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Harden: I have a technical question at this point. Why was the original name T-cell growth factor“ changed to interleukin-2?
Gallo: The original was a better name. It described what the substance did. It made T cells grow. The name was changed by a group of immunologists. I was not invited to the meeting. So, nobody from our laboratory made the change. The immunologists started to use the term interleukins. In fact, I think interleukin-2 appeared earlier than interleukin-1. I think it was the first cytokine that could be defined. But, because in the biology of T cells, it works after an effect of interleukin-1, I believe that is why they called it interleukin-2. In time, the changed name becomes a better name because we have learned that interleukin-2 can do more than grow T cells. But its major biologic activity is still the growth of T cells. It is a descriptive term. Remember, my background was more in cell biology than immunology. Cell biologists use terms such as growth factors, “fibroblast” growth factor, “platelet-derived” growth factor, and it is possible to go on and on. There are many growth factors and that was a common term. What interested me about interleukin-2 was the fact that it was a growth factor. It grew T cells for the first time. What other name would I give it?
But we actually did not call it T-cell growth factor; we called it “T-cell mitogenic factor” in the first paper about it. Then, with the influence of the collaborator, in our second paper we called it TCGF to keep up with the terminology of epidermoid growth factor, platelet-derived growth factor, and fibroblast growth factor. We used the name T-cell growth factor. I think it was roughly two years later, when they wanted to bring some order to the names of lymphokines–what were eventually just called cytokines, in general–and they started using this terminology of “interleukins.”
Rodrigues: In talking to other investigators, and based on our own research, one program that came up a number of times when we started talking about the [National] Cancer Institute and its research in the 1960s was the special Virus Cancer Program that Dr. Robert Huebner and Dr. George Todaro ran. You stated in your book that you disagreed with Dr. Huebner's theories about endogenous retroviruses, yet you found the arguments in favor of them highly stimulating. Could you elaborate on this and on the larger value of keen scientific argumentation as a mechanism to stimulate precise thought?
Gallo: The special Virus Cancer Program was actually not headed by Huebner and Todaro, but was first administered by [Dr. Frank] Dick Rauscher and then by [Dr.] John Moloney. But Dr. Huebner and Dr. Todaro were the two most obvious, visible, and famous virologists that were funded by the program and also, in turn, funded other people by a contract program that was controversial at the time. That led to the Zinder Committee's evaluation of it, but I think that was just the politics of science. There was a lot of money for the special Virus Cancer Program because people had ideas, and Huebner was among those who had the most ideas. Huebner was able to generate enthusiasm and funding for the Cancer Institute when he came in. I think many outside scientists, in time, saw that here was a chance to get good funding and that maybe they too ought to be in cancer research. They were not in favor of continuing the special Virus Cancer Program with its giant contract program.
The special Virus Cancer Program, however, in many respects, made contributions to molecular biology in this country. It contributed to the understanding of a wide variety of viruses and certainly to having reagents available for all kinds of viruses of animals and to some human virus reagents. These were reagents that we capitalized on greatly. How did I know HTLV-I was not an animal virus? We had used reagents from the special Virus Cancer Program to rule this out, before we had characterized HTLV-I chemically and immunologically.
Now, Bob Huebner and George Todaro had a famous theory called the virogene/oncogene theory. It is true that I did not believe in the literal aspects of that theory, and it is true that that theory was not correct. However, the catchy word “oncogene” certainly produced some thoughts about going after a particular gene, or genes. Huebner and Todaro thought it would be one gene originally, or maybe a couple, and it turned out to be a very large number. Their knowledge and ideas that cancer had to involve something in the gene, something in DNA, were already there, so that was not novel. But when you started to speak about it as a specific gene, or a few genes, I think that, in itself, helped to crystallize people's ideas on looking for such genes. But I could not imagine that the theory they were proposing, that virtually all of cancer, if not all cancers, was simply an activation of a set of endogenous retroviruses which included within them an oncogene, was the way cancer developed for many reasons. One reason was that all kinds of activation of endogenous retroviruses in animals were not associated with anything, except publication of papers. You would have it, you did not know what it meant, and there it was.
Also, I was impressed by the lack of evidence, after an intensive amount of work, that such viruses were ever playing a role in cancer. I was more impressed by the people–such as [Dr.] William Jarrett in Glasgow who had discovered feline leukemia virus–who pointed out that, when there was a clear cut viral cause of malignancy in an animal, it came from without.
But Huebner, in retrospect rightly, countered my argument, and not bashfully either, by saying that it was crazy to think of cancer being catching. You will raise the issue of catching. Well, the more I looked, the more I saw, and the more I thought of models that, increasingly, were showing an acquired virus. Bovine leukemia retrovirus came along in the early 1970s. There was not much virus replication. Maybe humans had the same kind of retrovirus. We did. And it was infective, maybe in utero, so it was not seen as a horizontal spread. That happens. We now know that happens in general infection. Quite frankly, I suspect more things happen congenitally in the causes of diseases that we do not have etiologies for right now than we know. I should rephrase that. I think we will see more diseases for which we do not now have etiologies that will be shown ultimately to be due to congenital causes.
Viruses are hard to trace. Epidemiology is almost impossible, especially if there is not high penetration, if you do not get disease every time. Such infections will look like genetic disease as Ludwik Gross pointed out earlier. So, I was impressed that, increasingly, when we knew that a cancer was caused by a virus, it came from without. Maybe it did not replicate much; maybe it infected in utero, maybe it came from mother's milk, maybe it made epidemiology complicated, but this was more impressive than the simple expression of an endogenous retrovirus.
However, to repeat, the virogene/oncogene theory crystallized the notion of a gene, or genes, that could be involved in transformation and also that such genes might be captured by a retrovirus–it turns out to be an infecting retrovirus, not an endogenous one. The first identification of an oncogene was in the Rous sarcoma virus and also they picked up such a gene in some of the mouse sarcoma viruses. But they are not just endogenous, then turned on, and cancer follows. The theory was wrong in its detail but it helped–really fermented–many issues, many questions, and promoted much research.
Harden: When you related the story of working on HTLV-I in your book, you talked about losing the cell line that was on a freezer plate and probably carried HTLV-I. This was before the Hershey meeting.
Gallo: Yes. Actually, a slight correction is needed. That mistake is often made because I put them too close in the chapter. It was not HTLV-I, it was just before HTLV-I.
Gallo: It would have been HTLV-I.
Harden: Yes. That was my point. You did not quite know what you had. It probably would have been HTLV-I.
Harden: We have heard many stories from scientists about freezer failures, yet, supposedly, the NIH has a very good back-up system to prevent this from happening. What happened in your case?
Gallo: I do not know. We had two disasters from freezer failures. I think we know the origin of one of them. You can get paranoid in the laboratory when things go wrong, and the person closest to the research gets the most paranoid. We found a plug not plugged in, and it was over.... That was on one of these occasions. I always get them mixed. But twice we had freezer accidents that were very costly.
In one of the two times it was over a holiday. We came in and found the plug pulled out. People began thinking somebody was sabotaging the experiment, and that sort of thing. But sometimes it is due to the cleaning people. We did not have any back-up in that instance. I do not know what happened. But we lost everything in that freezer.
Harden: What happened at that first meeting at Hershey? You described the disappointment of finding out that your cell line had been contaminated.
Harden: What surprised us was reading that the scientist who reported the contaminations apparently waited to do this in public. Why did they not call you privately? Why were they so bitter? Was this a personal matter or was it related to broader currents in the field of viruses and cancer?
Gallo: No, I do not think it was only personal. It may have been a little of both. Personal, but not really personal, because he thought maybe of the competition and maybe that we were going too far too fast. It would be better to ask someone else who was there that question, like [Dr. Stuart] Stu Aaronson, [Dr. Takis S.] Papas, who is now in Charleston, or [Dr.] Ray Gilden who was there and who participated in that. But, there were plenty of people there. [Dr.] Jeff[rey] Schlom, who is still here, was there. Many people saw that. And [Dr.] Peter Fischinger at Charleston. I think it would be better to ask them. I mean, to put it briefly, it was really long. It was a very difficult time over a two-day period actually.
Yes, I learned from that. I should have given out the samples for everybody to analyze. I went in to the meeting knowing the nature of the problem from our own work, not conclusively–I did not have as much data as they had–but it was already becoming apparent that this was a laboratory contaminant. It was an extraordinary phenomenon. It had never happened before. It seems that there were three viruses, three different monkey viruses, in one culture. This is not something you want to say for the record, but I should say it because it is the truth. It looks awfully suspicious, having three different monkey viruses in one specimen, the thing that would deceive you the most. I spent a long time analyzing what happened. You wonder if somebody was crazy and did it on purpose.
[Dr.] Robin Weiss came from England to help us in that work and, as previously, there was failure for a month. We could not transmit anything. We had these particles, but we could not transmit them. We asked his help. He came and he could not transmit them either. Then all of a sudden every culture was positive. Then, as the year went by, there were three different monkey viruses in those cultures. Not one, not two, but three. I do not know how this happened, but it was a real disaster at Frederick and it put the field...
Yes, there were. When you asked me about whether it was a personal matter or was it the field, I think there was an aspect in which it was the field, because there was a big push to get rid of the Virus Cancer Program. There was a big push to go completely towards chemical carcinogenesis and just forget all the virus work. So these events coincided. There was a big push to say that there would not be any more retroviruses, and there were already some–I would say in retrospect–silly disasters. There was a virus announcement from the M. D. Anderson Cancer Center and they actually had no data it was a human virus. It was announced as a human virus and it turned out to be a common mouse laboratory virus.
Then Bob Huebner himself had a problem with the so-called RD-114, an endogenous retrovirus of cats. This is an example where knowing something hurt. They put human tumors in a cat, and the tumor came out with virus that was not feline leukemia virus. At that time the concept was ingrained, “one species, one virus, one retrovirus," and that is why you had these type-specific antigens tied to that species in a group across some species. If it was not feline leukemia virus, then it had to be a human virus. In fact, it was a new feline virus; it was the endogenous retrovirus of cats.
I was an author of a publication to say that. I was involved as one of five laboratories. But I really did not feel I had the data. I mean, we all knew and understood. It was not done in a meeting. But in our case, at Hershey, it was done rather dramatically for a whole day and a quarter by one person after another, about ten people in all. So I do not know what drove it the most. I had not had so much success at that time that you could argue that there was somebody jealous or something like that. I do not think there was much to be jealous of. I am not really sure. I want to be honest, so I am going to say I think there was a degree of mean-spiritedness to that show on that day. But I think the story is better told by other people than by me.
Harden: Let me just verify one point again. A number of the people who were criticizing you were NCI contractors and people inside the program?
Gallo: One hundred percent. People at the meeting were either within NCI, in the special Virus Cancer Program, or contracted to the special Virus Cancer Program. You see, I was not part of the Virus Cancer Program. I was in the Division of Cancer Treatment, of all things, at that time. I am now in the Cancer Etiology Biological Carcinogenesis Area, but then I was not. John Moloney, whom I knew very well, was the head of the Virus Cancer Program, and he gave me extra funds from that program. He transferred money from one division to another because he wondered whether we would maybe find a retrovirus and he thought it appropriate that we would be linked. So we were linked in that way. I suspect that some people in that program were not happy about that, so the attacks came from my competitor and–in his last years of life–friend, Sol Spiegelman from Columbia [University], who was under contract, and one or two people in his laboratory. It came from Ray Gilden, with whom I have worked and collaborated subsequently, who is out at Frederick. He had always been a contractor to Bob Huebner at that time. The criticism came from his associates and from several people who came from George Todaro's branch, in several of the talks, for instance. That was not the end of it, but it was all Virus Cancer Program people. It was relentless, talk after talk.
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