Segment 1 Of 2     Next Hearing Segment(2)

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Tuesday, March 10, 1998.










    Mr. PORTER. The subcommittee will come to order. We continue our hearings for the Department of Health and Human Services with the National Institutes of Health overview of the budget for the fiscal year 1999. We are delighted to welcome Dr. Harold Varmus, the Director of the National Institutes of Health; Dr. Ruth Kirschstein, the Deputy Director, and the other representatives of NIH here with us today.
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    Dr. Varmus, this is your fifth appearance before the subcommittee. You have had many more appearances, but this is your fifth formal appearance on behalf of NIH before the subcommittee and as you know we place the funding for the National Institutes of Health at a very high priority in this subcommittee.

    I have to give you my short sermonette and that is that the President's budget is very encouraging to me in that he has offered an 8.4 percent increase for the next fiscal year and said that his goal is to increase funding for NIH by 50 percent over five years. The difficulty, the immediate difficulty, is that his spending increases, not only in this but in other areas, is supported by revenues that are very unlikely in my judgment to materialize, at least in this fiscal year.

    That will provide some difficulty for us in respect to our 302(b) allocation and in reaching the kinds of levels that we feel NIH should receive, but we will do our very best both with the allocation and with the markup of our bill because, as I say, the NIH is a very high priority for all Members, on a bipartisan basis, of this subcommittee.

    My second concern with the President's budget has to do with the cancer initiative and while I certainly support the importance of research in this area, I think that while it may be good politics, it is very bad policy to earmark any disease as being politically important and to take away from science the right to decide where scientific opportunity and progress lay.

    So I am very skeptical of the earmark for cancer, but very supportive of providing all the funds we possibly can for cancer research and research with respect to all the work that NIH does and funds.
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    We look forward this afternoon to hearing about the remarkable scientific advances that your fine institution makes possible and I would ask that you introduce the people who are with you and then proceed with your statement.

Introduction of Witnesses

    Dr. VARMUS. Thank you, Mr. Chairman.

    Let me introduce the members that you did not introduce. Dr. Michael Gottesman, Deputy Director For Intramural Research, on my far left, Dr. Wendy Baldwin, Deputy Director for Extramural Research, and Mr. Tony Itteilag, who is the Deputy Director for Management. You have introduced Dr. Kirschstein, whom you know well. On my right is Ms. Francine Little, Director of the Office of Financial Management, and the long-suffering and ever-present Mr. Dennis Williams, who is the Deputy Assistant Secretary for Budget and Management from the Department of Health and Human Services. I would also like to point out that arrayed behind me in a spectacular show of support are the directors of the various institutes and centers which hope to receive the good wishes of this committee.

     As you point out, Mr. Chairman, I am here for the fifth time and very pleased on this occasion to be presenting the President's Fiscal Year 1999 budget request for the National Institutes of Health.

Appreciation of Mr. Stokes

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

    I also appreciate the attention you have paid to the training of minority scientists, including your support for the undergraduate scholars program on the NIH campus and for our clinical research loan repayment program. You have made a big difference in those regards. Thank you very much.

Opening Statement

    Now, as part of his Research Fund for America, the President, strongly supported by Vice President Gore and Secretary Shalala, is asking for, first of all, $14.98 billion for the NIH for the coming year—an increase of $1.15 billion, which, as the Chairman has already pointed out, is 8.4 percent above our current 1998 appropriation level.

    Furthermore, the President has outlined a five-year budget projection that will allow us to anticipate a stable pattern of growth over the next several years to a level of over $20 billion—approximately 50 percent above our current appropriations—by the year 2003.
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    Needless to say, we are enthusiastic—indeed, jubilant—about the prospect of building vigorously on the handsome increases that NIH has received over the last few years, when budgetary prospects were more problematic. We believe that this generous request has come at an especially opportune time, and that this is true for two reasons.


    First, as I think this subcommittee is particularly aware, discoveries in biomedical research are occurring at an unprecedented pace, and those discoveries presage revolutionary changes in the practice of medicine. At the same time, we recognize that the improved methods of care that we expect to result from these discoveries will improve care at a time when the nation is confronting some very serious public health needs. There are at least three that we need to think about. One is the aging of the human population, both here and abroad. Second, the disproportionate growth of groups in the United States that have historically experienced poor health. And third the persistence of many serious diseases that we have been unable to conquer, not only in this country but in all parts of the world.

    I would like to speak for a moment about the promise of science based on accomplishments. As has been the case over the last several years, we come to you with a rich harvest of recent results, and those results come from both the laboratory and the clinic. My colleagues will give you testimony over the next three weeks that will describe in great detail some of this productivity, and some of the specific accomplishments are listed in my written statement. I will not spend the time going over them now.

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    I would simply point out two things. First, that they represent an array of laboratory findings which last year I referred to as ''inspirations'' for further work to achieve our ultimate mission of improving the nation's health. Those inspirations range from the isolation of new genes and our progress on a variety of genomes—the collection of genes—to discoveries about the brain and the rest of the nervous system, new insights into functions of cells, and the molecular basis of disease.


    We also will be reporting a large number of what I called here last year ''culminations'', the work that actually takes those results and puts them to use in the clinic. You will hear over the course of the next few weeks about a number of vaccines, new drugs, the use of devices to reduce morbidity and mortality, new important epidemiological findings, and diagnostic tools.

    But beyond these inspirations and culminations, I want to remind the committee of a few advances that have occurred over the last few years that have had dramatic objective effects on the health of this nation, indeed, the health of the world. In these several areas, NIH science over many years has had dramatic and important contributions to make.

    For example:

  —the virtual elimination of hemophilus influenza B meningitis, which previously occurred at the rate of 20,000 cases per year and was one of the major causes of mental retardation in this country;
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  —declining cancer mortality rates, that have gone down nearly 5 percent over the last six years;

  —a nearly two-thirds reduction in the transmission of HIV from mothers to infants, and now a reduction in rates that is almost as significant now with the short course of AZT abroad;

  —a decline in AIDS mortality rates of 44 percent for the first half of 1997 compared to 1996;

  —a marked decline in infant mortality that in recent years has been particularly ascribable to a decline in sudden infant death syndrome of 40 percent due to our Back To Sleep program that you will hear more about later;

  —the safety of the blood supply, further secured by definitive tests for HIV, hepatitis B and hepatitis C viruses;

  —and a decrease in disability rates for the elderly, to the tune of as many as 1.4 million fewer disabled in recent years than would have been anticipated from 1982 rates.


    In proposing a very substantial increase in the NIH budget, I believe it is appropriate to emphasize our future prospects. In the main what we expect to see, of course, are many new ways to prevent and treat illnesses, using methods that we expect to be based largely on the extraordinary discoveries and technologies that are currently being delivered in many fields of work, especially neuroscience, genetics, cell biology, bio-engineering, computer science and others.
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    One way in which we can see this change most vividly is by observing a passage that science is currently making from molecular biology to molecular medicine using our knowledge of the large molecules of life to prevent and to treat disease. We discussed here last year the marked improvement in the treatment of AIDS that serves as an incredible example of this approach and also serves as a harbinger of the rational mechanism-based approach to medicine that will be, I believe, the major legacy of current molecular and genetic science.

    You will recall that the new therapies for HIV infection are built on an understanding of the relatively few genes and few proteins of the virus. We are beginning to see this pattern now for much more complex illnesses that arise from our own much larger genome.

    The next venue in which I believe the impact of molecular medicine is going to be most dramatically perceived is the application of genetics and molecular biology in the study of cancer. This is true for a number of reasons. First, cancer is intrinsically a disease caused by mutations. Secondly, some of the genes affected by those mutations are among the first to have been isolated from animals of the vertebrate class. Thirdly, because the functions of many of those genes are now intimately understood through work in cell biology and biochemistry in the last couple of decades. Because of all of these things, it is now already possible to begin to predict an individual's genetic predisposition to several forms of cancer, to assess the specific genetic damage in individual cancers, to design novel ways to do the traditional things that we do in cancer therapy—destroy cancer cells—and also to take advantage of new knowledge to think about entirely novel approaches to cancer therapy.
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    In the very near future our ability to think about new ways to prevent and treat cancer and many other diseases is going to be based on a much more detailed and much more refined view of normal biology and disease. I want to illustrate this important point today by showing you a single new technique among the many recent technologies that have currently become available. [See figure 1]
    "The Official Committee record contains additional material here."


    This method is sometimes called the expression array. It takes advantage of the fact that the scientific community has already accumulated large collections of pieces of genes made available by the technologies used in molecular biology and genomics. If one takes hundreds or, indeed, thousands of such individual gene pieces and places them, by using a highly refined technology—based in part on the use of laser jet printers—one can put onto a little slide the size of the one that I am holding in my hand as many as several thousands of genes in an orderly array and then use this chip or array to ask about the activity in each of those thousands of genes in a single cell; to ask whether each gene is turned on or turned off, or to compare the activity of the gene in one cell or another.

    I would like to illustrate this with an example that comes from an actual case of a patient who had a T-cell lymphoma that was being treated at the University of Pennsylvania Hospital. During the course of this patient's disease, the tumor that was initially indolent, growing extremely slowly, turned into a much more malignant or aggressive form of the disease. By taking material from the tumor at both stages of development, it has been possible to look at 10,000 genes—10,000 of the available 80,000 to 100,000 in the human genome—and to examine the activity of each of those genes in the two phases of the disease. [See figure 1]
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    Now, the colors here indicate what is going on. If a gene is active, it turns up as a colored dot. If the color is red, then that gene is more active in the aggressive form of the disease. If the color is green, then the gene is more active in the indolent form. If the color is yellow, there is no difference. And that, of course, is the case for the vast majority of genes.

    As you can see in the blow-up of one small segment of this chip on the right, these results could in the future have direct bearing on the choice of treatment. For example, there is one gene, bleomycin hydrolase, that destroys a drug that is commonly used in chemotherapy for certain—not this one—but certain kinds of cancers. Some of the other genes that are turned on or turned off, such as the ATM gene, are genes that have been implicated in other kinds of cancer and could provide the kind of fingerprint of the cancer that would be useful for instructing the patient about the prognosis, or about the appropriate choice of therapy at that stage. [See figure 1]


    In presenting this single technical advance, which is going to have very wide ramifications in medical science, I want to make four additional points.

    First, this kind of technology, using modern molecular and genetic methods to look at the disease in the most precise terms, is going to have major applications not only to treatment of disease but also to prevention.

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    Second, the method that I am illustrating will have an impact not only on cancer but on a large number of other diseases. We are already using these techniques for AIDS, and they will be used in many other contexts.

    Third, this method is only one among many kinds of innovations that I could have illustrated to you today. Innovations that are on the horizon are going to be applicable to visualization of the disease process, to bio-engineering, to repair of disease, to development of devices that will measure brain functions and so forth.

    The fourth point is a subtle one. This experiment is the result of a collaboration between Government scientists, university scientists, and industrial scientists, illustrating the kind of interaction that is going to be essential if we are going to control disease in the long run.


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


    The first area is research grants. I have argued here before that the most important instrument that we use to achieve our goals is the individual investigator research grant. In Fiscal Year 1999 we plan to increase the number of grants substantially, to an all time record of over 30,000 grants. We will also set a record for our so-called new and competing grants—the grants awarded in this year of nearly 8,300. That will allow us to achieve an overall success rate for our grant applicants of close to one-third.
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    In addition, we are going to be increasing the average size of new grants by about 10 percent. I can describe later on some of the reasons why we feel that it is appropriate to do so.

    What are these grants for? The topics, of course, will not be precisely known until the proposals have been written and they have been judged. But we have identified, in priority setting discussions with the Institute Directors, many important research topics to which we expect to devote enhanced resources.

    As in recent years, we have approved most of these new initiatives within six broad areas of NIH research emphasis. And initiatives within each of these broad domains would address a wide spectrum of diseases: cancer, diabetes, heart disease, central nervous system disease, and many others. We expect that this expanded grant portfolio to accelerate our discovery and our approach to applications to health across a very large frontier of medical science.


    The second area is instruments. As medical science becomes more complex, it also becomes more dependent on innovation in instrumentation and multi-disciplinary work. There are many areas of science that have received the benefit of this expanded effort to improve the way in which we measure the performance of biological systems in health and disease. With the resources requested in the President's budget, we will develop new and more powerful instruments. We are going to attract trainees and scientists in many fields to problems posed by technology development in biology and medicine. We will allow more groups of investigators to share instruments through a shared instrumentation program and will expand the use of computers for storage, analysis and exchange of data.
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    The third area is talent. We all know that recruiting and training and retaining our most talented individuals is crucial to the success of biomedical research. Attracting people into our field has a long-range impact. Someone recruited this year may not make his most important discoveries until the year 2020; therefore, this is a particularly important responsibility for us.

    With this year's budget we plan several strategies to encourage young people to enter these incredibly exciting fields. We will have innovative research training programs that emphasize trans-disciplinary work. We are going to increase our stipends by 25 percent—both for graduate students and for post-doctoral fellows—to come close to the levels previously recommended by the National Research Council. By increasing our general support for research over many years, we will create a stable environment that induces our young and talented individuals in this country to enter medical research areas.


    The fourth general area I would like to comment on is clinical research. We all know that the promises of biomedical research cannot be achieved unless we strengthen the nation's commitment and capacity to perform clinical research. To do this, we have been putting into practice most if not all of the recommendations made by my distinguished Panel on Clinical Research.

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    We discussed some of these last year but I want to mention a few new ones that are currently going into the implementation phase. Most recently we announced new programs to enhance the training and support of clinical investigators, a program that will provide a supervised five-year apprenticeship for over 400 additional young clinical investigators; A program that will provide salary support for the clinical research activities of nearly 400 mid-career scientists who have distinguished themselves already and can serve as mentors for new clinical trainees; and a didactic training program that will bring organized programs in training of clinical research to over 20 institutions.

    In addition, we will be strengthening our programs at clinical research centers including the General Clinical Research Centers, and expanding new programs on the NIH campus that introduce medical and dental students to the joys and tribulations of clinical research. And we will continue our construction of the Mark Hatfield Clinical Research Center.

    We also have a variety of plans to increase our capacity to do clinical trials that are outlined in the written statement.


    Finally, I would like to address four issues concerning our administrative functions at the NIH, because we know that our ability to use money effectively is dependent upon strong administrative practices. First, in the area of grant review. We are renowned for our expert review of grant applications but, nevertheless, we feel that more needs to be done to ensure that we are appropriately reviewing proposals from our grantees. So the Center for Scientific Review has undertaken a thorough reexamination and restructuring of our peer review panels.
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    Second, in response to a suggestion from this committee, we last year commissioned from the Arthur Andersen Company a large-scale review of our administrative practices. While this review was generally complimentary, it did include roughly 80 recommendations for improvement and many of these we hope will be implemented in the coming year.

    Third, this committee and others have been interested in the way in which we identify priorities for research funding and we have just signed a contract with the Institute of Medicine to carry out a study of our practices in addition to many other activities we have undertaken in this area.

    Finally, as mandated by the Government Performance and Results Act, we have incorporated our first annual performance plan with goals and measures into this budget request.

    Mr. Chairman, committee members, we are in the midst of a remarkable phase in the history of biomedical research. We have an opportunity before us to create a stable environment for continued discovery that will benefit the citizens of this country and people throughout the world for decades to come.

    I hope we can work together to seize this opportunity and to realize its benefits.

    Mr. Chairman, thank you for the opportunity to speak at such length, and I am pleased to respond to any questions that you and your colleagues may have.
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    [The prepared statement follows:]
    "The Official Committee record contains additional material here."

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


    Dr. Varmus, I expressed in my welcome to you a concern about the President's budget in respect to the cancer initiative. I have expressed very frequently a concern about the politicalization of science. And I wonder if you had any opportunity during the formulation of the President's budget to raise the question or issue of disease earmarking before the budget or State of the Union message or both were offered?

    Dr. VARMUS. Mr. Porter, naturally we have had discussions with the Administration about budget formulation. Just as we discuss with members of this committee their interests, we have discussed the interests of the Administration in various diseases. But the budget was put together in our traditional manner—that is, in response to scientific opportunity and our sense of what is needed.

     Mr. PORTER. Did the cancer initiative idea come from NIH or from the White House?
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    Dr. VARMUS. Well, I think you would have to—it is, as the Secretary commented—it is a chicken and an egg problem in a sense. The budget as formulated afforded major increases to many cancer-related activities for reasons which I think I spelled out in my testimony—the remarkable opportunities that are available in cancer research, the fact that cancer is going to be a major area in which the fruits of molecular and genetic technology are first applied.

    There is the additional fact that many of the infrastructural issues in medical science—clinical trials development, training of clinical investigators—are going to be exercised. So the budget for cancer was large. The identification of a cancer initiative that the President and Vice President have emphasized is a decision made by the Administration but it is completely consistent with the budget numbers that we developed.

    There are other diseases that receive increases in the budget equal to or even greater than cancer. But in view of the magnitude of the cancer problem, the public's concern about cancer, and the remarkable advances that we believe have come and are in the immediate future, it has been featured in the President's display of the budget.

     Mr. PORTER. In other words, you are saying that the President did not necessarily vault cancer ahead of other diseases, he simply emphasized cancer in the increases that were being provided, and he could have emphasized other diseases in the same way?

    Dr. VARMUS. In fact, as I think the budget proposal makes clear, there is a very handsome increase for every disease area. I do not believe that the modest increase in advance of the average for cancer research is discriminatory to other disease areas.
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     Mr. PORTER. Thank you. We will treat it that way.

    Last fall we had some special briefings on the role of the mind in health and healing. Is there any important role of the mind in molecular medicine or does it simply become irrelevant? And if there is an important role, what is NIH doing in terms of its own work in grant funding in this area and what Institutes are involved?

    Dr. VARMUS. Well, Mr. Porter, I chose to speak about molecular medicine because it is at the verge of having a tremendous impact on changes in medical practice. But I hope that I made clear that it was only one of many profound changes that are occurring and represents only one area of our science.

    We believe that the mind is a manifestation of a physical entity, the brain. What is occurring in neuro-science and the understanding of how activities of the brain affect health are germane to a wide variety of activities carried out by at least a dozen institutes—I could name them if you would like, starting with the Institutes for Mental Health for Neurological Disorders and Stroke, and many others.

    The connections between mind and health are being explored by a variety of technologies, ranging from neuro-imaging to classical behavioral work, to attempts to understand connections, for example, between the nervous system and the immune system.

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    There is a coordinating function here that is carried out largely by the Office of Behavioral Science and Social Research that attempts to overview the activities of many institutes in understanding the relationship between mental attitude, behavior and health outcomes.

     Mr. PORTER. Is there any way that the brain, like other organs, can simply be reduced to dealing with it in respect to molecular biology and not worry about behavior or anything outside of the physical work of the brain?

    Dr. VARMUS. Well, I do not think that any of us are interested in learning about molecular interactions without knowing about their consequences. For example, to talk about one fairly simple thing, we know that when a patient uses a psychotropic drug, or uses a drug for the treatment of mental illness, or uses a drug in an illicit way, that there is an engagement between a molecule, namely that drug, and a receptor on the surface of nerve cells. We also know that there is a change in behavior and we can see the places in the brain that respond to the drug. They may even respond to the possibility of obtaining that drug.

    The changes that we can see by neuro-imaging combined with our understanding of the molecular events that transpire between the interactions of the drug with the nerve cell and the actual change in behavior, are things that we are trying to understand in order to intervene to prevent the events that produce ill consequences for health.

    So I think it is very difficult to separate the molecular components of your question from the behavioral, because what we are trying to effect are the behavioral changes that are desired, using molecular tools for understanding.
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     Mr. PORTER. You mentioned, in a general way at least, how you would use the increases that the President has proposed in his budget, a 50 percent increase over five years. Many are proposing a 100 percent increase for NIH over five years and other research components within the Federal Government. Can you tell us whether you could reasonably absorb an increase of 100 percent over five years and how, if it is different, you might use funding at an increased rate of that magnitude?

    Dr. VARMUS. Mr. Porter, I believe that what is going on in medical science at the moment is truly extraordinary, and that the capacity of our research community to make good use of funds is at an all time high.

    It is very difficult for me to calibrate exactly where the limit is reached. But we do know that there are many excellent grant proposals that go unfunded, many investigators who have been well-trained and are able to do work who are currently not working at peak capacity. We know that there are areas of research that we under-explore.

    And we also recognize—and I give malaria as one example—certain diseases that have greater impact abroad than they do in our own country.

    We also know that as we make this transition from a molecular-based science to molecular-based medical practice, there is going to be an expanded need for clinical trials, for general clinical research, both of which are more expensive than some of the laboratory work we do. Animal experimentation has become very important in the last few years as a result of our ability to build truly informative and accurate models of disease in experimental animals. And that kind of research, too, requires additional resources.
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    We know that science moves faster with good instrumentation. We have seen many of the programs to understand the full genetic blueprint of organisms moving at a pace that is slower than could be achieved simply because there is a limitation on methodology and on the number of machines available to advance research.

    We are entering into a whole new era, that I illustrated with that chip experiment, in which the talents of people who are currently in other fields will be required, mathematicians to help us to understand the dynamics of how a single cell works, or physicists and computer scientists to help us manage the information that has become available and to cope with a new way of thinking about normal and diseased tissues.

    So I believe the opportunities are extraordinary and that even as much as twice the current level of funding could be extremely well used.


     Mr. PORTER. I think you said we are funding about a third of the good science that is offered, is that correct?

    Dr. VARMUS. This year we will achieve an overall success rate of about 31 percent. But I would point out a couple of things about that number. First of all, that number is not uniform among all the institutes. And secondly, the number is higher for those who are competing for their renewal than it is for our new investigators.

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    On average, between 22 and 24 percent of our new investigators receive their first grant. And we know that, first of all, we believe that a higher number of those who went through NIH training programs should have a chance to show their mettle.

    We also have recently decided that new investigators should be better supported than they have been in the past. In the past, as you know, over half of our new investigators were receiving an award known as the FIRST award or the R29 award, which gave investigators only $70,000 a year for five years.

    In my view, this was not a fair start. A study carried out this year at the NIH strongly confirmed that perception. The Institute Directors voted to end the R29 award and instead ensure that at least the number of new investigators we had supported before would now be supported in our traditional R01 manner.

    That is going to cost us roughly $50 million this year and perhaps as much as $500 million over the next several years. But I feel it is very important that our newly trained individuals show what they can do with adequate support.


     Mr. PORTER. Is there any way of investigating if anything of that magnitude were possible; is there any way of estimating what percentage of the new proposals would be funded? Have you done anything like that?

    Dr. VARMUS. I am not sure I quite understand what you are asking.
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     Mr. PORTER. Well, we are at 22 to 24 percent, I think you said.

    Dr. VARMUS. Right. That is for new investigators. And that is the number we anticipate for 1999.

     Mr. PORTER. If funding were increased at the rate we are talking about, would that number increase appreciably? Would the 31 percent increase appreciably as well?

    Dr. VARMUS. Well, this is a difficult question to answer, Mr. Porter.

     Mr. PORTER. I know that it is.

    Dr. VARMUS. I have actually asked that we start to do some modeling to try to make some estimates. One of the things I have encouraged this year is that we increase the size of our competing awards as well.

    Over the last several years with tight funding it has been practice for most institutions not to allow a significant increase between the first award—that is the initial R01 award—that an investigator might obtain and the level of the competing renewal. The consequence has been that when an investigator is successful, in order to increase the size of the laboratory group it is necessary to apply for a second grant. And, indeed, there are several thousand of our investigators who carry two and sometimes even three awards rather than just one. I would like to move us back in the other direction. It simplifies administrative practices and review and program management, and that needs to be figured into the modeling of the system.
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    We are not intending to increase the pool of investigators by expanding the number of training slots. I think I have made it clear in the budget rationale that we expect to increase our stipend levels to bring the stipends up to a more humane level. But we do not expect to increase the number of trainees because we do not believe that it is appropriate to expand this universe forever. We want to make the universe a better one.

     Mr. PORTER. My concern is that we have young investigators who get discouraged and leave the field and obviously we want to keep them in if they have good science and good talent.

    Dr. VARMUS. If they are doing well, I agree. We have, of course, always had an exit rate. That has been roughly 9 percent per year. And that is a biphasic rate of departure. But we would like to ensure that everyone gets a very good chance to be in the system. If they do not succeed, then someone else is given their place, but I think we agree on this point.

     Mr. PORTER. Thank you, Dr. Varmus.

    Mr. Obey.


    Mr. OBEY. Thank you, Mr. Chairman.

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    Doctor, I have 31 questions which I will submit to you for the record of the Office the Director hearing and I would appreciate a response to them as soon as possible.

    Let me begin by going in the other direction from the chair. I, frankly, am skeptical that NIH—and I would appreciate it if you would keep your answers to about a minute apiece, so, I can get at least five questions in—I am very skeptical about whether or not NIH, in fact, has the capacity to absorb the kind of money which is being talked about in the President's budget, particularly in the last two years.

    I will ask you to expand for the record, but can you explain to me in one minute or less, why I should believe that that kind of huge expansion will be wisely spent without waste, especially in the last two years?

    Dr. VARMUS. Well, Mr. Obey, I think that it helps to recognize that not all the money would be going into grants. We are not simply trying to increase the grant pool and increase the success rate. What we are imagining are new kinds of initiatives and more involvement in clinical research, which is, as you know, expensive. We are interested in developing new aspects of the research portfolio. We see ourselves expanding into areas of instrumentation and bio-engineering that will bring the talents of people in other disciplines to medical research. As we cost out these programs and think about what is possible over the next several years, we do believe that certainly the President's request can be used very well throughout the next five years.


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    Mr. OBEY. Well, let me ask you if you would outline for the record how a 50 percent increase will be used for grants for clinical trials, for training, for intramural programs, for construction et cetera. I would like to know if you could use it. I would like to see how, in fact, you plan to use it right now. If you are still betting we can put a plan together sometime down the road?

    I would like to know what decisions have been made now as to where the money will go in the next five years.

    Secondly, if you take a look at the stability and the mechanism distribution over the years and you could take this year and last year, for instance, how much change between those categories? Is that a sign that the budget has become too stagnant and locked in, and how much do you expect that distribution to change if we allocate what you have asked us to provide?

    Dr. VARMUS. Actually, Mr. Obey, there are some significant changes in the mechanism for this year. One, of course, reflects the change in stipends for trainees. The dollar value is not enormous compared to our dollars invested in grants but, nevertheless, is a very substantial percentage of——

    Mr. OBEY. If you look at the percentage changes in your budget——

    Dr. VARMUS. It is a very large percentage change actually. And it is about 20 percent change in the training category—or 18 percent.
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    Mr. OBEY. I am talking about as a share of your, I am talking about——

    Dr. VARMUS. As a share, of course. Because that is, of course—because we have a very large commitment base, as you know. So, I think the important——

    Mr. OBEY. Right, but I prefer that we not change terms when I am asking you a question.

    Dr. VARMUS. Okay. I was just pointing out that the way we can make changes is by looking at the——

    Mr. OBEY. All I am saying is that if you look at what is happening from 1987 through 1996, you may have a 1 or 2 percent change for any of these categories, at most. I would say that is fairly stable.

    Dr. VARMUS. Yes, it has been very stable. I agree with that.

    Mr. OBEY. And I am simply asking whether that also means it is very stale.

    Dr. VARMUS. Well, I think there are two answers to that. First of all, it is only with this year's budget request that we have been able to forecast the kinds of increases that would make some differences in the way the money is divided up.
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    I would also point out that what is probably more important is to look within each of those categories at how we are spending our money—for example, on grants and intramural programs, and to ask: What is the quality of research? At this point, to envision an NIH that is fundamentally different in character—that it spends 20 percent of its money on grants and 80 percent on intramural programs, for instance—it would seem to me an arguable possibility for an abstract discussion but I do not think it would be terribly consonant with the reality of where our scientists are and where the buildings are.


    Mr. OBEY. Well, let me ask you with respect to clinical research, I confess that my bias over the years has been that given limited resources we should focus most of our resources on basic research and basic cell biology, et cetera, et cetera. But it seems to me that as the nature of health delivery has changed and as the HMO movement is driving out the ability of physicians to actually do research—they damn near do not have time to see patients.

    My question is are you confident that NIH is responding to that change by making a sufficient reallocation of resources to really strengthen what we provide for clinical research? What do you intend to do in the next five years?

    Dr. VARMUS. As I mentioned in my opening statement, we think part of the problem requires attention to recruitment and training and the sustenance of clinical investigators.
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    And that is why in the last few months the Institute Directors and I have put together a program of new training initiatives and stipends for early- and mid-career clinical investigators which, if they prove successful, could be further expanded.

    We are also aware of concerns that clinical research applications may not be getting a fair shake in the peer review process. The Director of the Center for Scientific Review, Dr. Ellie Ehrenfeld, has made special efforts to improve the oversight of that review process.

    Thirdly, we have done an evaluation of where our money is going. The numbers of our dollars that go into clinical research activities, as we define them, has been found to be over 30 percent—nearly 40 percent in terms of dollars, nearly 30 percent in terms of grants. And we feel this is a pretty substantial investment, although we expect to see it increase for some of the reasons I outlined a moment ago to Mr. Porter.


    Mr. OBEY. Let me make this point to follow-up on that, because I am concerned that NIH may be providing some response but frankly not sufficient response to that concern.

    Let me ask another question. I have a letter here that has been circulated by Congressman Rohrabacher, Congressman Campbell, Congressman Sanders and Congressman Patrick Kennedy, and it says, among other things, ''that President Bush instituted reasonable pricing costs for drug development largely with government resources at NIH.''
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    ''Unfortunately, under pressure from pharmaceutical companies NIH cancelled the clause in 1995,'' and then they assert that NIH spent 15 years and $32 million of the taxpayers' money to develop Taxol and then they go on to say that following the successful development of Taxol, the company involved was awarded exclusive marketing rights and extensive government information on the drug. They charge roughly 20 times what Taxol cost them to produce. So, the cancer patients will pay $10,000 a year while it cost the manufacturer only $500.

    I guess my question is simply, what do you think we ought to do about this? Is there some happy middle ground that we can find between the original proposition that was in effect under President Bush and the zero protection which we have now?

    Dr. VARMUS. It's probably best to dissociate the Taxol case which has been a very contentious one, from the general principle underlying our withdrawal from the reasonable pricing clause. The reasonable pricing clause was subject to a number of workshops early in my term here, and it became clear that the ability of NIH to interact with industry especially in the development of the so-called CRADAs—the cooperative research and development agreements—was being impeded by the existence of this clause, which we had not exercised. We really did not know how to exercise it; we are not a regulatory agency, and it is very difficult to do that. In fact, the interactions between our government scientists and industry have improved significantly with respect to exchanges, material agreements, and formation of CRADAs since then.

    I think we have made the right decision and individual cases like the Taxol case simply need to be looked at one by one. I think it is probably too complex to get into here.
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    Mr. OBEY. Well, I guess I would ask you to expand further on that for the record because it would seem to me that certainly I want drug companies to recover a reasonable cost and have enough incentive to get into the field, but I also do not want us to have no protection for patients under those circumstances.

    It seems to me we are stuck between the two poles right now. Mr. Chairman, let me simply submit the rest of my questions for the record.

    Mr. PORTER. Thank you, Mr. Obey.

    Mr. Bonilla.


    Mr. BONILLA. Thank you, Mr. Chairman.

    Dr. Varmus, nice to see you again. You said five years. This is my sixth year so we are almost to the line and I can remember when you first started. You used to have those flip cards you used every time.

    Dr. VARMUS. I still have them. I just do not need them any more.

    Mr. BONILLA. I would like to start out by thanking you for the comments that you made last fall while you were visiting the University of Texas Health Science Center with Dr. Howe down in San Antonio. We got feedback from some of the doctors there about the nice things you said about the work we are doing on this subcommittee and I appreciate that very much.
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    I also would like to get into specifics on diabetes in just a second but I would like a comment as well, I have some concerns not directly related to what Mr. Obey said, but sort of, the President's proposed budget has a great reliance on the tobacco settlement which is very, very tenuous at this point. And I think that, realistically, on this subcommittee we are going to have to assume that that is not going to happen unless we get some indication in the next few weeks or days that that is likely to happen.

    But at least it is a nice change to hear that the Administration is interested in giving you more dollars because, historically, this subcommittee has had to carry the water after the proposed budget that we felt was inadequate. So, it is nice to hear that he is finally listening to the need for biomedical research dollars out in the heartland. What I am getting to is diabetes because I am concerned that diabetes has a huge impact on each of these factors, yet it continues to be a low priority for NIH research. I will run through the numbers quickly.

    Close to 16 million Americans have diabetes. Diabetes costs this Nation $98 billion each year. Diabetes kills 187,000 Americans annually. Yet your budget request only calls for spending $388 million on diabetes research spending.

    The Speaker has noted, saying in speeches around the country, that almost one-third of every dollar we spend on Medicare in this day and age is directly related to problems with diabetes. The question is: Why does diabetes research continue to have a relatively low priority at NIH?

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    Dr. VARMUS. Well, Mr. Bonilla, I don't believe it does have a low priority. You will recall last year we had discussions of this topic at the hearings, and in response to some of the concerns that we received here and some of the concerns expressed to us by advocacy groups for patients with diabetes, the NIH underwent a very rigorous review of its entire program. We had a major meeting in September to look for unexplored opportunities in diabetes research, and to try to recruit new talent into the field. We have a very substantial increase for diabetes funding in the 1999 budget request—I believe it is a little over an 11 percent increase overall, which is, among the disease areas, one of the highest.

    As you are aware, under last year's Balanced Budget Act, there was a $30 million allocation per year for 5 years to diabetes, 90 percent of which is being used by the NIH through our trans-NIH diabetes research group, and there are many initiatives not only in the NIDDK but in several other institutes that address the problems of diabetics.

    So I would submit that we are paying special attention to diabetes at the present time and that it is difficult, in my view, to try to develop any simple one-to-one metric that relates what we spend to what is being spent on care. There are many other issues involved, including the number of years that we have been working on this problem, the scientific opportunities that are available for pursuing it and the number of other activities—for example, studies of the eye or of the vascular system or of the nervous system—that have profound effects upon our approach to the problems posed by diabetes but may not be counted as diabetes research. Those factors are extremely important.

    Mr. BONILLA. When I arrived here, just one year before you did, I was a big crusader back then for trying to give diabetes research a bump in funding because it was non-existent for several years prior to my arrival here in 1993. What about the factor, Dr. Varmus, of the country's aging population? And down the road—11 percent, maybe it is a good number right now, but as we escalate into the years, it is going to be even more of a problem than even the figures that I cited to your earlier.
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    Dr. VARMUS. We agree entirely that the problem posed by diabetes is one that will increase as the population ages, but that is also true of many other diseases, including cancer and nervous system disorders such as Alzheimer's disease and Parkinson's disease. So we have to consider the effects not just on diabetes but on other diseases as well.

    Mr. BONILLA. Well, rest assured we are supportive of the research dollars in those areas as well, so it is not a matter of picking the ones you mentioned over another.

    Dr. VARMUS. But I would like to point out, Mr. Bonilla, that I do believe, especially with the increased scrutiny that we are giving to diabetes at present, that there isn't a stone that people believe should be turned that is not being turned.


    Mr. BONILLA. The Diabetes Research Working Group, Dr. Varmus, what are your expectations of this group? And does the budget request include the resources necessary to begin implementation of their plan?

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

    Thank you.

    Mr. PORTER. Thank you, Mr. Bonilla.

    Mr. Stokes.


    Mr. STOKES. Thank you, Mr. Chairman.

    Dr. Varmus, welcome. Let me at the outset thank you for your very kind and warm remarks at the beginning of this hearing. Let me also say that it has been a pleasure for me to work with you, Dr. Kirschstein, and so many others at NIH over the years. I appreciate, in particular, the responsiveness and the sensitivity that you have had in many of the areas of concern that I have discussed with you, not only in the hearings but also in my office, at NIH and on other occasions we have had to meet.

    To remain constant relative to these concerns, let me start off with my first question in that area.
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    Recently, the President of the United States utilized his Saturday broadcast to speak to and address the very same concerns that I have discussed with you and your associates for many, many years. And, I guess that as I get ready to close out my career, I leave with some very real concerns in that area.

    Seated next to you and behind you are the finest scientists and doctors in the world, and it seems to me that I have to utilize whatever I can in order to try and impress upon all of you the absolute necessity for us to try to make some type of a dent in the disparity between white and minority health in this country.

    Obviously, the President is also concerned because he has included in this budget $80 million for a special race initiative. I think for the record it would be important to me if you could tell us where we have come since 1985 when we had our first report. That report told us about the excess deaths and other disparities, where we are today and whether our budget today really addresses our being able to seriously reduce, to cease, or terminate the disparate gap between white and minority health.

    If you could just tell us where we are, I would appreciate it.

    Dr. VARMUS. Well, as you know, Mr. Stokes, we have not narrowed the gaps as much as you and I would like. The President has selected six emphasis areas for the coming few years, and we have major investments in all those areas. We feel it is particularly important that we use our resources for communication of medical information.

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    For example, in the area of sudden infant death syndrome, we know that the reduction in death from that syndrome has been much more appreciable in the majority community than it has been in the minority communities. We believe that part of the problem is not using the right tools to reach the minority households where sudden infant death syndrome is still occurring at too high a frequency.

    I believe this is also true with respect to bringing individuals into screening for breast and cervical cancer and for making an early diagnosis of diabetes.

    In all the major areas in which the discrepancies exist, there is a deep investment in clinical and basic research, and, of course, that investment will improve outcomes for all Americans. But as you know, in the last several years in particular, we have focused our attention on the minority issues specifically and insisted on minority representation in those studies in the hopes that we will begin to level the playing field. But it hasn't been entirely successful.

    I would be happy to provide some numbers for incidence and mortality rates in the areas that you have highlighted in your Black Caucus meetings and provide those, as I mentioned, for the record.


    Mr. STOKES. Will this new initiative that the President has put in his budget help?

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    Dr. VARMUS. It has focused our thinking, and I believe it has been beneficial for us to have this initiative. As you know, we have ourselves been very concerned about these differences, both as a result of your drawing attention to them and our own perception of morbidity and mortality data that we collect and look at very closely as we think about the problems we are trying to solve.

    But I do feel heightened attention to some of the six specific problems that he has outlined as worthy of special attention will energize us.


    Mr. STOKES. How about the Office of Research in Minority Health? Do you see that office playing a larger role in this whole picture?

    Dr. VARMUS. Well, as you know, Dr. Ruffin, who runs the office, has been coordinating minority health efforts. His budget is slated for a very substantial increase in the 1999 budget. We have been working very closely with him and are about to meet with his advisory council to ensure that we are encouraging the institutes to follow all the appropriate leads on research that will benefit minority health.

    He is an integral player in the process, and his office has performed very well.


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    Mr. STOKES. Let me ask you about another area. The Centers for Disease Control testified here a few days ago, and one of the most stark facts that they brought out to us at that time was that the HIV/AIDS problem in the black community is now seven times that of the white community. This, of course, is a reason for great alarm.

    Can you tell us what NIH is doing relative to this problem?

    Dr. VARMUS. Well, we have been aware, of course, for some years that particularly in the inner cities and in minority communities—Hispanic as well as black—AIDS is having a disproportionate effect.

    The general approach that we have been taking, of course, is to understand the basic damage that HIV does to individuals, find therapies, seek leads that might allow us to make an AIDS vaccine, and do behavioral research that attempts to seek ways to better prevent the transmission of HIV infection.

    In response to the President's initiative, which includes, as you know, HIV/AIDS among the targets, we have some plans for improved efforts to communicate preventive strategies to minority communities, and we hope those will be successful. But the amount of additional investment in HIV/AIDS as a consequence of the initiative is relatively modest.

    Mr. STOKES. Thank you very much, Dr. Varmus.

    Thank you, Mr. Chairman.

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    Mr. PORTER. Thank you, Mr. Stokes.

    Mr. Dickey.


    Mr. DICKEY. Hi, Dr. Varmus. I want you to know that in some parts of my rural district we have people who are rather elderly now who don't know that after the Depression hit in 1929 things improved for the rest of the country. It has all been the same to them. As I watch the number of dollars that have been put into your agency increase every year, I just wonder if you know that there have been hard times for other agencies around here in Washington.

    Dr. VARMUS. I do know that.

    Mr. DICKEY. You are living in kind of an embryo of some sort, some type of protection, and I don't understand quite how we are going to justify it, but I guess we are going to. We have for the last three times I voted on this appropriation bill. I want to congratulate you on what you have done.

    Dr. VARMUS. I appreciate it.


    Mr. DICKEY. I understand that over the past year NIH has undertaken a number of critical initiatives related to diabetes and its complications. The budget for NIH has increased 101 percent, and diabetes over the past 10 years has only increased by 35 percent. If we were to find more money for diabetes, how would you put that money to use? What else could be done?
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    Dr. VARMUS. Well, Mr. Dickey, we in a sense faced that problem last year, and, you know, we are only as good as our ideas. It is not as though there is a cure out there to be purchased. When faced with this question last year, we pulled together the best minds in the country to think about the various components of diabetes research—genetics, clinical research, metabolism—and asked them, what are the things that are underserved? What should we be doing more work on? And we came up with a series of important initiatives. At least four major initiatives that emerged from that workshop and are being funded by the Balanced Budget Act funds, and there are several other intiatives that the NIDDK has put together.

    There may be others we ought to be initiating. Right now there are exploratory grants in certain areas. There is a very extensive interest on the part of several institutes to understand the genetic basis of diabetes. There are new drugs. We believe that there is reason to make an investment in the bioengineering devices that might allow us to sense glucose levels better.

    I don't think that there are totally unexplored areas. I think we could expand some of the areas that we are looking at. Right now I think, reasonably appropriate investments are being made in the current fiscal year and projected for the next fiscal year. Those could be strengthened, but I think in balance with our obligations and opportunities in other areas, we are making a reasonable set of decisions.

    Mr. DICKEY. Well, you say there is no stone being unturned and no one would complain, but I have a friend named Duke Roos and his wife, Barbara, who lost a 32-year-old daughter, Debby.
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    Dr. VARMUS. You mentioned that last year, yes.

    Mr. DICKEY. They would think that there is some stone that has not been unturned.

    Now, what I want to ask you is, you are saying that you are satisfied and everything is fine, but there are people out there who are not agreeing with you. How do we reconcile that?

    Dr. VARMUS. Let me draw a distinction, Mr. Dickey, between pursuing scientific possibilities and achieving the ideal outcome.

    We are very far from having a perfect treatment for diabetes. People suffer and die from the complications of both Type I and Type II diabetes every day.

    When I referred to stones turned and unturned, I was referring to identifiable areas of research in which we are investing in the hopes of finding better ways to control and revert the complications of diabetes and the metabolic manifestations.

    So I understand that we have not achieved the goal that we have set for ourselves in this area, but I do believe that all the identifiable research activities that we could undertake are in general being undertaken.

    Now, could we do more in those areas? Very likely. Could we attract more talent? Yes, very likely.
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    Mr. DICKEY. Okay. To stay within my time, let me change the subject. My developing interest in preventive health care leads me to ask questions of you related to obesity and nutrition. Can you tell us how obesity is defined?

    Dr. VARMUS. It is defined in relation to norms established, I believe by the National Center for Health Statistics, and it represents a certain percentage above the average. I would like to submit that for the record. I am aware of the definition, but I don't have the precise numbers.

    [The information follows:]


    Mr. DICKEY. Can you tell us—could you help me with how obesity is defined?

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

    Dr. VARMUS. It is the only risk factor for cardiovascular disease that is actually increasing. The other major risk factors—blood pressure, smoking, and cholesterol levels—are all declining. So it is a very appreciable problem, and the NIH has a trans-Institute obesity study group that is coordinating efforts to combat obesity. We believe it is one of the most significant health problems we face as a Nation, with many possible approaches. There have been tremendous advances in the last few years in our understanding of how appetite is controlled. We also understand the important component that is played by behavioral research and efforts to increase exercise activity and control diet by methods other than medication. And we understand that it affects a very large number of body systems.

    Mr. DICKEY. How much are you allocating to the research of obesity?

    Dr. VARMUS. I don't know if we collect that number. I don't believe we do. But I can tell you that it is a very large figure if we put together the behavioral and the metabolic—diabetes-related—and, of course, many kinds of studies of heart disease and cancer that deal with the problem of obesity. It may be rather difficult to sort out a totally accurate number for you.

    Mr. DICKEY. I will ask another question that might be difficult. What is the estimated cost to our society of obesity?
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    Dr. VARMUS. I would be hesitant—it would depend a great deal on how you decided to measure it, whether that would include the cost of trying to treat it, the cost of the illnesses that are influenced by it. Certainly many billions, but I would prefer to defer to my economic advisers before giving you a number for the record.

    Mr. DICKEY. Thank you. My time has expired.

    Mr. PORTER. Thank you, Mr. Dickey.

    Mrs. Lowey.


    Mrs. LOWEY. Thank you, Mr. Chairman.

    Dr. Varmus, I want to thank you for your testimony and welcome you and the other doctors who have joined you here to our committee this year. I am pleased that Dr. Kirschstein and Dr. Varmus as New Yorkers are here and that you understand the importance of medical research. He was originally born in New York. [Laughter.]

    Mr. HOYER. So many of us were.

    Mrs. LOWEY. I mention that, Dr. Varmus, you know, the incredibly importance of the National Institutes of Health to the medical community in New York, and we appreciate all the important work you are doing.
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    Before I move on to my questions, there have been several comments or questions about diabetes, and I just want to thank you for your comments, and if you could submit for the record or to my office the implementation that you feel will result from the conference findings. At the conference there were recommendations, and I would be most appreciative, because there are many of us on the committee who represent constituencies who passionately care about research in diabetes, and I would be most appreciative.

    Dr. VARMUS. We can send that to you very promptly.


    Mrs. LOWEY. With regard to clinical research, I appreciate your comments today. As you know, I have again introduced the Clinical Research Enhancement Act that was originally inspired by the 1994 IOM recommendations addressing the clinical research crisis. The lack of research resources and the financial barriers to attracting and maintaining a pool of talented M.D.'s to research careers as detailed by the IOM in their report unfortunately still exist today.

    I am very pleased, Dr. Varmus, that the NIH is proposing new clinical research awards. These awards, however, are very similar to those recommended by the IOM and echoed by the NIH clinical research panel led by Dr. Nathan.

    However, my concern is that in the 4 years since the IOM report was issued, the crisis facing clinical research has worsened, and there is concern that these awards may simply not be sufficient. In addition, my understanding is that at least one of these new awards is replacing a current clinical research award program.
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    I want to understand these awards, and, therefore, I would like to ask a few clarifying questions.


    The NIH is proposing K–23 awards to young investigators. It is my understanding that this new program will replace the 140 clinical associate position, or CAP, awards that are currently funded—it feels like alphabet soup here—through the GCRC. Is that the case?

    Dr. VARMUS. I am glad for the opportunity to clarify that. The award has been confused both the K08 and with the CAP award. But, indeed, what we are proposing here is in addition to those.

    Now, it is possible for individuals who currently receive these other awards, like the K08 or the CAP award to be converted to this new award, the K23. But we are committed to at least 80 new K23 awards each year over the next 5 years, and the number could indeed be larger as a result both of conversion of individuals from one of the others—but these are not substitute awards. They are in addition to the current level of clinical research training.


    Mrs. LOWEY. It's confusing and I have been trying to understand this. What number of K24 and K30 awards are you proposing in FY99?
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    Dr. VARMUS. Well, in '99 we are talking about roughly at least 80 new K23s. Those are the awards to clinical trainees who will have a mentor, who will be undergoing training over five years.

    The K24 awards are for more senior people who already have faculty positions—are at junior or intermediate or even possibly in some cases senior levels on faculties. Those individuals have already demonstrated their capacity to do clinical research and serve as mentors. There will be in the range of 60 to 80 new awards in that category in 1999. It is a five-year award and renewable once. We expect to build up to a cohort of roughly 350 to 400.

    The third award is a didactic award to institutions and we expect to make that award to at least 20 institutions that now have or will soon develop a significant number of clinical trainees. These may be sponsored by us or by other organizations, because, as you know, we are not alone in training clinical investigators. The didactic award is intended to develop a course program specific for clinical research training at those institutions that qualify.


    Mrs. LOWEY. Just for the record if I could request the total number of new clinical research awards that you are proposing for FY99 and the number of clinical research awards you are proposing to phase out. What are the new ones you are proposing and what are the numbers you are going to phase out?

    Dr. VARMUS. We are not proposing to phase out anything. The other award categories still exist, but the Institutes may decide to support those awards to convert them to K23s. That would be in addition. There is no simple conversion. The point is that the number of trainees is going to go up by a very substantial amount.
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    Mrs. LOWEY. Could we have for the record the total number of new clinical research awards you are proposing in FY99?

    Dr. VARMUS. I think I just gave you those numbers.

    Mrs. LOWEY. What is the total number?

    Dr. VARMUS. Of new ones?

    Mrs. LOWEY. Yes.

    Dr. VARMUS. It will be 80 new trainees, at least, in addition to the existing trainees.

    Mrs. LOWEY. Okay. So you are saying there will be 80 new ones but some of the old categories just may not be funded.

    Dr. VARMUS. No. If those categories are retained by the institutes, then they will continue to pay new individuals in those programs. There is no simple conversion of an old program to a new one. It is all additive. So whatever the base was before would be built on. This is not a hat trick. This is not a substitution. It is an increment.

    Mrs. LOWEY. Is my time up? Oh, my goodness. Let me just conclude, then.
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    If we could clarify for the record, I would be most appreciative because there seems to be some confusion or misunderstanding in the community as to the actual increase in clinical research positions.

    Thank you, Mr. Chairman, for your indulgence.

    Mr. PORTER. I don't know why, but seven minutes does seem a lot shorter than eight minutes. Thank you, Mrs. Lowey.

    Mrs. Northup.

    Mrs. NORTHUP. Thank you, Mr. Chairman and thank you, Dr. Varmus. I have really learned so much in the last year about what NIH means to this country and to so many people and how many challenges are unmet in so many different ways in terms of health itself and quality of life. And I really thank you for what you all wrestle with.

    Every day those of us on this committee meet people that represent organizations or actually constituents in our districts that are affected or afflicted and depend on NIH research for their future. I say it is the closest to trying to be Solomon that probably any of us have ever been.

    One of the things that I have most appreciated and learned from our committee chair, quite frankly, is how important it is not to let politics make decisions that science should make.
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    I would just like to ask you whether you agree. First of all, I feel like we are challenged not to let a political base divide up research dollars, and I wonder how effectively NIH itself is able to do this. For example, do you experience what many of us experience every day, where organizations that represent people with like afflictions come to see you and ask for increases in research dollars?

    Dr. VARMUS. I think in the aggregate that probably is true every day, that we do have our advocacy groups come to the NIH to describe their interest in our activities and to give us a hand. Frankly, what I find most useful about those interactions is not the concern for funding but the offer of help. Patients can provide a special perspective on the diseases we are trying to combat. Many of our advocacy groups are extremely well informed about the issues, understand the grant portfolio, know investigators, and are very helpful in our decision-making processes.


    Mrs. NORTHUP. Let me ask you, do you find that there are projects that are joint funded and does NIH agree with that, and do you ever find that a group might offer to joint-fund a project that might actually have a vested interest in what the research would come out? How do you make sure that the research is uncorrupted, I guess, uncorrupted in a broad sense?

    Dr. VARMUS. We do have such collaborations. We have quite a few of them. Sometimes they occur directly through our offices. Most investigators in this country are funded by more than one source, so we know that, in a sense, we are collaborating with many advocacy groups and professional societies because we are supporting the same investigators.
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    There are, however, a number of examples of actual cofunding. One of the most prominent is the cofunding that goes on between the Juvenile Diabetes Foundation and NIH of certain diabetes initiatives and centers. That is carried out, actually, with as many as four different institutes.

    The advantage to the outside organization is that we provide the peer review, and the advantage to us, of course, is that it allows us to extend the use of our monies.


    Mrs. NORTHUP. But is there any worry that, for example, if you know you have a million dollars and somebody is going to offer a $2 million match for that million if it is spent in a certain way compared to another disease or challenge that has no match out there for it, that you would be more likely to say, ''Well, we get $3 of research for every dollar here?''

    Dr. VARMUS. Well, I wouldn't deny the possibility of that happening. But among the many responsibilities with which my Institute Directors are entrusted, one of them is to evaluate such proposals, to bring those proposals to their councils, and to ask for an informed opinion about whether this is a good idea.


    Mrs. NORTHUP. I think one of the concerns I have is if those of us on this committee agree that there should not be a politicization of research and we try hard to resist that and depend on the most promising and emerging science to make those determinations, I would want to know that that didn't go on in any other area of government, too in the executive branch or in any of the Cabinet departments that may benefit from your research.
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    I wonder what reassurance you could give me that there is not this relationship, especially now that we see the cancer initiative. Maybe we would resist that sort of politicization, but that there would be forces equally unscientifically based that might succumb to it.

    Dr. VARMUS. Well, Mrs. Northup, I understand your anxiety on this topic and I share it. On the other hand, I would point out that the distribution of funds that is eventually achieved by looking at public health problems and scientific opportunities is not going to result in a budget in which everyone gets exactly the same level of increase or exactly the same number of dollars.

    I do think that it is appropriate for us, as we develop our budget based on scientific opportunities and new areas of emphasis, to say to the public, ''Here are some diseases that are going to be benefitted by the investment we are making across these scientific frontiers.''

    Mrs. NORTHUP. Yes, but it is only if you have one of those and your life depends upon that research that that really is very meaningful to you and there are some of those groups in my district and they are very concerned and they are very desperate. I would hate to think that I was depending on the purity of reasoning where not everybody else is playing by the same rules.


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    I would like to ask you another question. That is about the relative amounts of money that are spent for diseases. I think on this committee in particular we are constantly bombarded with organizations who tell us how little relative money is spent on the addressing of treating or investigation of their diseases and I wondered if those figures come actually from NIH and if they don't, how correctly independent organizations would be able to total up the dollars that are spent to investigate——

    Dr. VARMUS. I appreciate that question, Mrs. Northup. As I have said here before, it is difficult to come up with a number for a specific disease.

    The numbers that we determine are largely numbers that respond to requests from Congress—perhaps even five or ten years ago—and the numbers are developed with a definition that was provided at that time.

    As you can well appreciate, the way in which we ascribe research dollars to a certain disease can vary dramatically based on the definition. I think we have discussed before the difficulty of saying, for example, what constitutes research on, say, Alzheimer's disease or on diabetes. How do you tote up, for example, the dollars that go into the basic research that leads to discoveries about a specific disease?

    Now in the diabetes arena, for example, we are faced with enormous opportunities to intervene in the basic metabolic defect because of basic research on the way in which a cell senses a signal and responds by changing patterns of gene expression, as I was illustrating earlier. Such research was not classifiable as diabetes research in the past but its impact on our understanding of diabetes is profound.
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    Mrs. NORTHUP. Thank you.

    Thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Mrs. Northup.

    Mr. Hoyer.


    Mr. HOYER. Mr. Chairman, thank you very much. I do not think I will pursue the purity of peer group procedures and the total lack of politics with peer group review committees, but I have talked to a lot of my friends in the academic community and sometimes find that even they are somewhat involved with political influences.

    Indeed, we have a system of political influences and we are dealing with their dollars. And when they talk to us about how they would like to have their dollars spent, it seems to me it is not unreasonable for those of us who listen to them, who were sent here to represent them, to express their preferences.

    But that notwithstanding, let me talk a little bit about——

    Dr. VARMUS. I hope I didn't seem to say that those influences didn't exist. Of course they do and we are responsive to them, as you know.
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    Mr. HOYER. Doctor, there are a lot of people in the room to communicate with. I know exactly.

    Doctor, I want to thank you and Dr. Kirschstein in particular and all of you. Mr. Stokes and I were commenting and he referenced it, the incredible intellect and integrity that exists in this room at this very moment. It is always impressive to me, the quality of people that we have serving the American public and indeed all the people of the world, because obviously NIH has an impact worldwide as the premiere biomedical research organization.

    Mr. DICKEY. Which side of the table are you talking about? This side?

    Mr. HOYER. I am still praying for you. I want you to know that. [Laughter.]

    And there is an extra chair over here any time you want. We have, however, studying the neurological disorders that lead one to be a Republican but we have not come up with an answer yet. [Laughter.]

    Mr. DICKEY. Is his time over? [Laughter.]


    Mr. HOYER. We are the break in the monotony.
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    Doctor, going back to clinical research that Congresswoman Lowey was talking about, would you comment perhaps a little more broadly about the definition of clinical research because we are all hearing about 15 percent, 30 percent. The problem is how you define clinical research. Can PhDs do clinical research? Do MDs do clinical research? Would you comment on that? My office has received a number of inquiries on that.

    Dr. VARMUS. Let me just say, without going into boring detail on this topic, first of all, the definition used by the IOM—the Institute of Medicine—report a few years ago was much narrower than ours. Ours, however, encompasses many kinds of interactions, all of which involve patients. That is, it is not clinical research to simply work on a sample that comes from a human being. There has to be some need to interact specifically with certain patient groups. That does include certain kinds of behavioral research. It does include epidemiology.

    The definition that we use now includes a collection of clinical research activities that range from clinical trials to what is sometimes called translational research, in which the individual patient is under study with respect to the development of the disease or response to certain kinds of interventions.


    Mr. HOYER. Okay. Well obviously, you deal with that daily.

    Food-borne illnesses. Doctor, can you tell me briefly what kind of resources we are dedicating to NIDDK or other institutes as relates to food-borne illnesses, obviously a growing concern in this country?
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    Dr. VARMUS. We don't seem to have a number but I know that it is in the range of $53 million for NIAID for next year, and the number for NIDDK, I believe, is just slightly less than that. But both Institutes are aware of the increasing toll that food-borne illnesses are taking in this country.

    There was an interesting article in today's New York Times, in fact, about the impact of improved eating habits on food-borne disease, in the sense that we are importing a lot of fruits and vegetables. It is a little bit like being in a developing country every day and exposed to some of the things that a meat-eater and someone who eats stewed turnips is unlikely to be exposed to, as opposed to someone who is eating fresh strawberries and raspberries that have recently come off the fields in Central America.

    Mr. HOYER. One of the frustrations, I suppose, of us all is that today we are told that item A is bad for us and that item B is good for us.

    Dr. VARMUS. The food is still good. It is just that you don't want it contaminated with bacteria.


    Mr. HOYER. It is a moving target sometimes, of course but I am glad to hear that food is good for us.

    I will not ask you a specific question but I will at some point in time have a question about Rett syndrome. As you know, I am very interested in that. There is no reason that you should know about it particularly. It is a very small program.
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    Let me ask you about this. You have referenced and some others have, also, some compelling testimony from Dr. Rothman, Congressman Rothman's brother who has an autistic child. And we get this argument that you spend X here but there is a bigger problem over here that you do not spend as much on. Obviously you have to deal with that and we have to deal with it.

    But can you tell me where we are on autism, what your thought is on the relative contribution we are making to deal with autism?

    Dr. VARMUS. Well, in the several years that I have been at the NIH, the attention being given to autism by at least four of our Institutes has increased by leaps and bounds. We had a very important workshop about three years ago at which a number of scientific opportunities were identified in neuroimaging and genetics, molecular biology, and behavioral approaches to autism.

    It is now recognized that autism is actually a spectrum of disorders with very different characteristics, and the four institutes that are involved have increased their financial commitment to autism research by large percentages.

    Now, the current funding level is roughly $20 million but I could get the more precise numbers for you for the record.

    Mr. HOYER. If you would. I know Congressman Rothman in particular, is interested but obviously a broad spectrum of people are interested, as I am and everyone on the committee. Thank you.
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    I want to say also that Dr. Penn was very kind to come visit in my office and spend some time with me and bring me up to date. She gave me, I don't know whether it was a book or a report on the autism meeting. I don't know whether it was that meeting to which Dr. Varmus referred.

    Dr. VARMUS. It probably was. That was the large meeting we had.

    Mr. HOYER. I provided a copy of that to Steve Rothman and I appreciate, Dr. Penn, your coming by.

    Mr. PORTER. Thank you, Mr. Hoyer.

    Mr. HOYER. My time is up.

    Mr. PORTER. Despite your partisan comments I am going to call on two Democrats in a row. Ms. Pelosi.

    Mr. HOYER. Said in jest, Mr. Chairman, as you know.


    Ms. PELOSI. Maybe three, Mr. Chairman. Congresswoman DeLauro is here.

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    Thank you, Mr. Chairman. I want to join my colleagues in welcoming Dr. Varmus and Dr. Kirschstein to the committee today, as well as the array of excellent leaders of the NIH that are with you today. Although born in New York, you made a very valuable contribution to the University of California at San Francisco and any chance I get I like to talk about that great institution. And it was UCSF that Dr. Varmus attended.

    One of the advantages of coming late in the game here in terms of asking questions is that so many of the questions that I had have been addressed and I want to associate myself with the concerns of Mr. Dickey and his discussion of behavioral change, whether it is obesity or smoking, whatever those issues are. That is a very important issue in prevention and I will submit a question on that for the record.


    As far as diabetes in concerned—and I am sorry Mr. Bonilla left because I would like him and others to know that tomorrow my Medical Research Caucus is having the subject of diabetes as our focus. I think the Speaker is even coming to that and, of course, you know that our scientific leader of the caucus is Dr. Michael Bishop, chancellor-designate of the University of——


    Ms. PELOSI. I don't know if he will still be able to help us on this caucus once he takes his full responsibilities as chancellor, but he is the co-laureate with Dr. Varmus. [Laughter.]
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    Mr. HOYER. You are pleased to bask in the glow.

    Mr. DICKEY. Are you all just having a regular conversation? Would you like to share with us what in the world you are talking about?

    Ms. PELOSI. I just said great things about you. I associated myself with your remarks.

    Mr. PORTER. And you are going to be charged for the time, also. [Laughter.]

    Ms. PELOSI. Enough of that.

    Mr. HOYER. She is in a safe district or she wouldn't overcome it.

    Ms. PELOSI. Well, I will skip over the stuff about our distinguished leader, Mr. Chairman.

    Mr. PORTER. Well, I will give you extra time.


    Ms. PELOSI. I have to go really fast because I do have some questions. I would like to submit my specific question about clinical research centers for the record in terms of the budget priorities and ask a little different question.
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    In your testimony, Dr. Varmus, you said that in relation to the GCRC you will continue the loan repayment programs for clinical trainees from disadvantaged backgrounds. I wondered what else you were doing in terms of outreach for research patients at every step of the way in these clinical research centers to ensure that the position the President has about removing the disparities of race in terms of illness, using those centers as one place where we could implement an outreach into the communities.

    Dr. VARMUS. I am not sure of the focus of your question, Ms. Pelosi, but I would point out that——

    Ms. PELOSI. What are you doing other than loan forgiveness?

    Dr. VARMUS. Loan forgiveness, unfortunately at this point, only applies to clinical trainees at the NIH intramural program. We would be interested in trying to develop a loan repayment program extramurally but that requires additional authorization to NIH.

    Ms. PELOSI. But what are you doing at the clinical research centers?

    Dr. VARMUS. Well, a number of things. I point out that the ''general clinical research centers''—GCRCs—comprise roughly 25 percent of our clinical center activity. Much of the other is, of course, disease-specific—cancer, diabetes, Parkinson's.

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    Ms. PELOSI. If I may, is it so, and recognizing that large percentage, it is my understanding that your GCRC budget has declined as a portion of the NIH budget from 3 percent to 1 percent?

    Dr. VARMUS. Well, in the current proposal we are going to be increasing the number by, I believe, roughly 12 percent over the '98 level.

    The results of the deliberations of Dr. Nathan's clinical research panel suggested that the GCRCs ought to take on a more central role in clinical research training and coordination at the campuses at which they are located. We are trying to identify those that show the promise to carry out those extended activities and proposing to give them a larger stipend with which to operate.


    Ms. PELOSI. I would hope that they would be reflective of the problems of women in what they are set up to do in relationship to the President's initiative.

    Dr. VARMUS. Well, certainly all clinical research activities—all clinical trials proposals—now must include explicit descriptions of how women and minorities will receive equal treatment. That has been true for several years and that will still be true.

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    Ms. PELOSI. I appreciate your emphasizing that point. I am sorry to intervene.

    You note in your statement that the next dramatic transformation of medicine in molecular biology is likely to occur in the study of cancer and I draw from that that that is why this initiative on cancer is being set forth, because of the opportunity that you describe.

    Dr. VARMUS. Yes. And I don't mean to say that there are not similar opportunities for other diseases, but this is closest to the clinical interface, in my view.

    Ms. PELOSI. That is very good news.

    NIH's Office of Research on Women's Health. I will submit for the record some questions about what actions are currently being taken by NIH to meet the Office of Women's Research mandate because I want to put a couple of other questions on the record.


    When Secretary Shalala was here she talked about an international cast to some of what was happening and said you might elaborate on some of that when you were here. Some of us serve on the Foreign Ops Committee that does the appropriating and sometimes even on health issues.
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    Dr. VARMUS. Well, I am pleased to have that opportunity. My own view is that it is in the interest of this country to pay attention to health problems of countries abroad, not simply for altruistic reasons but also because the economic and political stability of those countries is strongly influenced by health.

    Moreover, health is an arena in which we can improve the cultural, and scientific, and educational infrastructures of those countries. I have seen this most clearly in my own activities on malaria, a disease which is clearly very uncommon in this country. It is largely imported when it occurs here. It is a tremendous global problem, causing as many as 3 million deaths a year and infecting 300 to 500 million people around the world.

    We are carrying out a strengthened program on malaria research. We think that genetics and immunology have taken us to the point where there are remarkable new opportunities to combat the disease, both through research carried out in this country and through strengthened our collaborative interactions with research partners in Africa, Asia and South America.

    Ms. PELOSI. Thank you very much, Dr. Varmus.

    Thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Ms. Pelosi.

    Ms. DeLauro.
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    Ms. DELAURO. Thank you very much, Mr. Chairman.

    Thank you and I apologize to you, Dr. Varmus and Dr. Kirschstein and the directors of the NIH for not being here at the outset.

    We had a wonderful visit from the President to the State of Connecticut at a meeting today in Bridgeport, Connecticut talking about child care and also talking about doing about the tobacco legislation, so we are very excited about that visit.

    Don't you have, Dr. Varmus, some connection to Yale University?

    Dr. VARMUS. I have spoken there. I am a friend of Dr. Kessler's.

    Ms. DELAURO. Let me ask a couple of questions. I know you all know this but two-thirds of those diagnosed with ovarian cancer die within five years of diagnosis, yet we still do not have a simple diagnostic test that detects the disease in the early stages.

    Last year the NIH devoted $41 million out of an overall budget of $13 billion for ovarian cancer research. If I could ask you how much you plan to spend this year on ovarian cancer research and what progress has been made toward developing a diagnostic test that could detect the disease and help save lives.
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    Dr. VARMUS. The anticipated number is $46 million for FY99. But I would emphasize that that number probably does not encompass all the things that are going on that will affect our approach to ovarian cancer—for example, to understand some of the genes that we know to be involved in ovarian cancer: The large attack that is being made through the cancer genome anatomy project, which you will hear more about from Dr. Klausner, has chosen ovarian cancer as one of its targets for development.


    Ms. DELAURO. I look forward to talking with Dr. Klausner when he comes up to talk about a whole range of activities with regard to this disease.

    Also I might ask you to talk a little bit about—I know NASA is doing some work in cancer research. I attended a luncheon last year where NASA talked about some of the work that they are doing in basic biology of cancer cells and how they grow, how they don't grow, how we can stop them from growing and, with regard to ovarian cancer, tumors using something that they have called the NASA rotating vessel in order to grow the tumors and monitor their progress.

    I would like to know about the collaboration between the NIH and NASA and what you are doing on this issue and other areas.

    Dr. VARMUS. We have quite a number of interactions with NASA, most focussed on neurological disorders. We are involved in some of the Neurolab projects. We have been studying balance and hearing and we also have a component of our research that is addressed to similarities between aging and time and space. But Dr. Klausner informs me that we are working with them to develop what is called a bioreactor, in which various types of cells are grown to extremely large numbers for a variety of purposes.
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    Ms. DELAURO. I am again interested in those kinds of collaborative efforts because last year I asked about some of the discoveries that were being made with regard to children's brains and when our children learn and what that process is about and how to make some of the leaps to education and Head Start and Early Head Start in the year 2003. Can you talk about that collaborative effort with the Department of Education? Are you working with them on this?

    Dr. VARMUS. We do work with them and you will hear from Dr. Alexander from the National Institute of Child Health and Human Development who will testify about some of those things.

    We have had some remarkable discoveries just in the last few weeks about the way in which the use of brain imaging can influence our understanding of reading disorders. You may have seen in the paper the pictures of brain images that show the different components of the brain illuminated in normal as opposed to dyslexic children. That gives us a very important focus for further studies of this disorder. And whatever understanding is achieved is, of course, shared with the Department of Education. I think you can get more details of that collaborative arrangement from Dr. Alexander.

    Ms. DELAURO. I am aware of Dr. Shaywitz's work.

    Dr. VARMUS. Yes. I omitted the fact that that work did come from Yale University. My oversight.
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    Ms. DELAURO. I have had the opportunity to hear her speak. What we are going to try to do in the next several weeks is to bring together people from the education field in the district, from superintendents of schools, parents and others to get the benefit of this research, to understand it in some way again, in the effort to take the knowledge that is being developed and move it into an arena for learning and for kids to be able to take advantage or for our teachers to be able to take advantage of research. It is real but to make it real in the classroom or real in doctors' offices, with the work that you are doing.


    Dr. VARMUS. I might just make one more general point about collaboration among federal agencies. Mr. Bonilla referred earlier to my flip cards. Well, I have a couple of flip cards that are full of the interactions that occur between individual NIH Institutes and a wide variety of federal agencies, both within the Public Health Service and outside it. I believe those are extremely useful interactions, and I think in all fields, including education, we are working very productively with other agencies.

    Ms. DELAURO. I think that that kind of information is very important to us because the work you do and its applicability, as I said earlier, to doctors' offices, to the classroom, to a practical setting, if you will, is important for us to know that, to make those connections, that this work does not exist for the sake of research alone, which is critically important—don't misunderstand me. I think you know what my sentiments are.

    But I think we need to be able to leave this committee and to take these collaborations and be able to explain that to other colleagues, to talk about these efforts.
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    Dr. VARMUS. We are especially proud this year of the very productive interactions we have had with the National Science Foundation, which led in part, among other things, to the development of a new training program in which NSF-sponsored physicists, engineers, and mathematicians will come to the NIH campus to become more involved in biological research.

    Ms. DELAURO. Thank you very, very much.

    Mr. PORTER. Thank you, Ms. DeLauro.

    Dr. Varmus, am I correct that you will also be present when each of the other directors of the institutes testify?

    Dr. VARMUS. I am looking forward to it, Mr. Chairman.

    Mr. PORTER. Well, we have had a request for a second round, but I think Members will have ample opportunity to ask further questions of Dr. Varmus, if they wish, when he appears during the coming two plus weeks.

    While the gentleman from Maryland is here, let me agree that all of us have matters within the bioresearch activities that we feel very strongly about and we not only express that; we encourage, cajole, pressure, for our viewpoints. But what we don't do is direct or earmark. In the final analysis, we believe very strongly that the decisions must be the decisions of NIH and not the decisions of the Congress, and I think that is the right policy and I think the gentleman agrees very strongly with me.
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    Dr. Varmus, let me thank you for your excellent testimony and your direct answer to all of our questions. We believe that NIH is truly one of the great treasures of this country. We believe in what you do. We want to do our very best to provide you with the resources you need to do your vital work. The existence of NIH, the wonderful people that it brings to it and the entire biomedical research enterprise of this country makes all of us very proud to be Americans.

    Thank you very much for your appearance here today.

    Dr. VARMUS. Thank you, Mr. Chairman.

    Mr. PORTER. The subcommittee will stand in recess until 10 a.m. tomorrow.

    [The following questions were submitted to be answered for the record:]

    Offset Folis 95 to 378 Insert here
Wednesday, March 25, 1998.



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    Mr. PORTER. The subcommittee will come to order. We continue our hearings for the National Institutes of Health with the National Cancer Institute, and we are very pleased to welcome Dr. Richard Klausner, the Director.

    I apologize to you, Dr. Klausner, for being a little late. We will be able to spend the next two hours with you, though, and we will, I hope, cover a lot of ground. So why don't you proceed with your statement, and then we will go to questions.


    Dr. KLAUSNER. Thank you, Mr. Chairman and members of the committee. I am pleased to appear before you for the third time as Director of the NCI.

    The President in his 1999 budget has proposed that the Institute receive $2,776,267,000, including the estimated allocation for AIDS, which is an increase of $228,953,000, or a little less than 9 percent over the current appropriation. This increase will allow us to accelerate the progress that I believe we are making against cancer.

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    Last year, as you will recall, we reported for the first time the first sustained significant decrease in cancer mortality rates since such statistics were first collected in the 1930s. At that time we said that we would have an annual report card on how we were doing by reporting cancer statistics, which we did 2 weeks ago. Those positive trends continue. Overall death rates continue to decrease by 0.5 percent per year after a prolonged rise of 0.4 percent per year.

    For the first time, this year we reported what is happening to cancer incidence rates. From 1973 to 1990, overall cancer incidence rates were rising by 1.2 percent per year. That increase has changed. It is now going down by about 0.7 percent per year.

    Decreased cancer incidence reaffirms that cancer can be prevented. Multiple strategies will be required to prevent cancer. The development and testing of new drugs to prevent cancer is a relatively new and growing aspect of our work. The NCI is currently sponsoring over 85 chemoprevention clinical trials for breast, colorectal, lung, prostate, and other cancers, and a growing number of these are based upon a real understanding of what these interventions are supposed to do. Twenty-five new prevention trials will be initiated this year.


    This past year, we completed accrual for one of the major prevention trials that we are engaged in, the accrual of 13,000 women at increased risk of developing breast cancer to a critical clinical trial to determine whether an anti-estrogen, Tamoxifen, can actually prevent this disease, and we anxiously await the results of that trial.
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    New possibilities for very selective hormonal manipulation for cancer prevention are emerging with the development of so-called designer estrogens, and we are actively evaluating clinical trials to examine their utility.

    Unfortunately, advances in treatment are often only incremental, and they take time to have an effect on cancer mortality. However, it is this incremental progress that, in part, explains the mortality trends for numerous cancer sites.

    Over the past 2 years, we have completed clinical trials that have established new standards for optimal therapy for women with node-negative and locally advanced breast cancer, for women with ovarian cancer, for patients with nasopharyngeal cancer, melanoma, childhood renal cancer, and others.


    A major explanation for the incremental nature of progress in treatment is that our therapies generally to date have not been designed to target the machinery of cancer, and that brings me to focus on what I think is the most dramatic change in the National Cancer Program.

    Thirty years ago, Peyton Rous, in receiving his Nobel Prize, in his lecture said, and I quote, ''Tumors destroy man in a unique and appalling way, as flesh of his own flesh, which has somehow been rendered proliferative, rampant, predatory and ungovernable * * * yet despite more than 70 years of experimental study, they remain the least understood.'' He finished by saying, ''What can be the why for these happenings?''
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    Three decades later, Dr. Rous would be amazed. With dizzying speed and growing precision, we are mapping the inner workings of the tumor cell. In the poster we see what Dr. Rous was looking at 30 years ago: basically a cell that we knew very little about. Now that has been replaced by a cell in which we see the intricate circuitries of cancer. The cancer genes so frequently reported in the news are altered relays in this circuitry. Viruses, carcinogens, radiation—all act by altering one or more of these specific pathways.


    Now, what is important about this and what is remarkable about this difference is that each circuit is now suggesting a rational target for prevention or therapy of cancer. This is shown in the next poster. Dozens of these are now being developed. This will be the new approach to prevention and therapy for the future.

    Ten years ago, 60 drugs were entering clinical trials for cancer. Today that number has increased to about 320. Let me briefly illustrate one.

    Thirty-five percent of breast cancers overexpress a particular protein called HER–2. These cancers tend to be more aggressive, and clinical trials have shown that women with such cancers require more intensive therapy to achieve the same outcome as women who do not activate one of those circuits, the HER–2 circuit.

    Last December, Genentech announced the results of the first clinical trial using an agent targeted against that specific cancer circuit relay. That agent, when added to taxol, showed a clinical response rate three times greater than taxol alone in women with advanced metastatic breast cancer—a cancer for which we desperately need new therapies. New clinical trials have already begun to rapidly build on this result for breast cancer but also for other cancers that overexpress HER–2, such as ovarian cancer and a fraction of lung cancers.
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    In one of the more exciting new tests of our new knowledge of cancer biology, we now know that altered circuits in cancer cells result in the production of molecules that stimulate the growth of blood vessels that nourish growing tumors, a process called angiogenesis. Without angiogenesis, the tumor will die or never grow beyond a microscopic size.

    Over the next year, we plan to have the first potent anti-angiogenesis agents into clinical trials for cancer. There are few new ideas in cancer therapy that have generated as much hope and excitement as anti-angiogenesis therapy.

    So what is the challenge? With the increased proposed in the President's budget, we can drive progress by increasing the success rate for the funding of individual investigator-initiated research. We will continue to build on and expand the infrastructure of the Cancer Genome Anatomy Project, which I introduced to you last year, to speed the discovery of the pieces of the machinery of cancer and especially to give us new molecular tools for early detection. This proposed budget will allow us to support a number of new initiatives. Among these are:


    The development of new chemistry-biology centers to capture revolutionary new approaches to the production of millions of small molecules and to couple this with so-called smart assays in order to find those drugs that interact with each of those circuitries;
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    To build a new program for the Rapid Access to Interventional Development, which we call RAID, designed to accelerate the movement from the lab to the clinic of the best new ideas for cancer intervention from investigators throughout the country;


    To build a redesigned, informatics-based clinical trials system to expand access to prevention, detection, and treatment trials, to improve the speed and value of those trials, and to allow what is clearly a growing number of compelling new ideas to actually be tested in people;

    To build a new imaging research network to rapidly evaluate emerging technologies in tumor imaging, both for early detection and for the new field of image-guided therapy;

    To fund new behavioral and health communications research, particularly to reduce tobacco use;

    And to enhance our cancer surveillance system so that we have a better understanding of the burden of cancer and where we need special efforts in cancer control so how we respond to some really remarkable changes that these cancer statistics are pointing out to us as well as others.
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    These new programs were designed through extensive planning and priority-setting processes. They are aimed at bridging the gap between the explosion of discoveries in basic science and our ultimate goal of reducing the burden of cancer for people. Many of these illustrate the transition from molecular biology to molecular medicine that Dr. Varmus spoke of in his opening statement at the beginning of these hearings.

    As always, I appreciate the opportunity to appear before you, and I am happy to attempt to answer any questions you might have.

    [The prepared statement follows:]
    "The Official Committee record contains additional material here."


    Mr. PORTER. Dr. Klausner, thank you very much for that excellent opening statement.

    You said the incidence of cancer, its rate, is going down, but you did not really say why. Is that for all cancers? Is it lifestyle changes? What is causing the rate to be less than it has been in the past?

    Dr. KLAUSNER. Well, of course, cancer is many diseases, and the answer we have to look at is disease by disease. The overall rate gives an aggregate report, but, in fact, to understand it we have to look at each.
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    For lung cancer, it is overwhelmingly the drop in smoking causing lung cancer rates to go down.

    For colorectal cancer, the rates are going down, and frankly, we are not sure why. Some of it may be detection of precancerous lesions such as polyps, and some of it may relate to changes in diet, the use of, for example, nonsteroidal anti-inflammatories. We actually do not know.

    For breast cancer, the rates had been going up for years by about 1.8 percent per year, and now they are flat.

    The reality is most of the incidence numbers, with the exception of tobacco-related cancers, remain mysterious. These numbers, as I said when we presented this, actually sound like they are exclamation points or periods, and they are not. They are question marks. They actually tell us what is happening in sub-populations—men, women, different ethnic groups. That then allows us to do research to try to answer some of the questions.

    Mr. PORTER. Will you permit a non-scientist to ask you for an explanation of the science?

    Dr. KLAUSNER. Yes.


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    Mr. PORTER. If you looked at the first poster, it basically showed a nucleus and the cytoplasm. Now, the second poster showed a great deal of detail. Can you tell us whether 10 years from now we will see a third poster that will show detail of the detail, or are we down to the smallest parts?

    Dr. KLAUSNER. No. In fact, we had to edit that so that we can even see it. We already know many more components of the circuitry. We have a lot more that we need to unravel.

    What is different now is actually we know how to get to those circuits. We know how to get at them much more rapidly, much more systematically, because of new concepts and new technologies. It will look much more complicated, and that is only part of the circuitry. That is simply the circuitry within the cancer cell.

    We know that there is an equally complex circuitry of how the cancer cells talk to other cells in places where the cancer may metastasize or not, the blood vessel cells, immune system cells. All of that is modified by the circuitries of what we are exposed to and how we deal with those exposures, which again relate to, for example, variations in genes.

    How these circuits might be affected by exposure, for example, to environmental carcinogens we know itself can only be interpreted by understanding the nature of each individual's filter. That determines why one person may respond, for example, to alcohol ingestion with an increased risk of oral cancer and another person does not.

    So the answer is we all need to be prepared. These diagrams are going to get much more complicated.
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    Mr. PORTER. Is it fair to say that we could have a genetic predisposition or a weakness to some type of cancer and that the probable causes are either lifestyle matters or environmental matters, that there are not outside agents that pass the disease?

    Dr. KLAUSNER. Absolutely. The whole area of predisposition to cancer is a very complicated area. One thing that is very important is few of these genetic changes guarantee that a person is going to get cancer. This idea that a gene determines your absolute fate is a misconception. It changes the probability that many of the same external factors—tobacco, reproductive behavior, exposure to infectious agents, et cetera—change the probability that those exposures will result in the development of first precancerous and then cancerous changes.


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


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    Mr. PORTER. There is one other thing I would like to ask about in that regard. We seem, anecdotally, to find people being afflicted at times of great mental stress. Is this a factor? And what are you doing to study that situation?

    Dr. KLAUSNER. We have been studying the relationship between attitudes, stress, a variety of psychological factors, and the incidence of cancer and the nature of the cancer that is diagnosed. And, in fact, we have been unable in multiple studies to actually find evidence that stress or psychological factors predispose people to cancer.

    There are some studies, however, that have looked at how well people do with cancer based upon what we might call psychological factors, specifically support groups or psychotherapy.

    There are a number of studies looking at breast cancer, melanoma, and a few other cancers that suggest a beneficial effect for individuals that enter, for example, group therapy. We are pursuing those studies through our community clinical oncology program to try to follow up to see whether those approaches can be generalizable beyond the institutions where they were developed and whether the positive results hold up.


    Mr. PORTER. When you came to NCI, you undertook a rather thorough reorganization of your Institute. Is that correct?

    Dr. KLAUSNER. That is.
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    Mr. PORTER. Can you tell us how all that has turned out? There was some talk that others have looked at your Institute as a model and have made changes in their Institutes based upon what you were able to accomplish at NCI. Can you describe any of that as well?

    Dr. KLAUSNER. Well, we made a large number of changes. Not only did we reorganize, but we examined many of our processes that relate to advisory structures, planning processes, how the different components of the Institute interact, as well as how we functioned administratively.

    Personally, I think that we are doing okay. I think it has been very beneficial. And one of the major measures of the benefit has been a remarkable change, an increase in our ability to recruit superb people from many different fields to actually come and be part of the NCI.


    Mr. PORTER. As far as the other Institutes, has there been any changes that others have done based upon what you did?

    Dr. KLAUSNER. Well, maybe I would ask Dr. Varmus to comment.

    Mr. PORTER. Dr. Varmus might answer that, yes.

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    Dr. VARMUS. Well, I think that the success that Dr. Klausner has had in obtaining opinions about how to develop scientific initiatives through use of outside consultants has been very effective. Many institutes, of course, have had other kinds of planning processes that use outside advisers, but I think some of those institutes that have been lagging in that regard may have taken a positive signal from what has gone on at the NCI and what has gone on at other institutes that effectively use outside consultants.

    Mr. PORTER. Dr. Varmus, are you satisfied that each of the Institutes has really looked at how they do things over the last few years and have made changes similar to the kinds of changes that NCI has made to do things better? In other words, has there been kind of a mini-revolution going on?

    Dr. VARMUS. I think that there has been much more engagement with outside advisers, and that is something that I think I would have to say does not emanate only from the Cancer Institute. It has been something that has actually been encouraged by this committee. When I came to the NIH in 1993, we had already received the direct advice from this committee to evaluate our intramural program with an outside advisory committee.

    Mr. PORTER. Are these non-scientists?

    Dr. VARMUS. No, no, no. These are scientists. But that is only emblematic of the kind of activity that brings people from outside the NIH, whether it is managerial as in the case of the Andersen report that we did in response to your suggestion last year, or the Marks-Cassel report that was done to evaluate the intramural program several years ago, or the Bishop Calabresi committee that provided advice to the Cancer Institute before Dr. Klausner came on board. It was addressed to the structural organization of the NCI. All those things have been highly successful and have been validations of the idea that NIH should not try to answer all its own problems with its own personnel, that it should depend more heavily on outside opinion.
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    That has been my own creed since I have been there; Dr. Klausner has certainly espoused it very forcefully, and I think many other institutes have.

    There is always room for further improvement. As you know, the Center for Scientific Review is currently undergoing a re-evaluation of its study sections, and that is being undertaken by a panel of distinguished outside scientists. That might not have been the case some years ago, and I think the ethos has been established by these many activities in which the Cancer Institute has figured importantly. It has been very beneficial.

    Mr. PORTER. Well, I would certainly commend both you and Dr. Klausner and others who have really made this a very dynamic process, and have not allowed things simply to be continued because we have done it that way in the past so we will do it that way in the future. I think that makes any organization, any enterprise, work much better, and I think you have done an excellent job of stirring up the pot and making things work better.

    Dr. VARMUS. Well, you have helped us with that, and I appreciate it.

    Mr. PORTER. Mr. Hoyer.

    Mr. HOYER. Thank you very much, Mr. Chairman, and welcome, Dr. Klausner.

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    Dr. Klausner, it is difficult for any of us to extricate ourselves from the personal involvement with cancer. I imagine there is no one in this room who has not been personally affected in a very real way by this disease.

    I was at a funeral yesterday for a very close friend of my daughter's mother. It was difficult for my daughter, as you can imagine. She went to high school with Andrea Vespoint whose mother died of breast cancer, fought it for 6 years. And as I went through the viewing and talked to Sal, her husband, he looked at me and he said, with real pain, as you can imagine, ''The right woman has not yet died of breast cancer.'' He was angry.

    And what he meant by that, of course, was that from his perspective, having gone through this 6 years, Rosemary's doctor saying she had had more chemotherapy and other extrinsic treatment than any other patient he had ever had, Sal's frustration and anger that those of us in power—anger at me, although he knew my wife very well, as well. But he was angry with us. He was angry with us because we are not spending enough money and we are not solving this problem, because he believes scientists like you, with the incredible capability that you have, can somehow save his wife and others.

    I told him, I said, Sal, I understand what you are saying, and obviously he knew I understood his feelings. But we are spending a lot of money, and we have some very good minds.

    You will also be interested in a comment of my daughter after we left and I took her to dinner. She was up from Florida to go to the funeral. She said, ''Dad, you know, I understand Mr. Vespoint,'' she said, ''but it is in the scheme of things that we will die.'' And, of course, that is true, but at a young age we do not expect that to happen. We do not want it to happen. That is why we spend this money.
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    Let me ask you first—and if you do not know the answer then for the record, how much money have we spent since 1971 or 1972 when we declared a major effort under the Nixon administration to try to eradicate or intervene or cure? How much money have we spent? Your budget this year is $2,300,000,000, not an insignificant sum of money. And, Dr. Varmus, perhaps with all the institute directors, we know that it is not just the $2,300,000,000, just as the $2,300,000,000 impacts on other institutes and other diseases and the research that is done, the research that is done in other institutes impacts and assists and moves us forward with respect to yours.

    But if you could do that, because I would like to be able to respond to Sal, and to all our constituents, and to everybody here, on how much we have dedicated to this effort. You may want to respond to that. But then I will ask you the question: Are we making sufficient effort? And the Chairman has asked this. Although we do not want to direct it by disease, quite obviously, we do want to assure our public that we are dedicating sufficient resources to do everything that we possibly can to eradicate or at least intervene more successfully than we have been doing.

    Dr. KLAUSNER. Mr. Hoyer, all of us who come before you hear and experience the burden and frustration about all of the diseases that we feel responsible for. Since the National Cancer Act was passed, about $36,000,000,000 in total has been expended. Of course, the dollars alone do not express the effort and commitment of countless thousands of people who are committed to doing as much as they can. Can we do more? Yes.
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    Have we invested that money well? I actually think we have, and I think we are beginning to see the impact of those investments. We want it to go faster. We are trying all possible approaches, I believe, and, in fact, as Mr. Porter pointed out, specifically in breast cancer, we have brought together hundreds of people over this past year in something called the Progress Review Group to advise us. For the first time, we are looking at what are all the things that we could do, and at the same time looking at everything the NCI and the NIH is doing, trying to match that and prioritize what are we missing, where are the gaps?


    We are learning better to early detect breast cancer and to treat it more effectively. The significant drops—not experienced by all women, but especially younger women and especially white women, that is, drops of over 3 percent per year for women in mortality rates for under the age of 50—per year for the last 5 or 6 years. That is really quite significant. Overwhelmingly, I believe that is due to advances in treatment.

    I think we see progress. I think we all feel that it is not enough, it is frustrating, and every time that we are confronted with the suffering and the failure of our ability to prevent the suffering and prevent the death from these diseases, it affects us deeply.

    I think not only have we invested a lot, I think we can actually point to the fruits of that investment. And we are seeing that, especially in breast cancer, in some very significant changes not only in incidence but, more importantly, in mortality rates.

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    Dr. VARMUS. Mr. Hoyer, I wanted to respond to your points that were addressed to me.

    First, as you properly point out, it is very difficult to say that money in one place is going to affect one disease. As we do our calculations, a little less than 90 percent of the overall cancer effort is in the NCI, and a little more than 10 percent is elsewhere in the NIH.

    With respect to whether could we do more: yes, we could always do more. We could do more in cancer. We could do more in many things. We have to balance that desire against other demands on the Federal budget.

    Mr. HOYER. Doctor, the reason for the question is—and the frustration that everybody has, including yourself; this is not accusatory. This is how do we deal with this and talk to the people we all represent. And, Dr. Klausner, there are tens of millions of people, obviously, who are relying on you, which is an incredible burden and an unfair burden, because there are thousands of you, around the country in and out of Government, in and out of the private sector.


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

    Mr. HOYER. That light was for me, not for you, Doctor. I am out of time. You are not.


    Dr. KLAUSNER. In those examples in the upper right of the poster, is this long name called Thiozolidinediones. These were approved by the FDA for the treatment of diabetes last year. It reduces the insulin dependence on diabetes.

    I raise this because what this drug does, with very little toxicity, is interacts with a molecule that sits in the nucleus of a cell and tells the cell to turn into a fat cell—irreversibly, it seems.

    The investigators that discovered this and discovered the target, up in Boston as well as UCSD, have recently reported that a significant fraction of breast cancer cells express that target, and when treated with this anti-diabetes agent, seems to irreversibly turn into nonproliferating fat cells.


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    Over the past year, we have helped them begin a clinical trial, first in a rarer cancer of sarcomas, liposarcomas, but we will be moving into clinical trials for both colorectal cancer—where almost every cancer expresses the target for this drug—and a significant fraction of breast cancers.

    This is one of these examples where research in one area, coupled with the ability to discover these circuitries and ask where they are, gives us new areas. There was no way we would have predicted that that would be a new approach potentially. We do not know if it is going to work, but we will be testing it for, in this case, breast and colorectal cancer.


    Dr. VARMUS. Mr. Hoyer, if I could comment just briefly on your bringing up the founders of the polio vaccine, I think the success that medical science has had with infectious disease and the prolongation of average life expectancy in this country has given people a sense that medical science can do more than we probably can do with respect to some of these much more difficult conditions. Cancer arises from within our own genes and our own cells. The pathways, as you have seen, are incredibly complicated contrasted with invasion from an outside, very simple virus. And the difference between those two kinds of problems is really immense.

    We all feel frustrated, but I think it is not simply a matter of luck that we were able to conquer polio long before we were able to deal with some of these chronic and much more complex diseases.

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    Mr. HOYER. Thank you, Doctor. And, again, I do not want this to be taken in any way accusatory. It is to try to better focus us on how we can meet one of the world's great problems.

    Mr. Chairman, I have other questions. I will submit them for the record.

    Mr. PORTER. We will have a second round. I should tell members we are operating under the 8-minute rule.

    Mr. HOYER. Thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Mr. Hoyer.

    Mr. Miller.


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

    Dr. KLAUSNER. Well, I think hopefully the numbers will all be much lower and we will be talking about some real successes.


    What I think is that the difference between that black box, which led to us using relative toxic, non-specific approaches to therapy, where we often did not know the cause and so we had these vague associations about what we might do—to prevent cancer, to what we are going to be seeing is a very new world where—the interventions that we will be using will be based upon knowing exactly what we are going after, analogous to the protease inhibitors for HIV, that is a very good model. They will be chosen and designed for the machinery that characterizes each cancer, that actually distinguishes one cancer from another.

    One of the problems with the black box is that we did not know whether all breast cancers were the same or all brain cancers were the same. We know that they are not. But how are they different? It is the different circuits that one breast cancer uses versus another, one prostate cancer versus another that makes them different.

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

    So I suspect 10 years from now that is what I or my successor will be talking about.


    Mr. MILLER. Will the trend continue like it has been over the past couple years as far as going down?

    Dr. KLAUSNER. From everything that we can see, we suspect this trend will continue over the next several years. Beyond that, I would be loath to make predictions. We certainly hope so.

    We are concerned with certain troubling trends, and that is the drop in lung cancer is a perfect measure of the drop of use of tobacco, primarily cigarettes. But we are now seeing in our young people a significant upturn in the use and the addiction to cigarettes. If that continues, then we will go back to this epidemic of lung cancer, and it has been an epidemic—an epidemic that tracks with the use of tobacco. So there is some uncertainty there.
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    Mr. MILLER. You mentioned tobacco. This committee does not expect to get involved in the tobacco settlement. But what is the solution to keep kids from smoking?

    Dr. KLAUSNER. Well, from all the studies that have been done—and we need to do more—the evidence suggests that decreasing tobacco use among kids probably relates to three types of areas:

    One is the price, and there is good evidence to believe that the higher the price, the less kids will take up tobacco, and that has been shown in different places.

    The second relates to decreasing access. Kids that have ready access to tobacco will use it.

    And the third is to decrease the appeal, and that is to make sure that kids are not assaulted with things that make it look attractive and sexy and good to take up tobacco.


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


    Mr. MILLER. Let me change the subject. You mentioned how you were able to recruit outstanding people. How are you able to compete salary-wise and benefit-wise for the top scientific minds and researchers? Are you able to?

    Dr. KLAUSNER. I believe that we are. Over the last few years, there has been some real changes in the flexibility we have in terms of mechanisms of hiring and in terms of some of what had been dramatic salary differentials, especially for clinicians. With a variety of new mechanisms, that gap has been closed, but more than just the gap, it is the flexibility of having a range of new opportunities.

    I must say that still we have to struggle with what are often cumbersome rules and regulations of a personnel system that is not necessarily designed and built to deal with the flexibility needs of science and clinicians, epidemiologists, et cetera. We are working on that, and I am sure Dr. Varmus may have more to say about that.

    Dr. VARMUS. Well, I think Rick has summarized what our situation is quite well. We are competing much more effectively in the clinical arena than we could before. We can pay up to $200,000 a year. We do have problems when we are competing for individuals in the highest paid specialties, especially when they are at the top of their fields.
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    Mr. MILLER. What is the flexibility you have? Is it just salary, or are there other——

    Dr. VARMUS. Well, we have a number of personnel mechanisms now. One is the Senior Biomedical Research Series that allows us to pay Ph.D. investigators up to as much as $151,000 now, and that has improved tremendously our ability to recruit Ph.D. scientists. We now have two other mechanisms—one called Title 42, one called Title 38—that allow us to pay a variety of individuals up to $200,000 a year. And those mechanisms markedly increase our ability to recruit.

    Mr. MILLER. You do not have endowed chairs like universities?

    Dr. VARMUS. No, we do not.

    Mr. MILLER. Did you ever look into that?

    Dr. VARMUS. It was actually proposed when the National Foundation of Biomedical Research was put into our reauthorization bill in 1993, but it seems to me that that is not really the primary charge to the Foundation, that what really matters is how much we pay our scientists and we are going to pay them with Government pay mechanisms. So I do not see any real benefit to endowed chairs. Perhaps when the foundation is better endowed, we might consider that possibility again. But right now I do not think it is the most effective use of the Foundation's time or money.

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    Mr. MILLER. Thank you.

    Mr. PORTER. Thank you, Mr. Miller.

    Mrs. Lowey.

    Mrs. LOWEY. Thank you, Mr. Chairman.

    Dr. Klausner, again, I welcome you with great pride. In addition to Dr. Varmus, whom many of us share as a native New Yorker, you are from Yonkers, New York. I just want to congratulate you again for your extraordinary leadership and for your enthusiastic approach to directing the National Cancer Institute. It is your enthusiasm and your great intelligence and this list of honors that makes me indeed feel fortunate that we have you there. We are doing something right in this country if we can attract the likes of Dr. Varmus and you and all the other outstanding scientists who appear before us. So I thank you.


    I would like to follow up with a question that was just asked specifically with regard to the report card on cancer which you issued. Generally, the news was heartening as you reported to us, the incidence of cancer and rate of deaths from cancer declined between 1990 and 1995. However, there were some very troubling trends.

    For example, as you mentioned, among the four major cancers—lung, breast, prostate, and colorectal—the most negative news was that lung cancer is still rising among women. So when we talk about the decrease in lung cancer, it is still rising in women even though it is declining in men.
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    We know so much more about how to prevent lung cancer than we do any of the other major cancers. We know that 80 percent of lung cancers are related to tobacco. So my question is: Number one, what is the NCI doing to stop this killer of women? And is more public education or more research needed?

    Dr. KLAUSNER. I suspect it is both, but primarily we need more public education because we know—we have done the research—we know that the issue is cessation of smoking.

    Now, the difference between what is happening with women exactly tracks the pattern of tobacco use. Women started smoking later, and they stopped smoking later.

    Now, smoking rates have declined in women, but lag the decline in men. In fact, while lung cancer rates are continuing to rise over the last few years in women, what we are seeing is that it is beginning to flatten, and we can be pretty confident because we can look back and see the tobacco use rates—that we will very soon reach the plateau of that epidemic in women, and it should start coming down. That actually is a relatively straightforward prediction because it tracks with smoking. I think that is the difference.

    Mrs. LOWEY. Although I hear that as we target decrease in advertising to children, we can increase advertising to women, as the NRA did with those ads that were specifically targeted to women, put a gun on every kitchen table for safety. So I think we have to watch what happens carefully. I would also be very interested in knowing whether there is any research in addition to just usage patterns, that clearly defines the difference between men and women, or is it all public education.
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    Dr. KLAUSNER. I think there is a need for a lot of research in a variety of areas related to the behavioral issues of smoking, which we are doing and need to do more. We had a recent review of that, and it does specifically point us to ways that we can attempt to intervene in groups that are dropping smoking less, such as women.

    There are other things, because it does not just end with the success of getting people to quit smoking. Unfortunately, after people have smoked, they continue to be, often, depending upon the disease, for decades, at an increased risk of developing disease, including cancer.

    And so one of the things we need to do is not assume that our job is done just by convincing people to stop smoking, which is hard enough. We are doing a lot of research in terms of new methods of early detection of precancerous lesions in the lung and new methods of prevention, for individuals, especially former smokers, who clearly are at increased risk.


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


    Mrs. LOWEY. And with regard to breast cancer, I personally appreciate the extraordinary leadership you have shown in your commitment to fighting breast cancer. And I am particularly enthusiastic about the progress that you have been talking about and the progress that will be coming. Yet, as you know, this year alone we see 180,000 new cases of breast cancer, 40,000 women will die of the disease.

    If the NCI had more money to spend on breast cancer research, my first question is: Could you continue to fund high-quality research? or Have we reached the point where we have saturated the research community with breast cancer grants? And, in addition to answering this question generally, could you also tell us the pay line for breast cancer grants; that is, what percentage of breast cancer grants that make it through peer review receive funding?

    Dr. KLAUSNER. Let me start with the last. We do not have a separate pay line for breast cancer. The general success rate for grants now, for NCI grants, is between 25 and 30 percent, and that is about the success rate for breast cancer grants as well. I must say I do not have the exact numbers, but we do not attempt to separate them.

    There is much that we are doing. There is no question that while there is a 25 to 30 percent success rate, that means that there is a 70 to 75 percent failure rate of getting that grant funded.
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    Mrs. LOWEY. These are the ones that have gone through the peer review process successfully.

    Dr. KLAUSNER. Well, these are the ones that have actually been submitted. What does it mean to go through it successfully? Of course, what we pay are the ones that do most successfully in peer review. There is a gradient. The way we determine pay lines is we ask the peer reviewers to rank them. It does not mean we would not very much like to pay very good ideas that are beyond our pay line, but certainly we attempt to follow peer review and we do follow peer review to fund that 25 to 30 percent that the peer review says are the most outstanding.

    Mrs. LOWEY. Right. So that there are 70 to 75 percent—is my math right?

    Dr. KLAUSNER. Yes.

    Mrs. LOWEY [continuing]. That could be funded if there were additional funds.

    Dr. KLAUSNER. Yes.


    Mrs. LOWEY. On colorectal cancer, we know that colorectal cancer is the Nation's second leading cancer killer, and each year in this country 131,000 new cases are diagnosed and 55,000 people die from this dreaded disease.
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    Can you update this committee on the research agenda with respect to colorectal cancer?

    Dr. KLAUSNER. Sure. There are several things about colorectal cancer. We do know that screening can reduce mortality. We also know that a very small fraction of the population avail themselves of screening. There are many reasons for this, and we have a number of research studies, and we are participating in a roundtable with the CDC and the American Cancer Society specifically aimed at trying to increase the use of screening, which has been demonstrated to reduce mortality rates, by looking at blood in the stool reduce the mortality rates by about 33 percent.

    We do not have as good data for other screening techniques. From a type of study called case control studies, there is a suggestion that sigmoidoscopy may reduce mortality by 60 to 80 percent in the region that the test can actually see.

    We are funding a variety of new ways to screen. There are different problems with the screening for colorectal cancer. One is the hesitancy of individuals to avail themselves of screening because of sigmoidoscopy or colonoscopy. It does not have a great reputation.

    One of the things that we are trying to develop is a new approach called virtual colonoscopy.

    Mrs. LOWEY. Can I put on the record that the test is not so bad?
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    Dr. KLAUSNER. Yes, you should put on the record it is not so bad.

    Mrs. LOWEY. I will not be any more cryptic.


    Dr. KLAUSNER. So a very important thing is our research agenda aimed at new detection technologies and trying to make sure that the detections that we have are used.

    Another very important thing in colorectal cancer is that it is one of the cancers where therapeutic interventions, at least for moderately advanced disease where much of the mortality is, seems to work. Recent studies from our cooperative groups have demonstrated up to a 35 percent reduction in mortality from the use of adjuvant therapy.

    Now, we need to improve on that. There are new trials going on. But we also need to make sure we understand whether those advances are being disseminated, whether they are being used, and if not, why not. There is much we need to do.


    There have been tremendous advances in understanding the circuitry and the genetic bases of colorectal cancer which has given us some new hints at prevention. Included are some new drugs that we are testing that we think may prevent the development of colorectal cancer, may prevent the progression from polyps to colorectal cancer. These have been established by a variety of studies, epidemiologic studies, and animal models which can mimic colorectal cancer. These are called COX-2 inhibitors. They are like nonsteroidal anti-inflammatory drugs. There are intervention studies looking at diet to prevent, again, the progression of polyps, which are precancerous lesions, to cancer.
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    It is an extensive research portfolio. I think it is an area where we are making progress and can certainly make more.

    Mrs. LOWEY. Thank you. I would love you to continue educating us——

    Mr. PORTER. We will have a second round. Thank you, Mrs. Lowey.

    Mrs. Northup.

    Mrs. NORTHUP. Thank you, Doctor. I have to echo what Mr. Hoyer said earlier, that probably there is nobody in this room that does not have close relatives that have been through cancer. And when it is your family, I remember my feeling was I cannot believe there are thousands of people that are going through this at the same time. And so, you know, I think that there is great cheer that we seem to be making progress.


    I have a couple of questions to follow up some of the earlier ones. The first one is, as you talk about the drugs that we may develop that will be very specific to the communications part of the cell, are there similarities in the base of those drugs? There are all sorts of antibiotics, say, but there are similarities between them, too.

    Is that the case with the drugs that we are developing for cancer, or do we have to sort of start from ground zero with every single cancer and is it an entirely different compound?
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    Dr. KLAUSNER. I suspect we are going to be looking at a very large range of compounds. But I mentioned something in the beginning, in my opening statement about these new chemistry-biology centers. Let me describe a bit about that.

    There is an entirely new technology of ways to discover drugs, to create not one drug at a time and then modify it, but literally billions of potential drugs at a time. It is called combinatorial chemistry. It is actually very interesting because it takes the principles of biology, the generation of diversity, and then selecting them. It is the principles of evolution, but now applies them to chemistry.

    What we are now funding is a series of centers where we are asking individuals to generate literally millions to billions of potential drugs and to then use new technologies that will couple the discovery of those new compounds that may look like almost anything. They are sort of randomly generated, but then we select them by linking them directly to those pathways. We call them smart assays. I hope I am not misheard with that.

    My feeling is that while I do not think there is going to be any single principle of drug structure that will answer all of these circuits, we actually have in front of us an actually quite revolutionary new paradigm that will potentially really change drug discovery from searching in soil, from searching in marine animals for one drug at a time, to being able to sample millions or billions of compounds.

    So I think at the same time where we see this, as you are worried about, this proliferation of how we are going to discover all these drugs, we have an entirely new way to sample many more possible drugs.
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    Mrs. NORTHUP. I think actually, now that you mention that, there is a place in Louisville where one of those companies exists. It was very interesting. They can multiply it with high-tech.

    Dr. KLAUSNER. That is right.


    Mrs. NORTHUP. The tests that you perform simultaneously.

    Can you give me some idea how much of the money that is spent and how many of those efforts are National Cancer Institute-initiated and how much are initiated by pharmaceutical companies, and what role the pharmaceuticals play in that?

    Dr. KLAUSNER. Well, the pharmaceutical industry plays a huge role in this, and, in fact, we have a very long history, the whole NIH and certainly the NCI, of working very closely with the pharmaceutical industry, which we are doing with this as well.

    Much of the development of this technology has been in the pharmaceutical industry. Some of it is in academia. The pharmaceutical industry has been very supportive of the expansion of this into academic research labs, which is what we are trying to accomplish with these chemistry-biology centers.

    There is no question that ultimately what we hope to discover are lead compounds which will feed into the industry, which will be transferred through technology transfer to industry, so that actually products for people can be developed.
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    Mrs. NORTHUP. I would like to ask you about tobacco use, too. You know, people think of it with lung cancer. In reality, I know that there are a number of cancers that are increased, even though you cannot exactly see the physical connection of where the smoke actually is taken in and affects the cell. I just wondered if you could give me some idea of the extent of the numbers of cancers that actually show higher increases based on smoking.

    Dr. KLAUSNER. Yes. It is, as you say, extensive. It is not only lung cancer. It is oral cancer, laryngeal cancer, esophageal cancer, interestingly kidney cancer and bladder cancer. There also is some evidence that colorectal cancer is increased among smokers.

    Recently, there have been some studies suggesting the possibility that breast cancer may be associated with smoking, and we are pursuing that now. That evidence is weak, but intriguing.

    So there is no question there is a whole variety of cancers that are associated. Pancreatic cancer is another one.

    Mrs. NORTHUP. Is my time up?

    Mr. PORTER. No.

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    Mrs. NORTHUP. Oh, okay.

    As you work through the grant process, do you allocate money specifically for some cancers, like this is what we are going to spend on colorectal, this is going to be what we spend on breast? And how do you divide that up? Do you feel like there are some cancers that are underfunded? Does it help to have the specific cancer groups come and argue on behalf of theirs?

    What is the best way and do you feel like we are at the best way of appropriating money for specific cancers?

    Dr. KLAUSNER. Well, this is a complicated and dynamic process. We do not sit down and decide how much money we are going to spend on individual cancers. In fact, our approach has been to bring individuals into the NCI and make them feel at home with our planning process that may begin by asking what are the critical things we need to do for prostate cancer or for breast cancer.

    And the incredible thing that we all see when we do that is we tend to get—not entirely—very similar answers. Then we can step back and say that we need to develop better animal models for each of those cancers and do that in a way that may or may not be specifically targeted to the cancers.

    The interesting thing is that while we do not distribute our money specifically or plan to distribute our money specifically by different cancers, when we look at the distribution it is intriguing that, by and large, there is some relationship between the incidence or death rates of cancers, of major cancers—it is not one to one—and the level of money that is expended. But interestingly, that seems to be emerging from the research community that recognizes those needs, recognizes the frequency, couples that with scientific opportunity, and then proposes the research they are going to do.
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    Mr. PORTER. Can I interject here and ask Dr. Varmus or Dr. Klausner something? It is because of a question that Mrs. Lowey asked and now one that Mrs. Northup asked. If you could describe when you decide where the research is on a specific disease. In other words, my understanding is you do not go out and say this research is breast cancer research. You have a proposal and only later when you see where it leads do you code it. Can you expand on that for the Members of the subcommittee so that they understand the process?

    Dr. VARMUS. Well, there are several phases to the process. When a grant comes in, of course, it is evaluated by the study section, it is given a score, and then a decision is made by Dr. Klausner's team, at the NCI, or by other institutes, wherever it has been assigned about whether that grant is going to be funded.

    Now, that decision is made based, in very large part on the score that the application receives from the study section, but the decision is also based on some general sense of what the research portfolio ought to look like. So when you get to a certain level as you go down the list, you may say, ''Well, we will fund this but not that one; the scores are very close, but we need more activity in a certain area.''

    Before that decision is made, there has been a planning process, and the Institute, using a variety of techniques, will have evaluated its research portfolio, looked at public health needs, looked at the distribution of scientific activity, and made some prior decision that in this year's grant funding it ought to pay more attention to developing stronger initiatives in certain areas.
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    That planning process can be linked to the award of grants by incentives to encourage applications in certain areas. Those incentives may be as mechanical as saying we are going to set aside a certain number of dollars to encourage research in a certain area, or we are going to develop a new program, like the biology-chemistry program that we just talked about. Or it may inspire the Institute or a group of Institutes to say ''Let's have a workshop and bring new people into the field so we are more likely to get applications, or let's have a program announcement.''

    All those things tend to move the science in that new direction.

    Mr. PORTER. Thank you, Mrs. Northup. Your time was over right as I asked the question. [Laughter.]

    Ms. Pelosi.

    Ms. PELOSI. Thank you, Mr. Chairman.


    Dr. Klausner, welcome. Thank you for your leadership. Many people have their hopes pinned on you. You carry a heavy burden.

    Dr. Varmus, once again, welcome. Thank you for providing such great leadership at NIH to attract the likes of Dr. Klausner and the other heads of your institutes and all the others there. It is just remarkable.
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    Having said that, I want to follow up on a couple of points my colleagues have made and then ask my own question.

    You were in the middle of talking about a virtual examination—and then I think the time was up—to detect colorectal cancer. Virtual?

    Dr. KLAUSNER. Yes, virtual.

    Ms. PELOSI. Cyberspace?

    Dr. KLAUSNER. It is through photons and electrons. It is by using x-ray technology. These x-ray technologies may be computerized tomography. Some of our technologies may fuse those images between standard x-rays, CT, and even magnetic resonance in order to actually allow the computer to generate a virtual trip through the entire colon. I can actually at some point show you a movie of it, what it looks like. It is actually quite extraordinary.

    It is being developed in a variety of places, and we are now testing it. It has a long way to go, but it is moving ahead both for bronchoscopy and colonoscopy because you can get the contrast between the tissue and the air, and actually with tremendous precision be able to, without any insertion of anything, be able to reconstruct a tour through the bowel or the bronchial tree. Through computers it very much looks like—if you saw the movie ''Contact,'' the travel that the person went through. You are going through these tubes, and you can stop and look and amplify it.
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    We are very optimistic about this type of technology developing to make these sorts of detection approaches more usable, more useful, easier to transmit the information electronically and have experts see it as a type of telemedicine, as well as, being much more acceptable to patients.


    Ms. PELOSI. That is very interesting. As part of Dr. Varmus' presentation—a couple of weeks ago, I guess—he talked about improved instrumentation as part of one of the initiatives at the NIH. Would this fall into that category?

    Dr. VARMUS. Yes.

    Ms. PELOSI. I did not know if it was just about research, or about detection as well.

    Dr. VARMUS. In the NCI plan for next year, there is increasing emphasis on using instrumentation for early detection, and they are linking their clinical trials networks to the use of more advanced instrumentation for early detection. You can see how that would interface very nicely with clinical trials.

    Ms. PELOSI. I am glad it is about detection as well as research. Along that line——

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    Dr. VARMUS. They are really inextricably linked.

    Ms. PELOSI. Yes.

    Dr. VARMUS. We have to do research to learn how to do better detection, just as we were doing research to learn about more accurate diagnosis and better therapies.


    Ms. PELOSI. Along that line, how much emphasis is being given to funding research into screening methods that can be used as an alternative to mammography, methods that do not involve radiation exposure and that are effective in women of all ages?

    Dr. KLAUSNER. We have actually a very extensive portfolio, looking at non-mammographic ways of visualizing—this is for visualizing—breast lesions. These include optical imaging techniques, some new ways of migrating photons through tissue, a near-infrared approach that now can penetrate up to 10 centimeters, which would be adequate for mammography, MRI, and magnetic resonance spectroscopy, which has the potential to look not only at whether there is an anatomic change, but whether there is a molecular change.


    We have an imaging working group, and we have challenged them with the challenge: Can we create imaging tools that will allow us to read in the intact body these networks so that we can actually see in small numbers of cells when genes are turned on or turned off? We think that is possible.
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    Ms. PELOSI. How soon is that possible?

    Dr. KLAUSNER. I have no idea, but we are beginning to move towards that. This is a whole new area. It is going to take a while to develop. But we are doing a fair amount of research in it.

    There are other possibilities besides ionizing radiation.

    Ms. PELOSI. I have the privilege of serving on the Intelligence Committee, and when I am up there, I ask some of the representatives of that community about detection and some of the technology that is available there. Are they part of your imaging working group?


    Dr. KLAUSNER. Yes. in fact, even with mammography, digital mammography was developed through a consortium that the NCI put together in 1993 that resulted in four different companies developing digital mammography. We are working with the DOD. In fact, I am going to meet tomorrow with DARPA, the Defense Advanced Research Projects Agency, about a memorandum of understanding between the two agencies specifically for what we are talking about is revolutionary technologies in detection, using different models of funding and different models of collaboration.

    Ms. PELOSI. Wonderful. Thank you. I look forward to hearing more about that.
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    I just want to make a point about lung cancer. You can hardly pick up a magazine without reading about—a woman's magazine, which you probably do not pick up too frequently, but maybe the next time you are at the beauty parlor. You can hardly pick up——

    Dr. KLAUSNER. Is this a suggestion? [Laughter.]

    Ms. PELOSI. No.

    Dr. KLAUSNER. It will not help.


    Ms. PELOSI. It was silliness. You can hardly pick up a woman's magazine without reading an article about breast cancer, somebody's experience or what women are doing themselves to organize, et cetera. And you never read about lung cancer. You never read about lung cancer in a woman's magazine. You do read about cigarette ads; you do see lots of cigarette ads. And I hope that when we are talking about getting the message out, somehow this message penetrates that world, as you said in your comments, the increasing rate of death among women from lung cancer. Education on that has to break through to that audience.

    Dr. KLAUSNER. You are absolutely right. There are some real myths about frequencies of different cancers. The number one cause of cancer death among women is not breast cancer. It is lung cancer.
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    Ms. PELOSI. And so this audience must be susceptible to a message because if they were not, the cigarette companies would not advertise in these magazines.

    Dr. KLAUSNER. I think that is right.

    Ms. PELOSI. So, by the same token, there has to be some way that we, the public, we, the Federal Government, or somebody says to them you have a responsibility, even if you are going to take the cigarette ads, to write about lung cancer as well. So there is equal time devoted to staying alive.

    Dr. KLAUSNER. Yes, and we have been over the past year working with a developing advocacy organization for lung cancer, and we cannot allow it to be a forgotten disease. There is no question one of the differences is that survival from lung cancer is much less than survival from breast cancer. So you have a large population of survivors who are very active in getting the word out.

    We all need to be advocates about lung cancer.

    Ms. PELOSI. That is very interesting.

    Dr. Klausner—oh. I was just going to ask a quick question.

    Mr. PORTER. You may continue.

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    Ms. PELOSI. Okay. I have a little beachhead here on this question, so I am going to continue. Thank you, Mr. Chairman.

    Last year, as you know, you had visited our community, and you noted the concerns that people have, and I thank you again for visiting the Bayview Hunter's Point area as well as meeting with people in our community who are concerned about the environmental aspects of—the impact of the environment on women. Many of us are concerned about the higher incidence of breast cancer in the area.

    Last year in your testimony before the subcommittee, we talked about high breast cancer rates in San Francisco. You noted the study was being done to try to determine the possible cause of these higher rates of cancer, and to see if you could tie that to the environment.

    Dr. KLAUSNER. Yes. That study I talked about from Stanford was published, and we were expecting it, and the results were very interesting. It asked the question whether the rates of breast cancer in the San Francisco area could be explained by the distribution of known risk factors. Most of these relate not to the environment as far as we know, but to the hormonal pathway, the estrogen pathway, reproductive patterns as well as they also included alcohol consumption, which seems to be a risk factor of breast cancer.

    In that study, the authors concluded that essentially 100 percent of the difference in the rates can be explained by the known risk factors: differences in age at first birth, differences in number of children, what we call the standard risk factors. Not that we necessarily understand the meaning of those risk factors, but it did suggest that it is going to be very difficult to find on top of that a specific environmental cause to explain the particular breast cancer rate in San Francisco.
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    I must say that over the last few years numerous studies have pointed out that it is the unequal distribution of risk factors in different cultures, in different cities, in different parts of the country. There are different rates of early pregnancy, of age at first pregnancy, of when one begins menstruating, when one enters menopause, et cetera. So that was an important conclusion.

    We continue to look and we continue to fund studies, including new studies, to examine the environmental causes or potential environmental causes of breast cancer. There were numerous reports suggesting that PCBs and DDT and a metabolite that is called DDE may be associated with increased risk of breast cancer. We still do not know, but this year a study was published from Harvard, I think the nurses health study, the largest study looking at whether exposure to DDT correlated with breast cancer, and in fact, it did not. This is the largest and I think the best study so far on that.

    We continue to look. We continue to fund studies. It is going to be hard to find.

    Ms. PELOSI. I thank you for your answer and for the initiative you are taking on it. It is still a question that many people find——

    Dr. KLAUSNER. It is.

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    Ms. PELOSI. It seems obvious, but obviously we do not have the science to support the link.

    Thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Ms. Pelosi.

    Ms. DeLauro.

    Ms. DELAURO. Thank you very much, Mr. Chairman.

    Good morning, Dr. Klausner.

    Dr. KLAUSNER. Good morning.


    Ms. DELAURO. It is wonderful to have you all here again today, and I thank you very, very much for your incredible contributions.

    Let me just pick up on a question on breast cancer, because I read in this morning's Washington Post—there was a small piece that talked about ''Gene testing questioned as a breast cancer screen.'' It says it is a new study which found that the genes BRCA1 and 2 were not as linked to breast cancer as was once thought.

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    I just wanted to get your view and your thoughts on the study.

    Dr. KLAUSNER. There are some other studies—these are recently published studies in JAMA, I believe, Journal of the American Medical Association—that continue what we sort of expected, and that is, these genes that do, in fact, predispose to breast and ovarian cancer, and that link is clearly there. The issue is how frequently are those genes altered in the general population.

    This is important in terms of whether screening would be valuable or not. If it is very rare, it would be very hard to imagine screening the entire population.

    So since these genes were discovered, many studies have attempted to answer a number of questions. What is the frequency in different populations of these inherited alterations in these genes to explain the breast cancer that you see? And even when you find alterations, what actually is the age-dependent risk of developing breast cancer? Because, of course, that is very important.

    It is very different in terms of decisions women might make in terms of prophylaxis, in terms of monitoring, in terms of being tested, to know what is the meaning of the test. Numerous studies over the last year have demonstrated that a very small percentage of women with breast cancer, even with early onset breast cancer, actually have detectable, inherited alterations in the BRCA1 and BRCA2 gene. I believe it was in this study for all women below—that have breast cancer even below 35, only about 7 percent—I am sorry, about 12 percent—between 7 and 12 percent in different studies actually will be found to have these alternations. These are important.
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    Another important study that was done at the NCI was to ask the question: If you find in individuals these inherited alterations, what is their ultimate risk of developing ovarian or breast cancer? The original studies began by looking at families where many individuals had cancer. That is how they came to our attention. But if you started the other way and you identified the gene and then you did not know the family history and tried to figure out what is the probability of getting cancer, what we found in those studies, the risk of developing cancer was much lower, significantly lower than we initially thought. Instead of 80 percent risk of lifetime risk of breast cancer, we calculate it is more like 50 percent. That is still very high, but less. Ovarian cancer had been quoted as high 60 percent. And what we found in that study is that it was 16 percent.

    These are very important pieces of information in terms of helping people make decisions about whether to be tested and, if to be tested, what to do about it.

    Ms. DELAURO. It is just that the headline is—you do not write, I do not write, but someone sits there and decides to talk about gene testing questioned, and, you know, it just sets people off in thinking about what is happening.

    Dr. KLAUSNER. Sure.


    Ms. DELAURO. I would like to ask, because I know you know that I was going to ask the questions about ovarian cancer. Let me just move forward on that.
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    There is no simple diagnostic test to detect ovarian cancer, and I understand that what you are doing is running clinical trials to evaluate new tools to identify women with early-stage ovarian cancer. I just want to be updated on the trials, how they are progressing.

    This is an unfair question, but I have to ask it. What do we believe is the time frame on finding something that is a reliable screen that will be available to women?

    Dr. KLAUSNER. I wish I knew the time frame, but I can tell you what we are doing to try to move it along, and I think significantly speed it up. This is one of the goals of this Cancer Genome Anatomy Project, to try to look at cancers, such as ovarian, which is one of the first that we have been studying. Now there are in our database about 30,000 sequences from ovarian cells or ovarian cancer cells. In the database there are now possibilities of 500 that are listed as potentially specific. We can now start working through these very quickly over this year to find out if there are. I do not know if any of those 500 will turn out to be true, but suddenly we have a menu of possibilities that we never had before.

    There is one particular marker that many people are interested in. That is something called the folate receptor. Ninety percent of ovarian cancers quite significantly overexpress a receptor for folate, which is a vitamin, on their surface. There are some agents that have been developed where you can link a molecule that can sense the folate receptor to a radioactive marker to see whether this would be a new diagnostic to detect early ovarian cancer.

    You have pointed this out, and it is absolutely true. The single most important thing we need for ovarian cancer are better early detections because only 20 to 30 percent are diagnosed when they are localized, and that is the major challenge.
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    But we have set up an infrastructure to try to discover possible tags in a way that we never have before that will be used—if you remember Dr. Varmus' poster, with those thousands of genes, these gene chips. That is exactly what we will be doing over the next year for these ovarian genes.


    Ms. DELAURO. And is the SPORE part of what you are talking about as well? Is that going to be an effective way to deal with ovarian cancer in the way it was with breast cancer?

    Dr. KLAUSNER. Well, that may be. We certainly are considering this year an ovarian SPORE. Our advisers are evaluating the SPORE program. We will have that evaluation by, I believe, June. I think it is going to be very positive, and our plan, assuming that is positive, is actually to move ahead with an ovarian SPORE.

    There have been advances this year again with ovarian cancer, and mortality rates are falling. There are a number of things, including some very new therapeutic ideas, for ovarian cancer that are being tried out. The virus that is being developed by the Onyx Pharmaceutical Company is being looked at for ovarian cancer. We are interested in local therapies within the peritoneum, where even if it has spread it is usually there, such as photodynamic therapy, which are compounds that are specifically taken up by tumor cells, and you shine light on them and they kill the tumor cells.

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    This year the FDA approved that for early lung cancer as a treatment as opposed to a palliation. It has been approved before for esophageal. This is going to be looked at for ovarian cancer. There are ideas. It is still a huge challenge.


    Ms. DELAURO. Let me ask you, because I know the Department of Defense is doing research on ovarian cancer, and they have applications out for grants to look at this. What kind of collaboration are you doing with DOD on this effort?

    Dr. KLAUSNER. We have a very good relationship with them and are coordinating all of their cancer activities. One of the things that we have been providing for them is a newly organized portfolio analysis that organizes all of our research on certain cancers, not just where there is an endless list called breast cancer, but it is actually divided into questions about breast cancer. And so we have had the community organize our portfolio, conceptually. Now we can say to anyone this is what we are funding in all these areas.

    Recently, the California breast cancer funding agency came, used this portfolio, feel that it is really useful for them, and we're working with the DOD so that they can use this portfolio analysis so they can see what we are doing, where there are gaps that they may be able to fill.

    Ms. DELAURO. They recently have put out this RFP, and it was to take a look at screening, et cetera. Do you review those applications as well as the DOD?

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    Dr. KLAUSNER. No.


    Ms. DELAURO. I just do not know if we are going—you know, it is hard to say reinventing the wheel. Do not misunderstand me. But I just want to know that we have got a pot of money here and we have one here that, in fact, what we are doing is making the most of the money we have.

    Dr. KLAUSNER. You are right, and we are concerned about that. We all are, the DOD and the NCI are working very well together. They do their own review. NCI individuals often participate in that. They participate in their oversight committees, and we meet with them to basically compare what we are doing versus what they might do.

    Ms. DELAURO. That is great. Thank you.

    Mr. PORTER. Thank you, Ms. DeLauro. We will have a second round. At this point, Bill Natcher would say, ''Now, then, Dr. Klausner.'' I can hear him saying it.


    If you took the statistics regarding incidence for lung cancer out of the overall incidence, what would it then show for all other cancers? Is the incidence going up or down? And if so, by how much?
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    Dr. KLAUSNER. Yes, the incidence is still dropping when you take lung out. Mortality rates then drop even more when you take lung out. And that has been true for some time.

    The other thing, of course, that is different with these statistics is how it affects, as I said, different populations and different ages. So the mortality drop is much more dramatic below the age of 65. It is just flattening and beginning to come down below the age of 65. So there is, again, a lot of details here.

    Mr. PORTER. Well, we seem to know that the lung cancer statistics come from lesser use of tobacco. If we took lung out, though, the incidence rates for other cancers we really do not know why. Is that correct?

    Dr. KLAUSNER. That is right. We have ideas, but we do not know for sure.

    Mr. PORTER. What are, again, the ideas regarding all the other types?

    Dr. KLAUSNER. Well, prostate, Dr. Varmus mentioned prostate.

    Dr. VARMUS. Well, by way of talking about the incidence rates and what that might mean.

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    Dr. KLAUSNER. Yes, that is an example. Prostate is a good example of the complexity of these numbers. Prostate cancer incidence has been going up over decades, but then in the mid to late 1980s, they started shooting up. And this was not a real increase in the incidence. What was happening, it was the introduction of a new test, PSA, that led to the increase of diagnosis of cases that would have probably been diagnosed the following year or 3 years or even 5 years—we do not know—or maybe never have been diagnosed.

    Now what is happening is, as PSA use is saturated, we are seeing, quote, the incidence rate dropping, but really what is happening is the real incidence rate is not dropping. What we have done is we have found what we call all the prevalent detectable cancers, and now we are getting presumably back to either the incidence rate that we saw before, or it may drop below. We will have to see. We are not sure.

    As I said, colorectal cancer, where the incidence is dropping quite significantly, especially among white women, we are not sure what that is.


    Mr. PORTER. Okay. Let me get some free medical advice here. If you had been a smoker but stopped 30 years ago, would there still be residual effects in your lungs?

    Dr. KLAUSNER. Yes.

    Mr. PORTER. In other words, how long does it take to clear, or is there such a thing?
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    Dr. KLAUSNER. Well, we are not sure if the lungs, especially at a detailed molecular level, ever entirely go back. We are just not sure. We do know that the risk of lung cancer does fall gradually, and it certainly is down very significantly by 20 to 30 years.

    Interestingly, for other cancers that are associated with smoking, such as esophageal and colorectal cancer, it looks like there is very little significant drop in the persistent risk over decades. That is very surprising. We are not sure why that is.

    Mr. PORTER. So your risk in those areas is raised permanently, it looks like, from having smoked?

    Dr. KLAUSNER. At least from recent studies over 30 years.


    Mr. PORTER. We talked earlier—and I believe that you were present then—about the President's emphasis on cancer, his initiative on cancer mentioned in his State of the Union address. My recollection is that Dr. Varmus said that this is not putting cancer ahead of other diseases politically. It is simply an emphasis on one of the increases in NIH's budget. Do you see it exactly the same way or do you see it differently?

    Dr. KLAUSNER. I see it exactly the same way as Dr. Varmus does.

    Mr. PORTER. Maybe I should have asked this question when Dr. Varmus was not here. [Laughter.]
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    Dr. VARMUS. Dr. Varmus is always here.

    Dr. KLAUSNER. For exactly that reason.


    Mr. PORTER. You are now spending about $2.5 billion in the Cancer Institute. That is more than the budget of many countries in this world. We are talking now about doubling the research expenditure over a 5-year period.

    If we were able to do that, 6 years or 7 years from now you would be dealing with a $5 billion budget. And this follows on the question that was asked in reference to, I think, breast cancer. Can you really reasonably handle that amount of money and get good results from it?

    Dr. KLAUSNER. I believe that we can, and I believe that we can handle it well. I actually think, if I can elaborate on that, there are four ways that we would deal with that.

    First of all, we know cancer is a complicated puzzle, but I actually believe we know what we need to do to push us much further to knowing what the puzzle looks like. I do not know how long it would take to finish, and I do not know what we will find. But we really do know what to do. That is coupled with something quite extraordinary. I think for really the first time in history not only do we know that, but we have the technology to actually do it, and do it in a way that is much faster, more efficient, and more complete than was ever imaginable, even a few years ago. So we need to do that so that we can actually really get answers to the nature of cancer, to how it develops, and new answers to what causes it. That is one thing. I think we can do that. I think we have laid out the types of investment—and they are significant—that we can very productively spend in order to achieve that.
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    The second thing is all of that information is going to have to be coupled, as Mrs. Northup asked, to the development of successful interventions, and so I think we need a significant new investment in new types of chemistry, chemistry that is built on biology, the new immunology, et cetera, to bring in those areas and target them to the molecular opportunities for prevention and treatment that we are going to have. And I think we have begun that, but we have begun it on a very small scale. It is the type of thing that is very scalable and, in fact, can utilize well a fair number of resources.


    But all of that then leads to a real significant demand on our clinical research system. We are going to need a much better, much larger, much more rapidly responsive clinical trials system than we have now in order to answer the types of questions we are going to have and to test what we know is going to be a dramatic increase in number of good ideas for interventions, whether it is prevention, for detection, for new diagnosis, and for treatment.

    As I said in the opening, we see just over the last 10 years going from 60 cancer drugs to well over 300. This is actually just going to increase based upon the science. We need to be prepared for it, and we have laid out a plan for expanding that system, which is, again, especially with the changes of the health care system, we are going to need to step in to support our clinical trial system.

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    And then the fourth area, just very quickly, is that we are going to need to make sure that once we have those trials done that we have effective ways to apply what we learn across the entire population, to all of our communities, changing behavior, making sure that not only do we know what to do, but we act on it.

    I think in those four areas, and we have laid out in great detail what we would do, I think we can accommodate such increases and I believe accommodate it well.


    Mr. PORTER. Let me ask one final question. You have raised this, but this is a matter of education for myself and for the subcommittee.

    Especially in reference, I think, to your Institute, there is a great deal of pressure to find the cure, and questions were asked about the amount of money spent and where we are in the process. But we often talk about NIH being primarily a basic research institution and that the concepts developed through NIH research are then applied in private industry. Can you describe the nature of this process as it applies to the Cancer Institute? What interface is there, if any, with private industry in these matters? How far do you go in developing the drugs that may be used after you find the mechanism? Is this typical of all our Institutes? Can you kind of give us an education on that? Maybe Dr. Varmus would want to comment on this.

    Dr. KLAUSNER. The NIH and the NCI is a research institution. Is it uniquely what we might call a basic research institution? No. It does clinical research. It does population-based behavior, epidemiologic research, as well as—often, basic research often means cellular or molecular research. It is all those things, but it is research.
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    Now, the NCI certainly for a very long time—and this will continue—is involved with the interface. That interface is getting much more extensive. It is an interface with industry at the level of basic research in terms of genomics and genomic technology, in terms of detection and detection technology, et cetera. It is an interface at the level of drug development. We have long had our own process, as academia does, of discovering agents, of developing them.

    We actually believe that the changes in research, in scientific research, even basic research in the types of laboratories that Dr. Varmus and I are from, are laboratories that can now discover potential drugs. They may be gene products. They may be actual small molecules.

    I think this is going to be a real change and increase the range of interface between basic research, between research laboratories and industry.


    We will continue to be involved in drug development. This program we call RAID is a program that will allow us to provide to researchers, wherever they are, when they have new ideas for a new antibody, a new vaccine, a new small molecule, access to any of the steps of development that they cannot access themselves through their interaction with either small or large industry, but our hope certainly is—it is not to compete with industry, just the opposite, to create more attractive possibilities for industry to then come in, work with us, and develop things.
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    In fact, I believe there are 70-some-odd drugs that the FDA has approved for cancer. All of them have been essentially involved with industry. But the NCI has held the IND for over 50 of those 73.

    Mr. PORTER. For the record, could you also describe whether—and I assume the answer is no—you are picking winners in the competition out there for treatments or other ways of addressing cancer? In other words, are you able to determine by whom you work with what company benefits as opposed to another and how you control this mechanism if it is a factor at all?

    Mr. STOKES, I was planning on calling on Ms. Pelosi next unless you have a need to be at another hearing.

    Ms. PELOSI. Please, call on Mr. Stokes.

    Mr. PORTER. All right. Mr. Stokes.

    Mr. STOKES. I am in hearings next door, and I just had a few questions and go right back to where I am the ranking member over there. I appreciate your accommodation very much, Ms. Pelosi.

    Ms. PELOSI. My pleasure.

    Mr. STOKES. Dr. Klausner, nice to see you. Always a pleasure.
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    Dr. KLAUSNER. Good to see you.


    Mr. STOKES. Doctor, over the years, you and I have had some discussions regarding the disparity in minority health and, in particular, the disparate situation as it relates to minorities as it relates to cancer.

    Is the situation still the same? Or do we note any changes taking place?

    Dr. KLAUSNER. Well, before I answer, may I just add to what Dr. Varmus said at the beginning of these hearings, how much we appreciate the consciousness that you have raised in all of us and how much we will miss interacting with you that way.

    Mr. STOKES. Thank you very much.

    Dr. KLAUSNER. The disparity in terms of cancer burden, first of all, overwhelmingly is disparity not between all minority communities, but in this case very much in the African American community. Overall cancer burden in Hispanics and Asian Americans, Native American men overall is lower than in the majority community. We need to learn from that.

    However, in the African American community, we are and have been very concerned and are very disturbed about the disparate burden of cancer, both for incidence and mortality.
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    Once again, as with anything in cancer, it varies from cancer to cancer. It is not all cancers. There are some cancers where mortality rates are lower among the African American community. But, unfortunately, for many cancers and some of the most common, incidence rates are high and mortality rates are way too high.


    Are we making progress? In the overall statistics, the group in whom the percentage fall in overall mortality is highest is in black men. So in our statistics this year, there is about a 1.4 percent per year drop in mortality among black men. The next group is white men, which is about 0.9 percent. We hope, if that continues, that can eventually reduce what is a significant gap between mortality rates in African American men in particular and majority men.

    What is really very important is that we look at each of these cancers, that we have good statistics so that we can begin to understand the whys, and for you to know that we are committed to having those numbers and then to acting on them to try to understand why they are different.


    Maybe I can use one cancer as an example. Breast cancer rates, mortality rates are about 20 percent higher overall for African American women than for Caucasian women. That disparity is even higher for younger women.

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    Why is that? First of all, mortality rates are falling for all white women under the age of 80. Actually, mortality rates are either flat or falling now for all black women under the age of 70, but above 70 and above 80, it continues to rise.

    What is the explanation? Well, it is correlated with two facts. One, the percentage of women diagnosed with breast cancer at later stages remains higher for African American women than for white women; 51 percent of white women are diagnosed with localized disease versus only 35 percent of black women. For distant disease, about 22 percent of black women diagnosed with distant disease versus only about 11 percent for white women.

    In addition to that, even within every stage, the tumors tend to be more aggressive and the outcome tends to be poorer. So why is this?


    Well, we certainly are concerned that the use of screening, the use of early detection is not as high, and historically that has been true, and that could certainly in part explain the difference in the stage of diagnosis.

    However, by 1992, our numbers show that for the first time African American women are using mammographic screening at the same rate as white women.

    Now, we do not expect to see the benefit of mortality for that for 7 or 8 years. That is what the studies have shown. Once you reach 60 percent, which we are over that we believe now, of mammographic screening, you should see that. So we should see the effective screening in the African American community now begin to fall.
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    There had been disparities in the delay between symptoms and diagnosis, and in terms of the aggressiveness of treatment for African American women and white women. Our latest data suggests that those differences are being reduced. We will be following that carefully.


    The final thing is that the biologic characteristics may be different. Now, what does that mean? Does that mean that it is genetic differences? I suspect not, although there may be some of those, and let me just point out one issue.

    We know that obesity is associated with later diagnosis, with poorer outcome at any stage, and with a greater risk of recurrence. And we know that there is a significantly different rate of being overweight or obese among the African American community women than men. Quite a significant—52 percent versus 34 percent. We have several studies specifically aimed at understanding dietary patterns and attempting to produce educational materials aimed at the individuals, schools, workplace, and the community to deal with this issue.

    I do not know if it is obesity, but that is one example where there may be a biologic difference that relates to cultural differences in behavior such as diet. So that just gives you a flavor of how we are analyzing it and what we are doing.

    We do know, for example—and I will just finish—that when black women and white women with breast cancer are in the same clinical trial and we look for a particular stage and characteristic of their tumors, when they receive the same treatment, they do equally well. We know that from NCI clinical trials. That is very important. What we need is to figure out why the tumors are being diagnosed at a later stage and why they appear to be larger or more aggressive even within stage.
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    Mr. STOKES. Very interesting data. How about prostate cancer? When you last testified here, I think you told us that African American men have the highest rate of prostate cancer in the world.

    Dr. KLAUSNER. They do.

    Mr. STOKES. And is that still the prevalent situation?

    Dr. KLAUSNER. That is still the case. Prostate cancer incidence rates, because of the PSA phenomenon, is now dropping in African American men as fast as it had been dropping in whites, although the drop is delayed by about 2 years.

    There are real changes going on in prostate cancer. Actually, probably the most dramatic changes we see in cancer in terms of these numbers are in prostate cancer. One of the most significant things is over the last 3 to 4 years there has been a 50 to 60 percent drop in the diagnosis and the detection of distant disease—not percentage but absolute numbers. And that drop is the same—and this is one example we are finally seeing it the same in both the African American and the majority community. We are very anxiously watching those numbers to see if they, as we hope they will, translate over the next few years to a significant drop in mortality. But that is a very dramatic drop, 50 to 60 percent of distance disease. But this is an example where we are seeing it in both.

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    One of the things is that there is still a disparity between the nature of treatment in the African American community and the white community. We are working very hard to understand that through, for example, the prostate cancer outcome study. We are working with black organizations and a variety of organizations to get the word out both to physicians and to individuals about treatment options to make sure that everyone is being treated optimally.


    Underneath all this, I must say, however, is an issue not of race but of poverty. Poverty rates are significantly higher among the African American community, and issues that relate to access to care and quality care that relate to poverty is not something we are going to solve by our studies, and this is something we need to continue to talk about.

    Mr. STOKES. My time has expired, but I just want to take a moment and thank you for your excellent response to my questions. I wish I could stay longer and pose some more questions, but you have been very helpful and I will submit the balance of my questions for the record. Ms. Pelosi, thank you very much for your accommodation, also.

    Thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Mr. Stokes.

    Ms. Pelosi.

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    Ms. PELOSI. Thank you. I thank Mr. Stokes for his questions because they are questions that we are all interested in. I was very pleased that in Dr. Varmus' opening remarks those many weeks ago he said that one of the priorities was to reduce the discrepancy in health status between different segments of society, and that would apply in incidence of disease but also in access to quality health care, which, as you mentioned, is not something we will solve here. But whatever the NIH is doing on that, I know they are doing more because of you, Mr. Stokes. So thank you.

    Mr. STOKES. Thank you.

    Ms. PELOSI. We will have more time to praise and be sad about Mr. Stokes' leaving us, but every chance I get, I like to thank him for his leadership.

    Mr. STOKES. Thank you very much. You are very kind. I appreciate that.

    Ms. PELOSI. Now, see, I do not have to ask my question about the incidence of breast cancer in African American women.

    When we started a couple of weeks ago, our chairman said we did not have as much time as we would all have liked with Dr. Varmus because we would have at him along the way. And I guess along the way is sort of coming to an end. I may not even be here Friday afternoon, so I have a couple questions for Dr. Klausner and a couple for Dr. Varmus. And, of course, each of them is welcome to weigh in on the other.
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    Dr. Klausner, just quickly, you mentioned to Mr. Hoyer that $30,000,000,000 had been spent on breast cancer research.

    Dr. KLAUSNER. No. That is the total——

    Ms. PELOSI. What does that include?

    Dr. KLAUSNER. That is the total dollars spent, and it is not a precise number but approximately $36 billion.

    Ms. PELOSI. But what does it capture? What is happening that the Federal Government has spent?

    Dr. KLAUSNER. Yes. That is the research budget for cancer research to——

    Dr. VARMUS. Real dollars.

    Dr. KLAUSNER. In real dollars, that is right, to the NIH over the years in cancer research. It is somewhat over $36,000,000,000.

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    Ms. PELOSI. Thank you. And while we are on the budget, I wanted to ask a budget question. Dr. Klausner, the FDA reform legislation provides for a consumer-friendly, one-stop shopping database of clinical trials for all life-threatening diseases. How much money would it take to establish the cancer section of the database and how quickly will the information be available to cancer patients? Is this funding in this 1999 budget?

    Dr. KLAUSNER. Well, of course, we actually feel that we have at least the basis of an accessible database about clinical trials. It is called PDQ. We are in the process of a redesign of PDQ. We had a meeting, a three-day meeting, I believe it was, in February where we invited all the institutes—and Dr. Varmus helped sponsor that—to actually look at just this issue, to build on the relatively long tradition now that we have of developing accessible databases. We brought in people from many different fields, cancer researchers, advocates—in fact, it was cosponsored and co-run by a breast cancer advocate—in order to define first what are the parameters that we want in a clinical trials database that would be accessible and useful and understandable to all the users.

    We are now getting the recommendations through the steering committee from that. We should have that over the next few weeks. And our plan is to undergo, one, a PDQ redesign that would be much more user-friendly, that would be available to a much larger array of clinical trials, including industry clinical trials. We have already worked out some through negotiations with industry, with the pharmaceutical industry and the FDA about simpler ways to put in industry information of clinical trials into this database. And we will be working through Dr. Varmus' office with all of the institutes to provide this infomatics system available through both telephone, through the Internet, the Web, faxes, et cetera, for this type of database.
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    I do not know yet what it will cost. The reality is, as I think you know, with databases it could probably cost almost anything, depending upon what you put in, what you demand of it. We are going to have to look at what the community told us they are looking for and they need, figure out what is technologically and resource possible, and then we will be working on designing that system. But we are committed to moving into a redesign that will make such an access point available.

    Ms. PELOSI. So in a few weeks, you will have the recommendations.

    Dr. KLAUSNER. From the steering committee, yes.

    Ms. PELOSI. From that point you will establish your priorities.

    Dr. KLAUSNER. Yes.


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

    Ms. PELOSI. Thank you. Dr. Varmus, if I may—forgive me, Dr. Klausner, for a moment—I have another question.

    Dr. VARMUS. He is enjoying it.


    Ms. PELOSI. As you know, Dr. Varmus, last year the NIH convened a panel of individuals to review the scientific research to tell us about the prevention of HIV, and one of the issues they addressed is the question of whether needle exchange programs promote drug use. The panel concluded a preponderance of evidence shows either no change or decreased drug use. In addition, the panel found that individuals in the areas with needle exchange programs have an increased the likelihood of entering drug treatment programs.

    As you know, in our legislation last year, we established some criteria that a needle exchange program should reduce the spread of HIV–AIDS and draw people into a drug treatment program.

    Last year you gave us your opinion about the efficacy of a needle exchange program. Would you like to——
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    Dr. VARMUS. Well, my opinion has not changed. As you know, the Secretary will be in a position to make a determination about whether or not we have met the criteria—which, as you know, apply differently to CDC and NIH as opposed to SAMSHA with regard to needle exchange program support. The criteria that need to be met for NIH and CDC is that these programs—have health benefits that decrease the spread of infection, and that they do not increase the use of drugs.

    From our review of the literature through the conference that you mention, we believe those criteria can be met.

    Ms. PELOSI. Thank you, Doctor.

    I know that the OAR was supposed to be here yesterday, but that hearing date was changed.

    Did the bell go off? I did not hear it. No? Okay. I was so engrossed.


    Dr. VARMUS. The OAR discussion will be on Friday.

    Ms. PELOSI. Yes. I would like to know if we have talked before about the Levine Commission—or do we call it the ''Levine'' Commission?—the Levine Commission report.
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    Dr. VARMUS. He calls it the ''Levine'' Commission.

    Ms. PELOSI. Well, that is what we call it, then, the Levine Commission.

    Can you tell us what the success has been of the Office of AIDS Research and the success you have had in following through on the Levine Commission Report?

    Dr. VARMUS. Yes. I think we did have a brief discussion of this somewhere along the line—perhaps you were not in the room, Ms. Pelosi—about the 14 recommendations the Levine Committee report made.

    Ms. PELOSI. Well, I did, but I wanted you to be more specific about the Office of AIDS Research.

    Dr. VARMUS. Right. We believe that the OAR is carrying out its function in a very admirable way. As you know, Dr. Paul has left the OAR to return full time to his laboratory. Dr. Jack Whitescarver has been overseeing the office very effectively. He will be here to testify on Friday, and we are in the final phases of a search for a new director. I hope to be able to deliver the name of a new director sometime in the next month.

    The office continues to carry out its major mandates, which is to coordinate and oversee AIDS research across all the Institutes, to help in budget formulation, to do program planning with the Institutes.
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    Ms. PELOSI. How do they plan their budget working with the other Institutes?

    Dr. VARMUS. First of all, there is a very extensive planning process that the OAR coordinates itself. That is a very important aspect of this. They have identified five broad areas of research activity that are addressed by working groups that come from both the extramural research community and from the NIH staff. Those groups develop a series of initiatives and work with the Institute directors to develop a research plan appropriate for each Institute.

    The budget for the AIDS effort across the NIH is developed through conversations between the OAR director and the director of each Institute. As you know, each Institute has an AIDS budget, and that process has been working extremely well.

    Through a few conversations with Mr. Porter and others, we have developed the means to award the money for AIDS research to the Institutes in a way that is acceptable to everybody.


    I think you have seen, especially when Dr. Fauci was here, that we have made some extremely dramatic progress in countering the transmission of HIV from mother to child and in reducing mortality from AIDS. We have reduced transmission between adults in some groups and not others. There are some tremendous challenges ahead as a result of the increase in HIV transmission in certain groups in our population and as a result of the rampant spread of HIV abroad, especially in Asia and Africa. Although we have hand in hand with industry produced drugs for the treatment of AIDS, we still are encountering very significant failure rates, and we think that many more drugs are going to be required if we are going to very effectively treat HIV infections.
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    We need a vaccine. We have many initiatives, as you know, that are being coordinated by the OAR to develop a much more effective vaccine research program, both within the NIH and through our innovation awards in the extramural community. The OAR plays a very, very significant role in developing and coordinating those programs.

    Ms. PELOSI. Well, I appreciate your laying out the challenge as you answered the question, the challenge that remains.

    My time now really has expired. Dr. Klausner, I am going to have to submit for the record my question on vinyl chloride vapors, which I will do.

    Once again, Mr. Chairman, I wanted to thank Dr. Varmus and Dr. Klausner today and all the others for this dazzling presentation of the last several weeks. I think we are very blessed on this committee to have the benefit of this testimony.

    Thank you for your leadership, Dr. Varmus, for attracting all of these great people to the NIH. Thank you for what you do.

    Mr. Chairman, I will submit my questions for the record and yield back the balance of my time.

    Mr. PORTER. We certainly are blessed. We have not asked Dr. Varmus yet, but I wonder whether we would benefit by having the Nobel Laureates come up after we finish our regular hearing schedule, say, in mid-May.
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    Ms. PELOSI. I think that is an excellent idea. We have benefitted in the past when we have brought them here.

    Mr. PORTER. Yes.

    Ms. PELOSI. It is a wonderful day.

    Mr. PORTER. It is the highlight of our hearing year. We are considering that right now.

    Ms. PELOSI. With stiff competition, mind you.

    Mr. PORTER. Dr. Klausner, let me thank you on behalf of the subcommittee. We not only appreciate your statement and your answering all our questions, but we will have additional ones for the record.

    You give us great confidence that with someone of your intellect, energy, and your enthusiasm for your work that we really will have breakthroughs and some day soon have control over this terrible disease that you cope with every day. So thank you very much for all that you do there and for the fine job you do for our country.

    Dr. KLAUSNER. Thank you, Mr. Porter.

    Mr. PORTER. The subcommittee will stand in recess until 2:00 p.m.
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    [The following questions were submitted to be answered for the record:]
    "The Official Committee record contains additional material here."

Wednesday, March 18, 1998.









    Mr. PORTER. The subcommittee will come to order.

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

    Dr. KUPFER. Thank you, Mr. Chairman.

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

Opening Statement

    Mr. Chairman, as in each year, we are continuing to be involved in many, many different areas of problems of the visual system, I'd like to highlight some of the more immediate developments that have taken place since last we met.

    The first area has to do with how well the interaction between the NIH and the private sector operates. Two new drugs were developed in the last year or two, both of which were supported initially by NIH funding through the National Eye Institute, for, in one case, 10 years and in another case, 15 years. Once the basic science was done, these two drugs were taken up by the pharmaceutical industries. We have two new drugs for the treatment of glaucoma—one called lantanoprost, which has the trade name, Xalatan and the other dorzolamide, which is known as Trusopt.

    These two new drugs have further made it possible to bring high levels of intraocular pressure under control and to ameliorate the progress of glaucoma, especially in those areas of the population at high risk for glaucoma.
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    A second area that has recently developed in a very interesting way has been the first breakthrough in trying to understand the genetic basis for diseases of the macula. We've talked many, many times about age-related macular degeneration, but there are a number of macular degenerations that occur in very young people. One of them is called Stargardt's macular degeneration.

    A group of cancer researchers were looking for genes that control the entry of molecules into cells to see how they can overcome the resistance that cancer cells sometimes develop to therapy. In doing this, they came across a family of genes, and looking through the genes that had already been identified, came across a gene that had been expressed only in the retina.

    To make a long story short, they quickly identified that this gene is present in almost all the cases Stargardt's macular degeneration.

    What has been particularly exciting has been the fact that in about 16 percent of patients with the age-related macular degeneration, which as you know is reaching epidemic proportions in our country, this gene also appears to manifest itself.

    We were very fortunate when this relationship became known that Dr. Varmus, dipping into his director's discretionary fund, gave us some additional funds to immediately jumpstart a collaboration between the Cancer Institute and the Eye Institute. We are now trying to confirm these findings in a very large population of age-related macular degeneration patients that we have in our clinical trial, the Age-Related Eye Diseases Study.
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    That was a very interesting example where cancer researchers were looking for a way to improve the treatment of cancer and came upon a gene that had implications in a serious eye disease.

    There is another reverse example which I think is particularly interesting also. That is, we had a vision researcher who was looking for small molecules that were under genetic control to regulate the growth of nerve fibers and nerve cells in the central nervous system in an effort to learn more about regenerative possibilities.

    In the course of doing this, it was found that this gene also affected the growth of cancer cells in the brain, so-called gliomas. Again, it turned out that when this gene was producing quite a bit of protein, these gliomas were able to grow very, very rapidly and if the glioma did not have this gene producing this stimulus, then the glioma would not grow very rapidly and would be more like secondary metastases.

    Again, here is a project that begins as a vision research project and ends having some very important implications in cancer.

    The area of diabetes research is moving very, very rapidly. Underlying the complications of diabetes in the eye is the proliferation of new vessels and there are now a host of inhibitors that are being developed, primarily by private industry, pharmaceutical companies, that inhibit the growth factors that stimulate the growth of new vessels.

    These are now being tested extensively in animal models and will soon begin in clinical trials. In fact, we're going to begin a clinical trial probably within the next three or four months looking at one of these inhibitors.
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    The area of myopia is moving very, very rapidly. Much of the animal work has pointed to environmental factors as having a major role and we're now beginning to try to apply those environmental factors in clinical trials.

    We have three clinical trials ongoing, trying to slow down the progression of myopia in children who are just beginning to develop near-sightedness.

    The retinal degenerations offer another challenge and there are a whole host of small molecules called neurotrophins that seem to be able to support degenerating cells so that they degenerate much more slowly or not at all, or allow regeneration to take the place of degenerating cells.

    Again, this entire group is in animal model experimentation and I think within the next two or three years, we'll be having clinical trials.

    Finally, the National Eye Health Education Program, in addition to its work in glaucoma education and diabetes education, has now entered the field of education in low vision in an effort to address that large segment of the population for which treatment has not been beneficial and who have lost vision and still want to maintain a high quality of life.

    Perhaps I'll stop at this point and be happy to answer any questions.

    [The prepared statement follows:]
    "The Official Committee record contains additional material here."
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    Mr. PORTER. Thank you, Dr. Kupfer.

    Often we read in the media of advances in certain areas and want you to give us the insights as to what the real facts are. Most recently, we read about the professional golfer, Tom Kite, having a laser surgery of some type on his eyes. His vision started at 20/100 the press said, and after surgery, is now 20/15. The operation cost around $4,600, but has completely changed his myopia from wearing ''coke bottle'' glasses to wearing no glasses at all after 40 years of struggling with poor eyesight.

    Can you tell us what this surgery was and is it applicable, without looking at the cost, to broad populations who suffer from simple myopia? Do you expect this to become a procedure of choice in the future?

    Dr. KUPFER. Mr. Chairman, I'm not familiar with the specific example but from what you said, I imagine he has had a laser treatment to reshape his cornea so that he would not have to wear thick glasses, which probably are correcting nearsightedness, and can perform hopefully better on the golf links.

    As I mentioned, we are very much interested in myopia. Our approach to myopia is to try to understand what the basis for the elongation of the eye is, which is really the major phenomenon and to prevent this elongation. We do know that signals from the retina go to the white coat of the eye and cause that coat to stretch. The signals are triggered by the fact that the image that a child is looking at is not in good focus on the retina.
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    We have the system to study myopia and we are now very aggressively going after looking at the sequence of signals between the retina and the white of the eye, the so-called sclera, to see what causes this elongation.

    What is happening in the community, of course, is that there are ways of reshaping the curvature of the cornea and if one makes the cornea less steep, flatter, then the nearsighted eye will be able to focus objects right on the retina. It will no longer be nearsighted because the cornea will not be able to refract the light as much if it can be flattened.

    If you remember, we talked about radial keratotomy which was a technique introduced about 15 years ago to flatten the cornea by making incisions in the cornea. This has now given way to what is called excimer laser treatment, which is a special laser that can peel off layer by layer of the cornea until you have the right shape.

    In the case of radial keratotomy, a group of ophthalmologists and health care professionals came to the Eye Institute and said, we don't know if this is safe and effective, let's do a clinical trial, which we did. We had ten-year data on what the results were, so a patient coming in wanting radial keratotomy could be told pretty much what they could expect in terms of results.

    We don't have that degree of information on the excimer laser, so it is very difficult to predict precisely what is going to happen. It has become very popular, it's very highly advertised. I would say thousands of people are going to be having this done every year and eventually, we will learn how beneficial it is in the long run.
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    I think it would have been very nice if we had better clinical data to be able to advise patients as to whether they should seek this treatment or not.

    Mr. PORTER. Was this treatment developed through research or is this laser treatment simply a different way of doing the same thing—another way to flatten the cornea?

    Dr. KUPFER. Yes, it really came from development of a new type of laser, the so-called excimer laser where literally you could take off the cornea several microns at a time.

    Mr. PORTER. Am I correct that there is some risk with this procedure, where you could make a mistake as to how much you took off?

    Dr. KUPFER. Yes. We know there are some side effects. We don't know what will happen after many years. There is scarring, there is haze, there are problems with glare at night when one drives. We really haven't a good handle on this.

    Mr. PORTER. Is any research underway in this area so you can follow people who have been operated on?

    Dr. KUPFER. We have supported animal work in trying to improve the healing of the cornea after the surgery is done, but our National Advisory Eye Council, and I think wisely, said unless there is going to be a clinical trial that will really look at this critically, we, the National Eye Institute, should not be involved in supporting any of the clinical studies unless they are done very, very well, and that did not come about.
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    Mr. PORTER. Is there evidence that myopia is genetically based? In other words, if a parent has it, is it likely that a child also has it?

    Dr. KUPFER. There certainly is evidence that there's a genetic component. As a matter of fact, we're going to begin several genetic studies of myopia looking at populations that have a very, very high prevalence and incidence of myopia versus those that do not, and then comparing what the potential risk factors may be that separate these two groups.

    On the other hand, there is also strong evidence that perhaps if we could control the environmental factors, this defocusing of the image, that we could provide some interim treatment and that's what we're doing. We're moving on both the epidemiological side and the clinical trials.

    Mr. PORTER. Is there any possibility that the muscles of the eyes can have anything to do with elongating the eyeball and putting the image out of focus?

    Dr. KUPFER. Yes. As a matter of fact, when one looks very close at an object, the muscles inside the eye, the ciliary muscle, must contract to allow the focus to be on the retina. If that muscle doesn't do it precisely, the image will not be focused on the retina. So there is an involvement of the muscle in the eye, not the muscles that move the eyes externally.

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    Mr. PORTER. To get input from the public, you posed two questions on the NEI home page requesting respondents to identify the most significant accomplishments or advances in vision research over the last five years and the most important vision research questions that should be addressed during the next five years. How many responded to this request and what were the consensus answers? Do you know?

    Dr. KUPFER. Dr. McLaughlin, who was in charge of that, says there were several hundred responses over the period of time that this appeared on the Web.

    Mr. PORTER. Was there a consensus as to what they were and what they should be?

    Dr. MCLAUGHLIN. I would say, first off, the responses were gathered as input to the expert panels which we then convened. I would say that most of the responses, as you might imagine, of course some of them were self-serving kinds of things—I'm doing research in x area, the area I know best—but I think in general, the program staff at the Institute and the people involved on the panels thought it was a very worthwhile exercise and something we might expand in the next go around.


    Mr. PORTER. Dr. Kupfer, there was a study published in the Journal of the American Medical Association last March which concluded that older persons may be at higher risk of developing glaucoma if they take high doses of asthma inhalants that contain steroids for months at a time.
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    There was some concern that this particular study was flawed and that more research was needed to confirm the link between glaucoma and steroids and inhalants.

    Then four months later, the results of a different study, also conducted on older people, was published which found that using asthma inhalants doubled the risk of one developing cataracts. Are you familiar with both of these studies and are there any followup studies being conducted?

    Dr. KUPFER. Yes, sir, I'm very familiar with both studies. These studies were a form of study called a case control, where one takes cases and compares them with controls. In both of the studies, people with and without cataracts were identified and then they were asked in questionnaires whether they took inhalants with steroids, how often, and that sort of thing.

    These sorts of studies are very important to do because they raise questions, as these two studies do, but they cannot do more than suggest an association, not a cause and effect. I think amongst the people who are in the glaucoma field, the jury is still out on whether this is a serious concern upon the part of patients with glaucoma using these inhalants.

    I think what probably is going to be done is a third study that will be constructed specifically to answer this question. The first two studies really weren't specifically looking at this but a whole host of risk factors. So I think if we design a study that will specifically look at this, we could perhaps get a better answer.
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    Mr. PORTER. Thank you, Dr. Kupfer.

    Ms. Lowey.


    Ms. LOWEY. Thank you, Mr. Chairman, and thank you, Dr. Kupfer.

    If I may follow up on the question of our Chairman because I'm puzzled and I, as many of us, have been hearing about the benefits of the surgery.

    You said the NIH is not doing a clinical study. I'm puzzled because there are thousands of these occurring, I believe you said. What assurance do we have that they are performed in the best professional manner?

    Dr. KUPFER. Ms. Lowey, the development of these lasers, and there are basically two companies, came about strictly on the basis of a small number of lasers being made available and ophthalmologists beginning to use them to learn more about how well they function.

    The FDA tried to bring into some working order a clinical trial but at the time, which now goes back seven or eight years ago, devices did not have to undergo clinical trials to be accepted by the FDA as opposed to drugs which did. Now devices are being brought under the umbrella of clinical trials.
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    So we were confronted with a situation where no one else wanted to do a clinical trial. We can't do a clinical trial unless there are people who are anxious to do this and to then study very, very carefully and follow up the patients, as we did with the radial keratotomy study. Unless we can do these trials, the free market is going to operate and individuals wanting this surgery will be able to seek it out.

    I would say that more than 90 percent of the insurance companies do not reimburse this procedure. It's considered cosmetic and I wish we would have been approached by a group of investigators saying we really should mount a clinical trial.

    We cannot really play a role when the companies themselves fund these trials. They are done in a way where they may or may not give us a good, clean answer and therefore, we're left not being able to say to a patient whether they are a good candidate or not for this particular procedure and what the long-term complications may be.

    Ms. LOWEY. Obviously, I'm puzzled by the response because I would think that we're almost caught up with the current laws that exist, but don't we have a responsibility in protecting the public and to what extent would this be the responsibility of NIH because it concerns the health of the eye or the FDA which may have responsibility for the devices? Maybe I'm not asking the right question, but I'm very puzzled.

    For example, my ophthalmologist, a very respected ophthalmologist, discussed it with me and I said, are you kidding, what are the risks, what are the studies? Forget it, I'll wear my contacts and my glasses.
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    Dr. KUPFER. You're absolutely right and there are individuals who approach it that way. There are others who say, I will do anything, anything to be able to get rid of my glasses. This is a personal preference sort of thing. I don't see any role that the Federal Government can play through NIH in trying to restrict this.

    There are many, many procedures out there in the medical world that have never been tested that are being done every day and it's a personal preference on the part of the public as to whether they wish to have this performed. I would love to be able to give them answers. With the radial keratotomy, we did it the right way.

    Ms. LOWEY. I just want to say that I share the concern of my Chairman. Should FDA have a greater responsibility? It seems to me that if thousands and thousands of these procedures are being done, some place in our government, if it's not the NIH, there should be some responsibility for validating either the justification for it or recommending that it's not justified.

    I would think there are enough ophthalmologists that would want, forgetting the two manufacturers of the product, to see some clinical trials done. Maybe I'm missing something.

    Dr. KUPFER. No, you're not missing anything, Ms. Lowey. It's just that once the horse is out of the barn, it's very hard to say let's back off and do a clinical trial on a procedure which, as I said, is probably being done on several thousands of people or more. That's the facts of the real world, I guess one would have to say.
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    Mr. PORTER. Would the gentlelady yield?

    Ms. LOWEY. Yes.


    Mr. PORTER. I don't think we need to do a clinical trial, what we need to do is a followup on those people who had the procedure to see what problems there have been. Wouldn't that be sufficient?

    Dr. KUPFER. Yes, and FDA is doing that.

    Mr. PORTER. They're doing that?

    Dr. KUPFER. Yes. This is post-approval surveillance and they are doing that. It will take some time before we see.

    Mr. PORTER. So there's no sense in doing a clinical trial after the fact?

    Dr. KUPFER. No. It should have been done seven years ago at the beginning.

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


    Ms. LOWEY. Thank you and I hope we can follow up with you on this since I know there is interest.

    Another area that I've been concerned about is the number of cataract operations that have been performed. If you go down to Florida, where members of my family reside, they are done by the tens of thousands. Can you update us on the status of surgical techniques to treat patients with cataracts? Ten years ago when laser surgery became available, patients could be treated for cataracts in a doctor's office and that was thought to be the cutting edge.

    Is the latest treatment an improvement on the original treatment, and again, what kind of consistency is there in the cataract operations that are being performed?
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    Dr. KUPFER. First of all, Ms. Lowey, I can make the statement that cataract is probably one of the most successful operations that's ever been devised. You're quite correct, it's being done as an outpatient procedure, very often done in the morning and the patient goes home in the afternoon. There have been many modifications in the type of artificial lens that is used, in the surgical procedure to reduce the time it takes for the wound to heal and things like that.

    I think that the operation is probably as good as it's going to be developed, unless there is some very, very unusual breakthrough.

    The number of cases being done is increasing, partly because I think that as people are getting into the age where they develop cataracts, they still want to be able to drive, they still want to be able to play golf and tennis, they still want to participate in all the activities and to do this, you need very good vision.

    So 20 or 30 years ago, an individual might not have cataract surgery until their vision was really interfering with their being able to function, but today, the cataract surgery can be done at an earlier time in the development of the cataract so that the individual's vision can be restored.

    Of course in Florida, there are many, many people who are retired and they do want to maintain a very high quality of life, and I think that's what we're seeing.

    Ms. LOWEY. Have there been consistent reports of success with this operation or have you had some other responses?
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    Dr. KUPFER. I think in general the perception is that it's been very successful. The American Academy of Ophthalmology is beginning to look at the results of cataract surgery by ophthalmologists who are willing to turn in the results of their surgery every month and then as the number increases, they will be able to come up with some indications. Perhaps by next year, I'll be able to report to you on that.

    Ms. LOWEY. Thank you.

    Thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Ms. Lowey. Mr. Stokes.


    Mr. STOKES. Thank you, Mr. Chairman.

    Dr. Kupfer, welcome to our subcommittee. It's nice to see you again.

    In your formal testimony under the category ''Age-Related Macular Degeneration,'' I'm struck by a statement that you make when you say, ''As the baby boom generation ages and in the absence of further prevention and treatment advances, the prevalence of AMD is estimated to reach epidemic proportions of 6.3 million Americans by the year 2030.''

    Dr. KUPFER. Yes, sir.
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    Mr. STOKES. That seems to create quite a problem, I would think, for us futuristically and it's something we ought to be thinking very carefully about. I'm sure in your Institute, you are thinking about it?

    Dr. KUPFER. Yes, sir. I would say that this is probably at the top of our priorities in terms of where we're trying to put our research efforts. As I mentioned, we had a very good development in terms of identifying a gene that occurs in a macular degeneration occurring in the first 10 to 20 years of life, Stargardt's macular degeneration, and the gene that is causing that condition apparently has been found in some of the patients with the age-related macular degeneration.

    We are moving very, very rapidly forward with the help of Dr. Varmus, from the funding he has available, to begin to collaborate with the Cancer Institute, where the original work was done, in looking at whether this gene is present in a very well defined population of patients that we have enrolled in clinical trials.

    We are moving very rapidly in the area of the laboratory with a number of animal models. We can begin to see in the two types of macular degeneration, where the one type of cell, the so-called photoreceptor, undergoes degeneration, whether there's some way to slow that down or even after it has begun, to rescue the cells and restore and regenerate these cells.

    This is a very high priority. We're doing genetic studies, population-based studies to see what the genetic basis is. Again, it's probably a multigenetic disease. This is really at the top of our priority list, Mr. Stokes. There is no doubt about that.
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    Mr. STOKES. I note that brain disorders in neuroscience are topics that the National Institutes of Health is emphasizing in its fiscal year 1999 budget. Tell us, what research is NEI doing in this area?

    Dr. KUPFER. There are three areas that we are concerned with and I might say these concerns are also shared by the Neurology Institute, the Mental Health Institute, those institutes that are looking at the brain as we are.

    We're interested in slowing down the degeneration of cells in the brain. In our case, it would be the retina or the different way stations between the retina and the visual parts of the brain. This is done by finding that there are a group of molecules called neurotrophins that can actually slow down the degeneration of these cells. A lot of work is going on in that direction.

    There is work going on in regeneration on two fronts. One, why is the central nervous system not able to regenerate when the peripheral nervous system can regenerate? We want to see why the central nervous system shuts down its capability in terms of not being able to continue to be able to regenerate when the infant is just several weeks or a month or two old.

    There is also research going on what it is that directs nerve fibers to the places they're supposed to go, because if we're ever going to get regeneration, whether in the optic nerve or the spinal cord, we've got to be sure that the nerve fibers go to the right places in the brain.
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    There now have been found small molecules that attract or repel growing nerve fibers and sort of direct them to where they should go. That research is growing very considerably.

    So I think we are moving ahead along with the other Institutes learning more and more about what is involved in the functioning of the central nervous system, farther into rescuing cells undergoing degeneration or maintaining the cells or allowing regeneration of nerve tracts.

    We have a particular problem in ophthalmology because, as you well know, the cells in the retina in glaucoma die and we are very actively involved in trying to understand what the mechanism of that is and to develop neuroprotective drugs that will prevent those cells from dying.


    Mr. STOKES. Dr. Kupfer, over the last several years, you and I have had some discussions about certain eye diseases, visual impairments and so forth that are more prevalent in African Americans than in White Americans. We've talked about diabetes, we've talked about glaucoma and things of that sort.

    Can you give me some type of an update on where we are in terms of that discussion?

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    Dr. KUPFER. There is no doubt now that the National Eye Health Education Program is beginning to have an impact by dissemination of information to African-Americans in terms of having a dilated eye examination after the age of 40 every year by an eye care professional. I think we are seeing that the knowledge is getting out there. We've done some demonstration projects to show that this can work.

    As discussed by Dr. Fauci earlier, the health care system sometimes does not accommodate an individual to have an eye examination every year, so we are trying to work with the health care maintenance organizations and convey to them this is a very important thing.

    It's been done successfully with diabetes. Most HMOs will now build in a dilated eye exam for every diabetic. I think that's been a major step forward. We'd like to be able to do the same thing while they're dilating the eye to look at diabetics, they certainly could do it to look for changes in the optic nerve. I think we're slowly making an impact.

    The diabetes story is a more complicated one and it appears that just informing the diabetic of the need for an eye examination is not enough. There's got to be the entire medical team of the diabetologist, the general physician, the family physician, to keep pushing the individual to see the ophthalmologist, to see the eye care professional to determine whether they are at risk for going blind and should receive laser treatment, which is very effective.

    We are now beginning to change our approach to try to bring these various groups together to present a united front to the patient.

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    Mr. STOKES. Do we know why we have this type of disproportionate disease in the African-American community?

    Dr. KUPFER. I think there are some suggestions that there certainly, probably, is a genetic—in the case of glaucoma, I'm almost certain there's a genetic predisposition. I think that would be my main concern as far as glaucoma is concerned.

    In the case of diabetic eye disease, I think it has more to do with the need for the diabetic to really keep blood sugar under control, to be concerned with diet and be concerned with continual monitoring of the eye complications. This is not an easy thing to do.


    Mr. STOKES. NEI has recently formulated a sixth vision research plan for fiscal years 1999–2003. Can you tell us how this plan, was developed and how do documents like this enhance the Institute's research?

    Dr. KUPFER. Yes, Mr. Stokes. For the last 20 years, the staff of the National Eye Institute has been collaborating with a subcommittee of the National Advisory Eye Council to have five year plans. As you point out, this is our sixth plan.

    We began by putting on the Web the two questions that Mr. Porter mentioned earlier to the research community and to anyone else who wanted to respond, what has been done in the last five years, what successful steps have been taken, and what do you think are the most important questions to answer in the next five years.
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    Following that, we convened seven panels to look at the different areas of research that we are involved in and each panel consisted of a dozen members and each of the members called upon up to 10, 20 or 30 colleagues in the field. So in the development of these priorities for the next five years, there's probably an input of 300 or 400 scientists in the vision research community that entered these ideas.

    This was presented to the Council, trimmed down, targeted so that we really were looking at the most important areas to focus on, especially in terms of where we could match not only the needs but the opportunities to solve those needs. We have many, many needs, but we have to look at opportunities.

    When we had a draft of the plan, we sent it out to all the organizations that were involved in vision research, public-private organizations, some 60 organizations, foundations and asked for their input because they are very important players in this entire field. We incorporated their ideas.

    Finally, just recently in January, the final plan was submitted to the Council, approved and hopefully we will have it published and more important, on the Web probably in the next two or three months.


    Mr. STOKES. How about hypertension? Does that create additional problems in persons who have hypertension?
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    Dr. KUPFER. You mean elevation of blood pressure?

    Mr. STOKES. Yes, sir.

    Dr. KUPFER. Yes. Hypertension, for instance, is an additional risk factor for the development of diabetic retinopathy, diabetic eye disease. That's been very well shown in several studies.

    It does not seem to play a role in glaucoma, although you might think it would but it doesn't. In other words, there is not a close association between high blood pressure and glaucoma.

    There is an interesting association of high blood pressure and high intra-ocular pressure but these people do not go on to get glaucoma, so there are some very interesting phenomena going on there.

    The other aspect is that when the individual has diabetic retinopathy and has high blood pressure, they probably do not respond as well to treatment with the laser as if we could get the blood pressure under control.

    So I think elevated blood pressure of course is a risk factor for many, many diseases and diabetic retinopathy is certainly one of them.

    Mr. STOKES. Thank you, Dr. Kupfer.
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    Thank you, Mr. Chairman.

    Dr. KUPFER. Before I move on, I'd just like to say, Mr. Stokes, I've been coming to these hearings since 1970 and you've been here since 1971, so I really appreciate all the efforts you've put in on behalf of the National Institutes of Health.

    Mr. STOKES. Thank you very much, Dr. Kupfer.


    Mr. PORTER. Dr. Kupfer, thank you for your testimony and answering our questions today. I have to ask you one final question. Both the New York Times and Time Magazine reported in January that as little as one glass of wine a month, red or white, may cut in half the risk of macular degeneration. Is there any truth to this statement?

    Dr. KUPFER. We'd all like to believe so. [Laughter.]

    I don't think the definitive study has been done yet, sir, but I think there is circumstantial evidence to suggest that this would be the case because some of the risk factors in macular degeneration such as elevated cholesterol might be ameliorated by a glass of wine.

    Mr. PORTER. So while the research is going on, maybe a little protective glass of wine will help us all, right?
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    Dr. KUPFER. Exactly. I think we should keep a baseline level.

    Mr. PORTER. Dr. Kupfer, thank you. You've been wonderful at NEI all these years and we very much appreciate your fine testimony, your direct answers to our questions, and the wonderful job that you're doing there.

    Thank you very much.

    Dr. KUPFER. Thank you very much.

    Mr. PORTER. The subcommittee will stand in recess until 10:00 a.m. tomorrow.

    [The following questions were submitted to be answered for the record:]
    "The Official Committee record contains additional material here."

Thursday, March 12, 1998.




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    Mr. PORTER. The subcommittee will come to order.

    We continue our hearings on the National Institutes of Health and are pleased to welcome Dr. Francis Collins, the Director of the National Human Genome Research Institute. Dr. Collins, it's wonderful to see you and if you would introduce the people who are at the table and proceed with your statement, please.

    Dr. COLLINS. Thank you very much, Mr. Chairman.

    At the table we have Mr. Charles Leasure, who is our new Executive Officer. Mr. Leasure has moved over from the NIEHS to us in the last month. We are quite happy and they are quite sad.

    Mr. PORTER. Yes, yesterday he was with them.

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    Dr. COLLINS. One foot in both camps, but rapidly moving in our direction.

    Dr. Elke Jordan, the Deputy Director. Ms. Erin Burgess, who's our Budget Officer. Dr. Varmus, who you've been conversing with for several days already and Mr. Williams, from the Department.

    I want to say how pleased I am that Mrs. Miller is here to listen to the proceedings this morning.


    I appear before you at a particularly interesting time for the Human Genome Project. In its short history, we are now just about at the halfway mark. Two weeks from now, we will hit the halfway point in the 15-year effort to map and sequence all the human DNA.

    I would say there is much to celebrate in the first half of the Human Genome Project. All of the original goals which were set in 1990 and then revised in 1993 have been achieved on or ahead of schedule, despite a budget which has been substantially less than originally predicted.

    Having completed or exceeded the mapping goals which were expected to occupy this first half, we are now turning in a big way to large scale human DNA sequencing. But why does this matter? Many people had assumed that we'd have to wait until 2005 when that sequence is in hand before the information would be of much use to medical research.
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    That has certainly proved not to be the case. Beginning almost immediately after the Human Genome Project started, and now dramatically accelerating, we see a remarkable harvest of gene discoveries, diagnostic abilities, and the beginning emergence of ideas about rational genetic medicine therapies that we have hoped for for many years.

    Probably every institute director who appears before you in these two weeks will talk about advances in genetics which have arisen in some part because of the tools and technologies and resources the Human Genome Project has produced. Every pharmaceutical company now has a genomics division, recognizing the power of this for their future.


    But I want to put a human face on this effort for this morning's hearing and tell you about Thalia. Thalia is 65 years old and is of Greek origin. She has Parkinson's disease, a disease which is usually sporadic. But in her family, others have been affected as well. Her brother is affected and her mother died of Parkinson's disease.

    To her great distress, one of her five children, only in her mid-40s, is now showing early signs of the disease.

    Decades of research on Parkinson's disease have taught us something about the ''what'' of the disease, that there is something awry in certain neurons in a part of the brain which seem to be dying prematurely. But we know very little about the ''why''. Thalia's family was part of a research study which was inspired by a workshop which came out of the National Institute of Neurological Disorders and Stroke interest in new opportunities in Parkinson's research. That interest in turn was somewhat inspired by the Congress, proposing that some new innovations would be appropriate.
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    Out of that workshop came a project to investigate families like Thalia's, which has in the course of the last year led us to a very surprising and interesting result. If I could see the first poster, please, Meg.

    [The information follows:]
    "The Official Committee record contains additional material here."


    What was done with families, including hers, was to collect DNA samples and, using the genetic maps that the Human Genome Project has produced in the last seven and a half years, in the space of exactly nine days it was possible to map the gene to chromosome 4. This is an activity which used to take us two or three years, but can now be done in just days.

    Knowing where the gene was on chromosome 4, Drs. Mihael Polymeropoulos and Robert Nussbaum, who are with the institute's intramural program, then went to the worldwide web and looked at a physical map, determined that investigators at the Whitehead/MIT Genome Center had already mapped this interval, so they didn't have to map the region, it was already done. Then they went to a different map, a gene map, which was put up by the National Center for Biotechnology Information about a year and a half ago, to see what genes were already known to lie in this candidate interval.

    The genes are the arrows that you see there on the chart. It's important to know that only about 5 percent of the human genome is actually coding, actually part of genes, and the rest is of unknown significance. If you're looking for the cause of Parkinson's disease, you want to see where the genes are located. Having them already mapped there for you helps a lot.
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    Dr. Polymeropoulos and Dr. Nussbaum identified an interesting candidate in that interval, simply from a computer search, and then set about sequencing that gene in the affected individuals. On the left what you can see is the gene in the healthy situation, there is a G in a particular position, whereas, all the affected individuals with Parkinson's disease had an A.

    This is a gene called alpha-synuclein, about which very little had been known prior to this time. By most people's recognition, this represents the most major advance in Parkinson's disease in 30 years. Here is an answer to ''why'', at least in these families. That very subtle change, one single letter out of 3 billion, is capable of causing this terrible disease in this circumstance.

    Pharmaceutical companies are intensely interested now in this molecule called alpha-synuclein. It appears that while having it mutated in this way is a very uncommon cause of Parkinson's disease, that the same protein participates in the common varieties of Parkinson's. So here we have a pathway that's ripe for exploration. That is a very exciting development.

    Now, you see that set of arrows in the gene map. At the time these investigators used this gene map, about 20 percent of the genes had been mapped. I'm happy to tell you something that's not yet published, but will be coming out in the very near future, is that a new version of the gene map will double the number of human genes that have been placed into precise locations on chromosomes, from 16,000 a year and a half ago to 30,000 in the next month or so.
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    [The information follows:]
    Offset folios 893 insert here

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


    Of the original goals for the Human Genome Project, the one that still mostly lies ahead is getting the DNA sequence itself. Three billion base pairs is a lot of information. We had expected to be starting about now on that part, figuring that you have to walk before you can run, you have to build maps and develop technologies before you can do that kind of high through put sequencing.

    We have been practicing very productively on other model organisms. Yeast is finished, the bacterial organism E. coli was finished in this last year, a very useful model. The round worm C. elegans will be completed before this year is over, also a very important milestone.

    Human sequencing of those 3 billion base pairs is already being piloted. And we are at the point now of having done a hundred million base pairs of human sequencing. While we're sitting here in this hearing today, 64,000 base pairs will be completed. We need to increase that through put by about a factor of six to get the job done by 2005.
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    [The information follows:]
    "The Official Committee record contains additional material here."

    This next diagram shows you that in fact the effort is vigorously underway. This is a diagram of human chromosomes. Shown in black on each one are regions of chromosomes where sequencing has been begun. It's not completed in these regions since only about 3 percent of the total has been completed.

    But for each area that you see blackened in there is an active effort underway in a sequencing center somewhere in the world to get that part done. And it seems very likely, Mr. Porter, that by the end of this calendar year, the first human chromosome, chromosome 22, will be completed. That will be a very exciting milestone.

    Sequencing needs to be done right. We have put a lot of effort in the last couple of years in these pilot projects to establishing standards. We are insisting on accuracy of no more than one error in 10,000 base pairs. In a recent exercise where we had centers check on each other, we are now achieving that accuracy target. We're insisting the sequence be assembled into large blocks, not little islands here and there, and it has to be affordable. Right now, sequencing costs about 40 to 50 cents a base pair, and we need to continue to drive that down.

    Perhaps most importantly, it needs to be accessible. If the scientific community can't use it, it doesn't exist as far as we're concerned. So we have instituted a principle where sequencing information is put into a public data base within 24 hours of the time a laboratory has determined it. That is now the international standard.
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    All of this has already led to a great deal of advance in the medical arena. I want to tell you about a new goal of the Human Genome Project which has arisen since last we met and which I think has profound significance for understanding the genetic basis of common illnesses.

    We have done a pretty good job in finding genes like BRCA–1 or some of the strongly hereditary colon cancer syndrome genes using this process we call positional cloning. But what of the common diseases? What about diabetes, which you talked about yesterday? What about finding the rest of the Alzheimer's genes? What about hypertension, the major mental illnesses, conditions that don't follow simple inheritance rules? How are we going to figure those out?

    Most scientists believe that those conditions come about because of an unfortunate combination of relatively common variants, variants which may be benign most of the time, but in a certain circumstance may not be. What we propose to do, and this is an initiative which is now supported by NHGRI and 17 other institutes of NIH, is to build the catalog of human variation. Basically we will look at as many of those 80,000 genes as we can, over the course of the next three years, and characterize the different spellings that occur at a reasonable frequency. Within that catalog will be the answers to the genetics of common disease.

    The next poster shows you how this might work.

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    [The information follows:]
    "The Official Committee record contains additional material here."

    I'm drawing as labels on particular people here, variants that would occur in a particular gene. Look at gene A, for instance. Now, here's a circumstance where 10 people who are affected with the disease—those are the 10 purple and green people on the top—have a certain frequency of purple or green versions of this gene. And the unaffected individuals have about the same frequency.

    So that would be a negative result. In that circumstance, there's no indication that gene A is involved in the disease being studied.

    But look at gene B. Here's a circumstance where when you look at that gene, there's a very different ratio of orange to blue, with the affected people primarily having the orange version, and the unaffecteds primarily having the blue, implying that this gene may very well be involved in this disease.

    This kind of an analysis, which we can only do once we build this catalog, should short-circuit what would otherwise take many years and many millions of dollars to try to understand the genetics of common diseases like diabetes. I think it is an extremely exciting opportunity.

    It's come about in part because of technologies like the one I have in my hand here, which is a DNA chip. To do this kind of catalog generation and then to be able to use the catalog, you need technologies that will allow you to look at very large amounts of DNA information in a short period of time. This chip is made by Affymetrix, a company which was founded, I'm happy to say, with support from an NIH grant about seven years ago, and which was featured this morning on NPR. This is the kind of technology that we've been waiting for.
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    This kind of analysis can now be applied to a wide variety of disorders, including those that affect certain populations. We have a new initiative with Howard University, a collaborative effort to try to study why it is that diabetes and prostate cancer are particularly common in African-Americans. I'm very excited about that partnership between our institutions, because I think minority genetic initiatives have been relatively few and far between. There has been a lot of concern about exactly how those initiatives would be organized and we're quite pleased to see this coming together.


    Coming back to Thalia, the woman with Parkinson's disease at 65: she is, of course, excited about the research, glad that somebody's working on her problem, hoping that it will help her, and if not her, her children, and worried about the other four children who are not yet symptomatic. We are now in the situation, since we know precisely what's wrong in that family, to offer her children the chance to find out whether they have inherited this alteration or not. Such a protocol has recently gotten underway.

    Her children, upon hearing about this, all expressed an interest in being tested. But after hearing the risks to them of having this information potentially misused, most have pretty much decided that they don't want to know. The final poster again brings me back to an issue which we discuss every year, where I'm happy to say there also has been substantial progress, and where the motivation to continue that effort is higher than ever. Because more and more conditions are becoming possible to test for.

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    [The information follows:]
    "The Official Committee record contains additional material here."

    As you can see from this cartoon here, I believe there are two things that we have to do. We have to build two pillars of a building if we expect the public to feel reassured about the ways that genetic information will be used to help them and not hurt them. One is the ''fair use'' pillar, to prevent genetic discrimination in health insurance, in the workplace, and in other places as well. And the other is the privacy pillar.

    And if we don't build both of those, I don't think people will be reassured that it's safe for them to find out this information, which many of them desperately want. We already know that this is having a dampening effect on research. People are afraid to find out this information.

    With the passage of HIPAA, we have achieved a major step forward for health insurance, since that legislation does say if you're in a group plan, this information can't be used against you. But we still have loopholes in the individual market which need to be filled.

    I was very gratified last July by the President making a major statement about the importance of plugging those loopholes. The Vice President in January said the same thing about employment discrimination. We have to get this job done. Thomas Jefferson said, ''Our Laws and institutions must keep progress with advances of the human mind. And we clearly need to do that on both fronts.

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    Our ELSI program has provided wonderful scholarship on this issue. We know what needs to be done. In a partnership between those of us on this side of the table and those of you on that side, I think we need to push this over the finish line, so that people can feel safe in finding out this critical information.

    In summary, Mr. Chairman, in just two weeks we will stand at the halfway mark of this 15-year project. Many people have called this the most important scientific undertaking of our time, or perhaps of all time—perhaps surpassing going to the moon or splitting the atom, an investigation into ourselves.

    As Director of NHGRI, I am very gratified at the stunning progress of our investigators, which allows me to come before you once again this year and indicate that we are ahead of schedule and under budget, words which I know are often welcome in this room. Our goals for the coming years are truly ambitious. But I believe they are achievable.

    The full benefits of this effort for transforming the practice of medicine still largely lie ahead, but not very far ahead. The research engine that will produce those breakthroughs is revved up and is roaring forward. We are gratified with the President's budget this year of $236,996,000, an increase of 10.4 percent.

    I'd be happy to answer your questions.

    [The prepared statement follows:]
    "The Official Committee record contains additional material here."

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    Mr. PORTER. Dr. Collins, thank you very much for your excellent statement.

    You mentioned Congress' role in looking at Parkinson's disease. I want to tell you that I think a great deal of the pressure from within Congress came from members of Congress who have suffered or are suffering the disease, beginning with Mo Udall and continuing with Joe Skeen and Joe McDade. Outside pressure comes within my knowledge, most strongly from Morton Kondracke whose wife suffers from Parkinson's disease.

    Dr. COLLINS. Yes, I understand.

    Mr. PORTER. It shows that the feelings of people can be reflected into initiatives and ultimately work out into policy and then into results. Sometimes the people in this country don't know how much power they have to change things and to direct things. The pressure comes, I imagine each one of them would tell you, from the people that have come to them because they knew they had the disease or in Morton's case, his wife had the disease and pressed him on it, or them on it.

    Dr. VARMUS. Mr. Porter, could I comment just briefly on this topic?

    Mr. PORTER. Yes.

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    Dr. VARMUS. This is a favorite example of mine with respect to advocacy and its good effects. Because what brought about the consequences that Dr. Collins just described is not money, per se, but instead, a response from NIH that include a workshop organized by Dr. Zach Hall, who was then Director of NINDS, that put into the same room geneticists and physicians taking care of patients with Parkinson's disease, and allowed the collaborative work that produced the genetic advances you've heard described.

    Now of course, there is money being poured into the follow-up. That to my mind is the right way in which to move the field forward.

    Dr. COLLINS. The consequence of that follow-up is already apparent. This month's issue of Nature Genetics reports the second Parkinson's gene mapped to chromosome 2. So we're on a roll.


    Mr. PORTER. I read a blurb, it wasn't very much, but I thought it had said that the Human Genome Project is only 5 percent complete, and that it's way behind schedule. I know that not to be the case, didn't I read this somewhere recently?

    Dr. COLLINS. The New York Times had a science piece on Tuesday, a long article about the Human Genome Project. I'd like to address that.

    Mr. PORTER. Please.

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    Dr. COLLINS. It is true when it comes to the sequencing part of the project that we have done only about 3 percent of the total sequence. So in a somewhat simplistic view, which is I think the source of that statement, you might say, well, come on here, you're halfway through 15 years and you've only done 3 percent of the work.

    Well, that's not the correct analysis, because the original plan was to have less than 1 percent of the sequence done at this point. The first half of the project was to be devoted, and has been, to the development of genetic maps and physical maps. The attention to sequencing model organisms, which are smaller and more gene-rich, and the improvement of the technology, to bring down the cost of sequencing was done first, so that it would be feasible to do the human at an affordable price.

    So if you look at the milestones that were set for this project in the initial five year plan in 1990, and then revised in 1993, in every instance we have exceeded those, including the sequencing goals.

    The prediction was that at the end of 1998, we would be sequencing at a rate of about 50 million base pairs per year. We're already at twice that. So once you step beyond the superficial level about what's been accomplished and how much time has gone by, it's clear that in fact the goals are being met very handily.

    Now, is it going to be a stretch to get the sequence done by 2005? You bet it is. I don't think this Congress would be enthusiastic about a project that set such limited goals that everybody said, well, of course, that's easy. We are going to have to work very hard. Our genome sequencing centers are ready for the challenge. We're going to have to bring the cost down about another factor of two over the next seven or eight years to be able to do this for the budget that's available.
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    But I'm quite confident with the talent that's being applied to this and given the track record in the past that we will achieve this goal. Can I tell you that 100 percent for sure? Again, if I could tell you that for sure, I think you'd tell me, Dr. Collins, you don't have very ambitious goals.


    Mr. PORTER. I don't think we'd tell you that.

    Let's talk about cost for a minute. You said it was something like 50 cents per sequence.

    Dr. COLLINS. Per base.

    Mr. PORTER. Yes, per base. Looking ahead, and looking back, do you have an idea of the total cost of the project, and can you relate that to the estimates that were originally made for it? And give us some understanding of the overall cost involved.

    Dr. COLLINS. Sure. The original prediction was that the Human Genome Project would cost $200 million a year for 15 years. So adding that up, that's a total of $3 billion in 1990 dollar equivalents.

    Up to the present time, between our effort and the Department of Energy's effort, which as you know is the co-supporter in the U.S. of the Human Genome Project, and spends about half what NIH does, a total of $1.5 billion in 1990 dollars has been spent in nine years. I'm including the 1999 budget in that.
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    You would have predicted at that point, if we were spending at the original plan, that we would be at $1.8 billion. Instead, it's at $1.5 billion. So we are significantly under the predicted budget.

    I think it is a little hard to predict how things will go in the last six or seven years. I would hope the Human Genome Project will be judged by the total budget that was required to get the job done. If it's possible to get the job done earlier, by having the budget go up faster, well, that would be all right. But I think it's fair to say, when you look at the predictions, in most instances the tasks that have needed to be done, have been done for somewhat less than expected.

    Now, it's a very critical question, what happens to the cost. The difference between 50 cents a base and 49 cents a base is $30 million worth of cost. That's how the numbers work out. So we are critically interested in driving that cost down in every way we know.

    We have instituted a new method of bringing together our genome sequencing centers, which will come into play in about a year and a half. They will form a cooperative agreement to share their technology ideas and to figure out who is saving money in this step and who's saving money in that step, and together let's see if we can move those costs downward even more quickly.

    Mr. PORTER. So it might cost us as much as $3 billion?

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    Dr. COLLINS. It might. At the current rate, you could say it's going to come in a little under that. But we have seven or eight years to——

    Mr. PORTER. Four B–2 bombers to map the entire human genome. [Laughter.]

    Dr. COLLINS. You could look at it that way.

    Mr. PORTER. Well, I think it's probably going to go down, as you've said, as the best money we've ever spent. I'm extremely pleased to hear that you are continuing under budget and ahead of schedule and that great progress is being made.

    I have to admit that I saw the front page blurb in the New York Times and thought, there's something wrong with this, and didn't read the rest of it, so I'm glad you could explain that to us.

    Dr. COLLINS. I appreciate the question.


    Mr. PORTER. Dr. Collins, we know that genetic testing isn't perfect. For example, cystic fibrosis can be caused by more than 600 different mutations in a particular gene. Because it's too expensive to test for all of them, labs usually test for the most common 70. So a negative genetic test doesn't necessarily mean you don't have a cystic fibrosis mutation.
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    Dr. COLLINS. Correct.

    Mr. PORTER. In another example, studies have shown that people with any genetic makeup can get Alzheimer's. They don't have to carry the gene that has been identified with the disease. So why should we spend billions of dollars to identify gene mutations, and why should anyone be tested?

    Dr. COLLINS. It's an appropriate question. Mutation testing, genetic testing, like most forms of diagnostic testing, is not perfect. False negatives and false positives will occur, not because of laboratory errors, but because disease is heterogenous. That's not a surprise. We've known that for most diseases for a long time.

    Cystic fibrosis is an interesting case in point. If you are tested to see if you're a CF carrier, and you test negative and if you're of northern European background, there is still about 1 chance in 250 that you might be a carrier because the test misses about 10 percent of the changes.

    Nonetheless, many people find that information quite useful. It is a challenge to offer that information in a way that truly explains the limitations of the test. That challenge is going to be one of the major issues for medicine in the coming decades. We are likely to see, five or ten years from now, the opportunity for any of us who wish to know our genetic risks of illness, to have testing done for perhaps 15, 20, or 30 different conditions.

    Most of those tests will move your risk up or down. But they will not be all or none. It will be necessary to convey that information about risk in a statistically sophisticated way, so that people don't get the wrong idea about what this information tells you.
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    It's still incredibly useful. If I knew that I was at three-fold increased risk for colon cancer, I'd be a lot more likely to go in and get that screening every year to see if I've developed a polyp that needs to be removed. For many circumstances, if we could individualize our preventive medicine efforts based on genetic testing, we could do a much better job of keeping people healthy and saving costs. That doesn't mean the test has to be perfect, it means it has to provide useful information.

    Mr. PORTER. I'll ask one more question. You're quoted as saying all of us are walking around with 5 to 50 flawed genes that place us at risk for some illness. If that's the case, how does an individual know which flaws to be tested for?

    Dr. COLLINS. Another good question. At the present time, very few conditions are in the circumstance where you would propose to offer testing to somebody without a family history. For cystic fibrosis, relatively soon testing will be offered to all couples who are contemplating a pregnancy, because it's such a common alteration. Sickle cell testing is now offered to African-American couples in many situations for the same reasons.

    But in most circumstances right now, being tested for susceptibility is preceded by the recognition that that person has a particular vulnerability because of their family history. Women are not tested in general for BRCA 1 alterations unless they have a family history, although some are suggesting that testing might be appropriate for Ashkenazi Jewish individuals. That proposal is still quite controversial, and I think most of us think that would be premature.

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    So at the present time, testing, if it's to be offered, depends upon the individual circumstances and particularly their family history. That may change over time. In another 15 or 20 years, when tests are more easily available and better understood in terms of their value, it is quite possible that a panel of tests would be offered to virtually anybody who's interested in having the information. Let me hasten to say that nobody should have such a test without deciding they want to know.

    Mr. PORTER. Thank you, Dr. Collins.

    Mr. Bonilla.


    Mr. BONILLA. Good morning, Dr. Collins. The work you're doing is fascinating. I can recall when I visited the NIH we got a nice briefing at your facility, and were very impressed.

    One thing that I'd like to ask is, I'm also on the Agriculture Subcommittee on Appropriations. Recently their research, education and economics division testified about the efforts there researching food and animal genes.

    My question is, do other agencies such as the Department of Agriculture play a role in your Institute's work and in what you're doing? For instance, does your Institute share technology with USDA's food genome strategy?

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    Dr. COLLINS. Yes. In fact, it's a very timely question. You may know that about a year ago, there was a great deal of enthusiasm, inspired by the Corn Grower's Association, to begin an initiative on the genome of corn.

    That is not the first interest in plants, however. Plants have the same DNA animals do, and already, for the past two or three years, there's been a significant effort underway, primarily led by the National Science Foundation, to determine the sequence of Arabidopsis, which is a simple plant with a manageable genome size. That research is going quite well. A number of our grantees are also working on that project. And we have contributed a lot of technology to that same effort.

    Out of this interest in plant genomes, a working group was formed last year and Dr. Elke Jordan of the National Human Genome Research Institute has been part of that group, to try to plan a plant genome initiative. A report has now come forward from that group which suggests that some $400 million, over the course of the next five years, ought to be identified to support plant genome analysis. This would include finishing Arabidopsis and putting a lot more effort into rice, a very important model with a relatively modest-sized genome compared to some of the other cereals.

    That effort will also collect mapping information and gene sequence information from other plants of agricultural value, particularly corn and wheat. USDA has been intimately involved in that working group, and will be very much involved in the implementation of this plant genome initiative, although the original allocation of funds has been primarily to the NSF.

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    So I think there is a lot of interaction. NIH's role in this will be to contribute technology as vigorously as we can, because the methods that we use to map and sequence a plant genome are the same as what you would use to map a mouse or a human.


    Mr. BONILLA. This is fascinating to a layperson like myself, I'm not a doctor and I don't have a health background, health care background, to think that there can be a link between plants and animals. I think the average person would be shocked to hear that there is a link and that they can be helpful to one another.

    Dr. COLLINS. It is remarkable.

    Mr. BONILLA. Do you find that when you talk about it?

    Dr. COLLINS. Yes. I think most people who haven't been exposed to this concept are surprised to hear that the same information molecule, DNA, with the same chemical structure, is at the root of the information content of all living organisms, from bacteria to plants to animals, and that the methods that we use to try to read that blueprint are generalizable.


    Mr. BONILLA. You learn something every day.

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    In your testimony, Dr. Collins, you discuss the tremendous progress you've made in identifying the genetic components in some forms of cancer. Along the same line as my previous question, please tell us about the coordination between various NIH institutes and the genome research project. For example, what role did the National Cancer Institute plan in these discoveries regarding the genetics of cancer?

    Dr. COLLINS. I think that's a very appropriate question, and given the current climate at the NIH, the number of collaborations between institutes has grown quite large. Cancer research is a very strong example of NIH collaborations.

    As Dr. Varmus said in his testimony day before yesterday, cancer is at a particularly exciting point, where uncovering the genes involved in this disease has been quite successful. We're now trying to move into the phase of using that genetic information to characterize at the most detailed level the difference between a cancer cell and a normal cell.

    The collaborations between the National Human Genome Research Institute and the National Cancer Institute have occurred on many levels. In our intramural program, for instance, we have a Laboratory of Cancer Genetics which interacts heavily with the NCI's intramural program in a variety of methods for genetic analysis. One method, development of expression arrays, was featured on this morning's NPR program. Dr. Varmus showed an example on Tuesday in a poster. That's been a very tight collaborative effort between the two institutes.

    In the extramural program, our ELSI program, which looks at ethical, legal and social issues, has been very interested in the question about genetic testing, and who wants to get tested and what happens after you've had that result. Out of that interest has come a Cancer Genetic Studies Consortium, which is co-funded by the NCI, ourselves, and of the National Institute of Nursing Research.
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    That Cancer Genetic Studies Consortium is the precursor for the National Cancer Genetics Network, which is about to get underway, and which the NCI has set up with a great deal of cross collaboration and coordination with NHGRI. So I think, and Dr. Klausner would probably echo this same statement, that this is a very appropriate area for a lot of cross-talk. I think it's been quite useful for both of our institutes to work together in this way.

    Dr. VARMUS. If I could just add one other example, Mr. Bonilla. You'll be hearing in more detail about the Cancer Genome Anatomy Project, which represents a coalition among the NCI, the National Human Genome Research Institute, and the Library of Medicine, which supplies the so-called bioinfomatics computer structure that absorbs the information and analyzes it, compares the genes discovered in cancer to genes that are isolated from other organisms, like the worm and the yeast. That three-way partnership has been very instrumental in expanding the number of genes available for mapping this year.

    Dr. COLLINS. That's another very good example.


    Mr. BONILLA. Well, what's the difference, when a person is predisposed to getting a certain kind of cancer, for example, because of their genetic makeup, because there's a family history and, let's say for example, a brain tumor or some other form of cancer that's generally not caused by bad habits like smoking or laying out in the sun too often, where you get skin cancer, or get lung cancer from smoking, is there a genetic predisposal to getting a skin cancer or lung cancer already in situations where people choose to take on those bad habits?
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    Dr. COLLINS. Yes, there does appear to be.

    Mr. BONILLA. Does that mean, for example, that a person who does have the bad habits of lying in the sun too much or smoking too much could also have a predisposal to not getting cancer because of their genetic makeup?

    Dr. COLLINS. That's correct, too. I think it's fair to think of all diseases, and cancer is a particular example, as an interaction between genetic susceptibility and environmental influences. Lots of people smoke two packs of cigarettes a day for 40 years, yet don't get lung cancer and others do. It's been carefully looked at, and it appears that there are familial factors involved in that susceptibility. There is recent evidence, in fact, of a couple of specific genes that are involved in detoxifying the carcinogens in smoke, which may play a role in that susceptibility.

    So if you have a particularly vigorous detoxifying system, you may get away with exposure to tobacco smoke, whereas someone else with a less extreme exposure may develop cancer just the same. This is a very fertile area for investigation, and I'm glad you brought it up. Because I think sometimes people make the assumption that if you're interested in genetics, you're saying environment's not important.

    That is not the case at all. Another institute we have a lot of interaction with is NIEHS. Clearly, where we're going to really get the answers to diseases, is figuring out which people are particularly vulnerable to which environment factors, on the basis of their genetic susceptibilities. With a few systems, like tobacco smoke, for instance, we're beginning to make inroads into that.
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    Mr. BONILLA. Thank you so much again for appearing here this morning, and keep up the great work.

    Dr. COLLINS. Thank you, Congressman.

    Mr. PORTER. The chair would advise members we're operating under the 10 minute rule. You actually have a couple more minutes.

    Mr. BONILLA. I'm finished, thank you.

    Mr. PORTER. Mrs. Lowey.

    Mrs. LOWEY. Thank you, Mr. Chairman.

    I want to join my colleagues in congratulating you on the extraordinary work that you've been doing and the progress that you are making. It's certainly a scientific feat of enormous importance, and I also want to thank you for your tremendous leadership in addressing the serious social and ethical issues that arise from this research.

    In fact, you've presided over several task forces dealing with discrimination, both insurance and employment-related genetic discrimination. These task forces have reported out meaningful recommendations that both Louise Slaughter and I have used as the basis for legislation. Your involvement in the ELSI working groups and related activities is critical. I personally appreciate it, and I wanted to just thank you.
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    Dr. COLLINS. Thank you.


    Mrs. LOWEY. First of all, can you please update us on the status of research regarding the BRCA1 and BRCA2 breast cancer genes? The genes, as we know them, are common in Jewish women of European descent, and at present, mean a greatly increased risk of developing breast cancer.

    Can you tell us what we have learned about these genes since our hearing last year? Are there any available results from the large Washington area study of Jewish families? What are the questions that we need to answer next?

    Dr. COLLINS. It's obviously a very important area, and one which is now in the midst of a frenzy of activity. Researchers are trying to get the answers to some of these questions, and appropriately so.

    Just by way of defining terms, BRCA1 and BRCA2 are two genes, which if misspelled, carry a high risk of breast and ovarian cancer. The original studies were based upon families that had many cases of breast and ovarian cancer already occurring and that's how they came to the attention of researchers.

    The estimates were that a woman with a BRCA1 or a BRCA2 mutation had about an 80 to 90 percent chance of breast cancer, and perhaps a 50 percent chance of ovarian cancer. Very high numbers, indeed.
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    The Washington study, which you referred to and which was published since we met here last, looked at a much larger group of individuals, over 5,000 volunteers, who came in to be studied. They gave a blood sample and they gave a very detailed medical history of themselves and their family members.

    The individuals understood in that study that they would not receive specific results about themselves. That was part of the informed consent procedure, in part because of the uncertainty about what to do in this circumstance if they had the misspelling. Other studies are now available that will allow people who want to know to find out the results. But in this particular study, these volunteers were providing this information, but they understood they would not get results back.

    From that study, it was confirmed that about 1 in 40 Jewish Ashkenazi women have, one of three possible misspellings in the BRCA1 or BRCA2 genes. This is a surprisingly high number, given that the estimates in other populations had previously been something like 1 in 500.

    But I think the answer people were particularly looking for is, what was the consequence to people in this group. The lifelong risk of breast cancer in that study came out at about 55 percent. This is still way too high and dramatically higher than the lifetime risk of 12 percent which all women face. But not the 80 to 90 percent that had previously been estimated.

    The risk of ovarian cancer came out at about 15 percent, again, substantially lower than previous predictions, but still much higher than the 1 or 2 percent baseline in the entire population.
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    Men, it turns out, who have one of these three alterations, faced an increased risk of prostate cancer. This had also been suspected previously, but this study seemed to confirm that rather strongly. That risk is not nearly as dramatic, however, as the ovarian and breast cancer risk in women.

    We have learned as a consequence of that study, that yes, these particular alterations are of great significance. The actual absolute risk is perhaps not as high, at least in this group of people, most of whom didn't have dramatic family histories, as we had previously thought.

    It still leaves us, though, in a quandary about how to use this information clinically. Many women who have a strong family history have chosen to find if they have one of these three alterations, and testing is available through either research protocols, which many of us believe is the ideal way at the present time to get this information, or through a non-research based clinical testing.

    There was a very compelling story about this in the New Yorker, about a month ago, by Jerry Groopman, which I would recommend to anybody who wants to look at the human side of going through this testing experience. It's quite powerful.

    The dilemma, of course, which we still don't have a good answer to, is what should a woman do who has one of these alterations. Is going through regular mammography sufficient to pick up a breast cancer while it's still small enough to cure? Or should more drastic measures, like prophylactic mastectomy and removal of the ovaries be strongly considered also?
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    The NCI is moving swiftly to try to get answers to those questions. But those are complicated studies to do. At the present time, we still don't have good guidance to know what to tell women in that circumstance. I wish we did.

    Finally, in the basic science area, we are learning a whole lot of information about what these genes are normally doing. They're not there just to get misspelled and cause cancer. They're doing something important.

    It appears that both BRCA1 and BRCA2 are involved in a similar pathway, a process of protecting DNA against damage. They're part of the early warning system that says, ''Something has happened here to DNA, we need to fix this, or if we can't fix it, we need this cell to die before something like a cancer cell arises.''

    BRCA1 and BRCA2, are involved in this pathway, although their exact roles are not entirely clear, and which other proteins in the cell they hold hands with is not yet worked out. But that research is going to shed light on a whole host of important issues, including, probably, the effects of radiation exposure.

    Mrs. LOWEY. Just to pursue that, women are living longer. And if this gene has been identified as damaged, and the 1 in 40, as you said, has this gene, is there any indication of at what age the woman would be at risk for breast cancer?

    Dr. COLLINS. Yes. The Washington study also provided the best data yet to look at that curve of the age of onset. It is clear that the breast cancers that do arise in this circumstance tend to occur somewhat earlier than breast cancer does in general.
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    As you know, most breast cancer in the general population occurs post-menopausally. And yet, in women with BRCA1 or BRCA2 mutations, the risk of breast cancer is already significantly elevated in the 30s and 40s. So it comes up somewhat more steeply than it does in the normal circumstance.

    Again, we now have that information. That's good. We didn't have it before. But it still leaves a woman in that circumstance in a dilemma about what to do.


    Mrs. LOWEY. And are you satisfied with the work you've been doing that the counseling and advice that is being given to women is adequate in the situations where the gene has been identified?

    Dr. COLLINS. I think most cancer centers that are staffed by qualified genetic counselors have been doing a good job of informing women. It's very challenging. We have a research protocol at NHGRI that is going through this. It takes a great deal of time and attention and sensitivity to help people think these issues through before being tested.

    I worry that as this becomes more commonplace, and the counseling is done by people who have had less training, that some of that sensitivity may not be as carefully sustained. This is a serious issue for the future, for genetic medicine of all sorts, not just for breast cancer testing. It will also apply to testing for diabetes, hypertension, or whatever the disease is that somebody's interested in.
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    We have to figure out how to move genetic medicine into the mainstream, how to have every primary care physician and nurse able to handle the kinds of questions that people will ask about this area. We have catalyzed a new National Coalition for Health Professional Education in Genetics, jointly with the American Medical Association and the American Nurses Association. This group will take this challenge on and try to achieve the kind of literacy about genetics amongst health care professionals. We need to move swiftly to do that.


    Mrs. LOWEY. I'm aware that the medical profession is beginning to disseminate information to their members about the ethical and social issues related to genetic testing, such as the recommendations made by your ELSI task force. Do you feel that there is sufficient work and sufficient interaction, as you mentioned, with the medical groups around these issues?

    Dr. COLLINS. I think it could be better. I think there's a great deal of interest and quite a vigorous discussion is going on in many instances. I will spend this weekend at a meeting organized by the American Medical Association for their members on genetics for the practicing physician. This meeting which has attracted several hundred primary care physicians who are interested in being leaders on this topic, many of them being presidents of their local medical societies.

    The American Medical Association has identified this as their number one priority for educating their members, comparing this challenge to the advances in antibiotics that occurred several decades ago. They see this as a very urgent matter, and they are interested in participating in a very constructive way.
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    I see that as a good sign. It's one thing if the geneticists are up there saying, you guys need to learn about this. It's another thing if the front line physicians are themselves saying, tell us about this, we're ready to hear it.

    Mrs. LOWEY. I think my time has expired, thank you.

    Mr. PORTER. Thank you, Mrs. Lowey.

    I will tell Mr. Stokes that there's a vote, so he's not going to have time for the full 10 minutes. We will save the time when we recess for the votes and come back.


    Mr. STOKES. What steps of your technology based research have you taken to ensure that your operations are year 2000 compliant?

    Dr. COLLINS. Perhaps you could define the term year 2000 compliant. You're talking about the computer problem?

    Mr. STOKES. The computer problem.

    Dr. COLLINS. Okay, now I've got you. We, as many other parts of the NIH, are concerned about this issue. There is a master plan already well underway to make sure that when the year 2000 comes, we don't find ourselves with a particularly difficult crunch.
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    I think actually this will have little affect on the Human Genome Project. Our computer operations are pretty new, for the most part. We are not, like the Social Security Administration, working with programs that were written 30 years ago. We didn't even know we were going to exist 30 years ago.

    In fact, the data bases upon which the Human Genome Project depend are all, for the most part, of construction within the last five or six years. And while I don't think one ought to be dismissive of this as a serious issue, the information I have at the present time is that the few areas that need attention can be dealt with relatively straightforwardly, more so perhaps that in other parts of the Government.


    Mr. STOKES. I understand that you have a collaborative project with one of the Historically Black Colleges and Universities, Howard University. Can you tell us what you're studying there and what you anticipate to gain from it?

    Dr. COLLINS. Yes, I appreciate the question. And by the way, Mr. Stokes, like others who have come here to this table, I would certainly like to thank you for raising the visibility of issues about disparities between minority and majority health care.

    That is a major factor in this new initiative with Howard University about which I'm quite excited, and which I'm spending a good deal of my own personal time on. I met with President Swygert of Howard University the day before yesterday. We talked about this initiative, which has now been underway for a couple of years. We both concluded that this is a truly exciting opportunity for joining together an NIH institute and an institution, Howard University, with a great deal of credibility and capability which is hungry for a presence in genetics and genomics as applied to minority illnesses.
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    We already have two very ambitious pilot projects underway. One is an effort to study diabetes, obviously a disorder which is disproportionately present in African-Americans. We are collecting affected siblings with diabetes in Ghana and Nigeria. This is a very challenging way to do genetic research, but it has many arguments going for it in terms of the likelihood of success because of the nature of the population structure.

    We have recently initiated, in the last few months, a second project on prostate cancer. This project will collect, in the course of the next three years, a hundred families with multiple affected males who are African-American, affected with prostate cancer.

    Our investigators, about a year ago, mapped the first prostate cancer gene to chromosome 1. The gene itself is still being searched for. But it appears that this gene is particularly important in African-Americans. And yet very few families have been studied.

    That effort, for which Howard University serves as the coordinating center, now involves seven institutions around the country, most of whom are led by African-American physician scientists. I think this is a very exciting opportunity to move genetics into this arena.

    I think the relationship with Howard University is an extremely gratifying one. We are making every effort to have investigators go back and forth between our institutions, to achieve some training opportunities which have not previously been as vigorous as they could be. At the highest levels of the Howard University administration this is being seen as a very high priority for their own program building.
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    Dr. John Ruffin, the Director of the Office of Research on Minority Health, has been a very enthusiastic supporter of this concept as well, and he and I have worked together I think very productively in trying to set this up.

    So for me right now, of the things we are doing in our intramural program, this is one of the most exciting.


    Mr. STOKES. I personally appreciate your kind remarks. Let me say, I also appreciate your sensitivity to these areas of concern that I've discussed with you and Dr. Varmus and others. I also appreciate the sensitivity that Dr. Varmus has displayed for these concerns over the years.

    What about African-American women? They also have a higher death rate for breast cancer than the white population.

    Dr. COLLINS. Yes.

    Mr. STOKES. Are you doing anything to address that?

    Dr. COLLINS. Dr. Georgia Dunston, who's an investigator at Howard University, did a sabbatical in my laboratory two years ago, studying breast cancer in African-American women. It does appear that BRCA1 and BRCA2 play a role, but they don't completely explain what's going on. There are probably other genetic influences, and undoubtedly environmental ones, as well.
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    What I dream of is a center at Howard University to look at diseases that disproportionately affect African-Americans, which could expand beyond diabetes and prostate cancer, which we've already started on. The center could expand to breast cancer, to asthma, to Alzheimer's disease, which we have learned in the last day seems to be at a higher risk in African-Americans, a rather surprising observation that needs an explanation.

    Mr. STOKES. Thank you.

    Mr. PORTER. Thank you, Mr. Stokes. You'll have additional time when we return.

    The subcommittee will stand in recess briefly for two votes.


    Mr. PORTER. The subcommittee will come to order.

    Mr. Stokes.


    Mr. STOKES. Okay. Dr. Collins, as you know, over the years, we've discussed the ethical, legal and social implications of genome research, with a focus on the possible discrimination implications that could stem from increased genome research findings. The Administration recently released a report entitled Genetic Information in the Work Place, and is urging employers not to discriminate against workers because of their genetic makeup.
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    What protections currently exist to address and prevent this form of discrimination?

    Dr. COLLINS. I appreciate the question. Clearly, when you ask the public about their concerns about misuse of genetic information, health insurance and the work place are the number one and number two answers you get. In a telephone survey of a thousand people done last year, 85 percent of the respondents said they did not believe that employers should have access to genetic information.

    So what are we doing about it? At the present time, the protections against this largely stem from a ruling of the EEOC based upon the Americans with Disabilities Act. Three years ago, the EEOC ruled that an employer who uses predictive genetic information about an individual to deny them a job is actually violating the ADA. Because that employer is regarding them as disabled, even though that person is healthy at the time.

    That was very gratifying. It was a strong statement that this is not something that should happen. And yet many people looked at that and said, well, it's a gratifying statement, but its ability to actually prevent mischief may be somewhat limited.

    The EEOC ruling has not yet been tested in the courts. And of course, it seems only to apply to a hiring decision. There are other decisions, like promotions, for instance, which remain vulnerable to this type of discrimination.

    Furthermore, there was nothing in that ruling that dealt with whether an employer could insist upon having someone tested. We sponsored a workshop on this issue which then led to a published statement jointly between the ELSI working group and the National Action Plan on Breast Cancer. This published statement, issued a year ago, outlined what needs to be done at the Federal level to provide legislative protections against the misuse of genetic information in the workplace.
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    I'm delighted to see a great deal of interest in that issue. And Congresswoman Lowey, who just entered the room, has played a major role by introducing a bill in the House. The companion bill has been introduced by Senator Daschle in the Senate. Both bills build on the recommendations from that joint effort of the ELSI Working Group and the National Action Plan on Breast Cancer. These two bills, I think, do exactly what needs to be done to prevent that kind of discriminatory practice.

    They are also careful to do it in a way that I don't believe damages the employer's situation. I think employers looking at these would be quite comfortable with what's recommended.

    There was recently a case in the Ninth Circuit, a California case, where a number of individuals who had been tested without their knowledge for sickle cell disease, for syphilis and for pregnancy, actually, by a Government agency, brought suit, because they felt their privacy had been invaded.

    After an initial lower court threw that out, the higher court said this is a serious issue. That's actually quite gratifying. It indicates a judicial opinion of a fairly significant sort that testing without the knowledge and consent of the individual ought not be done. So I would see that also as a positive step.

    Once again, we have a circumstance now where I think the scholarship that's come out of the ELSI program has outlined what needs to be done. There's a lot of enthusiasm in both parties and in both Houses. The Vice President of the United States on January 20th made a strong statement in this regard. There is this report which you've referred to. The Department of Labor has played a very significant role in this, and have been a wonderful ally in this enterprise.
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    So it's pretty clear what needs to be done, now we just need to do it. We need to get Mrs. Lowey's bill passed. [Laughter.]


    Mr. STOKES. You've got me.

    Let me give you a real quick question. What's being done to ensure that academic medical centers, other medical schools and continuing medical education programs include your recent Centers research findings in their curriculum and to ensure that the practicing health care community are aware of these advances as well?

    Dr. COLLINS. This is a very critical issue, both in terms of physicians and other health care professionals who are already out in practice, and those who are in the next generation, who are currently being trained. This National Coalition for Health Professional Education in Genetics, which I briefly mentioned a moment ago, is taking on a lot of interest and responsibility for both of those arenas.

    The Coalition has a working group which is developing an effort on curriculum development for medical schools and nursing schools. It also includes an effort to put together a clearinghouse for valid genetic information to be available through electronic means, through the web, but also as hard copies for those who need it.

    And the Coalition has a vigorous effort to influence licensure and certification, so that there is both a carrot and a stick here in terms of getting this information integrated into medical training. I think we've got a lot of work to do, but I think those are the right ideas, and we just need to roll up our sleeves and get it done.
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    Mr. STOKES. Good.

    Dr. VARMUS. Can I make one addition? This is the second time the Coalition has come up, and I wanted to point out that the Coalition is being managed and financed through the activities of the National Foundation for Biomedical Research, or the Foundation of the NIH to which you very kindly have appropriated a half a million dollars in 1998, and we're asking for $300,000 in 1999.

    This is one of the several activities of the Foundation and it's an important illustration of how the Foundation can work to achieve NIH's goals through mechanisms that wouldn't be very simple for us to carry out through the normal appropriation process, affecting both the intramural and the extramural activities of the NIH. I thank you for the support of the Foundation.

    Dr. COLLINS. I agree.

    Mr. STOKES. Thank you very much.

    Thank you, Mr. Chairman.


    Mr. PORTER. Thank you, Mr. Stokes.

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    Dr. Collins, and Dr. Varmus may want to comment on this as well, when a scientific investigator undertakes a research project, he or she has certain expectations as to what they might find. I wonder if you could tell us, looking back seven and a half years, whether you find a greater complexity, a greater feeling about the complexity and interrelationships within the human body than you expected to find. In other words, have you gained greater respect for the difficulty of this organism to be understood?

    Dr. COLLINS. That's an interesting question to think back on, and try to reconstruct what we all imagined we would find back in 1990. I think the answer is also a complicated one, and it is that in some instances, things have turned out to be simpler than we expected. In others, vastly more complicated.

    The simpler ones more immediately come to mind, because they are so gratifying, when you uncover something that you thought was going to be impenetrably difficult. Last week's New England Journal of Medicine had a really interesting example of that, if I can take 30 seconds to tell you. It also evidences that we've been on the right track in our approaches to disease.

    Tuberculosis, a disease that's obviously very prevalent in some parts of the world, is clearly an infectious disease. Who would have thought that genetics would have had much to offer this one, right?

    Yet it's clear that the same exposure doesn't always give the same results. Some people fight off the infection very quickly and never even know they were exposed. Others may go on to severe lung disease.
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    People studying mice seven or eight years ago developed a mouse model for this disease, and discovered that some mouse strains are more sensitive to tuberculosis than others. Using the tools of the Human Genome Project in 1993, they were able to identify a specific gene that seems to confer that resistance, a gene called N RAMP–1. This is a gene you could never have guessed, people still don't quite understand what it does. But it clearly is the major gene involved in TB susceptibility in mice.

    Well, so what? What about humans? Last week's New England Journal reports a study from Gambia where they looked at individuals with severe TB lung disease and compared them to others who'd been exposed but fought off the infection. This same gene, N RAMP–1, only the human homologue of it, seems to be the major contributor to that difference in host susceptibility.

    Seven or eight years ago, I would never have dreamed we could get to that point by now, that something as complicated as host factors that determine response to an infectious disease could get sorted out in this time period. The same, of course, has been done for AIDS, with a variety of different genetic alterations being discovered that confer resistance to that disease. And of course, there's the paradigm of malaria and sickle cell trait, which we've known about for decades, but which many people thought would be an exception.

    So in those instances, where we've gotten insights into the genetic basis of diseases that seemed impossibly muddy, I would say, wow, research has really moved more swiftly than I could have imagined.

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    When it comes to the work of the Human Genome Project, to building the infrastructure, getting maps and sequences and the technologies, it's hard work. Three billion base pairs is easy to say. When you have to actually contemplate doing it, there's no question that's enormously challenging. I think we're right now in the throes of absorbing just how hard this is going to be.

    I don't know that it's caught us off guard, but you certainly, when you get up to it, as opposed to talking about it, you perceive just how complicated it is. In that regard, it is wonderful that this is an international effort. We had a meeting two weeks ago of all the international groups. There are serious efforts underway, particularly in the United Kingdom, but also in France and Germany and Japan, as partners to try to make this happen.

    I think that partnership is going to be critical. The genome belongs to all of us.

    Dr. VARMUS. Could I comment just briefly, Mr. Porter?

    I think we always knew that understanding life systems would be a complicated process. I think what's impressed us is in the last year or so, as we've acquired so many tools for investigating how life works, either through the genome or through analysis of proteins made by the genes that have been identified, and by studying, very importantly, the way in which signals are transmitted within cells.

    All of us who are trying to understand how cells are controlled have been excited but also mystified by the number of interactions between individual proteins. At this point, when you draw out a map—and you actually see an example of such a map when Dr. Klausner comes—of what is interacting within the cell to transmit the message, we are at the limits of the ability of biochemists and biologists to understand these systems.
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    There's tremendous interest in bringing mathematics and physics and engineering to bear on the interpretation of these problems. I believe Dr. Cassman actually will tell you about some initiatives he's undertaken to bring new communities into the investigation of biological systems.

    For some organisms, like yeast and many bacteria, we have all the genes already, and we soon will have them, as you heard, for one complex organism, C. elegans, a round worm. I think now is the time to expand our efforts to broaden the community of scientists trying to understand the dynamics that control the life of any single organism.


    Mr. PORTER. And this would be the next step beyond the completion of the human genome project?

    Dr. VARMUS. It's actually a step that's coming now, because we do have genomes already fully understood. Even in the case of mammals, we have enough components of the signaling pathways that govern aging, cell death, and growth control, to be able to develop some much more interesting models—based on chaos theory or on the way in which homeostasis is maintained in an engineering system, in a machine.

    I was at Cal Tech this weekend, and met mathematicians who were invited to a workshop that Dr. Cassman organized and who were truly energized about the possibility of using their methodology, in this case pure mathematics, to try to understand how these systems work. It actually brings us back to the original question that got many people interested in biology, SchroAE4dinger's question of how does life operate, what are the thermodynamic principles that allow life to go on, such a complex event, with what seems to be such a small energy source.
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    Mr. PORTER. Did we contemplate that we would find these kinds of further complications in understanding when we began the project of mapping?

    Dr. VARMUS. I think you don't have to say we're going to do a mapping project to realize that we'd eventually have most of the components that allow cells to function. I think what's been incredibly exciting is that epiphany that occurs when we actually have so many of the elements that control the cell behavior in our hands and now it's up to us to decide how these things fit together.

    Of course, knowing how these things fit together normally is the other side of the coin of understanding what happens when things go wrong and cells die or disease occurs.

    Dr. COLLINS. I think it's a very important question, just to follow up. I think computational biology is going to be an area that flowers enormously in the next few years. At our Council meeting last month we talked about this and initiated two new programs to try to bring more people into this field who are really capable at handling both sophisticated computational approaches and understanding the biology. Because we're going to have this wealth of data about genes and proteins and a challenge to see how it all works.

    The Human Genome Project is building the periodic table for biology, and now we have to figure out how that table puts things together.

    Mr. PORTER. What I read from both of you is that you have no doubt that we will, in time, figure it all out. Is that correct or not?
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    Dr. COLLINS. I don't know what ''all'' is.

    Dr. VARMUS. Remember the display I showed you? I showed you a display on Tuesday comparing a tumor at different stages of growth and the number of genes turned on and off. You can do the same kind of experiment with single cells exposed to different environmental conditions. That's been done now for yeast. You put yeast in one growth condition, then transfer it to a different growth condition or expose it to a toxin or add a mutant gene.

    You can look at every gene in yeast and ask whether it's being turned off or turned on as you change conditions. How does an organism respond to altered conditions of life? We're now accumulating that information. There are bioinformatic specialists who are showing us how to group the genes that are affected in different ways, and try to relate them to the functional properties of the genes, most of which we have some understanding of in the case of yeast.

    And now the next step will be figuring out, what does that all mean? Why are these controls organized the way they are?

    I think we have a couple of decades of work before we understand that.

    Dr. COLLINS. And all is of course——

    Mr. PORTER. I didn't mean in anyone's lifetime here, but at some point.
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    Dr. COLLINS. Even if we knew all of those wiring patterns, would we understand some of the unique aspects of human nature, would we understand what love is, would we understand what personality is about, I'm somewhat reserved on that.

    Mr. PORTER. That's beyond the all I was trying to capture. [Laughter.]

    Dr. COLLINS. Good, then I don't need to go on. [Laughter.]


    Mr. PORTER. All right, let's see. When the genome project reaches the point where clinical trials are appropriate, do you envision your Institute actually conducting the trials or relying on the clinical trial expertise of other institutes?

    Dr. COLLINS. We do have some clinical trials already underway. In our intramural program, which is heavily involved in the applications of genome research to an understanding of disease, there is quite a long list of protocols. Each of these are trying to understand the biologic basis of certain genetic conditions and increasingly, also, gene therapy trials. There are some five or six of those actively underway through our intramural program, which has a rather different flavor than the extramural program.

    In the extramural program, we have had a series of clinical trials on genetic testing. For cystic fibrosis, we funded a whole series of such projects, and a great deal of useful information came out of that in terms of people's interests and how they adapted to the information. We are also still funding the Cancer Genetic Studies Consortium, which is looking at testing for breast cancer and colon cancer in a clinical setting.
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    But it is clear that our primary goals are not going to be such that our extramural program becomes heavily involved in clinical trials. We would like to be participants in such efforts. We're about to see in the near future a set of programs in hemochromatosis, where we join with the National Heart, Lung and Blood Institute and the National Institute of Diabetes, Digestive and Kidney Diseases to issue an RFA to study this disease.

    This is a fascinating disease, Mr. Chairman, which 1 in 300 people are walking around with, most of them unaware of it. It's a completely treatable disease if you know you have it. You build up too much iron. The treatment is, you go to the Red Cross and give your blood more often than other people. If you do this, you should prevent all of the consequences of heart failure, liver failure, and endocrine failure, which otherwise come about. So it's a really good example of the kind of genetic disease where population screening might be very sensible to initiate.

    But you don't want to launch into that until you've studied this on a research basis. And we're about to do that. But the major funding from that will come from the National Heart, Lung and Blood Institute. We will contribute something to the effort.

    But I think you're correct, that clinical trials are not likely to be a major focus of our extramural program.


    Mr. PORTER. Pharmacogenetics is a growing field of science which studies the genetic reasons why drugs affect people differently. It is thought that knowing the genotype of an individual will permit more effective prescription of drugs and more precise testing in clinical trials. If this goal were realized, would it force difficult choices between more precise medical care and the added costs of genetic testing for each patient?
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    Dr. COLLINS. That's a very interesting question. Certainly the pharmaceutical industry is voting with their feet that they believe that this is going to be a very significant part of the future of medicine. Why is it that if you take 10 people with a particular disease, whether it's cancer or diabetes, or whatever, and you try out the standard therapy, some fraction of them respond very well and some don't. Some occasional uncommon side effects pop up in some people and not in others.

    Presumably, in many instances, that is because of an interaction between the therapy and that individual's genetic makeup. The possibility, therefore, of using genetic testing to more individually prescribe the most effective therapy is something that has a lot of people excited. Dr. Klausner will certainly talk about this, I'm sure, when he comes before the subcommittee because of the hope that individualizing therapy will turn out to be more effective than using a standard therapy, just based on the pathological type in treating tumors.

    But I think it will generalize beyond cancer to virtually all diseases, once we have that kind of information. You're correct to raise the concern, is this just going to make everything more expensive. In order to avoid that, we have to drive the technology forward to do genetic testing at a much less expensive rate. Things like this chip, for instance, will potentially bring that cost down by orders of magnitude.

    I think the timing is likely to be about right there, as we gain enough information to figure out what kind of testing is appropriate in designing therapy, the cost of technology for doing that testing will be coming down quite substantially. I think it's a very exciting set of developments. I think it is a major chapter to this book about the future of medicine that we're trying to anticipate right now.
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    Mr. PORTER. I would tell my colleague from New York that I plan to call on her at 10 minutes of 12:00 and give her the last 10 minutes. Will that work? I didn't charge myself with the macro question. I figured we'd all learn from it. [Laughter.]


    We've talked in the past about private industry withholding genomic data out of a proprietary interest. Some reports indicate that the situation is improving with more data bases entering the public domain. But there still seem to be instances where refusal to share data is creating needless duplication. How serious a problem do you consider data hoarding at the present time?

    Dr. COLLINS. I think your statement is correct, that things have improved in this regard. But they're not perfect. Certainly from our perspective as a granting agency, which is distributing public funds, we feel that accessibility to the mapping and sequence information is just absolutely essential.

    So we have moved from a stance a few years ago where we said people had to put their data in the public domain in six months to a stance now where we say they have to do it in 24 hours, and in fact our genome centers are compliant with that. We regularly check on those things.

    That standard has also been adopted by the international community that has been meeting every year. There is still a concern in other areas other than sequence, however, particularly this business of building the human catalog of variation that I mentioned. We're in the throes right now of trying to figure out how to optimize the deposit of that information into the public domain as well.
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    Mr. PORTER. We've just changed our sequencing here.

    Ms. Pelosi.

    Ms. PELOSI. Having nothing to do with the Human Genome Project.


    Thank you, Mr. Chairman. Thank you, Dr. Collins.

    Again, forgive me if these questions have been asked in my absence, because of my other responsibilities. And if they're on the record, I'll just read the record.

    But I wondered, my colleague, Congresswoman Lowey, has been a leader in addressing the potential for discrimination. I heard her question, and I just wondered if perhaps you could just elaborate, and if you have, I'll read it, regarding what work you're doing regarding the maintenance of confidentiality of genetic records, and what you envision in terms of how a patient chart is kept. Would it still be in the same manner as now?

    Dr. COLLINS. I appreciate the question. I put up that poster of the two pillars of what we need to give people protection so that they're safe in getting genetic information, and one of the pillars was privacy and confidentiality.

    When you think of the medical record, and try to imagine whether you could provide protections that are specific for the genetic information, that are different from the rest of the record, it gets very difficult to do that. I can't take a patient chart and decide which part is which, they're all intertwined together.
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    So genetic privacy basically becomes medical privacy in general. There have been many developments in this area. As you know, HIPAA charged the Secretary of HHS to put forward recommendations about medical records privacy. That was done last September. The recommendations do not apply to information that has been obtained solely on the basis of research. They apply only to information that's part of the clinical record.

    The Congress is supposed to act in the next two years, or those regulations will become law. There's a lot of interest in the Congress, as you know, in this issue, with a number of bills, some introduced, some waiting to be dropped, on this topic. It's clearly very complicated.

    Ms. PELOSI. Do you have any recommendations in that area?

    Dr. COLLINS. Well, we've been very involved in the process. The National Bioethics Advisory Commission has been deliberating, particularly about things such as archived tissue samples, and when can you use them, and is that an appropriate part of this package.

    Dr. Varmus has set up a trans-NIH group to look at bioethics issues. This committee, has also now gotten very involved in questions about privacy, as they relate to genetics and other non-genetic information, particularly in the research arena. And they have come up with a white paper, which is being circulated amongst the institutes right now for comment.

    I could not at the present time tell you that I would have a strong recommendation about one piece of legislation or another. I'm not sure it would be proper for me to, anyway. But there's clearly a lot of overlap in the various proposals, but some significant differences. The balance, of course, is trying to protect people against misuse, without so ensnarling the medical care system that you can't actually deliver care, which could be a serious issue if you make a written approval necessary for every possible transaction.
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    If I could add one other thing, in the research arena, I think it's also really critical that we don't write legislation that is so onerous that it prevents the possibility of doing epidemiological research. We have learned a lot from medical record review, trying to figure out a common thread to some new illness.

    If you have to get individual permission for that kind of research, it will be very difficult for many studies to be carried out. That's something to think about very carefully. Even with the best of intentions, sometimes, people have notions about very rigorous forms of consent being required for every transaction, which could be quite damaging to research.

    Ms. PELOSI. Well, I recall just the other day, the Acting Director of the CDC said to us, am I correct, Mr. Chairman, she said, if it isn't counted, it isn't done, in terms of prevention, in any event.

    Dr. COLLINS. Counting is important.

    Ms. PELOSI. Dr. Varmus, did you have something?

    Dr. VARMUS. I just wanted to endorse Francis' comments on this topic, especially with respect to research. It's important to remember that the computer can be your friend in this circumstance, that while the computer tends to be criticized, in fact there are ways to set up security systems that allow us to use information and not go back to identifiers that would connect the information with individual patients.

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    If we can learn to stratify the experiments that need to be done—especially with things like stored tissue samples or stored DNA samples that will be of major benefit—and provide the kinds of protections that would allow us to not have to go back and get informed consent from everyone who may have been the donor of a tissue sample 20 years ago, we'll be able to make much better use of the resources that are available, while still providing the protections against misuse of the information that represents the dangerous aspect of what we appropriately look at.


    Ms. PELOSI. I appreciate your statement, because obviously science and technology have taken us to new places in basic biomedical research and instrumentation as well as in access to information that some could view as a problem. But your putting it in perspective that way is very helpful.

    I understand that gene therapy is a promising area of research in the area of hemophilia. Can you tell us more about your work with the Heart, Lung and Blood Institute to pursue vectors for gene expression in immunity needed to make gene therapy technology available to individuals with hemophilia?

    Dr. COLLINS. Hemophilia is a common blood disorder which affects primarily males, because it's a genetic disease where the alteration is on the X chromosome. Females who have two X chromosomes can carry the illness, but are usually not affected.

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    There are two different types of hemophilia, types A and B, due to two different genes. Clearly, this is a disorder where gene therapy is an appealing idea, because you only need about 5 percent of normal levels of this clotting factor to be normal. It's when you drop below 5 percent the disease begins to appear.

    The genes for hemophilia A and B have been cloned for some time. The notion of putting one of those genes into a viral vector or some other delivery system, and then transferring it to a boy who's affected with this disease is a very appealing one. And yet, as with all efforts in gene therapy, this has been a real challenge to reduce to practice.

    We have a number of vectors that we know can do this. But the delivery efficiency is usually not as high as you'd like. And when the gene is transferred and expressed, sometimes it doesn't last very long, because the immune system comes along and says, ''what's this,'' and gets rid of it.

    Nonetheless, I think there has been steady progress in gene therapy for this disease in animal models. And in fact, our intramural investigators are planning, in the near future, in collaboration with the National Heart, Lung and Blood Institute, to initiate a trial of gene therapy for hemophilia. The notion here is to put the normal gene into cells from individuals with this condition, so you can do this in a less invasive way. Do a skin biopsy, grow the cells up, put the normal gene in there, and then reimplant those as sort of a patch under the skin.

    And the hope is, and this has to be tested, that those corrected cells will make enough of this factor, which will find its way into the bloodstream, to provide that correction.
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    These are very early days for gene therapy. There are many diseases for which gene therapy might be applied. But hemophilia is probably near the top of the list of ones that are realistic targets in the not too distant future. Yet there are many hurdles ahead.

    Dr. Varmus organized a very useful review of gene therapy a couple of years ago by a number of experts to provide some advice about what we should be doing about this field. Out of that has come a very rigorous set of questions: are we going in the right direction, are we using the right vectors, are there new ideas out there that haven't been tested. And my sense is, that has provided a real impetus to move us in the direction we want to be going.

    Ms. PELOSI. You mentioned the immune system. I wondered if you could tell us about the potential import of the genome project for knowledge about the human immune system in general, and HIV in particular.

    Dr. COLLINS. Sure. The Human Genome Project is very democratic. We care about all the genes, no matter what diseases they're involved in. We're determined to find them all. And certainly, the immune system is an extremely important part of this goal.

    Dr. Varmus was talking earlier about getting to the point where it's hard to even put all the pathways into your head. Well, the immune system has a lot of pathways that are being worked out, which are clearly complex and which the Human Genome Project is contributing additional complexities to, challenging us to figure out how it works.

    There are many disorders of the immune system, some inherited, a few of which are actually the first targets of gene therapy, and some acquired, as in AIDS, for instance. We have a gene therapy trial in the intramural program on AIDS, which is looking very interesting. This is a very challenging strategy.
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    Dr. Rick Morgan and Dr. Michael Blaese have identified about 150 identical twins where one of the twins has AIDS and the other does not. The idea is to take cells from the unaffected twin, put into those cells a gene therapy vector, and then infuse them back into the affected twin. There will be no problem with compatibility, since they're identical twins.

    It gives you a very elegant system to see whether your therapy is working. If it does, the cells that you've put the gene therapy vector into should survive longer than the patient's own cells.

    There is some hint that this is beginning to show promise. These vectors have already shown promise in a monkey model, published this past month in Nature Medicine. So all of these tools certainly can be applied to that very challenging problem. And again, I think the Human Genome Project is in the happy circumstance of being able to say almost everything we do has the potential to help some disease.

    Ms. PELOSI. Thank you, I appreciate that.

    Is my time up, Mr. Chairman?

    Mr. PORTER. Yes, I'm afraid so. We were operating on the 10-minute rule.

    Ms. PELOSI. Thank you, Mr. Chairman.

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    Mr. PORTER. The Chair has just spotted Craig Higgins in our audience this morning, the former clerk of our Senate subcommittee counterpart. Craig, we are delighted to see you. We welcome you, we wish you well in your new position, and we know that you are intellectually challenged in it with the Institute. [Laughter.]

    Dr. COLLINS. He's intellectually challenging us, too.

    Mr. PORTER. I imagine he is.

    Mrs. Lowey, you have five minutes.


    Mrs. LOWEY. I'll be very brief, I just have two questions. I appreciate the time you've taken with us this morning.

    One is a puzzle to me. We spent some time talking about the bill that Louise Slaughter has and the one I have prohibiting the genetic discrimination. The pharmaceutical companies have not embraced these issues. You talked a little bit before about working with the private sector. It would seem to me that it would be in their best interests to embrace these bills, because of the important research they are doing, that they should be concerned about the public's concern about discrimination and stigmatizing.

    Do you have any recommendations? I wonder how we can work that out with the pharmaceutical industry and the biomedical research community in helping us move these bills along, which also would help them move their research along even more quickly.
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    Dr. COLLINS. Well, I think statements like the one you just made are very important. Because I think in fact the pharmaceutical industry is quite concerned about these issues. Clearly, their future depends on the public feeling comfortable with genetics as part of medicine. If the public is afraid to use this information, then all the investments that are being made now in gene-based therapies, and pharmacogenetics may fall on an unreceptive public, and that would be pretty bad for their business.

    So in that regard, I think they are actually very supportive of solving these problems of discrimination in health insurance and employment.

    Mrs. LOWEY. Quietly.

    Dr. COLLINS. Quietly. Traditionally, large industries do not take positions that are seen to be in opposition to other large industries' positions. And in this regard, I think pharmaceutical companies are reluctant to take a strong visible stance on a topic which the health insurance industry is not so happy about.

    I think that has led to some reticence to be as vocally supportive as might otherwise have happened. I think statements from people like yourself would be very helpful in that regard, because I think you have stated it correctly, that they have a lot at stake here, too.


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    Mrs. LOWEY. I thank you. And lastly, and this is probably a larger philosophical question, but I had a lunch meeting with a group of really outstanding scientists at Harvard just a couple of weeks ago. We got into quite a long conversation about why scientists spend hours and hours in the lab finding answers to challenging problems. And the scientists said to me, no names, in fact, quite a well-known scientist, that, we spend all weekend, and night after night working in the lab to find solutions to challenges, not because there is an application to human problems or to solve human problems, but for the joy and the gratification of solving the problem—Dr. Varmus is shaking his head.

    And I as a Congresswoman kept saying, I don't believe this. How could you just be working on solving a problem unless you know it can relieve human suffering such as cancer or can solve a problem directly connected to human life? I gather this is a larger problem and a larger question.

    But my direct question, which follows up on my colleague Ms. Pelosi's question, because I don't want to wait decades and decades and decades, and I wonder, what new therapies do you envision resulting from our mapping of the human genome and perhaps this will be a longer conversation, but I know that people in your institute are directly focused on solving the pain and suffering that results from human illness.

    So if you want to touch briefly on the first, or maybe go to the second.

    Dr. COLLINS. I can't resist touching on the first. I think scientists involved in an exciting mystery get caught up in that situation. You can glimpse that an answer is coming, but you don't quite have it, and then you do the right experiment and you get a clear result. Suddenly you realize you know something that nobody knew before. That in itself is an enormously gratifying experience.
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    But on the other hand, I think, the majority of people who went into biomedical research had a larger reason to do that. They wanted to do something for humanity. That's certainly true of myself.

    You can do both of those things. You can have this large goal, but also, to be realistic, it's hard to perceive that your little effort is making a major impact on humanity week by week. You can still get pretty jazzed about the experiment that gave a new result, gave you insight into something that's a purely intellectual problem. I think a scientist needs both of those features to be effective in biomedical research.

    So I think you did get a fairly accurate description. But I wouldn't lose heart that the scientific community out there is solely driven by intellectual academic interests, and that they don't care about finding cures for disease. I think they do.

    Mrs. LOWEY. Maybe at Harvard.

    Dr. COLLINS. Oh, yes, right, it was Harvard, after all.

    Now, to come to your specific question about the future that we could hope to see come out of the Human Genome Project, and I do feel pretty passionate about this, I think the reason we're doing this project is to cure illness and alleviate suffering. It may be wonderful basic science, and it is, and it may be exciting to see that latest revelation of a basic science, and that is true. It's good for biotechnology and it's probably good for the economy.
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    But the real reason we're doing this is your reason, to try to, as quickly as possible, get answers to unanswered questions that will lead us towards cures. Now, how are we going to see that happen? In some instances, the gene discovery itself will provide you with an idea. We talked about hemophilia as an example, where the normal gene becomes the drug.

    And after I think a number of years of really struggling to find out how to do this, gene therapy is beginning to provide new insights. And I think it will find a place for many diseases. But probably not all.

    Perhaps even more generalizable will be this notion that by understanding at the most precise molecular level what's wrong, which we haven't been able to do for most diseases, that you could then design a therapy that goes right to the heart of the problem, that really takes care of the issue, the way we have seen happen with protease inhibitors and HIV, for instance. But we need to apply that to diabetes or to hypertension or to coronary artery disease or to schizophrenia—not just treating the symptoms, not just relying on empirical good guesses to find the best drug, but really knowing at the molecular level what the problem is you have to solve. That's the hope for cancer right now that's leading to so much enthusiasm. Because that particular molecular puzzle is really beginning to reveal its secrets.

    To make that happen, though, we need this cadre of partly basic science, partly clinical investigators, to come up with those insights and then to try them out. I am delighted that at this very opportune moment, the NIH is enjoying this kind of enthusiastic support from this Congress and from the Administration as reflected by the budget that we're here talking about during these two weeks. There could not be a better time to have that happen.
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    Mrs. LOWEY. I thank you. And as you well know, our Chairman and this committee are all very strong supporters. We're even sorry to take you away from your important work. [Laughter.]

    Dr. VARMUS. I would just caution you, Mrs. Lowey, not to be disheartened by the attitude you heard expressed. Because while it is important to know that there are many of us who are focused on the applications of knowledge, we need to have a cohort that is simply excited about the solutions they're trying to come up with.

    Much of the great work that Francis Collins and his colleagues are trying to do now is only possible because 30 years ago there were people trying to solve this problem of why certain bacterial viruses couldn't infect certain bacterial cells. That is the basis for the whole recombinant DNA revolution. It was a problem as removed from disease as any you can imagine.

    Mrs. LOWEY. I thank you.

    Thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Mrs. Lowey.

    Dr. Collins and Dr. Varmus, thank you very much.

    Ms. PELOSI. Is the hearing over, Mr. Chairman?

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    Mr. PORTER. Yes.

    Ms. PELOSI. Don't I get another chance? [Laughter.]

    Mr. PORTER. Well, I'm reluctant to hold them past 12:00.

    Ms. PELOSI. All right.

    Mr. PORTER. You can if you wish and if they're willing.

    Ms. PELOSI. Just for a minute, if I may. I won't do my basic questions, but I'll just follow up on the theoretical questions that Mrs. Lowey posed.

    Dr. COLLINS. That's fine.

    Ms. PELOSI. First of all, I just want to make a statement, and I'll be very brief, Mr. Chairman, it is exciting that, what you're doing is exciting, and we're all so delighted to be so supportive of it, and it's no accident. It's about the talent that is at the NIH, of course, the distinguished leadership of Dr. Varmus, being a Nobel laureate himself, with his own scientific credentials, as well as the ability to have these collaborative efforts scientifically across the board, and then with universities, with business, as well as the imagination that we see there. And that takes me to my question.

    Once a distinguished scientist brought some other scientists to my office to talk about worms. Do you remember that, Dr. Varmus?
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    Dr. VARMUS. I do, very well.


    Ms. PELOSI. Before Dr. Varmus was on the national scene, well, he was on the international scene. And I appreciate what you were saying about that excitement, of course, that a person would devote her life to studying these worms. And the outcome, of course, would be beneficial to all of us. But she had to be encouraged every day to go back into that lab.

    And what you're doing now with all these breakthroughs in science that we see, are we still in the discovery mode or is there a creative mode at work as well? Are we discoverers or are we creators? Or both?

    Dr. VARMUS. Both.

    Dr. COLLINS. Yes, I think you wouldn't want to have a sort of dividing line where you said, okay, right now we're just discovering, don't create yet.

    Ms. PELOSI. No, but I just wondered if we still need to discover so much more or——

    Dr. COLLINS. That's true, too. But we have a sufficient collection of fascinating data and observations. I'm glad you mentioned the worm. The worm will have its complete sequence known by the end of this year. We will have it, the encyclopedia of how the C. elegans worm works.
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    That represents a lot of discovery, and creativity has already started to be applied in a big way. We've learned insights from the worm about aging, about diabetes, about development, about cancer, a whole host of issues. So it's a very good example of how these two things are intertwined. You do the discovery, but you do the creativity as early as you can.

    Ms. PELOSI. Dr. Borenstein, you know, has written about discoverers and creators. We're all finding out something new, it's just a question of if it's something that was there that we found, or it's something we created, and also where we go from there. Last year, Dr. Varmus divided his testimony, what was it, Dr. Varmus, illumination and—

    Dr. VARMUS. Inspirations and culminations.

    Ms. PELOSI. Inspirations and culminations. So following his lead of placing these things in categories, I just wondered.

    Dr. VARMUS. It's possible the distinction that Dan Boorstein makes may be more appropriate to the arts than to the sciences. We could pursue that.

    Ms. PELOSI. Well, he also talks about discovering things that aren't. You discover things that aren't, and that's knowledge as well. You discover places that aren't there.

    Dr. COLLINS. Right. Little harder to publish, but very important. [Laughter.]
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    Ms. PELOSI. Well, eliminating possibilities is a gain in knowledge.

    Dr. VARMUS. Published in different journals. [Laughter.]

    Ms. PELOSI. In any event, I want to join my Chairman, I told him I would be brief, I don't know if I was, but in any event, thank you very much for your work, Dr. Collins, and your leadership. Thank you, too, Dr. Varmus, and everyone here.

    Mr. PORTER. And let me add my thanks. You're doing wonderful work. I always like to hear under budget and ahead of schedule. That's wonderful as well.

    We're always fascinated to sit down with you and Dr. Varmus and we learn a great deal every time we do. So thank you very much for the fine job you're doing there, and for your testimony.

    Dr. COLLINS. Thank you, Mr. Chairman, for your leadership. Thank you for giving us a whole morning. That's a really wonderful luxury for the National Human Genome Research Institute to have that opportunity.

    Mr. PORTER. It's a luxury for us as well.

    The subcommittee will stand in recess until 2:00 p.m.

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    [The following questions were submitted to be answered for the record.]
    "The Official Committee record contains additional material here."

Wednesday, March 18, 1998.









    Mr. PORTER. The subcommittee will come to order.

    We continue our hearings on the budget of the National Institutes of Health and are pleased to welcome Dr. Anthony Fauci, the Director of the National Institute of Allergy and Infectious Diseases.
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    Dr. Fauci, would introduce the people that you brought with you, and then proceed with your statement.

    Dr. FAUCI. Thank you very much, Mr. Chairman. I'd like to introduce, on my far left, Dr. Milton Hernandez, who is the Acting Director of the Office of Research on Minority and Women's Health in our Institute; Dr. John La Montagne, who is the Deputy Director of the Institute; Mr. Thomas Williams, who is the Director of our Financial Management Office; and you know Dr. Varmus and Mr. Dennis Williams.

    I've submitted my written statement for the record, Mr. Chairman. I would like to take just a few minutes with some visuals to highlight some of the features of that if I could.

    One of the very impressive advances that has occurred in HIV/AIDS research and health care delivery over the last year has been the rather remarkable decrease in the number of deaths due to HIV/AIDS. [See figure 1]

    [The information follows:]
    "The Official Committee record contains additional material here."

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

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

    One of the very dramatic emerging and reemerging microbes has been malaria, something that is very under-appreciated in the developed world. [Figure 4] The statistics for malaria are staggering. Three hundred to five hundred million people are infected, with up to three million deaths per year. And the most dramatic figure of all is that every 20 seconds a child dies of malaria in this world, which is just absolutely tragic. What we've done at the NIH, under the leadership of Dr. Varmus, has played a major role in a multinational multilateral initiative on malaria, where we are lending our research and other efforts to a global effort regarding malaria research and the development of drugs and vaccines.
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    The importance of this is that we've involved host countries, particularly sub-Saharan and African countries, as well as selectively putting additional research resources, and, in addition to that, accelerate the development of a malaria vaccine program, including both the intramural program at NIH as well as the extramural program through our grants.

    Another example of an emerging and reemerging disease is the experience we had this winter with the H5N1 avian influenza. [Figure 5] This was an excellent example of the collaborative capabilities and efforts among Public Health Service and nongovernmental organizations, particularly with regard to the CDC who did an absolutely terrific job in their response to H5N1 in Hong Kong.
    "The Official Committee record contains additional material here."

    The NIH's role, being a research institution, was to use our capabilities, particularly the fact that we had already made an antibody to H5N1 that was in our repository. We gave the antibody to the CDC, and they used it in the development of their diagnostic kits. These kits were so important in the screening and surveillance in the Hong Kong area as well as to the State and local health authorities right here in this country. We moved very rapidly on this. In fact, this was a good example. Dr. Varmus utilized his Director's reserve and gave us money in the middle of the fiscal year to supplement grants for NIH grantees to actually go to Hong Kong and play a major role in this effort. And, as you know, it turned out very well, but we need to keep our guard up because this may not be the end of H5N1.

    Vaccines, as I've said to this committee several times in the past, are really the fundamental foundation of how you attack global diseases and have a major impact on public health. [Figure 6] Over the past several years, I have testified regarding each and every one of these vaccines to this committee. I just want to point out that the global impact of each of these has been most extraordinary. A very cogent example of the application of fundamental research all the way through to the delivery of health care.
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    "The Official Committee record contains additional material here."

    H. influenza type B is a very good example of this. When I first testified before this committee a few years ago, I told you that this had the potential to essentially wipe out the leading cause of mental retardation and deafness in children. If you look at the statistics in the United States, this disease is actually disappearing due to the vaccination programs. The impact is very impressive even in developing countries. There was a recent study from The Gambia in Africa in which there was equally as impressive results from vaccinating the children against H. influenza.

    Finally, one of the things I'd like to mention to you that—I see Ms. Pelosi walk in and she keeps asking me to talk about breakthroughs—I'm not going to say breakthrough, Ms. Pelosi, but I'm going to say this I think is going to revolutionize how we look at transplantation in immunology——

    Ms. PELOSI. Is it a culmination? [Laughter.]

    Mr. PORTER. Thank you, Ms. Pelosi.

    Dr. FAUCI. Close,—and that is the concept of immunological tolerance. [Figure 7] Again, another example of taking fundamental basic research discoveries of how the immune system works and literally tricking it into not responding to something you don't want it to respond to. The most cogent example of that is a solid organ transplant. But it also has impact on autoimmune diseases as well as allergic diseases.
    "The Official Committee record contains additional material here."
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    Let me give you a very brief example of what I'm talking about. The entire immune system when it recognizes something like an organ transplant, does so in the context of the cell that responds, which we call a T-cell, seeing the antigen in question. [Figure 8] If this were a transplantation antigen in the context of another cell that presents it, in order for this cell to respond and ultimately get rid of the graft, there has to be two signals. There has to be the recognition signal and what we call the co-stimulatory signal. When that happens, this cell responds and all the progeny cells from this cell will forever try to eliminate that transplant.

    However, researchers have discovered if, at the time that this cell sees that antigen, you block the second signal, not only does this cell not destroy the graft, but its progenies will never recognize the graft. If this works, and it has worked in animals, if this is successful, then we will not have to immunosuppress people who have organ transplants. And, as you well know, one of the major causes of morbidity and mortality in transplant patients is the immunosuppressive therapy that you give to people.

    I'd like to close with a slide, a version of which I show every year [Figure 9], and that is to reemphasize to you the important marriage and dependency back and forth between basic research—with regard to our Institute it's immunology and microbiology, but for other Institutes it can be any of the other disciplines—feeding into the practicalities, in our case drug development, vaccines, and diagnostics, and then the practical applications ultimately feeding back into the basic research. That's exactly how the progress has been. The examples that I have shown you in this testimony are good examples of just that.
    "The Official Committee record contains additional material here."

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    I'd be happy to answer any questions.

    [The prepared statement follows:]
    "The Official Committee record contains additional material here."

    Mr. PORTER. Dr. Fauci——

    Mr. HOYER. We're just going to cheer.


    Mr. PORTER. Well, we should all cheer. The successes that have occurred particularly with reference to HIV/AIDS has just been one of the great success stories of all biomedical research. AIDS deaths have dropped 44 percent when comparing the first six months of 1996 to the first six months of 1997. New AIDS diagnoses are also declining. The NIH and the researchers within NIH and the researchers that it has funded have done an absolutely magnificent job in addressing a real threat to humankind and have put it on the defensive, although we have not, as you've very carefully pointed out, yet conquered it.

    Dr. Fauci, you mentioned that HIV was only one of the infectious agents that you have to deal with; there are so many others, many causing more deaths around the world even than this. Today, if you look at your budget, AIDS research consumes about 52 percent of your entire spending on research activities. If you looked out five years to the outyears, where do you see that percentage number headed? Is there any way of telling where we might be five years from now in terms of how much you have to spend in that particular area as opposed to others?
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    Dr. FAUCI. Well, Mr. Porter, there are two components to my answer. The first is that it's very difficult to predict, particularly given the fact that we're still having an evolving epidemic. Although the numbers in our own country are going down, we cannot slack off on drug development and clinical trials. We have a very, very important goal that we need to fulfill with regard to vaccine.

    But in NIAID, and with Dr. Varmus and NIH as a whole, we're starting to look at the idea of emerging and reemerging microbes and to encompass HIV as one of them. So when you think in terms of where we'll be with HIV, I think that needs to be balanced with where we might be regarding our opportunities in malaria and tuberculosis and others. So I tend to like to look at the entire effort as global health and emerging diseases of which, as you conquer one, then you can accelerate an effort on the other. That's exactly the point that I try to make.


    Mr. PORTER. I don't need to tell you that, as the success in dealing with HIV/AIDS has shown itself, there is increased pressure on the Congress and this subcommittee to deal with other diseases that might, had we had no HIV/AIDS epidemic, have received more funding and a chance perhaps to make the same kinds of—and I know you don't use the word breakthrough, but I'll use it—that same kinds of breakthrough that we've had in reference to HIV/AIDS. So, obviously, we are vitally interested that we not only continue the progress on AIDS, but that we look at the other diseases that are plaguing humankind and attempt to reach the same level of success in dealing with them.

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    What about the liability issues regarding an AIDS vaccine, are you dealing with that subject?

    Dr. FAUCI. I do not think that with regard to a vaccine trial, Mr. Porter, that this is going to be a major issue. It always comes up as a potential disincentive for industry to get involved. But if one looks at the way a trial is conducted, you actually have the types of informed consent that I think would be satisfactory, as we do in any vaccine trial.

    If we develop an HIV vaccine and we do have a successful safe and effective vaccine, then I think the liability issues associated with them would fall under the same category of the liability issues that we have with virtually every vaccine. A few years ago, that was kind of circling around as a potential disincentive. In the interactions that we've had with the companies that have been involved or potentially involved in the development of a vaccine, I don't see that as a very prohibitive issue right now.

    Mr. PORTER. Dr. Fauci, we have a vote that has been called. As I understand it, it is the last vote of the day. We will have to take a short recess. The subcommittee will stand in recess briefly.



    Mr. PORTER. The subcommittee will come to order. Dr. Fauci, we've made a change in the way OAR is funded, as you know. Have you noticed any change in the way the funding mechanism now works from the way it did before? And, if so, is the change of substance as far as the funding for OAR and your Institute is concerned?
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    Dr. FAUCI. No. Actually, quite frankly, Mr. Chairman, in the interactions between OAR and the Institutes over the past few years really, there has been no noticeable difference with regard to the change in funding. The planning function, the coordination, and the interaction has been really quite good. Where the funding lands and evolves from really has not had a substantial impact, certainly not on NIAID and I don't think from my sister Institutes. It has worked well.

    Mr. PORTER. This is a question for Dr. Varmus, although you both may want to comment. At last year's hearing, you mentioned that the Office of AIDS Research had carried out a review of the entire AIDS portfolio and came up with a number of recommendations. They did not ask for more money; instead, they asked for better use of the money.

    My question is twofold. One, what were the recommendations from the OAR to make better use of the AIDS portfolio and what changes did you make to implement these recommendations? Secondly, why, since they didn't ask for more money, are we seeing an increase in the AIDS budget request?

    Dr. VARMUS. As far as the first question is concerned, among the many recommendations, a few were of special importance. One was a suggestion that more money go into tradition RO1s—that is, more investigator-initiated research. Indeed, there has been a major shift, I don't remember the exact percentages, but the shift is very substantial, nearly a doubling of the amount of money that goes to investigator-initiated research in the AIDS program.

    The second major recommendation that has a budgetary impact was for increased attention to development of an AIDS vaccine and to work on human immunology. As you know, in both of those areas there has been a very substantial realignment of the budget.
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    There were a number of other minor recommendations, virtually all of which have been carried out—I think very much to the benefit of the program—including increasing efforts to cope with the spread of infection through behavioral strategies and epidemiology.

    The budget increase requested for AIDS this year is substantial, of course, but it is below the NIH average and only slightly above the smallest increase that we were asking for any of the Institutes. We believe that there are very significant opportunities in the AIDS portfolio for further work. As Dr. Fauci has outlined to you, the problem is far from over. We are quite concerned that the 44 percent drop in mortality that we have seen is a drop that is caused by effectiveness of the drugs in those patients for whom drugs are going to work. We still don't know what's going to happen over the next few years. That graph may not continue to plummet, but may, instead, plateau because we know there is a very high frequency of drug resistance and a high frequency of a failure to tolerate the protease inhibitors.

    Moreover, we know that the drugs we're currently using are not usable in the parts of the world where AIDS is most prevalent, and we want to be able to develop drugs that will work in those situations.


    Mr. PORTER. Why is that? Why aren't they usable in other parts of the world?

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    Dr. VARMUS. Because they're too expensive.

    Mr. PORTER. So it has to do with the cost of them?

    Dr. VARMUS. Yes, the cost is prohibitory. Of course, it is not just the cost of the drugs. It's the cost of the entire care system required to use these drugs. The monitoring of efficacy is based on monitoring of what we call viral load, which at this point is still a sophisticated analysis that depends upon DNA and RNA hybridization. So the care is simply too elaborate for what can be performed in most developing countries where most of the AIDS cases reside.


    Mr. PORTER. Dr. Fauci, how do you view the long-term role of the pediatric AIDS clinical trials? Will the success of AZT and limiting prenatal transmission continue? Will it be difficult to find enough infected infants to test combination therapies and other therapeutics?

    Dr. FAUCI. I think ultimately that's our goal, that there will not be enough infants to be able to do that. But currently, at the present time, there are still enough infected infants that require the kind of clinical trial apparatus that we have. We will of course, as these mechanisms come up for recompetition, examine, as we've done with the adult ACTG and the CPCRA, the size, the scope, and the need for a particular approach that we would have. We constantly monitor that. Actually, our goal would be that we would not need that ultimately, but the goal has not been attained yet.
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    Mr. PORTER. Thank you, Dr. Fauci.

    Mr. Stokes.


    Mr. STOKES. Thank you, Mr. Chairman.

    Dr. Fauci, it's a pleasure to welcome you back before our subcommittee. As Mr. Hoyer said when you finished your presentation, rather than ask you questions, we wanted to cheer. I think all of us are proud of your preeminence in the field of medicine, and it's a pleasure always to have you before us.

    You started your presentation with a chart on AIDS and talking about the fact that we're now seeing some decrease in AIDS. However, you were present in the hearing room a few days ago when Dr. Brule, of the Centers for Disease Control, and I discussed the fact that AIDS in the black community is seven times that of the rate in the white community and three times the white rate for hispanics. In fact, I cited the fact that within the next hour seven persons will contract HIV/AIDS, and that of them, three will be minorities.

    So while you give us some good news in terms of the decrease in the number of aids deaths, we're dealing with these type of statistics. Is the news as good as it relates to minority communities?

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    Dr. FAUCI. No. The answer is, no, it is not as good. In fact, if you look at the decrease in deaths and the decrease in new cases, it is skewed with much less of a decrease among minorities and actually an increase among women and heterosexuals. Among the heterosexuals, particularly in the inner-city areas, there is a skewing of the curve towards African-American and Hispanics in those situations. So although the total numbers are getting better, at best they're holding steady, and in some cases actually not doing very well at all.

    At the NIH, we have tried to address that because, as you might imagine, it's a very complicated situation that's really very integrally related to the inadequacies of health care delivery to inner-city and disenfranchised populations. What we've tried to do is several things.

    One is, we have tried to keep the enrollment of minorities in our clinical trial program at least to the level, and even a greater proportion than the percentage of minorities that are infected with HIV and have AIDS. As I've told the committee over the past few years, we started off at what we all considered was an unacceptable number. But right now 35 percent of the AIDS cases are among African-Americans and 37 percent of the enrollment in our clinical trials is of that group. So we are keeping up with that.

    We also have other mechanisms that are fundamentally aimed at trying to bring minority populations into our research efforts: our HIV Network on preparatives and prevention, our Women's Interagency Health Study, and our Women and Infant Transmission Study. We've been relatively successful.

    We're not doing enough, but we're doing a lot. There are things that are beyond our control, and that's the health care delivery components that I have mentioned to you. But I share with you the concern you have that the numbers, if we broke them down for minorities and non-minorities, we would see something that wasn't as encouraging in the minorities.
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    Mr. STOKES. I appreciate very much your response.

    Let me ask you this. In terms of trying to engage in outreach, and I suppose your Institute does have some outreach aspect.

    Dr. FAUCI. Yes.

    Mr. STOKES. I'm concerned, for instance, about the fact that up at the Harvard AIDS Institute, with which I'm sure you're familiar, I sit on that advisory board up there, just recently reported that they fear that while the appropriations may be satisfactory, a lot of the money is not filtrating down to community groups, where outreach is prevalent, in order to try and attack this overall problem.

    To what degree are you engaged in outreach in this area?

    Dr. FAUCI. We have a significant engagement in outreach in our clinical trials and in our prevention efforts. A good example of that is our community groups that are associated directly as an integral part of our AIDS Clinical Trial Group. For every clinical trial group unit that we have, we have a community program that actually outreaches into the community.

    So, unlike what it was years ago, before we even begin to think about executing a clinical trial in a community, we have community representatives that are actually an up front part of the process of discussing the feasibility of it and whether or not it's going to fit with the community. That's something that we instituted several years ago and it's working very well. I've actually been personally involved in it and meet at least once and sometimes twice a year with the community groups.
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    Mr. STOKES. Good. You mentioned in your presentation an HIV vaccine. How far are we away from achieving a vaccine for AIDS?

    Dr. FAUCI. I can't tell you in terms of years, but I can tell you that we have mounted an accelerated effort to try and iron out some of the unknowns about it. Namely, what we call the correlates of immunity, to take some new innovative approaches to dissecting out some of the mysteries of how the body responds to HIV and contains it. It would not be appropriate for me to say it's going to be two years, or three years, or five years. But suffice it to say, that over the past two years, and as we go into the millennium, we are selectively having more activity and resources towards the HIV vaccine.

    We have a candidate approach right now that is in Phase II trials in many of our vaccine evaluation groups. It is predicated on the concept of priming someone with an HIV antigen that's incorporated into a vector, in this case a pox virus, a Canary pox or a vaccinia pox, and then boosting the person on multiple subsequent times. In that approach, we have what we did not have with the simple GP120 protein that we discussed here I believe three or four years ago. In addition to having antibody response, we have a cytolytic T cell or cell-mediated immune response. We're going to be evaluating that data in mid to late summer to make some sort of a decision of where we go with that; do we expand it or do we incorporate other limbs. So there is some promise in that regard.

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    Mr. STOKES. I was interested in your presentation this morning relative to emerging microbes where you talked about malaria and the fact that every 20 seconds a child dies from malaria. What part of the world are we talking about?

    Dr. FAUCI. About 90 percent of the malaria deaths that you're talking about are in sub-Saharan and Africa. So it's a very heavy burden in sub-Saharan and African countries.

    Mr. STOKES. Thank you, Dr. Fauci.

    Dr. FAUCI. Before you leave, Mr. Stokes, I just want to make mention of something that other institute directors have said. This is my 14th year that I've appeared before you now and I just want to say that we're going to miss you very, very much. You've been wonderful with us and we truly, sincerely appreciate it and thank you for everything you've done.

    Mr. STOKES. Thank you very much, Dr. Fauci. Thank you, Mr. Chairman.

    Mr. PORTER. Thank you, Mr. Stokes.

    Mr. Hoyer.

    Mr. HOYER. Dr. Fauci, again, all of us welcome you. I think the dramatic success that your chart and the work reflects is a powerful support of the support this committee has given in terms of some of the priorities. We needed to look at AIDS which, in terms of numbers is outranked by some in the United States in gross numbers, perhaps not in fatalities per infected, it may be the highest disease still?
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    Dr. FAUCI. Yes.


    Mr. HOYER. But from Presidents Reagan and Bush to President Clinton and this committee, the support that has been given to AIDS research has been very substantial. I think this is something we can point to and say, look, if you dedicate resources to it, it can have a pay-off. Quite obviously, I think we all look forward to the day when we will have similar statistics for cancer, a dramatic turnaround. That will be a great day for all of us.

    I wanted to ask you a question I obviously have a personal interest in. You have been quoted as saying, or you've mentioned at least, that some cancers are virus related, stomach cancer perhaps being one of those. Could you comment on that a little further? Obviously, that's the cancer which Judy died of and I have a real interest in that.

    Dr. FAUCI. Right. In the case of stomach cancer, it is not a virus, it's a bacteria, Helicobacter pylori. As we learn more and more about microbes, and as we have the capability of identifying microbial associations with cancers by molecular probes, as the years go by, we see more and more. We know there's an association of human papilloma virus with cervical carcinoma, a B virus with certain types of lymphoma, of Helicobacter pylori with gastric carcinoma, of hepatitis B and hepatitis C with carcinoma of the liver. The list goes on and on.

    There's a very important amount of information that needs to be learned, because all of us in the field believe that we will probably continue to see more associations, either direct or indirect, as cofactors that are involved in cancer. That's the reason why we're seeing a sort of crossroads of infectious disease and microbiology with cancer research. A very, very important area of research.
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    Mr. HOYER. One of the things that struck us as we faced that was the few number of instances of stomach cancer in women in the United States versus the Far East where there apparently is a very high incidence and, therefore, a much greater inclination for early diagnosis. One of the things in Judy's case that we were so taken aback by was that it took so long to find out, even after going the first three visits to Hopkins. They did not find it until the fourth visit when they finally diagnosed the cancer. It, of course, grew in the lining of the stomach and did not tumor. They thought it was an ulcer.

    What are we speculating? Is this diet related?

    Dr. FAUCI. It is probably, as is the case with many cancers, multifactorial, a combination when you think of it, a microorganism that contributes to people who have some sort of predisposition. Just because you have Helicobacter pylori doesn't mean that you're inevitably going to wind up with gastric cancer. Also, genetic makeup and genetic background, I'm certain that there is some genetic component to it that has not yet been deciphered out. Then you add on that dietary component and you have what we call the multifactorial nature of cancer.

    All the things have to be in the right situation for you to get a cancer, which is the reason why very rarely, if ever, do you see an absolute one-to-one relationship between a cancer and a particular factor, be that a microbe or a genetic factor. In some, there are very, very strong relationships, such as some of the breast cancer genes that have been delineated and shown to have in certain populations an extraordinarily high incidence. But it is usually a combination of multiple factors that just have to hit it right for you to get a cancer.
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    Mr. HOYER. Let me shift. I think it was on your last chart as you went around, you had the only malady, if I could use that term probably imprecisely, was asthma and other allergies in that chart.

    Dr. FAUCI. Right.

    Mr. HOYER. That interested me because you did not have any other specifics. I suffered from asthma. Why was that? And what are you doing in your Institute as it relates to the other Institutes that focus on asthma?

    Dr. FAUCI. The reason I put asthma there is because it's particularly amenable to the approach of immunological tolerance that I mentioned to you in the previous poster. There are two ways, well, there are multiple ways, but there are two major ways that we at the NIAID, and the National Heart, Lung, and Blood Institute also has a major effort on that, are looking at asthma.

    One way is from the concept of more of a health care delivery component, where our inner-city asthma program has identified certain factors, such as cockroach allergen and the proper way to take medications. So that when you have a counsellor or an outreach person who is there making sure the medications are being taken properly, they are also making sure that children who have an asthma diathesis are not in an apartment that has cockroach antigens all over it. The hospitalizations have decreased by a considerable amount over the couple of years that we've been doing it. That's the more practical approach to health care delivery.
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    On the more basic approach, the immunological tolerance and trying to tolerize the system when it sees the antigen that would normally trigger an asthma attack on you, would have the same sort of refractor as I was referring to regarding the organ transplants. I think that's in the foreseeable future.

    Mr. HOYER. Obviously, an allergy triggers a reaction and the mucus is formed. Did you see the movie ''As Good As It Gets''?

    Dr. FAUCI. No. No, I didn't.

    Mr. HOYER. It is a pretty neat movie. You'd like it. Part of the story is about a waitress who has Jack Nicholson as sort of a kooky client or customer. But ultimately he interfaces and becomes——

    Ms. DELAURO. Don't tell the end. [Laughter.]

    Mr. HOYER. I'm not going to tell the end. But he becomes someone who helps her get her child treatment for asthma. Her child suffers from asthma. But in the course of that, of course they excoriate HMOs because the HMO has not funded all of the processes that are necessary to find out what allergens the child is responding to or what's causing this problem. And, the bottom line is he gets better and that's great.

    How prevalent do you think that is? In terms of the children who do not have access to private health care but are getting clinic care or some other lower cost care, how prevalent do you think it is that a lot of children in America are suffering who otherwise could through intervention be relieved of suffering because they are not getting proper health care?
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    Dr. FAUCI. It's very prevalent.

    Mr. HOYER. Very prevalent.

    Dr. FAUCI. In fact, that's one of the targets of our inner-city asthma program. We were seeing that children in the inner-cities were not properly instructed on how to take their medications and there were many more hospitalizations and even some deaths among those children, merely because what is available to someone who has a physician, who on a consistent basis tends to them. The difference between that and someone who does not have that access is extraordinary.

    Mr. HOYER. Doctor, this may sound off the wall and you'll wonder why is Hoyer mentioning this. I am a big proponent of what I'm now calling full service schools. Full service schools would have a very strong health component to them, mainly in the elementary school. One of the reasons is in these communities where children don't have access to good health care, particularly when it is a relatively simple intervention and a relatively inexpensive intervention, it is criminal that in a country as wealthy as the United States of America is we are allowing children to go undiagnosed and unserved in terms of health care.

    In any event, Mr. Chairman, this is another reason why I'm going to hound all of you on the full-service school concept when we have markup.

    Thank you, Doctor.

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    Mr. PORTER. We like it, Mr. Hoyer. Thank you.

    Would Mr. Miller take the Chair, please.

    Mr. MILLER [assuming chair]. Ms. DeLauro.

    Ms. DELAURO. Thank you, Mr. Chairman.

    Dr. Fauci, as I came in during your presentation and was listening to you, and having listened to you in the past, my colleague, Ms. Pelosi, yesterday said to Dr. Alexander that he must have one of the best jobs in the world. I was just sitting here thinking as I was listening to the questions that I think we've got the best job in the world. We have the opportunity to listen and, hopefully, to learn something of what you, specifically, with the other directors in NIH are doing.

    It really is a remarkable opportunity that we all have. I don't mean to be hokey, I truly don't. I am so delighted that I have the opportunity to be in this institution and to serve on this committee and listen to the incredible kinds of research that is being done and what it means in terms of lives of people in this country. I just wanted to say thank you for all of that.

    Dr. FAUCI. Thank you.


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    Ms. DELAURO. The whole issue of sexually transmitted diseases continue to affect a large number of Americans, particularly women and minorities. Studies show that if we can reduce the number of new infections of diseases like syphilis we can also reduce the number of people who contract the HIV virus. My interest is in getting some update on your work that helps us to prevent and control the sexually transmitted diseases.

    Dr. FAUCI. We have an effort that we have been accelerating over the past couple of years that is centered around our sexually transmitted diseases centers, which have not only a fundamental basic research base looking at the biology and the microbiology of STDs, but also that have a behavioral component in it. In other words, a biologically based behavioral component.

    The point that you made about the relationship between sexually transmitted diseases and, for example, HIV transmission cannot be underestimated because there are definitive studies in other environments that show that. For example, a study in sub-Saharan and African countries showed that if you go into a village and treat just the sexually transmitted diseases and do not have anything else to do with HIV, you can markedly cut down the transmissibility of HIV merely by getting rid of those infections that leave genital ulcerations which markedly increase the efficiency of transmission.

    Another thing about sexually transmitted diseases that came out this year that I didn't have the opportunity to talk about last year because it happened just a few months after last year's hearing, is the importance of early diagnosis of chlamydia infection in women. Look at the relationship between chronic pelvic inflammatory diseases and chlamydia. If you go in and diagnose chlamydia in asymptomatic women and treat them, even though they don't have symptoms, as compared to waiting until the woman comes into the office with symptomatic chlamydia, the decrease in chronic pelvic inflammatory disease is extraordinary. It goes down by about 30 or 40 percent just by having the diagnostic capability and the health care delivery capability of bringing women in and diagnosing it even when they don't have symptoms.
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    Close to the majority of the chlamydia infections are essentially asymptomatic. Women do not know they have it until they wind up either having symptomatic pelvic inflammatory disease or they find out when they're trying to have children and they have tubes that are scarred. That's really a tragedy because the diagnosis can be made beforehand. You have just got to get them into the clinic and make the diagnosis. That, I think, has been an important advance over the last year.

    Ms. DELAURO. And getting them into the clinic, what's your sense of your advances in doing that? It's a little bit like what my colleague, Congressman Hoyer, was talking about with youngsters in school-based clinics.

    Dr. FAUCI. It's the same problem. Congressman Hoyer mentioned about asthma, Mr. Stokes mentioned it about the access to care among the minorities with HIV, and it's the same point you're making about getting women into clinics, it really relates to the adequacy of the access to health care delivery.

    Ms. DELAURO. Continuing on that just a bit, I'm interested in your work regarding HPV, and you made reference to it before. How has that research progressed? Are you continuing in your work with NCI on that?

    Dr. FAUCI. Yes. Actually, we have a very nice collaboration with the National Cancer Institute, ourselves fundamentally from the microbiological standpoint, the Cancer Institute from a oncologic and epidemiological standpoint. It is really working very well. It is again an example of needing to develop better diagnostic capabilities, the same sort of early detection that I mentioned with regard to chlamydia, as well prevention, certain types of outreach and education, in addition to ultimately therapies and vaccines which are always the bottom line of eliminating a public health threat like this.
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    Ms. DELAURO. Clinics with regard to breast and cervical cancer, if we can have these clinics in every State and so forth rather than just at random.

    Dr. FAUCI. Right.

    Ms. DELAURO. Or it takes us I don't know how many years to get there. I'm just sharing a frustration. I guess it's by virtue of your geography that could determine whether you live or die.

    Dr. FAUCI. Or your economy.


    Ms. DELAURO. Given the kind of work that's being done, given the rapid pace at which we're moving to understand some of these illnesses and the connections, it would just seem to me that that's the harder job. I just think that the easier part of the job is the outreach and the education portion of it. That is something that we should know how to do and we're being delinquent in getting what research and what information that we have that can save people's lives out to them in some way.

    Hepatitis C has emerged as a major cause of chronic liver disease. As you know, a large number of people may have unknowingly contracted the virus through blood transfusions and most likely will develop complications of the disease in coming years. Last year's committee report encouraged NIAID to develop an HCV vaccine, to conduct clinical trials research in order to find the best treatment for the disease. How have we progressed on the research and the carrying out of the clinical trials?
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    Dr. FAUCI. There has been some important advances that I think are going to lead to something that probably I'll be able to talk in more concrete terms about next year. But the research discovery is important; namely, that there has been a successful isolation of what we call an infectious cDNA clone of hepatitis C, which means that we have the molecular microorganism in our hands now so we can (a) use it in animal models to look at pathogenesis; and (b) that's the next step towards tailoring some more efficient and more effective antiviral therapies.

    Right now, the riboviren and the interferon alpha are the fundamental tools that we have for the treatment, but that is not a very effective treatment. The ultimate goal will be vaccination, obviously. Having the microorganism in its molecular form in our hands is the first major step towards developing a vaccine. If we could have the same sort of success that we've had with hepatitis A and hepatitis B and apply that to hepatitis C, I think we're going to have a major impact. As you well know, about 80 percent or more of the people who have hepatitis C go on to chronicity of infection. That's a very, very large percentage, whereas in, for example, hepatitis B, it is about 25 percent of adults and about 70 to 75 percent of children. But 80 to 85 percent is a lot. As you know, it is the leading reason for liver transplants today in this country.

    Ms. DELAURO. Thank you very, very much.

    Dr. FAUCI. You're quite welcome.

    Mr. MILLER. Ms. Pelosi.
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    Ms. PELOSI. Excuse me. I'm waiting for Dr. Varmus to bring in a picture of somebody with a chocolate addiction to see what their brain looks like. [Laughter.]

    Mr. VARMUS. It looks good, Ms. Pelosi, I hope. I suffer, too.


    Ms. PELOSI. I'm very happy. Sorry to do that. I was watching those charts before and I just had to go get some chocolate.

    Dr. Fauci, thank you and Dr. Varmus, all of you, for being here today. We've commended Dr. Varmus over and over again for his great leadership at the NIH. And you know what a hero you are to so many of us in the work that you do. We're just always happy each year that you're still there. That's my worry is that you won't be there one of these times.

    You co-chaired the HHS advisory panel which developed treatment guidelines for people with HIV. These guidelines have been critically important to health providers and policymakers as we work to maximize the benefits of the powerful new drugs in fighting HIV. In your opinion, how do the new treatments affect the scope of services that should be provided under the Ryan White Care Act?

    Dr. FAUCI. I think they're going to be very important in how we look at the various components of Ryan White, because we now have, as you know, looked very, very carefully at all the data and made strong recommendations that if an individual comes in with a certain level of virus and a certain degree of immunosuppression, that they need to be treated and they need to be treated with at least a triple combination of drugs. The other thing that we decided strongly on is that adherence to the regimens is critical, not only for the individual patient, but in order to avoid the emergence of resistance. So there are really two components of the Ryan White that are affected by that.
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    One is the Title II ADAP program. So there is no excuse right now for anyone to say that you can't give anything other than optimal therapy, which in this case would be triple therapy including a protease inhibitor. Now some of the recommendations are even going to be updated and might even include four drugs under certain circumstances. But, certainly, one or two drugs has clearly been said to be inadequate.

    With regard to the other aspect of the Ryan White; namely, the services component, the Title I, I think if we don't have that kind of case management, we're in danger of having people not have adherence to the regimen. To me, our recommendations do nothing but strongly fortify what is going on vis a vis the Ryan White provisions.

    Ms. PELOSI. I appreciate that and I thank you for your leadership in working to put out the treatment guidelines because they have been very important. I also appreciate your talking about the challenges that people face in complying with the complex drug regimens. Just doing sufficient outreach to people is difficult even in an area as sophisticated about this issue as my own. The physicians there tell me that we would be lucky if we can get 50 percent penetration into the market of people who should be availing themselves of these drugs.

    Dr. FAUCI. Right.

    Ms. PELOSI. And, of course, the other obstacle is the same old one, and that is sufficient resources for those who cannot afford the therapies.

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    But the guidelines, of course, went a long way in making it clear to the private sector as well as the public sector what needed to be done, and I thank you for that valuable contribution.


    I've asked Dr. Varmus and I've asked in my other committee, Foreign Operations, of the USAID director, what kind of intergovernmental cooperation you have on the international initiatives. I heard you when I came in earlier talking about malaria and AIDS as two initiatives. Can you talk about any interaction.

    Dr. FAUCI. Actually, it has been very good, Ms. Pelosi. One of the examples is the Multilateral Initiative on Malaria that has been led very nicely by Dr. Varmus himself taking a special interest in that. We have interactions with USAID, with the Department of Defense, with the FDA, with the CDC, and others, as well as international organizations. All of our AIDS efforts are grounded not only in national agency collaboration, but international collaboration.

    A very, very good example of the Public Health Service interactions and non-Public Health Service Government agencies, like the Department of Defense and others, was what went on in Hong Kong with the H5N1 flu. That was really quite remarkable. We have a flu pandemic plan in the Public Health Service that emanates out of Secretary Shalala's office. Right from the very beginning we all met, and each had a job to do; the FDA had a job, the CDC had a job, if necessary the DoD would have a job, and we had interactions with them. The NIH's role was to provide some of the science that was associated with developing the diagnostic kits that the CDC very, very efficiently got put together and distributed to do the surveillance that was necessary to see what the scope of the epidemic was.
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    You might recall that it was unclear whether or not there was efficient human-to-human transmissibility or whether it was just bird-to-human. The decision that it was only tangential evidence of human-to-human—namely, one or two health care workers had antibodies that they probably had through exposure to a sick child but they didn't get sick—was a spur to try and put an end to the chicken-to-human transmission as rapidly as possible. Based on that, the decision to slaughter the chickens in Hong Kong was made, which clearly the proof of the pudding is that it shut the epidemic right down. That was a good example of the interagency collaboration.

    Ms. PELOSI. Congratulations.

    Dr. FAUCI. Thank you.


    Ms. PELOSI. That could have been a terrible thing. In some of my time that I have remaining, I wanted to ask you if you would just for a moment talk about the percentage of AIDS funding, because earlier it was mentioned that now that we've spent all this money on AIDS, too bad we didn't have it to spend on other things if AIDS had never appeared. I happen to think that the issue of AIDS increased the NIH funding and the whole pie was increased at the same time. So AIDS wasn't taking up any other money.

    But I do know, because I've heard you say in the past and I want you to say again, what percentage of AIDS funding goes for basic research which is applicable to discoveries for a wide range of diseases, particularly what it has contributed to our understanding of the immune system, and some of the things we've learned—it's really a repetition of my first question—that would benefit us with other diseases.
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    Dr. FAUCI. If you look at the various aspects of what we call the functional categories—pathogenesis, drug development, vaccine—at least 50 percent, and probably much more than that, closer to 60 percent is involved in doing things that have rather striking extrapolation to other disciplines. I've given you examples in the past and I'll repeat some of them.

    For example, the whole question of diagnostics with molecular probes, although we had it before, it's been brought to a new level of sophistication. What we learned from the diagnostic capabilities with PCR and other techniques for HIV has played a major impact in the use of those, for example, in our diagnostic capability for chlamydia.

    When you talk about targeted drug design, there's an example that's more than a practical example. The development of Livimudine 3TC for HIV is now used very successfully in hepatitis B. So you have a drug that was developed for one virus that is now effective against another. But it really goes beyond that. It goes to the whole concept of targeted drug design, crystallization, tailor made components of drugs that are then used. That's the reason why I brought in the idea that when you think in terms of emerging diseases and what we're interested very much in is global health. The spin-offs from HIV research are almost going to be nonseparable from our approach towards other diseases. So it's a very strong component of positive spin-offs.

    Dr. VARMUS. Ms. Pelosi, I have one comment here. I'm going to endorse everything Dr. Fauci has said, and I want to add one further comment. I think it would be a mistake to take away from the decline in mortality the idea that if the money invested in AIDS had been invested in something else we would see the same decline in mortality.
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    One of the reasons that money was devoted to the AIDS fight in very substantial amounts is because we knew what the cause was. It was an infectious agent. It was like having an invader arrive on your shores, putting at risk of death as many as a million people, and knowing what that invader is, having some of the tools available that we thought could combat it. We haven't succeeded on all fronts yet—we don't have a vaccine, we don't have the ideal therapeutic armamentarium—but it is a very different matter to attempt to reverse the mortality rates in an infectious disease than it is in some of the other more chronic, difficult conditions that we also think we can make progress on, but where progress is going to be more difficult.

    Ms. PELOSI. I appreciate that addition, Dr. Varmus. Thank you very much, both Dr. Fauci and Dr. Varmus, and you, Mr. Chairman.

    Mr. MILLER. Mrs. Lowey.

    Mrs. LOWEY. Thank you, Mr. Chairman.

    I, too, want to join my colleagues in admiration of you, Dr. Fauci. In fact, as I look through your biography, I really wonder if maybe you can give us some answers to the secrets of life and success, and when do you sleep and when do you eat. [Laughter.]

    Dr. VARMUS. He won't even tell me, Mrs. Lowey.

    Mrs. LOWEY. Well, you're doing pretty well yourself. [Laughter.]
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    On this committee we manage to get some free medical advice as well. Since we don't watch ER, we depend upon this committee. [Laughter.]


    But I do join my colleagues in amazement at how you have enough hours in your day. I won't ask you to testify on that today, but before I ask a question, I just want to associate myself with the question of my colleague, Congresswoman Pelosi, and the response of both Dr. Fauci and Dr. Varmus. I do wish my colleagues were here to hear that because I think this is so very important that the investment in AIDS research and the paths that your answers are taking us on are really providing cures for so many other diseases. I think it's important that we understand that and mention it again. I'm so glad that my colleague, who has been a leader in this committee in investment in AIDS research, brought that up. I, too, appreciate your responses.

    I was very pleased, Dr. Fauci, to see in your budget justification that the Institute is participating in the public awareness and physician education activities of the Jeffrey Modell Foundation. Many of us on this subcommittee have met with the Modells and have been following their very important work. If you could either now or for the record tell us how much money the Institute has actually contributed to the Interactive Physicians Symposium that was cosponsored by the Foundation and several NIH Institutes in collaboration with the American Red Cross on October 31st of last year, that would be helpful.

    Many of us on both sides of the aisle have been interested in public-private partnerships and the Modell Foundation is certainly an excellent example of that.
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    Dr. FAUCI. The exact figure I'll supply for the record. But I can tell you that it has been a most fruitful collaboration. We've had very good interactions and I believe the product of the outreach that we've been able to accomplish has been productive.

    [The information follows:]


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

    Mrs. LOWEY. Have you had other examples of this type of collaboration, or is this rather unique?

    Dr. FAUCI. Actually, it's not unique. We have collaboration, for example, with the Juvenile Diabetes Foundation, with the Arthritis Foundation, a variety of others, and some of the infectious disease groups. We put a strong stock on reaching out to our constituency groups. We believe that they have a lot to offer to give us a really good feel for what is going on in the trenches and the directions that we need to go. That is one of the things that the Jeffrey Modell Foundation provided, because they took a very keen interest in childhood immunodeficiencies which, obviously, are an important component of what we do from an immunological standpoint.
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    Mrs. LOWEY. I thank you. I also see in the justification that in fiscal year 1999 you will be launching Centers of Excellence in immunology. I have a couple of questions related to these centers.

    First of all, how many centers do you expect will be funded in fiscal year 1999 and beyond?

    Dr. FAUCI. Four to five in 1999. Depending on how they do, which I believe they'll be successful because the pool of investigators that we hope will respond to that initiative are of the highest quality, so if we have a good response, then we will likely expand that in the future. That's part of our plan for expanding our efforts in that regard, depending on the budget.

    Mrs. LOWEY. You mentioned several immunology issues that will be addressed. Will one or more of these centers do research into inherited genetic disorders?

    Dr. FAUCI. Yes. As a matter of fact, particularly the genetics of the immune response. I believe a question came up, in fact, it was Mr. Stokes who asked, of the different components that go into the development of cancer—environmental, genetic, infectious, et cetera. The same thing holds true with the body's capability of responding immunologically to a particular stimulus; that is, understanding the fundamental genetic makeup that allows me to respond in a certain way to a particular disease. Why does someone get Lupus and someone does not? Why does someone get an inflammatory vascular disease and someone does not? Why do women get takayasu arteritis and men hardly ever do? All of that is going to be studied in that component of the immunological response.
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    Mrs. LOWEY. I won't even ask you to explain what that last one was. But you could for the record because others may be interested. I was going to ask as if I knew.

    Dr. FAUCI. It's a very interesting form of inflammatory vasculitis that I have actually studied prior to my life in AIDS when I was doing fundamentally rheumatologic disease. It's an inflammation of the large blood vessels around the aorta and around the valve that leads from the heart to the aorta. It is seen almost exclusively in women and it can be a very devastating disease leading to stroke and congestive heart failure and death.

    Mrs. LOWEY. Another question regarding the centers. Do you expect them to begin by themselves, or will they be connected to other centers?

    Dr. FAUCI. What they will be is a conglomerate of investigators, almost all of which have been RO1 or PO1 grantees of the Institute. The purpose of the centers, as we have done, for example, with the Centers for AIDS Research, are to bring them together with an infrastructure approach that would allow them to synergize better, as opposed to having individual components of the grantees.

    Mrs. LOWEY. So existing immunology centers would be able to apply?

    Dr. FAUCI. Without a doubt. There are no limitations on who can apply to that.
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    Mrs. LOWEY. Another area that we've had a lot of interest in in the committee, certainly with the Institute of NIDDK, is the area of diabetes. I know that there is cooperative effort in that regard, certainly with regard to the successful transplantation of insulin-producing cells.

    Dr. FAUCI. Right.

    Mrs. LOWEY. Could you give us some idea of the contribution your Institute is making with regard to that?

    Dr. FAUCI. Yes. Actually, that plays very nicely into the slide that I had put up about immunological tolerance. In fact, we presented to Dr. Varmus several months ago because this was such a hot area of immunological tolerance, and we had a proposal for trying to tolerize in islet cell transfusions for the treatment of people with established diabetes. Dr. Varmus actually used his 1 percent transfer authority to give the Institute $4.5 million to jump start that program which we are now in 1999, the budget that we're addressing here, going to try and accelerate that.

    Our role in that, in close collaboration with NIDDK, is to provide the immunological component towards the approach in diabetes. In this case, it fits in perfectly with immunological tolerance.

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    Mrs. LOWEY. On another area, could you give us an update on the status of clinical trials for over-the-counter spermicides as microbicides and for new topical microbicide products?

    Dr. FAUCI. Yes. We have several clinical studies that are ongoing right now. There is one going on with nonoxinol-9 and its effect on the prevention of HIV transmissibility. The definitive data is not in, but the study is off the ground and is doing very well.

    We also have some animal model studies that are being employed. One of the difficulties with using topical microbicides, that we haven't completely gotten over the hurdle yet, is the inflammatory component, the double-edged sword of killing a microbe but causing vaginal or cervical inflammation that might then propagate transmission of HIV. There's an animal model now of transplanting vaginal tissue and looking at what the components are of the inflammatory component, so that we can get the microbicidal effect without the inflammatory effect.

    So we have an actual clinical trial that's ongoing and we have a basic research animal model trial going. So I'm optimistic that it is going in the right direction.

    Mrs. LOWEY. Thank you. I think my time is up.

    Mr. PORTER [resuming chair]. Thank you, Mrs. Lowey.
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    Mr. Miller.


    Mr. MILLER. To start off with, I'm on the Budget Committee also and I have a great frustration, and Dr. Varmus and I talked about it the other day. In fact, we're going back into a meeting at 4:30 this afternoon, working to make sure that we have the maximum amount that we can work through our budget for biomedical research. We've been going through this debate in the Budget Committee of what do we do with our surplus issue, too. And it's always good to see when the Speaker of the House comes in and testifies that research has to be one of those priorities for any surplus revenue.

    But I feel we still have an educational issue that we need to work on for all 435 Members. As Ms. DeLauro said, it's exciting for the few of us who get to sit on this committee, but there's 400-some other Members and we need to do whatever we can to help educate them on the benefits of biomedical research. I think we're trying to work out a trip for the Budget Committee members. So we need to get some ideas of how we can excite other Members. This is one of the things we all should feel very proud about in the Federal Government. One of the crown jewels of the Federal Government is NIH.

    We need ideas of whether it's getting Members to go visit medical institutions in their communities and have them express that appreciation. But I don't have a medical research facility in my district. But we need some help along those lines to promote the overall need of NIH. Any comments about that? When people hear you speak about what's happening, you get excited about it.
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    Dr. FAUCI. Well, we've actually discussed this, Dr. Varmus and the Institute directors, about the need of getting the message out of what we do in the biomedical research capacity at NIH. Obviously, individuals going out, like the Institute directors, we do that, but that's only going to be a small dent in it. It has to be a much more general effort of getting out.

    What we do is we try to encourage, for example, our councils and our advisory groups to take the message back to their communities. We have noted a considerable amount of enthusiasm on their part. For example, our own council put together a program of actually providing slides and information for council members and the individuals in their respective institution to go out and talk about what NIH does and what the role of biomedical research is in public health. That's a small amount, but I think it is a good start.


    Dr. VARMUS. I think there is a very powerful effect upon any Member who hears about the work of any investigator who is NIH-supported. I know Ms. Pelosi frequently refers to a visit I made to her office about seven years ago in the company of a young, very enthusiastic worm geneticist, and the effect of that visit is still apparent, even in the questioning this year.


    Mr. MILLER. I will work on my end of it to try to encourage my colleagues, whether it is to go visit a nearby medical research institution, to spend some time shadowing a researcher, or whatever it is. I think we need to come up with some ideas because I think we have an education effort to the country. It's nice when a Mohammed Ali comes here and testifies about Parkinson's disease. And I think as long as that supports the overall goal of NIH, that's good.
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    Let me switch to something more specific. There's been a lot of success, obviously, with HIV and we have a lot of pride in having seen it progress to the stage we are today. Where are we going as far as longevity efforts, studies with this combination therapy? In the past you've said you're not ready to say that we've really conquered it. Are we moving towards a chronic disease yet?

    Dr. FAUCI. I can give you some of the numbers. If you look at the clinical trials, which is much more pristine than in the trenches, as we say, when you have someone who is in a clinic in an inner-city area, about 85 percent of the people have responded, their virus goes to below detectable levels, and about 65 percent total after a period of two years are still doing well. If you look at the people in the clinic who are not pristine, in the sense that they've had prior treatment of one or other drug which lessens the impact of when you come in de novo in an untreated person, the response rate there is about 60 to 65 percent, and it may go back down to 50 percent of breakthroughs.

    The thing that we're struggling with, and it really relates to the questions of several Members, is why we need to keep up the pressure of drug development. Because although the people who are responding are responding well, and by well, I mean no detectable or very little detectable virus and leading relatively healthy lives, those people are going out now two, three years, some of them, and the concern is will they be able to tolerate the drugs chronically over ten or fifteen years; and secondly, will there be breakthrough with resistant micro-organisms.

    There's two ways to approach that, and we're doing both. One is to develop newer drugs at the same target, or drugs at different targets of the virus; the virus has multiple targets that we aim at. The second is to make drugs that are more user friendly, and we've seen a lot of activity in that regard over the past year. Instead of having to take 35 tablets or capsules, which is the average amount that someone with advanced disease takes, to try and have, for example, a form of a drug that you only need to take once a day in the morning. That would be very important for what we call compliance. It is very difficult in the disruption of a lifestyle to tell somebody that they have to take a pill every hour or two.
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    If we can get that component of it, then I think the answer to your question is we're going to see long range survival with good quality of life. Whether that's going to last a normal lifetime, we can't say. That's going to depend on whether or not we're able to eradicate the virus. Thus far, it looks like the virus is rather stubborn. And even in people who we suppress virus so that you can't detect the virus in the plasma, there is still persistence of virus in the tissue.


    Mr. MILLER. One area I've been interested in is hemophilia. I guess the incidence of new hemophiliacs doesn't happen anymore because of blood control.

    Dr. FAUCI. Right.

    Mr. MILLER. The complications of hemophilia, does that make it any more difficult than other treatment? And then I'm going to ask you about the hepatitis issue with hemophilia, too, what's going on there.

    Dr. FAUCI. Actually, you put your finger on it, the complications. The the non-hematologic complications of hemophilia, the joint problems, the blood loss problems, generally are not made better or worse with regard to HIV. It doesn't impact negatively on the survival of a well-treated hemophiliac who is on appropriate antiretroviral therapy.

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    Since the incidence of hepatitides, because of the transfusions that they may need to receive because of bleeding episodes, is understandably higher in hemophiliacs, the negative aspects of the impact of HIV on hepatitis is seen more predominantly in hemophiliacs. So the secondary negative consequences of hepatitis as a co-infection with HIV by pure numbers alone segregates more heavily in the hemophiliac population.

    Mr. MILLER. I see my time is about to expire and I was going to ask a longer question.


    Mr. PORTER. You can ask the question.

    Mr. MILLER. Mr. Stokes had asked a question about the statistics for minorities with HIV being much greater. I guess the statistics for hemophiliacs is very much distorted, too, but it is different causes. Are we fractionizing our approach to treatment? I see Dr. Hernandez over here. Is drug use a better determinant of who gets AIDS than race? I get concerned whether we're trying to say, well, let's just look at it as a black disease. It's not a black disease.

    Dr. FAUCI. No. Not at all. Absolutely, not at all. In fact, if you look at the disproportionately higher percentage of, for example, African-Americans and Hispanics who are HIV infected and get AIDS, that's purely reflective of the conditions associated with transmissibility. If you live in an inner-city area where there's a high degree of IV drug use, the heterosexual transmissibility by definition will be higher in that environment.
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    Unfortunately, it happens that it is much more heavily weighed that that group is going to be a minority group. So they are going to be physically in an environment where exposure and transmissibility is greater than it would be if you had a middle class white person living, for example, in a place where there isn't a high density of either infection or IV drug use.

    Mr. MILLER. So, statistically then for African-Americans and whites under the same conditions of environment?

    Dr. FAUCI. Right. There is no difference whatsoever. If you have an African-American, a Hispanic, a man or woman in the same environment with the same degree of exposure, there is no segregation towards race or gender or what have you with infection.

    Mr. MILLER. But do you divide research separately?

    Dr. FAUCI. No, we don't. In fact, the vast majority, the bulk of the research is pathogenically related, drug development related, and vaccine related. That does not take into account race or gender. When we do either epidemiological studies or when we look at our clinical trial apparatus, since we have a disproportionate number of minorities that are infected, we make sure that in the entry into our clinical trials, that they are represented appropriately in the clinical trial. But the fundamental basic research impacts all races and genders equally.

    Dr. VARMUS. I hope it's also clear, Mr. Miller, that we keep track of AIDS cases or cases of HIV infection with respect to the probable mode of transmission. So we have data on the percentage of cases in any one year that are attributable or likely to be attributable to intravenous drug use, to men having sex with men, heterosexual sex, maternal to infant transmission, and so forth.
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    Mr. MILLER. Okay. Thank you.

    Dr. FAUCI. Thank you.

    Mr. PORTER. Thank you, Mr. Miller.

    Dr. Fauci, we apologize to you and Dr. Kupfer for the interruptions we've had this afternoon and the delays in our schedule. We all do applaud you, the NIH, and all of the Institutes for the wonderful work that you do. We can't be more proud of the Institution and of the scientists who are there or funded through NIH grants. We think you're doing wonderful work and we want to give you the resources you need to do it even better and faster.

    Dr. FAUCI. Thank you very much.

    Mr. PORTER. Thank you for appearing today.

    Dr. FAUCI. Thank you. It's a pleasure to be here.

    Mr. PORTER. The subcommittee will stand briefly in recess.

    [The following questions were submitted to be answered for the record:]
    "The Official Committee record contains additional material here."

Wednesday, March 11, 1998.
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    Mr. PORTER. The subcommittee will come to order. We continue our hearings with the National Institutes of Health. We are pleased to welcome this morning Dr. Kenneth Olden, the Director of the National Institute of Environmental Health Sciences.

    Dr. OLDEN. Thank you.

    Mr. PORTER. Dr. Olden, you and the other Institute Directors were all arrayed behind Dr. Varmus yesterday. It is good to see you again today. We thank you for coming to testify.
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    Why don't you proceed with your statement and then we will go to questions.


    Dr. OLDEN. Thank you very much.

    Let me just introduce the people to my left. Mr. Charles Leasure is the former Associate Director for Management for the Institute. Mr. Leasure recently left our institute to join Dr. Collins at the National Institute for Human Genome Research.

    And we have a national search to find a replacement for Mr. Leasure.

    The Deputy Director, Dr. Sam Wilson; and the Budget Officer, Ms. Laurie Johnson; and you know Dr. Varmus and Mr. Williams.


    Mr. Chairman and members of the committee, I welcome the opportunity to appear before you today to discuss the important work of the National Institute for Environmental Health Sciences. Today I want to accomplish just two goals.

    First, I want to direct your attention to a list of strategic investments which will have the potential to change the face of environmental health policy decisions. And second, I want to showcase an example of what can happen if such investments are indeed made.
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    If I could have the first exhibit, please.

    I have listed seven issues here that we have talked about before this committee in previous appearances. First, I think we should make an investment to develop high throughput approaches for carcinogenicity and toxicity testing.

    And in fact, I will devote most of my remarks to this issue.

    Second, we need to determine the basis for the wide variation and individual responsiveness to exposure to environmental toxicants. Third, we need to develop analytical techniques for direct assessment of human exposure.

    Fourth, we need to define the health effects of exposures to mixtures. Fifth, we need to elucidate environmental health and safety threats to children. Sixth, we need to investigate the possible complex interaction between poverty, environmental pollution and health disparities.

    And lastly, elucidate carcinogenic and toxic mechanisms.


    Now I will discuss the impact of alternative test systems that we have developed to respond to issue number one. And let me say at the outset, our ability to develop these test systems has been based on recent developments in our understanding of cancer genetics.
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    We now know that all cancers involve a disruption of the normal restraint in cell proliferation. For each cell type, there is a finite number of ways in which such disruptions can occur. In fact, changes in a relatively small number of genes appear to be responsible for much of the deep disregulation of proliferation in cancer.

    The identification of many of these genes has been one of the great triumphs of molecular biology over the past 20 years. These genes can either stimulate cell proliferation or they can inhibit it.

    Scientists at the NIH have used both kind of genes, that is stimulatory genes and inhibitory or suppressor genes, to create animals, mice, that are more responsive when exposed to environmental carcinogens.

    In the next exhibit, they have created four such animals, and I will describe three of those today. They have created animals that we call TgAC mouse and Hras2 mouse. Both of these are genetically engineered so that they contain a tumor stimulatory gene.

    The p53 mouse contains an inactivated tumor suppressor gene. So we have created mice that have stimulatory genes and mice that have inactivated inhibitory or suppressor genes.

    Such animals that are so genetically modified in this way are referred to as transgenics. To date, we have tested 32 chemicals in this system. In other words, 32 chemicals have been screened using the transgenic animal models.
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    The results shown here are typical of the results that we have obtained. In most cases, shown in the red bars and gold bars, the same result was obtained in both the conventional and transgenic models.

    If you will look at the first quadrant, conventional all red, p53 all red, TgAC and Hras2 are also all red. The question mark simply represents the fact that we have not tested that specific chemical in that transgenic animal model.

    If you move down to the next quadrant, again those chemicals that tested negative in the conventional model were also negative in the transgenic animal models as shown by the gold bars.

    And as you move across the three transgenic lines, you see again, in every case in which it has been tested, they also were negative. Now if you move to the last quadrant of the exhibit, you will see that we obtain mixed results.

    That is, the result obtained in the conventional model was not always repeated in all three of the transgenics. But you will note that the result obtained in the conventional model was repeated in at least two of the transgenic animal models.

    So today, we can conclude that if we use a screen of three transgenic animal models, we may be able to substitute for the conventional rodent bioassay.

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    Now the advantages of the transgenic model over the conventional is shown in the next exhibit. First of all, you will see that for the transgenic animal model, it costs us $110,000 per chemical versus two to six million dollars per chemical in the conventional.

    It takes 150 animals to perform the experiment in the transgenic animal model, and it takes 800 animals to perform the experiment in the conventional model. And most importantly, it takes six months in the transgenic model and two years in the conventional model. So we save time, money and animals.

    Now I am not yet prepared to declare victory, so today I cannot recommend the use of transgenics in lieu of the conventional rodent bioassay. Clearly more studies are needed. Nevertheless, these results are very exciting.

    And I am optimistic that within the next one to two years, we will have adequate experience with the new test systems so that a firm recommendation can be made with respect to their use in carcinogenicity testing.

    Now the potential impact that transgenic models will have on hazard identification is just one example of how the strategic investments that I outlined in Exhibit Number 2 can impact and modernize risk assessment.

    I indicated to you about four to five years ago that NIEHS would make the investment to develop these transgenic animal models. So today, this is the progress report. These models can provide you as policy makers with the information needed to make important public health decisions in a timely manner.
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    The President's budget request for NIEHS is $348,100,000, and I would be very pleased to answer any questions that you might have.

    [The prepared statement follows:]

    "The Official Committee record contains additional material here."

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