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Testimony on Healthy Nation by Medical Research by Harold Varinus, M.D.
Director, National Institutes of Health
U.S. Department of Health and Human Services

Before the Senate Committee on Appropriations
In Portland, Oregon
April 11, 1996

Mr. Chairman:

I am pleased to participate in this important hearing and to tell you about our efforts to improve the Nation's health through medical research sponsored by the National Institutes of Health (NIH).

Organization and Role of the NIH

In 1940, President Franklin Roosevelt dedicated the grounds of the NIH and first few buildings of the new Bethesda campus. As the Nation braced itself against a world defending into war, the President reminded America that our "total defense involves a great deal more than building airplanes and ships, bombs and guns. . . .We cannot be a strong nation," he said, "unless we are a healthy nation."

After five and a half decades of growth, the NIH of today is the largest and most successful medical research institution in the world, with a budget of nearly $12 billion and a major impact not only on this Nation's health, but on health status worldwide. More than eight out of every ten research dollars appropriated to the NIH flow out to the scientific community across the Nation, primarily in the form of peer-reviewed research grants. Today that community numbers more than 50,000 investigators affiliated with nearly 2,000 universities, hospitals, and other research facilities located in all 50 states, the District of Columbia, Puerto Rico, Guam, the Virgin Islands, and points abroad. Approximately 10 percent of the NIH budget supports a program of basic and clinical research activities administered and staffed by our own physicians and scientists. In addition to basic research laboratories, this in-house, or intramural, research program includes a research hospital, the NIH Clinical Center, Each year, more than 20,000 children and adults from all over the country, and some from abroad, are referred to the Clinical Center for experimental treatment and study.

Today's NIH is a federation of 24 Institutes, Centers and Divisions that seek to expand knowledge about living systems and apply that knowledge to improve human health. Perhaps the bed known NIH research institutes are those that focus either on a particular disease, such as the National Cancer Institute, or on an organ system, such as the National Heart, Lung, and Blood Institute. Other Institutes and Centers attend to overarching scientific needs and opportunities, such as the National Center for Human Genome Research, while others focus on stages of human development, such as the National Institute on Aging. Other NIH components are responsible for developing the array of technologies and resources that are vital to innovative and efficient research; for example, the National Center for Research Resources oversees the General Clinical Research Centers, which provide core resources, such as specialized personnel and sophisticated laboratories, to clinical investigators around the country.

Multiple Institutes and Centers often address different aspects of a single health problem faced by our citizens. For example, research on Alzheimer's disease takes place in Institutes devoted to neurology, aging and mental health, This feature, witch is essential to the research effort, requires dose interactions among the Institutes and Centers; these may be informal (such as scientists talking with one another), or they may be guided by inter-Institute committees or by NIH-wide coordinating offices that are located in the Office of the Director (e.g., the Office for Research on Women's Health.) This rich matrix of research activity requires open and Collegial dialogue among the Institutes and Centers and thrives in an atmosphere that maximizes flexibility in the pursuit of knowledge. A major objective of my administration at the NIH has been the enrichment of these interactions and a strengthening of the sense of unified purpose.

How NIH Works Toward the Goal of Improved Health

The human body is complex and the diseases to which it is susceptible are legion. So we approach the goal of improving the Nation's health aware that many experimental strategies require years, often decades, of effort to make major advances against each disease.

While no single pathway can be described as the common route to success, it is apparent that many advances demand the talents of laboratory scientists who work on fundamental aspects of living organisms; clinicians and epidemiologists who describe the conditions we attempt to prevent or cure; clinical investigators who use their knowledge of both disease and scientific advances to devise and test new therapeutic or preventive strategies; and industry-based scientists who finally develop new drugs and devices and help to bring them to market. This means that NIH must provide financial support for many lands of work and promote training programs that develop talented people to do the work.

It is important to understand that most NIH-funded research is "investigator-initiated,"That is, the research ideas we fund are proposed by the scientists themselves, not by the NIH. By mistaking our traditional standards of scientific excellence through peer review, the NIH uses competition among the most highly trained scientists in the world to ensure that Fed" funds are distributed to the most promising research projects; at present, only one out of four meritorious proposals can be funded. However, because of the broad constellation of public health needs, scientific opportunities, Executive and Congressional interests, and other factors that bear on the course of the Nation's investment in medical research, the NIH must constantly reevaluate its programs and have the flexibility to make necessary changes.

The process of examining research priorities is not reducible to a simple flow chart or time line. It takes place at several distinct levels in the NIH organization and is occurring all of the time, Priorities are set both within the Institutes and Centers by their Directors, but, as Director of the NIH, I assume ultimate responsibility for the overall distribution of funds among our research program.

The NIH must also ensure that the cadre of scientists we fund have adequate facilities and equipment to conduct their work. In fact, many of the advances in medical research that are leading to ever more effective treatments for illness reflect stunning innovations in sophisticated but often costly, research technologies that are far beyond the capacity of all but a handful of institutions to purchase, construct, or maintain. NIH recognizes that ensuring broad access to these research resources creates efficiencies that make the research dollar go farther, while providing critical resources to all scientists. Often, access to the needed tools by the largest possible number of scientists determines the pace of research on many devastating illnesses.

A partial solution to the problem of expensive technologies and scarce resources already exists, and is being practiced through innovative "'shared resource" centers funded by NIH. For example, NIH's National Center for Research Resources funds one shared resource network, built around its Shared Instrumentation Grant Program, that involves some 60 biotechnology centers around the country. At present, more than 7,000 investigators use the network for about 5,000 research projects. Another example is the Frederick Biomedical Supercomputer Center in Frederick, Maryland, a resource for the world's medical research community. Through this center, scientists working out of their home institutions can obtain assistance in the use of the latest computational methods to exploit and refine biological research techniques and amass data important to their research.

Emphasis on sharing research resources is a relatively new phenomenon brought about by increased sophistication and cost, but progress in medical research and the practice of medicine has always required sharing of information. The NIH has a longstanding tradition of providing a steady flow of information about important research discoveries and other medical information to the research community, to health care providers, and to the general public.

For example, one of the primary mandates of NIH's National Library of Medicine is to ensure that health professionals around the world have access to the latest published medical knowledge. Last year, users of MEDLINE, a database with eight million references and abstracts to medical journal articles, conducted 7,5 million searches. Half of these searches were for purposes of patient care and were conducted in hospitals, clinics and the offices of individual health care providers. This vital information base connects health care professionals in even the most rural area of the country to the latest medical advances.

Another way in which the NIH communicates the results of medical research is through "clinical alerts." These provide health-care practitioners with immediate news of significant research results that affect clinical care, The full range of electronic and print media are employed in these instances to ensure immediate attention to the lifesaving (or life-threatening) potential of the latest research findings.

NIH is also an invaluable resource for the general public, including the nearly two million people who directly request medical and health information each year, NIH's Cancer Information Service alone (1 -800-4-CANCER) handles more than 600, 000 telephone inquiries annually. The recently created NIH Home Page on the World Wide Web will soon include 110 of the "best selling" consumer health booklets from the NIH. In an effort to explore new ways of reaching the public, NIH recently funded two pilot episodes for Health Week, a Maryland Public Television news magazine about health covering such topics as spinal cord injury, angiogenesis in cancer and heart disease, melatonin, and the obesity gene. A unique aspect of the program is the provision of "access points"-phone numbers, Internet addresses and mailing addresses--to give the public avenues exploring the health issues covered in greater depth.

To fully reap health benefits from the knowledge gained through fundamental investigations, NIM must have in place efficient processes for transferring knowledge and technology from NIH-funded program to the private sector, where biotechnology and pharmaceutical firms are poised to translate what we produce into products that improve health and prevent disease.

NIH's technology transfer effort in its intramural research program relies on two principal mechanisms, Cooperative Research and Development Agreements (CRADAS) and the patenting and licensing of research inventions. Over the decade ending with fiscal year 1995, NIH intramural scientists negotiated 269 CRADAs with private organizations to support a wide range of research activities. Between 1985 and 1995, NIH was awarded 560 patents on inventions made by our intramural scientists, and we negotiated 713 licenses to develop commercial applications based on those patents. The products that resulted from these patents include a simple, accurate and inexpensive screening test for HIV infection that also can be used to monitor and ensure the safety of public blood supplies, two major therapeutics against HIV-infection, and vaccines for the treatment of Hepatitis A and for treatment of chronic B-cell leukemia.

Recipients of NIH support in the extramural community promote technology transfer by two analogous mechanisms. Each institution is entitled under the Bayh-Dole Act to seek patent protection and licensing arrangements for the inventions made by their employees while working with NIH funds. In addition, many of these institutions have negotiated agreements that allow NIH grantees to receive additional support from industries for separate research projects. Another extremely important means of technology transfer involves the traffic of personnel, especially from NIH-supported graduate and post-doctoral training programs to jobs in the industrial sector. The vitality of NIH research programs, therefore, has a direct impact on the strength of our Nation's industry, since the workforce in the pharmaceutical and biotechnology fields is trained to do science in the context of our training and research activities.

Advances in Medical Research That Have Led to Chances in Clinical Practice

To have an impact on improving health and combating disease, scientists need to develop and work from a body of basic knowledge. The path leading from now findings to changes in clinical practice can be very long, often measured in decades. Many of the dramatic changes that have occurred in American medicine over the past fifty years are based on insights drawn from the traditional biomedical sciences, such as microbiology, physiology, pathology, immunology, and chemistry. The following brief stories about important, relatively recent developments in the prevention and treatment of disease illustrate some of the ways in which new knowledge has gradually led to improvements in the country's health.

Haemophilus influenzae type b (Hib) is a serious bacterial infection that once affected almost 25,000 children in the U.S. every year, especially infants. Of the nearly I 5,000 infants affected by Hib-related bacterial meningitis, up to 10 percent died and 20-30 percent of the survivors suffered permanent health consequences, especially mental retardation. In 1985, based on an understanding of the unique chemical nature of Hib antigens and the epidemiology of Hib in children compared with adults, scientists developed the first effective vaccine against Hib for children older than two years. But to make a vaccine effective for infants, it was necessary to exploit decades of research in chemistry and immunology to develop a novel technology that linked sugars from the outer coat of the Hib bacterium to an immunity-boosting protein. Today, thanks to the new vaccines, Hib disease has decreased by over 95 percent among infants as well as children; the vaccines have been estimated to save more than $400 million per you.

Cancer of the testis is a relatively rare cancer afflicting about 5,000 men annually, but it usually strikes young men, 20-40 years of age. In 1965, a biophysicist working at Michigan State University made an unexpected observation that ultimately changed the outlook for men with testicular cancer: he found that when an electric current was generated with platinum electrodes in a bacterial culture, normal cell division was inhibited. The inhibition of cell division was soon found to be caused not by the electric current, but by the generation of a small amount of a well-known chemical, cisplatin, from the platinum electrodes. After much collaborative work with the National Cancer Institute and a pharmaceutical firm, scientists found that cisplatin could inhibit cell division in other cells, especially cancer cells. Later, it was recognized that testicular cancers responded especially dramatically to cisplatin. Today, after two decades of medical research based on an observation in biophysics, testicular cancer has been transformed from a nearly uniformly fatal disease to one that is 80-95 percent curable. Cisplatin is not only responsible for saving lives; a cost-benefit analysis of cisplatin-based chemotherapy estimated an annual savings of $150 million, mainly due to savings from the future earning potential of survivors.

A half million Americans each year suffer from strokes, four out of five of which are caused by a blood clot that blocks blood flow to the brain. Years of NIH-supported laboratory research on the biochemistry of blood clotting was essential to the development of clot-dissolving drugs such as tissue-plasminogen-activator (t-PA), which has been successfully used in treating heart attacks triggered by blood clots. More recently, researchers have shown that t-PA is an effective emergency treatment for stroke caused by blood clots when given within three hours of initial symptoms. Among stroke victim to whom the drug was administered in rigorous clinical trials, the proportion who made excellent recoveries after three months increased by 30-50 percent. This is the first effective therapy for stroke, stimulating work toward better therapies with even greater preservation of brain function.

Research begun as a study of cholesterol in a rare disease ultimately led to an effective treatment for all people suffering from high blood cholesterol, a condition that cm inhibit blood flow and lead to heart attack or stroke. This built-up cholesterol is derived from low density lipoprotein, or LDL, in the blood. Basic research more than two decades ago revealed that the level of LDL in the blood is regulated by the LDL receptor. This receptor, which is found on the surface of many cells, binds to circulating LDL and removes it from circulation by taking it into the cell, where it is broken down and used by the cell. In studying patients with familial hypercholesterolemia, a rare inherited form of high blood cholesterol investigators discovered that LDL receptors were either nonfunctional or severely defective. The discovery of this receptor has revolutionized the understanding of cholesterol and lipoprotein metabolism. Each step in the cellular processing of cholesterol has now been meticulously defined. For example, it is now known that the enzyme HMG CoA reductase is required for cholesterol synthesis. Inhibition of this enzyme by a class of drugs called "statins" forces the body to make use of cholesterol in the blood. Thus, these drugs significantly reduce blood cholesterol levels, decrease heart attacks and strokes, and extend life in patients with mildly to severely elevated cholesterol.

A long-term investment by the NIH in the molecular composition of viruses, especially retroviruses, is directly responsible for recent successes in the production of drugs effective against HIV, the cause of AIDS. The most potent of these drugs are inhibitors of an essential viral enzyme called a "protease," an enzyme that cuts viral proteins into their working components. Retroviral proteases were first discovered in viruses found in chickens and mice; later, research revealed that retroviruses cannot replicate--or reproduce themselves --without proteases. Because HIV is also a retrovirus, scientists theorized that, inhibiting HIV protease might block replication of the virus and could lead to a new treatment for AIDS. The pharmaceutical industry subsequently identified and developed agents that can inhibit HIV protease. These therapeutic agents appear to be the most effective and least toxic drugs now available to combat HIV.

Fundamental Research Findings Presage Advances in Human Health

Many of the recent advances in the control of disease, such as those described in the preceding section, emerged from discoveries made in the past several decades, and even a century ago, about microbes, the immune system, hormones, and metabolic pathways. Today, we are in the midst of a scientific revolution based on gene isolation, DNA sequencing, sophisticated molecular and cell biology, neuroscience, and study of the three-dimensional structure of proteins. Based on our collective experience with clinical advances developed from earlier discoveries, it is reasonable to anticipate that new and more effective means to combat a host of diseases will emerge over the next few decades from the Current transformation of biological sciences. Although it is impossible to predict exactly what those means will be, there are many signs of new trends in clinical practice.

Efforts to map human genes and determine the sequence of the human genome are progressing at a greater than anticipated pace. Over the past few years, investigators have isolated and characterized genes that cause or predispose patients to cystic fibrosis and many metabolic disorders; several neurological diseases, including Huntington's disease and some forms of Alzheimer's disease; and cancers of the breast, colon, kidney, and other tissues. These discoveries are paving the way to: (i) the more widespread use of genetic testing, to assess the risk of future disease, as well as to diagnose disease; (ii) the development of methods to introduce genes into appropriate cells to treat both acquired and inherited illnesses ("gene therapy"); and (iii) the design of new strategies against disease based upon a more profound understanding of the mechanisms that cause disease.

The advent of molecular cloning and the dramatic growth of the biotechnology industry have already produced several extremely valuable clinical tools. These include bacterially produced hormones, such as human growth factor, that offer advantages of safety and expense; blood growth factors, such as erythropoietin and granulocyte and platelet stimulants, that can reverse bone marrow failure and shorten hospital stays for patients with cancer, AIDS, and kidney disease; and new vaccines for hepatitis B virus and others.

New methods for determining protein structures and the interactions of proteins with other molecules are reshaping approaches to the development of new pharmaceuticals. For example, the cocaine receptor, a protein that transports dopamine into cells, has been found to interact with cocaine and dopamine at different sites, suggesting new ideas for medications against cocaine addiction.

The recent isolation of genes from mice, rats, and humans that regulate appetite and energy utilization and cause obesity and diabetes has revolutionized approaches to these common medical conditions. The genes govern an unexpected hormonal circuit dominated by the hormone called "leptin" that is produced by fat cells and responded to by the brain. New pharmaceutical products that interfere with this circuit are likely to become important agents in the control of obesity and its complications.

Clinical Research in Transition

A healthy biomedical research enterprise requires financial support excellent facilities and equipment, and talented personnel for a wide range of activities, from fundamental laboratory research to clinical trials. Only in this way can discoveries in the laboratory be converted to health benefits for our citizens. Yet clinical research, both at the NIH and in the extramural community, is threatened by deteriorating physical facilities, inadequate recruitment and training of patient- oriented investigators, and declining populations of clinical subjects. The increasing dominance of managed care networks, with their emphasis on cost control, further challenges research and teaching activities at the Nation's academic health centers, where most NIH-supported clinical investigation is conducted. We need to be prepared to respond to these trends if we wish to sustain the integrity of patient-oriented research programs at a time when advances in genetics and cell biology promise dramatic changes in the practice of medicine. During the past two years, I have worked closely with my colleagues in both the intramural and extramural communities to develop a plan to mounter this nationwide erosion of clinical research. Our accomplishments and further strategies include:

  1. Establishment of a Clinical Research Panel, chaired by Dr. David Nathan of the Dana Farber Cancer Center, to advise NIH on the funding of clinical research the training of clinical investigators, and the revitalization of sites at which such research is done. The Panel and its subcommittees have been meeting and gathering information for nearly a year and are expected to deliver recommendations to the NIH Director's Advisory Committee this June.

  2. Development and implementation of a pioneering core curriculum at the NIH to help prepare young physicians for careers as clinical investigators. The central feature of this curriculum is a course that runs throughout the academic year and consists of four modules. These modules introduce clinical fellows to important topics in clinical research such as epidemiologic methods, ethical issues, monitoring and regulating patient-oriented research, and approaches for funding clinical research studies. We are making course materials available to interested investigators and training program directors across the country w that this program can serve as a model for other health centers. We are, also now televising Clinical Center Grand Rounds via satellite to 100 academic hospitals around the U.S.

  3. Establishment of a loan repayment program, Translating advances from frontiers in fundamental science to the bedside requires a cadre of highly skilled clinical researchers trained in both laboratory and clinical research methods. However, just when the scientific Opportunities beckon talented physicians, we have seen a serious decline in the numbers of trainees entering and completing clinical research training. Part of the reason for this decline is the burden of debt from earlier education. The median debt for medical graduates in 1995 was $65,000, and debt is often $100,000. Students may well conclude that this level of debt is incompatible with pursuit of an academic career. For this reason, approximately a year and a half ago, the NIH established a loan repayment program in clinical research for physicians from poor and disadvantaged backgrounds. We are just now beginning to reap the fruits of that investment. Nineteen physicians currently enrolled in clinical research training on the NIH campus are receiving repayments of their educational loans at $20,000 per year.

  4. Rexamination of the review of clinical research proposals. Two years ago, a panel of scientists from wadeniic institutions examined the fate of clinical research gmt applications at NIH and recommended significant changes in the review process for these grants. Once a new director is selected for the NIH Division of Research Grants, an initial task will be to find innovative ways to implement some of these recommended changes in peer review.

  5. Improved monitoring of NIH-funded and conducted clinical trials. Last summer, the NIH Office of Extramural Research evaluated clinical trials supported and conducted by the NIH Institutes, Centers, and Divisions in order to spring mechanisms for oversight of these trials. These findings will be further considered by the Clinical Research Panel.

  6. Negotiated agreements for reimbursement for participants in clinical trials. Last month, the National Cancer Institute (NCI) signed an important agreement with the Department of Defense that will permit members of the armed forces and their dependents to enroll in NCI clinical trials under the CHAMPUS health care system. This could become a model for reimbursement by other health care providers and insurers for experimental treatments for many diseases and help to reverse the trend that is drawing patients away from research projects into forms of care thought to be less costly.

  7. Construction of a new NIH Clinical Research Center, In the FY 1997 budget for NIH the President requests a total of $310 million to replar-e the existing 43 -year old NIH Clinical Center, much of which is now functionally obsolete, inefficient and potentially unsafe to operate, and expensive to maintain. The Clinical Center houses nearly half of all federallyfunded clinical research beds in the country and accounts for one-fourth of all federally funded outpatient clinical research visits. These patients account for approximately 65,000 inpatient days and 70,000 outpatient visits for experimental treatment and for the study of frequently occurring as well as rare or "orphan" diseases.

  8. Improved NIH Clinical Center operations. This year, the DHHS Secretary commissioned a review and report on options to improve the efficiency of Clinical Center operations. The review panel reconunended changes in the governance, funding and management of the facility. Many of these changes are already being made, but others can be fully implemented only when the new Clinical Research Center is in operation.

  9. Increased clinical collaboration with physician-scientists in academic health centers. NIH intramural scientists are already collaborating with extramural scientists on clinical projects, fbr example through sabbaticals at the Clinical Center, via telemedicine, and through programs that provide one-day-a-week use of the facility for extramural researchers. Once the new 250-bed Clinical Research Center with its associated laboratories is completed, extramural-intramural collaborations will increase, thereby strengthening both intramural NIH and the Nation's overall medical research enterprise.

Economic Benefits of NIH-Sponsored Research

NIH-funded discoveries not only improve the Nation's health, but also result in economic benefits to the nation and the individual. NIH research helps support skilled jobs both at academic institutions and in the many U.S. companies that provide materials and instruments used in research. Many of the successes in the biotechnology and pharmaceutical industries are related to NIH support of clinical and laboratory research. In 1994, the 1,311 U. S. biotechnology firms employed 103,000 people and generated $11.2 billion in revenues. Recent research suggests a direct linkage between the presence of highly productive scientists, most of whom receive NIH support and an increase in start-ups and the growth of new biotechnology companies. In addition, the top 15 U.S. pharmaceutical industries--whose work is based upon fundamental research funded by NIH for decades--employed more than 350,000 people and earned profits of $13.3 billion on sales of $84.8 billion.

NIH-supported research has also led to many "spin off" technologies including: agriculture (genetically altered plants and animals are improving yields and extending the shelf life of common foods); manufacturing (genetically-engineered enzymes are revolutionizing the production of many chemicals); and the environmental sciences (modified bacteria and biophysical methods are inexpensively restoring soil and water to their natural states following industrial contamination).

In some cases, medical research does not yield marketable products, but still contributes to public health and yields substantial cost savings. For example, NIH-funded research has demonstrated that weight training for the frail elderly reduces the risk of falls and the associated costs of hospitalization. By helping to create and sustain a healthy, productive population, NIH provides immeasurable benefits to the Nation.

Economic studies will increasingly be called upon to demonstrate how the Federal funds received by NIH significantly improve public health, enhance the productivity of health-related industries, and contribute more generally to the well-being of society and the Nation. For example, the development of law-based photocoagulation treatment for early stage diabetic retinopathy can arrest impairment of vision at a later stage and has been estimated to save the Nation over $1 billion per year. The use of clozapine as maintenance treatment for schizophrenia reduces the need for hospitalizations costing $1.4 billion per year. Estrogen replacement therapy lowers the rate of hip fractures among women aged 65 and older and is estimated to save $333 million per year.


For more than five decades, medical science supported by NIH has benefitted from the unwavering support of our Nation's citizens and their leaders. The resolve to create and sustain a program of superlative medical research has yielded multiple benefits, including vast improvements in human health and well-being; significant contributions to the economy; and an extraordinary store of knowledge related to basic biologic mechanisms, the causes and course of disease, and innovative treatments.

The pace of progress in medical science is astoundingly rapid. But it is clear that the most critical scientific discoveries and the clinical applications of these discoveries still lie ahead. I believe the great potential for continued progress merits consistent federal support for medical research.

I will be pleased to answer any questions you may have.

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