CLINIC AND LABORATORY

Many research projects require observation of patients for longer periods of time and the use of a greater variety of techniques than are possible in most hospital environments. The Clinical Center's facilities and its operational scheme meet these needs to an unusual degree. Patients are admitted on referral by their physicians when they have a condition required for a specific research project.

Patients are expected to remain in the Center as long as they are needed for study purposes and to cooperate in prolonged follow-up observations after their discharge. General medical, nursing, and related services in the Center are of the high quality provided in good hospitals everywhere. Occupational and physical therapy services, religious ministry, and recreation programs are available. These services, provided by the staff of the Center and volunteer workers, help to maintain the patients' morale. During the year, the total staff and the patients participated in a wide range of studies which ultimately will produce important findings related to the diagnosis and treatment of serious diseases and to the improvement of individual health.

The study of healthy individuals helps scientists to understand the meaning and underlying causes of phenomena observed in ill patients. Arrangements have been made with certain religious groups and the National Selective Service Board whereby the Clinical Center may recruit and accept healthy volunteers as study patients. The procedures employed are carefully designed to prevent the exposure of these volunteers to undue hazards.

Research Grant and Fellowship Programs

The Public Health Service encourages independent research in the medical and allied fields by scientists throughout the country, and supports locally conducted field investigations and demonstrations. In fiscal year 1954, an increased proportion (68 percent) of the funds appropriated by Congress to the National Institutes of Health went to non-Federal agencies in the form of research grants, fellowships, traineeships, training grants, teaching grants, and field investigation and demonstration programs.

The National Institutes of Health, through its Division of Research Grants, administers research grants and fellowships within the programs of its seven Institutes, plus a general grants program. National Advisory Councils, made up of national leaders in medicine, research, education, and public affairs have been established by law to select research projects for approval by the Surgeon General, and to advise the Public Health Service on broad research problems. To assist the

councils, study sections composed largely of nongovernmental specialists in medical and allied research areas undertake technical review and evaluation of the grant applications.

During fiscal year 1954, 3,596 applications for research grants were considered; 2,855 recommended awards, totaling $29,951,150, were approved for payment. The Public Health Service also awarded fellowships totaling $2,132,004 to 490 successful candidates in 130 research institutions. In addition, 323 teaching grants amounting to $5,894,184; 251 training grants totaling $4,222,806; and 488 traineeships totaling $7,444,832 were made to physicians and other graduate students for advanced clinical study. Eighty-five grants, totaling $1,091,344, were awarded for the conduct of field investigations and demonstrations.

Table 3, page 167, presents the numbers and amounts of research grants, fellowships, and field investigations and demonstrations awarded in 1954, by State and county. Table 4, page 168, shows similar data for the teaching grants, traineeships, and training grants. Some of the significant findings in studies supported by the Public Health Service are described in the reports of the various institutes. GENERAL GRANTS PROGRAM

Many of the most important problems confronting medical research do not fall within the specific interest of any particular institute. The general grants program supports research in various biological, clinical, and public health areas. Because such research requires longterm support, 69 percent of the grants during fiscal year 1954 went to continuing studies.

A considerable part of the general grants was awarded for research on the living cell. During the year, one group of grantees made significant progress toward the yet-unsolved problem of duplicating cell protein manufacture by synthesizing oxytocin, a substance secreted by the posterior pituitary gland. Another group has succeeded in building an amino acid, arginine, into proteinlike materials, removing one of the obstacles to the synthesis of such complex compounds as ACTH and vasopressin.

Clinical studies have invalidated the commonly held theory that hyperacidity is necessary to produce peptic ulcer. Other grantees report definite progress toward an understanding of how hydrochloric acid is produced in the stomach.

Radioactive isotope tracers are being employed in research on hay fever, contact dermatitis, and other allergic conditions. Another group of investigators has constructed an artificial smog generator which will permit study of the injurious effects of various chemical components of atmospheric pollution.

Arthritis and Metabolic Diseases

An operating program of clinical investigation, set up by the National Institute of Arthritis and Metabolic Diseases at the Clinical Center, has contributed significantly to medical knowledge. Meanwhile, continued basic research has thrown new light on such metabolic disorders as arthritis, diabetes, obesity, and diseases of the liver and endocrine glands.

With the American Rheumatism Association and the Arthritis and Rheumatism Foundation, the Institute sponsored the first National Conference on Research and Education in the Rheumatic Diseases, held at the Clinical Center on November 19.

RESEARCH PROGRESS

A new and simple procedure has been devised to separate and purify the anti-hemophilia factor from blood, in quantity and purity previously unobtainable. The absence of this factor in the blood of persons with hemophilia is apparently responsible for their tendency to bleed excessively. Work is proceeding toward further purification and identification of the factor.

Rheumatoid arthritis is often accompanied by an associated anemia, which decreases the patient's resistance and complicates successful treatment. The nature of this anemia has now been determined. In such patients, red blood cells are destroyed at an increased rate and red-cell-producing tissues fail to compensate in a normal fashion. These findings should lead to more successful treatment, increasing the resistance and stamina of the arthritic patient.

Work is continuing on the development of a new diagnostic test for rheumatoid arthritis, first reported last year. Now about 90-percent accurate, the test is based upon an agglutination reaction that occurs when a patient's blood is mixed with sensitized red blood cells of sheep. The reaction is caused by a factor found to be in the plasma protein fraction of the patient's blood plasma. Although the protein has been concentrated 300 times, the active factor has yet to be completely purified.

A study recently completed by NIAMD scientists reveals that Philadelphia school children at 6 to 9 years of age averaged 2 inches taller and 2 to 4 pounds heavier in 1949 than children of the same age in the late 1920's.

In collaboration with the United Nations, the Institute is conducting extensive research to identify the geographic sources of opium, thereby assisting the U. N. in controlling illicit drug traffic. Methods being investigated include infrared analysis, ash analysis, chromatography, X-ray diffraction, and studies of methoxyl and organic nitrogen content.

New and ingenious tools have been devised to measure cortical hormones and their metabolites in body fluids, as an aid to determining exactly what happens to these hormones in the body.

Growth hormone has been shown to affect profoundly the production of collagen, an important constituent of connective tissue. In certain endocrine imbalances, such as thyroid insufficiency, collagen is produced faster than all other proteins. This discovery is of additional importance because abnormalities of connective tissue are known to be present in rheumatic diseases. The availability of growth hormone in pure form now permits a definitive study of its relation to arthritis.

Rice, which is quite deficient in protein content, is a major item in the diet of millions of people. It is also a major constituent of a diet used in the treatment of high blood pressure. Institute scientists have found that its value in laboratory animals can be increased threefold by the addition of two essential amino acids, lysine and threonine. Clinical investigations are now underway to determine the effect of enriched rice diets on human nutritional status.

Employing a specially constructed "respiratory chamber," Institute clinicians are undertaking a new series of energy and mineral metabolism studies. The chamber is a specially equipped room designed to measure continuously the total energy expenditure of human subjects at various time intervals. Such studies are particularly important with relation to obesity and its influence in predisposing its victims to early development of high blood pressure and diabetes.

RESEARCH GRANTS AND SOME RESULTS

Research grants totaling $3,272,307 were approved for payment to 359 projects by the National Advisory Arthritis and Metabolic Diseases Council from 1954 appropriations. These projects were conducted in 38 States, the District of Columbia, and one foreign country. Research fellowships totaling $174,834 were awarded to 41 applicants, and training stipends totaling $238,836 to 69 trainee physicians.

Results include the determination of a quantitative relation between a hormone and its metabolic effect on a specific process. Methods for the preparation of radioactively labeled insulin have been developed and described, permitting the study of insulin action in the body.

The long-term effects of treated diabetes in humans are under close study. Approximately 200 diabetic children, under observation since the onset of the disease, have been given exhaustive chemical and clinical examinations at 6-month intervals. It is hoped that most of these patients can be studied for at least 30 years.

Cancer Research and Control

An expanded search for new knowledge on the causes, prevention, and cure of malignant diseases continued under the National Cancer Institute's program. The Nation's investment in cancer research and control during the past 17 years has yielded important results. New methods are available which give greater hope for the control of these diseases than could be entertained in the past. However, data on cancer incidence indicate that, even if the risks of cancer remain constant, the number of people affected by the disease can be expected to increase by 50 percent in the next 25 years. This is because the total population has increased and a higher proportion are reaching the ages where the cancer risk is greater.

LABORATORY AND CLINICAL STUDIES

The study of proteins has been hampered by their resistance to separation and isolation. Institute biochemists have devised a new chromatographic method for separation of soluble proteins in their natural state. Human serum can apparently be fractionated into at least 14 different components, and enzymatically active proteins may be separated from one another.

Drugs used in the treatment of clinical cancer sometimes have undesirable effects. In a project designed to develop more effective and less toxic drugs, the Institute is studying the pharmacological properties of drugs that have potency in affecting established tumors in laboratory animals.

Institute scientists and members of several non-Federal institutions collaborated in studies of the tendency of leukemic cells to become resistant to, or dependent on certain drugs. It has been found that resistance or dependence induced by antipurine drugs renders cells of some experimental leukemias unusually sensitive to drugs with antifolic action. Combined therapy, with each drug exerting its activity independently, has strikingly increased the survival time of leukemic mice and has even resulted in cures.

Studies in endocrinology have shown that massive parenteral estrogen therapy of mammary cancer with water-soluble estrogens is clinically feasible. Results indicate that more profound and more rapid regressions of breast cancer can be obtained by massive doses than by conventional oral administration of estrogenic substances.

The search continues for effective means of protection against large doses of irradiation. One experiment showed that lyophilized cortical bone from rats will protect mice against lethal doses of X-rays in much the same manner as bone marrow. This makes it more probable that a humoral factor is responsible for this phenomenon.