Office of NIH History
In Their Own Words: NIH Researchers Recall the Early Years of AIDS
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Harden: Going back to 1984, was there much interaction between your laboratory and Dr. Gallo’s laboratory? We noticed that you published several papers with him in that period, and you were reviewing treatment avenues in one of them. Could you just elaborate a bit on how his work in etiology and your work in treatment might have fit together in the context of the intramural program?

Broder: There were many interactions, on many levels. This included making sure that the Gallo lab received tissue samples and peripheral blood specimens, which accelerated their discoveries in AIDS. The Gallo group made a number of seminal contributions, and it is my view that their location on the main campus, within easy reach of the Clinical Center, made their lives a lot easier. It is worth noting that there were substantial criticisms about all of our efforts at that time, based on a lack of awareness of precisely how much was actually getting done.

Harden: This would be from outside.

Broder: Yes. I did not stop what I was doing in the clinical oncology program. I still was supposed to run the cancer intramural treatment arm and function as the clinical director, and no one said,”Okay. Well, you do not have to do that job.” This was an add-on. And Gallo had other things that he was doing, too. And it could have all gone nowhere.

Harden: That is a theme that we have heard again and again, too, that AIDS research in the early years became an add-on and that people simply stayed later and worked nights and weekends.

Broder: Right. For a substantial amount of time, there were certainly no additional resources available.

Harden: Would you comment on a strong misconception by AIDS activists during the early years of AIDS that science was just another political force, and that if they yelled loud enough or obtained enough money, a cure would be discovered.

Broder: This issue is not simple, and I think it cannot be reduced to a simple analysis. Activists or patient advocates are human beings, so they are subject to the full range of human frailties as well as noble features There is a constructive form of advocacy and a destructive form, and some of the premises are built on the principle that if we yell loud enough, we’ll get more money, and money will translate to progress. And that is partially true. There is no way of getting around it. It would be unrealistic to say that is not true. My concerns over the advocacy in that era, or advocacy in general, is usually not focused on whether patients want more resources. Of course patients want cures, not excuses. I agree with that philosophy. Patients want their government agencies, particularly the NIH, to solve problems that concern their health or the health of their loved ones. I do think that there were many areas of misunderstanding. I believe the patient advocacy community was correct in their concerns that there was an unwarranted detachment in some elements of the scientific community who conveyed a sense of indifference, perhaps not intentionally so.

The “obligation” of any patient is to get better. Doing something for science, or for a greater good, is something that we cannot compel in our society. Patients do not have such a duty, nor can any centralized government authority say otherwise. Some members of the scientific and clinical community just assumed that patients would be willing to enroll in placebo-controlled trials, and they did not initially do enough to work with patients, to listen to their needs, and to look for constructive ways to develop new drugs, using placebo controlled trials when necessary, but exploring a range of other approaches when not absolutely necessary. One of the really powerful memories that I have is when the AZT randomized clinical trial was completed. At one point in time, there were approximately 19 deaths in the placebo arm, and there were zero or, maybe at most, one death in the AZT arm at a certain interval of time. I remember that Vince DeVita had been hospitalized for some emergency surgery. I had to track him down while he was recovering from the surgery to show him the data. We were then in the process of reviewing what to do. And there was an enormous air of uncertainty and doubt about what to do at virtually all levels of the scientific community involved. I remember Vince clearly and calmly saying that we should stop the study. He knew when to do a study, and when to stop a study. He is a great thinker on these issues. There were some members of the scientific community who were not quite so in touch with reality. Whenever clinical researchers are dealing with a potentially lethal disease, they need to carefully assess these issues, and make sure that they do what is necessary to explain what’s at stake to the patient community.

Hannaway: I would like to come back to your early contributions to AZT research. Your laboratory was important, of course, in developing a precise anti-HIV screening assay known as ATH8, and Dr. Mitsuya, of course, was involved in this work with you. Could you discuss the development of this assay a little for us and explain in some detail how it worked.

Broder: We made a decision in the early 1980s that we would begin screening for compounds that had several properties: speed, reliability, simplicity. Hiroaki Mitsuya made several contributions. He developed a very rapid system, backed up with other confirming, longer tests, for checking whether a drug would work to suppress the AIDS virus in tissue culture. And he developed a sensitive cell line that died upon contact with the virus, to actually see the cytopathic effect of the virus under very rapid conditions, adaptable for selecting candidate drugs that might go into the clinic. His techniques were robust, and as events have proven, predictive for success in the clinic. For a time, his work was the foundation for a large number of ideas that went into clinical trials.

He also was courageous, and kept the morale of the lab at a high level. In working with live AIDS virus in that era, you did not know whether you would be infected. You did not know what the issues were. It was a real concern then. And I think Mitch was very dedicated, worked very long hours, and, out of respect for others in the lab, would work after hours so that other people would not have to fear the work he was doing. He did not complain, he just did what he had to do. And we could take his discoveries right to the clinic. Even those few people who were screening for new anti-AIDS drugs had essentially no effective clinical arm.

Hannaway: So they could only work in the lab.

Broder: They could only work in the lab and then publish some paper somewhere and hope that somebody would pick it up.

Hannaway: Were there any technologies, in addition to being so near the clinical arena, that helped in development of these assays?

Broder: Well, a lot of the technologies were dependent on the Gallo group, because one of their earliest things they did was to develop new viral isolates. There were various isolates. Some isolates grew only in certain types of tissue-culture conditions, some isolates grew in T cells, some grew in monocytes. We could conduct a whole area of research based these tissue-specific isolates.

And we learned things about AIDS drugs. For example, some of the nucleoside analogs we used are inert in their own right and have to be anabolically phosphorylated or activated inside a cell before they begin to work. How they are handled, or activated, in monocytes or macrophages is different from how they are handled in T cells. We were learning how to manipulate this system and how to get the maximum activation, if you will, how to pick rational combinations based on biochemical pharmacology. AZT, for example, works especially well in dividing cells. Another drug, ddI, works particularly well in non-dividing cells or resting cells, and, therefore, could block the initial entry into cells.

Harden: You obtained potential anti-retroviral drugs from pharmaceutical companies. Was this your initiative? Was it their initiative? Could you go into some detail about how this process worked?

Broder: Yes. One of the things that was very clear to me early on was that we would need partners in the private sector, and that we would eventually need them, if nothing else, to circumvent what would be an inevitable bureaucracy. Scientists from the Burroughs Wellcome company and I got together largely through the help of [Dr.] Dani Bolognesi. They were willing to do things, to develop products, and not just to talk. They were willing to exchange information and provide drugs that could be tested. And they were pretty clear that they would make a commitment to try to develop and commercialize a product that looked good. Even they had trouble with their own internal corporate bureaucracy, however. It turns out the private sector has its own share of bureaucracies. At one point, the company could not obtain its own supply of thymidine, a starting block for the synthesis of AZT. We at NCI were able to send them a large shipment.

Hannaway: Where had you obtained it from?

Broder: The NCI had a repository of thymidine from another era. We were one of the world’s few places where you could get it. But Wellcome scientists were bummed out. I mean, if they were honest, they will recall that they were unable to produce it. There were going to be dramatic delays. And then, voilà, a shipment of thymidine arrived in the company loading dock. New drug development is complex, expensive, and not something that just any group at NIH has the infrastructure to do.

Harden: I want to pursue a little further the question of private and public collaboration, because this became the bone of contention in the lawsuit over who was to have the patent on AZT. And just for the record, I would like to get more details of your version of how you became involved with Burroughs Wellcome in AZT research.

Broder: Sure. Dani Bolognesi, a Duke University professor, helped to arrange a meeting. I do not remember exactly when it was. But early on in the process, I went down and talked to the company about our capabilities. I exchanged some of the early results we were obtaining. I explained what our capacity was in terms of clinical trials and essentially offered a collaboration with them, with the promise that we would, whatever came up, develop drugs as fast as we could and that they would get a product out of it. There was no other way to encourage pharmaceutical companies. They were not the only company that I visited, but to their credit, they were the first to make a serious commitment.

Harden: Would you have done it differently after the Technology Transfer Act was passed? Would you have done it differently to try to tie down these legal things after what happened?

Broder: No. I think this is one of those areas that, again, cannot be viewed easily in the optic of hindsight. AIDS was a public health emergency, and it was essential to get things started. AZT is out there. It is an approved product. I view that as successful example of a public/private collaboration. It laid the foundation for almost every other product because, in my view then and now, the failure of AZT would have had very dramatic effects, would have induced people to say, “It is all a waste of time. Why are you wasting the government’s efforts?” There were many people who were very skeptical, who cautioned me almost to the point of warning me not to continue in this area–or at least not to be so visible in this area–saying that I was making a bad career move. Most of the people who were involved were adopting a sense of that, “we will do an orderly process of science, we will do it step by step, we will do rational drug synthesis,” whatever that means. The AZT collaboration stimulated a lot of science, and laid the foundation for better drugs in the future. And it also provided patients with a measure of hope, at a time when there was none. I felt very confident at the time that there would be all sorts of people not connected to the science or clinical aspects, well-meaning and sincere government employees, perhaps working in the Office of General Counsel, perhaps working elsewhere, who would have found thousands of reasons why what we were doing was not appropriate, and required a lot more paperwork. And those forces tend to become very quiet after a project seems to have worked. They do not come forward at that point.

Hannaway: But they are prominent before that.

Broder: Because once there is a success, they see the department [Department of Health and Human Services] has embraced the results and everybody’s happy. But beforehand, they would have clearly, in my view, clearly introduced barriers. We would have had, at a minimum, two separate teams of lawyers talking to each other forever. I had been in government long enough to know that. There would be the lawyers from the government and the lawyers from the private sector. They operate under a different sense of time and urgency.

Harden: You began Phase 1 trials on AZT in July of 1985.

Broder: That is correct.

Harden: And we’d like to have you talk in some detail about the process, what you were seeing in Phase 1, how Burroughs Wellcome moved on into Phase 2, and I believe they were quite concerned about their people being infected.

Broder: Oh, they were extremely concerned. They refused to accept live virus, and at one point refused to accept patient samples. That was a little unusual. They basically put the entire onus for the Phase 1 pharmacokinetics and related issues on NCI.

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