In particular, the investigative work has been developed as follows: 1. Development of techniques for determining inherited biochemical differences between individuals, including those characterized as polymorphisms. 2. Discovery of new inherited traits in humans and lower animals. The animal studies may be utilized in experimental work on selection, and for an evaluation of the evolution of the inherited biochemical traits. 3. Epidemiological studies on the distribution of the inherited traits in different selected populations, particularly in those still living under primitive conditions, and under widely different environmental stresses. Thus, West African, Eskimo, and Central Pacific populations have been studied recently. 4. Study of the biochemistry and genetics of these traits. 5. Elucidation of the relationship of these traits to disease. Several investigations have been conducted during the past year, and some of these will be described: Beta amino isobutyric acid (BAIB) excretion Some humans excrete (in the urine) very small amounts of an amino acid, beta amino isobutyric acid (BAIB), which is a breakdown product of purine, a chemical constitutent of many cells. Others excrete large amounts of this material, and it has been shown that they possess two recessive genes for this trait. Persons excreting small amounts of BAIB have either two of the alternate dominant gene for low excretion, or one of each of the genes. This character may be changed by environmental conditions; thus, individuals who have received radiation, or who develop certain kinds of leukemia, have an increased BAIB excretion. Very little is known concerning the distribution of this gene for high excretion in different world populations. During a recent field trip to Alaska, it was found that American aborigines had a high prevalence of individuals excreting large amounts of BAIB (Eskimo, 23 percent; Indian, 56 percent, compared to U.S. whites, 10 percent), with no apparent association with disease. Of even greater interest was the finding that Micronesians from the atoll of Rongelap in the central Pacific had an extremely high frequency of individuals excreting large amounts of BAIB-nearly 90 percent. These people had been subjected to high levels of radioactive fallout, but it is unlikely, though not impossible, that the increase in urinary BAIB excretion was due to the radiation. The alternate explanation is that the high prevalence is due to a focus of high frequency of the high excreter gene in this population. We now wish to determine whether this high frequency of individuals excreting large amounts of BAIB is present in other related populations, and if so, why this distribution should exist. Studies in populations from Vietnam, Java, Tahiti, and South America are in progress. Further studies on other populations in South America and the Pacific are contemplated, as are investigations into the relationship between this trait and diseases which affect purine metabolism. Prevalence of arthritis in the Alaskan Eskimos During the course of fieldwork in Alaska, a survey of the prevalence of osteoarthritis of the hands and wrists (as detected by X-rays) in the Eskimos was completed. When this was compared to a similar study on U.S. white subjects, it was found that there was very much less osteoarthritis in the Eskimos when suitable corrections for sex and age were made. It is not clear why this difference exists, and no obvious environmental cause for the difference has as yet been detected, although such a cause may eventually be found. It is possible to specnlate that the present low prevalence in the Eskimos may be due to selection during the course of many generations against those who might develop osteoarthritis, since such individuals would be less likely to withstand the rigors of arctic life; that is, the present situation is a result of the special evolution of the Eskimos. Much more work must be done before this notion could be substantiated the findings should be rechecked in Alaskan and other arctic populations (including Lapps and Siberian arctic people), and in particular, possible environmental causes for the difference should be sought. Haptoglobins The haptoglobins are a family of proteins found in the serum of humans and other animals. They are characterized by their ability to bind hemoglobin, a protein of the red blood cells; and this appears to be related to their physiological function in the body. Three patterns are seen in most human populations which are hereditary, and are probably due to the presence of two paired genes. The frequencies of these inherited haptoglobin types in different popula tions vary enormously. Thus, the haptoglobin 11 type is found in more than 50 percent of some African tribes, but in only 7 percent of some Eskimo or Indian groups. Also, some individuals appear to have no haptoglobin in their serum at all. As it is probable that these proteins are in some way involved in hemoglobin transport in the blood, it appears likely that the physiology of the individuals without haptoglobin would be markedly affected in some manner. Further research is needed to determine why these genes vary in different populations and how exactly they are related to physiological and pathological conditions. Other studies in progress concern inherited biochemical traits and include the following: 1. The beta-globulins (transferrins) which are involved in iron transport in the blood; 2. The gamma-globulins, which may be involved with differences in the immunological responses of individuals to disease antigens ; 3. The taste-test phenomenon (the ability to taste phenylthiocarbamide and a wide variety of related chemicals) which almost certainly has some relationship to susceptibility to thyroid disease. Special studies in South America, the Pacific, and arctic communities are contemplated, in order to assess more fully the distribution of this and other traits, and their relationship to the endemic diseases. Studies on the chemical and physiological properties of the inherited chemical traits and clinical studies on their relationships to disease are also planned. Working seminar on genetic polymorphisms and geographic variations in disease In February 1960, a small group of distinguished scientists drawn from such fields as biochemistry, epidemiology, medical genetics, and medical anthropology met at the National Institutes of Health to discuss studies in progress and to assist in the planning and development of the expanding program of the Geographic Disease Studies Unit. This pilot seminar was limited to workers in the United States; contemplated followup of this session includes exploration with appropriate international agencies, including the WHO, in expectation that a larger group of competent investigators may be brought together at a later date for further exchange of information and the planning of cooperative studies on a worldwide basis. GERM-FREE ANIMAL RESEARCH-NATIONAL INSTITUTE OF ARTHRITIS AND METABOLIC Growth regulation factors DISEASES Germ-free animals appear to be the only means whereby unequivocal answers can be secured to such problems as the contribution of the flora in the gastrointestinal tract to the nutrition of the host. Studies are underway on the mechanism whereby antibiotics and large amounts of ascorbic acid in the diet reduce the animal's requirement for the B vitamins. Unless conventional rats receive pantothenic acid in their diets, they do not grow. When pantothenic acid is replaced by either 0.5 percent ascorbic acid or 100 mg. percent penicillin, the rats grow almost as well as those receiving pantothenic acid. There has been some controversy as to the exact mechanism whereby ascorbic acid and the antibiotics spare the animal's requirement for the B vitamins. When the above work was repeated with germ-free rats, no sparing effect of vitamin C or penicillin was seen, indicating that the growth-promoting action of the latter compounds was mediated through their biochemical action on the intestinal flora. These growth regulation studies were amplified by observation of germ-free rats after they were brought out of their special tanks into the animal room where they become infected. Within a few days, these animals lose most of the physiological and histological characteristics of germ-free animals. It has been assumed that the ex-germ-free rats after contamination would be the same as conventional rats. That this may not be so is suggested by the observation that the ex-germ-free rats respond to ascorbic acid and penicillin in the same way as do the germ-free rats. K vitamin deficiency studies A severe vitamin K deficiency develops in germ-free rats fed rations free of this vitamin. Conventional rats can maintain a normal blood clotting time without any dietary source of this vitamin. On a low-fat diet, the vitamin K deficient germ-free rats died in 30 days. Increasing the fat in the ration decreased the survival time. A normal clotting time develops within 24 hours after the germ-free rats become contaminated on removal from the tank. It has been shown that sulfaquinoxaline functions not only as a bacteriostatic agent but also as a vitamin K antagonist. When germ-free rats are fed vitamin K-free diets containing sulfaquinoxaline, they develop hemorrhages within 2 weeks instead of the 4 weeks required on the basal diet. Another method of studying the contribution of the intestinal flora to the rat's nutritional requirement is to work with the animals having a cup over their anuses in which the feces are collected. Such rats excrete almost 11⁄2 times as much feces as the rat that has access to its own feces. These "cupped" rats develop signs of a folic acid deficiency when a diet low in this nutrient is fed. Rats that have access to their feces show a normal blood picture on such a diet, suggesting that the folic acid synthesized by the bacteria in the gastrointestinal tract of the rat is absorbed only after the animal consumes its feces. The above explanation is limited by the observation of a change in the intestinal flora as a result of the "cupping." The Lactobacilli count in the feces of rats with tail cups was only 0.1 percent that seen in their feces prior to cupping. Studies of liver cirrhosis and necrosis Studies in germ-free rats indicate that choline deficiency develops in these animals as readily as in conventional animals, establishing the nutritional deficiency basis for experimental liver cirrhosis. As in conventional rats, fat accumulates in appropriate locations within liver lobules, ceroid is formed (cod liver oil in diet) and phagocytosed, liver cells degenerate, lobules become distorted, and connective tissue is greatly increased in amount, appearing in trabeculae separating remnants of lobules or largely replacing parenchyma in main lobes near portal hiatus and the papillary lobes. This study resolves the controversay concerning bacterial products versus nutritional etiology of experimental cirrhosis. In fact, the situation could not have been clarified without the use of the germ-free rat. An unexpected finding was that this type of liver disease developed somewhat faster in the germ free than in the conventional animal. This suggests that intestinal bacteria in some direct or indirect way offer partial protection against the development of this type of experimental cirrhosis. These studies were carried out in collaboration with the germ-free unit of the Walter Reed Army Institute of Research. CIVILIAN NUTRITION SURVEYS-NATIONAL INSTITUTE OF ARTHRITIS AND METABOLIC DISEASES AND INTERDEPARTMENTAL COMMITTEE ON NUTRITION FOR NATIONAL DEFENSE In accord with plans described last year at this time and with funds allocated from the 1960 appropriation, an effective start has been made in the program to extend to civilian populations the very useful nutrition surveys conducted during the past several years chiefly on military groups in 13 countries throughout the world by the Interdepartmental Committee on Nutrition for National Defense. In February 1960, the National Institute of Arthritis and Metabolic Diseases and the Interdepartmental Committee on Nutrition for National Defense entered into active collaboration with the Office of Naval Research, U.S. Navy, in support of nutritional survey work among the civilian population of the Middle East, based at the Naval Medical Research Unit No. 3 (NAMRU-3) in Cairo, Egypt. Extensive clinical and laboratory studies will be conducted principally with the people of Egypt and the Sudan. For the past several years the National Institute of Arthritis and Metabolic Diseases has participated with the Department of Defense, the State Department, the Department of Agriculture, the Atomic Energy Commission, and the International Cooperation Administration in the activities of the Interdepartmental Committee on Nutrition for National Defense. Under this sponsorship, and at the invitation of the countries involved, studies have been made of nutritional conditions in Iran, Pakistan, Korea, the Philippines, Turkey, Libya, Spain, Ethopia, Peru, Ecuador, Vietnam, Chile, and Colombia, with particular attention to the nutritional status of their military manpower. Where indicated, corrective measures were suggested by our survey teams and initiated by the countries. Excellent results have been achieved. On a relatively small scale in conjunction with the studies of military groups these nutritional surveys have already been extended to civilians in several countries. Followup studies and analyses of survey findings in both military and civilian populations are this year being conducted in Ethiopia, Vietnam, Chile, Colombia, and Ecuador. Establishment of the collaboration with ONR in Egypt, however, now places the civilian nutrition surveys program on a firm basis from which it can and will be extended, as requested by the countries involved, to many additional nations. The objective of the Egyptian-based survey studies is to investigate those nutritional problems in the Middle East and Africa which will allow for maximal accumulation of knowledge of importance and potential benefit not only to the region but to civilian groups in the United States. Clinical, biochemical, and dietary survey techniques are being applied to kala-azar in the Sudan, to the several types of anemia ranging from Ethiopia to Pakistan, to patients with abnormal hemoglobins and abnormal serum proteins in the Middle Eastern region, and to pellagra. Work is also being continued on earlier studies of possible vitamin A deficiency in Ethiopia and of the nutritive value of various foods unique to the countries of that area. The nutrition program directed by the Interdepartmental Committee on Nutrition for National Defense (ICNND), initiated in fiscal year 1955 as a part of the U.S. mutual assistance program, has thus far contributed to our mutual security by the following means: (1) It has provided technical assistance in improving nutrition, food and health in the Armed Forces of the countries surveyed which has had a beneficial carryover to the civilian populations. (2) It has increased efficiency of mobility of these armed forces due to improved utilization of their own food resources and development of emergency-type rations. (3) It has assisted in defining the major nutrition and feeding problems in the various countries. (4) It has assisted the countries concerned in establishing nutrition services by training local personnel and supplying the nucleus for a nutrition laboratory. (5) It has bettered U.S. friendship through medical, scientific, and technical channels. The nutrition surveys, although sponsored by the U.S. Government, constitute a cooperative, reciprocal program. The participating country furnishes personnel equal to or twice the number of the U.S. team for training in survey techniques. It also furnishes logistical support such as laboratory housing and transportation. To date, 25 U.S. universities and colleges, and the U.S. Army, Navy, and Public Health Service have furnished over 100 doctors and specialists for the survey team. The program affords an excellent opportunity to learn much from these countries regarding nutritional disease, indigenous foods, food habits, customs, and practices. Such information is useful to our Armed Forces, U.S. Operations Missions and the Foreign Agricultural Service for planning current programs and in the event of an emergency. Senator HILL. Is there anything else you would like to add? Dr. DAFT. I believe that is all. Thank you very much, Senator Hill. Senator HILL. Anything you would like to add on this, Dr. Shannon? Dr. SHANNON. No, sir. Thank you very much, sir. Senator HILL. Dr. Daft, we are certainly very grateful to you, sir. We think you are doing a fine job out there. CONSTRUCTION OF HEALTH RESEARCH FACILITIES STATEMENT OF DR. KENNETH M. ENDICOTT, ASSOCIATE DIRECTOR FOR EXTRAMURAL ACTIVITIES; ACCOMPANIED BY DR. JAMES A. SHANNON, DIRECTOR, NATIONAL INSTITUTES OF HEALTH; DR. LEROY E. BURNEY, SURGEON GENERAL; HARRY L. DORAN, CHIEF FINANCE OFFICER; AND JAMES F. KELLY, DEPARTMENT BUDGET OFFICER APPROPRIATION ESTIMATE "For grants pursuant to the Health Research Facilities Act of 1956, as amended by the Act of August 27, 1958 (72 Stat. 933), [$30,000,000] $25,000,000." 11 Grants, subsidies, and contributions (total obligations)____ $30,039, 868 Summary of changes Enacted appropriation 1960-- Unobligated balance brought forward_. Total funds available 1960__ Estimate for 1961_- Total change--- Decreases: Reduction in total amount of Federal support in the construction of health research facilities.. 1961 budget 1961 House allowance |