
their voice in their work, as of course we all do, but 
particularly in public speaking, who have chronic problems with 
their voice. And at the periods of time when the voice has to 
be used more than others, that hoarseness recurs.
    That's really a very common problem. But I really can't 
give you any data on the matter.

                 government performance and results act

    Mr. Porter. Of all the people, I know two people who have 
voice loss, one is being treated with the injections, the other 
one is the result of voice loss from an injury, and apparently 
can't be treated. But those are the only two I'm aware of.
    Much of the research that NIH supports does not lend itself 
particularly well to measurement under the Government 
Performance and Results Act. It does seem, however, that GPRA 
standards could be appropriate for your research in the 
development of hearing aid technology. Have you considered 
performance goals and time frames for your contracts and grants 
in this area?
    Dr. Snow. No, we have not done that as yet. But we can 
certainly do that, as we develop the plan.

                            clinical trials

    Mr. Porter. Last fall, you announced the creation of a 
clinical trials branch within your Institute. How many trials 
do you expect to have in operation at one time, and what are 
the major research topics you would like the clinical trials 
branch to focus on?
    Dr. Snow. We are in the process of awarding two clinical 
trial cooperative groups. These are two of the major 
professional organizations in the field, and within each of 
those cooperative groups, there are 15 to 20 clinical centers.
    In the case of one of these, the first protocol is on the 
treatment of immune-mediated inner ear hearing loss, either 
with corticosteroids, methotrexate or cytoxin. This problem of 
immune-mediated inner ear hearing loss is really a very serious 
problem. It often begins in mid-life, 35 to 45 years of age. 
And often goes on to bilateral deafness in an individual who 
had otherwise had healthy hearing.
    This is quite a dilemma for the clinicians to know what 
form of treatment is to be used. And of course there is 
treatment that will prevent the progression of the hearing loss 
to deafness. So we consider this a very major and important 
study to be undertaken.
    The other study that has undergone peer review and is ready 
to begin is the one on the aspiration of fluids in the elderly. 
And this clinical trial will compare two forms of therapy that 
are thought to be effective, one due to head positioning and 
the other due to changing the viscosity of the food and fluids 
that are ingested. This is particularly a problem in the 
elderly who are demented, either with Alzheimer's disease or 
some other form of dementia.
    We look forward to a series of clinical trials in each of 
these cooperative groups, probably not starting one each year, 
although that would be very desirable. Because each have four 
more proposals, important studies such as the use of diuretics 
in Meniere's disease, again a prevalent disease, and it's quite 
unclear as to what the efficacy of this form of therapy is.
    I'm very keen to see the carrying out of the next protocol 
in the other group, which will deal with the use of magnesium 
sulfate in the prevention of noise induced hearing loss. As you 
know, there are 10 million people in the United States that 
have noise induced hearing loss. And there are another 20 
million that are exposed to hazardous noise in the work place. 
And so this is a problem of enormous magnitude.
    About three years ago, an Israeli study was done of Israeli 
army recruits who were given magnesium sulfate during the 
period of time that they were in basic training. And those that 
received the magnesium solution did not develop as much noise 
induced hearing loss as those who did not receive it. We are 
very anxious to replicate that study to see whether it can be 
corroborated or not. That, of course, involves impulse noise 
and we need to determine whether magnesium solutions can 
prevent noise induced hearing loss of the impulse type. And 
then the next step would be to move on into the industrial kind 
of noise where it is more continuous due to machinery.

                        vaccine for otitis media

    Mr. Porter. Dr. Snow, we've heard for a number of years 
about a vaccine for otitis media. Are there multiple types of 
bacterial pathogens responsible for otitis media, each of which 
requires its own vaccine?
    Dr. Snow. Yes, there are. The three principal organisms are 
the pneumococcus, the non-typeable Haemophilus influenzae, and 
the Moraxella catarrhalis. More progress has been made in the 
pneumococcal vaccines. In order for these vaccines to be useful 
in otitis media, they have to produce the immune response 
during the first few months of life, just like with the 
hemophilus influenza type B vaccine, which is given to prevent 
meningitis, and is given during the first month of life, and 
then there are booster doses at three and subsequent months.
    We need the same sort of vaccines for otitis media. And in 
the case of the pneumococcus, the same strategy that was used 
in the Haemophilus influenzae type B vaccine, that is to 
conjugate the polysaccharide coating of the organism with a 
protein led to immunogenicity early in life, in the first month 
of life. We need to do the same thing.
    Well, the pneumococcal vaccines are now in a stage 2 trial. 
And so that's going very well. We now have the non-typeable 
Haemophilus influenzae vaccine which is ready for the stage 1 
trial: if it is found to be safe in adults, then we will move 
on to a stage 2 trial that will very likely be conducted by a 
pharmaceutical company that manufactures vaccine. Our work will 
probably stop at that time, and we will turn it over to the 
appropriate vaccine manufacturer.
    We are just starting the same process with the M. 
catarrhalis and carrying out a similar strategy of conjugating 
the polysaccharide that is the endotoxin of the organism with a 
protein and then seeing if it produces immunogenicity.
    Mr. Porter. Assuming you are successful in that, will there 
ever be a vaccine that handles all three different types?
    Dr. Snow. Yes. Probably the three vaccines will be combined 
in a single injection, and so just as youngsters receive their 
immunization against Haemophilus influenzae type B meningitis, 
they will also receive their immunization against otitis media 
at that time.

                      specific language impairment

    Mr. Porter. I was not familiar with the condition called 
specific language impairment, SLI, in which children have 
unexpected and unexplained difficulties learning and using 
spoken language. Is this thought to be a single condition or a 
family of disorders?
    Dr. Snow. I believe it is best looked at as a family of 
disorders. One of the early epidemiologic studies that we did 
through a contract was to determine the prevalence of specific 
language impairment in children. And we, as the whole 
scientific community, were shocked to learn that 8.36 percent 
of the population has this disorder. And these youngsters have 
difficulty, academic difficulty, difficulty reading, they often 
speak late, and develop speech relatively late in childhood. 
And this turns out to be a lifelong problem for these 
individuals.
    This encompasses all of those who are spoken of as having 
dyslexia, and yes, there are receptive forms of this, there is 
the motoric form of it, the expressive form of it. But there 
are commonalities among these children that make it reasonable 
to lump them together for certain purposes. And now that the 
incidence or prevalence of this is known, we are now pursuing 
the molecular genetics of this problem.
    Mr. Porter. And this could be severe enough to require them 
to be placed in special education classes?
    Dr. Snow. Yes. There is variation from mild learning 
disability to very severe learning disability.
    Mr. Porter. Dr. Snow, you've answered all of our questions 
very forthrightly and candidly. We thank you for the wonderful 
job you're doing at NIDCD and thank you for coming before us to 
testify today.
    Dr. Snow. Thank you very much, sir.
    Mr. Porter. Thank you, Dr. Varmus.
    We stand in recess until next Tuesday at 10:00 a.m.
    [The following questions were submitted to be answered for 
the record.]

[Pages 821 - 863--The official Committee record contains additional material here.]


                                            Tuesday, March 4, 1997.

                NATIONAL HEART, LUNG AND BLOOD INSTITUTE

                               WITNESSES

DR. CLAUDE LENFANT, DIRECTOR, NATIONAL HEART, LUNG AND BLOOD INSTITUTE
DR. CARL ROTH, ASSOCIATE DIRECTOR FOR SCIENTIFIC PROGRAM OPERATIONS
JAMES WEHLING, FINANCIAL MANAGEMENT OFFICER
SHEILA MERRITT, EXECUTIVE OFFICER
DR. HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF 
    HEALTH AND HUMAN SERVICES

                       Introduction of Witnesses

    Mr. Porter. The subcommittee will come to order.
    This morning we will hear from the National Heart, Lung, 
and Blood Institute. We're very pleased to welcome the 
Director, Dr. Claude Lenfant. And if you would introduce the 
people who are with you, Dr. Lenfant, and proceed with your 
statement, please.
    Dr. Lenfant. Thank you, Mr. Chairman.
    On my far left is Sheila Merritt, who is the Executive 
Officer of the Institute; Mr. Wehling, with the Budget Office 
of the Institute. On my right is Dr. Roth, the Associate 
Director for Scientific Programs of the Institute; and of 
course, Dr. Varmus.

                           Opening Statement

    And I'm very, very pleased to be here today, Mr. Chairman, 
to present the 1998 budget of the Institute. It's especially 
meaningful to us because 1998 will be the year that the 
Institute will celebrate its 50 anniversary.
    As we look back on what has been accomplished during the 
last 50 years, we see considerable progress. For example, when 
the Institute was created in 1948 under the name of the 
National Heart Institute, the country was experiencing an 
epidemic of heart disease, of which heart attack, coronary 
heart disease was the most common. If we adjust for the aging 
of the American population, the death rates that existed at 
that time have been reduced by more than half during that 
period of time.
    A very recent study has shown that the decline in the death 
rate can be accounted for 25 percent from primary prevention, 
that is preventing people from developing heart disease, and 75 
percent from improved treatment. The net result of all that is 
that coronary heart disease which was50 years ago a very acute 
condition, from which most people would die very quickly, has become a 
rather chronic condition which today affects between 12 and 14 million 
Americans. The good news of all that is that we clearly have added 
years to the life of the American people.
    As we look at the years which are ahead of us, we see many 
researchers with new ideas, new directions which, if 
successful, will continue to improve the life of patients, and 
new treatments will certainly be developed.

                           imaging technology

    One of the questions that is most important is: Can we 
prevent further this coronary heart disease? And last week, Dr. 
Varmus mentioned to you the advance of new technology, new 
imaging technology, and in the next few minutes I would like to 
tell you how these technologies are going to help us to, in 
effect, help to prevent more of these diseases.
    On your right side, what you see here is the conventional 
angiogram, which is an invasive procedure that requires cutting 
up the skin, opening up a blood vessel, introducing a catheter 
up to the heart, injecting dye and exposing the patient to x-
ray. On your left side, you see a magnetic resonance imaging 
angiogram, which is non-invasive. Basically, it takes the 
patient into a magnet and that's what you get.
    [See figure].

[Page 867--The official Committee record contains additional material here.]


    Let me spend a minute to show you what we see here. Those 
two circles are the aortic valve, which keeps the blood from 
returning into the heart after it has been ejected by the heart 
into the aorta. On both sides, you see coronary arteries, this 
one here which originates from the aorta, and this one, which 
is the one that is most often obstructed in the case of 
coronary heart disease.
    The point I would like to make is that this very small 
vessel that you see here has a diameter which is approximately 
half a millimeter, and so that you visualize what half a 
millimeter is, I would like you to see the piece of pencil lead 
that I have attached to the picture in front of you. That is 
what half a millimeter is. And that is what you can see with 
this technique.
    The beauty of course is that if, through this process, 
using this technology, we can see abnormalities inside the 
arteries, then we can act upon them and basically do something 
before the development of overt disease.
    The advantage of such technology is that it can be repeated 
without any danger as many times as one would want. One thing 
that I should tell you is that conventional angiogram is a 
procedure that costs approximately between $6,000 and $8,000. 
This one here is in the order of less than $1,000, and that's 
what it costs today. I would expect the devices would be 
further developed and the technique itself would be further 
developed, it would cost much less than that.
    So basically, I think that we have amazing opportunities to 
help in the prevention of this disease by basically detecting 
abnormalities in the arteries before the development of 
symptoms and clinical problems. And the opportunity therefore 
to do something about them.

                        lung and blood diseases

    So far I have talked exclusively about heart disease. But 
in the late 1960s or early 1970s, the Institute changed from 
the Heart Institute to the Heart, Lung and Blood Institute. I 
would be remiss not to underscore that the research programs of 
the Institute in lung diseases, such as for example asthma, or 
the pulmonary complications of cystic fibrosis and research on 
blood diseases, have been just as successful.
    For example, 20 years ago, most patients with cystic 
fibrosis died from the pulmonary complications that developed. 
They would die in their teens or early 20s. Today, the same 
patients live to their 40s and 50s. They have jobs, they have 
families and although they have to take care of themselves on a 
daily basis, they can really enjoy life.
    With regard to asthma, let me remind you that three of the 
gold winners that we had at the Olympics last year were 
asthmatic patients. Twenty years ago, it is not certain that 
their condition would have been properly diagnosed. In 
addition, if it had been diagnosed, the treatments that are 
available today were not available then.
    Regarding blood diseases, I would like to mention that 25 
years ago, the Congress enacted the Sickle Cell Disease Control 
Act. Then, many patients with sickle cell disease died in their 
second or so decade of life, after a life of suffering. Today, 
these patients live later with much less suffering.
    So to conclude my remarks, I would like to say that as we 
reach 50 years of age, and after 50 years of investment by the 
American people, you can point to remarkable public health 
benefits with regard to heart, lung, and blood diseases. And I 
should say, in the future, maybe the next 50 years, I believe 
the potential of the research that we're undertaking will bring 
about results which I believe will eclipse the accomplishments 
of the past.
    I will be pleased to answer questions, Mr. Chairman.
    [The prepared statement follows:]

[Pages 870 - 872--The official Committee record contains additional material here.]


                           imaging technology

    Mr. Porter. Dr. Lenfant, thank you very much for your 
statement.
    We very definitely congratulate you on 50 years of great 
progress. We want, obviously, that progress to continue. Is 2.4 
percent for the next fiscal year going to allow that progress 
to continue?
    Dr. Lenfant. Well, it will allow some to continue. Maybe 
not as much as one could do with more, but we will be able to 
undertake very significant, useful and important projects.
    Mr. Porter. You're a good soldier.
    Let me say preliminarily that when we looked at the 
schedule of hearings for the Institutes, I decided that we had 
them much too compacted and wanted to provide a little extra 
time. This morning, since there are no recorded votes scheduled 
for the floor of the House, our members are not probably in 
town, with the exception of Mr. Bonilla and Mr. Miller. Mr. 
Miller we expect later on, but if he does not arrive in time, I 
have received from him some questions that he wants me to ask 
you. And I will ask those as well.
    Let me also apologize for the condition of my voice, which 
is the result of having a very bad cold. And let me ask about 
MRI as opposed to a conventional angiogram. Can you use MRI to 
tell the degree of clogging of arteries just as well as you can 
use an angiogram?
    Dr. Lenfant. Yes, indeed. The picture that I showed you 
here is from a normal person. But as you can see, if you look 
at the smaller vessels at the bottom of the yellow rectangle, 
or even much higher, you could detect irregularity on the line 
that separates, if you want, the vessels from what is next to 
it. And that would be an indication of the development of 
abnormalities in the arteries. That can be seen, and there are 
also some examples which I didn't bring where you can see very 
clearly the beginning of an obstructive process of these 
arteries.
    Mr. Porter. And would a physician go directly from an MRI 
angiogram that showed clogging to an operation, a heart bypass, 
let's say, or would they perform a conventional angiogram 
following up on it?
    Dr. Lenfant. One thing I would like to say, Mr. Chairman, 
is that the conventional angiogram, the invasive procedure, is 
a diagnostic tool. The other one, the MRI, assumes that you 
have patients, somebody who is part of a family where there is 
a history of heart attack, where you know that this person has 
elevated blood cholesterol, but yet does not do anything, 
because an elevated blood cholesterol is a little bit too 
abstract.
    A physician might say, well, let me see if there are some 
abnormalities which are developing in your arteries, and that 
is before the occurrence of symptoms. And that is the beauty of 
it, to find the abnormalities in these arteries. And to show a 
picture to the patient would be much more convincing than just 
the result of a blood cholesterol test. And we believe, and 
there is some evidence, actually, that people would respond to 
that. Because that's something that they see inside themselves.
    One thing I should underscore is that these little arteries 
that you see there, the smallest ones, are basically three or 
four inches below your skin. So it's quite remarkable what we 
see there.
    Mr. Porter. So it could tell you that you don't have 
clogged arteries, and you would end your investigation of that 
as a problem. But if it told you that you did have clogged 
arteries, you might then go to see the extent of how they're 
clogged?
    Dr. Lenfant. No, I don't think you would go. You would 
initiate a medical treatment for this patient, telling this 
patient to check their blood pressure, if that's the case, if 
this patient has an increased blood cholesterol, it would be a 
much more convincing argument for that patient to do something 
about that elevated cholesterol than just if you see a number 
on a piece of paper.
    Mr. Porter. I guess my real question is, is MRI imaging 
going to replace conventional angiograms completely?
    Dr. Lenfant. It might. It might also become a diagnostic 
tool, that is correct. And in this case, it would be much 
cheaper. But again, the conventional angiogram today is used 
exclusively as a diagnostic tool. You have a patient who comes 
to you and says, I have chest pain, I have this, I have that, 
and the physical examination reveals that this person is a 
likely candidate for coronary heart disease, and you want to 
confirm it, to set up a treatment which is a very serious 
treatment, such as, for example, angioplasty or coronary 
bypass. And that's what you would do.
    The other one, we see that as a tool of the future to 
basically try to detect abnormalities before the occurrence of 
clinical symptoms. And if that works, and we do believe that it 
will work, basically what you can say is that the development 
of an overt disease is no longer inevitable. You can do 
something before it becomes overt.

                  in utero bone marrow transplantation

    Mr. Porter. Last December, the New England Journal of 
Medicine reported what sounded like an extraordinary finding, 
that a bone marrow transplant had been done in utero to 
successfully treat severe immunodeficiency disease. Does this 
research present the possibility of a new form of treatment for 
other diseases, like Cooley's anemia?
    Dr. Lenfant. The answer is yes. Yes, it offers that 
opportunity. I think there is much more work that needs to be 
done before it is done. But the potential exists.
    In fact, almost any, or many genetic diseases could be 
corrected that way.
    Mr. Porter. Does this in utero transplant bypass some of 
the difficulties that have been encountered in transplants 
after birth?
    Dr. Lenfant. Yes, yes. In fact, the paper that you refer 
to, was a story of a woman who had two children. The first one 
died with that inherited immunodeficiency which is, I should 
say, very rare. And the first child received a bone marrow 
transplantation after birth. But that was not successful, and 
eventually the child died. And the new pregnancy was a child 
with the same disease, that was diagnosed in utero, and that's 
what led to the treatment, the in utero transplantation.
    The reason is that during fetal life, the immune system is 
not developed or not as developed, and therefore you know, you 
do not have the problem that you would have after birth dealing 
with immune reaction to bone marrow if you don't have a perfect 
match.

                              gene therapy

    Mr. Porter. Last August, a Tufts University research team 
reported the successful treatment of gangrene through gene 
therapy. A gene that codes for vascular growth was coated onto 
an angioplasty balloon, which was inserted into an artery to 
stimulate the growth of new blood vessels and restore blood 
flow. Could this type of procedure some day be a less invasive 
alternative to heart bypass surgery?
    Dr. Lenfant. Yes. In fact, in our laboratories on the 
campus of the National Institutes of Health, we do have a 
protocol which is studying this very question. That is, to 
insert this growth factor in the coronary arteries and see if 
we can elicit the sprouting of new blood vessels.
    The case that you report is quite interesting. And not all 
of its aspects would be applicable to what you could do in the 
coronary arteries, owing in great part to the size of the 
arteries, and things of that sort. But eventually, you can 
conceive that it would become possible.
    Mr. Porter. Are there other examples of successful gene 
therapy?
    Dr. Lenfant. To my knowledge, I think that is the only case 
which is successful. I think one of the reasons for it is the 
following, that this gene, the naked DNA, if you want, can go 
directly into the smooth muscle cells which surround the 
arteries. These particles of DNA, the naked DNA, go directly 
into the smooth muscle cells. And that has greatly facilitated 
the issue of the transplant insertion of that gene into the 
cells.
    In other areas, the issue of vector is one which is often 
hampering the gene therapy.

                               cell death

    Mr. Porter. Your research on congestive heart failure is 
targeted to stopping cell death and generating cell growth. 
This seems similar in many ways to the strategies being pursued 
in other diseases, like neurological disorders, spinal cord 
injury and stroke. Is it likely that lessons learned with heart 
tissue would be transferrable to these other disorders or vice 
versa?
    Dr. Lenfant. I think it's going to work both ways. 
Apoptosis, which is the cell death process, we learned about it 
relatively recently. The process and what triggers it is being 
investigated in many cell systems. I think that what we learn 
from the heart would be applicable to the other systems and 
conversely.
    In the old days, we saw cell death being caused by 
necrosis, that is, the matter that was around the cells would 
be altered for some reason. And that would lead to the cell 
death. The deaths occurred from alteration, from the nucleus, 
for example, inside the cells. But it's an entirely different 
process. And there is a lot of work which is going on to try to 
understand the differences which lead to it.

                                 asthma

    Mr. Porter. Your statement mentioned the findings reported 
in Science magazine in January that asthma prevalence may be 
increasing because of the lack of exposure to respiratory 
infections. Children in Eastern Bloc countries are much more 
likely than children in the West to contract these infections, 
and paradoxically, seem to be protected against asthma. How can 
these findings be used to develop asthma treatments for 
children who have not grown up with the disadvantage of 
frequent respiratory infections?
    Dr. Lenfant. This is a very interesting issue which has 
really become apparent during the last few years. Because a few 
publications have occurred in various journals, showing that 
indeed, an infection in the early age of individuals modifies 
or alters the immune system in such a way that later in life it 
would offer prevention against exposure to allergens. And the 
mechanism is really not fully understood. And actually our 
Institute, at this very moment, is preparing the initiation of 
a program to explore these mechanisms so that we can understand 
it.
    You are making a reference to the East European countries. 
In fact, this argument can be taken to other parts of the 
world. There are many developing countries such as New Guinea, 
for example, where they have very high prevalence of acute 
respiratory infection in the early months of life. And in fact, 
it's responsible for the deaths of many of these children.
    But there, although there is considerable exposure to 
pollutants, since they are living in huts and so forth, the 
prevalence of asthma is very low. And for years, 
epidemiologists, as well as asthma experts were wondering, how 
could that be, with the same level of exposure in the United 
States or developed countries, we would have a very high 
prevalence of asthma, but not there. And these publications, 
which have occurred, and these studies which have been reported 
during the last few months, shed an explanation which needs to 
be pursued quite actively.

                     sleep disorders and melatonin

    Mr. Porter. Dr. Lenfant, melatonin seems to be widely 
extolled in the popular press as a therapy for sleep disorders. 
Yet the National Sleep Foundation commissioned a paper which 
concluded that the use of melatonin cannot be justified for any 
sleep disorder at this time, since neither the therapeutic nor 
potential toxic effects of prolonged use have been documented. 
Do you agree with this assessment of the current scientific 
data? Do you think melatonin should be categorized as a drug 
rather than a food supplement and regulated by the FDA?
    Dr. Lenfant. The question is difficult for me to answer at 
this time. All I can say is that there is no question that the 
use of melatonin, based on public consumption, raises hopes 
that it will do wonders without too much evidence. If used for 
pharmacological purposes, if that becomes the case, I would 
think so. We are beginning to believe that it suppresses the 
perception of light, meaning that when melatonin increases in 
our system, then weunderstand that it's time to sleep, and vice 
versa.
    Now, if the melatonin is used pharmacologically and taken 
freely, I think that it may certainly have some adverse effects 
which in this case could be controlled by way of calling 
melatonin a medication.
    Mr. Porter. Is the Sleep Disorder Center within your 
Institute supporting any research on melatonin?
    Dr. Lenfant. Not at this time. But we are in the process of 
supporting a very significant program on the molecular biology 
of circadian rhythms. And in effect, melatonin is very closely 
tied to a study on this, and I think it's become incorporated 
to this line of work.
    Mr. Porter. Thank you, Dr. Lenfant.
    Mr. Bonilla.

                            stroke research

    Mr. Bonilla. It is nice to see you again, Dr. Lenfant.
    I'd like to start out by asking you something about a study 
that was just released in the last 30 days about dealing with 
strokes and the ability to pump blood in reverse to the brain 
through the veins. I suppose this technique is to quickly 
reverse the negative impact and paralyzation or the after 
effects. It seems to be a profound way of dealing with stroke. 
And I'm wondering if this is going to be more widely used or 
what is the status?
    Dr. Lenfant. I don't know if it's going to be widely used. 
What I would like to say before commenting on your question on 
that issue is that this approach is something that has been 
taken from cardiology. Years ago, when a patient had a heart 
attack, in some centers, these heart attacks were treated by 
what we call retrograde perfusion, that is, a catheter was put 
into the venous side and blood or liquid with anticoagulant was 
forced against the normal current, if you want, into these 
vessels, in order to push back whatever the obstruction was.
    In the heart, it has been found to be not, or it has been 
found to be a fairly complex procedure. In the brain, when you 
have stroke, I don't know if it will be developed in such a way 
that it could be used everywhere. In specialized centers, yes.
    Having said that, the usefulness of this approach cannot be 
denied. Any way that a physician has to take to the clot, if 
you want, an anticoagulant or something which is going to 
destroy the clot, would be of tremendous benefit to these 
patients.
    The advantage of doing it this way is that not only are you 
putting in a drug which is going to eliminate the clot, the 
blood clot, but also you can push it out which you could not do 
if you were doing the same thing on the artery side. Because 
the clot would have to go through very, very small vessels and 
it wouldn't be possible to push it out that way.
    Mr. Bonilla. I heard that the recovery is remarkable in 
these cases where they actually pump the blood in reverse back 
into the brain. And if it's done within a short period of time, 
it's almost as though nothing had happened. In the past, these 
patients were oftentimes never able to use the left side of 
their body, or speak, or whatever the side effects would be.
    Dr. Lenfant. The great issue with stroke, Mr. Bonilla, is 
that there is a diagnosis that needs to be done before you 
start the treatment. There are two types of stroke, one which 
is an obstructive stroke, like what we are talking about, and 
another one which is due to a vessel being ruptured and the 
blood leaking out into the brain and causing the same kind of 
damage as if the blood does not go through.
    And of course, in the latter case, knowing what we are 
talking about would considerably worsen the condition of the 
patient instead of improving it. And that brings me back to the 
MRI. One of the best ways that we have today to diagnose 
between an obstructive and an hemorrhagic stroke, is to do 
magnetic resonance imaging of the skull, of the brain.

                         genetic predisposition

    Mr. Bonilla. And don't forget, Dr. Varmus, I remember, no 
imaging institute. I remember that.
    Moving to a different area now, Dr. Lenfant, it's just 
something we discussed before----
    Dr. Lenfant. I was here, I remember the question. 
[Laughter.]
    Mr. Bonilla. I understand that the NHLBI has found the 
approximate location of three stroke related genes. I know the 
Chairman touched on genetic research a moment ago. Would you 
tell the subcommittee about this progress and what it means for 
stroke detection, prevention and rehabilitation?
    Dr. Lenfant. Well, I think, if I understand your question, 
there are two approaches which are under study now. The first 
one is to identify the genes which are determinant factors for 
high blood pressure, which is the number one cause of stroke. 
The second is that we do know today, and that has been found 
through genetic studies, we do know today that individuals 
susceptible to complications of high blood pressure, whereas 
other people can have high blood pressure for many years and 
not develop any of the complications.
    And indeed, this genetic susceptibility to one of the 
complications such as stroke has been found in animals, not yet 
in human beings. And that is an avenue of research which is 
extraordinarily exciting, actually. Because it's true for 
stroke, it's true for congestive heart failure. It's true for 
kidney failure, which are all three being consequences of high 
blood pressure.
    And I should say, the same thing is true for cancer. It's 
true for chronic lung disease. You have people who smoke all 
their life, for 50 years, 60 years, and never develop any 
disease. But somebody else does, very quickly. And that is in 
fact caused by this genetic susceptibility, which we are 
talking about here.
    Mr. Bonilla. Someone just used the example last week about 
Deng Zao Peng, and how he had a cigarette in his hand all his 
life, and seemed to live a pretty full and prosperous life. I 
think he was 92 when he died. So we can see how your genes 
affect--how you're predisposed to a great degree.
    If someone is predisposed, though, for example, to have a 
stroke, and you could determine that through genetic research, 
how much can good diet, exercise and doing all the right things 
change that? Is there a figure you could put on it, like if 
you're predisposed to have a stroke and your chances are, let's 
say, 40 percent, can you cut that back to 20 percent?
    Dr. Lenfant. Well, before you came in, I was telling the 
Chairman that the death rate from coronary heart disease and 
heart attack has been reduced by more than 50 percent during 
the last 50 years, actually, since the Institute has been 
created. And that it has been reported out from various studies 
just recently that 25 percent, a quarter of this decline in 
death rate, is due to prevention of the development of coronary 
heart disease, and 75 percent is dueto better treatment.
    Now, that 25 percent, that's what we are talking about, you 
see, it's better lifestyles, it's not smoking, it's keeping the 
cholesterol low and appropriate diet and so forth.

                        latino outreach program

    Mr. Bonilla. Let me ask now about your Latino community 
outreach program, Dr. Lenfant, because as you know, heart 
conditions are prevalent in every ethnic group, but because of 
the diabetic factor among Hispanics, it's an additional 
increase in risk that they suffer. Can you tell me about the 
program to reach out to the Latino community and how that's 
working?
    Dr. Lenfant. Yes. We, first of all, our Institute and of 
course our sister Institute for Diabetes and Digestive 
Diseases, are supporting very substantial research on diabetes, 
which is indeed a risk factor of heart disease. Diabetes, for a 
reason which is not clearly or fully understood, is more 
prevalent in the Hispanic Americans than people from other 
ethnicity.
    The way we address that, besides the research, is to have 
community outreach and to be able to communicate to the 
communities what needs to be done to minimize the risk of 
diabetes developing and coronary and heart disease. We have a 
model program here in Washington, actually, which we are 
pursuing with the Hispanic community that involves community 
leaders as well as church leaders and so far, it has been 
fairly effective.
    One of the biggest problems that we have with this 
community outreach is really, there are two problems. The first 
one is, what message do you give, and second, who gives the 
message. And it is true for Hispanics, it is true for African-
Americans.
    The message must be culturally sensitive to the needs of 
that community. It must not be, you know, turn your life upside 
down. We have to adapt what we want to say and communicate to 
the way of life of the community in question.
    And the second thing is that it is very important to have a 
member of the community to go and deliver the message. That's 
why we are working with the community leaders here in 
Washington and in Texas where we have several activities, to 
communicate these messages.
    Mr. Bonilla. Just a comment on that subject, because I 
think in minority communities, churches are often the most 
influential entities within the community. If you could somehow 
channel those programs through those organizations, I think 
they somehow are more effective and listened to more carefully 
by people in those communities.
    Thank you, Dr. Lenfant.

                      sickle cell disease advances

    Mr. Porter. Thank you, Mr. Bonilla.
    Mr. Stokes, as a ranking member on another subcommittee, 
has requested that he be taken out of order so that he can 
return to his other assignment. And the Chair recognizes Mr. 
Stokes.
    Mr. Stokes. Thank you very much, Mr. Chairman. Thank you, 
Ms. DeLauro. Appreciate it also from you.
    Dr. Lenfant, it's always a pleasure to welcome you back 
before our subcommittee. Dr. Lenfant, as you know, this year 
marks the 25th anniversary of the National Sickle Cell Disease 
Control Act. What has been the most significant progress the 
Institute has made in sickle cell research and treatment over 
this quarter of a century?
    Dr. Lenfant. Well, there is more than one, Mr. Stokes. As I 
hear your question, I am reminded that I have appeared before 
you some 15 times. And each year, you say, well, what have you 
done since last year. And when I give you an answer, you say, 
but you already told me that last year.
    If you ask me over a span of 25 years, I think there are 
lots of very important things which can be said. The first one, 
as I mentioned in my opening comments, is that 25 years ago, 
patients with sickle cells disease, many patients with sickle 
cell disease, were dying in their teens. Today the same 
patients live to their fourth or fifth decade or even later. 
When they were dying in their teens, they were dying after 
years of suffering. For many of these patients, that suffering 
has been alleviated, so that in effect they can have an active 
life and participate in the community.
    Now, the most significant achievements have been, number 
one, to realize that the treatment of patients with sickle cell 
disease must not be fragmented, must not be when somebody has a 
crisis, but it must be a continuous treatment. And that is the 
result of the Comprehensive Sickle Disease Centers that we have 
had.
    The second thing that has been established during this 
period is the development of the prenatal diagnosis of the 
disease. Now, the prenatal diagnosis of the disease has led 
subsequently to the prophylactic treatment of many of these 
infants who, as you know, develop pulmonary infection and in 
fact, approximately 30 years, 25 years ago, the newborn infant 
with sickle cell disease could die from that pulmonary 
complication. That is no longer the case. Now we know how to 
treat this, and they survive. And we know that we can stop the 
treatment when they are five or six years of age.
    In addition, because of that, the legislature I believe for 
42 or 43 states has passed legislation requiring that prenatal 
diagnosis of sickle cell disease.
    Another advance, which I reported to you some years ago, is 
that the hydroxyurea, which is basically the first effective 
treatment of pain crisis in these patients with sickle cell 
disease, and that has been controlled quite effectively. And 
then the last thing that I would like to mention, which is work 
which is now ongoing, is treating these patients with bone 
marrow transplantation, and of course the prospect that 
successful gene therapy will have in the years to come. So I 
think a lot has been accomplished on sickle cell disease.
    Mr. Stokes. I appreciate very much the type of improvement 
and progress that has been made, as you have referenced here 
this morning. But ultimately, we must be talking, hopefully, 
about a cure. How far, Doctor, are we from being able to arrive 
at a cure?
    Dr. Lenfant. Well, there is one cure for which we have 
great hope. But not all sickle cell patients will be eligible. 
And that is bone marrow transplantation. Bone marrow 
transplantation has been used relatively rarely in children 
with sickle cell disease. I believe that today, only 30 or 
maybe 40 children have received a bone marrow transplantation.
    What is remarkable about it is that 92 percent of these 
children, basically 35 or so, are now cured of their sickle 
cell disease and have had no difficulties. And in the others, 
the treatment has not been successful. But when it is 
successful, it seems to result in long-term treatment.
    The second treatment that is being investigated by 
ourprojects is that of gene therapy. And there is very significant work 
which is ongoing on two avenues. The first one is to, if you want, 
modify the abnormal mutations that exists in the gene. And the second 
is to find vectors which would permit the implant of normal genes in 
these patients.

                  cardiovascular disease in minorities

    Mr. Stokes. Thank you. Doctor, let me ask you this. I 
happen, here in the Congress, to be a co-chairman of the 
Congressional Heart and Stroke Coalition, a coalition between 
members of the House and the Senate. And this coalition is very 
concerned about the impact of cardiovascular disease on 
families across the Nation.
    I understand that cardiovascular diseases cause a death 
every 33 seconds in the United States. And so it's rather 
shattering to think that in the span of the time I pose a 
question to you and the time that you respond to that question, 
more than three people could conceivably die from 
cardiovascular disease.
    According to the World Health Organization, heart disease 
is projected to replace pneumonia as the leading disease cause 
of premature death and disability worldwide by the year 2020. 
Let me zero in on an area already touched upon by Mr. Bonilla, 
who articulated some concerns in this same area. And I have 
some similar concerns. What is the extent, Doctor, of 
cardiovascular diseases among African-Americans, Hispanics and 
other minorities, and is the onset of the disease earlier than 
that of the general population?
    Dr. Lenfant. In African-Americans, the prevalence of heart 
disease is a little bit higher than in Americans of European 
descent. Among Hispanics, however, although it is high, it is a 
little bit lower. And the risk factors are very different 
between the two populations. Among Hispanics, it is 
predominantly diabetes that is the most important risk factor. 
In African-Americans, the risk factor, the dominant risk factor 
is high blood pressure and also elevated cholesterol.
    In the Institute and elsewhere, there is considerable work 
which is done to determine these risk factors, as I mentioned, 
when I talked about Hispanics. With African-Americans, the same 
kind of program is being developed. But there I have to say 
that we are a little bit ahead of what we do with Hispanic 
Americans, because we have been working on that for a longer 
period of time.
    One thing that we have, and which I will say we are very, 
very proud, we have developed a physician network. Basically 
it's working with the National Medical Association and with the 
Association of Black Cardiologists to enroll them in this 
effort of prevention and treatment in the community. And we 
hope that it will give us the opportunity to make very 
significant headway.
    Mr. Stokes. Thank you.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Stokes.
    Ms. DeLauro.

                            cooley's anemia

    Ms. DeLauro. Thank you, Mr. Chairman.
    Dr. Lenfant, pleasure to see you here today. And I'm glad 
to see you after my hiatus. It's good to be here.
    Let me ask several questions. First, last September, the 
Institute convened a special emphasis panel that looked at new 
therapies for Cooley's anemia. Let me just, from my point of 
view, Cooley's anemia disproportionately affects individuals of 
Mediterranean heritage, particularly Italian-Americans, so I 
was happy to see the Institute express an interest in the 
disease.
    The panel recommended that the NHLBI establish a network of 
collaborative clinical centers to address interventions, 
clinical interventions to the illness. I know that the 
Institute has had success in establishing these centers in the 
areas of heart disease, asthma, and other diseases. The 
recommendation of the panel to address Cooley's anemia, how has 
that been implemented at the Institute?
    Dr. Lenfant. Well, the recommendations of the group, to be 
very honest, were a little bit of a surprise to us. Let me 
explain why.
    You mentioned clinical networks and centers, a network of 
centers for asthma or sickle cell disease, for example. It is 
difficult to do that. Because asthma, for example, there are 12 
million people with asthma in this country. So any center 
somewhere in the country has a large group of such patients.
    For Cooley's anemia, there are only 1,000 or 1,200 patients 
in the United States. And they are scattered all over the 
country. There is admittedly a prevalence, a high prevalence in 
New York. But they are really scattered all over the place. And 
for that reason, it makes it difficult, not to say impossible, 
to develop a network.
    So what can we do instead? We are prepared to work with the 
institutions and the medical centers where they have a 
substantial population, so that within that population studies 
can be conducted. And we have done that in the past, very 
successfully, looking at the iron chelator, for example, which 
has been and is still one of the most significant treatments 
for the disease.
    So we are still, this group met about two or three months 
ago, and we are still looking at what they have recommended. 
Whether it will be possible to implement it or not, I cannot 
tell at this time.
    Ms. DeLauro. So what you're going to take a look at are 
population centers where this is more common?
    Dr. Lenfant. Yes.
    Ms. DeLauro. Is there any sense of a time frame? For 
instance, is there something that can be done, and I would rely 
on you for the information, in the northeast for example, the 
tri-state region of New York, New Jersey. You've got the 
statistics. Are there places where the networks can be 
established in these particular places, rather than your point 
about asthma, which is where there's 12 million people.
    Dr. Lenfant. There is in the tri-state, which I assume is 
New York, Connecticut and New Jersey, a high prevalence of 
patients with Cooley's anemia. Our intention is to work with 
the people there who are doing this research and see what needs 
to be done.
    One thing, though, that I should point out, is that at the 
present time, unfortunately, there is no new treatment which is 
being developed. And therefore, you would want to have a 
network of centers to test something, try out the new 
procedures or what have you, if the procedure or new treatment 
exists, but at the present time, these patients are still 
treated with blood transfusion, iron chelators and that's where 
we are at this time.
    There are some, you may have heard that there is some 
discussion and some ideas which are emerging that 
perhapshormonal treatment may be of some value in these patients. At 
the present time, we really don't have enough with that to go ahead 
with the implementation of a network, which is what was recommended in 
this report.
    Ms. DeLauro. That doesn't give me a sense of real hope here 
for at least the immediate future, Dr. Lenfant, of pursuing 
this. And I don't mean that in a disparaging way. It just seems 
that it's a small population, and there's no new work or 
information about potential treatment. And I understand it's a 
small population, but these are----
    Dr. Lenfant. Well, I don't want my comments to be perceived 
that because it's a small population, it is being ignored or 
neglected, not by a long shot. In fact, I would say that 
proportionately, we have a very significant program of research 
on this disease.
    What I am really saying is that to create a center, a 
network of centers, we want to maximize use because it costs 
lots of money, where there is a network like this one. And 
unless we have something that we can feed to this network to 
do, there is really no point at this time for the network.
    Ms. DeLauro. I understand. I would just comment that if 
there is a way to, as I said, not as expansive as what may have 
been recommended in terms of a network, but some way in which a 
network can be tailored to what the size of the population is, 
that some thought with regard to that area, to begin to scale, 
if you will, the recommendation to the need.
    Dr. Lenfant. I can tell you, and you have a commitment on 
my part, any recommendation which can be implemented, we will 
do it. There is no question about that. Here I am basically, 
well, the question is how to do it, not whether we are going to 
do it.
    Ms. DeLauro. I understand that as well, and how in terms of 
a timely fashion to be moving. I know you have lots of other 
priorities.
    Dr. Lenfant. That one is very important, basically for two 
reasons. First of all is that, while it is a small population, 
it is one that we are very concerned about. Also, we know that 
what we can learn from the disease will be applicable to many 
other conditions. And vice versa.

                          smoking among youth

    Ms. DeLauro. I understand that recently the Institute 
supported a lung health study that examined effects that 
stopping smoking has on lungs. As I've said on this committee 
before, I'm a strong advocate of people stopping smoking, 
particularly our young people. I have instituted a program in 
my district called the Kick Butts Connecticut campaign to get 
youngsters in middle school to have an impact on their younger 
peers in terms of not starting to smoke at all.
    Did your study examine the effects of smoke on youth and 
their lungs, and if so, what kind of results did you obtain? If 
not, are you doing anything in regard to this area that targets 
youth and smoking?
    Dr. Lenfant. Yes. The answer is yes to both questions. The 
population that was looked at for this particular study, which 
incidentally I should say, to my knowledge is the largest 
epidemiological study on the effects of smoking and smoking 
cessation in the United States, in men, women, African-
Americans and Caucasians. It has been a huge study. And in 
fact, it's being continued now through research grants.
    And the results which we found are really applicable to 
everybody, irrespective of age or job. That is, the benefits of 
smoking cessation and the goal of the study is for us not only 
to look at the benefits of the smoking cessation but also to 
have a program whereby the cessation would last. The big 
problem with smoking cessation is that people return to smoking 
very quickly.
    In this particular study, which is now, I think it started 
close to eight or nine years ago, the number of, well, it's--
the second phase started in 1993. So therefore, I would assume 
that the first phase probably started in 1989 or 1988, close to 
nine years ago. The number of individuals that stopped smoking 
is still very high, something like 85 percent. And that is not 
a modest success.
    Now, because of that, actually, the Institute now is moving 
into a new activity, which is a lung health educational 
program, in order to disseminate to a larger group or community 
what we have learned from that study. And many investigators in 
the country are getting together to develop this program. And 
hopefully, working with the American Lung Association and all 
kinds of professional groups we will be able to disseminate the 
results from this lung health study.
    Mr. Porter. Thank you, Ms. DeLauro.
    I would remind members that we will have time for a second 
round.
    Mr. Wicker.

                        preventing heart disease

    Mr. Wicker. Thank you very much, Mr. Chairman.
    And Dr. Lenfant, it's a pleasure to have you before the 
subcommittee.
    You discussed in your prepared testimony fixing the failing 
heart. And we've had several rounds of questions already 
concerning heart disease. Let me just say that I appreciate the 
work that you're doing. This is an area of vital concern to the 
Nation, but particularly to me. Because I represent the State 
of Mississippi, which leads the Nation in the rate of death 
from heart disease.
    And I want to ask you if you have any idea why that might 
be. In 1994, according to the CDC, and this is a fantastic 
figure to me, cardiovascular disease contributed to 46 percent 
of the deaths in my State, according to CDC. And 33 percent of 
the deaths under the age of 65. So I'm very, very much 
concerned about doing something about this.
    And that leads to my question concerning prevention versus 
treatment. In that regard, I want to bring to your attention a 
study that you're probably already familiar with from the 
Harvard School of Public Health. It appeared in the Journal of 
the American Medical Association recently. I cite an article 
from the Boston Globe in February of this year which says that, 
for all the talk about exercise and low fat diets, a new 
analysis finds that the most recent progress against heart 
disease has come from better management of existing disease 
rather than from prevention.
    And the figures given are that adopting healthier 
lifestyles accounted for only about 25 percent of our progress. 
Treatment, such as clot busting drugs for heart attacks and 
coronary bypass accounted for about 43 percent, and another 29 
percent was saved by drugs to lower blood pressure or 
cholesterol.
    The article goes on to say that the study suggests that 
efforts to prevent cardiovascular disease need to be redoubled. 
But points out that many authorities worry that our biggest 
gains in the area of prevention have already been won. So with 
all of that information, I wonder if you could comment on these 
two different approaches to heart disease.
    Dr. Lenfant. Well, I'm very familiar with the study that 
you just mentioned. But I would like to disagree on the 
conclusion which is the statement that all that could be gained 
from prevention is now behind us. In fact, I think the 
prospects for more effective preventions are enormous. And 
that's what I was discussing at the beginning of this hearing. 
At the risk of being redundant, I may go through that again.
    What we have today is an approach to recognize that in 
people who have no symptoms, no other disease, no nothing, that 
they may have some alterations in their cardiovascular system 
which are not visible when you look at them, and they don't 
complain about anything. But problems are there. And if you can 
identify people that, you've got a problem and here it is, I 
can show it to you, then we have here a tool to change the 
approach of people to their own behavior and their own well 
being.
    Having said that, I would like to comment on what you have 
there, on this poster. On your right side, you have what we 
call the conventional angiogram, which is a diagnostic tool to 
really look at the heart arteries of people when they come to 
the physician complaining about chest pain and whatever. And so 
if the physician, after the physical examinations and having 
spoken to the patient, says, aha, that must be somebody who is 
developing heart disease, an angiogram will be done.
    Now, what you see on your right side, that is the 
conventional way to do it, which is an invasive way to do it. 
You have to cut the skin, open a vessel, push a catheter into 
the heart and all those things, which of course you cannot do 
very often. Now, what you have on the left side is a non-
invasive angiogram. That is, basically all you do is to take a 
picture of the patient, like taking an x-ray if you want, 
you're putting, it's not behind a screen like an x-ray, but 
inside a magnet, that's what it is. And you can do that as many 
times as you want. There is no invasion, no skin cutting, no 
vessel opening, no putting dye into the patient. Therefore, it 
can be done as often as you want.
    And the idea here is that if you have somebody who has, 
say, a high blood cholesterol or a high blood pressure and you 
want to know if these indices have already caused some 
alterations in the arteries, you can do what you have here, a 
non-invasive angiogram, and see whether inside the small 
vessels, the smallest vessels, which are here, you see, at the 
bottom, have some alterations and may be the precursors of 
overt disease. And you can determine that and prevent the 
development of physically overt conditions.
    For that reason, I believe that this kind of technology is 
opening the door to further preventive interventions which in 
effect will be much more successful than looking at blood 
pressure or taking a blood cholesterol. Because most people, 
you tell them, well, you have elevated blood cholesterol or 
high blood pressure, they may be concerned, but they won't pay 
too much attention to it, because they don't feel it. However, 
if you take them inside their body, as we do here, and show 
them some alteration, they will pay attention to it. I mean, 
that's the way people are.
    Therefore, I think that the option, the opportunities for 
further prevention, not in everybody, not all the people in 
this country, but in selected cases, are really quite 
remarkable.
    Mr. Wicker. Well, getting back to that poster, what is the 
difference in the cost of both of these procedures?
    Dr. Lenfant. That is the thing. The invasive one is $6,000 
to $8,000, it depends where you have it done. But that's what 
we are talking about. The non-invasive one that you have on 
your left here is in the order, is less than $1,000 today. But 
with the developments which are taking place in the kinds of 
instruments that are needed to do that, I would expect that in 
the future, the devices will be much cheaper than what they are 
today, and therefore, the examination will also be much 
cheaper.
    One thing that I would like to point out, again, the 
smallest vessels that you see here have a diameter which is 
half a millimeter, and half a millimeter, few people recognize 
what it is. On the poster which is in front of you, you can see 
a pencil lead which is stuck there with a piece of tape. And 
that lead is half a millimeter. So as you see, it is really 
seeing what is going on inside the individuals with a high 
level of sensitivity.

                 cardiovascular disease in mississippi

    Mr. Wicker. Just a follow-up, you heard my statistics about 
my State.
    Dr. Lenfant. Yes.
    Mr. Wicker. Would you speculate? I realize it would 
probably lead to speculation, but what is it that would cause 
us to lead the Nation?
    Dr. Lenfant. We know in part what's going on in your State. 
Your State is part of what we call the stroke belt. There are 
nine States which are in the southeast of the United States, 
beginning with Virginia, Maryland, and going south and a little 
bit to the west where you are, where we know that the 
prevalence of coronary heart disease and stroke is highest in 
the country.
    And that's why, actually, we began a few years ago a 
program which is called the stroke belt, because there's a high 
prevalence of stroke there, in order to work with the local 
communities, civic leaders and religious leaders, to basically 
send a message to the communities of what needs to be done to 
reduce this risk.
    And I should tell you that if you are concerned with the 
numbers that you see today, and I don't know from what year are 
the numbers that you quoted--1994. But I can tell you that 10 
years before that, they were much higher than what they are 
now. I can tell you that we have been very successful in 
reducing the death rate from stroke and heart disease in these 
States.
    Mr. Porter. Thank you, Mr. Wicker.
    Ms. Northup.

                          black lung research

    Ms. Northup. Dr. Lenfant, let me direct this question to 
you. The Office of Workers Compensation Program has prepared 
new regulations that refer to black lung, and whether or not 
somebody qualifies for workers compensation. Apparently, it 
intended to make a lot more people qualify for black lung 
benefits or workers compensation benefits. This is at the 
Federal level.
    I believe I'm right that these definitions were tried in 
the 1970s and so many States and the Federal Government were 
swamped, everybody that had ever been in a mine, practically, 
qualified for these benefits. They were starting to sink the 
systems, and the Federal Government reduced them, every single 
State except Kentucky reduced them.
    Finally, Kentucky reduced its in December in an emergency 
special session. It's not just the benefits and the cost of the 
program. It's also the fact that we have a whole sectionof 
Kentucky of people that are on these benefits and can't go to work. 
They lose the benefits if they work, even though they're perfectly 
capable of working.
    We thought that when we changed this, this was actually a 
new governor, a governor that was from the mining area and had 
the support of the mine community. I guess I'm wondering if you 
have any research that would support these mining regulations, 
or do they just have political support?
    Dr. Lenfant. Most of the research on black lung is 
supported by the National Institute of Occupational Safety and 
Health, which is under the CDC. And I have to admit that I 
cannot comment on the basis of that regulation. I'm aware of 
them, but I am not aware of the reasons why these regulations 
were reactivated, so to speak, after a period of interruption.
    Ms. Northup. Can you go back and look, or do you know off 
hand, why NIH hasn't done any additional research in the last, 
recent years?
    Dr. Lenfant. No, and our Institute certainly does not do 
any research in this area. The other Institute which could 
possibly look at that would be the National Institute of 
Environmental Health Sciences. I would surmise that, it has got 
to be looked at, but I would surmise they probably do very 
little, because you have an Institute under the CDC whose 
responsibility is to do that.
    Ms. Northup. Okay. So you're sure that there's nothing that 
NIH has done?
    Dr. Lenfant. I'm sure for our Institute.
    Ms. Northup. Okay. That's all, Mr. Chairman.
    Mr. Porter. Thank you, Ms. Northup.
    Mr. Hoyer.

                      allocating funds by formula

    Mr. Hoyer. Thank you, Mr. Chairman.
    Dr. Lenfant, I apologize for missing the bulk of your 
presentation. I'm the ranking member, as so many people on this 
committee are, on another subcommittee. It's very tough to make 
them both, obviously. But I wanted to come by, mainly to say 
hello and to congratulate you on the continuing excellence of 
the work that you do, and your leadership.
    Dr. Varmus, Dr. Lenfant has been, as you know, with us a 
long time. And I'm always intrigued by his presentations. I'm 
sorry I wasn't here earlier to learn about the diagnostic 
capabilities and the savings that are being effected.
    Doctor, one of the reasons I wanted to be here is that you 
head up the agency where, if you look to Medicare, I suppose, 
it's pretty close to the top in terms of consequential costs 
incurred. Therefore, if we use sort of formula based funding, 
relative to incidence, not just of old people, although I 
increasingly believe that old people now is a relative term 
starting at about 80. I have an 83 year old mother-in-law who 
wouldn't say that she's old at all, Mr. Chairman.
    But, in any event, your Institute would presumably be one 
of the beneficiaries of such a formula based funding. And 
because of your expertise both in terms of your particular 
discipline, but also in terms of your expertise in dealing with 
the internal discussions. I, of course, would not call it 
politics related to NIH, but the internal discussions at NIH 
relative to the allocation of resources. I would like your 
comment for the record now on the issue of the appropriateness 
of funding by incidence of or cost consequences of Medicare or 
some other yardstick of particular diseases as it relates to 
NIH.
    Dr. Lenfant. Let me answer that in a generic way, by saying 
that I suppose all of us are coming into this committee and all 
of us would say, we think any amount of money you can give us, 
go ahead and do it. The issue as I understand it, is whether 
this committee thinks we should get more than this one and so 
forth, irrespective of what the incidence and prevalence of the 
disease might be. And as I hear there are several ways to----
    Mr. Hoyer. Doctor, as I understand the question, it is more 
pointed than that. You sort of stated the obverse. It's the 
reverse, I think, which is to say, it ought to be funded based 
upon the incidence as it writes the cost consequence to 
Medicare in the particular discussion. But I presume because 
Medicare deals with 65 and over, presumably you'd have a 
broader spectrum of dealing with children, and young adults, 
and middle aged, etc., so that you would take as a formula, a 
yardstick for funding, the incidence of the disease.
    As opposed, for instance, to AIDS, where the incidence of 
disease as it relates to heart is relatively minor in the 
United States, notwithstanding its consequences 
internationally. And the epidemic nature of it, I would use 
those two as examples; there are others, diabetes being one, 
that's focused on as well.
    Dr. Lenfant. I think that the incidence and prevalence of 
diseases are one factor, but they cannot be the only one. 
Because it also depends on whether you can do it, and I would 
say that at any one time, there may be opportunities which 
exist in one field, and you have to support these opportunities 
so that this field moves ahead. Because it can do it. In 
another area, your opportunities are different, or even the 
needs, the importance of the public health issues.
    Relative to our Institute, as I'm sure you know, the most 
important component of our Institute is that concerned with 
cardiovascular disease. It's approximately 60 percent or so of 
the Institute. And then we have 20 for the lung and 20 for the 
blood. To look at that 60 percent and say, why shouldn't it be 
80, or why shouldn't it be 60 but in twice as big of an 
envelope, I consider that deceptive. Because in effect, there 
is research which is supported throughout the NIH. Earlier we 
were talking about diabetes, well, now that the Director of the 
diabetes institute is not here, but I would submit that 
whatever that Institute is spending on diabetes is in effect 
working for the cardiovascular diseases. Because of the close 
relationship between this condition and our diseases.
    And so the way I look at it, you see, is that to look just 
at the budget of our Institute and not see what is being done 
with regard to the entire establishment relative to 
cardiovascular diseases may lead to an erroneous 
interpretation. You may be interested to know that we consider 
that, of the whole budget of the Institute, our Institute, 
approximately $800 million is cardiovascular.
    But the fact of the matter is that if you look at the 
Diabetes Institute, the Aging Institute, neurology and what 
have you, NIH is spending approximately $1.2 billion on 
cardiovascular. Basically, there is 50 percent of the monies 
that are allocated to this disease category that do not come 
from our Institute.
    So if you look at that in relation to the incidence, look 
at my $800 million, you say, well, you know that is maybe not 
as much as it should be. But I think that we should look at the 
$1.2 billion. And that is significantly different.
    So, that's a very difficult question, which during the last 
two or three years has come up regularly during these hearings. 
My answer to that is that we, sure, everybody could use more 
money. But I don't think that that money must necessarily be 
allocated based on either of the incidence or the prevalence or 
the number of people who die from that condition. I think there 
are many other factors.
    And again, returning to how the diseases work. You know, as 
you heard, the decline that we have in death rates are due to, 
a quarter of the decline is due to primary prevention. And so 
we could say, well, we've got to increase primary prevention. 
And we all agree with that. But you see, primary prevention is 
not an activity where we have as many opportunities as we may 
have in another area.
    And so you know, to me it would be important to allocate 
money where more opportunities exist and more progress can be 
made.

                         benefits from research

    Mr. Hoyer. Thank you, Doctor. With respect to your 
particular Institute, Doctor, remind me, when did you start as 
the Director of the Institute?
    Dr. Lenfant. I am in my 15th year.
    Mr. Hoyer. So you and I are on a parallel track; I think I 
started in this committee about 15 years ago.
    As it relates to when you started, you may have had a 
chart, and didn't repeat the information. Maybe we have it, but 
one of the things that, frankly, I'm a little better able, I 
think, this week to deal with is, my wife's illness; I thought 
of all the billions of dollars we had spent on cancer since the 
war on cancer started in the 1970s under President Nixon, and 
how, notwithstanding those incredible sums of money, it was 
still impossible, except in the very late stages, to diagnose. 
She had an MRI. In fact, the interesting thing is, she had a 
stint put in, because she became jaundiced on December 17th, 
and on December 19th, which was her birthday, they put a 
permanent stint in. I believe it was the MRI, but it may have 
been the CAT scan operator came back in preparation for that 
incident, and told Dr. Yo, the surgeon, ``I can't find the 
cancer''. Her stomach was replete with cancer at that time, and 
she died, of course, some 45 days later from the cancer.
    But one of the things you think about, and the Dental 
Institute always talks about, is that they get a relatively 
small sum of money and a big payoff in terms of the very sharp 
decrease in dental disease, particularly long-term, as you grow 
older. But also cavities and fluorides and obviously all those 
things. If you presented it, I'll just look at it.
    But for instance, we've spent so much money but that $1 
invested has had a $10, or $20, or $40 payoff because of the 
decreased incidence, decreased loss of work, decreased loss of 
family support, and all those sorts of things that result from 
either very serious or terminal outcomes?
    Dr. Lenfant. Yes. I don't have this data here, but we could 
produce this kind of data. But you could also look at it the 
other way, you see. Earlier this morning I explained, and 
reported to the Chairman that in 1998, we are going to be 50 
years old, the Institute. And it's an interesting time to 
reflect to see what we have done during that period of time, 
after all, lots of money has come from the American people.
    So I feel strongly that after 50 years, it's time to give a 
report. Well, today we know that about half of the people, 
well, the death rate, if you want, of coronary heart disease, 
let's take that simple disease, which is not so simple, 
actually, but everybody knows what that is. But the death rate 
from that is half today what it was 50 years ago.
    Now, admittedly, there are problems with that, in a way, 
because you have many more people today who are running around 
with coronary heart disease than there were 50 years ago, 
because they didn't die. But they have the disease. We are not 
as successful to prevent it from occurring as we are to fix it. 
So the net result of that is that you increase the number of 
people with the disease. But the fact of the matter is that 
these people are walking, they are producing, they are very 
income producing citizens for many years.
    So you could say, sure enough, the fact that today we have 
many more people with that disease, it's costing the country. 
But I would like to submit to you that in effect, many of these 
people are paying their way, because they can work and before 
they didn't produce, they were not contributing to society. So 
these are very complex issues. And that's why I think that, you 
know, I don't want to put words in Dr. Varmus' mouth, but I 
think what he advocates is that the best way for us to make 
progress is to go where we have the opportunity, scientific 
opportunities.
    And I think the second part of this is that today, because 
of the very nature of the science that we are doing, the 
opportunity which is good for this disease is also important 
for that disease and for the third one. And so there is a great 
deal of overlap among the disease categories.
    And so you know, the net result of all that is to focus on 
the opportunity, what can be done, where we see a payoff is a 
good way to do it. Now, that does not mean that, coming back to 
cardiovascular disease, there are no opportunities. In fact, we 
are full of opportunities.
    But I think that the opportunities that we have now are 
being met with the way the judgements are made. In fact, for 
1998, with the discussions that took place at the NIH, an 
allocation was made, a special allocation was made to this 
Institute in order to meet an emerging opportunity where we 
think that we can do something and we can do well
    Mr. Hoyer. Thank you, Doctor. I think it would be a 
ballpark hypothesis, because as you point out, if you live 
longer, you sustain more medical costs with a disease. On the 
other hand, if you died, your productivity, your support of 
family, your payment of taxes, etc., would be lost to this 
society. But what I think we all believe is that there is a 
great plus, both in terms of dollars and in terms of society as 
a whole.
    But that might be an interesting thing. As we debate this, 
the Chairman has been extraordinarily supportive, as you know, 
of funding for NIH. His predecessor used to always say, the 
budget for NIH is x billions of dollars. If it were $3 billion 
or $4 billion more, it would not be too much. His premise being 
that whatever resources we could apply was in fact paying off 
both in a dollar sense and in a societal sense.
    And I'm pleased to serve with a Chairman who shares that 
view, because we're advocates of investing in what we think is 
a very significant payoff for all our taxpayers in our country, 
and indeed, because we're the leader in the world.
    Thank you, Mr. Chairman, for giving me the time.

                         human cloning research

    Mr. Porter. Thank you, Mr. Hoyer.
    Dr. Lenfant, we're going to give you a rest for just a 
minute, so I can ask Dr. Varmus several questions. Dr.Varmus, 
we understand you've been to the White House this morning discussing 
the human cloning issue. And today's radio reports indicate that the 
President intends to issue an executive order prohibiting human cloning 
in Federal research programs, and requesting a voluntary moratorium on 
private experimentation.
    Are the news reports correct?
    Dr. Varmus. Yes, he actually has signed that order.
    Mr. Porter. Is the executive order thought to be necessary 
because the human embryo research ban in our bill does not 
cover the entire Government? Or did the White House lawyers 
disagree with the NIH position that the provision in our bill 
covers human cloning?
    Dr. Varmus. My understanding is that the former provides 
the bulk of the motivation, not all of it. The bill covers HHS 
and there's concern about, we want to make it perfectly clear 
that no Federal dollars in any agency can be used, regardless 
of the intent of the manipulation, if they're intended for 
research or for reproductive purposes, solely.
    Mr. Porter. The President's 1998 budget proposes to lift 
the human embryo research ban in our bill. And you cautioned 
last week against quick legislative action on cloning before 
ethical and scientific factors could be fully considered.
    Is this executive order inconsistent with these views?
    Dr. Varmus. No. The intention is to have that order in 
place to reassure the public until the National Bioethics 
Advisory Commission, headed by Harold Shapiro, who was also in 
attendance this morning at the signing and discussion, can 
fulfill its responsibility to return an evaluation of the 
potential of performing human cloning and the ethical 
considerations around it.
    Mr. Porter. And does the White House, has the White House 
indicated whether the rest of the ban on human embryo research 
should be lifted, the portion that does not deal with cloning 
in our bill?
    Dr. Varmus. I think the position remains the same with 
respect to----
    Mr. Porter. Regarding the rest of it?
    Dr. Varmus. Correct.

                      laser surgery for the heart

    Mr. Porter. Thank you, Dr. Varmus.
    Dr. Lenfant, last September, the Journal of NIH Research 
reported on a laser technique called TMLR for patients with end 
stage heart disease. The laser essentially burns a series of 
small holes through the heart to allow the blood and oxygen to 
seep through and into the heart muscle. Early results are 
promising in terms of increased blood flow and patient 
endurance, and the procedure is currently being tested in a 
clinical trial. But scientists readily acknowledge that they 
don't understand why TMLR works. Is it troubling to you that 
the FDA could approve a procedure drilling holes into the heart 
simply if it shown to be safe and efficacious, even if the 
reasons for its benefit are unknown?
    Dr. Lenfant. Well, I think the procedure is being used in 
Europe. There is quite an extensive experience in Europe.
    I do not think that the FDA has anything to do with the 
procedure itself, but rather the approval of the device to 
drill the holes inside the myocardium. That's what they are 
going to be concerned with. To my knowledge, the FDA is not 
getting involved with surgical procedure. In fact, that's a 
problem, that emerging surgical procedures which have doubtful 
validity, but there is nobody to regulate that, unless the HCFA 
gets into it because there is a reimbursement issue.
    I think that we need to have the results of that clinical 
trial, which is going on. I have to say that we know very 
little about who is doing this clinical trial. We know it's 
sponsored by the company that makes the laser device. But I 
really don't know anything about the exclusion or the inclusion 
of the subject criteria that they have. We don't know for sure 
what the end points are.
    I think that for something like that, I would hope that the 
end point would not be after six months, but rather after maybe 
two or three years. I think the verdict is still out on that 
one.

                              sleep center

    Mr. Porter. Last year, we discussed a problem being 
encountered by the Sleep Disorders Center in the low number of 
research applications it was receiving. Has that situation 
improved over the last year?
    Dr. Lenfant. Yes, yes, indeed. And I would say, it's to the 
tribute of the Director of that center, who is extraordinarily 
active, working with all the Institutes at NIH and developing 
all kinds of programs and things. For example, the research on 
melatonin that we were mentioning earlier, the bottom line is 
that we are indeed increasing the number of research grants and 
support. Last year, in 1995, the support at NIH was about $73 
million. It was $76 million last year. This year, it's 
anticipated to be over $81 million.
    So we keep on increasing, and I think the center is doing 
quite well. I don't know if Dr. Varmus would agree with that, 
but that's my opinion.

                  funding for public education prgrams

    Mr. Porter. Dr. Lenfant, as you know, this subcommittee has 
been concerned about administrative costs and has taken steps 
to limit these expenditures. But we want to be careful that we 
are not inadvertently limiting program activities.
    Your Institute's public education programs are included in 
the admin costs line. How much is your public education budget?
    Dr. Lenfant. Well, the public education budget is made of 
three components: paying the employees who work in there, and I 
would say that the number of employees has been reduced over 
the last few years. At one time we had 39 employees, we are 
down to 34. The second component is the support of the contract 
program, which manages the development of brochures and things 
of that sort. And the third thing are direct costs within the 
Institute.
    The total in 1995, taking that as a base, of these three 
components, was $10.5 million. This year it is going to be $8 
million, is our projection. However, what you should know, is 
that the direct costs which were $3 million in 1995, are going 
to be less than $800,000 or $900,000 this year.
    And I have to say that that is reaching a very, very 
critical point, especially at a time when there is increased 
pressure on the Institute to further develop some of its 
educational activities, not least from the sleep community. We 
have been mandated to develop a sleep disorder educational 
program. And basically, it is very difficult, if not 
impossible, to do.
    Mr. Porter. Have you considered displaying the public 
education activity separately in your budget so it is not 
artificially constrained when administrative costs are frozen?
    Dr. Lenfant. We have considered that in other years a 
number of times. And I have to say that we really 
vacillate,sometimes for, sometimes against. And the reason is the 
following, that it is a relatively small amount of money. And it is 
going to be, you know, we are talking about, the whole thing is in the 
order of, well, in the happy days it was about $13 million, $15 
million. Now it's down to half that.
    And if you see that from a total of almost $1.4 billion, I 
think nobody's going to understand what that $10 million does 
by itself there. And that is the reason that sometimes we think 
we should do it, and some other time we say, well, no, we 
should not do it, we should leave it where it is. It is a very 
difficult thing. But the bottom line is that we are exceedingly 
concerned to see the reduction of our flexibility and therefore 
the loss of opportunity for further development of our 
educational program.
    Mr. Porter. Dr. Varmus, from a centralized NIH perspective, 
would you have any problem separately identifying public 
education activities in the mechanism table?
    Dr. Varmus. No, I wouldn't. In fact, I think I'd prefer it 
in the long run. One of the outcomes of the administrative 
review that we're undertaking in response to your suggestion, I 
hope will be a more uniform way to account for expenditures 
across the Institutes.

                            service centers

    Mr. Porter. Dr. Lenfant, you've established three service 
centers which provide services to other Institutes in the area 
of procurement, committee management and technology transfer. 
How many Institute and center customers do you have for your 
three centers, and is there any other Institute competing with 
you to offer these same services?
    Dr. Lenfant. Well, the first part of your question, in the 
procurement, we have three Institutes. In the technology 
transfer, we have four Institutes. In the committee management, 
we have four Institutes. And they are all different. And I can 
say that we have a few of other Institutes, not least the 
Office of the Director, who utilize our services for some of 
their functions.
    It is very labor intensive, and we are having discussions 
with Dr. Varmus' office to see how we can better set that up. 
My reaction is that it has been very successful for the 
Institutes which are being served. And I have to assume that 
they agree with that statement, because if not, we would not 
have other Institutes coming and asking to be part of our 
service network, especially the Office of the Director.

                 government performance and results act

    Mr. Porter. Dr. Lenfant, you have the reputation of being a 
skilled Institute manager. How are you contemplating applying 
the analysis of the Government Performance and Results Act to 
your Institute's activities? Is it possible, for example, to 
link mortality and morbidity measures to the performance of 
your programs?
    Dr. Lenfant. Well, first of all, that's an activity which 
is emerging at NIH, and we are working to set up these measures 
of performance.
    The thing that I have to say, which I find interesting, is 
that we have done that to a point for many, many years. For 
example, you are familiar with our educational programs. And 
every so often, we do surveys to establish whether we have met 
our goals, which is to increase the number of people who are 
aware of their blood pressure, who keep it under control, or 
the number of people who do something about lowering of 
cholesterol, and so forth.
    In addition, we also have done it to some of our clinical 
trials to assess whether the practicing community has actually 
implemented some of the recommendations or outcomes coming from 
these clinical trials. Whether the death rate would be an 
appropriate measure, in all honesty, I would have to think 
about that. I don't know.
    But I think the whole thing is positive, but difficult. And 
we have to be very careful. Because research is not as 
predictable as building bridges or roads, or planting trees 
along the water.

                     lung volume reduction surgery

    Mr. Porter. Last year, we found ourselves in the middle of 
the dispute about HCFA's refusal to reimburse lung reduction 
surgery. We had hoped the controversy would be settled by a 
clinical trial of the procedure, which your Institute and HCFA 
have jointly agreed to support.
    Instead, the outside groups seem to think that the trial 
you are developing is too narrow, and won't test the full range 
of procedures being used in the field. Can you review for us 
the status of this trial and how you are responding to 
criticisms of its design?
    Dr. Lenfant. Let me answer the second question first, which 
procedures are being used. Today, there are three approaches to 
excising, if you want, a part of the lung, so that the rest can 
expand and work better. One is a sternotomy, that you open the 
chest in the middle and do what you want to do. The second one 
is video assisted. And the third one is a laser excision. The 
clinical study that we have designed includes the two first 
approaches, that is the sternotomy and the video assisted, but 
not the laser.
    Why not the laser? Well, there are several questions, 
several reasons. The first one is that to do a serious study, 
you have to be able to compare this procedure with that 
procedure, otherwise, you cannot determine what is best. But 
the problem is that the surgeons, while doing the laser 
excision, do not do any of the two other procedures. And 
therefore, if you were to include it, you would never know 
whether it's better or worse, because of the surgeon or because 
of the procedure. Do you follow me?
    Mr. Porter. Yes.
    Dr. Lenfant. The second reason is that to have a clinical 
trial with the three procedures would be extraordinarily 
expensive. In fact, it would cost about three times what is 
underway. And the third reason, which is probably the most 
forbidding one, is that we know of two centers where they have 
a fairly large experience with laser excision. One of them has 
given up because of the number of complications. And they 
decided not to use it any more. And the second has not given 
up, but they have published a report to show that the number of 
complications is much higher than the two procedures which we 
are using.
    So the study is done to answer specifically two simple 
questions. The first one, is excising a piece of the lung 
beneficial to the patient. And second, which patients would 
benefit.
    As we went out designing the study, we thought that it 
would make no sense to include a procedure which at the outside 
was already so controversial. Of course, the people who do it 
don't think it's controversial. But the community at large 
does.
    Now, the other question, which is, are we too rigid in our 
approach to clinical trials, we now have 18 centers which are 
involved with it throughout the country. And their job now is 
to develop the protocol which will be implemented in acouple of 
months. Some of the participants say, but we have the answer, we have 
the data, we don't think we have to go through the protocol.
    The response of the Institute has been, fine, bring your 
data, we will have it independently assessed and reviewed, and 
if the independent review says, yes, these data should lead to 
excluding these kinds of patients, or making this change or 
that change, we will comply. But so far, that hasn't taken 
place.
    The position of the Institute, Mr. Chairman, has been very 
clear. If new data becomes available as we proceed, we are 
prepared to modify what we are doing. But so far, we haven't 
seen any of that data.
    Mr. Porter. So the criticism that the clinical trial, which 
is expected to take seven years, is too long a time to be 
useful for HCFA's reimbursement decisions, if I understand what 
you're saying, you're saying you're going to review whatever 
data comes along in the meantime, and even if new procedures 
come along in the meantime, if there's data to support their 
efficacy, that would be included in your study.
    Dr. Lenfant. That is correct. And I can tell you, that if 
we had included the laser excision in the design instead of 
taking 7 years, we were going for 10 or 12 years.

                               hemophilia

    Mr. Porter. I was hopeful that Mr. Miller would arrive. 
He's at a budget hearing where Alan Greenspan is testifying, 
and that's the reason he's unable to be here.
    These are questions that Mr. Miller of Florida would have 
liked to have asked had he been here, and I want to ask them 
and have you answer them for me.
    What are the latest developments by your Institute in the 
area of hemophilia?
    Dr. Lenfant. Well, this year has been kind of a golden 
year, actually, in the sense that there have been some very 
significant advances. The first one, which is really novel and 
did not exist before, is that the recombinant DNA factor IX has 
been produced. The deficiency in two clotting factors, if you 
want, which are responsible for hemophilia, are factor VIII and 
factor IX.
    We have had a substitute for factor VIII for quite a few 
years, and I'm going to come back to that. The one for factor 
IX, we didn't have. But now we have it. And it is my 
understanding that it's being reviewed now by the FDA to decide 
whether they can approve it or not.
    Now, the second thing that has happened is that factor 
VIII, which I said we have had for quite a few years, was still 
including some human albumin in it in order to stabilize the 
product. And that in fact was responsible for some immune 
reaction when it was given to patients.
    Now what is being developed, and is almost developed, is a 
new factor VIII which does not include any human albumin, and 
therefore would be much safer for the patient. And then the 
third thing is that a new animal model has been developed. We 
have had hemophilic dogs, now we have hemophilic mice. And the 
advantage of having these two species is that it's going to 
enhance the capability for gene therapy development and 
assessing the effectiveness of gene therapy a great deal.
    Mr. Porter. Representative Miller's son is a hemophiliac. 
And he would also like to ask, are there any new developments 
on hemophilia from any biotech companies that you may have 
heard about?
    Dr. Lenfant. Yes, as a matter of fact, the recombinant DNA 
factor IX that I just mentioned is developed by a biotech 
company. As is often the case, the commercial outfits are 
picking up the result of the research which is conducted by the 
Institute. I have to say I don't know which company that is. 
But I could find out.
    Mr. Porter. Dr. Lenfant, thank you for your good testimony 
this morning, for your very candid answers and direct answers 
to our questions, and for the wonderful job that you're doing 
there at the Institute. And 50 years is a great milestone for 
the Institute. You've been its director for almost a third of 
its existence, and we appreciate the fine work that you're 
doing.
    Dr. Lenfant. Thank you, Mr. Chairman.
    Mr. Porter. The subcommittee will stand in recess until 
1:30.
    [The following questions were submitted to be answered for 
the record.]

[Pages 898 - 982--The official Committee record contains additional material here.]


                                            Tuesday, March 4, 1997.

                    NATIONAL INSTITUTE ON DRUG ABUSE

                               WITNESSES

ALAN I. LESHNER, M.D., DIRECTOR, NATIONAL INSTITUTE ON DRUG ABUSE
RICHARD A. MILLSTEIN, DEPUTY DIRECTOR
DONNA M. JONES, BUDGET OFFICER
LAURA ROSENTHAL, EXECUTIVE OFFICER
DR. HAROLD VARMUS, M.D., DIRECTOR, NIH
DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF 
    HEALTH AND HUMAN SERVICES

    Mr. Porter. The subcommittee will come to order.
    We're pleased to welcome Dr. Alan Leshner, the Director of 
the National Institute on Drug Abuse. I apologize for being 
late. I was stuck on a phone call that I couldn't get off of.
    Dr. Leshner, why don't you proceed with your statement 
right away?

                       Introduction of Witnesses

    Dr. Leshner. Thank you, Mr. Porter. Let me just introduce 
the people I brought with me. Donna Jones, NIDA's Budget 
Officer; Laura Rosenthal, our Executive Officer; Richard 
Millstein, our Deputy Director; you know Dr. Varmus and Mr. 
Williams from the Department.

                           Opening Statement

    I'm very pleased to tell you that we've had another 
outstanding year in drug abuse research and its application. As 
you know, NIDA supports over 85 percent of the world's research 
on the health aspects of drug abuse and addiction. And we do 
that through a very comprehensive and broad ranging research 
portfolio.
    Because NIDA plays such a dominant role in drug abuse 
research, we've come to understand that doing great science by 
itself is not enough. And we know that if our scientific 
findings are not both useful and used, we're not fulfilling our 
mission. And that's why NIDA and its staff are continuously 
holding discussions not only with the scientific and 
professional communities, but also with policy makers and the 
general public.
    We do that both to share the results of NIDA-supported 
research, and to get input from the users of our findings about 
the information that they need to do their jobs. Our ongoing 
series of town meetings across the Nation exemplifies NIDA's 
commitment that our research both be useful and used.
    As just one example, we recently brought together community 
leaders and leading scientists at a town meeting in San 
Francisco to help confront the emerging drug problem of 
methamphetamine. And as one result of that town meeting, NIDA 
has launched a major methamphetamine research initiative to 
increase our knowledge about this drug's effects and what to do 
about them.
    I'd like to share with you just one of the very important 
new findings described at that meeting. Last year, I showed you 
brain images showing your brain on drugs, and then I showed 
some brain scans of persistent effects of chronic cocaine use 
on general brain metabolism that last at least four months 
after the addict has stopped using cocaine. Well, research 
published this year demonstrates just how pervasive, how 
devastating and how long-lasting other brain changes can be 
after chronic heavy drug use. And they're adding important 
specificity to the kinds of more general effects that we 
discussed last year.
    I'm going to use the case of methamphetamine. We know well 
that acute use of both methamphetamine and amphetamine produces 
very dramatic changes in brain function, particularly through 
the release of the neurochemical dopamine, and that spike in 
dopamine release is how the amphetamines produce their 
psychoactive effect.
    Well, we now also know that long-term amphetamine use 
produces dramatic changes in dopamine activity that persist 
long after the individual stops using the drug. And the effects 
are not limited to the toxic effects of amphetamines, since 
those effects in fact recover over time. This poster to my left 
shows the effects of 10-day exposure to heavy doses of 
amphetamines on the brain's ability to synthesize, to produce 
this substance dopamine. These are positron emission tomography 
``PET'' scans, of verdant monkey brains.
    [The information follows:]

[Page 985--The official Committee record contains additional material here.]


    And the top row shows you in white and red normal levels of 
compound fluoro-dopa, or fluoro-dopa activity, an index of the 
ability to synthesize dopamine. Red, yellow, and white are more 
activity, blue is less activity there. The second and the 
subsequent rows show a dramatic decrease in dopamine synthesis 
capacity that lasts at least a year after amphetamine dosing 
was stopped. So what you see there is the pre-amphetamine on 
the top row, amphetamine for 10 days, and then after you stop 
giving amphetamine, four weeks, six months, by a year it's 
coming back. The important point is it will recover by two 
years. And that bottom line is basically similar to the top 
line.
    Mr. Porter. Excuse me, it's just 10 days of the use of 
amphetamines?
    Dr. Leshner. That's right, it's 2 injections a day for 10 
days.
    Mr. Porter. And that has an effect for at least a year?
    Dr. Leshner. Yes, sir.
    What's important about this is that these persistent brain 
changes are accompanied both by severe amphetamine addiction 
and by dramatic changes in social and emotional behavior 
processes that also persist for a very long period of time. And 
of course, it's not surprising that there are these behavioral 
effects, since we know dopamine is critically involved in 
social and emotional behavior processes, including particularly 
the regulation of human mood states.
    Turning to a very different domain, we've also been working 
very hard to try to improve the prevention of initial drug use, 
particularly among young people, which I know you know is a 
major problem in this country. In September we held the first 
national conference on drug abuse prevention research, bringing 
together over 500 researchers and community practitioners. And 
as a result of that meeting, in the next few days, we will be 
releasing the first ever science-based guide to drug abuse 
prevention.
    We'll be sending this guide to thousands of practitioners, 
community anti-drug coalitions and other lay leaders all over 
the country. This user-friendly booklet articulates the 
principles that we've learned from prevention research, and it 
gives practical guidance on how communities can apply these 
principles to address local drug problems.It even includes 
science-based checklists of criteria against which communities can 
evaluate local programs.
    NIDA is also working to continue to improve drug treatment 
approaches. We've mounted a new Institute treatment initiative 
this year that, among other things, is taking behavioral and 
pharmacologic therapies that our studies have shown to be 
effective in small-scale laboratory studies and evaluating them 
in real life, large, multi-site clinical trials. Behavioral 
approaches such as cognitive behavioral therapy and contingency 
management therapy that have been studied in academic settings 
but have not been applied very broadly in the real world will 
be further evaluated.
    We will also continue to develop new medications to restore 
a degree of normalcy to brain function and behavior, so that 
other therapies and rehabilitative measures, such as counseling 
and psychotherapy, can be more effective than they are now. 
Although behavioral and pharmacologic treatments can be 
extremely useful when employed alone, NIDA-supported research 
has taught us that integrating both types of treatment is the 
most effective approach.
    In fact, these integrated approaches are typically 
essential to restoring an addicted individual to normal 
functioning.
    We've also made tremendous progress in one of NIDA's top 
priority areas, the development of an anti-cocaine medication. 
One of the most promising and consistent basic science findings 
of the last year or so is that stimulating one of the brain's 
dopamine receptors, called the D-1 dopamine receptor, seems to 
suppress cocaine craving and cocaine seeking behavior.
    We're now in discussions with chemists from academia, from 
other NIH institutes and from industry to develop and acquire 
dopamine D-1 stimulating compounds that we can examine as 
potential medication.
    In addition, to expedite the path from these types of basic 
science findings, to actual changes in clinical practice, NIDA 
has just funded the first three grants of its Strategic Program 
for Innovative Research on Cocaine Addicts--SPIRCAP--program, 
which is that program I mentioned last year that we were 
inaugurating, to force the collaboration between basic 
scientists and clinical scientists to do the kind of 
translational research that I know many institutes have been 
talking with you about.
    These are just a few of the past year's findings in NIDA's 
new initiatives. Some others are spelled out in my full 
statement. I hope that they make clear that NIDA-supported 
research is providing us with a solid scientific foundation to 
better ensure that our Nation is equipped to respond not only 
to the problems of today, but to the challenges of tomorrow.
    To paraphrase a recent report by the Institute of Medicine 
of the National Academy of Sciences, the success of our 
national investment in addiction research will be measured in 
lives saved and reclaimed and the development of our youth into 
productive and healthy adults, and in the restoration of 
families and the security of communities. This same Institute 
of Medicine report applauded NIDA's past successes and stated 
the Institute of Medicine's belief that we're working in the 
right direction and are well on our way to meeting these 
important societal goals.
    To meet the challenges and opportunities now presented to 
us, NIDA requests $358,475,000 for fiscal year 1998. A hallmark 
of this request is the $30 million increase proposed by the 
Administration. This is a part of the Administration's cross-
cutting efforts to combat drug abuse, which has been increasing 
in some populations.
    I would be pleased to answer any questions.
    [The prepared statement follows:]

[Pages 988 - 991--The official Committee record contains additional material here.]


                        relationship with ondcp

    Mr. Porter. Thank you, Dr. Leshner.
    Mr. Hoyer has another subcommittee that he has to attend, 
and I'd like to recognize him first. Mr. Hoyer.
    Mr. Hoyer. Thank you very much, Mr. Chairman. That's very 
thoughtful of you.
    Doctor, thank you for the report and it is indeed, as you 
said at the outset, a hopeful report. I think all of us are 
very hopeful that we will sort of get a magic formula by which 
we can suppress the desire that you speak to in your larger 
statement; the craving for drugs, particularly for those who 
have been on and are off. Obviously recidivism is a major, 
major problem for the medical side of the question, as well as 
for the law enforcement side of the question.
    Just a couple of questions. First of all, in my other 
subcommittee, the Treasury, Postal Subcommittee, General 
McCaffrey's Office of National Drug Control Policy, is budgeted 
there. Would you tell me what interface you have with ONDCP and 
General McCaffrey?
    Dr. Leshner. I will. We have been very fortunate, I think, 
to develop a fairly close relationship with ONDCP and with 
Director McCaffrey in particular. He has the unique 
characteristic of being very interested in science, and 
therefore, he has been known to track me down on vacation and 
ask literal scientific questions. He's met with Dr. Varmus and 
has been very interested in much of what we're doing.
    Our relationship is informational, primarily, that is, we 
brief him probably every few weeks on whatever issue is in 
front of him at the moment. Our staff went down recently, for 
example, to talk about the science of prevention, in 
particular, and they've been very interested in our medication 
development program.

                          vaccine development

    Mr. Hoyer. I'm glad to hear that. Of course, one of the 
things I was struck with in my first meeting with General 
McCaffrey before he'd been confirmed but after he'd been named 
by the President, was his emphasis on prevention and 
rehabilitation. This is a four-star general, the most decorated 
soldier in America right now who is living, and he does not 
like to refer to the war on drugs. He sees prevention and 
rehabilitation as a major, major component, as you know.
    Toward that end, in your statement you refer to both 
identifying genetic markers for proclivity to use, as well as 
suppression of further desire. How far away do you think we are 
to, I know you referred to this, but to perhaps, I guess, an 
inoculation? What am I looking for? The word?
    Dr. Leshner. A medication? A vaccine?
    Mr. Hoyer. Vaccine. In effect, is that conceptually what 
we're looking toward?
    Dr. Leshner. Well, let me give you a slightly longeranswer 
than you might want, but I'll try to keep it brief. Actually, the 
problem of developing appropriate medications, and I need to say, I 
don't think we'll ever have a magic bullet, so anyone who's waiting for 
that, I apologize. The cycle of addiction is from a clinical 
perspective complex, obviously. There's an issue of initial drug use, 
there's an issue of once an individual becomes addicted, which I 
believe is a different, and qualitatively different state. Then there's 
the issue of how do you keep someone off drugs once they're off. I 
believe that we may actually need different pharmacological approaches 
for each of those stages, and worse, more stages.

    There has been a lot of interest, and NIDA has made a 
number of grants, actually, in three different places, to look 
at the potential for developing some kind of a vaccine based 
approach. We actually have a company called Immunologics that 
just got a very large grant from us in order to further the 
development of a potential vaccine.

    I don't think we're at a point yet where we really 
understand the complexity of how that might be used. That is, 
that it might be that for some individuals you would want to 
give them this vaccine which has been preliminarily developed, 
in animals, of course. That might help control their initial 
drug use.

    It's much more complex. An even more complex ethical issue 
is what you do for the long term with vaccinating somebody. 
Technologically, I would say that we're beginning to get close. 
That is, we have in fact in rodents developed a model where 
antibodies have been produced to block cocaine, and they do in 
fact block cocaine's entry into the brain. They do in fact 
block cocaine's initial psychomotor effect, that is, they block 
the stimulant effect of cocaine.

    What we don't know is if they would also block craving for 
someone already addicted, for later drug seeking. So at most, I 
think, a vaccine approach will be an initial stage. I think 
we'll need other kinds of medications, particularly to deal 
with the craving, which is the most difficult and the most 
complex aspect for an addict.

                      alcohol and substance abuse

    Mr. Hoyer. Doctor, the last question, and I again apologize 
for having to leave to be on the other subcommittee, but we're 
going to hear from the National Institute of Alcoholism and 
Alcohol Abuse. Clearly, very closely related. I was interested 
to see in the paper today that although parents and teenagers 
or young people differed on a lot of things, in terms of drug 
use and what parents are telling students or their kids and 
what kids were hearing, they agreed on one thing 
overwhelmingly, that alcohol abuse was the major problem that 
confronted young people.

    Clearly, without getting into the political definition of 
alcohol and tobacco versus cocaine and heroin and making an 
analogy there, which I'm not making at this point in time, but 
clearly there is an analogy; presumably all these substances 
have a similar effect and are driven by similar drives which 
lead to addiction or overuse. Am I correct on that? And if 
that's correct, I presume there's a great deal of cooperative 
effort between the two Institutes.

    Dr. Leshner. Well, there are both similarities and 
differences among individual drugs. It's true that many, many 
abusable substances have common effects, particularly on the 
dopamine system in the brain. We do work very closely with the 
National Institute on Alcoholism and Alcohol Abuse. And we have 
a lot of programs 
that we do together and things that we study together. At the 
same time, there are separate sets of issues that pervade it.
    But the questions of adolescent substance use are very 
broad and cut across issues of value as well as issues of 
science. And they are pervasive, as you suggest.
    To answer your question, there are similarities and there 
are things that are different, including the nature of the 
metabolic effects that are going on with the use of different 
substances.

                           nicotine addiction

    Mr. Hoyer. I said that was going to be my last question, 
but one thing occurs to me, Mr. Chairman. Alcohol is obviously 
a legal substance. What do we do, and this is going to be a 
controversial question, what do we do with respect to nicotine? 
We don't have a National Institute for Nicotine Addiction.
    Dr. Leshner. We actually study nicotine addiction. We 
coordinate, of course, with other institutes, the National 
Cancer Institute, the National Heart, Lung, and Blood Institute 
who study other aspects of nicotine and smoking. We actually 
are responsible for the primary research on the addictive 
properties of nicotine.
    Mr. Hoyer. Mr. Chairman, you've been generous to me in 
time, and I appreciate that very much, and for recognizing me 
first. Thank you.
    Thank you, Doctor.
    Dr. Leshner. Thank you, sir.

                       drug abuse budget increase

    Mr. Porter. Thank you, Mr. Hoyer.
    Dr. Varmus, I think I want to begin with a question to you. 
And this is not a hostile question, but merely one to determine 
how you reach conclusions. The NIH budget specifically 
identifies, as Dr. Leshner has said, a $30 million or 9 percent 
increase for non-AIDS drug abuse research.
    In general, you've tried to avoid disease-specific 
increases and have instead constructed your budget on the basis 
of six areas of emphasis. But only $17 million of the $30 
million non-AIDS increase for NIDA is associated with these six 
areas. Do you see any inconsistency in the way your budget 
provides such a large proportionate increase to drug abuse?
    Dr. Varmus. The extra money for the Drug Abuse Institute 
represents an Administration decision that there ought to be 
more emphasis placed in that area of research. The Drug Abuse 
Institute was slated for substantial monies, which you've seen 
represented in the areas of prevention and neuroscience. The 
increase is more than it might have been had there not been a 
coordinated decision by us, in collaboration with the 
Department and the White House, to make a special push this 
year to try to advance medications development and other topics 
that Dr. Leshner will discuss.
    Mr. Porter. Do I understand then that this was not in your 
original proposals sent to the Department?
    Dr. Varmus. That's correct.
    Mr. Porter. And came from the White House instead?
    Dr. Varmus. It was a coordinated decision to go ahead and 
do this.

                         alaska needle exchange

    Mr. Porter. Thank you.
    Dr. Leshner, there's been a great deal of publicity 
recently about research on needle exchange programs, and in 
particular, a study NIDA is supporting in Alaska. First of all, 
can you summarize what we know and what we do not know on the 
basis of existing studies about the effectiveness of needle 
exchange programs in preventing the transmission of AIDS?
    Dr. Leshner. Well, I think if you look at the converging 
evidence as summarized now by a large number of reports, pretty 
much whatever measures we use are indicating that in the 
context of a broad set of prevention activities, needle 
exchange can be an effective vehicle for reducing the spread of 
blood-borne infections, including HIV, hepatitis virus and 
other kinds of blood-borne infections.
    The question that's more difficult to demonstrate, of 
course, is the question of how it affects drug use. And I 
should say that there is no evidence that it increases drug 
use. It is a very effective strategy for bringing people into 
treatment. Somewhere, in our various studies, somewhere between 
15 and 25 percent of the people who come to those programs in 
fact enter into treatment.
    Mr. Porter. Now, can you describe the needle exchange study 
you were sponsoring in Alaska and the reasons it has been 
opposed by Public Citizen?
    Dr. Leshner. I'll try. The needle exchange grant at the 
University of Alaska is actually a, what we might think of as a 
second generation project. That is to say, it's comparing the 
efficacy of two different approaches to providing sterile 
needles.
    I should make clear that in any studies of this kind, and 
in any of the studies of needle exchange that we are doing, we 
recognize, and the protocols are created in such a way that the 
first attempt by all investigators is to get people into 
treatment and to get people to stop using drugs. The best 
prevention strategy, of course, for the spread of blood-borne 
infections, is for people to stop injecting drugs. However, we 
know that we're nowhere near as successful as we might be, and 
therefore, these are public health approaches that are being 
studied in a way to deal with this public health problem that 
goes beyond just an individual's drug use.
    Having said that, a question that needs to be asked is not 
really whether or not using sterile equipment is a good idea. 
There's no question that the use of sterile equipment prevents 
the use of blood-borne infections. The question here is, what 
is the best way for making sterile equipment used; that is, how 
to do that. Each of the studies NIDA supports in this domain 
includes a formalized protocol of outreach, education, 
counseling on drug use, counseling on treatment, and then after 
that doesn't work, then the study starts.
    This particular study, is a randomized trial, comparing the 
efficacy of a needle exchange program, supported locally. We 
don't provide the needles. It compares the efficacy of that 
approach to the approach of having people buy needles in a 
pharmacy, which in Anchorage, Alaska, are quite available.
    The questions that have been raised about the study had to 
do with whether in fact one needed to demonstrate that using 
clean needles works. We never thought the investigator was 
demonstrating that. What we thought the investigator was 
demonstrating is which is the most effective technique for it. 
And as you know, Dr. Varmus asked a group to look at that. And 
they came to a similar conclusion.
    Other than that, there was some discussion about the 
provision of hepatitis B vaccine. And we have made provisions 
to ensure that every individual in the study has access and is 
encouraged to get vaccinated against hepatitis B.
    Mr. Porter. And Dr. Varmus recommended you proceed with the 
study after making a change in its design?
    Dr. Leshner. A subset of the subjects in the study would 
receive free vaccine from the Indian Health Service or from 
other local service providers. A subset would not have had 
access to free vaccine. Dr. Varmus recommended, and we 
concurred fully, that we should provide vouchers for those 
individuals who would not get free vaccine, to make sure that 
everybody would be as encouraged as possible, if that's the 
correct phrasing, to get that vaccination.

                        disease specific budgets

    Mr. Porter. Dr. Varmus, regarding my first question to you, 
I wonder if you would submit for the record a list of all those 
areas in the budgets of NIH that were suggested, either by the 
Secretary or by the White House that weren't contained in your 
original budget that are disease-specific? Would you do that 
for us?
    Dr. Varmus. I should perhaps point out that these are areas 
that were in the budget, not as an expansion, that we initially 
intended to ask for.
    Mr. Porter. And quantify them for us, too.
    Dr. Varmus. Sure.
    [The information follows:]

         National Institutes of Health Disease-Specific Budgets

    The following information is provided in response to Mr. 
Porter's request that NIH identify and quantify areas in the 
NIH budget that were suggested either by the Secretary, DHHS, 
or by the White House. It is important to note that these areas 
had already been identified by NIH and that the increases 
resulted from a coordinated decision by NIH, in conjunction 
with the DHHS Secretary, and OMB.
    NIAID's FY 1998 budget for Non-AIDS research included an 
increase of $3,000,000 for the support of Hansen's disease 
research at the Hansen's Disease Center, to be funded through a 
reimbursable agreement with the Health Resources and Services 
Administration.
    In the FY 1998 budget, NIDA received a total of $30,000,000 
for Non-AIDS drug abuse research. Of this amount, $17,000,000 
was for NIH special areas of emphasis as follows: Biology of 
Brain Disorders, $5,000,000; Preventive Strategies, $5,000,000; 
Therapeutics/Drug Development, $5,000,000, and Advanced 
Instrumentation, $2,000,000. In addition, an amount of 
$13,000,000 was included in NIDA's FY 1998 budget for research 
on drug activity.
    The FY 1998 passback level includes $15,000,000 for third 
party payments to the Clinical Center in addition to 
appropriated funds. The collection of third party payments is 
consistent with initiatives currently underway at NIH to 
encourage public and private insurance support of costs of 
patients who participate in NIH-sponsored clinical research.

                            needle exchange

    Mr. Porter. Thank you.
    The Secretary of Health and Human Services has recently 
submitted a report to Congress on needle exchange programs. Can 
you describe her major conclusions?
    Dr. Leshner. Secretary Shalala's conclusions were basically 
similar to the conclusions that I just mentioned, which is that 
on the basis of the studies done to date, on the basis of the 
report of the Institute of Medicine and the recent NIH 
consensus conference, we were to pull together all of those 
data. The best models of this came from Yale. But the best 
models indicate that needle exchange programs can reduce the 
spread of blood-borne infections by as much as 33 percent.
    Secondly, the Secretary's report acknowledged that needle 
exchange programs are an effective vehicle for getting people 
into treatment. She did not draw a firm conclusion on the issue 
of whether or not needle exchange could reduce drug use, 
although she recognized that there are not data suggesting that 
it increases drug use. I believe that's accurate.

                        medical use of marijuana

    Mr. Porter. Dr. Leshner, the medical use of marijuana and 
the Federal Government's position on it have generated 
considerable controversy. The National Drug Policy Director has 
ordered that an 18 month review of the science be conducted by 
the Institute of Medicine. And NIDA has recently convened a 
two-day workshop on the issue.
    At the moment, is scientific opinion truly divided on the 
medical benefits of marijuana for particular conditions?
    Dr. Leshner. Let me just clarify. First, the workshop that 
we just held, which I helped organize as an NIH-wide event, 
actually was not a NIDA-specific event, because of course, any 
research that would be conducted likely would come from another 
NIH Institute. NIDA would only provide support in the form of 
providing the marijuana itself. If the research were for a 
particular medical indication, the appropriate Institute would 
do that.
    This workshop, in fact, represented the joint efforts of 10 
NIH Institutes, centers and divisions. Certainly in my 
experience, second to some of our neuroscience efforts, it was 
the most collaborative thing we've done.
    I would say that a reasonable conclusion, and again, all of 
this has to be seen in the context of the broad public health 
discussion that's going on at the moment, is that the existing 
data base is relatively thin for smoked marijuana. That is, 
there is not a large body of data suggesting smoked marijuana 
is a viable medication for any particular indication. There are 
a lot of anecdotes, and we can come back to that if you'd like.
    However, there are indications for which THC, tetra- 
hydrocannabinol, the main psychoactive ingredient, have been 
approved, such as AIDS-wasting, and nausea associated with 
cancer chemotherapy. Therefore, given the extensive nature of 
the discussion going on, I think it would be a reasonable 
question whether additional research should be done. That was 
in part a reason that NIH held this workshop and the workshop 
hasn't submitted its report to us yet.
    But what we did was to have experts in each of those areas 
summarize the literature, and give us advice, particularly 
about clinical trial issues. You can imagine how complex it is 
to do research on a medical indication for a smoked preparation 
that has psychoactive properties to it.
    Mr. Porter. And you have a marijuana farm in Mississippi 
that provides your research marijuana supply?
    Dr. Leshner. We do. On contract to the University of 
Mississippi, NIDA maintains a farm that grows research-grade 
smokable marijuana. The majority of it is used either for those 
remaining compassionate use IND patients who receive smokable 
marijuana from the Government through the FDA, and for research 
purposes in our research grants. We do have, as you would 
imagine, a large number or fairly large number of grants 
looking at the pharmacokinetics of smoked marijuana.
    Mr. Porter. How many grants is that?
    Dr. Leshner. We probably have five to seven grants using 
smoked marijuana. Let me just give you one example of the kind 
of research I'm talking about. This is on the top of my head, 
last week I was at our own intramural research program, where 
an investigator was looking at individual differences in blood 
levels of marijuana after smoking, and after a very controlled 
smoking experience, virtually an identical by all external 
measures, the blood levels were phenomenally different among 
all individuals, and that has to do with the smoking which 
affects the absorption through the lungs.
    So that's the kinds of studies that we do, and of course 
the abuse potential.
    Mr. Porter. Thank you.
    Mr. Miller.

                          methadone treatment

    Mr. Miller. Thank you. Just a couple questions.
    Understanding the idea of where we're going five or ten 
years in time, methadone has been the treatment for heroin, 
right?
    Dr. Leshner. It's one of the medications for heroin, yes.
    Mr. Miller. Is that the most commonly used one?
    Dr. Leshner. It is, yes.
    Mr. Miller. It's been around a long time, has it?
    Dr. Leshner. Actually, methadone was first developed in the 
early 1970s.
    Mr. Miller. But is it fairly common? I know in my 
community, at least there was a place that heroin addicts----
    Dr. Leshner. One hundred and twenty thousand people are on 
methadone.
    Mr. Miller. Is there a waiting list to get on?
    Dr. Leshner. Yes, sir, in some places, not everywhere.
    Mr. Miller. How is that funded normally?
    Dr. Leshner. Methadone treatment is typically funded 
through the State, not through the Federal Government. Some of 
it comes through the block grant to the States that is 
administered by the Substance Abuse and Mental Health Services 
Administration.
    But every State has to decide for itself whether or not it 
will in fact use methadone. And not every State does. And of 
course, not every country does. There's a lot of ideology out 
there about methadone as a compound, and a fair amount of 
misunderstanding. But it is a rather effective medication for, 
again, a subset of individuals. And typically, when combined 
with psychotherapy of some kind.

                           cocaine medication

    Mr. Miller. Would the goal be with cocaine to do something 
similar?
    Dr. Leshner. Actually, my hope is not to have a substitute 
medication. Methadone is a substitute medication, it does not 
produce the same level of euphoria that heroin does, in 
contrast to popular misunderstanding about it. And what it does 
do is occupy the same receptors. So it is a similar compound in 
the sense that it is working on the MU opiate receptor in the 
brain. And it does have some abuse potential, that is, if you 
could get it out on the street and inject it, you could get a 
high from it, not the same high as from heroin, because it's 
absorbed less readily.
    In any event, we are hoping that we can develop a compound 
that will actually work on the craving end rather than on the 
literal substance specific addiction. But I can't promise you 
that yet. I can tell you that we do have compounds that fit 
different categories for cocaine, some that would compete, as 
does methadone, for the same receptor. Some that might knock 
cocaine off its receptor, so it's just working in a different 
way. And some that might actually work on a craving itself, as 
opposed to the specific compound.
    Mr. Miller. So is that true for other types of addiction? 
Your goal, five or ten years, if you could choose what you 
could accomplish five years from today.
    Dr. Leshner. If I could decide what to walk out of the 
National Institute on Drug Abuse's having done, it would have 
been finding an anti-cocaine medication, sir. I think that's 
the biggest single need in this country's fight against 
addiction. We have nothing for overdose, we have nothing to get 
people to stop using the drug, and we have nothing to keep them 
not using the drug. And it's why we have put so much effort 
into this particular issue, since crack cocaine is in fact one 
of the most serious problems.
    Mr. Miller. Do you have any clinical trials right now?
    Dr. Leshner. We have 26 compounds in advanced clinical 
trials, and we have about another 8 or 10 compounds sort of 
lined up waiting to go into clinical trials. That's a part of, 
by the way, expanding on Dr. Varmus' answer, that's a part of 
what this initiative is, is to try to accelerate the rate of 
medication development. For example, we're screening the 
libraries of pharmaceutical companies. We have about 12 
strategies, I promise not to give you all of them.
    But we're trying to use converging strategies here.

                        successor drugs of abuse

    Mr. Miller. What are other drugs that are going to be 
successor drugs to crack cocaine?
    Dr. Leshner. Well, we worry about it. We're very worried 
about methamphetamine. That's why we went and had that town 
meeting in San Francisco. It was an interesting experience for 
me that here on the east coast, you almost never hear about 
methamphetamine. But methamphetamine has now replaced cocaine 
in San Diego as the drug most likely to draw people into 
treatment.
    That's a little statistic most people don't know. It's a 
regional problem. We were astounded, I was astounded, not 
everyone was, Ms. Pelosi was there, she was not astounded.
    Actually, we had representatives from five state 
authorities who came to find out about methamphetamine and what 
to do. We have the same problem, we have no medication for 
methamphetamine, although we've made a lot of progress in 
understanding its neurobiology. And that will help us.
    Mr. Miller. Well, all this research has a lot of personal 
benefit but also economic benefit.
    Dr. Leshner. Yes, sir.
    Mr. Miller. Crime issues, as you mentioned, AIDS issues and 
all that. So I find it interesting and obviously very 
supportive, as does everybody on this committee. So thank you, 
sir.
    Dr. Leshner. Thank you. Thank you for saying so.
    Mr. Porter. Thank you, Mr. Miller.
    Mrs. Northup.

                           nicotine addiction

    Mrs. Northup. Dr. Leshner. I'm sorry, Mr. Chairman, I was a 
few minutes late, so if this is repetitive.
    Does tobacco fall under the category of addictions?
    Dr. Leshner. Nicotine does. We do study nicotine addiction.
    Mrs. Northup. Do you study the relationship between people 
that start using nicotine at an early age, and then become drug 
addicted to something else later on? Do you recognize that as a 
gateway drug? Does it increase the chances of that happening?
    Dr. Leshner. It's a very important question. I'm a 
scientist, and so I feel that I should be very precise when I 
speak about the relationship of one drug to another drug. The 
term gateway, as used by some people, not by all people, 
implies direct causation. The data that we have are 
correlational.
    What they show are unequivocally that the odds on someone 
who uses tobacco or alcohol at an early age becoming addicted 
are incredibly higher than someone who does not use those 
drugs. That is between 65 times higher, and 85 times higher. 
However, that's a correlation, that's not a literal cause. That 
does not mean that if you smoke cigarettes, you will become an 
addict. It just means that the risk of it is substantially 
higher.
    The obverse is also true, that is to say, if you don't use 
alcohol, tobacco or marijuana by the age of 21, the odds on you 
ever becoming addicted to a substance is almost zero. It is not 
zero, but it's almost zero. However, again, that is not literal 
causation. It's sort of a funnel, if that makes sense. There's 
a funnel of all people who smoke, and the odds are very high, 
are much higher if you smoke than if you don't smoke.

                          essence of addiction

    Mrs. Northup. How much research have you done into the 
pathological reasons for that and the habitual user? In other 
words, do you have a rebellious child, or do you have any sort 
of evidence that the pathological, you were talking about here 
increases in dopamine that are created by the addiction. Does 
that then sort of draw a person, pathologically, to fulfilling 
a craving and the drugs seem to do that, then they get hooked 
in there even faster? I know that's a real novice way of 
explaining it.
    Dr. Leshner. It's absolutely not a novice way, it's 
actually very sophisticated. Almost every abusable substance, 
nicotine, marijuana, cocaine, heroin, causes an increase in 
dopamine secretion and a spike not dissimilar from the one, 
sadly you missed last year that I showed. We have come to 
believe, and I need to be cautious about this, because I think 
this is early in our understanding, but there appears to be 
some commonality to the brain mechanisms of addiction.
    At a minimum, there are certainly these similarities. What 
I don't know is whether in fact having one addiction makes you 
predisposed to have another addiction, literally. All I can 
tell you is there is some cross sensitization, across drugs. If 
you are addicted to heroin and then you go off, cocaine can 
prime you back to craving heroin. Then the reverse, of course, 
is amphetamines and cocaine.
    So there is some commonality, but I think we should be very 
careful about it.
    Mrs. Northup. So are you saying that there is at least some 
indication of it creating a pathological interest or a 
possibility towards other addictions?
    Dr. Leshner. I think, being careful, I need to say I don't 
know. But I myself believe from my reading of the literature 
that we are beginning, and we're in an early stage, to 
understand, and behaviorally of course, that there ought to be 
some kind of commonality, some common essence to the phenomenon 
of addiction.
    Mrs. Northup. Do you have any pathological studies as to 
why a 13 year old that picks up a cigarette is going to become 
addicted compared to a 21 year old? Does it happen that that's 
pathological, that your incidence of creating these dopamine 
trails are more inclined to occur with earlier cells, earlier 
in life, than later in life? Or is it that if you have the 
tendency towards that, that you just tend to gravitate towards 
tobacco earlier?
    Dr. Leshner. We don't know, is the answer. People have 
sadly not studied developmental changes in those particular 
brain systems. But we have actually, as an Institute, been 
posing this question recently.
    Mrs. Northup. Are you doing those things? They're so 
important to me.
    Dr. Leshner. We have a lot of studies going on, not only on 
the psychosocial risk factors, but the biological 
vulnerabilities and the biological risk factors for not only 
the abuse of a specific drug, but for drugs generically. And 
again, I don't want to be promissory, but there are some data 
to suggest that there are genetic components to the 
vulnerability to becoming addicted. We haven't made a lot 
ofprogress, in our case, in identifying any of those genes, of course. 
But there are familial differences and suggestions that there are 
individual differences and age differences.
    Mrs. Northup. The statistics show, I think, 85 percent of 
smokers become addicted, is that right? Fifteen percent of 
alcohol users become addicted. So there would have to be some 
genetic or physiological reasons----
    Dr. Leshner. There's no question in my mind----
    Mrs. Northup [continuing]. Why you're inclined to become 
addicted.
    Dr. Leshner. I actually believe that most people are 
ultimately susceptible to being addicted. That doesn't mean 
everyone will be. It just means that given enough drugs for a 
long enough period of time, I believe people can in fact be 
made addicted. That's, again, not totally clear.
    Mrs. Northup. That's all at this time.
    Mr. Porter. Thank you, Mrs. Northup. Mr. Stokes.

                          aids and drug abuse

    Mr. Stokes. Thank you, Mr. Chairman.
    Dr. Leshner, always a pleasure to see you.
    Dr. Leshner. How are you, sir.
    Mr. Stokes. Dr. Leshner, AIDS continues to take a 
devastating toll on people worldwide. In the United States 
today, it's the leading cause of death among people in the 25 
to 44 year old age group. These individuals are probably in the 
most productive period of their lives.
    Tell us what portion of the AIDS-HIV toll is attributable 
to drug abuse.
    Dr. Leshner. Actually, I think we have just reached the 
point where intravenous drug use, directly or indirectly, is 
over 50 percent of the cause of new cases of AIDS. In fact, 
these two pandemics are totally intertwined. Our research 
program reflects the connection between the two of them, I 
hope. It's our intention that it reflect that.
    A very large percentage of women who are infected with 
AIDS, I think the latest number is 55 percent, and 64 percent 
of children infected with AIDS are drug-related. There's no 
question that these are totally intertwined pandemics.
    Mr. Stokes. Can you tell us what major research initiatives 
you now have underway and what you are planning for fiscal year 
1998?
    Dr. Leshner. We have just about a third of our Institute's 
total budget, $116 million, that is devoted to HIV-AIDS. Our 
program runs the gamut from treatment approaches to using AIDS 
prevention as a part of treatment, so that we affect the public 
health aspect of AIDS, not just the individual's aspects of 
AIDS, of course. So treatment is one.
    Outreach to active drug users is another. As I said 
earlier, not everyone who uses drugs is willing to enter into 
treatment. We have to change the risk behaviors of those out of 
treatment individuals.
    We have a variety of studies looking at the medical 
consequences of the intersection between the two. We have some 
studies on the epidemiology of the intersection. We have a 
pretty broad program that spans almost everything from the 
molecule to managed care. And much of it is focused towards 
outreach to active drug users in order to reduce the public 
health problem as well as the problem for the individual.
    Mr. Stokes. How much of your Institute's budget is invested 
in AIDS-HIV drug abuse research?
    Dr. Leshner. I would say that a third of our budget is 
attributed to HIV-AIDS, and comes through that route. However, 
because of the intertwined nature of the two epidemics, it's 
difficult to give you a more accurate description. Much of the 
treatment research that we support is of course of great 
significance, because drug treatment is the best prevention for 
the spread of HIV-AIDS.
    Mr. Stokes. It would seem to me that this is probably an 
area in which there ought to be significant outreach. Is this 
the case?
    Dr. Leshner. Well, there has been. NIDA and CDC, have very 
extensive outreach programs. We have had a number of multi-site 
studies looking at the most effective AIDS outreach techniques. 
And I'm pleased to say that they've been extremely successful 
in reducing AIDS risk behavior, even in active drug users, by 
35 to 50 percent. And that's very significant. That's not only 
sharing needles. That's using bleach, that's re-using needles. 
And again, the implication of that goes beyond just the 
individual.

                   comparing united states drug abuse

    Mr. Stokes. In terms of understanding the nature and the 
extent of the drug abuse problem in the United States, how do 
we compare with other nations throughout the world?
    Dr. Leshner. Well, at the moment, we have probably as a 
percentage as high an overall drug abuse problem as most 
countries. I'm sorry to report, most countries are trying to 
catch up. We are at great risk. NIDA has done some 
international work, trying to come to understand emerging drug 
problems and see how we can help other countries prevent their 
drug problems, such as China and countries in southeast Asia 
and Russia, and countries within Eastern Europe.
    But at the moment, particularly because of the crack 
epidemic, we have very high levels of relative drug use in this 
country. Most other countries have predominantly heroin 
problems.

                        demographics of addicts

    Mr. Stokes. What is the extent of the problem in the United 
States across racial and ethnic populations?
    Dr. Leshner. The distribution across racial and ethnic 
groups, if you just take large groups, is about equal, the 
percentage of addicts who are Caucasian, who are African-
American, or Hispanic. However, as adults, minority group 
individuals are heavily over-represented in the population of 
addicted individuals.
    It's been informative that in younger people, actually, 
minority individuals begin using drugs later than Caucasian 
individuals. That may be tied to socioeconomic status, 
obviously. That's probably the most likely cause. But there are 
substantial differences in the demographics.

                       minority related research

    Mr. Stokes. Doctor, can you bring the Committee up to date 
on targeted research and research training that is currently 
underway to further advance knowledge across racial and ethnic 
populations?
    Dr. Leshner. Well, we, as you would imagine, maintain a 
very large program that's geared towards understanding the 
particular problems of various cultural and ethnic groups. We 
spend about $67 million a year focused on specific, 
particularly minority populations.
    One of the things that's been most important, and I won't 
take very long with it, is that we've come to understand the 
need for culturally appropriate prevention and treatment 
programs. It's obvious once said. However, it's unfortunately 
not frequently done.
    The places where we've learned this, for example, are in 
traditional therapeutic communities. Those ethnic groups that 
don't like confrontation don't do very well in some of those, 
and they've had to be modified. This is a result ofthe kind of 
research that we support that's looking at a focus on the specific 
needs and the specific problems of different ethnic groups. It's a 
large part of our portfolio.
    Mr. Stokes. Can you tell us, what is the plan for fiscal 
year 1998, and how much is included in your fiscal year 1998 
budget request for this activity?
    Dr. Leshner. Our total best estimate of minority-related 
research is about $76 million for fiscal year 1998. Some of 
that is devoted to our focused efforts to increase the number 
of minority investigators that NIDA supports. We believe it's 
very important for a variety of reasons to have a larger number 
of minority investigators. As far as we can tell, we've been 
quite successful at recruiting additional minority 
investigators in the last few years.
    So we spend, actually, probably on the order of $3 million 
or $4 million a year just on targeted recruitment activity to 
bring minority investigators into the pool of researchers.
    Mr. Stokes. Thank you, Doctor. I suppose I'm at the end of 
my time, Mr. Chairman.
    Mr. Porter. You actually have two more minutes if you'd 
like.
    Mr. Stokes. Maybe we can get in another question here.
    Dr. Leshner. Sure.

                        needle exchange programs

    Mr. Stokes. Earlier on, as I came in, you were about to 
talk a little bit about needle exchange. And of course, my 
concern is, to what extent are there needle exchange programs 
in the United States, and whether or not the Institute has any 
major research underway in this area.
    Dr. Leshner. We have about 15 grants at the moment on the 
efficacy of needle exchange, and on various aspects of the use 
of needle exchange as a device to prevent the spread of blood-
borne infections. There are many needle exchanges operating, 
either legally or illegally, in this country. Those are of 
course not supported by the Federal Government and are not 
supported by our Institute as part of the Government.
    The decision whether or not to have needle exchanges and to 
fund them is done at the State and local level.
    Mr. Stokes. Thank you, Doctor.
    Thank you, Mr. Chairman.
    Mr. Porter. I have about three or four more questions. Do 
other members have additional questions they would like to ask?
    Mr. Stokes. I have a few more.

                     cocaine medication development

    Mr. Porter. Let's see how fast we can talk.
    Finding an effective treatment for cocaine abuse, which you 
referred to earlier, Dr. Leshner, has been a Federal priority 
since at least 1988. And now, almost 10 years later, although 
some promising research leads have been identified, there still 
is no medication to treat cocaine abuse. Do you find that 
record disappointingly slow, or is it unreasonable to assume 
that we're going to be able to find something, say in 10 years?
    Dr. Leshner. Well, NIDA's medication development program 
actually came into being in 1992. And so our focused effort has 
really only ramped up then. I think the truth is that it's only 
been in the last two to four years that we've had the 
fundamental neuroscience to give us the molecular targets at 
which to approach medication development.
    As I hope I've made clear, we've had unbelievable advances 
in understanding the ways in which drugs of abuse affect the 
brain and produce addiction. But that's really come in the last 
three to five years. Those targets are why we're so optimistic 
now that we have an opportunity to come up with these 
medications, and we're doing what we call strategic medication 
development, that is, focusing in on real biological targets, 
rather than screening thousands of drugs and hoping.
    So, we are optimistic. I would like the drug yesterday.

                          prevention programs

    Mr. Porter. With reports of increasing drug abuse among 
teens, it's especially important to have good information about 
which prevention programs are effective. Your Institute 
supported research which indicated that, contrary to popular 
perception, the DARE program is not effective. What types of 
prevention programs do work, according to your research?
    Dr. Leshner. Let me just make clear, we believe the DARE 
program is an evolving program. So any study done of a 
particular program as a snapshot in time ought to be viewed 
carefully. And I will tell you that we have been working with 
DARE to help them evolve their approaches according to the 
scientifically based principles we have been talking about.
    I think that there are again a number of principles one 
could delineate. But one of the most important ones, which will 
sound obvious, is persistence, that is, if you begin a program 
early in middle school, you need to have another program later 
and another one later. It needs to involve not only one mode, 
like media, or basketball games or whatever, it has to be a 
much more comprehensive kind of a program.
    As I mentioned earlier, we have our new guide that we're 
sending out to only 100,000 of our closest friends, which will 
delineate the kinds of principles we were talking about, based 
again on the scientific research we've supported.

                               bupropion

    Mr. Porter. Your budget justification mentions pending FDA 
approval of a drug, Bupropion, as the first non-nicotine 
prescription drug. Is this drug thought to be more effective 
than the transdermal nicotine patches currently available?
    Dr. Leshner. I think it's a fundamentally different 
approach. Bupropion is typically used as an antidepressant. It 
works on the norepinephrine system in the brain. It is used to 
treat the dysphoria that occurs during withdrawal from nicotine 
addiction and to treat the craving. We also are trying a 
compound, by the way, for cocaine addiction. I'd give it about 
a B minus. I don't know yet whether it will be better than the 
transdermal patch. It may be that it needs to be used in 
combination.
    Mr. Porter. Was the drug developed with NIDA financial 
support?
    Dr. Leshner. A lot of research has been done on the drug 
supported by NIDA. But I don't know, the research done by the 
pharmaceutical company was done before I came to NIDA. I don't 
know the degree of relation.
    Mr. Porter. Mr. Miller.

                     cocaine medication development

    Mr. Miller. On cocaine, are the pharmaceutical companies 
involved in this? Is there much of a market for them? Nicotine 
you see a market for the product, as a motivation. Is there a 
market for cocaine?
    Dr. Leshner. Actually, there isn't a market for cocaine. 
No, there is not. It's been a terrible problem for us. It's why 
we've developed our own medication development program and 
worked so hard with pharmaceutical companies tomake their lives 
easier so they will become more interested. You will recall that Dr. 
Varmus a couple of years ago changed the CRADA policy so that there was 
a change in the pricing laws. It brought about six more companies into 
collaboration with our Institute, when they began to see financial 
incentives to help. So the market is a very big issue for us.
    Mr. Miller. Thank you.
    Mr. Porter. Mrs. Northup.

                       prevention principles book

    Mrs. Northup. Yes, I'd like to go back to some questions 
about drug use. You know, in here, I noted somewhere you 
mentioned that you all had actually created a book that was a 
very user-friendly guide to the prevention principles. I'd like 
to see a copy of that, if you could have that sent to my 
office.
    Dr. Leshner. We will.

                        prenatal drug use study

    Mrs. Northup. Also, you've done a study on the neurological 
effects of prenatal drug use. I'd love to see that, too.

                  effectiveness of prevention programs

    Mrs. Northup. Now, to go back to questions, I think 
especially following the line of my earlier question about 
creating the dopamine trail or whatever, it's pretty clear that 
prevention is really important. And in terms of the use of your 
budget, that's really important. I know that you say that's one 
of your goals, but I'd be interested in knowing what percentage 
of the $30 million are actually going to prevention strategies.
    I also know that you've talked about these guides to 
prevention. Have you created a best practices sort of scheme 
that is then communicated to the Department of Education and 
Health and Human Services through appropriate agencies that 
they oversee, so that best practices are actually in effect in 
their programs?
    Dr. Leshner. Let me start with the second part, if I may. 
We have worked very closely within the last year or so with the 
Department of Education and the Drug Free School program. And 
of course, within the Department, Secretary Shalala has been a 
very strong supporter of our prevention program, and of our 
principle of using science to increase the effectiveness of 
prevention approaches.
    So we've had very good, actually, cooperation. We are 
planning a very broad dissemination of these principles that 
have been derived.
    What we are not doing, just to be clear, what we are not 
doing is endorsing one or another extant program. Because we 
think that what we get from science is principles, not a 
program that necessarily would work in all sectors.
    Mrs. Northup. Let me then ask it a little bit differently. 
Do you look at existing programs, for example, the DARE program 
that we have seen some disappointing statistics from. Do you do 
a different kind of analysis, examining how they address the 
medical research that you might do, and do you propose changes 
to make them more effective?
    Dr. Leshner. We do some studies looking at the efficacy of 
existing programs. But candidly, we're not very interested in 
the yes-no question for a particular program. We're more 
interested in, ``does it work; why does it work; what's the 
essential element that might make it work.''
    However, having said that, we do have a number of 
relationships, particularly with very large programs like DARE 
or the Partnership for a Drug Free America, where we work 
collaboratively, and some days they think we bother them too 
much. But we do in fact try to take the science we support and 
make sure it's used.

                       information dissemination

    Mrs. Northup. In my opinion, one of the most critical 
parts, lowering the use of drugs among teenagers, is real clear 
information. It's amazing the sort of conventional wisdom these 
kids pass around to each other about how marijuana helps you 
concentrate more and longer and better and all those things. I 
wonder how much you do to disseminate the clear effects of 
these drugs, so that their own pass-around information doesn't 
take root.
    Dr. Leshner. Well, I think your fundamental point is a very 
important one. We have learned the hard way that hyperbole and 
exaggeration is the worst form of drug prevention. So we have 
been working hard to provide science-based information. We are 
now, I think, on our second millionth copy of our brochure on 
marijuana facts for teens and marijuana facts for parents. So 
that in fact it's all science-based.
    Mrs. Northup. You can send a few of those copies over, too.
    Dr. Leshner. We will, we'll be happy to.

                          prevention increase

    Mrs. Northup. Also, I don't think I got an answer about the 
$30 million that's in prevention. If you don't have that, could 
you please provide that?
    Dr. Leshner. Sure, I will.
    [The information follows:]

    Dr. Leshner: Fifteen to twenty percent of the $30 million 
increase that NIDA has requested will go to prevention 
research.

    Mrs. Northup. Okay.
    Mr. Porter. Thank you, Mrs. Northup.
    Mr. Stokes.

                        needle exchange and aids

    Mr. Stokes. Thank you, Mr. Chairman.
    Dr. Leshner, one follow-up question on needle exchange. As 
a researcher, and as the Director of the National Institute on 
Drug Abuse, in your professional judgment, what should our 
Nation be doing with regards to AIDS-HIV and needle exchange?
    Dr. Leshner. I do believe, sir, that needle exchange can be 
an effective part of a constellation of HIV prevention 
programs. I believe that the statement that needle exchange can 
reduce the spread of blood-borne infections, including HIV, is 
wholly supported by the data.

                       medical marijuana concerns

    Mr. Stokes. Okay. Doctor, the debate continues to focus on 
marijuana, especially as it relates to the use for medical 
purposes and the implications for contributing to increased 
drug abuse. What are your concerns regarding this matter?
    Dr. Leshner. My concern is that the question be resolved 
through science, and that the question not be resolved through 
political decision one way or another. I would like to have 
questions like this handled, just as we do for any other 
compound that's purported to be a medication. I would like to 
have it resolved through scientific study. We do that for all 
other kinds of medicines in this country. That's my own belief.

                            drug abuse costs

    Mr. Stokes. Doctor, last year the Institute indicated that 
drug abuse costs the Nation an estimated $67 billion, and that 
new estimates under development would incorporate data 
reflecting each of the following major components: drug-related 
criminal justice expenditures, crack cocaine, AIDS epidemic, 
medical and social costs associated with the resurgence of TB 
and hepatitis, and prenatal exposure to drugs.
    Doctor, what is the cost of drug abuse to the Nation?
    Dr. Leshner. Sadly, we don't have a figure better than that 
1990 number of $67 billion. I can tell you that a study done by 
the Center for Addiction and Substance Abuse at Columbia 
University tried to do the analysis you're referring to just 
for New York City, and found the number of $20 billion. The 
number, in my own belief, is substantially higher than $67 
billion. We're in the process, we have a study that we've 
contracted for jointly with NIAAA that's looking at it, and the 
results are not yet quite in.

                       effective drug treatments

    Mr. Stokes. I hope you will share that with us whenever you 
have that data.
    Doctor, what can you tell us this year that you could not 
tell us last year with regard to how close we are to having an 
effective treatment for any of the major drugs of abuse, like 
cocaine, and equally important, treatments that do not 
themselves create another adverse dependency?
    Dr. Leshner. I would like to say that we have very 
effective behavioral forms of treatment for drug abuse. They're 
not panaceas that work identically for all individuals. But 
there are a number of clinical trial documented efficacious 
treatments. Sadly, they're not used as broadly in the real 
world as we would like. That's a part of our treatment 
initiative.
    But in the last few years, we've seen tremendous 
development in the techniques of psychological therapies like 
cognitive behavioral therapy, family therapies that work 
particularly well for young people. We are in the process of 
having these manualized, we're putting them into manuals so 
they'll go out to the field.
    But there are treatments that can be very effective. It's a 
big task, of course, to find the right treatment for the right 
individual.

                            cocaine craving

    Mr. Stokes. I understand that cocaine craving studies have 
been conducted, and two studies have used brain imaging 
techniques to determine which areas of the brain are activated 
during craving. Can you tell us anything about this?
    Dr. Leshner. There has been, as one chart showed, we are 
very interested in using the wonderful tool of brain imaging to 
help us understand what's going on in living, breathing 
individuals who are awake and craving. There has been a 
convergence of evidence now from three discrete laboratories, 
beginning to lay out the brain circuits involved in craving, 
and some of the mechanisms involved in craving.
    So there's been tremendous progress, particularly in the 
last year, three separate papers have been studied identifying 
a particular site of the brain called the amygdala, part of a 
circuit where craving is involved. And of course, the frontal 
lobe of the brain is activated during craving.
    So we have made a lot of progress in the neurobiology, the 
basic neurobiology, without yet a great deal of specificity. 
But again, we have a number of grants underway to look at that.
    Mr. Stokes. Thank you, Dr. Leshner.
    Mr. Chairman, I have a few additional questions which I'll 
submit for the record.
    Mr. Porter. Thank you, Mr. Stokes.
    Each of us has additional questions we would like to submit 
for the record.
    Dr. Leshner, thank you for your good testimony and the fine 
job you're doing at NIDA. We appreciate your coming here and 
testifying today, and we want to work very closely with you on 
one of the Nation's most serious problems.
    Thank you.
    Dr. Leshner. Thank you, sir, for your support. Thank you 
all.
    Mr. Porter. The committee will stand briefly in recess.
    [The following questions were submitted to be answered for 
the record.]

[Pages 1011 - 1090--The official Committee record contains additional material here.]


                                            Tuesday, March 4, 1997.

           NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

                               WITNESSES

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

    Mr. Porter. The subcommittee will come to order.
    The subcommittee is now pleased to welcome Dr. Enoch 
Gordis, the Director of the National Institute on Alcohol Abuse 
and Alcoholism. Dr. Gordis, it's nice to see you. We appreciate 
your patience, we're running a little behind schedule. But we 
intend to give you a full hearing on your budget.
    Please proceed with your statement after introducing the 
people at the table with you.

                       Introduction of Witnesses

    Dr. Gordis. At my left, your right, is Mr. Steve Long, 
who's our Director of the Office of Policy Analysis; Mr. Martin 
Trusty is our Executive Officer; Ms. Carmen Richardson is our 
Budget Officer. To my right, is Dr. Mary Dufour, who's the 
Deputy Director of the Institute. I think the other two 
gentlemen you know very well.
    Mr. Porter. I do.

                           Opening Statement

    Dr. Gordis. With your permission, I will not simply read 
the formal statement. I just want to comment on some of the 
issues in it. And I think this will open up the questions in an 
effective way.
    As you know, the Institute is charged with providing the 
scientific basis for improved prevention and treatment of 
alcohol problems, and as such, we support about 90 percent of 
the alcohol research in this country. Alcohol problems cost the 
country a lot. The last estimate is about $98 billion to $100 
billion a year. Somewhere between 10 and 50 percent of all 
hospital admissions are due to the complications of alcohol in 
many different organ systems.

                      vulnerability to alcoholism

    This has been a really good year for NIAAA in the sense 
that many of the investments which Congress has seen fit to put 
into our scientific enterprise are beginning to show fruit in 
very important ways. And I'm going to touch on some of them. 
The first is the issue of the vulnerability to alcoholism, 
which we know from fifteen years of studies on twins and 
adoption studies, indicate that a significant portion of the 
vulnerability to becoming alcoholic upon exposure to alcohol is 
inherited.
    Based on these important population studies, seven years 
ago, we embarked on a collaborative study on the genetics of 
alcoholism, which is now taking place in six centers across the 
country. The first two years were devoted to creating 
assessment instruments to clearly define who had the condition 
and who didn't. Important surveys for doing that were defined, 
written up and have been translated and used internationally.
    And over the course of the years, many thousands of people 
were interviewed extensively. And what has been culled are 300 
so-called informative families in which there is multi-
generational alcoholism, that is, some people have it and some 
don't. From them, we have obtained blood samples of various 
biological markers for DNA and have preserved and stored cell 
lines, which are held in two repositories.
    We are pleased to inform the committee that during the past 
year, several striking findings are beginning to emerge in the 
genetic study. I should preface this by saying that over the 
course of the last few years, some important spinoff studies 
have occurred. But I will emphasize the findings related to 
genetics in this discussion.
    The first is that several chromosomal hot spots, that is, 
areas of the genome where the genes related to alcoholism are 
likely to be found, have been identified on chromosome numbers 
1, 4, 8 and 16. The next task, of course, will be to work on 
these zones for the next few years to find those genes which 
are related to the vulnerability to alcoholism.
    I should point out that unlike many of the disorders in 
which there have been genetic triumphs, like cystic fibrosis, 
Huntington's, sickle cell and a very long list, complex 
disorders like alcoholism are due to the effects of a mix of 
genes. And therefore, the task of finding them, not one of 
which singly is responsible for the whole condition, is 
immeasurably more difficult. But with modern technologies, 
which are improving, even during the course of this study, that 
is being accomplished.
    The resources of this study, both the data as well as the 
blood samples and the DNA, will become a scientific resource 
for the general scientific community in 1999. And at that 
point, other investigators, in addition to the current ones, if 
they are qualified, will have access to it, too, because it's a 
very important national resource.

                             animal models

    The other area where our field is distinguished is in the 
use of animal models for studying the genetics of alcoholism. 
Many of the behaviors related to alcohol can be mimicked in 
animal models. And for that reason, we are pleased to inform 
you that during the last couple of years, several of these loci 
on the animal genome, particularly the mouse, have been found 
relating to alcohol preference and to other aspects of alcohol 
related behavior. If the committee is interested, I'll be 
pleased to enlarge on the details later.
    And finally, we are using the contemporary techniques of 
knockouts, where a single gene theorized to have an effect on 
the condition is knocked out so it does not get expressed in 
the adult animal. And it turns out we've had two very 
interesting successes here in which knockout genes have shed 
light on what possible circuits in the brain are related to 
alcohol misuse.

                    application of research advances

    Not stated in the written testimony I think is something 
important. And that is, what is the payoff for all this kind of 
work. Because there is a major payoff. I think they're in three 
real areas that are important. Once we find the genes which 
code for certain proteins, and we know what the functions of 
those proteins are, it's going to give us a clue to the 
physiology of this disorder and permit us to develop even more 
medications than we have now, although there's been progress on 
that front, as I'll tell you in a minute.
    The second thing we're going to be able to do is more 
targeted prevention efforts. There aren't human or financial 
resources adequate to do all the prevention we'd like to do. 
And by focusing on those most likely to get into trouble, we 
can make that route more efficient.
    And finally, by the more precise delineation of genetic 
influences, we will better understand the role of the 
environment. Because no one is saying that alcoholism is solely 
a genetic disease. Many environmental factors, beginning in the 
uterus and going through early development in the home and then 
all the environment around us, contribute as well.
    Another area where we've had major advances is in the area 
of neuroscience, which is influenced by genetics but really a 
separate discipline in some ways. The main task with alcohol is 
somewhat different than with illegal drugs. Alcohol does not 
act on a specific receptor like cocaine and heroin do. It seems 
to act on a multiplicity of receptors. Alcohol kicks up some 
activities and inhibits others. And the delineation of that 
activity has been a very important aspect of our work.
    Important advances have been made in understanding, on the 
one hand, the reward system which is more complex than dopamine 
in the case of alcohol. This is a positive feeling that makes 
people want to drink. And the other side of this, which is 
coming into the fore again, is interest in understanding the 
withdrawal state, or the dysphoria or the discomfort of not 
having alcohol once you are dependent upon it. Alcohol 
withdrawal seems to involve different neurotransmitters and 
differentcircuits. And both of these processes, of course, are 
candidates for understanding and for future medication development.
    The imaging which Dr. Leshner addressed is very effectively 
used in our field as well. In the interest of time, I will not 
touch upon it, except to say that the issue of different 
cravings is very important here, too.
    On a theoretical basis, although it sounds rather remote, 
our new understanding of how alcohol acts on cell membranes is 
leading to a total revision of how we understand alcohol's 
effect on the nervous system. We are learning in toxicology how 
alcohol damages the brain, the liver and the fetus, which I 
know is of great concern to the committee. And I'll be glad to 
enlarge upon that as well during the questions.

                           treatment research

    I want to take the last couple of minutes on treatment and 
prevention. There are two kinds of treatment research which the 
Institute does. As you know, much of alcoholism treatment 
develops outside the mainstream of medicine. And therefore, 
many of the things which have been done by tradition and by 
convention did not develop with the usual rigorously controlled 
trials which are typical of other branches of health care.
    One aspect of our treatment research is to apply 
contemporary clinical approaches in research, blind design, 
randomization and so on, to therapies that have been used 
traditionally without testing. One example of that is the 
Project MATCH, which examined in a large-scale, 6-year study in 
1,700 patients randomized to three arms of behavioral therapy: 
12-step facilitation, cognitive behavioral therapy, and 
motivational enhancement, to see whether by typing the patients 
precisely it would be possible to define a patient treatment 
match that would yield better treatment outcome.
    Despite smaller studies in the literature and the hope from 
the Institute of Medicine that that would pan out, it turned 
out that by and large, no major matches were found. It turned 
out that all the patients did quite well. Except for 
psychiatric severity, where the patients with low psychiatric 
severity did somewhat better in the 12-step facilitation, the 
patients did equally well and no matches were found in the 10 
that were explored.
    The other side of treatment research is the development of 
new medications, and we've also been doing very well on this. 
During the last two years, we've told you about the FDA 
approval of naltrexone for the treatment of alcoholism after 
withdrawal. Nalmefene and other opioid antagonists have 
likewise been shown effective.
    And a drug which has shown promise in Europe, which works 
by a different route called acamprosate, has been finally given 
an IND--investigational new drug--approval by the FDA. NIAAA 
has been helping the company design a treatment trial which 
will be conducted in this country during the next year and a 
half or two.

                               prevention

    I know there's been interest in the last discussion on 
prevention. This is a very important part of our portfolio. The 
part I'd like to emphasize is somewhat parallel to what Alan 
Leshner mentioned in the previous testimony. It's very easy to 
think of interventions which have a surface plausibility, which 
are expensive and which don't work. The experience of science, 
and I'm glad to say it's happening, is that the same techniques 
of rigorous analysis of what works for medications development 
are the same as those which work in prevention. It's a more 
difficult field because we cannot account for everything that's 
going on in the world around us.
    But I'm happy to say that by virtue of rigorous studies of 
what is going on, several important trials have yielded 
important results, which hold promise for prevention of alcohol 
problems in the young, especially. Community trials are going 
on in several paired communities in California and South 
Carolina. A very interesting study by Dr. Cheryl Perry called 
the Northland study, in 20 communities, 10 which used the 
interventions and 10 which didn't, among kids between the 6th 
and 8th grade years, showed 25 percent reduction in the 
initiation of drinking and several other positive outcomes.
    [Clerk's note.--Later corrected to ``28.'']

                         research dissemination

    I'd like to conclude by talking about the importance of 
research dissemination. We have major publications which have 
come out, some of which have been prize winning, on a variety 
of topics, including prevention, including genetics, including 
imaging. We have a booklet called Primary Care Recognition and 
Intervention which has just come out. It's been distributed to 
about 200,000 people, including primary care doctors.
    We have had help in this distribution from General 
McCaffrey's Office of National Drug Control Policy to the tune 
of about 60,000 copies. Dupont Pharma, which makes naltrexone, 
has distributed yet another 100,000. And this has been very 
widely received. The publications are here on the table, and 
during the course of this discussion, if you're interested in 
my discussing any elements, I'll be happy to do so.
    The budget request for NIAAA for 1998 is $208,112,000, 
exclusive of AIDS. I'll be happy to answer any questions.
    [The prepared statement follows:]

[Pages 1096 - 1100--The official Committee record contains additional material here.]


                    trends in adolescent consumption

    Mr. Porter. Dr. Gordis, thank you for that very good 
statement.
    I was struck by the statistic in your budget justification 
that alcohol is used by more Americans than any other drug, 
including tobacco. We're all concerned about the increase in 
drug use among teenagers. What are the recent trends in alcohol 
use among teens?
    Dr. Gordis. There have been some minor decreases, fractions 
of a percent, in high school kids, for example, Mr. Porter. But 
it is still distressing that by the time kids reach their 
senior year of high school, a little under 80 percent of them 
have used alcohol, and about a third of them have had five 
drinks on one occasion during the previous two weeks.
    So there is a welcome trend in the slight decline, but I 
think we still have a major issue of alcohol use among 
adolescents.
    Mr. Porter. In 1994, U.S. per capita consumption of alcohol 
sank to the lowest level in 32 years. How is the pattern of 
consumption distributed? What share of the population doesn't 
drink at all, and what share are heavy drinkers?
    Dr. Gordis. About one-third of the adult population does 
not drink. Among heavy drinkers, if we define it by people who 
are drinking, say, five drinks a day or more for men andfour 
for women, then we're in the range of 10 to 15 percent. And the rest 
are drinking less, but not zero.
    Mr. Porter. Alcohol-related traffic deaths rose in 1995, 
reversing a 10-year decline. How does that data fit with the 
declining per capita consumption?
    Dr. Gordis. I can't explain this one-year change in the 
direction, Mr. Porter. There has been a decline over the last 
10 years, and whether this represents a new trend or not, I 
think we're going to have to see in the next couple of years. 
It's very difficult for the change in one year to be accounted 
for.

             rigorous design and findings of project match

    Mr. Porter. You described your Project MATCH, which to the 
surprise of many found that matching different patient 
characteristics to different therapeutic approaches does not 
substantially alter outcomes. This has been heralded as good 
news by those who point out that inexpensive treatments seem to 
work as well as expensive ones.
    But what does the study tell us about the ultimate 
question? How well do any treatments work? What is the 
retention rate in treatment for patients, and what is the 
relapse rate after one year of treatment?
    Dr. Gordis. This is a very important and complex issue. 
However, I'll do my best to summarize it.
    I think Project MATCH delivered contemporary treatment 
about as efficiently as can be done. The treatments were all 
standardized, that is, there were manuals of therapy which 
defined exactly what transpired during these verbal encounters 
between patient and therapist. This was not a trial of 
medication.
    And as you know, it is easy in the course of a 
conversation, even in a therapeutic one, for the quality of the 
therapeutic encounter to be degraded by informal conversation 
and so on. In order to ensure that that didn't happen, the 
treatments were standardized, that is, there were three 
separate books, which defined the treatments precisely. And in 
fact, they've been in wide demand outside this research 
protocol, about 30,000 copies have been printed and circulated 
throughout the country.
    The second way to ensure the quality is that many of these 
sessions were videotaped, so an outside observer could 
guarantee that the treatments were discriminable by somebody 
who didn't know which arm of the therapy was given. The 
therapists were all very well trained people. The reason I'm 
saying this preface is because it's important to understand 
that under the conditions of this study, I think we are 
maximizing the effects that current behavioral approaches can 
have, independent of the matching issue.
    Now, how well do the patients do? Aside from the fact that 
the three groups did more or less the same, the absolute 
sobriety rates for the year ranged between 25 and 40 percent, 
depending on whether the patients had had a period of inpatient 
treatment or not. This abstinence rate, which is quite good, is 
probably a little bit better than most current programs 
achieve.
    It's important to understand that alcoholism and other 
addictions are chronic relapsing disorders. So the way we would 
look at a condition, for example, arthritis, is not whether we 
can cure it absolutely, although that's the hope, but rather 
how many days free of symptoms and pain can we afford the 
patient by the best treatments that are available.
    We hope to cure alcoholism in our lifetime. We hope to get 
total abstinence or no problems from alcohol as a goal of all 
of our research. What we can say now is that somewhere between 
25 and 35 percent of patients are likely to remain abstinent 
for at least a year. And as we know from long-term longitudinal 
studies like those of Dr. George Vaillant, the longer you stay 
in the abstinent state, the longer you are likely to stay in 
it. And the biggest dropoff tends to be in the first few 
months.
    Most treatment programs, and I think this is a precise 
answer to your question, will lose the majority of their 
patients, I believe, to relapse. Many of them will come back, 
but sometime during the first three or four months they will 
stop treatment. That's the most dangerous time for relapse.
    So in summary, I would say that a minority of patients 
remained permanently abstinent. A good chunk of the patient 
population will have intermittent abstinence, which is far 
better than drinking continually, both in human, financial and 
medical terms. And a fraction of the patients, which is not 
inconsiderable, will not do well at all.
    Mr. Porter. Dr. Gordis, some of the popular press coverage 
of the trials' findings gave the impression that the Federal 
Government spent $27 million on a study, and now we don't have 
any better idea than we did before on what works in alcoholism 
treatment. How have you responded to that characterization?
    Dr. Gordis. Well, the only accurate part of that statement 
is the cost. Other than that, the conclusions, I think, are 
erroneous. First of all, this was the largest, most carefully 
controlled study of behavioral treatment of alcoholism ever 
conducted. And it told us several important things. It told us 
first of all that among the 10 criteria which were selected a 
priori as patient characteristics for matching with these three 
very popular and well written up kinds of treatments, none 
offered particular matching advantage to one arm of the 
treatment or the other.
    On the other hand, it shows the limits of what we can 
accomplish with contemporary behavioral treatment. It also 
assures the treatment community that when you consider the 
dramatic drop in drinking that the patients in all three arms 
of the treatment showed from the time before they came in to 
the time they completed the study, that treatment actually is 
quite effective. Project MATCH demonstrated that any treatment 
program that delivers one of these treatment modalities in a 
quality way is likely to do a lot of good for the patient.
    The kind of statement which you made, which we've heard 
occasionally also, simply is not so.

                  evaluations of alcoholics anonymous

    Mr. Porter. We discussed the fact last year that Alcoholics 
Anonymous had never undergone rigorous scientific evaluation. 
Does Project MATCH provide the scientific evidence that has 
been lacking, since it included an AA component?
    Dr. Gordis. Not in the strictest sense. But it does shed 
some light on the AA-related component of Project MATCH. 
Sometimes people have misunderstood the arm of Project MATCH 
dealing with 12-step facilitation as meaning, simply sending 
people to AA. That's not what happened here. All arms of the 
treatment involve a one-on-one therapeutic series of events 
between the patient and the therapist.
    The one involving 12-step therapy was a detailed 
examination of the first three steps of Alcoholics Anonymous 
with the patient by a professional trained therapist. Then the 
patient would go to AA meetings, was encouraged to do so, and 
would come back to this professional trained therapist to 
explore his or her reaction to the meeting, and what 
attitudinal changes might be suitable in view of 
thesereactions.
    That's not the same thing as sending patients to the AA. In 
fact, if we look at AA's own data from the headquarters office 
published about six years ago, AA is not a scientific 
organization but one must commend them for their candor in 
looking at this issue, AA was very concerned about meetings in 
general, and about the large loss of people who go to meetings 
early on. And it turns out that within about three months of 
the time that people go to their first AA meeting, only about 5 
or 10 percent of them are still going to meetings. It doesn't 
mean that many people don't come back and finally get it 
together.
    But AA is quite aware of the tremendous loss in meeting 
attendance, even during the first few months. And I must say 
that the 12-step facilitation arm of Project MATCH did a lot 
better than that.
    The more general answer to the question of effectiveness of 
AA cannot probably be studied in its pure form. Let me tell you 
the reason why. If we were to study, for example, a medication, 
and it's been done with antabuse, which is a drug used in 
alcoholism treatment to provide an aversity of response to 
alcohol if you drink, you don't take people who take the drug 
and compare them to people who are unwilling to take it. In the 
antabuse study, which was done by Dr. Richard Fuller of our 
Institute some years ago in the VA system, he compared 
patients, all of whom were willing to take antabuse. Some 
patients got it, some got placebos. This was an excellent 
study.
    Ideally, to study AA, one would want to do the same thing, 
that is, take a group of people who would be willing to go to 
AA and some who don't. That kind of idealized situation could 
probably not be practicably applied to AA. And there are major 
problems with anonymity, and there are major problems with 
destroying the very phenomenon you're studying by too much 
observation.
    There have been studies on sponsorship in AA and some 
ancillary questions like that. But I think in the long run, the 
kind of rigorous control trial that's been applied to virtually 
every other aspect of health care, including alcoholism now, 
probably would be, it would be difficult to do AA studies along 
those lines, in my view.
    Mr. Porter. Thank you, Dr. Gordis.
    Mr. Miller.

                   medications for alcohol treatment

    Mr. Miller. Where do we stand with respect to a medical 
treatment of alcoholism? What's available?
    Dr. Gordis. If by medical treatment you're talking about 
medications for alcoholism, there are several. The oldest one 
dates from the late 1940s. It's called antabuse. And it was a 
drug which did not obliterate the craving for alcohol. What it 
did was threaten the patient with an unpleasant reaction if he 
or she were to drink.
    It turns out that although there's been a loss of interest 
in that drug, because of the excellent control study on 
antabuse which I just referred to in my response to Mr. 
Porter's last question, it turns out that probably it needs a 
little bit more exploration. Because there's some evidence that 
under supervised conditions, or even in a marriage where one 
spouse stays in the marriage on the condition that the other 
takes it, the results can be better. It's a very interesting 
drug.
    And one of the things that we are supporting now is the 
development of a derivative of the drug. Its metabolism has 
been studied extensively by Dr. Morris Faimen in Kentucky. And 
we know now that the first metabolite of antabuse that the body 
produces is a sulfoxide derivative of the half of the antabuse 
molecule that is probably the business end of the antabuse 
molecule. And there's some hope that this would be a more 
effective use of antabuse and that it would have fewer side 
effects. So that's one thing we are actually working on. We 
have contracts out now to prepare the chemically pure new 
compound, and to try it out for toxicity.
    The more hopeful areas that I addressed in my opening 
remarks have to do with drugs which seem to abolish the hunger 
for the substance during the time the patient is off it.
    Two years ago, the FDA approved naltrexone, which is an 
opioid antagonist, for the maintenance of sobriety during 
abstinence after detoxification has been complete. Two things 
were demonstrated by studies, three, actually. First, 
naltrexone was not being used independent of counseling but in 
parallel. That's very, very important.
    But the second thing was that among the patients who took 
naltrexone, it did two things. It lengthened the time to the 
first abstinence violation or the first relapse. And among the 
people who did slip, that is, they started experimenting with 
alcohol again, it reduced the likelihood of them going on to a 
full-blown binge.
    So naltrexone was shown to be effective in these carefully 
controlled studies by investigators both in Philadelphia and at 
Yale, and FDA approved it, and now it is increasingly being 
used in the treatment community, but at a rate which I wish was 
faster. But it is being generally incorporated, but not to 
replace counseling, but as an addition to it.
    Nalmafene, which is another orally active opioid 
antagonist, has been studied extensively by Dr. Barbara Mason 
in Florida. And it turns out to be very promising, indeed.
    The drug in Europe called acamprosate, which is calcium 
acetyl homotaurinate, is a drug which probably acts differently 
than the other two. Originally thought to react on the GABA 
receptors, it's now known probably to act on the so-called NMDA 
receptor, which is a subtype of the glutamate excitatory 
receptors.
    And in European trials, this drug has shown promise also of 
helping to maintain abstinence. They've had larger numbers of 
patients in the European trials than here. But the design of 
the trials and the attention to detail I think were as good as 
with our naltrexone trial approach.
    What's happened is, Lipha Pharmaceuticals, the company that 
manufactures it, has obtained an IND to begin experiments in 
this country. And as I said before, the NIAAA is helping them 
design the experiments to test out this drug in this country. 
And in fact, the books that were developed with Project MATCH 
are turning out to be very useful to the pharmaceutical 
industry in the behavioral side of the treatment.

                         a cure for alcoholism

    Mr. Miller. You mentioned a desire to have a cure for 
alcoholism. What would be the definition of a cure, a realistic 
one, five years from today?
    Dr. Gordis. I don't think we're going to have it five years 
from today, but I'm an optimist. The goal is to find a cure, 
but meanwhile to decrease the consequences of drinking and its 
abuse. A cure would be, I think ideally a cure would be 
somebody who either drank or didn't drink at will, who had no 
tremendous craving to have it, a social drinker, in my 
definition, is somebody who doesn't really care very 
muchwhether he has it or not. And a cure would be to restore alcohol to 
normal life priorities where it doesn't dominate one's life.
    Mr. Miller. Is that the medical route? The behavioral 
versus the pharmaceutical route, so you're having, I guess to 
do them together?
    Dr. Gordis. Yes, I would accept what you said absolutely, 
with one caveat. It's not versus.
    One of the nice things that's happening in research in 
general now is that this gulf between the behavioral world and 
the so-called biomedical world is narrowing. We know, for 
example, that in the case of obsessive compulsive disorder, 
something outside of our domain, but somewhat related, that 
behavioral therapy, when successful, has the same effects in 
PET scans in the head of the cordite neural regions of the 
brain as serotonin uptake inhibitors do in those patients who 
are successfully treated with medications for that disorder.
    This just shows that the potent therapy, even of a verbal 
kind, has the potential of altering the chemistry and the 
circuits of the brain much as drugs do. Drugs may be more 
efficient, on the other hand, they're somewhat more global. 
Behavioral therapy is somewhat more targeted to the behavior 
you want to change. And I think that this distinction between 
the two is gradually becoming obliterated, and we need both.
    Mr. Miller. One final question. I was talking with Dr. 
Leshner about this. The private sector is not spending a lot of 
effort and money on cocaine addiction. But the private sector, 
probably, and I hate to assume anything, the private sector is 
probably pursuing alcoholism, because there is a potential 
return for them, is that right? Is there a very large effort 
there?
    Dr. Gordis. There is some effort. I think there's probably 
more effort in the case of alcohol than there's been in the 
case of the illegal drugs. You see, naltrexone has been 
available already for 20 years or so. It was developed 
originally, of course it's an opioid antagonist, hopefully as a 
treatment for heroin use. By and large, it has only been 
slightly successful. Because although it does block the effect 
of heroin when taken, it does not abolish the craving for the 
drug, which is the thing that drives the relapse.
    So except for a small group of very well-motivated people, 
say like doctors who are addicted and are threatened with loss 
of their license, naltrexone has not turned out to be a potent 
therapy for heroin addiction. But it's interesting, in a 
confluence of both clinical and basic research, the basic 
research finding was that naltrexone in animal models inhibited 
certain kinds of ingestive behaviors, including alcohol and 
including calories, especially those from carbohydrates.
    That animal research, together with an observation made 
during drug treatment of heroin addicts who were also using 
alcohol, combined to lead to the experiments using naltrexone 
for alcoholism. And that's what led to this.
    Now, since the drug was already available, it had been 
manufactured by Dupont Merck under the name Trexan, the drug 
was made available for the treatment of alcoholism under the 
new name, naltrexone. We don't have anything in the pipeline in 
this country for new drugs created just for alcoholism, but 
there are several existing medications that I didn't mention 
that are being tried.
    Acamprosate, from Europe, is destined to be used only for 
alcoholism as far as I can see right now; that's a second 
example.
    There probably is some market for acamprosate. And I think 
as one company succeeds and makes some money, it will be an 
incentive for other companies to proceed along those same 
lines.
    Mr. Miller. Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Miller.
    Mr. Wicker.

              practical applications for genetics research

    Mr. Wicker. Just one question, Dr. Gordis. Your testimony 
mentions significant strides in demonstration that 
vulnerability to alcoholism is inherited. And you go on to talk 
about a study and an assessment about genetics. And strides in 
chromosomal locations. You say each chromosomal location 
contains these genes, the next step is to identify the precise 
genes. So we're not quite there yet?
    Dr. Gordis. That's correct.
    Mr. Wicker. If you could just tell me, what do you envision 
as the practical application for this research, once you 
finally get the research over with?
    Dr. Gordis. I think there are several practical 
applications here. Two of the payoffs, I think, which I 
mentioned briefly earlier, are very practical. The most 
important one, I think, is that when we find a gene, we find is 
a recipe for the body's making of proteins. The protein is the 
functioning part of the body's machinery. The enzymes, the 
receptors, the structural elements of the cell and so on, much 
of that is protein.
    So the gene is a recipe which tells the body how to make a 
protein. If the gene is different in alcoholic individuals than 
it is in normal people, it means that there's something about 
the protein which is being made which is different. If it's 
different, it has a slightly altered function. It can be very 
different, or subtle differences which combine with other 
genetic changes, cause a whole picture where the patient is 
sufficiently different to be at risk.
    The first payoff from this kind of research will be, once 
we understand what these genes are and what their function is, 
to then find medications which are going to interfere with this 
abnormal function. Genetics research is going to be, I think, 
one of the most potent routes for developing new medications 
for the treatment of alcoholism.
    A second payoff from genetic research will be prevention. 
Because it's clear that the highest risk people are the ones 
most likely to get into trouble. So there will be an aspect of 
genetic research which will permit us, I think, to target 
prevention in a more effective way.

                            genetics testing

    Mr. Wicker. When do you anticipate that individuals, that 
don't yet have a problem with alcohol, would be tested?
    Dr. Gordis. That remains to be seen, and that raises the 
whole issue of genetic testing in general. And I don't know if 
you want me to go into it. Dr. Varmus certainly is a person who 
has had to discuss these issues in so many ways and in such an 
articulate way that I don't think I would do as good a job.
    But the fact that we can test----
    Mr. Wicker. That remains to be seen. [Laughter.]
    Dr. Gordis. The issue of when we do genetic testing for 
anything is a problem which I think genetics-oriented ethicists 
are discussing in many spheres of medicine. Even issues which 
are much closer to a very practical payoff as far as therapy 
and so on, such as testing for breast cancer genes, are under 
some debate. I think the issue ofalcoholism gene testing is a 
more complex issue. But we will wrestle with this when the time comes, 
bearing in mind all the potential traps there are in the ethics of 
genetics testing.
    Mr. Wicker. I'm guessing that you might have to test 
children or adolescents?
    Dr. Varmus. You might want to start with children in 
families where there's a known history of alcoholism. And you 
probably would want to start at the time when they become of 
legal age. It depends a little bit on what kind of remedies 
might be available. At that point, there may be a variety of 
strategies for trying to employ behavioral methods for averting 
alcoholism. I think that would be one of the key issues, what's 
available. That's the issue that we face in other spheres where 
genetic risk assessment is an issue.
    Of course, underlying all of this is the need to have 
protections in place so that people are not stigmatized, so 
they don't have a poor self-image, there are a whole host of 
things that pertain to testing of this kind.
    Dr. Gordis. We share some of the issues which this problem 
raises such as: discrimination in employment and in insurance. 
But in our field, there's the extra level of stigmatization, as 
Dr. Varmus just alluded to. And these are issues we're going to 
have to deal with. But it's not right down the pike yet.
    Mr. Wicker. Thank you.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Wicker.
    Ms. Northup.

                comparing drug and alcohol use and abuse

    Ms. Northup. Yes, Doctor, I'd like to pursue a line of 
questioning comparing drug and alcohol use and abuse. Let's 
just see where you all are going on these questions.
    Do you see alcohol as a drug?
    Dr. Gordis. Oh, yes.
    Ms. Northup. Okay. And do you see a difference between the 
other drugs and alcohol?
    Dr. Gordis. Yes, there are many differences.
    Ms. Northup. Including, and especially in my mind, rate of 
addiction?
    Dr. Gordis. Yes, there are differences in that, too. Would 
you like me to comment on some of the points you just raised?
    Ms. Northup. Well, do you have a rate of addiction for 
alcohol that you would think would be about the average in the 
adult population in this country?
    Dr. Gordis. Well, one can make some guess of the likelihood 
of addiction for alcohol, say, compared to cocaine. Cocaine is 
a far more addicting substance than alcohol, and so is heroin.
    Ms. Northup. And tobacco?
    Dr. Gordis. And tobacco is probably also more addictive. 
The reason why the alcohol problem is bigger as far as number 
of lives lost and cost is because so many more people are 
involved with it, and it's a legal substance and much easier to 
get.
    As far as the addiction potential of the substance, alcohol 
is somewhere in the middle.
    Ms. Northup. That's sort of contrary to the statistics that 
I have used and talked about in the past.
    I have heard there is about a 12 percent rate of addiction 
for alcohol, versus 60, 85 percent depending on what drug 
you're talking about.
    Dr. Gordis. Well, we know that most adults in this country 
who drink don't get into any trouble from alcohol.
    Ms. Northup. Right.
    Dr. Gordis. Only about 10 percent of them do. So that's 
telling you something. On the other hand, if you experiment 
with cigarettes, the chance of becoming an addicted smoker are 
quite high, and cocaine likewise. So addiction potentials, 
meaning the odds of any individual becoming addicted once 
exposed, are higher for tobacco, cocaine and heroin. The size 
of the alcohol problem is bigger because the population 
involved is bigger, and there are other reasons, too, such as 
cost. Alcohol has a whole range of medical complications, which 
by and large, these other drugs don't have to the same extent.
    [Clerk's note.--Later corrected to ``15''.]
    Ms. Northup. Well, let me ask you about another factor that 
I think would distinguish them. I sort of forgot where I was 
going on that.
    Dr. Varmus. I think you're saying the same thing.
    Ms. Northup. Yes, I think that you're saying the same 
thing, too. I guess the question I have is, what is your goal? 
I know what the other question is. Would you agree that in most 
other substances, maybe because of the addictiveness of them, 
and also because of other potencies, that what we would 
recommend to most people is that they don't use those 
substances at all.
    Dr. Gordis. Correct.
    Ms. Northup. And do you all make that recommendation to the 
entire population?
    Dr. Gordis. No.
    Ms. Northup. Okay. I guess that's the question I'm getting 
at, that is prevention. Your goal is not to begin recommending 
to the American public in general that they don't use alcohol?
    Dr. Gordis. Oh, not at all. Let me make another point in 
line with what you're talking about. You know, alcohol kills 
more kids and costs more than all the other illegal drugs 
together. It's the biggest problem for adolescents. But most of 
these people are not diagnosable alcoholics. You see, there are 
several aspects to this. When people talk, even among adults, 
about moderate drinkers, moderate drinkers can get into 
terrible problems also.

                              consumption

    Ms. Northup. Right.
    Dr. Gordis. Because moderate drinking, the way we define 
these terms, is in terms of average use.
    Ms. Northup. Sure.
    Dr. Gordis. So if you drink seven drinks a week, that's one 
way of doing it. You can have those seven drinks in a two and a 
half hour period on Saturday night, that's also listed in many 
of the data analyses as seven drinks a week.
    So the issue of concentrated or binge drinking is 
important, even for the moderate drinkers.
    Ms. Northup. Sure.
    Dr. Gordis. But most of the kids who are killed on the 
highway, get into violence and so on, are not alcoholic by any 
formal diagnostic criteria.
    So the issue of alcohol abuse, which is the misuse of 
alcohol causing harm short of a dependent syndrome, is a 
terrible problem which affects adolescents in a very, very big 
way.

                   effects of alcohol on development

    Ms. Northup. I have a question of alcohol and 
addictiveness. Let's go to addictiveness, do you find that age 
at which the onset of use of alcohol is a factor? For example, 
if a 13 year old uses alcohol, are they more likely to become 
addicted to alcohol?
    Dr. Gordis. Yes, in general that's probably true. I think 
it's true of alcohol or tobacco, the longer the initial 
experience with these substances can be postponed, the lower 
the odds of addiction or dependence setting in.
    Ms. Northup. Is there any pathological reason for that, or 
is it just that a future adult that's going to be attracted to 
drinking is going to be attracted at an earlier age, and 
therefore they are more prone to be addicted? Or do you think 
that the youngness of their cells and so forth actually make 
the addiction more likely?
    Dr. Gordis. A very deep and complex question.
    Ms. Northup. No answer.
    Dr. Gordis. The question you're asking is a developmental 
one. Is there something in the partially mature, but not 
completely mature, nervous system and the other organs, which 
makes the risk of addiction if you initiate alcohol at that 
time greater than if you initiate it at 20. Or are these issues 
of simply a psychosocial nature, like for example, by the time 
you're 20 or 21 or 22, you may be married, and we know that 
that has a beneficial effect on abusive drinking, short of 
dependence. You may have a job where the threat of losing it is 
more severe and so on.
    We know that there are indicators of risk in youth from a 
behavioral standpoint. People with behavioral disorders in 
youth, a mixture of shyness and aggressiveness at 5 years of 
age, for example, predict more trouble than at the age of 15 
and so on.
    But the question you're asking, frankly, I don't know the 
answer to without looking it up or thinking about it some more. 
Because the question of the immaturity of the nervous system at 
age 13 making it more vulnerable for future addiction than at 
19 is a very interesting one. And I'm not sure of the answer 
right now, but I'm certainly going to think about it.
    Ms. Northup. This strikes me as very important.
    Dr. Gordis. Yes, I think you're right.
    Ms. Northup. Let me ask you another question, though. Do 
you recommend no drinks to pregnant mothers?
    Dr. Gordis. Absolutely.
    Ms. Northup. Okay. And have you disseminated that 
information?
    Dr. Gordis. Oh, yes, in many, many ways. First of all, the 
Federal Government has helped us by mandating that on all 
beverage alcohol, there's a warning label which includes a 
warning about drinking during pregnancy. NIAAA has supported 20 
years of research on this topic, in which we've looked into 
social aspects of it, as well as very interesting new 
neurological or biochemical mechanisms, which define how 
alcohol damages the fetus.
    Our prize winning publication, ``Alcohol Health and 
Research World,'' published this issue on fetal alcohol effects 
and drinking during pregnancy a couple of years ago. It's a 
kind of a bible for the field for people outside science. I 
think it's wonderful, and I commend it to your attention.
    This booklet, ``Drinking and Your Pregnancy,'' has just 
been prepared. It's being circulated by the thousands, with the 
help of NOFAS, an organization dedicated to fetal alcohol 
problems. We have a wide range of research on this topic. I 
think we're doing a pretty good job of circulation.
    Ms. Northup. So any doctor that would tell a patient, one 
drink a day would go contrary to any sort of evidence you show.
    Dr. Gordis. It's contrary to our recommendations. It is not 
contrary to everybody's opinion. I must say that there are 
still a minority of people who feel that since we haven't shown 
definitively what the threshold for danger is, that to say they 
shouldn't have one drink a day would impose a fear and a guilt 
on women and so on. But the tendency in research, based on very 
sophisticated tests of infant development and, intellectual 
function, has been to reduce the recommended level of drinking 
which is safe.
    Now, obviously, the heaviest drinkers are the ones who have 
the most physically malformed children. But there are very 
subtle and yet important neurological, psychomotor and 
intellectual development deficiencies which can be shown on a 
group basis, even at levels of alcohol consumption which are 
considered moderate.
    My own feeling is, and the way I put it is, you've got nine 
months to make the best baby you can. Save the drinking for 
later.
    Ms. Northup. I agree. Unfortunately, I don't think that's 
the universal message that is told to every woman in every 
doctor's office.
    Thank you. That's all, Mr. Chairman.

        correlation of heavy drinking to fetal alcohol syndrome

    Mr. Porter. Thank you, Ms. Northup.
    Let me follow up on that and ask, do researchers have any 
idea why only about 6 percent of children born to women who 
drink heavily during pregnancy show signs of fetal alcohol 
syndrome?
    Dr. Gordis. We don't know the answer to that question yet, 
Mr. Porter. There are wide ethnic variations in that number, 
too, by the way. In Native American population, it goes up 
higher, to 29 percent and higher birth rates with fetal alcohol 
syndrome. Among African Americans, the incidence is a little 
bit higher. We know many of the mechanisms now which are 
purported to cause malformations. And if you're interested in 
the scientific aspects of this, I'll be happy to answer that.
    There may be other factors, those we don't know yet, which 
contribute to differential risks. Some of them may be 
environment, such as different nutritional issues. People have 
different diets, and some of them are not so hot. There's a 
possibility there's a genetic issue here as well. That is that 
some of the babies may be born with certain genes, that is, 
those which deal with the rate of alcohol metabolism. They may 
even inherit such genes from the father, rather than the 
mother, which make them more likely to be vulnerable to fetal 
alcohol effects, given the same dose of alcohol taken during 
pregnancy.
    This is being explored now, but right now we don't know the 
answer to that question.

                     effect of alcohol on estrogen

    Mr. Porter. Research findings were reported in December, 
that even small amounts of alcohol, like half a glass of wine 
consumed by women taking oral estrogen, causes their estrogen 
level to rise dramatically. This seems to put women in a 
dilemma. The combined effect of estrogen and alcohol could be 
beneficial in preventing osteoporosis and heart disease, but 
could put women at greater risk of breast cancer, since these 
outcomes are associated with estrogen levels. What should 
physicians be recommending for their patients at this stage?
    Dr. Gordis. A very important question. The studies you're 
referring to are done by Dr. Nancy Mello and her colleagues at 
Harvard, and there were similar studies done by Dr. Judith 
Gavalier at Oklahoma. And it turns out that even moderate doses 
of alcohol, that is, doses of alcohol which bring the blood 
level up to 30 or 40 milligrams percent, equivalent to say, two 
or three drinks, were able to kick up the estrogenlevel 
rapidly. This was estradiol, the so-called E2, among women who were 
taking that compound.
    And estradiol, of course, has a multiplicity of effects, 
especially in post-menopausal women. On one hand, it protects 
against menopausal symptoms, it protects against osteoporosis, 
the thinning of the bones which can lead to fractures and so 
on. On the other side, it increases the risk for breast cancer. 
And even without alcohol use, of course, these things should be 
explained by the physician to the patient.
    With alcohol use, I think the physician is obligated to 
explain that regular, moderate drinking, will increase, in 
effect, the dose of estrogen the woman is taking, and therefore 
probably has a modest increase, I would guess, on the risk of 
the negative side of estrogen-taking, given all its benefits. 
And the woman has two options, or the doctor does. One is to 
reduce the amount of the drinking, which may be the easiest 
thing to do, because the doctor then is in better control of 
what's going on. But the doctor might recommend a diminution in 
estrogen dose.
    The problem with that is, since the drinking is irregular 
and unpredictable, it puts the medical recommendation, I think, 
in a bit of a limbo. So my recommendation, given the literature 
that I read on this, and my thinking about it from the point of 
view of a clinician, would probably be to recommend that the 
alcohol be taken gingerly.

                               serotonin

    Mr. Porter. You referred to findings researchers in Oregon 
reported that in knockout mice, the loss of a single gene that 
affects the neurotransmitter serotonin is enough to turn 
healthy rodents into heavy drinkers. The mice were also found 
to be abnormally aggressive. Serotonin seems to be implicated 
in a variety of diseases in which impulse control is impaired. 
Are you working jointly with the Drug Abuse and Mental Health 
Institutes in this research field?
    Dr. Gordis. As a matter of fact, serotonin is one of the 
topics which is being heavily investigated within our 
intramural program. And there are many collaborations going on, 
especially with the National Institute of Mental Health, on 
aspects of serotonin physiology and genetics, which relate to a 
variety of disorders, other than alcoholism.
    The experiments that you're referring to were done by Dr. 
John Crab and his associates in Portland, Oregon. And what it 
amounted to was the use of a model mouse where the serotonin 1B 
receptor had been knocked out by other researchers. So this 
animal was available. And its aggressiveness was already noted.
    But because of the fact that serotonin seems to be involved 
in many functions, such as sleep, sexual behavior, sedation, 
and also alcohol use, he decided to see what their behavior 
would be in relation to drinking. And it turned out that 
compared to the wild type animals from which the knockouts were 
derived, the animals drank about twice as much alcohol as their 
wild type colleagues.
    And there was another very interesting finding here, and 
that was that the physical dependence and withdrawal upon 
cessation of alcohol and tolerance could be distinguished. The 
animals which were the knockouts developed tolerance to the 
effect of alcohol much more slowly than the wild type animals. 
And yet, the ability of these two kinds of animals to 
demonstrate physical withdrawal upon cessation of chronic 
alcohol use was identical.
    This is a very important issue, because the question of 
whether tolerance and withdrawal share the same neural circuits 
has been argued in literature for a long time. And this 
experiment tends to distinguish them as far as their neural 
circuits not being identical.
    In the presence of Dr. Varmus, I hate to talk about an 
issue which is so close to his great skills on knockouts. It 
suggests that the serotonin 1B receptor is involved in the 
behavior relating to alcohol preference. It's not an iron-clad 
proof. Because as we know from knockout experiments, whether 
it's the lack of a serotonin receptor or the compensations that 
the animal may undergo by virtue of not having it since birth, 
which may affect other systems aside from the 1B receptor, is 
not certain yet. But certainly, it's a very promising avenue of 
research.

           liver transplantation for alcoholic liver disease

    Mr. Porter. Your Institute co-sponsored a meeting with 
NIDDK last year on liver transplantation for alcoholic liver 
disease. What were the conclusions from that meeting?
    Dr. Gordis. Well, the conclusions were those which have 
been collecting in the literature over a period of several 
years. About 25 percent of liver transplants for chronic liver 
disease, which is going to be fatal without transplantation, 
are done for alcoholic end stage liver disease in this country. 
There are about 3,000 done a year, and about 700 were done for 
alcoholic liver disease.
    It turns out that the survival rate and rejection rate of 
these patients with alcoholic liver disease is no different 
than the best survival groups for other categories of liver 
disease. That's number one. The second conclusion was that the 
recidivism rate to drinking again is considerably lower in this 
group than it is in general treatment programs, a question that 
you asked me about before.
    The reason for that second finding is likely to be the 
selection bias by which patients are selected and sorted before 
they enter the transplant program. Most programs demand a 
several month period of sobriety. When we're talking about 
trends we say that once you get through the first three months 
of sobriety, your likelihood of remaining sober later, is 
better. Second of all, they often are required to have 
efficient social supports and be involved already in some sort 
of treatment for alcoholism.
    So it turns out that among these patients, the survival 
rate was good as any other. Their return to drinking was less, 
and among those who died, it wasn't drinking which killed them, 
it was the same reasons that killed other people who died after 
liver transplant, rejection, failure, viral infection and so 
on.
    As for suggestions for the future, several recommendations 
were made. And in fact, we're now engaged in a collaborative 
effort with the National Institute on Diabetes, and Digestive 
and Kidney Diseases to put out a grant announcement on several 
issues which are of common interest to both Institutes.
    I think the two prominent questions which we'd like to 
investigate following this liver transplant issue are number 
one, can we improve the results if what we've learned about the 
efficient ways of doing alcoholism treatment can be brought to 
this community. There are two worlds here. There's the 
alcoholism treatment community on one hand, and then there is 
the liver transplant community on the other.
    But all the techniques that we've learned about treatment 
of alcoholism have really not been applied in a systematic way 
to post-transplant care. And that's one area where wereally 
ought to do some research, although in answer to one of the questions 
before, one of the grants we have on naltrexone is actually studying 
the use of naltrexone in post-transplant patients, just as an aside.
    The second issue, which is probably more difficult to do 
and more expensive, has to do with whether the genetic 
background of a donor liver has any effect on its survival in 
the alcoholic recipient. And I think you can see the 
implications of this, both as far as the theory and as far as 
the dimensions of such a project. But it's been raised as 
something that might be worth considering.
    Mr. Porter. Dr. Gordis, listening to you, it's like an 
encyclopedia on everything that's transpired in the field. 
You're obviously extremely knowledgeable and we appreciate the 
excellent job you're doing at NIAAA. Thank you for your 
testimony this afternoon.
    Dr. Gordis. 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 1115 - 1176--The official Committee record contains additional material here.]


                                          Wednesday, March 5, 1997.

    NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

                               WITNESSES

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

                       Introduction of Witnesses

    Mr. Porter. The subcommittee will come to order.
    We're pleased to welcome Dr. Phillip Gorden, the Director 
of the National Institute of Diabetes and Digestive and Kidney 
Diseases, to testify. And Dr. Gorden, would you please 
introduce the people who are with you at the table and then 
proceed with your statement.
    Dr. Gorden. Thank you, Mr. Chairman.
    To my far left is Mr. Charles Zellers, our Budget Officer; 
Mr. Earl Laurence, our Deputy Director; Dr. Varmus and Mr. 
Williams I think you know.

                           Opening Statement

    Mr. Chairman, Mr. Wicker, members of the committee. The 
NIDDK leads the national biomedical research effort to combat 
some of the most important, chronic and costly diseases in this 
country, including diabetes, endocrine, and metabolic diseases; 
digestive diseases and nutritional disorders; and diseases of 
the kidney, urologic tract and blood.
    In meeting this challenging research mission, we forge 
collaborations with other NIH components as well as with non-
profit foundations and commercial enterprises. Our approach is 
to deploy resources and capitalize on emerging technologies 
across the spectrum of the diseases we address. We seek to 
understand the underlying cause and course of disease, and 
develop effective treatments and preventive strategies.
    At different points in time, based on scientific 
opportunities, we pursue all or some of these avenues, ranging 
from the most basic studies of molecular biology to major 
clinical trials.
    As a special way to emphasize this broad NIH approach, Dr. 
Varmus and I will co-sponsor a conference in the near future 
related to diabetes research. The conference will include all 
Institutes involved in diabetes research and will focus on 
special opportunities and directions that this broad 
interdisciplinary approach brings to diabetes research.
    This forum will offer a special opportunity for the 
Director of NIH and a number of ICD directors to meet directly 
with leaders of the diabetes research community. We believe 
this will be a constructive and informative approach.
    This continuum of research, from clinical science to very 
basic science, to which I have referred, is best illustrated by 
a few examples. Let me describe the point on this continuum 
that is closest to medical practice. For example, we are 
currently engaged in four multicenter clinical trials, all of 
which were made possible through knowledge derived through 
basic and pre-clinical research about biologic mechanisms. In 
diabetes, one trial focuses on immune modulation, to halt or 
delay the onset of insulin-dependent diabetes in high risk 
children and adolescents.
    A second diabetes trial centers on the use of drug therapy 
and lifestyle changes to prevent or delay the onset of non-
insulin dependent diabetes, which usually occurs in later life 
and disproportionately affects minorities.
    Fundamental research also made possible our ongoing trials 
studying methods to ameliorate the course of kidney function 
deterioration in African-Americans with hypertensionand to 
pursue non-surgical approaches to treating benign prostatic 
hyperplasia, or BPH, one of the most prevalent conditions in our aging 
population.
    At the middle of the continuum, we are funding cutting edge 
research where clinical applications appear promising but are 
not yet completely feasible. A prime example is found in the 
NIH special emphasis area, ``The Genetics of Medicine.'' This 
includes NIDDK studies to sequence and clone the disease-
causing genes; identify proteins they produce; and develop the 
means to replace or repair them, or circumvent the defects they 
cause.
    Diseases targeted here for which major discoveries have 
occurred include cystic fibrosis, polycystic kidney disease, 
diabetes, hemochromatosis, and hereditary pancreatitis. Other 
cutting edge research relates to the special emphasis area, 
``The Biology of the Brain.'' This includes the NIDDK funded 
discovery of the obesity gene and its hormone product, leptin, 
which works in the brain to regulate both energy intake and 
utilization. Spinoff research has had an enormous positive 
impact on the U.S. pharmaceutical and biotechnology industries.
    Also at the center of the NIDDK research continuum are 
studies focused on the special emphasis area, ``New Approaches 
To Pathogenesis.'' An excellent example is research following 
up on the discovery that the bacterium, H pylori, is a 
causative agent of peptic ulcer disease, and possibly gastric 
cancer.
    In closing, I would like to turn to the first part of the 
NIDDK research continuum, the engine of basic science that 
drives all of our success stories. One example is transgenic 
technology. Another example is the development of experimental 
mouse models in which a particular gene has been deleted or 
``knocked out'' to confirm hypotheses about disease-causing 
genes and to help researchers then develop and test therapeutic 
strategies. Examples here include models for Tay-Sachs disease, 
inflammatory bowel disease, bone developmental abnormalities 
and many others.
    Another technology of the future is structural biology, 
which enables us to visualize the three-dimensional 
architecture of molecules in order to study drugs to inhibit or 
to enhance activity in a very special way. Major examples of 
this technology include the integration of the AIDS virus; the 
mechanism of tumor suppressors; and the action of inflammatory 
mediators. It is the continuum of research from fundamental 
science to clinical science that we will vigorously support 
with our 1998 appropriation.
    Mr. Chairman, the budget request for the NIDDK for fiscal 
year 1998 is $821,164,000. I would be very pleased to answer 
any questions you may have.
    Thank you very much, Mr. Chairman.
    [The prepared statement follows:]

[Pages 1180 - 1183--The official Committee record contains additional material here.]


                           diabetes emphasis

    Mr. Porter. Thank you, Dr. Gorden, for your fine statement.
    As we discussed last week, I don't want to participate in a 
body count approach to Institute funding allocations. I agree 
with the position of the NIH leadership of identifying and 
funding cross cutting areas of scientific emphasis. But I think 
it is legitimate for the committee to try to ensure that all 
diseases share in these areas of specific emphasis to the 
extent their scientific promise permits. For example, diabetes 
research seems to dovetail nicely with at least three of the 
areas of scientific emphasis: new approaches to pathogenesis, 
new preventive strategies and genetic medicine.
    Dr. Gorden, do you plan to apply the $10 million increase 
in your Institute's budget for areas of special emphasis to 
diabetes research?
    Dr. Gorden. Yes, we certainly do, Mr. Porter. Of course, 
this will have to be balanced to some extent with our other 
programs. But certainly those areas are ones that diabetes 
research is included in.
    Mr. Porter. Dr. Varmus, we have already heard from the Eye, 
Genome and Allergy Institutes on their diabetes research. From 
your perspective of looking at NIH research in the aggregate, 
is diabetes increasingly a campus-wide effort with more 
institutes involved, and who are the other institute players in 
diabetes research?
    Dr. Varmus. Well, there have always been a large number of 
institutes involved in this research. In fact, I recently had a 
look at a report by the National Diabetes Research Coalition, 
which lists at the end of the document about nine offices, 
centers and institutes that play a role in diabetes research.
    As Dr. Gorden mentioned, he and I have decided to have a 
workshop in the near future, not so much to hear the latest 
findings as to define the various areas of diabetes research, 
including research on diabetes complications in the kidney, the 
eye, and the heart. We want the fundamental aspects of diabetes 
research aired in a trans-institute setting so that institute 
directors and program officers, as well as other scientists and 
advocacy groups, can hear about the opportunities that exist 
and assess the degree to which we are adequately supporting 
them.

                 identifying areas of research emphasis

    Mr. Porter. Dr. Gorden, when the NIH leadership meets to 
discuss the areas of scientific emphasis that will be reflected 
in the budget, have you proposed new areas that would match 
your Institute's research portfolio well?
    Dr. Gorden. We certainly try to, Mr. Chairman. We put 
forward what we think are the most promising areas of research 
across the five or six particular categorical areas. And we 
believe very strongly in pursuing those areas, and we will do 
our very best to pursue them.

                            budget increase

    Mr. Porter. Do you think a 2.2 percent increase in your 
budget is sufficient to pursue them?
    Dr. Gorden. Well, it will basically permit us to continue 
the things that we have in motion. It will not permit us to add 
any really substantially new items to our research agenda 
without something else having to give in its place.

                           stress in diabetes

    Mr. Porter. Dr. Gorden, regarding type II diabetes, we 
often hear discussions of weight, diet, exercise and the like 
in reference to this form of diabetes. Has any research been 
done relating to stress and the ability of the individual to 
handle stress in their lives and whether this has a role in 
this disease?
    Dr. Gorden. There have been a number of studies that relate 
to glucose control and various aspects of stress in 
relationship to this. This is a somewhat difficult area to get 
a complete handle on. But there's no question that one's 
ability to care for themselves and one's ability to maintain 
the regimen that they are placed on is governed to some extent 
by what kind of stress they suffer in their lives, or they are 
exposed to.
    Certainly, stress is something that stimulates certain 
endogenous functions such as the sympathetic nervous system. 
The sympathetic nervous system has a great deal to do with 
glucose homeostasis, that is, the levels of glucose in the 
blood. So there are lots of indirect reasons that we could 
relate to stress, and certainly, it's a promising and important 
area that we need to consider.
    Mr. Porter. Is there any research being done now in this 
area?
    Dr. Gorden. We have several grants that relate generally to 
stress and glucose control.
    Mr. Porter. Thank you, Dr. Gorden.
    Mr. Wicker.

                     immune modulation in diabetes

    Mr. Wicker. Thank you, Mr. Chairman.
    Dr. Gorden, it's good to have you before the subcommittee. 
And members of the subcommittee will note from Dr. Gorden's 
vitae that he was born in Baldwyn, Mississippi, which is in the 
first Congressional district. And I'm mighty proud to see him 
testifying so well before the subcommittee.
    I have a particular personal interest in the subject of 
diabetes, because of my little niece, Rebecca, who lives in 
Virginia Beach, and who was diagnosed several years ago with 
diabetes. She's doing quite well. She takes insulin every day.
    And I guess I would want you to comment on what progress 
has been made in that type of diabetes. I notice in your 
testimony you say there's a trial that's focused on the immune 
modulation to halt or delay the onset of insulin dependent 
diabetes in high risk children and adolescents. And you 
mentioned knowledge gained in that regard concerning the 
development of highly accurate tests for predicting the risks 
of developing diabetes.
    I wonder if you could elaborate for the subcommittee on 
that subject.
    Dr. Gorden. There are several aspects, Mr. Wicker. The 
first is that the individual who has diabetes already is one 
that clearly should, I think, gain an enormous comfort from a 
recent study called the Diabetes Control and Complications 
Trial, which was one of the largest clinical studies ever 
conducted in diabetes research.
    In fact, it was the largest. It was completed approximately 
three years ago. It was a multicenter trial involving 1,440 
patients. It demonstrated unequivocally that careful glucose 
control can ameliorate or prevent the eye complications of 
diabetes by about 75 percent, the kidney complications by about 
50 percent, and the neurologic complications by about 60 
percent.
    So that this is the first time that we have known that 
therapeutic intervention clearly can ameliorate the rate at 
which these complications occur. So that we can tell this young 
woman that there's a great future for her, in a much more solid 
and positive way than we could before.
    This opens up the question, we now know that this is very 
effective. So we have two different kinds of problems. First, 
we have a problem related to any particular siblings that she 
may have. And that is, the possibility that they could develop 
diabetes. And so this is what this prevention trial refers to. 
It refers to the development of technologies to recognize 
children at high risk for developing diabetes. And it falls 
back on some really very imaginative research having to do with 
what we call tricking or modulating the immune system.
    Now, conventionally, we use words like vaccination or 
immunization and that has kind of a general meaning. We know we 
can prevent the measles and other things like that. For 
diseases like diabetes, it's possible to think about it in that 
way. So exposing a child prone to developing diabetes to an 
antigen, meaning something that might be related to triggering 
the disease, insulin in this case, which is a somewhat 
complicated explanation, but this is one that is being used, 
could be devised in some way to block this immune response. 
That's what we mean by immune modulation.
    That clinical trial is in effect. We have two phases of it. 
The second phase has just begun. So the first research issue is 
developing methods to recognize these children, and the second 
is having an intervention strategy, based on a lot of 
fundamental research and some results in animal models that 
suggest feasibility. So that's the second aspect of this 
pursuit.
    Now, the third aspect is one that we're really in the midst 
of right now. And it's a terribly important area. We refer to 
it as the Diabetes Prevention and Treatment Initiative. Because 
the Diabetes Control and Complication Trial, which was so 
seminal in its results, doesn't tell us how to achieve its 
effects. And for your young niece, she takes insulin, and we 
know that that's a very difficult thing for her. There are a 
lot of things about treatment regimens that this trial has 
taught us that we can transfer to her to make it easier. But we 
know it's still difficult. We've got to close that therapeutic 
gap. We've got to find ways to make that treatment more 
achievable and easier. And that's the goal of what we're really 
into right now. That's a difficult area. But it's one that we 
must and we will pursue.
    Mr. Wicker. If somehow we could have known years ago, 
before this little girl came down with diabetes, we could have 
known that she was at high risk, do we now have the technology 
to prevent, do we now have the knowledge to actually prevent 
that child from coming down with diabetes?
    Dr. Gorden. This is the nature of the experiment. And we 
don't know the outcome. The only thing that I can tell you is 
that, in animal models that simulate the human condition, the 
maneuvers that we're using will prevent diabetes in these 
animal models. And it is that basis primarily that has led us 
into the human experiment. We don't know the outcome.It's too 
early for us to get a hint about what this is going to be.
    But we're convinced that we're on the right track. We're 
convinced that this is an appropriate approach. If this is the 
wrong reagent, it's the one that is safe now and we have 
approval to use the forms of treatment that we're using. But 
there are others in the pipeline, and they may prove to be the 
right trigger. But this is a real thrust of research, and we 
think we're clearly going in the right direction. And the 
answer, we hope, will be a very positive one, which we clearly 
could not have given to you several years ago.
    Mr. Wicker. As a scientist, are you willing to speculate 
about a time line?
    Dr. Gorden. I'm always hesitant, Mr. Wicker, because I like 
to talk to you as I would to a patient. And I don't want to 
create a sense of false hope about setting a time because I 
don't really know if I could deliver, and I wouldn't know quite 
what to say to you then.

                      restoring insulin production

    Mr. Wicker. What about research in the area of restoring 
the defective organ, I guess it's the pancreas?
    Dr. Gorden. Yes.
    Mr. Wicker. How are we doing on that?
    Dr. Gorden. There are fundamentally two approaches, each of 
which has a set of ramifications. First, it's clinically 
possible to do pancreas transplantation. It is being done, and, 
in fact, it works. It is not a type of transplantation that we 
would do, except under very special conditions. And so it's 
generally done in the context of kidney transplantation, which 
has been a great miracle for the diabetic patient.
    There has been some experimentation using pancreas 
transplantation without kidney transplantation. But at the 
present time, for a child, this would involve very toxic 
immunosuppressive agents. Because we do have alternatives, we 
would not want to use that approach.
    The other approach is to use what we call islet cells, that 
is, the insulin producing cells of the pancreas. And there are 
techniques to isolate those cells and there have been very 
successful animal experiments in which this has been carried 
out.
    There are two fundamental problems. One problem is the 
immune problem, that is, the same problem you have with any 
transplantation where the body will attempt to reject something 
that it sees as foreign. That's one problem. And there's a set 
of approaches that are being taken to deal with that. One is 
some sort of shielding device that one might use. One is a sort 
of an immune policeman that would sit there and help guard 
those cells against the attack by the immune system. And there 
are a number of examples of that that I could elaborate on.
    Mr. Wicker. There you're talking about transplanting a few 
cells----
    Dr. Gorden. Yes.
    Mr. Wicker [continuing]. Into a non-functioning organ?
    Dr. Gorden. Exactly. The cells would be transplanted into 
some other area, not the pancreas, where they normally exist. 
We put them in the liver or some other place in the body. And 
this is actually being done.
    But just to mention the second problem. One problem there 
is the immune rejection, the second problem is the ability to 
sustain the growth of these cells. That is, these cells don't 
appear to like particularly being isolated themselves and 
growing in a sustained way. So the problem really has been not 
getting it to work. It does work at a clinical level, and it 
works in patients. But it works over a relatively short term, 
and we don't have very many examples where we've been able to 
get this to go out, say, a year. We have a few, and so that 
offers us an approach. So that this is an area that we continue 
to look at and we continue to support, and we continue to 
recognize the problems. It's really not moved quite as fast as 
we would like to see it move. But we're still encouraging this 
area of research. So this is something I think we will look 
forward to, but we can't give you, as a final clinical product.

                         prevalence of diabetes

    Mr. Wicker. Is it true that the number of Americans with 
diabetes has skyrocketed since 1983, and to what would you 
attribute this?
    Dr. Gorden. Well, certainly the prevalence of diabetes, 
that is, the total number of diabetic patients has increased. 
There's another term that we use, we call it incidence, which 
has to do with the rate of new people entering the system. We 
believe that this is due largely to the fact that people are 
healthier and living longer, there are more diabetics of an 
older age, that this would increase the prevalence of the 
disease, if diabetics are not dying at a younger age, and 
doesn't necessarily infer that there's an infusion of something 
that's causing more people to have diabetes.
    We think that's relatively stable, although we do know that 
certain groups are more prone to develop diabetes. For example, 
Native Americans, Hispanic Americans, and African Americans, 
have a higher prevalence of diabetes. So in particular areas, 
particular regions where there are larger populations like 
this, then one will see an increase in the prevalence of 
diabetes, because of the population admixture.
    Mr. Porter. Thank you, Mr. Wicker.
    Mr. Dickey.
    Mr. Dickey. Dr. Gorden, how are you doing?
    Dr. Gorden. Fine, thank you, sir.
    Mr. Dickey. I knew who you were, I didn't have to look at 
your name.
    Dr. Gorden. You could just tell when I spoke. I just wanted 
to get a little credit, if I could, because the Chairman wanted 
to be certain that I had spoken at the Rotary Club in Baldwyn, 
Mississippi, and Mr. Wicker and Mr. Lott can attest to the fact 
that I've done that. And so I want the Chairman to know that, 
and thank you.
    Mr. Dickey. Now, can we get on with other things?
    Dr. Gorden. That's right. [Laughter.]

                     funding for diabetes research

    Mr. Dickey. In the last 10 years, overall funding at NIH 
grew by 63 percent, or 7.25 percent per year, while funding at 
NIDDK grew by just 40 percent or 4.95 percent a year. When 
diabetes is the fourth leading cause of death by disease, can 
you explain why NIDDK did not receive the same rate of growth 
as NIH as a whole?
    Dr. Gorden. Well, Mr. Dickey, I think that what's important 
for us and what's expected of us is to take the resources that 
we have and do the very best job we can. I believe that's what 
the Director of NIH expects of us, and I believe that's what 
you expect of us. And that's what we try to do.
    I can't really explain beyond telling you what we're trying 
to do and telling you of the directions that we're trying to 
take, and to tell you how we're trying to make things really 
happen with the resources that we have, and how we're trying to 
augment those resources in a variety of ways.
    Mr. Dickey. Does this reflect, this reduction in your 
increase, your decision or your Department's decision, or is it 
happening without your consent or against your request?
    Dr. Gorden. Mr. Dickey, as you know, we take the 
appropriations that we receive that start with the 
Administration and end in the Congress and that's what we 
basically use as our resource base. We have a variety of inputs 
into that at various times. But as I say, in the end, I think 
our responsibility is to do the very best with what we have.
    Mr. Dickey. Are you saying that we as laymen could better 
decide how much you could spend adequately to combat----
    Dr. Gorden. No, what I'm saying is that I think our 
fundamental responsibility is to use the appropriation that we 
receive in the very best way that we can.

                      professional judgment budget

    Mr. Dickey. Have you ever asked for any more than you've 
received?
    Dr. Gorden. Well, we do submit a professional judgment 
budget at the very early phase of the process. And that budget 
is something that we routinely do, and it clearly is larger 
than the budget that we receive, so that we do clearly ask for 
things that we do not receive, yes, sir.
    Mr. Dickey. How much more did you ask for this year than 
the President's budget provided?
    Dr. Gorden. I could give you a percentage. The professional 
judgment budget that we submitted was an 11.4 percent increase 
over the 1997 budget, and our President's budget is 
approximately 2.23 percent. I believe that's correct. The 
number of dollars is $75 million.
    Mr. Dickey. Thank you.
    What are you having to not do because of this 9.2 percent 
reduction from your request? Let me ask you this, particularly. 
How much of that has had to be taken away from the research 
that has as its target the finding of a cure for diabetes?
    Dr. Gorden. Well, I think that fundamentally, our search 
for the cure, as you have put it, is framed in a number of 
different ways. It's framed around clinical trials and it's 
framed around very basic research. And so it's very important 
that we continue some balance in these two areas.
    Just to give you an example of what we've tried to do to 
maintain a momentum, Mr. Dickey, we were just discussing two 
clinical trials that we have in operation now. One is an 
attempt to prevent Type I or juvenile onset diabetes. We were 
just discussing the nature of that trial and some of the 
ingredients in it.
    We had also discussed a trial called the Diabetes Control 
and Complications Trial, which was a major multicenter trial, 
which was very expensive. We knew that we could not begin new 
trials until we ended the first trial, because of the expense 
of this trial. As that trial ended, we began to focus on what 
we were going to do next, and how we were going to focus that 
money.
    So we planned on two separate clinical trials, one in non-
insulin dependent diabetes, the adult onset diabetes which we 
had further developed and had this ready to go. But then, our 
basic science research was really showing some promise, and 
indicated some ways that we might interdict the process of Type 
I, the juvenile onset diabetes.
    Now, what do we do? We felt we needed to go ahead and do a 
study of Type I. We basically put a plan into motion. We asked 
two institutes to help us, the National Institute of Child 
Health and Human Development and the National Institute of 
Allergy and Infectious Diseases. We asked the Juvenile Diabetes 
Foundation, the American Diabetes Association, and we asked for 
some industry support. We told them why we wanted to do this 
and what this was all about, and we received support.
    Then we got to the Type II trial. We actually had just 
received, in addition to this kind of support, funds from two 
different NIH Institutes, just to give you a flavor of the 
multi-institute collaboration, and the way that we go about 
trying to get things done. We've completed a negotiation with 
industry because of a new drug that has just been approved by 
the FDA, which we think has a great promise in treating 
diabetes, and in possibly preventing Type II diabetes. But we 
had no budget to include that trial. So we went to industry. We 
told them what we wanted to do; we said it would be very 
important to include them in our trial. And we've used the 
Federal Technology Transfer Act to achieve that kind of 
balance, so that we can address some of the concerns that they 
have.
    My major point is that diabetes is a very difficult 
problem. There are many people who suffer from it. There are 
children, adults, and their families. Research needs to be 
supported.
    Our responsibility is to get things done across NIH and 
within our Institute. We're the lead Institute for diabetes 
research. It's our responsibility to get things done. We feel 
that's our responsibility to you and to the Director of NIH. 
And that's the way we're trying to do it.
    Now, there's no question that we need resources and we 
certainly want to emphasize the fact that that continues to be 
important. Because it's a very, very mature and very moving 
research agenda.

                          genetics of diabetes

    Mr. Dickey. What is the state of research into the genetics 
of diabetes?
    Dr. Gorden. We've made several, I think, important 
discoveries. Sometimes when we use the word diabetes, it sounds 
as if we're talking about a single thing. When we talk about, 
say, high cholesterol or high blood pressure, we think we're 
talking sometimes about a single disease. In fact, these are 
manifestations of multiple different kinds of things, and so is 
diabetes.
    So we broadly separate diabetes into, we call it insulin-
dependent Type I and non-insulin dependent Type II diabetes, 
and that, there are two different diseases. But the blood sugar 
goes up and there are complications in the eye and the kidney 
and the nerves that are the same. And that seems to be a sequel 
to the fact that the blood sugar is very high and it's not what 
the body is accustomed to having.
    So there are different sets of genes involved in these two 
different conditions. So we've made a lot of progress in 
identifying the locus, that is, the place in the human genome 
that these genes exist. And to some extent, we've identified 
genes in Type I diabetes.
    In Type II diabetes, we've identified at least four causes, 
that is, we've identified the insulin receptor, which is a 
major component of how insulin works, as a geneticabnormality 
in diabetes. In the last year, we've identified three genes in what's 
called ``Maturity Onset Diabetes of the young.''
    And we've also made, I think, as much progress in the area 
of what we call ``complex genetic diseases.'' When we talk to 
you about a disease like cystic fibrosis, this disease is due 
to a single gene. You injure that gene and you have this 
disease.
    Non-insulin dependent diabetes seems to be a complex 
genetic disorder, that is, you have susceptibility areas that 
get weakened within the genome. And there may be three, there 
may be five, there may be ten. We really don't know.
    But we've made progress in beginning to try to identify 
where some of these genes are, and we think we have an approach 
to this. And so it's a terribly important area, it's one that's 
very important in hypertension and Alzheimer's disease and 
depression. Those are diseases that are fundamentally this type 
of complex genetic disorder. And I think that is one that we're 
clearly in the forefront of, but it's one that we can't sort of 
bring to final fruition right now.

                       diabetes education program

    Mr. Dickey. I understand that NIH will be participating in 
the diabetes education program. What additional funds will be 
needed to carry out this important endeavor,and will the funds 
be taken out of diabetes research?
    Dr. Gorden. What we've done, Mr. Dickey, as I mentioned, at 
the completion in 1993 of the Diabetes Control and 
Complications Trial, which showed such a dramatic effect on 
control, that is, how you control your blood sugar, we began to 
hear from the community we felt that there was a need for us to 
develop models similar to what had been developed in 
cholesterol and hypertension, which had been so successful. We 
started what we called an ``outreach program,'' and we started 
in a small way to deal with aspects of diabetic foot care.
    But in the last year, we have sort of begun to call this an 
``education program,'' and we have put funds in it up to 
approximately $1 million. We have also gotten co-funding from 
the CDC for this project. And we're looking for some other 
support. We think it's very important to get this message out 
to the public and to the practicing physicians about the 
importance of glucose control.
    And so yes, funds for everything we do come from 
essentially the same place. So this program does affect our 
research budget. And we're trying to do this in a measured way, 
so that we can really achieve the most practical effect from it 
with the least impact on our research budget possible. We have 
clearly got it moving, and we will build on it as we have the 
opportunity to build on it.
    Mr. Porter. Thank you, Mr. Dickey. Did you have a follow-up 
question, a short one?
    Mr. Dickey. Mr. Chairman, I don't have any more questions.
    Mr. Porter. Well, I would say to members, the ones who were 
here early like Mr. Dickey got extra time, you got 13 minutes, 
Mr. Dickey.
    Mrs. Lowey.

                   special research areas in diabetes

    Mrs. Lowey. Thank you, Mr. Chairman.
    And I do want to apologize to you, Dr. Gorden, Dr. Varmus 
and colleagues, for being detained. But I'm delighted to be 
here today.
    One of the questions I'd like to begin with is whether you 
think there are any particular areas of research in diabetes 
that deserve special emphasis that currently are underfunded.
    Dr. Gorden. Well, there are a number of areas, and we've 
talked about two fundamental areas, that is the clinical 
science arena, the numbers of clinical trials we have, and the 
sort of basic science arena. As I mentioned in my statement, 
this sort of continuum which is, and diabetes research is well-
represented by that, from the very fundamental basic science.
    And we have certain areas, as everyone does, where 
opportunities sort of lend themselves to more immediate 
application and some that move at different rates. So that it's 
difficult, there are certain areas that we were talking about 
before that have to do with prevention and treatment. These are 
very important areas for us to pursue.

                      upcoming diabetes conference

    And one of the things that we plan to do in the very near 
future, Dr. Varmus and I plan to co-sponsor a conference in 
which multiple NIH Institutes, which are involved in diabetes 
research, will be present, and we will interface, essentially, 
with leaders in the diabetes research community that relate to 
all these different components that we have and other 
Institutes have.
    And we'd like to kind of see what the meeting of the minds 
would bring out. We clearly have an agenda that is ongoing. 
We'd like to see where that agenda perhaps ought to be turned 
or moved or enhanced in one way or another. And this would be 
one of the important goals of this particular conference that 
we will certainly be talking to you about more in the future.

                     locating diabetes information

    Mrs. Lowey. One of the questions I have asked in past years 
is whether there is, is there a national directory, does NIH 
actually have a directory of research projects? The response I 
have gotten in past years is that there are forms and people 
who are working in an individual area, whether through the 
internet or their own journals, really know what other people 
are working on.
    But is there any national directory, I would say, for all 
research, or for diabetes research, so that you really have a 
handle on who is doing what?
    Dr. Gorden. NIDDK is the lead Institute for diabetes 
research. We have a home page in which one can feed into and 
really get a great deal of the information base that either 
would give you the information that you would be seeking or 
lead you in a direction in which you could get that 
information. I think most Institutes do have that kind of 
facility available. And I think that now that this sort of 
thing is being utilized more and more, this is probably a good 
avenue for one to approach this. It would be difficult to sort 
of encompass all of NIH research in one place. I think it would 
have to be decentralized to some extent.
    But as long as one would simply focus on where the lead 
application of that kind of research was coming from, I think 
one could easily get that information.
    Dr. Varmus. Could I interject a note of caution here? Many 
people are interested in the idea of assembling all the people 
and information available regarding any specific research area. 
I think one has to be very careful about the purpose of such an 
aggregation of information. Because it's very expensive to put 
it together, very hard to keep it updated. One also has to be 
very careful about the purpose of such a data base. If it's 
simply to identify the investigators around the country who are 
working on diabetes in order to send outnewsletters, that's 
fine. If it's an attempt to keep up the complete repertoire of ongoing 
projects and results, it would become extremely burdensome to 
investigators. It's very difficult to coordinate centrally and, 
frankly, not as useful as having national meetings on diabetes to which 
investigators go.

                             women's health

    Mrs. Lowey. Thank you, Dr. Varmus and Dr. Gorden.
    I'm also interested in an update on the status of your 
research collaboration with the Office of Research on Women's 
Health, which is looking at cardiovascular disease in women 
with Type I diabetes. I understand that this is a long-term 
study, but can you tell us what progress has been made thus 
far, and what you hope to accomplish in the coming year.
    Dr. Gorden. Yes. we were talking about our Diabetes Control 
and Complications Trial just a moment ago. And we have a 
program in which we are following all of those patients. And 
one of the important things that this particular project is 
involved in is studying what we refer to as macrovascular 
disease. And one of the initial thrusts of this project was to 
get a baseline measurement of this population that we continue 
to follow, that we call carotid ultrasound, to get some idea of 
the vessel status of those individuals as they have been 
treated with these different regimens. That initial measurement 
has been made. It has been made with the resources that we 
received from the Office of Research on Women's Health. And we 
plan to continue that, both the collaboration with them and 
this project. And it is a very active, ongoing project in which 
we have many other things to do. And it's one that we're 
pursuing with some vigor.

                          artificial pancreas

    Mrs. Lowey. I thank you. And lastly, what is the status of 
efforts to perfect a biomedical pancreas, which would enable 
people with insulin-dependent diabetes to make their own 
glucose, in medical terminology, to achieve----
    Dr. Gorden. Euglycemia.
    Mrs. Lowey. Okay, euglycemia.
    Dr. Gorden. Good.
    Mrs. Lowey. Thank you.
    Dr. Gorden. This is an area that relates to finding ways to 
take cells that make insulin, islet cells that make insulin, 
and do two things. One is to find ways to protect them from the 
immune system, so that when they're put into an individual, 
they will not be recognized as foreign. And the second goal of 
this research is to find ways to get these cells to grow in a 
sustained way over a long period of time.
    And these are two areas, there are a variety of techniques, 
some very basic, that are very interesting, that are being used 
for immune protection. Some have to do with the co-expression 
of cells that can serve as sort of ``policemen'' in a sense, 
and guard these transplanted cells from the immune system. Some 
involve mechanical encapsulation devices. And some involve 
still other types of technology. So this is an area that is 
actively being explored. But at the present time, it only has a 
relatively limited clinical application with respect to long-
term results. So we're continuing to try, and we're continuing 
to press this area. But we are not able to present it as a 
therapy that would be available to someone tomorrow.
    Mrs. Lowey. Thank you, Dr. Gorden.
    Thank you, Mr. Chairman.
    Mr. Porter. The gentlelady returns one minute of her time.
    Mrs. Lowey. Oh, I'll take it. [Laughter.]

                       costs of treating diabetes

    Mrs. Lowey. Actually, I remember a few years ago, one of my 
constituents testified before this committee and talked about 
the extraordinary expense that she faced with her daughter in 
being diagnosed for juvenile diabetes. And I was thinking about 
that this morning, wondering, with the impact of managed care, 
how has that affected this process? She was talking about 
something like $25,000, it still rings in my head, because it 
was so amazing to me.
    But I assume this included a whole battery of tests and the 
other procedures that had to be taken. And she said that she 
retired from her job to take care of her young child, but thank 
goodness, she had that insurance while this battery of tests 
was being done.
    Do you have any first-hand information on that? Have the 
tests gotten cheaper? Or how has one fared under managed care 
with this, based upon your information?
    Dr. Gorden. Well, we would certainly hope that the message 
that managed care would receive is that this treatment works, 
and this treatment reduces the complications of the disease. 
And if a managed care company plans to have an individual as 
one of its clients for a number of years, it would be cost-
effective for the managed care company to permit that patient 
to use the most modern facilities, and resources that are 
available. And we have actually some quantitative data to show 
the cost-effectiveness of that approach. And looking at the 
difference in cost of say, equipment, for more conventional 
treatment versus what we would call intensive treatment.
    And we have data to show that the increase in initial costs 
is more than offset by the savings that one has in the 
morbidity of the complications of the disease. That's the 
message that we're giving managed care. And I have the sense 
that that's being heard. We certainly have seemed to have 
gotten the message into the Medicare system. And I think that 
there are a variety of efforts that are being made to do that.
    And the feedback that we're getting suggests to us that 
this is really having an effect. So I can't answer your 
question completely, certainly, for every managed care 
orgainzation. But, I think the message is clear, and I think we 
will continue to press that message. And I'm very optimistic 
that that's going to be heard, and that they will understand 
that.
    Mrs. Lowey. Are the costs still so high? I was amazed at 
that initial diagnostic work and treatment.
    Dr. Gorden. It would depend to some extent on what you're 
actually including. If you were to truly take the measures that 
were used in this trial, it may approach those costs. Our 
estimates are something under $5,000 for intensive treatment. 
But then it would depend to some extent on the numbers of 
people who were involved. Is there a dietician; is there a 
nurse practitioner; is there another trial coordinator of some 
kind helping manage your care?
    So one could imagine that this could, and also depending on 
where you are in the country, costs could range up to perhaps 
what you say. But it depends on this constellation of things.
    Mrs. Lowey. Thank you.
    Thank you, Mr. Chairman, for that additional minute.
    Mr. Porter. It ended up being an additional four minutes. 
[Laughter.]

                          intramural research

    Mr. Porter. Mr. Miller.
    Mr. Miller. I'd like to take a few minutes to get a better 
understanding, in a more generalized question, but using your 
Institute to understand better intramural versus extramural, 
and the role of the small business setaside. And again, I'm 
just trying to get a grasp of the issue. Dr. Varmus may want to 
chime in here.
    A little bit over 10 percent goes to intramural research?
    Dr. Gorden. Eleven point four percent, yes.
    Mr. Miller. For your Institute?
    Dr. Gorden. For our Institute.
    Mr. Miller. What is the average for the entire NIH?
    Dr. Varmus. Well, it was 11.3 percent when I came on board, 
and now it's about 10.5 percent.
    Mr. Miller. Is it basically all in Bethesda, or is that 
nationwide?
    Dr. Gorden. We have two components. Our major component is 
in Bethesda, and we have another very significant component in 
Phoenix, Arizona, a study in diabetes. This is located at the 
Phoenix Indian Hospital, and is involved in a longitudinal 
study and clinical studies of the Pima Indians, that have the 
highest prevalence of diabetes in the world.
    And so this has been an extremely productive study in which 
we can follow the population of patients and follow them over 
time, and also study genetic factors and what we call 
pathophysiology, the sequence of events that develop in the 
individual before they develop diabetes, during the 
intermediate phase and, finally, what happens when they develop 
the full-blown disease.
    So this has been an extremely valuable resource. We have 
done this in collaboration with the Indian Health Service. And 
it's worked out extremely well for us over a long time. It's 
extremely highly regarded internationally.
    Mr. Miller. How much money do you spend in that program, 
for example?
    Dr. Gorden. Let's see if we could give you a reasonably 
accurate number. It's about $7.5 million a year.
    Mr. Miller. Okay, out of your $90 million.
    In making intramural decisions, do you start new programs 
versus phasing out current studies? And have you phased out any 
to conclusion and say, we really want to start a new program? 
How do you go about making that decision and have you made any 
such decisions?

                       intramural decision-making

    Dr. Gorden. Yes. We make those decisions all the time. It's 
a continuous process. It works in several ways. In our 
Institute, and in I think most NIH Institutes, we have a 
division of intramural research, and we have a director of that 
division. And we depend very much on that individual to help 
guide and advise about how that ought to be and where resources 
should be put. Should we put more resources here and less 
resources there? This is a continuous process. We have a Board 
of Scientific Counselors that meets on a regular basis to 
review all of our laboratories in a continuous way. We take 
their review and their advice and we put it together with our 
own sense and assessments.
    I meet on a very regular basis, having been part of the 
intramural program for many years myself, with the Director of 
Intramural Research. And we forge a program collectively with 
the advice of the Board of Scientific Counselors, and with the 
advice of a number of other people, including our National 
Advisory Council, who are briefed on a regular basis about the 
activities in the intramural program.
    So that we will make a major commitment to enhance 
promising areas. As an example, we have perhaps one of the 
leading structural biology programs in the world. We have 
garnered a group of people who are world class, and they are 
using the most advanced technology that is available.
    For us to support that, it means that that has to be a very 
high priority, because this is very expensive. We have to 
really know that this is productive. And so that this facility 
has a major trans-NIH presence, everyone, not only just on the 
NIH campus, but essentially nationally and internationally, 
knows about this group and what they do. That's a kind of a 
fundamental commitment that we will make to enhance a 
particular area.
    We also make it a point to keep abreast of our clinical 
activities. We have clinical activities in diabetes, digestive 
and kidney diseases, and nutrition and areas that represent the 
sort of fundamental mission of the Institute.
    And we're constantly looking at ways to enhance those. 
We're very much a part of the new NIH Clinical Research Center. 
We're very active participants in the Clinical Center, so our 
Institute should be one that has a very strong clinical 
presence. We have done a number of pilot studies or sort of 
inventive types of clinical studies that have come out of our 
intramural program, a number of which I could discuss.
    Mr. Miller. So that you'll start them there and then----
    Dr. Gorden. Absolutely. A very good example would be, in 
sickle cell disease, in which we started a program to use a 
particular compound to enhance hemoglobin concentration in 
individuals with sickle cell disease. We have a very talented 
investigator who began those programs as part of a clinical 
pilot study. That was so successful that it then translated 
into a multi-institution study that was primarily sponsored by 
the Heart, Lung and Blood Institute.
    We've done this with the treatment of hepatitis, where we 
made pivotal observations about the use of certain drugs like 
interferon. Then multicenter clinical trials have been 
sponsored by the National Institute of Allergy and Infectious 
Diseases.
    So the intramural program has been a resource in which we 
can rapidly move into clinical and fundamental areas, and then 
we can exploit those either ourselves, or with our colleagues 
in other Institutes.
    Mr. Miller. You have the same job as Dr. Varmus has, you 
have to allocate limited resources and make those tough 
choices, as we do up here, too.
    Dr. Gorden. Absolutely.

                        small business research

    Mr. Miller. So I respect that.
    May I ask one more little set of questions, and that is the 
small business set-aside. I'm just trying to get a better 
understanding of it, rather than questioning everything you're 
doing. How much is there in that area? What is the total amount 
of money in your budget that's in effect a small business 
setaside? Dr. Varmus, we talked about it briefly on the 
telephone before these hearings.
    Dr. Gorden. The percentage in the 1997 budget is 2.5 
percent. That is the official percentage. The actual dollar 
amount for NIDDK is $17,878,000.
    Mr. Miller. Okay, because I was just looking at the--on 
this book here for the 1997 fiscal year SBIR is $15,878,000 
under research projects.
    Dr. Gorden. Right.
    Mr. Miller. And then you drop farther down and I see the 
$23 million. I'm trying to figure the difference.
    Dr. Gorden. It falls into two categories, which to some 
extent get a little bit blurred. But we do categorize them as 
grants and contracts. In our case, we have $15.8 million in 
grants and $2 million in contracts, which is the total that I 
gave you for fiscal year 1997. That's the $17,878,000 of the 
total of those two.
    And just as an example, Mr. Miller, of what we were just 
talking about in answering Mrs. Lowey's question about devices 
for treatment of diabetes, we would like very much to see the 
encapsulation devices, how we grow cells, how we use this sort 
of resource, we would like very much to see this go into 
industry. We would like to stimulate industry to do this in the 
whole glucose monitoring area, where we're trying to develop 
devices to measure glucose.
    We have devices now that are somewhat detached from the 
person that we use, strips and things to measure glucose 
control. This type of device development we would very much 
like to steer towards small business. And we make a very big 
effort.
    The recent work with the obesity gene has had an explosion 
in the biotechnology industry. We would like to see more of our 
small business resources go into those really promising areas. 
And we make a great attempt to see that happen.
    Mr. Miller. Has the quality of your small business 
applicants improved in recent years? There's been a concern 
that they don't rate as high. You have a difficult time because 
your demand for grants is far greater than the money you have 
available. Have you seen an improvement?
    In addition to that question, answer this and then I'll 
conclude. Basically, the small business all goes to the private 
sector, I assume?
    Dr. Gorden. Yes.
    Mr. Miller. The rest of extramural, what percentage of that 
goes to the private sector versus the non-profit academic 
sector?
    Dr. Gorden. 100 percent of this goes into industry, small 
business.
    Mr. Miller. Right.
    Dr. Gorden. In the area of the non-small business funds, 
the vast majority goes to either research institutions that are 
either academically affiliated, but are generally non-profit 
institutions, or to academic institutions. I can't give you an 
exact number. I could try to get that for you. I don't have an 
exact number. All I could do is give you a qualitative answer. 
Clearly, the vast majority goes to research institutes, or to 
academic institutions.
    Mr. Miller. Do the big pharmaceutical companies get NIH 
grants, like a Merck or somebody?
    Dr. Varmus. Extremely small. Not Merck, as far as I know. 
It's almost all small business.
    Mr. Miller. So the remainder of extramural basically goes 
to the non-profit sector, or research institutes and all that?
    Dr. Gorden. Yes.
    Mr. Miller. So there's a very small amount that would fall 
in that area.
    Dr. Gorden. Right.
    Mr. Miller. Thank you.
    Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Miller.
    We're delighted our ranking member, Mr. Obey, can join us. 
He is ranking on the entire Appropriations Committee, and it 
means he has responsibility for 13 subcommittees, and his time 
is very, very dear. So you're recognized.
    Mr. Obey. Thank you, Mr. Chairman.
    I apologize for not being here. We've got three Cabinet 
Secretaries up here today, and we have a Democratic caucus, 
which was absolutely fruitless to attend, but I did anyway. 
[Laughter.]
    Mr. Obey. I hope you are not going any better. [Laughter.]

                                 ulcers

    Mr. Obey. Let me just ask one question about ulcers. Can 
you tell us, what is the status of our knowledge now with 
respect to ulcer causation and treatment? I know in the old 
days, people used to think, they used to try to reduce tension, 
take plenty of Maalox, all the rest. Now we've discovered that 
the significant portion of the problem is bacterial.
    How would you sum up what we now understand about that 
problem?
    Dr. Gorden. I would say first, Mr. Obey, it's really one of 
the seminal events in medical research, to make a discovery of 
the real cause of a disease. With respect to duodenal and 
gastric ulcer, we believe that there is a very, very strong 
correlation with this bacterium, H. pylori, and that it is the 
etiologic or causative base of most ulcers with perhaps two 
exceptions. Those exceptions are the ulcers that occur in the 
context of the so-called non-steroidal anti-inflammatory drugs 
that people take for arthritis or pains. The Motrin type of 
drugs or that general nature, or aspirin. Those drugs lead to 
ulcers in a certain proportion of patients.
    There's another relatively uncommon but very important 
tumor that produces a substance, gastrin, which causes the 
gastric acid to go very high. And that is another important 
cause, although relatively rare.
    So those two, with those two exceptions, we believe most or 
all peptic ulcers are associated with helicobactor. And the 
most remarkable thing about it is that this has been a chronic 
disease, that is, we could treat it and we had, as you pointed 
out, Maalox, and we even had better things than that. We had 
drugs, such as Zantac, we had acid blocking drugs that were 
actually very good.
    But what those drugs did was control a chronic disease. Now 
what we've done is taken a chronic disease and converted it to 
an acute disease. That's really something we'd like to do with 
a lot of things. Because now, we can treat ulcers for two weeks 
as an acute illness, and we believe we can completely eradicate 
peptic ulcer disease.
    Mr. Obey. What percentages are you talking about?
    Dr. Gorden. We believe we can eradicate----
    Mr. Obey. No, I mean the percentage of ulcers that are 
caused by that problem.
    Dr. Gorden. I would say that the percentage is about 85 
percent is caused by the H. pylori process, and about 15 to 20 
percent are this other category, which are associated with non-
steroidals and aspirin and other drugs of that nature.And this 
syndrome called Zollinger-Ellison syndrome. Those ulcers will not be 
affected by the H pylori treatment.

                               nutrition

    Mr. Obey. Mr. Chairman, just one other question. And maybe 
Dr. Varmus would like to comment on this, because it goes 
beyond your Institute.
    I often have constituents express confusion, and my wife, 
who's interested in nutrition, also expresses it. The confusion 
people have with respect to dietary recommendations, because 
they often seem to be conflicting in terms of what reduces the 
chance or what increases the chance of cancer, versus what 
increases the chance of other diseases, including heart 
disease.
    What can you say with respect to those tradeoffs, and what 
we know about them and what wise people would do?
    Dr. Varmus. I'll just make one brief, general comment and 
then turn it over to Dr. Gorden, whose Institute has a 
coordinating office on nutrition that is overseeing a lot of 
these activities.
    Attempting to correlate diet with disease has been 
traditionally one of the trickier areas in epidemiology. That 
is so in part because the attempts to assign a pathological 
effect to a certain kind of diet tends to be based on fairly 
small effects. And such effects are very difficult to 
substantiate unless you use very large populations in multiple 
studies, because many other variables affect the population: 
where they're living, other aspects of lifestyle, genetic 
composition of the population, and so forth.
    That being said, there are nevertheless some clear 
indicators that have developed with respect to the role of fat 
in the causation of coronary artery disease, especially in the 
generation of late onset diabetes, and perhaps in the causation 
of certain cancers, particularly cancer of the colon.
    Do you want to comment?
    Dr. Gorden. I think that it is a complicated area, and I 
think that, with respect to the Federal Government, there's 
been an attempt to try to channel what is usually referred to 
as ``a single voice,'' that is, between the Department of 
Agriculture, that has a major input, and the Department of 
Health and Human Services, including the NIH, which has a major 
input.
    So that as Dr. Varmus says, there are certain fundamental 
things that can be recommended. That issue I think is the 
clearest one. The weight issue is very clear. In other words, 
dietary guidelines that would help people maintain a normal 
weight, that's a very clear guideline.
    We have supported in the past something called the RDA, the 
Recommended Dietary Allowances. And the recommended dietary 
allowance is the amount of a nutrient, either a vitamin or 
other nutrient, that is consistent with a healthy lifestyle, so 
that there are a variety of things that are there, but there 
are also a variety of opinions about different things.
    And sometimes it has to do with food additives and whether 
we should be adding things. And sometimes, as Dr. Varmus 
mentions, the epidemiologic studies with food suggest certain 
kinds of things that don't turn out to be true when you purify 
a particular substance. Beta carotene would be an example.
    These are the things I think that lead to tremendous 
confusion. And of course, there's a lot of advertising and 
things that people are constantly being barraged with. It is a 
very difficult area. I think we need to constantly try to 
produce the very best science we can, and then we need to 
basically find ways to translate that in a meaningful way. And 
I think it continues to be an ongoing struggle. You're 
absolutely correct in pointing out the confusion.

                           effects of alcohol

    Mr. Obey. I swear to God, any time that there's any study 
at all that relates to alcohol, the networks have it and 
trumpet it. What do we know about the ``beneficial'' versus 
negative effects of alcohol, example, wine?
    Dr. Gorden. Well, of course, there was always tremendous 
reluctance to add alcohol into the Federal dietary guidelines.
    Mr. Obey. I'm not suggesting that. [Laughter.]
    Dr. Gorden. Well, no, in fact it actually has been added 
into the Federal dietary guidelines. But of course, the major 
concern is that when you recommend something at a given level, 
it gets exaggerated, and then all of a sudden, it becomes 
something that, if you take a little bit, and that is good, 
then if you take a lot of it, it must really be good. This is 
really a problem.
    There does appear to be some basis for a benefit of alcohol 
with respect to say, cardiovascular disease. We do have some 
evidence to support the notion that there's a so-called good 
and bad cholesterol. The so-called LDL, which is referred to as 
bad cholesterol, and HDL is referred to as good cholesterol. 
Alcohol actually has a component of stimulating the good 
cholesterol.
    Now, that ought to be good, and there have been some 
studies to demonstrate that a modest intake of alcohol actually 
will improve cardiovascular outcome. And this is the basis for 
this sort of recommendation. And of course, as you say, it is 
very easy to get confused.
    Mr. Obey. What about counterbalancing that with the 
concerns that alcohol causes cancer?
    Dr. Gorden. This is the real concern, because we certainly 
know the morbidity that alcohol can cause in so many ways, in 
terms of morbidity of liver disease, accidents, on and on. This 
is the problem with this sort of recommendation and this is why 
there's been so much reluctance to make this kind of 
recommendation.
    Dr. Varmus. One of the difficulties here is defining what's 
meant by moderate alcohol use. That was sometimes considered to 
be one or two drinks a day. Dr. Gordis informs me that there is 
increasing evidence that as few as one or two drinks a week may 
have beneficial effects. It's obviously important to determine 
what is actually required to get the modest beneficial 
cardiovascular effects.
    Mr. Obey. Are there any studies that compare the benefits 
that accrue from that with the negatives on the cancer side?
    Dr. Gorden. I don't think most of the studies have been 
done to do exactly what you say, but have been done to actually 
try to show the efficacy of what we refer to as moderate 
alcohol intake. They have not been done to try to show the 
other side, that is, what if you exceed what we call moderate.
    I don't know of studies that would actually point to that. 
I think people have just simply accepted that excess alcohol 
has a major risk and have not really gone into the comparative 
studies.
    Dr. Varmus. The problem here, as elsewhere, is defining 
very low risk levels. When the dose is very low, it's very hard 
to saywhether there's no effect or a small effect on cancer 
incidence.

                         h. pylori applications

    Mr. Obey. Thank you, Mr. Chairman.
    Mr. Porter. Thank you, Mr. Obey.
    Going back to H. pylori, some in the clinical research 
communities cite the H. pylori case as an example of what they 
see as NIH's reluctance to fund clinical research, because the 
researcher involved was repeatedly turned down for NIH funding. 
Why do you think this research didn't fare well in peer review?
    Dr. Gorden. It's a little bit difficult to answer that 
question. I can give you certain, I guess, conventional 
answers. We're talking about basically Dr. Barry Marshall, who 
did apply for several NIH grants and did not receive them.
    Dr. Marshall, of course, is responsible for a major 
discovery, that the bacterium H. pylori causes most ulcers. The 
fact that the grants were not awarded has to do with the fact 
that we depend largely for advice from expert panels on how we 
make awards. The fact that they weren't awarded means that we 
did not get promising reports from these expert panels.
    But I'd like to say, Mr. Chairman, that this is something 
that is a fact and something that we're not very proud of, and 
I hope that this would not convey the idea that this is 
representative. This is clearly an aberration. It's a major 
aberration. And we can point to many other areas in which we as 
an organization or as an institution should be wiser than our 
expert panels. I don't for one minute accept that as an excuse. 
But it did happen.
    And I believe that we have to learn from that example, and 
hope that we can do better in the future.
    I think that many of the things that this related to were 
sort of fundamental observations. And I'm not really sure that 
this would be an example of any sort of negative aspect of the 
peer review system on clinical research. Because I think this 
was a failure of both the study section, the expert panel; 
council, which is the second level of peer review; and the 
Institute, including myself, to recognize this sort of thing.
    All of us basically can serve as a checkpoint. And we all 
are responsible for being certain of support for clinical 
research. So this is clearly an aberration. It is certainly an 
embarrassment, and we have to accept that and accept 
responsibility for it.
    Mr. Porter. I didn't mean to suggest otherwise. I just 
meant to suggest that it probably is a learning process for 
everyone.
    Dr. Gorden. Yes, absolutely.
    The conventional answer is that the grant was really not 
well constructed. It may very well be that the way the grant 
was constructed that it really wouldn't lead to any practical 
significance, and that one could argue that.
    On the other hand, I think we have to be a little wiser 
than that, and we are many times, when we look at something, we 
say, this is really a grant that's not constructed well, but we 
have a responsibility to try to get this reconstructed in some 
way that will be more acceptable. So I think that we do this 
all the time.
    Mr. Porter. I believe that Dr. Varmus has told me a major 
effort is underway to do exactly that.
    Dr. Varmus. Well, let me comment about the notion that this 
might be indicative of a general pattern of not funding 
clinical research. As you know, I've been very responsive to 
the claims by the clinical research community that we're 
undervaluing their efforts. And the NIH clinical research 
panel, headed by David Nathan, has been looking carefully at 
the extent to which we support clinical research.
    There clearly are difficulties and things that need to be 
repaired in that area. But one of the surprises, I think, to 
everybody is the very large segment of our research portfolio 
that is in the clinical arena. The number is something on the 
order of 30 percent.
    Dr. Gorden. And certainly, that's quite representative of 
NIDDK where we have 30 to 35 percent. So it wasn't in any way a 
deviation from our clinical research that had to do with this. 
This is clearly an aberration.

                     ulcer diagnosis and treatment

    Mr. Porter. Do you expect to see an increase in H. pylori 
diagnosis with the availability of the new breath test, which 
is cheaper and less invasive than the current diagnostic 
methods?
    Dr. Gorden. Yes, we certainly think that this would be a 
valuable tool. The other advantage of the breath test, there 
are really three ways to detect H. pylori. One is by an 
antibody test. The other is by endoscopy and actually biopsy. 
And the third is the breath test. And the breath test actually 
detects active infection. It's simple and straightforward, it's 
non-invasive.
    And we think that it will have an extremely positive effect 
on detection and just working out what we need to do about H. 
pylori in general. We have a considerable discussion going on 
about the whole issue of H. pylori's role in ulcer disease.
    Mr. Porter. Today many of the things that were previously 
used as treatments for peptic ulcer are now on the market as 
non-prescription drugs like Pepcid AC and Zantac and there are 
so many of them, they advertise so heavily you can hardly keep 
up with them. Do you think that has given a kind of a alternate 
message as to the cause of peptic ulcer, and what's your sense 
of how widely known the H. pylori finding is by both 
practitioners and patients?
    Dr. Gorden. Well, Mr. Porter, one of the things that we did 
when we all began to recognize the importance of H. pylori, I 
think Dr. Varmus mentioned this in his opening statement, is we 
held a consensus conference. And one of the purposes of this 
consensus conference was to really put a national imprimatur on 
the importance of this discovery and how ulcer can be treated.
    And I think it had an enormous effect. The feedback we get 
suggests that it was perhaps the timing, whatever reason, it 
had an extremely positive effect. We think throughout the 
digestive disease community that this is part of the culture of 
the physician. We believe that this is permeating very much the 
entire medical practice community in a very significant way.
    Now, there are other issues here that are under intense 
discussion. Now, many of the reasons that people take the kinds 
of drugs that you mentioned are really not due to peptic ulcer. 
They are due to conditions that we call non-ulcer dyspepsia. We 
don't know exactly what that is. But we know it is a syndrome 
that simulates the symptoms of an ulcer. It may be pain, it may 
be bloating, it may be a variety of symptoms. And that this is 
the reason that peopleare taking this.
    We're looking into the question of now if individuals come 
in with this sort of a general diagnosis, should they be 
screened for helicobactor, and if there's evidence, say, from 
the breath test, should all these people be treated? These are 
things that are being actively discussed now.
    But it's not the issue of ulcer. I think that knowledge 
really has penetrated very much into the community. It is the 
ancillary, other conditions that we're not certain, about the 
effect of the relationship of H. pylori to these conditions in 
which they simulate the same symptoms. And I think we'll come 
out with a sensible kind of recommendation that will take a 
little bit longer to percolate through the community Because it 
won't be quite as straightforward as the ulcer recommendation, 
which I think has really penetrated to a very significant 
extent.
    Mr. Porter. I was thinking more of the patient community 
and people taking these kinds of readily available drugs, which 
provide them some relief from a peptic ulcer, but never allow 
them to get to a physician and receive a real cure.
    Dr. Gorden. I think there is a risk of that. And what we're 
encouraging is, if someone has something that's sustained for 
several weeks to several months, that that is the time they 
really should stop the self-medication and actually see a 
physician, and that we would hope then to have the broad 
practice community sort of channeled into this whole notion of 
the possible relationship of H. pylori to that condition.
    But I think it's a little bit tricky, and there are some 
problems related to the over-the-counter medication. But we 
believe that the more people become aware, the better this will 
work itself out.

                      drugs that work selectively

    Mr. Porter. The science section of yesterday's New York 
Times described interesting work underway to produce custom 
designed drugs that would offer many of the benefits of 
estrogen, without the risks that dissuade many women from 
taking it. We discussed yesterday the dilemma women face in 
deciding whether to take estrogen to prevent osteoporosis and 
heart disease, but risk breast and uterine cancer. When will 
these new designer drugs be available to relieve women of this 
difficult decision?
    Dr. Gorden. This is again one of these really modern kinds 
of miracles of science. Our endocrine program has been involved 
in the study of how steroid hormones work for a number of 
years. Estrogen falls into the class of steroid hormones. And 
previously, it was thought that estrogen and the receptor for 
estrogen bind each other and you give a signal and that's sort 
of an all or none signal, that you don't modify that signal.
    It's becoming clear through a number of studies that it's 
not quite that simple, that there's a whole constellation of 
things that go on when that signal in these two proteins come 
together. And they have to do with things that are called co-
factors and co-stimulators and repressors and certain other 
terminology that's used.
    So it turns out that this receptor, this estrogen receptor, 
has a certain kind of plasticity. And the conformation of this 
receptor seems to be able to communicate different things, and 
we might then be able to make this much more tissue-specific. 
That is, what we would like is to generate positive effects in 
the cardiovascular system and in bone, and actually to not have 
those effects occur in, say, uterus and breast, which is the 
major concern.
    And it would certainly appear that we have the wherewithal 
to do that, there are a variety of either agonists or 
antagonists or other kinds of reagents that are being looked at 
now. And this is really, I think, an extremely active area of 
research that we're involved in and several other Institutes 
are involved in. And it goes beyond estrogen. It certainly goes 
to the whole cascade of steroidal hormones, so that one could 
begin to see implications for prostate cancer and other 
cancers, which we know are hormone--responsive types of cancer. 
So I think the ramifications of this are enormous.

                           digestive diseases

    Mr. Porter. Research indicates that a group of peptides 
known as trefoil proteins act to repair various forms of 
gastrointestinal tract injury. They are being studied for 
possible use in preventing the ulcers that are sometimes the 
result of prolonged use of anti-inflammatory drugs. Would these 
drugs also potentially treat other gastrointestinal 
inflammations, like the inflammatory bowel disease?
    Dr. Gorden. We certainly have a lot of preliminary evidence 
that that may be true. These are natural products that are 
stimulated when the intestine needs to repair itself. They seem 
to be involved in both the protection and reparative processes. 
And as I mentioned earlier, this technology involves so-called 
``knockout genes,'' where you could actually eliminate this 
particular protein. It has several different forms. If you 
eliminate one form it does one thing, another form, it does 
another.
    It seems that, when you eliminate it and don't allow it to 
be expressed, certain types of intestinal injury take place in 
terms of inflammation. When you eliminate another form of this 
trefoil peptide, neoplasia or cancer seems to occur.
    So we think that this is an extremely promising clue to the 
mediation of gastrointestinal injury. You allude to the non-
steroidal anti-inflammatory drugs and how they injure or have 
the potential to injure mucosal linings. We think that this is, 
we would say it is in sort of a pre-clinical stage, that is, 
pre-clinical testing.
    But we would imagine that this kind of approach would very 
rapidly move into some sort of drug development program in the 
near future. This is being primarily spearheaded from our 
Digestive Diseases Center in Boston, among other places. But we 
have indications from them that this is likely to be the case.

                                urology

    Mr. Porter. Dr. Gorden, you and NIH have been under 
pressure for some time from the advocacy groups to establish a 
new study section dedicated to urology or to increase the 
number of urologists in existing study sections. An innovative 
pilot study is underway to address these concerns. Can you 
describe this effort, and give us your impression of how it is 
working?
    Dr. Gorden. Yes. There's been considerable discussion with 
the Division of Research Grants. We had the new Director of the 
Division of Research Grants, Dr. Ehrenfeld, meet with our 
National Advisory Council the last time we met. And I think 
we're making a considerable amount of progress. One of the 
possible solutions for the concerns of urologists that they're 
not being totally represented within the context of these 
review groups is to have what we call a ``special emphasis 
panel,'' in which we might, say, take a set or subset of grants 
that are generally related to urology and havespecific time 
receipt for them, so that they would be reviewed perhaps somewhat less 
frequently than in the routine study sections.
    But this would permit a larger aggregation of these grants 
to be reviewed at one time. And this has been piloted, and we 
have seen the result of it. And my impression is that the 
urology community is very pleased, it is very excited about 
this approach. And when discussing it with Dr. Ehrenfeld, she 
felt that this was something that we probably ought to 
encourage.
    And so we've been involved in trying to help relate the 
urology community to the Division of Research Grants. We're 
very pleased to see some resolution of this. There are other 
ways that we have of dealing with this. We've dealt with it in 
our own review process to review special aspects of urologic 
research.
    And in fact, urologic research has been one of the fastest 
growing areas of the Institute. So that clearly it's thriving, 
it's becoming a very scientifically competitive research group. 
And I think all those things are going to bode well for this 
process, which I am pleased with.

                              prostatitis

    Mr. Porter. This is a related question. The prostatitis 
community is very anxious for your Institute to support 
research in this area. An NIDDK workshop concluded that several 
preliminary steps must first be taken, including an agreement 
on diagnostic criteria and the development of treatment outcome 
measures. How long do you think it will take to complete this 
preliminary work so that prostatitis research can productively 
be supported?
    Dr. Gorden. This is again one of the areas that we really 
haven't gotten a research handle on, Mr. Porter. We convened 
this workshop to try to give us a focus on this. We do a lot of 
work that relates in an indirect way, for instance, in our 
longitudinal prostate study, the prostate biopsies, we have a 
lot of information on this kind of thing.
    But to kind of energize what I think this community is 
asking us to do, we're proposing a set of grants that would 
help us define diagnostic criteria so that we can develop a 
research focus. We have what we call an RFA, or a Request for 
Applications, out right now. We expect to have applications 
back in the near future and fund those this fiscal year. And 
this will give us an entree into how we might better conduct 
research in this area. It's one of the important things that we 
need to deal with, but we need to find our way before we can 
really expand this area.

                               hepatitis

    Mr. Porter. Hepatitis seems to be an expanding target for 
research. As soon as a vaccine is developed for one type of 
hepatitis, scientists identify yet another variant. Can you 
describe the universe of hepatitis infections and the state of 
knowledge about the various forms?
    Dr. Gorden. Well, certainly it's been a very exciting area 
of discovery in the last several years. Hepatitis has sort of 
grown a little bit like the alphabet. And we used to use the 
term infectious hepatitis, and that refers to what we now call 
hepatitis A, which is the type of hepatitis that one gets from 
eating contaminated foods. Fortunately, now we have a vaccine 
against that hepatitis. It usually is a self-limiting illness 
and doesn't usually lead to chronic disease, although rarely it 
causes a very acute fulminant type of hepatitis.
    Hepatitis B is a type of hepatitis that approximately 10 
percent of people develop a chronic form, and when they develop 
the chronic form of this disease, it can result in one of two 
things. It can result in scarring or cirrhosis of the liver, or 
it can result in liver cancer. There have been some important 
inroads in the treatment of hepatitis B. It basically has been 
eliminated from the blood supply, because there are clear-cut 
tests. And now fortunately, we have a vaccine against hepatitis 
B. So two of the forms of hepatitis we have vaccines for.
    The third very important form of hepatitis, we used to 
refer to the terminology, non-A, non-B. But then in the last 
several years, there's been a new form defined called hepatitis 
C, which is probably the most prevalent form of chronic 
hepatitis. And it was the type of hepatitis that people who 
were getting multiple blood transfusions were receiving. And 
we're still seeing that reservoir of patients who got hepatitis 
from blood transfusions. It's still a very important part of 
hepatitis. Although the transmission through the blood supply 
has decreased virtually to zero.
    In approximately 40 to 45 percent of the cases, we really 
don't know how it's transmitted. And this is an important area 
of scientific investigation now.
    We do have some treatments for it. They are not ideal. 
We're having a consensus conference this month to talk about 
the treatment of hepatitis C and the sort of impact of 
hepatitis C on liver disease. Unfortunately, we do not have a 
vaccine. But we do have a very accurate way of testing for it.
    Now, beyond that, there are several other forms. There's a 
new form, something called Delta hepatitis, which is a variant 
of hepatitis B, and there's a new hepatitis virus, which we 
call hepatitis G. And at the present time, we really don't know 
the exact significance of hepatitis G. But it is an area that 
is under active investigation.

                       polycystic kidney disease

    Mr. Porter. The past year has been a fruitful one in 
research on polycystic kidney disease. How does your Institute 
plan to capitalize on the new scientific opportunities?
    Dr. Gorden. Mr. Porter, this is an example of what we 
really call scientific opportunity. For many years, we knew 
that there was a genetic form of cystic kidney disease, 
referred to as polycystic kidney disease. The early chromosomal 
methods to localize the genetic defect, because it ran in 
families in a way that we knew was familial, gave us an idea 
that there was more than one form, in other words, we knew that 
more than one type of gene was involved.
    And then a very pivotal discovery was made, and that was 
what that gene is, or what we call ``polycystic kidney disease 
1.'' And that has led to the discovery of the protein that's 
abnormal. We supported two years ago a group of research 
applications to exploit what the function of this protein is. 
And in the last several months, we've seen enormous fruits of 
those grant applications, and we've seen some really important 
findings come out about the mechanism by which this genetic 
defect possibly leads to this cyst formation.
    And it really has a lot of ramifications that relate to the 
concepts that are being investigated in cancer and tumor 
suppressors and other types of things. Very interesting 
phenomenon.
    Almost on the heels of that discovery, our investigators at 
Albert Einstein discovered the cause of the so-called second 
form, ``polycystic kidney disease 2.'' And we now have two 
separate proteins that we feel might in some way interact with 
each other, but might have sort of a separate etiologic track 
of their own.
    We know that there are other rare forms of cystic disease, 
but now we know the fundamental cause. And so we think it's 
incumbent that we vigorously pursue this to understand 
completely what this genetic defect causes in terms of the 
protein that's abnormal, what this protein does and how it 
leads to cyst formation. We even have some clues about some 
therapeutic manipulations that might be actually instituted for 
this disease. But these are in a very, very preliminary stage.
    So I think it's really an extremely promising area, one 
that we plan to vigorously pursue and I look for some really 
important things to come from that in the near future.
    Mr. Porter. Dr. Gorden, last year you indicated that you 
did not favor the development of research centers specifically 
for polycystic kidney disease. Is PKD a research focus for any 
of your existing George O'Brien Kidney Research Centers, or the 
Pediatric Nephrology Centers?
    Dr. Gorden. Well, it certainly is a venue for those 
centers. And we welcome and openly encourage people with that 
interest to apply for these centers. So it's a completely open 
field in either of those two areas, either the George O'Brien 
or the pediatric centers.
    The fundamental reason, and so that that venue is open to 
individuals who have an interest in polycystic kidney disease, 
the reason that we have not encouraged yet another set of 
centers is because we believe we have more versatility in 
pursuing this through the research project grant mechanism, 
since we already have these centers which are available to 
individuals. And the important thing is for investigators to 
put together a real consortium that really constitutes a 
center.
    If that isn't possible or isn't necessarily one that is the 
most fruitful approach, it's best done by project grants, which 
we can control in a much more rapid sort of way. And we have 
much more versatility with the project grant mechanism.

                            cooley's anemia

    Mr. Porter. Dr. Gorden, the committee has encouraged for 
some time the development of oral chelator drugs for Cooley's 
anemia patients, to spare them the painful daily 12-hour 
administration of the only currently approved drug. Are you 
close to initiating clinical trials for alternative therapies?
    Dr. Gorden. We have actually had under study several 
compounds, Mr. Porter. As you mentioned, this is a very 
devastating disease, particularly for children and young adults 
who develop this iron overload syndrome, because of the severe 
hemolytic process, that is, the breakdown of blood cells and 
the accumulation of iron.
    We have an excellent treatment that can be given 
parenterally, that is by injection, and it works very well. But 
it's very difficult, and it's very hard to get people to do 
this over a very long period of time. And that's why there's 
been this interest.
    We have tried to get pharmaceutical companies to develop 
these compounds, but without much success. So we've taken it 
upon ourselves, and we've investigated at least three or four 
compounds. Unfortunately, what seems to happen is that, when we 
get a compound that has some reasonable efficacy, we have two 
kinds of problems. One is that the sheer amount of the drug 
that patients have to take to accomplish what we're trying to 
accomplish is large. And it's sometimes more debilitating than 
actually the parenteral injection.
    And the second problem we've had is toxicity. We've been 
unable to develop a compound so far that we really feel is 
safe. It's an area that we're continuing to pursue. We just had 
a group of experts come in and advise us in this area. It's one 
that we're totally open to in terms of pursuing. We truly 
understand the need for it. And we're going to have to either 
continue this, if we can find some other promising compounds to 
pursue, or try to steer the course of research in a little bit 
different direction.
    But it's certainly an area that we will aggressively 
pursue.

                            diabetes regimen

    Mr. Porter. Dr. Gorden, you mentioned your diabetes control 
and complications trial, which indicated that diabetes can be 
managed through a precise program. Have there been any follow-
up studies to determine if the regimen can actually be 
maintained in everyday settings by ordinary families?
    Dr. Gorden. There have been no formal studies, Mr. Porter. 
But one thing that we do have is the population itself, that 
is, the population that participated in the Diabetes Control 
and Complications Trial. When they were involved in the study, 
we had the so-called conventional arm of the study, and we had 
the intensive arm of the study. We were able to maintain the 
level of what we call hemoglobin A1C, which is a chronic 
measure of blood glucose concentration, about in the range of 
about seven for the intensively controlled group, and around 
nine for the conventional group.
    At the end of the study, the patients were basically taken 
care of by their own private doctor. Now, these are people who 
have had a lot of experience in treatment. Now, what's happened 
over the last two years? What's happened over the last two 
years is that both groups have tended to come together. Our 
very latest analysis suggests that the conventional group is no 
longer nine, they're eight, and the intensive group is no 
longer seven, but they're eight.
    And one of the most important things that we found is that 
this beneficial effect that I have told you about in terms of 
protection, let's say, from retinopathy of the eye, is 
remembered. That is, there is a memory for the fact that they 
were in the intensive group. So they continue to do much 
better, continue to maintain the benefit that they received at 
an earlier time.
    Something that we know from other sorts of pharmacologic 
interventions, is that, when you intervene over a period of 
time, that effect will be sustained over a longer period of 
time. We believe that the trend for diabetes control is getting 
better. And we believe we're seeing this in this sort of 
microcosm of patients.
    But we really do not believe that we have in a national 
sense the facilities to maintain this level of control that was 
maintained. This is why it's so important that we try to 
develop alternative treatment strategies. We've got to find 
ways that can make this possible for people in the real world 
and real time. And that's really a goal that we have. And it's 
one that has been rather resistant to our achieving, but we're 
committed to that area, and we plan topursue it vigorously.

                        impact of diabetes trial

    Mr. Porter. I think you just answered this, but let me ask 
it in any case. We've heard the concern voiced that an 
unintended consequence of the control and complications trial 
may be an impression that diabetes is a manageable disease and 
that this may discourage further research. I think you just 
said it will not.
    Dr. Gorden. I'd like to comment on that, if I could, Mr. 
Porter. I think that's a slightly different issue.
    Unfortunately, this really doesn't relate so much to the 
insulin-dependent form of diabetes, but it relates more to the 
non-insulin dependent form of diabetes. There was a kind of 
view that if your blood sugar was just kind of moderately 
elevated and you really didn't have any symptoms----
    Mr. Porter. What would that be?
    Dr. Gorden. Well, let's say 150 to 200. And you had no 
symptoms, because that level of blood sugar elevation, say 
anywhere from 50 to 100 percent elevation, usually does not 
cause symptoms. So everyone felt fine.
    And unfortunately, the community of physicians and so forth 
was somewhat content with that, because no one really 
complained. Well, this is really one of the major points of our 
prevention trial in Type 2 diabetes. Because we clearly know 
now that the complications of diabetes are related to two 
things: the chronicity of blood sugar elevation and the 
intensity. So it is both the magnitude and the intensity. So 
that if you have mild elevation over a very long period of 
time, it clearly is doing you harm.
    So what we're trying to do is to say that we can interdict 
that process while it's still mild and prevent the occurrence 
of actual hyperglycemia for a period of time. We'd like to 
believe we could do it forever. But even if we could do it for 
five to ten years, that would be extremely important in this 
chronicity effect.
    So one would be exposed to hyperglycemia for a shorter 
period of time. And this would create a healthier patient 
population. We can't completely eliminate diabetes, but it 
would create a healthier population of patients with diabetes. 
And this is the goal.
    So we're really focused on two things. One, prevention. And 
treatment of mild diabetes. Because the more severe form, that 
I think is abundantly clear what we have to do about that. 
We've got to focus and get people to understand that we've also 
got to treat the mild form of diabetes as well as the more 
severe form. So I think that's a little bit different twist to 
the question that you asked.
    Mr. Porter. But the question was, is this going to 
discourage research. And I think you said no.
    Dr. Gorden. It absolutely should not. Because the problem 
still remains. In other words, why is this true? We're 
desperate to find alternative approaches to controlling the 
blood sugar.
    For instance, we're looking at inhibitors of so-called 
``advanced glycosylation products.'' We're looking at certain 
kinds of inhibitors of chemicals, enzymes that we believe might 
be related to the complications of diabetes. If we could find 
ways to control this tertiary effect of the elevated blood 
sugar at the cell level, then the need for control would be 
somewhat diminished, if we could add those two things together.
    This would be a tremendously additive effect in trying to 
achieve our goal of less intense effect of the blood sugar and 
less intensity of the elevation of blood sugar. So we're 
working at both fronts to try to achieve that.
    Another example of that kind of thing is the recent 
clinical trial showing that certain types of blood pressure 
controlling agents, so-called ``ACE inhibitors,'' have an 
effect in ameliorating the progression of kidney disease of 
diabetes independent of their blood pressure controlling 
effect. So there's something else that these drugs do, probably 
related to the microvascular circulation of the kidney. It's 
that kind of thing that we're trying to achieve. We can show 
that we can decrease the deterioration of renal function in 
those patients by 50 percent with these drugs.

                                obesity

    Mr. Porter. Last December, your Institute's Task Force on 
the Treatment and Prevention of Obesity published the results 
of its literature review on the effect of prescription weight 
loss drugs. The Task Force concluded that the drugs may help 
patients lose weight and maintain weight loss in the short 
term, but that very little is known about the effects past one 
year. The Task Force did report that most patients regained 
weight when they stopped taking the drugs. Should obesity be 
treated as a chronic disease like diabetes where patients will 
be medicated for their entire lives? And what research is your 
Institute supporting to address some of the questions 
identified in the Task Force's report?
    Dr. Gorden. First of all, I'd like to say that we put 
together this task force of experts on obesity to address this 
very important problem of both the dissemination of information 
and the direction of research. And it's been extremely 
successful.
    The issue of pharmacologic treatment of obesity is a very 
important issue. I think what you've said is essentially what 
we know about it, that is, there are drugs that have been 
approved and can be used, we believe, over a relatively short 
period of time. We're uncertain about the effects of these 
drugs over a very long period of time, in terms of either their 
efficacy or potentially, their toxicity.
    Now, to kind of amplify the point is that here's an area 
that there's been an absolute explosion in the science of 
understanding weight control and the mechanisms of weight 
control. There's been an explosion that has really kind of 
penetrated the entire biomedical research community and had a 
tremendous impact on the biotechnology and pharmaceutical 
industry.
    And we believe that this is going to have tremendous 
ramifications. I mean, just in the last two years, we've had 
more of a molecular understanding of the events involved in 
weight maintenance, weight gain, or weight loss than perhaps 
we've had in the last 2,000 or 3,000 years.
    It's really been dramatic, and it's something we could 
amplify on. But we've talked about this before, the concept of 
this newly discovered hormone, leptin. But it's not just that. 
It's the ramifications that that had on other discoveries, 
which have been so rapid over the last two years, it's been 
incredible.
    Mr. Porter. I have two questions on leptin. We've talked in 
previous years about the complex relationship between the 
hormone leptin and obesity. How do researchers explain the fact 
that despite the evidence implicating leptin and its receptor 
in weight control, mutations of their genes do not seem to be 
at fault in human obesity?
    Dr. Gorden. Well, at the present time, we can't totally 
explain that. There is an attempt to find mutations in human 
obesity. And they of course could occur either in the 
leptinsystem or some other place.
    But we have to sort of fall back on analogies that we 
understand a little bit better, say, non-insulin dependent 
diabetes, where we understand and have studied the relationship 
of insulin to so-called ``insulin resistance'' over the years. 
So that even normal or elevated amounts of insulin are typical 
of non-insulin dependent diabetes, just like normal or elevated 
amounts of leptin are typical of most patients who are obese.
    So the concept of leptin ``resistance'' has grown. And this 
is an area that is being pursued. But what I think is going to 
be important is to understand in a much more complete way the 
connections that this leptin system is involved in. Very 
recently, our Phoenix group that I mentioned earlier, that 
studies the Pima Indians, found that in fact, those individuals 
who were prone to gain weight over a period of, say, two to 
three years, were individuals who had relatively low leptin 
levels.
    So there's a lot we clearly don't understand yet about the 
role of leptin in this sort of biology and the potential role 
of leptin, either as a therapeutic model or something that's 
going to lead us to a more appropriate therapy for this 
condition.
    The answer to your question, should it be treated as a 
chronic condition, absolutely.
    Mr. Porter. And what role might leptin have in controlling 
diabetes?
    Dr. Gorden. Well, that's a very interesting question also. 
We have two different kinds of approaches here. In one 
approach, a recent paper suggests that perhaps leptin could in 
fact increase the resistance of diabetic cells to insulin. But 
that type of study has been conducted largely in isolated cell 
systems, and we don't really understand what that means in the 
whole body context, which may have a completely different 
context.
    Certainly there is a very strong link between non-insulin 
dependent diabetes and obesity. At least 80 percent of patients 
are obese. We know that weight reduction ameliorates the 
hyperglycemia; we know that weight reduction can prevent the 
onset of disease, from a variety of epidemiologic studies, so 
that anything that relates to obesity is going to have clear 
implications in diabetes.
    So here's an area that has really literally just opened up 
for investigators who are interested in obesity and diabetes, 
just in the last two years.
    Mr. Porter. Dr. Gorden, we were hoping that Mr. Bonilla of 
Texas would be able to join us. We had an indication that he 
would be here. And I've kept asking you questions not only 
because I wanted the answers to them, but because I wanted to 
give Mr. Bonilla a chance to arrive. He has not arrived. I have 
a meeting with the Speaker right at this moment.
    So let me end by complimenting you on the fine work you do 
at your Institute. You also are well known for controlling 
administrative costs better than most of your colleagues, and 
we admire that as well. We thank you for your tremendous 
knowledge and ability to speak in such a way that we can 
understand what it is that the answers are meant to convey. 
That has been very, very helpful to all of us, and we very much 
appreciate the wonderful job that you're doing there.
    Thank you so much.
    Dr. Gorden. Thank you very much, Mr. Porter. I appreciate 
it.
    Mr. Porter. The subcommittee will stand in recess until 
1:30.
    [The following questions were submitted to be answered for 
the record.]

[Pages 1214 - 1307--The official Committee record contains additional material here.]




                           W I T N E S S E S

                               __________
                                                                   Page
Adderly, Donna...................................................  2155
Alexander, Duane.................................................  1635
Baldus, A.C......................................................  2001
Baldwin, Wendy...................................................     1
Barros, C.F......................................................  1915
Beldon, Bill...................................................711, 805
Benowitz, S.C....................................................  2249
Berkowitz, S.J...................................................   583
Burgess, E.S.....................................................   495
Bursenos, S.J....................................................  1443
Casady, D.S......................................................  1635
Cassman, Dr. Marvin..............................................  2095
Collins, F.S.....................................................   495
Counts, G.W......................................................   583
Cushing, Mary....................................................  1377
Du Buy, Y.H......................................................  1737
Dufour, Dr. Mary.................................................  1091
Fauci, A.S.......................................................   583
Ficca, S.A.......................................................  2249
Fitzsimmons, W.T.................................................  1809
Fivozinsky, C.L..................................................   419
Fulton, B.E......................................................  1635
Gekas, Hon. George...............................................  2431
Gorden, Phillip..............................................1177, 2431
Gordis, Dr. Enoch................................................  1091
Gottesman, Michael...............................................     1
Grady, Dr. P.A...................................................  1377
Hall, Dr. Z.W....................................................  2001
Haseltine, Dr. F.P...............................................  1635
Hausman, Dr. S.J.................................................  1491
Hodes, R.J.......................................................  1915
Hodgkins, G.E....................................................  2095
Hudson, Kathy....................................................   495
Hyman, S.E.......................................................  1809
Itteilag, Anthony...............................................1, 2249
Jaron, Dr. Dov...................................................  1573
Johnson, Laurie..................................................   711
Jones, D.M.......................................................   983
Jordan, Elke.....................................................   495
Katz, Dr. S.I....................................................  1491
Kerr, W.D........................................................   805
Kerza-Kwiatecki, M.S.............................................  1491
Kirschstein, Dr. R.L..........................1, 1377, 1443, 1915, 2249
Klausner, R.D.................................................199, 2431
Kleinman, D.V....................................................  1737
Kupfer, Carl.....................................................   419
Laurence, L.E....................................................  1177
Leasure, C.E., Jr................................................   711
Lenfant, Dr. Claude...........................................865, 2431
Leshner, A.I.....................................................   983
Levine, S.U......................................................  1309
Lindberg, D.A.B..................................................  1309
Lipman, D.J......................................................  1309
Little, Francine.................................................     1
Long, Stephen....................................................  1091
Luecke, D.H......................................................   805
Maddox, Dr. Y.T..................................................  1635
McGowan, J.J.....................................................   583
McLaughlin, Jack.................................................   419
McManus, Edward..................................................   419
Merritt, Sheila..................................................   865
Miller, Richard..................................................  1443
Millstein, R.A...................................................   983
Mink, Hon. P.T...................................................  2431
Moore, Marshall..................................................   805
Morella, Hon. C.A................................................  2431
Moul, Ellen......................................................  1377
Nakamura, R.K....................................................  1809
Nethercutt, Hon. G.R., Jr........................................  2431
Olden, Kenneth...................................................   711
Paul, W.E....................................................2155, 2431
Penn, Dr. A.S....................................................  2001
Pine, J.R........................................................  1809
Pine, Martha.....................................................  2095
Poppke, D.C......................................................  1309
Rabson, Alan.....................................................   199
Ramm, Dr. L.E....................................................  1573
Richardson, C.M..................................................  1091
Rosenthal, Laura.................................................   983
Ross, K.S........................................................  1915
Roth, Dr. Carl...................................................   865
Schambra, P.E....................................................  1443
Shafer, Dr. W.S..................................................  2095
Sherbert, R.L., Jr...............................................  2001
Slavkin, H.C.....................................................  1737
Smith, K.A.......................................................  1309
Snow, J.B., Jr...................................................   805
Sparks, P.T......................................................   805
Strachan, R.J....................................................  1491
Summers, A.E.....................................................  1573
Taylor, E.S......................................................  1737
Trusty, M.K......................................................  1091
Vaitukaitis, Dr. J.L.............................................  1573
Varmus, Dr. Harold.....1, 199, 419, 495, 583, 711, 805, 865, 983, 1091, 
     1177, 1309, 1491, 1573, 1635, 1737, 1809, 1915, 2001, 2095, 2155, 
                                                             2249, 2431
Vennetti, J.C....................................................   495
Wehling, James...................................................   865
Weiblinger, G.M..................................................  1809
Wertheimer, Wendy................................................  2155
Wetle, Terrie....................................................  1915
Williams, D.P........1, 199, 419, 495, 583, 865, 983, 1091, 1177, 1309, 
     1377, 1443, 1491, 1573, 1635, 1737, 1809, 1915, 2001, 2095, 2155, 
                                                             2249, 2431
Williams, T.D....................................................   583
Wilson, S.H......................................................   711
Zellers, C.R.....................................................  1177






                               I N D E X

                              ----------                              

                 National Institutes of Health Overview

                                                                   Page
Administrative Costs.............................................    53
AIDS/HIV:
    AIDS and Minorities..........................................   111
    AIDS Research................................................    83
    Culminations in HIV Research.................................     3
    HIV Vaccine..................................................    29
    Inspiration in HIV Research..................................     4
Areas of Research Emphasis.......................................    79
Awareness Relating to Biomedical Research........................    67
Biomedical Engineering Research..................................   116
Budget Estimates:
    Budget Estimates.............................................    11
    Budget Estimates, Justification of...........................   148
    Five Year Budget.............................................    91
    FY 1998 Budget Request.......................................    43
    Funding for NIH..............................................    96
    Impact of 7.5 Percent Increase...............................    22
    1st President's Budget Proposal..............................     5
    Professional Judgment Budget.................................    11
Cancer:
    Ovarian Cancer...............................................    33
    Advances in Ovarian Cancer Research..........................    34
Child Abuse and Neglect..........................................   134
Child Development and the Brain..................................    34
Clinical Research:
    Clinical Research at Academic Medical Centers................   143
    Clinical Research Panel....................................129, 144
    Clinical Research Program....................................    80
    Funding for Clinical Research................................    80
    Initiatives for Clinical Research............................   145
    IOM Recommendations................................19, 81, 142, 145
    Peer Review of Clinical Research.............................   145
    Progress in Support for Clinical Research....................    22
    Subscribers Participation in NIH Protocols...................    21
    Third Party Payments, Impact of..............................    35
Cloning:
    Cloning......................................................    13
    Cloning of Humans............................................    26
    Earlier Cloning Experiment...................................    14
    Ethical Implications.........................................    17
    How Genes Turn On and Off....................................    16
    Legislating Cloning..........................................    18
    Medical Uses of Cloning......................................    15
    Scientific Significance of Cloning...........................    15
    Use in Bone Marrow Transplants...............................    16
Comparison of Medicare Costs and Disease Research Costs..........    36
Congressional Earmarks...........................................    85
Consensus Development Panels.....................................    23
Contraceptive and Reproductive Health Training Programs..........   136
Contraceptive Research...........................................    70
Coordination with Other Agencies.................................    82
Culminations of Research.........................................     2
Department of Defense, Collaboration with........................    89
Department of Education, Cooperation with........................   130
Diabetes:
    Commitment to Diabetes Research..............................    30
    Diagnosis and Detection of Diabetes..........................    31
    Increase in Diabetes Research................................   131
    Initiatives for Diabetes Research............................   131
    New Approaches to Pathogenesis...............................    65
    NIH-Wide Diabetes Research Efforts...........................    64
Direct and Indirect Costs........................................    72
Director's Discretionary Fund, FY 96 and 97......................    45
Employment Rates for African-American Males......................   120
Ethical, Legal and Social Implications Working Group.............    94
Ethics Training..................................................    29
Extramural Construction..........................................   107
Extramural Programs..............................................    86
Full Time Equivalents (FTES):
    FTE Detail by Grade Level....................................    59
    FTE Ceiling..................................................    61
    FTE Total by Institute.......................................    48
    FTE Total by Mechanism.......................................    49
Human Embryo Research............................................    92
Grants:
    Administrative Burdens on Grantees...........................    88
    New and Competing Research Project Grants....................   142
    Number of Applications.......................................    51
    Research Project Grants......................................   104
    RPGs as Priority.............................................   113
    Success Rates...............................................12, 110
Imaging Research.................................................    32
Indirect Cost Cap................................................    66
Inspirations of Research.........................................     3
Instrumentation..................................................    61
Intramural Programs..............................................    87
Mammography:
    Mammography..................................................   108
    Mammography Policy...........................................    25
Medicare Spending by Disease, 1995...............................    37
Minorities:
    Inclusion of Minorities in Clinical Research.................   122
    Investment in Minority Research Programs.....................   116
    IOM Study....................................................   103
    Minority Health Standing Advisory Committee..................   102
    Minority International Research Training Program.............   100
    Minority Investigators.......................................   113
    Number of Minority and Women Investigators...................   105
    Pipeline.....................................................   127
    Reseach Centers in Minority Institutions.....................   128
    Research Related to Minorities...............................    95
National Bioethics Advisory Commission...........................    28
National Center on Sleep Disorders Research......................    52
Needle Exchange..................................................    24
Neuroscience.....................................................   126
Obstetrics and Gynecology, Research in.........................135, 138
Office of Research in Minority Health (ORMH):
    Funding for Office...........................................96, 97
    ORMH Co-funding..............................................    99
    Role of the ORMH.............................................   103
Opening Statement................................................     6
Oversight and Administrative Activities..........................     4
Panel on Potential Research on Marijuana.........................    24
Pediatric Research:
    Number of Intramural Pediatricians...........................   138
    Pediatric Research...........................................   137
Permanent Separations Profile....................................   121
Pipeline for Young Investigators.................................    93
Population Research..............................................    70
Prenatal Research................................................    71
Public Education.................................................    50
Pulmonary Hemorrhage Among Cleveland Infants.....................   104
Priority Setting:
    Allocation of Research Dollars...............................    40
    Criteria for Funding Allocations.............................    40
    Establishing Priorities......................................    12
    NIH Priority Setting Process.................................42, 73
    Priority Setting at NCI......................................    76
Reducing Health Care Costs.......................................    41
Research Infrastructure..........................................   114
Research on Learning.............................................   130
Research Management and Support (RMS):
    Cap on Management and Support Costs..........................    94
    One-Percent Evaluation Funding In............................    49
    RMS Funding 1990-1998........................................    50
Research Spending Per Death for Selected Disease.................    67
Research Training................................................    86
Shannon Awards...................................................    61
Small Business Innovation Research Grants........................   115
Spending by Disease..............................................    56
Taps and Assessments:
    One-Percent Evaluation Set-Aside.............................    61
    Taps and Assessments.........................................    63
Toll-Free Numbers................................................    54
Women in Clinical Trials.........................................   141

                       National Cancer Institute

Abortion and Breast Cancer.......................................   255
Access to Care...................................................   236
Advances Against Cancer..........................................   273
Angiogenesis.....................................................   231
Areas Impacting on Cancer........................................   232
ASSIST...........................................................   252
Behavioral Research..............................................   321
Breast Cancer-ABMT...............................................   236
Cancer Genetics..................................................   259
    Cancer Genetics Network......................................   260
    Cancer Genetics and Molecular Biology........................   305
    Genetics Testing.............................................   261
Cancer Survivors...............................................230, 272
    Breast Cancer Survival.......................................   235
    Five-Year Survival Rates.....................................   230
    Office of Cancer Survivorship................................   242
Cancer Vaccines..................................................   263
Cancer Centers Program Review Group..............................   269
Cancer Genome Anatomy Project....................................   269
Cancer Mortality by Race.........................................   317
    Decline in Cancer Mortality..................................   271
Cancer Prevention................................................   203
Clinical Trials................................................204, 278
    African American Women and Clinical Trials...................   299
    Breast Cancer-Molecular Markers..............................   207
    Clinical Trials in FY 1998...................................   286
    Clinical Trial Educational Efforts...........................   267
    Clinical Trial Agreement with The Department of Defense......   265
    Clinical Trial Agreement with The Veteran's Administration...   266
    Dissemination of Clinical Trial Results......................   284
    Women in Clinical Trials.....................................   328
Clinical Treatment...............................................   236
Cloning..........................................................   318
Collaborative Efforts............................................   307
Combination Therapies............................................   308
Comprehensive Cancer Centers.....................................   251
Construction.....................................................   246
Coordination Efforts with DOD..................................237, 238
Coordination of the National Cancer Program......................   251
Detection Technologies For Breast Cancer.........................   225
    Other Detection Technologies For Breast Cancer...............   224
Diet and Cancer................................................258, 311
Dissemination of Cancer Information..............................   319
Environmental Links to Breast Cancer.............................   233
    San Francisco Bay Area.......................................   234
Environmental Justice Research Activities........................   313
    Environmental Justice Collaborative Activities...............   315
Estrogen and Breast Cancer.......................................   325
``Five A Day'' Program...........................................   249
FTE Decrease.....................................................   245
Funding Allocation Decisions.....................................   226
Funding for NIH..................................................   228
Gynecologic Cancer Research......................................   328
Human Papillamovirus.............................................   241
Imaging..........................................................   263
    Imaging Technologies.........................................   297
Infectious Causes of Cancer......................................   294
Institute of Medicine Cancer Study...............................   317
Intramural Program at Frederick..................................   244
Justification of The Budget Estimates............................   331
Mammography....................................................221, 295
    Mammography Imaging..........................................   265
    Screening....................................................   223
Measure of Successes.............................................   268
Minorities and Cancer............................................   229
    Advances in Minority Health..................................   227
    Cancer in Minority Population................................   312
    Excess Cancer Death Rate.....................................   271
    Office of Special Populations................................   229
Molecular Characteristics of Cancer..............................   310
NCAB Subcommittee................................................   224
NCI Panels and Advisory Boards...................................   329
New Cancer Drugs.................................................   268
NIH Reauthorization..............................................   231
Opening Statement................................................   199
Ovarian Cancer.................................................240, 327
Professional Judgment Budget.....................................   238
    Opportunities................................................   239
Prostate Cancer................................................236, 278
    Prostate Cancer Initiatives..................................   300
    Prostate Cancer Treatment and Early Detection................   302
    African Americans and Prostate Cancer........................   304
Radiation Therapy................................................   246
Role of Stress in Cancer.........................................   277
San Antonio Cancer Institute.....................................   251
Science Information System.......................................   323
    Implementation of The Science Information System.............   324
Statement of The Director........................................   212
Tobacco Use and Children.........................................   247
Biology of the Brain.............................................   431
Cataract Surgery.................................................   437
Contact Lenses...................................................   437
FDA Approval.....................................................   429
Fetal Tissue.....................................................   434
Glaucoma Gene..................................................427, 429
Introduction of Witnesses........................................   419
Long-Range Research Plan.........................................   436
Macular Degeneration...........................................429, 434
Marijuana use for Glaucoma.......................................   434
Neuron Survival..................................................   428
Nutritional Supplements for Retinitis Pigmentosa.................   436
Opening Statement................................................   419
Private Foundations..............................................   435
Professional Judgement Budget....................................   426
Radial Keratotomy Versus Laser Technique.........................   428
Retinopathy of Prematurity.......................................   430
Statement of Director............................................   422
Transplanted Retinal Cells.......................................   433
Vision Conditions Needing More Research..........................   437
Budget Increase..................................................   506
Bureaucratic.....................................................   531
Center for Inherited Disease Research.....................497, 529, 543
Cloning:
    Cloning and Ethics...........................................   547
    Cloning Humans...............................................   515
    International Cooperation....................................   511
    Potential for Hoax...........................................   514
    Scientific Opportunities...................................507, 536
    Why a Sheep..................................................   515
Designer Drug Strategies.........................................   513
Diversity........................................................   544
Ethical, Legal, and Social Implications........................499, 535
Finding the Gene...............................................497, 505
Finishing Faster:
    Additional Funds Needed......................................   525
    Finding A Cure...............................................   507
Future Health Care Delivery......................................   512
Genetic Discrimination and Privacy.............................519, 529
Genetic Testing:
    Breast Cancer................................................   508
    Counseling and Control.......................................   510
    Guidance.....................................................   526
Health Insurance Portability and Accountability Act of 1996......   537
Howard University Center.........................................   543
Human Embryo Research............................................   516
Human Genome Project:
    Creation of..................................................   541
    Mapping Progress.............................................   534
Intramural Program...............................................   540
Minorities and Women.............................................   533
Newest Research Institute.................................495, 523, 532
Opening Statement................................................   501
Oral Remarks.....................................................   495
Ovarian, Breast, and Cervical Cancer.............................   546
Prostate Cancer..................................................   496
Protection of Patient Medical Information........................   538
Sequencing:
    Complete DNA Sequence........................................   498
    Beyond the First Sequence....................................   498
    Large Scale Sequencing.......................................   528

         National Institute of Allergy and Infectious Diseases

Introduction of Witnesses........................................   583
Opening Statement................................................   583
AIDS:
    AZT...................................................586, 588, 618
    Behavioral Research..........................................   614
    Clinical Trials............................................602, 606
    Global Threat................................................   612
    Minorities...................................................   632
    Office of AIDS Research......................................   611
    Pediatric....................................................   657
    Protease Inhibitors..............................601, 605, 614, 623
    Therapy....................................................605, 608
    Treatment Strategies..................................586, 605, 612
    Vaccines.........................................593, 601, 609, 633
    Women........................................................   654
Asthma...........................................................   636
Basic Research............................................594, 599, 601
Benefits of AIDS Research........................................   654
Budget Estimates, Justification of...............................   661
Cholera..........................................................   619
Chronic Fatigue Syndrome.............................603, 623, 631, 641
Clinical Trials..................................................   649
Cloning..........................................................   640
Diarrheal Diseases.............................................602, 630
Drug Issues......................................................   617
Emerging Infectious Diseases.....................................   647
Grant Success Rate...............................................   648
Hansen's Disease.................................................   620
Hemophilia.......................................................   617
Hepatitis A......................................................   626
Lyme Disease.....................................................   603
Malaria........................................................618, 633
Media Involvement................................................   616
Multiple Sclerosis...............................................   603
Patient Registries...............................................   639
Primary Immune Deficiency........................................   622
Priority Setting.................................................   628
Research Accomplishments.........................................   643
Rotavirus........................................................   602
Sexually Transmitted Diseases........................602, 628, 652, 658
Topical Microbicides.............................................   655
Tuberculosis.........................................619, 626, 630, 640
Vaccines.............................................596, 597, 603, 642

          National Institute of Environmental Health Sciences

Air Quality......................................................   763
    Air Quality Standards.................................730, 736, 745
Artificial Sweeteners............................................   725
Asthma.........................................................728, 763
Autism...........................................................   731
Beryllium........................................................   770
Breast Cancer....................................................   766
Budget...........................................................   747
Budget Formulation...............................................   762
Cancer...........................................................   764
Clinical Program...............................................748, 750
Clinical Research................................................   754
Clinical Trials..................................................   762
Cloning..........................................................   756
Collaboration with Industry......................................   723
Collaborations...................................................   757
Congressional Visit..............................................   719
Contract Mechanism...............................................   727
Endocrine Disruptors...........................................719, 723
Environmental Genome Project.....................................   720
Environmental Health Hazards.....................................   756
Environmental Justice..........................................752, 767
EPA..............................................................   749
Funding Increase.................................................   717
Grant Funding Mechanisms, Major..................................   758
Gulf War Syndrome................................................   724
Justification of the Budget Estimates............................   772
Knowledge ``Bottleneck''.........................................   754
Link Between Science and Public Health...........................   721
Minorities, Improving Health of..................................   752
Mixtures.........................................................   718
Nanofabrication..................................................   726
National Toxicology Program....................................734, 768
New Testing Methodologies......................................720, 734
Opening Statement................................................   711
Particulate Matter...............................................   736
Pulmonary Hemorrhage Among Cleveland Infants, Epidemic of........   764
Retesting of Chemicals...........................................   728
Secondhand Smoke.................................................   746
Smoking..........................................................   730
Statement of the Director........................................   713
Success Rate.....................................................   759
Superfund......................................................734, 750
Toxicity Test Systems............................................   747
Vitamin D and Prostate Cancer....................................   718

    National Institute on Deafness and Other Communication Disorders

Autism Research..................................................   811
Balance Disorders in Elderly.....................................   816
Clinical Trials................................................818, 831
Cloning Technology...............................................   828
Collaborative Effort in Hearing Aid Technology...................   822
Eating Behavior and Nutrition....................................   815
Government Performance and Results Act...........................   818
Hair Cell Regeneration...........................................   811
Hearing Aid Research.............................................   827
Hearing Impairment:
    Consensus Conference Findings................................   813
    Incidence....................................................   824
Introduction of Witnesses........................................   805
Investigator-Initiated Research Applications.....................   832
Justification of the Budget Estimates............................   834
Loss of Voice....................................................   816
Multi Cultural Language Assessment...............................   830
Opening Statement................................................   805
Otitis Media.....................................................   823
Partnership Program..............................................   832
Public Information Activities....................................   821
Presbycusis......................................................   826
Research Funding.................................................   821
Sense of Smell...................................................   816
Sensory Regeneration.............................................   815
Specific Language Impairment.....................................   820
Statement of Director............................................   807
Stochastic Resonance.............................................   812
Vaccine for Otitis Media.......................................819, 826

               National Heart, Lung, and Blood Institute

Allocating Funds.................................................   888
Asthma.........................................................876, 928
Benefits from Research...........................................   890
Cardiovascular Disease in Mississippi..........................887, 926
Cell Death.......................................................   875
Child and Adolescent Trial for Cardiovascular Health (CATCH).....   916
Chronic Obstructive Pulmonary Disease..........................921, 922
Clinical Trials and Research..............................925, 939, 942
Comprehensive Heart, Lung, and Blood Center......................   911
Cooley's Anemia..................................................   882
Cost Recovery....................................................   902
Diet and Blood Pressure..........................................   936
Education Programs........................................893, 900, 932
Folic Acid.......................................................   918
Gender Differences...............................................   930
Gene Therapy..............................................875, 878, 914
Government Performance and Results Act...........................   895
Heart Disease Death Rate.........................................   915
Heart Diseases...................884, 892, 902, 912, 926, 927, 932, 938
Human Cloning Research.........................................892, 941
Hypertension and Children........................................   935
Hypertrophic Cardiomyopathy......................................   905
Imaging Technology.............................................866, 873
Infants and Congenital Heart Disease.............................   934
In Utero Bone Marrow Transplantation.............................   874
Knowledge ``Bottleneck''.........................................   940
Lung and Blood Diseases..............................868, 880, 887, 896
Lung Volume Reduction Surgery..................................895, 924
Major Opportunities..............................................   927
Minority Health............................879, 881, 925, 931, 933, 938
Organ Damage.....................................................   935
Primary Pulmonary Hypertension.................................906, 909
Salt Intake......................................................   901
Selected Areas of Research.......................................   898
Select Pay.......................................................   903
Service Centers..................................................   894
Sleep Disorders Research.........876, 893, 901, 907, 908, 922, 923, 936
Smoking........................................................884, 927
Specialized Centers of Research..................................   899
Statement of the Director........................................   870
Stroke Research................................................877, 919
Women's Health............................................913, 920, 944

                    National Institute on Drug Abuse

AIDS and Drug Abuse..............................................  1002
AIDS/HIV and Drug Abuse..........................................  1017
Alaska Needle Exchange...........................................   995
Alcohol and Substance Abuse......................................   993
Biology of the Brain.............................................  1028
Brain Development in Adolescent Drug Users.......................  1050
Brain Imaging....................................................  1032
Bupropion........................................................  1006
Clinical Research................................................  1038
Clinical Trials..................................................  1041
Cloning..........................................................  1040
Cocaine Craving..................................................  1009
Cocaine Medication...............................................   999
Cocaine Medication Development...............................1005, 1006
Collaborative Effort.............................................  1027
Comparing United States Drug Abuse...............................  1003
Cost to the Nation...............................................  1029
Craving..........................................................  1012
Demographics of Addicts..........................................  1003
Disease Specific Budgets.........................................   996
Drug Abuse Budget Increase.......................................   994
Drug Abuse Costs.................................................  1009
Drug Intoxication................................................  1030
Effect of Welfare Reform on Addicts..............................  1052
Effective Drug Treatments........................................  1009
Effectiveness of Prevention Programs.............................  1007
Essense of Addiction.............................................  1001
Extent of the Problem............................................  1020
Genetic and Environmental Influences.............................  1034
Impact of Drug Abuse.............................................  1030
Improving the Health of Minorities...............................  1037
Information Dissemination....................................1007, 1048
Introduction of Witnesses........................................   983
Justification of the Budget Estimates............................  1054
Knowledge ``Bottleneck''.........................................  1039
Marijuana for Medical Purposes...................................  1026
Medical Marijuana Concerns.......................................  1008
Medical Use of Marijuana.........................................   997
Methadone Treatment..............................................   998
Minority and Women's Health......................................  1044
Minority Related Research........................................  1004
National Institutes of Health Disease-Specific Budgets...........   996
Needle Exchange...............................................997, 1023
Needle Exchange and AIDS.........................................  1008
Needle Exchange Programs.........................................  1004
Nicotine Addiction............................................994, 1000
NIDA-SAMHSA Coordination.........................................  1053
Opening Statement................................................   983
Our Nation's Youth...............................................  1047
Outreach.........................................................  1037
Prenatal Drug Use Study..........................................  1007
Prevention Increase..............................................  1008
Prevention Principles Book.......................................  1006
Prevention Program...............................................  1005
Prevention Programs for Elementary and Secondary School Students.  1016
Prevention Research..............................................  1012
Progress.........................................................  1031
Relationship Between Marijuana and Abrupt Termination of 
  Pregnancy......................................................  1011
Relationship with ONDCP..........................................   992
Research.........................................................  1012
School Based Drug Prevention.....................................  1014
Search for a Cure................................................  1046
Statement of the Director........................................   988
Successor Drugs of Abuse.........................................   999
Tobacco..........................................................  1014
Vaccine Development..............................................   992

           National Institute on Alcohol Abuse and Alcoholism

Adolescent Consumption, Trends of................................  1101
Alcoholics Anonymous, Evaluations of.............................  1103
Animal Models....................................................  1092
Brain Function in Adolescents....................................  1140
Chromosomes Associated with Alcoholism...........................  1123
Clinical Research................................................  1136
Clinical Trials..................................................  1139
Cloning..........................................................  1138
Comparing Drug and Alcohol Use and Abuse.........................  1108
Consumption......................................................  1109
Coordination.....................................................  1122
Coordination of Research Findings................................  1142
Cure for Alcoholism..............................................  1105
Dissemination of Research Findings...............................  1131
Effects of Alcohol on Development................................  1110
Estrogen, Effect of Alcohol on...................................  1112
Extent of the Problem............................................  1124
Fetal Alcohol Syndrome, Correlation of Heavy Drinking to.........  1111
Fetal Alcohol Syndrome...........................................  1125
Fetal Alcohol Syndrome and Early Childhood Development...........  1143
Genetic Testing..................................................  1107
Genetics Research, Practical Applications of.....................  1107
Incidence by Gender..............................................  1121
Institute of Medicine Assessment.................................  1132
Justification................................................1145, 1176
Knowledge of ``Bottlenecks''.....................................  1137
Liver Transplantation for Alcoholic Liver Disease................  1113
Major Research Opportunities.....................................  1125
Medications for Alcohol Treatment................................  1104
Medications, Promising...........................................  1118
Minorities, Improving the Health of..............................  1135
Moderate Drinking................................................  1117
Naltrexone Research..............................................  1133
New Opportunities for Developing New Drugs.......................  1119
Opening Statement................................................  1091
Pregnancy........................................................  1128
Prevention.......................................................  1094
Prevention Research versus Behavioral Research...................  1121
Project Match, Rigorous Design and Findings of...................  1101
Project Northland: Positive Outcome and Lower Drug Use...........  1121
Research Advances, Application of................................  1093
Research Dissemination...........................................  1095
Safe and Drug Free Schools.......................................  1115
Serotonin........................................................  1112
Significant Research Opportunities...............................  1125
Statement of the Director........................................  1096
Tobacco and Alcohol Use..........................................  1134
Treatment Research...............................................  1094
Vulnerability to Alcoholism......................................  1091
Welfare Reform...................................................  1141
Witnesses, Introduction of.......................................  1091

    National Institute of Diabetes and Digestive and Kidney Diseases

Administrative Issues............................................  1218
Artificial Pancreas..............................................  1194
Budget Estimates, Justification of...............................  1184
Chromium Diabetes Study..........................................  1236
Clinical Research................................................  1251
Clinical Trials..................................................  1254
Clinical Trials--Participation...................................  1249
Cloning..........................................................  1253
Collaborative Efforts........................................1225, 1246
Cooley's Anemia..................................................  1209
Costs of Treating Diabetes.......................................  1194
Crohn's Disease..................................................  1257
Diabetes Education Program.......................................  1191
Diabetes Education and Research..................................  1224
Diabetes Emphasis................................................  1184
Diabetes Gene....................................................  1243
Diabetes in African Americans....................................  1256
Diabetes in Minorities...........................................  1244
Diabetes Initiative..............................................  1240
Diabetes Prevention..............................................  1237
Diabetes Prevention Trials.......................................  1225
Diabetes Regimen.............................................1209, 1219
Diabetes Research............................................1228, 1231
Digestive Diseases...............................................  1205
Disease Funding..................................................  1214
Drugs That Work Selectively......................................  1204
Effects of Alcohol...............................................  1201
End-Stage Renal Disease..........................................  1241
Funding for Diabetes Research..........................1189, 1217, 1223
Genetics of Diabetes.............................................  1191
Helicobacter Pylori..............................................  1249
H. Pylori Applications...........................................  1202
Health Status of Women and Minorities............................  1245
Hepatitis........................................................  1207
Hepatitis C......................................................  1214
Identifying Areas of Research Emphasis...........................  1184
Immune Modulation in Diabetes....................................  1185
Impact of Diabetes Trial.........................................  1210
Improving the Health of Minorities...............................  1251
Intramural Decision-Making.......................................  1196
Intramural Research..............................................  1195
Introduction of Witnesses........................................  1177
Justification of the Budget Estimates............................  1258
Knowledge ``Bottleneck''.........................................  1252
Liver Disease in Children........................................  1221
Liver Disease Information........................................  1219
Locating Diabetes Information....................................  1193
New Methods for Treating Diabetes................................  1237
Newly Diagnosed Diabetics/Early Intervention.....................  1227
Nutrition........................................................  1200
Nutrition and Diabetes...........................................  1255
Obesity..........................................1211, 1222, 1241, 1244
Opening Statement................................................  1177
Organ Donations..................................................  1250
Outside Input for Diabetes Research..............................  1226
Peer Review......................................................  1230
Polycystic Kidney Disease..............................1208, 1217, 1255
Prevalence of Diabetes...........................................  1188
Professional Judgment Budget.....................................  1189
Prostate Cancer..................................................  1247
Prostatitis......................................................  1206
Public Education Activities......................................  1216
Public/Private Research Partnerships.............................  1255
Research Centers.................................................  1215
Restoring Insulin Production.....................................  1187
Review Process for Clinical Studies..............................  1226
Risk for Diabetes................................................  1239
Small Business Research..........................................  1197
Special Research Areas in Diabetes...............................  1192
Statement of the Director........................................  1180
Stress in Diabetes...............................................  1185
Treating and Preventing Diabetes.................................  1223
Ulcer Diagnosis and Treatment....................................  1203
Ulcers.......................................................1199, 1228
Upcoming Diabetes Conference.....................................  1192
Urology......................................................1206, 1218
Women's Health...................................................  1193

                      National Library of Medicine

Bioinformatics...................................................  1325
Electronic Patient Records.......................................  1338
Genetic Databases............................................1336, 1346
Gpra Standards...................................................  1341
High Performance Computing...................................1337, 1347
Human Genome Map.............................................1316, 1324
Iaims Program....................................................  1337
Internet.........................................1312, 1326, 1331, 1339
Justification of The Budget Estimates............................  1355
National Information Infrastructure..............................  1309
Next Generation Internet Initiative..........................1326, 1352
Opening Statement................................................  1309
Outreach.....................................................1324, 1330
Personal Services Contracts......................................  1337
Project Phoenix..................................................  1342
Pubmed.......................................................1339, 1348
Statement of the Director........................................  1319
Telemedicine.........................1314, 1327, 1328, 1334, 1343, 1351
Toxicology Center................................................  1337
Underserved Populations..........................................  1345
User Fees........................................................  1349
Video Tapes......................................................  1349
Visible Humans...................................................  1310
World Wide Web...............................................1333, 1343

                 National Institute of Nursing Research

Aging............................................................  1402
Alzheimer's Disease..............................................  1400
Breast Cancer....................................................  1399
Breast Self-Exams................................................  1389
Cardiovascular Disease...........................................  1378
Cardiovascular Disease in Children...............................  1396
Chronic Illness..................................................  1395
Clinical Research Conference.....................................  1385
Collaborative Efforts............................................  1401
Communication with Health Care Providers.........................  1384
Counseling for Genetic Screening.................................  1389
Cultural Diversity...............................................  1378
Currency with Research...........................................  1386
End of Life......................................................  1379
End of Life Care.................................................  1397
Future Research Emphases.........................................  1379
FY98 Budget Request..........................................1379, 1413
Infant Colic.....................................................  1396
Irritable Bowel Syndrome.........................................  1378
Justification of the Budget Estimates............................  1384
Minority and Women's Health......................................  1406
Minority Researchers.............................................  1403
Nurse Education Act--FY 1988 Budget..............................  1393
Nursing and Oncology.............................................  1410
Nursing Publications.............................................  1385
Opening Statement................................................  1377
Opportunities for Ethnic Nurses..................................  1392
Outreach and Information Dissemination...........................  1405
Pain Research................................................1377, 1399
Professional Judgment Budget.....................................  1384
Provider Care....................................................  1398
Quality of Care..................................................  1393
Quality of Life..................................................  1394
Research Training Issues.........................................  1387
Rural and Ethnic Populations.....................................  1391
Sister to Sister Study...........................................  1405
Stroke...........................................................  1406
Targeted Research................................................  1404
Transplantation..................................................  1379
Traumatic Brain Injury........................................1386, 397
Women's Health...................................................  1411
Women's Health Issues............................................  1388

                      Fogarty International Center

Biodiversity Program.............................................  1455
Budget Increase..............................................1460, 1461
Emerging Infectious Diseases.................................1463, 1464
External Panel Review............................................  1452
Fellowship Programs..........................................1450, 1451
Former Soviet Union--State of Science............................  1454
Human Frontier Science Program...................................  1453
International Agreements.........................................  1460
International Activities Expenditures........................1458, 1459
Justification of Budget Estimates.............................1466-1489
Minority International Research Training Program.............1462, 1463
Opening Statement................................................  1443
Other Countries Leading in Biomedical Research...................  1450
Vitamin A Supplementation....................................1464, 1465

 National Institute of Arthritis and Musculoskeletal and Skin Diseases

Antibiotic Treatment.............................................  1507
AIDS Research....................................................  1529
Arthritis Treatment..............................................  1522
Breast Cancer and Osteoporosis...................................  1535
Breast Implants and Autoimmune Diseases..........................  1512
Budget Estimates, Justification of...............................  1537
Budget Request, FY 1998..........................................  1494
Cartilage Repair.................................................  1512
Central Nervous System Lupus.....................................  1514
Clinical Research................................................  1530
Clinical Trials..................................................  1533
Collaborative Research...........................................  1515
Depression and Osteoporosis......................................  1513
Epidemiological Data Concerning Repetitive Motions Injuries......  1520
Ergonomics...................................................1500, 1502
Fibrodysplasia Ossificians Progressiva...........................  1514
Funding for Disease Areas........................................  1517
Gender and Autommunity...........................................  1511
Gulf War Syndrome................................................  1513
Human Cloning....................................1502, 1503, 1505, 1532
Health Status....................................................  1528
Low Back Pain....................................................  1518
Minority Health Research.........................................  1530
Musculoskeletal Disorder.....................................1500, 1518
Osteoarthritis...................................................  1526
Osteoporosis...........................................1493, 1509, 1510
Psoriasis........................................................  1535
Professional Judgment Budget.....................................  1507
Repetitive Motion Injury.....................................1499, 1525
Research Centers.................................................  1517
Research Opportunities...........................................  1522
Research Challenges..............................................  1532
Rheumatoid Arthritis.............................................  1493
Sexualy Transmitted Diseases.....................................  1536
Skin Cancer..................................................1493, 1524
Statement of the Director....................................1491, 1495
Stress and Arthritis.............................................  1511
Success Rate.....................................................  1536
Systemic Lupus Erythematosus.................................1493, 1528
Total Joint Replacement..........................................  1492
Trauma Injuries..................................................  1521

                 National Center for Research Resources

National Center for Research Resources.......................1573, 1604
Broader Participation............................................  1602
Clinical Research................................................  1591
Chimpanzees in Research..........................................  1579
Chimpanzee Retirement........................................1580, 1581
Coordination of Imaging Activities...............................  1586
Education........................................................  1597
Euthanasia of Research Animals...................................  1583
Extramural Construction..........................................  1600
Extramural Facilities Construction...............1585, 1587, 1588, 1592
Extramural Programs..............................................  1596
Faculty Investigators............................................  1598
Funding for Selected Programs....................................  1588
General Clinical Research Centers................................  1583
Interest in Biomedical Research..................................  1590
Introduction of Witnesses........................................  1573
Minority and Women's Health......................................  1600
Minority Research Investigators..................................  1597
NCRR Appropriations..............................................  1595
NCRR Strategic Plan..............................................  1582
Near Infrared (University of Kentucky)...........................  1590
Office of Research on Minority Health............................  1597
Opening Statement............................................1573, 1575
Pipeline.........................................................  1596
RCMI Clinical Initiative.........................................  1601
RCMI Cofunding...................................................  1600
Regional Primate Research Centers............................1586, 1587
Research Centers in Minority Institutions........................  1592
Research Infrastructure in Minority Institutions.................  1595
Review Committees................................................  1598
Shared Instrumentation Grants....................................  1588
Use of Animals in Research.......................................  1579
Virtual Laboratories.............................................  1585

        National Institute of Child Health and Human Development

AIDS.............................................................  1681
Alcohol and Drug Addiction.......................................  1673
Asthma...........................................................  1649
Autism...........................................................  1643
Autism Centers...................................................  1644
Autism Research Investigators....................................  1644
Child Day Care...................................................  1674
Childhood Nutrition..............................................  1667
Children with Learning Disabilities..............................  1660
Children with Reading Disabilities...............................  1655
Clinical and Basic Research......................................  1689
Clinical Research................................................  1665
Clinical trials..................................................  1691
Cloning..........................................................  1691
Diabetes Research................................................  1679
Drug Dosages for Children & Pediatric Pharmacology Res. Units....  1653
Drug Use before Pregnancy........................................  1657
Early Child Care.................................................  1646
Funding--Disease Areas...........................................  1671
Grant Funding....................................................  1666
Health Status of Minority Children...............................  1684
Infant Mortality.................................................  1676
Infertility Research.............................................  1656
Infertility......................................................  1673
Intervention Programs............................................  1660
Intramural Clinical Research.....................................  1669
Justification....................................................  1693
Learning Disabilities............................................  1688
Learning Disabled Children.......................................  1644
Learning to Read.............................................1648, 1654
Maternal Mortality...............................................  1656
Middle School Children...........................................  1652
Minority Representation in Basic Research and Training...........  1689
National Center for Medical Rehabilitation Research..............  1672
Obesity Research.................................................  1680
Opening Statement................................................  1635
Perinatology Research--District of Columbia......................  1665
Phonics Based Reading System.....................................  1659
Phonics Based System.............................................  1661
Phonics..........................................................  1663
Premature Labor and Delivery.....................................  1646
Prevention Problem Behavior......................................  1651
Protection from Asthma...........................................  1650
Pulmonary Hemorrhage in Infants..................................  1687
Research Bottlenecks.............................................  1690
Research Centers.................................................  1670
Research on Fatherhood...........................................  1663
Research Opportunities...........................................  1685
SIDS Back to Sleep Campaign......................................  1645
SIDS.........................................................1670, 1688
Spinal Cord Injury...............................................  1668
Strengthening Families...........................................  1670
Teenage Drug Use and Pregnancy...................................  1658
Vaccine Development..............................................  1666
Web Page.........................................................  1649

                 National Institute of Dental Research

50th Anniversary.................................................  1772
AIDS/HIV.........................................................  1775
Biomimetics......................................................  1749
Bone Research................................................1762, 1780
Cleft Palate.....................................................  1755
Clinical Trials..................................................  1768
Clinical Research................................................  1777
Cloning..........................................................  1778
Congressional Justification......................................  1782
Dental Amalgams..................................................  1748
Dentist Scientist Program........................................  1756
Diabetes, Oral Complications of..................................  1750
Flouridation.................................................1749, 1754
Future Expectations..............................................  1750
Health Status....................................................  1767
Immune Systems...................................................  1770
Introduction of Witneses.........................................  1737
Knowledge ``Bottleneck''.........................................  1771
Medicare Coverage for Dental Care................................  1755
Minorities, Improving the Health of..............................  1776
Minority Groups, Reaching Ethnic and.............................  1762
NIDR Strategic Plan..............................................  1759
Opening Statement................................................  1737
Oral Cancer............................................1757, 1764, 1769
Osteoporosis and Oral Bone Loss..................................  1751
Pain Research................................................1752, 1780
Priority Setting.................................................  1760
Public Education.............................................1774, 1780
Research Centers.............................................1759, 1765
TMD..........................................................1750, 1753

                  National Institute of Mental Health

Basic Neuroscience...............................................  1852
Brain as the Touchstone of NIMH Research......................1828-1829
Brain Development and Mental Illness..........................1840-1842
Children...........................................1854-1856, 1866-1867
    Prevention of Childhood Mental Illness....................1823-1824
    Proceedings of Workshop (Inclusion of Children in Clinical 
      Research)...............................................1837-1839
    Research Needed on Childhood Disorders....................1829-1830
    Treatment of Mental Illness in Children...................1834-1840
Circadian Rhythms and Mental Illness..........................1843-1844
Clinical and Services Research...................................  1852
Eating Disorders.............................1844-1845, 1849-1850, 1856
Funding Amounts FY 1996-FY 1998..................................  1846
Gene Therapy..................................................1868-1869
Global Burden of Disease......................................1818-1819
    Table 1......................................................  1811
Inclusion of Women and Minorities.............................1865-1866
Initiative to Track Enrollment of Women and Minorities...........  1827
Justification of Budget Estimation............................1870-1913
Managed Care..................................................1857-1858
Mental Illness in the U.S.....................................1859-1862
Mental-Physical Relationship..................................1867-1868
Minority Employment..............................................  1826
Minority Investigators and Research Subjects..................1825-1827
Needle Exchange Programs......................................1821-1822
New Drugs for Schizophrenia...................................1831-1832
Nutritional Factors...........................................1850-1851
Opening Statement of Director.................................1809-1817
Prevention of Childhood Mental Illness........................1823-1824
Proceedings of Workshop (Inclusion of Children in Clinical 
  Research)...................................................1837-1839
Regulation of Emotion............................................  1853
Relationship of Mental Illness to Other Physical Illnesses....1842-1843
Research Needed on Childhood Disorders........................1829-1830
Schizophrenia....................................................  1859
Setaside for Mental Health Services Research.....................  1821
Sexual Abstinence in AIDS Prevention.............................  1823
Social Work Research.............................................  1830
Suicide and Suicide Prevention................................1862-1865
Training.........................................................  1858
Training of Minority Researchers.................................  1831
Translation of Research into Treatment........................1832-1834
Treatment of Mental Illness in Children.......................1834-1840
UNOCCAP (Use, Needs, Outcomes,and Costs for Child and Adolescent 
  Populations)................................................1819-1820
Victims of Torture............................................1846-1849
Vulnerability....................................................  1854
World-wide Burden of Disease (Table 1)...........................  1811
World-wide Burden of Depression...............................1824-1825

                      National Institute on Aging

Aging--The Exercise and Nutrition Linkage........................  1955
AIDS.............................................................  1963
Alzheimer's Disease and Ibuprofen................................  1941
Alzheimer's Disease..................1915, 1934, 1935, 1948, 1954, 1960
Alzheimer's Disease Genetic Discoveries..........................  1917
Biological Processes.............................................  1958
Biology of Aging.................................................  1920
Caloric Restriction..............................................  1949
Collaborative Activities.........................................  1959
Demographic Research.............................................  1934
Demography of Aging..............................................  1921
Disability Research..........................................1933, 1956
Embryo Research..................................................  1936
Falls in the Elderly.............................................  1939
Genetic Research.................................................  1943
Health Care Savings..............................................  1937
Health Status and Clinical Trial Participation...................  1861
Hypertension.....................................................  1952
Immune System....................................................  1963
Long Term Care...............................................1943, 1965
Managed Care.....................................................  1955
Menopause........................................................  1964
Number of Chronically Disabled Americans Age 65 and Over.........  1924
Nursing Homes--Individualized Care...............................  1950
Opening Statement............................................1915, 1926
Osteoporosis.....................................................  1937
Predictive Testing...............................................  1944
Projected Population Age 100 Years and Over......................  1931
Prolonging Independence--Delaying Disability.....................  1956
Prostrate Cancer.................................................  1940
Protective and Risk Factors for Alzheimer's Disease..............  1919
Quality of Life..................................................  1936
Research Centers.................................................  1946
U.S. Life Expectancy at Age 85, 1900-1995........................  1932
Unraveling Longevity.............................................  1963
World Population by Age..........................................  1922

        National Institute of Neurological Disorders and Stroke

Accident Prevention..............................................  2048
Alzheimer's Disease..............................................  2039
Amyotrophic Lateral Sclerosis....................................  2022
Brain Diseases in Children.......................................  2039
Childhood Diseases...............................................  2035
Clinical Research................................................  2041
Clinical Trials..................................................  2044
Cloning..........................................................  2043
Congressional Justification......................................  2051
Diseases of Aging................................................  2010
Epilepsy Research............................................2033, 2040
Estrogen and Stroke..............................................  2020
Future of Brain Research.........................................  2011
Human Embryo Research............................................  2023
Introduction of Witnesses........................................  2001
Knowledge Bottleneck.............................................  2042
Mad Cow Disease and Prion Hypothesis.............................  2021
Minority Research Investigators..................................  2037
Multiple Sclerosis...............................................  2034
Neurodegenerative Disease Initiative.........................2018, 2019
New Treatments and Discoveries...................................  2038
Nicotine, Possible Therapeutic Effects of........................  2020
NINDS Budget Increases...........................................  2012
Opening Statement................................................  2001
Parkinson's Disease..........................................2016, 2028
Prion Hypothesis and Mad Cow Disease.............................  2021
Research Centers Grants, NINDS...................................  2026
Specific Disease Funding.........................................  2026
Spinal Cord Injury Research......................2012, 2016, 2024, 2049
Statement of Director............................................  2005
Stroke Research......................2010, 2020, 2031, 2036, 2047, 2049
Targeted Research................................................  2018

             National Institute of General Medical Sciences

Biology of the Brain Initiative..................................  2121
Budget Policy....................................................  2142
Budget Tables....................................................  2144
Cell Biology and Biophysics......................................  2130
Compliance with NRSA Payback Requirement.........................  2112
Employment Prospects for Research Trainees.......................  2110
Evaluation of National Research Service Award Training...........  2112
Gender Differences in Response to Trauma.........................  2115
Genetics and Developmental Biology...............................  2133
Goals of the Director............................................  2108
Goals to be Accomplished and Priority-Setting Process............  2140
High Risk Research...............................................  2109
Inclusion of Underrepresented Minorities.........................  2118
Innovations in Management and Administration.....................  2141
Interim Funding..................................................  2108
Introduction.....................................................  2123
Justification of Budget Estimates................................  2124
MARC Program.................................................2122, 2138
MBRS and HBCU Participation......................................  2120
MBRS Program.................................................2119, 2137
Medical Scientist Training Program...............................  2112
Minority Opportunities in Research...........................2117, 2137
New Approaches to Pathogenesis...................2132, 2133, 2134, 2135
New Investigators................................................  2110
NIGMS Organizational Chart.......................................  2125
Opening Statement................................................  2095
Other Areas of Interest..........................................  2141
Percentage of Ph.D's Awarded to Minorities.......................  2114
Pharmacology Research Associate Program..........................  2140
Pharmacology, Physiology, and Biological Chemistry...............  2135
Protease Inhibitors..............................................  2118
Rationale for Stipend Increases..................................  2112
Research Advances................................................  2130
Research Areas Pursued by Young Investigators....................  2113
Research in Chemistry and Physical Sciences......................  2108
Research Training Collaborations with Industry...................  2111
Scientists Employed as Temporary Workers.........................  2111
Special Initiatives..............................................  2138
Special Programs.................................................  2137
Stimulation of Research Fields...................................  2110
Stipend Levels...................................................  2116
Story of Discovery: From Chemistry to Gene Therapy...............  2129
Training Programs of the Howard Hughes Medical Institute.........  2114

                        Office of AIDS Research

AIDS Statistics..................................................  2163
AIDS in Minority Populations.....................................  2170
AIDS in Minority Populations.....................................  2203
AIDS Research Proportion of NIH Funding..........................  2171
AIDS Research Addressing Minorities..............................  2170
AIDS Research Proportion of Total NIH Request....................  2167
Benefits of AIDS Research to Other Diseases......................  2164
Changing Faces and Scientific Priorities.........................  2190
Clinical Trials of New Therapeutic Agents........................  2188
Cooperation with Industry........................................  2183
Demographic Groups With Increasing AIDS Cases....................  2163
Direct Support for OAR...........................................  2174
Federal Biomedical Research Plan.................................  2175
Flexibility for OAR to Change ICD Distributions..................  2165
Inclusion of Minorities in AIDS Research.........................  2193
Justification................................................2205, 2248
Latest Advances in AIDS/HIV Therapies............................  2202
Minorities on Research Training Grants...........................  2168
Minority Participation in Clinical Trials........................  2197
Needle Exchange..................................................  2187
NIH Panel on Principles of Therapy for HIV Infection.............  2181
OAR Discretionary Fund...........................................  2176
OAR Collaboration with ORMH and ORWH.............................  2192
Opening Statement................................................  2155
Pediatric AIDS...................................................  2178
Prevention Science Working Group.................................  2172
Projected AIDS Deaths Without a Vaccine..........................  2164
Proportional Increases for NIH Institutes........................  2171
Prospects for International Availability of an AIDS Vaccine......  2163
Recipients of AIDS Research Funds................................  2177
Reluctance of Monitories to Participate in Clinical Trials.......  2171
Research Plan....................................................  2186
Role of the Office of the Director...............................  2167
Small Business Innovation Research Grants (SBIR).................  2196
Social and Behavioral Factors of AIDS............................  2192
Status of Minority and Women's Health............................  2167
Status of the Development of an AIDS Vaccine.....................  2186
The Investment in Minority Research Programs.....................  2196
The New Generation of AIDS Researchers...........................  2172
Three Percent Transfer Authority.................................  2166
Total AIDS Research Funding......................................  2166
Training for HIV Researchers.....................................  2184
Witnesses, Introduction of.......................................  2155

          Office of the Director and Buildings and Facilities

Administrative Cost Study........................................  2264
Area Program.....................................................  2301
Behavioral Research..............................................  2335
Budget Request for ORMH..........................................  2338
Building and Facilities..........................................  2257
Child Abuse and Neglect..........................................  2324
Cholestin........................................................  2262
Clinical Research Issues.........................................  2304
Concluding Remarks...............................................  2292
CRC Advanced Appropriations......................................  2262
CRC Cost Estimates...............................................  2263
Credit Card Purchases............................................  2303
Decrease in OD Funding Level.....................................  2323
Electronic Grant Submissions.....................................  2311
Employment Separation Rates......................................  2345
Enrollment for Women's Health Initiative.........................  2308
Extramural Associates Research Development Awards Program........  2328
Extramural Biomedical Facility Construction Research 
  Infrastructure.................................................  2344
Grant Scoring....................................................  2310
Herbal Medications...............................................  2266
Inclusion of Women and Minorities in Clinical Trials...2309, 2332, 2347
Institute of Medicine............................................  2343
Introduction of Witness..........................................  2249
Justification of Budget Estimates................................  2358
Listing of NIH Facilities........................................  2290
MARC and MBRS Programs.......................................2270, 2334
Medical Nutrition Therapy........................................  2266
Minority Health Initiative.......................................  2300
Minority Programs................................................  2336
    Funding for Minority Programs............................2338, 2345
    Funding for Minority Researchers.............................  2271
    Inclusion of Minorities in Research..........................  2330
    Increasing Minority Participation............................  2327
    Minorities in Clinical Trials................................  2351
    Minority Funding.........................................2270, 2291
    Minority Research Grants.....................................  2272
    Minority Researchers.........................................  2337
    Recruitment and Retention of Minorities......................  2350
    Representation of Minorities in Research Protocols...........  2349
    Underrepresented Minorities..............................2326, 2352
National Agenda on Research on Women's Health....................  2269
National Biomedical Research Service Positions...................  2298
National Foundation for Biomedical Center........................  2315
New Component for Women's Health Initiative......................  2308
NIH Organizational Structure.....................................  2289
Office of Alternative Medicine.........................2265, 2318, 2323
    Alternative Medicine Research................................  2316
    Office of Alternative Medicine Budget........................  2301
    Office of Alternative Medicine Clearinghouse.................  2302
Office of Behavioral and Social Sciences Research................  2315
Office of Dietary Supplements....................................  2266
Office of Research on Minority Health and NIEHS Collaborations...  2293
Opening Statement................................................  2249
Opening Statement--Dr. Kirschstein...............................  2251
ORMH--Standing Advisory Committee................................  2341
ORWH's Budget Level..............................................  2268
Pediatric and Neurodegenerative Initiatives......................  2306
Plans for New Institutes.........................................  2290
Progress of Minority and Women's Health..........................  2326
Quotas...........................................................  2274
Radioisotope Contamination.......................................  2295
Radiology and Imaging............................................  2262
Recombinant DNA Advisory Committee...............................  2314
Renovation of Clinical Center....................................  2263
Research Needs of Children.......................................  2323
Research of Human Subjects.......................................  2313
Re-Submission of Unfunded Grant Applications.....................  2313
SBIR Grants......................................................  2295
Science Education Activities at the NIH..........................  2275
Senior Biomedical Research Service Positions.....................  2295
Status of Minority and Women's Health............................  2326
The Ryan Commission..............................................  2316
Unified Information Technology System............................  2264
Women and Minorities in Biomedical Careers.......................  2333
Women in Biomedical Careers......................................  2269
Women's Health Initiative........................................  2298
Adequacy of Spending on Diabetes.................................  2484
Advice In Decision-Making........................................  2435
AIDS:
    Expenditures for AIDS and Other Diseases.....................  2473
    NIH Expenditures on AIDS Research............................  2494
    Research Coordination........................................  2482
    Research Funding.............................................  2495
    Scientific Opportunity.......................................  2471
    Stabilizing Infections.......................................  2494
    Vaccine Initiative...........................................  2500
AIDS and Scientific Opportunities................................  2471
AIDS Research Coordination.......................................  2482
AIDS Research Funding............................................  2495
AIDS Vaccine Initiative..........................................  2500
Areas of Emphasis................................................  2485
Biography, William E. Paul, M.D..................................  2468
Biography, Harold E. Varmus, M.D.................................  2459
Biography, Dennis Williams, Ph.D.................................  2470
Budget:
    Constraints..................................................  2436
    Doubling NIH's...............................................  2497
    NIH Budget for 1998..........................................  2508
Budgetary Constraints............................................  2436
Cancer:
    Mortality Rates..............................................  2488
    Ovarian......................................................  2501
    Ovarian......................................................  2503
    Ovarian, Detection of........................................  2490
    Research Article.............................................  2489
Cancer Mortality Rates...........................................  2488
Cancer Research Article..........................................  2489
Clinical Research............................................2501, 2502
Clinical Research Report.........................................  2505
Coding for Parkinson's Research..................................  2477
Commitment Base..............................................2434, 2476
Committee Report Language........................................  2472
Congressional Biomedical Research Caucus.........................  2475
Congressional Support............................................  2503
Cost Savings from Research.......................................  2500
Criteria For Decision-Making.....................................  2434
Curriculum Vitae, Phillip Gorden, M.D............................  2467
Curriculum Vitae, Richard Klausner, M.D..........................  2460
Curriculum Vitae, Claude Lenfant, M.D............................  2465
Detection of Ovarian Cancer......................................  2490
Disease:
    Imprecision of Coding........................................  2435
    Trans-NIH Categories.........................................  2478
Doubling NIH's Budget............................................  2497
Drug Rehabilitation..............................................  2506
Early Childhood Development......................................  2506
Earmarks in DOD for Research.....................................  2507
Effect of Public and Congressional Input.........................  2499
Expenditures for AIDS and Other Diseases.........................  2473
Factors in Resource Allocation...................................  2492
Factors In Resource Allocation...................................  2472
Final Authority for Decision-Making..............................  2486
Funding for Autism...............................................  2489
Funding for Population Research..................................  2480
Genetics Research Opportunities..................................  2496
Imprecision Of Disease Coding....................................  2435
Information Dissemination........................................  2503
Information Dissemination of Research Findings on Learning 
  Disabilities...................................................  2507
Information Transfer.............................................  2499
Information Transfer in Prevention...............................  2506
Information Transfer to Other Agencies...........................  2506
Learning Disabilities:
    Research on..................................................  2507
    Information Dissemination of Research Findings on............  2507
Limitations To Planning Science..................................  2434
NIH Budget for 1998..............................................  2508
NIH Definitions of Selected Population Groups....................  2479
NIH Health Funding By Group......................................  2481
NIH Expenditures on AIDS Research................................  2494
NIH Resource Allocation Procedures...............................  2485
NIH Spending On Minority Initiatives.............................  2479
Nobel Laureates..................................................  2474
Observations And Principles For Resource Allocation..............  2433
One Percent Transfer Authority...................................  2486
Opening Statement of the Director NIH............................  2433
ORWH's Priority Setting Process..................................  2504
Ovarian Cancer................................................250, 2503
Pace Of Research.................................................  2437
Parkinson's Disease..............................................  2436
Parkinson's Disease And Related Research Awards, FY 96...........  2457
Politics and Research............................................  2501
Prepared Statement Of Director, NIH..............................  2439
Priority Setting.................................................  2493
Priority Setting Interaction of ORWH and NIH.....................  2505
Public Relations for NIH.........................................  2482
Research on Learning Disabilities................................  2507
Resource Allocation By NIH.......................................  2437
Science Cannot Be Purchased......................................  2436
Stabilizing AIDS Infections......................................  2494
Statement of the Hon. George R. Nethercutt, Jr...................  2484
Statement of the Hon. George Gekas...............................  2476
Statement of the Hon. Patsy Mink.................................  2490
Statement of the Hon. Constance A. Morella.......................  2498
Strategic Plan...................................................  2478
Technology Transfer..............................................  2502
Trans-NIH Disease Categories.....................................  2478
Unanticipated Research Results...................................  2496