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Guerra: He has specifically said that if anything he asks for seems inappropriate for us to tell him. We have had an open door. I can say things to him that nobody else would say to him in terms of intramural administrative decisions, because he wants to make sure that he is protected and that the things are right or done right.
Harden: He wears so many hats. We will pursue some more of those in detail when we talk to him again. But this situation with his laboratory is his one major intramural connection at NIH, and I wanted to ask you about it.
Gallin: It is a major connection because he is the major person in the intramural program involved in clinical activities who is pursuing AIDS. I do not think that you would find an investigator in our intramural program who feels that he or she has ever been denied a resource for AIDS-related activities. This means that Dr. Fauci has never ordered anything at the expense of anybody else.
Harden: It is good, MaryAnn, that you are here because I think you also do the technology transfer for the Institute. I was curious about the development of the first experimental AIDS vaccine manufactured by MicroGeneSys.
Harden: I wondered what legal arrangements there were between the institute and that company. Was a CRADA [Cooperative Research and Development Agreement] involved? Tell me about it.
Guerra: There is a lot of history in terms of the relationship between MicroGeneSys and the Institute. Mal Martin initially worked with MicroGeneSys with a CRADA, and there was an exchange of materials. One of the materials that Mal provided to them ended up being used in one of their diagnostic kits. That related to gp160 and eventually to the vaccine that came out of it. There is ongoing discussion as to whether the MicroGeneSys patent may be based on an NIAID invention, or using an NIAID material as part of the vaccine.
It is an interesting story and Mal [Martin] can share it with you but it came about after the recent article in Science on whether MicroGeneSys was cooperating with the institutes. We have been trying to get MicroGeneSys to license Mal's patent because they were selling the test kit. They said they wanted to license it and that they had submitted the paper work but the license was never executed. An issue arose about whether Mal's patent was valid because of some mistakes made by the patent branch. MicroGeneSys backed off and would not license anything from us. Mal got nothing from that, and the institute got nothing from that. In one of our conversations, I said, “Mal, it sounds as though you might be an inventor of this vaccine.” We had our patent attorneys look into the situation, and if they are right, although we may have lost Mal's original patent, Mal may be an inventor on MicroGeneSys's patent. We have not got a resolution on that. We worked off and on with MicroGeneSys.
Cliff Lane also had a very active relationship with the gp160 research, in terms of the clinical trials that were done. He can give you the details on that. I prefer not to. That work was not done under a CRADA. Mal's work was done under a CRADA. The clinical trial work was just done independently, as we do a lot of clinical trials, where we use their drug and we do the trials [no agreement in place]. We have been getting more sophisticated over time in developing formal agreements so that misunderstandings do not occur.
Gallin: One of the things you might pursue, if you want more information on cooperative work, is the negotiation for use of large chimpanzees that MicroGeneSys initially had their vaccine injected into. You could get interesting discussion from Bob Purcell, Cliff Lane, and Mal Martin, in terms of what should be done with these chimpanzees, which have been immunized and which are very expensive to maintain, at NIAID's expense. For a long time, MicroGeneSys was reluctant to let us challenge the animals to see whether the immunization worked. Their argument, which, at the time, I think was a valid argument, was that they might not have achieved maximal immunity. They keep wanting to boost the chimpanzees and get more of an immunologic response. We have finally reached the point where we have decided that we will immunize the animals on our own to a stable level of antibody response. Then they are going to be challenged with HIV to see if there is any protection.
Harden: Wasn't it 1986 when the Technology Transfer Act was passed? This was something new happening that you may not have had to deal with before.
Guerra: It was interesting because I think the act was signed in 1985. I can remember the CRADA with MicroGeneSys. It was early on.
Gallin: No. The CRADA with MicroGeneSys maybe antedated the act.
Guerra: It was really a one-page CRADA.
Gallin: The act did not initiate all these rules and regulations. What the act did was to give permission to federal employees to reap some benefits from technology transfer and thereby to encourage technology transfer.
Harden: Has the act inhibited the work of the intramural scientist in any way? For example, industry sometimes wants to protect information.
Gallin: There are certain examples of where it has been a problem.
Guerra: They always ask for everything to be protected. You go into one of these agreements and, in your first negotiation, they say that everything that is generated through the CRADA is proprietary information. Then you go back and agree that you will let it be proprietary information until a patent application is filed, or until you have an IND [investigative new drug] approval. You will limit how long you will keep the information confidential. In general, they will agree to that. I would not say that our collaboration with MicroGeneSys is a shining example of a government-industry relationship. We have gotten better ones as time has gone on and CRADAs have become more customary. That was one of the first ones. Now we have many CRADAs that are really benefiting intramural scientists. Think of the work of Bob Purcell and Wyeth-Ayerst.
Gallin: Wyeth helps support our chimpanzee program for the development of hepatitis and respiratory virus vaccines.
Guerra: Some of the CRADAs have been terrific in many respects for carrying out the next stage of intramural research. The MicroGeneSys one was just one of the first ones. Mal Martin has not had any other CRADAs since then. Cliff Lane has a couple of CRADAs that he is working on now in terms of some of the AIDS research.
Harden: What have we not touched on that you would like to talk about in relation to NIAID intramural AIDS activities?
Gallin: You have not covered some of the clinical things: one is material that Dr. Fauci covered in his recent [G. Burroughs] Mider lecture on the pathogenesis of HIV and the fact that HIV is not a latent virus. He showed that HIV infection is a continuum of events which you cannot see because it is in the lymphatic system for a long time. When the lymphatic system becomes exhausted, and HIV breaks through that system of containment, then invariably you get total destruction of the immune system. Understanding the fine detail of immune destruction in AIDS has major implications in terms of identifying where therapeutic intervention is appropriate.
Dr. Fauci and his colleagues showed that AIDS does not have a latent phase. In patients infected with HIV, HIV is constantly active, and if you look in the right place you will find the virus. HIV is contained in the lymphatic system for a number of years, but eventually it explodes out of that system, goes everywhere, and kills the person. I believe the paper published in Nature just a few weeks ago is a landmark paper.
Harden: It certainly has implications for therapy, does it not?
Gallin: In terms of therapeutics, I think the use of immuno-stimulants in this disease is emerging as a very exciting area that you are going to read about in the next few months. In particular, I am excited about Cliff Lane's current studies suggesting interleukin-2 is capable of reconstituting CD4 cell numbers in patients with AIDS. These cells are the principal ones attacked by HIV, and when they drop below a certain number the patient becomes highly susceptible to opportunistic infections like Pneumocystis. What Dr. Lane has found is that if you give patients IL-2 in the right way–it is very critical thing what the right way is–the fall in CD4 T-cell counts is reversed. I think the use of IL-2 and other immune cytokines, such as gamma interferon, IL-10, or IL-12, in the management of patients with AIDS and other immune disorders is going to be very exciting in the next few years. It will have broad implications beyond AIDS.
Harden: It seems to me that research on AIDS has been a particular example of the unique opportunities in NIH intramural programs.
Gallin: When you think of that, you have to go back to the experiments of Dr. Wallace Rowe and Bob [Dr. Robert] Huebner and the people who early on recognized that retroviruses were important in human disease or had the potential to be of great importance. These were the people who set the foundation for others like Bob Gallo to jump in immediately and to relate retroviruses to disease. That is the unique thing about the intramural program. It allows people to do what sometimes seems like “way out," high-risk, long-term research.
Harden: I am going to ask one more question before I wind up. You have been very kind to talk at such length. Looking at my FTE chart, it appears that, in the beginning, the first burst of AIDS activity came out of the hide of the non-AIDS work. Have your people who do not work in AIDS felt as though their work has suffered from all the money going to AIDS?
Gallin: First of all, saying that the initial burst came out of the hide of non-AIDS work is an unfair statement. What that represented was people voluntarily shifting their directions. You had people like Tony Fauci and Mal Martin deciding to make major changes in the way their laboratory efforts were going. They went from non-AIDS work to AIDS, because of the intellectual opportunity and their own motivation. There was obviously a great concern during that period, and this is one of the effects of this whole era, that Congress would say targeted research is a must–“refocus what you are doing or we will not give you the resources.” That never happened, not in our institute. In our institute if you look at the actual dollars available for the non-AIDS work, and the rate of increase of the non-AIDS dollars, although it maybe lagged a little behind some of the other institutes, it was never dramatically behind. If you think of the fact that many of the intramural scientists have voluntarily redirected their activities towards AIDS. As a research institution, we are, in a sense, the beneficiaries of this public health disaster.
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