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Interview with Dr. William I. Gay
This is an oral history interview with Dr. William I. Gay, who formerly worked at the NIH. His last position was at the Animal Resources Program (ARP) of the Division of Research Resources, National Institutes of Health (NIH), Bethesda, Maryland. The interview was conducted in the NIH Historical Office on 15 July 1992. The interviewer is Dr. Victoria A. Harden, Director, NIH Historical Office.
Harden: Would you begin by talking about your own background-your education, and why you became a veterinarian?
Gay: I grew up on a farm in upstate New York, at the north edge of the Catskills, where I worked with livestock. If you were a farm boy and did not have any money, you could go to a state school like the veterinary college because you did not have to pay tuition. I worked my way through Cornell [University] from 1944 to 1950 and earned a DVM [Doctorate in Veterinary Medicine]. When I got through, there were lots of jobs for veterinarians–more than there are now. I indicated to one of my professors that I needed experience in treating small animals, so I went to work for a small animal practitioner in New York City. Now, I mean Queens, not Manhattan. The practice was located halfway between JFK [John F. Kennedy Airport] and La Guardia Airport. JFK was known as Idlewild Airport in those days. They were building a big connecting road right through our practice (animal hospital) area. We had a lot of business. I worked with cats, and with the more unusual animals that came into the practice. The old timers did not really care for cats and birds; they were happy to give those cases to a young, flexible guy.
When I was in college, World War II was on, and I came up for the draft. Because I had a low renal threshold for sugar, the authorities kept saying, “You've got diabetes; we won't take you.” I was deferred and went to school. In 1950, when I became eligible for the doctors' draft for Korea, they said, “You were deferred and went to school.” I said, “No. I was deferred because of a physical problem.” “Ah, but you were deferred and went to school.” Well, my number came up and, so in order to get around all of this, and to avoid going in as a foot soldier, I joined the Veterinary Corps as a first lieutenant. Those in charge looked over my curriculum vitae and said, “This guy has been in small animals. We'll send him to that laboratory animal place at Walter Reed [ Army Medical Center ].” It was the best thing that ever happened to me.
At Walter Reed, there were rats and mice with all kinds of health problems. The Center had lots of dogs. We were in the middle of the Korean War at this point and were working on technologies that would be used by the MASH [ Mobile Army Services Hospital ] hospitals. The movie “MASH," is the real thing. As a matter of fact, I shared an office with “Trapper John” in the NIH Westwood building for a while, and I saw those pictures before they ever made the movie. Those hospitals were the real thing, and we were working on technologies like kidney dialysis. At that time, one theory held that shock produced some product in the blood that could be dialyzed out with an artificial kidney. We had artificial kidneys operating as close as two miles from the front; but they did not protect against shock. Even so, we were able to provide the army medical staff with background studies in animals before they went to Korea. We also worked on problems like replacing segments of long bone, because the firearms that the soldiers were using could do a lot of tissue damage. If the bullets went through a bone they blew it apart, and a segment would have to be replaced. I got some nice papers out of that work.While I was at Walter Reed, I made friends with Dr. William (T. S.) Thorpe, who was in charge of what is now Veterinary Resources. They were building the NIH Clinical Center and the animal facilities south of the Clinical Center. Bill was looking for somebody in experimental surgery. I came to the NIH in 1954 for that job and I stayed in what is now Veterinary Resources for nine years. The place grew so much during those nine years that I found myself doing administration full time. I accepted an opportunity to move to the extramural program in administration with Dr. Willard Halsey [Hal] Eyestone, who was a well-known veterinary pathologist in the Division of Research Resources. I was with various extramural programs from then on–NIGMS [National Institute of General Medical Sciences] for four years, Allergy and Infectious Diseases [National Institute of Allergy and Infectious Diseases, NIAID] for ten years, and DRR [Division of Research Resources] for eight years.
Harden: You were in DRR in 1981 when AIDS was identified as a new disease. Before we discuss AIDS, however, could you define what an animal model is? How do people go about selecting one? What are the problems, etc.?
Gay: There are lots of people, especially animal rights people, who do not want you to do animal research. They love to quote, “The best study of man is man and mankind.” That is true. But if you examine the Helsinki Accord, which came about after the World War II atrocities, you learn that one does not do experiments on people. Of course, we have followed that way of operating at the NIH since the turn of the century. There are many things that we use animals for before you go to the clinic.
The basic point to remember about animal research is that animals are part of a spectrum of biological species. Somebody has an idea about, say, liver function, and you can get a little information, perhaps, from an isolated liver. You can get an idea from the isolated liver and the liver cell; but do not forget that the liver is functioning under the direction of the pituitary gland, the adrenals, and many other enzymes and hormones. Because of this, before you move into the clinic to apply your findings to humans, you want to test them in some similar creatures. What you do is to look through everything you can find in the literature about liver physiology. You may see that the woodchuck has a hepatitis virus. The cat gets cirrhosis. You then look around to see which animal has liver function most similar to that of the human. Even if sometimes the animal's function is not exactly similar, out of desperation you use the animal, because if you can define a biological principle in the mouse, and then if you find that the same principle applies in the rat, the dog, and the primate, it is pretty safe to move to the human. If the principle does not hold for each case, physicians must be very cautious before moving to the human. That is the animal model business. Comparative medicine in a nutshell is confirming your findings in a variety (spectrum) of species.
A good illustration of this is the thalidomide story. You are in the history business, so you remember thalidomide? This drug, when taken by pregnant women, caused the birth of babies with no limbs. In humans, thalidomide restricts the formation of the limb buds during the evolution of the embryo, resulting in very short limbs. Thalidomide was developed in Germany, thoroughly tested on rats and mice, and then was moved right into the clinic. It was a marvelous tranquilizer, especially for women who had hormone-related stress and behavioral problems. Many people in Europe were using it. It was licensed there right away. People wanted to have it here [in the United States ]; they wanted it very much.
When the application for an IND [Investigational New Drug] came in to the Food and Drug Administration [FDA], it went to the desk of a Dr. Frances Kelsey. Dr. Kelsey had been at the FDA for a long time. If something got on her desk, some said that it never got off. It was delayed and delayed, and it was all Dr. Kelsey's fault. But Dr. Kelsey was a stickler for details. She looked at the thalidomide protocol and said, “It hasn't been tested on any higher animals.” Studies were thus run on dogs, with no adverse effects. Dr. Kelsey, however, said, “I want to see what it does in primates.” When the studies were conducted, the baby primates were born with severely shortened limbs. If the Germans had ever tested thalidomide on monkeys, it never would have been marketed. Since the drug was legal in Germany, it was brought to the United States, carried in by a number of people, and so it inflicted some damage on embryos in the U.S.This illustrates that if you believe you understand a biological principle but it does not apply to a spectrum of species, watch out before you go to the clinic. This was a real “watch out.” That is why something like RU486 needs to be tested thoroughly on primates. The Primate Center in Oregon and one other center, have worked on RU486, and it appears to be pretty safe. In the end, testing a few monkeys is as important as many of the other tests in the laboratory.
Harden: It sounds as though you have a much better theoretical basis today for choosing an animal model than investigators had early in the twentieth century.
Gay: That is right. There is another thing that you can also do, which especially relates to AIDS. Did you see in Science in the last few weeks about the pigtail macaque as a model for AIDS? That is a marvelous illustration. Researchers looked at the literature about this monkey and also took the monkey cells to the lab. They used the cells from different species to see if the virus would infect the white cells in tissue culture. It would in the pigtail macaque, and that is why they went immediately to the pigtail macaque as a model for AIDS.
Harden: Have the animal rights groups had any impact on the kinds and numbers of animal models that are available?
Gay: They have not had any effect on the kinds and numbers of models available. But they have had an impact on animal use and it has become infinitely more expensive to use animals because of all the regulations. Many institutions now spend $100,000 a year on security. The NIH spends more than that because they are afraid of break-ins and so forth. Many people predict that the numbers of animals used in medical research are going to decline. I had a professor in pathology that used to say, “You know, Bill, there are three kinds of lies: lies, damn lies, and medical statistics.” You have to watch those medical statistics even when applied to laboratory animals.
What is happening is that a smaller number of animals are being bred for research, and probably smaller numbers are coming into the supply. What is getting bigger is the inventory. In many diseases being studied now–AIDS is a good example–it may take the animals anywhere from ninety days to a year to come down with the disease or show a pathological change. In the old days when we were working with influenzas, for example, the animal would be in and out in about four weeks. Now we are keeping them around for eight months to a year. This means that there is a tremendous inventory problem in the animal research business. When an administrator reads that there are smaller numbers of animals going into medical research, he or she says, “Why, then, are the costs going up?" The inventories are increasing. That is why.It is also more expensive to use transgenic animals that can now be specially prepared and bred. When you prepare about a hundred ova and inoculate them into mice or cows or whatever you are working with, and your yield is, at the most, five infants and one or two adults, this costs a lot of money. But once you reproduce those animals, you keep them around a long time. This means that many types of animals are accumulating. Although there are not many more animals going into research, the inventory does increase. Probably there are not more than 10 percent more animals used, and produced for research, this year than in 1985. If you look at the inventory, however, it is probably up 25 or 30 percent.
Harden: In your article on the history of the regional primate centers, you noted that the inspiration for these centers came when Dr. James Watt visited the Soviet primate centers in the 1950s. What was it about that trip that impressed him to create such centers and why did we end up with seven instead of one?
Gay: [Dr. James] Shannon was very sensitive to the regional philosophy. There is a history of the primate centers that [Dr. Leo] Whitehair and Animal Resources and Comparative Medicine wrote together, and they are producing another one now. [Dr.] Paul Dudley White was [President Dwight] Eisenhower's heart specialist, and he wanted to know what the Russians were doing in this area. He and Dr. George Burch from Tulane [University] were invited to the primate center in Sukhumi on the Black Sea, which is now in Georgia. Incidentally, since the breakup of the Soviet Union, the Georgians have thrown the primate center out. Dr. Boris Lapin was the director of the center until the breakup of the Soviet Union. Some of the baboons have been moved to a nearby Russian city called Adler.During the 1950s, Dr. Boris Lapin was producing various cardiac difficulties in the baboons. Because of their interest in heart disease, the Americans became acquainted with Boris, who spoke very good English. The Americans were very impressed with what had been done at the Soviet center over the years. They came back and said, “We should have a primate center like that to study heart disease.” This is why primate research was launched in the Heart Institute [National Heart, Lung and Blood Institute, NHLBI]. Although primate research is not any more related to heart research than it is to infectious diseases or metabolism or mental health, it started in the Heart Institute because of this trip by Dr. Paul Dudley White and Dr. Burch. It was Dr. Shannon's interest in the regional distribution of research that led to the creation of seven centers. At that time, the NIH budget was expanding at a tremendous rate.
Harden: In Dr. Murray Gardner's informal summary of the 1986 symposium on Simian AIDS, he noted competition between the centers. He implied it was not insignificant. Would you describe this competition?
Gay: It is the same as the competition between [Dr. Robert] Bob Gallo and [Dr. Luc] Montagnier. Everybody wants to be first.
Harden: Did the centers work on the same problems or did different centers address different problems?
Gay: You have to remember that this article was discussing Simian AIDS [SAIDS]. The disease appeared in at least three centers more or less at the same time. But it did not appear as the same disease. In California, it looked rather like AIDS, with the lymphatic increase, the gradual loss of weight, and then death due to some microbial infection. At the primate center in Washington, it was a disease of the peritoneum, and it showed up first as red cell or as white cell deposits on the peritoneum. It was first called retroperitoneal fibromatosis. This condition would gradually get worse and worse, and the monkeys would die in somewhat the same way. There was yet another manifestation of it at the Oregon center. The people at the New England center were very intrigued with this in late 1982. They were looking for Simian AIDS in some macaques that they had purchased. I believe that New England also had some cases early on. Eventually the centers found that there were three retroviruses of the macaques, and the one that most closely resembled the present day SIV [Simian Immunodeficiency Virus] was the one in California, which was isolated by an NIH researcher named Dr. John Sever in the Neurology Institute [ National Institute of Neurological Diseases and Stroke, NINDS], and [Dr.] David Madden, a veterinarian who worked for him.
Harden: Before we discuss the details of Simian AIDS, I want to ask one more preliminary question. Can you give us an overview of the kinds of problems the regional primate centers were working on before AIDS was identified in 1981?
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