Catalog. In 1956 this library was reestablished by act of Congress (Public Law 84-941) as the National Library of Medicine, within the Public Health Service. Other early landmarks in Federal support of medical science include the National Board of Health, set up in 1879 on recommendations of the American Public Health Association and the American Medical Association. Although the National Board lasted only 3 years, it was a prototype of Federal research activity to be undertaken at a more propitious time. It sent scientists to Cuba to study yellow fever, compiled vital statistics, and made research grants.

Even in this brief sketch of the early origins of American medical research, it is important, I believe, to give recognition to an extraordinary man, a giant in his time who was directly involved in each of the events I have mentioned and who, in addition, exerted a profound influence upon the course of the Nation's development in medicine. This man was John Shaw Billings, an officer of the Medical Corps of the Army. It was Dr. Billings who, at the request of the Secretary of the Treasury, made the study that resulted in the reorganization of the Marine Hospital Service in the post-Civil War period and recommended the establishment of the Commissioned Officer Corps for its administration. Dr. Billings was founder and first librarian of the Army Medical Library and initiated its major bibliographic instruments, the Index Catalog and Index Medicus. Dr. Billings was engaged by the trustees of Johns Hopkins University to plan the medical school and hospital of the university, which constituted a landmark concept in medical education. It was he who recruited as the core of the illustrious faculty of that school, Drs. William Welch and William Osler. Dr. Billings served as a member of the National Board of Health during its brief existence, and was largely responsible for the farsighted scientific approach of that experimental venture in a national organization for health.

I think it important to note here that the period at the close of the 19th century and the beginning of the 20th was one in which an impressive record of scientific accomplishment, exemplified by the work of Reed, Gorgas, Kinyoun, and Billings, was achieved under the aegis of the Federal Government. Here began the tradition of excellence which has characterized Federal activity in medical science to this day.

Thus the turn of the century reveals medical science activity in both private and public laboratories, with support from industrial, philanthropic, and governmental sources. Private funds substantially exceeded public. The Rockefeller Institute for Medical Research, originally endowed with $60 million, was spending upward of $200,000 annually by 1920, as compared with $36,000 for research that year by the Public Health Service. It may be noted that the leading causes of death at the turn of the century were pneumonia-influenza and tuberculosis-both communicable diseases and both plainly within the scope of public health authority.

From 1900 until World War I-the "progressive era"-science was increasingly applied to national problems emerging from rapid industrialization. Teddy Roosevelt espoused conservation and health. The food and drug laws were enacted. Specific research authority for the Public Health Service was legislated by the Congress. But the period saw some diminution of research in Federal programs, largely as a result of the rise of foundations and universities with broad research missions. The Rockefeller Foundation contributed generously to the application of earlier Government discoveries in hookworm and yellow fever, while the Carnegie Institution launched collaborative research and project grants.

World War I brought the Federal Government back into science, under the guidance of the National Research Council, which became an important negotiator, if not dispenser, of funds. The Government was active in war-related research, from ordnance to public health, from submarine detection to food production. Then, with the war over, Government expenditures for research and development fell. The Public Health Service retained a Division of Venereal Diseases born of the wartime Chamberlain-Kahn Act (Public Law 65-193); and the Hygienic Laboratory continued its small program of fundamental investigation, gaining greater recognition in 1930 through its designation by act of Congress (Public Law 71-251) as the National Institute of Health. The great depression of the thirties, however, was devastating to private and public research alike, and another decade was to pass before the Public Health Service could undertake major steps in a new direction.

2 U.S. Statutes at Large, vol. 20, ch. 202, p. 484.

This was the study of chronic degenerative diseases, spearheaded by the National Cancer Act of 1937 (Public Law 75-244). The Public Health Service (so called since 1912) had early recognized the importance of these diseases, which were now assuming a dominant position in morbidity and mortality. Gains in health since 1900 were predominantly against infectious diseases, many of which take their greatest toll in infancy and youth. As a result, the average lifespan progressively lengthened. More people were reaching maturity and old age, with a resulting increase in disability and death from chronic diseases, such as heart disease, cancer, and strokes.

Between 1937 and the end of World War II, the Public Health Service research programs-other than those directly concerned with disease controlwere reestablished at the National Institute of Health, in new laboratories erected on land donated to the Public Health Service at Bethesda, Md. In 1944 through the Public Health Service Act (Public Law 78-410), broad authority was provided for the conduct and support of research and research training. These events, the Cancer Act, the new facilities at Bethesda, and the modification and extension of statutory authority set the stage for the major developments of the postwar period.

The National Cancer Institute served as a prototype for other institutes established to increase fundamental knowledge of the major diseases. It was authorized not only to conduct research, but to make research grants to scientists in non-Federal institutions and to support research training. Cancer research grants were first awarded in 1937, fellowships the following year, and training grants to schools in 1947. The National Heart Institute was created in 1948 (Public Law 80-655) to investigate diseases of the cardiovascular system, by far the leading cause of death at midcentury; and the National Institute of Dental Research was established (Public Law 80-855) to apply to basic medical science to the most prevalent of the chronic disorders. The following year the mental hygiene program of PHS, created by the Mental Health Act of 1946 (Public Law 79-487), was transferred to NIH and expanded to become the National Institute of Mental Health. In 1948 the National Institute of Health, by virtue of the broadened scope of its activities, was renamed the National Institutes of Health (Public Law 80-655).

Another significant event in the development of NIH programs grew out of the transfer of research grants in the medical sciences at the time of the discontinuance of the wartime Office of Scientific Research and Development. These grants became an NIH responsibility, and were extended to provide much-needed support of general biomedical investigations, constituting the origin of a program of major importance in the general medical and related sciences.

Postwar development of NIH

Hiroshima and Nagasaki imprinted indelibly the significance of science on the public mind. The discovery of three groups of drugs-the sulfonamides, the antibiotics, and the antimalarials-also had a far-reaching influence. Increased recognition of the potential of science led to its support at a new order of magnitude. Important consequences were the creation of the Atomic Energy Commission (1946) and the National Science Foundation (1950). It is also significant that private support of medical research continued to rise after World War II, increasing threefold between 1947 and 1957. This is largely attributable to the increase in research opportunity and the mutually stimulating effect of private and Federal effort applied to the urgent problems of chronic disease. At the midcentury mark, PHS research authority was again increased by the "Omnibus Act" (Public Law 81-692), which extended NIH to encompass most of the major diseases of our time. The National Institute of Arthritis and Metabolic Diseases was formed from a nucleus of earlier laboratories, and the National Institute of Neurological Disease and Blindness was created. In 1953 the Clinical Center, a 516-bed research hospital, was opened at Bethesda headquarters, permitting all the Institutes to expand their study of patients. Two years later a renewed awareness of the problem of virus-induced infectious diseases and the probability of their conquest by vaccines, emphasizing associated regulatory responsibilities, resulted in a regrouping and expansion of activities under the titles National Institute of Allergy and Infectious Diseases and Division of Biologics Standards.

Throughout this period of development, the need to increase medical research resources-facilities and personnel-had become increasingly apparent. By 1955 appropriations for NIH grant and training award programs were twice those for the direct operations. The following year a major new resource program

was instituted by the Health Research Facilities Act (Public Law 84-835), a program of matching grants for research construction (extended by Public Law 84-777, 87-395, and 87-838). Thus, in fiscal 1957, 30 percent of NIH funds were budgeted for research training and construction in schools and other non-Federal institutions. Today the Nation is reaping the rewards of this investment through a larger pool of skilled investigators working in a much-improved environment.

The year 1957 marked a turning point in NIH programs. Three important facts had become manifest. First, that the problems of chronic disease, both in human and economic terms, had reached critical proportions. Second, that ample research opportunity existed for a much more aggressive attack on those problems. And third, that the only adequate source of the funds that would be needed for such an attack was the Federal Government. Accordingly, Congress made appropriations to NIH that were roughly double the previous year's sum. Substantial increases have been made each subsequent year, and the budget for fiscal 1963 totals $931 million. About 75 percent of this is awarded in grants for research projects, training, and construction.

Where does NIH stand at present in relation to other sources of medical research support? NIH conducts or supports 40 percent of the Nation's health and health-related research. Other agencies of the Federal Government account for another 22 percent, and private sources for the remaining 38 percent. Industry is the largest private contributor (25 percent). A considerable increase in private spending has accompanied the growth of Federal research programs in recent years. Total private support has doubled since 1957. Whereas the physical sciences are supported almost exclusively by the Federal Government, the life sciences continue to draw support from multiple sources. And if the Nation's medical research expenditure, roughly $1 billion in 1961, is compared with all research and development, it will be seen to have kept pace, remaining since 1950 at 5 to 8 percent of the total.

The development of NIH in the 1960's has been characterized by two major trends. The first is the extension of support to non-Federal institutions in forms enabling them to develop the research environment. Specifically, they have been able to create special resources such as clinical research centers, to expand career opportunities in research, and to augment their administrative capacity. The second trend consists in an internal reorganization to provide for better management of sizable support programs. This has included the creation of a Division of Research Facilities and Resources (1962), the establishment of two new Institutes-General Medical Sciences and Child Health and Human Development (1963) (Public Law 87-838)-and strengthening of program direction. Under authority of the International Health Research Act of 1960 (Public Law 86-610), international research activities have been concentrated and broadened through the Office of the NIH Director.

The significant accomplishment

It is difficult to assess the accomplishment of a single institution in the field of medical science, particularly when its support and leadership extend to a large portion of the total activity. Even accomplishments in the intramural operation are seldom quite separate from the broader scientific and medical movement. It is possible, however, to assert that NIH contributed in a major way to the attack on broad health problems that marked certain phases of our Nation's history.

Epidemic diseases characterized one such phase. Advances in the prevention and treatment of diphtheria, typhus, and tularemia were among early PHS contributions. The conquest of nutritional deficiency diseases, another important phase of the public health movement in this country, is typified by Joseph Goldberger's discovery of the cause and cure of pellagra (1915-23). The 1930's opened new opportunities through biochemistry, and the diseases resulting from internal chemical disorders-the metabolic diseases-came under attack. Early in the postwar period, biochemical approaches to cancer, heart disease, and mental illness were undertaken by NIH scientists. More recently it has become possible to study diseases at the molecular level, defining aberrations in precise chemical terms. Contributions are being made to the understanding of such fundamental phenomena as allergy, virus-cell interaction, and the genetic control of life processes.

In more specific terms, some pre-World War II achievements of NIH which stand out in historical perspective are as follows:

Explanation of the cause, spread, and prevention of hookworm disease.

Discovery of the cause and transmission of tularemia, and demonstration (postwar) of successful treatment by streptomycin.

The discoveries that pellagra and ariboflavinosis, diseases often confused clinically, respond promptly to small daily doses of B vitamins. Development of a typhus vaccine.

Development of a vaccine for Rocky Mountain spotted fever.

Establishment of fluoridation effects and water fluoridation levels for preventing dental caries.

Major accomplishments of the World War II period, in which NIH and several other organizations participated, included the clinical evaluation of chemical compounds useful in the suppression of malaria. Chloroquine and other drugs emerged in time to be of great value in the treatment of American soldiers. Malaria is a continuing interest of NIH, and recent new findings will be described in the pages ahead.

Some outstanding accomplishments of the postwar period are as follows:

Treatment of choriocarcinoma, a usually fatal tumor, with the drug methotrexate resulting in extensive remissions and demonstrating clinically that a solid cancer can be controlled by chemotherapy.

Synthesis of valuable pain-relieving drugs such as phenazocine, which is more effective and less addicting than morphine.

Identification of a virus which induces a wide variety of tumors in different species of animals, and preparation of an effective antiserum which prevents these tumors in hamsters.

Isolation of several viruses which cause leukemia in mice.

Technique for catheterizing the inaccessible left chambers of the heart, as an aid to the diagnosis of congenital heart defects.

Method for rapid laboratory diagnosis of influenza, based on virus-induced clumping and adsorption properties of blood.

Technique for detecting abnormal openings between the left and right chambers of the heart, a common congenital defect, through use of a tracer, the radioactive gas krypton 85.

Rapid colorimetric test for malignant carcinoid, a tumor often characterized by overproduction of a blood-pressure-affecting hormone, serotonin. Identification of the metabolic defect resulting in galactosemia, a condition in which milk is poisonous, and a simple test for application to infants. Discovery of the principal enzyme system by which the emergency hormone epinephrine (adrenaline) and its relative, norepinephrine, are inactivated after use in the body.

Clarification of the chemical transmission of inherited characteristics→→ "cracking of the genetic code."

NIH research highlights of 1962

Accomplishments of NIH scientists and grantees during the past year reveal that the fundamental investigations of the postwar period are now yielding important results in such formerly inaccessible fields as cancer causation and treatment, high blood pressure, mental retardation, inborn errors of metabolism. A selection of outstanding achievements from among the thousands of projects supported can be no more than suggestive. The following brief review, however, will indicate the variety, scope, and depth of present-day research operations, and will illustrate the areas of emerging opportunity that are receiving intensive stimulation and attack.

Two lines of research in cancer have held sufficient promise to warrant the creation of special task forces, which will mobilize resources and stimulate investigative effort. The first of these groups is concerned with leukemia therapy, the second with viruses as possible causes of human cancer.

In recent years the lifespan of patients with acute leukemia has been extended through use of drugs, blood transfusions, and other techniques. One of the more serious problems is bleeding, over which we have gained almost complete control through transfusion of blood platelets. A similar technique developed during the past year makes use of granulocyte transfusion in leukemia cases to combat overwhelming infections with a specific microbe which does not respond to other treatment. In clinical chemotherapy studies, two more drugs were found effective against some types of leukemia. One is vincristine, an extract of the periwinkle plant developed by Eli Lilly & Co., and the other is cyclophosphamide, synthesized in Germany. These drugs expand the arsenal of agents that can be used in combination or in sequence to induce remissions in acute leukemia of childhood.

Promising results were also obtained with the drug Methyl-GAG against acute myelogenous leukemia in adults.3

The possibility that viruses may cause human cancer has been recognized since the demonstration of a chicken tumor virus in 1908. One by one virus cancers were discovered in other species-birds, frogs, rodents. But the viruses seemed highly specific for particular species and types of tumor. Then, in 1957, NIH investigators indentified the polyoma virus in mice and extended its cancercausing ability to a variety of tumors in several species. This greatly stimulated the search for a cancer virus in humans. In a concerted effort to expand this field, both at NIH and through support programs, the Virology Research Resources Branch is working to develop experimental animals, viral diagnostic agents, and other tools. The human cancer virus task force is seeking answers to important research questions. Last year NIH scientists made another major contribution to this inquiry in their isolation of a virus that causes leukemia and red cell proliferation in mice.

Heart research conducted and supported by NIH progressed on two levelsbasic studies on the cardiovascular system and its function, and studies on the application of fundamental knowledge to clinical problems. A remarkable finding was reported during the year by grantees at the Southwestern Medical School, University of Texas. When rats were subjected to various diets, hormones, or the drug chlorothiazide throughout pregnancy, their young later developed a form of high blood pressure closely resembling essential hypertension in man. This may contribute to the understanding of prenatal influences in determining patterns of disease.

NIH scientists continued to study a spectrum of blood-pressure-lowering drugs. In previous years NIH reported on a new drug, alpha-methyl DOPA, developed by Merck Sharp & Dohme, which lowers high blood pressure in a significant proportion of patients. Additional experience with this compound indicates that it is useful both in malignant and less rapidly advancing types of hypertension. This valuable drug, already sold commercially in England, was recently placed on the market in this country.

It appears, however, that additional compounds will be needed to control high blood pressure in all patients. There are several biochemical processes concerned with the production or release within the body of chemical compounds, which probably have a great deal to do with the causation of hypertension. Scientists are already working on compounds that inhibit specific enzymes involved in these biochemical syntheses.

One or two results in mental health research will illustrate the impressive progress being made in that field. Grantees at Western Reserve University, reviewing early school records of adult schizophrenics, found that intelligence had declined markedly long before the psychosis was detected. The IQ of children who later become schizophrenic had dropped an average of 10 points between the second and sixth grades. It is hoped that this finding can be used broadly as an aid to detection of incipient mental illness.

In metabolic studies at NIH, a rapid and sensitive method was developed for detecting narcotics and other drugs in the urine. The method employs thin-layer chromatography for rapid identification of various organic compounds, such as morphine and barbiturates. It will undoubtedly facilitate studies now underway in many large cities on recidivism in narcotics addicts.

The

Basic studies in the genetic control of metabolism, or body chemistry, have been yielding results of clinical significance over the past several years. molecular diseases-so called when the inborn error of metabolism can be described in definitive chemical terms-include phenylketonuria, or PKU. This is a disease that can lead to mental retardation through the body's inability to utilize phenylalanine, a constituent of protein. While we now know that a diet low in this substance can protect the afflicted child's brain, it has not been clear just how long this exacting diet must be maintained. Last year NIH grantees at the University of Colorado Medical Center found that patients may outgrow their need for the diet by the age of 4.

The detection and dietary treatment of PKU have been developed to the point where control of the disease would seem practical. NIH has launched a 5-year program to demonstrate the detection of PKU and prevention of its effects.

Basic studies by grantees at the University of Maryland Medical School have thrown light on another hereditary disease, cerebromacular degeneration. The

3 Methyl-GAG was originally synthesized in 1957 by Frederic A. French at Mount Zion Hospital, San Francisco, Calif.