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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institute of Arthritis, Diabetes, and Digestive
and Kidney Diseases

Biographical Sketch

NAME: Dr. G. Donald Whedon

POSITION:

Director, National Institute of Arthritis, Diabetes, and
Digestive and Kidney Diseases (NIADDK)

BIRTHPLACE AND DATE: Geneva, New York, July 4, 1915

EDUCATION : A.B., 1936, Hobart College; M.D., 1941, University of
Rochester School of Medicine; Sc.D. (Hon.), 1967,
Hobart College; Sc.D. (Hon.), 1978, University of
Rochester

EXPERIENCE:

Director, NIADDK, 1962-present; Assistant Director,
NIADDK, 1956-1962; Chief, Metabolic Diseases Branch,
NIADDK, NIH 1952-1965; (Organizer for DGMS program of
General Clinical Research Centers Program, now in DRR,
1959-1961); Physician, Outpatient Dept., New York
Hospital, 1947-1952; Assistant Physician, Outpatient
Dept., New York Hospital, 1944-1947; Assistant Professor
of Medicine, Cornell University Medical College 1950-1952;
Instructor of Medicine, Cornell University Medical
College 1944-1950; Assistant in Medicine, University of
Rochester School of Medicine, and Assistant Resident
Physician in Medicine, Strong Memorial Hospital, 1942-1944;
Intern in Medicine, Mary Imogene Bassett Hospital,
Cooperstown, New York, 1941-1942.

ASSOCIATION MEMBERSHIPS:

Association of American Physicians; The
Endocrine Society (Postgraduate Committee, 1962-1965);
American Rheumatism Association; American Diabetes
Association (Board of Directors, 1970-1976, Postgraduate
Education Committee, 1971); American Federation for
Clinical Research; New York Academy of Sciences; American
Association for the Advancement of Sciences; American
Physiological Society; The Gerontological Society;
American Institute of Nutrition; Pan American Medical
Association; American Gastroenterological Association;
Aerospace Medical Association; Orthopaedic Research
Society; American Academy of Orthopaedic Surgeons
(Honorary Member); Dermatology Foundation, American
Astronautical Society; The American Society for Bone and
Mineral Research.

SPECIAL AWARDS, CITATIONS, PUBLICATIONS, OR ACTIVITIES: PHS Superior
Service Award, 1967; Citation to Alumni Award, University
of Rochester, 1971; NASA Exceptional Scientific
Achievement Medal, 1974; Endocrine Society Ayerst Award,
1974; Arnold D. Tuttle Memorial Award of Aerospace Medical
Association, 1978; Certified American Board of Internal
Medicine, 1950; Certified, American Board of Nutrition,
1968 Special Postdoctoral PHS Fellowship, New York
Hospital-Cornell Medical Center, January 1 - June 30,
1951; Subcommittee on Calcium Committee on Dietary
Allowance, Food and Nutrition Board, National Research
Council, 1959-1964; Editorial Board, Journal of Clinical
Endocrinology and Metabolism, 1960-1967; Editorial Board,

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Calcified Tissue Research, 1967-1976: Scientific Council
of the Maryland Academy of Sciences, March 1965-1971;
Council, National Program for Dermatology, 1971-1975;
Principal Investigator of Calcium-Nitrogen Metabolic
Balance Study on NASA Gemini-VII Space Flight, December,
1965, and for similar studies on Skylab series of NASA
space flights, 1973-1974; Consultant to Space Medicine
Division, Office of Manned Space Flight, NASA, 1963-
present; University of Rochester University Medical
Alumni Council, 1971-1976; University of Rochester
Trustees' Council 1971-1976; Chairman, 1974-1975; American
Institute of Biological Sciences Medical Program Advisory
Panel to NASA, Chairman, 1971-1975; Chairman, Life
Sciences Committee, NASA, 1974-1978; Member, Space
Program Advisory Council, NASA, 1974-1978; Board of
Trustees, Dermatology Foundation, 1978-present:
Consultant, Endocrinology and Metabolism Advisory
Committee, Bureau of Drugs, Food and Drug Administration,
1977-present.

Dr. Whedon is the author of over 70 scientific papers on
metabolic and physiologic studies of convalescence,
immobilization, paralytic poliomyelitis, diseases of
bone particularly including osteoporosis, human energy
metabolism and space medicine.

INTRODUCTION OF ASSOCIATES

Dr. WHEDON. Thank you, Mr. Chairman.

On my immediate left is my Executive Officer, Mr. Earl Laurence. On his left, my Budget Officer, Dr. Donald F. Cyphers.

I'd like to begin with a few general descriptive remarks about the Institute. It was renamed by very recent legislation, the National Institute of Arthritis, Diabetes. and Digestive and Kidney Diseases. We actually began in 1948 as the Experimental Biology and Medicine Institute, and as one of the older Institutes, have a sizable intramural research operation in Bethesda, strong in fundamental biochemistry, physiology, and pathology, also in clinical research, carried on with about 15 percent of our total resources. Of the various extramural mechanisms for support of research, 75 percent of the total Institute's funding is in research grants, and five-sixths of that is in the individual research project grants, the so-called RO1 grants.

As our new name indicates, among our 10 extramural programs. 4 have our highest priority: arthritis, diabetes, digestive diseases, and kidney diseases. Since 1977, diabetes has been the lead program. As our name implies, we have broad disease research responsibilities. Nonetheless. about two-thirds of the research we support is of a fundamental laboratory nature and indicates dedication to the principle that solution of disease problems and their ultimate prevention is most likely to be obtained through determining causes and mechanisms of development of disease.

I shall give some examples from just four of our programs of the sorts of research we support. In the arthritis area, research on rheumatoid arthritis. the great crippler with which we are concerned, has yielded much evidence that some agent or substance, possibly a virus or other microbe, after invading the body, ultimately disrupts the body's

supposedly protective immune systems in such a way that inflamed, swollen, and later crippled joints result. Much effort is being devoted by many investigators to increasing our understanding of this immunologic phenomenon and to modifying and suppressing it.

In diabetes, the most notable recent advances have been: one, the discovery of receptors on the surface of cells as the principal system through which the hormone insulin acts to activate the metabolism of glucose; and, two, an advance in transplantation research, so that the insulin-producing pancreatic islet cells of one species, rats, can be given to another, mice, and can be not only accepted but remain viable and effective. This latter development is a very significant step toward possible control of human diabetes, eventually, through transplantation of normal islet cells to diabetic patients.

In digestive diseases, investigators are taking advantage of the recent development of long, flexible fiberoptic instruments called endoscopes, to view the inside of the intestinal tract and to study various methods of controlling intestinal bleeding. But in this disease area, as well, there are many basic studies of normal and diseased bowel function and of pancreatic, gall bladder, and liver diseases.

In the kidney diseases area, we have supported much of the progress in artificial kidney and kidney transplantation technology, but the emphasis of our support is progressively more on fundamental studies of kidney stone formation and of the acute and chronic kidney diseases that lead to end-stage renal deterioration. Here's a prime example of attacking causation of a disease for the purpose of ultimate prevention. Throughout all 10 of our programs of extramurally supported research, there is a balance between clinical- or disease-related studies and fundamental studies needed for ultimate cure and prevention, but with emphasis on the latter.

I shall be happy to answer any questions, Mr. Chairman.

PROSTAGLANDIN RESEARCH

Senator SCHMITT. What is the status of prostaglandin research with respect to arthritis?

Dr. WHEDON. Prostaglandin research really runs through many of our programs. It is a set of complex substances derived from certain fatty acids which are made by many cells throughout the body. They were initially mainly of interest to endocrinologists for their effect on the actions of other hormones. Even in gastroenterology at the present time. there's considerable interest because of the discovery that certain prostaglandins appear to have the ability to protect the mucous membranes of the intestinal tract and, therefore, might be of some advantage in the treatment of ulcers, or at least in their management. This has come about through the finding that certain drugs, which are antiprostaglandin in nature, do seem to provoke or worsen peptic ulcer disease. Studies are now underway to try to find out the extent to which the direct application of prostaglandins will be effective in the treatment of ulcers.

You mentioned arthritis. I don't know the specific studies at the moment, but prostaglandins are intimately involved in the inflammatory process. I would be pleased to supply further information for the record.

[The information follows:]

PROSTAGLANDIN RESEARCH IN ARTHRITIS

The prostaglandins are a group of unsaturated fatty acid derivatives with potent physiologic effects in most of the organs of the body. Recent research has indicated that certain prostaglandins promote inflammatory reactions, and in this manner, play an important role in the cause of inflammatory types of arthritis.

There is much evidence that prostaglandins of the E type, e.g., PGE2 and PG12, prostacyclin, are mediators of inflammation when injected. The E prostaglandins cause inflammation: they potentiate other mediators of inflammation; and their concentrations in inflammatory fluids are elevated.

Most nonsteroidal anti-inflammatory drugs, such as aspirin, indomethacin, and phenylbutazone, which are widely used in the treatment of many types of arthritis, have been discovered to be powerful inhibitors of the synthesis of prostaglandins. This is also true for newer nonsteroidal anti-inflammatory drugs, such as motrin or naprosen. There is a good correlation between the potency of these drugs' ability to combat inflammation and their potency to inhibit prostaglandin synthesis. Indeed, many scientists think that most, if not all, of the important pharmacologic effects of these drugs can be ascribed to their inhibition of prostaglandin synthesis.

There is also evidence that prostaglandin E2 mediates the resorption of bone in rheumatoid arthritis, causing the bony erosions that are characteristic of this disease. Inflamed joint lining cells from rheumatoid arthritis patients grown in tissue culture release large amounts of PGE2 with a capacity to resorb bone. Therefore, adequate suppression of PGE2 synthesis by anti-inflammatory drugs may prevent or reduce bone destruction in this crippling disease.

In addition, it has been very recently demonstrated that when monocytes, white blood cells, are exposed to uric acid crystals. the cells phagocytize, eat the crystals, and in doing so, produce large amounts of prostaglandins. Thus, the mechanism by which uric acid crystals produce the extremely painful acute attacks of arthritis in gout is now explained.

IMMUNE PROCESS

Senator SCHMITT. You did not include this in your testimony. Does this mean that you think this is one of the less promising areas of research, or one you just didn't choose to highlight?

Dr. WHEDON. No, Mr. Chairman; I just didn't pick it. We have, as I said, 10 areas, and many, many things to talk about. And I thought I would just hit the general matter of the affected or altered immune process in talking about arthritis. It is easier to emphasize.

Senator SCHMITT. Prostaglandin research in arthritis was one area of research that I ran across, along with many others, where there seems to be an increasing focus on trying to duplicate what the body has evolved to do by itself. but sometimes does not do sufficiently, to protect against the more virulent or chronic forms of disease.

I haven't asked this question, but is that your summation of the current thrust of much research throughout the Institutes, Dr. Fredrickson, particularly this one, to try to understand more what the body does for itself-recognizing that it's had a lot longer to do research than we

have?

Dr. FREDRICKSON. Yes; I think just trying to understand nature`s secrets has been our principal preoccupation since we started. But you are right-we have got to understand the normal mechanisms, how the body does it, and where it goes wrong. and how we are able to facilitate that process.

Senator SCHMITT. In addition, the treatment that more closely duplicates natural body functions will tend to have less after effects or side effects.

Dr. FREDRICKSON. It would also be less costly; yes.

Senator SCHMITT. Particularly the new techniques for production of natural body chemicals that appear to be coming out of DNA research. Dr. FREDRICKSON. That is absolutely true.

DIABETES RESEARCH

Senator SCHMITT. In that regard, we discussed yesterday with the Center for Disease Control the issue of trying to duplicate natural body release of insulin.

Doctor, would you care to comment on that? You mentioned very briefly in your statement, are we putting sufficient priority on that area of diabetes research.

Dr. WHEDON. Yes; we are very interested in that area, and of course, many of our investigators are, as well. I mentioned briefly in my remarks some recent progress in transplantation research with respect to islet cells in the pancreas. Of course, if that can be achieved in human beings, that would go a very long way toward putting the diabetic patient back in link with the natural system of insulin supply and utilization which occurs in the normal human being.

There's another approach to this process of trying to get back to normal function. That has to do with artificial assistance to provide the diabetic patient with insulin, so-called insulin pumps. We are supporting studies of that sort.

The situation at the present time is that there are studies of the use of insulin reservoirs and pumps which can be worn attached to the waist of the patient. Most are about the size of a small hand calculator. There is a needle which is inserted in the subcutaneous tissue of the abdomen, and then, as a part of this whole package, there is a set of electronic controls in the apparatus which enable one to preprogram the rate at which insulin should be supplied to the patient during a 24-hour period. So, there would be a constant insulin infusion level with increasing amounts of insulin delivered just before meals. And I understand that these devices also have an arrangement whereby if there are any special requirements, these can be adjusted by the patient. So, these apparatuses are becoming more sophisticated and usable. Just how far they will go, and how far investigators will go in being able to apply this very broadly among diabetic patients has yet to be determined.

Senator SCHMITT. Wouldn't it be less expensive to use the brain as a computer, rather than one worn around the waist?

Dr. WHEDON. Except we don't know enough about how the brain works.

Senator SCHMITT. I mean, let the patient determine how much insulin he or she needs.

Dr. WHEDON. I think I understand what you mean. But the patient may not be able to tell by his own brain or otherwise exactly how much more insulin he needs at any one time so the approach at the moment is to have intensive study of the patient, for what his particular needs are in relation to his exercise and in relation to his food intake, and then program that into the device.

There are not many diabetic patients who can tell in advance exactly how much insulin they need for their particular problem. I know that

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