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.
