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We were certainly much, much better prepared for AIDS in 1981 than we would have been, had it occurred in the 1950s. Yet we would have made some advances even then. The principles for identifying sexual transmission of a disease were in place. We already knew about retroviruses. Rous sarcoma virus is a retrovirus. We knew about latent virus infections, so I think that, although we would not have understood all the intricate details, we would have used other methodologies rather than T4-T8 ratios and things of that sort to measure the immune abnormalities. Now we use a much more sophisticated approach, but I am not so sure we would have been entirely in the dark because we did not have the same methods that we have today. We would have used cruder immunologic techniques to make a diagnosis. After all, diagnosis of AIDS is still somewhat fuzzy clinically, the immunologic alterations, precise identification of the virus, its presence in the cells, the detection of anti-AIDS virus, the antibody. It would have taken us longer in 1950 to come up with a serological test. We did not have the ELISA [Enzyme-Linked Immunosorbent Assay] in those days. We did not have the radioimmunoassays. We did not have Western blots. We did not have the polymerase chain reaction [PCR] before 1986. Therefore, we had fewer and less sensitive serological tests. On the other hand, we would have lived with that because we had lived with the Wassermann test as the best test for syphilis (at best, 90 percent accurate).
I grew up in an age when we knew our laboratory tests were never 100 percent accurate, and you always took that into consideration. Today everybody wants a test to be absolutely accurate. But a test must always be used within the clinical context. A 1950s serological diagnostic test would have been somewhat more primitive, but I think we would have come up with something.
We would have been way behind in not knowing enough immunology or virology to come up with an antiviral drug or vaccine, if possible, for two reasons. First, we have had thirty years to gather a lot of basic information about virology and immunology. Secondly, there is now new technology. We could not sequence a protein or a nucleic acid then. None of that could be done. All of that technology is currently being used to develop drugs and vaccines for AIDS. This is rambling answer to your question.
Harden: No, it is a very good answer. Now, let us go back to 1981-82. Can you recall when you first heard about these unusual cases and how your own thinking about AIDS developed?
Krause: I do not remember the exact circumstances. I cannot remember now, although Dr. [Jack] Whitescarver or Dr. [Kenneth] Sell might remember. I do not remember whether or not I heard about these cases prior to the publication of the paper. I probably did, because I scanned the CDC Morbidity and Mortality Weekly Report. There are always a few cases occurring here and there of this or that that get reported. Some are quite a puzzle for a while, but then the mystery gets cleared up. They get investigated by the CDC, and it turns out that these often get written up in the New Yorker because they are interesting epidemiologic success stories. In one episode recently, they found that several hundred people in Iowa were wasting away unknowingly because the jowls of pigs or cattle, which contain a lot of thyroid gland, were being used in cheap hamburgers that were consumed locally. The patients were suffering an “epidemic“ of hyperthyroidism because they were eating the hamburgers rare, and the thyroid hormone was still active. The solution was to cook the hamburger thoroughly. These things get investigated and solved. These episodes are interesting and brought to one's attention by the CDC and are soon usually under control. I suspect that was my reaction to the first report of a few AIDS cases.
Later on, I remember hearing about Kaposi's sarcoma, and saying to myself, “Well, if it is Kaposi's sarcoma, it is Cancer's [National Cancer Institute] problem, because we [NIAID] have enough to do.” The CDC was doing the epidemiology. So I thought a very few cases of some sort of cancer were occurring. There was discussion at the time about the cause; by drugs, or by a combination of drugs and other virus infections that the patients had. We did not know if cytomegalovirus, hepatitis B, and other viruses resulted in some alteration that made the patients susceptible to these sarcomas.
You might say that, at a closer look, a sensible person would have recognized that it was an NIAID responsibility, also, because it was occurring among men who were very active sexually, and therefore AIDS should be an STD until proven otherwise. So I am prepared to take any blame for not immediately assuming that it was an STD. In retrospect, it was a disease of a sexually active group of people. Also, people of that age group do not usually get chronic diseases. In people of that age group, if they get a disease, it is usually infectious, unless, of course, the patient is the rare case who does get cancer, have a heart attack, and so forth. If there is a cluster of cases, one probably ought to think of a common source (infection, toxin, etc.), but then again, this is in retrospect.
When it was reported by the CDC that AIDS was sexually transmitted, I said, “Okay, it is in our ballpark, and we have to do all we can do.” I cannot remember the exact date when that was. About six months to nine months after the publication in the New England Journal of Medicine of the first cases, the CDC showed a diagram of a dozen or more transmitted cases on the West Coast and on the East Coast from one sexual partner with AIDS. That must have come out in about 1982, and then we began to gear up. Dr. Tony [Anthony] Fauci and Dr. Kenneth Sell were interested in the immunology side, and we alerted our STD centers to get involved, and they did.
One of the things that I had said to Randy Shilts, and to anybody else who would listen, is that we were prepared for AIDS because, in 1978, we established five interdisciplinary centers for research on immunologic diseases. One was at UCLA [University of California, Los Angeles]; in fact, that was the center that reported the first cases. We could not have been more prepared. These centers, as well as our STD centers, got involved right away when [Dr. Robert] Gallo had the nose to think that the cause was a retrovirus, and that was very perceptive. But we still did not know what the virus was.
I think it was in 1982, Ken Sell could tell you, that we held a meeting at the NIH, on the possible candidates for virus causes. A number of people attended. Albert Sabin chaired. He did a very good job. I do not know whether there is a transcript of that meeting, but Sabin did a very good job of summarizing, including asking the questions of why now, why these people, and so on. That meeting was a very good summary.
One of the things that I have been criticized for is that when we were asked whether we had enough money, I did not immediately ask for a lot more money. I guess this caution was from my early concern about running too fast after a few cases. It does not mean that we were not concerned about those individuals because they were gay. That was not it at all. Our budget requests were written in the context of numerous things that had to be done. This was one more problem with a limited number of patients. Also in my own mind, we were already tooled up. We had a lot of people ready to work, and they could work on AIDS. They already had money from research grants and center grants. Scientists are always going to say they need more money or they cannot do a thing with what they have. But that is not true. In 1968 when the STD epidemic began to heat up, we (at Rockefeller) began working on gonorrhea and used funds to do so at the start from my grant to do research on streptococci. So there is flexibility in the system.
Harden: A number of people have written quite emotionally that the scientific community should have realized the problem AIDS would become, should have spent more money on it, should have done a lot of things. A number of scientists with whom I have talked said that initially they thought of AIDS, like so many other disease phenomena, as an isolated thing, a curiosity that would probably go away.
Krause: Initially we thought that it was an outbreak of something, that the cause would be found and that would be it. For example, this strange outbreak of hyperthyroidism in Iowa–some of these people were desperately ill. These things happen all the time, but I do not agree with the complaint that the scientists did not jump on it just as soon as they realized that it was a problem. They jumped on it, first of all, because it was a medical problem, and second, because medical scientists cannot be kept away from rare diseases. They will go after a rare disease even if they have to go to New Guinea, let alone into a gay community in San Francisco. If they sniff out that this is going to lead somewhere, they act upon it. But there is a limit as to how much money can be allocated for every rare disease. On the other hand, if individual investigators sense the existence of scientific opportunity, that is up to them. It is not up to a manager in Washington.
I do not agree that we were slow to respond. Dr. Robin Weiss, who is the director of the Cancer Institute in London, made some remarks recently about how quickly scientific progress has been made since the first cases were reported. In 1981, AIDS was first reported, and in 1982, it was detected as a sexually transmitted disease. I do not think people realize how difficult that was, to identify a chronic disease with a long latent period of three to seven years and to show that it was sexually transmitted. It is one thing to show that venereal disease is sexually transmitted with symptoms appearing three or four days after contact. It is quite another matter to show sexual transmission for a disease with a long latent period. That is tough, and the researchers did it in one year.
In 1983 the AIDS virus was reported and in 1984 the isolation of the AIDS virus was confirmed. In 1985 the blood screening test to detect contaminated blood was devised and put into effect, along with the test for screening of the population on a voluntary basis. Prevention programs and information outreach programs were organized. In 1986 the first clinical trials of antiviral drugs were initiated. In 1987 and 1988 a prototype vaccine was already in trial. In 1988 clinical trials were underway to determine if a soluble CD4 receptor would prevent AIDS virus infection of cells. All of that in seven years. That is quite a response, and so I think we did respond very rapidly. Once it was clear that the disease was sexually transmitted, people began to work on it pretty fast.
If you review the work at the STD centers around the country–their annual reports, the reports of the immunologic and allergic centers that we established, and the reports of the centers of the Cancer Institute–you will find that recognition of AIDS as an STD was a big turning point.
I think NIAID needed more research money, not just for research on AIDS but for research on the immune system, on virology, on vaccines, on drugs and more research on the secondary infections. All AIDS patients get secondary infections, but research on some of these was not adequately funded.
Harden: One criticism of NIAID was that in its initial response to Congress, it listed a certain number of grants in basic immunological research as AIDS grants. What was the rationale for doing this? Did the Institute believe that more needed to be done in those particular areas, or was it really just padding the record?
Krause: I would have to go back and look at the congressional testimony. I think that we took the view, although I would have to go back and look at the notes, that a great deal of research in immunology clearly was relevant to research on AIDS, because early on we thought it was primarily an infection of the immune system. We now know it is more complicated than that. We certainly knew that it resulted in great aberrations of the immune system and therefore we were spending money on such things as the lymphokines, interferon, and the interleukins, etc., which certainly was research that had to be done to understand AIDS. Furthermore, these substances have since been used as candidates for treatments. Some of what we did was research that supported AIDS rather than AIDS research directly.
I do think that we stimulated scientists to move into AIDS research. I suppose, in retrospect, you could say that if we had come out with a program announcement involving megabucks, then people would have stopped whatever they were doing to work only on AIDS. My view is that, in general, if it is an interesting problem then clinical immunologists and virologists will start working on it. They will keep doing what they are doing, for example, working on lupus, but they will also start working on this new problem. Once they need more money, after some preliminary work in research, they will apply for it, and if it is in an important area, they will get it. One of the things we did do, perhaps in 1983, was to decrease the time it took to get the AIDS grants reviewed. If somebody had preliminary observations and wrote a grant application, and the study section approved it, the NIAID Council (secondary review) was polled by mail ballot. Therefore, we did not wait for the next Council meeting to get approval for funding. This decreased the time from application submission to grant award by three months.
Harden: One reason that we are here talking about this is because AIDS has become such a major concern.
Krause: Before we leave the subject, let us get back to another criticism. I went over this in considerable detail with Randy Shilts. He was very critical in his book [And the Band Played On] about something I said. The gay community was upset with us, and the doctors who were taking care of gay patients were upset with us. We were not directing research money to them. I said something to the effect that practicing physicians are not necessarily the people who can best use the research money. That does not mean that there are no practicing physicians who do research. Some do receive research support by the NIH. But, in general, they are not the primary recipients of these research grants. Randy Shilts took that to mean we did not want to fund research by any practicing physician, which I did not mean at all. It happens to be true that the best use of research funds is by people who primarily do research.
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