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So, AIDS began the way a lot of NIH events begin. There was a scientific issue, for which the atmosphere on campus was very attractive as an environment where one could study this kind of problem. We could get a lot of people who were free to choose their own interests. They all had an opportunity to take part in this because there was something in it for everybody academically, scientifically, and intellectually. It worked out very well. Now there are 85 committees trying to dole out resources, and it has become a much different kind of issue.
This is an example of what the intramural NIH can do very well as a community of basic scientists and clinicians. It really took a combination of basic science and clinical science to bring the patients in, to recognize the important patient-care-related problems, but also to do, very quickly, a lot of the groundwork in immunology and virology. It required the range of expertise that we have at NIH from basic immunology, basic retroviral studies, basic herpes virus studies, to very good autopsy studies. From the study group that we had, we got autopsies on patients to figure out what the range of the pathology was. The ophthalmologies were interesting. They enucleated all the patients who died, so they very quickly recognized what the retinitis was all about.
Because there were people here who were free to choose what they wanted to do, who had the resources to devote to it and the esoteric backgrounds to take advantage of it, it all worked out. There were people who had skills that might never have been publicly recognized because they were not very important until something like this came around. Suddenly there were retrovirologists who had been working on veterinary problems who found a human clinical application. If we had not had that group of people doing basic research at NIH, and if we had not had people doing electron microscopy on retinas who could recognize CMV, we would not have been able to make the progress that was made on campus. Progress was made as part of this integrated team. Other progress was made independent of the group, however. Dr. [Robert] Gallo's group, for example, was an independent entity that did not wish to maintain communication with our group. They got their own specimens and made progress independently of our group. That was the way it began.
Rodrigues: You mentioned that before AIDS there were only a small number of cases of Pneumocystis, 60 or 70, per year. Were almost all of those cases due either to malnutrition or to the effects of immunosuppressant drugs or cancer therapeutics?
Masur: Yes. There was an article in the Annals of Internal Medicine in 1972, which reviewed 180 cases in three years. In this country, they all occurred in patients with congenital immunodeficiencies or ones who had a previously diagnosed immunodeficiency. When they developed Pneumocystis, they were all known to have cancer, for example, or have had a kidney transplant. They did not walk in with Pneumocystis. There were a few unusual cases in the literature suggesting that it could appear out of the blue, but they were all questionable. Actually, looking back, it is conceivable that some of those were the first cases of AIDS, although they were not worked up for that. In this country malnutrition was not so much an issue, but in Africa, in Iran, and in post-World War II Eastern Europe, malnutrition was certainly an important issue.
Rodrigues: At that time, how effective were the available therapeutics for Pneumocystis infection?
Masur: The first successful treatment of Pneumocystis was about 1955 or 1956. Actually, NIH was involved very early on. The first successful treatment was by an Eastern European doctor who developed pentamidine. From the mid-1950s until the early 1970s, pentamidine and sulfadiazine-pyrimethamine were the only recognized drugs that were available. There was a group here that was interested in Pneumocystis. It included Dr. [Vincent] DeVita, though, in the middle 1970s. They did some work with pentamidine. There was a group in the Cancer Institute [NCI], led by [Dr.] John Whisnant, that worked with sulfadiazine. They published a monograph in 1976 that summarized the world's literature. At that point, intramuscular pentamidine was very toxic, and sulfadiazine-pyrimethamine was not always very easy to give. But, until the mid-1970s, those were the only two choices. Then, [Dr.] Walter Hughes developed trimethoprimsulfamethoxazole, which is a good, all-purpose treatment and is not terribly toxic. So, by the time the AIDS epidemic came along in the late 1970s, there were at least two alternatives: intramuscular pentamidine, which was very toxic, and either oral or intravenous sulfa-trimethoprim, which was very effective and not very toxic in cancer patients. However, it turned out to be relatively toxic in AIDS patients. But there were only those two choices in the late 1970s.
Rodrigues: You said, as have many others, that there was the feeling that these cases you were seeing represented an anomaly–something related perhaps to some environmental cause or to amyl nitrites. In your mind, when did you begin to move away from that thinking and to consider that there might be an underlying viral origin?
Masur: By about 1983 or 1984, the presumption was that it was something transmissible. Just as I was leaving New York at the end of 1981, we started seeing women with the disease, although they were mostly drug users. That was published by my group in about mid-1982, but by the end of 1981, we were beginning to see it in women. Then, in 1982 and 1983, it was clear that there were two main groups infected: homosexuals and IV drug users. The assumption was that it was something transmissible through blood. Although there were people speculating about a virus, there were a lot of different theories as to what kind of thing might be transmissible. For example, it might be lymphocytes that created some kind of graft-versus-host response. There were all sorts of crazy ideas, but I do not know anybody who was focusing on a virus and excluding other things. There were a number of people who felt strongly that it could be a virus, but until Dr. Gallo or the French, depending upon which you want to give the initial credit to, showed the strong correlation, viral etiology was just one of a number of different theories. Everything was so unprecedented that none of them seemed very likely.
Rodrigues: You mentioned the cases in women. I looked at that paper you just mentioned. In one case, an individual, patient number three, manifested symptoms 34 months before diagnosis. That suggests that AIDS was around practically in the mid-70s.
Masur: If you assume that the average incubation period for AIDS is 8 to 10 years, i.e., the time between acquiring the virus and developing clinical disease, the first patient that we saw in 1979 was probably infected in the early 1970s. There are some people in whom the disease is manifested as early as two years after infection, so maybe the first patient was infected in 1977 or so. At some point during the 1970s, the virus was widely introduced into this country, but it was not until the late 70s or early 80s that we began to see the clinical manifestations. One of the other interesting things about that first patient that had thrown us astray was that he was a hospital security guard who worked in a busy emergency room. So one of the first things we wondered about was whether he had been exposed to something in the emergency room.
If you look back in the medical literature, you see that at first they talked to practitioners. A lot of people had big AIDS practices, and for several years they had been seeing more lymphadenopathy. If you look back on some unusual cases in the literature, either from abroad or from the United States, you can find some cases that go back as early as 1960 that might have been AIDS. There are even some who say that they have serum that has been tested.
Harden: While we are on this subject, this incubation period is one of the things that [Dr.] Peter Duesberg has attacked in his arguments that HIV is not the cause of AIDS. He also notes the difficulty in detecting antibodies to HIV. As an infectious diseases expert, what is your view of his ideas?
Masur: I think one has to keep an open mind to all possibilities. I think the most compelling evidence is the transfusion cases where you can show that somebody got the virus from a transfusion and then developed the syndrome. You can say that maybe there is something else that is being transfused that we have not recognized. It is becoming clear that there is at least a logical explanation for long incubation periods. You can see a very slow, immunologic decline. It is just a chronic disease that takes a while to wipe out your immune response. The fact that antibodies are not produced is a function of the type of virus that it is. I think that there are logical explanations for what Duesberg considers to be discrepancies in the theory. Whether those logical explanations are accurate is another issue. Everything that we know about retroviruses right now at least makes a logical picture about their being the cause of AIDS. Duesberg has become well known because of his skepticism.
Rodrigues: In going through some of the past records I found a protocol for which you had provided a written description. I believe that it was the first formal protocol at NIH for AIDS patients? Was that so?
Masur: Yes. In 1982. It was a sort of “catch-all” for everything. I am impressed that you could find this in somebody's files.
Rodrigues: One of the things that you mentioned earlier was the considerable coordination taking place among the Dental Institute [NIDA], the Allergy Institute [NIAID], the Cancer Institute [NCI], the CDC, and the FDA. There were people from these agencies working together. Part of the criticism that the NIH has come under has to do with the expectation that first an agency should build an administrative mechanism, which then provides momentum to drive science and provides resources. What you are telling us, however, is that there is an unspoken, underlying logic behind research, and that this logic created this embryonic program simply by the steps that presented themselves in the conduct of research. Later, more formal programs grew out of these efforts rather than the opposite taking place.
Masur: Yes. My perception of scientists is that they are like businessmen in that, although there are some who are purists and will do what interests them regardless of what else is happening in the world, most of them are very practical. If they see a new disease that will help their careers in terms of publications, of getting a more prestigious job, and if they see opportunities, they will be attracted into that field. They are not going to be attracted by a dead issue no matter what the leadership suggests. If someone says there is going to be a war on Sjogren's syndrome, they are all going to look and say, “That is nice, but I don't think I am going to work on it, because I don't care about it.” Fortunately, somebody cares about Sjogren's syndrome. We are not going to have a war on it, however.
Sjogren's was a very interesting scientific opportunity, but I think people got involved in AIDS not only because it was interesting scientifically but because it looked like it was important clinically.
One of the things that to me reflects a real tragedy, in terms of the direction that science and NIH are going, is that there is not as much emphasis any more on clinical investigation on this campus. It means that the NIH is shifting more and more to very basic research. Nationally, research is being split into two camps. More and more of the basic science branches are going to Ph.D.s, and the physicians are doing the clinical studies. This pulls people out of opportunities to respond to the kind of situation that AIDS presented. Here there were clinically trained people who were involved in basic science, and it was these people who initially saw that this was something very interesting and that there was a social problem out there. They knew that there were patients coming in. When a patient comes in and has a problem, it stimulates a lot of people to go back to the laboratory and say, “We should look at that.” It is a lot different when you are a Ph.D. There is not that same stimulation.
I realize that not everybody sees things in the same way. I think this is a good example of how training physician investigators pays a dividend, however, because physicians, microbiologists, and other people who had both clinical and research skills were able to take on a problem that piqued their interests scientifically. It looked like it was going to be a problem for them to take care of patients clinically, so they went to the laboratory and came up with some of the initial answers. Admittedly, it took somebody like Dr. Gallo, who does only bench research, to come up with the important answer about retroviruses. But I do not think that he ever would have recognized that there was a problem unless there had been a group of people who brought things along to a certain stage where he could jump in. That is not to take any credit away from him, but I think that there is not a lot of recognition that physician-investigators are the bridge between two worlds: people who have to deal with public health problems and the people who come up with the answers.
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