[House Hearing, 105 Congress] [From the U.S. Government Publishing Office]DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, EDUCATION, AND RELATED AGENCIES APPROPRIATIONS FOR 1999 ======================================================================== HEARINGS BEFORE A SUBCOMMITTEE OF THE COMMITTEE ON APPROPRIATIONS HOUSE OF REPRESENTATIVES ONE HUNDRED FIFTH CONGRESS SECOND SESSION ________ SUBCOMMITTEE ON THE DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, EDUCATION, AND RELATED AGENCIES JOHN EDWARD PORTER, Illinois, Chairman C. W. BILL YOUNG, Florida DAVID R. OBEY, Wisconsin HENRY BONILLA, Texas LOUIS STOKES, Ohio ERNEST J. ISTOOK, Jr., Oklahoma STENY H. HOYER, Maryland DAN MILLER, Florida NANCY PELOSI, California JAY DICKEY, Arkansas NITA M. LOWEY, New York ROGER F. WICKER, Mississippi ROSA L. DeLAURO, Connecticut ANNE M. NORTHUP, Kentucky NOTE: Under Committee Rules, Mr. Livingston, as Chairman of the Full Committee, and Mr. Obey, as Ranking Minority Member of the Full Committee, are authorized to sit as Members of all Subcommittees. S. Anthony McCann, Robert L. Knisely, Carol Murphy, Michael K. Myers, and Francine Salvador, Subcommittee Staff ________ PART 4B (Pages 1683-3189) NATIONAL INSTITUTES OF HEALTH ________ Printed for the use of the Committee on Appropriations ________ U.S. GOVERNMENT PRINTING OFFICE 48-778 O WASHINGTON : 1998 ------------------------------------------------------------------------ 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 ESTEBAN EDWARD TORRES, California HENRY BONILLA, Texas NITA M. LOWEY, New York JOE KNOLLENBERG, Michigan JOSE E. SERRANO, New York DAN MILLER, Florida ROSA L. DeLAURO, Connecticut JAY DICKEY, Arkansas JAMES P. MORAN, Virginia JACK KINGSTON, Georgia JOHN W. OLVER, Massachusetts MIKE PARKER, Mississippi ED PASTOR, Arizona RODNEY P. FRELINGHUYSEN, New Jersey CARRIE P. MEEK, Florida ROGER F. WICKER, Mississippi DAVID E. PRICE, North Carolina MICHAEL P. FORBES, New York CHET EDWARDS, Texas GEORGE R. NETHERCUTT, Jr., Washington ROBERT E. (BUD) CRAMER, Jr., Alabama MARK W. NEUMANN, Wisconsin RANDY ``DUKE'' CUNNINGHAM, California TODD TIAHRT, Kansas ZACH WAMP, Tennessee TOM LATHAM, Iowa ANNE M. NORTHUP, Kentucky ROBERT B. ADERHOLT, Alabama James W. Dyer, Clerk and Staff Director C O N T E N T S ---------- NATIONAL INSTITUTES OF HEALTH VOLUMES 4A AND 4B Page National Institutes of Health Overview........................... 1 National Cancer Institute........................................ 333 National Eye Institute........................................... 627 National Human Genome Research Institute......................... 695 National Institute of Allergy and Infectious Diseases............ 801 National Institute of Environmental Health Sciences.............. 947 National Institute on Deafness and Other Communication Disorders. 1053 National Heart, Lung, and Blood Institute........................ 1131 National Institute on Drug Abuse................................. 1277 National Institute on Alcohol Abuse and Alcoholism............... 1377 National Institute of Diabetes, Digestive and Kidney Diseases.... 1481 National Library of Medicine..................................... 1619 National Institute of Nursing Research........................... 1683 Fogarty International Center..................................... 1753 National Institute of Arthritis and Musculoskeletal and Skin Diseases....................................................... 1807 National Center for Research Resources........................... 1913 National Institute of Child Health and Human Development......... 1975 National Institute of Dental Research............................ 2151 National Institute Mental Health................................. 2235 National Institute on Aging...................................... 2355 National Institute of Neurological Disorders and Strokes......... 2445 National Institute of General Medical Sciences................... 2549 Office of the Director and National Institutes of Health Buildings and Facilities....................................... 2619 Office of AIDS Research.......................................... 2855 Noble Prize Recipients........................................... 2943 Child Health Hearing............................................. 3019 DEPARTMENTS OF LABOR, HEALTH AND HUMAN SERVICES, EDUCATION, AND RELATED AGENCIES APPROPRIATIONS FOR 1999 ---------- Wednesday, March 18, 1998. NATIONAL INSTITUTE OF NURSING RESEARCH WITNESSES PATRICIA A. GRADY, DIRECTOR, NATIONAL INSTITUTE OF NURSING RESEARCH MARY LEVECK, ACTING DIRECTOR, DIVISION OF EXTRAMURAL ACTIVITIES MARY CUSHING, EXECUTIVE OFFICER DR. HAROLD E. VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. The subcommittee will come to order. We continue our hearings this morning on the National Institutes of Health with the National Institute of Nursing Research. We're pleased to welcome Dr. Patricia Grady, the Director of the Institute. Dr. Grady, I apologize for being slightly late. We understand that Dr. Lindberg had the same problem I had, and we appreciate your being here and being able to start. So if you would introduce the people that are at the table with you and proceed with your statement, please. Introduction of Witnesses Dr. Grady. Thank you, Mr. Chairman. Of course, Dr. Varmus is on my right, as he has been all week for you and for the staff. And Dennis Williams from the Department. On my left is Mary Cushing, the Executive Officer of NINR. And next to her is Dr. Leveck, who's the Acting Director of Extramural Activities. Opening Statement We are pleased to appear before you this morning and have an opportunity to discuss the research that the National Institute of Nursing Research is doing. This morning, the President's budget for us is indicated at $68.3 million. That is including the approximate appropriation from the Office of AIDS Research, which is separate. I would like to say this morning that nursing research is currently at the frontiers of science. We are helping to build the foundation of knowledge for the Nation's providers of health care. The research that we do encompasses health promotion and disease treatment issues. It covers multiple age groups across the age span, and also population groups of all types, and people in a variety of settings, as well as acute hospital settings. Therefore, the research that we do is broad based. And you will find us in nearly every avenue into which you venture. nursing research questions The questions that nurse researchers ask address the core of patients' and families' personal encounters with illness, and they also ask a number of questions that are very central to these issues. Examples of these questions, do men and women respond differently to therapeutic regimens used for relief of pain? We're finding out the answer is yes. What information is necessary and useful to help people reach decisions about genetic testing? We are funding that research. Also studies to determine what approaches will help to ease the symptoms of terminal illness. This is a central focus, studies that help patients maintain quality of life, dignity and sense of control throughout illness or at the end of life. Moreover, the research that we do involves multi- disciplinary teams engaged in answering these questions, and basic and clinical research in health care. We say nurses bring life to research and bring research to life. This is in fact quite true. arthritis self-management Let me give you some examples of how nursing research is making a difference. We funded a Spanish arthritis education and teaching self-management program which was translated into Spanish and tested for that population in California. The National Arthritis Foundation has adopted that program that was developed by the nurse researcher in Northern California, and is attempting to get the program adopted across the country. This researcher is also working with a local HMO to try to incorporate these principles into the care of arthritis patients. She is developing similar programs in Spanish for patients with other health problems such as cardiovascular and respiratory disorders. pain and gender effects Our research has shown that gender does make a difference in pain relief. Researchers in California have been testing out certain compounds of drugs which were thought to be previously ineffective. The population in which they were tested was all male. In testing in a population that was predominantly female, these drugs do provide relief, and gender does make a difference. These have important implications for intervention and drug therapy in the future. Another example, a third example is one in which a nurseresearcher developed a scale to predict, within several days of admission of patients in nursing homes, which of that population would develop pressure ulcers. As you know, this is a very costly and serious complication for patients in nursing homes. The results of that research were translated into national guidelines, and those guidelines are now being used to inform care. So this is an example of the study that has made a difference in care and implementation. early hospital discharge Another very important study that we funded and that is having impact is one that is a model for early hospital discharge. This model has been used in patient populations, including women with unexpected Caesarean deliveries, hysterectomies, and pregnant women with complications of diabetes. As a result of this program, which was nurse-run, patients have been able to be discharged earlier at a reduced cost in hospitalization and time spent. Moreover, and I think even more importantly, is that these patients report an increase in satisfaction in their quality of care and have stayed out of the hospital with a reduced number of unexpected re-hospitalizations and a reduced infection rate. This particular investigator is working with several HMOs to try to facilitate incorporating this model into their systems. end of life research Let me move on to an issue which is very central to the Institute, and that is end of life research. NINR has been named the lead Institute in this issue. It is one that is very central to all of us, and particularly important to the National Institute of Nursing Research. Advances in biomedical and behavioral research have greatly improved the length of our lives, and in many cases the quality of life. However, all disorders cannot be cured. And at some point, we do need to address the needs of patients who have reached that phase of the end of life. Last year, the NINR, in cooperation with several other institutes, convened a workshop to address issues of symptom management in end of life. As a result of this, a program announcement has been issued with the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and also the National Institute of Mental Health to encourage research in this important area. We hope to report back to you on the progress of that in the coming year. tele-health In closing, I would like to mention two ongoing studies which cover the gamut of some of the unusual areas that nursing has been moving into, and also address the 21st century. One of these is that of tele-health. We've been hearing a great deal about how technology can improve health and also health care delivery. We are funding a home monitoring project, the population of which is lung transplant patients. With the use of telemetry, home monitoring and computerized systems, these patients have enrolled and are able to monitor their symptomatology after they go home, post-transplant. As you know, the danger for rejection of such transplants is within the first year. So if patients can be monitored relatively non-invasively and safely at home, this could work toward positive outcomes and also decrease the cost of frequent visits to the hospital. So far, 100 patients have enrolled in the study and the compliance with this monitoring program is 82 percent. We think that's very good. pain relief and surgery Another study which is an unusual one, but is a result of an observation made clinically, is that typically, compounds of drugs called benzodiazapine, commonly known as Valium, are given to patients prior to surgery for their tranquilizing and beneficial effects. As it turns out, post-operatively, these interfere with the effects of morphine, which is used for pain relief. In one of the studies that we're funding relative to timing and management of pain medications post-operatively, the study is testing using a compound which neutralizes the effects of the Valium post-operatively, so that patients are able to be maintained more effectively on doses of morphine that are lower and also more effective. So this has an implication for adding to our basic knowledge for timing of medications and self-management by patients post-operatively. In conclusion, I would like to say that as we arrive at the 21st century, health research, health care and health choices are increasingly interdependent, and nursing research will play a vital role in all of these areas. Scientifically validated methodologies, communications strategies and effective interventions, coupled with a basic understanding of human nature and our Nation's diverse populations, will make a positive difference to the health and the quality of the American people. Thank you, Mr. Chairman, and I would be happy to answer any questions that you may have. [The prepared statement follows:] [Pages 1687 - 1692--The official Committee record contains additional material here.] Mr. Porter. Thank you, Dr. Grady. aids funding My first question is for Dr. Varmus and it has to do with money. I notice that about 10 percent of the NINR budget is the OAR transfer and I wonder, is that the highest among all Institutes? I assume not, but it's got to be fairly high. Dr. Varmus. No, NIAID has the highest. Mr. Porter. Yes. But isn't 10 percent fairly high? Dr. Varmus. It's probably---- Mr. Porter. As a percentage of the non-AIDS budget? Dr. Varmus. Probably close to average, since the AIDS budget is close to 10 percent of NIH. There are several others, including NIDA and NIAID that are higher. Mr. Porter. Let me ask Dr. Grady, then, what does the AIDS portion represent in your research portfolio? That is, what are you doing with that particular money? Dr. Grady. We have a very active program in HIV/AIDS research. It covers research with young adolescents in inner cities across the country to discuss prevention of transmission of HIV/AIDS, particularly young males in the Philadelphia and New Jersey area, as well as in California. It also is a program which works with young mothers who are HIV infected to try to prevent transmission of that disease. We are working with a number of teaching and education dissemination programs as well. We're also working with the babies of infected mothers and helping them to care for them, and to observe for signs of the disease, and to deal with that young population who is infected. health care delivery Mr. Porter. This is a policy question, I guess, or at least an observation question. We've had tremendous changes in our health care delivery system over the last five or six years. Can you describe how this has affected the profession of nursing, and are you supporting any research that affects how this change in our health care system is affecting nurses? Dr. Grady. There are many ways in which these changes are affecting nursing. You will hear negative reports and positive reports. We see this as a time of great opportunity for nurses and for nursing. The opportunity is now available for nurses to assume more independent roles, and they are preparing to do that. Some of the examples I gave you in terms of nurse managed clinics and programs where nurses will deal with patients in a variety of other settings, not just the acute hospital, but in nursing homes and extended health care settings, they're making a major impact. There are also studies where nurses are training nurse practitioners and also nursing assistants in nursing homes caring for the elderly. In particular, one study where the population of patients are patients with Alzheimer's disease. Previously restraints have been used heavily. It was almost incarceration in terms of trying to limit the motion or the movement of this patient population. We have a number of studies which are attempting to deal with the problems of agitation, problems of delirium and the problems of wandering and aggressive behaviors in these patients. And these are nurse-run programs with nurse practitioners or nursing assistants helping to implement these programs. So we think this is an example of many things that can be done across the country. nursing responsibility growing Mr. Porter. It seems that nurses have increasingly assumed more and more of the responsibilities that used to be exclusive to the physician and are therefore getting much greater training. Some of the mundane tasks that nurses used to do are being done by assistants of one type or another. Do you see this expansion of responsibility and professionalism extending into the next 40 or 50 years ahead and what are you doing within the Institute to anticipate those greater responsibilities? Dr. Grady. Yes, we do see these changes going into the 21st century and beyond. We're doing a number of things to try to prepare for the 21st century in this regard. First of all, more nurses are going into programs of higher education now than before. Many of those are nurse practitioner programs, but many of those are also research programs. We are supporting the research projects that will indicate which way the nursing role will go. Basically, we see nurses taking more responsibility for running programs in outpatient settings. We see them at the forefront at the variety of changes that are taking place. Recently in NIH, we had a bioengineering symposium that was very widely attended. There were two nurses on the program there describing their tele-health and informatics systems that they're using to help to deliver patient care. That's an area in which nurses are getting very involved. genetics counseling Another area that we anticipate a great deal of activity in and that nurses are preparing for and we are supporting that is in the area of genetics. Genetics counseling is a very important area. But in addition, we've talked about promotion and research in that area being very important. As you, I know, have heard Francis Collins say many times, in the misspellings in the genes that are discovered early on, we're looking at one gene, one disease. But approximately 95 percent of disorders are complex trait disorders. So a misspelling in a gene may put someone at a predisposition to risk of developing the disease. But that will be only one factor. The other risk factors will be factors such as environmental factors, dietary factors, exercise, etc., the kinds of risk factors that have been identified in other disorders, such as cardiovascular disease, stroke, cancer to some extent. These are areas in which nursing has always been active. And these are areas which involve behavior modification and teaching and issues that nurses deal with in other areas. I think that particular role will become even more important. And that is an area that physicians have not been as involved in, because they're doing other things. Nurses have been involved, and the responsibility will simply grow. There are many other examples I can give you, but I can give you those for the record. support for research in clinical practice Mr. Porter. We hear that physicians are finding it difficult to continue their clinical research because they're being pressed within the academic health centers to generate more practice revenues. Is this problem also one for nurse researchers? Dr. Grady. It is to some extent, Mr. Porter. There are nurses across the country in most university settings. A fair percentage of those nurses do have practices that they are running collaboratively or independently in limited practice. So those constraints, fiscal constraints, are also impacting on them as well. There are some very creative solutions that are being developed to try to deal with this. But it is a concern. More than 88 percent of what we fund in our institute is clinical research. So we do hear a great deal about the constraints in the clinical setting. We, in combination with other institutes at NIH, are supporting the new mechanisms to encourage people into clinical research and encourage them to maintain those clinical research careers throughout their trajectory. pressure sores in spinal cord injury Mr. Porter. In your budget justification, it states that you're planning a protocol to study the skin of patients with spinal cord injury. Can you tell us more about this? Dr. Grady. Yes. One of the programs that we've had almost since the inception of the institute that has been an important program is that of wound healing. This is a cross-cutting issue. In fact, our intramural program's scientific director, Dr. Annette Wysocki, who is in our audience, is an expert in the area of wound healing. One of the studies she conducted when she was in the extramural program looked at the wound fluids of a variety of patient populations, to determine what would be a factor in either promoting healing or in retarding healing. One of the areas of particular interest is that of patients with spinal cord injury. Because as you know, these patients can be very active in many ways, but their skin integrity is an area that once breached can cause long-term complications. So we are looking at those factors. That is a basic science study, but it is an observation that was made from a clinical setting that has then been taken into the laboratory and hopefully will go back into the clinical setting when the factors are identified. This is also an interesting problem in patients with diabetes, it's a complication of that. And it's also a problem in the elderly population, as well as anyone who's not very mobile. But in particular, those populations are very vulnerable. So we have started a wound healing clinic on campus, and would hope to deal with some of those issues, both intramurally as well as extramurally. collaborations with hrsa Mr. Porter. HRSA operates a number of nurse health professions programs. Can you tell us about your interface with HRSA? What do you do, how often do you talk with them? What's the relationship? Dr. Grady. The Division of Nursing is housed within HRSA.In fact, the early National Institute of Nursing Research, then a center, was formed with some of the staff and some of the research proposals that they had then been funding. The way things currently operate, we do meet on a fairly frequent basis, and our staffs meet. We are on a number of joint committees to deal with nursing issues. In fact, just last week I was at a meeting with the acting director of the Division of Nursing. They primarily fund programs related to manpower and early training issues. Our training, where we dovetail, is that we do fund a fair amount of training. Our training budget is for pre- doctoral and post-doctoral trainees, whereas they target the undergraduate and special programs. behavioral research Mr. Porter. Do you conduct any behavioral research, and if so, can you tell us more about that? Dr. Grady. Yes. We have a large program in behavioral research, and most of these programs are directed toward symptom management or in behaviors which are targeted toward modifying risk factors. We have two major programs in this area that I would like to mention. In the first case, in the Baltimore area, a program is directed at hypertensive inner city African-American youths, and consists of dietary modification, exercise program and healthy lifestyle types of approaches to try to change behaviors to decrease risk for developing heart disease and stroke. It's a fairly large program, and the early results are very encouraging. Another program of this sort is directed to younger children in the rural areas of North Carolina. That is a program which is really for young school children, pre- adolescent, and it is a program which has been very successful in early preliminary findings. The school system down there wishes to enlarge this program and take it to a larger population and an older group in the school. The investigator has also been invited to Japan to try to incorporate some of this program into that population to see if it is internationally transferrable. Hypertension and risk factors for heart disease are very much a problem over there as well. aids risk reduction So again, these are two programs which are directed toward behavior modification. Another one is in the area of HIV/AIDS, and this is directed at an inner city population in Philadelphia. It has been very successful. It's unusual in that it has a very high return rate of this population of young African-American adults. The males are harder to get into the studies, and the return rate is not so good. But this particular investigator has a very good record with that. And so we're seeing some signs of behavior change there. The program that she has started with a co-investigator is being adopted by CDC and used nationally for education of this group. Mr. Porter. This question is for you or Dr. Varmus. NIH did a recent study on needle exchange. Is that correct? Dr. Varmus. It wasn't a study, Mr. Porter, we had a conference. Mr. Porter. A conference. Dr. Varmus. It was actually not directed solely to needle exchange, it was a conference on behavior in risk modification, especially for HIV/AIDS. Mr. Porter. Within the Department, wasn't there a study done recently for the Secretary on this subject? Dr. Varmus. There was an evaluation of where we are. It was not a scientific study. It was a compilation of evidence that has been accumulated. And of course, the NIH consensus conference on behavior and HIV risk assessment was incorporated into that evaluation. We discussed that here last year. Mr. Porter. So the evaluation is over a year old? Dr. Varmus. That's correct. aging research Mr. Porter. Dr. Grady, there's increasing evidence that a decline in brain power is not an inevitable part of growing older. In fact, given the proper environment, the brain can continue to function and adapt to environmental and psychological challenges. Your institute is sponsoring the first test outside the laboratory of the ability to train older people to maintain underlying mental skills needed to perform every day tasks involved in remaining independent. When can we expect the results of this study? Do you think we will be able to keep more older people out of nursing homes and hospitals in the future? It seems to me this will become extremely important in a few years when the baby boomers start to reach older age. Dr. Grady. Yes, Mr. Chairman, this is an area of particular interest for us. In fact, in Alzheimer's populations where there is a physiological reason for mental decline, we have studies that a simple series of mental exercises performed two to three times a day. The family members are trained to do this with the patient population. This intervention was able to hold off the decline in mental capacity for up to nine months in the test population. And so this is now being taken into the ``normal elderly population'' that does not show signs of impairment. We have every reason to believe that the results of that will be positive. I can't promise you, because of course research always has its surprises, but we would expect to be able to report back to you on that within approximately two years. cognitive stimulation Mr. Porter. There's also some evidence that therapies such as art or music have an effect on patients. Can you tell us what's going on in that area, and whether those are also applicable to this kind of maintaining independence? Dr. Grady. There is a study that is being carried out in the midwest that has just recently started, a little over a year ago. It has several arms of testing the population. Besides the control population, it has a cognitive stimulation set of exercises for one arm of the population. And also, art therapy and music therapy for the other arm of the population. What is being tested here is mental alertness, mental capacity. Also the scales for depression are also being used. It is an elderly population, and the incidence of depression, we are finding out, is higher than previously thought. So they are looking at both of these, mental performance and also mood affected by this study. Mr. Porter. So this is the same study that we will hear about in a couple of years? Dr. Grady. It's another study, but it has several arms. The first one I mentioned is a separate study, but you will also be hearing about these at about the same time. diabetes research Mr. Porter. Proper blood sugar control for persons with diabetes may help prevent the onset and/or progression of the complications associated with the disease. However, control of the disease is very difficult to manage in children. Is your Institute conducting research in the area of family-centered care to promote better outcomes for diabetes? Dr. Grady. Yes, we are. We have several studies in this area. And it's an area which is of growing interest and particular concern in young people. Because with an early onset of diabetes, they have a long time to develop these very difficult and perplexing complications, very disabling complications. We have one study that is directed to young adults and teenagers in the New England area which is addressing behavioral modification and has been very successful so far in adherence to diet and also in blood sugar control. So it's a small study which is now going to be enlarged to a larger group, but so far has been very encouraging. We have another study which is addressing the Native American population in the northern midwest. As you know, the Native American population has among the highest complication rate or the highest diabetes rate, even higher than our Hispanic population. That group is being followed for behavioral modification and dietary modification. An interesting part of that study is that they are using a Native American cookbook to develop the recipes which will then help to alter the diet. So it is culturally sensitive. And we expect that it will be much more effective than trying to get a group to learn to eat and enjoy new foods that seem quite unpleasant or odd, at best. Mr. Porter. Dr. Grady, thank you for your excellent statement. You've answered all of our questions very directly and efficiently. And thank you for the fine job you're doing at NINR. Dr. Grady. Thank you very much, Mr. Chairman. We really appreciate the opportunity to come up and tell you about what we're doing. [The following questions were submitted to be answered for the record:] [Pages 1700 - 1751--The official Committee record contains additional material here.] Wednesday, March 18, 1998. FOGARTY INTERNATIONAL CENTER WITNESSES PHILIP E. SCHAMBRA, Ph.D., DIRECTOR STEPHANIE J. BURSENOS, DEPUTY DIRECTOR RICHARD MILLER, EXECUTIVE OFFICER HAROLD E. VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Opening Statement Mr. Wicker [assuming chair]. The subcommittee will come to order. Our next witness is Dr. Philip E. Schambra, Director of the Fogarty International Center. Dr. Schambra, we're delighted to have you, and we ask you to proceed in your own fashion. Dr. Schambra. Delighted to be here, Mr. Wicker. And thank you very much. Perhaps I can begin by introducing the other individuals at the table with me. Starting at my far left, Mr. Richard Miller, Executive Officer of the Fogarty Center. To my immediate left, Ms. Stephanie Bursenos, the Deputy Director of the Fogarty Center. To my right, Dr. Harold Varmus, Director of NIH, and to his right, Mr. Dennis Williams, Deputy Assistant Secretary for Budget for this Department. Mr. Chairman, I'm very pleased to appear before you once again to present the President's non-AIDS budget request for the Fogarty International Center for Fiscal Year 1999, the sum of $19.1 million. This reflects an increase of $1.4 million over the comparable Fiscal Year 1998 appropriation. Including the estimated allocation for AIDS, total support requested for the FIC is $30.4 million, an increase of $2.1 million over the Fiscal Year 1998 appropriation. Funds for the FIC efforts in AIDS research are included within the Office of AIDS Research budget request, as is the case with the other components of NIH this year. This year, the Fogarty Center enters its 30th year as a focus of NIH international activities. Our mission is to assist this Nation to deal with health problems that transcend national boundaries, that can be combatted most effectively through international cooperation. Through training and research support, the Fogarty International Center enables American universities and research institutes to cooperate in regions of the world that, due to disease burdens, provide unique opportunities to advance international health. Why international health? May I direct your attention to the chart on my far left, which pictorially displays why international health is important. First, to protect Americans against global health threats. With frequent international travel, vast movement of populations of refugees, and potential changes in our climate affecting health, global trends are of increasing importance for us all. One has only to consider the emergence and spread of AIDS to recognize the necessity of confronting health needs in a global context. Moreover, international commerce presents new risks for the transfer of infectious agents for both humans and livestock, as well as toxic substances such as pesticides and pollutants, and even biologic and chemical agents. Second, we pursue international health to fulfill a longstanding American humanitarian tradition. The Global Burden of Disease Study commissioned by the World Bank indicates that developing nations suffer over 90 percent of the burden of premature mortality as measured in lost years of life. These countries, constituting three-quarters of the world's population, now share a triple burden--the persistence of infectious diseases and malnutrition responsible for 16 million deaths each year, mainly children; a growing incidence of chronic disease and disability due to increased life spans and new risk exposures; and environmental and occupational health hazards which accompany industrialization. Third, we pursue international health to advance America's global interests. The United States is at the vanguard of scientific progress and produces more knowledge, publications and medical interventions than any country in the world. Because of our leadership, we share an opportunity and an obligation to influence the international community, international organizations, and developing and industrialized countries alike, to address the health problems of those most in need. Further, international cooperation in biomedical science not only enables the United States to share skills and knowledge, but cultural and societal values intrinsic to scientific progress as well. This Nation's investment in research on global disease prevention produces significant economic returns. For example, the Institute of Medicine of the National Academy of Sciences reports that the United States saves $450 million every year by not having to vaccinate our citizens against smallpox. The World Health Organization predicts that our efforts to eradicate polio will result in global savings of $500 million by the end of this decade. However, despite U.S. prominence in the creation of new drugs and medical devices as measured by percentage of world patents, our global share of exports to a market that exceeds $40 billion annually, namely developing nations, is a mere 15 percent. International cooperation in health is one pathway to emerging markets enabling millions of citizens of these countries access to more modern drugs. Now, how does the Fogarty Center meet these critical challenges? If you would, please turn once again to our chart, now with an overlay, which describes our major efforts. In the progress of biomedical science, one critical limiting factor is human talent. FIC's investment is in human capital, with a particular focus on developing nations. Scientific partnerships with these nations are of strategic importance. What follows describes our efforts to improve America's scientific capacity to conduct international research on global health priorities in collaboration with our sister institutes at NIH and the scientific community at large. With the support of this committee, the Fogarty Center's International Training and Research Program in Emerging Infectious Diseases was initiated this past year to improve our capacity to understand the fundamental biology and epidemiology of new or resurgent infectious diseases. Launched in collaboration with the National Institute of Allergy and Infectious Diseases, the program explores the changing patterns of infectious diseases due to microbial evolution, human behavior, and economic development and land use. The model for this new program is the Fogarty Center's AIDS International Training and Research Program. To date, under this program, over 1,300 foreign scientists from over 80 countries in Africa, Asia, Latin America and Central and Eastern Europe have received long-term HIV research training in the United States. Many former trainees are now co- investigators on NIH-supported research projects in developing countries where HIV/AIDS is epidemic. In addition, more than 41,500 physicians, scientists, nurses and laboratory technicians have gained new skills throughin-country training courses. The emerging infectious diseases and AIDS programs, in tandem, represent investments in training and infrastructure that will assist the United States to develop vaccines and other interventions for diseases that require international trials. These include HIV, tuberculosis, diarrheal and parasitic diseases, and acute respiratory infections. HIV and other pandemics demonstrate that disease is not confined to national borders. In some cases, disadvantaged groups in the United States exhibit similar health risks with populations in resource-poor nations, risks due to micronutrient deficiencies and perinatal infections and other conditions. There are lessons to be learned domestically from research conducted abroad. For example, studies in Tanzania demonstrated that unless treatment regimens are supervised closely, TB rapidly becomes resistant to available drugs. That finding now has been applied to community health programs in New York City and other urban centers. Another FIC global priority is to prevent adverse health effects of industrial and chemical pollutants. The FIC International Training and Research Program in Environmental and Occupational Health enables U.S. institutions to train scientists from regions of the world with high levels of contaminants in the environment and work place, such as Eastern Europe, Russia and the new republics. The program is co-funded with the National Institute of Environmental Health Sciences and CDC's National Institute for Occupational Safety and Health, and National Center for Environmental Health. Current studies in Ukraine and Belarus undertaken after the accident at Chernobyl include the effects of radiation on growth and development, incidence of thyroid cancer, and reproductive health disorders. One of the chief casualties of environmental decay is biologic diversity. There is a tendency to assume that our increasing technological sophistication moves us further from dependence on the natural world. However, it is likely that ecosystems maintained by diverse species are a part of our protection against diseases. For example, deforestation has introduced new infectious agents into human populations; the depletion of ozone in the stratosphere erodes protection against the damaging effects of ultraviolet radiation. The Earth's biota also is a continuing resource for new therapeutics. The FIC leads an interagency effort to discover new drugs from the earth's biological diversity. The International Cooperative Biodiversity Groups Program is funded in partnership with several NIH institutes, the National Science Foundation and U.S. industries. This program consists of academic-industry consortia, examining genetic resources from terrestrial and marine environments worldwide. The program is now in its fifth year, and together these groups have examined over 3,000 species for activity in 13 therapeutic areas. At this early stage in the drug development process, there are approximately 25 high priority leads, including several to treat malaria, viral diseases, and cancer. Of equal importance, by demonstrating the economic and humanitarian potential of new drugs derived from biodiversity, this program has influenced governmental efforts to sustain ecological balance in Argentina, Peru, Chile, Suriname and Mexico. A root source of global health problems is demographic pressure. The world's population is now expanding at the unprecedented rate of nearly 1 billion per decade. Demographers at the United Nations estimate that virtually all of this growth will occur in the developing nations of Africa, Asia and Latin America. There is broad consensus that more stable population growth will enhance the prospects for improved living conditions for billions in the decades ahead. Yet this will require new medical technologies and social adaptations generated through research. Through our International Training and Research Program in Population and Health, the Fogarty Center increases the capacity to conduct research on reproductive and neonatal health care and improves demographic capabilities in countries where population growth impedes economic development. The program is co-funded with the National Institute of Child Health and Human Development. Already, several collaborative projects have yielded discoveries. Scientists at the University of Virginia and the National Institute of Immunology in New Delhi, India, have identified a specific antigen on spermatozoa in primates that could serve as the basis of a male contraceptive vaccine. If ultimately developed, this vaccine would be a major breakthrough in the field of contraceptive development. Finally, in partnership with the National Library of Medicine, the FIC conceived an International Training Program in Medical Informatics to increase research capacity and health care through information technology. A pilot program with Africa will be initiated this fiscal year. The fundamental goal is to develop collaborative teams of U.S. and African researchers and information specialists who apply state-of-the- art telecommunications and computer technologies to challenges in biomedical science and medical care. Mr. Chairman, as we come to the conclusion of this century, it's worth noting an important historical symmetry. NIH began as a small laboratory on Staten Island, tending to the needs of merchant marine sailors at the turn of the last century. The Laboratory of Hygiene proved its worth after diagnosing cases of cholera among immigrant passengers on the steamship Alesia-- the first diagnosis of cholera in the western hemisphere. That landmark discovery was made possible through collaborations with the laboratory of Robert Koch in Berlin, who pioneered methods to isolate bacteria, and the laboratory of Louis Pasteur in Paris. This early discovery presaged the very practical benefits of public investments in basic research. It also signaled our reliance on international cooperation to accelerate the pace of discovery in medical science. This is our historic tradition, our public trust, and our mission at the Fogarty International Center. Mr. Chairman, my colleagues and I would be very happy to respond to any questions you may have. [The prepared statement follows:] [Pages 1758 - 1761--The official Committee record contains additional material here.] Mr. Wicker. Thank you, Dr. Schambra, for your very fine testimony. As Chairman Porter may have explained before he had to leave the room, there are a number of other meetings and hearings going on, as well as a very important Floor debate right now. I know that the absence of other members of the subcommittee does not indicate a lack of interest in the very fascinating subject matter. Dr. Schambra. We look forward to the questions that they may wish to submit for the record and would be delighted to respond to them. polio Mr. Wicker. Indeed. Well, I was in China last year and received a briefing about our international efforts with regard to polio. Can you tell us how the effort to eradicate worldwide poliomyelitis is going, and what other agencies besides yours are involved in this project? Dr. Schambra. Mr. Wicker, polio will probably be the second human disease to be eradicated from the face of the earth, after smallpox. Currently, North America is free of polio, and has been for a number of years. Latin America has become free of polio just within the past year or so. Other countries around the world have massive programs of immunization against polio. There is the exceptation that by the turn of the century or soon thereafter, the world will be free of polio. It willbe another great achievement for humankind in biomedical science. Mr. Wicker. All right, but you mentioned in your testimony the benefits of this global savings of $500 million. What is your agency doing in this connection, and what other agencies are participating? Dr. Schambra. Since this is principally a problem of delivery of a vaccine which has been well tested and well proven in other environments, this is not a typical first line endeavor of the National Institutes of Health. We've done our job some years ago in helping to develop that vaccine, by supporting early research that enabled us to cultivate the virus in tissue culture. The Centers for Disease Control, and Prevention, in the United States, has primary responsibility for vaccination programs at the Federal level. Around the world, the World Health Organization, of course, plays a prominent, and in fact, the leading role in the fight against polio. Mr. Wicker. So you mentioned polio in your testimony not to---- Dr. Schambra. Take credit for it, no. Mr. Wicker [continuing]. Indicate that you're involved in it, but just to demonstrate the importance of a global approach? Dr. Schambra. That's correct. And to support the argument that current efforts that are aimed at developing vaccines against a number of other diseases, including HIV, malaria, and tuberculosis, are worthwhile pursuing, considering the economic benefit alone that we will obtain from finding effective preventive measures. emerging infectious diseases Mr. Wicker. I see. And you just mentioned a list of other diseases. Do you, are you referring to them as emerging infectious diseases? Dr. Schambra. There is a whole range of existing diseases that have not gone away that we have to deal with, such as tuberculosis, which was very close to being conquered on a global basis, until multiple drug resistant forms began to emerge. That is certainly a high priority. Then there are other reemerging diseases such as malaria that had also come very close to being controlled in many regions of the world. Because we didn't develop an effective vaccine and slacked off on various control measures, we are now faced with a resurgence of that disease, oftentimes in drug resistant forms, particularly in the developing regions of the world and most prominently, sub-Saharan Africa. Mr. Wicker. So we have existing diseases, reemerging diseases. Are there any emerging diseases? Dr. Schambra. Probably the best example of an emerging disease in the last decade or so, of course, would be AIDS. We have also become more aware of some of the rarer forms of fatal diseases, viral transmitted such as the Ebola virus, which was first encountered about 10 years ago. Disappeared from human knowledge until recently, two or three years ago, it came back. So whether this is a new disease or a reemerging disease is probably more of a semantical issue than a scientific one. chernobyl Mr. Wicker. Tell us what we have learned about, you mentioned Ukraine and Belarus and the Chernobyl accident. Tell us what your agency, what involvement your agency has had and what we've learned in the history that we now have since that incident. Dr. Schambra. Our role has been to work with, and through various formal and informal agreements with the government authorities in Russia, Ukraine and Belarus to bring together the scientific talent and resources to bear to better understand, and measure what is going on, and then to understand what the consequences are. To date, I think the most profound or disturbing finding is the high degree of thyroid cancer among children who have been affected by the large scale release of iodine-131, a radioactive compound of iodine causing thyroid cancers. We are as well, of course, looking at other matters, and when I say we, I'm speaking of the Nuclear Regulatory Commission and the National Cancer Institute, the Department of Energy and other universities and academic and scientific institutions in the United States and around the world, looking at what the longer term health effects that the terrible accident at Chernobyl resulted in. Mr. Wicker. How old are these children now? Dr. Schambra. Well, let's see, when did the accident occur? It occurred about 10 years ago, about 1986. So the children probably were in utero at that time, or a little more than that age, or within six months of birth. Mr. Wicker. You're looking at the results, according to your testimony. Do you have an opinion as to whether there are other potential Chernobyls out there right now? Dr. Schambra. Well, there are certainly potential Chernobyls, whether there is another Chernobyl only time will tell. The particular reactor at Chernobyl, it was a reactor built by the Russians, had as it turned out some inherent instabilities in its operation, especially at low power levels. And it was in the course of running experiments, unauthorized, it's my understanding, on that particular type of reactor, that led to the runaway nuclear excursion, and the massive, essentially chemical and heat explosion. aids in africa Mr. Wicker. I appreciate your trying to answer the question, and I'm mindful that you're not in the nuclear regulatory business. Tell us about the effect in Africa on the demographic pressure that you mentioned of the AIDS epidemic. You hear some people say that that is a continent that may be depopulated unless we do something to stem the spread of AIDS. And yet, in your testimony, you mentioned that you expect the unprecedented rate of growth to continue there. Do you have an opinion about that? Dr. Schambra. Yes, sir, I can share some of my thoughts with you. Certainly on a global scale, Africa was the region most early affected by the epidemic of HIV. It continues to be the most affected region of the world, with current estimates of the rate of the degree of infection, the number of infections, being probably understated by a factor of five to ten. Mr. Wicker. Understated? Dr. Schambra. Understated. This is just part of the problem in the developing world, where the basic capabilities of doing epidemiology and careful health statistics just do not exist. So one has to rely on extrapolation from smaller numbers and smaller samples to make those sorts of estimates. We do know that there have been communities within certain countries in Africa that have essentially been depopulated of those in their most productive years of life, leaving only elderly grandparents and orphans behind. I can provide some more details for the record, Mr. Wicker. Mr. Wicker. I would appreciate that. [The information follows:] Demographic Impact of HIV in Africa The demographic impact of HIV in Sub-Saharan Africa is sobering. During 1985-1995 the epidemic killed 4.2 million people in Africa. This represents 90% of all deaths due to AIDS in the developing world. In Africa, AIDS mortality is projected to reach its peak in 1995-2005 when the number of AIDS-related deaths will reach 9.4 million. Because of the pandemic, life expectancy has stagnated and even declined in several African countries. This trend is projected to continue through the year 2000. Botswana, Malawi, Uganda, Zambia and Zimbabwe are most affected by the epidemic. Currently, more than 10 percent of the adult population in these countries is infected with HIV; the HIV-related death toll in this region for the period 1985- 1995 is estimated at 1.5 million deaths and life expectancy at birth has decreased from 48 to 44 years. The pandemic also has reduced rates of child survival, reversing gains achieved over several decades. For example, by 2010 Zimbabwe's infant mortality rate is expected to rise by 139 percent because of HIV and its under-five mortality rate by 109 percent. Although the AIDS epidemic increases the number of deaths in each age category, its largest mortality affects age-groups in otherwise productive years of life. It is estimated that in these five most affected countries, mortality during 1985-2005 will increase by 160 percent in the 35-49 age group, compared with 33 percent for the population in general. However, under most scenarios population growth rates in African countries will remain strongly positive within a 25 year projection period. With no behavioral change, and HIV epidemic such as that in present-day Kampala, Uganda (perhaps the most affected metropolitan area in Africa) might reduce population growth by 1 percent. As yet, no country-wide epidemic of such proportions has occurred. Negative growth would result only with a country-wide epidemic two to three times as severe as the worst urban situation in Africa today. international cooperation Mr. Wicker. Dr. Varmus, certainly there appears to be an impressive 30 year history of international cooperation with the Fogarty Center. Do other institutes partner internationally now in a similar way, and would it therefore be better for the subcommittee to increase other institutes' budgets at the expense of the Fogarty Center? Dr. Varmus. As you know, Mr. Wicker, there has been extensive involvement abroad by virtually all the institutes. And the Fogarty International Center has always been intended to be a focal point for international activity, to stimulate and coordinate, facilitate the international efforts made by the institutes. NIH overall has an investment of nearly $200 million each year in various kinds of international activities, training here and abroad, center development and collaborative research. The Fogarty International Center's budget has always been a fairly small fraction of that. As you've heard me say before, we are interested in expanding our efforts to combat disease in other parts of the world. We think that is an effort that is very much in the national interest. But I see that expanded effort going on in the institutes primarily, with coordination from the Fogarty. Fogarty's resources are important to sustain the coordinated efforts and to provide seed money for new projects, to help with a number of training programs, to help coordinate our international training programs on the NIH campus. We certainly don't think there's a need to reduce the Fogarty support to expand the others. We are currently seeking someone to serve as the associate director for international research in my office. That will be a further means to strengthen the way in which the international effort that the NIH is hoping to sustain and indeed expand will be benefitted by direction from my office. accomplishments Mr. Wicker. If we had to list five top accomplishments over the past 30 years, for the Fogarty Center, what would we list? What are you most proud of? Dr. Schambra. Going back over the 30 years of the existence of the Fogarty Center and its precursor organization, the Office of International Research, in the Director's office at NIH, I think the first accomplishment we could point to and take a great deal of credit for is the role that the NIH and the American biomedical community has played in the post-war, post World War II era in which large parts of Europe and Asia were devastated in all aspects of their economy and society. Through the generous actions of the institutes at NIH and the Fogarty International Center, the support economically from the Congress and programmatically as well, we were ableto provide training opportunities for more than 20,000 foreign scientists since the late 1950s. I'd say that this was a major factor in the reconstruction and restoration of European science and Japanese science and technology in the biomedical field, and other fields of science as well. But certainly, emphatically and constructively in the field of biomedical science. So that would be the first one that comes to mind in response to your question. I'd say a second accomplishment has to do with the efforts that we, largely in the Fogarty Center, but also working with the institutes, put into developing formal relations with countries behind the Iron Curtain, Russia, Eastern European nations, China, and other countries denied free access to the outside world. So we were a window for them into not only modern science, but contemporary western culture. For us, it was a window into their closed societies, not only to understand them better, but to take advantage of sharing of scientific information that would advance a common humanitarian goal, which is health for all people around the world. A third highlight, I would say, has come up in more recent years. And I think Dr. Varmus touched on it in a way in discussing our role in the Fogarty Center in stimulating the institutes to deal with what we've termed global health threats or global health issues, looking at new and emerging infectious diseases such as AIDS in conjunction with the Allergy and Infectious Diseases Institute and CDC. Our biodiversity program that Mr. Porter played a very important role early on in encouraging us to undertake involving the National Science Foundation, the U.S. Agency for International Development, and other NIH institutes. I could mention the population program and the environmental and occupational health programs as well. So we have started along a path of getting the institutes and other components of the public health service, as far as that goes, more directly involved in the current time frame, but also hopefully in the future, involved in addressing health problems from a basis of American scientific expertise, but extended in a humanitarian tradition abroad, particularly in developing countries. I could probably name a few more. biodiversity program Mr. Wicker. Let me just back up and I'll end with this. Would you expand on your testimony about the biodiversity program, give us an update on the program. That's one of the questions Chairman Porter wanted to make sure we asked. Dr. Schambra. Indeed. And I'm very pleased to do so. The program has just completed its fifth year. We have had an outside evaluation of the program, which turned out to be very favorable and encouraging us to continue and expand. Mr. Wicker. Who conducted that? Was that conducted internally? Dr. Schambra. I think it was the Battelle Institute. Correct. It's the Battelle Institute. And if I could just summarize briefly their principal conclusions, they found that the program represented ``a daring and well thought out concept, secondly, the group activities were already making a difference in most of their host countries, third, that at the rate of $2 million to $2.5 million a year, the program was an incredible value, fourth, that the program be renewed with the participation of all three agencies, that is, NIH, NSF and USAID, if at all possible, with sufficient funds to support the current five groups as well as two new groups. And finally, that the product research target areas be broadened to include herbal remedies already used traditionally in host countries as well as agricultural chemicals and veterinary agents. We have enlisted the participation of the Department of Agriculture in a renewal of that program as well. I think that in spite of it being a relatively young program and one trying out new ways of doing business, that the discovery of about 300 active species, pharmaceutically active species, strikes me as a signal accomplishment, particularly when 10 percent of that number show promising pharmaceutical value, and one or two are well on their way toward being patented, a sign that the scientists and companies see likely products emerging. Mr. Wicker. So tell a taxpayer what they're going to get out of this program. Dr. Schambra. Well, we hope that we'll get a number of new drugs and therapeutics that will protect their health. I think if you judge the future by the past, something like 57 percent, if I recall the figure, 57 percent of the most prescribed pharmaceuticals in the United States today come from natural products. Aspirin came from a natural product, quinine to treat malaria came from a natural product. Two of the most effective compounds against certain kinds of cancer, vinblastine and vincristine, came from the rosy periwinkle plant discovered in Madagascar. And I could go on, and on, penicillin, of course, comes from a natural product. So if we look at the past and have that as a guide to the future, I think we can be very confident, confident, I repeat, that we will discover useful products from natural sources. Taxol is another well-known chemotherapeutic that recently has become widely known with of its origin from the Pacific yew tree. Mr. Wicker. Dr. Schambra, I want to thank you and the other panel members for being willing to stay well after the noon hour. I know I've enjoyed the hearing. I'm sure other questions will be submitted for the record. Mr. Wicker. And we want to wish you well. Mr. Schambra. Thank you very much, Mr. Wicker. Mr. Wicker. This concludes this morning's hearing. [The following questions were submitted to be answered for the record:] [Pages 1768 - 1806--The official Committee record contains additional material here.] Tuesday, March 17, 1998. NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES WITNESSES DR. STEPHEN I. KATZ, DIRECTOR DR. STEVEN J. HAUSMAN, DEPUTY DIRECTOR MARGARET S. KERZA-KWIATECKI, EXECUTIVE OFFICER ROBYN J. STRACHAN, BUDGET OFFICER DR. HAROLD VARMUS, DIRECTOR; NATIONAL INSTITUTES OF HEALTH DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. The subcommittee will come to order. We continue our hearings on the National Institutes of Health and welcome Dr. Steven I. Katz, Director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr. Katz, it is nice to see you. Please introduce the people who are with you and then proceed with your statement, please. Dr. Katz. Thank you very much. To my far left is Margaret Kerza-Kwiatecki who is our Executive Officer, and Robyn Strachan who is our Budget Officer, and Steve Hausman who is our Deputy Director. Also you know Mr. Williams, and I assume Dr. Varmus will be along momentarily. I am delighted and honored to appear before the committee as the Director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases. tribute to Mr. Stokes I consider it a privilege to tell you about the exciting science and plans in our research areas. I would like to begin by acknowledging the significant contributions of Congressman Stokes to the NIH and to the American people. He has been a tireless advocate for improved public health for all Americans, and an ardent supporter of the NIH in its quest to accomplish this goal. We at the NIAMS have within our research mandate many diseases that affect minorities and women disproportionately, diseases like systemic lupus erythematosus, and we are actively addressing various issues raised by Mr. Stokes for the past many years, and we are very grateful for all of his contributions. You have heard my past testimony, that virtually every household in America is affected by some disease of bones, joints, skin or muscle, and that these diseases have an enormous impact on one's quality of life. I would like to spend a few minutes focusing on my outlook for the future, where we seize upon unfolding scientific opportunities and invest in the unprecedented tools of medical research and on the bright minds that are being recruited to do this research. I believe that we can make an enormous difference in people's lives, if we wisely invest the funds proposed in the 1999 budget. bone diseases Let us start with our aging population. Imagine a future where quality of life is not compromised by pain and suffering brought on by bone fractures and arthritis--where people are productive and independent well into their senior years. We have learned an enormous amount about how bones become strong, and how they are constantly being built up and broken down. This past year, in an important series of discoveries, researchers supported by NIAMS, and the National Institute of Dental Research, identified a gene essential for the build-up of bone, thereby opening up exciting opportunities for the development of potential new bone strengthening interventions to prevent bone fractures, and also perhaps to repair them more expeditiously. This finding has clear implications for osteoporosis, Paget's disease, osteogenesis imperfecta, and many other bone diseases. building bone mass Move now to the younger years, to the schools. We are heartened to see children and adolescents benefiting from programs targeting their strong bones and reducing sports injuries. We know that calcium is critical for maintaining the integrity of bones and that people build up their bone ``bank account'' during the first three decades of life. During the past year, in studies in Mexican-American girls, we learned how the vitamin D receptor gene is related to bone mineral density, and why some girls are much more susceptible to low bone mineral density than others. We are supporting studies that will identify factors that may alter or reverse this susceptibility. osteoarthritis In arthritis, we know much more about the changes that occur in cells of the joints in people with osteoarthritis, and we are focusing increased emphasis on identifying appropriate markers to determine diagnosis, prognosis, and severity of osteoarthritis, the most common of the over 100 forms of arthritis. During the past year, we have learned how certain genes are turned on and produce products that cause cartilage cells to die. Until recently, it was very difficult to cultivate and propagate these cells in a test tube, but during the past year certain growth factors have been identified that enhance cartilage cell growth. These findings provide important scientific opportunities for increasing our knowledge of osteoarthritis. We are also continuing to increase our identification of risk factors such as obesity and knee and thigh muscle weakness in osteoarthritis, and we are supporting studies to identify preventive measures in this disease. Even small increments of knowledge may have an impact on this important and very prevalent public health problem. autoimmune diseases Move now to diseases that occur disproportionately in women. A major overarching category of diseases under study in our institute is autoimmune diseases, those in which the bodies' own cells turn against the body and cause diseases such as rheumatoid arthritis, lupus, Sjogren's syndrome, as well as alopecia areata, scleroderma, and many others. We are making progress in all of these, and advances in understanding one of these diseases has implications for all of them. rheumatoid arthritis Studies in tumor suppressor genes, long an integral component of cancer research, have revealed new insights into rheumatoid arthritis. Investigators have reported this year that synovial tissue from the joints of patients with severe chronic rheumatoid arthritis contain a mutated tumor suppressor gene that controls the growth of normal cells. This may, in part, account for the chronic overgrowth of joint-lining cells in rheumatoid arthritis and may suggest new approaches to treatment. familial mediterranean fever Another important discovery was made by researchers in our NIAMS Intramural Research Program. These investigators identified the gene responsible for the disease called Familial Mediterranean Fever or FMF. Attacks of this disease are characterized by widespread inflammation as manifested by arthritis, chest pain, abdominal pain, recurring bouts of fever, as well as skin rashes. This discovery will provide important insights into causes of inflammation in FMF and many other inflammatory diseases and provide for new and improved treatment for this and perhaps many other diseases that are characterized by inflammation. Funds provided in Fiscal Year 1999 budget will facilitate the development of animal models, diagnostic tests, andfurther identification of some of the mutated genes in this disease. skin cancer Move now to the beach, and other recreational sites. Here we see people of all ages enjoying time outdoors while taking informed and proven precautions to avoid the complications of skin cancer caused by sunlight exposure. During the past year, we have learned more about how certain mutated genes cause cancer of the skin, the most common form of human cancer, and we are now trying to understand how these effects might be reversed or altered. These brief highlights provide a glimpse of the hope that research offers for the many people suffering from the common, costly, crippling, and chronic diseases within the mandate of the NIAMS. future research plans What are the challenges to reaching the future that I described earlier, and how do we plan to invest the budget to address these challenges? The increased budget will allow the NIAMS to support more research grants in key areas of opportunity and need, and we will expand our research portfolio in a number of priority emphasis areas such as skeletal morphogenesis and growth, mechanisms of central nervous system damage and cardiovascular disease in lupus, blood and immune system effects on bone physiology, gene therapy in arthritis and skin disease, and structural biology of muscle membrane proteins. Also as a result of discussions that occurred during four clinical research working group sessions this year in arthritis, bone, orthopaedics and skin, we will expand our focus into more support of clinical research training and development and of patient oriented research in general. In closing, I want to express my thanks to the Members of this subcommittee for their strong and unwavering support of medical research. The budget request for the NIAMS for fiscal year 1999 is $295,576,000. I will be happy to respond to any questions you may have. [The prepared statement follows:] [Pages 1811 - 1817--The official Committee record contains additional material here.] building bone mass Mr. Porter. Thank you for your excellent statement, Dr. Katz. I think you said, and if you didn't, it was said earlier-- that we form our bone structure early and it can be only strengthened up to a certain age, early to mid-20's, something like that. Is that true? Dr. Katz. There have been many studies that we have supported over the years, that have demonstrated that once you build bone mass, which I call the bone ``bank account,'' that is a major factor in what happens subsequently. So it is really during that time, those first three decades, with a peak, perhaps, between the ages of 20 and 30, that once you hit your peak bone mass, it is all downhill from there. So the higher you start, the better off you are. You are constantly building up and breaking down bone, beyond the third decade. But the major mass of bone is built between the second and the third decade. Mr. Porter. So taking calcium supplements is not going to get you beyond your peak, but it may help you hold your peak longer? Dr. Katz. Exactly; exactly. If one looks at all of the interventions--and now there are many interventions we have, for example, to prevent osteoporosis, whether it is calcium and vitamin D, whether it is estrogen as hormone replacement therapy, whether it is one of the bisphosphonates, whether it is some of these new selected estrogen receptor modulators--all of them are used to block that downfall of bone that occurs in the older ages. Mr. Porter. Is an individual limited in how strong their bones can be by their genetic makeup, or can one do something in the first three decades to go beyond that? In other words, is there a way to reach a higher peak by what you do? Or is the peak limited by your genetics? Dr. Katz. In studies that were reported this year, for example, in the study that I quoted from Los Angeles in Mexican-American girls, it has been shown that the vitamin D receptor gene will correlate with bone mass. However, there are things that one can do to enhance bone mass. Calcium intake is one. There are many recommendations in terms of how much calcium one takes in, whether it is in the very early years, whether it is in the teenage years. There are other recommendations for exercise, for example. Exercise is an important factor in how much bone one builds up early in life and later in life. Mr. Porter. So you have control over that and can go to whatever limit that you choose? Dr. Katz. You have no control over your genes. But you can modify the amount of bone that you have by certain activities, and these are the activities that we try to educate the public about. Mr. Porter. Okay. Now vitamin D is necessary for calcium to be assimilated and used to build bone mass, is that correct? Dr. Katz. Right. Mr. Porter. Is it true that most people get enough vitamin D from their food, and from sunlight, that they do not need to take a supplement? I guess I am asking some medical advice here. [Laughter.] Dr. Katz. Many people get sufficient vitamin D in their diet, and by virtue of being exposed to sunlight, minimal sunlight, minimal outdoor light. There are studies that show that 15 minutes of exposure to the back of the hands is enough to develop your vitamin D for a one-day period. However, there are recommendations for vitamin D to be taken in individuals who do not get that minimal amount of exposure and there are large parts of our population that are not exposed. People who are homebound, for example, are not exposed to the ultraviolet radiation, and they may not get the vitamin D in their diets. As a consequence they are recommended to take vitamin D supplements. Mr. Porter. What part of the diet gets you vitamin D?What foods is it found in? Dr. Katz. Basically vegetables. It is also fortified in dairy products. rheumatoid arthritis Mr. Porter. What is the therapy of choice today for rheumatoid arthritis? Dr. Katz. There are many therapies, depending on the extent and severity of rheumatoid arthritis. There has been a change in the philosophy about the treatment of rheumatoid arthritis in the last several years, and that is it is currently thought that early, aggressive treatment is probably better than just a palliative treatment that coincides with how severe the rheumatoid arthritis is. So there are many studies, now, that are actually looking at early intervention with much more potent medications. Conventionally, one would start with non-steroidal anti- inflammatory drugs, and then go on in patients who are not responding to more potent drugs like---- Mr. Porter. Like steroids of some type? Dr. Katz. Of course, also steroids. Methotrexate is currently being used extensively. Methotrexate, which was developed as an anti-cancer drug, is being used extensively in rheumatoid arthritis, not only in adults but also in children. There are certain patients who do not respond to methotrexate, and as a consequence more potent drugs are used, like cyclosporin. And then there are developmental drugs that are being looked at right now, experimental drugs, to look at reversing some of the inflammatory effects. These are drugs that are being developed by pharmaceutical and genetic engineering companies. Mr. Porter. Cyclosporin. What is that? Dr. Katz. Cyclosporin is an agent which is called an immunosuppressive agent. It is formed from a fungus, but now, it is synthesized. It is used mainly as an immunosuppressive for transplantation biology. It was the major change that we saw in improvement of transplantation of organs--the advent of cyclosporin. Now there are other drugs like that which suppress the immune system by actually interfering with the internal workings of T-cells, which are very important in causing transplant rejection. That same type of inflammation is thought to be very important in the genesis of rheumatoid arthritis. calcium intake Mr. Porter. Studies have led to an increase in the recommended daily dietary allowances for calcium for all ages. It seems especially important for children, through their teenage years, to have an adequate supply of calcium in their systems daily. The new recommendation for children ages 9 to 18 is 1,300 milligrams per day. What do they have to eat, or drink, to get to this level of calcium intake? Dr. Katz. Well, a glass of milk is 300 milligrams of calcium. One glass of milk. So basically, they can get there with four glasses of milk. If they do not get there with four glasses of milk, they can get there with certain vegetables. Calcium is also contained in bread. Or many of them will take vitamins. Many multi-vitamins, for example, contain about 150 or 165 milligrams of calcium per vitamin tablet. Mr. Porter. Do calcium tablets have the same effect as food intake? In other words, can you supplement your diet with the pills? I guess you are saying yes, you can. Dr. Katz. Yes. Mr. Porter. And is this recommended for children? Dr. Katz. Generally not. Generally, it is recommended that they have a good diet, a good balanced diet that contains milk and milk products. As you have seen, our Secretary of HHS Dr. Shalala, has demonstrated with her milk mustache, promotion of the low fat or nonfat milk. Several glasses a day will provide the nourishment that one needs in terms of calcium and in terms of the required amount of calcium for young people. osteoprosis Mr. Porter. Some nutritionists believe that fat-free diets and the adherence to them has contributed to a rise in osteoporosis. Do you agree with that statement? Dr. Katz. I just do not know enough about it to make that correlation, but I can certainly provide that information to you. [The information follows:] Fat-Free Diets and Osteoporosis In trying to reduce dietary fat, individuals may potentially remove dietary sources of calcium and vitamin D. An inadequate intake of calcium and vitamin D in the diet many contribute to osteoporosis. Since diary products are the major source of both calcium and vitamin D in the American diet, the best way to promote skeletal health is to include fat-free or low fat dairy products in any fat-reducing diet. Although dairy products provide the most concentrated source of calcium and are fortified with vitamin D, other foods that are components of a low fat diet--broccoli, beans, kale, calcium-set tofu, fortified cereals, and orange juice--also provide sources of calcium. Exposure to the sun--15 minutes, both hands--can provide sufficient active vitamin D through conversion of a skin precursor, but this may be limited during the winter months at some northern latitudes. If an individual cannot take in adequate dietary calcium and has no sun exposure, calcium and vitamin D supplements may be indicated. Currently, at least 1,000 mg. of calcium (more in adolescents and people over 50) and 400 IU of vitamin D are recommended for optimal skeletal health. public education Mr. Porter. Let us talk for a minute about how you get the message out. We talked about it this morning. How do you get the message out to young people especially, that taking in adequate amounts of calcium is something that is going to help them later in life, or is that a message that never resonates with young people? Dr. Katz. Well, it is a message that we are trying to get out. Certainly, the milk moustache message is a good one. We have funded for the last 4 years, and have a request for applications for the next 5 years, an information source for getting out the message with regard to osteoporosis and related bone diseases. This has been carried out through the National Osteoporosis Foundation, through our Osteoporosis and Related Bone Diseases Resource Center, which we have funded in the amount of about $500,000 for the last 4 years. This is one of the ways that we have been able to get that message out. There is a particular focus that the Department, in general, has tried to make with regard to young people, not only with regard to calcium but also with regard to exercise. epidermolysis bullosa Mr. Porter. You state a couple of times in the budget justification that epidermolysis---- Dr. Katz. Epidermolysis bullosa. Mr. Porter. EB--EB is what I should have said--that EB is a prime candidate for gene therapy. How do you know which diseases are more receptive to gene therapy than others? Dr. Katz. Well, epidermolysis bullosa is a true success story in terms of investment of our Government funds. About 10 years ago, there was an investment in an epidermolysis bullosa registry as well as a repository of material. As a consequence of that repository, a tremendous amount of information was gained about the basic function of the area of skin that is affected in epidermolysis bullosa. There are actually about 18 different forms of epidermolysis bullosa, so we expect at least 18 different mutations, and in the last 7 years, or 8 years, a tremendous amount has been learned about what those mutations are, and those mutations are in genes that encode for various parts of this basement membrane zone. In fact, the success of that repository was so great that we have maintained just a part of the repository, but not the registry, because we have tremendous amounts of material there. So these gene mutations have been identified, and those that are most susceptible to gene therapy are currently being looked at in not only epidermolysis bullosa, but also in certain forms of ichthyosis which is a widespread fish-skin- like picture. Many of the genes have been demonstrated to be mutated in those diseases as well. There has been some correction of these defects. For example, in the last year, in a form of ichthyosis where it is known where the mutation is, one can now grow what we call keratinocytes, which are the main skin cells, epidermal cells, and one can insert genes that will then provide the integrity that the skin needs. So at least in culture this has been done in certain areas of the skin. Mr. Porter. Let us see if Mr. Hoyer can do better with the medical lexicon than I did. Mr. Hoyer. Mr. Hoyer. I have got a couple of questions to test me on that, and I was not sure, after your efforts, that I was going to try mine. Dr. Katz, I want to welcome you to the committee. Dr. Katz. Thank you. psoriasis Mr. Hoyer. Thank you very much for your leadership and what you do. It is very important work. Let me first ask, and Mr. Chairman, it is my understanding that the word I am going to use is not a word but a P-U-V-A as opposed to PUVA or PUVA. Mr. Porter. Good; you got it. Mr. Hoyer. But in any event psoriasis, obviously a pretty widespread disease, with 2 percent of the public suffering from it. Your institute has played an important role in developing an effective treatment, to which I have just referred. P-U-V-A. But there is also now, as I understand it, an article in the journal which says there may well be some relationship between the use of this therapy and the advent on the skin of a skin cancer, a melanoma. What are you doing about that to both educate users of this therapy and/or seeing whether or not there is a direct correlation, and if that correlation relates to particular skin types or users? Dr. Katz. Well, that is a very important issue that we are dealing with, and in fact we have been dealing with it for about 20 years. With the advent of the treatment, that is, where one takes, orally, a medication called Psoralen, and then exposes the skin to long ultraviolet, which is the UVA--that is why it is called PUVA--we anticipated, 20 years ago, that there would be problems on the skin in terms of long-term adverse effects of sunlight, which it is actually accentuated. So about 20 years ago, the institute developed a registry of all patients who were being treated with Psoralen and ultraviolet radiation. That registry is being handled at the Beth Israel Hospital in Boston by Robert Stern, and he has followed a cohort of individuals who have received this treatment. There are about 1,400 individuals who he has followed for close to 20 years now, to try to determine whether we would or would not see these adverse effects, these skin cancers. At about 15 years, he and the group started noticing, statistically, and through epidemiological studies, that there was an increase in the number of squamous cell cancers that were formed on the skin. As you may know, there are three main forms of cancer of the skin. Basal cell is the most common, and it is relatively easily treated. Squamous cell carcinoma is less common, but certainly can produce severe morbidity and mortality. It can spread to other parts of the body, and we have shown that this type of cancer does occur in these patients. So as a consequence, those patients are followed that much more closely. Now, the third type of skin cancer is a melanoma, which I think most people know can be an absolutely devastating disease, if not detected early. But if detected early, it is totally curable. Well, in this prospective study of 1,400 patients, Stern and his co-workers demonstrated that there is an increased frequency of melanoma in these patients who have had long-term PUVA therapy. Now, there are certain correlates that they have learned from this study. The correlate is the more therapy you have had, the more likely you are to get this type of melanoma. So immediately, one becomes rather cautious in the amount of PUVA that one gives these patients. Furthermore, patients who have had these large doses of PUVA are now more closely scrutinized to try to identify these lesions. If they are identified early, as I said, they are totally curable. So we continue to support this registry in order to try to identify what risks are really associated with PUVA therapy. The Europeans have done a very similar thing. This therapy started in the United States. The Europeans have used it extensively. They use a lower dose of UVA and have not found the association with melanoma. However, I do not know that they are following their patients as closely as Rob Stern is in Boston. Mr. Hoyer. Thank you, Doctor. I presume, in addition to that, that you are following patients more closely who use these therapies, not just the UVA, but the others as well, and warn them to be on the lookout for certain symptoms. Dr. Katz. It is an important balance here because one might say why would you expose any patients to the potential devastating effects of skin cancer, whether it is squamous cell cancer or melanoma? But these patients have severe, widespread disease. The alternative treatments carry risks in and of themselves, and it is a balance that is reached by the physician and the patient. osteoporosis Mr. Hoyer. Let me move on to a different subject, which the Chairman mentioned. I came in late, and I apologize if this question has been asked. Osteoporosis, obviously, is a very significant concern. I am told that it affects 709,000 men and women in Maryland. That would be somewhere in the neighborhood of about, I guess, 17 or 18 percent of our population. I do not know whether in answer to the Chairman's question you gave us an update on where we are on that. Perhaps it is in your statement, but could you tell me where we generally are on osteoporosis, other than having the milk ads, which I think are terrific ads, personally. But other than that what are we doing? Dr. Katz. I should say that across the NIH there are many Institutes that are investing in obtaining knowledge about osteoporosis. Actually, 14 different Institutes invest in various aspects of osteoporosis. The NIAMS, as the lead Institute, has invested in a broad spectrum, in a multi-pronged approach, from the very fundamental studies of learning about how cells lay down bone and break down bone. As I said in my opening statement, bone is no longer thought of as being just a stone that withers away. It is constantly being built up and broken down, and there are various cellular elements that are involved in the build-up and breakdown of this bone. This year, and I have outlined it in my opening statement, a very important series of discoveries were made from groups around the world. Some were supported by the NIAMS program, and they have demonstrated that there is a certain gene that is involved in the cells that actually buildup bone. So, once one knows that this gene exists, many investigators are now looking at the function of that gene to determine how one can produce more of what we call mineralization of bone to build up the bone more strongly. There are also animal models of osteoporosis and osteopetrosis that are being funded. Osteopetrosis is a human disease where there is too much bone being made, and there is certain information that one can learn from that as well. Last year the Chairman, Mr. Porter, asked me the question about the fibrodysplasia ossificans progressiva. You remember that question that you asked me. [Laughter.] Mr. Hoyer. I am sorry, but I did the very best with that question. [Laughter.] Dr. Katz. He did ask that question, and we continue to invest in our understanding of this disease. This is a really unfortunate disease that has been studied extensively, because what happens in these patients, usually young people, is that there is a deposition of bone throughout the soft tissues of the body. One might say, obviously, that this is terribly unfortunate, but is there something one can learn from that? And we have learned a lot from some of the studies that Dr. Kaplan has done in Philadelphia to try to understand what produces bone in the soft tissues, because perhaps we could utilize that knowledge for producing bone in the right place. We also support many studies of calcium metabolism in young people. We support studies that Connie Weaver in Indiana does every summer called ``Camp Calcium.'' She brings groups of teenage girls together, not only to educate them, but also to do metabolic studies, where their precise intake and output of calcium are studied very carefully. We are also, supporting clinical studies in these areas, so we cover the spectrum in terms of support. resurging enthusiasm Mr. Hoyer. Mr. Chairman, I know my time is up. Can I ask one more question? This is a general question, Doctor. I should have asked this of all the directors, and Dr. Varmus, of course, spoke to it in his initial presentation. How long have you been the Director of your Institute? Dr. Katz. 2.5 years. As director, 2.5 years. Mr. Hoyer. You have been at NIH for how long? Dr. Katz. At NIH for about 24 years. Mr. Hoyer. There was an extraordinary member of this committee, who knew more about NIH than almost all of the rest of us put together. It is unfortunate that he is no longer in the Congress because he was an extraordinary member. He hid it very well, but Joe Early was somebody who really cared about what we were doing. In that context, this is sort of a Joe Early question. He was very concerned as he saw the reducing pay lines in all of the Institutes and particularly concerned about are we giving encouragement to young people in medicine who would go into basic biomedical research, but as they see the pay lines withering and they see the opportunities decreasing, are discouraged from going into basic research. Frankly, I should have asked all of the research directors. What is your observation of the impact in terms of the extramural, grants over which you have sort of perspective of any adverse impact that is occurring as a result of reducing pay lines? We are trying to reverse that, I know, which is good. Dr. Katz. Well, you all have done a lot to really reverse that in recent years. Very clearly what you have done, what this subcommittee has done has created an air of enthusiasm for young people. Mr. Hoyer. Good. Dr. Katz. Before that---- Mr. Hoyer. The Chairman is due a lot of that credit. He has been a real giant in terms of this, I might add. Dr. Katz. We still see the results of the despair that some of the young people had in terms of the pay lines going down. These are really smart people, and they are thinking, ``Well, gee, why should I have to suffer in terms of worrying about whether I can actually do research, if even highly meritorious research is not being funded?'' So there was a lot of despair. I think a lot of that is being reversed in the last several years. There was despair in the clinical research community for a while, because clinical research was thought to be funded to a lesser extent than more fundamental research. I think with some of the activities that Dr. Varmus talked about--new incentives for clinical research, support of clinical research training and development, support of institutions for development of curricula that address patient- oriented research, and in talking about this to our professional societies--I feel that there is a resurgence of hope and enthusiasm. So I think that you all are really the cause of that resurgence of hope. Mr. Hoyer. Thank you, Doctor. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Hoyer. Mr. Stokes. Mr. Stokes. Thank you, Mr. Chairman. tribute to mr. stokes Mr. Porter. Maybe Dr. Katz would like to repeat a portion of his initial testimony for your benefit now thatyou are here. Dr. Katz. Well, I was extolling your virtues and thanking you very much on behalf of not only the NIAMS Institute that you have interacted with for so many years, not only with me, but also with my predecessor, Dr. Shulman. Even before the Institute was established 12 years ago, for many years before that, you were not only raising issues with regard to diseases that we are particularly concerned with that disproportionately affect women and minorities, such as lupus and vitiligo, but also showing sensitivity in terms of the importance of bringing minority investigators to the bench, and to the laboratory, and to the clinic to do investigation on all diseases. So thank you very much. Mr. Stokes. Thank you. You make me want to yield back my time. [Laughter.] Mr. Porter. I was going to say we are not even going to charge you with that. Mr. Hoyer. My suggestion would be that you yield it to Dr. Katz. [Laughter.] Dr. Katz. I could go on. [Laughter.] lupus Mr. Stokes. Thank you so much, Dr. Katz. It has also been a pleasure to interact with you over the years that you have been with the Institute and, as you mentioned also, your predecessor, who I worked with for quite a while. Unfortunately, I am next door at another hearing, and I was not able to be here during your presentation, and I appreciate your taking the time to repeat what you said so eloquently. You may have mentioned lupus in your formal presentation or in the questioning here, but, as you have mentioned, this is one of the areas I am particularly interested in. Did you discuss at all the association between heart disease and lupus today at all? Dr. Katz. I did. Actually, it is virtually impossible for me to talk about what the Institute does without talking about lupus. Lupus is a disease that we are very concerned with. We support research in all areas, from the very fundamental to the clinical. I did mention in my opening statement that, with the increased funds in the Fiscal Year 1999 budget, we are going to emphasize two areas of lupus erythematosus; one is in the area of central nervous system lupus erythematosus, an initiative that we are going to take with the Neurology Institute, and the other is the issue of arteriosclerotic disease in patients with lupus. There are concerns, obviously, with any of the patients who are taking long-term corticosteroid therapy. But there seems to be a 40 to 50 times increase in the amount of cardiovascular disease in women with lupus from the age of 30 to 50. We are tremendously concerned about that. We have convened panels of investigators, rheumatologists, to discuss this issue and an initiative that we can take. Before we undertake that initiative, we will certainly be working with the Heart Institute and getting experts in that area to work together on this as a special emphasis area, and that is one of the emphasis areas that was submitted to Dr. Varmus as one of our initiatives for 1999. Mr. Stokes. Dr. Katz, what part or how much of your funding is devoted to investing in the study of lupus and in lupus public education and outreach? Dr. Katz. In lupus erythematosus, our funding for 1997 was in excess of $24,000,000. It is anticipated that in 1998 it will be in excess of $26,000,000. We have, through our clearinghouse, as well as through our Office of Science and Health Communications, created many publications for the public about lupus, including publications that are particularly geared towards vulnerable populations. Two years ago we put out a booklet about what black women should know about lupus. We put that out in regular form and also in large print, so that people who had difficulty reading would have more access to information on lupus. With regard to our outreach programs, in terms of minority health and assistance, we have made contributions to the National Institute of General Medical Sciences for the Minority Biomedical Research Supplement program. We contribute in excess of $500,000 a year, and our minority health and assistance program is in excess of, for 1997, $30,000,000. lupus and vulnerable populations Mr. Stokes. I appreciate the data that you provided for us here in reference to minority women, in particular, because this is an area that you have concentrated on and which we are seeing some results. I noticed in your Congressional justification it discusses that recent research has found an association between lower socioeconomic status and higher morbidity and mortality in African Americans with lupus. What are the implications of this finding and the opportunity for further research advances. Dr. Katz. The study to which I referred and you referred just now is a study that came from one of our centers in Boston at the Brigham Hospital done by Matthew Liang and his coworkers. The implications of that study are that, number 1, vulnerable populations probably have less access to early diagnosis and early therapy for lupus erythematosus. As I told the Chairman, for treatment of rheumatoid arthritis, and lupus erythematosus, and many of these diseases, early diagnosis and treatment is very important in terms of curtailing some of the more devastating effects of these diseases. So, not only are we concerned with early diagnosis and treatment, we are also concerned with education. The educational programs that we have within the Institute, within our Office of Science and Health Communications, only represent one small part of our initiative in this area. Another part is supporting various centers that we have around in the country, in terms of their educational programs. For example, I have recently visited our Multi-purpose Arthritis and Musculoskeletal Disease Center in Michigan, where a particular focus is on how to educate people who do not have general access to the Web, for example, or access to fax lines, where they can utilize our resources on a regular basis. So this type of educational research is also ongoing, particularly in vulnerable populations. Mr. Stokes. Are the historically Black Colleges and Universities being utilized in the kinds of research in which you are involved, that particularly and uniquely impact the African American population? Dr. Katz. They are. I think all of the Institutes make contributions to the HBCUs through various programs. We do it through our supplement program and through some of our MBRS grants. The dean at Morehouse University is a rheumatologist and, before he went there, he was funded by the Institute in the area of lupus erythematosus. So there is an interaction. Should it be more? Yes, it probably should be more. clinical trials Mr. Stokes. How about clinical trials in your type of work, your research, are there some major clinical trials underway currently? Dr. Katz. There are major clinical trials. If one starts with lupus, again, one of the major clinical trials that we have is what is called the SELENA trial, which is addressing the question of whether oral contraceptives or hormone replacement therapy in post-menopausal women are deleterious or provide a negative effect in lupus erythematosus. For years it was thought that patients with lupus could not take oral contraceptives, could not take any type of estrogen, because it worsened their disease. Well, estrogen provides an important form of treatment or preventive treatment for osteoporosis. So there is a large populationthat does not have access to this. Two years ago we initiated a study, which is a multi-center study, addressing the question of the safety of estrogens--that is the ``SE'' part, the S-E of the SELENA--the safety of estrogens in lupus erythematosus. Those studies are ongoing, and they are accruing patients around the country. A large percentage of those patients are African American, because they are more frequently affected by lupus, and we look forward to the results of those trials. We have many other trials in lupus. We have one that is being started within our intramural program looking at cytoxan and fludarabine, which is an adenosine compound, to try to improve patients who have lupus nephritis, for example. That study has just recently begun. There was another study that was just completed within our intramural program looking at DNase treatment for lupus erythematosus. In many patients with lupus, they have immune complexes, which are made up of an antibody, plus the antigen to which the antibody targets. The antigen, in many cases, is thought to be DNA. So with this treatment one injects DNase to try to get rid of that part of the complex, so that it no longer can deposit within the kidneys. So these are the types of studies that we are supporting, clinical studies that relate directly to patients and translate not only to the patients whom we are treating, but also to patients who are affected by these diseases nationally and internationally. Mr. Stokes. Thank you very much, Dr. Katz. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Stokes. We have time for a second round. Let me get an indication of who has questions for round two. Mr. Hoyer or Mr. Stokes do you have questions for a second round? Mr. Stokes. I have questions which I will submit for the record. collaborations with the office of alternative medicine Mr. Porter. Dr. Katz, it seems your Institute works more closely on research initiatives with the Office of Alternative Medicine than many of the other Institutes. Do the diseases associated with your Institute lend themselves better to alternative methods of treatment? Dr. Katz. Well, our interactions with that office are considerable. I think one of the reasons is because underlying many of the diseases that we are concerned with is the symptom of pain. As you know, there are many alternative approaches to pain control, and that is one of the reasons why there is so much interaction. That interaction includes our supporting or administering three of the ten centers--actually, now it is four of the 11 centers--that the Office for Alternative Medicine supports. Three of these have been supported for about three years. They deal with all aspects of pain; some widespread pain, some pain that is particularly associated with low back pain. The recent Consortium for Chiropractic Research has been funded in Iowa at the Palmer College of Chiropractic, and the purpose of that Center is to try to help the chiropractic community develop the critically and scientifically important questions and ways to go about answering those questions using the conventional scientific approach, and we certainly hope that that will be successful. Also, we are, with the Office of Alternative Medicine, looking into the question of supporting a study looking at glucosamine and chondroitin sulfate for the treatment of osteoarthritis. So there is considerable interaction between our staff--we have an orthopaedic surgeon on our staff who works very closely with the office, as well as the head of our Rheumatic Diseases Branch. Mr. Porter. NIDR is the lead Institute on chronic pain. Are they involved with you in these matters? Dr. Katz. Not when it comes to the specifics of the Office of Alternative Medicine. We are all a part of the pain consortium that was started last year. I think most of the Institutes at NIH are a part of that because most of us deal with some aspect of pain. We each come to the table with our particular areas of concern. Our particular areas of concern are the pain of arthritis, the pain of fractures, and low back pain. So that is where our interaction with the Office of Alternative Medicine comes in. Mr. Porter. On the chiropractic grant, how many applications did you receive for that? Dr. Katz. There was one application. What that application represented was a consortium of not only schools of chiropractic, but also medical schools. For example, one of our grantees from Iowa, Malcolm Pope, is a part of that Center, and it is really to focus and to help the chiropractic community compete more successfully for funding with regard to conventional scientific approaches to questions. Those questions should be able to be answered using the conventional double-blind studies when possible. Mr. Porter. Are you saying that the chiropractic community responded well to this or did they respond very sparingly? Dr. Katz. The NIAMS and the Office of Alternative Medicine worked with the community long before the RFA was even put out. I think they responded in a way that they thought could bring together the best of the resources to build up the field nationally. So the Center does not represent just one school of chiropractic, but many schools of chiropractic because there are many investigators who are involved in this consortium. stress and low back pain Mr. Porter. You are aware that we had a briefing last fall on the role of the mind in health and healing and, as part of that, one of the persons who briefed us talked about the role of stress in respect to low back pain. Are any studies going on in that regard? Dr. Katz. We have many studies that we are supporting with regard to low back pain; none that deal very directly with the question of stress and low back pain. But one that I would like to cite is the study of Margareta Nordin, who is looking at workers at Con-Edison and the Transit Authority in New York. She is looking prospectively at individuals who have acute low back pain to try to identify those determinants that will result in chronic low back pain. Whether stress is one of those factors, we are yet to see the results of those studies. collaboration with the office of research on women's health Mr. Porter. Osteoarthritis is a major contributor to functional impairment and a major cause of disability. It also causes many individuals to undergo joint replacement surgery. Arthritis is more common in women and women receive a higher percentage of both hip and knee replacements than men. Do you plan to undertake any studies in conjunction with the Office of Research on Women's Health to better understand why arthritis is more common in women and why the incidence of joint replacements are higher in women? Dr. Katz. We do an enormous amount of collaboration with the Office of Research on Women's Health. As I said in my opening statement, there are so many diseases that we are concerned with that disproportionately affect women--all of the autoimmune diseases, as well as osteoporosis. We do co-fund grants with the Office of Research on Women's Health in all areas of arthritis, not only in osteoarthritis, but in rheumatoid arthritis and lupus erythematosus, et cetera. With regard to areas of osteoporosis, we will have some co- funding with them on some of the grants that deal with information about what is called periprosthetic osteolysis. Periprosthetic osteolysis is what happens when an artificial joint no longer fits into the bone, and one of the reasons it does not fit into the bone too well is because particles are released from this artificial hip or knee and produces inflammation around the bone, and it causes loosening. The problem, fortunately, does not occur very often. It occurs in 10 to 15 percent of hip or knee replacements. But when it does occur, it makes putting back an artificial hip or an artificial knee that much more difficult. So those are some of the areas that we co-fund with theOffice of Research on Women's Health. Also, the SELENA trial, for example, the one that I spoke to Mr. Stokes about, was co-funded by the Office of Research on Women's Health and many others as well. gender and autoimmunity Mr. Porter. Do we know why autoimmune disorders have a disproportional effect on women? Dr. Katz. No, but we are trying to find out. About a year and a half ago, we put out a request for applications along with the National Institute of Allergy and Infectious Disease, the National Institute of Diabetes and Digestive and Kidney Diseases, and other institutes that are concerned with autoimmunity. Many of these autoimmune diseases occur more frequently in women than men. We have put out a request for applications dealing with gender and autoimmunity. This year, we put out an RFA again with these other institutes on autoimmunity mechanisms, genetics and pathophysiology to address this question of gender. We have gotten applications. We now fund applications in gender and autoimmunity. NIAID got the bulk of those applications, and they now fund direct responses to that RFA. Excuse me; it might have been a program announcement. But we all fund applications in response to that announcement. cartilage restoration Mr. Porter. It was reported in the Washington Post on January 28 that a new surgical procedure called biological resurfacing, developed at the Mayo Clinic, has successfully restored cartilage damaged by injuries to the knee and other joints, delaying or preventing the need for joint replacement. Are you familiar with this procedure, and can you describe it to us? Mr. Katz. There are several resurfacing techniques that have been popularized. The one that recently received FDA approval is when one has an injury to the knee or to any articular cartilage where there is a specific defect, one can take cartilage cells from that individual, grow up the cartilage and then return those cartilage cells to that particular defect. Now, that does not really correct osteoarthritis. It corrects a specific defect that is usually due to injury. Those studies were initially done in Sweden and now have been done extensively in the United States. Whether that is really extrapolatable to osteoarthritis is another question. There are many people who are trying to address the question of taking and growing cartilage cells or chondrocytes and then inserting certain genes into those chondrocytes to make them more likely to take in the joint. hair loss Mr. Porter. This question is on hair loss. I remember reading somewhere that Americans spend $7 billion a year trying to fight baldness with drugs, cosmetic surgery, and wigs. An article published in Science this past January stated that the first human gene ever linked to hair loss has been identified in Pakistan. This gene causes a rare condition found only in a Pakistani village, not the more common types of baldness, but like all gene discoveries, you have to start somewhere. Do you have any studies planned to expand on this discovery? When do you think we will have a gene therapy for baldness? Dr. Katz. Well, I was taught that one never gives a time frame for these things. [Laughter.] And certainly, as a dermatologist, I would not venture a guess with regard to that. But I think it is important to identify that the study that was reported, really derives from many of the investments we have made in developing animal models, because that gene, that hair loss gene was first identified in a mutant mouse that was identified, I believe, at the Jackson Labs in Bar Harbor, Maine. And it is from those types of studies that Angela Christiano and her co-workers, who are supported by the NIAMS in an early career award, what we call an R-29, and now I think she has another award, a small grant, to support her work, they have demonstrated that this gene is defective in this particular family that has seven generations of individuals who are actually born with hair and then lose the hair shortly thereafter, and the hair does not regrow. Now, the title of that paper was unfortunate, because it talked about alopecia universalis. Alopecia universalis is a term that is usually used for acquired hair loss in children or adults. It can be a devastating disease, devastating, as you can imagine, psychologically. But the alopecia universalis that was identified by these investigators was the inherited form of alopecia universalis. Will this help us understand hair growth? It certainly will. Mr. Porter. I cannot imagine why the staff wanted me to ask that question. Mr. Hoyer? Dr. Katz. You cannot? Mr. Hoyer. Well, I cannot understand either, Mr. Chairman, but it is my understanding that if there is not a quick answer to that, the budget for this Institute is in trouble. [Laughter.] success rates Mr. Hoyer. Doctor, let me go back to my pay line question, and Dr. Varmus may want to comment on this, too. First of all, can you remind me, because I do not know, where we are now on the pay line on your extramural grant and where that relates to, for instance, we were 5 years ago or 10 years ago? Dr. Varmus. Do you want to know for the whole NIH? Mr. Hoyer. Well, either the whole of NIH or this institute, if we have it. I would like both, sure. Dr. Varmus. Well, the overall success rate for all of NIH this year is going to be roughly 28 or 29 percent. We are forecasting 31 percent in the coming year. I mentioned the other day the importance of an equitable success rate for new investigators. The success rate that we have been talking about includes people applying for a new grant, who may not be new investigators---- Mr. Hoyer. Right. Dr. Varmus [continuing]. And those applying for their continuation grants, the competitive renewal. Of course, those who have achieved a grant before tend to do better. New investigators have success rates of around 22 to 24 percent at the moment. Five or 10 years ago, the success rates had declined overall at NIH to the low twenties. In some institutes, the success rate was as low as 10 or 13 percent. And when you disaggregated that further and looked at the R01 specifically and excluded, for example, the health services research grants or the R03s, which are smaller awards, some categories, the success rate could be as low as 5 or 8 percent. So, we have come quite a long way, and we envision going further. We are especially pleased with the President's budget request for this year because it forecasts 5 years of continued increases, allowing us to maintain a very stable environment that gets us back to your earlier point about providing an inviting environment for doing science, one that allows innovation and encourages the best people to come into the field. I appreciate your bringing up this issue. Mr. Hoyer. Following up on that question, have we had enough experience or has there been sort of a lineal study done with reference to what level you become at risk of losing a flow of researchers into basic biomedical research? In other words, have we drawn any conclusions from this experience that if you are up in the forties as opposed to if you are down in the teens? Dr. Varmus. That is a very difficult question to try to answer. I think you would find that if you went to the very best training sites that very, very good young people have been entering the system even in those periods of relative drought, but that when you go to, perhaps, one peg down, you might find that the quality of new entries into medical research has declined. I think that the place we have seen the decline in interest most profoundly is in the clinical research arena, because the training program is less well developed; the risks to clinical investigators who have an alternativecareer as practitioners is greater; and the support that can be provided to clinical investigators through patient revenues has declined as a consequence of the incursion of managed care into the academic health centers. Mr. Hoyer. Doctor, let me ask you another question on that. Assuming unlimited resources, for the sake of argument, what would you speculate would be an appropriate pay line, unrelated to resource availability? In other words, what I am saying is---- Dr. Varmus. I understand. Mr. Hoyer. Of the cohorts of applications, how many really good ones are there to do good science, and therefore, if it is 60 percent or 70 percent, we have 30 percent out there if we are doing 40 or 35, that is really good science that we are not funding. Dr. Varmus. This really is a somewhat subjective judgment. Mr. Hoyer. Sure. Dr. Varmus. But most people that I have talked to feel that if we were funding in the range of 30 to 40 percent of the applications, that would be about right. In my view, there should be a basement level; that is, all institutes should be up to that kind of level, and we should be supporting new investigators at roughly 30 or 35 percent, because I am particularly concerned about investing in 10 years of training and then not letting at least a substantial portion--a third to a half of those trained people--have a chance at doing research with NIH grants. Mr. Hoyer. Given that, Doctor, and you said we are going to be at the 31 percent average---- Dr. Varmus. That would be an average. Dr. Katz. An average, but it cuts across many institutes. Dr. Varmus. Yes, and not all institutes are at that level, and not all the new---- Mr. Hoyer. My question, therefore, is what is the low, and what is the high, if you know? Do we know? Dr. Varmus. Oh, I believe we do have those numbers. The highest numbers are for competitive renewals, and that would probably be in the range of 55 percent or so. The lowest numbers would be for new investigators at certain institutes, and the number is probably about 20 percent or a little lower. Dr. Katz. Our level for success rate last year was about 24 percent. Mr. Hoyer. For new competitive---- Dr. Katz. For total. Mr. Hoyer. Total. Dr. Katz. Total; but that may not be the right way to actually look at it, because, as Dr. Varmus said, if one looks at new investigators, our new investigators, we have maintained our new investigators at that level. We would like to be higher, but we have maintained them at about the same rate as the established. Mr. Hoyer. It seems to me this is a pretty key question for this committee, to make sure that we do not fall below an at risk. Obviously, we will never be given all of the resources that we need, but we do need to have some sort of feel that we can go to the floor. The chairman can go into the 602(b) allocation discussion with the other subcommittee chairs, and say look, here is where we are, but we need to be is here. And, Doctor, that is particularly true in light of your comments in your statement, which I have now read while I have been sitting here. That it is, particularly for those of us that it has become more relevant to as time goes by, the kind of world which you express in your statements is a pain free or substantially less problems in the aging process than now exist and the amelioration of a lot of the quality defeating aspects of growing old. And you paint a picture which is certainly exciting. Certainly, I think, many of us believe that we are on the threshold because of the findings that have gone on to a major spurt, which you seem to indicate, in the next decade or two decades of a geometric increase in our knowledge and ability to cope with problems that confront the health of Americans and the people of the world. Dr. Katz. I am certainly enthusiastic that we can achieve those goals and attain that type of world. Mr. Hoyer. Well, it is exciting. Thank you. Mr. Porter. Thank you, Mr. Hoyer. Can I follow up on questions that Mr. Hoyer asked? Ten years ago we were in the low twenties, I think you said, Dr. Varmus. Dr. Varmus. That is about right. I would have to take a look at it. Mr. Porter. Now, we are almost to the low thirties. Dr. Varmus. Almost. Mr. Porter. Ten years ago, we were funding NIH very strongly. There has always been strong support for NIH. What made the difference? Dr. Varmus. Well, there was a time in about 1990 or 1991 when the numbers of grants that came up for renewal was high, and I would have to look back exactly at the level of funding. There were a couple of years that were not so strong, and one of the lessons I took away from this experience was that even one or two years of a very low funding rate could have a really disastrous impact on the system, because it meant that many investigators were denied their renewals or failed to get a first grant. Of course, they submit a reapplication. Then the system backs up with a lot of high quality grant applications in the system that are not getting funded. The reviewers get very discouraged, because they are giving high marks to grants that do not get supported, and the impact on the mood in the scientific community is probably much larger than you might have expected from the moderate difference in the number of grants actually supported. Mr. Porter. I am not sure whether that means that scientists got discouraged because there were not as many being supported, and, therefore, we did not get as many proposals of good science or what it means. Dr. Varmus. No; the number of applications was high and, of course, stayed high because people were resubmitting applications. But we have talked before about the effect of discontinuation of a productive laboratory--it means that you lay people off and it is very hard to reconstruct a laboratory. Senator Hatfield used to make the analogy of the lumber mill. If you lose funding, and if you take the mill apart send your lumbermen home, by the time you try to reinvest, it is very difficult to get restarted. So, that has kind of a widespread effect, for example, on a timber-oriented culture. Mr. Hoyer. Mr. Chairman, excuse me. Mr. Porter. Mr. Hoyer? Mr. Hoyer. If you will yield. Mr. Porter. I yield. Mr. Hoyer. Joe Early, to whom I referred earlier--I do not know how many of you--most of you know Joe Early; he was and is an extraordinary fellow, and I learned a lot about NIH from Joe Early, and I sat--I was where Mrs. Northup sits now for about 6 years. I think I filled the last rung on the ladder. And Mr. Porter---- Mr. Porter. I was the last rung on the after end, which was the minority end. Mr. Hoyer. I was going to say: Mr. Porter, did you start in January of 1983? Mr. Porter. No, I started on the subcommittee in January of 1981. Mr. Hoyer. Okay; Mr. Porter was on the committee 2 years before I was. But I can remember, John, as you can remember, as the eighties went on, the pay line went down,and Mr. Early used to raise the specter of the pay line, and I know it got down into the teens in a number of institutes, and I believe these were first time grants, not renewals. And he kept remembering, and then, we would have the markups. And he would come in with, we thought, an unbelievable amount of money. He would ask for a half a billion dollars more for NIH, and we all sort of rolled our eyes. And he was pretty successful. As you recall it, during those days, we had one vote on the committee. Mr. Natcher told us what we were going to do, and we all did it. But we tried to urge him to agree to our position. That was really what the deal was. But I can remember, Mr. Chairman, Joe got very concerned about how that pay line kept going down, even though we kept putting more money in NIH, and, to wit, your question of what has made the difference. Is my recollection right on that? Dr. Katz. For the NIAMS, it is certainly true in 1992 and 1994, we were below 20 percent. We were in the high teens but below 20 percent. There is another factor, I think, going on here, and that is that in the eighties, particularly in the area of clinical specialties and support of clinical research, there was much more money within departments to provide for investigators who were not being funded. And now, as Dr. Varmus said, those people cannot stay in the system for as long and be rejected for as long, because that other support that used to come from patient care revenues and other sources of funding through pharmaceutical companies is much less today. So, we do not have that resilience that we once had. Mr. Hoyer. Mr. Chairman, that may be interesting. If you have those statistics, that analysis might be a good one, Mr. Chairman, for you as to why this is important, because the pharmaceuticals and the universities have less resources available to them. And so, even though we are spending more, the net resources are either even or declining. Mr. Porter. Yes; we have been talking about what can be done in this respect, because obviously, it is a very serious problem. Mr. Hoyer. Thank you, Mr. Chairman. Dr. Varmus. I did not give you entirely correct numbers. It was 25 percent in 1990, and some of the other numbers are higher. I would like to gather the numbers, if I could, and submit them for the record. Mr. Porter. Please. Dr. Varmus. And supply a more accurate rendition of what I just told you. Mr. Hoyer. Mr. Chairman, could you go back further, going into, say, 1985? Dr. Varmus. Oh, we can, yes; at that time, or earlier, it was really extremely high, in the forties. Mr. Hoyer. Well, it seemed to me it must have been high in the beginning eighties. And then, as we got into 1987 and 1988, it must have gone down, because I can remember: that is when Mr. Early really got concerned and a lot of questions to every institute director: what are your pay lines? And that is when I got into what pay lines were. I had no idea what he was talking about to begin with. But I learned, and obviously, the consequences of it were made known to us. So, Mr. Chairman, if, in your statistics, we can see that flow and then relate it to what resources are available from the--or the secondary or primary sources, however they looked at it---- Mr. Porter. Dr. Varmus, since you will be here over the next few days, can we raise this question then rather than---- Dr. Varmus. Sure. Mr. Porter [continuing]. Answering it for the record? Dr. Varmus. Sure. Mr. Porter. Can I ask one further question, since Mr. Hoyer raised it and you referred to it in your remarks earlier? And this is not a partisan question, although it may sound like it, but a year ago, when the President submitted the budget for the current fiscal year, he had NIH at a very low increase. I think it was like 2.6 percent. Dr. Varmus. Last year. Mr. Porter. Last year, which was the budget for this fiscal year. And, as a result of the balanced budget negotiations, NIH was not put at a high priority; in fact, we figured out that the outcome would be at 1.2 percent if we followed the President's budget at that point a year ago. This year, the President has come back and said gee, we have got to give NIH an 8.4 percent increase and double their funding over the next 5 years. What within the administration-- -- Dr. Varmus. Forty-eight percent over the next 5 years. Mr. Porter. I am sorry; 50 percent, yes, 50 percent increase over the next 5 years; we are more ambitious than the White House. But what has caused this change of heart within the administration about this subject that seems to those of us who are on the subcommittee on both sides of the aisle to have been a high priority all along? Dr. Varmus. Well, I do not believe that there was lack of enthusiasm for the NIH in previous years. I think there was concern about how to meet the demands of balancing the budget. The President has always signed the bills and has been outspoken in praise of medical research and other forms of research. We actually were doing better in his budget proposal last year than some other agencies. Obviously, his proposal was not as beneficial to us as the ultimate appropriation bill was, but I would not see this as a change of heart so much as a change of circumstances and a response to it that is obviously welcome to both of us. Mr. Porter. Are you confident that the President will not come back next year and suggest another very low increase? Dr. Varmus. I believe that he will stay by his word, and the 5-year projection will be a good starting point in our negotiations. Mr. Porter. The President's budget included substantial revenues that are unlikely to be voted this year, and those are revenues that support discretionary spending which, of necessity, comes after entitlement spending. If the revenues are not there, what would your budget look like under the President's figures? In other words, if you took the amount out for this next fiscal year, which I think is something like $16 billion, with $100 billion over 5 years, and you allocated it to NIH, what would his number be? Have you calculated that, by any chance? Dr. Varmus. I am not sure I follow the question. Are you asking me---- Mr. Porter. Well, if you assume that you will not have the $100 billion worth of revenues in the President's budget that is partially the support for all discretionary increases, what would your increase drop to? Dr. Varmus. Well, what the President is proposing for NIH is an increase that is based on revenues that are brought in by tobacco legislation. Mr. Porter. All of it? Dr. Varmus. The increase. Mr. Porter. So, you would be level-funded if there are not any new revenues? Dr. Varmus. Well, let me finish. He is making that proposal as a way to request more money than would be available to us under the current caps that were imposed by the Balanced Budget Act of last year. He has said that he believes that tobacco legislation will be passed. If that does not happen, he will work with the Congress to find other ways to fund the research proposal that he has built. Obviously, at that point, he and the Secretary and the Vice President would have to negotiate with Congress to find another source of funds for those things that he considers high priority. Mr. Porter. My worst nightmare in this respect is thatCongress does very well by biomedical research, not so well by some of the other priorities that the President has in mind, and we end up in a negotiation with the White House where the President decides it was not such a high priority after all. And without the revenues being present, I think we are going to face possibly the kind of problem that I am worried about. I am hopeful that that is not the case and that this is a real look at all of the priorities, and we have many of them within our portfolio, and that the President feels that biomedical research is at or near the very top of the list. Dr. Varmus. So I have been assured. Mr. Hoyer. Mr. Chairman? Mr. Porter. Mr. Hoyer? Mr. Hoyer. We have another problem, of course, in that the Senate bill and, I presume, the House bill, when it comes to the floor, will have another $26,000,000,000 in ISTEA, which will be $5,000,000,000 a year against the caps, which is going to impact on all of the rest of discretionary spending if we do not change the caps. So, we have some very significant funding challenges that confront us, notwithstanding whether the tobacco settlement is adopted. Mr. Porter. I think it is very clear we are not going to change the caps, and that is why I have been saying as often as I can I think we have to realistically look at the start of this 5-year increase, whether it is 50 percent over 5 years or 100 percent over 5 years next year, not this year, because things are going to be pretty rough to get the budget finally into balance, and that all assumes that we have an economy that is expanding at the rate that it has been recently. It is a very tough question for us here. Dr. Katz, we thank you for the fine job you are doing. Dr. Katz. Thank you very much. Mr. Porter. We thank you for your excellent testimony and appearance here today, and the subcommittee will stand in recess for 3 minutes. [The following questions were submitted to be answered for the record:] [Pages 1839 - 1912--The official Committee record contains additional material here.] Tuesday, March 17, 1998. NATIONAL CENTER FOR RESEARCH RESOURCES WITNESSES DR. JUDITH L. VAITUKAITIS, DIRECTOR DR. LOUISE E. RAMM, DEPUTY DIRECTOR DR. DOV JARON, ASSOCIATE DIRECTOR FOR BIOMEDICAL TECHNOLOGY ANNE E. SUMMERS, BUDGET OFFICER DR. HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. The subcommittee will come to order. We continue our hearings of the National Institutes of Health with the National Center for Research Resources, and we are pleased to welcome its director, Dr. Judith L. Vaitukaitis. Dr. Vaitukaitis, if you would introduce the people you have brought with you and then proceed with your statement, we would appreciate that. Dr. Vaitukaitis. Thank you, Mr. Porter. To my left is Dr. Dov Jaron, who is the associate director for Biomedical technology. To his right is Dr. Louise Ramm, who is the deputy director for NCRR. To my immediate left is Ms. Anne Summers, who is our budget officer. And you know the gentleman, Dr. Varmus to my right and Mr. Williams to my far right. ncrr request Mr. Chairman and members of the committee, I am pleased to present the President's budget for the National Center for Research Resources for fiscal year 1999, a sum of $423 million which is an increase of $51 million or 13.9 percent above the comparable fiscal year 1998 non-AIDS appropriation. Including the estimated allocation for AIDS in both years, Federal support proposed for NCRR is $514.8 million or an increase of $60.9 million over the 1998 appropriation. It is a pleasure once again to have the opportunity to discuss the accomplishments and future directions of the NCRR, which fills a unique and indispensable niche in the family of NIH institutes and centers. Unlike the other components of NIH, which focus on particular biomedical disciplines, diseases or organ systems, NCRR provides the essential tools and infrastructure that facilitate all lines of NIH-supported research, ranging from basic to clinical investigations. NCRR can best be described as a catalyst for discovery, for without advanced instrumentation, up-to-date research facilities with access to specialized expertise, and animal models for human diseases, the scientific enterprise would be slowed and more costly. Each year, more than 15,000 investigators, supported by more than $1.8 billion from the NIH categorical institutes, utilize NCRR-supported research resource facilities as integral parts of their research. Shared instrumentation grants and repositories for both biomaterials and animal models are also invaluable resources to thousands of additional investigators. Our fundamental objectives are to direct NCRR's support to maximize sharing of research resources and technologies, enhancing multidisciplinary research by fostering collaborations among investigators and leveraging Federal funds. advanced instrumentation and computers Advanced instrumentation and computers have a fundamental role in most biomedical studies, yet, they also account for some of the largest expenses. To help reduce costs while providing access to the most sophisticated research tools, NCRR supports shared instruments and resources, including a network of more than 60 biomedical technology resource centers that develop and provide access to critical technologies for health research, ranging from those for degenerative brain disorders, cancer, and cardiovascular diseases to AIDS. Shared resources are essential tools in efforts to unravel the complexities of the human genome as well as to define the genetic defects that lead to diseases such as sickle cell anemia, cystic fibrosis and a variety of cancers. This enormous undertaking requires an array of sophisticated and costly instruments such as sequencers, mass spectrometers, analytical ultracentrifuges and nuclear magnetic resonance imagers. By awarding grants for these instruments as shared resources, their utilization is greatly increased. On average, more than 15 investigators share each instrument provided through NCRR's Shared Instrumentation Grant program. In fiscal year 1999, NCRR will significantly expand this unique program to assure that investigators have state-of-the-art research tools. In recent years, it has become increasingly clear that a complete picture of the genome can only be obtained if gene identification efforts are supplemented with studies to characterize the proteins produced by the genes. At anNCRR- supported microscopy and imaging resource at the University of California, San Diego, scientists are developing microscopic methods that permit mapping of both genes and their products in situ for Alzheimer's Disease, for example. Resource facilities like this and others will accommodate investigator access and permit remote control of sophisticated instruments over the Internet and facilitate electronic communication with colleagues at other sites. Such arrangements will permit interactive tasks as if the collaborators are in the same laboratory. Continuing developments in computer technology and establishment of the ultrafast Internet-2 will allow extensive scientific collaboration and sharing of research resources and technologies. In fiscal year 1999, NCRR plans to expand these initial efforts, so in a few years, cooperating university Internet sites will provide gateways to access sophisticated technologies, investigators and databases across the research community. X-ray crystallography provides the ultimate details of molecular structures. The ultrabright synchrotron-generated x- rays have made it possible to increase resolution to levels that were not believed possible just a few years ago. For example, NCRR-supported scientists at Stanford University recently determined the detailed structure of the protein fibrinogen, which is essential to stop bleeding but also contributes to heart disease and stroke. As the human genome project identifies more genes, more proteins of unknown structure and function will require characterization in order to define the causes of disease and to develop novel therapies for them. In fiscal year 1999, NCRR plans to increase its support for investigator access to synchrotron beamlines. advanced technologies As research problems become more complex, their solutions require more sophisticated technologies that demand an integrated approach. For example, the attached figure summarizes the interaction of several costly, advanced technologies that contribute significantly to the development of novel drug therapies. This approach is commonly referred to as structure-based drug design. Either high-energy x-rays, high field nuclear magnetic resonance or both technologies provide essential data about the structure of a purified protein. In the figure before you, high-energy x-rays, generated at the Advanced Photon Source at the Argonne National Laboratory, provide a key tool to analyze a crystallized protein. However, that crystallographic data may not be enough. That same protein may also need to be studied by high field nuclear magnetic resonance at an NCRR-supported research resource facility such as the Massachusetts Institute of Technology's Center for Magnetic Resonance to gain additional information to discern the protein's molecular structure. Data from synchrotrons or NMRs can be analyzed by special software designed to run on a supercomputer, which may be located at the University of Pittsburgh. That processed information may then be moved over the Internet and analyzed by 3D visualization tools, using the investigator's own workstation. The image in the center of the figure was created with a molecular graphics system at the NCRR-supported University of California at San Francisco's Computer Graphics Laboratory. Visualization tools help identify the site on the molecule at which a drug may interact. Candidate drugs and proteins which may bind at the active site can be selected from databases over the Internet at sites somewhere in the U.S. or Europe. The molecule displayed is HIV- 1 protease (shown in green and yellow) along with a drug candidate (depicted in magenta) bound within the enzyme's active site. The drug inhibits or blocks the biologic action of the protease and is a potential new treatment for HIV infection in man. The structure of HIV-1 protease was solved by members of the Crystallography Laboratory of the National Cancer Institute. Structure-based drug design is a faster and more cost-effective approach to drug development than the empirical approaches used in the past. Other recent developments in areas related to genomic research will generate major new multidisciplinary initiatives. Areas such as laser light source technology and design of extremely small-scale tools using nanofabrication and nanobioengineering techniques are now so advanced that engineers and scientists are constructing devices for detection of single molecules and miniaturizing instruments that will save expensive reagents and man hours. For example, the development of microchips for ultrasensitive DNA analysis is a revolutionary approach to miniaturization. Manufacture of these chips requires multidisciplinary expertise in production of computer chips, molecular biology, optics, and gene sequencing that will bring together physicists, engineers and biologists. NCRR plans to extend its support to provide these powerful tools to identify genetic risk factors which may be modulated by diet, changes in lifestyles or other approaches to prevent, delay or treat disease. biology of brain disorders Thanks to powerful new technologies such as functional magnetic resonance imaging, or fMRI, and multiphoton laser scanning microscopy, scientists have gained increasingly detailed insight into the biology of the human brain. NCRR- supported researchers at Carnegie Mellon University, University of Pittsburgh Medical Center, and Pittsburgh Supercomputing Center have combined the powers of fMRI, high-speed networks and a supercomputer to produce high-quality 3-D images of the working brain within seconds of recording. To capitalize on these technological enhancements, NCRR will support development and acquisition of instruments that provide images of the brain, including images of tissue damaged by neurodegenerative diseases such as Parkinson's or Alzheimer's, in even more detail than currently possible. In addition, NCRR will support development of user-friendly database structures to facilitate investigator analysis and synthesis of vast data sets. genetic medicine Nonhuman biological and disease models are indispensable to biomedical research. To understand gene function in cancer, diabetes and cardiovascular diseases, for example, scientists have developed thousands of genetically altered animal models in mice and rats. To assure preservation of these models, which are expensive to maintain, NCRR will create additional national and regional repositories to assure that novel genetically altered mice and rats can be distributed to investigators nationwide. Certain studies with great implications for human health can best be carried out in nonhuman primates. Examples include development of a vaccine against AIDS and in-depth understanding of the immune system. Scientists at NCRR- supported Regional Primate Research Centers have developed procedures for producing genetically identical monkeys. Availability of these animals will facilitate development of an AIDS vaccine and provide a unique model to more effectively study tissue rejection associated with organ transplantation. NCRR plans to further develop this model. Gene therapy is still at an early age but holds great promise. NCRR, in collaboration with the National Cancer Institute, the National Heart, Lung and Blood Institute and the National Institute of Diabetes, Digestive and Kidney Diseases, supported the establishment and maintenance of three National Gene Vector Laboratories that produce clinical-grade gene vectors or carriers. These gene carriers are used in human gene therapy to transport therapeutic genes into cells where they are needed to alleviate or cure diseases such as cystic fibrosis, atherosclerosis and an array of cancers. But the technique still needs refinement, and additional vectors need to be developed and studied. Because the safety of new vectors must be extensively examined, NCRR plans to support the development of additional vectors as well as their preclinical evaluations at NCRR-supported research resource facilities. research capacity NCRR administers an NIH-wide extramural construction grant program that requires matching institutional funding. The awards support renovation or new construction of researchfacilities at medical schools, hospitals, universities and research institutions. According to a 1996 survey conducted by the National Science Foundation, academic institutions had deferred $3.6 billion worth of needed biomedical construction and repair or renovation projects. To help alleviate this need, NCRR plans to continue funding of construction projects to upgrade biomedical research facilities. General Clinical Research Centers play a key role in patient-oriented research, and that research reflects that supported by the NIH categoric institutes. The GCRCs host nearly 9,000 investigators who conduct nearly 6,000 research projects annually. The GCRCs provide infrastructure to academic institutions through the support of inpatient and outpatient research facilities and other resources vital for state-of-the- art, patient-oriented research. The GCRCs also provide an effective forum for training and junior career development for mentored, patient-oriented clinical research. The GCRCs need to expand research activities into less traditional GCRC research areas, such as intensive care, emergency rooms, trauma units and other specialized units. Seriously ill patients are increasingly studied at GCRCs, and the need for specialized testing and research nurse staffing to support those research studies has increased markedly. To address this need, NCRR in fiscal year 1999 will enhance support for the network of GCRCs which provide a critical interface to assure that scientific advances for rare diseases, cancers, diabetes mellitus, AIDS, cardiovascular and many other diseases are transferred from the laboratory to the patient. To enhance research on diseases such as renal disease, diabetes mellitus and cancer that disproportionately affect minority populations, NCRR will support establishment of Centers of Clinical Research Excellence at NCRR-supported Research Centers in Minority Institutions that are affiliated with medical schools. The centers will recruit new faculty, established investigators in clinical research, who will serve as mentors to junior investigators in an effort to build effective clinical research teams. Congressman Louis Stokes played an essential role in getting the Research Centers in Minority Institutions program started in 1985 and fostering it along to the great success it has become. We all owe him a debt of gratitude for his foresight and tenacity, not only for his support of that program but also for his support of NIH programs in general. His retirement from this Congress is a loss to the biomedical research community. The activities of the NCRR are covered within the NIH-wide annual performance plan required under the Government Performance and Results Act. The fiscal year 1999 performance goals and measures for NIH are detailed in this performance plan and are linked to both the budget and the HHS GPRA strategic plan which was transmitted to Congress on September 30, 1997. NIH's performance targets in the plan are partially a function of resource levels requested in the President's budget and could change based upon final Congressional appropriations action. NIH looks forward to Congress' feedback on the usefulness of its performance plan as well as to working with Congress on achieving the NIH goals laid out in this plan. My colleagues and I will be happy to respond to any questions you may have. [The prepared statement follows:] [Pages 1919 - 1925--The official Committee record contains additional material here.] ncrr resources Mr. Porter. Thank you, Dr. Vaitukaitis. Lou's staff will make sure he hears your very kind comments about his work, with which we all agree on the subcommittee. We also appreciate that your examples came from Illinois with Argonne; MIT which I have had some contact with, and the University of California at San Francisco. Ms. Pelosi will be pleased. I need a little more basic education, so let me ask you some very basic questions. Do the resources that you provide get distributed both intramurally and extramurally; in other words, do you provide them on the NIH campus and to NIH grantees? Dr. Vaitukaitis. Our resources are primarily for extramural investigators funded with their own research project grants. We do host some intramural investigators who use those resources; for instance, they may go to some of the high field NMR sites or to a synchrotron site that we support. Mr. Porter. So, if it is on-campus research, that is someone else's responsibility, not yours. Dr. Vaitukaitis. Yes. Mr. Porter. And yours are all, except for those instances you just named, for NIH grantees. Dr. Vaitukaitis. That is correct. Mr. Porter. In other words, when a grant is made by NIH, the grantee may then apply to you for resources that they need to carry it out. Dr. Vaitukaitis. The investigator who applies for an NIH grant, for instance, to the National Institute of General Medical Sciences, may need to do crystallographic studies at a synchrotron site. He or she has an award received from NIGMS, and then, he or she applies to the synchrotron site to access the synchrotron beam line for a certain length of time. Mr. Porter. Okay; but some of these are mobile resources such as animals for example, aren't they? Dr. Vaitukaitis. The animals can be mobile enough. They can be shipped to the research laboratories to investigators who make appropriate requests. Mr. Porter. And some of the things that you provide are not used up but merely lent, in effect. So, when the research is finished, they return them to you; is that true or not? Dr. Vaitukaitis. It depends on the nature of the resource. Mr. Porter. You said many of them are reused many times, right? Dr. Vaitukaitis. They are shared. Mr. Porter. Ah, shared, not reused. Dr. Vaitukaitis. For instance, a DNA sequencer may be used by 30 investigators, depending on where and when they need it. It is a cost-effective approach for a university and for us. Mr. Porter. So, is there any way of determining what percentage of the resources used in extramural research are actually provided through NIH or through NCRR? Dr. Vaitukaitis. We carefully monitor the number of users who are funded by NIH as principal investigators who access the resources. For instance, at the network of 75 General Clinical Research Centers that we currently support, those investigators receive competitive support from other NIH institutes to the level of a little over $1 billion. For the network of biomedical technology resource centers, those investigators receive something on the order about $800 million of research support from the other components of NIH. We track all of this information to make sure that the resources are being used by many investigators from multiple sources. The investigators may also be supported by the National Science Foundation or from private sector funds as well as by private societies. shared resources Mr. Porter. And the academic institutions, do they have an investment in their own equipment and resources? Dr. Vaitukaitis. There are institutional funds for instrumentation through the Shared Instrumentation Grant program, which is the best example of that. We request that they provide those instruments on a wide basis to their facultythrough a shared facility if at all possible or at least to multiple groups of investigators. Mr. Porter. Who pays for those resources? Dr. Vaitukaitis. We pay for the instrument itself. The institution pays for the maintenance of that equipment at their institution. Mr. Porter. So, the capital investments in almost all research resources are NIH's? Dr. Vaitukaitis. If they are at our resource centers, we pay for a major portion of them but not all of them, because they are quite expensive. Dr. Varmus. Well, I think you are asking a question we probably cannot answer, which is how much of the equipment infrastructure available to our investigators is actually paid for with NIH money as opposed to institutional money. Mr. Porter. What percentage, yes. Dr. Varmus. It is hard for us to answer that question, because we do not really know what the Institutes are spending. Mr. Porter. What they have. Dr. Vaitukaitis. What the denominator is. Dr. Varmus. Certainly, traditionally, there was a fairly substantial investment, especially at academic health centers, in the equipping of new investigators for that money. Mr. Porter. Their own investment. Dr. Varmus. Right; they would provide setup funds for new investigators as part of a recruitment package. That actually is one of the instruments of supporting new investigators that has been undermined by the change in patient care revenues to academic health centers. But in any case, we do not really have the numbers that would allow us to determine what our percentage would be in providing the equipment that any investigator would be using. Mr. Porter. Am I correct, then, that the reason your center has the largest rate of increase in NIH is simply because we have to address this problem that is not being addressed otherwise? Dr. Varmus. We have cut back on, for example, shared instrumentation grants, which as Dr. Vaitukaitis has just pointed out, is an incredibly efficient way for us to supply equipment, high-quality equipment that reflects technological development to our investigators. So, I feel strongly that is a program that we should be supporting as our budget prospects brighten. They were cut back at a time when we were simply trying to find the money to fund new grants. human genome project Mr. Porter. With respect to the human genome project, what sort of drawdown do their grants have on your resources? Has that caused a large utilization of your resources? Dr. Vaitukaitis. The genome project has created opportunities. In the NMR and synchrotron facilities, the increased demand for access is a reflection of what is going on with the genome project, as well as at our mass spectrometry facilities, which help characterize the proteins that are expressed by those genes. There is a ripple effect, and the investigators need shared instrumentation equipment for doing sequencing work or doing crystallographic work where it is appropriate at their own university. Mr. Porter. Was these a need to create new research resources that did not exist before the project, or were the types of things that they use already in existence and they simply utilized them more? Dr. Vaitukaitis. There were resources already in place, but they had to be modified for enhanced throughput. For example, mass spectrometry has been markedly changed because of the requirement to look at what happens to the proteins after they are translated--referred to as post-translational modifications--as well as the need for high-throughput for looking at the components of DNA as well, not just looking at the proteins. internet Mr. Porter. What effect has use of the Internet had on what you do? Dr. Vaitukaitis. It is an enabling tool. The current problem that we have with the Internet is its slowness, and with the advent of Internet-2, which will have greater speed and a wider bandwidth, it will allow near-real time transmission of data. In the example that we showed here, we cannot adequately do what we would like to do with the instrumentation over the current Internet, because it is too slow. Several universities now, about 120 of them, have gotten together and created what is known as Internet-2, and that will allow us, in real time, to send information from those resources to the supercomputer then back to the investigator in San Francisco, to look at drug interactions at a binding site, or any other structural biological question. It is really an enabling technology. It is going to allow real time access to a wider range of technologies across the country that investigators in the past had to physically go to, but it creates an extra demand on our resources to provide more staff to service more investigators. Mr. Porter. And this is really going to revolutionize further the whole research enterprise, is it not? Dr. Vaitukaitis. Absolutely. Mr. Porter. Mr. Stokes? Mr. Stokes. Thank you very much, Mr. Chairman, and Dr. Vaitukaitis, nice to see you again, and thank you for your nice statement. Mr. Porter. She said some very nice things about you when you were not here. Mr. Stokes. I see her statement here, which I have read. It is very kind of her, and I appreciative of it very much. Dr. Vaitukaitis. We have really appreciated your help over the years. research centers in minority institutions Mr. Stokes. Thank you. It has been a pleasure working with you, and I am going to miss working with some very fine people when I leave here. It has been a great experience for me, too. Dr. Vaitukaitis, in last year's committee report, the subcommittee recommended that NIH programs which focus on improving minority health receive an increase in funding at a level that is at least proportionate to the overall NIH increase in funding. Has this occurred with respect to Research Centers in Minority Institutions, the RCMI program and others under the center's auspices? Dr. Vaitukaitis. The RCMI program received a 10 percent increase in its budget for fiscal year 1998, which is significantly greater than the NIH budget increase, as well as NCRR's budget increase. We were pleased to be able to provide that additional support for the RCMI program. Mr. Stokes. That is great, I appreciate knowing that. Thank you, Dr. Varmus, also. How will the increases be invested? Dr. Vaitukaitis. The increases are to be invested in helping to recruit junior faculty to the RCMI institutions to conduct both basic and clinical research. There is a concerted effort to try to increase the clinical research capacity at these institutions by bringing in established mentors to help develop junior faculty to work on those diseases which disproportionately affect minority populations. In addition, they will support some initial efforts that we have with the neurology institute to develop neuroscience centers of excellence at selected NCRR-supported RCMI sites. There is also a new application from an institution that formerly was not supported by the RCMI program which will probably be funded this fiscal year. extramural construction Mr. Stokes. Good. Dr. Vaitukaitis, the fiscal year 1998 funding level for facility construction is $20,000,000. Has the center been able to comply with the statutory requirements that focus 25 percent of these funds on institutions of emerging excellence? Dr. Vaitukaitis. Yes; in fiscal years 1996 and 1997, we were able to use 29 percent of the $20,000,000 appropriated for each of those respective years. Among the four awards that we made to Centers of Emergency Excellence in the last fiscal year, 1997, two of them were to HBCUs which are badly in need of this source of funds. The applications for this year have been received but have not yet been reviewed. So, yes, we have been able tomeet the setaside. Mr. Stokes. What is the fiscal year 1999 budget request for NCRR extramural facility construction? Dr. Vaitukaitis. It is $20,000,000, the same as in 1997, and 1998. rcmi clinical research initiative Mr. Stokes. Your budget justifications, Doctor, mention that RCMI recipient medical schools will be the focus of a clinical research initiative. Can you elaborate on what the initiative is intended to do, and the size of that investment? Dr. Vaitukaitis. The size of the investment may be something of the order of between $2,000,000 and $3,000,000. It is to be modelled on a program we currently have underway in collaboration with the neurology institute at the Morehouse School of Medicine that focuses on neuroscience, where we bring in an established investigator who can serve as a mentor to more junior faculty to help them develop research expertise in a specific area, neuroscience in this case. We are hoping that comparable activities can be initiated at other institutions within neuroscience or in other disciplines that the applicant institution decides are best for them. hbcv competitiveness Mr. Stokes. Okay. During previous hearings, the center indicated that it would work to strengthen infrastructure at the HBCUs in an effort to help them better compete for NIH research grants. What specifically is the center doing in to facilitate this? Dr. Vaitukaitis. Each year for the past couple of years, we have held technical assistance workshops for HBCUs and other institutions who wish to submit grant applications to the construction program that we talked about earlier. In addition, through the RCMI program, there are workshops held approximately twice a year in areas of possible investment, where staff talk to them about different opportunities for research, and about submitting research project grants or other types of applications for enhancing their research support. clinical training and career development Mr. Stokes. What is the center doing to enhance training and career development for clinical researchers, and what is the condition of the pipeline? Dr. Vaitukaitis. The clinical research pipeline needs to be fixed. Between 1994 and 1997, there is almost a one-third drop off in the number of M.D.s applying for new grants from NIH. It is very disturbing, because the pool size is very small, probably for several reasons. The impact of managed care has placed greater pressure on physicians' time to see patients to generate parts of their salaries or their entire salaries. The relatively low success rates for junior investigators in the past and inadequate salaries provided through training grant mechanisms or through junior career development programs are other reasons. About 2 weeks ago, I presented the new K-23, K-24 and K-30 programs for clinical research support to the leadership of the GCRC program across the country, and they were ecstatic, because the K-23 provides, for the first time, adequate, robust support for clinical research career development in terms of competitive salaries, adequate research support and the length of time of support that gives them a fair chance to learn the tools of clinical research and complementary laboratory research. A separate program, the K-24, will provide 5 years of additional support after the K-23, for protecting physicians time to do clinical research and complementary laboratory research within their institutions. Academic health centers are under a lot of stress because of the impact of managed care. There is a lot of pressure for investigators to see more patients, to generate more income, which takes away from their productive research time. They are so exhausted, they cannot even really come up for air to think creatively about their next research project. We are very pleased with the new mechanisms that are about to be initiated in the early part of fiscal year 1999. shared resources Mr. Stokes. Dr. Vaitukaitis, how critical is the center's shared resources program to the conduct of biomedical research? Dr. Vaitukaitis. NCRR provides critical infrastructure for shared resources on a regional and national basis as well as providing institutional support for shared instrumentation; it provides biological models and disease models to investigators across the country. It provides high-end technology access at no cost to investigators along with appropriate expertise to help them interpret their data. Because of the consequences of the genome project, which are considerable, investigators will not be able to learn to use every single technology that is out there; there just are not enough hours in the day or days in the week. It is necessary to provide additional expertise for interpreting data and helping them with handling their samples at our sophisticated resources, in order to get the most information we can out of the research that NIH collectively supports. research infrastructure Mr. Stokes. Let me ask you this: research infrastructure is a major determinant of a university's ability to successfully compete, to compete for and conduct quality research. What is the state of the research infrastructure at the NIH's leading grantee institutions? Dr. Vaitukaitis. I cannot specifically address the NIH's leading institutions. I am aware of no data that specifically addresses that. new rcmi institutions Mr. Stokes. Okay; all right. I am told there may be new schools added to the RCMI program. Is the increase in the budget proposal adequate enough to provide funding to the new schools while ensuring that existing programs do not suffer? Dr. Vaitukaitis. In fiscal year 1998, we will probably be making a new award to one institution, and we can do that within the budget that we have for 1998. In last year's report language from the Senate, we were asked to consider the University of Alaska as an institution to be included in the RCMI portfolio. We currently have negotiations going on with Alaska, and they will be submitting an application. There is also one other institution that will be submitting an application. So, it is possible that one or two additional institutions could be funded in fiscal year 1999, and we would have to work within our budget to support those institutions. We have no idea of the scope of their needs at this point, because we have no applications in hand. Mr. Stokes. Dr. Vaitukaitis, I want to thank you for the work that you are doing in these areas in which I have specific concern. I do not know of any other institute that has given us a better report, than you, on these areas. I also want to congratulate you and express my appreciation to you. Dr. Vaitukaitis. Thank you, Mr. Stokes. Mr. Stokes. Thank you. Thank you, Mr. Chairman. rare diseases Mr. Porter. Thank you, Mr. Stokes. Dr. Vaitukaitis, it is often difficult to develop and test new therapeutic agents for rare diseases because the limited number of affected patients makes it difficult and expensive to get statistically significant data. To accelerate development of new therapies in a more cost-effective manner, you plan to initiate a pilot project with the Cystic Fibrosis Foundation to establish a data monitoring center. Would you describe this initiative in more detail? And do you think this venture will lead to more collaborative public-private partnerships? Dr. Vaitukaitis. Rare diseases are not so rare across the network of GCRCs. Collectively, rare diseases account for about 15 to 20 percent of all of our research protocols. Of the over 6,000 protocols supported across the GCRCs, cystic fibrosis is a key disease that is studied to a limited extent by a number of them. This partnership that you have described that we intend to set up will help foster cystic fibrosis research in collaboration with the Cystic Fibrosis Foundation, and we are hoping that it will be successful, because there are many other rare disease organizations which have similar interests. The Cystic Fibrosis Foundation has come forward towork with us in supporting the clinical trials for cystic fibrosis on the GCRCs, which is totally permissible and facilitates clinical research not only for cystic fibrosis but for other rare diseases. We see this as likely leading to partnerships with other rare disease organizations and probably with some of our sister institutes, to help support some of the primary research within some of those rare disease areas. collaboration with nci Mr. Porter. How do you handle the circumstance where one of your general clinical research centers is located at the same facility as an NCI cancer center? Do they share patient populations and researchers or are they totally separate entities? Dr. Vaitukaitis. A little bit of both; currently, we have an initiative where we are working with the National Cancer Institute to bring together the resources of the NCI comprehensive cancer centers with those from the GCRCs. Many of the clinical research studies are carried out either in some part of the hospital that is not part of the GCRC or on the GCRC. With the impact of managed care, more and more of the clinical research that has been sponsored by the comprehensive cancer centers are moving to the GCRCs. We can accommodate it, and we are working it out so that if there is a disproportionate pressure from cancer-based research on the GCRC above one-third of all its resources, that NCI will help fund, the amount that is above the one-third, in order to protect other areas of research. This arrangement between the GCRCs and the comprehensive cancer centers will decrease the administrative burden for review of protocols as well, so that the investigator does not have to have his or her protocol reviewed at both the cancer center and the GCRC; there will be one review; the process will be streamlined. The cancer centers will share some of their research resources, and we will share ours with them, which is a natural partnership. There is no reason why this partnership should not work out extremely well. clinical research Mr. Porter. How will you implement the recommendations made in the NIH Director's Advisory Committee report on clinical research? Do you have a plan of action? Dr. Vaitukaitis. One thing we are going to be doing is changing the Clinical Associate Physician award program to, instead of using a competitive supplement to a GCRC, use a K-23 type of mechanism that we are currently developing in order to provide more robust support to young investigators at GCRC sites for junior career development. In addition, we are enhancing the role of the GCRCs as an institutional resource for clinical research where it is appropriate; in some cases, the institutions have the GCRCs as the lead for helping direct clinical research at that institution. In addition, the President's budget request for the GCRC program is the largest President's budget increase that I have known over the last 25 years. research collaboration Mr. Porter. You have partially answered this question, but let me allow you to expand on your answer. Your center has been a leader in fostering an environment where collaborative research opportunities are conceived and evolve. However, we have heard that private industry withholds data out of proprietary interest. In your opinion, do you believe the environment for collaborating has gotten better or worse over the last few years? Dr. Vaitukaitis. I think the environment has gotten much better for collaborative, multidisciplinary research, because research has become much more complex. The kinds of resources that we support require the multiple disciplines to interact with investigators from other institutions. We see research becoming much more multidisciplinary and much more collaboration going on. Mr. Porter. Dr. Vaitukaitis, thank you for your good statement and answers to all of our questions. Obviously, the request that you have made is a very important one and a high priority for all research, and we are going to do the best we can to get you the resources you need so that you can get them to the investigators so they can carry on their research at the highest possible level. So, thank you for appearing today. We appreciate it very much, and thank you for the fine job you are doing. Dr. Vaitukaitis. Thank you. Mr. Porter. Thank you, Dr. Varmus. Dr. Vaitukaitis. Thank you very much. Mr. Porter. The subcommittee stands in recess until 10:00 a.m. tomorrow. [The following questions were submitted to be answered for the record:] [Pages 1935 - 1973--The official Committee record contains additional material here.] Tuesday, March 17, 1998. NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT WITNESSES DR. DUANE ALEXANDER, DIRECTOR DR. YVONNE T. MADDOX, DEPUTY DIRECTOR DR. FLORENCE P. HASELTINE, DIRECTOR, CENTER FOR POPULATION RESEARCH BENJAMIN E. FULTON, ASSOCIATE DIRECTOR FOR ADMINISTRATION ARTHUR D. FRIED, BUDGET OFFICER DR. HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. The subcommittee will come to order. We continue our hearings on the National Institutes of Health with the National Institute of Child Health and Human Development. We are very pleased to welcome Dr. Duane Alexander, the Director of the Institute. Dr. Alexander, good morning. Dr. Alexander. Good morning, Mr. Porter. Mr. Porter. Happy St. Patrick's Day. Dr. Alexander. The same to you. Mr. Porter. I forgot to wear my green. Dr. Alexander. That is a nice green tie you have. [Laughter.] Introduction of Witnesses Mr. Porter. Yes. Why don't you introduce the people at the table with you and then proceed with your statement, please. Dr. Alexander. Thank you, Mr. Porter. On my left is Dr. Florence Haseltine, the Director of our Center for Population Research; next, Mr. Ben Fulton, our Executive Officer; our Budget Officer, Mr. Art Fried; Dr. Varmus; my Deputy Director, Dr. Yvonne Maddox; and you know Mr. Williams. Opening Statement Mr. Chairman, it is my pleasure to appear before the committee and talk about the request for the NICHD. Congress established our Institute 35 years ago to help the people of this nation have healthy children at the time that they want them and to help those children survive, learn, and develop in ways that allow them to reach adulthood free of disease and disability and able to contribute fully to society. research accomplishments As we have been celebrating our 35th anniversary this year, we have looked back at some of the accomplishments of our research that have made major progress toward achieving these goals. For example, NICHD-supported scientists developed and demonstrated the effectiveness of newborn screening tests for PKU and hypothyroidism. Every newborn infant in the United States now receives these tests, and thanks to their use, we prevent over 1,200 cases of mental retardation each year. Another example was NICHD's diabetes and early pregnancy study. It showed clearly that rigid control of a diabetic mother's blood sugar before and during pregnancy markedly reduced her elevated risk of having a stillborn or malformed infant. That regimen has now also become standard care. NICHD scientists conceptualized and developed a vaccine to prevent Hemophilus influenza Type B meningitis, and with that vaccine now standard care for all infants, this disease has gone from being the leading cause of acquired mental retardation in the United States to near elimination. Through a combination of improvements from NICHD research on our ability to care for premature infants, such as better ventilation, surfactant to prevent respiratory distress syndrome, improved nutrition and better control of infection, this nation's infant mortality rate has fallen by 70 percent in those 35 years. Leading the way in this decline in the last four years has been a marked reduction in sudden infant death syndrome. As shown in the poster over to my left, for many years, SIDS deaths were really remarkably stable, at about 5,400 per year, or 1.4 deaths per 1,000 infant births. Following the recommendation of the American Academy of Pediatrics in 1992 to place infants to sleep on their backs and the NICHD-led ``back to sleep'' campaign launched in 1994, back or side sleeping has increased from 28 percent to 78 percent and the rate of SIDS deaths has declined dramatically, from 1.4 to 0.5 deaths per 1,000 births. This represents a reduction of nearly two-thirds from the old steady state condition. [The information follows:] [Page 1977--The official Committee record contains additional material here.] birth defects Dr. Alexander. While strides have been made in reducing several causes of infant mortality, less is known about its leading cause, birth defects. Our studies here range from basic investigations in genetics and developmental biology to epidemiologic studies of cause and therapeutic and prevention research. We are working to translate leads from basic studies in animal models to understand human disorders such as neural tube defects, skeletal anomalies, primary immune deficiencies, and disorders in the formative stages of the nervous system that lead to mental retardation or learning and behavior problems. vaccine research Progress in science is incremental. One example is the E. coli 0157 vaccine. This organism is a bacterial food contaminant that causes mild to fatal disease in about 20,000 people a year in the United States. The new vaccine was produced by our same intramural scientists who developed the Hib vaccine. We recently reported success in inducing high levels of antibody production against E. coli in adults and we are now testing whether this vaccine can prevent the disease in humans by eliminating the organism at its source by vaccinating cattle. genetics Applications of advances in genetics, especially from the Human Genome Project, continue to benefit NICHD. One case in point is microarray technology, which Dr. Varmus displayed in a poster in his opening presentation. This technique permits study of thousands of genes at once to determine which ones are functioning or turned on at a given time. premature labor Our scientists are applying this technology to study gene expression in women in premature labor with the goal of determining at a genetic level its causes and mechanisms. These studies also offer the potential to develop a much-needed diagnostic test to determine whether a woman is truly in premature labor, as well as identifying targets for therapeutic intervention. Research to reduce prematurity is a critical part of our effort to eliminate racial differences in infant mortality as part of the President's initiative on race. reading development and disability Other new scientific technologies are allowing us to combine studies in biology and behavior to achieve a fundamental understanding of the origins of problems such as reading disability. One technique being used is called functional magnetic resonance imaging. The pictures you see displayed on the poster on the left are composites of images reflecting brain activity during reading tasks by adults with good reading ability on the right and adults with significant reading disability on the left. [The information follows:] [Page 1979--The official Committee record contains additional material here.] Dr. Alexander. The disabled readers show none of the activity in the three regions at the back of the brain used by the good readers in the reading tasks, and increased activity in the front area of the brain, reflecting intense effort to try to overcome the apparent block in function at early stages of the task. This study provides the first clear evidence of organic brain dysfunction in reading disability. child day care Results of research on the association between characteristics of child day care and children's development are continuing to come from NICHD's study of early child care. This year, scientists continued to find that family income, quality of home environment, maternal education or language ability, and mothers' behavior toward the child are stronger predictors than child care itself of children's cognitive, language, and social development. Our scientists also found that children in exclusive maternal care do not have a cognitive or language advantage over children in child care. Most recently, investigators reported that the characteristics of quality child care provision that can be regulated, such as adult-to-child ratio, group size, provider education and training, are related to cognitive and social outcomes of children at three years of age. women's health research With the funds provided by the Congress in fiscal year 1998 and requested in fiscal year 1999, NICHD will be launching two major initiatives to improve women's health. First, to increase the number of obstetrician/gynecologists engaged in research, NICHD, with support from the Office of Research on Women's Health, is establishing a group of women's reproductive health career development centers. At these sites, newly-trained OB/ GYN clinicians will be given training to assist them in pursuing research careers, focusing on problems of women's reproductive health. Second, we are working with the OB/GYN community and other institutes to expand research directed toward the long-term consequences women suffer as a consequence of childbearing-- incontinence, uterine and rectal prolapse, chronic pain, and other harmful and disabling conditions. pediatric pharmacology There is great hope that the proposed new FDA rules requiring drugs to be tested in children, in combination with the pediatric pharmacology network established by NICHD, will finally end the decades-long era of children being therapeutic orphans. To further facilitate the testing of drugs in children, the funds requested for fiscal year 1999 will allow NICHD to expand this network from seven to ten sites and to initiate a broad range of studies to help guide drug testing in children. Mr. Chairman, the President's budget request for NICHD for fiscal year 1999 is $727,000,000, including $72,000,000 for AIDS, an increase of 7.7 percent. I will be glad to answer any questions. [The prepared statement follows:] [Pages 1981 - 1985--The official Committee record contains additional material here.] family planning Mr. Porter. Thank you, Dr. Alexander. Let me first focus on one of your opening remarks where you refer to the Institute being created, to help the people of this nation have healthy children at the time they want them. Why did you mention ``at the time they want them'' and what relationship does that have to the health of children? Dr. Alexander. This Institute focuses on families and children and improving the health of children overall. One factor that improves the health of children is the wantedness of that child. A major component of our Institute is our Center for Population Research that focuses on family planning research, among other activities, including both infertility research and research focused on contraceptive development. So we go at both ends of the issue of helping families have children at the time they want them, approaching research on infertility as well as research on contraception. Very clearly, children who are born wanted and at a time that parents want them fare better than children who are born when they are not wanted, at a time that is bad for parents to be having a child. Unfortunately in this country, we are in a state of affairs where more than half of pregnancies are unwanted or unintended at the time that they occur. This has been running at about 54 percent. The most recent figures show that this has dropped just a little below 50 percent. So there has been some improvement in recent years in the wantedness and timings of pregnancies that occur. But still, close to half the pregnancies in the United States occur at a time that they are not wanted or when they are not wanted at all. Clearly, our research in contraception needs to be pursued further to try and address this problem. Mr. Porter. You may not have done any quantifying of this issue, but let us say that every child in the United States could be born at the time they were wanted. What effect would that have on the health of the population in the long term? Would that have a significant effect or a minor effect? Dr. Alexander. We think it would have a significant effect. First of all, there are data to support the fact that infant mortality rates would decline significantly if pregnancies were wanted rather than unwanted. Clearly, our abortion rate would virtually disappear if we had conceptions occurring that were wanted rather than unwanted. Overall, children are healthier when they are born wanted. Their developmental course is more favorable and their long- term health aspects as well as their achievement, accomplishments, and social and educational performance all improve when they are wanted children and when they are born at a time that the parents want them, can afford them, and really want to have them. Mr. Porter. Dr. Alexander, we have had a debate going on here in Congress for some time now on the whole concept of abortion, which to me is understandable as a moral issue. At the same time, we have a direct assault on family planning, although it is couched in terms of opposition to abortion, and we have barely won enough votes in the House on Title X programs that provide family planning services to poor women in our country. How do you, if you can, reconcile these matters and don't you agree that it is very short-sighted for people who morally oppose abortion to also oppose family planning? Dr. Alexander. The surest way, as you point out, Mr. Porter, to reduce the need for abortion is to provide adequate family planning services with agents that are effective and that can be used by people and are accepted by people of varying beliefs. Part of our problem is ineffective use of contraceptive agents that are available. Part of it is failure of the agent itself. This is why it is important for us to continue our research to develop better and more effective agents, as well as methods to increase their acceptability and effective use. But if we are, in fact, serious about reducing the abortion rate in this country, a key component of that effort must be provision of adequate family planning services.Women and men must have access to contraceptives that are safe, effective, and acceptable to them in terms of their particular values. If we do not provide contraceptive programs, family planning programs, we have no hope of ending the unwanted abortions. Mr. Porter. I could not agree with you more. In fact, I believe that it is a basic human right of every person on this planet, every family on this planet, to plan their children including the number and spacing of them and that our programs, both domestically and internationally, for people who cannot otherwise afford the services are probably one of the most important things that we can do. I cannot understand a view that says this is not a basic human right that ought to be supported. dyslexia Let us talk a minute about dyslexia, which effect many young children. We find that a lot of people who are diagnosed as dyslexic somehow overcome this difficulty during their lifetime. Is there any evidence from research that later pathways are developed that changes this look at the brain? Dr. Alexander. That is a very interesting question, Mr. Porter, and one that we are eager to pursue and actually are pursuing. This particular study reported from Yale University by the Shaywitzes and their colleagues was done in adults, so the images that were obtained and reported were done on adults. The group is currently studying children, as well, and looking at whether we see similar patterns of brain abnormalities and function in children that we have demonstrated here in adults. What we want to do, if we find these abnormalities in function in children before they have had reading experience, is follow them as remediation is applied to see what happens to these patterns of brain functioning on functional magnetic resonance imaging. We will look to see whether the pattern sort of corrects with training, such that these other areas do start to function, or whether alternative pathways develop as the child overcomes the problem and learns to read. If the child is not able to overcome the problem and never learns to read, we will examine what kind of brain pattern and functioning we see. These studies are underway. I hope maybe next year I will be able to give you an answer to your question. child care Mr. Porter. The administration has a major initiative on child care and I wonder if you could tell me what input you had in formulating that initiative as it was developed as a policy matter. Dr. Alexander. There has been intense interest in the Department of Health and Human Services in this study. The Child Care Bureau, people in the Administration for Children and Families have been in close contact with us, have kept up to date with all the reports of the research that have come from this study to be aware of what the findings were in terms of impact on child development of the child care experience, the impact on the children's development, on family relationships, and so forth. I think that, in part, it was with some reassurance from the findings of the child care study that people felt comfortable in moving ahead with a larger investment and program of support for child care programs. In addition, I think the information that our study has provided on quality of care has been extremely important for the people in the Child Care Bureau. There are two things that are most consistent in these studies. First of all, the family situation and the mother are far more important an influence on virtually all aspects of the child's development than the child care situation. Number two, the quality of the child care that is provided is extremely important. Whether we are looking at language development, cognitive development, behavior, social interaction, health, whatever, quality of care makes a significant difference to kids. And also, they have demonstrated very clearly that there are regulable aspects of child care, as I mentioned in the testimony, such as group size, education and training of providers, adult-child ratio, and so forth that also correlate very clearly with the quality of care overall and with better outcomes for kids. So with this information in mind, the Administration for Children and Families and the Department worked with other parts of the Administration in developing this initiative to help support child care with Federal assistance. Mr. Porter. Can I conclude from what you said that it is not enough just to put some money out there, we have to make sure that the child care that is being given is regulated so that the quality is maintained? Dr. Alexander. I think that is a very clear message, Mr. Porter. The quality does make a difference as do regulations, probably formulated at the State level as they are now, that are developed in accordance with standards suggested by organizations such as the American Academy of Pediatrics, the American Public Health Association, and the Society for Education of Young Children. Mr. Porter. Thank you, Dr. Alexander. Mrs. Northup? reading disabilities-early screening Mrs. Northup. Yes. Thank you, Doctor. I have a couple of questions. I would like to start with the question of dyslexia. I have read a number of reviews of studies you all have done and know that there are a significant number of children that fall behind in reading and actually never catch up that may not actually be diagnosable as dyslexic, but come to the system perceptually immature and never catch up. Can you tell me, I was interested also interested in this subject last year, when you think there will be on the market an early diagnostic test and how early we can apply that to a child? Dr. Alexander. There are several tests that purport to serve as screening instruments for picking up children early. One has come from our research that looks very, very promising in identifying kindergarten children as having potential problems with learning to read. It probably identifies maybe 25 to 30 percent of children who are in this category. Now, these are not dyslexics. Mrs. Northup. Right. Dr. Alexander. These are kids who are going to have more difficulty than usual in learning to read and probably need some kind of special help tailored to their particular problems. The dyslexics are probably a hard-core group of three, maybe five, perhaps as much as seven percent of kids, but probably in the three to five percent range, who, in spite of some added instruction, the phonemic awareness approach that we have championed in particular, still need additional assistance. These are probably the children who have the brain functioning abnormalities that are demonstrated in the adult study by the Yale group that I showed in the poster. But what we can do with the particular screening instrument that we have available now is check these kids in kindergarten, determine in advance which ones are the ones most at risk of having problems in learning to read, and focus efforts on them in a classroom tailored toward their particular problems. Mrs. Northup. And you say that can be done in kindergarten, but I am not sure whether you said when that test will be on the market. Dr. Alexander. It is available now. I am not sure that it is actually sold on the market. It has been published. People know about it. reading--when to diagnose disabilities Mrs. Northup. Doctor, I continue to be concerned about the schools and the old fashioned, and I consider it old fashioned, perception that no child should be diagnosed as struggling with reading. Actually, I sort of consider dyslexia and being behind in perception sort of a long continuum and sort of where you fall in it. But there was the idea that we should not diagnose children as challenged in reading until maybe even third grade. Would your more recent studies dispute that? Dr. Alexander. Absolutely. Third grade is too late. If they have not been diagnosed and had some sort of remedial interventions attempted before then, they are going to haveextreme difficulty learning to read. There is probably with reading what we refer to in other areas as sort of a critical period where you are primed to learn. If you do not get it at that time, you have extreme difficulty in getting it later on. Third grade is certainly, by all the research that we have done, too late to have this picked up. It is important that these kids be identified early, not stigmatized, not singled out, but identified at least to a teacher as someone who is going to need some extra help with the reading process. In most instances, this could probably be accommodated in the regular classroom so that there is no need for pulling kids out for a special effort outside the classroom. Our research again is trying to address these kinds of issues. reading development--getting the word out Mrs. Northup. What are you all doing to get the message out to those many school districts that still insist that children should not be tested or diagnosed or screened even until later? Dr. Alexander. Well, the message is getting out. We are publicizing the results of our research ourselves. We are also working with some of the reading organizations, such as the National Center for Learning Disabilities, the Learning Disabilities Association, to publicize results of this research. In addition, some of our staff members have made presentations out in the field to school districts, to State school systems, to other groups about the results of the research and the importance of early identification of children likely to have problems with reading and the importance of teaching reading in a scientifically demonstrated, effective manner. I think you are also aware of the fact that the Congress in last year's appropriations bill directed me to work with the Secretary of Education in establishing a national reading panel. The purpose of that panel is to review the current research literature and make judgments about what in that literature is ready for application in the classroom and ready for application in the preparation of teachers to teach reading. That panel has been appointed. We will have our first meeting in April and our intent is to finish our report and get it to the Congress and the Secretary of Education and HHS by November. We are also collaborating with the Department of Education in publicizing the results of our reading research and working extensively with them to get this information out. child care and long term effects Mrs. Northup. I also noticed that you talked about emotionally connected teenagers to their families and that often their health and other factors were affected by those that are emotionally connected to their families. I wondered if you are doing any long-term research to help give us some answers. I know you talked about the child care research that you are doing. Can you give us some quantitative and qualitative insight into the long-term effects of what are good day care options. I know you talked about specifically children that are in an organized day care system, but I think we are also struggling in this country with whether or not to enhance our day care systems. As more and more moms are in the workforce, we must ask is grandmother taking care of the child, is an aunt taking care of the child. Does that build the relationship, the nurturing side? You spoke so well about how important the relationship is with the mother and the child. So when the child is away from the mother for long periods of every day, every week, is an organized, structured day care program better for the child in terms of learning and lifelong habits or would being in a home--and I realize it depends on the home, but you seem to be wandering into the area or getting into the area of trying to make some determination in that area, and I just wondered what sort of long-range studies you are doing. the adolescent health study Dr. Alexander. Okay. There are two major NICHD studies that feed into the answer to your question. The first relates to where you started, which was the feeling of connectedness in relationship with the family. These findings come from the National Longitudinal Study of Adolescent Health, the adolescent health study that NICHD has supported. The first results from this study were reported last September. There were two very striking findings here. One was that there was an association between children who were doing well, staying away from risky behavior, performing well in school, and that was a feeling of connectedness with the family, a feeling of wantedness, of interaction with parents, of comfort in a home setting and of sharing as a family member. And closely associated with that was a connectedness to school feeling, a sense that teachers were interested in them, that teachers were fair and that the school setting was one in which they were encouraged to do well and perform. The investigators doing that study are doing further analyses of the data to try to see what is it that creates this sense of connectedness, this feeling of belonging and a positive sense of value in association with both family and with school. In addition, we are, as part of the adolescent health study, doing a one-year follow-up, and we expect to get a proposal for an extended five-year follow-up, of all the sample that was included in the original adolescent health study so that we can see how these factors play out over time in terms of all the data that we have collected on these children as they become young adults. the nichd day care study Then the other part is day care and how these kids get started in life and get these kinds of habits established and the feeling of connectedness with family, if you will, and a connectedness with some other kind of a care setting. The NICHD day care study has looked at different kinds of settings and different kinds of care provision to try to tease out whether these differences in the setting are associated with the child's performance and interaction with the family as well as the child's cognitive language and social development. So we will have that. The original child care study was to end at age three. It has been extended once to carry these children through age seven and we anticipate there will probably be an effort to extend that for another five years to follow these children longer, at least into adolescence, to try and get at some of the very issues that you raised. So we will be following these as questions and I think they are very important ones for us to be addressing. Mr. Porter. Thank you, Mrs. Northup. The subcommittee is currently proceeding under the ten- minute rule, and if any more members of the subcommittee come in, we are going to be in trouble time wise. Ms. DeLauro? child care effects Ms. DeLauro. Thank you, Mr. Chairman. Dr. Alexander, it is good to have you back and it is good to see everyone here today, Dr. Varmus, and also I have to mention my friend and colleague and constituent, Dr. Haseltine. I would like to pursue the child care issue for a moment if I can, because we have talked about the study, we have talked about the connection, the relationship between quality care and development, bonds between children and parents. There have been several articles that have used quotes from NICHD- supported articles to come to a conclusion that I personally find troubling, but in any case I want to get your views to this, that putting children in day care while a parent is working is bad for children and is particularly bad for low- income, disadvantaged, or at-risk children. Again, the conclusions are being drawn out of studies that you all have done, and what I would like to hear from you is are these conclusions in the studies consistent with the findings of NICHD. Dr. Alexander. Ms. DeLauro, I have seen at least several of the articles that you make reference to and they have been a little bit disturbing to me because I believe that some of the findings have been cited out of context to make points that are not supported by the overall study. Let me say at the outset that this study was not set up to say whether child care is good or bad for kids. It was an attempt to look at various factors within the child care setting and in the family setting and make judgments aboutwhich of those contributed positively or negatively to child development in the language, cognitive, and social arenas, as well as to parent-family interactions, and that is what we have tried to stick to. First of all, it is not possible to conclude that child care overall is good or bad for kids. Some child care settings do very well by children. The quality varies enormously and some child care settings are not real good and they do not benefit children. Our effort, though, should not be to brand all child care as bad. It should be to make all child care as good quality as it can be, and the findings from our study, I think, help us to identify further the qualities of child care provision that are associated with good outcomes. child care concerns Now, all child care features that we examined did not turn out to be positive. There are some concerns, some red flags raised. The articles that you make reference to picked out these concerns and waved several red flags. Now, these are legitimate concerns and they relate to primarily mother-child interaction and relationships. There was a segment of the child care population that had a finding of diminished quality of mother-child interaction when they were studied at 15 months and again at 24 months of age. These were confined primarily to children of mothers who were low in self esteem and low in interaction with the child to start with and this was the population that this finding was largely confined to. Here again, though, the child care setting tends to ameliorate the severity of this kind of a finding and the children who were in better quality care tended to have less of this finding show up. child care study fact sheet We are in the process at NICHD of putting together a fact sheet on the child care study with all the findings that have been reported to date assembled in one place. It will probably be about a 15-page fact sheet. It puts the whole study in its context and lays out all the findings that have been reported so far in terms of language development, cognitive development, social development, parent-child interaction, health, behaviors of children up to age three. Now, we are still following these kids. We have done the four-and-a-half-year evaluations. We are in the process of analyzing the data, and we are just now starting the seven-year evaluations in these kids. So there is a lot more data to come, but we are going to pull all the available data together in one place so we can give a composite picture of what we have learned from this study. This should be available probably within two weeks. I will be glad to make a copy of that available to you. Ms. DeLauro. I would appreciate that. I expect that other members of the committee would appreciate that, as well. The work is, in my view, critically important because I believe that we are at a threshold with regard to child care in this country, particularly ages zero to three. What we do not want to do is to make similar mistakes, if you will, that we did with the Head Start program. We are trying to correct and evaluate the Head Start example so that we know what we can try to do with Early Start. What we do not want to do is to go down a road where conclusions are pulled out of context and used to the disadvantage of looking at quality child care, environments in which we are creating an environment for development for children. That is the kind of, in my view, what we ought to be searching out and seeking because economic realities today do not make it possible for all parents to stay home, one or the other, or to have aunts or uncles around. I went to my grandmother's after school, my grandmother's pastry store, and had lots of aunts and my grandmother. Those days, for the most part, are gone, so that aunts, uncles, grandmothers, everybody, are in the workforce. So how do we then ensure that our babies, that our kids are in environments in which they can grow and develop in a way that we would want them to. So your work is critically important to what decisions can be made here, I believe in the next few months, if we do the job that we are supposed to do with a piece of child care legislation that is on the table. That kind of contact with you and this kind of reporting, I think is enormously helpful to how we proceed further and to use your help, if you will, to dispel any of the misinterpretation, on either side of the debate, of the data that you are producing, which can only help us really to conform and to move forward in this arena, and we thank you for the work. testing prescription drugs on children Last year, we also talked about the importance of testing prescription drugs on children because we know that kids do not always react to drugs as adults. You said that the Institute was encouraging the pharmacological industry to take advantage of metabolic studies that you have done, as well as your network of pediatric pharmacology researchers. Has the industry shown a willingness to work with you on this? Has the FDA's new rule affected your level of research into this area? Dr. Alexander. Yes. The pediatric pharmacology research unit network has been a very positive force in encouraging testing of drugs in children. I believe that it was a factor in the FDA's decision to be comfortable about requiring drug testing in children of new drugs put out by the pharmaceutical industry, the fact that there was a quality place for these tests to be done. We had shown that it could be done in an effective way and that it could be done safely and ethically in children. Industry has shown an increasing interest in the pediatric pharmacology research network. We get more inquiries and more studies funded by industry in the network all the time. As a consequence, we are increasing the number of sites in the network from seven to ten so that we can do more studies and do them faster. Also, since the FDA's proposal, we have had even more interest on the part of the pharmaceutical industry in the network as a test site. So yes, I think the network has been extremely important in this whole movement to get drugs that are used in children tested in children. Ms. DeLauro. What is your sense of timing on information that will be useful in terms of getting it moved to doctors' offices and so forth and so on? I mean, I know we are at the beginning of the process, but what is your assessment of the time frame? Dr. Alexander. It depends on the phase of study for a drug. Some drugs are already marketed for adults and they need additional studies in children just to get labeling for safety and dosage for children and FDA approval. Those can get done relatively quickly. They do not require large numbers of children. But if we are talking about an earlier phase study, a drug that is still under development for adults and we are starting at a phase two process and including children at that time, it is a much longer process, in terms of several years rather than several months. So it depends on the stage of drug development that we are talking about. But having that number of sites available with expertise, with recruiters, with data collectors, and a central data management point in this network enables us to do these studies very efficiently. Ms. DeLauro. Thank you very much. Mr. Porter. Thank you, Ms. DeLauro. Ms. Pelosi? Ms. Pelosi. Thank you, Mr. Chairman. Dr. Alexander, Dr. Varmus, all of you, welcome. Thank you for your testimony. Dr. Alexander, I think you must have the best job in the country. Dr. Alexander. I think so. I often think as I am driving to work in the morning how lucky I am to be in the position that I am. I would rather be doing what I am doing than anything else in the world, and not everybody gets to say that. Ms. Pelosi. Well, how lucky we are that you are there, because you are working with our most important resource, our children, and child health and human development, I think that has to be the most important subject that we address. So we are all well served by your enthusiasm as well as the experience and judgment that you bring to your job. Dr. Alexander. Thank you. child care as public policy Ms. Pelosi. My colleague, happily for me, used a gooddeal of her time on the child care issue, so I will associate myself with the concerns that she expressed in terms of the balance that we need to hear so that some negative aspects of the child care experience could not be extracted without us understanding the context within which they were presented. I think this is an important issue and it is a crucial time because we as a country, I think, have not addressed the child care issue soon enough and we all stipulate to the importance of it. I see it all differently now as a grandmother, of course, telling my daughters to stay home and take care of their children. [Laughter.] Ms. Pelosi. But what does that mean from the standpoint of public policy? I do not want to bring that bias to the table. Some people do not have that option. What is interesting to me is that when you say that in a situation where there is a less optimal mother-child interaction over the first three years, child care can ameliorate the situation for the child. Dr. Alexander. That is correct. pediatric environmental health Ms. Pelosi. It would be interesting to see that in the scheme of things. Certainly, it would be better, of course, to have a better mother-child interaction, and is this amelioration just improving that situation or is it bringing it up to a level that would be acceptable? Is that good enough is, I guess, what my question is. In any event, when we get this fuller report, I am sure those kinds of questions will be answered. If you want to address that, that is fine. I wanted to go on about environmental health. We have talked about this other environment that children are in, the child care environment, but then more specifically the environment as we know it. How the Institute see its role in the field of pediatric environmental health? In what areas are your specialties? Where do you feel the Institute has a special leadership role? How does the Institute do, working with other agencies such as the National Institute of Environmental Health Sciences, the CDC, or the Agency for Toxic Substances and Disease Registry, to leverage resources to further understanding in this field? Dr. Alexander. It varies with the particular issue at hand, Ms. Pelosi. For the most part, the National Institute of Environmental Health Sciences has taken the lead at NIH in relation to children's environmental health. They keep us closely posted on their activities. We have a number of opportunities where we work together with them. The President, by executive order, has just created an interagency committee on children's environmental health and safety. NIEHS represents NIH on that committee and keeps the other institutes, including NICHD, apprised of those activities and opportunities for program development and collaboration. Our interest focuses primarily on birth defects and environmental causes or triggers of birth defects, as well as what we might call the social environment of children as much as the physical, and research related to keeping that social environment in which children develop as healthy and as positive an influence as possible. welfare reform and children Ms. Pelosi. I appreciate that. Speaking of the social environment, clearly, welfare reform legislation has led to important changes in the lives of many families and their social environment. Does NICHD do any research which can help us understand how changes in our welfare system are affecting poor children in our country? Is there research relevant to understanding children's needs and services during experiences like this? Dr. Alexander. We supported research over a period of many years that relates to many of the issues associated with children's development as it may be affected by the welfare reform activities. In response to the specific things that are happening in the country with welfare reform, we have in existence a child and family research network, a group of seven different university sites with data sets and interest in a number of these developmental issues. This network has been poised to serve as a vehicle for conducting research related to welfare reform and changes in children and families as they occur as part of this process. We have been working very closely with the office of the Assistant Secretary for Planning and Evaluation in the Department in terms of design of studies that others might do as well as studies that could be done in this network and have just initiated several studies to look at issues related to impact on child, family, mother as a consequence of the welfare reform activities that are going to be taking place. So we are right in the middle of it. Some of the resources of the Institute are going into this. Some resources are coming from the office of the Assistant Secretary for Planning and Evaluation and from others. It is a major issue and one that we want to stay involved with. Ms. Pelosi. And will we see some data that will come from that? Dr. Alexander. Yes, you will. They are just getting started. pelvic floor disorders and urinary incontinence Ms. Pelosi. Thank you, Doctor. As you know, a significant percentage of NICHD funds are allocated for reproductive-related research. You mentioned before birth defects. It is my understanding that two of the aspects of women's health that have not received adequate research attention were pelvic floor dysfunction and urinary incontinence. Can you tell me what your Institute is doing in conjunction with the National Institute of Diabetes, Digestive, and Kidney Diseases to enhance fundamental basic and clinical research in these areas? Dr. Alexander. Yes. We have been very interested in this area, which we agree with you is one that has been not researched as intensively as probably it should be in the past, the whole area of pelvic floor disorders, urogynecology, urinary incontinence. I met with the leaders of the American UroGynecological Society about these issues and, in fact, Dr. Haseltine worked with me to organize a meeting that was held yesterday with representatives of the American UroGynecological Society, other institutes at NIH, and our own staff within NICHD, to plan a conference on pelvic floor disorders, urogynecology, and incontinence that will probably be held in September. This will be a research planning workshop format to identify particular needs for research in these areas, which will be followed by solicitations for research applications in these areas. As part of Dr. Varmus's areas of emphasis that are included in the fiscal year 1999 budget, we have a urogynecology initiative to focus on these disorders and have received additional funds to begin this effort in fiscal year 1999. smoking prevention for children Ms. Pelosi. Thank you, Doctor. I have a general and specific question. I will be fast because I do not have much time left. We have had a number of questions over the last week about changing behavior and learning more about promoting healthy behavior in children, and then specifically to the tobacco issue. Could you tell us, do you have any research findings to share with us that would be relevant to the current tobacco control issues before Congress, particularly the use of educational messages and policy approaches to prevent the initiation of smoking by young people? Dr. Alexander. We have supported some research in that area over the years. The key issue is keeping children from starting smoking, and we know that just telling them not to does not work. There have to be other ways to deliver that message, and the earlier that message is delivered, the more effective it is. It cannot wait until middle school. It has to start in elementary school. We have been part of a solicitation spearheaded by the National Cancer Institute for research applications related to prevention of initiation of smoking among children. We funded one grant from that last year. It has been issued again and we are part of it again this year. So that is an active area of research activity and I do not have any specific findings above and beyond that to report toyou, but these are studies that are getting underway. Ms. Pelosi. It is interesting, just anecdotally, one of the elevator operators here told me that she stopped smoking because she saw a picture of her lung, and we have said before we should show kids pictures of their brain, what happens if they use drugs. I used to say to my children when they were growing up, you can smoke if you want, if you want to have wrinkled skin, tobacco breath, and yellow teeth. Mr. Porter. I hope it worked. Ms. Pelosi. That worked for the girls, anyway. But I thought when Bonnie said, ``I saw a picture of what it was doing to my lung,'' and I know kids all think that they are invincible. I come back to my basic point all the time. If we tell them that they should not smoke because it is injurious to their health, then we should make their health a very important priority by giving all of them access to quality health care, and I think nothing would deliver the message more clearly about the importance of maintaining good health. Dr. Varmus. I happen to have with me a picture that Dr. Leshner from the NIDA provided me that shows the brain on tobacco. Ms. Pelosi. That is so compelling. Dr. Varmus. It shows a measurement of an enzyme that is important, because it metabolizes dopamine. It compares a 34- year-old normal man and a 31-year-old smoker. So the brain on cigarettes is also quite illuminating. Ms. Pelosi. Very eloquent. Hopefully, you will have that blown up for us one of these days. Dr. Varmus. It has been. Ms. Pelosi. Oh, it has been? I think that that will send a very important message. Unfortunately, my time has expired--unfortunately for me. Thank you all very much for what you do and for your testimony. Dr. Alexander. Thank you, Ms. Pelosi. Ms. Pelosi. Thank you, Dr. Alexander. Mr. Porter. Thank you, Ms. Pelosi. Mr. Hoyer? Mr. Hoyer. For those of you in the audience who could not see it, the picture depicts a yellow, wrinkled brain. [Laughter.] Dr. Varmus. The yellow is good in this case. Ms. Pelosi. The green part. [Laughter.] Mr. Hoyer. I was shocked that Ms. Pelosi did not observe in saying something about Dr. Alexander, who is indeed one of the bright lights in America, in my opinion---- Ms. Pelosi. That he is from Baltimore. Mr. Hoyer [continuing]. That he graduated from Johns Hopkins University. It was not the University of San Francisco, but it was Johns Hopkins from Baltimore when her brother was the mayor of Baltimore. Ms. Pelosi. I did not want to sound too chauvinistic. I am very proud that Dr. Alexander was born in Baltimore. Mr. Hoyer. And we happen to believe that Nancy has been assigned by Maryland to represent California temporarily. [Laughter.] Ms. Pelosi. Do not tell my constituents that. Mr. Hoyer. No, I will not. sids and the minority community The Back to Sleep campaign has been very successful, but it has not been as successful in the minority community. Can you explain the disparity and what we are doing to determine why that disparity exists? Dr. Alexander. I would like to address that, but I would also like, if you could put the Back to Sleep and SIDS poster back up again, you missed this, Mr. Hoyer. Mr. Hoyer. I apologize for being late. Did you mention this? Dr. Alexander. Not the minority issue. I am going to get to this. But I just want to make sure you see this poster, which demonstrates the dramatic drop with the Back to Sleep campaign in SIDS deaths. It was a very stable public health measure for many years until the Academy of Pediatrics recommendation for back or slide sleeping and then the Back to Sleep campaign, which has really dropped it by almost two-thirds from where it started. So it has been a very dramatic public health activity. You are right on two accounts. Just like infant mortality overall being double the rate in blacks as in whites, the SIDS rate is also double in blacks as in whites. Actually, in Native Americans, it is about three times as high as in whites. With the back-to-sleep campaign, the rate of SIDS deaths has come down in both the black and the white population, but it has come down about parallel. We have achieved about only 20 percent tummy sleeping in the white population. We still have about 40 percent tummy sleeping in the black population. We are intensifying our efforts to get across the message within the black population as well as the Native American population about the importance of back or side sleeping, ideally back, but avoiding the tummy sleeping position at all costs. back-to-sleep outreach efforts We will be increasing our outreach efforts in this area. All along we have included messages in Spanish for the Hispanic population. Our videotapes, our brochures, our other materials are in Spanish, so we have tried to reach that minority population. We have so far not been as effective as we would like to be in reaching the African American population and we are intensifying our efforts to do that in the course of this year. Mr. Hoyer. I know my colleague and I and everybody on the committee is at least pleased to hear that there apparently has been a commensurate reduction, notwithstanding the fact that the disparity remains. Dr. Alexander. That is right. It has come down. It has come down parallel, but it has not---- Mr. Hoyer. That is the two-thirds that we have seen in the white community? Dr. Alexander. Yes. Mr. Hoyer. That is real progress and I am pleased to hear that. Dr. Alexander. Yes. rett syndrome Mr. Hoyer. I want to associate, as Ms. Pelosi did, myself with the remarks of Rosa DeLauro. I am very interested in your findings with respect to maternal child care as compared to non-maternal child care and the quality of both. I think those are very important findings and will be very important in the debate. I will not ask further questions about child care, but I am very pleased with that. Doctor, as you know, you are doing a lot of work and we have now seen pictures in the neurological development area. As you know, I am very interested in Rett syndrome. Can you give me just a couple of seconds on where we are on Rett syndrome? Dr. Alexander. Yes. We still have not found the cause, Mr. Hoyer, but I think we are getting closer. Research in the two program project grants at Hopkins and at Baylor is continuing to do well. One of the exciting things is that they recently identified a family from South America where there are three affected girls with Rett syndrome. They have been brought to Hopkins, studied there, evaluated, tissues have been obtained for genetic studies, imaging studies were done, and these tissues are being shared with investigators elsewhere in the research community so that we hope that this will help us with this cluster in one family to try and identify the gene that must be on the X chromosome, since it affects only girls, that is causing this particular disorder. We are continuing with our natural history study, with the imaging studies that are going on at Hopkins, and along with this, some efforts related to improved feeding and dietary treatment of these girls. We still, however, do not have an effective treatment or an effective diagnostic test--it is still a clinical impression--or a specific diagnosis of where that gene is or what it is doing. Mr. Hoyer. I hope and pray that there is going to be a dramatic breakthrough in light of the fact that there appearsto be normal development for the first 14 to 20 months of development of the female children that are affected. Maybe there can be an intervention prior to whatever goes wrong. Dr. Alexander. Yes. There is some hope along that line because it seems that there is an arrest of development rather than a death of cells. Mr. Hoyer. Yes. Dr. Alexander. It may be that we are, in fact, able, once we know what is exactly going on here, to intervene to correct that process. There is probably a window of opportunity to intervene because these girls do start out apparently normal. Mr. Hoyer. Thank you. Doctor, last question. The President is doing a Medicare press conference at ten o'clock here on the Hill---- Ms. Pelosi. At eleven. autism Mr. Hoyer. I am sorry, eleven o'clock. What did I say, ten? It is eleven o'clock. We had some compelling testimony by Congressman Steven Rothman and his brother. His brother has an autistic child and his brother is a medical doctor. We had a discussion, about what kind of resources we devote to autism or other neurologically similar disorders. Can you tell me where we are? Dr. Penn, as you may have heard me say, and I know Dr. Varmus did, was kind enough to come by my office and give me a copy of the conference that was held on autism. Dr. Alexander. The state of the science conference? Yes. Mr. Hoyer. Can you tell me where we are on autism and what your thoughts are? Dr. Alexander. Yes. The investment in NIH research in autism has more than doubled in the last couple of years. Dr. Varmus has directed some of his discretionary funds to autism to assist the four institutes that are involved with autism research. Following up on the state of the science conference, we formed an autism coordinating committee among the four institutes that Dr. Hyman from NIMH and I co-chair. We have issued a request for applications from NICHD and the National Institute on Deafness and Other Communication Disorders for research focusing on the neurobiology and genetics of autism. From that, we have funded ten different sites, called Collaborative Programs of Excellence in Autism, that represents an investment of $27,000,000 over the next five years for a coordinated approach with interaction and collaboration between these different sites and studying a large number of children in families with autism and trying to get at the genetic or neurobiologic underpinnings of this particular disorder. This is not a single gene defect. There are probably several different genes involved. It is going to be complicated, but we have some good leads that we are pursuing and I think people are very optimistic that we are going to come up with something with regard to autism. Our other studies in autism have also increased, from not only NICHD but the other institutes, as well. The investment is well over $20,000,000 now, with about $11,000,000 from NICHD and a similar amount from NIMH and some from neurology and from deafness. We are also meeting with the parent advocacy organizations at least once a year, and in the summer we are going to be sponsoring with them and with several of the professional societies a conference growing out of our diagnostic procedures within the autism network on the diagnostic workup and evaluation of a child thought possibly to have autism. This will serve as guidance to the medical community, from the medical professional organizations to practicing physicians, on when to suspect autism and what you do as part of an initial diagnostic workup and referral and management of children thought to possibly have this disorder. Mr. Hoyer. Thank you very much, Dr. Alexander. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Hoyer. Mr. Stokes? minority children health disparity Mr. Stokes. Thank you very much, Mr. Chairman. Dr. Alexander, it is nice to see you. Let me start with a reference to your formal testimony here today. As I look at it, I see you have it broken down into several subcategories. For instance, you tell us about research accomplishments, birth defects, vaccine research, premature labor, reading development and disabilities, child day care, women's health research, pediatric pharmacology. I am just wondering, in light of the testimony that you just gave to Mr. Hoyer relative to the health disparity that exists between majority children and minority children, was that not important enough for you to perhaps give us at least a subcategory here of this disparity in health care between minorities and majority people in this country? Dr. Alexander. Mr. Stokes, I would probably have had to put it in many of the categories. It is specifically referenced in the category related to infant mortality and premature labor, where we talk about trying to reduce the disparity between white and minority populations in infant mortality and premature labor. Premature labor is really the basic problem in the black- white discrepancy in infant mortality. As just one indicator, in white infants, the leading cause of infant mortality is birth defects. In black infants, it is premature labor and premature delivery. If we want to get at the difference in the racial discrepancy in infant mortality, the key to approaching it is premature labor. In many of the other areas that I emphasized, as well, an undertone, if you will, in many of these is majority/minority differences, whether it is in reading disability, in the need for day care and the importance of day care as a developmental experience, or in many of the other categories. Unfortunately, there is a racial disparity in many of those. Rather than separate it out as a different category, it is subsumed in each of those. I very much appreciate what you have done over the years in your emphasis in these areas and you have always been a very staunch supporter of the Institute and its efforts to try and attack the racial differences in infant mortality, premature labor and delivery, and other areas. I guess the only one where I specifically singled it out was in premature labor, but there are differences in many of these other areas, as well. lung hemorrhage in infants Mr. Stokes. And I guess that is what disturbs me so, because not only do you not have a category on it but even in the subcategories where you treat it, you do not highlight that particular fact, and that is disturbing to me. Let us talk about lung hemorrhage in infants. As you know, that is a recent illness that has brought a tremendous toll on infants, particularly in the Cleveland area. Dr. Alexander. Right. Mr. Stokes. Is there not a large disparity there between white and African American children in lung hemorrhage? Dr. Alexander. There does seem to be a difference. This is a condition that was initially misdiagnosed, I guess, as sudden infant death syndrome came to light with some epidemiologic investigation and was associated with a fungus as a cause of the condition. I do not think we have enough epidemiologic data yet beyond the Cleveland area to say with respect to this condition, whether it is a black-white discrepancy, whether it is an income discrepancy in terms of its epidemiology, whether it is just associated with certain kinds of housing, or even a geographical finding. So I cannot really give you a good answer on that. I do not know the data well enough and I think it is probably too soon in our investigations of this particular condition to say whether this is a racial discrepancy-disparity kind of an issue. Mr. Stokes. Are we doing any research in this area? Dr. Alexander. No, we are not. This is a condition that has been focused largely as an infectious condition within other institutes. NIAID has been the primary institute thathas been investigating that, along with the Centers for Disease Control. We have not been doing research on pulmonary hemorrhage other than its association with sudden infant death syndrome as a misdiagnosis. mental retardation and gender Mr. Stokes. Dr. Alexander, according to the budget justifications, fragile X is considered to be the leading cause of mental retardation in children, appearing in one out of 4,000 males and one out of 8,000 females. Have researchers been able to determine why the incidence is half as high in females? Dr. Alexander. This is a condition that represents an abnormality on the X chromosome. It is passed on from a female carrier to a male offspring. It is a very unusual disorder in that a woman who may have a very small abnormality of her chromosome can have that abnormality expand and grow in the egg that she produces that becomes her son. What happens in this condition is what is called a triplet repeat disorder, where there is an amplification of a specific part of the gene that becomes abnormal, produces an abnormal protein, then, that results in the mental retardation and some of the other findings of this particular disorder. The males are affected more than females with this condition, much more severely, because the female has a normal X chromosome that functions to counterbalance, if you will, the abnormality on one X chromosome. So males are far more frequently affected, and, in fact, we used to think that this was only a condition that affected males until we actually discovered the genetic basis of the disorder and studied females, as well. Males are much more severely affected in terms of their mental retardation. Females tend less frequently to be retarded and often just to have some mild learning disability, although they may be retarded, as well. It depends on a variety of things, how large this amplification is of the triplet repeat as well as which particular cells get X inactivation, a very complicated process which determines which expression of the X chromosome there is in particular cells in the female's body. violence and children Mr. Stokes. Dr. Alexander, violence, of course, is one of the major public health problems in our country today. Is your Institute doing very much in terms of violence as it relates to children? Dr. Alexander. We are. We have been supporting a number of cooperative agreement studies in cities around the country, looking at community-based interventions for risky behavior, including violent behavior. These projects have worked with a number of different interventions, usually with targeting middle school youth as a means of reducing violence-prone behavior. We also have a study going in Charles County, Maryland, of risky behavior, again in middle schools, where violence is one of the behaviors which is targeted for reduction by the particular interventions that are being undertaken. health profiles in children Mr. Stokes. Last year, the Institute reported that in order to get an accurate profile of the health of children, researchers must go beyond looking at just mortality and morbidity data. Are you doing that yet? What has the Institute done in that regard? Dr. Alexander. We are going beyond mortality and morbidity. We are looking at health behaviors, to start with, that are the generators of morbidity in the long term. When we look at, for example, the prevalence of smoking, the prevalence of risky sexual behavior, the prevalence of eating disorders, whether it is eating too much or too little, or other things like calcium intake in the diet, all these are risky behaviors that may not have any morbidity associated with them at the time, but do have morbidity associated with them in the long term. In a number of instances, we have interventions developed or underway trying to make a difference in influencing these health behaviors. As part of the fiscal year 1999 budget request, there is included in that a health behavior research initiative where we particularly seek to expand research in these areas of pre-morbidity, if you will, that portend problems later on. Mr. Stokes. Thank you, Dr. Alexander. Thank you, Mr. Chairman. information dissemination Mr. Porter. Thank you, Mr. Stokes. Dr. Alexander, with the indulgence of the subcommittee, I want to ask you one or two more questions. We talked about getting the message across earlier. You have detailed for us this morning a great deal of progress being made in research, and I understand it is not your direct responsibility to get the message across, but is there any way you can tell us what percentage of your resources is spent on getting the message across as opposed to the research itself? Dr. Alexander. It is a relatively small percent, Mr. Porter. Most of the ``getting the message across'' funding comes from the Research Management and Support line in the budget, which has been extremely constrained, so probably no more than two percent of our overall budget is directed toward getting the message across specifically in terms of public information. Now, much of what we do in terms of publishing the results of our research is part of getting the message across. But I gather from your comments that you mean to the general public, to the practicing physician, to get the research results actually implemented. Here, we have things like the Back to Sleep campaign, a very successful example of getting the message across. Another campaign from the Institute that---- Mr. Porter. How did you do that? back to sleep campaign Dr. Alexander. We worked collaboratively with a number of organizations, with the American Academy of Pediatrics, with the SIDS professional organizations and SIDS program people, with a number of public health organizations in the States and elsewhere throughout the Public Health Service, first to make sure that the message was understood, to encourage its distribution and its dissemination. With Back to Sleep, we had a very specific target audience, newborns. Every newborn in the country was our target, to get the message to the mother at the time she took the baby home from the hospital that her baby should be put on its back rather than on its tummy to sleep. So we targeted a mailing to all newborn nurseries in the country, for starters, in addition to our work with the American Academy of Pediatrics, and asked that they make sure that the message was given to every mother taking the baby home from the hospital to put her baby to sleep on its back. We also provided brochures and stickers to put on the crib. These brochures were in Spanish as well as in English. In this way, we very specifically focused that information. We also produced public service announcements.Later on, we enlisted Mrs. Tipper Gore as the national spokesperson for the Back to Sleep campaign, who has been effective in carrying the message to the media as well as to senior citizens, the American Association of Retired Persons, because grandmothers and grandfathers were among the last to get this message and were traditionally still putting babies when they cared for them to sleep on their tummies. We are also getting the message out to day care centers, which is a place where many infants sleep these days, and had not effectively gotten the word about the importance of back sleeping. We have industry partnerships, as well. Gerber Products Company put the Back to Sleep message on the back of 5,000,000 boxes of Gerber rice cereal. We are working with other industries at the present time, trying to get messages, for example, on diapers. This is an example of a campaign, part of it done with NICHD resources, part done with resources elsewhere in the Public Health Service, including provision of a hotline, an 800 number for parents to call, and partnerships with industry. milk matters campaign We are doing a similar thing with the ``Milk Matters'' campaign, getting the message out on the importance of calcium in the diet of children, the fact that the window closes by 21 to 24 years of age for adding more calcium to your bones. If you do not get it in before then, you do not get it. It is important to maximize calcium in the skeleton before you start the inexorable process of calcium loss that can eventuate in osteoporosis. The more calcium you take in to start with, the longer it is going to take for you to lose enough to develop osteoporosis. The Milk Matters campaign is a public education, public information activity. Here again, we have managed a partnership with industry, the Milk Producers Association as part of the milk moustache campaign. This has been extremely successful in promoting the idea of milk as a source of dietary calcium for kids. We work in other areas, as well. For example, I met yesterday with Fred and Vicki Modell from the Jeffrey Modell Foundation, where again we are partnering with them in getting information out about primary immune deficiency disorders to the practitioner, to the public. We are producing a booklet about the disorder, producing a treatment algorithm for physicians, and also working in other ways to get that information out. Those are three examples of the approaches we use. information based interventions Mr. Porter. Dr. Alexander, we talked earlier with Dr. Varmus and other directors about how a great deal of our health care costs result from lifestyle. Last year, you and I participated in an event put on by Dr. Ernst Wynder of the American Health Foundation focusing on children's health and what we can do to get the message out to children, and presumably also to those who most affect their lives, to develop healthy habits early in life. What can we do to further that kind of effort? And the macro question I want to leave you with is, if we were to double your resources over the next five years, how would you use them? Would you use a portion of those to get the message out? Dr. Alexander. We certainly would. Part of it is learning how to get the message out most effectively and what interventions work versus what interventions do not work. There is still a research agenda here, as well as a get-the-message- out agenda. As part of the fiscal year 1999 request, again, as part of Dr. Varmus's areas of emphasis, NICHD includes a health behavior research initiative, that focuses on research related to some of these behaviors, to calcium in the diet, to obesity, to smoking, to other health habits in kids. I have said here before and I will just say it again, the most effective time in life to get this information when it can have its maximum benefit is in childhood. That is when these lifetime habits are formed. Once they are formed, it is very, very difficult to break them or change them, and so it is important to reach kids early with the message in the most effective way that we can when they are very receptive and open and we can have the maximum influence. We need to learn how to deliver those messages most effectively. One objective of our health behavior research initiative is to learn how to do that most effectively. Another part will clearly be public information campaigns like Milk Matters, like Back to Sleep, like the Jeffrey Modell Foundation campaign on primary immune deficiencies and other disorders that we would like to get into. So this is a very useful area for investment, both in the research to learn how to deliver the message most effectively and in the actual funding of delivering the message. Mr. Porter. You may have the best job in the world. You probably also have one of the most important jobs in the world and we are delighted that you are there and doing it so well. We appreciate your excellent testimony this morning and your very direct answers to all of our questions. We have additional questions for the record that we will ask you to answer. Thank you, Dr. Alexander, for your testimony this morning, very much. Dr. Alexander. Thank you, Mr. Porter. Mr. Porter. The subcommittee will stand in recess for three minutes. [The following questions were submitted to be answered for the record.] [Pages 2008 - 2149--The official Committee record contains additional material here.] Tuesday, March 17, 1998. NATIONAL INSTITUTE OF DENTAL RESEARCH WITNESSES DR. HAROLD SLAVKIN, DIRECTOR DR. DUSHANKA KLEINMAN, DEPUTY DIRECTOR YVONNE DU BUY, EXECUTIVE OFFICER EARLENE TAYLOR, BUDGET OFFICER DR. HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH DENNIS P. WILLIAMS, ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. The subcommittee will come to order. We continue with our hearings on the National Institutes of Health and are pleased to welcome Dr. Harold Slavkin, the Director of the National Institute of Dental Research. Dr. Slavkin, let me apologize to you. I grossly underestimated the number of Members who would arrive and therefore we lost a lot of time that I thought was going to be available to you, but we will do our best. Why don't you proceed with your statement after you introduce the people who have come with you this morning. Introduction of Witnesses Dr. Slavkin. Thank you, Mr. Porter. Immediately to my left is Yvonne du Buy. Yvonne is our Executive Officer; Earlene Taylor, who is our Budget Officer; our Deputy, Dushanka Kleinman; Dr. Varmus; and Mr. Williams. Opening Statement This year is a very, very special year to come before you because this is the 50th anniversary of the National Institute of Dental Research, created on June 24, 1948, when tooth decay was rampant in this country, when being edentulous was a normal expectation of men and women turning 45 years of age, when there were essentially no strategies to address that. Since that genesis and the very wise decision of Congress to create the National Institute of Dental Research, we have come a long way. Through your investment over 50 years of $3,200,000,000, we are now saving the country $4,000,000,000 per year as a consequence of the investment in the National Institute of Dental Research. When you look at this country today, with 50 percent of our nation's children having no tooth decay in their permanent teeth whatsoever, where edentulism in the adult population is now below seven percent, where people today expect to be with their teeth into the eighth and ninth decades of life, free of pain and discomfort, that has been derived by public health measures and an investment in science. When you go to your dental office and look around at the high-speed drills, the panorex x-rays, the digitized radiography, the infection control, the marvelous dental materials that have been developed, the dental sealants, the pre- and post-operative management of pain and inflammation, all of that comes to bear on America having the finest oral health in the world. It can be better. When we look at the opportunities today and anticipate the future, we, like many of the other institutes on the NIH campus, have taken an audit of where we are, we have formulated a vision of where we would like to be, and we have made a plan of how to get there. In so doing, we have come up with a strategic plan referred to as ``Shaping the Future.'' We have reorganized our intramural program, our extramural program, and our Office of the Director, to focus on six major areas of research. First, the genetic diseases that are either inherited or acquired. Second, infection, meaning viral, bacterial, and yeast infections, as well as host immunity. Third, mouth cancer, oral and pharyngeal cancer. Fourth, chronic disabling diseases, such as temporomandibular joint, chronic facial pain, osteoarthritis, the consequences of diabetics in this country on the premature loss of teeth, et cetera. The fifth area is biomaterials or biomimetics, a whole new set of opportunities that are truly remarkable and are being pursued by many other institutes at the NIH. And then finally focusing on human behavior and the opportunities to do a better job in health promotion, both to the professions as well as to the many publics that we serve. To highlight three of the areas that are, we think, extremely exciting and promising, we have made a couple of visuals. The first one is an area of emphasis on the role of genetics in medicine and dentistry, and here in this diagram, what has happened through work that began at the early part of this century, researchers have basically mapped the genes responsible in establishing the geometry of the body form of a fruit fly, Drosophila melanogaster, and somewhat counter- intuitively, genes that are involved in the head of forming Drosophila are highly conserved and reappear in the formation of zebra fish, in the formation of frogs and mice and human beings. In this particular example, a gene that is exclusively expressed in the head of the fruit fly is also expressed in the head of mammals, including human beings. Last year this gene turned out to be responsible for a human craniofacial syndrome called Rieger syndrome, located on chromosome number four that not only affects tissues of the head, face and teeth, but also is involved in eye defects, a predisposition for glaucoma, and also heart and limb deformities. Another area of emerging opportunity is the development of novel and innovative therapeutics. Once a knowledge base is established, either from doing the genomic studies and the post-genomic or functional studies to understand proteins and how they function, the next opportunity is to focus that knowledge on improving diagnosis and therapy, and this is work going on at the NIH campus, focusing on a very interesting non- inherited but genetic disease called McCune-Albright syndrome. This is work that is done in collaboration with NIDDK, NICHD and the Clinical Center, and, in these studies, the idea is to isolate cells that normally reside in our bone marrow. These are so-called stem cells or stromal fibroblast cells. These cells normally help in the repair of bone. By modifying them, by adding bone morphogenetic protein to them, a class of genes was discovered by scientists supported by the NIDR over many, many decades of research and involving several other institutes. Those stem cells can be enriched and used to provide an incredible delivery system to enhance skeletal bone healing, whether it is in the head or the jaws or the rest of the body. This work is being published in April in the Journal of Clinical Investigations and is a ``proof of principle'' using biomimetics, the background of genetic understanding, and now applying it to humans to be able to heal bone. Our third example is a whole series of opportunities that are opening up around us. In the oral cavity, there are roughly as many bacteria as there are people on the planet earth, well over 6,000,000,000, but they live in an ecosystem, in an ecological unit called a biofilm, and they grow and live on the surfaces of our teeth. In a healthy, robust individual, they can be controlled through oral hygiene. But in many individuals, from children through senescence, they can become pathogenic and associated with cerebral vascular stroke, with cardiovascular disease, or with the induction of premature babies; about 250,000 babies are born every year in a premature, low-birthweight situation. Some very interesting new data indicate the importance of the oral healthstatus of the mother--these are young women between the ages of 20 and 25 in a study we are doing in collaboration with NICHD in northern Alabama, that is opening up a very interesting association in which the status of the oral health of these reproductively active women is responsible for a seven-fold increase in the incidence of premature, low-birthweight babies. This is an opportunity that we will pursue. In addition, infections in the oral cavity, in particular yeast infections, often are transmitted into lung tissue and can be a cause of death for immunocompromised and elderly individuals. So the role of biofilm in systemic disease is becoming a significant set of new opportunities for the institute and its role, working with other institutes at the NIH and with other agencies. With that in mind, the effort of the NIDR strategic planning effort was essential to identify three major strategic initiatives. First, to pursue the scientific opportunities that we have attempted to highlight. Second, to address the research capacity, the training of clinical scholars, men and women who can cross-over between different disciplines and take advantage of this knowledge base in the delivery and management of disease. And the third area is to significantly improve health promotion--how we transfer knowledge from discovery into the practice of clinical medicine, dentistry, pharmacy, nursing, and all the other related areas. A variety of changes in the institute has positioned us, I think very effectively, to meet these challenges. Looking at ourselves in the context of changing patterns of disease, changing demographics in this country, changing patterns in the management of health care, changing opportunities of how we do science, and the kind of consortium efforts that are now practiced, the new public/private partnerships that are available--this all makes the future look very bright. These developments I believe are fostering a climate of increased cooperation, collaboration and communication, not only within our NIH community, but also between the NIH and the many other communities that we serve. Communicating the facts of biomedical science is the best means we have to empower Americans to make decisions and life style choices to improve their health and prevent disease. That goal was intrinsic to the NIDR 50 years ago and it continues to be a driving force as we look forward to the next century. My colleagues and I will be very happy to answer your questions. Thank you, Mr. Chairman. [The prepared statement follows:] [Pages 2155 - 2165--The official Committee record contains additional material here.] fluoridation Mr. Porter. Dr. Varmus, I think I said this last year, but it is wonderful to see the enthusiasm that Dr. Slavkin brings to his testimony and to his work. It is just infectious, I think. [Laughter.] Am I correct, Dr. Slavkin, that when I was in, I guess the 7th or 8th grade in 1948, that was about the time that fluoridation of water began to be undertaken across our country. In my town of Evanston, I think it was either 1947 or 1948, that water fluoridation began. There was initially some negative political reaction to it, but it was pushed ahead. That was at the same time that the NIDR was created, as you mentioned in your testimony. Is about the right time frame? Dr. Slavkin. Yes, from 1948 into 1954 is when the studies were undertaken across the country, but really starting in the Midwest. Studies in Grand Rapids, Michigan, and in Illinois, were really the beginning of this public health measure. future directions Mr. Porter. Now let us look 50 years down the line. We have had 50 years; let's look 50 years into the future. It seems to me, from what you have told us this morning and what you told us previously, that we could very likely have no more dentists in America. That every child will be formed with a perfect set of teeth, that look like movie stars, and that we will live until 100 years old with no oral problems at all. Is that entirely possible? In other words, could you be the first Institute to go out of existence because you have nothing left to do? Dr. Slavkin. Being very serious, I think it should be intrinsic to the goal of our entire enterprise. I mean, if we can--and regardless of whether it is 50 years or whether it is 100s of years, I think all of us are really trying to maintain health, and contribute so that diseases--like smallpox and polio and dental caries and so forth--are eliminated, and I think that has been demonstrated by many institutes. What we are looking at today--and 50 years I believe is not a realistic projection into the future--is that the problems of chronic diseases and disorders are incredibly complex. Many of us thought that many diseases would be explained by mutations in one gene. Now we have coined the phrase, complex human diseases, and acknowledge that there may be a dozen different genes, with a different burden or load, that predisposes some of us for certain conditions and others of us to be resistant. The other formidable issue that this morning you have repeatedly addressed, and throughout your career, is human behavior. The issues of really improving prenatal care, the early childhood development, K-12 development, those issues are linked to health literacy and to people making choices,wise choices to reduce the preventable diseases. I think that this is really an area that is not our strength, and that we need to do better on the basic understanding of how people make choices. I think there is an enormous challenge before us. But there will be dentists in 50 years. [Laughter.] Mr. Porter. They may be doing a lot different things than they do now. Dr. Slavkin. Yes; exactly. change in institute name Mr. Porter. I have heard that there is a legislative proposal to change the name of your institute. What is the proposed name change, and what is the reason behind that thinking? Dr. Slavkin. Right. We started the process of strategic planning when I had the privilege of joining the institute two and a half years ago. We have had focus groups from organized dentistry, from various patient advocacy groups, from scientists, and most people feel that our name does not describe our portfolio, either three decades ago or two decades ago, or currently. The NIDR is very much involved in temporomandibular disorders. It is very much involved with cleft lip and cleft palate and all the craniofacial malformations. So, in working closely with the American Dental Association and their leadership as well as the leadership of the American Association of Dental Schools, the American Association of Dental Research, Dr. Varmus, and a large number of people, the thought was to add a C to our acronym, and convert it to NIDCR, the C being craniofacial. So the name change would clarify the scope of what we are trying to attain, which is really the health of the human face, inclusive of the mouth and the oral issues. oral and pharyngeal cancer Mr. Porter. Can you describe for us the national strategic planning conference for the prevention and control of oral and pharyngeal cancer you are sponsoring along with CDC and the American Dental Association. What other collaborative efforts are you planning with nongovernmental organizations? Dr. Slavkin. The problem of--depending on the language-- mouth cancer, or oral, tongue, pharynx, tonsillar area--is linked to fairly well-established risk factors. All tobacco products, alcohol, and direct sunlight are very well- established causative factors in inducing this particular condition. It is also clear, like all other cancers, that these are multi-gene mutations that go from normal to a pre-malignant to a malignant stage. Therefore, to address that problem, which is sixth most prevalent in this country, fourth most prevalent in African American populations, it is necessary, essentially, to bring a lot of different people together. So we have partnered with the National Cancer Institute, the National Institute of Deafness and Communicative Disorders, which has a large number of otolaryngologists associated, with the National Institute of Environmental Health Sciences, with the American Dental Association, with CDC, and with a number of not-for-profit outreach groups that deal with Little League baseball, teachers who coach and model behavior in various parts of the country, and we are trying to leverage our resources with the other groups to address this challenge. In Bethesda, in the Intramural Program, we have a new branch that focuses exclusively on oral and pharyngeal cancer, with input from many institutes. Our extramural activities involve the American Cancer Society, and there is an oral cancer advocacy group in Atlanta, one in New York, one in Chicago and one on the West Coast that we are working with. We are trying to raise the consciousness of all the American dentists and dental hygienists. That is 140,000 dentists and another 100,000-plus dental hygienists who see 200 million Americans every year, and can perform a wonderful function in early detection. One of the problems with this malignancy--it is detected too late, and the prognosis, therefore, after 5 years, is that half of the patient population is dead. So at this rate, we think that this private/public consortium, using professional organizations as well as NIH and other governmental agencies, is the way to really reduce the burden of oral and pharyngeal cancer. gender differences in pain Mr. Porter. Thank you. It is thought that men and women have different pain pathways contributing to the fact that women report greater sensitivity to pain. It is also thought that men and women react differently to pain medication. How does this information affect the way you design clinical research studies? For example, do you require that the studies be comprised equally of men and women? Dr. Slavkin. Well, as you know, and before I arrived, and I think through the efforts of Congress, an Office of Women's Research was developed at the NIH, so there has been an increasing sensitization to all of us who are in the different institutes. In the area of pain, in particular, Harold Varmus created a trans-NIH pain consortium which includes 21 of the institutes who share an interest in pain. We are having a conference next month on gender and pain. A paper came out in November of 1996 from a group in San Francisco, showing for the first time that the kappa receptors on women's cells were very different than on men. The response to analgesia was very different. Since the end of 1996, that information has defused to the scientific community. We had a trans-NIH major meeting on ``New Directions in Pain Research'' where gender biology was discussed, and I think there are a lot of bright people who had not previously thought that there would be a gender difference of this magnitude, who have become interested, scientifically, and I think are going to ``push the envelope'' of this problem area. periodontal disease and low-birth-weight babies Mr. Porter. Dr. Slavkin, periodontal disease itself is not a life-threatening disease, but it may lead to other life- threatening conditions. For example, women with periodontal diseases are seven times more likely to deliver low-weight babies prematurely. Dr. Slavkin. Right. Mr. Porter. A Seattle-based company that produces a Sonic toothbrush has donated 2,000 of them to low-income expectant mothers. Is your Institute or someone else following these women to see if they make a difference in the incidence of premature births? Dr. Slavkin. Yes. That issue has two interesting parts. In the Small Business Inovation Research program, the NIDR provided the start-up money for a project conducted by a company in the State of Washington to develop the Sonicare oral hygiene device. It was one of the fastest-rising companies in the country, earning, from 1992 to 1996, well over $100,000,000 a year. This company has in fact donated these tooth devices, the Sonicare. The study is going on, which is a consortium effort between the University of North Carolina, the University of Alabama, and Meharry University, and it is focusing on women at risk for low birthweight, premature babies. By a modest investment of improving oral health, we hope that this will dramatically reduce the number of children requiring neonatal intensive care, the costs of which are remarkably high, sometimes $225,000 per child. The investment in oral hygiene is a very cost-effective way of reducing that burden. Mr. Porter. Dr. Slavkin, we are pleased to welcome to the subcommittee Mr. Jay Dickey of Arkansas. Mr. Dickey. Mr. Dickey. I have no questions but I appreciate the deference from the Chair. public health education Mr. Porter. Thank you, Mr. Dickey. I understand that about 40 percent of the population doesnot see a dentist. Dr. Slavkin, do we know why this is? It seems to me that if more people started seeing a dentist on a regular basis, even once a year, we could save a lot of personal pain and suffering and a lot of money on health care costs. We now know that dental caries and periodontal diseases are infections associated with bacteria. We think that there is a link between periodontal disease and the incidence of low- weight premature deliveries and cardiovascular disease. With some 400 species of bacteria living in the mouth, who knows what other problems poor dental hygiene is causing. What is being done to address this problem? Do we need to spend more on education? Do we need to get outside groups involved? What suggestions do you have? Dr. Slavkin. Both of the suggestions you just raised would be very important to the approach to this problem. This is going to sound like an extension of Duane Alexander's beautiful testimony earlier this morning--and that is the emphasis on very early childhood development when habits of mind and certain kinds of behavior are established, including oral hygiene, would be the best investment to focus on, to really reduce these problems. People who form these habits, and then they are modeled by their caretakers, typically go on and are not problematic with oral hygiene conditions. So a major effort is health promotion using preschool and K-12 education, and giving people the empowerment to properly take care of their oral health, as well as all of their health. We have, coupled with Duane, tried to sensitize all the dentists in the country to be cheerleaders for the use of drinking low-fat milk, among children, to not only build the bone density of the whole skeleton but also of their dentition. Many of these strategies carry over between institutes, very effectively, with the same target--early childhood development, and beyond. It really becomes a collaborative effort between a number of school districts around the country, it involves athletic coaches who have incredible influence on children, the modeling of some of the bigger-than-life athletes who children often emulate--all of these kinds of influences could reduce this problem and promote health. diagnostics Mr. Porter. Is it true that everything in the blood is also found in saliva and that early signs of disease such as diabetes or AIDS can be detected in the oral cavity? Dr. Slavkin. Yes. Mr. Porter. Then why aren't doctors using saliva tests more often instead of blood tests? Wouldn't these tests be less costly and painful for the patient and provide the doctor with quicker results? Dr. Slavkin. Right. Using saliva is clearly noninvasive, and some of us believe could be very cost-effective, and I think one of the things that our institute wants to do, and I believe other parts of the NIH and Government, is really to move dentistry much closer, or integrate it into medicine. This is an experiment, as you probably are aware, the segregation of these fields in the mid-19th century, and clearly, primary care physicians need to have a better education of oral health, and various dental health professionals need to have a much better understanding of principles of internal medicine, and how to work together effectively to address these problems. So we are trying to broker the American Association of Medical Colleges and the American Association of Dental Schools to come together and share curriculum and have more crossover. We are also trying to achieve that through a new initiative called Centers of Discovery, where we are trying to stimulate in major research centers in the country, in an academic health setting, much more integration between pharmacy, dentistry, medicine and nursing, to the enhancement, I think, of all the fields. biomimetics Mr. Porter. You are making great strides in a new area of science called biomimetics, which aims to create replacement parts for bones and body tissues. Do you see a future where we will be able to grow body parts such as knees and hips on demand for surgery, and no longer use artificial replacements? Dr. Slavkin. Yes. This--as Dr. Varmus knows, because we have had a chance to talk about this on a number of occasions-- is a tremendous opportunity. The FDA, as you may know, has already approved a cartilage tissue approach for knee injuries, so that in that case biomimetics has gone from the bench to application, and now to clinical trials. The NIH sponsored, the end of February, a tremendously successful conference on bioengineering, involving about 800 people from around the country, with a very, very significant interest. We have teamed up with the Heart Institute and the Arthritis Institute to put out an RFA to support and stimulate research in this area. We received 124 applications. They were truly remarkable, from all over the country. A significant number will be funded in the summer councils of the participating institutes. They will be funded, probably, in July of this year. There is a real excitement between physicists, mathematicians, engineers, clinicians, molecular biologists, putting their minds together and really developing a newgeneration of materials. In dentistry, thinking of silver or gold fillings will become obsolete. That will not be the way to restore teeth. We hope to regenerate enamel and dentine, to replace bone, hips or jaws, instead of using metal or plastic, to be able to augment normal bone repair and regeneration. That is the goal, and whether it is nerve tissue or muscle tissue or salivary gland--whatever part of the body--many, many very bright people are trying to find out how to understand the biology, and then mimic it in the design and fabrication of new materials or new strategies to address these issues. professional training Mr. Porter. There are numerous diseases and illnesses such as bulimia, diabetes, and vulnerability to strokes that can be detected in the oral cavity if dentists and hygienists know what to look for. Do you think enough training is provided to them to look for these signs? Dr. Slavkin. No. This is an area of terrific opportunity. We need to catalyze our efforts with the health professions, to raise the awareness of men and women who practice dentistry, to be able to identify eating disorders appropriately, and to really be part of the network of being able to provide the patient with the venue to get the kinds of various therapies that would be effective. This also applies to child abuse, to heighten the awareness of health care professionals, to be able to identify and provide better venues for people to be addressed in those areas. We need a much better education, and I am hoping that the American Dental Association, the American Association of Dental Schools, our colleagues in medicine, nursing, pharmacy, will do more crossover, so we will be more effective. budget increases Mr. Porter. Dr. Slavkin, some might say that NIDR is making so much progress, that your area would be the one where you would least need the doubling of your budget. What would your answer be to that? Dr. Slavkin. I think we could use some modest encouragement. If you look at our portfolio and everything that I have described, I think the plan that we have outlined is very appropriate. We have identified the key areas, and what we really need to do is establish the bench strength to make these things happen. We need to train more people and much better in the new tradition. We need to increase our efforts to bring these things to fruition in a more focused and in a more effective fashion, and I think with combining training with the scientific opportunities, looking 5, 10 years down the road, the training is the most important. We need to train people in the kind of modern genomics, modern physical chemistry, modern statistics and epidemiology, and behavior, to be able to address these issues, and I think that is going to be a major issue. The loan that students have when they graduate from medical and dental schools today, somewhere between $60,000 to $70,000 on the low side, to a couple of $100,000 on the high side, is a significant deterrent to recruitment of all the bright young people in the pipeline, to bring them into these areas, and for them to be able to contribute. From a policy point of view, that will be very helpful for us. Mr. Porter. Dr. Slavkin, I wish that Mr. Hoyer were here, so I could claim to him that you are Chicago born. Dr. Slavkin. Yes. Mr. Porter. But then Ms. Pelosi would say you deserted Chicago and went to California. So maybe I am glad they are both not here. [Laughter.] Mr. Porter. Let me thank you for your excellent testimony today, and not only for your enthusiasm, but obviously the tremendous intelligence and imagination you bring to your work at NIDR, and thank you for the tremendous job you are doing there. Dr. Slavkin. Thank you. Mr. Porter. Thank you so much. Thank you, Dr. Varmus. The subcommittee will stand in recess until 2:00 p.m. [The following questions were submitted to be answered for the record:] [Pages 2173 - 2234--The official Committee record contains additional material here.] Thursday, March 19, 1998. NATIONAL INSTITUTE OF MENTAL HEALTH WITNESSES STEVEN E. HYMAN, M.D., DIRECTOR RICHARD K. NAKAMURA, ACTING DEPUTY DIRECTOR WILLIAM T. FITZSIMMONS, EXECUTIVE OFFICER J. RICHARD PINE, BUDGET OFFICER GEMMA M. WEIBLINGER, SPECIAL ASSISTANT TO THE DIRECTOR Mr. Porter. The subcommittee will come to order. We continue our hearings this afternoon on the budget of the National Institutes of Health with the National Institute of Mental Health, and we are pleased to welcome its Director, Dr. Steven Hyman. Dr. Hyman, it is good to see you. If you would introduce the people to your left and then proceed with your statement? Dr. Hyman. Thank you, Mr. Chairman. To my far left is Gemma Weiblinger, who is my special assistant and congressional liaison; my budget officer, Mr. Richard Pine; the Acting Deputy, Dr. Richard Nakamura; and my executive officer, Mr. Bill Fitzsimmons. Mr. Chairman, it is indeed a pleasure to be here. The President in his fiscal year 1999 budget has proposed that the NIMH receive $701.8 million, an increase of $52.4 million over the comparable fiscal year 1998 appropriation. Including the support for AIDS, the total budget for the NIMH would be $809.7 million, an increase of $59.5 million over fiscal year 1998. excessive disability stems from mental illness Mr. Chairman, mental illness is a serious burden for the American people and for the entire world. The Global Burden of Disease study, which no doubt you have heard about more than once, sponsored by the World Health Organization, the World Bank, and the Harvard School of Public Health, has clearly established the enormous contribution of brain disorders to disability. As you can see, this poster on the left shows all causes of disability in what are called established market economies, that is, the United States, Canada, Western Europe Japan, and Australia. And as you can see, in the United States the leading cause of disability is unipolar major depression, a disorder that in its most serious forms affects 17 million Americans. [The information follows:] [Page 2236--The official Committee record contains additional material here.] Dr. Hyman. Also high on the list are three other mental disorders: schizophrenia, manic depressive illness, and obsessive compulsive disorder. Also on this list are alcohol use, dementia, stroke, and drug use. Thus, eight of the ten leading causes of disability in the United States are seen to be related to brain and behavior. Mental illnesses are in this top ten list not only because they are disabling, but also because they begin early in life. It is common for mood disorders and schizophrenia to begin during young adulthood, just when families and society as a whole are waiting to see a person flower as a result of their investment in upbringing and education. Not only do mental illnesses begin early, but they are also often chronic or recurrent. Fortunately, we are making substantial progress in the treatment of these real and diagnosable disorders. But progress in treatment and prevention begins with basic research. For the NIMH and, indeed, for all of the brain-related institutes to fulfill their missions, this research must be both bottom-up, based on genes and molecular biology, and top-down, based on the study of behavior, how it emerges from the workings of the brain, and, conversely, how the environment changes the way the brain works. mechanisms of cellular memory Today, I would like to describe for you one example of ``bottom-up'' research, which concerns how the brain records experience. There are many forms of memory besides our conscious memories of persons, places, and events. Some of these forms of memory, such as emotional memory, initiate powerful physiologic cascades in our bodies even before we are aware of them. Each of the 100 billion or so nerve cells in our brain makes thousands of connections with other nerve cells. These connections, which are called synapses, are the fundamental sites of information transfer. Whenever we remember something, whenever we learn something, the physical structure of our brains is actually altered. Memory is the result of physical changes in these synapses or connections. Using a variety of animal models, including recently mice with experimentally altered genes, neuroscience has provided many details about the precise molecular changes that are required to produce memory. What has remained elusive, however, has been the ability to correlate actual learning due to experience with direct physiologic evidence of a functional change in the strength of these synaptic connections. Several months ago, two separate research groups provided evidence for this long suspected correlation between learning and a physical change in the brain. The discovery was made in response to learned fear in a part of the brain called the amygdala, deep in the temporal lobes of humans or, in this case, rodents. Preceding this research, several labs using rodent models had traced the pathways responsible for fear and found them to involve the amygdala, which in turn activates the sympathetic nervous system, racing heart and so on, and a variety of physiologic mechanisms that would save us from becoming, for example, a carnivore's lunch. With this model and with this knowledge from animal models, several investigators have now used functional magnetic resonance imaging, or fMRI, to demonstrate that if you show an individual a fearful visual stimulus, such as a fearful face, we can literally see the representation of fear in the human brain. In this poster (figure 2), you will see vividly the activation of the amygdala in response to an individual seeing a projection of visual scenes designed to elicit negative emotion. [The information follows:] [Page 2239--The official Committee record contains additional material here.] Dr. Hyman. To survive, an organism, including a human being, must be able to predict danger. Thus, a major function of the amygdala is to record in memory the circumstances under which we have experienced and can expect danger. brain mechanisms underlying panic disorder What does this mean for human health? Well, for example, we believe that panic attacks, which affect a substantial number of Americans, with disaproportionate numbers of women affected, result from internal false alarms that activate the amygdala. What is the role of memory in all of this? If an individual experiences a spontaneous panic attack while, say, on a bus or in a shopping mall, they will develop powerful emotional memories telling them falsely that this bus or this shopping mall is a place of extraordinary danger. The life of afflicted individuals often constricts progressively, leading to a profoundly disabling condition called agoraphobia. In addition, emotional memories have important negative consequences following trauma. As befits a system that evolved to predict and respond to danger, the amygdala matures very early in life. However, the hippocampus, another part of the brain, which is required for conscious memories, matures much later. And as a result, none of us have continuous memories before the age of 4 or 5. If a child is abused or neglected early in life, he or she will not, of course, remember consciously because the hippocampus is not mature. And the conscious memories of these episodes, despite recent controversies, cannot be recovered in any way because there was no substrate on which to record them. However, the emotional memories, which don't rise to consciousness, are undoubtedly recorded by the amygdala, with consequences that we are now only beginning to understand, but which at a minimum reset the brain's control of the stress response in the direction of over-responsiveness with potentially harmful subsequent physical effects. How will this kind of research be translated to the benefit of patients with anxiety disorders, mood disorders, and so on? brain molecular anatomy project Among NIMH priorities listed in my written testimony, we want to clone essentially all of the genes expressed in the brain under both resting and stimulated conditions. This is the so-called B-MAP project, which is a collaboration with NINDS, the National Institute on Aging, and several other institutes. This project will involve cloning the genes for neurotransmitter receptors and signaling molecules that are actually found in the amygdala. These receptors and molecules can become targets for drug development. We also plan top-down research, that is, research to map behavior onto the brain. What you saw in the MRI I showed you (Figure 2) is the result of a great deal of preparatory animal work that has helped us understand brain circuits. We also want to emphasize various imaging technologies because we obviously want to bring these applications to the human as quickly as possible. Finally, NIMH is working to establish clinical trials networks, something that we have not previously supported but has been supported by other institutes. Clinical trials networks will permit us to test new psychotherapies and pharmacotherapies in a more rapid and efficient manner and, by incorporating health services research, will produce results which will be applicable to the real world. I thank you, and I will be pleased to respond to any questions. [The prepared statement follows:] [Pages 2242 - 2248--The official Committee record contains additional material here.] neurobiology of fear and anxiety Mr. Porter. I was just thinking I could listen to you all afternoon. It is a fascinating subject. Can I ask an unrelated question? It's something that interests me. We are talking about a fear reaction. If a person goes to a horror movie and they know very well that what they are seeing is not real, do they have the same kind of imaging that your chart would show? Dr. Hyman. Actually, probably yes, but not the same kind of emotional memory. And the proof of it is that during a horror movie, even if you know cognitively that it is not real, you notice your heart is racing. If we measured your blood pressure, it would be up. If we measured adrenalin levels, they would be increased. If we measured cortisol levels, they would be up. So, indeed, you get this physiologic response. Now, I have asked my children why they actually like going to horror movies and being frightened, and they swear to me that they enjoy it, but they cannot actually tell me what it is about it they find so enjoyable. Mr. Porter. The rush from all those-- Dr. Hyman. I guess all those hormones, that is exactly right. [Laughter.] Mrs. Lowey. Same thing on a roller coaster. Dr. Hyman. That is right, yes. Mr. Porter. Yes, but with a roller coaster, you might have a reasonable fear that there is a chance of being injured. [Laughter.] Dr. Hyman. It is actually true, in all seriousness, these stress hormones are meant actually to sharpen cognition. They do create arousal and alertness because in evolution these would be here in order to help you escape real danger. And I think part of the enjoyment is this intense arousal. Mr. Porter. But we don't need them anymore, usually. Sometimes we do. Dr. Hyman. Well, we don't need them all the time, but actually we do more than we think. Some of these same systems help teach us to avoid things that could hurt us by virtue of their causing pain, for example. But it is true these systems evolved a long time ago, and now when they work to excess or get activated without good reason, they lead to problems for physical health that we need to learn how to manage. Mr. Porter. Part of what we call mental illness you described, I think, is an over-response to certain stimuli. Dr. Hyman. In the case of anxiety disorders, that is right. We believe--and, actually, there is increasing evidence--that there might be a false alarm setting off this cascade and setting it off at full tilt. And, of course, the person will have what is known as a panic attack, this overwhelming feeling of anxiety and dread. Mr. Porter. What is the relationship between that and autoimmune diseases where your system also has an over-reaction to whatever the stimulus is, but it is more automatic? Dr. Hyman. Well, I think the metaphoric connection is that systems evolve which are required to protect us from real dangers. But we pay a price. These systems have a certain threshold set, so they are not supposed to go off with a mild or inappropriate stimulus. But sometimes, as in the case of anxiety disorders, the thermostat, by virtue of genes and environment, is set wrong. In the case of autoimmune disorders, a mistake occurs in which a molecule which is part of our normal body is mistaken for an invader. Now, there is also a non-metaphorical connection between the two in that the activation of these stress hormones does have an impact on our immune system. Indeed, cortisol, one of the major stress hormones, actually suppresses immune function, this may occur during a period of danger, famine, or escape. In these situations, You don't want to use your metabolic energy, presumably, to be activating your immune system. There is a big metabolic cost. In addition, an escape is not the time to get a swollen knee if you have been injured. You want to suppress that and wait until later, and then you can get a swollen knee when you are safe and you want to splint it so you don't hurt it again. I am obviously speculating. explanation of functional mri Mr. Porter. Is the chart the brain of a human or an animal? Dr. Hyman. This is a human. This is a normal volunteer. This is from Richie Davidson at the University of Wisconsin. Mr. Porter. Could you just for my edification give me an indication of how you go about doing brain imaging? Dr. Hyman. Yes. Mr. Porter. This procedure is used in many of the Institutes. Dr. Leshner was here talking about NIDA, and, of course, they use it. Dr. Hyman. Yes, absolutely. I have dabbled in it, actually, myself before I came to NIH. Basically what happens is that a subject will go into a magnetic resonance imaging machine. Now, this is rather forbidding at first. Some people feel claustrophobic inside. And the other thing is, when the machine is on, it makes rather loud noises. Mr. Porter. I have done this, several times. Dr. Hyman. You have done it for your back, so you know---- Mr. Porter. Exactly. Dr. Hyman. It is not the optimal environment for cognitive and emotional tests. You have to allow people to habituate. Often you will train people in a mock magnet for a while so that they get used to it. In addition, you can give them earphones, depending on the experiment, to keep those awful bangs from disturbing them. And then what you can do is you can project from the rear onto a screen various images. So in the case of experiments having to do with fear, you can put up various scenes, such as an auto accident, or a happy face versus a fearful face. And the person sees it, and then--literally, while you are scanning--the scanner provides an indirect measure of the activity of nerve cells in the brain. When nerve cells fire, they produce carbon dioxide, they need oxygen and glucose. And so the micro-circulation in the brain responds after about a one-second delay to these metabolic needs. And there is a fairly tight correlation between this change in blood volume and blood oxygenation which alters in some way the actual magnetic properties of hemoglobin, the oxygen-carrying part of blood, which can be detected and then reconstructed in a computer. Mr. Porter. So it is completely non-invasive. Dr. Hyman. Completely. Mr. Porter. And you can actually do it quite easily. Dr. Hyman. That is correct. It is completely non-invasive. Now, there are a lot of frontiers that we would love to get to. One, because we are dependent on the change in blood flow, we have to work with one-second delay, but one second is an eon in the nervous system. The actual nerve cell firing events are on the order of milliseconds. We would love to be able to combine this technology with things like magneto- encephalography so that we could get both the temporal and the spatial dimensions and actually see processing. I know you saw recently pictures of dyslexia when Dr. Duane Alexander of NICHD testified. Again, he showed images not just of the anatomic locations of dyslexia but of the actual order in which the brain does things. Timing and sequence are very important to understand when thinking about problems with reading, for example, or problems processing information. nimh plans for effective use of significant new funds Mr. Porter. Now for the macro question. If we were able to double the funding of NIMH over the next--maybe not the next 5 years, but soon--could you reasonably use that money in an effective way? How would you use it? Dr. Hyman. I believe we really could. I think that neuroscience in general is a field that is just coming into maturity. Based on the complexity of the brain, it has taken a long time to have the tools to truly investigate the brain. Now, frankly, some of the tools are provided by the genome project. Some of the tools are provided by molecularbiology coming, say, from the Cancer Institute. At this point we have both genetic and molecular tools; that is, we can clone important genes in the brain and understand the products of those. But we can't just end up with a pocketful of DNA. We have to put it back together into a whole brain. So we have to understand what these genes are doing in development, how they are regulated by environmental experience. We need to get more behavioral scientists and neuroscientists working together to map things like emotion as Figure 2 depicts, and cognition onto the brain. So we would utilize more funds literally to understand the building blocks of the brain at a molecular level, how the brain is built both as a result of genes and of the environment, how the brain works as a whole, including how the environment impacts on the genes. Then the next issue for us is how does this kind of knowledge get translated into clinical research that is going to help people with mental illness? Here, on the one hand, you see an image that is very helpful in understanding the circuits, and, again, if we had additional funds, this is the sort of thing I think we ought to be doing more of. We know there is something wrong with the amygdala in this disorder. We suspect there is something wrong with parts of the frontal lobes in schizophrenia. This will pinpoint postmortem studies in human brains. Instead of searching for a needle in a haystack, we will have directed research looking for the molecular pathology, the better to produce novel treatments. Once one has novel treatments, which in our case also would include psychotherapies, we have to prove their effectiveness. We have been, I think, lacking in the past at NIMH because we have not had the kinds of clinical trials networks which would allow us to test rapidly the kinds of complex treatments that are needed for patients with mental illness. The pharmaceutical industry does a lot, but we can't expect them to test combinations of psychotherapy with pharmacotherapy. That is something we really have to do. accomplishments during the decade of the brain Mr. Porter. We are nearing the end of the decade of the brain. Can you tell us generally what we have accomplished in that endeavor? Dr. Hyman. It is staggering what has happened in the last ten years, or eight and a half. It is also staggering how much we still have to learn. When I started as a post-doctoral fellow or, better yet, got my own laboratory, which was just about 10 years ago, it was still amazing us that, for example, environmental experience turned genes on and off in the brain. This is now commonplace, and we know the detailed mechanisms. At that time, MRI was a new tool just to look at brain structures. No one could imagine that we would actually be able to use this wonderful tool to look at brain function. Clinically, we were treating people with depression with drugs that were effective, like Elavil and Tofranil, but which had awful side effects. And as a result, some people didn't know whether their illness or the treatment was more of a discomfort. Now we have a whole variety of wonderful medications. But what remains for us to learn is the specific pathology of this whole variety of extremely disabling mental disorders that I have described to you. And it is with both humility but also excitement that we begin to apply the tools we now possess what I think really has to be the century of the brain. I think it was a bit of hubris to think that a decade of the brain could really solve the problems that we need to solve in order to do well by our patients. Mr. Porter. We have difficulty getting Congress to think in more than 2-year terms. [Laughter.] Thank you, Dr. Hyman. Mrs. Lowey. Mrs. Lowey. Thank you, Mr. Chairman. I just want to welcome you again, Dr. Hyman, and tell you what a real privilege it is for me to be here listening to you, reading your testimony, and although we did loan you to New Haven and Cambridge, I am particularly proud that New York reared you. Dr. Hyman. Fair enough, yes. The Upper West Side. Mrs. Lowey. Exactly. And I just want to bring greetings to you from an admirer and someone who has really been a partner in this effort, the Liebers. Connie Lieber is a good friend and a constituent of mine, and she has the greatest respect for you and all you are doing. And you can see in talking to her the excitement she feels that we are on the verge of some tremendous breakthroughs. So I just want to thank you. Dr. Hyman. Thank you. medication and psychotherapy in treating depressive illness Mrs. Lowey. I have several questions, but, first, I wanted to ask you about a question related to your budget justification. You refer to a recent study on patients with manic depression, showing that those who are treated with medication and psychotherapy do better than those treated with drugs alone. I am very concerned that managed care plans are relying too heavily on drugs and too little on psychotherapy for those with serious mental illness. First, can you comment on why psychotherapy is an important component in the treatment of patients and the care of the mentally ill? And, second, can you comment on trends in the care of the mentally ill who are in managed care plans? Are they receiving adequate psychotherapy? And I just want to comment from an experience with a constituent, where I became aware of this serious problem with this young woman, and checked with the person who was managing her case at the HMO. I think they call it an assist--I don't even remember the name or the title, the assistant who was giving her medication, one week, two weeks, three weeks, four weeks, five weeks, until I called again, and they said this does not kick until, whatever, six weeks, and I said, ``Well, who is the doctor seeing her?'' At any rate, I pursued it; she got an additional opinion; she went into psychotherapy. If it were not that I called, she still would have been seeing this assistant or practitioner, whatever you call it, and I expect this is a major problem. Dr. Hyman. It is, Mrs. Lowey. Actually, it points to the fact that there have been profound misunderstandings of mental illness, but also of psychotherapy. Now, I have to confess that part of the misunderstandings are due to the history of psychiatry. We are emerging from an era where there were dominant psychoanalytic theories, but we have emerged, and I do not think everybody has realized that. Now, let me just use the example, before I get to psychotherapy, of treatment for coronary artery disease. Let us imagine somebody had coronary artery disease. You wouldnot just write a script for several medications. You would prescribe changes in diet, changes in exercise, perhaps rehabilitation. If the patient had side effects, say, from a beta blocker-- very common--you would engage in the proper handholding and dosage adjustment. Well, in many ways, psychotherapy is analogous to treating a heart patient. It is analogous to the rehabilitation, to the changes in diet, to the changes in lifestyle that are critical. There are reasons for this, one of which you pointed out. Many of our medications take many weeks to work. They work wonderfully, once you have given them four or five weeks. But in the meantime, a despondent and depressed patient, for example, who may be experiencing even mild side-effects, and no therapeutic effect, may give up on the medication, may give up on the treatment. In addition, during this period, individuals may be suicidal, and psychotherapy is not simply a matter of handholding. It is actually helping; in the case of depression, giving people appropriate coping skills, dealing with their inappropriately negative thoughts. I do not want to take too much time, but I think you can get the gist. I think what you point out, which is that the lack of available comprehensive treatments, which involves psychotherapy in managed care, is a grave concern. One of the things that we at NIMH really must do is to provide the data on the value of these treatments because it is clear that without this kind of data we are not going to get them accepted. Mrs. Lowey. I appreciate that. I will get on, too, because I know we are limited in time. But I think this is such a serious problem, and I am very concerned that the cost benefit analyses are accurate and are thoughtful. The chart is not up there now. Dr. Hyman. We can put the other chart back up. opportunities for expanded genetics research and clinical trials Mrs. Lowey. No, that is okay. I have it here someplace. But it is clear that serious mental illness, such as schizophrenia, a manic depression, are enormously costly to society. In your testimony, you do include this chart, which shows that very clearly. The illnesses can be extremely disabling, resulting in increased costs for programs such as Social Security and, of course, the productivity lost when individuals simply cannot function in society. Are we devoting adequate attention and resources to these severe mental illnesses and does NIMH have plans to increase funding for them? I am hoping we will double them, at least, as our Chairman has said, and can you please comment now or for the record how many new awards in manic depressive illness and schizophrenia do you intend to fund this fiscal year? Dr. Hyman. We can give you the number of awards for the record, but I think the issue, to my mind, is the quality and the focus of research. I just want to illustrate important areas where I have made significant changes in the last two years. These are genetics and clinical trials. The area of genetics is critical for mental illness, but nature has handed us a pretty stacked deck; that is, we have no mental disorders, that are called mental illnesses, which result from a single gene, or so-called Mendelian disorders. All mental disorders involve many genes in interaction with the environment. Last year, I supported the National Advisory Mental Health Council in convening what I considered to be the best group of geneticists imaginable in the United States. They have given the NIMH advice on how to proceed with the study of manic depressive illness, schizophrenia, and depression. We already have issued a request for applications seeking new approaches to the genetics of these disorders. This a very substantial beginning. In addition--and this is a good example of the really important inputs we get from advocacy groups--it was pointed out to us by a number of groups that we really had lagged in our support of clinical trials in manic depressive illness. We were not spontaneously getting these applications from the field, and I think there are a lot of reasons for that, which boil down to the fact that such trials are very difficult. But we have just issued a request for proposals, again, for a very substantial trial, to test promising new anticonvulsant drugs alone or in combination with lithium in manic depressive illness. Finally, one of the things that I have learned about priority setting, which is really quite striking, is that NIMH had a National Plan a number of years ago for schizophrenia, and what that plan did was to rob Peter to pay Paul; that is, people who had been investigating manic depressive illness moved over and started studying schizophrenia. I recognize that we have to plan our priorities in a more holistic way to avoid making these errors again. childhood mental disorders Mrs. Lowey. Dr. Hyman, I am very interested in the treating of mental illness in children because I feel that if we can identify it early the costs to society are clear, notwithstanding, the decreased pain and suffering. If you could highlight for us this afternoon the major advances you are making in diagnosing mental illness in children. For example, I understand in conversations that there is a link, not necessarily one following the other, but there is a link between Attention Deficit Disorder and later development of manic depression. Can you comment on the diagnosing of mental illness as early as possible in an individual's life as a way to impact the disease later on? Dr. Hyman. First, let me say that you raise a point that I feel is absolutely critical. We often worry a great deal about the cognitive development of children, and we think that if their IQ is at a certain level everything is all right. But, in fact, children who have emotional disturbances may have fine cognitive equipment, but cannot learn and may get into a great deal of trouble. You may have seen an article on the front page of the New York Times just a few weeks ago talking about the mentally ill in prisons, and it pointed out that at least 20 percent of incarcerated children have a diagnosable mental illness. Clearly, if that diagnosis had been made earlier, the child likely would have been on a very, very different life course. Now, indeed, we have inadequate knowledge about diagnosis of mental disorders early in life. And, it is very difficult for parents, for pediatricians to tell the difference between a passing stage and a serious warning. We, therefore, plan to initiate a series of longitudinal developmental studies aimed at precisely this: learning which child who is inattentive, impulsive, and hyperactive has Attention Deficit Hyperactivity Disorder versus which one is likely to go on and exhibit manic depressive illness. I think only by doing longitudinal studies and, again,these are major undertakings, will we see, if a child looks this way now, what he or she is going to look like later. I think we now have the tools to ask wise questions in these kinds of studies. Mrs. Lowey. If I may, you are saying you have the tools to identify this? Dr. Hyman. No, no. The tools to do these studies; meaning we now have an appropriate group of epidemiologists and people who understand what the issues are in pediatric diagnosis, so that we can actually launch longitudinal studies and expect to gain valuable information that will provide answers to the very good question that you asked. Right now, pediatric mania is an extremely poorly understood diagnosis. NIMH recently convened about 20 experts to talk about just this. I have to tell you there was a great lack of unanimity on this difficult problem. Mrs. Lowey. Are we going around again or should I just beg your indulgence for one more question? Mr. Porter. We have time, so we are going to have a second round. Mrs. Lowey. Go right ahead, Mr. Chairman. You are the Chairman. progress in research on eating disorders Mr. Porter. NIMH has been supporting a longitudinal study of anorexia and bulimia for the last nine years. What have you learned from this study and can you give us at least some of the highlights? Dr. Hyman. We have learned--and I think it is an important finding--that anorexia and bulimia, once thought to be entirely distinct, are actually not so distinct; that is, many women-- and it is largely women--who start out with anorexia nervosa may actually develop bulimia later in life. Now, as dire as that sounds, indeed, it turns out that bulimia is more treatable, and this may actually be a step toward recovery. We know from this longitudinal study, actually, that anorexia nervosa is often a chronic disease with a lifetime 10 percent mortality. We really do not have ideal treatments for anorexia nervosa. In research on bulimia, on the other hand, we have found that the SSRIs, the Prozac-like antidepressants, plus psychotherapy really have a marked effect on improving the outcome, on both binging and purging and also a person's self- concept. I would say that eating disorders, in general, is an area where we should encourage additional research. I would point out that a great deal just has been learned about the biology of satiety with the discovery of molecules that act in the brain, such as leptin and, are produced by fat cells. These molecules, their brain receptors, and many other novel leads are key to understanding satiety. I think it is time, with modern tools, to revisit these very problematic and morbid clinical disorders. Mr. Porter. You mentioned Prozac. What is the status of the study on the effectiveness of St. John's Wort as an alternative treatment for depression? What would be the advantage of St. John's Wort over other commonly prescribed antidepressants such as Prozac? Dr. Hyman. Well, all medications come with side effects, and different people have different side-effects. One person can tolerate one medication and not another. St. John's Wort, which we do not yet know to be efficacious has had very few side-effects in European trials. So, if indeed it turned out to be efficacious, it would be a wonderful addition to the armamentarium. Indeed, some people who are currently on one kind of antidepressant who have difficult side effects might want to switch. Now, the issue is we do not know whether it is efficacious. As you know, we have embarked on a three-year clinical trial comparing St. John's Wort to placebo, but also to a standard Prozac-like antidepressant, specifically Zoloft. We feel we need to do this because the European studies, which point to the possibility that St. John's Wort may be very helpful, were rather short-term and, also, enrolled people who were very mildly depressed. We really want to study people who are more seriously depressed. The coordinating center for this trial is an excellent group at Duke University. The trial is underway and will take about three years, as I mentioned, for patient enrollment. Mr. Porter. We will have the staff make a note for three years from now. Dr. Hyman. Absolutely. [Laughter.] I think the newspapers will remind us. They are very interested. behavioral clinical trials Mr. Porter. The management of certain diseases such as diabetes and congenital heart disease can cause significant psychological problems for children and young adults. Is NIMH conducting research in this area? Dr. Hyman. Yes, we are. We have a very substantial developmental psychology portfolio, and we have a great deal of research aimed at developing ways to help young people, but also caregivers, cope with stress. What I think we are lacking, however, is research that is the equivalent of a clinical trial; that is, asking whether the behavioral approaches that we might use to help people cope with stress are truly efficacious in broad populations. Now, these kinds of behavioral clinical trials are certainly more than possible as illustrated by our AIDS behavioral prevention portfolio, and I think that would be an important area to pursue. Mr. Porter. The National Advisory Mental Health Council Work Group on Mental Disorders Prevention Research was scheduled to release its report on the status of NIMH prevention research, along with the recommendations for future research directions. What were the findings and recommendations of this group and do you agree with what they reported? Dr. Hyman. There was an extraordinary array of recommendations. I want to give you what I think is the intellectual highlight, which I find very gratifying. Prevention of an infectious disease is very different from prevention of a mental disorder. For an infectious disease, for example, you can give a vaccination. We cannot vaccinate people against schizophrenia or depression or manic depressive illness. Rather we have to understand these illnesses as affecting the whole life course. So, for us, prevention is not simply a matter of primary prevention, but, in a broad public health sense, decreasing prevalence, incidence and, above all, disability. What this panel did is expanded the definition of prevention for our portfolio to include prevention of relapses, which are common in all of these diseases and prevention of disability, and it has given, I think, a new and healthy public health focus to our prevention portfolio. Indeed, it has made it relevant to serious mental illness. Previously, given the lack of knowledge and inability to do primary prevention for mental illnesses, the portfolio studied important problems, but not actually diseases like schizophrenia or depression. Dissemination of Research Results and Science Education Mr. Porter. Dr. Hyman, this was, I think, just before your watch began, but often research projects sound strange to the public ear. There have been groups that have criticized some of the research that NIMH particularly was doing, saying that it was a waste of public funds. Now, Prime Time Live did a report on this and said that was not true; that they were very important research findings. What are you doing to educate the public that the work you do is of very great significance and importance to them? Dr. Hyman. We do have very substantial public education campaigns on mental disorders; in particular, on depression and on anxiety disorders that have been useful to broad groups of people, both consumers, providers, but also, interestingly, employers. This is something of a problem for us. Much of our public education campaign is in this so-called RMS budget, and we feel that, in prioritizing this money, the most important thing we can do is to destigmatize mental illness and get mental illness understood to be treatable brain disorders. What we have not done adequately is to talk about the basic science, which is exactly what was attacked. As I remember, one of the things that was attacked was research on bird song. Now, what could bird song possibly have to do with mental illness or the human brain? Well, it turns out that song birds are the only higher species that actually reproduce new neurons, new nerve cells on a regular basis in their brains. Thus, it is the premier model for studying the production of, in this case, a whole new organ. Now, interestingly, there is recent evidence in primates and rodents of new nerve cells being born, but nothing like the concomitant development of organization there is in these song birds. So, in fact, it is rather simple to explain, but we are in a difficult position in terms of explaining things like that proactively. How NIH Educates the Public About Medical Science Mr. Porter. Dr. Varmus, beginning three years ago we talked about the need for NIH, in general, not to thwart negative things or things that people think are negative, but to put out a positive message of what is being achieved in respect to the investment of public dollars in biomedical research. Can you describe for the subcommittee what you are doing in that area, generally. Dr. Varmus. As you know, Mr. Porter, the amount of money we can devote to these issues is not as large as I would like. We do have a public education program that spends something on the order of $150,000,000 a year. Of course, that addresses a large number of problems, not simply advertising the usefulness of what we do, but actually describing the results, so they are available to health care providers and to patients. I think one of our most effective means of talking about research is through our appearances on television and through newspapers. Many of our Institutes have been featured in stories in papers. For example, the Aging Institute [NIA] was featured this week in a discussion of perimenopause syndrome in the Washington Post. The Mental Health Institute [NIMH] has been featured in a number of major publications. You heard yesterday about the way in which the National Library of Medicine's work has appeared on E.R. Dr. Leshner was very modest this morning and neglected to point out his own involvement in guiding E.R. in their display of drug addiction in a current series of episodes. That does not directly address the NIH efforts, and I think the problem we face there is we try to take advantage of the news media, which has a large audience, to display our wares. They, of course, are looking for news, not so much seeking to be vehicles for advertising what the NIH, as a Government Agency, does. Mr. Porter. That is true. But on the other hand, there is a response mode and an initiative mode and, to the extent that you can initiate something that they would find is of great interest to the public at large, I think you have a ready resource available to you. Dr. Varmus. Well, we do, and we have taken advantage of that to a much more appreciable extent in the last couple of years. The director of our Communications Office, for example, is putting out weekly or monthly announcements of NIH research that appears in journals. The journals, themselves, are advertising that research. I think the average reader of a newspaper is seeing an increasing number of articles about our science. Now, I think there are potential pitfalls there. One has to be careful that we do not over-advertise and we do not make claims that would be excessive in the interest of getting news for our Agency. One of the most effective ways for us to be portrayed is through a kind of article that does not all that frequently appear in the newspaper, but we try to encourage reporters to cover it, and that is a story about a scientist at work. The New York Times sometimes does this. But the human interest of a young scientist or a middle-aged scientist, actually, engaged in bench activities for the good of humankind is a story that can be interesting. Mr. Porter. I agree with that. There are news articles and then there are feature articles. There are articles that are written by reporters, and there are articles that are written by publicists and picked up by publications that do features in some depth on what NIMH does or how they go about doing it. I think, to the extent that you can initiate features that give people some insights as to what NIH is all about, I think that is all to the good. Now, a year or two ago we had a public television series that was being considered. Can you tell us what happened there or what is happening there? Dr. Varmus. Yes. That show does exist. It is called Health Week, and I believe it is still being run out of the Baltimore station of public television as a weekly show. It does not have a primarily NIH purpose. It talks about health advances, and some of us are advisers to the show. Some weeks the show does report NIH-supported research, but most weeks it simply reports advances in health. Mr. Porter. And that is Maryland Public Television, right? It is not picked up in---- Dr. Varmus. Oh, it is many stations. I could find out for you. Mr. Porter. It is run outside---- Dr. Varmus. We can find out for you how many of the affiliates have picked it up, but I believe it is quite a few. Mr. Porter. I should know this, but I do not have time to watch television. Dr. Varmus. We are in a similar position, Mr. Porter. Mr. Porter. Mrs. Lowey. Mrs. Lowey. Thank you, Mr. Chairman. I do not watch too much television either, but I have a feeling that showing the scientists at work would not be quite as compelling to viewers as talking about St. John's Wort or ginkgo. I had a wonderful meeting with Dr. Kirschstein and some other people previously because right now, as we are saying, the health food stores and E.R. are really providing consumers with their information and health care. So, to the extent to which you could get the public involved by providing information that would directly affect their lives---- Dr. Varmus. The St. John's Wort story actually has appeared in many newspapers, including---- Mrs. Lowey. Right, that absolutely. Dr. Varmus. Including extensive descriptions of the study that Dr. Hyman's Institute is conducting. Mrs. Lowey. Great. Dr. Varmus. So that has gotten a lot of publicity, and I assume it will help accrual of patients and move the study along. Multiple Audiences for Science and Health Education Mrs. Lowey. In fact, I had a meeting in my district recently on eating disorders. The Chairman mentioned anorexia nervosa, and the sad stories that we heard were really extraordinary. What I have found from following up with these cases, whether it was the young girl who was a gymnast and she thought the most important thing in the world was to stay thin, and the tragedies of the parents who had no idea what was happening or the coach who had no idea what was happening. So I think the question that we were talking about before, and I feel very strongly about, is what are the connections that are made between the research that is being done, and the public health service--the dissemination of this information. I just think it is vital, whether it is on television, that we just have to get that information out. Anorexia nervosa was a perfect case, where they felt if only they had known. Dr. Hyman. I think you have actually hit on a very interesting and troublesome area. In some sense, we need to educate ballet instructors, gymnastics instructors, athletic coaches about the risks to young women, especially, but also to young men, about losing that extra three pounds to do this, that, and the other thing. I have to tell you, though, that this is an area where prevention programs, well-meaning, have sometimes backfired; that is, there was a prevention program at a major leading university for bulimia which, actually, when studied--it was sort of an educational program--increased the incidence of bulimia. So we, basically, have to be not only getting the news out, but we also have to study who the targets are and how to do it. Research to ensure the Safety Of Medications for Children Mrs. Lowey. I asked a question before about the research on children and the critical necessity, in my judgment, of being able to identify those children who are at risk earlier. In a related question concerning psychiatric medication on children, it is my understanding that the medication used for children is, essentially, the same as that used for adults. Is there research that is supporting medication specifically for children? Dr. Hyman. Yes, but it is really very inadequate research at this point. One of the things that I have been struggling with--and this is, in some sense, different from the answer I gave you before about epidemiology--is the need to recruit people into the field of childhood treatment. A director ought to be competing to lure the very best investigators to these problems. I believe that actually, there, are not enough child psychiatrists. We need to build that area. But, at the same time, I would like to lure some adult psychiatrists, some pediatricians, some pediatric neurologists into this area. It was only in the last calendar year, and you may have seen it in my written testimony, that we had a really well- designed trial showing that Prozac actually works to treat depression in young people. One troubling finding, however, is that it did not work quite as well as it works in adults. We already know that the older tricyclic compounds do not work particularly well at all in children. So we really need to enhance both the development of treatments and clinical trials. Now, I should tell you that just to stimulate this, we have issued a request for applications in the area of pediatric clinical trials. But, across NIH, we need to make a stable long-term investment in building this field, making it an important and attractive career in order to serve children well. Protecting Clinical Research in the Evolving Health Care System Mrs. Lowey. I think that is a very important answer to a question that I was about to ask. So I really thank you because this has been my concern, as you know. I have a strong interest in developing more clinical research, and you have pretty much answered it. But if there is anything you want to add in addition to the importance of clinical research to the field of mental health and, essentially, what you are doing to increase clinical research at the NIMH, and is there any way that Congress can assist you in attracting new individuals to this field? Because Dr. Leshner, in fact, this morning commented on that, and I would be interested to know what you are doing to recruit new, talented researchers. Dr. Hyman. Yes. Well, certainly, NIH, as a whole, under Dr. Varmus' leadership has just been working on new training vehicles, and I recall that you asked about them when he gave his testimony and, indeed, this represents a real increment in our training awards---- Mrs. Lowey. You had a feeling I would be asking that. Dr. Hyman. Yes. But I think I have already, in some sense, said the most important thing. It is a place where you do play a role. Clinical researchers now, to some degree, are demoralized. Managed care has squeezed all of the discretionary funds out of clinical departments. NIH cannot possibly fill that gap. I think one of the critical things that young people need to understand is that there will be a stable investment in their future; that is, that if they choose now to go into acareer in clinical research, NIH will not simply be supporting them maybe for one year or two years, but that, together, we intend to maintain a long-term vision about the health and vigor of clinical research. I think there is no more important message, and I think it is one that you all have given in a way that is often more credible and stronger than we can do. contribution of neurobiology to panic/anxiety treatment Mrs. Lowey. Lastly, if I have time, because I know my colleague has just arrived, I was particularly interested in your testimony concerning agoraphobia because it is so widespread, and it is so debilitating, and so many people really cannot function as a result of it. You are saying there information processing events occur and the mechanism by which they are--may permit us to develop highly targeted treatments--and you are connecting it to depression, and anxiety---- Dr. Hyman. Yes. Mrs. Lowey. And I am sure you can give us some additional information. But if you can just give us some comments. Dr. Hyman. Yes. Very briefly, we actually have fairly reasonable treatments for panic disorder with agoraphobia. These are Prozac-like antidepressants, plus behavioral psychotherapies, which literally slowly expose people to their phobic stimuli. If you have abolished the panic attacks, now they can go to a place where they used to experience panic attacks. The panic attack does not occur and slowly they can increase the breadth of their lives. But there are many people who are treatment refractory. Understanding the pathways in the brain that underlie these disorders will allow us to not rely on luck or variations on old themes, but really to develop novel and really focused treatments. And the really wonderful thing about this research is these are not only pharmacologic treatments, but they are potentially also behavioral treatments. Mrs. Lowey. I thank you. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mrs. Lowey. Mr. Stokes. Mr. Stokes. Thank you, Mr. Chairman. Dr. Hyman, nice to see you. Dr. Hyman. Nice to see you. co-occurrence of mental and general medical illnesses Mr. Stokes. Thank you. Doctor, it is often said that if we would address patients' mental health problems on the front end that this would dramatically reduce compromising physical health conditions. What is your position on this relationship? Dr. Hyman. I think, Mr. Stokes, that this is a really critical relationship. There was last year a spate of reports, for example, that showed that after cigarette smoking and treatment of hypertension the leading modifiable risk factor for coronary artery disease and, indeed, for heart attacks--myocardial infarctions--was depression and that the major risk of reinfarction, again, after somebody had had a first heart attack, was depression. This is just a symbol of the way in which our stress systems, our minds, our mental health are intimately and inseparably connected with the body. I could go on, but I think it is---- health status of under-privileged minorities Mr. Stokes. Sure. I think you have answered, with respect to my question, what I was trying to get on the record. Let me ask you, in terms of children's mental health, and I noticed in your formal testimony that you talked about it a little bit, but I would like to ask you what the extent is of mental conditions in children and across racial ethnic populations? Dr. Hyman. We are currently engaged in studies to refine our understanding--there are a whole variety of statistics--but we believe that, perhaps, 10 percent to 20 percent of children have, at some time, mental conditions that actually interfere with their ability to form normal peer relationships or to do well at school. The actual rates of mental disorders are not different between minority populations, including underprivileged minorities, and the remainder of society, but often the access to early diagnosis and treatment is quite different. One of our major concerns is--and I know this has come up previously in testimony--is the gap in health status between underprivileged minorities and the rest of our society. We are hoping to undertake a series of longitudinal studies in both minority and in nonminority populations in order to understand those differences in health status in a way that will make them addressable. In the meantime, I am happy to say we are funding a number of minority research centers. This year we have just begun funding James Jackson at the University of Michigan and Margaret Spencer at the University of Pennsylvania, both studying African Americans and looking at the specific factors having to do with illness and, interestingly, with resilience in minority populations. I just have to say people often are only looking at risk and never looking at the social and cultural sources of strength, and both of these centers are addressing not only risk, but also the strengths conferred by their communities. Mr. Stokes. I am glad to know that you are looking at that because those who are sociologically disadvantaged are the ones who often times get their hospital care in emergency rooms, as opposed to doctors' offices. Dr. Hyman. That is right. Mr. Stokes. I think we are talking about that category. Dr. Hyman. Absolutely. We know, tragically, that in primary care settings--we do not know about emergency rooms--but in primary care settings the likelihood of a child having an appropriate diagnosis, for example, of depression is only one in five, and this is where issues of public education really come to the fore, as well as additional research. nimh efforts to reduce stigmatization of mental Illness Mr. Stokes. In that very same vein, I would just like to ask you this: Because of the negative stigma that is still associated with the label ``mentally ill,'' children's mental health problems, it seems, are often ignored. What is the National Institute of Mental Health doing to address this very serious problem? Dr. Hyman. Yes, sir. I think there are many factors leading to it being ignored. I think none is greater than the factors of ignorance and stigma. I think that our society really has it wrong. If a child has appendicitis, the parents will bring the child to the doctor. If a child is depressed or if a child is starting to fail in school or get in trouble, the parents either treat it as simply a lack of will on the part of the child or, alternatively and frequently, are too ashamed.They feel it reflects something about their parenting and that inhibits their willingness to bring the child for medical attention. It is very important that we make it understood that a child having depression or Attention Deficit Disorder or being over-anxious is not a parent's fault. This, just like any other illness of any other organ, represents a complex gene environment interaction. There is no cause for shame. But this is going to take an extraordinary effort to educate parents, but also teachers and pediatricians. At the same time--and Mrs. Lowey had asked, but at the risk of repetition--the research we are now engaging in and really have to do is research which will provide easier and better diagnostic tools to caregivers and also improve treatments. I think doctors tend to recognize things more readily if they know they can do something. If they feel helpless, they tend sometimes not to make these diagnoses. So I think this is a matter of public education, but also a very important matter of research, both in diagnosis and in treatment. Mr. Stokes. While acknowledging precisely what you are saying in terms of your Institute, what are you doing in terms of this kind of outreach in order to educate physicians on the diagnosis and treatment of mental health problems in children as well as the public, parents and others? Dr. Hyman. Well, right now we are only in a position to do some of that, and we have chosen depression, through our DART/ campaign, and anxiety disorders as our initial targets because we think these are very common and very much misunderstood and underdiagnosed. I would really like to be in a position to be able to participate in broader efforts to educate the public in these matters. One other area where it is really critical and where there is a lot of ignorance is within the criminal justice system. I mentioned it previously, but a recent New York Times article pointed out what we know, which is that 20 percent of children and abolescents who are incarcerated have a mental disorder. There is really no appropriate or available treatment in those circumstances, which condemns these children, I think to having no future. Mr. Stokes. To what extent, Doctor, is the research that is conducted by your Institute designed to also study the social, cultural, and environmental factors that are associated with these types of disorders? Dr. Hyman. These factors are critical, and we do study them. To be specific, just, actually, these two minority centers I just mentioned--the James Jackson Center and Margaret Spencer Center--are perfect examples of treatment research centers where cultural and community factors are very much taken into account in the pathogenesis and treatment of these illnesses. linking clinical trials to health services research Mr. Stokes. Doctor, to what degree do you utilize clinical trials in terms of the work of your Institute? Dr. Hyman. I have to say that one of the things that I have undertaken in my now merely two years at NIMH is to expand our capacity to do clinical trials, but also to change how we do them. I do not want to launch into a long discussion of clinical trial design, but in just a minute, there are trials that have a design that are really aimed at the FDA, sort of a regulatory design, where everything is very rigorous. But you exclude, for example, in a depression trial, any potentially confounding subjects who might have heart disease or drink too much alcohol. The result is that the trial, although it may produce very important results, is not really applicable to general populations, where there are people with other medical disorders or people from minority populations or elderly people or young people. So we are, in important cases, trying to wed our clinical trials program with our health services research program and perform trials that not only have this wonderful, crystalline, internal validity, but also sort of external validity with respect to the real world. This is challenging, it is expensive, but I feel that we really must engage in those kinds of trials. Mr. Stokes. I am glad you took the time to explain it because I think it is important for us to understand that sort of unique approach you are taking in your clinical trials. I hear the bells, so that means my time has expired. Thank you very much. Dr. Hyman. Thank you very much, Mr. Stokes. Mr. Porter. Thank you, Mr. Stokes. Dr. Hyman, thank you for the very enlightening testimony and answers to our questions that you have given this afternoon, and thank you for the wonderful job you are doing at NIMH and the wonderful job NIMH is doing within NIH. Dr. Hyman. Thank you very much, Mr. Porter, and the committee for your support, which makes it a pleasure to do these things. Mr. Porter. Wonderful. Thank you. The committee will stand briefly in recess. [The following questions were submitted to be answered for the record:] [Pages 2267 - 2353--The official Committee record contains additional material here.] Thursday, March 19, 1998. NATIONAL INSTITUTE ON AGING WITNESSES RICHARD J. HODES, DIRECTOR TERRIE WETLE, DEPUTY DIRECTOR COLLEEN F. BARROS, EXECUTIVE OFFICER KARYN S. ROSS, FINANCIAL MANAGER HAROLD VARMUS, DIRECTOR, NIH DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DHHS Mr. Porter. The subcommittee will come to order. Next we welcome Dr. Richard Hodes, the Director of the National Institute on Aging. Dr. Hodes, thank you for appearing. We would ask that you introduce the individuals that you brought with you and proceed to making your statement. Opening Statement Dr. Hodes. Thank you, Mr. Porter. At the far end of the table is Ms. Colleen Barros, the Executive Officer of the Institute; Dr. Terrie Wetle, the Institute's Deputy Director; and Ms. Karyn Ross, the Financial Manager. Mr. Porter, thank you for this opportunity to highlight some of the efforts of the National Institute on Aging to extend, through research, the quality of life and active years of all Americans. Over the past years, a steady and dramatic increase in research findings has led to what is now an unprecedented opportunity for further investment in discovery and research. In the case of aging research, this comes at a particularly opportune time, as some 75 million members of the baby boom generation approach age 65 over the next 10 to 15 years. biology of aging Basic biology research over the past decade has fueled a real revolution in aging research. This progress is illustrated in the award over the past year of a Nobel prize in medicine to Dr. Stanley Prusiner, a long-time grantee of the National Institute on Aging, the National Institute of Neurological Disorders and Stroke and other NIH components, for his discovery of prions, a new genre of disease-causing agents. Over this past year, Dr. Prusiner has elucidated the relationship between the structure of prions and the transmission of diseases such as kuru and bovine spongiform encephalopathy or ``mad cow'' disease, an elucidation which will have implications in basic research and also for efforts to prevent spread of such diseases. Another area of basic scientific discovery has been in understanding the processes that regulate the ability of cells to divide. One mechanism illustrated on this first poster has been that which is mediated by structures called telomeres. These are protein DNA complexes that cap the end of all chromosomes and that appear to be necessary for maintaining the stability of these chromosomes. [The information follows:] [Page 2357--The official Committee record contains additional material here.] Dr. Hodes. The nature of DNA replication is such that in the absence of any compensatory mechanisms, every time a cell divides, every time a chromosome divides, a bit of the end of each telomere is lost from the cell. And so, again in the absence of any compensatory mechanisms, as cells continue through division they reach a point at which telomeres are short, cell division is no longer possible, and cells have reached a state of what is called senescence. Over the past years, discovery has been made of an enzyme called telomerase which has the ability to synthesize new telomeres and so to compensate for the loss that occurs with cell division and DNA replication. In the past year, the important achievement was made of cloning the gene, encoding a critical component of telomerase, and showing that it could be introduced into cells that are nearing the point of senescence. As a result of that introduction, cells acquired the ability to synthesize telomeres and to continue dividing. This very basic and impressive intervention in the regulation of cell replicative capacity is the kind of discovery that will have implications both for basic research and for its applications. These unprecedented scientific opportunities extend, as well, to disease-targeted research. alzheimer's disease Alzheimer's disease remains the most common cause of dementia in older Americans, afflicting some 4 million Americans, their families, caregivers and society with disastrous and profound consequences. Over the past years, fortunately, there has been translation of genetic identification of risk factors, and of the mechanism of action of gene products in the generation of disease. Most recently the creation of animal models has occurred by introducing Alzheimer's related genes into mice, reproducing some of the pathologic and behavioral defects in these animals, and creating for the first time a chance to useanimal modeling to understand the disease and the design interventions. Perhaps of most immediate importance to those suffering from or at risk for Alzheimer's disease are the opportunities in the area of clinical intervention in disease, involving a number of strong candidates for clinical trials. The results shown in this poster are the outcomes of one clinical trial completed and reported in the New England Journal of Medicine this past year, which looked at the effect of one class of compounds, antioxidants--vitamin E and selegiline--treating patients who had mild or moderate Alzheimer's. The line in blue, representing those individuals who received placebo, a noneffective treatment, showed that in 440 days on average individuals with this disease progressed to the point of losing their ability to sustain independence or of requiring institutionalization, and that the use of drugs, in this case selegiline or vitamin E, was capable of inducing a modest but nonetheless significant prolongation of quality of life before those end points were reached at 655 or 670 days. [The information follows:] [Page 2359--The official Committee record contains additional material here.] Dr. Hodes. This important progress in delaying the progression of symptoms in individuals with Alzheimer's will now lead to design of studies which for the first time will attempt to treat individuals before they have a diagnosis of Alzheimer's disease; that is, to treat individuals at high risk and attempt to prevent or delay onsets of disease. Two additional lines of epidemiologic evidence have pointed to additional candidates for intervention trials. On the left is the outcome of a study carried out in the intramural program of the National Institute on Aging. A 15-year-old longitudinal study, part of the Baltimore Longitudinal Study of Aging, found that those individuals who had a history of taking NSAIDs, or non-steroidal anti-inflammatory drugs, such as ibuprofen had a dramatic 50 percent decrease in the prevalence of Alzheimer's disease. [The information follows:] [Page 2361--The official Committee record contains additional material here.] Dr. Hodes. Similarly, on the right, the results of another study also carried out as a part of the Baltimore Longitudinal Study on Aging, and matched by additional studies supported by NIA in extramural institutions, demonstrated that women who had a history of postmenopausal use of estrogen had an even more striking, that is, somewhat more than 50 percent decrease in the prevalence of Alzheimer's disease. Now it should be stressed that these are epidemiologic, or associative, studies as opposed to direct medical trials. However, they will lead most surely to clinical studies that directly test the hypotheses that these drugs are capable of slowing the onset or progression of disease. reducing disease and disability As we succeed in extending the life span, we must continue to look for interventions to prevent morbidity and disability, from a variety of the common causes of disease and mortality in older Americans, including cardiovascular disease, cancer, diabetes, and osteoporosis. An example of clinical studies already ongoing in this area is shown here, a study carried out collaboratively between the National Institute on Aging and the National Heart, Lung and Blood Institute, attempting to reduce disease by treating individuals with hypertension, in this case isolated systolic hypertension. Treatment in this case was with a low-cost and relatively well tolerated drug, a low dose diuretic. [The information follows:] [Page 2363--The official Committee record contains additional material here.] Dr. Hodes. In 1991 early observations from this study indicated there was a significant decrease in stroke as a result of treatment. Now in this past year still more encouraging results were reported, an analysis demonstrating a decrease of 50 percent overall in heart failure, which has come to be a leading cause of hospitalization and death among older men and women. Even more striking, for those individuals with a prior history of heart failure, therefore at still greater risk for congestive heart failure, there is an 80 percent decrease in congestive heart failure in this population. This study, too, now will lead to further studies to understand the mechanisms of these effects and the design of even more effective interventions and treatments. behavioral and social research The use of behavioral and social research tools is also an important part of the Institute's portfolio and provides an important means for enabling individuals to maintain the quality of both physical and cognitive life. NIA, for example, supports the development of strategies for promoting long-term health behaviors that will decrease risks of disability and disease. There has recently been established a program of centers, established jointly by the National Institute on Aging and the Office of Research on Minority Health, to better understand the specific problems of minority elder populations and to address them. Cognitive research is being carried out to both understand and modify cognitive function in older individuals, and this year will see the initiation of a novel intervention study, a clinical trial designed to examine the ability of interventions to promote cognitive function in older Americans. Mr. Chairman, members of the committee, NIA looks forward to continuing its efforts and commitment to maintaining the quality of life in older Americans. The proposed President's Budget for fiscal 1999 is $556,070,000. I would be happy to address any questions that you might have. [The prepared statement follows:] [Pages 2365 - 2370--The official Committee record contains additional material here.] alzheimer's disease Mr. Porter. Thank you, Dr. Hodes. Can we go back to the chart that depicts vitamin E and selegiline? Dr. Hodes. Yes. Mr. Porter. Now does selegiline have any relationship to selenium? Dr. Hodes. No. Selegiline is a drug with anti-oxidant properties that has also been used in treatment, for example, of Parkinson's disease. It is a prescription drug, in important contrast to vitamin E, which, as we all know, is among those agents which are freely available. Mr. Porter. There was some thought in the popular press that selenium had something to do with preventing the onset of Alzheimer's disease. Has that ever been tested? Dr. Hodes. There have been no positive data confirmed, certainly to my knowledge, of the role of selenium. Similarly, there was a proposal that aluminum played a role, and there were people very much concerned about that. Mr. Porter. That was a negative role, though. Dr. Hodes. Yes. But these trace elements, although they have been proposed to have a role, have not been rigorously established in epidemiologic or intervention studies. Mr. Porter. Now looking at the chart, I suppose it is not possible or maybe it is, but can you conclude from the chart that taking vitamin E might help to prevent the onset of Alzheimer's disease? This is a treatment rather than a prevention, correct? Dr. Hodes. Yes, correct. Your question is an extremely important one. Alzheimer's disease, by the time that symptoms have occurred, is associated with anatomic lesions on the brain and death of nerve cells, which make it particularly difficult to envision treatment that will reverse or prevent serious symptoms. The initial trials of most agents are of necessity carried out in patients with mild forms of the disease to see whether progression can be arrested. Because the effects at a later stage in disease are so difficult to achieve, there is hope and hypothesis that the same treatments which have even modest effects in progression of already established disease, may be effective, if instituted at a stage before symptoms have appeared, in preventing disease in process. That is the kind of study which will be novel in the history of Alzheimer's disease therapy, and that is now being planned. Individuals who have demonstrated high risk of developing Alzheimer's disease but, who do not have the disease diagnosed, will be the subjects in a clinical trial which will compare, for example, vitamin E against a control. Mr. Porter. Since vitamin E is something you can get from food, how do you find a proper placebo, since people may be ingesting it outside the capsule form? Dr. Hodes. That is a very important point in design of the studies. The doses which appear to be effective are at a level which are far in excess of what practically can be achieved by normal dietary intake. Mr. Porter. What sort of doses? Dr. Hodes. In the range of 800, 1,000 and 2,000 units per day. However, although these are nearly impossible to achieve through diet, they are not so uncommon in the vitamin supplementation of a large portion of the population. Increasingly, in studies of this sort, it does become a challenge to attempt to carry out responsible studies in the face of what at times is public consumption of agents of not yet rigorously demonstrated efficacy. That, indeed, will be a challenge in construction of this study, but one which pilot studies indicate can be met, meaning a population can be identified as a control which will not be using vitamin E in anything near the hypothesized therapeutic levels. depression Mr. Porter. Depression is said to be a very serious problem of aging. Do you work with Dr. Hyman, or do you have studies of your own underway dealing with depression as relates to aging? Dr. Hodes. The studies of depression in aging are predominantly carried out by the National Institute of Mental Health, with whom we work very closely. Your question provides an opportunity to emphasize the importance of that kind of cooperation across institutes. In the Alzheimer's area, for the past three years, research at NIH has been carried out with very effective cooperation across institutes. This past week was the most recent meeting of Steve Hyman and myself and the directors of the National Institute of Neurological Disorders and Stroke and the National Institute of Nursing Research, who regularly meet to coordinate our efforts in areas of common interest, e.g., Alzheimer's disease, neuro- degenerative diseases, and depression in the elderly. nasa collaboration Mr. Porter. Senator Glenn is going to go back into space this fall. Have you or your Institute been involved in preparing for that? Is there anything we can discover about the aging process resulting from his next mission? Dr. Hodes. The National Institute on Aging and many institutes at NIH have had a longstanding and ongoing collaboration with NASA. On the mission in which Senator Glenn is now scheduled to fly, there are several scientificstudies that have been planned long prior to identification of crew members, as a result of common interests of NASA and the National Institute on Aging. These include, for example, a study of the use of melatonin and effects on circadian rhythm and sleep. Sleep disorders are a common problem in the elderly, also clearly a problem in astronauts whose circadian cycles are very much perturbed by the in-orbit day-night cycles. This is the kind of research which we are carrying out jointly. It is one study in which Senator Glenn, together with other crewmen, will be participating. Senator Glenn has been particularly interested in exploring potential common scientific interests of NASA and of NIA as they reflect on problems of aging and those of space flight, as the example I just mentioned of circadian rhythm disturbances and sleep. Others include vestibular problems and balance disorders, also in astronauts and in the elderly; bone resorption as a result of weightlessness and prolonged flight, again with a relationship to bone loss and osteoporosis in the elderly. These are some examples of the scientific areas of interaction between these two fields of science, and they have been the grounds for joint funding and reviewing of scientific projects. parkinson's disease Mr. Porter. Dr. Varmus, you may want to comment on this, as well. Morton Kondracke has been a very, very strong proponent for additional spending on Parkinson's disease, and Dr. Varmus, you were present as the Master of Ceremonies when he was recently honored for his advocacy in that regard. He pointed out on the Today Show this morning that NIH spends only about $30 per year per Parkinson patient, versus $2,000 per year per AIDS patient. How do you respond to this criticism that is made? Dr. Hodes first, and then Dr. Varmus. Dr. Hodes. The majority of research support for Parkinson's research is, of course, carried out through the National Institute of Neurological Disorders and Stroke. It is one of the neuro- degenerative diseases in which our multiple institutes are working cooperatively. Certainly I am happy to defer to Dr. Varmus---- [Laughter.] Dr. Hodes [continuing]. But there is a large body of the research carried out, for example, in support of Alzheimer's disease, as another neurodegenerative disease, which crosses the boundaries of disease specificity and which serves the common research base for these multiple diseases. I think we attempt to use a strong structure of basic research to support related disease-targeted research, and that indeed we are driven primarily in our scientific planning, within NIA and NIH-wide, by the search for scientific opportunity and the allocation of resources accordingly. Dr. Varmus. We recognize Mort Kondracke's special interest in Parkinson's but we also appreciate his advocacy for the work done by NIH in general and his interest in ensuring that we have the resources we need throughout the NIH. With respect to the funding of Parkinson's research, as you know, I prefer to look at this as a major challenge for medical research, not to carry out a comparison disease-by-disease, but instead to say, what is there we can do in addition to what we are already doing to help patients with Parkinson's disease? Indeed, the advocacy that Morton and his colleagues represent has been a stimulus to some of the work you have heard presented by Dr. Collins and you will hear further presented when Dr. Penn testifies next week: that is, the identification of a gene that is mutated in certain Italian and Greek families that have familial Parkinson's disease, a gene that encodes a protein that appears to be a major component of one of the classical histopathological features of the disease, namely Lewy bodies. We think this is one of the great clues that has emerged in Parkinson's research. In addition, there are many other ways in which Parkinson's research is being furthered by discoveries that have been made in allied fields. Of course, as is always the case, the numbers that represent the amount we spend on this disease are subject to discussion, depending on whether one narrowly focuses on that money which is explicitly devoted to studies of treatment of Parkinson's disease as opposed to studies of dopamine and dopamine-producing cells and the metabolism of dopamine. Then the amount becomes larger. Furthermore, we are learning that this is a disease like many others with respect to the way in which nerve cells die. Research in many allied fields is having a very salutary effect upon our approach to this disease. Mr. Porter. Am I right or wrong that Parkinson's is considered a disease of aging? It generally strikes older people, although it can strike younger people. Is that correct? Dr. Hodes. Yes, exactly. It is a disease that has a very strong age-related increase in risk. Dr. Varmus. But it is fair to say that not all patients who have the disorder are aged. In fact, many of us have friends in their forties and fifties who have the disease and---- Mr. Porter. Such as Morton's wife. Dr. Varmus. Yes, and when the disease occurs in families it is particularly likely to occur at an early age. alzheimer's disease Mr. Porter. Mr. Stokes. Mr. Stokes. Thank you, Mr. Chairman. Dr. Hodes, nice to see you. First, what form does selegiline come in? How is that administered to patients? Dr. Hodes. A pill. Mr. Stokes. That is also a pill? I see. And that is only utilized for those who have had some diagnosis with reference to Alzheimer's? Dr. Hodes. This study was reported just this past year and is the first study showing effectiveness. As is typical under some circumstances, there is caution as yet in generalizing as to whether this now should achieve status as a general therapy. Rather than award that status as yet, from a research perspective we think this is now strong impetus to confirm and extend the finding. It has not yet---- Mr. Stokes. Had a clinical trial. Dr. Hodes. Precisely. Mr. Stokes. Right. Okay. According to your opening statement, we are facing a century with 75 million baby boomers who will turn 65 years of age. It is specifically this magnitude that causes a number of health providers to suggest that the study of Alzheimer's disease should be the Nation's highest priority. In your professional judgment, are we doing enough inthis area of research, and if not, what specific research should we be doing in this area? Dr. Hodes. I think the area of Alzheimer's research, as I illustrated in my remarks and testimony, has seen enormous progress, but that very progress has now created opportunities of a magnitude that far exceed what has existed before. Yes, I think we could wisely invest increased amounts of resources to fund research in Alzheimer's disease. The spectrum of areas that need further investment now include clinical trials of the sort that I mentioned, which are critical and clearly expensive. It also involves, however, a need to continue the basic science studies that have led us to the verge of these clinical opportunities. And it is perhaps worth pointing out that some of the most dramatic successes, the research findings in Alzheimer's, have come from a broad base of research, the outcome of which was unanticipated. For example, the identification of apolipoprotein E as a genetic polymorphism and a strong risk factor was facilitated very much by research on cardiovascular disease, where this protein that is important in lipid transport is most active. Some of the other genes that were uncovered as risk factors had previously been studied only in worms. So we need to continue studying the basic mechanism of what determines the life and death of cells in neurodegenerative disease, and to understand those basic mechanisms and translate them in tandem with our attempts to provide clinical tests to new therapies. There is also an enormous amount to be gained in the epidemiologic area. I commented that two of the drugs being tested have received their initial support from epidemiologic studies. I should point out that perhaps an important exemplar of future epidemiologic studies is one reported this past month which looked in greater detail than had been done before at genetic risk factors and overall risk for Alzheimer's disease in populations that were ethnically diverse. In this case comparisons involved Caucasian, African American, and Hispanic populations. The striking finding from the study was that although in Caucasians the well-described increased risk of expressing ApoE4 was again observed, ApoE4 was not a risk factor of the same magnitude in African Americans or in Hispanics. Although the risk of Alzheimer's disease was similar in individuals with ApoE4 regardless of their ethnic origin, African Americans, for example, who lacked ApoE4, had four times a higher risk of Alzheimer's disease than Caucasians who did not have the disease. So among the opportunities arising are those which come from a greater appreciation of the complexity in genetic, ethnic, as well as in potentially environmental factors which establish risk for Alzheimer's. It is in all these areas that NIA and Alzheimer's research would hope to share in increased research support NIH-wide. Mr. Stokes. And so if I understand your testimony correctly, we are not yet at the point where we know how to slow the onset of Alzheimer's? Dr. Hodes. I think that is a fair statement, in the sense that there has been no demonstrated effective intervention which will prevent or slow the onset of disease. However, it should be pointed out that only now are we for the first time prepared to do studies to test that; that only now will we begin to do studies in high-risk populations who do not yet have the disease to see, by direct clinical testing, whether we can prevent onset, indeed an important juncture in Alzheimer's research. Mr. Stokes. Nor, doctor, do we understand at this point in time the causes relative to the disparity that exists between African Americans, Hispanics, and the white population in terms of the higher existence of the disease in minorities. Dr. Hodes. We do not. One kind of epidemiologic data pertaining to this question is from an interesting study carried out comparing Japanese living in Japan, Japanese Americans living in Hawaii, and Caucasians. The evidence from this study is that not only are genetics important in the risk of Alzheimer's disease, but apparently some environmental components are also. That is, there is an apparently lower incidence of Alzheimer's disease in Japanese living in Japan than there is in Japanese Americans living in Hawaii. This simply points out that there are environmental factors to be identified. Their identification has not yet occurred. baltimore longitudinal study on aging Mr. Stokes. Doctor, in terms of the Baltimore Longitudinal Study on Aging which is now in its 40th year, can you tell us anything that may have been learned from that study about the impact of Alzheimer's disease on African Americans? Dr. Hodes. The data which I showed looking at overall risk factor analysis in Alzheimer's was generated from the Baltimore Longitudinal Study on Aging. There are as yet, however, no data from that study which have looked at the effect of race or ethnicity on Alzheimer's disease, and the major reason for that is simply that the size of the overall study is limited. Currently there is a participation of about 16 percent of African Americans in that study, but the total number of individuals in the study is around 1,000. Not all of them have reached the age at which risk is high for Alzheimer's disease, and so that particular study has not yet contributed information in that arena. But, again, these two demonstrations of reduced prevalence of Alzheimer's disease associated with use of anti-inflammatory drugs or estrogen do derive from that Baltimore Longitudinal Study on Aging. They are not in sufficient numbers to ask whether subgroups, such as those of different race or ethnicity, have differential risks. clinical trials Mr. Stokes. Doctor, you mentioned clinical trials. What is the size of your investment in clinical trials? Dr. Hodes. The overall clinical trials budget anticipated in the next year is approximately $21 million. I should point out that over the last two years this will represent increases of approximately 13 percent in both years above previous investments. Given the kinds of opportunities that I have mentioned in the clinical trials arena, we are expanding clinical trials at a rate even greater than the overall growth of the Institute's budget. Mr. Stokes. Do you have any clinical trials that are currently unfunded? Dr. Hodes. We certainly have trials that are unfunded because of judgments of scientific merit. There are, however, a number of clinical trials which are under review and being considered during this year, which will certainly stress theability of funds accessible. We certainly would anticipate, with increased budgetary allocations next year and in subsequent years, using such resources to take advantage of meritorious clinical trials in increased numbers which are currently in hand and which we anticipate in future years. Mr. Stokes. Do I still have more time? Chairman Porter. About a minute. genetics of aging Mr. Stokes. Okay. Doctor, according to your opening statement, the Institute plans a new initiative to identify genes that modulate the rate of aging in humans. This appears to be a critical component of the Institute's research portfolio. What major activities were already under way in this area and how much is included in your Fiscal Year 1999 request for the new initiative. Dr. Hodes. I should point out briefly the context for these studies. Over the past years, there have been some striking observations in animal models to indicate the enormous impact that genetic differences can have on longevity. Some of the most noteworthy have used species such as c. elegans, a roundworm, or drosophila, a fruitfly, and have indicated that changes in individual genes can even double the life span of some of these organisms. It is much less clear at present to what degree genetic polymorphisms, differences in genetic makeup, contribute to overall longevity. We are therefore at an early stage of discovery in this area, in which we will be convening some major planning meetings this year to provide us with evidence of best future direction. These future directions will tie to the NIH-wide efforts, including those led by the Genome Institute, which is identifying polymorphisms through the whole genome, the markers against which we can compare the phenotype, the observed characteristics of longevity. We are anticipating investments in the overall genetics area of approximately $27 million next year. The balance of that will be directed to phenotyping, genotyping of human populations. How much will need to be done still in subhuman species will be determined by the outcomes of some of our planning meetings. Mr. Stokes. Thank you, Dr. Hodes. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Stokes. Ms. Pelosi. alzheimer's disease Ms. Pelosi. Thank you, Mr. Chairman. Dr. Hodes, Dr. Varmus, all of you, welcome. Thank you for your testimony. Can we go back to the previous chart? Because I want to make sure I am drawing the right conclusion from it. Thank you. It looks to me that each of these is more effective than taking them in combination. Is that correct? Dr. Hodes. That is correct. The numbers for selegiline and vitamin E alone are higher than the number for selegiline plus vitamin E. When one looks to ask whether any of those differences are statistically significant, the answer is no, so that it is not clear whether there is any real difference between them. The conclusion which can be drawn, perhaps most importantly, is that there is no evidence that the two together are any better than either alone, which was one of the hypotheses being tested. This has indicated that in designing further studies, there does not appear to be compelling reason to use this combination of drugs as opposed to testing one alone. Ms. Pelosi. And then for the placebo, that is statistically significant? Dr. Hodes. Yes. Ms. Pelosi. How did the placebo work, just---- Dr. Hodes. The placebo essentially reflects the natural history or the course of progression of Alzheimer's disease. Presumably people not taking the placebo would have done as well as those taking the placebo. This is consistent with the natural history of untreated Alzheimer's disease as has been observed for some time. A progression from the state of diagnosis to the state of dependent living has typically followed a time course such as shown in the placebo group here. Ms. Pelosi. Our Chairman has enabled us to hear the stories of many families from across the country, very sad stories to tell of how they are affected by illness, but I don't think I ever was as struck or surprised as the day we had the gentleman with Alzheimer's who was about 45 years old. He was here with his wife, and their children were college age. He was the breadwinner, and now he was--his wife was doing everything for him, really. But he did attend. How prevalent is Alzheimer's in younger people? Dr. Hodes. Approximately 10 or 15 percent of Alzheimer's disease falls in a category that can be related to specific genetic mutations, and the vast majority, nearly all of individuals who will have onset of disease in the age range that you were discussing fall into that category. The larger category of disease, the remaining 85 or 90 percent of disease which is not yet associated with single gene mutations, has a very much more age-dependent onset. For example, in individuals in the age range 65 to 74 there is approximately 3 percent prevalence rate of those affected. This goes up exponentially with age. Those 85 years and older are associated with estimates as high as 47 percent. If one extrapolates the aging of the American population without change in that kind of prevalence, the magnitude of suffering, emotional and social cost is indeed staggering. Ms. Pelosi. So that would be very bad news for this gentleman's children, as well? Dr. Hodes. Each individual case must be diagnosed separately, but if his early onset disease is associated with a known mutation in one of those genes associated with early onset Alzheimer's, sadly, there is a substantial chance of inheritance of that gene. Ms. Pelosi. And what other reason would there be for someone to have Alzheimer's so young? Dr. Hodes. It is possible, at the far end of a probability scale, that such early onset could occur in the absence of one of these familial mutations, though extremely rare. estrogen and vitamin e Ms. Pelosi. Interesting, interesting. Well, your report is pretty exciting, actually, in terms of slowing--why aren'twe all on estrogen and taking vitamin E? Is there a down side? Perhaps not for you, but some of us. Is there a down side to it? Dr. Hodes. It is a very important and timely question that is clearly driving the behavior of many people. Let me answer at two levels. The first is to emphasize again that the study of those agents, estrogen, for example, is based to date on epidemiologic data that show an association, but, as yet, no direct demonstration by clinical trial of effectiveness. Estrogen clearly has potential implications for many important aspects of health: cardiovascular disease, cancer risk, and others. The possibility that estrogen may play a role in risk of Alzheimer's, if confirmed in a clinical study, will become a part of this very complex equation and decision for each woman of the relative risks and benefits of estrogen. In the case of vitamin E, this is a first study, and although it was indeed a clinical trial and shows significance, it shows a modest effect which clearly needs to be retested before acceptance as a generality. We don't know, for example, how applicable this advantage will be to a more generalized population than that used in this particular study. The second level associated with your question of why not take it if it might be good, relates to the fact that there are reported risks associated with each of these agents, estrogen and vitamin E. We work very hard in our public information function to inform the public of both what is known but also what is not known and may constitute risks about using as yet unproven or incompletely characterized agents. information dissemination Ms. Pelosi. Well, since you ended on the note of information dissemination, I wanted to ask you about your research findings on both osteoporosis and osteoarthritis. Can you talk a little bit on how valuable research like this is disseminated? Are we doing enough to reach seniors with health information that could help them lead longer and more enjoyable lives? Dr. Hodes. Yes. We have an important component of our mission at NIH related to the dissemination of information. The findings which are newly reported are communicated initially as scientific findings in the scientific community. The way in which these are translated to the public is critical. We communicate these findings to the public through multiple modes, including television, ``Age Pages'' which are informative sheets distributed widely and in bulk at institutions such as supermarkets, as well as through direct responses to the public. More and more widely used is our electronic web access. But, of course, we understand that none of these reaches the full breadth of the population who needs to be aware of and profit from our findings. So we continue to work, as Dr. Hyman was pointing out, with at times restrictions in our budgets allowed for public information function, to, through all media available, communicate to the public, findings at an appropriate time. I should point out that in addition to communicating to the public, the communication is often best coordinated through informing health care providers. One recent example of this kind of communication strategy involved the importance of immunization against flu or pneumococcal pneumonia. The approach taken was first through a series of meetings and then through bulk distribution of information to target general practitioners. This was a result of studies which showed the primary reason elders were not being immunized was because their doctors never brought up the subject. So we carried out an extensive nationwide campaign with the cooperation of health care providers and medical organizations, followed immediately thereafter by communication to the public, so that when individuals go to their doctor to say, ``I heard that it might be appropriate for me to receive immunization,'' they were not confronted by caregivers who were unaware and unable to confirm or act upon that information. This is typical of the kind of exercise we try to carry out to inform the public. special populations Ms. Pelosi. I appreciate that. You know, my colleague, Mr. Stokes, has been a leader in making sure that all of the information that we have for the opportunity for clinical trials or the training of health care scientists and health care providers, et cetera, reaches into the minority communities. And many of us share his concern in that area. I had a little more specific question in that regard. I have the privilege of representing a very diverse district, San Francisco. And for a long time now, I have been approached by people who deliver health care services to seniors in the gay community about the specific needs of lesbians in regard to aging. Is there anything going on at your institute in that regard? I do not know what the specific health needs might be, but I am told that there are such concerns. Dr. Hodes. We serve, as we should and must, all components of the population. An example of some of the special concerns that we have tried to address has been in studies of HIV in older Americans and in older men and women, including gay and homosexuals. One of the major emphasis areas in the Institute's AIDS arena is, in fact, in the behavioral area. We attempt to understand both risk factors, risk factor modification, but also the social and support structures that are there for older people, be they married, single, in homosexual or heterosexual relationships. To that extent, we have involvement with this, among other, special populations. Ms. Pelosi. I appreciate that. Thank you, Dr. Hodes. Thank you, Dr. Varmus. Thank you, Mr. Chairman. funding stability Mr. Porter. Thank you, Ms. Pelosi. Can I ask one final question, and that is--and if Dr. Hodes could answer first again, then Dr. Varmus, to what extent does the availability of funding influence scientific opportunity? In other words, I think you were here when Dr. Hyman talked about moving funds from one area to another and how scientists and the science then moved where the money went. Can you give us some insight, both of you, as to what influence the dollars have on scientific opportunity in a general way? Dr. Hodes. I think for the vast majority of scientists, the original components of motivation have to do with scientific interest and service of public good. I think during a time when resources are stably assured--and I would strongly agree with Steve Hyman that an enormous good can be served by this Committee'sefforts to assure stability of growth--that under conditions where stability of growth is reasonably secure in the perception of investigators, that they will follow these joint motivations of scientific interest and public service. That judgment may be altered by a perception of differential funding and stability itself is threatened, and that becomes a tertiary aspect of motivation, secondary to those two which I first mentioned. Dr. Varmus. Well, I think the answer is not a simple one because it depends on the context in which the shift in funding is made. As Richard points out, if times are hard and people are underfunded or unfunded for their research, then they turn their interests to an area where there seems to be a greater availability of money. Of course, under those circumstances, it is likely that many of those who shift fields are those who have not been so successful and may not be the highest caliber of investigators. Under circumstances where the money is being moved into one area because of specific need--for example, when we had a clear indication a few years ago that there was an increased incidence of drug-resistant tuberculosis and we were underfunding tuberculosis research and had, in fact, failed to nurture a cadre of people who were skilled at working with tuberculosis--extra money then moved highly competent people to that area, recognizing there was a new, important intellectual problem that had big public health import. There was a real need. There was also an incredibly interesting scientific opportunity and new tools with which to approach the question of how we develop better therapies for drug-resistant tuberculosis. Then that shift was very appropriate. The question has been asked of me many times: can't you, in fact, develop a field by investing more heavily into it? I think the answer is yes, you can. But when money is limited, as it always is in some sense, you have to ask yourself: How much ground do I gain for each dollar? I would argue that if you are simply moving the money because this is what you care about and you are not paying attention to the other issues that are involved in priority setting, like scientific opportunity and public health need and the actual balance that currently exists, I would contend that you are likely to make a shift that would result in less progress than might have occurred in areas where things are moving faster. Yes, some progress, but not an optimal level of progress would occur in an area that has been expanded by that shift. Mr. Porter. Let me thank you. We always thank you, Dr. Varmus, because you have been here for the last two weeks. Dr. Hodes, let me thank you for your very good testimony and your good answers to our questions and for the fine job you are doing at the National Institute on Aging. Thank you for appearing. The subcommittee will stand in recess until 10:00 a.m. Tuesday. [The following questions were submitted to be answered for the record:] [Pages 2382 - 2444--The official Committee record contains additional material here.] Friday, March 27, 1998. NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKES WITNESSES AUDREY S. PENN, M.D., ACTING DIRECTOR, NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE CONSTANCE W. ATWELL, Ph.D., ACTING DEPUTY DIRECTOR ANDREW C. BALDUS, BUDGET OFFICER HAROLD VARMUS, M.D., DIRECTOR, NATIONAL INSTITUTES OF HEALTH BILL BELDON, DIVISION DIRECTOR, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES MARY MIERS, PLANNING AND LEGISLATION JOHN H. JONES, ACTING EXECUTIVE OFFICER Mr. Porter. The subcommittee will come to order. Today we have Dr. Audrey Penn from the National Institute of Neurological Disorders and Stroke. Dr. Penn, welcome. Will you please introduce the people at the table with you and proceed to your statement? Dr. Penn. Yes, sir. Mr. Chairman and members of the committee, today I appear before you as the Deputy Director and Acting Director of the National Institute of Neurological Disorders and Stroke. I should like to introduce the others at the table of NINDS with me today: Mr. Bill Beldon, Office of the Assistant Secretary for Management and Budget; Dr. Harold Varmus, Director, National Institutes of Health; Dr. Constance Atwell, Acting Deputy Director; Mr. John Jones, Acting Executive Officer; Mr. Andrew Baldus, Budget Officer, and Ms. Mary Miers, Planning and Legislation. As a neurologist, a former grantee of NINDS and a former member of its Advisory Committee, I welcome the opportunity to be able to personally discuss with you the promise of new insights into some of our most difficult disorders. We have been a part of some amazing success stories over the past several years. I'd like to tell you more about two of them today. Parkinson's disease is a neurodegenerative disorder in which neural cells in specific regions of the brain die off. Affected individuals show tremor, rigidity of movements, stooped posture, and they slowly deteriorate in their ability to move and function. We would like to tell you about the exciting implications and possibilities coming from the investigations of some of the inherited forms of Parkinson's disease. As you know, a gene has been identified. Now we know that this gene is the blueprint for a protein that has been known for some time, but not in this context. The protein was named for its localization in synapses, the connections between nerve cells or nerve and muscle. So it was called synuclein. At first, relationships seemed obscure, but investigators at the University of Pennsylvania, following the findings by our Genome Institute, have found that synuclein is present in a structure which is a hallmark of Parkinson's disease called a Lewy Body. This is particularly intriguing because this Lewy Body occurs in Parkinson's which is not inherited. So we have good reason to believe that our new knowledge of the gene product involved in the uncommon inherited form of the disease has much to teach us about the more common sporadic form. The Lewy Body is an abnormal clump of protein which we call an inclusion body and it is found within brain cells. Here you see a Lewy Body as it appears in an affected Parkinson's cell after a regular tissue stain used in pathological examinations. Here is a Lewy Body stained with a specific probe in the form of an antibody to synuclein. This inclusion body may result from abnormal breakdown of this protein, so that it piles up and results in cell damage or it may be a product of the tendency of the abnormal synuclein to stick to itself and to other proteins. In either case, current evidence suggests that interference with the tendency of the abnormal synuclein to form clumps may provide treatment. Not only that, but synuclein is a precursor for one of the components of the proteinaceous material called plaques, found as a hallmark of Alzheimer's disease. This has also galvanized the field because it provides a link between two major neurodegenerative disorders--Parkinson's and Alzheimer's--and reinforces the idea that abnormal interactions between proteins resulting in actual deposits of protein aggregates in cells leads directly to cell death. This idea is generating much new investigation using cells in tissue culture and experimental mice made to express the defective gene--with almost monthly new information reinforcing this evidence. This, then, is an excellent example of the catalytic effects of scientific opportunity upon well-known observations from the clinic. The idea of interaction between proteins resulting in abnormal deposits in cells has been also raised by the so- called ``triplet repeat'' diseases. As you know, the genetic code which resides within DNA produces proteins. The coding units of DNA designate the building blocks of a protein molecule called amino acids: each DNA coding unit consists of three bases, hence triplet. Each triplet codes for a specific amino acid. Over the past several years, a whole group of unexplained serious neurodegenerative disorders have been shown to result somehow from abnormal genes in which a single triplet code is repeated many times, so that the resulting protein contains long stretches of the same amino acid. Here you see a segment of a gene with typically varied coding units which produces a protein with varied amino acids, including occasionally a short repeat sequence; here you see a ``triplet repeat,'' with its product, long sequences of an amino acid called glutamine. The long glutamine repeat folds upon itself and binds one portion to the other in a ``hairpin'' and the involved protein molecules bind to each other in aggregates. The disorders in which these overly-long stretches of the amino acid, glutamine, are found are some of the most disabling neurological disorders with which we deal. The strength, balance, or mentation of affected individualsdeteriorate, and we have been unable to treat. These disorders vary from Huntington's disease in which there is dementia and abnormal dancing movements of the limbs called chorea to a series of disorders of balance called the hereditary ataxias and even to one of the muscular dystrophies. Some of these disorders affect young children. They are often inherited in a dominant fashion, so that one-half of the children in such a family will be affected. The explosion of new information linking these neurodegenerative disorders to abnormal chemical interactions between proteins raises exciting possibilities. The abnormal clumps of protein are found within dying brain cells in the regions of brain which are affected by the disorders. The new information represents an excellent example of bench research finally providing new insights into baffling diseases and of how finding a gene may open really new lines of investigation. It energizes the clinicians who provide materials from patients, so that investigators can add to their findings. The clinician-investigators may confirm or extend the findings on their own patients within their own laboratories. Patients and families are important partners in these efforts, and we are gratified by their help. It also provides encouragement for all to begin to think about the disorders as potentially treatable and to plan toward drug therapies. The new hypotheses--that protein-protein interactions which result in abnormal aggregates in vulnerable brain cells may be critical to specific neurodegenerative disorders--form the basis for one of the major initiatives in our budget request. As you can tell, Mr. Chairman, we are very excited about the pace and promise of neuroscience research and its impact upon neurological disorders. I would be pleased to answer any questions. [The prepared statement follows:] [Pages 2448 - 2452D--The official Committee record contains additional material here.] Mr. Porter. Just so I can try to understand this a little better, if Parkinson's is a genetic-based disease, then presumably you have this abnormal gene from the time you're born. Why does it only show up later in life then? Dr. Penn. Presumably, this gene will continue to slowly produce an abnormal protein, and it does take time, and we know this from many of the disorders that I've already referred to, for some of these to fully express themselves. These do come on slowly and stay a long time. It also would suggest that there are other influences; other proteins must be present. Perhaps the normal systems in which these proteins are broken down are in place and for a while they are managing the situation, and then later those systems are overwhelmed. There are, obviously, other pathways and other proteins that are binding in to make these clumps, but this is just such a wonderful clue to what's going on. We haven't known what's going on. Dr. Varmus. It might be worth mentioning, Mr. Porter, that in the families in which the mutation has been identified, the onset of the disease tends to be earlier than in the sporadic cases that occur in the general population. Dr. Penn. Yes. Mr. Porter. I think I know the answer to this question, and the answer would be no, but let me ask it anyway and see if I can understand this further. You talked about drug therapies that might be developed to address this kind of condition for Parkinson's disease. Is there any possibility that a drug therapy used to control the disease would, perhaps after a period of time, not control it? In other words, is there any possibility that the nature of the disease could change in a way that would defeat the kind of drug therapy that would be given? For example, with respect to bacteria, there are strains that have developed to avoid our antibiotics and seem to do so more and more successfully, which is a real problem. Is it also a problem in this kind of therapy? Dr. Penn. Potentially, it's a problem. I think we may have seen something like that, because what we have tried to do for the past 30 years is to replace the normal chemical, which is missing in these disturbed cells. When we did that, other cells continued to die off, and we were faced with the situation where some of the things that we were giving caused side effects that were somewhat unacceptable. So that this disease is a gradual die-off of cells that have this chemical. So, yes, indeed, you could do that. Mr. Porter. So I didn't know the answer because the answer is yes. Dr. Penn. You have to try to get around that. We'd like to put the cells back someday. Mr. Porter. Well, then, I think we go back to the larger question, and that is, of all the work that we now do to unlock these secrets and develop therapies for them, because there is an ability to metamorphosis into a different form, can this work be defeated? In other words, can the disease change and require constant development of new therapies? Dr. Penn. I see where you're coming from. I do not want to imply that it will change that radically or that often, but I will say with you that there are times when we start a new therapy with the best intentions and, as we learn more about the disease, we have to deal with its effects on either normal cells or the fact that the abnormal cells just do not respond when they're totally gone, like the frozen addict story. We're working on that, too, to try to find out what we can to do when the cells are just gone. Dr. Varmus. We wouldn't expect in this case for cells to undergo genetic changes that would allow them to escape treatment, as is true in the case of bacterial resistance, when bacteria undergo mutations that make them resistant to antibiotics and give them a growth advantage. The brain cells are destined for death, so the cells that would survive would be the ones responding to therapy. Mr. Porter. In respect to bacteria, we know that changes can occur. With respect to viruses, don't we also know that changes can occur as well? Dr. Varmus. Absolutely. Mr. Porter. So you can have in those two instances at least, two different forms of infection or invasion of the body. You can have changes, but not in this type---- Dr. Varmus. Well, there are two important differences. One is that viruses and bacteria are turning over extremely rapidly, so they're generating a lot of genetic change just by growing. Secondly, in therapies addressed against viruses and bacteria you're trying to kill the bacteria and viruses. Here the therapy will be intended to allow the cells that are programmed for death to instead live. We'd be encouraging the cells that respond to the therapy to survive. Mr. Porter. Is there any importance in the fact that bacteria and viruses both come from outside the body, and these diseases are within your cell structure? They are not an invasion of the body by some foreign---- Dr. Varmus. That makes it much more difficult. Understanding the complexity of a human cell is obviously a greater challenge than trying to understand the complexity of a simple bacterium or virus. Mr. Porter. It helps my understanding. It's a curiosity more than anything. Dr. Penn, the budget request includes funding to pursue new approaches in neuroradiology for diagnosis and treatment of brain disease. Would you describe the process of neuroradiology in further detail, as well as your plans in this area for next year? Dr. Penn. Neuroradiology is a specialty that is allied to ours, and it's extremely important to the diagnosis, and really at times, treatment of neurological and neurosurgical disorders. Over time we have evolved the computerized tomography, the CT scans. We've evolved magnetic resonance imaging. We now are into a phase where we can actually detect function of the brain as the brain does certain tasks, with functional MRI. So that it adds a diagnostic component as well as a research component. We perceive that over about the next certainly five years that neuro-imaging, as we are also calling this, has a tremendous future. It can give us enormous amounts of information. The positron emission tomography, the PET scanning, and its similar SPECT scanning, a lot of it has been used on the NIH campus for a long time. It's given us enormous amounts of good information. Those entities are extremely expensive, and not every place in the country can have one, partly because it requires isotopes of very short half-life. We feel that over time this would be an enormous thing to have, not only to look at people, but in the research arm there are actually magnets in the magnetic resonance imaging studies that can be used for some of these mice and rats that are expressing these genes. And therefore, we've put a considerable emphasis on the future of neuro-imaging as it not only applies to basic science, but to disorders. Mr. Porter. Dr. Varmus, let me ask you a question at this point. The idea of creating a new Institute of Radiology is being heard again. Can you tell us what position NIH has on that idea? Dr. Varmus. Well, we haven't fully formed an official position as yet. As you know, we begin from the assumption that imaging of various kinds is important to the activities of virtually all our institutes, and that creates, in my view, a reason for not segregating radiology and imaging into one place. I believe it should be integrated, just as any fundamental technique, like molecular biology or DNA sequencing would be integrated into the fabric of many research institutes' activities. Furthermore, I'm always reluctant to set up yet another administrative structure in an organization that's already extremely complex. I have yet to hear the compelling argument that we should do so. As you know, a year or two ago, we created the Bio- engineering Consortium, which includes among itsprincipal components imaging technologies and radiology. We believe that within the confines of that consortium the concerns of the radiology and imaging community can be satisfactorily met. I am perfectly willing to meet with individuals from that community, as I have in the past, to see whether that claim is true. Mr. Porter. Often these are matters of pride and recognition that the institute or the existence of an institute gives a specialty within the profession. Perhaps there's some way that the recognition of the importance of radiology can be made without creating a separate institute. Dr. Varmus. We'll also look at that possibility. Mr. Porter. In public witness testimony before the subcommittee, it was brought to our attention that NINDS was spending 13 percent less on Batten's disease in fiscal year 1997 than it did in fiscal year 1994. Is this an accurate assessment of the situation? And if so, can you tell us why funding has been reduced in this area? Dr. Penn. The reason that the numbers seem to have gone down is that we have had enormous success because we now have the genes for all four forms of Batten disease. During that period of time, our grantees have actually found the gene for the late infantile form of this problem, and that means that the emphasis and the research should be toward, again, finding out what the gene product is in terms of the protein, and working toward developing all the models that are necessary to figure out what they do. That way we can really impact the disease. Also, several very successful projects over time which are not directly into the genetic areas have somewhat lapsed. So we have not given up on Batten's disease, but we are working toward really the cutting-edge new frontier for it. Mr. Porter. After finding the gene, is it a harder job often to find a therapy or is finding the gene initially the harder task? Dr. Penn. I would say in 1998 perhaps finding the gene. It cannot always be easy; we have several diseases in which it took well over five years--Huntington's is an example of that and the Facio-scapulo humeral dystrophy is an example where they're still looking. They find a locus on the chromosome, but they don't have the gene yet. But I would say finding the therapies is not going to be easy, either, and I would equate them in difficulty. Mr. Porter. Thank you very much, Dr. Penn. Mr. Stokes. Mr. Stokes. Thank you, Mr. Chairman. Good morning, Dr. Penn. Dr. Penn. Good morning, sir. Mr. Stokes. Dr. Penn, generally speaking, do the victims of stroke receive some type of warning signals? Dr. Penn. They may. It is particularly important that everybody be aware that there are warning signals for stroke, and those warning signals are derived from where in the brain the blood vessel is being blocked. So that you could have sudden weakness or difficulty using a hand. You could have one eye in which you suddenly couldn't see, and you could have difficulty feeling. If you begin to think that that is really happening to you, and that it isn't going away within seconds, then you have to be aware that it could be the onset of a stroke. We have something called transient ischemic attacks. Those are a signal to get in, get your arteries looked at, and perhaps have therapy. Unfortunately, in some of our stroke victims this happens really early in the morning, so we don't always have that much time. However, there is enough warning, when you feel, as people will tell you, their face just sort of feels like it's hanging; they can't move their tongue very well. In some situations they suddenly can't talk. I mean, everything should happen--911, the emergency services should be called promptly; people should be gotten to an emergency room promptly and handled promptly. These are all available to us now. They were available before, but we have to make sure that people know about it. Mr. Stokes. I ask that question because I suppose what you have just said to me is news, perhaps, to a lot of people in this room here this morning. To what degree is the Institute trying to utilize outreach and education, to increase the general public's awareness and understanding of the warning signals relative to stroke? Dr. Penn. We're relatively horrified that so many people do not know the warning features of stroke the way they do of heart attack. And so we've tried to rename this ``brain attack,'' and we've begun a public information campaign to try to tell people about these symptoms and to get them into the hospitals, into the emergency areas of the hospitals, promptly. Because one of our major therapies can only be really successful if it's used within the first three hours from the symptoms. So when your face begins to droop and your speech goes, you've got to move. Therefore, we have used the media. Media have been wonderful to help us put this message out. As you know, we've actually had a segment of ``ER,'' and we've actually had a workshop where we brought people from the EMS services, the emergency rooms, every conceivable step in the process, the neuroimagers, all together to say, look, we've got to get this going. We have a lot of help from the Stroke Association on this, and so on. Mr. Stokes. Do you find that people go into a state of denial with reference to this, in the same manner that many do with reference to heart attacks? I understand that one of the problems relative to heart attacks is that people say, ``ah, this couldn't be happening to me,'' and they sort of ignore the signals or ignore the signs. Do you find that to be true with stroke? Dr. Penn. I'm afraid it is true, but it is different. In heart attack, every once in a while people think they've just got indigestion. Stroke symptoms really don't really represent anything else perhaps except the beginnings of a migraine. A lot of people do not have migraines. So they have to be aware those are serious and they should be checked out right away. Mr. Stokes. Let me ask you this, Dr. Penn; It is thought that African Americans have a two-to-threefold greater risk of stroke and are 2.5 times more likely to die of stroke? Do we know what causes this increased risk amongst African Americans? Dr. Penn. There are several, components of that risk. Part of it is environment. Part of it is not perhaps paying proper attention to things that we all know about that we have heard repeatedly: If you're diabetic, if you have hypertension, if you're overweight and don't exercise, there's all of that. There's also just an intrinsic risk, which I would have to say is another genetic influence. It's also the issue offolks not particularly wanting to go to doctors right away, which comes back to your other question. Mr. Stokes. To what degree do you work with national African American organizations and groups in order to try to facilitate outreach toward African Americans in general? Dr. Penn. We have several investigators working in order to do the trials of the clot-busting drug. The African American community, all of the minority communities were involved in that. We also work with the National Medical Association. We work with the Student National Medical Association, and our folks go to their meetings and will be presenting some information to them further on the TPA story. In the brain attack coalition, they are involved. Mr. Stokes. As you're keenly aware, spinal cord injuries take a devastating toll on families across the Nation. What success are we having in this critical area of research in general, and with respect to spinal cord regeneration in particular? Dr. Penn. We have more success than we used to because we understand it better. I mean, the research has told us that. We've had a tremendous breakthrough in confirming that a corticosteroid--namely, methyl prednisolone--will really benefit, if given within the first eight hours after injury. We know now, that this whole study's been extended, that patients receiving it within three hours can benefit from a 24-hour dosage, and those treated within three to eight hours, should be treated for 48 hours. Exactly which pathways of destruction that it is hitting are still to be worked out. We have many investigators working on how to get cells and pathways to regenerate. We had a very large workshop sort of in honor of both Mr. Reeve and Dr. Bunge of the Miami Project, to discuss all of these issues and to try to galvanize the field to get going. So we've had this wonderful model of the rat in which the peripheral nerves were stretched over the hole in the spinal cord, and the rat begins to move, but we need a lot more information than that. It has to be reproduced and worked on. If we could find out about that kind of thing, we're going to find a lot about stroke and head trauma as well. Mr. Stokes. Dr. Penn, I'm very concerned about the impact of cerebral palsy, autism, and other neurological disorders on children. Do we know the extent of the problem with regard to neurological disorders in children in the United States? Dr. Penn. To give you an exact number, I am not quite able to do that, though we could certainly supply that number for you. [The information follows:] Neurological Disorders in Children The extend of neurological disorders in children is enormous. The developing brain and nervous system are particularly vulnerable to damage, whether genetic or environmental, and as many as 4 of every 1,000 babies born in the United States die because of disorders in which the nervous system fails to develop properly. Of the more than 4,000 known single gene disorders, it is estimated that as many as one- third are primarily neurologic or have significant neurologic involvement. More than 1 of every 15 babies is born prematurely; these babies are uniquely vulnerable to damage from brain hemorrhage (stroke) which can lead to lifelong mental deficits, epilepsy, cerebral palsy, and behavioral problems. At least 5,000 children with moderate or severe congenital cerebral palsy alone are born each year. Defects in the formation or maintenance or brain cell connections may result in mental retardation, learning disabilities, and neurobehavioral disorders such as autism. During a child's first five years of life constant remodeling of neural networks allows noxious insults to produce lasting effects in brain function. Dr. Penn. It is a major problem. Cerebral palsy is one of the leading problems in neonatology and for infants to make sure--because prematurity and low birth weight are the highest causes of cerebral palsy. So it is something we are very concerned about. We have currently a major clinical trial going to try to prevent cerebral palsy in low-birth-weight infants, using something very simple, which is used on hypertensive mothers, called magnesium sulfate that we will be able, hopefully, to report further on. We also have done things to reduce hemorrhages which happen in low-birth-weight and premature infants, using a drug for inflammatory arthritis called indomethacin, and this has been carefully studied in appropriate clinical trials. Mr. Stokes. Last year the Institute discussed its collaborative and co-funded activities with the Office of Research on Minority Health and the Morehouse School of Medicine. What progress do you have to report on these initiatives? Dr. Penn. We continue to work with this office very productively. We are very proud of what's going on at Morehouse. They really have a major neuroscience program and center under the leadership of Dr. Peter McLeish and Dr. Sullivan, who is the president of Morehouse. We've just had regular site visits of their program, meaning by that that they have been asked to compete as everybody else is competing. They have been successful. So we moved to the next phase, adding more investigators and building that program, and so far we're using it as an example to other minority institutions and we're moving toward adding a program, on a competitive basis, of course, at some of the other institutions, to see if we can get neuroscience added to the minority institutions' research. Mr. Stokes. Thank you, Dr. Penn. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Stokes. Mr. Hoyer? Mr. Hoyer. Thank you very much. Dr. Penn, welcome. Dr. Penn. Thank you. Mr. Hoyer. It's nice to see you again. I want to thank you for taking the time to visit with me in my office. I gave, the folder or the paper that you gave me on autism to Congressman Rothman, and he was very appreciative. Dr. Penn. Thank you. Mr. Hoyer. So I thank you. Doctor, as you probably know, I'm very interested in Rett syndrome because of a personal experience I've had with a Rett syndrome child, but, obviously, as well, thegeneral application of why the neurological development is arrested after about 18 months in female children. Can you tell me the status of Rett syndrome, your involvement, your Institute's involvement. And if you don't know, that's understandable, and you can put that in the record. Dr. Penn. We will, again, give you more information, but it is among several disorders in which there are really sort of growth arrest for the brain or great difficulty with attention and cognition. We have more than one. As I understand it, we don't have a specific grantee at this moment, but we do work, along with Child Health, and we are, as you know, very much into autism. In fact, the autism group is a consortium of four institutes, of which we are one. [The information follows:] Rett Syndrome Children with Rett syndrome apparently develop normally until 6 to 18 months of age. These children then show signs of impaired language, loss of purposeful hand skills, and repetitive hand movements. The cause is not known. Rett syndrome is one of the many brain disorders of childhood, such as autism, learning disabilities, mental retardation, and cerebral palsy in which NINDS and the National Institute of Child Health and Human Development (NICHD) share interest. NICHD is the lead institute for research on Rett syndrome. However, NINDS has been involved to the extent that we support basic research on the development of the brain, and research on related brain disorders, such as autism, that can contribute to research efforts in Rett syndrome. NINDS also provided support for an international conference on Rett Syndrome, held in 1994, and NINDS staff participated at a recent conference sponsored by NICHD on genetics of Rett syndrome. I am committed to furthering NINDS efforts in brain disorders affecting children. We plan to continue to work closely with our colleagues in other institutes which share our interests in neurological disorders of childhood. Mr. Hoyer. I am pleased with that, and we will work with your office on some language on autism becoming a bill. I talked to Steve Rothman about it. I asked a general question of the previous directors. What pay-line level will your institute be at, do you think, in terms of extrinsic grants--extramural grants? Dr. Penn. Extramural? Our success rate is up 28 to 29 percent, and---- Mr. Hoyer. Twenty-eight to 29 percent? Dr. Penn [continuing]. Yes, we hope to go higher---- Mr. Hoyer. Fine. Dr. Penn [continuing]. All things being equal. Mr. Hoyer. At that level, do you think we have sufficient investment in basic research to encourage both the retention of those researchers that we now have and the encouragement of young researchers to come in? Dr. Penn. We hope that--I mean, we do work very closely, and there are some really staunch supporters, the Society for Neuroscience, and all the basic researchers, because, without them, we can't go on with these breakthroughs that we desperately need. In terms of training and development, we have been very much into this, both in terms of the basic scientists and the clinician investigators, and we have several developmental awards to keep the clinicians in this. It's fine for clinicians to be practicing in their wonderful specialities--my colleagues know what they're doing--but we also need people who can ask the questions on their own patients. This is to say patient- oriented research. So we have made an investment in that, and we are going to continue to do that, to develop people who can sort of work at both the bedside and the bench, and go on to full faculty status successfully. We will use the new award that Dr. Varmus has announced to you, this new award for patient-oriented research and development, as well, but we will continue also to train people to do both. Mr. Hoyer. Thank you. Doctor, Parkinson's disease, you started your testimony with reference to Parkinson's disease. Obviously, our friend Morton Kondracke, as you may know, his wife is suffering from Parkinson's disease, and Moe Udall. Can you tell me--you reference in your statement, obviously, some breakthroughs or some progress. Do we foresee the ability to reverse, do you think, the effects of Parkinson's disease, as well as to intervene in its onset? Dr. Penn. I would say we would be working at the moment--we are trying. There are several things which happened sort of simultaneously, and it's not just what I started with in the testimony. Various of our industrial pharmaceutical companies are trying to make sort of drugs that last longer and do somewhat of a better job. But, again, this requires that you have some residual cells that are able to function. We would like to intervene very early. Therefore, the diagnostic criteria or markers for this are critical. We think we have them, but it would be a very good idea to have even better ones, because there are other disorders in which there are features of Parkinson's disease. So that there will be a multi-pronged, we hope, pharmaceutical attack on this, and we hope actually at some point to be able to put back cells and/or factors that will preserve what's there and add to it. Mr. Hoyer. I note that also, when you talk about regeneration on spinal cord injuries, obviously, that has been a great challenge for the scientific community, to see whether or not we can regenerate cell activity, nerve activity, so that it is possible to regain, after a traumatic spinal cord injury, regain some use or maybe total use of limbs and the body. Where are we on that? You reference it in your statement, but where do you think we are on that? How close are we? Dr. Penn. I think we have major investigators working extremely hard on this. I think the good news is that thereare stem or progenitor cells in the central nervous system, as well as in the periphery--you know, because nerves in your arms and legs will grow back. It takes forever, but they do it. We would like very much to permit them to grow, so we need to know all the things that are acting against them and all the factors that are positive. It's almost like cooking. You're going to add a little of this--we have to figure out what it is that makes the whole thing proceed. Remember that the experiment that I described had to do with peripheral nerves used to carry signals, and so we need to get the nerves and central nervous system to regenerate. I'm more hopeful than I used to be. Mr. Hoyer. And you used to be of the opinion that this would not be possible? Dr. Penn. We were taught that it didn't happen, that nerve cells did not regenerate in the central nervous system. Now there's considerable evidence that they actually do. There are cells left and they can be turned on in the proper places, but we have to be able to control that, if we're going to do it. Mr. Hoyer. I suppose that one of the secrets to being a successful basic researcher is that you get over very quickly that which you were taught could not begun. [Laughter.] That's a constraint on all of us---- Dr. Penn. Yes. Mr. Hoyer [continuing]. In whatever endeavor we are. Dr. Penn. Right. Mr. Hoyer. Thank you very much, Mr. Chairman. Dr. Penn, again, thank you. Mr. Porter. Thank you, Mr. Hoyer. We will have a second round. Dr. Penn, in the area of Parkinson's disease, you have a clinical trial in progress to evaluate the replacement of dopamine cells by transplantation of fetal tissue. Can you update the subcommittee in this area? Dr. Penn. We have one trial that has finished accruing its 40 patients and is now about to assess the results in those patients. I am blinded to the results as are those who are actually conducting the study. We have a performance and safety monitoring committee that's right on top of this. Things so far are reasonably positive in terms of gathering the needed information. The other trial is just getting going, and they're in the middle of their patient accrual. So that we should have some hard evidence for you, I would say, in about a year, because you have to watch and see what happens with people that got it. We don't know who got it. Mr. Porter. Since fetal cell therapies probably are not likely to be widely used, is there anything going on to develop a substitute for fetal cells? Dr. Penn. Several major investigators are working--it's almost back to the question of Mr. Hoyer--to try to develop cell culture systems, cells, that can be used. Again, I would have to check on exactly where each group has gotten, but it's a major area of endeavor. [The information follows:] Parkinson's Disease Several approaches for creating alternatives to the implantation of primary fetal tissue are being developed. There has been progress in the effort to persuade primary fetal cells to grow and proliferate in culture. One of the most exciting research approaches to develop neural cell lines is the use of embryonic stem cells. These cells can be expanded in culture to provide a limitless supply of neurons. Many laboratories across the country are attempting to enrich this neuronal population and create dopamine producing cells. Other groups are using viral vectors to replace lost synthetic enzymatic machinery for the production of dopamine or to re-engineer cells to produce growth factors which would help cells survive. The use of synthetic polymer capsules containing growth factors is being used to provide the slow release of molecules necessary to maintain neurons. Mr. Porter. What research is planned to advance basic and clinical research and treatment for forms of seizure disorders that are uncontrolled, like epilepsy? Dr. Penn. This is a major problem. It's especially a major problem in children. There are certain seizure disorders that are controllable, and people have to be followed and take their medications and actually not do foolish things like drink alcohol. However, there are other seizure disorders in which we've never had really good control. There is a surgical approach to one of them called partial complex seizures, which emanate from lesions probably in our memory centers in our temporal lobes. That's been very, very successful, and a lot of major medical centers have that capability. However, some of the others are still very hard to treat. We have in our extramural program a drug development program for this, and it's been going on for 40 years, because we feel that there's such a need for good and better drugs. Again, we've got some better ones, and we're currently using them. It doesn't seem to be perfect, and often you have to use combination drugs, but we're well aware that it's not perfect. Mr. Porter. If the epilepsy community was to say to you that you're not doing enough research in this area, what would your reply be? Dr. Penn. I would say we would talk with them and work with them to do more. We work very closely with both the voluntaries and the professional societies in epilepsy. They are actually working on the genetics type of thing that went on with Parkinson's themselves. We talked about it, and they said, well, we're ascertaining the families and we're going to figure this one out. We have advisory committees for both our drug program and to deal with the community--so far, I think they think we're trying; we're really out there for them. Mr. Porter. There was a study released by the National Academy of Sciences last year that leads to the conclusion that dyslexia is a neurological disorder. What research is NINDS currently funding to study learning disabilities such as dyslexia? Dr. Penn. I would say that we are probably on the edge of this. This is partly the imaging story, because you find out, from the functional MRI and using certain groups of patients, what's going on, and you find out that very important areas of brain are involved when you try to speak or write or read. Learning disabilities as part of cerebral palsy, as part of mental retardation, as part of all of these diseases of children that we have, are clearly very important to us, until we can figure out how to put an enzyme back or treat. This is also under the purview of Child Health, and we work with them. So we're doing more of what I discussed before, trying to prevent cerebral palsy or actually make sure who's got cerebral palsy at birth and deal with it that way. Mr. Porter. Your Institute has supported scientific symposiums on dystonia research. Have these efforts led to more research being supported, and do you collaborate with the National Institute of Deafness and Other Communication Disorders in this area? Dr. Penn. Well, dystonia is another movement disorder, which is not as common as Parkinson's disease, but it's in that ball park with Parkinson's disease and Huntington's. Again, it turns out to be rather more often genetic, and we have something like eight forms of dystonia, and we just had a major lecture in that area this week describing those eight forms. We're sort of where we are with several of our other diseases, including Huntington's, trying to figure out what the gene makes, so we can get on to what that protein is actually doing in the nervous system, and then try to deal with it that way. Otherwise, we certainly deal with the Deafness Institute, and I will have to check on exactly what we're doing with them on this area, dystonia. Mr. Porter. Thank you, Dr. Penn. Mr. Stokes. Mr. Stokes. Thank you, Mr. Chairman. Dr. Penn, in 1985, the Secretary's Task Force Report on Minority Health was released. This critical report explained the disparate situation that exists between the health status of majority and minority Americans health. That was approximately 13 years ago. Stroke and low birth weight were two of the specific areas cited in that task force report. Have we made much progress over the last 13 years in terms of those two areas? Dr. Penn. I would say we've made a lot of progress on stroke in the minority population. We have a series of investigators who go on out to find out the scope of the problem, then to ascertain in mixed populations which influences are important toward stroke, some of the things that we mentioned. We found that there's a lot more stroke than we thought because, once they got into communities, for instance, in Cincinnati, we found that the numbers of strokes are much higher because a lot of folks in the African American community don't always report these. So we know that stroke has been impacted since that report. We're pretty sure that infant mortality is better, but how much better is a little difficult to get the hard numbers, and we're actually working on that answer for you. Mr. Stokes. I'm glad you mentioned the infant mortality situation because I've got a copy of this international comparison of infant mortality health statistics where they say that the United States ranked 25th among selected countries for infant mortality. The latest figures tell us that we're 25th in the world. Am I correct? Dr. Penn. Well, I think you're right. As I said, we can't compare it yet to 1985. We're still trying to answer those questions. My sense is that it should be much better. Mr. Stokes. Tell me, Doctor, in terms of infant mortality, for instance, the rate per 1,000 live births for Japan is 4.4; the United States is 8.4, and there are 23 other countries in between--Finland, Singapore, Hong Kong, countries of that sort. Do we know why this type of disparity exists in a country that is one of the most affluent countries in the world? Dr. Penn. Yes, I would like to know which areas are most impacted. I think we can suppose as to which areas are most impacted, and there's been a lot of work to improve this. In a hospital that I'm very familiar with they work very hard to get at the infant mortality in the community of Harlem, but it takes time and it takes multiple persons involved. It takes good perinatal care. It takes access to intensive care units at this age, and needs a lot of these descriptors that we're beginning to development. When you have low birth weight which can occur, there are all the influences that you're well aware of in the community, too, unfortunately--drugs and alcohol. Mr. Stokes. Doctor, obviously, clinical trials are a major component of biomedical research. What type of investment is your Institute putting into clinical trials? Dr. Penn. I'm delighted to say that, as a neurologist, that we're finally ready to do some clinical trials. We've done several major clinical trials in stroke over time. We're now into the magnesium sulfate study for cerebral palsy in low- birth-weight infants. We're doing the clinical trials of the cell transplants in Parkinson's and also of pallidotomy, the surgery. We have full intent of doing more, and, as our communities or our investigators actually understand these diseases and we have more therapies to test, we want to be able to do it. Currently, we're up around $32 million in clinical trials. Mr. Stokes. Do you have any major clinical trials that are currently unfunded? Dr. Penn. Currently, absolutely unfunded, it's hard to say that. Some are in the pipeline. In the pipeline also includes some work to get the best possible clinical trials by helping the community--through feasibility studies, we call this a pilot grant, and also throughplanning, because if they don't plan, then they don't get funded the first time around, and everybody spends time and effort to try to bring these about. But we have I don't think any major unfunded ones. They're just waiting. They're not really totally unfunded. Mr. Stokes. Thank you, Dr. Penn. Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Stokes. Mr. Hoyer. Mr. Hoyer. Thank you, Mr. Chairman. One area, Alzheimer's, you do not mention it as a specific topic in your statement, as a specific screening topic, but, obviously, you deal with that. Would you expand somewhat on where you see your institute as it relates to Alzheimer's and where you see our research generally on Alzheimer's? Then we will have you comment on the treatability of Alzheimer's. Obviously, one of the problems Medicare has had is that it has not been historically perceived as a treatable disease. Dr. Penn. We work very closely with the Aging Institute from whom you've heard in the area of Alzheimer's. We tend to be more involved in the basic science of this, and we're working on how Alzheimer's actually starts in the cells or brain and its connections. We have had a working group with the Aging Institute, the Nursing Institute, and Mental Health for about the past year and a half to look at issues like that: Who exactly is doing what, and can we identify areas that aren't covered? There are a lot of my clinical colleagues who are working on Alzheimer's disease for sure, and they have been working on the risk factors, the APOE-4 business, and some of the others. They happen to be getting more money at the moment from the Aging Institute, but we are all, again, working more closely together to try to solve this. Therapies--there is no perfect therapy. There are some things that probably, again, if you give it early, help people think a little better. All of the things that we've been mentioning pretty much for stroke even could pertain because there are forms--if you get hit on the head, get a serious head injury, it makes your Alzheimer's worse. Certainly, if you have small strokes throughout the brain, it can make an appearance of Alzheimer's and it probably makes Alzheimer's worse. So there are multiple things that we would like to do early for these people. This gets into an area that I really don't want to discuss in terms of, if you identify people, what it does to your insurance and all this stuff. But there will be markers for this coming; there are already. But to say that you can take a pill today and clear your mind, your mentation, it's not really ready--you had to have a good heart and go exercise, I guess. [Laughter]. They don't have a perfect therapy. Mr. Hoyer. I'll tell you a story about that. I seem to be the member on this committee here with a lot of personal stories. I have a cholesterol problem, and the doctor said stop eating, you know---- Dr. Penn. Everything. Mr. Hoyer [continuing]. Milkshakes, ice cream, eggs, all that sort of stuff. So for about five months I was very religious--I'm into McDonald's. I'm sort of a junk food freak, potato chips, all the wrong things. So I stopped eating most of that. Five months later, I went in for a cholesterol check. My cholesterol had been 260; it went down to 259. [Laughter.] The doctor shrugged his shoulders. So I'm into drugs. [Laughter.] Thank you, Mr. Chairman. Mr. Porter. Thank you, Mr. Hoyer. Dr. Penn, thank you very much for your excellent testimony this morning and for the fine job you're doing at NINDS and for your appearance. Dr. Penn. Thank you very much. [The following questions were submitted to be answered for the record:] [Pages 2467 - 2547--The official Committee record contains additional material here.] Friday, March 27, 1998. NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES WITNESSES DR. MARVIN CASSMAN, DIRECTOR, NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES DR. W. SUE SHAFER, DEPUTY DIRECTOR, NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES MARTHA PINE, EXECUTIVE OFFICER, NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES G. EARL HODGKINS, FINANCIAL MANAGEMENT OFFICER, NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES DR. HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH BILL BELDON, DIVISION DIRECTOR, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES Mr. Porter. We're very pleased to welcome Dr. Marvin Cassman, the Director of the National Institute of General Medical Sciences. I want to note, and I wish Ms. Pelosi and Ms. Lowey were here, that Dr. Cassman is a Chicagoan, educated at the University of Chicago. Ever since Nancy started this with Dr. Varmus and California, we've gone back and forth. Dr. Cassman, it is wonderful to welcome you again. Why don't you introduce the people on your left and then proceed with your statement, please. Introduction of Witnesses Dr. Cassman. Thank you, Mr. Chairman, and good morning. To my far left is our Executive Officer, Ms. Martha Pine. Next to her is the Deputy Director of the Institute, Dr. Sue Shafer. And to my immediate left is Mr. Earl Hodgkins, our budget officer. Mr. Porter. Just to be further provincial, I will note that Dr. Shafer is from Illinois as well. Opening Statement Dr. Cassman. That's right. There are quite a few of us, even at NIH. The goal of the National Institute of General Medical Sciences is to ensure the continuing productivity of basic biomedical research. This has provided the foundation for many of the really outstanding advances in biomedical sciences. It is difficult to quantify our contributions, but one reflection of how well we've done is that in the roughly 35 years since the Institute was established, we have supported over 60 percent of the American Nobel Laureates in chemistry and in medicine or physiology. But I don't have to go back 30 or 35 years to trace the contributions of the basic research of NIGMS. I want to provide just a few striking scientific advances from this past year. They are all characterized by the fact that they were done in model systems, that is, organisms such as yeast, bacteria and the fruit fly. Nevertheless, even though they were done on these comparatively simple organisms, they shed light on such diverse concerns as Lyme disease, neurodegenerative disorders and cocaine addiction. Now the first example is a study that may lead to a significant therapeutic approach to Lyme disease. It was done in a rather esoteric class of bacterium called the archaeobacteria. These are found in inhospitable environments: the deep ocean floors, hot acidic springs and high salt environments. One of our investigators was interested in the very fundamental question of how these organisms carried out protein synthesis. This is a basic phenomena that is a necessary process in all living organisms. He found, when he examined it carefully, that apparently one of the keycomponents needed for protein synthesis was missing in this bacterium, and he was curious to see how the organism survived without it. Well, when he looked more carefully, it turned out that the component was present, but in a form unrelated to that found in all other bacteria and higher organisms, or almost all. When he looked more carefully at the genomes of the organisms that cause Lyme disease and syphilis, he found that in those pathogens, there exist compounds with similar structures to the material found in the archaeoabacterium, but with quite different structures from those found in humans. This structural difference may be exploited to develop new antibiotics to treat Lyme disease, because you could develop a drug that would selectively address just those organisms without affecting its human host. And I would like to say that parenthetically this is just one illustration of the importance of having genomic sequences of organisms other than humans, something that I think many of us are becoming familiar with. Now, a second example is a discovery in yeast that sheds lights on certain kinds of neurodegenerative disorders in humans. And this sounds inherently unlikely, certainly it couldn't have been predicted. After all, even if a yeast cell did have a form of dementia, how would we know? But the relationship is not in behavior but in the existence of a particle called a prion. Prions are thought to be infectious protein particles that are implicated in the initiation of diseases such as the Mad Cow Disease that we've heard so much about recently. An NIGMS investigator has recently shown that there is a protein in yeast that has many of the same characteristics as the prions found in mammalian brains. For example, the yeast protein generates the same kind of fibers formed by mammalian prions, and those are comparable to those found in autopsies of humans and animals that have died of diseases where prions were implicated. And in the figure to my left, on the left hand side you see the fibrils that are generated by the yeast proteins, and on the right, the long extended fibrils that are formed by mammalian prions. [The information follows:] [Page 2552--The official Committee record contains additional material here.] Dr. Cassman. These studies now provide a model system to investigate an immensely complex problem in a comparatively simple organism, yeast. And they even begin to suggest a new target for potential therapies. Finally, we arrive at the common fruit fly, which is a nuisance to most people, but an invaluable tool to biomedical researchers. One of our investigators has spent many years studying fruit fly genes that are involved in the nervous system and in behavior. In the course of his work, he used volatile or crack cocaine as a tool to stimulate neurological responses in flies. That led him to observe that flies and mammals respond to cocaine in strikingly similar ways. Now, it's very difficult to show you a behavioral response in a static picture, but the image you see over here is a time lapse photograph of the very familiar fruit fly going around in circles. This is a characteristic display of movement patterns that one finds in rodents and primates in response to crack cocaine. [The information follows:] [Page 2554--The official Committee record contains additional material here.] Dr. Cassman. This, along with other behaviors, suggests that the fundamental neuralpathways involved in cocaine response and in the linkage to behavior are retained across species. This now seems to be a very promising model to look at cocaine sensitization, for example. I'd also like to point out that this investigator was one of the first whom we supported through our interim funding mechanism. He resubmitted within a year, he did extremely well in peer review, and he's once again fully supported without having a potentially damaging hiatus in his research, just exactly what we hoped would happen when we initiated the interim funding mechanism. Now it's striking that in all of these examples, health- related applications emerged almost immediately from basic research studies. Of course, I don't want to implythat this is the norm for the research that we support. And yet, it's not so far from the reality of modern biology. The mosaic of scientific research has expanded to the point at which basic research and its applications follow very closely. I'd like to quote a comment made by Louis Pasteur in 1871, who said, ``There does not exist a category of science to which one can give the name `applied science'. There are science and the applications of science bound together as the fruit and the tree which bears it.'' What I hope I have given you are examples of a few such trees and their early fruits. Now, it's clear that the past and the present have produced a bounty of information, important outcomes from basic research that can be applied to the problems of health and disease. I only want to give you a few examples of initiatives that we're planning for the future that I think will be even more exciting. One is an attempt to bring mathematicians, physicists, and engineers into the biological sciences, particularly to look at the question of the analysis of complex systems. This involves the integration and understanding of large numbers of interacting components. A second area that I want to discuss is a new training effort. A new initiative we are planning for the coming year is to enhance traditional post-doctoral training by promoting the development of teaching skills through innovative programs that involve assignments at minority-serving institutions. We feel that this initiative will provide several benefits. First, it will be of particular value to many scientists who, during their graduate careers, become interested in teaching, but have little or no opportunity to develop these skills. We have lots of evidence there are many such individuals out in the community who would like to have the opportunity to learn how to teach, as well as to learn how to do research. The other benefit is that it will provide minority-serving institutions with access to individuals who are on the cutting edge of their disciplines, while relieving scientists at those institutions from some of their teaching burden and allowing them time for research and collaborations. Finally, before I conclude, I want to point out that over the past 25 years NIGMS has been involved in many efforts, such as the one I just discussed, to increase the number of underrepresented minorities involved in biomedical research. I would like to take this opportunity to especially thank Mr. Stokes for his continuing effort and support of these activities. This is just one important part of his legacy on this subcommittee. The proposed Fiscal Year 1999 budget for NIGMS is $1.145 billion--I always have a hard time saying billion, but that's what it is. This is an increase of $79.5 million over Fiscal Year 1998. I would be pleased to answer any questions that you or the committee may have. [The prepared statement follows:] [Pages 2557 - 2564--The official Committee record contains additional material here.] Basic Research at NIH Mr. Porter. Thank you very much, Dr. Cassman. You characterize 100 percent of your work, your grants, as basic research. Is there any way to characterize a breakdown of the other Institutes as basic or disease-specific research. In other words, other Institutes do basic research as well. Do we have a breakdown? Dr. Varmus. We do. Mr. Porter. Where would the next highest concentration come, do you recall? Dr. Varmus. That I would have to look up, but overall, I believe basic is 57 percent overall. Mr. Porter. Of all research done through NIH or its grantees?. Dr. Varmus. That's correct. And then we categorize the rest of it as applied or developmental. Sharing Research Information Mr. Porter. You had the fruit fly chart up there and you talked about the effect of cocaine. Can you describe for us, Dr. Cassman, the mechanism by which you would bring this information, let's say, to Dr. Leshner at NIDA. What structures do you have for doing that? Dr. Cassman. There are really not a lot of formal structures, but there are a great many informal structures. We collaborate very closely with many of the other Institutes, and in fact, there are a number of examples I can give you where grants that began at NIGMS as basic research, as they moved into more directed areas--I won't even call them applied--but more directed areas of research, moved to the appropriate Institute. One very recent example is a research project that looked at the genetic basis of various forms of behavior, a very general project. It wound up having very specific relevance to the National Institute of Mental Health and it's now being supported by the National Institute of Mental Health. So there are a number of ways, including common discussion groups in which we all take part, that allow for exchange of information. Mr. Porter. You don't see a need for more formal structures, then. Dr. Cassman. I don't really think so. I think we actually do a pretty good job, given the diversity of NIH and its size. We interact on a variety of levels, including the individual program people who talk to their counterparts in many different venues. Research using Synchrotrons. Mr. Porter. I read in the budget justification where you plan to provide funds to support and enhance the capabilities of your grantees to utilize shared synchrotrons. Why are you doing this instead of the Center for Research Resources? Isn't this really the job of Dr. Vaitukaitis? Dr. Cassman. We're doing it jointly, as a matter offact. The National Center for Research Resources has specific resources located at various synchrotrons for specific purposes. However, there are broad uses, basic service needs that are more generally required. We also have a few initiatives that we are considering that will require heavy use of synchrotron facilities. For those initiatives in particular, we plan to try to make synchrotron facilities more available. We are working very closely, not only with NCRR, but also with the Department of Energy and the National Science Foundation, to develop integrated schemes for supporting research at synchrotron facilities. High Risk, High Impact Research Mr. Porter. Dr. Cassman, last year, you announced a program to provide support for innovative research proposals that have the potential for highly significant outcomes but involve substantial research risk. You received 100 applications by the first submission deadline. Can you tell us how many were you able to support and give us a few examples of some of these proposals. Dr. Cassman. We are still in the very early stages of that program. I expect that we will be able to support probably 40 applications or thereabouts for perhaps $4 million. These proposals span a very wide range of research, including some very innovative concepts of how cells integrate their behavior through genetic and cellular mechanisms. It's a little early to be able to tell--in fact, it probably won't be for three to five years before we can really tell--how successful this program has been in stimulating truly innovative approaches. Because it's high risk research, I assume there may be a high failure rate. That's the necessary consequence. What I'm hoping is that a significant proportion will provide significant benefits. Research Centers Mr. Porter. You're proposing to establish 12 new specialized research centers in fiscal year 1999. What will be the areas of research in these new centers? Dr. Cassman. We are beginning one specific initiative that I think will use centers. That is an attempt--and again, this is a collaborative effort with other agencies, with the Department of Energy and with the National Science Foundation, in particular--to develop a classification and structure resource of all of the ways that proteins fold, all the ways their separate motifs align themselves, and to try to relate that to function. This will probably be best done through central activities, integrated centers, and a number of these centers are designed for that purpose. Mr. Porter. Thank you, Dr. Cassman. Mr. Stokes. Mr. Stokes. Thank you, Mr. Chairman, and welcome, Dr. Cassman. It's good to see you again, and thank you for your very kind remarks. Dr. Cassman. Thank you, Mr. Stokes. UnderRepresented Minorities in Research Pipeline Mr. Stokes. I appreciate, in your formal statement and also your oral presentation this morning, your reference to underrepresented minorities. You state, in fact, in your formal testimony, that ``we continue our efforts to train tomorrow's scientists and to bring more underrepresented minorities into careers in biomedical research''. Then, you talk about the things that you are doing. I appreciate that very much. Also, in your budget justification, you mention that the Institute plays a vital role in bringing an appropriate number of new investigators, including those from underrepresented groups, into the biomedical research system through both training and research support. Dr. Cassman, what is the condition of the research investigator pipeline and the current workforce of career researchers in general, and particularly as it relates to African-American and other underrepresented minorities? Dr. Cassman. The best indicator of the nature of that pipeline for us, particularly, is Ph.D. production. That's still woefully low, because the level of underrepresented minorities receiving Ph.D.'s in the biomedical sciences is about six percent. And for African-Americans, I believe it's about 2.3 percent. This is nowhere near where we would like to have it. The efforts we are making are designed precisely to affect the pipeline at the levels at which we can influence it, that is, at the graduate school level and in the senior and junior years of undergraduate training. I must say, however, that I think a lot more work has to be done at earlier stages, at the K through 12 level, in order to really produce the kinds of results that we would like to see. Evaluation of National Research Service Award Program Mr. Stokes. I quite agree with you that if we are going to really attack this problem, it has to be attacked early on in the early stages of development. What's the status of the evaluation of the National Research Service Award Program, and what results do you have to report? Dr. Cassman. That's being done for NIH centrally. I think it's pretty well along. I don't know when the report is due, but it's---- Dr. Varmus. It's being carried out in a quadrennial process by the National Research Council. Dr. Howard Hiatt is the chairman of the committee, and we expect a report, I believe, in the fall. Dr. Cassman. But there's also an analysis being done at NIH of outcomes in our NRSA program, and I believe sometime later this summer that report will be completed as well. Funding for Historically Black Colleges and Universities Mr. Stokes. Okay, thank you. Dr. Cassman, I understand that initially Historically Black Colleges and Universities received 86 percent of the Minority Biomedical Research Support Funds. Last year, you reported that they received 40 percent in Fiscal Year 1996. What was the percent in Fiscal Year 1997, and what is the anticipated percent in Fiscal Year 1998? Dr. Cassman. The percentage in 1997 was essentially identical to that in 1996; it was just about 40 percent, in MBRS. Mr. Stokes. Is that right? Dr. Cassman. Yes, in MBRS, in 1998, we hope to have it higher. At the moment, the last data we have is for 1997, and that's still about 40 percent. Mr. Stokes. All right. I am going to ask you to include in the record, if you will for me, a chart that displays the amount and percent of MBRS and MARC funding that the NIGMS provided to Historically Black Colleges and Universities, Hispanic-Serving Institutions and non-HBCU's and non-HSI's, over the last 10 years, if you'll do that for me. Dr. Cassman. Yes, sir. [The information follows:] RECIPIENTS OF MARC AND MBRS FUNDS ---------------------------------------------------------------------------------------------------------------- Historically Black Hispanic Serving Other institutions Colleges Institutions \1\ Fiscal year ----------------------------------------------------------- Funding Percent Funding Percent Funding Percent ---------------------------------------------------------------------------------------------------------------- 1989................................................ $17,191 46.2 $8,302 22.3 $11,707 31.5 1990................................................ 18,516 45.8 7,981 19.7 13,967 34.5 1991................................................ 20,185 45.0 8,741 19.5 15,908 35.5 1992................................................ 20,219 43.3 10,337 22.1 16,148 34.6 1993................................................ 20,076 43.7 8,722 19.0 17,100 37.3 1994................................................ 21,731 43.8 10,905 22.0 16,945 34.2 1995................................................ 23,035 42.8 12,571 23.4 18,152 33.8 1996................................................ 16,961 30.2 12,379 22.0 26,878 47.8 1997................................................ 18,491 32.5 13,498 23.7 24,944 43.8 1998 est............................................ 18,583 31.1 13,566 22.7 27,639 46.2 1999 est............................................ 21,185 30.0 15,465 21.9 33,858 48.0 ---------------------------------------------------------------------------------------------------------------- \1\ The ``Other institutions'' column reflects institutions either that serve Native Americans or Pacific Islanders or that have mixed student populations with significant numbers of underrepresented minorities. research related to lupus Mr. Stokes. As you are aware, lupus affects 500,000 Americans, 90 percent of which are young women and African- American women. As your budget justification indicates, African-American women have a high rate of the disease. It is estimated that one in 250 will get the disease. What major research studies are supported by your Institute that would help to further advances in the study and treatment of lupus? Dr. Cassman. We don't deal significantly with lupus, Mr. Stokes. Mr. Stokes. I understand that NIAMS is the lead institute. However, your budget justification did speak to your Institute's direct involvement. Dr. Varmus. It's mainly NIAMS, and to a lesser extent, NIAID and my Institute, NIGMS. Mr. Stokes. Okay, on another very important matter, last year, the Institute indicated about 40 percent of its past supported trainees have gone on to receive NIH research grants. This percentage is higher than that for others that are preparing for careers in biomedical research. Do we know what percentage of minorities that have been NIH-supported grant trainees have gone on to receive NIH research grants? Dr. Cassman. I don't have that exact number for you. We will try and get that. Mr. Stokes. For the record. Dr. Cassman. For the record. [The information follows:] Unfortunately, it is too early to provide good information on the percentage of minority trainees who go on to receive NIH research grants. NIH has only recently been given approval to begin collecting information on the race/ethnicity of its trainees, and even now, it is provided on a voluntary basis. So, although we do have information on the race/ethnicity of recent trainees, a substantial period of time would be required for these students to achieve positions in which they would be able to apply for and receive NIH research grants. In addition to the time required to complete their graduate training, many will need to complete post-doctoral training, and will then need to secure positions that would allow them to apply for NIH research grants. research on hiv Mr. Stokes. Your Institute has played a role in terms of research relative to AIDS and HIV, am I correct? Dr. Cassman. Yes, sir. Mr. Stokes. And I think especially as it relates to the development of protease inhibitors. Dr. Cassman. We had, I think, a significant role there, yes. Mr. Stokes. Can you tell us what progress has been made by the grantees that are working to determine the structure of potential new targets of HIV drugs and to understand the structural basis of resistance to HIV drugs? Dr. Cassman. Yes, there has been a great deal of progress. Many of the proteins that are involved in the virus's infectivity or in the locations where the virus interacts with the cell have been elucidated or to some degree or another--not all of them, as yet, but very many. Probably the most exciting recent results are the structures of the surface proteins of the virus, which have given some very important clues as to the nature of the residues involved and how the virus links up to the cells and so on. I think those studies will have significant influence. In addition, we continue to support research to develop a detailed understanding of drug interactions with various structural components of the HIV virus. support for marc and mbrs programs Mr. Stokes. Dr. Cassman, last year's House report included language indicating that the Committee expects theInstitute to continue to support the MARC and MBRS programs at levels reflective of their importance. What was the Fiscal Year 1997 and Fiscal Year 1998 funding level for each of these programs? And, tell us what percentage change is reflected in each of these figures. Dr. Cassman. For NIGMS funding the 1997 level was just a bit over $38 million for MBRS. The 1998 appropriation was almost $41 million. For MARC, the increase was smaller, as with most training programs. The only significant increases with all of our training programs was the stipends. It was a small increase in stipends, so the MARC program went up just slightly. I think the stipend increase was about 2.2 percent. But that's, as I say, consistent with all of our training programs. Mr. Stokes. What's the Fiscal Year 1999 estimated funding level? Dr. Cassman. Yes, the Fiscal Year 1999 increase is going to be considerably larger. For MARC, it should increase about nine percent. For MBRS, we expect the increase to be over 20 percent. fellowships funded by more division Mr. Stokes. I understand the NIGMS MORE program awarded 29 new fellowships in 1997. How many of the applicants are there each year, and what percentage are accepted? Dr. Cassman. The total number--you are talking about national predoctoral fellowships or--yes, the MORE, right. Mr. Stokes. It's the More Opportunities in Research, what you call the MORE. Dr. Cassman. Right, it's the national fellowships. The 1997 total numbers were 93. They've been moderately stable at about that level for a while. I'm not sure I know what the success rate is, but I believe it's pretty high, about 50 percent, I would guess, at least on that order. I couldn't give you an exact number for the success rate, but it's a very substantial success rate. Mr. Stokes. You can provide that for the record for us. Dr. Cassman. Sure, yes. [The information follows:] In FY 1997, the NIH success rate for National Predoctoral Fellowships was close to 50%. For NIGMS, the success rate was 87%. Mr. Stokes. I appreciate that. Thank you, Dr. Cassman. Thank you, Mr. Chairman. mstp evaluation Mr. Porter. Thank you, Mr. Stokes. We will have a brief second round if the gentleman from Ohio wishes to ask further questions. Dr. Cassman, at last year's hearing, I asked what information you had on the career outcomes of researchers who've completed the Medical Scientist Training Program. You were in the process of studying the program and hoped to be able to give us a report this year. What can you tell us now? Dr. Cassman. We are not quite finished with the report, but we are pretty far along. This has required accumulating a great deal of information, not only from the MSTP graduates, but if you want to make a reasonable comparison, you need control groups. So we have three separate control groups that we're looking at as comparison. We do have preliminary indications and not surprisingly, the MSTP graduates, by every indicator that we use, do better than any of the control groups, including--to me, somewhat surprisingly--M.D./Ph.D. graduates from the same institutions. So it's really quite impressive. The important piece of information that I can't give you as yet is the nature of their research activity, which is something that we're very interested in--where they're located, and in what kind of departments. I think we know, but not statistically. We have a good idea of what that data is, but we will know in much more detail when all of the data is analyzed. potential initiatives under budget increase Mr. Porter. You are asking for a budget of $1.1 billion. What if, five or six years from now, you had $2.2 billion to work with. Dr. Cassman. I'd be pretty pleased. Mr. Porter. Obviously. [Laughter.] But what would that allow you to do that you can't do now, and since you're not disease-specific, how would thatdiffer from what other Institutes do? Dr. Cassman. Well, I would like to break it down into categories. First, there are a number of initiatives that we have in the works, some we are currently planning, and some that we've already begun. I think that many of those would be able to develop to a much better degree than we could currently hope for at this point. Of course, when you're talking about five years down the road, what I would certainly hope is that there would be many things that we can't now imagine that would be important to support at that time. If that were not true, I would be very distressed. A second area is equipment and facilities. There is no doubt in my mind that over the last decade, for example, the ability of our investigators to carry out state-of-the-art research has diminished because their access to significant pieces of equipment and facilities has not kept up with the opportunities available. We would certainly want to do something about that. A third area is simply to increase the capabilities of existing investigators. We have put a number of constraints on our current supported investigators, limiting the increases in their grants to a point at which they are not fully able to take advantage of all of the opportunities that exist for them. And finally, I think, is the area of training. I think there are some opportunities for expansion, both in dollars and numbers. I'm not talking necessarily about huge expansion, but some. Again, there are constraints that we've put on over the years. One of them Dr. Varmus has already addressed in the Fiscal Year 1999 budget by increasing the stipend levels for students. There are also new areas of research training that we would like to address. One of them I have already alluded to, that is, we would like to bring more mathematicians, physicists, engineers into the system. It isn't only a matter of saying here are the ideas, here is some money, come and get it. You have to break down cultural barriers when you're bringing in people from diverse disciplines. You have to get them to be able to talk to each other, to understand each other. This requires a number of things. We're planning some week-long workshops where fundamental ideas can be explained and understood. But this also requires cross-training at the graduate and post-doctoral levels. So I think all of those areas would be very important and would be impacted significantly. Mr. Porter. Thank you, Dr. Cassman. Mr. Stokes. Mr. Stokes. Mr. Chairman, I may have one or two other questions to put into the record, but I don't have anything additional at this time. Mr. Porter. Dr. Cassman, thank you very much for your testimony this morning and for the excellent job you are doing. It is good to see a fellow Chicagoan over there. Dr. Cassman. Thank you, Mr. Porter. Mr. Porter. We will stand briefly in recess. [The following questions were submitted to be answered for the record:] [Pages 2573 - 2--The official Committee record contains additional material here.] Friday, March 27, 1998. OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH AND BUILDINGS AND FACILITIES WITNESSES DR. HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH DR. RUTH KIRSCHSTEIN, DEPUTY DIRECTOR, NATIONAL INSTITUTES OF HEALTH ANTHONY ITTEILAG, DEPUTY DIRECTOR FOR MANAGEMENT, NATIONAL INSTITUTES OF HEALTH STEPHEN A. FICCA, ASSOCIATE DIRECTOR FOR RESEARCH SERVICES, NATIONAL INSTITUTES OF HEALTH FRANCINE LITTLE, DIRECTOR, OFFICE OF FINANCIAL MANAGEMENT, NATIONAL INSTITUTES OF HEALTH DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES DR. JACK WHITESCARVER, ACTING DIRECTOR, OFFICE OF AIDS RESEARCH BILL BELDON, DIVISION DIRECTOR, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES DR. ANTHONY FAUCI, DIRECTOR, NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES Mr. Porter. The subcommittee will come to order. I've asked Dr. Varmus if we could do one of the portions that we had originally scheduled for this afternoon this morning so that we might be a little bit ahead, because we expect some votes early in the afternoon that will take substantial amounts of time. So we are going to proceed now with the hearing on the budget of the Office of the Director. Dr. Varmus, do you have a presentation? Dr. Varmus. I do. Mr. Porter. Please make your statement, and then we will proceed to questions. Dr. Varmus. Thank you, Mr. Porter. Opening Statement--Director, NIH Let me very briefly review for you some of the major issues that face the Office of the Director. Let me begin by introducing Mr. Itteilag, who is the Deputy Director for Administration; Mr. Steve Ficca, who is the Director for Research Services, and will be here to answer questions about buildings and facilities; Dr. Whitescarver, who is the Acting Director of the Office of AIDS Research; and Dr. Kirschstein, my Deputy Director. The four major functions of the Office of the Director are as follows: management, that is, oversight of grants, intramural programs, and many fiscal information functions; second, policy, which involves a wide range of issues I will mention in a moment, next, oversight of buildings and facilities; and finally, oversight of many research activities, including those that involve transfer authorities, administration of my discretionary funds, as well as a number of coordinating offices, including the Office of AIDS Research, which you'll hear about from Drs. Kirschstein and Whitescarver. The President's budget request for the Office of the Director for FY 1999 is $254.7 million, a 5.4 percent increase. On the opening day of these hearings, we talked about the report of our administrative functions and I don't want to spend time reviewing that now. You'll recall that that report proposed a better relationship between the Office of the Director and the Institutes and Centers, made many recommendations that we're in the process of implementing, and gave us good marks for many things; but it also offered a number of important criticisms that we're trying to respond to. Let me give you a sampling of the policy activities, without going into detail, to give you some sense of the very high level of activity within my office on a variety of issues that affect the conduct of science and our relationship to society. Bioethics has been a major issue on a variety of topics, and recently, we formed a trans-NIH Bioethics Committee that is dealing with issues of privacy, with international standards for conduct of research, and many other issues that are created by innovation in biological science. We've been more involved in science education in areas such as the design of curricular supplements that are being used in a variety of schools, creation of web sites, and bringing interns to the NIH to learn about science issues that can be used in educational settings. We've been more involved in public education, as you yourself have asked us to do. We have more consumer health information on the World Wide Web. We have developed a number of web sites for communication of health to selected populations, and we are giving guidance to our Institutes and Centers with respect to their outreach activities. We have been very instrumental in thinking through issues regarding clinical research and clinical research training, and developing a data base for clinical trials as we're directed to do under the FDA Reform Act. And we've been developing a series of discussions with the managed care industry, and the pharmaceutical industry to try to make more effective our efforts in clinical research and clinical trials. We retain a good deal of supervisory activity in the area of gene therapy. In transitioning from our previous mode of oversight of gene therapy protocols, we have developed a series of gene therapy policy conferences that have beenextremely effective. We've been working with other members of the Department on xenotransplantation and through the National Foundation for Biomedical Research, we've been involved, as we discussed with Dr. Collins, in the development of better methods for educating medical personnel about genetic testing. Let me say a couple of things about buildings and facilities; you can ask further questions of Mr. Ficca. We are continuing construction of the Mark O. Hatfield Clinical Research Center, asking for an additional $90 million to support construction activities in this year. We are nearly on schedule but are a few months behind, partly as a consequence of having to make some design changes in response to the potential cost overrun that I was not prepared to permit. We are now back, certainly on cost schedule, and nearly on time schedule. Mr. Porter, you were present, I am happy to say, at our groundbreaking ceremony in the fall. Construction is going well. We are asking for another $9.1 million to complete construction of a vaccine research center, funds for which were appropriated last year, we are very grateful for these as we discussed earlier, the Center is also being formed intellectually, as well as being planned structurally. I would just mention that we are still on schedule in the construction of so-called building 50 (the Consolidated Laboratory Building), for which funds were appropriated in earlier years; it's important to note that the construction plans are proceeding on schedule and we expect to be occupying that building by the year 2000. A few words about research oversight. There are several research oversight activities that are uniquely mine. One is continued reviews of the intramural programs of the various Institutes and Centers and reviews of the activities of the individual directors, which we now carry out every five years. In addition, I maintain another kind of oversight of research activities that applies to my use of the one percent transfer authority and the expenditure of my discretionary fund. Details of how we have used those monies are available to you, but I do want to make the point that the use of one percent transfer authority has been an extremely useful tool for me in each of the years in which I have had it. We have been transferring $20 million or $30 million each year as a result of a very careful effort to identify initiatives at the beginning of each fiscal year. We bring outside advisors in to make recommendations to me about which of those proposals should actually be supported. Dr. Kirschstein is going to talk in a moment about the various offices in the Office of the OD. I do want to mention specifically two that have attracted special attention. One is the Office of Alternative Medicine, which as a result of activities on my part and the part of Dr. William Harlan, has gotten into a much more productive mode during this past year, with cooperative ventures with the Institutes and Centers to carry out high quality clinical trials of alternative medicines. In addition, we've created a transagency coordinating committee for alternative medicine that involves the FDA, the CDC, and AHCPR, and that has engaged the attention of many of my Institutes and we feel we are working much more collegially and much more productively with the Office of Alternative Medicine. Secondly, we talked several days ago about the Office of AIDS Research and the leadership that has been afforded by Dr. Whitescarver, subsequent to Dr. Paul's departure, and the fact that we will soon enter the final stages of our search process for a new director. Also, we talked previously about the steps we've taken to implement the recommendations of the Levine Report. I will leave it to Dr. Whitescarver to comment briefly about those efforts. At this point, I think it's useful to turn the microphone over to Dr. Kirschstein to hear about the coordinating offices, other than the Office of AIDS Research. [The prepared statement follows:] [Pages 2623 - 2632--The official Committee record contains additional material here.] Office of Research on Minority Health Dr. Kirschstein. The directors of those offices are sitting behind us and if necessary, can provide details. But I would like to use several examples to talk to you about how the program offices coordinate other activities in their particular areas. The first is the Office of Research on Minority Health. It's been deeply involved, not only in NIH studies and programs, but also in the Department's initiative to close the disparity in health between the minority and majority populations. As you know, the initiative has selected six areas: infant mortality, breast and cervical cancer, heart disease and stroke, diabetes, AIDS, and immunization. In the area of infant mortality, NIH, in cooperation with the Health Resources and Services Administration and CDC, will invest in perinatal research to increase the identification of problems that Mr. Stokes was mentioning earlier this morning: risk factors and biological markers for adverse pregnancy outcomes, low birth weight, and preterm births, and for Sudden Infant Death Syndrome among minorities. The NIH will launch a $1.25 million new outreach effort targeted to racial and ethnic communities. It will include new media efforts to reach non-English speaking parents and to reach health professionals who serve primarily minority communities and will better use ethnic radio stations to raise parental awareness of what we know about SIDS. Office of Research on Women's Health In the area of breast and cervical cancer, the National Cancer Institute, along with the Office of Women's Health in the Department, in June of 1998, will host a major meeting on the racial and ethnic issues involved in breast cancer. There will be a breast and cervical cancer education initiative designed to provide clear, user-friendly information and advice to women, particularly minority women. The program has been developed in consultation with black, Hispanic, American Indian, Alaskan Native, Asian and Pacific Islander women to find out what they would like to know. We will put together a hotline for the National Cancer Institute's Cancer Information Service and form numerous other partnerships with community-based entities. heart Disease and Stroke In the heart disease and stroke area, NIH is going to launch a new web site for health care professionals who provide care primarily to black patients. And this will report on new ideas that can be used to decrease blood pressure in hypertensives, decrease cholesterol levels as needed, and increase preventive health behaviors. And there will be a real attempt to put together materials such as cookbooks with recipes that will be attractive to and be available to both African-Americans and Hispanics. Similarly, we have launched, in conjunction with CDC, a National Diabetes Education Program with a public awareness campaign that will be funded at about $1.5 to $2.5 million in the next year. In that regard, Mr. Stokes, I would like, as everybody else has, but on a very personal basis, because you and I have been interacting for 25 years or more, to tell you how much I am going to miss you and to thank you for all you have done to help us with our minority programs and all the other programs. This is a very personal thank-you. Mr. Stokes. Thank you very much. Office of Research on Women's Health Dr. Kirschstein. The Office of Research on Women's Health has just completed its review of what has happened over the five years since the original Hunt Valley Report. And Dr. Pinn and her colleagues put together a series of regional meetings culminating in a Washington meeting. There will be new initiatives as a result of this, in the area of women's health, in the inclusion of women in clinical trials, and also in advancing career development for women scientists, something that both she and I have a great interest in. Office of Behavioral and Social Sciences Research One more example is the Office of Behavioral and Social Sciences Research, which works cooperatively with the Institutes to refine methodologies used in such research, and which has been particularly concerned with issues related to preventing risk-taking behaviors, smoking, lack of exercise, improper diet, and alcohol abuse. These are but three of a number of examples that I could have given you. Thank you very much. [The prepared statement follows:] [Pages 2635 - 2643--The official Committee record contains additional material here.] Mr. Porter. Thank you, Dr. Kirschstein. Dr. Varmus, my staff has just reminded me that we cannot proceed with the entire panel and finish before the hour of 1 o'clock without notice to the minority because people may have questions, particularly for Dr. Whitescarver and yourself. So I'm going to ask if Dr. Whitescarver would hold his statement. And Mr. Ficca, could you withhold your statement until 1 o'clock as well? I'm sorry, I thought perhaps we could go straight through and finish by 1:00 or 1:30. Apparently, we cannot do that. Can you stay after 12:00 briefly? Mr. Ficca. Of course. Mr. Porter. Well, let's see if we can go a little ways into this with you and come back, say, at 1:00, and finish up hopefully before 1:30 because we're expecting a number of votes right about that time. So at this point I think we'll have questions. I'm going to ask Mr. Stokes if he has questions right now to proceed. Women and Minority Programs Mr. Stokes. Thank you very much, Mr. Chairman. Dr. Kirschstein, let me take a moment and personally express my appreciation for your very kind remarks. And, I dowant to say on the public record, that probably over the last 25 years I've worked closer with you than any other director of the National Institutes of Health. And, our interaction goes all the way back to the MARC and MBRS programs many years ago. I think one of the areas in which I have the greatest pride, if we've had any impact at all, has been that particular area that I've seen as a result of some of the things that you've done working with that program. Young minority scientists have done such outstanding work in the field of science. That's just one of the areas in which you have been very, very responsive to my concerns and I want to express to you my appreciation for it. In your statement, you indicate that minorities in all stages of life suffer poorer health and higher rates of premature death than does the majority population. I appreciate the fact that you have taken time to highlight these areas of concern. As the Deputy Director of NIH, do you specifically go about helping to further the work of the Office of Research and Minority Health and the Office of Research on Women's Health in an effort to address these critical health concerns? Dr. Kirschstein. As Deputy Director of NIH, I have worked very closely with Dr. Ruffin and Dr. Pinn in order to enhance the activities of their offices in regard to coordinating activities with the Institutes. And I think we can't stress that too much; that their offices are in place in the Office of the Director to help plan and work with the various individual institutes regarding the diseases and the training programs, about which you heard from Dr. Kasman this morning, that sometimes require a jump start, sometimes further coordination, sometimes the knowledge that one institute is doing something that another institute ought to be involved. The offices can coordinate across institute lines, and also provide some funds that can make things possible that might not have been possible otherwise. I work very closely with both of those programs. Mr. Stokes. Dr. Kirschstein, were you present the morning that we received testimony from the CDC? Dr. Kirschstein. No, sir; I was not. Closing the GAP in Minority Health Mr. Stokes. All right. Well, let me tell you, when they testified here, the agency indicated that the gap in minority health could be closed if an approach is used that is similar to the Nation's concentrated and targeted immunization efforts. My question to you is do you think that this statement could apply to the NIH's efforts with respect to closing the gap in minority health? Dr. Varmus, you may have been here when that statement was made. Dr. Varmus. I was not here, sir. Mr. Stokes. No? Okay. Dr. Kirschstein. Mr. Stokes, I believe the immunization issues is somewhat simpler than closing the gap in the disparities in the health of minority populations and the majority populations. We know what the target is in immunization. We have to get to the school children who should receive the vaccines that are needed and there is a way of directly approaching this through public health methods. I think, first of all, we do not totally understand, yet, all about the diseases that afflict all of the people of the United States, but those that, in particular are of a greater consequence in minorities--hypertension, cardiovascular disease, prostate cancer, et cetera. And, therefore, we have much knowledge, much more basic information, that we must gain. In addition, the ability to have a way of really preventing the risk-taking behaviors that the Office of Behavior and Social Sciences Research is undertaking is very difficult and we need to know more about how to approach that. We need to know how to reach the communities in a very broad way. We need to have minority women who become pregnant go for prenatal care much sooner than they are very often able to do often now. So I think it's a much more complex problem. Mr. Stokes. Let me pose this particular question to either you or Dr. Varmus, or both of you may want to comment. The President has recently taken very specific interest in the disparity in minority health and he has addressed it in his statement to the Nation, and so forth and so on. With the tobacco settlement that's on the horizon, some of the national minority health groups--the National Medical Association and others--have been thinking that perhaps some of the settlement funds should be placed over in such offices as the Office of Research on Minority Health. I wonder if there's been any thought at all given to whether this might be something that NIH would consider? Dr. Varmus. Well, as you know, Mr. Stokes, there has been a tremendous amount of thought given to the question of how that money would be spent and there, of course, is considerable uncertainty about whether the money will actually appear. There have been many formulas for how such money would be provided to the NIH. My own inclination is to side with what the President has done in his current budget. That is to say that, if there are revenues from the tobacco legislation, it would go to the NIH to be distributed to the NIH in accord with its overall direction. I think we run some danger if we start parceling up these anticipated revenues in a narrow way without using our priority-setting to address the concerns that we believe are most important. The President has already identified minority health as a major priority. I would prefer not to try to link that to a repackaging of any money that comes from the tobacco settlement. Dr. Kirschstein. We should add that the NIH has a deep commitment to working with the Department on what is called the race health initiative and Dr. Ruffin's office's and my attention to this is very great. Dr. Varmus. But that is a separate question. We have identified a number of initiatives, some of which you've heard about during the hearings, as extensions of what the President has spoken to. Newly Appointed Advisory Committee Mr. Stokes. I appreciate that response. You tell us also, Dr. Kirschstein, in your opening statement about the advisory committee that will convene its first meeting in April. Dr. Kirschstein. On April 3rd there will be the first meeting of the newly-appointed advisory committee. Dr. Varmus will be present for opening remarks, and I will be there, and Dr. Ruffin will, of course, be there as well. Mr. Stokes. I think that's an important step. Dr. Kirschstein. We agree. Mr. Stokes. Can you give us some idea of the intended objective or goals of this group? Dr. Kirschstein. I think it is to have an outside group which can look at the activities that the office has undertaken not only on its own part, but in conjunction with the various institutes, to learn everything there is about these programs; to assure themselves and us that the quality of these programs is what we all would desire them to be; and to, perhaps, make suggestions about how we can go about doing what we all want, namely, to close the gaps, if you will, and increase the number of minority research scientists in more innovative and better ways. Dr. Varmus. I don't see this as special treatment for the office, Mr. Stokes. It's part of my general philosophy that everything that we do at NIH is very much helped by ongoing advice from extramural scientists and others in the community. violence Mr. Stokes. I appreciate that. Dr. Varmus, as you know, violence is now one of the Nation's most challenging public health problems. It impacts every one of us in every community. We're seeing daily, through the news media, what's happening in our society. I see the bells have gone off and it is nearly time to vote. I would just like to finish my question, Mr. Chairman. Thank you. Tell us, Doctor, what major research and outreach activities are underway or planned by the NIH that are designed to address youth violence in general and minority youth violence in particular? Dr. Varmus. Well, I've been provided with a list of many of the things that are being done. Of course, much of the violence research is conducted by the National Institute of Mental Health, but there are at least four other Institutes that have major portfolios in that area and much of it is coordinated by the Office of Behavioral and Social Science Research and other agencies are involved as well. There is a new initiative conducted by several institutes that addresses, specifically, violence against women, violence within the family, and this too is being coordinated by the Office of Behavioral and Social Science Research. We can provide more detail of these projects for you for the record. Mr. Stokes. Yes, please feel free to expand upon them in the record. Dr. Varmus. We'd be happy to do that. [Pages 2648 - 2649--The official Committee record contains additional material here.] Mr. Stokes. Thank you, Dr. Varmus and Dr. Kirschstein. Thank you, Mr. Chairman. tobacco settlement Mr. Porter. Thank you, Mr. Stokes. Dr. Varmus, I have some titular questions left over from other Institutes and some policy questions, and then I'll save the remainder of my questions on your office and OAR and buildings and facilities for this afternoon. First off, on the issue of a tobacco settlement. There's a lot of action going on, particularly in the Senate, and my question really relates to what input you have to the Administration's policy in this area because it seems to me that the basic proposal is to provide a settlement whereby the tobacco industry can continue with some protection from liability and paying some costs for the past additions to health care costs as a result of tobacco use plus some protections regarding the use of tobacco by minors. There are many people in this country, and I count myself among them, that believe that this entire industry has forfeited any right to exist because it has engaged in a clear conspiracy to addict our children; to undermine our health when they knew very well what the effects of tobacco were on health; and that we should not, in fact, have a tobacco settlement. We should allow them to be picked apart by the lawyers and the Attorney's General and pay the price that they should pay for what they have done to the health of the American people--recognizing that there was a period when they didn't know, but also recognizing there's been a period where they knew all of these things. What impact do you have on the President and his policy in this area, if any, and what advice have you given him? Dr. Varmus. Well over two years ago, Dr. Klausner and I wrote a letter to the President describing the effects of tobacco use on health. I can't measure the impact of that letter, but I think it certainly was in accord with the views of many others of his advisors. Since then, most of our conversations with the administration about policy toward tobacco legislation has been conducted within the Department. The role of the NIH has been mainly to provide information about the effects of tobacco on health; about the kinds of research that are done in the tobacco arena; and perhaps most especially, in light of today's discussion, about what we view as beneficial to NIH in health research that would be part of any tobacco legislation. The position that I have taken and that has been outlined in the letter I wrote to Senator Jeffords, which we could make available to you, is that we strongly endorse the President's position that if money is made available to NIH through tobacco legislation, it should be basically a block grant to the NIH that we wouldthen divide among the institutes in accord with what we see as ongoing priorities for health research. We think it's a mistake to try to set boundaries between what is tobacco-related and not tobacco-related research, or even worse, to try to specify in advance how much money should go to certain programs or to certain Institutes because the money comes from tobacco. Mr. Porter. I have to say, I've told the Speaker very directly--and some think this Republican heresy--but I've told him very directly I would support tomorrow, with nothing attached to it whatsoever, a substantial increase in the tobacco tax so that we could afford some of the things that the President has mentioned in his budget, particularly additional support for NIH. I doubt that that is going to occur, but it seems to me that that makes a great deal of sense both in light of the burdens that tobacco and its use have placed upon our society, the health care costs attached to it, and the need to prevent young people from getting access to it easily. So I hope, in fact, that we don't go to a tobacco settlement, and we go straight to an increase in the tobacco tax. I think that makes a lot more sense then to take people off the hook for things that they knew were wrong when they did them. Let me ask you another question. Tell me about your concern for the affect on our academic medical centers of the changes occurring in our health care delivery system, particularly the managed care component and their desire to cut costs and not use the services that have been available to our teaching hospitals? Dr. Varmus. Mr. Porter, as you know, we've discussed this problem before. There have been various attempts to estimate the loss of patient care revenues to academic health centers from the NIH perspective because many of those revenues have been devoted, in the past, to research, to research training, and to general sustenance of an environment in which much of our research is done. We can't simply make up that differential, but we can do things to try strengthen the ability of academic health centers to conduct research, particularly clinical research. Some of the initiatives we've announced this year as part of the 1999 presidential budget request are intended to repair some of the damage that's been done by this change in patient care reimbursement. I think most obvious is the effort we're making to train clinical researchers through the new programs I've described earlier to provide early-and mid-career awards for investigators who would now otherwise be imperiled by the directive to spend more of their time doing clinical work to generate revenues for their institution. In addition, we are taking a more active role in the development of clinical trials and the general sustenance of clinical research in a variety of ways. So I think that's going to be the way in which we approach this--by being sure the clinical investigators are given a chance to be recruited and trained and sustained, and by being sure that our clinical research portfolio is diverse. chronic fatigue syndrome Mr. Porter. Finally, for these catchall questions, there is some concern within the CFIDS community that research in this area is decreasing. Can you tell us what's happening and what progress you are making in CFIDS research? Dr. Varmus. I'll probably have to provide details for the record. I do have some numbers here indicating that we--we spend about $7 to $8 million a year. Those numbers have not shown any appreciable increase. We estimate $8 million in research activity in 1999, as well as in 1998. This has been a difficult problem for medical research because the syndrome has not been very precisely defined. We don't have a cause. There are, as the numbers suggest, perhaps a dozen or two dozen investigators working on the problem. There have been many claims for infectious and immunological causes for the disorder, and the NIAID has been devoting efforts to try to define this syndrome more precisely. My own view is that until a cause is found, it is going to be difficult to try to solve the problem. It remains a syndrome that's still somewhat vague in its characteristics. Mr. Porter. Wouldn't additional available funding help to find the cause? Dr. Varmus. I think that's hard to say. Many leads are being pursued. I think the opportunities become much more clear and the mode of address to the problem becomes a good deal more apparent once something has been identified. Whenever we receive a proposal to make a legitimate stab at finding a cause of a new disease, then that grant would be supported. I can try to supply through NIAID a more detailed response to the question of whether there are leads that are not being appropriately pursued. Mr. Porter. I'm sorry to spring this question on you. It is simply one that was left over that I wanted to ask and couldn't ask at the time. Thank you very much, Dr. Varmus. We stand in recess until 1:00 p.m. [Recess.] [The following questions were submitted to be answered for the record:] [Pages 2653 - 2854--The official Committee record contains additional material here.] Friday, March 27, 1998. OFFICE OF AIDS RESEARCH WITNESSES DR. HAROLD VARMUS, DIRECTOR, NATIONAL INSTITUTES OF HEALTH DR. RUTH KIRSCHSTEIN, DEPUTY DIRECTOR, NATIONAL INSTITUTES OF HEALTH ANTHONY ITTEILAG, DEPUTY DIRECTOR FOR MANAGEMENT, NATIONAL INSTITUTES OF HEALTH STEPHEN A. FICCA, ASSOCIATE DIRECTOR FOR RESEARCH SERVICES, NATIONAL INSTITUTES OF HEALTH DENNIS P. WILLIAMS, DEPUTY ASSISTANT SECRETARY, BUDGET, DEPARTMENT OF HEALTH AND HUMAN SERVICES DR. JACK WHITESCARVER, ACTING DIRECTOR, OFFICE OF AIDS RESEARCH DR. ANTHONY FAUCI, DIRECTOR, NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES Mr. Porter. The subcommittee will come to order. Dr. Varmus, we understand that the votes will begin at precisely 17 minutes after the hour and will last---- Dr. Varmus. I didn't know the Congress operated with such precision, Mr. Porter. Mr. Porter. Yes. They'll last perhaps, close to an hour, which is not good news at all. I suggest that when the bells ring, we go the extra 5 or 6 minutes and then we'll recess. It's probably reasonable to plan on 45 minutes. People can take a break and then we'll come back and finish. Is that acceptable? Dr. Varmus. Whatever you say. Opening Statement--Acting Director OAR Mr. Porter. Why don't we go ahead with Dr. Whitescarver's statement first, and then go to questions. Dr. Whitescarver. Thank you, Mr. Chairman. My message this afternoon is a simple one. AIDS is not over. In the battle against the pandemic, it's the best of times and the worst of times. With new combination therapies, protease inhibitors and other antiretroviral drugs, death rates, infection rates, and hospitalizations are declining in many U.S. populations. We've dramatically reduced the number of infants born with HIV. Mr. Chairman, these drugs are not the silver bullet. We do not know how long their benefit will last, or if the immune function can be restored. And whereas the drugs have been effective for many people, there are others who simply can't tolerate the side-effects. We're now identifying adverse metabolic effects that may be the result of long-term use of these therapies. And drug resistant HIV is a very dangerous reality. AIDS cases continue to rise among women and minorities in our country. And AIDS is also increasing in another group-- people over 50 years of age. The news around the world is far worse. WHO now estimates that 2.3 million people died of AIDS last year, which is a 50 percent increase over 1996. And more than 30 million people worldwide are living with HIV, with 16,000 new infections each day. And most of them in the world's poorest nations. Thus we face two great disparities: the disparity that exists among different populations within our own country, and the even greater disparity between the industrialized and the developing worlds. The NIH AIDS comprehensive research plan which is developed each year with the advice of non-Government and other experts, addresses these dualities. It balances the need for new and better therapies with the global imperative for a safe and effective vaccine. The plan is utilized each year by the institutes to develop their budget request. And it also continues to implement the recommendations and the priorities in the Levine report. Key among these recommendations was vaccine research, which is echoed by a specific challenge from the President. This budget request reflects an unprecedented commitment to this critical area of research. And the NIH has already taken a number of important steps to move the science forward: Dr. Baltimore's committee is established and working; the innovation grants; and the new Vaccine Research Center, which we'll hear a little bit about. We also have the OAR prevention science working group that has met on a regular basis and given recommendations for other priority areas of prevention research. NIH programs are pursuing their search for newer and more effective and less expensive drugs with increased potency, less complicated treatment regimens, and fewer toxic side-effects. And also the clinical trials for AIDS reflect a shift in demographics of the epidemic with increasing numbers of minorities and women being enrolled. I firmly believe that the steps taken by the OAR, along with the NIH institutes over the past few years, and the progress that's been made in this area of research, demonstrate that the Nation's investment is indeed well spent. That investment is also reaping rewards in our ability to understand and treat other infectious, malignant, neurologic, autoimmune, and metabolic diseases. But I say again, Mr. Chairman, the battle is far from over. But we do certainly appreciate the support that this committee has given for AIDS research. [The prepared statement follows:] [Pages 2857 - 2862--The official Committee record contains additional material here.] clinical research capacity Mr. Porter. Thank you, Dr. Whitescarver. Let me first ask two questions of Mr. Ficca. Can you update us on the cost estimates to renovate the existing clinical research center building so that it can be brought into conformance with modern design stipulations? Mr. Ficca. The Marks-Cassell report recommended, and the NIH has been following a plan, that upon occupancy of the new CRC, the vacated spaces in the existing clinical center--that is the core E and F wings would be used to carry out a phased renovation of that facility. A specific plan is not yet developed. There is a concept of a phased renovation that would entail renovating first the E and F center wings upon their vacancy, and then one distal wing which would be to the west and then to the east. That total plan would probably take about 12 years after it's started. And the cost estimates would vary, but it is anticipated that the annual amounts would range from $30 million to $50 million per year. Mr. Porter. For 12 years? Mr. Ficca. There is no specific cost estimate. That's strictly based on the number of square feet and the unit cost that might be required to do that renovation. Mr. Porter. How does that compare with the cost of the entire new clinical center? Mr. Ficca. The CRC budget, as you know, including the design, is $333 million. Mr. Porter. So this actually could be more than that? Mr. Ficca. Well, it would be if it were to be completed over that time frame. But as I said, the specific plans have yet to be developed. Mr. Porter. What would be the first fiscal year where you would have outlays? In other words, when would you complete the building--and assuming you had a plan, then begin the renovation? Mr. Ficca. At this juncture, the concept entails beginning in the year 2002. vaccine research center Mr. Porter. Of the $9.1 million requested for the completion of the vaccine facility, $3 million is being requested from the Buildings and Facilities account, and $6.1 million is being requested from the Office of AIDS Research. Why aren't you proposing to fund the full amount from the buildings and facilities account? Dr. Varmus. Perhaps I should answer that Mr. Porter. The reason is that we consider the vaccine research lab to be directed, ultimately, to more than just AIDS vaccine. We expect to use the vaccine technologies we're developing there to address a number of other important vaccine problems, including tuberculosis and malaria. Mr. Porter. But aren't you answering it the other way around. Because if that's the case, why isn't all the money taken from buildings and facilities? Dr. Varmus. Oh, I'm sorry. [Laughter.] Because we feel that the first thrust here, the major thrust--usually the question is asked the other way--but the major thrust here will be AIDS. Mr. Porter. And that justifies taking the money out of the OAR account. Dr. Varmus. Correct. consolidated aids appropriation Mr. Porter. Dr. Whitescarver, I know you are contemplating, or anticipating, this question and I don't want to disappoint you. Your budget again, proposes a consolidated appropriation for the Office of AIDS Research. I know you are obliged to support the President's request, but can you tell me if the approach we have used in the past few years for AIDS funding was workable, and if there are any differences between the approach we're using now and the one that we have used earlier? Dr. Whitescarver. Thank you, Mr. Chairman. Indeed I was anticipating that question. I might refer back to Dr. Fauci's answer, when as an institute director you directed that question to him, and his response that the way things are going now is working very well. The ideal situation would be a single appropriation. But to specifically answer your question: it is working well. I think it's important as this committee has provided us the opportunity to make any shifts across the institutes according to scientific priorities or changes in the scientific opportunities up through the time of conference, with both the Director of OAR and the Director of NIH making those decisions. hiv/aids affected populations Mr. Porter. Dr. Whitescarver, a great deal of progress has brought about a longer and better quality of life for many HIV- infected individuals. In fact, AIDS deaths have dropped 44 percent from the first 6 months of 1997 compared to the first six months of 1996 and new AIDS diagnosis have declined by 12 percent during the same period. However, are there demographic groups that are not sharing in this positive trend, or does it go across all demographic groups? Dr. Whitescarver. No, there are groups within the U.S. population among whom instead of decreases, in fact, there are increases and that's in the minority groups--Black, Hispanics-- and also among women. Both of those are increasing. Mr. Porter. How do we account for that? How do we account for that difference? Dr. Whitescarver. Probably due to the disparity of access to treatment amongst those, as well as the incidence of IV drug abuse. Mr. Porter. What can we do to improve those numbers? Dr. Whitescarver. We have to work harder in getting the behavioral models that are specifically directed to those populations, and continue our efforts, which we've been very successful with thus far, in recruiting these populations into clinical trials. inexpensive drug therapies Mr. Porter. Dr. Whitescarver, researchers in Los Angeles and Washington have identified what may be the first inexpensive AIDS drug. The drug is inexpensive, no more than $30 per month, compared to the $1,300 monthly cost for protease inhibitors. Clinical trials are due to begin later this year. How long do you believe it will take before this drug may be made available to AIDS patients? Dr. Whitescarver. May I refer that question to Dr. Fauci, please, as he's the expert on treatment issues? Mr. Porter. Surely. Dr. Fauci. Are you referring to hydroxyurea? Mr. Porter. I think so, yes. Dr. Fauci. Mr. Chairman, the information that you are referring to is a preliminary study that was presented at two meetings--one in Chicago and one at the last International Congress--indicating that when hydroxyurea, which is already approved for chronic myelogenous leukemia, as well as sickle cell anemia and is a rather inexpensive drug, actually has an important effect on decreasing certain substances within the cell that actually is necessary for the replication of the virus. The reason it's important is because the virus cannot develop resistance to that because of the fact thatyour effect is on the cell. The clinical trials are necessary because some anecdotal reports originally from here in the United States and then some reports from Germany have shown that individuals that take hydroxyurea together with the drug DDI have a decrease in viral burden. In fact, if you look at the cells of these individuals, they seem to have much less of a reservoir of HIV. Given that result, these drugs are now being tested in NIH-supported clinical trials. If it proves to be effective, then certainly the company would ask for approval by the FDA to use and advertise for HIV. So we're optimistic about the concept, but as is always the case, the proof of the pudding is going to be in the clinical trial. Origin of the HIV/AIDS Virus Mr. Porter. Thank you, Dr. Fauci. Last month it was reported, and Dr. Fauci you may want to answer this one as well, last month it was reported that researchers have identified the AIDS virus in a blood sample drawn in 1959 from a man, in what was then the Belgian Congo, making it the oldest definite case of the infection in a human being. Can this discovery help us establish a more precise time frame for when AIDS began? Can this information help us better understand how AIDS and other emerging infections behave over time? Dr. Fauci. The answer is yes, but what it has been, Mr. Chairman, is that these dates of about earlier than 1959, namely the late 40s and early 50s, were actually projected by what we call phylogenetic trees. When you look at the virus itself, and you determine what you can determine, the mutation rate--if you look at a virus that you isolate in 1980 and look at a virus that you isolate in 1998, you can actually map out these phylogenetic trees. The virus that was isolated in 1959 gave investigators a very good anchor of knowing about when it made the jump from a non-human primate and adapted itself to humans. So the fact that we know that this probably occurred, if you back calculate, somewhere in the late-40s early-50s, which interestingly, was what was projected from the modelers a few years ago, even before we had that sample. In answer directly to your question, it does give us now a broader more comprehensive look of the rate of change of the virus so it will tell us more definitively, even though we were on the right track anyway, where we're going to be if the virus keeps changing in the year 2000, 2100, 2200 because the phylogenetic map, as we call it, is now more complete because you have more of an accurate assessment of the source point. So it is important information of historical interest. Mr. Porter. The map that you referred to, is it ever complete? You kind of indicated it keeps changing. Dr. Fauci. No, well, actually the map keeps changing as the different branches of the tree go out. But when you know what the source point is, you have a much more accurate historical perspective of where it started from. So right now, the information we have now, as we see mutations and greater diversity occur over the next 5, 10, 15 years, you will just see more branches on that tree. Mr. Porter. Is this true for all viruses or just this one type of virus? Dr. Fauci. It's more true of HIV because of its extraordinary ability to mutate. If you look at the less mutable viruses, the ones that generally stay conserved over generations, you'll see some divergence but nothing like the type of divergence you see with a retrovirus, which has a very poor ability to replicate itself in an exact replication of what it was before--we call it poor proofreading of the genetic code. Mr. Porter. Ms. Pelosi. Ms. Pelosi. Thank you, Mr. Chairman. As fate would have it, we're here. Mr. Porter. I was actually going to complete the hearing by about this time by going straight through the lunch hour and then we decided that wouldn't be fair because you might not be here. Ms. Pelosi. Oh, aren't you nice. Mr. Porter. So we put it over so you could be here. Long-Term Nonprogressors Ms. Pelosi. As always, thank you, Mr. Chairman, for your graciousness and your leadership on this issue, and your recognition of how important this is to our community, and really, obviously, to our country as well. I know that the chairman has asked some very important questions on this issue, and in the interest of time--probably we'll have a vote--I may submit some of my questions for the record. But I wanted to join you in welcoming Dr. Whitescarver today, and Dr. Fauci, and Dr. Varmus, and Dr. Kirschstein, and everyone once again. Specifically, to OAR, and maybe you all would chime in on it, Dr. Levy at UCSF has announced that the study of people with HIV who are not progressing to disease may help us develop a vaccine for AIDS. I'm sure you're familiar with his announcement. There are these people who have had scores of exposures and have still not contracted HIV. Do you think that can tell us more that is useful in research? Can you tell us more about the evidence on nonprogresses and the implications for vaccine research? Dr. Fauci. What Dr. Levy was referring to was what as you said, long-term nonprogressors. For many years, Dr. Levy has been working on a factor that's secreted by a certain type of lymphocyte called CD-8 positive T-cell. He clearly was the first to identify it. Subsequent to that, a number of other factors that are made by this particular cell have been shown to be potent blockers of the binding of HIV to its cell--they are called chemokines. What Jay is dealing with is something that's above and beyond that; it's not that; it's a substance that he has not yet isolated to the point of being able to molecularly characterize it. The interesting thing that he found is that the CD-8 cells of these long-term nonprogressors secrete a large amount, disproportionately, of this suppressor substance that he calls a CD-8 suppressor substance. The point that he made at the meeting in San Francisco last week and that was reported in the press, is that if you can immunize individuals and induce CD-8s, when they recognize the virus as it gets into an individual initially--namely when you vaccinate somebody--that the CD-8 cell will recognize the virus and start secreting this suppressor substance and so block the ability of the virus to take hold and hence be an effective vaccine. It's an interesting thing because it diverges a little bit from classical immunology, which is a highly specific phenomenon of blocking a microbe. What he's talking about is something that is specific in its ability to be induced, but nonspecific in its ability to suppress the virus. So it's an interesting concept that he's closing in on. Ms. Pelosi. Well, what I reread in preparation fortoday, when I reread the press on Dr. Levy's announcement, I was reading it in light of your presentation last week. It was very interesting. Of course, the issue of a vaccine is one that we're all very hopeful and optimistic about. Vaccine Research Center Dr. Whitescarver, or any of our guests, last year, the President announced the creation of a new vaccine research center at NIH to focus on HIV and other vaccines, can you bring us up to date on where we're going on that? Have we appointed a new director yet? Dr. Varmus. If I can comment briefly, Ms. Pelosi? We are still in the search process for a new director. However, the center is working as a center-without-walls. There are biweekly meetings; outside speakers are brought in. Those who are involved in vaccine activities on the NIH campus are interacting with Dr. Baltimore's outside advisory group. The construction plans, for which we already have about two-thirds of the funds from last year's appropriation bill, are in progress. We have designed the building, and we expect to have the building completed in about 2000. Ms. Pelosi. So we could infer from your remarks that the work of the vaccine center is complementing the work of NIH and the development of an AIDS vaccine. You're working---- Dr. Varmus. We think that we are as far along as we could be. I would like to have a director for the center. I don't have one ready to name. The search process is still ongoing. International AIDS Activities Ms. Pelosi. I want to just throw out two words. One is: international, and the other is: women. And whatever you said, I'd like you to say in light of those two things. I have a big long question, but I'm just going to cut to the chase to Dr. Whitescarver. Is there a formalized process in your office to share information and engage in joint planning on global AIDS activities? How does the OAR coordinate its research agenda and prevention efforts with other agencies in the U.S. Government in recognition of the great international threat that AIDS poses? Dr. Whitescarver. The OAR serves as a coordinating body on behalf of the Institutes, but the actual coordination efforts are handled almost at a program--or right down to the program level--in the various institutes. We do work with the CDC and other sister agencies on our international efforts, notably amongst that is the NIAID effort of the HIVNET and linked with that are some behavioral studies supported by the drug abuse institute and the National Institute of Mental Health. HIV in Women Ms. Pelosi. Women? Dr. Whitescarver. Virtually the same holds true of women. We have studies in, again, the NIAID, an interagency women's health study, that includes other agencies like the CDC, and multiple institutes at the NIH. Ms. Pelosi. Do you work with the Office of Research on Women's Health? Dr. Whitescarver. Yes, we work very closely with Dr. Pinn's office on our research programs in planning and coordinating, as well as outreach activity. Ms. Pelosi. And including women in research? Dr. Whitescarver. Correct. Ms. Pelosi. Now, in terms of women and microbicides: in the United States, women represent, as you know, an increasing share of people with AIDS, unfortunately, and the latest estimates from the World Health Organization are that 40 percent of new adult infections in the world occur in women. What is the status of research being performed through the Office of AIDS Research on STD and HIV prevention? When can we hope to have a proven microbicide, a proven, effective microbicide to prevent HIV, and what have you done to assure the availability of such a product in the developing world, where it's desperately needed? Dr. Whitescarver. The planning effort for microbicides specifically and STD in general, both treatment and prevention, is coordinated by the OAR's Prevention Science Working Group, newly established and chaired by Dr. James Curran, formerly of the CDC. The specific answer to the question of the likelihood and when of the microbicide, there are several trials ongoing now, including international sites, that are managed by the NIAID, and maybe Dr. Fauci might have a specific---- Dr. Fauci. There are about two or three trials that are ongoing now. The most likely candidate is Nonoxynol 9, as an anti-HIV, which is a spermatocide that is used. One of the difficulties, that I mentioned during our hearing, is still we're not satisfied with our ability to avoid inflammatory response when they're used. So there's the possibility that women who use the topical microbicide, that they will have a dual effect, one of blocking HIV and other STDs, but the other in increasing vaginal and cervical inflammation which might actually propagate transmissibility. So that's still an obstacle that needs to be overcome, and what they're doing right now on animal models. It has been an interesting animal model of transplanting vaginal tissue and looking at different compounds, and different bases that you put the compound in, to see if you can get a noninflammatory response while you maintain the antimicrobial activity. So, I'm optimistic that it's going to happen. But it's something that, unfortunately, we've been inhibited by this inflammatory response that continually occurs when you apply these spermatocidal gels. Ms. Pelosi. So the challenge is still the same in that regard? Dr. Fauci. Yes. Dr. Whitescarver. May I just add a word to that insofar as the responsibility of the OAR is concerned. As you know, we have these coordinating committees which are made up of Institute representatives, and microbicides happens to fall within the purview of several of these coordinating committees. When they all come together, as a planning group, to establish the plan, and then the plan goes back to the Institutes to develop their specific projects, we play a very major role in behavioral research. In addition to the prevention science working group I've already mentioned, natural history and epidemiology, and the therapeutics group, all have an interest in microbicides and other treatments for women. Ms. Pelosi. Thank you. How are we doing on time, Mr. Chairman? Mr. Porter. We're a--I didn't keep track. [Laughter.] HIV Therapies Ms. Pelosi. Oh, okay. I like it, I like it. We have you all to ourselves. Dr. Whitescarver, you mentioned in your opening statement efforts to develop drug combinations which are easier for people to take and can improve adherence to a therapy. Can you give us an idea of how therapies for HIV are likely to change over the coming year, in terms of the new drugs, andthe complexities of drugs that you mentioned? Dr. Whitescarver. I can begin the answer on that, and then Dr. Varmus and Dr. Fauci may have some specifics to add to it. The OAR just sponsored, in conjunction with several of the Institutes, an adherence conference which addressed the problems with the advent of the combination therapies and the problem associated with the complexities of taking these drugs, and the regimens. The recommendations from that conference will soon be out, and we will be distributing those for future research planning efforts. Now, some of the pharmaceutical companies have already come along with their second generation and third generation of drugs, which offer less complexities to the patient. Instead of four or five times a day, there are one or two drugs now that can be taken twice a day, as I recall. Dr. Fauci. A couple of things have happened. The companies are now putting a major effort, in addition to developing new drugs, to developing drugs that can be taken in combination. For example, there's one Glaxo Wellcome now has an administration that's a combination of the Zidovudine and Lamivudine, called Combovir. So you take one tablet and it's just like taking AZT and 3TC together. The other even more important one is drugs that have a longer half-life and a better tissue distribution. So that instead of having to take the total of 28 to 35 tablets and capsules a day, you can maybe take one in the morning. There's one particular drug that is at the stage that it only has a number, it doesn't have a name yet, that you can actually take it once in the morning. It has a greater than 12 hour half-life, which means you could probably just take one a day, which would be wonderful. It doesn't have to be taken in association with meals and drinking, so it doesn't disrupt the eating habits of an individual. If we can get four or five of those over the next couple of years, then I think we would have made a major advance towards getting people to be more compliant, and make it more user friendly. Ms. Pelosi. That's very exciting. Dr. Fauci. Yes. youth and hiv Ms. Pelosi. Because obviously part of the problem is to reach people and to have them comply with a routine. I did want to ask one more question about youth and HIV, following up on the America Agenda Report, Youth and HIV, can you bring us up to date on your Institutes' involvement in addressing the concerns raised in the American Agenda Report? When I say your Institute, I mean, the question is really addressed to Dr. Whitescarver, but I throw it out there to the National Institutes of Health. In our community, the emerging advocacy groups, continues to be young people They are emerging an even stronger voice, and they want a seat a the table. And I just wondered, your report states that, ``While NIH has opened pediatric clinical trials to adolescents up to 18, and the adult trials to those who are as young as 13, adolescents continue to face barriers in their participation to clinical trials. Basic research on adolescent reproductive and immune system development is lacking. Additional studies are needed to understand the natural history of HIV in adolescents, as well as expanded study of youth and their behaviors.'' That you may respond for the record, if you would? Dr. Fauci. Well, actually the National Institute of Child Health and Human Development has a major effort in that in looking at, as you eluded to, our clinical trials efforts. Unfortunately, in the past the adolescent has been that sub- population that has sort of slipped between the cracks. Not that we were not trying to outreach to them, but because they, no one knew, no one was responsible for them. They didn't classically get into the pediatrics because many of them were runaways, and people who didn't have access, and yet they were not part of the adult establishment. But right now, as of at least a couple of years, that's been very heavily addressed by all the Institutes, NIAID, as well as Child Health. The NICHD has played a major role in trying to delineate the behavioral determinants that will allow us to better access those individuals. Dr. Varmus. The NIH, Ms. Pelosi, has just put together a position paper on the inclusion of pediatric patients in clinical trials. That would apply, of course, more generally to the problems we deal with, not simply AIDS. Ms. Pelosi. Well, I appreciate that, and our, again in our, speaking from the experience in our community, I meet with these young people and to talk about, well, AIDS is a very big issue for them, and they will give me the benefit of their experience in terms of what's out there in the community, and then I'll find out that they're 15 years old. And, I think, I hope, you know, I'm thinking of them as 18, 19, 20, and then I'll say, ``Well, now how old are you?'' Fifteen, 16, 15, 16, so they are, they fall into the category of pediatrics, but some of the behavior is very adult, and the challenge is great. And they know more about it than we ever could because they're living it. Thank you, Mr. Chairman. I want to thank everyone for this presentation. I'm particularly interested in the Office of AIDS Research, and I'm so delighted to see that this has all worked out, and everyone is, every Institute is reaching its fulfillment, and the Office of AIDS Research is able to do its job effectively. And I commend Dr. Varmus for his leadership on that, and Dr. Fauci for his cooperation on that. I thank you all for your testimony today. Thank you, too, Dr. Kirschstein, Dr. Whitescarver. Thank you, Mr. Chairman. arthur andersen study Mr. Porter. Thank you, Ms. Pelosi. Let me advise the panel that we will have a 15 minute vote, a 5 vote and a vote on final passage, so I would judge that we would not be back here before 2:00 at the earliest. The subcommittee will stand in recess pending the votes. [Recess.] The subcommittee will come to order. Dr. Varmus, you talked in your opening remarks about the Arthur Andersen study, and the question I want to ask is, are there going to be follow-up reviews by Arthur Andersen to monitor your implementation process? In other words, do you plan to use them to assess what you're doing, and make certain you're following the recommendations? Dr. Varmus. We haven't contracted for that activity yet, but we are considering doing that, or having Jack Mahoney, who has been helping with the study as an intermediary with Arthur Andersen, help with that. We have established a panel of Institute directors, and other high-level executives to carry out an implementation plan, and I think the directions that were given to us by Arthur Andersen are clear enough that we can follow themand make some judgments ourselves about how we're doing. But we have given thought to having a more specific review of the implementation at some future date. Mr. Porter. Quoting from their report, they said, ``Identifying and tracking costs and benefits by core function would better enable NIH to assess the costs and benefits of its basic functions, and better portray to Congress the full range of NIH activities.'' How do you plan to implement that particular suggestion? Dr. Varmus. That's a part of the plan that we're not so enthusiastic about. Mr. Itteilag has given a lot of thought to this issue and might want to respond briefly to summarize some of the concerns we've had about that part of the plan. Mr. Itteilag. The concern, Mr. Chairman, is that if we were to carry out what we believe to be the intent of the Andersen recommendation, it would give us much less flexibility in managing our administrative costs within the categories of extramural research, intramural research, and general administration, and it would put us in the position, potentially, of having more re-programming actions, and not having what we think is as smooth of an operation with the needed flexibility to be able to change during the fiscal year. Dr. Varmus. I thought I would emphasize here that this is the only major recommendation that was provided by Arthur Andersen that we disagree with. complementary and alternative medicine Mr. Porter. Well, I'm not proposing that you should necessarily agree with all their recommendations by any means. They come in from outside and don't necessarily understand all the implications of some of their suggestions, but I just wondered about that particular one. A recent survey of complementary and alternative medicine, called CAM, in the United States, appeared in the New England Journal of Medicine, and estimated that 65 million Americans used complementary and alternative medicine to treat a serious condition in 1990 at a cost of $13.7 billion. Regional surveys indicate that millions of children are treated with CAM therapies. Last year, the Appropriations Committee provided $20 million to the Office of Alternative Medicine, and specified that not less than $7 million should be used for peer-reviewed complementary and alternative medicine research grants and contracts that respond to program announcements, and requests for proposals issued by the Office of Alternative Medicine. Can you tell us what kinds of grants and contracts were funded with this $7 million? Dr. Varmus. We have followed those directives and we have initiated as you've heard in some detail, a study of St. John's Wort. In addition, we will fund a chiropractic center in the State of Iowa, and there's a study of acupuncture and its role in osteo-arthritis that will be funded jointly with NIAMS. Also, a trial of glucosamine in osteo-arthritis is also in the planning stage. These have not yet been funded, but they will be funded soon. Mr. Porter. Do you believe that this is a good use of the money, and should we be spending more in this area, Dr. Varmus? Dr. Varmus. We have had an increased budget for the OAM, and I believe that now we do have things on a better track. As I mentioned earlier in my testimony, we developed a trans- agency advisory group that will meet intermittently to look for frequently used, promising therapies that will be then subject to further evaluation by William Harlan, the director of the Office for Disease Prevention, and by the OAM to make determinations in conjunction with the Institutes of what should be subjected to a careful clinical trial. I pulled together the Institute directors that have special interests in the areas of alternative and complementary medicine. That, of course, is virtually all of our Institutes that do clinical research. I asked them to try to identify targets. That's been done by the Cancer Institute, Mental Health, Aging, Arthritis, and quite a few other Institutes. There are now, in addition to those things I mentioned that are already slated for clinical trials activity, a number of other candidates that are undergoing further review. When these prove to look promising, based on anecdotal data and on the extent of the public health importance--for example, St. John's Wort is very widely used--we will carry out clinical trial and try to settle these issues for the American public. Mr. Porter. Dr. Varmus, are you aware of any other enterprise or institution that does clinical trials for research regarding alternative medicine therapies? Dr. Varmus. Well, there are many such trials carried out in Europe. One of the functions of the Office of Alternative Medicine is to try to pull together the published studies from such activities. In addition, there is an organization called the Cochran Group that tries to pull together what are frequently fairly inconclusive studies, but the effort is to try to assemble all the data, do what is called a meta- analysis, and then try to determine whether or not these therapies show some promise. Mr. Porter. If I can say so, my concern is equally the other direction, and I understand why it would be to look for those that work. But it seems to me there's a lot of information out there that is bought by the American people about therapies that don't work, and they pay inordinate amounts of money for, and lose the benefits of good therapy in the meantime. There's nothing to tell them that it's a bad buy, that it doesn't work, and there's no scientific basis for it whatsoever. So it seems to me, part of the mission of NIH ought to be, not only to look for good therapies that do work, but to also test those that claim to work and show that they, in fact, don't. Dr. Varmus. Well, as I mentioned, one of the criteria that we use is the degree to which any thing is being used. One of the difficulties we face, of course, is that there are hundreds, indeed probably thousands, of alternative therapies in the marketplace. Many of these are very difficult to approach with clinical trials because they are not made by standardized methods, and they're not pure preparations. It's very difficult to do a trial with material that's not been subjected to a high degree of chemical analysis, and we simply have to sift through what is out there, and respond to the public health need. I agree with you, if something is very widely used and shows no evidence of efficacy, that should be something that gets better established than it has been to date. But I think that usually when things are very widely used, there are reports, perhaps anecdotal, perhaps not rigorous, that suggest that there is efficacy. That certainly has been the case with St. John's Wort and some of the other things thatI've mentioned today. third party payments Mr. Porter. Well, there's other things in the market that could be dangerous that someone ought to test, especially under the law that was passed in 1992 that allowed health claims to be made without any scientific basis. It seems to me that NIH and the Office of Alternative Medicine is, or should be, the kind of first line of defense against these kinds of therapies that could be even dangerous, not only benign, but could be worse than benign. Dr. Varmus, our subcommittee, has provided one year authorizations for NIH to collect third-party payments for the cost of clinical services that are incurred in NIH research facilities, and specified that those payments should be credited to the NIH management fund. Can you tell us how much was collected in Fiscal Year 1997 and credited to that fund, and do you anticipate that this amount will remain constant from year to year? Dr. Varmus. Nothing has been collected, and we have given this issue to the Board of Governors at the Clinical Center for further discussion. They have looked at this matter carefully. They've consulted with outside experts, and they feel that it would be detrimental to our overall operation to try to collect third-party payments, that it would not be cost-efficient, and they recommend that we do not do so. And, as you may note, in this year's budget request there is no offset for third-party payments. Mr. Porter. Why would it be detrimental? Dr. Varmus. Because one of the traditions of the Clinical Center that has encouraged recruitment is that we don't make any distinction among patients who are and are not insured. To do so would create a large amount of paperwork that we have not been burdened with before. And we know that a substantial portion of our patient population which frequently comes from families with hereditary diseases or involves those with longstanding diseases are not insured. We think this might act as a means to either impair our ability to recruit such patients, or in fact change the direction of our research in a way that would really not be favorable to the Institution. Mr. Porter. I'm at a loss to understand why it would impair their willingness to come there since they haven't any coverage, and there wouldn't be any third-party payment to collect in regard to those patients anyway. Dr. Varmus. Well, the issue might be that we would be creating additional burdens for the referral physicians who would feel that there might be some additional paperwork and that we would be looking for financial return from patients who come. I can provide you with the report that was provided by our Board of Governors, if you would like further information. Mr. Porter. Why don't you put it in the record. Dr. Varmus. I'd like to do that, thank you. [The information follows:] [Pages 2875 - 2891--The official Committee record contains additional material here.] information technologies Mr. Porter. During last year's hearing, we discussed your efforts to integrate all computer systems on the NIH campus into a unified information technology system, as well as your plans to hire a chief information officer. What is the status of NIH's chief information officer position? Could you update us on what this project entails in terms of staffing and expenditures? Dr. Varmus. Well, I'm pleased to say, Mr. Porter, that we have not only completed our search, but just a couple of days ago, we received a final approval from the Office of Personnel Management to allow us to announce the appointment of Mr. Al Graeff to be the chief information officer. This was a prolonged search. I went through quite a few candidates before finding the person we wanted. Mr. Graeff and I are planning a series of meetings to decide exactly what his personnel and budget needs will be. Mr. Porter. So could you give us an estimate for the record of the cost-savings that might be expected to be achieved? Dr. Varmus. Yes, we can. [The information follows:] Information Technology--Cost Savings The new Chief Information Officer (CIO) of NIH will provide leadership for comprehensive and consistent Information Technology (IT) planning across the NIH and will coordinate trans-NIH infrastructure and systems. A first priority will be an analysis and evaluation of current NIH systems as the basis for recommendations for improvement. Efficiencies resulting from compatible systems for shared information and resources will eventually accrue cost savings; NIH will continue to keep the Committee informed of its progress. year 2000 Mr. Porter. I don't think this is relevant because you don't have any kind of benefits to distribute to the public at large--but are you going to have, have you looked into year 2000 problems? Do you have any problem with the year 2000 computer configuration? Dr. Varmus. We have looked at this, and we appear to be well ahead of the game. Mr. Itteilag may want to correct me on this, but as far as I can tell, we think we're going to be well-equipped to make that transition from 1999 to 2000. Mr. Porter. I'm so concerned about this with the rest of our portfolio before the subcommittee that we're going to hold a special management hearing with each of the departments and agencies to see where we are overall in this area. Dr. Varmus. We would be happy to help with that hearing, if you like. Mr. Porter. Would you? Dr. Varmus. We can provide our advice about our experience with that transition. Mr. Porter. Yes, because we're very worried, particularly in reference to the larger institutions that have a lot of benefit payments that there could be serious problems, and, obviously, we don't want that to happen. Dr. Varmus. Right. Our major concerns, of course, have been pay checks and grant funds. the foundation for the national institutes of health Mr. Porter. The Foundation for Biomedical Research began operations last year. Can you tell us which projects it intends to concentrate its efforts on first, and what size of annual budget do you expect it to have? Dr. Varmus. Well, we, of course, hope in the long run that enough funds will be raised to pay for personnel out of the funds that are solicited. But, at the early stages, we have been very grateful for the monies that have been received from this Committee--$500,000 in the current fiscal year. The Foundation has, thus far, undertaken most of its activities in two areas. One is to support the clinical research training program for medical students who are currently spending time on the NIH campus. This year there are nine such students, recruited from a variety of medical schools. We expect to see that program increase in size over the next few years. One further supplementary activity in that area would be to raise money to build housing for those students commensurate with the housing offered to the Howard Hughes medical students who come to the campus to do laboratory research, as opposed to clinical research. The second area has been related to the training of health care professionals who do genetic counseling. When Dr. Francis Collins was here, we discussed the coalition formed by about 100 groups interested in various aspects of genetics and clinical medicine, and the way in which that coalition is working with the Foundation to develop a program for instruction of nurses and other health care professionals to do genetic counseling and to prepare for an era of more activity in the arena of genetic testing. The pharmaceutical industry has made some contributions already to support these activities, and the Foundation is acting as the coordinating center and the bank for these very important educational activities. The Foundation is also interested in providing support for our AIDS vaccine effort, but to date there's been no need for financial contributions on that subject. women's health initiative Mr. Porter. Thank you. The women's health initiative is a $628 million, 15 year project, involving 164,500 women, age 50 to 79. It is a trans-NIH activity which focuses on strategies for preventing heart disease, breast, and colorectal cancer, and osteoporosis in older women. Have you kept this initiative on budget and on schedule? Dr. Varmus. The budget actually has increased in our proposal for 1999 as a result of additional costs that were not expected but are not incommensurate with the kinds of additional costs that frequently occur in a large clinical study of this kind. As you know, the Women's Health Initiative has been transferred---- Mr. Porter. That's my question. Dr. Varmus [continuing]. To the Heart, Lung and Blood Institute. Mr. Porter. My question is why did you transfer it?. Dr. Varmus. Because the Heart, Lung and Blood Institute has had tremendous experience in managing large clinical trials of this kind, and we feel it is best suited to oversee the initiative at this stage, as data are accumulated. Dr. Kirschstein. Mr. Porter. Mr. Porter. Yes. Dr. Kirschstein. To add to that, the Heart Institute has developed a consortium since, as you mentioned, there are several diseases, and so, the Cancer Institute, the Arthritis and Muscular-Skeletal Diseases Institute, and the Aging Institute, since the study is in elderly women, are part of a consortium that the Heart Institute has developed to help manage that study, and contribute personnel and, perhaps, some funds as well. Mr. Porter. You anticipated my next question. Dr. Kirschstein. I'm sorry. [Laughter.] pediatric research Mr. Porter. Last year, the Appropriations Committee provided $38.5 million in funding for the pediatric research initiative. These funds were made available directly to the Institutes through the NIH, areas of special emphasis which target those areas of research opportunity most likely to yield greater results on the Federal investment in biomedical research. Is this an effective approach, or would it be more effective to provide funding to the Institutes directly? Dr. Varmus. I believe it's more effective to provide them directly. There has been interest on the part of some Members of Congress to encourage the NIH to focus more attention and monies on pediatric disorders and to include children in research, particularly clinical research. We feel we have responded to that. The initiatives to be undertaken under areas of emphasis are one indication of our response. As those Members interested in expanding our efforts in pediatric research acknowledged, the areas of emphasis initiatives that we have developed include more pediatric projects than even they had anticipated. Last year, in order to simplify the distribution of money, we simply identified components of ouralready laid out plan as a pediatric initiative. At this stage, I don't believe that any further labeling of subdivisions of our plan as pediatric initiatives, with money flowing through the Office of the Director, is a very useful way to proceed. Mr. Porter. Dr. Varmus, you and your team of directors, indeed all the people at NIH, give us great confidence that the entire enterprise is in extremely competent hands, and that the public money is spent, not only wisely, but with a degree of imagination that leads us to results, and so we want to thank you for spending the last three weeks with us. We know it is a burden on your time, and we appreciate very much the opportunity to spend time with you, and each of the directors, and learn more about the fascinating things that are happening within NIH and its grantees. Thank you all very much. Dr. Varmus. Mr. Porter, I appreciate personally the attention you have paid to these hearings, and the very high level of questioning that we've had. I think it has been useful for all of us to reflect on what we do in this annual process, and I appreciate you spending so much of your time with it. Mr. Porter. Thank you, Dr. Varmus. Thank you all very much. The subcommittee will stand in recess until 10:00 a.m. on Tuesday. [The following questions were submitted to be answered for the record.] [Pages 2896 - 2941--The official Committee record contains additional material here.] Wednesday, May 20, 1998. NOBEL PRIZE RECIPIENTS WITNESSES DAVID BALTIMORE, PRESIDENT OF CALIFORNIA INSTITUTE OF TECHNOLOGY STEVEN CHU, THEODORE AND FRANCIS GEBALLE PROFESSOR OF PHYSICS AND APPLIED PHYSICS, STANFORD UNIVERSITY STANLEY B. PRUSINER, M.D., PROFESSOR OF NEUROLOGY AND BIOCHEMISTRY, UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, CALIFORNIA JOSHUA LEDERBERG, RESEARCH GENETICIST ALFRED GILMAN, BIOCHEMIST, PROFESSOR OF PHARMACOLOGY, UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER PETER DOHERTY, IMMUNOLOGIST, CHAIRMAN OF THE DEPARTMENT OF IMMUNOLOGY, ST. JUDE'S CHILDREN'S RESEARCH HOSPITAL, PROFESSOR, UNIVERSITY OF TENNESSEE MEDICAL SCHOOL Mr. Porter. The subcommittee will come to order. This is a special hearing on medical research. The subcommittee would like to welcome six of our Nation's most prominent researchers, each of whom has won the Nobel Prize. What I plan to do is make a very brief introduction of each, and then we will hear their individual statements. And we'll get an opportunity then to hear all six statements before we begin questions. Gentlemen, let me thank each of you for taking time from your very, very busy and full schedules to be with us. I begin with Dr. David Baltimore, who's a biologist, born March 7, 1938 in New York City. Nita Lowey's not here to remind us, but she will be, I think. He's President of the California Institute of Technology and won the Nobel Prize in Physiology or Medicine in 1975 for his work on virology. He was 37 years old when he won the Prize. He was appointed Chairman of the NIH AIDS Vaccine Research Committee in 1996. And Dr. Baltimore, we're very delighted to have you with us this afternoon. Mr. Baltimore. Thank you very much. I've been President of CalTech now for about seven months. Before that I was a Professor at MIT for many years and was for some time the President of the Rockefeller University. I have worked on viruses and on the immune system for over 35 years. I received the Nobel Prize for discovering the enzyme that allows cancer-inducing viruses to grow and to associate themselves permanently with cells. Howard Temin and I were jointly honored for this work, a colleague of Mr. Obey's. The enzyme we discovered came to be called the reverse transcriptase. This work established the notion that there existed retroviruses in the world. Ten years later, AIDS appeared and was discovered to be caused by a retrovirus. The reason we knew that was because it has the reverse transcriptase. So the discovery we had made 10 years earlier provided the basis for discovering how AIDS was caused. The enzyme is also central to the development of biotechnology, because it allowed important genes to be captured and used to make therapeutic products. Although it was an interest in cancer that fueled the discovery, it turned out to be central to other fields, proving once again that science often has unforeseen consequences. Because my worked turned out to help with the discovery of the AIDS virus, HIV or immunodeficiency, I followed the development of the field, and in 1986, I was asked by the national Academy of Sciences and the Institute of Medicine to co-chair a committee to evaluate the research on this awful disease. My committee recommended a greatly increased research effort that we estimated needed to reach $1 billion a year. In a few years, the U.S. was spending that amount of money, and the work led to the exciting advances in therapy that we are now seeing. At the end of 1996, Harold Varmus asked whether I would head a panel to oversee the U.S. effort in AIDS vaccine development. I agreed to do that, and in spite of my duties now as President of Caltech, I continue to chair the AIDS Vaccine Research Committee of the National Institutes of Health. It is advisory to both the NIAID and NCI efforts in vaccine development. I am committed to this work, because I believe that nothing is more important to public health world-wide than a vaccine against AIDS. There are about 30 million people in the world infected with HIV, and they are transmitting the virus at a fierce pace of about 7 million new infections per year. In the U.S., HIV infections continue, and although the new drugs can hold the disease in check in many people, the drugs are imperfect and exceedingly expensive. Only a vaccine is going to rid the world of the scourge of HIV. Making an HIV vaccine is testing all of the world's knowledge of virology and immunology. The reason is easy to see. Other viruses for which we have vaccines are ones that the immune system usually controls. The vaccine just helps the immune system get one step ahead of the virus. HIV, however, is almost uniformly fatal when untreated. Therefore, the immune system is unable to cope with it effectively. For other viruses, we need only harness the activity the virus ordinarily elicits. For HIV we have to be smarter than nature. Can we accomplish this feat? I have faith that the U.S. research community can do miracles and therefore an AIDS vaccine should be possible. But it's going to tax our knowledge base and perhaps require much new knowledge before we reach the goal. HIV is the prototype of an emerging infectious disease. We have no record that it ever infected people except perhaps sporadically, until the late 1970s. In less than 20 years, it has spread to become the most deadly virus in the world. In retrospect, we were lucky that it emerged in the 1970s. If it has come 10 years earlier, we would have had no reverse transcriptase assay, and we could not have found HIV. Since the world have never heard of a retrovirus in the 1960s, we would have been at a total loss for how to find the cause of AIDS. And you can be sure that the confusion and fear of an unknown killer on the loose would have been monumental. If you remember, the disease was recognized a few years before the virus was found, and even in that short time, the social consequences were disconcerting. To be prepared for emerging diseases, we need the great possible knowledge of the whole world of biology. We need to know what bacteria, fungi and viruses lurk in our environment, and we need to study them in detail, so that if they ever do cause disease, we are ready to identify and cope with them. Luckily, Howard Temin and I were interested in retroviruses, without knowing that they might cause an epidemic. But we need to be equally vigilant about other organisms, and that means having strong biomedical research across the board. Not only do we need to study the organisms, we need to know how animals and humans react to the organisms. We need to study the immune system in all of its excruciating detail, so that we can marshal responses when we need them. In this sense, the attempt to make an AIDS vaccine is likely to have many spinoffs, because it will be a paradigm for responding to other organisms, even ones we do not recognize today. Finally, let me speak as a new university president. Caltech is a remarkable part of the U.S. educational system, because it is a school focused on basic research and its engineering applications. Caltech is very small by some measures, 900 undergraduates, 300 faculty. It is huge, however, in the innovation it spawns and in the range of its activities. I have learned at Caltech how much can be accomplished in a community that is devoted to interdisciplinary approaches to the toughest scientific questions. As the U.S. Congress debates whether to double the NIH budget, let me give one piece of advice. Be sure that the funds are able to bring to biomedical research the strengths of the other sciences, because they have much to offer. As a corollary, it is crucial that we expand research opportunities across the board in science, because the 21st century is going to see a cohesion of the sciences and a disappearance of their borders. Biomedical research will lead the way, because it so readily absorbs the power inherent in the other disciplines. Thank you very much. [The prepared statement follows:] [Pages 2946 - 2954--The official Committee record contains additional material here.] Mr. Porter. Thank you very much, Dr. Baltimore. Next is Steven Chu, a physicist, professor of physics and applied physics, at Stanford University. Dr. Chu won the Nobel Prize on physics in 1997 for the laser cooling and trapping of atoms. Dr. Chu. Mr. Chu. Thank you. I just want to say how glad I am to be invited here and be on the same panel with these biologists and medical researchers. Because I'm a physicist and don't do medical research, I'm going to depart a little bit from the script and talk first about how the interplay between physical sciences and biology is actually occurring. Two messages I want to bring to you, that science is an interdisciplinary enterprise, and that many of the successes in medical research are the result of scientific and technological infrastructure that have taken a century to build. The other message is that I want to echo Dr. Baltimore's statements that there are indications that the biological sciences, and particularly at the cellular and molecular level, and the physical sciences, are drawing together intellectually. As physicists examine atoms and nanostructures, let's say 10- atom science structures, they see the study of bio-molecules as a natural extension to this interest. And because of the remarkable success of molecular biology, biologists and medical researchers are beginning to ask the same type of questions that physicists like to ask. So first, what are the contributions of the physical sciences to medicine. They are very powerful diagnostictools, x-rays, CAT scan, MRI. These were, I would say, accidental discoveries in the sense that the inventors were not seeking medical solutions. Roentgen discovered x-rays quite by accident, but within a few weeks, I understand, he discovered that x-rays could cast shadows on film, but the bones would block those and create shadows. The roots of magnetic resonance imaging, or MRI, go back to methods developed in the 1930s to measure magnetic properties of atomic nuclei. That initial development led initially to magnetic resonance imaging, or MRI, which is one of the most powerful non-invasive medical imaging tools we have today. More recently, the discovery of functional MRI, namely, that you can use it to measure brain activity, has allowed researchers to study humans for long periods of time and how their brain is working. So instead of exposing them to radiation now, you can actually see an individual when they're thinking, what parts of the brain are lighting up. In the early 1900s, physicists found that x-rays could be scattered from crystals. And they used this to determine the size of crystals. Later this technique was extended and developed by many researchers and it eventually has been used to determine the structure of molecules, such as DNA and proteins. Knowing what molecules look like formed one of the real foundations of modern biology. Computer-assisted tomography, or CAT scans, developed by Al McCormick, who was a physicist working for a hospital, and assigned the task of improving the quality of x-ray pictures. He devised a conceptually simple method of taking three dimensional pictures. But while he did this, he was sure he invented something old, it was too simple, too obvious. And maybe it was. But what was new about it was that he was in unusual circumstances. He was in an environment working in a hospital, and he was aware of a problem and he had the resources to develop a solution. There's no reason to suspect that the developments in physical sciences would not continue to provide new tools for medicine. And I'll cite my own research as an example. I realize it's really conceited to suspect that my work in physics will have the same impact as x-ray diffraction or nuclear magnetic resonance, but stranger things have happened, I could get lucky. I shared the Nobel Prize in physics for laser cooling and-- I'm already lucky---- [Laughter.] Mr. Chu. For laser cooling and trapping of atoms. We're able to cool atoms to about a millionth of a degree above absolute zero. That's 10 billion times colder than room temperature, where if you use the same energy scale, the temperature of us to the surface of the sun is only a factor of 10. So these are very, very cold atoms. Once the atoms are that cold, they're easy to hold on to. You can move them around at will at a distance to a vacuum chamber. And this type of work has led to more accurate atomic clocks, gyroscopes and so on. So it has had impact in physics. But while we were doing this work in 1986, we decided to do another experiment. The same principles should have worked on a more macroscopic object, a 1 micron glass sphere. And a colleague of mine, Art Ashland, showed indeed that would work, and later went out to discover, again, by accident, that you can hold on to individual cells, live cells, bacteria, this way. Move them around in an optical microscope, turn off the light, and they would swim away. Other researchers found you can actually hold onto chromosomes within the nucleus of the cell without puncturing the membrane. And when I got to Stanford, I said, well, let's take this one step further. Can we hold onto individual biomolecules by gluing little plastic handles to the molecule and moving them all around, and so started to develop techniques to move single molecules of DNA around. What actually is going to come of this work, we don't know. Already other researchers have jumped in and are essentially doing experiments, looking at how individual biomolecules interact with one another and actually doing experiments in a very, very different way. Instead of looking at both samples, look at individual molecules. What is going to come of that work is hard to say. But we do know every time we have looked at individual molecules or individual surfaces instead of averages, we have discovered something new. It's happened with looking at atoms on surfaces, and it's happened in polymers. So it may happen again in biology. Again, one banks on being lucky. These are exciting opportunities. There is a marriage of the techniques and a marriage of the type of thinking of the physical sciences and the biosciences. And so instead of diverting, historically, I see them coming together. But these opportunities have to be nurtured. It's going to be a challenge, but I think it can be done. Thank you. [The prepared statement follows:] [Pages 2958 - 2960--The official Committee record contains additional material here.] Mr. Porter. Thank you, Dr. Chu. Dr. Stanley Prusiner, born May 28, 1942, in Des Moines, Iowa, professor of neurology and biochemistry at the University of California, San Francisco. Dr. Prusiner won the Nobel Prize in Physiology or Medicine in 1997 for his work in understanding degenerative diseases of the central nervous system. Dr. Prusiner. Dr. Prusiner. Thank you, Mr. Chairman, members of the subcommittee and guests. In order to place my own work in perspective, I'd like to say a few words about two common neurodegenerative diseases that devastate the lives of millions of Americans. Such disorders are both chronic and progressive. While neurodegenerative diseases are relentless in their attack on the nervous system, the speed with which they kill the patient often varies for months up to decades. The first of these two illnesses I'd like to remark about is Alzheimer's disease, from which former President Ronald Reagan suffers. As most of you know, Alzheimer's disease is the fourth leading cause of death in America, after heart disease, cancer and stroke. Approximately four million people are afflicted with Alzheimer's disease in the United States, and 200,000 die annually from this illness. The cost of caring for patients with Alzheimer's disease is estimated to be about $100 billion a year, making it as costly as any illness that we know about. To depart from the prepared statement a little bit, I'll skip a few of the paragraphs. But I want to remark a little bit more about Alzheimer's disease, and say that 15 years ago, we did not know the cause of Alzheimer's disease. Over the past decade, mutations in three different genes have been discovered that cause early onset familial Alzheimer's disease. This is a small number of people with the disease. And a fourth gene has been identified that seems to modulate the age of onset of all forms of Alzheimer's disease, yet we still don't know the cause in most cases. The second neurodegenerative disease I'd like to make brief remarks about is that called ALS, or Lou Gehrig's disease. Jacob Javits, whom many of you knew, died of ALS. Patients with ALS are really the antithesis of those with Alzheimer's disease. These people have their intellect preserved, but the motor neurons in their spinal cord degenerate. Eventually, the patients with ALS die of asphyxiation because their diaphragm and chest wall muscles can no longer receive signals from the spinal cord. The motor neurons that degenerate in ALS are the same cells that are attacked by the polio virus. We are all aware that vaccination against the virus has made poliomyelitis a disease of the past. The polio vaccine was developed by the pioneering work of John Enders and his colleagues for which they received the Nobel Prize many years ago. What Enders did was to grow the polio virus with very high titres in cultured pieces of tissue. This was the breakthrough that allowed Jonas Salk and Albert Sabin to produce vaccines. Without these vaccines, I think it is easy to imagine that the iron lung industry would be bigger than General Motors today. After spending three years at the NIH working on proteins and bacteria, I returned to San Francisco to do a residency in neurology at the University of California in 1972. Two months later, I admitted a 60 year old woman from Marin County who was suffering from progressive loss of memory and difficulty performing routine tasks. I think back to this patient often, because she had trouble putting her car keys in the car door and the ignition. I was surprised to learn that she did not have Alzheimer's disease, but instead was dying of a disease called Creutzfeldt- Jakob disease, or CJD. Only four years earlier, scientists at the NIH had shown that CJD could be transmitted to apes and monkeys. These transmission studies led them to believe that CJD was caused by a slow-acting virus. As I learned more about CJD, I found that some scientists were unsure if a virus was really the cause of CJD, since the causative infectious agent displayed many unusual properties. The amazing properties of this presumed ``slow virus'' captivated my imagination. I began to think about the molecular structure of this elusive agent. Scrapie of sheep was thought to be caused by a similar mysterious agent, and we now know that ``mad cow'' disease in Great Britain is caused by the same infectious agent. After nearly eight years of work, it seemed likely that the infectious agents of scrapie, CJD and now ``mad cow'' disease were not viruses, but infectious proteins. And to distinguish these infectious proteins from viruses, I introduced the term ``prion'' in 1982. Over the next ten years, there was remarkable skepticism. I should say considerable, it wasn't remarkable. It was to be expected, in many corners of the scientific community. [Laughter.] But a large body of experimental data was accumulated that eventually convinced most scientists of the existence of prions. Prions represent an entirely new and unprecedented kind of infectious pathogen. All other infectious agents, as Dr. Baltimore has been talking about the AIDS virus, bacteria, fungi, parasites, carry a nucleic acid, DNA or RNA, that instructs the replication of their progeny. But prions are very different. They contain no nucleic acid. They are composed of a misshaped protein that can stimulate the production of more of itself. As I look back over the past 25 years, I am sure that the discovery of prions would not have been made in any other country besides the United States. Let me explain. First, few countries have a system for support of biomedical research like ours. The NIH investigator-initiated grant system allowed me to apply for support as a newly-appointed assistant professor in 1974. Only some young, brash iconoclast would have chosen such a difficult and unusual problem to pursue. Secondly, our country is sufficiently large that the reviewers did not know me personally, so they could be more objective. Third, this work was very expensive. The NIH spent more than $56 million over the past quarter of a century on these studies. And fourth, I needed an outstanding institution like the University of California at San Francisco, with a large group of superb biomedical scientists to provide the proper intellectual environment for such research to flourish. But I hasten to add that the institutions of all my colleagues sitting here are among the 25 or 30 wonderful academic institutions where pioneering biomedical research occurs in this country. I'd like to look ahead briefly for a moment, which is of course always hard to do. Discovering the causes of diseases is not sufficient. We must also devise effective therapies. There are many wonderful opportunities emerging in all fields of the biomedical sciences to develop meaningful interventions. Neurology and especially neurodegenerative diseasesrepresent only a few of these opportunities that confront us now. Advances in our understanding of diseases like Alzheimer's disease, Parkinson's disease, ALS, prion disease, CJD, need to be exploited in the development of rationally designed effective drugs. But to make these discoveries, I think it's necessary that we continue to bring the brightest and the very best young people into the biomedical sciences. They need to perceive an exciting career path. And the best way to do this is to make the NIH grant system less stressful and less grueling. The only way we can do this is to increase funding for NIH. I think it is very urgently needed. I'd like to say in closing that my colleagues and I greatly appreciate the opportunity to share with you our excitement about the future of biomedical research. We are poised to exploit many discoveries made over the past two decades and develop unique therapies that I think were unimaginable five years ago. We are capable of stopping the devastation that so many dreaded diseases cast upon not only the victims, but also the families of these unfortunate people. I think with proper funding, we can deliver to the American people some remarkable advances in the fight against disease. Thank you. [The prepared statement follows:] [Pages 2964 - 2968--The official Committee record contains additional material here.] Mr. Porter. Dr. Prusiner, thank you very much. Next, Dr. Joshua Lederberg, research geneticist, who won the Nobel Prize in Physiology or Medicine in 1958, for his work on bacterial genetics. He was only 33 years old when he won the prize. Dr. Lederberg retired as President of Rockefeller University in 1990. But he continues his research activities there in the field of DNA secondary structure and mutagenesis on bacteria. Dr. Lederberg. Dr. Lederberg. Thank you very much, Mr. Porter. I'm very grateful to you and the committee for the opportunity to be with you and make this presentation. Very appropriately, most of my colleagues have stressed their analysis of the public benefits that ensue from the overt products of biomedical research. It has been the pride of NIH to have sponsored innumerable discoveries on the biology of the human organism and of our microbial predators, discoveries that have assisted the ongoing defense against disease. I have a background paper which I have made available to you that has some graphics to illustrate these points. Even despite terrible setbacks like the HIV epidemic, life expectancy in the United States has steadily improved throughout this century, from 47 years in 1900 to 76 at the present time. Pushing up that expectation is even harder as we face the more difficult challenges of cancer, heart disease, cardiovascular disorder, neurological deterioration. But our progress has been steady in many areas, very exciting, especially with the insights derived from genetic analysis. But I will assert that equally important to the exclusive discoveries is the human capital, the skills, ideals, imagination and motivation of the scientific investigators, whose work depends absolutely day by day on research support from the NIH. We have discovered a deep fount of creativity in the young people we are training. And they have spilled over from academia as well as into government and industry. In the process, they have generated enormous economic advantage for the Nation. Most explicitly in biotechnology and pharmaceuticals, where the United States has unquestioned world leadership, directly derived from the support for basic research for which the NIH has been famous through these years. But even as generous as it has been, NIH funding has not kept pace either with the scientific opportunities nor with the talents that could be cultivated and brought to bear. So the prospect of the new acceleration in this domain are very encouraging. There can be no doubt that the investment will be repaid many times over. I will just put two topics on the table: infectious disease and aging, in its most fundamental aspects. In terms of the first, my own research for 55 years has focused on genetics and evolution of microbes, and has left me with a profound respect for their versatility in finding ways to adapt themselves to take advantage of us, to be the micropredators, the only organisms that dispute our place at the top of the food chain. In fact, one could remark that whether we live or die isa consequence of microbial viral infection is an unintended side effect of the machinations of these organisms. No virus or bacterium really gets much advantage by killing us, or even by making us very ill. And many of the most successful viruses and bacteria have more benign relationships that they have evolved in their association with us. It's their mistake that they are sometimes more lethal than they might have wished, if they had the intelligence to understand that. But we're the ones who suffer even more so. So we need really a very deep understanding of the vagaries of microbial variation, the tightrope that they walk in their attack on us. They have to be vicious enough to get a foothold and not so vicious, at least most of the time, they allow us to continue to work for them, to continue to provide the fodder that they need for their continued existence. This is a rather different perspective about microbial infection than people working on the front lines and seeing the tip of the iceberg, the killing effect of the microbes, will often have, when derived from genetic inquiry. The global pandemic of AIDS has been a poignant reminder of the need to maintain and strengthen our vigilance about the evolution and emergence of microbial threats to our health. We had another reminder last year with the episodes of avian influenza in Hong Kong. These had a very high mortality ratio. Six out of the 18 cases diagnosed as H5N1 in Hong Kong died, a very high proportion, 1 out of 3. As events turned out, we were very lucky. This flu was not readily transmitted from human to human. And what might have evolved into another 1918-like catastrophe, where influenza ravaged the world and killed 25 million people in the course of a single year, was nipped in the bud. This positive outcome, positive for the time being, was no accidental circumstance, but the rest of well-tuned international collaboration and energetic response on the part of the Hong Kong health authorities. In turn, they depended on studies of virus biology and diagnosis that had deep roots in NIH funded investigations over the past 30 years. All authorities in the field caution that such episodes will recur, if not influenza, then any of scores of emerging and reemerging infections. Similar problems challenge us in the spread of antibiotic-resistant microbes and the need to understand how these evolve, and how better to approach the design of new generation drugs, so that we can continue what we once called the miracle drugs, our capacity to suppress bacterial infection of kinds that used to be uniformly fatal. I'm sorry I have to bring up another point, but coping with new infectious disease has also become a depressing element in our national security planning. With the end of the Cold War, we are no longer locked in strategy of lethal deterrents with another superpower. Instead, rogue states, guerilla groups and psychopathic individuals have become endued with the powers of mass destruction through the use of chemical and biological weapons. At a basic level, our long-term strategy for defense is hardly different from that of protecting against naturally emerging infections. That will be the level at which NIH will operate. The need for prompt and accurate diagnosis, surveillance, powerful vaccines and drugs to prevent and treat infections from many exotic agents. Curiously, even the eradication of a disease, as we've had with smallpox, evokes new vulnerabilities with a population no longer exposed to immunizing doses, focusing sharply on the need for agile and multi-pronged agents to help protection to guard against the possibility of this ever recurring. NIH does not operate in a vacuum. Its research strategy needs to be and is informed both by scientific opportunity and public health priorities. Its creative people and findings must be and are readily transferred to the health care sector and to industry. All this is working quite well. And I particularly wish to commend the initiatives to make medical information universally available through the electronic media of MedLine from the National Library of Medicine, a component of the NIH. To turn very briefly to another topic, one could pick many areas of challenge and promise. But the biology of aging is one that seems especially ripe for advancement through the applications of medical molecular biology. This has not been the field of my own research, but I have been educating myself as an advisor to a new medical research foundation funded by Larry Ellison, working closely with the National Institute of Aging, to try to find the most creative ways for a private foundation to complement the very good work of NIH. What we have learned about the risk factors and the biochemical basis of Alzheimer's disease, as Dr. Prusiner has touched on, has already transformed our concepts of senility. We don't even use that word any more in medical parlance, because there are specific syndromes that are responsible for, and if taken care of, I think would abolish that notion that age is ipso facto connected with severe neurological and psychological deterioration, so much of which, in fact, has turned out to be Alzheimer's disease. But there are other conditions, as well. And these insights provide the hope that homing in on specific disease syndromes can offer substantial enhancement of healthy life extension well into the ninth and tenth decades. Thank you very much. [The prepared statement follows:] [Pages 2972 - 2973--The official Committee record contains additional material here.] Mr. Porter. Dr. Lederberg, thank you very much. I'm informed that we have a series of four votes. What we will attempt to do is have Dr. Gilman make his statement, and then we probably will have to break at that point for as much as half an hour or 40 minutes, depending on how fast the votes go, and then resume. There's no other way we can do it, so we apologize to all of you in advance. Dr. Alfred Gilman, a biochemist, born July 1, 1941, in New Haven, Connecticut. He's a professor of pharmacology at the University of Texas Southwestern Medical Center. And he won the Nobel Prize in Physiology or Medicine in 1994. Dr. Gilman, we're delighted you could be with us. Dr. Gilman. Thank you, Mr. Chairman. It really is a privilege to be here this afternoon. Because I have very passionate feelings about the value of the bioresearch research enterprise in the United States and the appropriateness of Government support for this effort, if I somehow fail to convey that passion this afternoon, I will have done a very poor job. I was raised in the northeast, mostly in New York, and obtained my undergraduate degree from Yale University in 1962. I was then attracted to a new experimental program at Case Western Reserve University in Cleveland, a so-called combined degree program, where you obtain both an M.D. and a Ph.D. degree, hopefully in seven or eight years. A wonderful learning experience, and this program was the progenitor of the medical scientist training programs now funded by the National Institute of General Medical Science. I found that biomedical research appealed to me more than did actually clinical practice. So I then did a post-doctoral fellowship in public health service at NIH prior to obtaining a faculty position at the University of Virginia. I spent 10 happy years in Charlottesville before moving to the University of Texas Southwestern Medical Center at Dallas, where I have been a professor of pharmacology and chairman of the department of pharmacology for the past equally happy 17 years. When I was considerably younger and at Virginia, I began to try to learn more about how cell function was controlled by chemical signals. For example, if you're suddenly startled or frightened, the hormone adrenaline is released from a gland called the adrenal medulla. This hormone orchestrates a very complex series of responses to get you ready to fight or run. Your heart rate increases and your heart beats more forcefully. Your liver breaks down stored sugar as fuel for your brain and heart and muscle. Some blood vessels contract to elevate blood pressure, while others relax to increase blood flow to muscle. Many other things happen as well. How do all of these tissues respond in these different ways to just one hormone? We now know a great deal about how this and related signaling systems work. There is an extremely sophisticated molecular switchboard that is built into the membrane that separates the contents of the cell from the rest of the world. Within this switchboard, there are three kinds of proteins that function together, together transmitting the message from the outside of the cell to the inside and telling the cell how to respond. The first type of protein in this pathway is called a receptor. It looks at the world outside the cell, and it recognizes hormones that are there and binds them. This activated receptor then communicates with a special kind of protein, called a G protein, which integrates information from many different kinds of receptors, and then in turn regulates the third type of protein in the pathway, the signal generator, to send a message inside the cell. There is enormous diversity in these systems. There are hundreds and hundreds of different kinds of receptors, many dozens of different kinds of G proteins and signal generators. And it does indeed form a very, very complex switchboard in the outer membrane of the cell. Before I go on and explain the practical significance of this research, I'd like to mention just one other aspect of the basic science. Several of the molecular players in these switching systems were discovered in lower organisms, in yeast or worms or fruit flies. Nature is extremely economical. If an effective molecular mechanism is created, it is retained and used over and over again in evolution. You may not be aware of the fact that there are two different kinds of sex of yeast, for example, and that yeast have a sex life. Mating between yeast is controlled by chemical signals or hormones. Each kind of yeast sends out a chemical signal to the other, a signal that says, get ready to mate. The yeast perceives and responds to this signal in exactly the same way that we do when we react to the hormone adrenaline or to add another example, exactly the same we do when light strikes our eyes. So believe it or not, sex in yeast and vision in humans are accomplished by essentially identical molecular mechanisms, the same three kinds of protein are used to get information from the outside of the cell to the inside. If there's a twinkle in your eye, it was indeed inherited from a yeast cell getting ready to mate. [Laughter.] Now a few practical consequences of knowledge of these systems. Over one-third of all known prescription pharmaceuticals work by either activating or blocking receptors that are the gateways to these G protein-regulated signaling systems. This includes drugs that are used to treat heart attacks, asthma, to alleviate pain, drugs that are used to control schizophrenia, drugs that have put the ulcer surgeons out of business, and many, many others. But importantly, we do not yet know the nature of the hormone or the neurotransmitter that acts in well over 100 of these G protein coupled receptors. Because we don't know who acts on them, they are called orphan receptors. This orphanage, this collection of orphan receptors, represents an enormous resource for the discovery of new biology and new pharmaceuticals. Almost all the major pharmaceutical companies and many biotechnology companies have discovery programs to find new drugs that work on both known or orphaned G coupled protein receptors. Thanks to this approach, a new hormone called orexin was just discovered a few months ago that may be a critical link in controlling human eating behavior. And effective control of this behavior will be of enormous value in the treatment both of obesity and diabetes. How are new drugs discovered for these receptors? There are several different techniques, and I'd like to mention just one. Armed with the very, very basic knowledge that I just mentioned, that these receptor systems work in yeast and control such fundamental phenomena as cell growth and replication, one biotechnology company in New York takes the cloned genes for human receptors and expresses these receptors in yeast. Thousands of chemical compounds can then be checked to see if they change simple behaviors in yeast. And this is the first step to discovery of a lead compound that acts on the desired human receptor. In fact, this discovery system encompasses most of the elements of modern drug discovery: the use of cloned human genes, high throughput, robotically based screening techniques, and new methods of combinatorial chemistry to synthesize chemical libraries with many, many thousands of novel chemicals that can be tested for activity. In some cases, with help from physicists, drug developerscan determine the atomic structure of these receptors with the new drug candidate bound to it. This provides invaluable information for optimizing the chemical structure of the potential drug, so it does its job as potently and as specifically as possible. The future for drug discovery looks incredibly bright to me. In the not too distant future, we will know the chemical structure of all products of the human genome. We will thus have many new targets for drug action. Greater knowledge of the biological functions of these gene products will point us in the right direction, telling us which targets to exploit in individual diseases. Collaborations with the chemists and physicists will ultimately lead to truly rational drug design, done mostly with computers rather than experimental animals. Drug specificity and efficacy will be optimized and toxicity will be minimized. Mr. Porter. Dr. Gilman, I'm sorry to interrupt, but they are informing us we're going to have to recess very briefly. We will pick up right where you are when we come back. We apologize. The subcommittee will stand in recess. Ms. Pelosi. Mr. Chairman, as you're leaving, may I just have 30 seconds? Mr. Porter. You may. Ms. Pelosi. Thank you. We're having a markup in the Intelligence Committee and I'm going to have to go over there to vote. I just wanted to welcome all of the Nobel Laureates here. It is truly a proud day for us when you are here. But I have to say, this is the way it is around here. As a Californian, I'm particularly proud to be so well represented, both from public and private institutions. Dr. Baltimore, I particularly wanted to acknowledge the outstanding contribution you have made to the AIDS Vaccine Research Committee. As you know, that's very important to us in San Francisco and in our country. Dr. Chu, I'm so pleased to hear your presentation. When Dr. Varmus was here, he talked about improved instrumentation and what that means to biomedical research. Thank you for bringing it all together for us today, and congratulations to you on what you've done. Of course, in San Francisco, we talk about ECFF around here all the time, any regular attenders of these hearings can tell you. We're very proud of your work. It's a sad subject, how some of our loved ones are taken from us even before they're taken. I am pleased to hear Dr. Lederberg's presentation on the effects of aging. It's becoming more and more important to all of us all the time. And Dr. Gilman, when you said you were passionate about biomedical research in the United States, I didn't know that was going to extend to the yeast. [Laughter.] But it got our attention. Dr. Doherty, I'll look forward to hearing you later. But I can tell you that all year we talk about what you tell us here today. So thank you so much for the time that you've taken to be here. It's very, very important to us. And forgive my chauvinism about California. Thank you all. [Recess.] Mr. Porter. The subcommittee will come to order. Dr. Gilman, you are in the midst of your statement. Please proceed. Mr. Gilman. I think I've just come essentially to the end of what I wanted to say, about the future of drug discovery. I will summarize that. I think it's going to be spectacular. We will have much better drugs than we have today. I just wanted to close with a few comments on my opinions about what makes American science great. Adequate funding is obviously necessary. But it's not sufficient. In the United States, we allow our brightest young people to become independent and to receive funding to pursue their own creative ideas at the most productive times in their careers, when they're in their late 20s and 30s. While this strategy seems obvious, it is nearly unique in this country. In effect, we give our scientists a franchise to go to the equivalent of Queen Isabella and say, may I please have money for ships, because I want to discover the new world. We strive to find the right balance between basic and applied research. Both are critical. I appreciate the fact that it can be difficult politically to fund the seeming esoteric when there are very many critical immediate needs. However, we often do not know where to find the best leads for practical problems. I certainly never envisioned a biotechnology company searching for new drugs using human genes expressed in yeast. My father was a scientist, and I vividly remember when I was quite young how incensed he was one day when a cabinet officer in the Eisenhower Administration said, who cares what makes the grass green. Believe me, we really do care. The sun's light, captured by chlorophyll in plants, is the source of all energy on the earth. Even great statesmen and intellects have sometimes had difficulty in appreciating these concepts. I found the following from Thomas Jefferson. In 1806, Mr. Jefferson said, Harvey's discovery of the circulation of the blood was a beautiful addition to our knowledge of the animal economy, but on review of the practice of medicine before and since that epoch, I do not see any great amelioration which has been derived from that discovery. Mr. Jefferson would be thoroughly embarrassed with that statement today. [Laughter.] While there are some graybeards like us at this table today that occasionally still have a good idea, the true engine that drives the system is our extraordinarily bright, creative and energetic young people who thrive on the thrill of discovery. There are thousands of really smart young graduate students and post-doctoral fellows and junior faculty members who are working 80 hour weeks and receiving very modest compensation, but who would not trade their jobs with anyone. One way that we can really impair scientific discovery in this country is to disillusion the individuals who constitute this extraordinary resource. Unfortunately, there has been some disillusionment in the recent past. And our laboratories are becoming filled with foreign students and fellows, rather than our own. But there is hope in the air at the moment, as the scientific establishment watches your efforts, and thanks you very much for your interest. [The prepared statement follows:] [Pages 2979 - 2985--The official Committee record contains additional material here.] Mr. Porter. Dr. Gilman, thank you very much for your excellent statement. I apologize again for the interruption for the votes. Finally, Dr. Peter Doherty, immunologist. Dr. Doherty was born October 15, 1940, in Australia. He's Chairman of the Department of Immunology at St. Jude's Children's Research Hospital in Memphis, and professor at the University of Tennessee Medical School. He won the Nobel Prize for Physiology or Medicine in 1996 for his work on immunity to viruses. Dr. Doherty, we thank you very much for your patience and for your willingness to be with us this afternoon. Dr. Doherty. Thank you, Mr. Chairman. I'll be fairly brief, because 90 percent of what I would have said has already been said by my colleagues. I grew up in Australia, and I'm still an Australian citizen, but living and working in this country as a resident alien. My initial training was in veterinary medicine, and I'm actually the first veterinarian to win the Nobel Prize. Last year, I was also made the Australian of the Year, and I've had a strangely schizophrenic existence over the 18 months, trying to talk up the cause for basic science and basic biomedical research in Australia while also working in the United States. I can tell you that the situation is much more positive in this country than it is in Australia. But we're still working on it, and I leave for Australia again on Thursday. My first nine years as a research scientist were spent working on infectious diseases of the food producing animals, initially in Brisbane, the northern state where I grew up, and later in Edinborough in Scotland, where I did experimental neuropathology, studying virus infections and working on systems that are somewhat similar to those that were described so beautifully by Stan Prusiner. After that period, I returned to Australia, to John Kirkland School of Medical Research in Canberra. Canberra, of course, is Australia's answer to DC. My aim there was to do basic immunology, returning to my career in veterinary research. But I never made it back. A young Swiss colleague and I made a discovery which later led to the Nobel Prize some 20 years later. We found, working with a virus, a leukocytic cardiomeningitis virus, which is a little known virus that often affects mice, mice in the field and also affects humans. We found the way the cell media immune system works. That is, we found how the immunity, lymphocytes, killer T cells, kill off the virus-infected cells, the little factories that produce virus, and thus terminate an infectious process. This is a normal mechanism of recovery in any virus infection. It changed the way people thought about the immune system, because we discovered that how that operates is through the virus changing the transplantation molecule, the structure that's recognized when a graft is rejected. And the virus changes that molecule, and then the immune system sees it as foreign, and then turns on to destroy it. Just in the way it would turn on to destroy a graft. The reason we were able to work that out, and we worked it out very, very quickly, was because of some 20, 30 years of research that had gone on in this country and in Britain on transplantation in laboratory models. This is work that was done particularly at the Jackson Laboratory in Bar Harbor, Maine, that was NIH funded. These people had worked out the whole transplantation system, they mapped it in genetic breeding experiments in mice. And as two young scientists, we were able to pick up on that system, use it immediately to work out how these T cells work. So that is a very good example of how the serendipitous discovery builds on technology that is developed for a completely different purpose and provides a major illumination as a consequence. I left Canberra in the mid-1970s, went then to work at the Whistner Institute in Philadelphia, where I was also a professor at the University of Pennsylvania. During the time in Philadelphia, we discovered that the immune T cell response, the same sort of response the influenza viruses, which are extraordinarily variable in the way they survive in nature and continue to infect us, was highly cause-reactive. We realized for the first time what was being seen by these cells was very different from the things that are seen by the antibody molecules that people have been studying for a very, very long time. I returned again to Australia, didn't work out too well, I missed the United States very much. I missed the openness, I missed the access to funding, which is what drives all scientists, you've got to have funding. And I came back to St. Jude's Research Hospital some 10 years back, they made mea fantastic offer. And I now live on the muddy banks of the Mississippi instead of the Pacific beaches of Australia. I think the things I particularly would like to bring before the committee have already been mentioned. The danger of infectious disease, the enormous threat, particularly respiratory infections. Dr. Lederberg alluded to the massive influenza outbreak which followed the first great war. We still don't really know what happened there, but we think a swine virus got into humans and caused this enormous pandemic. It was called the Spanish flu, because the Spaniards acknowledged they had the infection, whereas the Germans and the English, who were still fighting the war, didn't admit it. So the Spaniards got blamed for it, but it crossed all barriers. It also probably had an effect on the peace process, because I believe one of President Wilson's key advisors, who was a moderate, died from the influenza before the Versailles Congress. And as a consequence, the people who were much more rigorous and much more determined to extract retribution from Germany played a much greater part in that process, which probably led to some extent to what happened in the second war. So infectious disease has had enormous effects on human history. The flu still is a major threat to us, the influenza viruses that have been circulating over the last 30 years or so probably come to the human population from birds. They're what's called the H3 viruses. As we heard earlier, the H5 virus that came across in Hong Kong, again came across from birds into humans, and with very good public health and extraordinarily good application of research, largely again funded in this country, my colleague Rob Webster, at the St. Jude Children's Research Hospital, a New Zealander whose specialty is the avian influenza virus, played a very, very prominent role, and the CDC also played a prominent role. So I think we have to be extraordinarily careful with these viruses. In the 1980s, there was an incident where a chicken virus mutated, killed millions of chickens very rapidly. Just one mutation or change turned this from a relatively mild infection to something that was extremely lethal, extremely deadly. And of course, as we know, with rapid air travel, we realize how quickly these viruses can spread. Also, I'd like to reinforce Dr. Baltimore's point about the AIDS vaccine. I think this is the greatest single challenge that we face in practical terms at the moment. We have to learn how to deal with this virus by vaccination procedure. We cannot hope to control it in the developing countries by any other mechanism. Therapies are very expensive. It's killing very large numbers of children. There's only one way to do this, and that is to make a vaccine. The thing that also worries me is that there is a related virus in sheep called visma, which spreads by a respiratory mechanism. It spreads by mucosal, oral, respiratory means. We are putting the AIDS virus under enormous selective pressures that we don't understand all that well with the drugs that have been used. And it does scare me. I don't think it's likely, but it's possible, that this or something like it could emerge as a respiratory infection. I think also when we think about infectious disease and we think about children, for instance, there are figures, five children a minute die of malaria. We have no vaccine for malaria. We have no very good vaccines against many of the respiratory infections that infect children in preschools, we all suffer from them. Respiratory and simple virus comes back, infects us as babies, comes back and can kill us in nursing homes. So I think there is enormous need for more research in this area. I'd like to close by saying that the NIH is, to my mind, the greatest enterprise that has been funded by any government on the earth. I think what you've funded through this committee may well stand as the single most positive contribution of this century and probably the next century. This is an extraordinarily enterprise for government to undertake. I also believe that medical research has enormous implications for world peace. To some extent I'm in contact with the international agricultural community and the work that people are doing to try to promote food production and so forth. But it's also through infectious disease, by controlling infectious disease, we can hope to persuade people to limit population growth, which will again, in turn, have an enormous effect on world peace. Finally, we need to keep in mind the international nature of science. I'm an Australian working in the United States, I've moved backwards and forwards between Australia and the U.S. We depend very much on the interchanges from young scientists, bringing people here, having them go home again and so forth. It's very important to keep that whole process open, not to close down that interchange in its most international of all human enterprises. Thank you very much. Mr. Porter. Thank you, Dr. Doherty. I want to tell you that I've had the pleasure of being in both Brisbane and Canberra some 10 years ago, at the 200th anniversary of the founding of Australia. Let me thank all of you for excellent statements. I know that you realize that our questions are going to be on policy and not on the technologies that each of you represent. I want to begin with Dr. Baltimore, by asking, of course you talked extensively about HIV/AIDS. We have had, over the last four or five years, a very strong impact on patient advocacy groups who say that we have been, while fighting the AIDS pandemic, neglecting research in heart disease, cancer, diabetes, diseases of aging. And that the priorities represented by the funding in NIH really ought to be changed. Have we been doing that? Can we now, with the progress that has been made in respect to AIDS, look at those diseases that affect broader populations within our own country? What are your thoughts in regard to those charges? Mr. Baltimore. I don't think this is a time when we should be pulling back on our commitment to solving the AIDS problem. This is a new problem, in the last couple of decades. It's a problem which has unknown dimensions to it, as Dr. Doherty pointed out, and we don't know what the future holds with a virus like that. The international dimensions are monumental. There areprobably more people dying of AIDS today internationally than any other infectious diseases, except maybe malaria. I don't think that it's a wrong priority, I think it's an absolutely correct priority. I think there's a scientific perspective that needs to be remembered. HIV is a small virus, as viruses go. It has about 10,000 nucleotides, which is the measure of its information content. We know every nucleotide, and we know all the proteins it makes. We know everything about it. It's a target of opportunity. I think one of the reasons why funding for HIV has ramped up so rapidly over the last decade and stayed so high is because it is something that we know about and we can really make a difference. With heart disease, and other diseases, we need to study those in great detail, and do. But they're not so close to the sort of development edge as HIV is. The reason we got drugs so rapidly against HIV is because we knew the proteins, because it is a small virus. And being a virus, it's a particularly good target for research. So I think we need to maintain our focus on it. I think we need it from an international perspective, and we need it from our local perspective. Drugs are terrific. They're expensive, but I think worse than that, they're probably a stop-gap. Because the virus can become resistant to them. And one by one, I think we will find the drugs, as we are finding even with antibiotics today, less and less effectively. It's really only a vaccine that's going to put HIV back in the box. Mr. Porter. Let me ask a related question, and then anyone who wants to comment on either of these questions, please feel free to do so. To what extent do resources drive research opportunity? In other words, if we put more funding for AIDS, does this attract the kind of scientific interest that might not be there if the funds weren't there? And if we put more money in respect to cancer, let's say, or diabetes or heart disease, would that attract more of the scientific effort in those directions? Dr. Baltimore. To my mind, it depends upon the opportunity. The opportunity with HIV/AIDS is significant, because we know all the basic things we need to know, that is, it's a virus disease, we know the virus causes it, we know a lot about that virus. So the developmental opportunities are there, we can determine the structures of the genes, we can find the drugs. And that has attracted people. There's no question that having funds available has attracted many more people to working on this virus than would have otherwise. There are now more people working on HIV than any other virus in the world. Probably than all of the viruses in the world. And that is a consequence of the priority that we've put on the funding. So yes, you will attract people. And you will attract some very good people who can make a real difference. Mr. Porter. Would anyone else like to comment on that? Dr. Lederberg. Mr. Lederberg. Yes. I will second what Dr. Baltimore has been saying and add a few other particularities. If we could be confident, and we're confident that it's wrong, that AIDS would not move further in its march around the world than it's already done, one might take a cold-blooded examination and say, let's stack up our investment in AIDS versus other kinds of diseases, or other existing mortalities. One of the reasons it's extremely urgent to get after AIDS is it was a nascent, burgeoning situation. It's still open- ended. We still don't know what the full global outcome of this epidemic is going to be. There are new varieties of AIDS we're seeing in southeast Asia that have a very different sex ratio, where heterosexual transmission seems to play a much more significant role. Dr. Doherty's also referred to the speculative prospect that it might find other modes of transmission. So it isn't just those poor people who already have AIDS that are the issue. Everyone else is in fact subject to the looming threat if this epidemic isn't controlled. So I think that's one reason it does deserve a disproportionate emphasis. Now, in fact, other diseases do take a larger toll. More people today die of tuberculosis, and more people today around the world die of malaria than of AIDS. If there were a comparable ratio of malaria and TB in the United States, we would see much more attention to those diseases than they get, and I think it's inappropriate that they be so poorly funded. But there's also a larger issue at stake. Yes, allocating funds with the headline of AIDS does attract people who are looking for various modes of opportunity. If you're interested in viruses, if you're interested in retroviruses, it doesn't matter very much for the pursuit of the more basic questions whether you use HIV or another virus as the medium for that inquiry. Even work more narrowly directed against HIV has a spillover into many other fields and vice versa. It's not an automatic reallocation of scientific resources, because that's where the scientific opportunities lie. In fact, almost all of the very early work in this country on the identification of HIV was done under the aegis of cancer, at the National Cancer Institute, because of the historical peculiarities of where retroviruses were first developed. So things don't come in such neat, tidy packages. That may be frustrating to someone who wants to see all resources devoted to a given diseases. If we knew enough and were able to do that. The fact is, we're groping around in the unknown to a very large degree. There's in any area enormous spillover into every other level. Mr. Porter. Would anyone else like to comment on that question? Dr. Prusiner. Mr. Prusiner. I'd like to comment on it from a slightly different perspective. I think that one of the things that we really need to do in the future is try and keep the NIH at steady growth and to bring more and more young, bright people into biomedical research. We've seen this constant worry about, is the NIH budget going to go up or down, each year, make a number of young people at various points in their career paths, some of them in college, others when they finish their Ph.D.s, others when they finish their post-doctoral training, say to themselves, I'm not going to go into biomedical research, it's too hard and too difficult. I think we have made remarkable progress in AIDS research. I would hate to see this change right now. We're on a wonderful path, a wonderful trajectory to get a vaccine eventually. And in the interim, to develop even more effective drugs to treat this disease. So I think it would just be very wrong to make mid-course corrections because we happen to put a lot of resources into a very important lead. The other side of the coin is, we should be putting these kinds of resources into many other diseases. Not that we should withdraw from what we've done. I think that would be a very big mistake. Mr. Porter. Let me very much agree with you, the best way to aim at all of these questions is to put more resources into all research and make certain that none is neglected. I have to say that over NIH's 50-year history, I don't think there has been a year when funding has not gone up. There might be one. And if you look at the inflation statistics from the same time frame, the rate of growth has been pretty steady, right around 3 percent in real terms. So that while it is subject to appropriations and there are decisions made every year in respect to the level of funding, the support has been through administrations of both parties, through Congresses of both parties. It's always been very strong and placed at a high priority. Mr. Prusiner. But I think what happens is very frequently, the Administration's budget for NIH tends to be a little lower. Congress tends to pull this up at the end. Mr. Porter. We don't pay any attention to them. [Laughter.] Mr. Prusiner. Right. But the rest of the community does, the research community does. And young people see this. And for 10 months out of the year, it looks like the NIH budget is going to go down. Then at the end, the Congress saves it. This kind of, the politics of this, make the young investigators very weary of what's going to happen to them. They are constantly under this black cloud for 10 months out of the year. Then all of a sudden, the black cloud is lifted by the Congress only for a couple of months, then another black cloud comes over. This is something that psychologically has a bad effect. When I talk to various people around the country, whether they be older people or younger people, I hear this constantly from them. Mr. Porter. Dr. Gilman. Mr. Gilman. I was going to say very quickly that I think that black cloud of two or three years ago diverted a large number of people out of Ph.D. training programs in this country. Mr. Porter. Dr. Chu. Mr. Chu. I just wanted to turn the conversation a little bit and say that sometimes, I think Dr. Baltimore said this, and I really want to emphasize it, there are some times when things are ready for larger investments, and other times they're not really ready. You think of starting from an idea, to a start-up company, to where the start-up company needs, where are you putting infusions of capital. There are very good times to put it in, and other times when it would be wasted. If people are doing extremely exploratory things and they're not really sure what's going on, you have to keep it going. So not saying particularly, it appears that AIDS is at a time where continued strong funding will be well spent. Other times, when you think there may be some breakthrough coming along, but you don't see anything, perhaps not so wise to put it in there. Because that will raise a lot of opportunistic organisms that maybe wouldn't be there otherwise. So its' a very delicate thing in the sense that when you have this slow, steady increase, it's really how you apportion that in the wisest way. Mr. Porter. Mr. Wicker. Mr. Wicker. Thank you. Dr. Prusiner, thank you for acknowledging that the Congress provides funds for NIH for research. Let me also apologize for coming in at the tail-end of this hearing. We on the subcommittee have a lot of confidence in our chairman. And there are a lot of things going on today on the Floor. So I'm sorry if I missed most of the testimony. Who are the potential young investigators that might go elsewhere? And where is the best research done in this venture? Are the universities doing the job? Mr. Prusiner. I said earlier that I thought there were 25 to 30 lead research institutions across the country who do wonderful biomedical research, as well as the NIH intramural program in Bethesda. I think that the young people who disappear from science disappear at all levels. They disappear when they're in college, and they don't perceive from their professors that biomedical research is an area where they can have an exciting career path and expect to get funded at a reasonable rate. They disappear in the Ph.D. programs. They disappear in medical school. One of the areas that really deeply concerns me is that of physician-scientists. Because we've seen a steady decline in the number of physicians who are scientifically trained and choose this as a career. Now, we may see this increase a little bit, because managed health care is becoming so brutal. We may see a few people come back in for that reason. But I don't think it's going to be significant. So we're seeing people at all stages of their training run because we have not had sufficient funding, enough funding to increase steadily year after year, to take account of these wonderful opportunities that are being created by new knowledge. So I think we have the manpower as it exists right now. What worries me is the future. Because we're not seeing, I think, all the best and all the brightest young people find biomedical research as an extremely attractive career. I would hope that we could do something about this, in terms of increasing the funding level for NIH to a point where we'll have a more reasonable number of new grants funded, and the esprit d'corps in the research community will increase sufficiently to where the message will be given to the young people that this is really a great opportunity for themselves, to devote themselves to a really worthy cause, to find causes and develop cures for some of these devastating diseases. Mr. Wicker. Yes, sir. Mr. Gilman. I think we'd be naive not to also acknowledge that perhaps we're not doing a very good job in science education in this country from first grade up. And we need major improvements there, we're not doing a very good job interesting the young people in this country. I think the numbers of people, I could easily get the statistics on this, I think the numbers of U.S. citizens going into Ph.D. training programs, at least in the biological sciences, has been quite flat for a long time, at least particularly the numbers of males. The situation hasbeen salvaged to a certain extent by a much greater number of women going into Ph.D. programs. But all in all, we are relying much more on foreign students filling our graduate training programs and filling post-doctoral training slots. Mr. Doherty. I think it's a real problem when the students who come through the universities complete their post-doctoral training, which has become a formal training process in this country, where often these people will be 31, 33, 35 years old, earning only $25,000 to $30,000 a year. They look at their colleagues who have gone to law school, who are now well established and have a straight career path in front of them. Many of these people don't have a straight career path, and they're earning at a low level. We need particularly to develop better mechanisms for taking the most promising of those people and giving them a career path. There's been a shortage of jobs in the universities with the health maintenance organizations causing turmoil in university hiring. So if we had a mechanism that was coming from NIH to support those people through the first five years of their research careers after the post-doctoral period, a stronger mechanism. Mr. Wicker. How do we develop that? Mr. Doherty. There was a mechanism called the Research Career Development Award earlier on. I think maybe we need something like that again. We're doing that to some extent at St. Jude Children's Research Hospital with our own resources, particularly the initial investigators, taking people who have had limited research, giving them a good situation where they can develop their careers and get themselves to the state where they can compete in science. And the good science is now extraordinary. Mr. Wicker. Let me just ask one other question. With all this new knowledge that has been referred to, how much time would you gentlemen spend on the ethical questions raised, and what are the ethical issues in the near future in terms of science and medicine? Mr. Lederberg. I think there's a great deal of ferment about that. I can hardly think of any except the scientists I know are very alert to the fact the work they're doing does have large implications for what we think of ourselves, as human life and so on. You'll get different opinions on where are the most urgent matters. I know that almost anything that has to do with genetics will raise a storm very, very quickly. But I think that may be missing the main point. The main point is that the termination of life is becoming more and more voluntary. People can be put on life-sustaining machines, they can be kept going more or less indefinitely. If all you care about is that kind of technical artifact. That's becoming a grim consideration, the voluntarization of death. We've had discussions about assisted suicide, one far extreme of that kind of consideration. We have trouble defining death, when the issues arise about when it's legitimate to take organs for transplant, and so on. The reason I put an emphasis on this is that the other matters are going to be sporadic. They're going to be just a few odd cases where we're talking about cloning or field research and so on and so forth. I think life termination affects everybody. I put that as the utmost ethical issue. Mr. Prusiner. My comment on this, in the world of neurology, we see this as a problem constantly. Because we see people who are brain dead and yet their bodies can function. We see people who become demented and we constantly are faced with choices that we have to tell families about, that the patient's becoming very profoundly demented, and now the patient develops a urinary tract infection or pneumonia. And you're forced to counsel the family about, should this be treated, should it not be treated. We see this constantly. Sometimes I'm surprised at some of the things that some physicians do who are, for lack of a better word, I think they're uninformed as to just how profound these conditions are in some of these patients. So I think people in medicine and in biomedical research are constantly thinking about these kinds of issues and what can be done. Of course, the simplistic answer with respect to dementias is to figure out how to stop them. But we're not close. We've made a lot of progress, but we need much more research. Mr. Doherty. I think it's very difficult for scientists to really address ethical issues in their actual work. I think we probably get it wrong. Rutherford, the great physicist, describing the atom, said there'd be absolutely no practical consequences of knowing anything about this, and so forth. So really the ethical consequences of what we do and how that's handled really has to rest at a level beyond the actual research scientist. It has to involve lawmakers, people associated with religious organizations and so forth. It has to be a much broader set of people than the actual scientific community as such. Mr. Lederberg. Could I add a further comment? Actually, the National Institutes of Health has taken this matter under very serious advisement. It is now substantially mandatory that every institution which receives NIH funding for graduate training institute formal programs, seminars and courses, discussions, on ethical issues as part of their graduate training. I think that's helped to ensure that there's a lively discourse on these matters on every campus that I'm aware of. It's not been neglected. Mr. Wicker. Thank you very much. Mr. Porter. Thank you, Mr. Wicker. Ms. Pelosi, I imagine you claimed Dr. Prusiner and Dr. Chu and Dr. Baltimore when I was out. Ms. Pelosi. And partially Doherty. He has some California connections. And I'm working on the other two. Mr. Porter. Ms. Pelosi. Ms. Pelosi. Mr. Chairman, I defer to you if you want, because we may have a vote soon, if you had some further questions. Mr. Porter. All right. Ms. Pelosi. I do have some, but I defer to my chairman. Mr. Porter. You may proceed if you like. Ms. Pelosi. Well, okay. I'm going to be a little controversial. Mr. Porter. No. [Laughter.] Ms. Pelosi. There are two issues that I wanted to put on the table for our distinguished panel. One is budgetary and the other is more scientific. In the budget area, it's moreof a comment. That is that certainly no one speaks more eloquently to the need for more funding for basic biomedical research than you all do, and from the vantage point of the successes that you have had, certainly, the investment is clearly worth it to the American people, to the extent that there are other Nobel laureates out there. But the problem is that we only have a finite budget appropriation here. As I've said so often, this is a ``lamb eat lamb'' committee. Everything in here is probably something you would not want to cut. You don't want to cut any assistance we have for public education or early childhood education, because that is your seed corn and I know others have testified to the importance of our educational system, developing our scientists, giving us candidates to be scientists, great scientists, as you are. But the fact is, somehow or other, we're going to have to mobilize these intellectual resources, along with the others in the universities and elsewhere, to increase the size of our budget. Because it's easy for all of us to say, as I do, I want to double the NIH budget for the next five years. But where does that money come from? So while it's wonderful to have this support, we have to understand that there's a bigger budgetary issue, a wall that we have to crack in order to get the resources. So I would hope that you understand that some of us who say the only way we have a right to say we're for doubling the budget in five years, is if we're willing to make the other spending decisions that are necessary. That means going beyond the 602(b) allocation that we have in this committee, figuring out a way. Our chairman has been a distinguished leader in this respect. He has not been one of those who has fenced off any other opportunities for the committee. Nonetheless, those who make these decisions at a different level here put us in this place. Then my controversial question is this. From your vantage point, if you're willing to, you can comment on the budget if you wish. But in our committee, when we come to full committee, this subcommittee goes to full committee, we will have an array of amendments that come before the full committee. At the same time, there will be, shall we say, well, that's precisely what it is, it's a Christian Coalition alert. Anything to do with fetal tissue research or embryo research or funding teaching hospitals that train physicians to perform every reproductive need that is there for, address the reproductive needs of women, the list goes on and on. And we are regaled by the scientific community of all the missed opportunities that are there because we're not able to venture down that path, even though some of the ethical standards were established during the Reagan Administration. Could you speak to that issue? Because I think that we're not going to be able to win that fight in the Congress unless the scientific community weighs in. Up until now, it's been sort of considered an abortion issue, so the pro-choice community and the rest has weighed in on it. But that's not anywhere near the fire power that we need, if indeed the scientists, scientific pursuit is worth the trouble. Do you think it is, and do you think there's the will in the scientific community to weigh in on it? Mr. Baltimore. Let me try to answer that. Just very personally, reproduction is one of the most important aspects of biology and human biology. We've allowed ourselves to ignore research in that area, because it touches on ethical issues, some very powerful political forces. I think that's a great shame. Because I think there's nothing you need to understand more than reproductive biology, there's nothing we need to understand more than early embryonic development. We should be making every effort to see that decisions about these very intimate and very important areas of life are made with the fullest possible understanding. We've basically given up the ability to do that kind of work in the United States because of the political forces that you alluded to. I don't know if you or any other members of Congress are in a position to change that. I suspect the answer is probably no. But I think personally that it is a great shame. Because it's such an extraordinary scientific area. Ms. Pelosi. Thank you. Mr. Prusiner. Might I just mention and amplify on what Dr. Baltimore said. It seems to me that he's correct, that many areas of reproductive biology have their ramifications extend far beyond the course of the fetus. There are many illnesses, particularly when we see young children who are, for instance, autistic, we have no understanding of autism, or very little understanding. It may well be rooted during a very early embryonic period. And we have other forms of nervous system dysfunction in children that undoubtedly occur during pregnancy. And we need to understand, we need to try to prevent these. I think we're being seriously hampered by having all these restrictions. So I think that the scientific community, medical community, the physicians who see these children, the pediatricians, the pediatric neurologists, the pediatric psychiatrists who become involved in the many kinds of care for these many children who create such pain for their parents, would be more than delighted to try to help with this. I think we've all become a little discouraged at times by the political forces that seem so overwhelming. And that don't seem to be based on anything actual, and are somewhat--I don't want to use the wrong terms, but perhaps self-serving. Ms. Pelosi. Well, I'm very respectful of the religious beliefs of my colleagues. But I do think that with proper ethical standards, which I heard you talking about when I came in, and the rest, there must be a way. Because beyond the important work that you're talking about, Dr. Prusiner, there's also the whole idea, what we're told anyway, that Parkinson's, in the fetal research area, Parkinson's and any array of other illnesses could reap some benefit, in embryo research, how cells multiply is very important to cancer research as well. So beyond children, well, that's our most important issue here, children, but even beyond that, the health and well-being of those children's families, their parents and grandparents, are of concern to them as well. Did any of the others wish to weigh in on this? Mr. Doherty. Just to say that I think we must study human development, but if for instance, the situation you alluded to, the Parkinson's, where potentially one could use fetal tissue to correct an abnormality, if we understand what it is that makes that tissue what it is, we may not have to usefetal tissue. We may be able to produce an equivalent cell. But unless we do the study, we're not going to know how that works. So I think it has to go forward. We can't ignore a great segment of human biology as we attempt to define disease. Ms. Pelosi. I'm sure you would agree, as I'm sure everyone here would, that we're not talking about producing any of this fetal tissue or any of these embryos strictly for science. But rather than squander what is available to us, for reasons other than science, that's really what we're talking about. Mr. Doherty. There's also the issue of gene therapy applications in the fetus, that it may be possible to correct some genetic abnormalities. It could be quite predictable on the basis of what's happening with the genome project. We could treat the fetus, but we need to know what's happening with the fetus if we're going to treat the fetus just as we would treat an adult. So if you stop that research, you won't have that process available. Mr. Gilman. I would like to come back to the budgetary issue. It seems to me that medicine touches the lives of the American people many, many times in their lives. Nothing, I think, is more painful than the loss of a loved one or to see loved ones suffer. Never before, I think, in the history of mankind, have we had so many opportunities to begin to really intervene. This new biology that has really occurred over the last 30 years places so many new technologies, so much new knowledge at our disposal. It hurts me to see every day that passes when we're not able to push forward as fast as possible the acquisition of new knowledge, which will make new therapies possible. What I think our government has to do is it has to have a vision which goes beyond the individual person. It is always remarkable to me that people in the prime of their lives who happen to be healthy give medical science very little thought. They never really think about the fact that one day they're going to suffer from one of these devastating diseases. Everyone does. Everyone dies. And they almost have this sort of immortal view of themselves, and they don't really want to face up to what's going to happen later to them or to their loved ones. It's been, I think, you know, great foresight of our predecessors to build the NIH, as we've heard others say already, and to start this really rich tradition of biomedical research to try and develop these therapies, and many of them very successful. Enormous numbers of advances have come out of the NIH program over the past 50 years. I just think it's incumbent on us, trying to look ahead, to do something which is dramatic, something which will take advantage of all that we've learned, so that doubling the NIH budget is a very reasonable target. It's not pie in the sky. The dividends will be enormous. Ms. Pelosi. Well, I appreciate that. It's not the price, it's the money, as you said. [Laughter.] Mr. Gilman. I had a little fantasy scheme a year or two ago. It's probably simply humor. But on the wild chance that it might not be, I'll risk embarrassing myself. Ms. Pelosi. We do that all the time around here. Mr. Gilman. It starts with the fact that we spend less than 2 percent of the Nation's health care budget on research, which is a really disgraceful figure. And there is no technologically oriented industry that would survive such a level of expenditure. I think that fact was in no way better emphasized by, I believe it was Senator Hatfield's proposal that a 1 percent tax health insurance bills would do incredibly wonderful things. It would, since we only spend 2 percent of the budget. My joking comment on that is, I think they picked the wrong insurers. I have a tendency to open my mouth too much, and I'll do it one more time. The health insurers perhaps weren't really very interested in prolonging life. Maybe the life insurance industry would have been a better one to take a look at. I have no idea what the magnitude of life insurance premiums versus health insurance premiums are. But perhaps the life insurers would be much more interested in accepting a tax. Ms. Pelosi. If I may just say, Mr. Chairman, may I? Mr. Porter. Certainly. Ms. Pelosi. I appreciate what you're saying. Just harking back to what Dr. Lederberg said in the beginning about life expectancy going from, what, 49 at the beginning of the century---- Mr. Lederberg. Forty-seven. Ms. Pelosi [continuing]. To 74? Mr. Lederberg. To 76. Ms. Pelosi. That's remarkable, in such a short span of time, such a remarkable change in light of all the years people lived on the earth before that. And so any family, one accident, diagnosis or growing old, people are raising their children, their parents, everybody is very, this is very immediate to many people in the country, as I said, it's an accident or a diagnosis away, or God willing, their parents are alive, they may have to be compromised to get coverage for their health. I think there is a big market for it, but I do think it's going to have some almost radical change in how we budget if we're going to get what we need. In my view, we have a moral responsibility, where we need scientific opportunity, tremendous need, almost a Biblical power to cure at the NIH, to put those resources there. Mr. Gilman. I sometimes also think that part of the problem in getting the public support to committing more resources is that our memories are a little too short. I believe the public thinks that progress has been rather slow. I'd like to point out that there's nothing that could be further from the truth on that. If you look back at drug therapy, for example, over the span of my lifetime, your lifetime, it is amazing. I was born the same year as the first edition of a major pharmacology textbook was published, it happens to have been written by my father, which is why I know that. In that book, there is a three-page table describing the ``routine'' treatment of syphilis with a 123-week regime of treatment with bismuth and arsenic and mercury. The book contains no antibiotics. The second edition of the book, published in 1955, contains no treatment of any sort for anyone with a mental disorder. In my childhood, I remember hearing one of the big problems was, how could we possibly build enough mental hospitals to encompass all the schizophrenics in this country. A few years later, those mental hospitals were being emptied by the discovery of drugs called phenociazines. The progress in the last half of the century has been extraordinary. And the progress will accelerate. So the opportunity is huge. I don't think the public really realizes it. Ms. Pelosi. Thank you very much, Mr. Chairman. Mr. Porter. Thank you, Ms. Pelosi. I and members of the subcommittee have been talking a great deal and strongly advocating doubling the funding for NIH over a five-year period, I have to say, not counting the current year, because I think it's going to be a very, very difficult year this year to make the kind of progress that will lead to doubling the budget. And it will have to start next year. But we spend $13.8 billion at NIH, but the total funding of basic research by the entire Federal Government, all basic research is about $34 billion. And I don't talk just about doubling NIH, I talk about doubling all basic research. Dr. Chu, is this a wise thing to do? Or should we just aim in one direction that maybe looks more promising than others? Mr. Chu. With basic research, you don't really know where to aim. In the sense that surprising things come out, as I tried to indicate, in the line of physics, where the people doing that work didn't really realize, that was not their focus, they were not training to develop a new technique in medicine. Roentgen was playing with gaseous discharge tubes, and found a tool that diagnosed broken bones. So you have to realize that many of the scientific enterprises come from different areas, especially in terms of instrumentation, I think that physical scientists, by their very nature, love to tinker at some level, have contributed a lot to the development of various tools based on conceptually new ideas. You can take a developed idea, magnetic resonance, for example, and say, maybe I can use this idea. The step before that, I don't think, could have been taken by biologists. But once you have been there, who would have thought that fooling around with the magnetic nuclei would have told me how to do my advanced work. So I think, bear in mind that there are some areas more ripe for development than others. There is also another issue, that is, I'm predicting that biological scientists are going to get better and better, there are questions that are going to be asked, they are questions that don't seem so foreign to physical scientists any more. In fact, some of the questions I actually ask myself when I go to my colleagues in medical school and biology, I say, is this an interesting question. I don't want to think about something and have them say, I don't care. Because in the past couple of decades, I think physicists have done that. They've gone toying around with something and biologists say, well, I don't care. But nowadays, I go and they say, that's fantastic. Not only fantastic, I've been doing this for the last three years, we've been trying to go to that goal as well. So if you now see divergent goals, there is an increased swing of the physical sciences not to accidentally something that can see would be useful to the medical profession and just hand it over, but they say, you know, I've been playing with this, too, and I want to join you in the fun. In coming together with the biologists, then you bring something you didn't have before. Because you now have not just a formal handle, but let's work together now. All sorts of new information and synergies and things you just couldn't have before. Mr. Porter. Dr. Lederberg. Mr. Lederberg. I'd like to give some validation and perspective about what the options are for useful results from these budgets. I'm a little surprised this has not been done, as far as I'm aware, I've been making this proposal for quite a few years. I was taught in high school economics to talk about the last dollar rather than the first dollar when you're talking about the merits of different kinds of expenditures, the marginal expenditure. My specific proposal is that you get your staff to get the cooperation of all the other science agencies, give you the panorama of the grants that are at the margin, the ones that were just not funded, and do it right across number of fields. Because that's what you're losing by not increasing your funding capability. You'll find it variable from one discipline to another. But pay lines run around 15, 20 percent. That's the fraction of proposals which are intrinsically quite worthy that end up being funded. If you could actually see what's being left out because there wasn't enough money to go around at the 23rd or 24th percentile on the pay line, you'd get a much more vivid picture of what it is that could be remediated by enhanced funding. I urge you to do that. Mr. Porter. I think we're running now, according to Dr. Varmus, at something close to 30. And the intention is to push that up higher as we go. Dr. Baltimore. Mr. Baltimore. Let me take a perspective that looks more broadly at science. I'm now the president of an institution that really focuses on the broad scale of science. So I've been exposed to people working in a whole range of fields and talking with them. I am impressed that the other sciences intrinsically, never mind their relationship to biology, but the other sciences are in general as vibrant, as exciting, as full of opportunity as the biomedical sciences. Astronomy, astrophysics, cosmology, is giving us a view of the universe with parameters we have never before imagined. The earthquake, seismologists and earthquake engineers are coming together to try to understand the forces at work in the earth, both from a practical point of view in trying to ameliorate the consequences of earthquakes and from the very scientific point of view that an earthquake is a remarkable probe into the earth's structure. And in fact, a prize was just given to two scientists, one from CalTech, who had studied the structure of the earth using earthquakes as a probe. Physics, chemistry, and I can go on, are all in a position now to take advantage of increased levels of funding. So when you talk about increasing the funding across the board in the sciences, I don't think the reason for that need be that it helps biology, although I certainly personally think that's a terrific opportunity. But because of the intrinsic power that the sciences have today. Mr. Porter. Let me add to what each of you has said. There's two other reasons I think are important. One is, we don't want to set disease against disease, which is what you do when you keep a static amount of funding. Neither do we want to set one science against another. I think they haveto all be valued and brought along at a relatively equal pace. Or you do set them one against the other. And while we have, over the last three and half years, increased funding for biomedical research rather dramatically compared to the rest of the budget, a lot of basic science funded by the Government has not done nearly as well. That worries me, from a political standpoint, a strategic standpoint. Secondly, it seems to me that from an economic standpoint, the future of our country lies in education and technology. If we don't make the investments now in both of those areas, we're going to have serious problems in the future. So from the standpoint of the economic quality of life, 30 or 40 years from now, I think the investments have to be made now. With the economy doing as well as it is doing, this is obviously a very good time to engage in the debate as to how this money ought to be spent. And just to lobby all of you, your speaking out on the importance of investment in basic science and research is very, very important. We've got a lot of priorities being argued for here. Protecting Social Security and Medicare and building more roads and bridges, and cutting taxes and paying down the debt. It's hard to argue that those aren't important priorities. But I think if we don't make the case for science, we can easily be left behind. The problem is that it did not needed to be made in the past, because we were doing a fairly good job of funding the available science that was there, the good science that was there. But now there's so much more good science there, that even with the kinds of increases we've had over the history of the NIH, we're funding too little of it to bring the young investigators to the table and keep them there. So this is a time when we really have to make a case for biomedical research and all basic research, more than ever before, in a certain sense, which is strange but I think true. Mr. Prusiner. Can I give you an example, that takes us all the way, I think, from physics and chemistry right to the patient? I think this is very illustrative of what we need. When we are able to use molecular biology and get at the gene, we now have a protein. The next thing we want to know from translating the gene to the protein sequence is how this protein folds up. We want to know its three-dimensional structure. The reason we want to know that is so that if that protein is involved in a disease process, we can develop a small drug which will modify the structure of that protein and make the bad form of that protein harmless and cure the disease. The problem, the biggest problem that faces us is really very similar, prior to the wonderful gene cloning technology that was developed. Before that, we could do very little in genetics. All of a sudden, with gene cloning, recombinant DNA, the whole science of molecular genetics evolved before us. It's very simple to access the sequence of genes. Then from that to translate that into amino acid chains, the protein. But what we don't have are very good techniques at determining the three-dimensional structure of proteins. We only have really two of these where we can know this in detail. One of them involves x-rays and the other one involves, as Dr. Chu said, magnetic resonance. We need desperately much better techniques, much better technology. And when we get it, it will revolutionize our ability to rationally design drugs for illnesses, just the way recombinant DNA technology revolutionized genetics. So I think there, biologists really need the help of physicists. They really need the help of chemists. And we don't have good ideas on the horizon. That's why we need a lot of basic research in an area like this, which is so fundamental to moving medicine forward and coming up with new therapies. We're beginning also to learn, particularly from my own work on prions, that where we thought that each protein had only one three-dimensional structure, we're finding out it can have more than one. It can be two, it can be many more. We just don't even know the limits, because our technology is so primitive. Mr. Chu. When I was speaking, I was addressing you as the chair of the appropriations subcommittee for NIH. I applaud your wisdom regarding the physical sciences. There are no hearings like this in DOE, the NSF, that I know of, and I inquired around a little bit. The whole structure of the scientific community, the whole enterprises, it toggles back and forth. If one could see a doubling at the end, where it will be money well spent, the time is right. I also agree that the time is also right for large increases in other sciences as well. It's just fantastic what's happening. And the two are coming together in very strange ways that I find both fascinating and exhilarating. People working on better and better transistors, we're going to smaller and smaller scales. Making things at the scale of a dozen atoms wide, developing technologies to see what they're seeing at this scale. And those same technologies are now being transferred over into the biomedical sciences. I myself am beginning to work on these things. Again, as a different type of imaging technique. So here you have something pushing transistors in electronics, which is a huge industry, where the United States, fortunately, is the inventor and remains the leader. And all the scientific energy and engineering energy being put into that area can now be used in another area. And likewise, I think the solid state engineers, chemists, physicists, can learn a lot by studying things that have been engineered over roughly a billion years. [Laughter.] Mr. Porter. Let me give you some reassurance on this. Because we're about 10 months into the time when the Speaker of the House was convinced that we have to address this in a very broad way. He's brought together the appropriations subcommittee chairmen that fund research, and fund it in a lot of different places in our Government. It covers maybe 8 of our 13 subcommittees. He's also set up a task force that will work through the Science Committee, the authorizing committee, to look at all science funding across all departments of Government, and bring together an overview of what we should do in respect to all that funding. The commitment's already made, though, to double funding for basic research throughout the Government. The question is, where do we get the resources to do that, obviously. Let me ask a question before I call on Ms. Pelosi, let me ask a question of Dr. Doherty. I understand you have to catch a plane. You raised an issue that might seem in a way not relevant to our discussion regarding population growth and world peace, stability. I'd like you to expand. This is one of mine and Ms. Pelosi's very strong interests. I wonder if you could expand your thoughts in that regard for us. Mr. Doherty. I think the perceptions of those who work with infectious disease, and especially the perceptions of the group that put together the methods to vaccinate all the world's children against the common infectious diseases, the initiative that was launched two years ago, in fact, it was called the year of the vaccine. I believe that's gone ahead. It was a very broadly based coalition that involved physicians and involved Rotary, who provided all the polio vaccine, for instance. Something like 10 million children in India were vaccinated in one day. Now, part of that perception is that the only way we're going to be able to see people in developing countries limit family size is if we can ensure them that children will survive. There are no social security systems. Your only social security system in a country of that type is to know that your children will be there to care for you when you're old. And of course, the children are also in many ways involved in the economic health of the group. So unless we can do that, we can't expect the process of rational reduction that we've seen happen in all western societies will occur. Now, that's no guarantee. There are some signs, I think in Pakistan, it's a bit disturbing, that as disease is being controlled that it hasn't necessarily resulted in more control of family size. But I think it is the only way we can see forward to deal with these issue. Mr. Porter. My understanding is that it takes a while to adjust. Mr. Doherty. It does. Mr. Porter. That it won't happen in a generation. Mr. Doherty. We were talking earlier about broad ethnic considerations. I think various of the groups that have a great ethical say in our society haven't yet even taken on board the consequences of the medical revolution in antibiotics, and so forth, for population size. We've disturbed, if you like, the natural order of things, by stopping children dying. If you lived in the 1920s or 1930s, or in the 19th century, death of your children was common. Much of the children's rhymes of that period reflect this sort of thing, the fact that children did die. We don't expect children to die any more. St. Jude Children's Research Hospital gets an enormous amount of money to work on childhood cancer, which actually kills relatively small numbers of children. But it's just seeing a child die, it seems so incredible. Mr. Porter. I don't think the scientific community often speaks out on the question of what the effects of a population growth that we're seeing now in the world has on our future. Mr. Doherty. It's been stabilized in a lot of countries. I think what we saw in Rwanda was clearly a situation exacerbated, that where you have a bad political situation, exacerbated by the fact, I think, in that state, was the most overpopulated country on earth. And now in areas of Kenya we're also getting to the stage where we're seeing rural economies with 1,000 people pre square mile. These are not cities, these are people supporting themselves in a rural environment in the density of 1,000 people per square mile. Kenya is becoming substantially destabilized from what I can see recently. Partly it's political, because of the situation with the president. But partly, it's due to the fact that the population's been growing extremely rapidly, both by natural growth and by refugees coming down from sub-Saharan Africa. And also by the number of arms that have been coming down from the north of them, particularly. Mr. Porter. There are also obviously environmental effects from overpopulation. Mr. Doherty. Environmental effects are disastrous, yes. Denudation of forests, and so forth. And there's also the effect of course that in general, AID dollars, particularly in Africa, are being pulled, as aid is going more into central Europe, people have given up on some of the African governments. There's a general tendency in international aid communities now to only want to give money for very, very short-term type of results that will look good politically. It's understandable that it is having that constant response. Mr. Porter. Ms. Pelosi? Ms. Pelosi. Thank you, Mr. Chairman. I think it's appropriate that we went down the international path for a moment, anyway, because so many issues know no borders. Dr. Doherty, I was thinking about what you said about the need for, the concern about population. That's one of the reasons why we're going more in this direction, not just talking about family planning, but talking about saving of children. Because if we can say, says I, who had five children in six years,--but if we can say to these mothers that if you want two babies, have your babies two years apart, there's a better chance for them to survive, in the environment these people are in, it may be a little more accessible to them, that they will be able to have children, that they will continue to have children, but that they're spacing them in finite lengths of time, that will produce fewer children. Mr. Doherty. The international agricultural research community has a major concern with the empowerment of women. To give women economic power can make an enormous difference. That gives them the power to make their own decisions. For instance, there's a very interesting program in India, where, funded through international aid, they are encouraging women to sell milk. Women control the cows, the cows produce the milk. If they sell the milk, they get an income. If they get the income, they get certain other status with their husbands and so forth. So empowerment of women is part of this whole thing. Ms. Pelosi. Chairman Porter and I also serve on the Foreign Operations Subcommittee Appropriations where many of these international family planing-child spacing, empowerment of women and economic development, all those issues are important to us and what you're saying is music to my ears. I know it would be to Mr. Porter also if he were in here. We were both actually declared champions by the Eradication of Polio Coalition just a couple of weeks ago. So we're very familiar with that wonderful effort. I know you have a plane to catch, so I will not dwell on that. But perhaps another time, you could come before our Internationalsubcommittee. Mr. Doherty. I'd look forward to it. Ms. Pelosi. Our scientists, I talk to Dr. Varmus when he's here, and I talk to USAID when they're there, to tell Dr. Varmus that we're interested in international collaboration, then he tells the USAID, to share what they are finding here. To get back to the Chairman's point, though, about the other physical sciences impact on the biomedical research, I recently attended a conference put on by the Council of Competitiveness that was at MIT. Perhaps some of you were there. But over and over again in the workshops, and in the general sessions, etc., they talked about the fact that there was such a little bit, such a small amount of heavily-funded R&D in those other sciences. Not that they were--Dr. Varmus was there, he heard people say how it wasn't pitting one science against the other, but the message is clear, there isn't enough money. That sometimes is the case. It made such a, there is such a strong argument for us doing much more R&D. Because I believe, Mr. Chairman, that in addition to expanding our industrial and technological base, we're also increasing our revenue base. So I don't even think it's going to cost us anything to make those investments. I don't think it costs us anything to make the investment in biomedical research, because it increases our competitiveness internationally as we move these products along. I had the occasion to ask Andy Grove about the possible synergy between the physical sciences and what's happened to ECFF. Perhaps you were at that meeting with him, it was an ECFF meeting. We asked about any marriage between the ECFF type research and what was happening in Silicon Valley. He thought the cultures were very, very different. He pointed out what the challenges would be there. Nonetheless, as with many of the business people that have come before our committee, what they need most from the Federal Government is investment in biomedical research, so too, in order for us to remain competitive on the technological side investment is needed there as well. Over and over again we were hearing from the captains of the technology industry that they need the government to help fund research. And we have dropped off. I'm interested to hear what the chairman says, with this leadership that he's proposing. Because under this leadership, of course, we've lost other sources of funding for this research. I see this on the Intelligence Committee, as a member of that committee, where we have had some attrition in the funding of the other sciences. So I'm very encouraged to hear what you say about the intention. I'll be interested to see how they're paid for as well. But we keep saying, in the Intelligence Committee, we want that science that we have for imaging, for satellites to photograph the earth, to be available for mammograms. We see a translation from that kind of research to help us in biomedical fields, as you have so eloquently testified to. It's all related. Again, I'm pleased to hear what the Chairman had to say about it. I don't have any further questions, Mr. Chairman, except to say thank you once again for making this wonderful opportunity possible for our committee to have this excellent panel. I thank all of you. Mr. Porter. Ms. Pelosi, let me say, I think I've learned that what I must do is have, to ask the Nobel laureates to come early in the year, before we have votes to interrupt us, and members that have so many responsibilities outside. We'll try to, I hate to say this, try to plan it for January, maybe, rather than this time of year. And while Washington isn't nearly as pleasant as it is now, we hope that you can also attend at that time. Let me ask, we talked a little bit ago about life expectancy and how it has grown. Ms. Pelosi highlighted that. We've also talked about the research enterprise in this country being so much stronger than it is in other parts of the world. But life expectancy has grown in other parts of the world even faster than it's grown here, apparently. Have they simply adopted our technologies to their health care systems, or why is that true? Mr. Lederberg. Well, the short answer is yes. The knowledge that we can use for health is fungible and exportable to other economically advanced countries. We're about a year behind Japan, which I think is the world leader. Part of the other European countries. You have to look very carefully, because obviously different economic and social strata within our own country benefit to different degrees from these advances. They're all progressing, but some are further behind than others. One that's worth remarking on is that men aren't doing as well as women, by a long shot. That's been true for many, many years. Life expectancy for women in the United States is 79, and it's 73 for males. That gap, if anything, is widening. Women are experiencing a more rapid advantage from improvements in health inputs than men. Now, they may be making up for it as more women take up smoking and things of that sort. They may be equalizing the balance to some degree. But one should also look at these numbers as an opportunity. If we more thoroughly understood the difference between the outcomes in males and females, I think there may be ways of--I hope there's no objection to this--of removing some of that differential advantage. Whether this is intrinsic to the two Xs, there being two X chromosomes in the female and only one in men, so there's less buffering against genetic adversity, or whether it's direct effects of estrogen, there are some pretty strong hints that estrogen can be an important protective factor against atherosclerosis. And that might be a significant element of these distinctions. But the short answer to your question is, yes, other countries get advantages, some within their own social systems, not having the heterogeneity we do in this country, be able to provide them even more quickly to a broader advantage. But a rising tide is floating up all the boats in this arena. Mr. Porter. Perhaps on the male and female difference, we're spending too much money on diseases affecting women. Is that the case? [Laughter.] Mr. Lederberg. Whether you like it or not, there's a spillover that affects the health of males as well. Mr. Porter. I'd like to raise with you the question of personal reward of scientists. And by that I mean, I think it was Dr. Prusiner who said that we have to be concernedabout attracting, well, I think all of you touched on this, but Dr. Prusiner in particular, that we have to attract young people to come to scientific research. I wonder if you could delve into the more practical side of personal reward. Obviously, people are motivated by more than economics. But the economics plays a role in this as well. Are we providing the kind of support that leads people who might be inclined to a career in science and research by the economic rewards, or are we failing in that area? In other words, is it a tough thing to put all this investment in and see not much ahead in terms of your family, educating your kids? Mr. Prusiner. Well, I think to begin with, we are under- investing at the level of post-doctoral training fellowships. There are proposals to increase these by 25 percent. We are so far behind in terms of making this attractive. We certainly need to do that. The second thing we need to do is to provide, as talked about earlier, perhaps reinstituting these research career development awards, which were so successful. I myself had one of these from the NIH in the beginning. So this helps create the kind of early funding which is needed. And of course, we need to increase the size of those awards, not just reinstitute what they were 15, 20 years ago. I think scientists, on the other hand, are not people who, they of course need to be able to earn a respectable living. But I think that's not what's driving a lot of people away from science. What drives them away from science is the uncertainty of having their research proposals funded. When the numbers have gotten very tight, at the 10 percent, 15 percent level in some institutes at the NIH, and the 20 percent level, not only do they see their mentors having enormous problems, but they can't imagine themselves being able to survive in such a system. So they don't see this as a kind of life they want to take on, because they see it as being so uncertain, so difficult. And of course, their ability to gain research support and do this consistently is directly related to their ability to advance within a university system. If they aren't able to acquire research support and then get their grants renewed, they're not going to be promoted. So again, the personal economics is tied to that. But I think it's more than personal economics. It's really the grueling and very stressful nature of the competitive grant process. We need to make it just a little less competitive by having more funding available. I think we also at this edge, as Dr. Lederberg was talking about, the grants that aren't funded, that's probably where most of the most innovative grants are. It's very hard for people, for that scientist, to step back and judge what's going to be successful five years and ten years down the road and who the very best people are going to be who emerge. Because just by the nature of science, we don't know what the very best science is going to be. None of us have a crystal ball. So I think it's extraordinarily important that those grants at the margin, so that we increase from 25 or 30 percent up to 40 percent, which is what doubling the NIH budget will do for us, that those grants be funded. That will then increase, I think, the excitement among the established investigators for continuing their work. It will bring the young people into this. And people, I think, on all levels, all stages in the system, will find careers much more attractive. Mr. Porter. Dr. Baltimore. Mr. Baltimore. Let me address that perhaps from a slightly different perspective. Training in biomedical science today is a long process. People go through as undergraduates, they go to graduate school, they get post-doctoral fellowships. It's not unusual for somebody to start their first independent position in their mid-30s. We ask those people to live on pittance during that time. Many are willing to do it. Not many, but the ones who do it are willing to do it, they have no choice. Almost none of them have resources of their own. They tend to be immigrants to the United States, or born of immigrants. They see it as a way to find a place for themselves in the American firmament. That's terrific. But we really do have to ask why so few people born into second, third generation, later, American households, are willing to go into this kind of field. One of the reasons, I believe, is because the ability to earn a living up to age 35 is so limited, that it's really impossible to imagine having a balanced life of any sort on the amount of $21,000 a year, or $23,000. Impossible to imagine having a family. So I think we put a very high bar up to a career in our field. Mr. Porter. Dr. Chu. Mr. Chu. I just also, in addition to this suffering when you're young, people are amazing. They're willing to put up with a lot of things when they're young, if they see a light at the end of the tunnel. So you can pack all sorts of students in dormitories, if they know five years or ten years down the road that they're going to hit a point. In fact, when I was flying here, I was flying next to an airline pilot, a pilot for United Express. Well, United Express means you go up and down many, many times every day. He's a co- pilot. But the light at the end of the tunnel is, once you get into this program, he sees some days later, maybe 20 years later, or 30 years later, he will be piloting a 747-400, and getting $250,000 for it. What the young scientists remark to me, when I say, I'm worried about funding, I'm worried about where the next years of continuous funding are. They're saying, they literally have said to me, if you're worried about this, what chance will I ever have. And if you're stressed now, I mean, forget about getting started. If you're stressed now, how could I think of not being any less stressed 20, 30 years down the road. So there's no light at the end of the tunnel. Lots of people are willing to work for $25,000 a year for a few years. Look at insurance. Because there is a light at the end of the tunnel. And so it's the whole package. It's not actually the money. We're not talking about paying scientists $4 million a year. They don't need that. They don't even need half that, for the most part. What they need is less stress, and enough to make a comfortable living and see, okay, now I've arrived, I can do things I wanted to do, and I don't have to worry literally from year to year where the next meal is coming from. Mr. Porter. Dr. Lederberg. Mr. Lederberg. I'd like to concur, and I'd like to add aspecific remedy from which a rather botched experiment has been done. It was totally misunderstood. This has to do with relief of stress. It's quite typical for grants, when they are successful, to be for no more than three years, sometimes just two years. When you look at the dynamics of what this means, in terms of how long it takes to submit a proposal, have it reviewed and have the reply, from the time that you've received one award, you have about a year clear time between when you have to start preparing your renewal grant application. You're living in a guillotine. And I think that's just an absurdity. My simple remedy is simply to expand the typical term of grants from two to three years to four to five years. In fact, the great majority of those renewals will be satisfied, an enormous amount of commotion is generated in the process of that reaffirmation, they make you drop out before you come back again and so on. Unfortunately, the way the bookkeeping was done, in order to achieve, and there was an interim experiment some years ago, an extension of grants, it appeared as if it was going to be at the expense of new grant applications, which it was not at all. It was just the bookkeeping heart attack. I think a re-examination of that issue, about the merits of looking fundamentally about reducing the number of times you have to have your neck in the noose, so you could spend more time doing your research. Now, obviously, some accountability is important. You do have to have periodic revisits. But it's too much, too often, too severe. And I think it really burns up a lot of the energy that should be going into the research itself. Mr. Porter. Let the record show that Dr. Ruth Kirschstein was nodding yes as you were saying that. Dr. Kirschstein. I think the average length of a grant now is four years. Mr. Porter. I'm glad we corrected that. Dr. Kirschstein. We have increased the length and probably will try to continue to somewhat do so. Mr. Porter. Dr. Prusiner, when you said that if we double the funding for NIH, we will be funding hopefully at 40 percent level, that probably won't last, though. Because we will again increase the body of knowledge, and there will be more good science being offered, and probably driven down again, so we won't be funding as much as we want to at that point in time. That leads me to another question for Dr. Gilman. Dr. Gilman, you said we spent 2 percent of our entire health care costs on research, I believe, is that correct? Mr. Gilman. That's the number I've heard. Mr. Porter. Isn't part of that problem, though, that you've been so successful? In other words, aren't the discoveries outstripping our ability to provide the fruits of those discoveries to our population, costing us a great deal of money? When we learn to replace a liver or a heart, then obviously there are people who need those replacements, and the demand for them goes up, they're very expensive. We can't always afford to do everything that we know how to do. Mr. Gilman. No, we can't. I think when new technology comes along, it inevitably is going to cost quite a bit at the beginning. And I think those costs will come back down. I think also as a country, I would hope that we would be happy enough to pay for its success. And that if the problem is increased appropriations bringing us a great deal more of additional knowledge, we'll face the problem how to pay for even more with smiles. Mr. Porter. I agree with that, but I wanted to get your answer. Yes, Ms. Pelosi. Ms. Pelosi. I heard Dr. Gilman's statement quite differently. I was thinking when he said it that we don't spend enough on early intervention, on research on addiction, which leads to other health care spending. And I thought that if we spent more on research, with these new discoveries, we need to spend money to make them available to more people. But on the other hand, in terms of prevention, early intervention, knowledge that we gain in the genome project and the rest---- Mr. Gilman. It clearly works both ways, just what the individual problem is. Some new technologies are very expensive. Some very cheap drugs eliminate entire classes of surgery. We can cite many different kinds of examples on both sides. Ms. Pelosi. Thank you. Mr. Chairman, I just wanted to comment that on other occasions such as this, we have, at the kindness of our Chairman, had this opportunity before with other Nobel laureates, we talked a great deal about the brain, in this decade of the brain. I don't know when I was at the Intelligence committee if much discussion went on about that. I think not. But it seems to me that must be a given, now, that that's so important, that the strides are so great that it almost goes without saying, when we've asked the scientists before, where is the area of the most promise in science, biomedical research, a number of them in earlier years said the area of the brain. By that, they did not mean psychiatry. Well, that's what they said. Not to put down psychiatry, but just in other areas of the brain. So I assume we are not focusing on that today, it hasn't been brought up. Actually, it has been brought up in your testimony, but not so much in the way it was before, because the benefits have been so overwhelming and so clear. Mr. Baltimore. I don't think it's so much that the benefits have been so extraordinary as that it is now widely understood that the greatest challenge we have is understanding the brain. But I think one could easily reiterate that. It's not that we learn so much that the problem's gone away, it's just that we widely recognize that that is our challenge. When we talk about new methodology coming in from physics, coming in from computational science into biology, one of the places that we look for the benefit is in neurobiology, neuroscience. Because the brain is still, by many orders of magnitude, the most complicated biological problem we have to face. We don't know how many different neurons there are. But we know that the number is enormous. We don't know what the codes are that neurons use, but we know that they're complicated. We need to answer questions like that, simple anatomical questions, very complicated questions in the information process. And we probably can't do that with the technology we have now, we are very much technology limited. So this is an area of tremendous opportunity, tremendous promise, should, in fact is receiving increasing consideration, increasing resources. And promises tremendous excitement, both in dealing with the kinds of problems that Dr. Prusiner emphasized, the diseases of the brain, and in understanding how the brain works, so that we can actually understand what learning is about, what memory is about, that we can teach people within the context of how the brain works, rather than just doing it the same way that our grandparents did. Ms. Pelosi. When I said the benefits, I meant we had inspiration that the prospects were clearer to us. I take it by your remarks that the cohesion of the sciences, biology, physiology, etc., together with medicine and the convergence that you referred to earlier---- Mr. Baltimore. Very much is around neuroscience, yes. Mr. Gilman. Everybody talks about the fact that we're entering a new age in biology, which we are. It also means we're finishing an age in biology. I think over the last several decades, many of us have been real reductionist. We've been looking for the pieces, identifying the molecules, taking the system apart a lot and learning what it is made from. This reductionist age is going to soon be concluded with the human genome project, etc. We're going to know all the pieces, and all the millions of puzzle pieces are going to be on the table in front of us. That's going to be the time that we're really going to be able to start putting the puzzle back together. We've been trying to put the puzzle back together, but because we don't have all the pieces, it gets to be sort of a pain in the neck. Now we have all the pieces. And I think this is going to be one of the things that will be enormously profitable to concentrate on if more money becomes available, will be real interdisciplinary, multi-institutional consortiums of efforts to really begin to be truly integrated in the way all this information gets put back together. And there's no place like the brain where, that will require supreme effort there. But that will really be the ultimate goal, I think. Ms. Pelosi. Very exciting. Mr. Baltimore. Yes, it is. Ms. Pelosi. All we need is the money. [Laughter.] Mr. Chu. Let me also say that I agree, there are more tools we need in order to really get inside and look at what's happening. Before it was a matter of really, literally being wired to electrodes. Sometimes you just can't do that. So there are many new tools that are being invented now, being developed. There is the opportunity, when you speak of, I would say systems engineering now, as we get more and more, why is it the systems have been built this way, what are the design rules that made this engineering trade off. But finally, there is something else that I find fascinating, and that is, there are, I worked at the lab for nine years. There is one biology group that still lags, and that has to do with the neurobiology. Why? The brain is a wonderful computer. Based on what it can do, what it has and the fact that its internal switches are going very slowly, it actually can process many, many, especially visual information and pattern recognition, in ways that our biggest investigators can't do. So here again we have the engineering experience, let's find out how this thing works, and maybe we can do that, use some of these ideas and things we build from scratch. So again, some of the driving forces in neurobiology, on the physical sciences and engineering side, are also taking us closer. But ultimately, on the biological side, we need much better, more powerful tools. It really is an area where many scientists and biologists are realizing the opportunities. Ms. Pelosi. Any of the tools necessary for cosmology helping us in the lab? Mr. Chu. It's hard to say, but I would say, surprisingly, some of the mathematical models have a way of popping up here and there. Mr. Baltimore. The imaging technology that's used to gather information with the most powerful telescope does have its application in gathering information. Mr. Chu. Pattern recognition actually, in mammography, that type of imaging technology is now in use. That was developed by NASA. Mr. Prusiner. Let me just respond in a little more practical sense. I made a list, I'll try to be very brief, seven areas where I thought in the nervous system, there were real opportunities just around the corner in terms of horrible brain disease. I touched on the neurodegenerative diseases, so I won't go back over those. But for instance, in alcoholism and drug addiction, we're learning a lot about signaling. I think a lot of that new information is not far away from being able to really intervene in a meaningful way in these conditions. And of course, coming back to what was said before, I think you raised that, the benefits from being able to treat alcoholism, in terms of cutting down on the number of criminals who occupy our jails, and the benefits from treating drug addiction, cutting down the crime that goes on all the time, it would be just enormous to our society. The savings would far outweigh the research monies that would be spent. If we look at stroke for a moment, we're all very excited about PTA, using this protease to treat early stroke. But it's really pretty primitive in the fact that we have to recognize the stroke, do a scan of the brain and in three hours institute the therapy. We need much better therapies. It's the third leading killer in America, stroke. The devastation in terms of chronic illness that's created by stroke is just huge. We go on to another area, schizophrenia, bipolar disorders. Neurologists are fond of saying, well, you know, some day, hopefully in the not too distant future, these will be neurologic diseases, not psychiatric diseases, because we'll we understand the chemical balances that go on, and we'll understand why they go on. And I think we're just very close to having some meaningful genetic studies that will tell us something about this. There have been some results and they haven't been confirmed. That tells me that we're not far away. And we look at a disease like multiple sclerosis, the greatest crippler of young Americans in the prime of their lives. And we're still struggling with this. We need desperately more investment and more young people to get into this field and try to figure out what is going on. It's been such a roller coaster. People thought they had therapies, people thought they had a cause or causes. And we still have tremendous numbers of questions. And in the field of cancer, we've been making a lot of progress, obviously, but brain tumors have been increasing at an alarming rate. And we don't understand why this is. We have no idea. I think all of us look at traumatic damage to the nervous system, spinal cord injuries, injuries to the cranium, and there's such a need for drugs to promote regeneration of nerves. This would be so wonderful. So there are so many areas that are just right or close, and a few that just need enormous amounts of research. We just can't tell where these breakthroughs are going to come at any moment. But I think there are so many opportunities, we're losing the opportunities by not pushing harder. Ms. Pelosi. We've had big changes, don't you think? Mr. Prusiner. We've had big changes, but I think we've had more of a sort of an enlightened period, where many studies in neural biology are beginning to catch up to some other areas. We're just really at the beginning. We're sort of at the beginning of the decade of the brain, after spending a decade thinking about it, seeing the progress. Ms. Pelosi. I thank all of you again. Mr. Porter. I know several of you have to catch airplanes, and Dr. Doherty slipped out before I could thank him, but I think if all the members of Congress could hear what we've been privileged to hear this afternoon, they would flock to the concept of increasing funding for research in the way that we hope they will be inspired to see all the opportunities that are lost if we don't provide that kind of increased funding. Let me ask each of you who want to comment on this, and I hate to talk about practical things, but I think it's necessary. Our scientific research infrastructure, something that Dr. Varmus has put at a much higher priority this year than previously, what do you think we need to do in that area to provide the kind of structures and equipment that is needed to conduct research, and are we doing enough? Mr. Baltimore. I think there's no question that the future of biomedical research will depend to an increasing extent on the quality of the instrumentation that exists in laboratories. We are more and more able to take advantage of very high resolution machines, of whatever sort. But with those increased resolutions come increased costs. And increases to the point where you can't put things like that onto a grant. They just are so out of scale with the size of the rest of the grant. So they need to be separately funded. Nothing has been knocking on my door as the President of CalTech more in the last six months than needs for equipment. For chemists, many of them working on biochemical problems as well as the biologists. New methods of visualizing molecules and methods of visualizing cells, there are tremendous microscopic advances in looking at cells, live cells in real time. But they're very expensive techniques. Because you can't put much energy into frying the cells, so you've got to be able to work at very low energy. I think Dr. Varmus is correct in making infrastructure a very serious issue. Mr. Gilman. That's absolutely true, and I'll second what David said about large instrumentation, the shared instrumentation programs in particular. I'm not sure how many of them cross institutes at NIH, but they should cross institutes. These are absolutely critical. I'll just put in a little pitch for more mundane instruments, too. I think budgets have become so tight over the last several years, the institutes have been trying to stretch the pay lines, that even replacement of modest equipment has been extremely difficult. We've had a grant for 10 years, 15 years, we've got something as silly as a broken freezer that has been difficult at times to replace, a $5,000 equipment replacement. So both small and medium equipment on individual grants, and major equipment on shared grants is really very important. Mr. Chu. Also, I would say in terms of beating some of the stress, sometimes principal investigators have to run the whole show. They have the instruments, whether they're large or small. When they break, they're constantly worrying about this. Quite often, in many departments, schools, whatever, institutes, you're beginning to see people getting together and saying, okay, someone, something is going to run the cold room, run this or that. And in physics, there would be similar sorts of things, the electron microscope. So you take your sample and you give it to someone and say, here, look. Take care of it. It's very hard to get funds for this continued maintenance work. It's impossible to get endowments for that type of work. And if I look at the contrast between what I had at the laboratories, it just took your mind off a lot of things, you could concentrate on the science, not having to maintain something you needed, but had no desire in becoming professional across spectrums. Mr. Baltimore. Could I just comment on that? The other day I was talking to a young scientists who had been interviewed at the Whitehead Institute. The Whitehead Institute is an institute that I helped Mr. Whitehead found in affiliation with MIT. It's a quite wealthy institution. It initially had a $100 million endowment. This guy who had just visited the Whitehead Institute said, you know, the atmosphere there is terrific. Of course, I remembered that, I tried hard to help that develop. He said, people are not stressed. I thought back to it, and I said, you know, that's really true. And it's true because we had sufficient money to do the kinds of thing Steve was just talking about, to provide help for people who need help, to provide resources so that if somebody finds themselves without a grant, they know that the ceiling is not going to fall in on them. Those kinds of institutional resources that make for a more effective research environment and a less stressful environment also make for a much more creative, productive and effective environment. Now, I don't know what you can do about that. Because we're talking about really institutional infrastructure. But there was at one time grants from NIH basically focused on institutions rather than individuals. I think those things can make a huge difference. Mr. Chu. One addition to that. Sometimes we are asked the question, how much time do you spend writing grants. That's not the right question. How much time do we spend worrying about grants. [Laughter.] Mr. Porter. Dr. Lederberg, when you were making your statement at the beginning, I wrote down virus wars. You were talking about death being an unintended consequence of microbes trying to survive, I think is the way you put it. And the question, then you talked about antibiotic- resistant microbes, and the problem we face by their becoming resistant to the drugs that have been developed. If you look at the whole picture, is there a way that we will ever win? In other words, will we ever overcome all the afflictions, or will they simply metamorphose into a different form and keep us battling on into eternity? Mr. Lederberg. I think the latter is closer to the likelihood. We share the planet with a lot of species. We can be quite successful in eliminating some of the endangered ones. But these are the fish and the birds and the mammals, and we do that inadvertently. We're certainly never going to eliminate microbes. And God forbid that should happen. They are truly part of the balance of nature. I think we have to face up to the fact that some of the most grievous infections might be controlled, or in a rare number of cases, eradicated. Polio is well on the way, smallpox has been. But there's also the reservation that you then put yourself in a state of great vulnerability if they should ever come back, if you can't maintain, it's not as if we can drop our continued vigilance and have preparations to be able to deal with these issues if there should be a recurrence. Right now, for example, our stocks of vaccinia that might be brought into play if there should be a resurgence of smallpox are down to a few hundred thousand doses. And there's no manufacturing facility, there's no industry ready to back them up. I don't know whether I'd recommend investing a lot in that or not, but it is something to worry about. For the microbes, it will be ongoing trouble. We'll take the edge off, we'll learn how to live with them more successfully. We may be able to blunt the disease that they cause if we understand better how they moderate themselves and how that moderation is broken through, that will be a path through it. Learning to live together, rather than eradication, I think will be the outcome for a great majority of infectious diseases. Mr. Porter. Anyone else want to comment on that? No. There's been a lot of discussions about whether we ought to be having more directed research rather than more basic research. I wondered if I can get your insights and thoughts on that whole question. Mr. Baltimore. It's a very sticky issue. Because the ethic of the scientific community has been that research should be investigator-initiated. And there is no question that creative, inventive ideas come from investigators, they don't come from people who are thinking about how to do research, they come from people who are in the trenches doing research. And if you want the best of research, you certainly want to support an investigator-initiator. But there comes a time when you really want to focus resources on it. And it's not a time when necessarily you want to give up creativity. But when you have an idea where the goal is and you want to get to the goal, and I've seen this in particular with the fight against HIV. Because there was a problem that presented itself, and we very quickly understood its dimensions. It still poses extremely difficult basic questions. And those ought to be investigated by investigator-initiated methods. But it also posed some pretty straightforward questions, like what's the structure of the protein. Those kinds of questions really should get intensive investigation in a way that's coordinated from some central place. So I think as research comes closer to development, in a sense, it certainly comes closer to focusing on the solution of a problem, rather than gathering information, there is a place for direction in research. That's something that I think NIH has to come to grips with. Because NIH has not been well organized to provide that kind of research. Mr. Gilman. In addition, I think it's become really obvious over the last 15 years or so that very basic scientists are not averse to doing translational research if they see how to do it. Molecular biology really brought that to the fore. As soon as this whole area opened up and practical applications became clear, the joke was that there wasn't a full professor in California without his own lab techniques. Even very basic people have been very quick to translate when it's been obvious how to do it, or not necessarily obvious, but when it's been possible to do it. Mr. Porter. Dr. Lederberg, you have the last word. Mr. Lederberg. I think it can be said that for most circumstances, market-oriented mechanisms provide the best way for direction. The directed research, in a sense, I think you meant, has to do with the developmental stages of bringing concepts to market in the form of drugs. The large majority of that can be done very well by the private sector. And there you have issues of allocation resources that are driven by competition, potential markets and so on. I think once in a while the Government has to step in, but there will be market failures. These kinds of applications are just not going to be supported, there are too many risks, questions of identification and so on. But I think those generally speaking are the exception, not the rule. I think Dr. Gilman was hinting at that, because I think a lot of the technological translation he's talking about goes on in an entrepreneurial setting which professors and others may be consultants or may be indirectly involved. So it does need some balance. But most directed research, I think, can be done by the private sector. Mr. Porter. Thank you, Dr. Lederberg. This is another series of votes, unfortunately. You have been very patient, and gentlemen, I can't tell you how much I appreciate your taking your valuable time to come here today and talk with us. It has been, and I think I speak for all of us who have had an opportunity to talk with you. We've been inspired by what you tell us, and we're going to do the best we can to provide dramatically increased resources for research, and to do those things that are necessary to bring the best minds to science research and to keep them there, and see some light at the end of the tunnel, which I think is terribly, terribly important. So thank you all very much for being with us today. The subcommittee will stand in recess until notice of the Chair. Wednesday, October 29, 1997. CHILD HEALTH HEARING WITNESSES DR. DUANE ALEXANDER, DIRECTOR, NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT DR. ALAN LESHNER, DIRECTOR, NATIONAL INSTITUTE OF DRUG ABUSE DR. STEVE HYMAN, DIRECTOR, NATIONAL INSTITUTE OF MENTAL HEALTH AUDREY NORA, M.D., ASSOCIATE ADMINISTRATOR FOR MATERNAL AND CHILD HEALTH, HEALTH RESOURCES AND SERVICES ADMINISTRATION JAMES S. MARKS, M.D., DIRECTOR, NATIONAL CENTER FOR CHRONIC DISEASE PREVENTION AND HEALTH PROMOTION, CENTERS FOR DISEASE CONTROL AND PREVENTION ERNST L. WYNDER, M.D., PRESIDENT, AMERICAN HEALTH FOUNDATION Mrs. Northup [presiding]. The subcommittee will come to order. Today the subcommittee is venturing into new territory about conducting hearings on a topic that is not specifically related to the budgets of the agencies that we fund. We wanted to spend more time looking at the issue of child health both from a research and a services and prevention perspective. Improving child health is a key objective of many of the programs we fund, and we have selected from a broad range of activities three witnesses for this morning and three for this afternoon. The subject of child health clearly merits much more extensive treatment than we have been able to give it in just two hearings, and we will not be able to deal with these issues such as health insurance coverage and a new children's health initiative. This morning, we will hear from three NIH witnesses who are very familiar to the subcommittee: Dr. Alexander from the Child Health Institute, Dr. Hyman from the Mental Health Institute, and Dr. Leshner from the Drug Abuse Institute. I am confident that our three witnesses will bring us up to date on the latest research and findings in the area of child health and describe the scientific opportunities that exist to generate knowledge, improving the health and the well-being of this Nation's children. Gentlemen, I think we will have each of you give us your statement and then proceed with questions. That way, the members will have a chance to direct questions to anyone of the three of you upon completion of your three statements. As members of the audience know, the Congress is in the final weeks of the session. With members pulled away in different directions, we are all here at the same time. We may have some interruptions this morning and members may not be able to spend as much time at these hearings as they would like. Nevertheless, we are all vitally interested in the questions before us today. Dr. Alexander, why don't you start first. Dr. Alexander. Thank you, Mrs. Northup, members of the subcommittee. I am pleased to have this opportunity to address child health research at the NIH. My colleagues join me in expressing our appreciation to the subcommittee for holding this hearing to focus on some of the most exciting achievements and promising opportunities in our efforts to improve the health of our children. We all agree our children are our Nation's greatest resource and that the quality of their health and well-being will greatly shape the future of this country. What we will be like as a nation 25 years from now and what our health care costs are going to be 40 to 50 years from now are being shaped by how today's children grow and develop and learn, by the kinds of health problems they experience as children, and by the kinds of social and health-related behaviors they develop in childhood. A recent Government report on ``America's children: Key National Indicators of Well-Being,'' pointed out our children are as important to our Nation's future as is the economy and that we should pay as much attention to indicators of how our children are faring as to how the economic indicators are doing. The picture presented by that report was a mixed one. On the positive side, we have achieved an all-time-low infant mortality rate and an all-time-high infant immunization rate, with virtual disappearance of numerous infectious diseases of childhood. Unfortunately, at the same time, cigarette smoking, drug abuse, and alcohol use by our children are all increasing and deaths from handgun violence among black adolescents have risen to alarming heights. Most of the improvements and positives cited in the report are traceable to advances from research, and most of the problem areas identified need research to guide corrective intervention efforts. The importance of investment in research in child health and development can't be overstated. The direct and immediate benefits to our children's health are obvious, and we owe it to them to focus the same effort in protecting and improving their health that we devote to the health of adults. But there are other benefits from investments in research on children as well. Actions to improve health in childhood have the longest- term impact. There is nothing to equal the 75-year cure or prevention. In the area of health behaviors, childhood is the time that lifelong patterns are formed, and it is far easier to establish healthy behaviors in the first place than it is to change unhealthy behaviors in adulthood. Witness the difficulty adults have in stopping smoking, losing weight, changing dietary patterns, or even increasing exercise. Patterns established in childhood are likely to be permanent and be transmitted to the next generation when today's children become parents. The long-term benefits of interventions in childhood to prevent adult disease are enormous. The time to prevent osteoporosis, a devastating problem for the elderly, is in childhood, by providing the dietary calcium intake necessary for maximum bone calcification. Research has documented the amounts needed but now must help to show effective ways to achieve this intake. The time to establish healthy food choices and exercise habits to prevent adult cardiovascular disease and obesity is in childhood. The way to prevent cancer and lung diseasethat develop as a consequence of cigarette smoking is to stop initiation of smoking in early childhood. In all these areas we are obviously failing in part in whatever we are doing or not doing now. Only by investing in research on how to influence these behaviors successfully in childhood do we have any hope of preventing adult diseases that result. Fortunately, those of us who are involved in child health research today are both proud of our accomplishments and optimistic about the array of challenging opportunities that are emerging in this field. Many new biomedical research technologies will enable us to develop the ability to prevent, cure, or better treat many of the diseases that affect our children today or may affect them when they become adults. The prospects for significant breakthroughs in the field of child health research have never been brighter. These exciting new opportunities in child health research are emerging across the broad range of NIH institutes and centers, most of which support some research related to child health. Let me cite just a few examples of what that research has accomplished. Cancer is the chief cause of death by disease in children under age 15. Since 1960, children's cancer mortality rates have declined 62 percent. When I was a pediatric resident 30 years ago, children diagnosed with acute lymphocytic leukemia had an average life expectancy of less than a year, and less than 5 percent survived 5 years. Our most recent data show that 75 percent of such patients are surviving at least 5 years past diagnosis and may be considered cured. Pediatric AIDS is a relatively new problem. A major advance in preventing transmission of HIV from mothers to their babies was the NIH-supported development of the use of AZT treatments administered to HIV-infected mothers during pregnancy, labor, and to their newborns. Development and testing of this treatment was a collaborative effort at NIH and has proven to reduce such transmission by two-thirds. Among the most pervasive advances in our children's health has been the remarkable decline in incidence of dental caries through a combination of fluoridation of water, fluoride toothpastes, dental sealants, and improved oral hygiene, all developed through research. We have progressed from nearly all children having dental caries to 55 percent of 5- to 17-year- olds having no caries at all. As the lead NIH institute for child health research, NICHD has supported and conducted research that has significantly contributed to improving the health of children. Since our institute was established in 1962, the U.S. infant mortality rate has declined by 70 percent. Much of that decline is due to improved survival of premature infants as a result of research advances. One of those is the development of surfactant for respiratory distress syndrome. Another advance in lowering infant mortality is our progress in reducing Sudden Infant Death Syndrome. After research demonstrated that back sleeping position reduced SIDS risk, NICHD initiated a ``Back to Sleep'' public information campaign. Over the 3-year history of the campaign, deaths from SIDS have declined 38 percent. Difficulties in learning to read affect 10 million children nationwide. NICHD research has developed inexpensive assessments to identify which kindergarten or first grade children are likely to have difficulties learning to read, and classroom interventions that have been very successful in helping the children to overcome their reading difficulties. While reading ability may not seem at first glance to be a child health issue, it is a key determinant of future life opportunities as well as a predictor of health risk-taking behaviors such as smoking, drug abuse, and alcohol abuse. Perhaps most striking of all is success of research in preventing mental retardation. Thanks to research, we have eliminated congenital hyporthyroidism as a cause of mental retardation in this country; we will have no more children retarded from having PKU. The development of Rhogam through research has eliminated RH disease as a cause of mental retardation and cerebral palsy. New vaccines have nearly wiped out measles encephalopathy and congenital rubella as causes of mental retardation, and development of the Hemophilus influenzae type B vaccine by NICHD's own intramural scientists has brought to near total elimination the meningitis that was once the leading cause of acquired mental retardation in the United States. All these diseases are gone as a source of fear for parents for causing mental retardation in their children, thanks to knowledge gained from research and its speedy application in our health system. Even with these dramatic advances, more remains to be done in these areas, as well as many others. Examples of special opportunities and needs and steps being taken to address them include autism, where there is a special initiative to stimulate promising new research, focusing on neurobiology and genetics of this order, and asthma, one of the most common chronic diseases of childhood where the number of affected children has actually been rising. Major advances in vaccine development are continuing to try to prevent some of our most common childhood diseases that threaten the health of children. These efforts take on increasing importance as antibiotic resistance becomes a greater problem. NIH researchers are developing new or improved vaccines for such conditions as tuberculosis, diarrhea caused by such pathogens as salmonella, shigella, rotavirus, and E coli, Group A and B Streptococcus, several forms of pneumonia, and otitis media, and even dental caries. Birth defects are the Nation's leading cause of infant mortality and a major source of lifelong disability and morbidity. Advances in developmental biology and genetics, especially from the Human Genome Project, hold great promise for understanding causes of birth defects and providing possible means of prevention or correction. Diabetes is a major chronic disorder of children, with long-term health consequences, and a major clinical trial is now under way to try to prevent or delay the onset of diabetes among children. For many years, child health professionals and clinical investigators have stated that the needs of children have not been adequately addressed by many clinical research practices. Because of this gap, many of the medical treatments applied to children are based solely on testing done in adults. For example, the large majority of drugs have no pediatric specifications, although physicians can and do prescribe them for children. To address the problem of testing medications in children, NICHD established a national network of pediatricpharmacology research units. These units provide sites with expertise in pediatric pharmacology, experience in the conduct of drug studies in children, and access to a pediatric population to encourage industry to do the studies in children necessary for pediatric labeling. This approach is working, and NIMH has recently built on this experience to establish a comparable network for studying psychoactive drugs in children in collaboration with several of the NICHD units. Beyond this approach, the appropriate inclusion of children in research is a topic of great interest and importance to the NIH. A year ago, NIH and the American Academy of Pediatrics convened a workshop on inclusion of children in clinical research. Workshop participants concluded that there is a need to enhance the participation of children in clinical research and that NIH should take the lead in changing the climate for inclusion of children and set the expectation that investigators should include children unless there is a good reason not to do so. Last January, NIH published a notice apprising the scientific community of its intent to develop and implement a policy in which applicants would be expected to include children as subjects in clinical research unless they justified exclusion, and encouraging investigators meanwhile to voluntarily include children in their clinical research projects. NIH will continue to involve the scientific and professional communities, as well as patient advocacy organizations, as it moves forward with efforts to develop, implement, and oversee policy in this area. While child health research is a major focus of NIH activities, this subcommittee's interest in this important area is beneficial to its continued growth and development. My colleagues and I are committed to a strong and comprehensive child health research program to better serve the health needs of our Nation's children and youth and focus on the opportunities in childhood to prevent adult disease. I will be pleased to answer any questions you and the members of the subcommittee have. [The prepared statement of Dr. Alexander follows:] [Pages 3024 - 3037--The official Committee record contains additional material here.] Mr. Porter [presiding]. Let me apologize to our eminent witnesses this morning. When we originally scheduled this briefing, we thought we would be clear. We put it over, as you know, because we thought we would be clear. We are still working on our bill. We are supposed to go to conference this afternoon. There are major differences that remain. I had a meeting this morning that began at 9:40; I thought I would be here by 10:00. I apologize to each of you for my inability to do that, and I thank Anne Northup for chairing and our members for being present, and I just want you to know that we tried to schedule this in an appropriate way and it just-- you know how these things work; it did not work out. Dr. Hyman, we welcome you this morning and look forward to hearing what you have to tell us. Mr. Hyman. Thank you, Mr. Chairman, and thank you to the members of the subcommittee. I am delighted to be here in the company of my colleagues, Dr. Duane Alexander and Dr. Alan Leshner. I am particularly grateful to you for convening a hearing that will permit me to highlight the extremely pressing problems created by our as yet limited understanding of mental disorders of children and by our all too common failure as a nation to apply what we know. Dr. Alexander has just reviewed for you many extraordinary triumphs in the area of child health. I am instead going to focus on a number of challenges. I think the area of child mental health is an area that has come along a bit more slowly, partly because of the difficulties of understanding the developing brain but also because of the inappropriate stigma that has been attached to childhood mental disorders--indeed, all mental disorders--and the shame experienced by families in coming forward to report these kinds of problems. It is obvious that for a child with an unrecognized or an untreated cognitive or emotional disorder, it is impossible for them to live up to their potential. Children with these disorders cannot learn adequately in school or readily form the kinds of healthy peer or family relationships that undergird the emergence into adulthood of healthy or productive citizens. We know the children, moreover, are at heightened risk for school failure and dropout, drug use, risk behaviors for HIV, and many other difficulties. Perhaps the most dramatic evidence of ongoing problems is the steady increase in the suicide rate of both our preadolescent and adolescent populations, a suicide rate among adolescents which is now equivalent to that among adults, despite targeted attempts to lower the rate of suicide deaths in this age group. We also know there is severe stress and extraordinary disruption and interference in the productivity of their parents and for their families. Brain and behavioral research offers increasingly firm ground for confidence that we can correct our scientific and, in turn, our current clinical limitations with respect to children's health needs. The yield of our investment in research has enormous implications, enormous for any child who benefits and enormous for our Nation, and I think Dr. Alexander made these points very well indeed. Before briefly describing exciting lines of research focusing on the development of the brain, I would like to acknowledge the enormous distance that we must travel. The diagnosis of childhood mental disorders lags behind capabilities of diagnosing adult disorders. Significantly, we have an inadequate ability to distinguish the early symptoms of disorders that portend lifelong difficulties from the still serious dysfunctions that might be due to passing problems during development. Our lack of information denies rational treatment to our children, leaving some children's problems unrecognized or undertreated, including many who are disabled by severe disorders such as depression, childhood manic-depressive illness, severe attention deficit disorders, anxiety disorders, and eating disorders. We are aware of substantial benefits of some pharmacotherapies for these children but at the same time lack an adequate understanding of the long-term effects ofdrug treatments on the developing brain. The point has been made many times but remains critical, children are not simply small adults. In the case of both psychotropic drugs and psychotherapies, different stages of brain development and the change in handling of drugs by the body mean that specific developmentally appropriate information is needed at every stage of child development. While there persists a dearth of skillful researchers in the area of childhood mental disorders, NIMH is committed to building that infrastructure. In addition, we must address and resolve difficult ethical challenges in conducting clinical research on children, mindful of the fact--and the point was made to me by a parent of a child with autism--that the least compassionate and least ethical option would be to remain in our current state of ignorance. Mr. Chairman, to me as a neuroscientist, the process of brain development really borders on the miraculous. More than 100 billion nerve cells, and, in aggregate, maybe a quadrillion--I don't even know what that number means--a quadrillion connections among many possible alternatives. How are these connections chosen? How are they right? This complex miracle, the brain, is built by an equally complex interaction of genes and environment. It is true that single defective genes have been identified that can cause serious brain disorders like Huntington's disease, but we know normal emotional and cognitive development as well as vulnerability to the brain disorders, that have traditionally gone under the moniker of mental illnesses, is the work of a large number of genes, most likely acting in different parts of the brain at different times of brain development. Perhaps two-thirds of the genes that are being identified by the Human Genome Project are involved either in building the brain or in its subsequent functioning. As complex as the gene- gene interactions are proving to be, they do not explain everything. Equally complex and important are gene environment interactions. How might the environment cause our brains to develop in one possible way rather than another? The environment produces biochemical changes in nerve cells within our brains. When such biochemical changes are large enough, of enough magnitude, they turn genes on and off inside those cells as part of the normal processes that get the name, brain plasticity. During development, as these little tweaks of experience accumulate, our brains get wired up. New connections are built, useful connections are strengthened, and connections that go unused are actually eliminated. Neuroscience has made the greatest headway in understanding plasticity in the developing visual system. Genes are largely responsible for the initial wiring up of the brain, but the fine-tuning is dependent not simply on genes but on use, in this case, visual experience. As light excites nerve cells in the retina and they signal to the brain, those connections that are used effectively are strengthened, those that are not used are pruned away. This use-dependent sculpting of the brain is illustrated by the condition of congenital cataracts in which an opacity in the lens blocks the light from entering the eye. It has been found that if such a cataract is removed, an optically perfect eye can be restored, but the success of the surgery in actually restoring vision, the ability of the child to see, is highly age dependent. If the surgery has begun too late in childhood, after the age of 4, even though you restore an optically perfect eye, the child will be blind in that eye, and that is because there is a critical period for plasticity in which light, and the use of these nerve cells, is required to strengthen these synapses. After a certain period of time, this is no longer possible. This is a particularly interesting time in clinical neuroscience because we are beginning to obtain information beyond things like the visual system, about the cognitive and emotional development of children, and it again points to the remarkable plasticity of the brain in response to environmental influences. Researchers have demonstrated, for example, that rearing rat pups in a complex or enriched environment, as opposed to the normal laboratory conditions--a rather boring, narrow cage--dramatically alters brain function as measured by improved performance on behavioral tests. I think more remarkable is that one sees a different cortical thickness, different rich dendritic arbors in the brains of the rats raised in an enriched environment; recent research has actually shown, in some smaller areas of the brain, there are even additional cells. In addition, research published only last week in Science magazine shows that early experiences can have lifelong effects on how the brain subsequently handles stress and elaborates stress hormones with, I think, pervasive implications for health. Now let me emphasize, these studies are conducted in animal models. It is a long leap indeed from these studies to specific interventions for humans. What we can say for humans is that deprivation and neglect may produce long-lived and even permanent alterations in the brain, with serious functional consequences. For example, consider the plight of the Romanian orphans, many of whom spent their first crucial years in environments marked by extreme emotional deprivation and even abuse. Even after adoption, often in the United States, many children are growing up highly vulnerable to stress, and they exhibit marked difficulty in coping with normal human interactions. It is a dramatic example, but I think these kinds of things can go on all the time in our children. What basic science is telling us is that our cognitive maps and our emotional maps of our worlds are plastic in response to the environment. We are just at the beginning of knowing how the brain produces these maps and at what periods of development their plasticity begins to wane. There is much research needed to translate these basic science ideas into effective and deliverable clinical interventions. We recognize that the eventual application of this information to preventive and clinical interventions requires that the interventions be shown to be efficacious, deliverable, affordable, and useful in the real world, and free of serious harm. If we fail to recognize the cognitive and emotional disorders of childhood, we will be permitting a kind of malign plasticity. A congenital cataract that is neglected and leaves a child blind is now an avoidable tragedy. Less well understood but far more pervasive, I believe, are the unrecognized and as yet untreated mental disorders of childhood or situations of abuse and neglect. These situations also impact the developing brains of our children, with devastating consequences. Thank you, Mr. Chairman. I will be pleased to answer anyquestions. [The prepared statement of Dr. Hyman follows:] [Pages 3042 - 3051--The official Committee record contains additional material here.] Mr. Porter. Thank you, Mr. Hyman. Dr. Leshner, nice to see you. Dr. Leshner. Good morning, Mr. Chairman, members of the subcommittee. I, too, am very pleased to be here with my distinguished colleagues to discuss a topic of tremendous importance to every person in this country, and that is the health of our children. But I have to say I am also very sad to have to tell you that drug use and addiction are becoming more and more issues of children's health. Drug use is beginning at earlier and earlier ages, and overall drug use has continued to increase among youth at all ages. Moreover, children are being dramatically affected by the drug use of other people, particularly their parents. It is for these reasons, NIDA has made children and adolescents one of its highest priority areas and why we are dedicating a large portion of our research portfolio to the study of the effects that drug abuse and addiction have on infants and on children and adolescents. Drugs can affect the health of children in three significant ways. The first is exposure through maternal use during pregnancy; second, by growing up in a household where drugs are used; and the third is by using drugs themselves. And I am going to speak a little bit today about each of those topics. Our best estimates are that in any year about 221,000 women used an illicit drug at least once during their pregnancy. That means 221,000 babies were born drug exposed. Cocaine was used by 1.1 percent of women, or 45,000 of them. Babies born to mothers who abused drugs during pregnancy are often prematurely delivered; they have low birth weights and smaller head circumferences. But determining the precise effects of maternal drug abuse, per se, is very difficult, and determining the dangers of specific drugs to the unborn child is even more problematic, given most drug users use more than one substance. Factors such as inadequate prenatal care, poor maternal nutrition, and poor postnatal parenting are just some examples why it is difficult to determine the exact effects of prenatal drug exposure. This complexity is why we believe we need to be very cautious in drawing any causal conclusions about prenatal drug exposure effects. Two weeks ago, the New York Academy of Sciences, with support from NIDA, just held a very important conference that brought together for the first time all of the major basic and clinical researchers to discuss what they know and what they don't know about prenatal cocaine effects. A decade ago, crack babies, or babies born to mothers who used cocaine while pregnant, were written off as a lost generation. They were expected to suffer from severe irreversible brain damage, including reduced intelligence and social skills. And of course we now know this was a gross exaggeration. Most crack babies appear to recover quite well. However, the fact that most of these children appear quite normal also needs to be interpreted cautiously. As we continue to study prenatal cocaine exposure effects on later behavior, as our cohorts of crack-exposed babies are just now entering elementary or middle school, we are finding some, though not all, children are in fact affected, although perhaps more subtly. Under the leadership of our colleagues from the National Institute of Child Health and Human Development, we have cosponsored the Maternal Lifestyles Study that has been examining the health and developmental sequelae of 1,400 infants and children exposed to illicit drugs during pregnancy, and this is one of a series of studies we are using to follow large cohorts of drug-exposed children through their school years, and researchers are looking not only at the children's intellectual status but at their behavioral, emotional, and social development as well. We are now seeing exposure to cocaine and other drugs, in addition, during fetal development can lead to subtle but significant deficits later on, especially with behaviors that are crucial to success in a classroom, such as blocking out distractions and concentrating for long periods of time. Some prenatally exposed children are also showing subtle cognitive and learning problems as they enter middle school. Because effects can be subtle and only expressed as children develop, long-term follow-up is needed, and that is why we have a number of long-term longitudinal cohort studies going on. To best understand the biological mechanisms by which prenatal drug exposure can affect later behavior, scientists need to rely heavily on animal models, and those models are providing important hints about the mechanisms of these effects. As just one example, most people, for a long time, believed that most prenatal drug effects resulted from the effects of drugs on the mother's circulatory system, and that meant that drug use was altering the amount of nutrients and oxygen getting to the babies. But a recently published study at the University of Massachusetts has shown the actual presence of cocaine receptors in the brains of fetal rats and showed that cocaine is able to bind directly to these brain sites. And that is what this poster on my left is showing you. It is showing in yellow and in red the high distribution of cocaine receptors, actually on something we talked about during the hearing, the Dopamine reuptake joints border, showing presence in a fetal rat brain--this is a ratbrain--presence in fetal rat brain of a high concentration of cocaine receptors in the base of the brain but also in areas important for later memory like the hippocampus and later cognitive function, if you look at the bottom at the right at the cortical plate area. The point is that we are now beginning to understand that these effects are not just generalized effects of drugs on the mother being passed to the baby but, rather, are modifications in the brain that might be expressed later on as the brain is more fully developed. Another aspect that affects the overall health of the child is the family environment in which he or she is brought up. A variety of studies, including a major research center we support at the University of Miami, are dedicated, first of all, to understanding the family effects and, second, to developing family-based interventions that might be useful in preventing the expression of some of these effects. There also are a whole series of issues surrounding initial drug use by youngsters, and of course there is no single factor that is responsible for abusing drugs; drug use evolves from an interaction of complex biological behavioral and social environmental determinants, or risk factors. It is also important to remember that we have identified many of the protective or resilience factors, such as parental involvement in the life of a child, that typically reduce the chance of even those children with many risk factors from actually becoming drug users. And a major focus of current prevention research is understanding how specific risk factors, like unstable family environments, can be offset by increasing the impact of protective factors, like surrogate parenting or mentoring programs. We have been working hard at night to make sure the principles of effective prevention we are learning from our research will be used in real life programming, and I would like to mention two products of which I am particularly proud. One is preventing drug use among children and adolescents. This easy-to-read brochure is the first ever research-based prevention guide that a school or community can use to develop prevention programs specifically tailored to meet their own community's particular needs. This user-friendly guide provides practical guidance that can be applied by a community and lays out some of the principles and the criteria that should be used in evaluating prevention programs. The publication of this has resulted in an initial distribution by request of over 100,000 copies, and we are getting additional requests at about 20,000 a month, which shows the tremendous need and the tremendous interest. The second set of materials I want to mention is this colorful new ``Mind Over Matter'' series that I unveiled 2 weeks ago at the annual meeting of the National Association of Biology Teachers. This is a set of drug education brochures, based on science, developed for students in grades 5 to 9, to spark their curiosity and to inform them with specific research findings of the effects of drugs on the brain. This series also includes a teacher's guide with suggested activities to encourage students to become engaged in discussion and thinking about the issues, since the other one, the prevention guide, pointed out that the only effective prevention programs engage students in thinking about the issues. Simply lecturing to them, as I am doing a bit to you this morning, in fact is not a very effective prevention technique at all. I want to mention that we are also working in the important area of treatment of drug abuse, particularly among adolescents, and I am sad to tell you we don't know a tremendous amount about that, but we have been working on a number of topics, including, along with our colleagues at NIMH, co-morbid child and adolescent mental disorders like depression or attention deficit hyperactivity disorder. We have been working on techniques to help match young people to the most appropriate treatments, and of course we are trying to help develop better and more appropriate treatments that will help young people become engaged in treatment, which of course is the most difficult problem, and, secondly, how to handle aftercare. All of these activities are a part of what we are calling our child and adolescence research initiative. The outcome will include much better understanding of the roles of risk and protective factors and what to do with and about them. They will also include the development of improved targeted treatment approaches that are tailored to the unique needs of young people. We will also conduct additional research to prevent or diminish the health and developmental consequences associated with direct or indirect, through their parents and other people, exposure to drug abuse and addiction. We are very encouraged that some basic but extremely important questions, such as what works in prevention, have been at least partly answered and that this information is now being disseminated to communities. However, there remain unanswered many important questions about how to move from these general principles of prevention to their application in specific ways in a diverse array of real-life settings, and there are many unanswered questions about how drug abuse and addiction affect our children. It has only been within the last few years that our understanding of basic neurobiology has matured enough andonly with the emergence of new noninvasive technologies we have become able to study intensively underlying biological responses of humans to various drugs of abuse. And I will remind you of a question Mrs. Northup asked me during the Appropriations Subcommittee hearing about the differential effects of drugs on a young adolescent's brain versus an older adolescent's brain. And, sadly, I still don't know the answer to the question, but we are working on it. To the extent there are differences among children and adolescents and adults, this new knowledge will provide an infrastructure from which we can develop more appropriate prevention and treatment strategies so that our children can live healthy, productive, and drug-free lives. Thank you very much. [The prepared statement of Dr. Leshner follows:] [Pages 3056 - 3067--The official Committee record contains additional material here.] healthy behaviors and lifestyles Mr. Porter. Dr. Leshner, thank you very much. Let me thank all of our witnesses. Unfortunately, I didn't get a chance to hear any of Dr. Alexander's testimony, and perhaps he has already discussed this, but I want to take my question time to ask really one question, because the thesis of this briefing is a little bit outside, in fact--you might think substantially outside--some of your responsibilities and your roles, and that is, how we can address early in life the matters of life-style that may determine the health of children and how we can translate the knowledge that we have into action that can change those and channel those into a positive experience for each individual, and talking about diet and exercise and alcohol and drug use, and societal interaction and the like, that can lead to a better health throughout the adult life of that individual. So what I want to ask each of you, and ask you to respond to it--and, again, I realize this is outside, in some degree, your role, and Dr. Leshner did touch on this in a very positive way a moment ago. But how can we take this knowledge that we have and translate it into action in such a way that we are helping people prevent the kinds of problems that they may have in their health throughout their lives, both mental health and physical health and, in the process, obviously, save a great deal of the money we spend today on treating disease by preventing disease. If each of you can respond, Dr. Alexander, how can we do this? How can we get from where we are to where we want to go? Dr. Alexander. First of all, I don't think it is outside our realm of research interests and responsibilities at all, it is very central to what we are trying to do. Today, we really know what healthy behaviors are and what healthy life-styles can mean long-term to people's health. And I did touch on this a little bit at the beginning part of my testimony. What we don't know is how to shape those behaviors most effectively. We know what should be done, we don't know how to get it done, and we are working on that, in a wide variety of areas. Let me mention one that NICHD is doing, and that relates to prevention of osteoporosis. We don't think of osteoporosis when we think of kids. This is a late adulthood disease for the most part, but the prevention of this disorder is primarily the responsibility of childhood. If we get adequate calcium into our bones when we are children, the chance of our developing osteoporosis as adults is markedly diminished. The problem is, we stop putting calcium into our bones by around age 21, and shortly after that a long slow process of loss of calcium begins. The more calcium we have in when the loss process begins, the longer it will take us to get into difficulty from osteoporosis. So we know exactly how much people should be taking in, in terms of calcium, at different ages in their diet; we know the best source is dairy products, milk; what we don't know is how we can achieve the intake that is necessary. We also know children are not getting anywhere near the dietary intake of calcium they need for appropriate calcification of their bones. If you look just in adolescents, about 15 percent of adolescent girls are getting adequate dietary, and they are the ones that are going to get into the most trouble when they become adults. We are working with research of our own, in looking at ways to encourage milk consumption, ways to encourage use of calcium supplements included in diets and other means to try and promote calcium intake by children. We are working with the National Dairy Council, the Milk Processors Association, on the milk mustache campaign, for example. You have seen some of the pictures of celebrities with a milk mustache. This is one way we are trying to get the message across to children and families about the importance of appropriate dietary intake of calcium. We are also working with the health care providers, especially the American Academy of Pediatrics in trying to get pediatricians to get the message across, that, you never stop milk as the drink of choice at a meal for children. This is an extremely important part of the message and the way to do it. So that is the story with osteoporosis as just one example. Another is smoking cessation or smoking prevention. Prevention is a lot easier to achieve than is cessation, as many people know. Here again, if you talk to kids, they very clearly know that they shouldn't be smoking, but 22 percent of 12th graders are now smoking on a daily basis, and the numbers, unfortunately, are going up, not down. So clearly we need to find and develop better ways of getting that message across and getting these healthy behaviors adopted and avoiding unhealthy behaviors. Very similar issues pertain in the areas of drug use, of alcohol use, and other areas, and maybe Dr. Hyman and Dr. Leshner would like to address those. Mr. Porter. Thank you, Dr. Alexander. Dr. Hyman. Dr. Hyman. Well, you have heard my diatribe on brain development, and in some ways it is exactly analogous to the story of osteoporosis. What Dr. Alexander told us is, even though osteoporosis is a disease of older years, calcification of bones occurs during childhood. What I told you is, increasingly we recognize that the brain, while its sort of coarse wiring may be set up by our genes, it is fine-tuned by experience, and it is literallythe hard wiring that is fine-tuned during childhood. We know a great deal about simple sensory systems like the visual system, which is the first obvious place to begin scientifically. But we are now recognizing that childhood, including early childhood, is a time when the wiring of the brain, in some sense, gets finalized and therefore greatly influences our talents and our abilities to function, first in school and then at work, and interpersonally. While I am not a pessimist, I believe insofar as we all learn, brain plasticity continues throughout life. I think we all recognize, both based on science and common sense, a great deal happens in early childhood. Therefore, I think it is really critical that we translate what we know about useful interventions for healthy development into action and early childhood. Let me give you some examples where I think we really know something. And here I am not talking about massive social programs or anything of the sort. What we recognize is that, tragically, the age of onset of serious depressive illness in our society is going down; it is getting younger and younger. The reasons for this are not fully understood, and this is partly reflected in the increasing suicide rate in preadolescence and adolescence. We are fully aware that serious depression is often not recognized by families, it is not recognized in school settings, and often, unfortunately, is not recognized by pediatricians. Now why is this? First of all, mental disorders, although they are disorders of the brain, have long been misunderstood and stigmatized; families are ashamed. Schools don't want to stigmatize children with mental health labels, and so sometimes it is almost perverse, sometimes you almost feel it is better for a child to end up sort of in the bad box instead of in the sick box because of the risk of labeling them. Of course, then they don't get treated, and the consequences are obviously problematic. Pediatricians increasingly are trained to recognize mental health problems, but in the current health care delivery setting, they have a short time with the child and may not have the opportunity to ask the kinds of questions about mental health and functioning that often take a bit more time. I have a great deal of sympathy for them. Now how can we change this? First of all, we have to disseminate information not only to families and schools, but also I think we have the responsibility to educate health care providers. Secondly, in the area of mental disorders, it is critical that we destigmatize, because without destigmatizing, I think no amount of disseminating cold facts is going to make a difference. The other thing, just to take this example, is we have to acknowledge what we know and what we don't know. For example, we know that untreated depression has dire consequences with respect to ability to learn, with respect to ability to form peer relationships, and of course the most dramatic negative outcome is suicide. But, as I told you, we also have to be concerned about the long-term effects of psychotropic drugs on the brain. So while we know enough to intervene now, we have to continue our research so that we develop age-appropriate knowledge about interventions. We know enough to be disseminating the information better than we are, but we continue to need to really understand what is going in the brain in childhood. I don't want to take too long. We could talk about many other areas, again, the controversial area of attention deficit hyperactivity disorder and Ritalin, where, again, there is an imbalance between knowledge and practice. In some school districts, Ritalin is overprescribed; in others, particularly in inner city minority neighborhoods, it is never prescribed; and these kinds of irrational patterns, I think, have set up lifelong problems for our children down the road. Mr. Porter. Can I interject a question that your answer touched on for me? It seems to me that, increasingly in our country, we are going to see great concentrations of wealth in private foundations, and we are already seeing the effect of that, and private efforts are going to mean a great deal, in addition to government efforts, in addressing serious problems for our country. Right now Rob Reiner, who is the chairman, I think, of Castle Rock Productions, has undertaken an early childhood initiative on his own and has put together a number of high- profile people and a lot of resources to emphasize to the American parent or parent-to-be the importance of childhood development from birth to age 3, which is exactly what you are talking about. I wonder if any of you have had any contact with him in respect to this and whether he is drawing on your research and your talents to help his efforts. Dr. Hyman. I think Duane helped organize that. Dr. Alexander. Mr. Reiner was very much involved with the White House Conference on Early Learning and Brain Development in April and also had some involvement with the one last week on child care. And he has drawn, in his videotape presentations that he has made, as well as the activities of his organization, very heavily on NIH research, some from NICHD, some from Mental Health, from Drug Abuse, from the Neurology Institute, all of which Dr. Hyman summarized very nicely in his testimony about the importance of early brain development. All these neural connections that are established, unless they are reinforced, disappear; thus the importance of this zero to 3 age time in establishing these connections and establishing patterns of brain development. So, yes, Mr. Reiner has been very much involved with the NIH in gathering information from research and translating it in a way that the public can grasp its importance. Dr. Hyman. I think it is a wonderful beginning, but we should remember that brain development, fortunately, does not stop at age 3, so while that focus is critical, we also have to consider all of childhood. The other thing is that we have to also be careful to recognize the steps it takes to go from this basic science knowledge into any really effective, cost-effective, and deliverable intervention, whether it is medication or psychotherapy or some other intervention. Mr. Porter. The intervention we want to have is into the minds of parents so we don't have to make the clinical interventions later on. Dr. Hyman. I agree, absolutely. Mr. Porter. Dr. Leshner, you largely answered the question I posed, but if you want to add to that. Dr. Leshner. I will just make a brief comment, which is, we are all saying basically the same thing. The answer is straightforward but difficult, and that is public education,and we produce tons of material; we have been holding town meetings around the country trying to educate the public. I am off to the health professionals; I am speaking to a group of pediatricians over the weekend. But the problem we have--and this is true in any of our domains--is to make sure not only that the messages are persistent, that is, over and over again, but that they are consistent across the variety of people who speak about this. And in the drug abuse business, it is particularly important because you have many people who think that they are experts and need to expound it. One of the things we have learned from people who study what works and doesn't work in public education generally is that the messages have to be scientifically accurate, as we have said, they have to be science based: That is what worked to get people to stop smoking. And third--and this is much more difficult--we need to figure ways that we fail miserably at of getting nuance into the discussion. The world likes medical answers to be a yes or no, but the truth is, almost nothing is yes or no. The crack baby example I gave you is a good one. When we thought the situation was horrendous, everybody was nervous. Then the pendulum swung in the other direction, everybody was relieved. Now we have a different problem. The problem is, the effects are subtle and it is on some kids, and we need to figure out how to talk to the public about that without stigmatizing all of the kids and without getting in the way of actually doing something. Mr. Porter. Because your responsibility is mainly on developing the science, but you also help to disseminate that science, should we have a separate government corporation or foundation, because the Government can marshal more resources than anyone, to do the further effort of taking this body of knowledge and bringing it out into the consciousness of the American people and really working on sending messages on not using tobacco or moderate use of alcohol or not using drugs or proper diet or exercise, all of the things that can affect health later on? In other words, are we putting too much on your plate for you to accomplish and not giving you either the time or the resources to do that, and should we do it in a different way? Dr. Leshner. Let me say that NIDA is in a somewhat unusual situation. Since we support 85 percent of the world's research, we feel a tremendous obligation to get that out, and we are sort of the holders of it, and we feel we need to get that out to everybody. And I think every NIH institute has major campaigns that they are engaged in, and we are all concerned about public education and public understanding. There are other agencies of the Federal Government that do these things as well, and, candidly, I think the Federal Government can't do it by itself. I think unless we get partnerships with other sectors, we are not going to be able to do it. We cannot mount the massive educational enterprises that have to be mounted. We need private foundations, but we need private groups of citizens. We in the drug business have the Partnership for a Drug- Free America. I could never mobilize the advertising industry in the way that they do it. But I think it is a complex set of players that have to get brought into it. Dr. Alexander. It is also an issue, Mr. Porter, of developing the knowledge of how to do this. Part of our role and responsibility in this effort, I think, is research to learn how to effectively deliver this message and have it translated into behavior change. In some areas we have done this relatively well, but in many of these areas we don't know yet how to deliver that message and have it believed, adopted, and taken. Maybe the Government is not the best source of the information, of delivering of that message, and in fact the foundations and the private organizations may be better at delivering it than we are, but we have to help develop the information on how to deliver that message most effectively. The partnership that Dr. Leshner mentioned is important. I mentioned with osteoporosis and calcium intake, the partnership with the Academy of Pediatrics, the Milk Processors, the Dairy Association. The resources and the message delivery capability of those organizations is far bigger and better than we have or could mount. Our role is trying to develop means, effective means, of delivering that message. The same applies if you are looking at cardiovascular disease and obesity and diet and so forth. Again, we know a lot of what the message should be, we don't know how best to deliver it, and we are testing that partly in the Government, partly in the private sector. We have a study in a school system in a local area looking at ways to deliver health-related messages on health behaviors to middle school students. When Dr. Wynder testifies this afternoon, he will probably talk to you about their efforts in the public schools also, a ``Know Your Body'' program targeted toward elementary school students, when the message needs to be delivered. That is the time we need to get started, not later on, with these health messages, and we need to study this and learn how more effectively to deliver this. The school population and the schools are in an area where we have not been successful in utilizing that resource to deliver this message. Health programs and health messages in schools are notoriously ineffective, but the population is there, the kids are there; they are a captive population, if you will; they are easily targeted, if we knew how to deliver the message most effectively, and that is what we need to work on. Mr. Porter. I am delighted to hear you are working on that, because I think that can make a huge difference in the future. Let me apologize in advance; I have been called to another meeting with the Senate and House leadership at 11:30, so I will have to leave at that time. Mrs. Lowey, you have been very patient. health education Mrs. Lowey. You have been very kind, Mr. Chairman, and I thank you. And I do apologize that I missed so much of your testimony. Before I get on to another area, I would just like to follow up, Dr. Alexander, on your comments, and I just wonder why, it seems to me that we have been--and I look forward to Dr. Wynder's testimony as well--we have been focusing on delivering these messages for a very long time. The health education courses in most of our schools are a disaster. I am very involved with Students Against Drunk Driving and Mothers Against Drunk Driving, and I got into a debate--and perhaps you can enlighten me--with some kids justthis last week: They said: Okay, so we will stop drinking; we will use marijuana because that doesn't affect our coordination as much. And I quickly said, read this. But I really provoked a major confrontation between the drinkers and the drug users in that room, and the drug users-- now this is Westchester County. I mean, it is not an area--I shouldn't say that; I don't want to insult anyone. But the kids were arguing with each other about, smoke pot because it doesn't impair your coordination, and the other kids were saying, yes, and then I said, I will send you more information. They thought they really knew the truth. I can remember 15 years ago, I was working with Matilda Cuomo on education, and many people in this audience have been working on that as well. We have done a terrible job of somehow, whether it is convincing them, I am not sure if it is the communication that is ineffective or the lack of information, but the kids don't believe drugs and alcohol are harmful, and then it becomes a situation of habits built, then they are addicted, then you have to get them off the cigarettes or the alcohol, the drugs. But even when we try and start early, we are just not doing a good enough job. Now maybe you answered, Mr. Porter, earlier. Don't you get enough cooperation? It seems to me a case of deja vu; we have been discussing this, I remember--grandchildren now, too--I remember, going back to my childhood, and we just can't seem to do a good job. Why not? And then I will get to another area. Dr. Leshner. Let me address this, just because you mentioned marijuana and driving. Mrs. Lowey. I would love that for the record, so I can show them what you said. Dr. Leshner. Yesterday, at the Society for Neuroscience meetings in New Orleans that both Dr. Hyman and I were at, I had a long discussion with one of our investigators who is, as we speak, refining what we know about it. And I can assure you that there is a large body of data, studies done over the course of the last 30 years, to demonstrate that marijuana, even a small amount of marijuana, interferes both with motor coordination and with perception, and therefore there is a large body of data to suggest that it is a problem for people driving. One of the problems we have had---- Mrs. Lowey. If you can send that to me, again, if it is more recent, I would appreciate it. Dr. Leshner. Sure. I will. [The information follows:] Marijuana and Driving Marijuana is the most commonly abused illegal drug in the United States, and it is of particular concern that this drug is abused by large numbers of adolescents. Cannabis is a term that refers to marijuana and other drugs made from the same plant. All forms of cannabis are mind-altering (psychoactive) drugs; they all contain THC (delta-9-tetrahydrocannabinol) the main active chemical in marijuana. Within a few minutes of inhaling marijuana smoke, the user will likely feel, along with intoxication, a dry mouth, rapid heartbeat, some loss of coordination and poor balance, and decreased reaction time. For some people, marijuana raises blood pressure slightly and can double the normal heart rate. This effect can be greater when other drugs are mixed with the marijuana; but users do not always know when that happens. As the immediate effects fade, usually after 2 or 3 hours, the user may become sleepy. Marijuana can be harmful in a number of ways, through both immediate effects and damage to health over time. For example, marijuana smoking affects the brain and leads to impaired short-term memory, perception, judgment and motor skills. The user may have trouble handling complex tasks. With the use of more potent varieties of marijuana, even simple tasks can be difficult. With regard to long term effects, research findings so far show that the regular use of smoked marijuana may play a role in cancer and problems in the respiratory, immune, and reproductive systems. As is the case with alcohol, marijuana intoxication is often associated with impairments in sensory, psychomotor, and cognitive functions. Marijuana has adverse effects on many of the skills needed for driving a car. These effects may include difficulty in judging distances and delayed reactions to sights and sounds that drivers need to notice. There are data showing that marijuana plays a role in traffic accidents. When users combine marijuana with alcohol, as they often do, the hazards of driving can be more severe than with either drug alone. Studies of insured drivers suggest that driving under the influence of drugs other than alcohol is a growing cause of traffic injuries in the United States. A study of patients in a shock-trauma unit who had been in traffic accidents revealed that 15 percent of those who had been driving a car or motorcycle had been smoking marijuana, and another 17 percent had both THC and alcohol in their blood. In Memphis, Tennessee, researchers found that, of 150 reckless drivers who were tested for drugs at the arrest scene, 33 percent showed signs of marijuana use, and 12 percent tested positive for both marijuana and cocaine. While the effects of marijuana on equilibrium and driving have both been studied separately, a critical gap in existing knowledge of marijuana effects on driving is the lack of a rigorous examination of these effects within the same group of subjects. NIDA is currently funding a study which is comparing the effects of placebo and two potencies of marijuana on equilibrium and simulated automobile driving. Adult volunteers are undergoing a battery of tests of reaction time, balance, nervous system activity, and risk-taking driving maneuvers at various potencies of delta-9 THC via smoked cigarettes. Dr. Leshner. One of the issues is, a lot of prevention efforts were initially based on intuition and common sense, and I myself believe that it is only in the last 4 or 5 years that we have begun, in the case of drug abuse, to know what doesn't work as well as what does work. A big problem we have is moving science to be the focal point, or the basis, rather than ideology, intuition, and common sense. I mentioned before, we actually have a science-based guide to how to do drug abuse prevention. Everybody wants a copy of it. Most or many programs don't use the principles that are derived from research. The problem is on both ends. It is on our end because we haven't disseminated it well enough, and it is on the other end because these are programs, some of which have been very longstanding. It is also a tough thing to do. Dr. Hyman. There is one very important thing that, often we have the assumption that any intervention is benign; whether it works or not, it can do no harm. But, indeed, we found there are a number of behavioral interventions that can be counterproductive, or even harmful. For example, at one university, an intervention against eating disorders, against bulimia in women, appears to increase the incidence of bulimia. So we have to take seriously studying the behavioral interventions. Something I say a lot, it goes for psychotherapy, for behavioral interventions: Anything powerful enough to dogood is also powerful enough to have side effects, and we actually have to be skeptical in the same way we are with a clinical trial with medication. Now, having said that, I think, as both Dr. Alexander and Dr. Leshner have focused on, we have used principles of basic behavioral science and other principles to develop a certain number of preventive interventions I think would be very useful. We have to study them in the real world. I think the arena of AIDS behavioral prevention illustrates the potential for making a real public health impact, but it is really serious business, getting these interventions in place. In terms of health curriculums--and here now I am afraid I am working on intuition--one of the things a lot of us have been talking about is where in a school program health education would be most effective. Given the fact we are all so concerned about science literacy in the United States, rather than separating health education, as something other or some less serious part of education, whether, in fact, shouldn't some of it be incorporated into science education, because children are absolutely fascinated by their bodies. And, again, this is something Dr. Wynder is likely to talk about, and it would be one way of getting accurate information to children that might be useful in the preventive arena. Mrs. Lowey. I will get to another area, but I would be very interested in pursuing this with you, because I think we have all been a real failure. And for those of us who have been involved in overeating programs, one can understand something about those who have addictions to more dangerous substances. I mean, cigarettes, I never smoked and I don't drink, but I have problems with food like ice cream, and we know a lot of that stuff is just no good for you. Dr. Alexander. Ice cream is. I am sorry. Mrs. Lowey. I am really very serious. Dr. Hyman. It is a serious point. People are differentially vulnerable, and this is the issue of nuance that Dr. Leshner raised. Everyone will say, I had a grandmother who smoked for 90 years and she was fine, or, I know somebody who tried this or that and they didn't get addicted. The problem is, this is a game of Russian roulette, and while one person might be vulnerable to alcohol or nicotine, to starting or getting trapped, another might be vulnerable to poor eating habits, to obesity. A lot has to do with our genes and early gene-environment interactions, and the difficulty in the messages is precisely the issue of nuance. Everybody sees somebody who has gotten away with it, and we have to learn to say, ``but you don't know that you will.'' And, as we all know, any message that is nuanced in children is a very difficult one to deliver. Mrs. Lowey. In any event, I think it would be worth pursuing, certainly here, and I would be interested in any available scientific method that could be applicable, because we all know behavior modification is much easier when you address it early on to children. Another area that I know we touched on briefly before, several of the major mental illnesses, such as manic depression, schizophrenia, don't commonly appear in children until late adolescence. What have we learned that would enable us to predict earlier in a child's life that they had a likelihood of developing a major mental illness, and what is most important that would enable us to begin treatment early? I understand that some would rather be considered a bad kid, rather than a child who has a mental illness, but what really enables us to identify it and begin treating earlier that can help that youngster later on? Dr. Hyman. I don't think at the end of the day any child is happy that a kid gets put into the wrong system. I think, actually, before answering your question directly, there are many youngsters in the criminal justice system who actually have mood disorders and we would have been much happier identifying and treating them, and the fact that stigma doesn't permit us to do that is a disaster. Let me just say that these mental disorders--major depression, manic depressive illness, schizophrenia--are extraordinary scientific challenges and we do not yet know, as is the case for many of the serious chronic disorders that affect human beings, exactly what the risks are. Obviously, if we could identify, if we knew the precise risks, we might find modifiable risks where we could intervene. The fact is, we do know a few things. Especially for the mood disorders, we know there is great risk conferred by family history; that genes, unfortunately, have a lot to say about risk, not fate, but they have a lot to say about risk. And I think that what we could do, quite readily, if we again disseminated information correctly, is to make sure that if a child is behaving in such a way that is consistent with a mood disorder--and, here again, telling a passing stage from something that is serious is challenging but not impossible. Are the symptoms pervasive? Are they long lasting? Are they changing the ability of the child to function at school and at home? These should raise questions, and the presence of a family history, for example, should redouble our concern for early interventions. And I believe that with early identification of mood disorders, one potentially can initiate behavioral programs. But, again, I think we need to develop more age-appropriate psychotherapies, and if symptoms are really severe, to initiate pharmacotherapy, but, again, with the caveat, we have to observe carefully. While I am happy there is the first evidence that the Prozac-like drugs are effective in treating early adolescent depression, I am also keenly aware of the fact that we don't know when to stop, we don't know what the impacts are. So we know enough--we actually do know enough to identify the kids early; we are not effectively using that knowledge in a variety of settings. Schizophrenia is much more complicated. I don't want to go on for too long, but let me say that although there is an important genetic component, family history is often less strong. I think, once again, if we pay attention to really pervasive, disturbed behavior, unaltered behavior in children, and don't write it off, don't sort of see no evil, I think we will be able to make the diagnosis earlier and intervene earlier. I have to tell you, at NIMH we have just convened a whole expert panel to study our prevention portfolio and we are in the process of implementing some of their recommendations so that we don't have to know what all of the risk factors are to intervene early and get treatment started. safety and efficacy of drugs for mental health problems Mrs. Lowey. One other question, Madam Chair, following up on your last statement, and, in fact, in your testimonyyou mention the lack of adequate knowledge about the safety and efficacy of drugs for children suffering from mental health problems. Dr. Hyman. Yes. Mrs. Lowey. What is the institute actually doing to correct this lack of information? What can and should drug companies do to provide more information about the special needs of children, with regards to psychotherapeutic drugs? Dr. Hyman. As you know from appropriations hearings, when I arrived at NIH, now almost a year and a half ago, I was rather appalled at the knowledge base in pharmacotherapies and actually psychotherapies for children, and we have begun a concerted effort to initiate drug trials. Obviously, the pharmaceutical industry also has to be a partner in this, and we do talk to the pharmaceutical industry and also FDA. At the same time, we actually did not have the infrastructure; that is, we did not have the base of investigators who could actually go forward with these trials, and we have a number of programs in the works to increase the base of investigators. Perhaps the most exciting is our cooperation with NICHD which had an existing network of centers to study pharmacotherapies; NIMH has taken advantage of that with cooperation to piggyback on so that we can begin to learn some of these things. Mrs. Lowey. I thank you, Madam Chair, and I am sorry Mr. Porter left because, following up on his statements about the public-private partnership, I am honored to have in my district Connie Lieber, who has probably been one of the major leaders in the private sector contributions to this important field of research. Dr. Hyman. I have enormous respect for Connie Lieber. She is someone who really raised money from scratch, and her foundation, the National Alliance for Research in Schizophrenia and Depression, in the last year funded, I believe, 60 young investigators to get them to a stage where they would have the data to be able to apply for Federal grants. challenges in science Mrs. Northup [presiding]. Thank you. We will move on, because we want to give everybody an equal chance. Let's see; Dr. Alexander--really, anybody can answer this-- I have listened to some of the questions that are posed, some of the challenges we have in front of us, and I think it must be a constant frustration to hear people promote certain remedies, or antidotes, to the challenges we face. And have those promotions run counter or certainly not been backed up by the science that you have seen? Is that a regular occurrence? Dr. Alexander. I think it occurs in children, it occurs in adults, it occurs pretty much across the board. One of the problems is that when we lack an effective treatment, all kinds of things jump in to fill that vacuum, and it is often not possible to test each of them in a trial that is able to prove one way or another whether they work. Some of them, just on the surface, are so unlikely that they can almost be dismissed. But one of our jobs is trying to sort out the ones that may be likely to work and pursue those and try to document whether they are effective or not. This applies in a wide variety of areas; it applies in the health scene, it applies in the learning area, it applies in drug treatments, it applies in many different areas; and one of our issues is to try and determine where to focus our efforts to test scientifically what may hold the greater promise and target our resources to those. Sometimes it is particularly important to try and demonstrate whether something that seems popular is effective or not, and then we have to invest resources in actually testing that, using a comparison with another treatment approach to see which is a preferred method and whether one of them actually works or not. So, as I say, this applies across the board in many of the areas we focus our research on. Mrs. Northup. Well, following up, particularly, you mentioned when there are diverse ideas on how to address them. On this committee, we have talked about learning. I think Time magazine and Newsweek both did an article about children and learning, and they talked about all the different models and schools that have been successful. They did, however, talk at great length about the seemingly increasing number of children that are not reading. One, I think, used a 60 percent figure, another used a 70 percent figure, number of children that seemingly will learn to read any way they are taught, and then the growing number of those that fall into the balance, that are not learning the way we are teaching. And I am reminded of just, with six children, the sort of different popular ideas that have come forth saying this is the way all children read. What ability do you all have to evaluate, for example, the research that is being done to determine whether or not it is legitimate research and whether it has been effective? Dr. Alexander. Well, the research that we have focused on in this area has been on the basic learning process and how children learn to do various things, reading being one of them, also mathematical function, how they learn other things as well, how they learn health behaviors. And probably, in this area, the most success we have had has been in reading, and we have had that success because we have started to go back to basic principles of how kids learn and whether all kids learn in the same way, and methods by which most kids learn. There are some who have that method blocked, and they use an alternative pathway to learn. But we have started off by, as I say, trying to use basic principles to examine how children learn, and learn to read, and then to develop means to apply those learning principles, scientifically demonstrated, to actual methods of teaching reading and, as a consequence of doing that, have been very successful in demonstrating methods and testing them in the classroom that actually are effective in reaching the vast majority of children, and relatively easy to apply by the teachers, succeeding in teaching most of the children in any given classroom to read. Some of these methods are more applicable to children with specific disabilities in reading that are identified, and then they can be applied in the regular classroom or with special assistance to these kids who have special difficulties. But what we have been able to do, as I say, by applying the basic principles in scientific evaluation of how children learn is to take that and translate it into teaching methods, and that is where we are at the present time with that research. public-private partnership Mrs. Northup. To go further, though, we talked about the public-private partnership and we have talked about the importance of collaboration and so forth. I think that my concern is who can assess, when, let's say, if somebody says this is scientifically based, research based, or whatever--who can look at that research and see whether that is market research, or research that makes a difference in outcome, and what capacity do you all have to do that? Dr. Alexander. Well, we don't do it alone, we do it with the scientific community. We have a wide variety of experts out in the scientific community who are doing research, who understand basic research methodology, that understand how you do studies and ways that you can get appropriate answers versus inappropriate answers or misleading answers, and the things that go into study design, that lead you correctly or incorrectly down the path. And these people can work with us in evaluating--they do it all the time--in evaluating proposals to do research that are submitted to the NIH. Our whole peer review system is based on the scientific community evaluating proposals that are submitted to us to do studies, as to whether the research is set up appropriately to answer the question in the first place, and the research that passes that test is what we fund. We also have methodologies for looking at research that has been conducted and published, and assessing, again, in the judgment of the scientific community, a system of peer review, whether or not this research was conducted according to certain standards: Did it have an appropriate design to answer the question that was being posed? Was it conducted appropriately? Were the subjects selected in an appropriate way? Were the subjects appropriate to answer the question? How long did they follow up the subjects? And was it long enough to tell whether the test worked or not? So we can do that retrospectively as well in making judgments as to whether this research that was reported meets scientific standards of excellence and acceptability and should be considered to prove the point that was at issue. Mrs. Northup. And in other areas of NIH, are you aware that this goes on at this degree, at this level of assessment? Does the NICHD place where those sort of assessments take place any place else? Dr. Alexander. We do that in the health arena. The NIH does it, for example, with our system of consensus conferences, where we pull in an expert panel of people who have not done the research themselves but can serve as a jury, if you will, an impartial jury, to review what the state of knowledge is in a particular area, often a controversial area, and make judgments as to what has been conducted that is acceptable and what decisions should be based on. Mrs. Northup. But even in those cases, the assessment to research methodology is under the institutes of the NIH; is that right? Dr. Hyman. I think Duane has made a series of critical points. Let me illustrate with an example right now. NIMH is funding a very large trial of St. John's Wort, an herbal remedy for depression, and I feel we have a public health requirement to do that. St. John's Wort is, you know, flying off shelves at health food stores, and there is, ``research'' to say that it works. This research was actually collected in what is called a meta analysis in the British Journal of Psychiatry. In looking at the studies, largely done in Europe, some of them funded by the manufacturers problems were evident. St. John's Wort, is an herb, so some of the product used in the study had flowers and some had leaves; the preparations were different; the duration of the studies was, by and large, too short. And, you know, we had concerns that people would be self-medicating. And, I mean, I am interested in anything that works and I am very open minded, but I was afraid this research was not exactly research, and I think that gets to the heart of your question. Mrs. Northup. Right. Dr. Hyman. And we selected this area to invest money appropriated by you precisely because we felt it was a public health necessity, so many people were using it, and we are going to compare St. John's Wort to both placebo and to Zoloft, the standard effective treatment. We can't do this in every arena. There are an immense number of claims made, not only for health but for educational methods, something you referred to, and this is well beyond our arena. But one of the reasons I think we all have concerns about the scientific literacy of our children is because eventually individuals do have to be able to read and somehow assess the kinds of claims that are being made for either health supplements or educational methods, and there is no one clearinghouse to help people through this maze or jungle of information. Mrs. Northup. Except you all. Dr. Hyman. Well, in biomedical science, except us, I think. dissemination of results Mrs. Northup. And, finally, I would just like to ask you what you are doing in the area of disseminating the results of your information to other areas of the Government. In particular, I think there was a conversation in the earlier testimony, earlier in the hearing process, about, how research on how kids read was being disseminated to the Department of Education. You know, I would like to carry that forward--to talk about drug use and how research is being disseminated to SAMSHA and Health and Human Services. I think that there is a lot of focus. I still believe that cigarettes are the gateway drug, and that for psychological reasons and for social reasons, kids, when they are about 11 or 12, decide that maybe having their mom and dad's approval isn't as important as their fellow 7th grader. And a fast way to be somebody, if you are afraid you are going to be nobody, is to smoke cigarettes, and that is a step towards not doing what your track coach wants you to do, but hiding behind the garage or whatever. And I think we are talking a lot about regulation and changing the laws so that kids don't have such easy access to cigarettes, and I think that is very important. I have authored a number of those bills myself. But even if we made it very tough for kids to buy cigarettes in convenience stores, I don't think the use would go away. You can't buy marijuana across the counter, and they don't advertise it either, so you have to get to a kid's heart and mind--their heart by engaging them by not wanting them to smoke and their mind by educating them as to why it is bad for them. And it seems to me like, rather than you developing the delivery system for that, there is already one there and it is through SAMSHA or any other programs, CDC, and HHS. And I am afraid from the conversation that we had regarding how kids read, if you carry that forward, theconcern about, will the information on using cigarettes, using drugs, and so forth be communicated to the agencies that we already have, so that they may be able to incorporate that in their programs. Dr. Leshner. Let me just make a comment about that. Over the last few years, we have always had good relationships with SAMSHA because it is a sister agency and we all originally came from the same agency, but in the last 18 months, actually, a group of people from the Department of Education, the Department of Justice, and HHS have been meeting together, actually, under General McCaffrey's leadership, to talk about things like principles of prevention: You know, why don't you use it? And we have been very encouraged. The problem is, many programs everywhere are longstanding and therefore, for any program to change dramatically is not easy, but we do have communication links, at least in the drug abuse arena, that I think are working pretty well. Mrs. Northup. I know my time has run out, so I will defer now to Mr. Obey. international travel Mr. Obey. Thank you, Madam Chairman. First, let me ask on a totally different question, as something you may remember, we had quite a scare a couple years ago when NIH was intending to send about 400 scientists to a conference in Florence, Italy at a huge cost. I have a number of questions I would like to submit for the record with reference to the international travel engaged in by your agency, and I would be interested in knowing what the responses are. I won't ask them now, but I will submit them for the record. [The information follows:] [Pages 3083 - 3096--The official Committee record contains additional material here.] support for education policies and reform Mr. Obey. Secondly, I think everyone on this subcommittee recognizes your fine work with respect to research on child development, on cognitive development, and on reading, but I want to make certain that that expertise is not drug in, as Dizzy Dean would say, or doesn't fit. It is one thing to assess research on reading. It is quite another thing to assess how you fix screwed up schools. I appreciate receiving a letter from you which reads as follows: Because the NICHD's area of expertise relates to cognitive research on the development of reading and learning skills and to research methodologies, we believe comprehensive school reform which involves the development and school restructuring goes beyond NICHD in this area of expertise. I agree with that letter, and I would simply like, for the record, you to respond to the following questions, because I am interested in determining whether or not there is a significant overlap and duplication between you and the Department of Education which could enable us to save some money. So I would be interested in knowing what research grants and contracts have you awarded in order to determine how student performance is best raised in the areas of math, algebra, social science, study science, geography, or history. I would be interested in knowing what grants and contracts you have produced to determine effective school reorganization and governance, including decentralized and school-based management. I would be interested in knowing what grants and contracts you have awarded to help State schools and communities to design and implement policies and procedures that help raise student performance at the most effective cost to the taxpayer. I would be interested in knowing what grants and contracts you have awarded which relate to how you change the relationship between school administrators and teachers to effect better motivation. Also, as you know, there are lots of salesmen running around selling their version of technology reform, and a lot of them are good and a lot of them are turkeys, and a lot of them are very expensive and a lot of them are rip-offs. I would like to know what contracts and grants your institute has let that assess competing types of education technology. I would also like to know what contracts and grants you have issued which would help us to determine how to get greater accountability out of schools for the performance of students, in individual school buildings as opposed to school districts, because kids learn in buildings, they don't learn in districts. I would like to know what research and grants you have provided in the area of building effective high schools that discourage dropouts and what contracts and grants your institute has financed in order to strengthen community support for school reform efforts around the country. And if you have any general comments in response to those questions, I would be interested. Dr. Alexander. We will be glad to submit that for the record, Mr. Obey. I assure you, the answers will be shorter than the questions because in most of those the answer is, none. Our studies have focused on how kids learn, which has general applicability, and how children learn to read in particular. We are working in a small area on how children learn math skills, which is also important for us to study, I think, but in most of the areas you addressed in your questions, we have no studies whatsoever. Mr. Obey. I think that is a point that needs to be made. Thank you. [The information follows:] Support for Education Policies and Reforms In response to the questions asked, the answer is that the NICHD has funded no grants or contracts in the areas specified. Mrs. Northup. As a follow-up question, I would like to ask, while you have no grants or studies that you have done on how kids learn--I mean programs on geography and so forth--I think, what you said in your letter I was glad to hear said, is that your expertise is in evaluating the research that others submit, the research methodology, and if it is valid and if in fact the results are verifiable. Is that correct? Mr. Obey. Well, if I could simply observe, I don't think that is what the testimony indicated. I think the testimony indicated that they had expertise in the development of reading skills, but their area of expertise does not extend to many of the areas I just raised. So the research that you are qualified to evaluate is research that is related to your very specific and narrow mission of learning how children develop cognitively and how you can especially improve their reading performance, but you have no special capacity above that of anybody else to evaluate these other issues that I raised this morning. Isn't that correct? Dr. Alexander. Our area of expertise is in cognitive development and learning and research related to that. We do not have expertise in areas of school structure, organization systems, architecture, motivation of teachers, any of those areas. Our area of expertise has been in how children learn and cognitive development. That is the area where we have done research. Mrs. Northup. Again, I would like to follow up. I think Mr. Obey may have been on the phone, Dr. Hyman, when you were talking about evaluating other people's research and your ability to do that, even in areas where you haven't had the grants on your own. Dr. Hyman. That is true, but, again, that is in the biomedical arena. I think we have--this was in the case of St. John's Wort, where lots of people are taking a treatment, and so we felt that we had a public health responsibility to evaluate these claims because people with illness were self- medicating. So we do evaluate these other areas of research, but as they pertain to our biomedical and behavioral mission. Dr. Alexander. The methodology for doing the evaluation is pretty much the same, whatever area you are looking at, in terms of evaluating the quality and caliber of research. The principles are the same. The area of expertise of the people who are doing that evaluation needs to be relevant to the area that is being evaluated, and our area of expertise really lies in cognitive development, learning how children process this information, how they can best learn, either on a one-to-one situation out in the world or in a classroom. And so the methods that we use to evaluate that area are fine and we know the people to do that. The methodology is the same if you are looking at organization structure or nuclear physics, dairy science, or whatever else, but the people who would do that would be different from us and our scientists. Mrs. Northup. When you have different programs that say they are research based and they work, who is able to look at their research and evaluate whether the research is valid, whether or not it has been done over a long enough period to give long-term results, whether or not the sample is sufficient size, whether it is anecdotal evidence or scientific? Who would be able to do that? Dr. Hyman. In the biomedical sciences, that is really fundamentally our job, and if there is an area of controversy, I think Dr. Alexander has already mentioned the consensus conference process where we bring in all the appropriate expertise. I think what we would all try to say is that we, however, have to have humility about the boundaries of our expertise. We can evaluate research, you know, within the diverse institutes within the biomedical arena, but as I think Mr. Obey's commented, as things start to extend well beyond the biomedical arena, for example, in the area of school buildings, Dr. Alexander or I or Dr. Leshner wouldn't even know what expert to call up to get an opinion. Mrs. Northup. That is right, but would you be able to evaluate whether or not children learned more over a long period of time? I mean, the whole point is not how we organize the financial arrangement and the governance relationship. The whole question is, at the end of fifth grade, do the children do better in school or worse in school, and is there evidence or testing or whatever to verify that the children have done better under one model than another? Dr. Alexander. If those issues had been studied, a panel of experts would be able to be assembled to judge the quality of that research and say what that research had shown, and whether the answers that had been obtained from that research were valid because the research methodology was valid and appropriate and the samples were large enough and so forth. A panel with expertise related to that area, using these general principles of research evaluation, would be able to do that. Mrs. Northup. So if you had 10 different groups saying, we have a research-based proven way of reorganizing schools where kids learn better, you could empanel a group of people that could evaluate that research as to its validity? Dr. Alexander. Someone could assemble such a panel. Dr. Hyman. We wouldn't know how to put together such a panel. Perhaps the Department of Education ought to do it. But the point is that the methodologies for that kind of rational evaluation are there. Mr. Obey. Aren't you really saying there is a scientific method that holds, regardless of what field you are talking about, and your field of expertise is biomedical research and not school reorganization and the school administrative reorganization, and don't you in fact stand by your letter which says that you believe that comprehensive school reform proposals which involve the development of effective schools and school restructuring go beyond your area of expertise? Dr. Alexander. That is what I wrote, and that is correct, I stand behind that. Mrs. Northup. Were you asked to write a letter? Dr. Alexander. Was I asked to write a letter? Mrs. Northup. Yes. Dr. Alexander. The NIH was asked to write a letter explaining what our position and capabilities were in this area, and that is the letter we wrote. Mr. Obey. Let me be clear about that. I asked the NIH to make clear what your area of expertise is, because a lobbyist came to see you and represented that she in fact was there at my behest when she was not. And so when I found out my staff was being quoted in order to provide insight to that meeting, I asked what is your area of expertise, and are you suggesting you can do researchthat is supposed to be done by the Department of Education? And your answer spelled out what your area of expertise is and is not. And what is going on here, very frankly, is Mrs. Northup is trying to drag you into the school reform controversy, where, as you know, you have no business being drug into it, except insofar as your expertise can be used to help us assess what kind of progress has been made in areas such as reading, and I welcome that evaluation, but I don't think that school organization is a charter of NIH. Dr. Alexander. Mr. Obey, let me try to make clear that our staff met with your staff purely with the intent and purpose of discussing our research related to how children learn to read. It was not our intent or purpose at that meeting to discuss school reorganization. We have done no research on school reorganization; we have no special expertise on school reorganization; we have no position on school reorganization. Our area of expertise is in cognitive development and how children learn, including how children learn to read. We are eager to do anything we can to get the information about that research out to the public, the Congress, to anyone else, and any way that we can be helpful in doing that, we are eager to do. I regret very much that our efforts in doing got misinterpreted in some way as carrying over into the area of school reorganization, where we do not have expertise. Mr. Obey. Well, the fact that happened is not your fault, it is the fault of people who have tried to make your comments into something that I don't think they were. Mrs. Northup. Well, with that said, since I may be the person referred to, I would just like to say I am very eager to see us find ways to make schools work better, and there are a lot of people that are talking about science-based methods, and I would like to see the science because I know I don't know the right methodology. The results I have seen have been anecdotal; they have been short lined instead of long lined. Many of your publications regarding this have talked about how important it is to have long-term benefits instead of short-term benefits. So I am not reassured by groups that want to sell their services and don't have any long-term results. And so, you know, I am very eager to ask which agency is in the best position to evaluate research, that has been done, and provide those answers to a Congress that really doesn't know what science-based research is either. So I thank you for the questions you have answered for me, both here and before, and if there are no more questions, we are adjourned until 1:30. Mr. Porter. The subcommittee will come to order. This afternoon, we continue with our second session of hearings focused on child health and the public health approach to prevention. This morning, we heard from the directors of three NIH institutes that have responsibility for developing the research base for public health prevention measures. This afternoon, we are pleased to have three witnesses, two from Federal agencies and one from a nonprofit foundation, to talk about health prevention and education programs for children and adolescents. We are pleased to have with us Dr. Nora from the Health Services and Resources Services Administration, Health Services and Resources Administration; Dr. Marks from the Centers for Disease Control and Prevention; and Dr. Ernst Wynder from the American Health Foundation in New York City. If each of you could give your statement, and then we will proceed to questions after that. And in that way, members who I think will be here will have a chance to direct questions to any of the three of you upon completion of your statements. As was mentioned at this morning's hearing, Congress is in the final weeks of the session, with Members pulled in many different directions. We may have interruptions this afternoon, and Members may not be able to spend as much time at the hearing as we would like them to have. And I want to apologize to the witnesses. We just had a vote, which is still on. We are hopeful that Members will come back and join us as time permits. And, finally, you should know that this subcommittee will have its conference with its Senate counterpart at 4 o'clock, right after this hearing concludes. So there is a lot going on behind the scenes to prepare for the conference in an attempt to resolve final issues that has occupied our time. So you will have to blame me for scheduling this at the wrong time. I had assumed originally that we would be past the conference by this date; in fact, by the original date; and then had to put it over. And we thank our witnesses for indulging us and apologize for the problems that this causes. But we are doing the best we can. Dr. Nora. Dr. Nora. Thank you. Good afternoon. I am Dr. Audrey H. Nora, director of the Health Resources and Services Administration's Maternal and Child Health Bureau (MCHB). I am a pediatrician with an academic and private practice background who made a career change to public health when I realized that children needed a much broader, family- centered approach to care. I want to thank you for convening this hearing on child health. I am pleased to be here with my colleagues, Dr. Marks from CDC and Dr. Wynder from the American Health Foundation. The Maternal and Child Health Bureau has collaborated with their institutions around a number of issues such as infant mortality reduction, immunization, and health promotion, and we expect to continue working with them in the future. Today, I would like to discuss with you the child health activities administered by HRSA's Maternal and Child Health Bureau. The bureau has roots that go back more than 80 years to the creation of the Children's Bureau in 1912. Today, Maternal and Child Health (MCH) administers programs that comprehensively address maternal and child health for all of our Nation's mothers and children, stressing health promotion and disease prevention. In this regard, I would like to highlight an exciting recent bureau achievement, the publication of "Bright Futures: Guidelines for Health Supervision of Infants, Children and Adolescents." It provides state-of-the-art health guidance for children at four developmental stages: Infancy, early childhood, middle childhood, and adolescence. The services prescribed for each of these areas are designed to improve the overall health of children and families, enhance the way professionals practice, and foster partnerships among families, health professionals, and communities. For example, in ``Bright Futures,'' there is always interaction between the care giver and the family around healthy habits, around the social competence, around family relationships, and community interactions. More than 250 academic institutions that train health professionals are currently using ``Bright Futures'' as a required text. Many States are using it, as well as policymakers, families, health plans, and State health officials. With its recognition of the multiple social and cultural factors that impact children's development, we expect ``Bright Futures'' to be the health supervision system of choice for the 21st century. The MCH block grant which funded ``Bright Futures'' is authorized under Title V of the Social Security Act and has provided national leadership in developing health care systems for America's mothers, children, and families for more than 60 years. It links Federal, State, local government, and private resources to help improve health outcomes and is the largest bureau program at $681 million in fiscal year 1997. The maternal and child health block grant is a true Federal-State partnership with Federal Title V investments leveraging and facilitating local, State, and other Federal resources for maternal and child health services. The Title V partnership strives to assure mothers, infants, children, adolescents, and children with special health care needs a brighter future. The partnership developes systems of care to improve access and to deliver individual family and community health care, especially primary and preventive care. Examples of what the States use their block grant funds for include needs assessment, quality assurance, standards development, newborn genetic screening, lead poisoning prevention, injury prevention, SIDS counseling, outreach, transportation, case management, and services for children with special needs. Having affordable health care is a prerequisite for healthier children. But in order to guarantee that children actually receive the care they need, complementary public health services provided by Title V State programs are necessary to make the difference. Congress has recognized this relationship by legislating that State MCH programs play an integral role in the development and operation of State Medicaid programs. The Title V partnership stresses accountability for achieving ``Healthy Children 2,000'' objectives and interagency collaboration between Title V Medicaid and now Title XXI, the new State Children's Health Insurance Program. In addition, Title V provides needed supplementary services to children, especially those children with special health care needs, and supports for their families. Approximately 17 million children and families, including pregnant women, directly benefit from such services. The Federal-State partnership is enhanced and strengthened by the two grant programs authorized under Title V. The Special Projects of Regional and National Significance (SPRANS) and Community Integrated Service Systems (CISS), these programs address the many high-priority needs that continue to exist for providing health services to mothers and children at the State and community levels. They support leadership for working with States and communities to more effectively deliver services to moms and kids. They allow rapid, effective responses to threats to America's children and families, as well as to such national policy health concerns as early hospital discharge of newborns, early childhood brain development, teen pregnancy, youth violence and suicide reduction, genetic diseases, and newborn genetic screenings. The Title V CISS program began in 1992 and is designed to overcome fragmentation and inefficiencies in providing maternal and child health services in community-based systems development. CISS funds, for example, were used in partnership with the Administration for Children and Families in 53 States and territories to develop family preservation State plans which integrate child health and child welfare services with an emphasis on home visiting. My State colleagues tell me that the seed money provided through our CISS funds has been the most effective way of assuring that health care people are at the table working with welfare workers to integrate these services. Of particular importance today to this hearing is MCHB support through our SPRANS program for new knowledge through research. The bureau's research program is different from that of basic research in that it applies biomedical knowledge, puts that knowledge together into clinical interventions that emphasize prevention and promotion, and then assesses those interventions for effectiveness and quality. Beginning with the first U.S. study on infant mortality in 1913 and continuing to the present with studies and the science of caring for the neonate, MCHB research partnerships have yielded proven results and made significant contributions. The unique character of the bureau's research and our close collaborative relationships with our sister Federal research agencies help us avoid duplication. We currently maintain close contact with the National Institute for Child Health and Human Development, the Agency for Health Care Policy and Research, the National Center for Nursing Research, and the Centers for Disease Control. There are examples where the bureau has been supportive in collaborating with NICHD around pediatric pharmacology, and certainly around the ``Back to Sleep'' campaign. Our network is the way in which the ``Back to Sleep'' campaign materials are disseminated throughout the Nation. We also are funding interagency agreements to support research on early discharge of newborns from the hospital, nurse home visiting as a way to avoid hospitalization of children, and ways to improve preventive care in private pediatric practices through ``Bright Futures.'' In addition to the MCH block grant, the bureau administers other related child health programs. The Healthy Start program, initiated in 1991, is an excellent example of how the bureau has addressed the ongoing need to improve infant health through research and through experience gained from Title V. Healthy Start has the objective of decreasing infant mortality in targeted urban and rural communities. In the past summer, we had a competition and awarded 40 new grants to communities which have infant mortality rates 1 and one-half times the national average. The Emergency Medical Services for Children program established in 1984 funds grants to States to develop or enhance emergency service programs for children who have been critically injured or who have life-threatening diseases. The program is designed to ensure that all children, no matter where they live or where they travel, can receiveadequate care in a health emergency. In the last decade, the EMSC program has assisted 47 States, the District of Columbia, and Puerto Rico in incorporating pediatric components into their EMS systems. In summary, I believe that we can improve the health of our Nation's children through health promotion and disease prevention, through partnerships, both public and private, corporate, foundations, professional organizations, and all entities who have an interest in the future of children, and, thirdly, through interventions based on good science and good judgment. Mr. Chairman, this concludes my remarks. I will be pleased to answer any questions you may have on the bureau's programs and activities. Thank you. [The prepared statement of Dr. Nora follows:] [Pages 3106 - 3119--The official Committee record contains additional material here.] The Chairman. Dr. Nora, thank you very much. As you can see, we are having a series of votes, unfortunately, and what I am going to have to do is to recess the hearing until we finish that series of votes and then come back. Excuse me. But let me give you kind of a heads up, because what I really want to discuss with each of you are the broader issues of what we can do to intervene in childhood to establish good health habits, as I said this morning, dealing with diet, exercise, no use of tobacco, no use of drugs, maybe moderate use of alcohol, and good societal relationships that--in other words, the mental health side of a child's health; and how we can bring the minds of this country and the resources of this country to bear on preventing the kinds of diseases and negative outcomes that happen to too many of our young people later in life. In other words, giving up on the present generations, looking at youth and seeing whether we can start the country on a new track that will really make the difference and save, by the way, billions and billions of dollars in resources that we spend trying to cure diseases that afflict us because of our bad health habits. So I am going to have to ask that you, again, be patient with us. We are going to have to stand in recess, subject to the call of the chair. Thank you. [Recess.] Mr. Porter. The subcommittee will come to order. Dr. Marks, why don't you proceed. Dr. Marks. Thank you. Good afternoon, Mr. Chairman. Dr. James Marks, director of the National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention. I am pleased to be here to discuss our activities related to child health and pleased to be at this table with my colleagues. My written testimony provides many examples of the child health activities and programs at CDC, such as childhood asthma, disabilities, drugs and tobacco. I would like to have that entered into the record so that I can shorten my remarks for today. Mr. Porter. It will be received. Dr. Marks. Because of the limitations of time, I want to focus my oral remarks on the health behaviors among youth, specifically the increased opportunities that school health programs can offer to improve the health of our Nation's children. As you are aware, today's most serious and expensive health and social problems are caused in large part by behavioral patterns usually established during youth, including tobacco use, high-fat diets, inadequate physical activity, drug and alcohol use, violence, risky sexual behaviors, et cetera. These behaviors place children at increased risk for severe health problems both presently--that is, during their adolescent and youth years--but also in the future. Among 5- to 24-years-olds, only 4 causes account for nearly three-quarters of all deaths in that age group, principally related to issues of injuries, motor vehicle crashes, other unintentional injuries, homicides, and suicides. Additionally, the high prevalence of sexual intercourse among school-aged youth contributes to major health and social problems. Only three causes account for two-thirds of all deaths among adults 25 and older: Heart disease, cancer and stroke. Many of these deaths are caused by a limited number of health- related behaviors that are established in youth. CDC works to monitor the prevalence of these behaviors, and, as you are aware, these health problems are widespread. For example, among youth surveyed from our youth risk behavioral surveillance system, 39 percent rode with a drinking driver in the past month, 33 percent had 5 or more drinks on at least one occasion, 53 percent engaged in sexual intercourse in the past month, and 35 percent smoked cigarettes in the past month. A number of these risk behaviors are worsening. Yet, all of these behaviors are preventable. Why schools? Every day, about 50 million young people attend over 100,000 schools across the Nation. School health programs are one of the most efficient means the Nation might employ to improve the health and education of Americans. With more than 20 years of research, we know that school health education programs can be effective. CDC has done several large-scale evaluations that show that comprehensive school health education curricula reduce the use of tobacco, alcohol, or drugs, among junior and senior high school students. Others have had similar results with their studies, Dr. Wynder here among those. Preliminary studies indicate that for about every dollar spent on comprehensive school health education, an estimated $14 are saved in avoided health care costs. Yet, comprehensive school health programs are not widely implemented. Ninety percent of States and districts require schools to offer some health education, but only about 2 percent of schools provide school health education programs of the types shown to be effective in research studies. What does CDC do? First, as I mentioned, we monitor the prevalence of the key behaviors among youth. We do this nationally, and we work with the States so that they can have information that allows them to compare themselves to other States and to the Nation as a whole. In addition, we look at the characteristics of policiesand programs that are in schools. For example, a study that we did of the school health policy and program study showed that less than 5 percent of teachers of health education majored in it. That is far lower than other academic disciplines. Further, despite all the effort in HIV, only 31 percent of teachers that taught HIV education had had training in it after college. We also conduct prevention research, compile the findings from the studies that we do and other studies about the effectiveness of interventions to influence behavior among youth, and we convert these findings into guidelines that are useful to school districts. This is an example of our guidelines related to physical activity. It grew in part out of the work for the Surgeon General's report, and we brought in a group of experts to work through what might be possible in a school based setting. We have developed other guidelines for lifelong healthy eating, prevention of tobacco use, promotion of HIV prevention. Our goal is to make sure that local and State school districts have access to the state of the science in ways that they can use to implement successful programs. We also help States and large cities plan and implement comprehensive school health programs, especially for HIV. We fund every State and 19 large city departments of education to help local school districts implement HIV prevention programs. In addition, we support 13 State departments of health and education to jointly work with their local school districts to implement school health programs. This support provides each State with the capacity and flexibility to determine and address its own unique needs. For example, in Arkansas they have set up a network of representatives from the State departments of education, health, and human resources to help schools implement effective programs. This network has been successful and serves as a model for some of the smaller rural districts. For example, Paris and Magazine, have duplicated this model to help implement programs in their districts. We also support national education, health, and social service organizations, most of which have working affiliates at the State or local level. For example, the National School Boards Association conducts workshops, with our support, for school policymakers and school district teams to develop and improve school health policies and programs. The Council of Chief State School Officers provides materials and technical assistance to State school officers and State education agencies. The National Association of State Boards of Education is developing a guide featuring model policies and programs for promoting healthy eating and physical activity and prevention of tobacco use for children in all grades. Lastly is prevention research and evaluation. We help constituents evaluate the impact of interventions over time by conducting prevention research, dissemination research, and evaluations of programs. This helps the State and local education agencies evaluate and improve their own programs and to learn what has been proven effective elsewhere. Given that these leading causes of death and disease in the U.S. have their roots and behaviors established in youth, school health programs can help young people develop the skills they need to engage in positive, health-enhancing behaviors rather than those that put them at risk. Even though I have had to shorten my remarks here, I do want to say I have focused on schools, but I want to be clear that changing behaviors of our youth to positive, health- enhancing ones is not just a job for the schools. Families, health care workers, media, religious organizations, community organizations that serve young people, have to be systematically and consistently involved. I firmly believe that we cannot achieve the kind of results that we would all like to see without the schools being a key partner. We are firmly committed to working with the schools and communities to improve the health of our Nation's youth and the lives and well-being of our youth. Their future and our future depend on it. Thank you. And I will be happy to answer any questions you might have. [The prepared statement of Dr. Marks follows:] [Pages 3124 - 3144--The official Committee record contains additional material here.] Mr. Porter. Dr. Marks, thank you very much as well. We have saved Dr. Wynder for the last witness because I wanted him to get a chance to hear the previous five witnesses and what is being done, and he has heard from NIH, from HRSA, and from CDC. Dr. Wynder is the president of the American Health Foundation, the man who conceived Child Health Day. And I would like to know, Dr. Wynder, what you think we are doing right and what you think we are doing wrong and what we can do better in a different way. Please. Dr. Wynder. Mr. Chairman, first of all, I would like to thank you for convening this particular meeting and for your leadership for the NIH. And being a member in NIH, I can tell you that the research community owes you a great deal of debt, you and your colleagues, for making so many funds available to the NIH and to institutions such as ours. We are a designated cancer center going from basic research to applied research. Historically, I have learned from a long time ago that I do not need to know the precise cause of a disease in order to prevent it. That was true for lime and scurvy, for smallpox, for Semmelweis of childbed fever, and it is certainly true for life-style-related-diseases today. You so aptly called our problem a problem of life-style medicine. What is life-style medicine? It relates to what wesmoke, what we eat, what we drink, our sexual behavior, our exposure to sunlight, our lack of exercise, in all the kind of things that, after a while, when you lecture about it, it makes you one of the more unpopular people in your city. But the fact is that these are the causes, and in terms of treating these diseases in adulthood, we make but very slow progress. Therefore, for academic and economic reasons, we must follow what you so aptly call the principle of life-style medicine. Now, in my written testimony I have said a few words about how we should do this as adults, and the key variables that we learn from adults that our life-style practices, to a large extent, relate to our education. So education is crucial for life-style medicine, with respect I have for myself. And if you look at smoking as an example, while smoking in the general population is 25 percent of adults; among less educated, it is 45 percent; among adolescents that drop out of school, it is more than 60 percent. So the more educated we become as a Nation, the healthier we will be as a Nation. So the good news is that we know many of the life-style variables. The bad news is, we have to do it ourselves. And here we could talk forever about the barriers of preventive medicine, there is no economics, the self-denial that we all have. And so what are we going to do? And the focus of our work at the foundation, what I call application research, is the realization that our life-styles begin very early in life. Dr. Hyman Eppley called attention to the fact that it is a critical curve of learning to which we not only learn our language--and as you have often said, and the audience behind me may wonder how come I still speak with an accent, I still speak with an accent because I didn't come over to this country on the Mayflower. And so what we need to learn, that for language, as for behavior and emotion, we are baked in the first 8, 9 years of life, and probably earlier. So we need to focus our search. Why is it so? Can it be corrected? It probably cannot be corrected. And therefore our strategies, not only for children, but for adults, we must focus on behavioral medicine as it relates to children. And then we divide children into teens and preteens. Now, we and others have learned that if you do antismoking programs, programs on sex education, programs on nutrition in the high schools, they are largely failing. And the reason they are failing, we are starting too late. And so we are working, and we need to work as a Nation, on educating our children from zero to 8. How do we do that? First, as parents. We talk a lot about parenthood, and as we look around today, we see many children born to a single mother. We have a high divorce rate. In certain population groups, as many as 67 percent of children are born out of wedlock. When we just look at a PTA meetings in some of our inner cities, we are lucky if 5 percent of those parents come to such a meeting. So to begin with, parents is where we need to start. And we know that if we have two parents, you smoke less. If you have one parent, you smoke more, or if you have no parent. If you have two parents who smoke, you smoke more than if your one parent smoked. If a parent is obese, you become obese. If a parent is on drugs, you are likely to get on drugs. So we need to recognize that parents are our first obligation. In effect, when I talk about parents and school and community and media, they all come together, and we need to recognize that, in prevention, like in therapy, it is a dose that makes the therapy. So first, parents. Secondly, as Jim said, comprehensive school health education, very, very important. It becomes age 2 or 3 or 4. Transition or universal education for 3- and 4-year-old of everyone in France. And I would encourage a Head Start program. In fact, all children need to be educated when they are 3 or 4 years old. We have a major campaign that we ought to leave to our children. It is a very good campaign because the more we eat, the more our brain develops. The more our brain develops, the more we are likely to take care of ourselves. So this is a comprehensive program. I am against unifactorial education programs, be they drugs, be they smoking, be they alcohol, be they teenage pregnancy, because we know that they are all interrelated. It was said earlier that tobacco is often the gateway to other health habits, and, in fact, if you do a correlation between smoking and all other variables that are good behavior in children, they all correlate. So it has got to be comprehensive. It has got to be run what I call in this city a Vince Lombardi teacher. You have got to be a teacher with absolutely experience, interested, and almost emotional for a subject, because children relate to such teacher who is caring. And the third segment is a community, and within the community, I am particular calling on the television industry. I find it--I was going to say disastrous. If you look at the fare that we feed to our children today on television, including Saturday mornings, of violence, the sexuality, it is certainly misleading our children. So I am calling on the television industry, and perhaps you could help us there, at least on Saturday morning; give us a program that teaches children self-respect and self-esteem, because that is the crux of a comprehensive school education which we call ``know your body,'' self-esteem. So the American Health Foundation is developing a little character called Dr. AAAH. He speaks a little bit like me. He is the healthy people doctor. And Dr. AAAH has got one saying; he says, remember, nobody takes better care of you. And, you know, you could be rather humorous about this. And the children relate to humor and relate to care. Finally, in summary, let me make a couple of specific suggestions. I suggest the creation of an office or a czar for child health behavior that encompasses all the different activities that go on at NIH and elsewhere that deal with child health behavior. Secondly, I am calling for a health report card that would be issued each year on data that are only 1 year old. And on this data, we can see whether we fail or whether we succeed. Thirdly, I suggest, within the NIH, a study section that deals with behavioral research particular to young children. I call on all States to get involved in comprehensive school health education with proper annual evaluation, including attitude, knowledge, and behavior. And I call for an enhancement of Head Start to include comprehensive health education. We need, as Jim Marks said, to get the PTA, the workplaces, the places of worship, the medical profession, the community schools, television, health insurance company,HMO's, all together behind the move to enhance the health of our children. I believe, Mr. Chairman, that for children to grow up to be healthy with healthy behavior, it is not a privilege, it is a right. And for us, as adults, we need to recognize--and I cannot express it better than Confucius said many centuries ago: Tell me, I forget; show me, I remember; involve me, I understand. If we are a more involving society, all of us here, our children will become healthier and more educated and more productive for our Nation. [The prepared statement of Dr. Wynder follows:] [Pages 3148 - 3164--The official Committee record contains additional material here.] Mr. Porter. Dr. Wynder, thank you for your very comprehensive testimony, including the things you think we ought to do in detail. The first thing I want to ask you is a little bit about the suggestions--the first thing I want to ask you is, have you ever talked to Rob Reiner? Dr. Wynder. No. But as you can imagine, a lot of people said, you ought to meet Bob Reiner. And I stand ready to meet him any time. Mr. Porter. Well, he was in my office last week, and I brought up the fact that he ought to meet you. So we have got you both in a mode to meet one another. I am going to set this up so you can talk, because he is doing a part of what you want to do and focusing on early childhood and its importance, which I think is very much a part of what you are attempting to do, but in a broader sense through zero to 8. You know, we often say to our schools, you have got to teach this or that. When I was in the Illinois General Assembly, we put a mandate on Illinois schools to teach private enterprise, and then it occurred to me, none of the people that teach in our schools are in private enterprise, and they don't know anything about private enterprise; they are government employees, like I am. How do we get people in our public school system to teach comprehensive health education who are qualified to do so and who can be effective in bringing these concepts into the minds of our children? Dr. Wynder. Well, in years gone by, many schools had nurses, we had physical education teachers who more or less could have been trained into this. But the American Health Foundation, through funding from the Department of Education, we are part of a National Diffusion Network where we trained several hundred teachers in health education, and as part of a lease and budget cut, the National Diffusion Network was cut out, and so therefore we can no longer train these teachers. We at American Health Foundation stand ready to launch a program to teach teachers. And there are sufficient teachers around the country who have an interest in health, who, with very little education, could be taught to be effective health education teachers. Mr. Porter. So you would teach the teachers--you said earlier we have 100,000 schools; or maybe that was Dr. Marks that said that. There are a lot of schools. Those are just the number of schools, not the number of classes. And, presumably, you have got to teach this every year, not just once for a 3- week period or something. Dr. Wynder. Well, I believe that if we had one health education teacher per school, who again might be called the healthy people teacher, this teacher, by affecting parents or other teachers, by affecting school luncheon, by affecting exercise program, and by involving her or himself in all of the factors that we discussed today, would be one of the best expenditures this country could make, because if we create a healthier group of children early on in life, we do not have to pay for all these major disorders. I was just reading the other day the most common operation in the country is coronary bypass, 350,000 per year. And if your cholesterol is under 160, and you don't smoke, and normal blood pressure, we could send all the coronary bypass surgeons back to do something different than that operation. So that, economically, the best way to deal with life-style medicine, have one of those factors beginning in school, and particularly in preschool. Mr. Porter. What is the grade now? C minus, is it, or was it C? Dr. Wynder. Well, we gave it this year, Mr. Chairman, a C. Mr. Porter. C. Dr. Wynder. And the other day, when we had to celebrate a child health day in the White House, Mrs. Clinton said, can we make it a B, and I said this depends on what we as adult society provide as a motive for our children to do better. Mr. Porter. Okay. Well, Dr. Marks and Dr. Nora, Dr. Wynder is giving you a C. What do you say about that? And what should we be doing? And after hearing Dr. Wynder, what are we doing to head in his direction? Dr. Marks. In some ways, I think his grade is actually a little bit on the generous side for our country, because while the grade may be a C, I think in many ways we actually have been worsening as far as our health status for our children. So if it is a C, it is not as if we are heading towards our B. We have talked about what we can do with regard to school health education, where the data is, in fact, quite strong when it is done in the ways that we know work. But in fact, as you mentioned, it is very hard to get the schools to take this on. That is why we have said that it needs to be done jointly by the health departments and the departments of education working together. Where we have seen that this has happened, it is, I think, having an effect. It is not nearly as effective as it could be on an individual basis in the local schools. One of the things that Ernst talks about is also showing the impact. Any teacher, any school, any person providing care to children feels good when they see that they are making an impact, and we need to show that where it is happening and show that if they did things the way that we know work, they would have an impact, and they, I think,would in fact do that. The area of physical education is one that I did not mention in my remarks but is one example of what I am referring to Illinois is the only State that still requires daily physical education in the schools, and in fact in the last 5 years, physical education has fallen; the number of students, the proportion of students participating, has fallen from 42 percent to 25 percent. This past week in U.S.A. Today---- Mr. Porter. Excuse me. Is that strictly budgetary? Dr. Marks. It is not strictly, but it is often largely budgetary. There are issues of trying to get in other events as well, other things that they are asked to teach, but it is often heavily budgetary. There is an article in U.S.A. Today about the Army increasing a 70 percent higher rate of washout because of physical condition alone. They have now remedial physical conditioning programs, and they say it is the first time in the history that the physical conditioning of parents is better than that of incoming soldiers. There is just a tremendous amount to do, and yet the science is there that says we know what we can and should do. We need to make sure that the science that I have gotten from NIH, and from other places, is disseminated and is translated out there. It is like we have a new computer chip that is better than anything we have had before, but we have not done any work in designing the programs that will take advantage of it. We don't have marketing to get it out to the States and communities so that they are aware of it. We don't have any technical support so, as they try to implement it, and they have glitches, they have backup and we don't have people looking at how to improve it for the next generation. Mr. Porter. If we are going away from teaching physical education and we are going away from having even a school nurse, in most cases, how can we go toward providing health education? I mean, we seem to be going in reverse. We don't even emphasize the importance of exercise. Dr. Marks. I think that with the kinds of support that we provide for the comprehensive states, they have been able to do this in a few areas as demonstrations. But it is not to the extent that they need to or that we need to as a country. But by starting to show this in, not just in university settings, by showing it in rural communities like I mentioned in Arkansas and other places in schools, the prevention research center we have in Illinois is working with inner city schools at the school of public health. By starting to show that we can make these differences in regular settings, I think that, in fact, we can generate the kind of momentum that is needed. We also need to do the teaching, though. As mentioned, less than 5 percent of health education teachers have majored in it. We have so far to go in getting those that are now trying to teach it to where they really know what they are supposed to teach. Mr. Porter. Before I call on Dr. Nora, I want to ask Dr. Wynder, Dr. Wynder, does the American Health Foundation have any Federal grant funds to teach health teachers, teach teachers to teach health? Dr. Wynder. No, we do not. Mr. Porter. You mentioned the National Diffusion Network. Dr. Wynder. The only grant we had was a very small grant, I believe, of $75,000 to train teachers around the country about health education. And the fact that so many people wanted to be taught indicates that there is a great need and interest. I believe a problem, Mr. Chairman, we have, we have the Department of Education, we have a Department of Health, but they don't interconnect in terms of health education. But Assistant Secretary Towaldy, with whom we are meeting next Monday could be asked, and of course the Department of Education could be asked, how this could be corrected, because I believe there is the interest, Jim, among teachers. Health education is at least as fun to teach as Greek mythology, I believe, and it has a lot of people out there, particularly among young women these days, who are very interested in physical fitness and in health who would make terrific teachers. Mr. Porter. Dr. Nora, are you aware of any programs that provide funding for educating teachers to teach health in the public schools? Or does the Department of Education, to your knowledge? Dr. Nora. Let me just share some of the things that the Maternal and Child Health Bureau is doing. Two years ago, we funded a distance learning project at the School of Nursing at the University of Colorado which did distance learning through a national hookup for all of the school nurses in Montana, bringing them up to speed on new developments in school health. This was a very, very successful program and is just one example of such a program. We have supported and funded training programs in comprehensive adolescent health including health education for health care providers. The behavioral and social changes that take place in adolescents really need to be addressed. In addition, we have also funded behavioral training programs where health care providers are trained in early childhood behavior--what to look for, how to intervene when children began acting out, that type of thing. We have mentoring programs that are particularly effective in minority communities and low-income communities. We work through our school health services programs to coordinate mentoring with school health education so that there is balance and a comprehensive approach. There is no question that more needs to be done. I would also like to point out that I think that health education really needs to begin earlier than at the school-age level. And that is one of the reasons why, in our ``Bright Futures'' document, we have promoted healthy habits from the prenatal period through early infant visits on up to early and late adolescence and encouraged discussion between the care giver and the family about the ``anticipated challenges'' that the family and the child are going to be addressing, whether this is bicycle helmet safety, smoking, drug abuse, any of those kinds of issues. This is a challenging area to try and improve. Mr. Porter. How long have you been doing that? Dr. Nora. Well, ``Bright Futures'' came out in 1994. Our behavioral training programs have been in existence for several years, and the adolescent training programs for about 15 years. Mr. Porter. And do we have any data on at least theolder ones telling us whether we are being effective, whether it is making any difference? Dr. Nora. Well, the information that we have is that we need more and that care givers really need to be comfortable in dealing with adolescence. By and large, parents aren't comfortable in dealing with their own adolescents, and many physicians are in the same dilemma, so there is a need for some educational programs in that direction. Mr. Porter. Dr. Wynder, are we doing enough in this area? What should we be doing that we are not doing? Dr. Wynder. Well, our problem among our scientists, you know, we have basic scientists in the American Health Foundation, behavioral scientists, and sometimes the behavioral scientists do not get the kind of credit that they really deserve from our scientific colleagues, because we are putting so much emphasis on gene and molecular research and so much on therapeutics that sometimes I feel the best among us do not go into behavioral scientists. So, clearly, we must do much better. As Jim properly said, probably the passport should continue on C minus, because obesity is worse, smoking is not getting any better; this morning, reported drug use in very young children has gone up. So we have, I believe, a very fundamental societal problem that can only be corrected if all of us, including all the corporations who make a large income on children, ought to put something back to provide better health education to children. We need professionals, as pediatricians, as physicians, put much more emphasis in talking to our young people. Our young people today feel kind of lost because of the disintegration of many families, because of television, because of the way we talk to one another as public figures. It is not easy to be brought up today as a young person and not succumb to these temptations that many risk factors develop. So I believe that we need to do much better, and we need to determine, CDC and your office, Dr. Nora, and the NIH, and all the associations that deal with children come together, because what our children need is a much more concerted effort, a much more coordinated effort. And, as Jim said, we must have these reports every year. Some of the data, Mr. Chairman, we have in here are 2 or 3 or 4 years old, because we don't collect these data every year, and we must have them on 8-years-olds and 12-years-olds and 16- years-olds, we have got to have them by different minority groups, because in certain subpopulations we do work than in others. And if these were made public to the American public every year, perhaps there would arise a concern among all of us who are in a position to make a difference to make a change, because if you ask me whether we can do much better, we can, and we must do much better, not only for the sake of our children but for the sake of all the diseases that will not only happen in their future but in the long future as they continue under this state of behavior they have today. Mr. Porter. Dr. Marks and Dr. Nora, Dr. Wynder suggested we have a czar of child behavior, a special, presumably assistant secretary. Is that a good idea or a bad idea? Dr. Marks. I can't really speak for the administration's position on this, but I think the key issue, in my professional judgment is, in fact, that the emphasis needs to be on the behaviors and disseminating what we are learning from the research more widely. And I think that--I can't speak for Ernst, but of course-- because he will tell me if I am trying to--we need to make sure that the science and the dissemination are hand in hand and we put as much effort in getting it out there as we do in doing the science. Whether or not that requires a czar, it certainly requires coordination. It requires more than Federal coordination; it requires it at the State and local level as well. A czar as a symbol is perhaps nice, but it is really what happens at the State and local level that is much more important. Mr. Porter. Dr. Nora, what do you think? Dr. Nora. Well, I have to agree with Dr. Marks that I really think it is a bigger problem to get the information disseminated. And we attempt to do that through all of our partnerships-- through State and local communities, through our relationships with professional organizations such as Dr. Wynder's or the American Academy of Pediatrics, and through corporate working groups, foundations, and all kinds of other mechanisms. And I think there really needs to be more emphasis in that direction. Mr. Porter. We have talked about that kind of dissemination and about the role of our public schools, all of our schools, in educating children. But isn't the most powerful medium television? And can't we reach their minds more easily there than perhaps anywhere else, if we can get there? What do you think, Dr. Wynder? Dr. Wynder. We need two things. You know, there needs to be less violence, less sexuality, on television. I am sure this has been said by many, many others. But obviously what guides our television industry is the Nielsen rating. Some time ago, I was in Europe and I saw on prime time a program on how the Dutch recovered land from the sea. I think this would get a Nielsen rating of minus 10 here, but in Europe it was on prime time. But what we can do, I believe, is get the industry, particularly on Saturday morning, to give us the opportunity to have half an hour to impact on children. And it must be done in an entertaining manner. And there are marvelous writers out in California who, in addition to writing a comedy on Seinfeld, could write a beautiful scenario for children to laugh at and be educated at the same time. This is what I am calling for. We are going to start with Dr. AAAH as a health minute. You remember in the Bicentennial, you had the Bicentennial minute. And Jim Burke, who collects a lot of money for the Partnership for a Drug-free America, tells me again and again it is through television that could be accomplished. So I would like to get the Bob Reiners of the world and some major industries to help us to establish these health minutes. And I believe what Dr. AAAH could do what little Bonnie is doing, what Big Bird is doing, to teach children early on, 2 or 3 years old, that, I am responsible for myself is only, of course, one step, but together with all the other things we have mentioned are very important, sir. Mr. Porter. Are you assuming that our television networks or industry is going to provide this time free? And if so, where does that assumption come from? Dr. Wynder. No. I would hope that initially they wouldgive us the 1 minute free as a PSA. In the long run, I hope that there are major companies who makes a living on children who would support such an activity as part of the advertising campaign. For instance, these writers in Hollywood came up with an idea--I was talking about glasses, and I said, give me a little minute on glasses, and they came up with the idea that Little Red Riding Hood goes to the forest to bring food to her grandmother, but she didn't want to wear glasses because she was ashamed to wear glasses. So she runs into Big Bad Wolf. Fortunately for her, he didn't wear glasses either, so he didn't recognize her. And that is the beginning of a little story in 1 minute that, by the end, the kid says, hey, ma, I don't see too well. You better buy me some glasses. So it is just one idea where--of course, it is easier on glasses, on dental hygiene, than it would be on drugs and smoking. But I believe we could--certainly, if I were Mr. Reiner, I could, and therefore I would be delighted to meet with him, because there are some people in Hollywood who have enormous power, and perhaps we could influence them to make programs that some commercial company might want to endorse. Mr. Porter. Dr. Marks. Dr. Marks. I would like to support Ernst on this but also to talk about what we know. We know that in some other countries they have used TV very effectively. In Mexico, they had a soap opera that was very popular that had as its story line a father who couldn't read and had--there were a lot of interpersonal problems, and eventually he comes to the conclusion that he is going to go to the literacy clinic and learn to read. The TV station let the Government know about this ahead of time. They (the Government) didn't do anything. The next day, and the day that the father--after the father made the decision to go himself, they were swamped. They could not handle the calls that they were getting, the numbers of people, men especially, that were signing up. We cannot just model and tell children what to do, but we can model the kinds of family behaviors in the stories that are already popular, and the shows that are already popular, the things that can encourage children and their families to have more positive behaviors. We know, for example, when we do a survey of children and their physical activity, the thing that predicts more than anything their physical activity rates, children now in their early adolescence, is whether their parents were physically active with them, played ball, took them for walks. It is not whether their parents told them to. It is not even whether they have school health education, physical eduction in the schools, it is whether their parents did something with them to be physically active. That is the kind of thing that could easily be modeled in a number of the popular shows, so that the time doesn't really have to be donated, the creativity does. Mr. Porter. Does the concept that Murphy Brown recently did in highlighting breast cancer--is that kind of a model for---- Dr. Marks. That is a very good one, yes. Mr. Porter. Bringing this up to a level on TV where you can reach people's consciences with a positive message. Dr. Marks. That is a very good one, yes. I don't know how effective it was, but I do know, for example, when Nancy Reagan had breast cancer, you can see in the next month an increase in the number of women who signed up to get mammograms. These kinds of events have reached millions of people. And if what we are asking people to do is not so difficult, we can get them to start to make those changes. You can't get them to sustain it unless they like it, but we can start it. Mr. Porter. To what extent does HRSA use this kind of approach through television, I mean, as a medium to reach people with health messages? Dr. Nora. I would have to say that I agree wholeheartedly with what Dr. Wynder and Dr. Marks has said. As far as our use of television, we are certainly interested in trying to influence the development of programs. We have done a few documentaries with organizations like the National Parents Network, for example, that have focused on relationships of parents and children, trying to emphasize the importance of those relationships. We have targeted a national PR campaign on early prenatal care to young pregnant women through our Healthy Start program and through partnership with the State health departments, all of which have established a 1-800 number for people to call to find out where the closest prenatal clinic is to them and where they can go for their care. Our national information number is designed to roll over to the State and the local numbers. This campagin has truly been a partnership, one that has been very, very successful, with both the English- and Spanish-speaking communities. I would just like to add something to Dr. Wynder's comments about television. My own personal experience was that our children were watching too much television, and we, as parents, decided that it was important to limit the amount of time. We limited our children's TV time to 2 hours per week per child, that they could select. So the family had 6 hours of television. It was very interesting to me that suddenly these children were coming home from school and not sitting down in front of the TV. They were out interacting with other neighborhood children. And our decisions were influencing not only our children but the children of the neighborhood, because they had all been congregating at our house, and I said, no more. They were out riding bicycles, playing at sports, and being creative in what they were doing after school. I have to say that I really believe parents have to assume a role in this and that it is important that parents instill the values they want to share with their children at a very early age. Mr. Porter. We have talked about the role of parents. We have talked about the role of the school. We have talked a bit about television. We have talked about the role of the Government in influencing those sources. Are there any other ways, Dr. Wynder, that you can bring across the message of a healthy life-style, if you want to call it that, that need to be explored? Dr. Wynder. Well, if you look at the rest of our community, you certainly need to look at a place of worship that has a profound influence. And many studies have shown that churchgoers smoke a good deal less than those who do not. We need to look at a place of work where there could be work-related good health habits, including not smoking. One could look at the health insurance companies who could put afocus on good health behavior for which they might give some incentives. One could look at the health maintenance organizations who could give incentives for all the young people. I always say, if I were going to run a health insurance company, I would like to have people who don't smoke, who drink in moderation, who are normal weight, who exercise, who don't use drugs, and are happily married, and who go to church once a week. I bet I could make a lot of people compared to all the rest of the people. And you read in the papers the other day that our managed care organizations are running a deficit. And the deficits are probably relating to all these diseases that we are talking about which have their beginning early in childhood. So it seems to me also as a government--and I know we are concerned about Medicare and Medicaid; there only one reason that we need to die, and that is when the genetic time clock has run its course. The chairman has often heard me saying we should all die young as late in life as possible. Now, if we do that, we can take all the money we saved from Medicare and Medicaid and put it in the health education of young people. I don't know whether I could be elected to office on that agenda, but it makes a good deal of sense. Mr. Porter. Yes. Ideally, we should all live 100 years and die without being ill a day and save a lot, of course. I think it is possible, or something close to it. We may not see it in our lifetimes, but if you keep working on this, Dr. Wynder, and we give you a hand, perhaps it is; we can bring it closer to realization. I want to thank each of our witnesses today. We have, I think, focused on a very, very important subject. And I want to commend Dr. Wynder for the leadership he is providing to the Nation. I said this morning that I think, 20 or 25 years from now, a lot of what is accomplished in our country will be accomplished through--and it already is, but a lot more will be accomplished through private foundations, private money, that is directed to achieving specific ends. And yet, in the meantime, we are going to need government resources brought to bear on problems like this and the degree of government direction as well. And it seems to me, Dr. Wynder, you have given us some--not only some food for thought but some real suggestions as to how we can make changes here that will help in this endeavor. And I want to work with you to bring those to fruition. In the meantime, I am going to set up this appointment with Rob Reiner and get you two together. Thank you all for being here today. I thank each of our witnesses. You did a wonderful job. I think we have made some progress. Thank you. The subcommittee stands adjourned. [The following questions were submitted to be answered for the record:] [Pages 3174 - 3189--The official Committee record contains additional material here.] [Pages i - xxxii--The official Committee record contains additional material here.]