« PreviousContinue »
STATEMENT OF DR. CLAUDE LENFANT
It is my pleasure to address this committee once again on behalf of the
National Heart, Lung, and Blood Institute (NHLBI).
I have much good news to
report about our quest to reduce the impact of cardiovascular, pulmonary, and
blood diseases on the American people. Indeed, this has been a year when we
have consolidated many gains and moved ahead in a variety of new directions.
Over the years, much attention has been focused upon the use of fundamental
scientific approaches to understand the basis for health and disease.
past, I have reported a number of innovative findings from such disciplines as
cell biology, molecular biology, and genetic engineering that, while not
always of immediate applicability, held great promise for future health
Today, I am pleased to highlight the fulfillment of that
scientific promise in a number of disease areas.
A recent development in asthma research offers a striking example of how
basic understanding has provided a foundation for advances in treatment.
NHLBI-supported basic research on the inflammatory mechanisms underlying
asthma has implicated a class of chemical substances, the leukotrienes, in the
pathobiology of asthma.
The leukotrienes appear to trigger asthma attacks by
causing airways in the lungs to tighten. Building upon this information,
scientists recently experimented with the use of a newly developed inhibitor
of leukotriene biosynthesis in experimentally induced asthma.
significantly blunted asthma attacks without producing the side effects that
can accompany current asthma therapy.
Because this new approach addresses the
basic mechanism underlying asthma, it offers much therapeutic potential for
the millions suffering from this disorder.
As we pursue this line of
research, the National Asthma Education Program will continue its efforts to
disseminate the most up-to-date information about the diagnosis and management
For example, the recent release of the Expert Panel Report on
Asthma Management is expected to greatly facilitate treatment by primary care
Molecular biologists have recently reported the identity of a gene
responsible for familial hypertrophic cardiomyopathy (FHC), one of the most
common causes of sudden death in young athletes. Knowledge of the mutation
responsible for FHC paves the way for the development of genetic tests for its early detection and of animal models to facilitate detailed investigation of
Moreover, understanding the molecular basis of FHC may provide
clues to the treatment of other disorders that cause heart enlargement, such
as hypertension, atherosclerosis, and valvular heart disease.
The NHLBI also
supports population-based studies that are using new echocardiographic
techniques to assess cardiac structure.
The findings will improve our
understanding of why heart enlargement is a major, independent risk factor for
The emerging area of gene therapy provides another example of how
fundamental research may lead rapidly to clinical applications.
techniques of molecular biology, it is now possible to analyze human DNA, to
identify, isolate, and purify specific human genes, and to insert genes into
the DNA of human cells.
NHLBI intramural scientists, in collaboration with
scientists from the National Cancer Institute, recently performed the first
gene therapy on a patient with adenosine deaminase (ADA) deficiency, a
condition characterized by severe lack of immune function.
A normal gene for
ADA was inserted into the patient's lymphocytes, which were grown in tissue
culture and returned to the patient.
Since treatment began last September,
the patient has done well and the function of the cells of her immune system
has improved steadily.
The current success of bone marrow transplantation between two different
individuals had its origins in basic immunology research.
Discovery of the
human leukocyte antigens (HLA), used by the immune system to distinguish self
from non-self, provided an answer to the puzzle of graft rejection and a
foundation for "matching" marrow donors and recipients.
The National Marrow
Donor Program, originally initiated to demonstrate the feasibility of
unrelated-donor transplants, has evolved into a major national resource with a
registry of more than 240,000 potential marrow donors. During the past year,
special donor recruitment measures adopted by the Institute increased the
representation of racial and ethnic minorities in the registry fivefold.
Institute has also undertaken a new research program to determine the degree
of HLA matching required for a successful marrow transplant and to develop HLA
typing procedures based on molecular biology techniques.
The results of this
work will improve the efficiency and decrease the cost of HLA typing, and
thereby increase the pool of potential marrow donors.
Although marrow transplantation and gene therapy have evolved separately,
they are now coming together to provide a potentially powerful tool for
treating, and perhaps curing, many human diseases.
The NHLBI has taken the
lead in this area by developing a marrow transplantation unit within its
clinical hematology branch-a resource that will be shared with other
interested components of the NIH.
It will be the first research unit in the
NIH clinical center devoted exclusively to the study of the fundamental
biology and clinical application of marrow transplantation.
At the same time,
research on marrow transplantation will be closely integrated with an expanded
research program directed toward gene therapy of human diseases.
alterations of stem cells, the cells of the bone marrow that give rise to all
blood cells, may be the key to successful treatment of hereditary blood
disorders, such as Cooley's anemia, sickle cell anemia, and hemophilia.
researchers have made significant strides in overcoming the many technical
obstacles to clinical application of this approach.
To appreciate the
magnitude of this progress requires an understanding of the problems faced:
fewer than one in 1,000 marrow cells is a stem cell; stem cells can
incorporate new DNA only when they are dividing; and stem cells divide
infrequently. Thus, producing large quantities of genetically altered stem
cells has been a formidable task. During the past year, we have developed.
techniques to purify (concentrate) stem cells 50-fold and have explored ways
to accelerate the process of cell division.
Moreover, a clinically useful
protocol for inserting genes into stem cells has been developed.
Much evidence suggests that patients with either Cooley's anemia or
sickle cell anemia may benefit from increased production of gamma hemoglobin,
the normal hemoglobin produced in fetal life. Ongoing research is attempting
· to uncover ways to turn off the gene that produces the defective beta globin
associated with these diseases and switch on the gamma globin production gene.
The Institute has initiated a grant program to encourage Investigators
interested in gene therapy to refocus their efforts on the globin genes, with
particular reference to Cooley's anemia.
A parallel effort is also under way
to develop pharmacologic methods to increase fetal hemoglobin production.
Researchers participating in a small, multicenter study of sickle cell anemia
patients recently reported that fetal hemoglobin levels were raised to 15
percent or more through treatment with hydroxyurea, a common chemotherapy
If confirmed in larger studies, this approach may represent a
significant stride in reducing both the suffering and the high hospitalization
costs now. incurred by sickle cell disease patients.
The identification and cloning of the defective gene in cystic fibrosis
(CF), which normally codes for a protein called cystic fibrosis transmembrane
conductance regulator (CFTR), have produced many research opportunities and
raised hopes for a cure through gene therapy.
recently demonstrated that the insertion of the normal CFTR gene into cultured
human CF airway epithelial cells corrected the CF defect in vitro. Further,
investigators in the NHLBI intramural research program have reported success
in inserting the CF gene into the airway epithelial cells of living rats and
obtaining measurable indicators of gene expression in lung tissue.
advances have greatly improved the prospects for the possibility of gene
therapy to cure the disease,
The tools of molecular biology , have also
produced two advances that may have applicability to the short-term clinical
management of CF.
Administration of aerosolized alpha-1 antitrypsin into the
airways of individuals with CF has been shown to counteract the enzymes that
cause the tissue, destruction associated with CF infections.
Related work has
demonstrated the effectiveness of DNase, an enzyme that digests DNA, in
reducing the thickness of CF mucus.
All together, these findings represent
significant advances toward better treatment and ultimate cure of CF.
Studies of the natural history of atherosclerosis and hypertension have
enhanced our understanding of the development of cardiovascular disease in
An examination of autopsy material from young victims of
accidental death found that arterial fatty streaks were much more extensive in
Blacks than in whites of comparable age.
The appearance of these lesions was
significantly associated with elevated serum lipid levels and cigarette
The association with smoking is a new observation that could provide considerable interest that this phenomenon seems to be unique to American
powerful impetus for controlling smoking in the young.
In other studies,
measurements of 24-hour blood pressure patterns revealed that blood pressure
is much less likely to drop at night in Blacks than in whites.
It is of
Blacks and has not been observed in studies of Blacks born in other parts of
This so-called blunted nocturnal decline imposes additional
cardiovascular strain which may help explain the greater morbid consequences
of hypertension experienced by Blacks in the United States.
Women's health issues are being addressed in a number of new and ongoing
research programs of the Institute.
A pilot study to assess the efficacy of
various treatment interventions for asymptomatic myocardial ischemia is of
particular relevance to women in light of evidence that women experience
unrecognized myocardial infarction more frequently than do men.
As part of
this study, an assessment of the psychophysiologic characteristics of
myocardial ischemia will be conducted.
The Institute also has a strong
interest in how health-related behaviors become established and can be
This year, NHLBI-supported researchers presented evidence that
excess body weight is a strong, independent risk factor for coronary heart
disease in women.
A recent conference explored reasons for the greater
prevalence and more serious consequences of obesity in minority women.
Preliminary data from an NHLBI observational study comparing the development
of obesity in Black and white preadolescent girls indicate that differences
exist between the two races in height, body mass, and eating habits at ages
The Institute also recently sponsored a conference on smoking and
body weight, a topic of considerable interest in light of the observation that
smoking cessation results in more weight gain for women than for men.
Although the association between elevated cholesterol and heart disease
is well established, the implementation of a nationwide strategy to lower
cholesterol levels has been controversial.
This past year, the NHLBI
sponsored three conferences to reexamine the science base for the
recommendations of the National Cholesterol Education Program (NCEP).
conferences assessed data concerning the extent to which serum cholesterol
levels predict coronary heart disease in older persons and in women,
the evidence for associations between low serum cholesterol levels and certain
specific causes of morbidity and mortality, and addressed the costs and health
implications of cholesterol lowering.
The conclusions reaffirmed the
Institute's current approach to cholesterol lowering, and recommended