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Testimony on Chronic Disabling Diseases by Claude Lenfant, M.D. Director, National Heart, Lung and Blood Institute
Stephen I. Katz, M.D., Ph.D.
Director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and
Richard J. Hodes, M.D. National Institute on Aging

U.S. Department of Health and Human Services

Before the Senate Committee on Labor and Human Resources
March 7, 1996

Madam Chairman and members of the Committee, we are pleased to appear before you today to discuss our programs at the National Institutes of Health (NIH). During its long and distinguished history, the NIH has maintained a strong tradition of addressing society's most pressing public health needs by capitalizing on science's most promising opportunities.

When the NIH was established in 1887, the public health needs were infectious diseases, and the opportunities lay in the emerging field of bacteriology. The great killers of 1987-cholera, tetanus, typhoid, diphtheria, tuberculosis, pneumonia-have since yielded much of their mystery, and life expectancy has soared. Today's great killers are diseases that stay with the patient for many years and resist all attempts at a cure.

Chronic and disabling diseases affect millions of Americans in all strata of society. They constitute an incalculable public health burden in terms of pain and suffering, loss of function, and health-we resource utilization. Some (e.g., cystic fibrosis, cerebral palsy) are present at birth; others (e.g., Crohn's disease, sarcoidosis) become manifest in youth or middle age; others (e.g., osteoporosis, macular degeneration) strike in old age; and still others, like alcoholism, appear through all phases of life. Many ultimately lead to death; all compromise the patient's quality of life. The demographics of our population are changing rapidly, and it is clear that with increasing life expectancy come increasing opportunities for people to fall prey to chronic and disabling diseases. This is the "epidemic" of the modem age.

The biological, behavioral, and societal consequences of these diseases are manifold, and so are their causes. Both genes and environment contribute to every pathological process, but each chronic disease is unique in terms of how it is likely to come about and who may be affected. Down syndrome, for instance, is almost entirely genetically determined. At the other end of the spectrum, cirrhosis and chronic obstructive pulmonary disease are strongly influenced by environmental exposures to alcohol and tobacco. In between are widespread disorders, such as hypertension, that confound us because they stem from complex and interactive factors.

Among the most daunting challenges that we face are the increasingly prevalent chronic diseases that reflect, to a great extent, the fruit of our efforts to combat more short-lived maladies. In the case of diabetes, for instance, the discovery of insulin mitigated what had been a certain death sentence for its victims. However, the long-term survival of diabetic patients has given rise to a very large population of Americans who not only require chronic treatment, but also are subject to an array of devastating complications, such as heart attack, stroke, kidney failure, limb amputation, and blindness. Similarly, our remarkable success at saving babies born before their time has left us with a host of problems, including the chronic lung disease bronchopulmonary dysplasia, that must be addressed. What we have learned has benefited society enormously, but we still have far to go.

The good news is this: We have the tools to solve these problems. Although the NIH has never lost sight of its public health mission, it has achieved that mission by building a solid foundation of knowledge about the basic processes that determine birth and death, growth and development, health and disease. Modem approaches to scientific investigation are now revolutionizing our ability to understand how the human body functions at the most fundamental level of the cell and the molecule. By capitalizing on these new opportunities and integrating their findings into the vast body of knowledge acquired over the past century, we can substantially decrease the burden of disease.

Because chronic and disabling diseases affect every part of the human body and every age group, they are the concern of all the NIH Institutes and Centers. A coordinated research effort in this area ensures that multiple perspectives are brought to bear on these diseases, and that knowledge gained in one organ system stimulates new approaches to the study of other systems. The following examples illustrate only a few of the many ways in which chronic and disabling diseases touch the fives of all Americans, the remarkable progress that has been made, and the bright promise of future research.

Heart disease. Heart disease is a long-term process that spans many decades of fife and exemplifies the potential and complexity of the research enterprise. Because cardiovascular diseases have been a large part of the twentieth century public health problem, their amelioration has also been a large part of the solution, and it is gratifying to observe that declines in their death rates contributed to 85 percent of the decline in total mortality that occurred over the last 20 years. Nonetheless, they are formidable foes. In enacting the National Heart Act of 1948, the U.S. Senate noted that "the Nation's health is seriously threatened by diseases of the heart and in the circulation, including high blood pressure .... These diseases are the main cause of death United States . . . ." Half a century later, that statement remains true despite the great progress we have witnessed.

The NIH's challenges are illustrated by the hi story of our assault on heart disease. Since the late 1960s, the decline in heart disease mortality has been substantial and unarguable; it has occurred in men and women, in whites and blacks, and at all ages. Much of this declining mortality appears to be due to a decreasing case-fatality rate, that is, the proportion of patients who die shortly after a heart attack. Several decades ago, the physician faced with a heart attack victim had only a handful of tools--the stethoscope, the blood pressure cuff, the electrocardiogram, and the x-ray-and prolonged bed rest was the mainstay of treatment. Our coordinated, multidisciplinary research effort has yielded a wealth of diagnostic and treatment options, including cardiac catheterization, coronary artery bypass surgery, balloon angioplasty, thrombolytic ("clot-busting") therapy, and a vast array of new drugs to help the heart patient. Further improvements may be anticipated as new activities such as the National Heart Attack Alert Program facilitate rapid application of these technologies.

Another likely reason for the decrease in heart disease deaths is recognition and treatment of modifiable risk factors such as hypertensions strategy that emerged from decades of basic, clinical, and applied research. The National High Blood Pressure Education Program, now in its twenty-third year, has had a strong impact on awareness, treatment, and control of hypertension in the United States. Its effect on heart disease is unquestionable, and the even more striking declines that we have witnessed in stroke mortality are due in large part to the success of this endeavor.

While the decline in mortality is, of course, wonderful news, there are several substantial trade-offs. One is that public concern about heart disease as a major killer has lessened, a situation that may, in turn, reduce emphasis on primary preventive efforts such as staying fit and eating a healthy diet, and may also lead to neglect of the early symptoms of heart attack.

The second consequence of our success in saving many heart disease patients from premature death is a sharp upturn in the prevalence of congestive heart failure. Heart failure represents the all common pathway for most primary cardiovascular diseases, including coronary heart disease, hypertension, diseases of the heart muscle, and valvular and congenital malformations. Most treatments slow the course of the primary disease, but do not abolish it. As a result, an increasing proportion of the population is living with heart disease and is susceptible to heart failure. Currently, heart failure affects an estimated 4.7 million Americans and causes about 40,000 deaths annually. Of particular concern is the observation that the death rate for heart failure for all ages has more than tripled since the late 1960s. Because heart failure is a major cause of hospitalization, its economic burden is substantial.

Fortunately, a comprehensive program of basic science studies is providing vital understanding that will ultimately enable us to solve the problem of heart failure, be it through better preventive methods or new strategies for treatment. A number of exciting clinical accomplishments have already resulted. For example, researchers at the NIH Clinical Center have uncovered the genetic defect that causes an inherited form of hypertrophic cardiomyopathy, a primary heart muscle disorder; as a consequence, it is possible to diagnose and treat this condition before onset of heart failure. Clinical trials and studies have identified effective treatments for heart failure, such as use of ACE (angiotensin-converting enzyme) inhibitors and heart transplantation. Patients with endstage disease awaiting a suitable donor heart may be kept alive by use of a ventricular assist device that was developed through NIH-supported research and is now commercially available. The efficacy of an implantable automatic defibrillator (a device that corrects the abnormal rhythm that causes sudden death ) is currently under investigation.

Recent developments in cellular and molecular techniques offer exciting promise for new strategies to restore heart function. Various forms of injury lead to the death of individual cardiac myocytes (heart muscle cells). Because adult cardiac myocytes can not reproduce, their loss leads to heart failure. However, new studies raise the possibility that heart cell transplantation may be a feasible and effective approach to replacing these cells. First using mice, and then extending the work to dogs, researchers have shown that cardiac myocytes can be grafted from embryonic donors into adult hearts. The transplanted cells appear to become part of the recipient's heart tissue and to function normally. This cellular transplantation technique could be augmented through gene transfer technology to enhance cardiac myocyte function. Recent experiments using transgenic and gene targeting methods to create genetically altered mice suggest that a number of promising targets exist to improve the heart's pumping ability.

Finally, we have reached a new frontier in the area of heart transplantation. Although transplantation of human hearts is an effective treatment for end-stage heart failure, a major drawback is the shortage of donor organs. Recent developments using transgenic methods are now breaking down the barriers to using animal organs in human bodies. Specifically, transgenic pigs have been engineered to produce human proteins that suppress the body's immediate tendency to reject the "foreign" heart. When the hearts of such pigs were transplanted into baboons, they survived longer than had ever been possible. With further development, this "futuristic," approach to the problem of heart failure may become a reality.

Asthma. Asthma is a world-wide health problem that has been with us for centuries, and there is much evidence that its prevalence and severity are growing. In the United States, an estimated 12 million people have the disease, many of them children. It is becoming increasingly apparent that many commonly held notions about asthma-that children usually "outgrow" it, or that one can be "too old" to develop it-are erroneous, for asthma appears in all age groups. Deaths due to asthma are uncommon, but those that occur tend to be sudden and to strike the young. The major burden of asthma stems from its chronicity and associated disability, as measured by school absences, lost job productivity, and other activity limitations, as well as by visits to physicians, emergency room utilization, and hospitalizations.

Recent years have witnessed tremendous advances in asthma treatment based on a new understanding that chronic and persistent inflammation of bronchial tissue is the driving force of this disease. Research has made it clear that continuous attention to this inflammatory process, rather than episodic response to acute attacks, is essential to break the vicious circle that leads to airway obstruction. A variety of drugs are now available for this purpose, and the recent establishment of an Asthma Clinical Research Network will ensure rapid evaluation of new therapeutic strategies as they are developed.

Asthma management in special populations is being given particular attention. For youngsters with asthma, the challenge is to achieve adequate symptom control while optimizing lung function and overall growth and development; a clinical trial of drug regimens is addressing this issue. Asthma in pregnancy can produce complications for both the mother and the baby, and studies are under way to identify safe and effective treatment approaches. Still other research has successfully developed a model program of preventive and continuing care for a population that has traditionally been very hard to reach-inner-city minority persons with asthma. If this intervention is found to reduce emergency room utilization and hospitalization rates, its widespread application could greatly reduce the societal and economic burdens of asthma. Asthma in older Americans is receiving increased attention as scientists study complications from coexisting heart and lung diseases.

Beyond investigation of pharmacological treatment regimens for patients with asthma, the NIH has invested many years in the application of behavioral sciences research to the problem of asthma management. Model self-management approaches developed during the early 1980s have demonstrated that patient education and involvement is crucial to achieve optimal control. The National Asthma Education and Prevention Program has proven to be an effective vehicle for disseminating the results of this research. Its central theme, "Your Asthma Can Be Controlled: Expect Nothing Less," emphasizes that modem treatment should enable patients to control their symptoms, prevent attacks, be physically active, and breathe normally.

Much as we applaud these improvements in asthma management, we have not lost sight of our ultimate goal to cure or prevent asthma. No other chronic disease so vividly illustrates the interplay between genetic and environmental factors, and research in this area is the hope and promise of the future. For instance, it is becoming clear that development of asthma depends on the pathways followed by the immune and pulmonary systems during early fife. A person's genetic background interacts with a predisposing environment at critical stages to determine the pattern of response to these systems for the rest of fife. Extension of such knowledge may ultimately pinpoint the timing and nature of preventive strategies.

We are pleased to announce that scientists have now uncovered the location of major genes that control the allergy and hyper-reactivity of the airways, two important risk factors for asthma. The genes are located in regions of chromosome 5 that are rich in cytokines, molecules that are thought to regulate the process of inflammation that leads to development of asthma. In parallel studies, a large number of families with well-defined asthma are being characterized in an attempt to identify all the genes that confer susceptibility to asthma. Scientists will then proceed to examine more closely specific genes of interest. These findings represent the first important step in unraveling the genetic basis of asthma. With the genes in hand, it will then be possible to explore their interactions with environmental factors that play such an important role in causing the disease. Identification of the genes responsible for allergy and asthma is expected to lead to a better understanding of the primary defects in asthma, to development of better techniques for early diagnosis and disease prevention, and to new approaches for treatment.

Sickle cell disease. Sickle cell disease, the most common serious it United States, is also one of the most tenacious and inexorable of chronic diseases in that afflicts its victims from cradle to grave. It is characterized by recurrent bouts of pain ("crises"), chronic anemia related to accelerated destruction of red blood cells, increased susceptibility to certain infections, and acute or chronic damage to various organs. Children inherit sickle cell disease when the gene for defective ("sickle") hemoglobin is passed on from both parents. In this country the illness occurs predominantly, but not exclusively, in persons of African ancestry; about 50,000 to 60,000 American blacks are affected. Health-care costs for patients with sickle cell disease can be extremely high, quality of life is impaired, and loss of time from school or employment is common. Thus, sickle cell disease is a problem of significant medical, psychological, social, and economic importance.

Although NIH research on sickle cell disease began less than 25 years ago, progress has been rapid. Few patients used to survive beyond the third decade, but now many are living into their 50s and beyond. In contrast to the situation with regard to heart disease and asthma, for which molecular and genetic techniques are just beginning to be applied, our study of this. disorder began with sophisticated, fundamental investigations. In fact, in 1977 sickle cell disease became the first human malady to be described at the level of DNA and RNA. Breakthroughs that rapidly followed made it possible to apply gene mapping techniques to prenatal diagnosis and to use placental tissue rather than fetal blood samples for this purpose. This substantially increased the safety of prenatal diagnosis for sickle cell disease, and rapidly led to the application of molecular genetics for prenatal diagnosis of other inherited diseases.

At the same time, basic research supported in scientific laboratories throughout the country brought a tremendous revolution in our understanding of sickle cell disease at the molecular level.

One of the earliest NIH programs focused on research to determine the mechanisms that regulate the "switch" from fetal to adult hemoglobin during infancy. It had been recognized for some time that sickle cell patients who were fortunate enough to have inherited a tendency to continue producing fetal hemoglobin beyond the first year of fife had relatively benign disease. Therefore, it seemed logical to pursue therapeutic modalities that would enable patients producing adult sickle hemoglobin to "switch back" to producing normal fetal hemoglobin. This research catalyzed the field of molecular biology, and became the cornerstone for development of new therapeutic approaches. It produced news headlines last year when the results of a landmark clinical trial showed that administration of hydroxyurea, a common chemotherapeutic agent that boosts fetal hemoglobin production, not only reduces the frequency of crises and their attendant hospitalizations, but also reduces episodes of acute chest syndrome, a pneumonia-like complication, and the need for blood transfusions.

Very early on, it became apparent that although much was known about the molecular basis of sickle cell disease, little was known about its natural history or clinical course. Only the sickest patients were described in the medical literature, and most clinical reports of patient outcomes were anecdotal and retrospective. The Cooperative Study of Sickle Cell Disease addressed many of these unknowns. It clarified issues of growth and maturation patterns among children with sickle cell disease; defined the causes of death in the pediatric population; described the epidemiology of painful episodes and documented, for the first time, that the frequency with which such crises occur is a predictor of premature death in adult patients; and pointed out the risks of alloimmunization for sickle cell patients receiving repeated blood transfusions. This research program redoubled efforts to search for new therapeutic agents, and also provided a model from our Comprehensive Sickle Cell Centers, for a revised management approach that places the central focus on the patient. Care that was previously fragmented, impersonal, and episodic has been replaced with a team approach, involving a cadre of trained personnel that includes not only physicians, but also nurses, social workers, psychologists, nutritionists, counselors, and allied health professionals.

Subsequent clinical research demonstrated the value of prophylactic penicillin in preventing major infections in infants and young children. Before that discovery, approximately 30 percent of sickle cell deaths occurred before 5 years of age, most in children under the age of 2, and the majority were due to pneumococcal infection. This work also provided impetus for recommending that d newborns be screened for sickle cell disease, which is currently being carried out in 42 states. Infants at risk could then be referred for comprehensive care, and prophylactic penicillin therapy could be given by 3 months of age. A follow up study determined that this therapy can safely be discontinued in most patients at 5 years of age, thereby decreasing the risk of promoting drug-resistant infections in this vulnerable population.

We see a new era of optimism for treating and, indeed, curing sickle cell disease patients, because we are on the threshold of moving molecular medicine even closer to the bedside. Gene therapy and bone marrow transplantation offer great hopes for eliminating this disease. Bone marrow transplantation has been successfully used by several investigators in Europe, as well as a small . number in the United States. Although early reports are Promising, patient selection, donor availability, and complications of the procedure continue to be potential problems that prevent widespread use of this therapeutic modality today.

Basic research on gene therapy is advancing, with the possibility of inserting normal genes for hemoglobin production into bone marrow precursor or stem cells, thus enabling the production of normal hemoglobin. Our ability to obtain highly enriched quantities of stem cells from cord blood, peripheral blood, and bone mar-row will facilitate continued advances in gene transfer strategies. However, the efficiency of gene transfer must be improved before this procedure has the potential for therapeutic benefit in sickle cell disease. This approach is receiving active attention by many researchers around the country, who are optimistic that a cure for sickle cell disease can be achieved within the next decade.

Arthritic Disorders. Arthritic disorders are chronic and disabling diseases that occur at all ages, destroy the quality of life, and require long-term medical care. By the year 2020, when the babyboom generation approaches the prime year of onset of certain forms of arthritis (osteoarthritis), a large percentage of the population could be afflicted. Studies are focusing on many of the over one hundred forms of arthritis-related diseases, with major emphasis on rheumatoid arthritis, systemic lupus erythematosus, and osteoarthritis.

Rheumatoid arthritis is a chronic inflammatory disease that usually occurs in early adulthood or middle age. The joints of the body become painful, swollen, stiff, and in severe cases, deformed. Rheumatoid arthritis involves the hands, wrists, elbows, shoulders, and knees. The disease can also cause widespread inflammation in blood vessels throughout the body.

Scientists have discovered that white blood cells have specific cell adhesion molecules that facilitate their movement into joints. Considerable evidence has also indicated that chemicals, such as tumor necrosis factor-alpha and interleukin- 1, are released by white blood cells that invade the joints and cause the inflammation. This is thought to indicate that rheumatoid arthritis is a form of a self-destructive, or autoimmune, process. Efforts are being directed at blocking the movement of white blood cells into joints, as well as blocking the action of the chemicals released by the white blood cells, thus preventing or controlling inflammation.

Other research efforts are focusing on the growth of new blood vessels (angiogenesis), which can deliver white blood cells that cause the destruction of joints. A novel angiogenesis inhibitor that can slow and even prevent the chronic inflammation of arthritis in several experimental disease models has recently been identified. The inhibitor is currently undergoing preliminary clinical trials. Better understanding of the angiogenesis process, its role in destructive diseases such as rheumatoid arthritis, and the effects of angiogenesis inhibition could provide new and possibly more effective means to manage a wide range of joint problems.

Another arthritic disorder, systemic lupus erythematosus, also called SLE or lupus, is a disorder of the immune system in which the body produces abnormal antibodies(autoantibodies) that react against the person's own tissues. Lupus can affect many parts of the body including the skin, joints, heart, lungs, kidneys, and nervous system. Lupus primarily affects women of childbearing age, at a ratio of nine women to one man, and it is three times more common in black women than in write women.

Over the past several years scientists have developed more sensitive laboratory tests for autoantibodies in blood serum, enabling recognition of milder forms of lupus. Hormone-like chemicals called cytokines, which are produced by white blood cells, marshal the body's immune response to foreign substances and stimulate the production of multiple autoantibodies. Researchers hope to learn more about environmental and other factors that result in the production of harmful antibodies so that they can develop intervention strategies.

Research into the genetic basis of lupus is also ongoing. In a recently identified mutant mouse strain that develops a lupus-like illness, there is a defect in one of the genes that causes apoptosis, a normal process by which the body eliminates unnecessary, damaged, or potentially harmful cells. When this defective gene is replaced with a normal gene, the mice no longer develop signs of lupus. Better understanding of the role of apoptosis in lupus may lead to new, targeted treatments for humans. Other researchers have found various features of lupus are affected by distinct but additive, genetic contributions. This work is important because a similar effort to identify genetic susceptibility is now being made in humans.

Long-term clinical trials by NIH intramural scientists using various immunosuppressive drugs to treat lupus nephritis--a form of lupus that can be life-threatening-have demonstrated that prednisone combined with intravenous cyclophosphamide is very beneficial. This approach has now become standard clinical practice for the treatment of patients. These scientists are now exploring other drugs as well as biological agents, such as new monoclonal antibodies, for treating lupus nephritis. Such agents would enable physicians to circumvent the toxic side-effects associated with powerful immunosuppressive drugs. At the present time, women with lupus are generally advised not to take any medications that contain estrogen in the belief that it will worsen their disease. A recently-initiated clinical trial win provide scientific evidence to support physicians' decisions about the safety of providing oral contraceptives and hormone replacement therapy to woman with lupus.

It remains a puzzle as to why in patients such as those with rheumatoid arthritis and systemic lupus erythematosus, the body's own immune system reacts against other cells and tissues. The major histocompatibility complex (a group of inherited genes) has emerged as the single most predisposing factor for autoimmune diseases ranging from rheumatoid arthritis and lupus to insulin dependent diabetes mellitus. Yet, in spite of this striking association and the abundant information about the structure of major histocompatibility complex molecules, mechanisms underlying their role in determining whether or not the body's own cells will be tolerated. or attacked, as in the above-mentioned autoimmune diseases, remain a mystery. The major histocompatibility complex may affect disease predisposition through several mechanisms. The increased capacity to predict the interaction between the major histocompatibility complex and small components of proteins called peptides, and the availability of methods to test for major histocompatibility complex involvement have provided new and challenging opportunities for identification and analysis of self and foreign peptides in the production of autoimmunity.

Osteoarthritis, or degenerative joint disease, is another form of arthritis that occurs mainly in older persons. Osteoarthritis affects cartilage, the protective material that covers the ends of bones, causing it to fray, wear, and, in extreme cases, disappear entirely, leaving a bone-on-bone joint.

Osteoarthritis can cause pain stiffness, and swelling of the joints and loss of function. Disability results most often from disease in the knees, hips, and spine. About one-third of adults in the United States have x-ray evidence of osteoarthritis in the hand, foot, knee, or hip-, and by age 65, as much as 75 percent of the population has x-ray evidence of osteoarthritis in at least one of these sites. Research into the causes and treatment of osteoarthritis is multi-faceted and includes population-based studies, basic research at the molecular and cellular level, and investigations into designing more effective and longer lasting artificial joint replacements.

Much of the basic research on osteoarthritis has focused on differences between the cells of normal and osteoarthritic cartilage. A key component of cartilage is collagen, a widely distributed connective and supportive tissue protein. This fiber-like protein has the ability to trap water and become sponge-like. The resiliency that collagen imparts to normal cartilage makes it possible for joints to withstand the pressure of body weight. The degradation of cartilage that leads to joint damage in osteoarthritis is sometimes caused by enzymes acting on collagen. As this enzymatic breakdown of collagen takes place, cartilage can become damaged by weight and other mechanical forces. Scientists have recently discovered inhibitors of these destructive enzymes. Several are being tested in small clinical trials supported by pharmaceutical firms in the United States and abroad. Other investigators are carrying out laboratory studies on molecular mechanisms to suppress collagenase genetically. Major efforts are also being expended in trying to understand how growth factors and bone and matrix morphogenic proteins, which are known to enhance cartilage formation, can be used the rapeutically in osteoarthritis.

The current widespread use of joint replacements represents a singularly significant advance in the treatment of osteoarthritis. At present more than 120,000 artificial joints for hips are being implanted in the United States annually, the majority in patients with osteoarthritis. Past research has contributed to development of improved prostheses and joint replacement procedures. Current studies are attempting to identify causes of prothesis failure and why various protheses and particles released from protheses cause bone resorption.

Osteoporosis. Among the bone diseases that afflict Americans, osteoporosis is by far the most prevalent. Patients with osteoporosis have thinned bones that result in bone fragility and an increased risk of fractures. In the United States, women are four times as likely to develop osteoporosis as men. The major fracture sites associated with osteoporosis are the hip, the spine, and the wrist. Of all injury sites, hip fractures have the greatest morbidity and socioeconomic impact. In the six months following hip fracture, there is an overall 12 to 20 percent reduction in . expected survival, and 15 to 20 percent of patients will need to enter a long-term care institution shortly after the fracture.

A great many research efforts. in osteoporosis are underway at the NIH. Fourteen institutes, centers, and divisions at the NIH currently support basic and/or clinical research on osteoporosis and related bone diseases. Much of the research is done collaboratively; both within the NIH and ,with agencies and organizations outside the NIH and outside the Federal Government. Studies being conducted range from investigations of the causes and consequences of bone loss at cellular and tissue levels to clinical trials testing strategies to maintain and even enhance bone density. Evaluation of skeletal status is of major concern as scientists explore the roles of such factors as anabolic hormones, calcium, vitamin D, drugs, and exercise on bone mass. The influence of environmental factors (e.g., cadmium lead, boron) is also being examined. Some scientists are investigating bone matrix formation and the effects of mechanical strain; others are assessing the regulation of osteoblasts (bone-forming cells) and osteoclasts (bone degrading cells). Numerous studies are focusing on various aspects of fractures, including identification of risk factors; associated with racial differences, as well as development of treatment interventions. Researchers are also looking at osteoporosis in men, the influence of alcohol on bone mineral density, and the abnormal development of cartilage. The association between osteoporosis and lupus is being explored, and a recently established bone clinic at the NIH is facilitating the development of diagnostic and treatment protocols.

All of these activities contribute to advancing science in this area, and have been made possible by recent breakthroughs in areas such as genetics and the development of cell lines and of osteoporosis-prone mouse models. Another recent advance--ultrasound measurements of bone offers a faster, cheaper,and radiation-free alternative to other measures of bone density. This valuable new technology will help to identify those patients at a higher risk for fracture and will facilitate the targeting of individuals for preventive therapy. Exciting therapeutic avenues being pursued include the use of slow-release sodium fluoride, parathyroid hormone, and recombinant growth factors.

The Basic Osteoporosis: New Experimental Strategies (BONES) Initiative is an excellent example of a comprehensive NIH research approach that incorporates many different aspects of osteoporosis research. The goals of this initiative are to 1) encourage established bone biology investigators to address osteoporosis-related problems with novel approaches and the most powerful methodologies available; 2) increase the pool of investigators working in osteoporosis-related basic science areas by drawing researchers from genetics, cell and molecular biology, and structural chemistry into bone research; and 3) foster the development of interactions among laboratories originating in different disciplines.

Another new NIH initiative will investigate the remodeling (renewal) and repair of bone and connective tissue after damage from injury or degenerative disease. Natural repair is often insufficient, resulting in improper fracture healing, the failure of wounds to heal, and persistent joint dysfunction. This new initiative will look at a variety of factors that influence the tissue repair process, including how materials produced by cells affect the repair process, which cell populations are responsible for the repair and how these cells perform their functions, and whether techniques can be developed that would enable us to facilitate the repair processes.

Several new clinical studies have also been launched to learn more about this crippling disorder. For example, a clinical trial has been started to determine the complementary and synergistic effects of exercise and hormone replacement on bone density and bone loss in postmenopausal women. Another clinical study is examining ways to correct calcium deficiency in young women thereby helping to prevent the likelihood of osteoporotic fractures later in life. In other efforts, a study of fluoride exposure and fractures has been initiated to learn more about the positive effect of slow-release fluoride in decreasing vertebral fractures in osteoporotic women.

Public education efforts also play an important role in the battle against osteoporosis. In this regard, the NIH awarded a grant to a consortium of the National Osteoporosis Foundation, the Paget's Foundation, and the Osteogenesis Imperfecta Foundation to develop the Osteoporosis and Related Bone Diseases National Resource Center. The Center's purpose is to expand awareness and enhance knowledge and understanding of the prevention, early detection, and treatment of osteoporosis and related bone diseases and to broaden the knowledge base to enhance primary prevention of osteoporosis and reduce its consequences among at-risk populations.

The future is ripe with opportunities to build on recent progress. The previously-cited BONES and remodeling initiatives should yield important knowledge with regard to bone and connective tissue repair. Continued basic research into the molecular mechanisms of hormone action will provide additional insight into the causes and consequences of osteoporosis and related bone diseases. Clinical trials will be conducted with a goal of reducing the morbidity and mortality associated with these diseases. Human models and markers of skeletal aging are being developed. More functional prosthetic and orthotic devices will be designed, and additional outcomes of medical rehabilitation interventions will be measured. With every increment in knowledge, researchers will be better able to combat the devastating effects of bone diseases.

Muscular Disorders. Muscular dystrophy is but one of many degenerative muscular disorders that cause tremendous suffering. Muscular dystrophy is an inherited muscle disorder in which there is slow but progressive wasting of muscle. Although there are several forms of muscular dystrophy, the most common is known as Duchenne muscular dystrophy. With this type, infants are slow in their ability to sit up and walk. When they do, it is with difficulty. Degeneration of the skeletal muscles that control movement proceeds rapidly. Eventually, the lung muscles become affected, leading to respiratory failure. Duchenne muscular dystrophy results from a defect in the gene that codes for a membrane-associated muscle protein called dystrophia. There is considerable support for research into understanding the function of this protein and for the utilization of muscle cells in gene therapy for correction of this disorder in humans.

Skin Diseases. The NIH also supports research into the causes and treatment of many types of disabling skin diseases. For example, epidermolysis bullosa represents 20 different forms of rare, hereditary blistering disorders that involve the skin and mucous membranes. Epidermolysis bullosa can range from a relatively mild condition to a severely disabling and sometimes fatal disease. The skin of patients with epidermolysis bullosa is extremely fragile, and the slightest friction can cause painful blistering. In severe or dystrophic epidermolysis bullosa, blisters can cover most of the body and occur in the digestive tract. Often wounds from severe epidermolysis bullosa resemble serious bums. Epidermolysis bullosa is a life-long disorder and can cause extreme physical, emotional, and financial hardships for the afflicted patients and their families. Researchers have identified the precise location in skin that is affected by epidermolysis bullosa and the genes that are mutated in the various forms of these diseases. Research results such as these continue to shed light on the genetic origin of the various forms of epidermolysis bullosa and have generated a renewed optimism for altering the course and for improving treatments for these diseases.

Alzheimer's disease. An as yet unexplained loss of nerve cells in areas of the brain involved in cognitive functioning results in Alzheimer's disease (AD). The disease causes gradual loss of memory and what is, at present, an irreversible decline in intellectual abilities, as well as other impairments that may in extreme cases leave the patient incapable of self-care. Personality and behavior changes may cause patients to become agitated, sometimes to the point of causing harm to themselves or others. These devastating effects on patients and AD's long clinical course impose heavy personal and economic burdens on families, care givers, and society. The direct and indirect costs are estimated to be as high as $I 00 billion per year for the four million Americans now afflicted with AD.

Because the prevalence of AD doubles every five years beyond age 65, the rapid growth of the oldest old population is expected to place a significantly greater number of people at risk for the disease. Some scientists have projected a tripling of AD patients by the year 2050 to 14 minion individuals, potentially overwhelming the Nation's capacity to care for those affected. Fortunately, this scenario is not inevitable. While not long ago the symptoms of AD were referred to as "senility" and assumed to be a feature of growing old, research has since shown that AD is not a part of normal aging. Without disease, the human brain functions well throughout fife. As understanding of the disease grows, therefore, so do the chances of developing methods of early . detection and interventions that halt or slow its progress.

Sixteen NIH institutes and centers participate in research on the basic neuroscience, diagnosis and detection, treatment, and caregiving issues of AD, with regular meetings of an NIH AD working group to facilitate planning and coordination. NIH's neuroscience efforts (which are also discussed in testimony by the Neuroscience Panel) include exploration of the structure and function of nerve cells, cell-to-cell communication, brain structure and function, and the processes of cognition. They also aim to understand the complex mechanisms that cause nerve cells to die or gradually lose their ability to communicate with each other. Besides making significant progress in AD research, these efforts are expected to contribute to advances in understanding and treating a wide range of neurologic diseases, including other neurodegenerative diseases such as Parkinson's disease, stroke, Huntington's disease, and amyotrophic lateral sclerosis (ALS).

The breakthroughs that may eventually enable physicians to prevent the nerve cell destruction and onset of Alzheimer's disease symptoms are expected to come from basic neurobiology research. Highly interdisciplinary and integrative research is necessary to understand the biological basis for nerve cell function and mental activity. A special focus of AD research is to learn the genesis of .the "plaques" rich in a protein called beta-amyloid and "tangles" of collapsed nerve cell fibers, first described by Dr. Alois Alzheimer in 1907, that remain the most characteristic features of the brains of AD patients.

In just the past five years, reflecting a remarkable pace of research, genetic mutations linked to AD have been found on four separate chromosomes, with the two most recent discoveries coming in the past year. At least three of these genetic loci, found on chromosomes 1, 14, and 21, are associated with early-onset, familial AD, an aggressive form of the disease that can cause symptoms as early as 30 years of age. Inheritance of just one copy of these genes confers susceptibility. The success of this work is owed to intensive cooperation of multiple research groups working in the fields of epidemiology, genetics, and molecular biology.

These genetic findings apply to the approximately 10 percent of AD cases that are known to be familial and may also be involved in the development of other, more common, types of AD. Scientists are now trying to discover precisely what abnormal protein or process these mutations generate. This effort will be aided by earlier basic research such as that which identified and functionally characterized, in the roundworm, a gene very similar to the genes associated with two forms of familial AD. Further research on these genetic mutations is expected to clarify key steps which, together with environmental factors, play a role in the disease process.

In 1992, scientists discovered that the risk of developing the more common, late onset form of AD was linked to inheritance of variants (alleles) of Apolipoprotein E (ApoE), determined by a gene located on chromosome 19. Of the three alleles of ApoE, ApoE4 is associated with greatly increased susceptibility and earlier age of onset. In contrast, ApoE2 may confer some protective effect. Subsequent epidemiologic studies have shown that the age of onset can vary by as much as 20 years depending on which ApoE allele or alleles a person inherits. These important observations, confirmed in laboratories around the world, have touched off a flurry of activity to discover the molecular mechanisms underlying the effects of ApoE on AD pathogenesis, including its possible contribution to the development of the "plaques" and "tangles" characteristic of AD. If ApoE is directly involved in susceptibility for AD, this protein would then become an attractive target for interventions.

Creation of a "knockout" mouse that lacks a"gene for ApoE is beginning to define the role of ApoE in neuronal degeneration. In addition, the techniques of molecular biology and transgenic technology have combined in the past year to generate a mouse that expresses a mutant betaamyloid protein seen in certain families with AD. This advance may enable scientists for the first time to study AD using an animal model.

While genetic etiologies dominate recent findings, environmental factors, such as a history of severe head trauma, may increase the risk of AD. In contrast, recent studies have linked high levels of educational or cognitive ability in early fife to lower risk for developing AD in late fife. In some forms of AD, there may be multiple factors influencing disease progress. These factors may include oxidative damage that occurs with aging as a result of our own normal metabolism and the effects of inflammation and of differences in hormone balance which may also contribute to the disease process. Research is ongoing to follow up on these leads.

The dual goals of accurate diagnosis and early detection have long been central to AD research. After an extensive international effort coordinated by NIH AD can now be diagnosed during life with better than 90 percent accuracy, enabling patients to benefit from proper care and therapies. In addition, a recently reported study that combined the use of ApoE4 typing with brain imaging by PET scanning showed that it is possible to identify abnormalities in brain function of individuals who are at high risk for Alzheimer's disease, but who have no detectable disease symptoms, as much as 20 years before they would be expected to develop symptoms. This advance opens the opportunity for benefitting from interventions early in the preclinical course of the disease, before the brain has suffered the damage seen in fully developed AD. These findings suggest that significantly delaying the onset of AD is a realistic goal.

In order to speed the discovery, development, and testing of new compounds to treat AD, NIH -complements its broad basic research efforts with mechanisms that encourage the translation of basic research findings to the development of interventions to be tested in clinical studies. An innovative approach to fostering this process is the establishment of NIH's Alzheimer's Disease Drug Discovery Groups. These research teams are expanding the range of pharmacologic approaches to the treatment of AD and exploring the development of novel delivery systems.

NIH also funds a program of Alzheimer's Disease Centers to promote research, training and education, technology transfer, and multicenter and cooperative studies of diagnosis and treatment. A separate consortium is working to standardize methods for evaluating the status of AD patients. This effort will permit pooling of information collected by investigators at 27 university-based Alzheimer's disease centers and nearly as many satellites, which provide outreach to minority, rural, and other underserved populations for health information dissemination and recruitment for clinical studies.

The Alzheimer's Disease Cooperative Study coordinates the efforts of 3 5 institutions to conduct clinical studies for the treatment of cognitive impairment and behavioral disorders associated with AD. The design of this consortium makes it possible to conduct multiple clinical studies simultaneously. Four clinical studies are now underway.

Researchers also are evaluating the impact of alternative strategies to improve social support and ease the significant burdens of family caregiving. In addition, investigators are assessing special care units for Alzheimer's patients in nursing homes with the aim of designing model environments responsive to these patients' specific needs.

The rate of important discoveries in Alzheimer's research during the last few years provides reason for optimism that ongoing efforts will lead to success in understanding the causes of AD, delaying onset and progress of disabling symptoms, and reducing the personal and economic costs of care. The probability of producing findings useful for combating neurologic disease is multiplied by the presence of a strong infrastructure of basic neuroscience research in combination with mechanisms for promoting the translation of this basic research to methods of early detection and treatment.

Multifaceted approaches to preventing disability. Chronic disability is sometimes caused by a single injury or disease process, but for many individuals, particularly older persons, disability is the result of multiple, complex, and interacting factors. In addition to basic and clinical research to prevent and treat chronic diseases, successful new strategies now being developed and tested can make a critical contribution to quality of life and help prevent the disability that leads to long-term care. These strategies determine major risk factors for a specific disability, or disabling condition or event, based on epidemiologic research, and develop interventions for each major treatable risk factor. They then apply interventions to each individual on the basis of his or her specific risk factors, using simple, inexpensive technologies to prevent complex, expensive problems.

During the past year, researchers conducted the first randomized controlled trial using this multiple risk factor approach to reduce falls in older people. The interventions targeted risk factors for falls, such as bone fragility and muscle weakness, postural hypotension, use of sedatives or multiple medications, impairments of motion such as balance and gait, and environmental hazards. Participants received individualized treatment, including medication adjustments, strength and balance training, and instruction on safe practices to avoid lightheadedness and environmental hazards. Over a one-year follow up period, the participants' rate of falls was reduced by nearly half compared to that of the control group, which had received only social visits. The intervention was also shown to be cost-effective, particularly among individuals at high risk for falling. Since more than 250,000 hip fractures occur each year among persons over age 65, a substantial national cost savings should result from incorporating the tested strategy into the usual health care of older persons.

Research on risk factors can also be applied to predicting disability. One such study of older nondisabled persons found that three short tests of physical performance abilities strongly predicted disability as much as four years in advance. Combining this knowledge with interventions such as the multiple risk factor approach has the potential of preventing or delaying onset of diseases such as diabetes and arthritis, disorders such as urinary incontinence and mobility impairments, adverse drug effects, and -nursing home admission. The potential impact on associated health care expenditures is estimated in tens of billions of dollars.

Researchers are identifying the behaviors that place individuals at greater risk for poor health, depression, and other negative outcomes. The well-documented benefits for health and longevity that come as a result of adopting healthy lifestyle practices, such as physical activity and nutrition, and terminating health impairing habits, such as smoking, apply at all ages, even to the very old. A large research portfolio is dedicated to find ways to overcome the impediments that can prevent people from initiating and maintaining health-enhancing behaviors or adhering to medical regimens that can extend the healthy years of life.

Investigators are also monitoring the nation's disability rates. Studies have shown that these rates were significantly lower in older people than those predicted by prior analyses. Research is underway to determine the causes underlying the decline and to apply this information where possible to reducing disability.

One of the most exciting research frontiers involves the examination of the interaction among behavior, central nervous system structure and function, and neuroendocrine and other hormonal factors. NIH supports an active research portfolio on behavioral correlates of specific biological changes and relationships between biological and psychosocial factors. Care givers of persons with chronic disabling diseases have been found to be prone to negative health outcomes because of the stresses inherent in the often difficult aspects of caregiving. Research promises to develop effective interventions to help alleviate the burdens of long-term care for care givers.

Conclusion. The progress presented here illustrates a process and a philosophy that have prevailed for many years at the NIH Although the ultimate objective has always been betterment of national health, the path for realization has often been through innovative basic research, even when not directly related to specific diseases. Other advances have been achieved through population-based studies, through behavioral research, frequently through clinical trials and, in recent years, through outreach programs to inform practicing physicians and the public. Over the years, the goals of the NIH have changed in response to emerging national health needs, new technologies, and increasingly sophisticated approaches to biomedical research.

This concludes our remarks. We would be pleased to answer any questions you may have.

**There are 5 charts attached.

Chart #1

Molecular Medicine and Heart Failure

  • Transplantation of Embryonic Heart Cells

  • Transplantation of Genetically Engineered Heart Myocytes

  • Xenotransplantation

Chart #2

Death Rate for All Cardiovascular Diseases A chart of Death Rate over time (year) 1940-1995 per 100,000 Population. Shows from 1947 to 1995 that the rate of cardiovascular diseases have continuously decreased.

Chart #3

Percent Change in Coronary Heart Disease Mortality

A chart of the percentage change over time(year) 1963-1993. The percentage of change of coronary heart disease mortality has continuously decreased.

Chart #4

Annual Heart Failure Deaths

A chart of the number of deaths over time (year) 1970-1995. The number of annual heart failure deaths have continuously increased over a 20 year period with a few periods of little of no growth.

Chart #5

Annual Hospitalization for Heart Failure

A chart of the number of Hospitalizations over time (year) 1970-1975. The number of Hospitalizations over approximately 20 years have continuously increased with some periods of little or no growth.

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