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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.

In the

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

related dividends.

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.

The drugs

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

of asthma.

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

this disorder.

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

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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.

NHLBI-supported researchers

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

American Blacks.

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

the world.

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

9-10 years.

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

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