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This is an oral history interview with Dr. Flossie Wong-Staal on , Ph.D. about the National Institutes of Health’s response to AIDS.   The interview was conducted at the National Institutes of Health (NIH) on 10 December 1997.   The interviewers are Dr. Victoria Harden, Ph.D., Director, Office of NIH Historical OfficeHistory, and Dr. Caroline Hannaway, Ph.D., Historical Contractor, NIH.

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Harden:                       Dr. Wong-Staal, we’d like to start by talking about your personal background and education.   You were born in China, and your family moved to Hong Kong in 1952, where you attended an all-girls’ girls school.   Can you tell us about your family, your father, your mother, and your education prior to going to college?

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Wong-Staal:                Yeah.  I grew up in a family of four children, two boys and two girls.   My father Sueh-Fung Wong, was , is in the import-export business.   My mother Wei- Chung Chor, was a housewife.   She did not attend college.   She stopped at the high school level.

Among my brothers and sisters, I’m really the only one who went to college.   So people often ask me whether I have a role model in my family, and, actually, I can’t really say there is a role model.   But, on the other hand, my parents have been very supportive of my pursuing my education.   They’ve never , you know, had the concept that girls should not be, have higher education, and, on the contrary, they were very happy and pleased and proud of my accomplishments.   And I think in part, you know, I always think that my mother is very intelligent, and she probably was frustrated that she never had the opportunity the opportunity to have a career, and she was happy to sort of see me having have the opportunity.

Harden:                                              Where did you come in the birth order?

Wong-Staal:                                I was the third.

Harden:                       You were the third?Wong-Staal:                Yeah.
Harden:                                              Were you interested in science as a child?

Wong-Staal:                                I was interested in a whole range of things.   But I was interested in science but also interested in literature and poetry and novels and so on.   But the The way the high school system is in Hong Kong is that , you have to choose to go into science or non-science , really, early on in high school, I guess starting from high school, you know, after junior high.  But, so, part . Part of the mentality is that if you’re smart, you should go into science.   So it’s almost like , you know, you’re told that you should go into science.   And people are usually accept that because they feel it’s feel it’s an honor and a privilege.   So I can say that it’s almost by default that I was _____ in steered into the science path.   But I, of Of course, never regretted it.   I enjoy science, and I’m very happy with what I’m doing.

Hannaway:                  So the                   The high school was on the British model.?

Wong-Staal:                                Right, exactly, yes.

Hannaway:                                    And was it an English-speaking high school that you went to?

Wong-Staal:                                Yes.   The high school --it Maryknoll was actually run by American nuns, but the system in Hong Kong is the British system.

Hannaway:                  My sister and brother-in-law lived in Hong Kong for many years, so I know a little bit about the schooling system.

Wong-Staal:                Right, right, yeah.

Hannaway:                                    Why did you decide to move to America rather than Britain for your college education?

Wong-Staal:                                It was sort of arbitrary, I think.   I also applied to Canada _____.  But Canada’s McGill University. I had friends or classmates who were coming to America, and specifically going to UCLA [University of California, Los Angeles], where I ended up.   So it It was part of the desire of being to be with people I know that made that choice.   And the other thing I think is that, just for people in Hong Kong, they’re more familiar with, I think, --through the television, movies, whatever, you’re more familiar with--the West Coast in America is more familiar.

Hannaway:                                    Was there a particular person or instance that influenced you to study bacteriology as an undergraduate?

Wong-Staal:                                Not any particular person.   I was interested in biology as a whole, but I think microbiology, bacteriology, was of particular interest to me.   I just , you know, like liked the subject.

Hannaway:                                    There was not a teacher or a specific person .who inspired you?

Wong-Staal:                                Not anyone particularly that inspired me.   But I have to say that I had very good teachers at UCLA for those courses.

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Harden:                       Would you comment a little bit on your graduate training.  ? Were there professors at that level who influenced you particularly?

Wong-Staal:                                I think at the time when I chose molecular biology because that , it was an era when there were a lot of exciting things happening, and I think there was cloning . Cloning was discovered with the restriction enzymes, so things are were just becoming possible.   And I think also the oncogenic viruses and the reverse transcriptases also were discovered around that time, maybe a little bit later, but close to that time.   So it was a very exciting field.   I mean, it was sort of what physics was like a decade before.

So I--even though at At that time , you know, I remember that there was an article by Gunther Stent [Gunther S. Stent, Ph.D.] published somewhere, “The Rise and Fall of Molecular Biology.”  ” He thought that it was the peak of molecular biology, but then, and from then on, it could only go downhill.   But, of course, that was very premature.   So I think it was , I mean, again, the right choice, but at . At the time I think , a lot of people in my generation or in my peer group seemed to choose that direction.

In terms of my professor, my thesis professor, he’s he was an older botanist, in fact, an older botanist, but that then became, he turned into a molecular biologist.   He was very nurturing, although he is sort of like the grandfather type.   But overall, it’s Overall, it was a very good experience because of his attitude, and caring attitude , towards his graduate students.   And had good interaction because At UCLA, the molecular biology was not a department.   It was an intradepartmental institute.   So we actually We got to interact with people in chemistry and in microbiology and so on.   So it It was a very positive experience.

Harden:                                              What was the name of your thesis advisor?

Wong-Staal:                Sam Wildman.                  Samuel Wildman, Ph.D. Again, you know, as I said, he’s an older person who worked mostly on tobacco , _____ TMV _____ virus, but also mosaic virus (TMV) but also on the tobacco plant, fraction 1 protein, which is an enzyme, carboxydismutase,  which which turned out to be very important

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Hannaway:                                    Did you ever think of going to medical school, or you were always focused on being a Ph.D. research scientist.?

Wong-Staal:                                I think I had an aversion to the blood and guts of medicine.   I mean, I like the biochemistry, molecular biology approach.   But I don’t think I could have gone through all the medical training.

Harden:                                              And you’ve never changed your mind since.?

Wong-Staal:                                No.   It’s better to work with M.D.s rather than to be an M.D.

Harden:                                              I want to come back to the excitement of molecular biology in the early ‘70s’70s, because you arrived at the NIH in 1973, and so you were right there as all these new things were happening...

Wong-Staal:                                Right.

Harden:                                              In thinking back in terms of what we know now and what was known then and how exciting it was to be learning these new things, are there particular things that stick in your mind as being just the most exciting kinds of things that you remember personally that really impressed you?

Wong-Staal:                                I think really the cloning aspect, the ability to purify genes and to amplify them enough to study every detail was something that wasn’t possible before.

Harden:                                              You saw that as something that would be . . .

Wong-Staal:                                Revolutionary and open up all kinds of possibilities.   And, of course, now there’s there are so many new technologies that have been developed, and we . I always thought that if we can I could use the techniques we have now to go back to our thesis, we I could have done so much more, you know.

Harden:                                              When you arrived at the NIH in ‘731973, you were a Fogarty fellow.   First, several questions.  What led you to come to the NIH at that point?

Wong-Staal:                                Well, at that point, I think it was partly personal, because my husband, Stephen, [Stephen Staal, M.D.] was assigned to NIH, so--and . I had just was been married for a year or a couple of years then, so that was the clear necessity.   But also, there are several labs at NIH that have had interests that match mine, so...  For example, I mean, one . One of them, of course, is was Gallo’s lab [Robert Gallo, because of the idea to go after M.D.], because he was trying to identify a pathogenic human retrovirus.   At that time, the studies on animal retroviruses was were in full swing, and I think, again, there’s there was a lot of excitement with the about oncogenes and so on, of retroviruses.   So I think thought that was a very attractive area to get into.

Harden:                                              So you all were able to arrange a dual appointment when you came.  Your husband had an appointment and you had an appointment simultaneouslyyour husband and you both had scientific appointments when you came to NIH.

Wong-Staal:                                Right.   He had an appointment first, and then I started applying, I think, applied to a few labs, and then I ended up...

Harden:                                              As a Fogarty fellow, does that imply that you were not a U.S. citizen at that time?

Wong-Staal:                                At that time, I was not.   I came from Hong Kong, so I...   I was married, as I said, a couple of years to an American citizen, but it takes five years before you can become a citizen, so I was still in transition.

Harden:                                              When did you become onea citizen, just for the record? Wong-Staal:                Well,                 I think it was 1976.

Harden:                       Nineteen seventy-six.

Wong-Staal:                Yeah.

Harden:                       Now, which Which laboratory were you in when you first came to the NIH, and what did you do for your first research project?

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Wong-Staal:                I came to Bob Gallo’s lab, and initially I was working on different things.  One is   One was intracisternal A - particles, you know, how they replicate, you know, the biochemical analysis of intracisternal A particles.   And the other is, at that time, David Gillespie David Gillespie [David Gillespie, Ph.D.] was a section chief within the lab, and he’s the person who actually innovated the hybridization procedure with Sol Spiegelman [Sol Spiegelman.  So I was , Ph.D.]. I also trained with him to learn some of these molecular techniques, hybridization.

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Hannaway:                  You decided , as we know, to stay at the NIH, and then you had held positions as a visiting associate and cancer expert.  Can you tell us what made you decide to stay, and would you comment on the environment for young researchers in the intramural program at that time.?

Wong-Staal:                                I think NIH is a wonderful place to build a career, because , you know, you don’t have to write grants grant proposals, and you don’t have the teaching obligations, and it’s there are a lot of opportunities for interaction.   And it’s It’s also where the center of biomedical research, sort of the mecca.   The people People come and give seminars.   So it’s It’s a very exciting place.   And it’s It’s hard to really find a comparable environment outside, I mean, especially in a period when you want to have the maximum productivitymaximum productivity, because every any move really means downtime , you know, at critical points in one’s career.   So I think once you’re at NIH, often there is a great inertia to leave NIH just because you’re used to all these privileges.   But at the same time, at some point, I guess, it’s good to have the a change.

Hannaway:                  You can decide that                   We will come back to your later career.   We’ll come to that later.  Could you just Would you make a comment about whether the NIH was receptive to female researchers at that time?   Or did you feel it was perhaps somewhat of an old boys’ club or young boys’ club?

Wong-Staal:                Actually                I, I personally, throughout my career, have not experienced any overt discrimination on the basis of being a female or on the basis of being a foreigner.   I mean, sometimes Sometimes it’s hard to dissociate these two minority standings.   But, obviously, I see it happening sometimes, and sometimes it’s real really subtle.   It could be at At the higher level , you know, high-level of decision-making, and that’s when the old boys’ club operates.   But when you’re I was young and starting out, I think I don’t did not see too much discrimination.

Hannaway:                                    In 1978, you became a senior investigator in the laboratory of tumor cell biology Laboratory of Tumor Cell Biology at the National Cancer Institute [NCI].   Can you tell us a bit about the about the research you were focusing on in the period before the advent of AIDS?

Wong-Staal:                Yes.                  We were looking at using, looking at the primate retroviruses, particularly the gibbon ape leukemia virus and some of the animal transforming viruses, simian sarcoma virus, AMV [avian myeloblastosis virus], and so on, so, to look at them as models for eventual application to the human system.   The monkey virus, of course, is very relevant because they are exogenous viruses that cause it is an exogenous virus that causes disease and is horizontally transmitted.   And then the We were studying oncogenes, because they’re _____ genes, we homologues of cellular genes. We were interested in whether they may, or the expression, you know, regulation of expression their expression may play a role in some of the cancers, so we were looking at that, at those issues.  And, of course, also the . We were also doing basic molecular composition and structure and structural function type studies, so that kind of studies.  But, so ‘78, I said.   I think at that time already we by 1978 we already had HTLV-1 , so that’s [HTLV-1 was originally known as “human T-cell leukemia virus type 1” and later as “human T-cell lymphotropic virus type 1”]. It was another thing that was very exciting at the time.   I mean, I’m not personally‑-I wasn’t personally involved in the discovery of HTLV-1.   It was done in the virology of, cell biology section at the time.   My group was more focused on molecular biology.  But once the virus--and it HTLV-1 was the first human retrovirus to be discovered.   And once Once that virus was isolated and propagated, then my group got a chance to actually work on the cloning it and doing some of the sequencing.  So that  That was very exciting, too.   So I think all All that was going on at the time of that transition.

Harden:                                              In 1982, you achieved one of those NIH milestones when you became chief Chief of the section Section of molecular genetics of hematopoietic cells. Now, the first question, was Molecular Genetics of Hematopoeitic Cells. Was this section created for you and your research, or did you inherit it from someone else?

Wong-Staal:                I think it’s more                 It was an inheritance , because from David Gillespie, the man I mentioned about, he was head earlier. He was chief of--I don’t know recall if it’s the section had the exact same title, but certainly there it was a section that related to molecular biology that he was section chief of, and after he left, I suppose I was acting . After he left, I was acting chief for a while, but it was in ‘82 that I was formally recognizednamed section chief.

Harden:                                              When you became chief, presumably you reviewed where the section was going and what you wanted.   Would you describe your goals at that point, what you wanted that section to do?

Wong-Staal:                Well, I think it’s very simple, because that was the time when HIV was available, and almost everything we do, we did, was important in the discover.  So I think that the plans were straightforward.  We need to understand what the virus is at the molecular level.  And as it turns out, the virus was very complicated, so we had to identify each gene.  There are a number of novel genes not found in other retroviruses.  We have to not only to show that they are exist, but what they do.  So, again, the structural function of...

Harden:                       We were just on the verge of it in ‘82.  You were then--the virus is not defined yet.

Wong-Staal:                Oh, absolutely.  Yeah.  I get the chronology _____.

Harden:                       So that’s why, before you hit, we’re going to get to _____.

Wong-Staal:                It was in ‘83, in ‘83.

Harden:                       Eighty-three is when it really starts to get real.

Wong-Staal:                Yeah, that’s true.

Harden:                       Now, in ‘82, we had HTLV-1, so we were doing those things with HTLV-1.

            Now, the efforts on trying to find a retrovirus for AIDS were ongoing in the lab.  And we were participating in it, but only, you know, doing things like looking at samples from AIDS tissues to see if we can detect sequences related to then known viruses, including HTLV-1.  So I think that’s the kind of work.  But, of course, that’s only a part of the program.  The other part is really to continue on with HTLV-1 and oncogenes and...

Harden:                       Well, what I was getting at here was, in the pre-AIDS era, how did you see your career developing and this section developing, and you would have stayed, continued to work on retroviruses.  That would have probably been your focus?  Or do you think you would have tried to...

Wong-Staal:                I think we would--at that time, we were, in fact, doing a lot of interesting things with retroviruses and oncogenes, you know, as many other labs in the country.  But we were, I think, competitive in that area:  looking at mechanisms of transformation, looking at, you know, again, what the various oncogenes do in the cells, whether they’re transcriptional activators, whether they’re signal transducers, you know, whatever.  So I think that                 At that time, we were doing a lot of interesting things with retroviruses and oncogenes, as were many other labs in the country. We were, I think, competitive. We were looking at mechanisms of transformation, looking at what the various oncogenes do in the cells, whether they’re transcriptional activators, whether they’re signal transducers, whatever. I think that the whole program certainly could have continued had HIV not HIV come along.

Harden:                                              Would you just name some of the investigators who were working with you in this section in 1982?

Wong-Staal:                Mm-hmm.  Ricardo Dalafaber.  Actually, he’s                 Riccardo Dalla-Favera [Riccardo Dalla-Favera M.D.] was one. He’s done really well.   He’s a full professor at Columbia now.   He’s the first one to show mic to show myc gene amplification in primary leukemia cells, in primate leukemia.  Jennifer Fontini, I mentioned before.  She . Veffa Franchini [Genoveffa Franchini, M.D.] was working with me on , for example, mapping the fas fos gene from the feline sarcoma virus.   And, in In fact, we published one of the first papers on showing that the cell, the cellular counterpart of this gene , had intervening sequences .  There wasn’t, you know...  But now it’s sort of (introns). Now it’s obvious, but at that time, it was a new concept.   We were the first to characterize the simian, the sis gene , for the simian sarcoma virus transforming gene.   In fact, I think we gave named the name gene sis.   That was in our first paper looking at that.   And the person who was involved or the people who were involved is, I think Ricardo was involved in that too, Phil Lefavre, and also as was Steven Josephs [Steven Josephs.  He , Ph.D.].  Steven was a technician who then became a graduate student.   He got his Ph.D. from American University, and I was his thesis advisor.   He’s now a scientist at, I think, Baxter Pharmaceutical Company.  He’s a scientist there now.  And, let me think, maybe Mandy Mon [?] could have been involved at that time as wellthink, Baxter Pharmaceutical Company.

Hannaway:                                    Do you recall --this is a more general question-- the debate over whether human retroviruses existed?

Wong-Staal:                                Yes.   I think, you know, at At that time, the dogma at that time, because most was that they did not exist. Most of the retroviruses retrovirus work was done in the murine system and in the avian system, and where there was a are very high level levels of virus replication.   And at At the same time, people who were looking for human retroviruses had some mishaps.   I mean, I mean that there were a few so-called discoveries that turned out to be contaminations, artifacts, whatever.   So it sort of This soured people on the concept of, you know, maybe they don’t exist.  that human retroviruses even existed. If they existed, then you would it should have been easy or obvious to get find them by now.   So I think that there was an--even Even the really well-respected scientists, and --particularly the well-respected scientists, --were very strongly against the idea that human retroviruses existed, with a few exceptions, and I think Bob is one of the few exceptions, that he . He very strongly believes believed that they do did exist.      

And around that time, I think the model of the bovine leukemia virus [BLV] came about, and one of...  I mean, Bernie, who works . Arsene Burny [Arsene Burny, Ph.D.], who worked on the system, happened to be a very good friend of Bob’s, and he had a hard time , I mean, Bernie _____, isolating BLV from tumor tissues or whatever.   So it It was understood found that the virus replicates at very low level.   So Bob then said, “Look, here’s a model that in which you don’t necessarily have very high titer virus, you know, with retroviruses, retrovirus, so there may be exceptions and maybe humans are more like the cow than the mouse.  So ” I think that’s the sort of thing that kept him going.

Hannaway:                                    What convinced you that human retroviruses existed?

Wong-Staal:                You know, I think it’s                 It was more or less along the same line.   I mean, it’s sort of not hardly conceivable why that humans should be that much different from animals.   I mean, there There was example after example of retroviruses, be they endogenous or exogenous, found in different animal species.

Hannaway:                                    There was no reason humans would be exempt, so to speak.

Wong-Staal:                                                    Right, right.

Hannaway:                                    Would you describegive us, even though you were not directly involved in it, but give us some general description about the research conducted in the Gallo laboratory related to the discovery of HTLV-1.

Wong-Staal:                                Yes.   I think, really, the The discovery or the breakthrough that led to the discovery of HTLV-1 preceded was the real discovery, is the discovery of T-cell growth factor, what is now called IL- 2 [interleukin 2].   And maybe what preceded that before, even, was the incidence presumed finding of so- called HL-23 virus.   I mean, that was supposedly a virus isolated from leukemic patients that.   I mean, it’s still not clear whether that, there was ever a real virus.   Certainly, in the early days, they detected reverse transcriptase activity, and that looks it looked real.   But then, subsequently, suddenly the that virus that was not growing well. It became very replicated, highly replicatedreplicative, and then it turned out that it was artifact contaminationartifact contamination.   I shouldn’t say contamination.   And when When they tried to go back to re-isolate, they ran out of factors that supported _____.  So that really led the program, or one program, or the leukemia cells.

That really led one branch of the lab , to look for factors that support growth of leukemic cells in vitro.   And out of that effort came the discovery of T-cell growth factor, IL-2. Once that’s possible

Once they had the growth factor, then they were able then to grow cells particularly from T-cell leukemias, and so getting these cells, that . The first patient, I think he had cutaneous , had cutaneous T-cell lymphoma or leukemia.   At that time, they thought _____+ or something like that.  Yeah.  So that using the Using IL-2 to long-term culture those cells over the long term, they were then able to isolate the virus.   And, still, it was they did not see a high-level replication, so they-- on top of the long-term culture requirement, they also need needed a sensitive detection method, which was also developed in the lab.

Harden:                                              I just would like to ask one question along these lines, too.   Did you happen to be at that fateful meeting at Hershey, PA, where it was disclosed that the first Gallo retrovirus was a contaminate  in other words...  ? Do you remember this?

Wong-Staal:                                Right.

Harden:                                              The question has never been asked, been answered to my satisfaction is, why did people wait to do this in public?   Why didn’t they come to him privately?

Wong-Staal:                                I don’t think I was at the meeting, but I certainly heard about it.

Harden:                       Certainly.  You                        Do you have any thoughts on this, just out of curiosity?

Wong-Staal:                                Well, who knows.  ? I mean, do you understand human nature? Harden:                       Well, I just think it’s...Wong-Staal:                I think some people enjoy seeing other people crucified in public.   Right?

Harden:                                              Yes, they do.   That’s what I’m getting at.

Wong-Staal:                Yeah, yeah.

Harden:                       It really is.  You So you think it was a vindictive sort of...act?

Wong-Staal:                Yeah                Yes.   Bob polarizes people.   I think he has There are people who are very close to him and supportive of him, and he but there are also has people who are very antagonistic.

Harden:                                              So we’re I’m not missing some scientific nuance.   It probably was a more personal thing attack to let it happen in public, is all I’m saying.?

Wong-Staal:                Yeah                Yes, I think so.Harden:                       I’m not trying to get any things.   But it just was not entirely...Wong-Staal:                Yeah.  I think it was almost like a set-up .  Yeah.  To to humiliate him.

Harden:                       All right.                         Now let’s move into AIDS and get some chronology here.   We had the first Gottlieb publication in June of ‘81The first Gottlieb [Michael Gottlieb, M.D.] publication was in June 1981, and you became the section chief in ‘82.   And, as I recall, Jim Curran [James Curran came up , M.D.] came to NIIH from the CDC to make a presentation to the National Cancer Advisory Board, where he saw Bob Gallo and urged him to get into this.  And this was mid-’8...  Well, this was begin a research program to identify the AIDS virus. This was in August or September of ‘82.   So this is where we’re going.

But let’s back up now.   We’ve got a whole year there.  When do you--can Can you recall when you first heard about this disease?   Even before you were involved in the research, what did you hear about it?

Wong-Staal:                                I think it’s it was probably around the same time.  You know, we have We had M.D.s in the lab.  Ed Gelman, for example, you know, you , Ed Gelman [Edward P. Gelman, M.D.], for example. The physicians go to meetings, clinical meetings, and they come in the case of AIDS, they came back and saysaid, “Oh, this “This is a very interesting new disease that’s going on around right now,” and so on.   And so I think that’s when we first heard about it.

We As we began to know think more about the disease, I think, based on the experience with HTLV and also based on the experience with feline leukemia virus [FeLV], particularly, because FELV have sort of the opposite effect.  You . HTLV and FeLV can cause leukemia, but at the same time they can also cause cytopenia, so two opposites.   And what seems seemed clear after the typing of the disease in AIDS, is was that it’s it was the T cell that’s that was in trouble.   It’s It was getting depleted.   So because the tropism of HTLV is so specific for T cells, the same kind of cell that’s being depleted, so you sort of have the yin and yang phenomenon.   On one side you have abnormal proliferation, and on the other side you have depletion.   So it It raised the possibility ...Well, first of all, because the transmission pattern and all, so I think that AIDS was caused by a retrovirus. I think that particularly Bob was very convinced that it smells the cause of AIDS “smelled” just like a retrovirus.   And then, secondly is that, because of the tropism of for T cells, that made Jim he and others to think that it could be caused by a virus related to or in the same general family as HTLV.

Harden:                                              And it didn’t strike anybody as mystical that the first human retrovirus had just been identified one year and we have this major, what turns out to be a worldwide pandemic of a human retrovirus disease immediately thereafter.?

Wong-Staal:                                Well, it may be.   But, on the other hand, it should also have broken the discovery of the first human retrovirus, HTLV-1, also broke the barrier of credibility.   Right?   I mean, before, people probably weren’t even entertaining would not have even entertained the idea that a retrovirus could be involved.   But the fact that you do have a human retrovirus that targets particular T cells , it makes this, I think, had been identified made a retrovirus as the possible cause of AIDS more plausible.

Harden:                       Oh, I forgot another question here.                        In September ‘811981, NCI sponsored a conference on opportunistic infections opportunistic infections and Kaposi’s sarcoma, and this . This was the first official meeting relating to AIDS at the NIH.   Do you remember this at all?   Were you involved in it?

Wong-Staal:                That’s probably prior to _____.

Harden:                       Okay.  Let’s then move right in _____.

                No, I don’t recall that meeting.

Hannaway:                  When Hannaway:                  Well, now we want to ask, when did you begin to work on AIDS and...?

Wong-Staal:                I think it’s in the period of...  Well, I mean, in terms of working on AIDS, I                 I would say in the late ‘831983, early ‘84 period, when we, as I said, when we were just 1984, when my section was looking at samples, looking, trying to detect sequences homologous to HTLV.   In fact, we got a couple of samples from France, for example.  And--oh, that’s in ‘84.  Was that in...  I think it’s in ‘84.But that was only a part of our program. The other part was to continue on with our work on HTLV-1 and oncogenes. With respect to the AIDS work, we got a couple of samples from France.

Hannaway:                  Hannaway:                  Is this Monsieur Shaddon?

Wong-Staal:                Shaman                Chermann?

Hannaway:                                    Shaddon, the man from Haiti, the...

Wong-Staal:                                Oh, the Shaddon virus.

Hannaway:                                    Yes.

Wong-Staal:                Now, that’s...  Those samples.  But I don’t know that that’s from France.  But I                 I was thinking of the Montagnier [Luc Montagnier, Ph.D.] group.   But this is But that sample came from a different source.   The Shaddon is sample came from Leibowitch [Jacques Leibowitch.  I think it’s from , M.D.], who was a member of a different French group.

Hannaway:                                    Yes.

Wong-Staal:                Right.  But at the time, we also got some                 My group looked at the samples from Montagnier’s group that my group looked at and try to see if there’s there was any homology between HTLV, HTLV-1 and that virus.   But as it turned it turned out, we couldn’t any, you know, it was water.  I mean, there find any. There was nothing in there that we can could detect. But   But the Shaddon , you know, he’s sample came from an AIDS patient.   I think what we We ended up is cloning HTLV from him.   He turned out to be doubly infected, with HIV and with HTLV.

Hannaway:                                    Infected, yes.   He was the famous case.

Wong-Staal:                Yeah, right.  So that was the sort of                 Yes, but that was a confusing part of the process.

Hannaway:                                    So this was a very intensive but also confusing period in the research.

Wong-Staal:                Right, right, exactly.                  Exactly. I mean, we didn’t realize at the time that, in fact, many of the AIDS patients were infected with HTLV as well as, of course, HIV.

Hannaway:                                    Would you discuss concerns within your section, or in the Gallo lab generally, about biosafety issues relating to AIDS, working with AIDS viruses and so on.?

Wong-Staal:                Right, right.  It’s funny, you know.  There                 Looking back, there wasn’t a lot of concern about biosafety.   I mean, people would say, you know, “Well, we’re careful,” as if , I mean, the same precaution one used for hepatitis .  I mean, they work was adequate. They would work in the hood and so on.   But certainly there was no BL-3 .  There wasn’t, you know--things like that didn’t even exist.  Right?  So people were...  I mean, in [biosafety level 3]. Things like that didn’t even exist. In general, you used tissue, aseptic technique tissue culture proceduresculture procedures, you work in a hood, you glove and gown.   But other than that, I don’t think there were really additional precautions.

Harden:                       And you                        You didn’t have folks in your lab who were really afraid to work on this disease, then.?

Wong-Staal:                                No.   Now, my lab was really sort of the a molecular lab.   I mean, if we say If we know that you get AIDS from blood or tissues, we immediately dump STSin SDS, pheno phenol extract, so you really get rid of any possibility of infection, infectious material, right away.   So we’re We’re not really working so much with high-risk material.   So you’re We’re working with naked DNA .  They’re or RNA [deoxyribonucleic acid]. That is not very infectious, so that’s not...

Hannaway:                                    We’d like you to describe as best you can the evolution of research on AIDS in the Gallo lab.   And I’d like to read a quote from you that was cited by Bob Gallo in his book, Virus Hunting.   I don’t know if you recall making this or when you made it, but you said, “Working with this virus is like putting your hand in a treasure chest.   Every time you put your hand in, you pull out a gem.”

Wong-Staal:                Yeah                Yes, I think that’s true because it’s it was a new virus.   But not only is was it a new virus, it’s it was a very interesting and complicated virus.   So that means that there’s That meant that there were a lot of discovery discoveries to be made, you know.   The new trans-activated genes, they really...  I mean, every gene is , transactivator genes were one example. Every gene provided a new paradigm for a virus-host interaction.   So I think that That time was a very productive period.   I mean, it’s sort of It was dizzying, you know, because there’s there was so much to do.   You can’t really--you don’t even know what to do first.   So, you know, I would say that’s really that those years were the highlight of my career, is really that period of discovery, intense discovery.

Hannaway:                  So a period of two to three years there that...

Wong-Staal:                Right, mm-hmm.

I should mention that the most actively involved people in my group at that time were Beatrice [Beatrice Hahn, M.D.], George [George Shaw, M.D.], Sasha [Surresh Arya, Ph.D.], Mandy [Amanda Fisher, Ph.D.], Lee [Lee Ratner, M.D.] and Mark [Mark Feinberg, Ph.D.]. It was a fantastic team.

Harden:                       Harden:                       Could you outline quickly the...  Well, we’re going to go through it, but keep in mind that I want to make sure that we cover all of the major contributions that you see that your lab made to the research as we go. One of the first things that you all did in 1984 was to clone and characterize the AIDS virus and published in 1984, _____ the sequence.   Now, Mel Martin Mal Martin [Malcolm A. Martin, M.D.] was doing similar work, and in 1986 he published a similar paper at [?].   Can you tell me how the work of the two labs were different, or were they just repeating each other?

Wong-Staal:                I think Mel Martin                 Mal Martin’s work came much later .  Didn’t he?  Because that ours. I know that in terms of the cloning, we were the first, the French group was the second, and the San Francisco group was the third.   So if Mel did anything, it was further down in terms of cloningSo Mal published later. And then , sequencing, again, it’s with publishing the viral sequence, it was the same three groups that first published the sequence:   our group, the French, and Jay Levy’s [Jay A. Levy, M.D.] group.

Harden:                                              Was that done before the question of priority in discovering the virus arose?   Because I ask because Dr. Martin apparently was the person who said the two viruses were identical.

Wong-Staal:                Oh, that’s before.  I mean, that’s from the sequence that they say that.

Harden:                       I see, right.  But this--what I’m trying to get at is that you all were doing this early on as well.  You were doing the...

Wong-Staal:                Not as well.  We were doing the sequencing first.

Harden:                       YesFrench and American viruses were identical.

Wong-Staal:                Oh, we did that before the priority question arose. It was from the viral sequence that the two viruses were shown to be identical. We published the entire sequence, and the French group published the entire sequence, and the French...  I mean the San Francisco group published the entire sequence.   And then, in fact, we submitted a paper to--not a paper, a letter, to Nature for publication of these three papers.   We submitted a letter to Nature and said these three isolates obviously belong to the same family, but our isolate and the sequence of the isolate the French isolate seem much more related than the San Francisco isolate.

Harden:                       San Francisco.

Wong-Staal:                And we We were thinking that about the spectrum of relatedness, which is not wrong.   I mean, if you look at HIV, you really have a whole spectrum, some of them more closely together related than others.   Depends It depends on what end of the spectrum you look at.   So the question that Mel maybe Mal took issue with is that, was whether the similarity of the French isolate and the isolate that we sequenced really can could be justified on the basis of strain-to-strain variation or where there’s there was too much to be expected from that.Now, there

There was really no point of reference, because if you lo ok look at HTLV-1, isolates from, diverse isolates are very similar.   I mean, they’re as related as two HIV isolates from the same person.   Okay?   So it’s not that we have

some standard to go by what should be the degree of variation.   So that was totally, you know, So there were no guidelines, in other words.   But as we, you know, But as more isolates are were sequenced, then, of course, then you see we saw more of a pattern of what, how much variation there usually exists among different isolates.

Harden:                                              It became an issue later.   That’s why I asked.

Wong-Staal:                                Yes, obviously.   But, on the other hand, however, I should point out, however, that at the same time, I mean, you know, it’s almost sort of that it was an unfortunate coincidence that the first isolate that we really did the most extensive studies on turned out to be a potential contaminant, because there were other isolates at the same time from the lab that were sequenced later that was very were divergent, you know.   One of them is was the isolate called RF, and it’s used extensively now because it was is viewed now as a prototype that’s very different from the 3B isolate and LEI isolate , you know, that were available in the early days.   So that virus RF was around at the same time that the 3B virus was.   But it’s just because it wasn’t being produced at as high a level as 3B that 3B was chosen for the sequencing and analysis.   So it’s it was sort of a stroke of fate that ...

Hannaway:                  It’s the luck of the draw...

Wong-Staal:                Right.

Hannaway:                  That that was chosen instead of this _____.

we used the 3B virus for sequencing and analysis.

Harden:                       Harden:                       In 1987, you described the R gene of HIV, and I want to show you a couple charts I’ve been trying to put together here.   This was from a 1986 publication confronting AIDS that was put out, , “Confronting AIDS,” and, as you can see, that gene is not known at this point.   And then this one was in ‘88.   It was the update for

this book.   And the R gene is described as “function unknown” at this point.   And if I’m understanding it correctly, this is the current list of the way the genes are described, since many different groups were coming up with genes and naming them different things.   Your gene--this is the one that you all identified, as I understand it‑it--is now called vpr.

Wong-Staal:                Right.

Harden:                       Correct?

Wong-Staal:                Correct.

Harden:                       Now...

Wong-Staal:                                Right. Vp just means viral protein, so this was the gene that coded for viral protein r, which became vpr.

Harden:                       That’s what I thought.  All right.  Would you explain?  It’s described here                        Would you elaborate a bit on this? In this publication it is described as an accessory gene.   What does it do, and what did you...  ? Tell us about discovering the gene and learning about it.

Wong-Staal:                                Right.   You know, at At the time, we discovered it as an open reading frame.  That means that we, you know, from the sequence, it’s hard to tell because it’s , i.e. a stretch of nucleotide sequence uninterrupted by stop codons . In other words, it has the potential of coding for a protein. From the sequence, it was hard to tell more because it was a very short sequence, smaller than most genes that we’re used to.   But what that paper described is that we can could actually show that that sequence is expressed into a protein and that patients who are infected actually make antibody against that protein.

At that those sequences express into proteins, and I’m not sure if it’s in the same paper, but if not, then subsequently, is that patients who are infected actually make some antibody against that protein.  So that’s saying that that protein not only...  So at the time, we show that open reading frame was expressed as a protein, and, furthermore, that patients infected with HIV actually make some antibody against that protein, so suggesting it’s also expressed in the patient.  At the time, we called it an accessory gene, function unknown, because it doesn’t didn’t seem to be critical for virus replication, at least not in T- cell lines that , you know, that’s what people usually use used in the laboratory, because if you remove you removed that gene by deletion, mutation, the virus seems seemed to do just fine.   So it It was very puzzling.

Now it turns It turned out to be a very interesting gene.   It has had unique properties.   It helps the...  Actually, one One of the unique properties of HIV is that it can infect a cell that is resting, not actively dividing.   And a A typical example of that is the macrophagethe macrophage.   Macrophages are totally differentiated.   They’re no longer actively dividing.   And most retroviruses, at least all the laboratory retroviruses that were known at the time, cannot could not infect such cells.   They need cell division to do it.   And what it turns out is that those viruses are stuck from getting into the nucleus.  Those viruses were stuck because they could not get into the cell’s nucleus. Their viral RNA/DNA complex cannot could not penetrate the nucleus unless there’s there was cell division, and that’s because that is when the nuclear membrane dissolves. Now it’s

It has now been shown that vpr plays a very critical role in the process in allowing the virus to get into the nucleus in non-dividing cells, so _____ across an intact nuclear membrane.   So it’s It is critical.   Or if If you delete that gene, even though the virus can do well on infecting T cells, but its ability to infect macrophages is very much impaired.

            And then there’s another effect of resting cells at a certain stage of the vpr on inducing cell cycle arrest in G2.   So from a biology point of view, it’s also the vpr gene is very interesting.   But it’s a very It is a highly conserved gene, so which made it is clear that it does play played an important role in the virus virus’s biology and pathogenesis and so on.

Harden:                                              Now, you were looking at a lot of, all the different genes at this time, too, and one of them was the envelope gene, coding for the envelope protein.   And I believe you were involved in the earliest assessment of antigenic drift in that envelope protein and its implications for vaccine development.   Could you talk about that a little bit?

Wong-Staal:                                Yes.   I think, you know, from, again, From the early isolations and sequencing from by different groups, it was clear that HIV is not a single genetic entity, that there’s there is variation among different isolates.   But what was found--and I think we’re one of the earliest, if not the earliest, group to show--is that there’s also, even from the same patient, if you look at different clones from the same patient, you can see variation as well.   So there’s intra-patient variation.   And a lot of the variation is in the envelope gene, so that suggests...  I mean, that . That kind of phenomenon has been described for other RNA [ribonucleic acid] viruses, and this is referred to as a quasi species.   Where you don’t have a single species of viral genome, it’s a quasi species.   And, furthermore, this quasi species can drift.   The composition can change with time, with external pressure.   And our Our observation at the genetic molecular genetic molecular level corroborates corroborated studies from other scientists in terms of virus re- neutralization also, you know, that very often is type specific that, you know, --an antibody from one patient that may neutralize its own virus may not neutralize other virus isolates.   But, furthermore, within the same patient, neutralizing an antibody against an earlier isolate may not neutralize a later isolate. This, so again suggesting the , suggests antigenic drift.   So what we’re--our description is really Our description was at the molecular level, and then other people have . Other people had immunological data.

Harden:                                              But it was quite apparent to you early on that it’s it was not going to be easy to make a vaccine because of this.?

Wong-Staal:                Yeah                Yes, correct.Harden:                       Okay.

Hannaway:                                    We’re interested as well in the large issue of the effect AIDS research had on the NIH and the various institutes.   So we wondered if you could comment on what overall changes did you see in the Gallo lab and in your section in response to the emphasis on AIDS research from 1982 until 1989.   The sort of things we’re interested in are changes in the program of research, in funding, and in personnel.

Wong-Staal:                Right.                  I think the biggest change with AIDS is was that suddenly, the research that we do becomes or catch did caught the attention of the public, because prior to that, I think no one cared about oncogenes, I mean, even oncogenes, but particularly if it’s it was a yeast gene or , you know, any regulatory mechanisms and so on.  So I--and I think that’s a regulatory mechanism, etc. I think that was both good and bad, of course.   I think the good part of it is that you feel was that even though what we’re we were doing is actually very basic, you know, we’re still was very basic—we were looking at fundamental gene regulation and structure, gene structure function studies, but suddenly it has structure—suddenly it had a relevance for something important, an important disease.   But the negative part is that, you know, you’re was that we were under the microscope all the time, and people have maybe undue expectation.  So the pressure is always on, you know:  when’s the cure, when’s the vaccine, what’s next?  had undue expectations. The pressure was always on. When will there be a cure? When will there be a vaccine? What’s next? And that part of it sometimes can could be too much.

In terms of the funding, I think at the time , I think at NIH, it wasn’t too much of a problem.   We were getting good support and I think in part it was justified because of all the progress that was being made.   Even outside the NIH intramural program, AIDS research was less supported.   But maybe that actually, that led to the perception that if you label labelled your research as AIDS“AIDS research,” you can could get grant money.   So I think that’s there was also a lot of abuse of the system, that people who were not really working on AIDS but they label labelled their research as related to AIDS and get so got money.   And, as As a result, I think, in fact, trying to get AIDS money becomes became very competitive because you have had so many people coming in.   So I think at this At that point, I don’t think it’s it was a particular advantage to be, I mean in terms from the grants level, to be competing for funding, to say that you’re working on AIDS.

Hannaway:                  So that’s been a transition.

Wong-Staal:                Yeah.

in obtaining grants to say that you were working on AIDS.

Hannaway:                  We are also Hannaway:                  Well, then, our next question relates to what you’ve just been talking about.  We’re interested in the effect of all of the publicity and debate over who discovered AIDS on the working of the Gallo lab, and particularly also, did . Particularly, we want to know if the Freedom of Information requests alter the way in which research was conducted?

Wong-Staal:                                I think also what changed with AIDS was the issue of patenting.   Prior to that, again, you know, we hardly thought of patenting one’s work because, you know, the our interest was in the scientific discovery and the gaining new knowledge, but not the commercial the commercial implications.   So, with HIV, you know, the process of diagnostics and, of course, the cloning and subsequent other things, we With HIV, the diagnostic test was based on our basic science work. We were actually told by NIH people officers from the Institute Director that we should _____ patents, and I think--and that’s right because it’s file for a patent because AIDS was an important public health problem, and in order to attract the pharmaceutical companies to make a diagnostic test, you we really need needed patent protection of your discovery.  But I think because of that, because for our discovery. Because of the commercial issue, then you also bring in other aspects of profits and rights and shares of equity, royalty, whatever, had to be dealt with, and that, I think, escalates escalated the problem tremendously.

Harden:                       That would, and I was going to come back to this, but I’m just going to add this question in.  As we go about the Technology Transfer Act of 1986, now, the first patents, of course, for the Elisa test and others came before that, before the ‘86 act.

Wong-Staal:                ‘86 act.

Harden:                                              The first patents for the ELISA test for AIDS came before passage of the 1986 Technology Transfer Act that required federal scientists to submit discoveries with potential commercial application for patenting by the government. So, you all were getting instruction then from the administration that you should pursue a patent on the test and what have you.  Was this...  And, as you were suggesting, I suppose . Did this put some pressure in terms on you, not only of the thought about profit or about other things, but but also about sharing samples, sharing information, whose name went on which paper, etc...?

Wong-Staal:                                Exactly.

Harden:                       All these sorts of things.                         Was there a lot of conversation about this within the lab, among the investigators themselves?   Did you all talk about it and sit down formally and discuss it, or talk about it informally, or was it a real hassle?

Wong-Staal:                Not                 There was not so much discussion at our level .  I think, you know, at the time, I think most of the, I mean, the most critical patents is really the blood test, and that--as researchers. The most critical patent was the blood test. With respect to that, I was not involved.   That was really pre-molecular biology, if you will.  It’s the virus-producing cells and so on.  And subsequent Subsequent to that, I think we just patent patented everything and we include included everybody in our patents, --I mean, all the people who worked in on the labproject. I also have to say that the, we didn’t have the best patent lawyers at NIH, so a lot of those things, so I don’t know whether they later discoveries ever resulted in anything.  But...patents.

Harden:                       But to                        Let’s go back , then, to Caroline’s question.Wong-Staal:                Yes, you had a second part of the question .

Harden:                       Just about the publicity.

Wong-Staal:                Oh, the publicity.

Hannaway:                  And the debate about the controversy over who discovered the AIDS virus.

Wong-Staal:                Right.

Harden:                       And the inquiries and the whole thing.

Wong-Staal:                Right, right, right. You know, as                 As I said, there’s there was no question that Montagnier’s group first had the right virus, although what they published was not very convincing and is was only from a single patient.   Okay?  And our Our laboratory had multiple isolates from different patients.   They have, I think, much more--they have Multiple isolates made a much stronger case for etiology.   And , again, repeating what I said earlier, I think it was unfortunate that we had focused on this one isolate that seemed to grow the best, and, as it turns . As it turned out, the reason it’s growing it grew so well is because it’s...  I mean, that’s why it contaminates, because it’s growing so well.  So...  And to really be it was a contaminant that took over. It was the first prototype that we analyzed and patented, you know, that .  It produced the cells used for the blood test patent, and so on.  So I think, you know, . But a lot of people are not aware that it contamination didn’t happen only one in our lab.   It, in In fact, it happened in Montagnier’s own lab, the contamination, because when they subsequently, because of all this issue, they went back and sequenced the early samples, that their earliest LAI isolate was not the same as what is subsequently was subsequently defined as LAI.   So they have They had contaminated their own cells cell line with a more replicative virus.       That happened also in Robin Weiss’s lab.   I mean, Robin Weiss [Robert Anthony Weiss, M.D.] in England has published the first British isolate , of HIV isolate.   In fact, we got samples from him.   Turned out to be the same virus. So I think it’s just, you know, it happens this viral isolate happened to be a very highly replicating virus and that it’s it easily contaminating contaminated other cultures. So really, the The thing to stress is that there were was more than one isolate in Gallo’s lab, that we could have chosen any one of those to expand our studies on.  So it was, you know, again...

Harden:                                              Have you given any philosophical thought to why Gallo took such a beating over this in the United States and was seen as a villain, as opposed to Montagnier in France being seen as a hero and...  I mean, it’s more than the fact, is what I’m getting at.  And is ? Was it Gallo’s personality, or is it, I mean, the fact that you said he polarizes people, or is there ...some other reason?

Wong-Staal:                                I think a lot of it is his personality.

Harden:                                              Or is could it be the fact that he works for the U.S. government?

Wong-Staal:                                I’m not sure that’s it’s that.   You know, I think also, that Americans have a very different mentality from Europeans.   I mean, you know , I know of no scientist, whether European or American, that who really respects Montagnier for being as a scientist.   I mean, he’s He’s not a good scientist.   I mean, I can say that on tape.   But, and And yet , the Europeans rally against, you know, the Europeans rally around him.   They protect him, they want to push him as the discoverer.   But Americans want to want to destroy their own heroes, so...  And I think that’s the major difference.  That could be, you know, competitiveness, it could be jealousy, and it also could be a lot of people who don’t like the style that Bob goes around doing science.  I mean, he’s very aggressive, he does, you know...  I mean, sometimes he does, in which Bob does science. He’s very aggressive. Sometimes, if other groups make a discovery and , he would might say, “Well, why can’t we,” you know, “Why couldn’t we have done that first or thought of that first?”  And so _____ ” I have even thought, you know, “Bob, let other people do something first.   We don’t have to make all the discoveries and do everything first.”  So, I mean...  ” But he does have this attitude that , the lab’s goal is to win, you know, to achieve, and I think that turns off a lot of people.   So I’m sure a lot of it is personality.

Hannaway:                                    But he’s not the only competitive scientist out there.

Wong-Staal:                No, no.  I think there are.  But I, you know...

Harden:                       Well, I think that...out there.

Wong-Staal:                                He’s not the only scientist that’s being persecuted either, so...Hannaway:                  Right.   Well, some people have...Wong-Staal:                The bigger you are, the harder you fall.

Hannaway:                                    Some have said that what’s not understood, which I think you were talking about just a moment ago, is the way that people, especially virologists , interacted, you know, the way different labs, interacted.   They would routinely send each other samples and tell each other of their findings in informal ways.

Wong-Staal:                Prior to all the _____.

Hannaway:                  Prior to all the...   And this aspect of the sort of what historians or _____ call the culture of virology is not understood in general.

Wong-Staal:                                Right, right,  rightright.

Harden:                                              And I think that there is also the an assumption that I think is out there that scientists working on medical research should have , know the goal, to be Marcus Welby and the demeanors of TV characters like Marcus Welby, to want to hold people’s hands and comfort them. In this view, and the intellectual give and take and the personal goals for achievement are not considered in thisimportant.   When someone is --what’s the word I’m looking for-- strong enough to let that show that he wants to achieve. . . .

Wong-Staal:                                Well, they’re human.

Harden:                                              They’re human, yes.  Then it can sometimes , and the condemnation of some parts of society may come down on them because of it. Let’s   Let’s broaden it the discussion a little bit here and see ask if you will talk a little bit about what kind of interaction you saw on the NIH campus among the various institutes working on AIDS, especially NCI and NIAID .  [National Institute of Allergy and Infectious Diseases]. Were there NIAID people collaborating with you, for example?

Wong-Staal:                Let me think.

Harden:                       Again, I’m still in the ‘80s.

Wong-Staal:                Right.  Well, we                 We were collaborating with Warner Greene [Warner Greene, M.D., Ph.D.], but I think he’s he was in the NCI, I don’t think he’s not NIAID.   But also, mostly Mostly on HTLV rather than HIV, although I think we did exchange...  I mean, we . We certainly gave reagents to NIAID people, clones.  That’s how the whole...

Harden:                                              Were you going to the same seminars?

Wong-Staal:                                Oh, definitely, yeah, yeah.  I mean, yes. Especially in the beginning, yeah.

Harden:                       Yeah.

Wong-Staal:                I’m sure they, we have...  yes. Gallo has this annual _____ lab meeting that was open to other people at NIH.   I think a lot of Tony Fauci’s people come[Anthony S. Fauci, M.D.] people came, for example.

Harden:                                              What about interactions in the Clinical Center?   I know we We interviewed Sam Broder .  He was talking [Samuel Broder, M.D., Ph.D.]. He talked about being able to see a patient today and , get the latest results from your lab, and then try to put things togetheruse that knowledge in the clinic.

Wong-Staal:                                Oh, yeahyes.   I forgot about Sam.  Yeah.   I think Sam Broder was very close to the lab, and he . He was very involved in , you know, trying to treat HIV infection.   So there was We had a close interaction there.

Hannaway:                                    You didn’t see any competition between institutes or for getting recognition for their AIDS research or...?

Wong-Staal:                                There may be have been some, but I think in the early days, our lab just so dominated the field that really, you know, I think there wasn’t any attempt by any other lab to take that away from us.   So there’s It was more a collaboration situation, I would say, you know.  Like, for . For example, Broder’s expertise or and interest is was complementary to ours rather than competitive.   And the same thing with Tony Fauci’s.   I mean, he’s he was more immunological aspectinvolved in the immunological aspects of AIDS, and certainly we’re we were not immunologists, so it’s it was more a productive interaction.

Harden:                       So it was a breaking down of the problem.  In other words, you had expertise in this area, and he was an immunologist.  We were looking at the elephant in many different ways.                       So in your view, the different labs looked at the AIDS problem from their own area of expertise?

Wong-Staal:                Yeah                Yes, exactly.

Harden:                       But                        And you think that this was probably the most productive way to go.?

Wong-Staal:                Right, yes, because you...  I mean, studying HIV is                Yes, because to study HIV, you really need needed a multidisciplinary approach, so it’s and it was good to have all the expertise together.

Hannaway:                                    The NIH, as you well know, has been criticized by activists and in the media for the slowness of its response to AIDS.

Wong-Staal:                Mm-hmm.

Hannaway:                  How would you personally characterize the NIH’s response to the AIDS epidemic, with special reference to the intramural program?

Wong-Staal:                                I don’t think we’re we were particularly slow in response.  I meanresponding, certainly not at the laboratory level.   I mean, we We did the best we cancould, and I believe we were getting the support from the institutions.  It may be at institutes. Perhaps they were criticizing the second level of the problem, the translation of the discovery to into implementation of whatever, you know, diagnostics or other types of..diagnostics, etc.

Hannaway:                                    You think that was not as effective or...

Wong-Staal:                                No.   I’m not saying that I don’t think that’s that was as effective.   But what What I’m saying is that their the activists’ comments could have been directed at that aspect of the process.

Harden:                                                  Well, they were dying, and it was a new disease, and nobody knew what to do.

Wong-Staal:                                Right, yeah.  Because, I mean, what yes. What we do in the laboratory is not immediately, you know, immediately available to them anyway, so...  And also, and if they’re infected, they’re not interested in the diagnosis.   They’re They are really interested in the treatment.   And of course, you know, we still don’t have very good treatment, so it’s a big problem.

Actually, now that I think of it, I didn’t respond to one part of your earlier question, which is the, you know, about all the Freedom of Information and all thatAct (FOIA) requests. I actually am was very lucky because I left right at that time, when the timing was starting, because I left in the at the beginning of 1990.   I think that process the FOIA requests started, you know, in 1989, ‘90, around the same time.  ’90. So I wasn’t really subjected to a lot of that.   But I do did have, you know, of course, interaction and contacts and discussions with people who stayed behind, and I know it was very demoralizing, and it sort of almost paralyzed the lab.   I mean, it’s it was really to the lab’s great credit that it continues continued to make discovery discoveries and progress because, you know, as you can might imagine, it’s it was not only the mechanics of the process, you know, they’re to provide documents upon documents, and it’s all-consuming.  But it’s also from the the spirit process—to provide document upon document, which was all-consuming—but it also depressed the esprit de corps, the spirit of the lab.   I mean, no No one wants to be criticized and, you know, to be looked at under the microscope and so on.   So I think it’s it was a really a very dark period, at least in the history of that lab.

Hannaway:                                    Yes.

Wong-Staal:                                Maybe not all of NIH.

Hannaway:                                    When you were at the NIH, were you involved in any of the inter-institute committees or task forces relating to AIDS?

Wong-Staal:                Well,                 I was on the task force that Gallo formed, but it’s it was not really inter- institutional but it’s rather international, because he was including a lot of people, actually, a lot of scientists from Europe, including Chermann and Montagnair.

Hannaway:                  Yes.

Wong-Staal:                But also Leibowitch and also _____.  I mean, [Jean-Claude Chermann, Ph.D.] and Montagnier. He also included Leibowitch. There were people from all over the country participating, and from other countries too.

Hannaway:                                    So this was really a Cancer Institute-organized task force?

Wong-Staal:                                Well, it’s it was actually an NTCLTCB-organized task force .  It’s a self, you know.

Hannaway:                  Yes.

Wong-Staal:                [Laboratory of Tumor Cell Biology]. I don’t think it has had the mandate of the Cancer Institute.

Hannaway:                  No.

Wong-Staal:                But Sam Broder certainly was a part of that, and he’s he was the director of itNCI.

Hannaway:                  Yes.

Harden:                                              We’ve asked everyone, and gotten a lot of different answers.  Were the following question of everyone we interviewed and have received a variety of answers. Did you or your family , did you ever encounter any negative reactions when people found out you were working on AIDS?  Did   Did they stop shaking your hand or get up and leave your dinner table or anything like this?

Wong-Staal:                                No, actually, on it was the contrary.   I mean, when they find found out I work worked on AIDS, usually they’re they were very interested.   It’s It was a good dinner conversation.   They’re curious, you know, They were curious about what’s going on and so on.   I think, actually, I think people are pretty‑-I mean, surprisingly, that know that the virus is not that easily transmitted.  I think that part of it, how you catch the virus...

Harden:                                              Even early on.?

Wong-Staal:                                Oh, I see, you are asking about the very early days.   I think maybe there were a couple of instances when people , you know, they don’t...  were wary. But it wasn’t a general phenomenon.

Harden:                                              Your brothers and sisters didn’t say, “Are you crazy”?

Wong-Staal:                                Oh, no.   I mean, my mother was saying, you know, “Are you sure it’s safe?” and I explained to her that , you know, you do protect yourself I protected myself with gloves and so on.   So it wasn’t a big issue.

Harden:                                              Now, you have moved, through your career, from hands-on work in the laboratory to being a section chief and then, of course, now you’re a chaired a chaired professor.   How do you feel about the different roles of people in the laboratory, and do you miss having your more hands-on activity in the laboratory more when you’re directing as an administrator, if I’m making my question clear?

Wong-Staal:                Mm-hmm, yes.                   I think part of it.  I think it is fun to work in the lab.   But it’s also very frustrating because , you know, things only work part of the time, you know.   I mean, I think the euphoria is probably outweighed by the frustration.   So, in In that sense, I think being a group leader and having a group working with you is a little better because, first of all, you can step back and look at the whole picture instead of being obsessed with the minute details.   And you determine the general direction of where things can go.   And, you know, I mean, I’m not experiencing the daily frustrations, for one thing, but people actually come to me when they have something interesting, and then we discuss , oh, you know, what should we do next, and it’s...  So, and even that be done next. That part of it is a more positive experience, although, you know, it is not _____.  I mean.

On the other hand, I don’t feel like I make the discovery with my own hands.  So that part of it is...  So it’s hands. So it is a tradeoff, I would say.   It’s a tradeoff.  But I feel now, at this stage of my career, that I’m better at doing the overall direction than working at the bench.Harden:                       At the bench. Wong-Staal:                I can probably even accomplish, I mean, I know I can accomplish more this way than being hands-on.

Harden:                                              The Gallo lab was very large, and some people were criticizing, when they were looking at some of the problems that arose in the with respect to various international questions, that maybe it was too big a lab and some people criticized the lab for being too large, saying that it was not easy to keep tabs on 60 people.   And then there was the situation when the Cancer Institute cut back on administrative on administrative support people .  And do for the lab. Do you recall any of this as being major problems in the research on AIDS while you were there?

Wong-Staal:                                I think there are pros and cons of a large program.   I think, on one hand, NIH is the only place really where you can have a research program at as a group; . I mean a larger, a that there can exist a reasonably large group , but with a central mission to do something, and then you have this, again, you know, different multidisciplinary approach that at the same time have a multidisciplinary approach within that large group so that the different sub-groups complement each other to achieve a defined goal.   You can’t do that in a university, because in the university, each lab is , you know, on its own, . It has its own set of goals, and , you know, you have individual investigators that really sometimes collaborate, but they’re not forming part of a whole program.   So that part of it, you know, I think it’s a tremendous opportunity to it is tremendous that the NIH can have intramural programs like that.

But, of course, I mean, there are instances when you can’t , you just can directly manage a group directly of that size.   So then it really depends on the leadership and capability of the lab chief, whether he’s able to delegate to competent people to oversee a subset of those groups, and how they can still centralize all the resources and coordinate and so on.

You So you can say that maybe it’s anti-intellectual individual because you’re really everyone is working as a group rather than , you know, individual, sort of our own type as individuals on investigator-initiated type research.  But, you know,   But perhaps that’s what NIH should be about, that you can have group efforts.   So people People always talk about Manhattan Projects.   I think that is like a Manhattan a Manhattan Project when you have different groups working towards a common purpose as we did on AIDS.

Harden:                                              Before we move into more recent work, I want to stop and think back over what you have told us about your contributions to AIDS while you were here in the intramural program, and tell us now what we’ve left out, perhaps, if anything, that you think ought to be noted.

Wong-Staal:                No.  I mean, we                 We were the first to obtain a molecular clone, well, the first clone and then multiple clones to actually show that molecular clone clones have biological activity; that activity—that is, it has the same--it the clone depletes T cells in culture also.  So I think that really proves . That really proved that the virus is was the agent, because , you know, sometimes you can isolate a virus from a patient, but it could be opportunistic, and that doesn’t mean that there’s a causal relation.   But if what you see that the virus can do in tissue culture and , using molecular clone, that clone—that is, there’s no other , you know, genetic information associated with it that it—what a candidate virus from a patient can do the job, then I think it provides a stronger proof that the this particular virus is the causative agent.   So I think the so-called _____ hypothesis Koch’s postulate should be put to rest.

We also , I think, were the first to describe the genetic diversity of HIV from different patients, both inter-patient and intra-patient.   Our group, my group, My group also first described the detection of HIV in the brain.

What else?   And then There were all these genes.   I mean, we We actually were the first one group to identify the tat geneand rev genes, which is a critical regulatory gene for HIV--it’s transcription activated--and then are the critical trans- activator genes for HIV expression. We also defined some of the mechanism and function of other regulatory genes.

Harden:                       Okay.  Why don’t we move on, then.

Hannaway:                                    In 1990, you were appointed to the Florence Rifford Riford chair in AIDS research at the University of California-San Diego.

Wong-Staal:                Mm-hmm.

Hannaway:                  Left the Cancer Institute.

Wong-Staal:                Mm-hmm.

Hannaway:                  , San Diego [UCSD], and you left the National Cancer Institute. Would you tell us how this came about?   And also, what differences do you find between doing research in Bethesda at the NIH and working in an academic university setting?

Wong-Staal:                I think                 I was at a stage of my career that where I feel felt that, much as I admire Bob as a leader and as a scientist, his visibility is was really overshadowing me.   Although I think we really have had complementary expertise, and people recognize recognized that I’m I was doing molecular biology and he’s he was not.   But still, I think the association is sometimes , you know, works worked against me.   So I thought it’s , “It’s time for me to move.  And I think, also” Also, part of it was also because of the , in fact, the Quidson (?) article Crewdson article [John Crewdson, “The Great AIDS Quest,” Chicago Tribune, November 19, 1989] that came out and marked the beginning of all the process for Freedom of Information Act requests.   So I thought, you know, I “I need to get out of here.  So--and ”  I chose San Diego because I did a year year’s postdoc there after UCLA, and I loved the place, and I think it’s a very good scientific environment because it’s not only the university there, there’s . There is also Scripps [Scripps Research Institute] and Salk [Salk Institute for Biological Studies] and, you know, the La Jolla Institute for Allergy and Immunology.   So it’s It’s a very rich scientific environment. So, in

In terms of the differences in operation, well, first : First of all, you know, really for the first time, I’m I was completely my own boss, so that’s and that was very exciting.

Hannaway:                  Mm-hmm.

Wong-Staal:                The ability to have students and young people is also very exciting.   Everything When I was at NIH, you know, at least when I was here, it was very difficult to have students.   I’ve I had a couple of students, you knowsuch as Steven Josephs, my technician who went to ...Hannaway:                  American University. Wong-Staal:                Yeah, American University, and so on.  But, you know, it’s very rare instances.  And at But, it was very rare at NIH.  At the time, most of the postdocs at NIH were hired only through the Fogarty Center, so you really only get the got foreign postdocs, and then the rest , you know, are of the NIH staff were much older people.   So I think the difference between university and the NIH is really the youth and the energy that you get from students and from younger people at a university.

Of course, it’s also a very different environment in that, you know, now I have to worry about also my financial situation, you know, grants writing grant proposals and so on.  So that

That part of it is somewhat of a struggle, I mean, especially . Especially in the beginning, because I have had to learn the process , you know, and transition from being , from in a protective protected NIH environment to that.  But securing my own funding. And it’s not getting very much easier, I have to say.   And then, you know, having to teach, which I was worried about in the beginning...

Hannaway:                  You were discussing granting and teaching.

Wong-Staal:                Yeah, oh grants and teaching. Teaching, in the beginning, I was not looking forward to having to teach, but now I’m beginning to enjoy it.   I think it’s good to have the interaction with students and so on.

Hannaway:                                    Would you tell us about the Center for AIDS Research that was set up in 1994 and of which you’re the director.?

Wong-Staal:                Right, yes.  Well, I mean, actually, the                 The Center program is from NIH, as you well know.   It’s sponsored by NIAID, at least at the this time.   Now I think they’re bringing in other institutes as well.   So they They wanted to establish different centers of excellence , I guess, in AIDS research in different parts of the country, the ideas that, you know, if there’s already active research there, maybe they can . The idea was that if active research already existed in an institution, NIAID could provide the glue that pulls pulled things together by providing for resources and administrative structure and so on.   So we We put in an application for competing, and we received , I think, one of 11 Center awards.

Separate from that, the university was also , wanted to start an AIDS research program, sort of something the equivalent of a department, but it’s it would not be called a department, it’s . It was called an organized research unit.   And we We refer to that it as the AIDS Research Institute just to be different from the Center, because the Center is a temporary...  I mean, hopefully it’s not a temporary thing, but it may be a temporary thing.   So what we’re hoping is We were hoping that the AIDS Research Institute would will be permanent.   So it the proposal went to the dean, and then it went through the agent--not the agent, the regents, and it’s really a universally it was approved. It is university wide.   It’s not just UCSD, but UC University of California and the whole UC system.

Hannaway:                  Yes.

Wong-Staal:                It was approved.  So UC system. I was named director of both .

Hannaway:                  Yes.

Wong-Staal:                So it’s, we’re, you know, it’s a big challenge.  But I think because with all the both the Center for AIDS Research and the AIDS Research Institute. It is a big challenge, but I think with all the basic and clinical research and work at the university, and in the region, in San Diego, it’s very necessary to have this structure therehere.

Hannaway:                                    Have you become more involved with the clinical side of AIDS research since you’ve been in this new position?

Wong-Staal:                                In a way, yes.   I’m actually, since Since I moved to UCSD, I’ve become interested in gene therapygene therapy.   It’s really a marriage of molecular biology and medicine.

Hannaway:                  Yes.

Wong-Staal:                So--and I’ve been pushing for that, and we We actually have one of the earliest gene therapy trials for HIV patients in the country, so... 

Harden:                       I want to come back and go in a bit more detail...

Wong-Staal:                Okay.

Harden:                       Through all of that.  And                        I want to start by dropping back and showing show you two schematic diagrams.   This one, Howard Temin did [Howard M. Temin, Ph.D.] drew in 1986 of the HIV life cycle, and as near as I can tell, this was the diagram that informed the first efforts to develop antiviral drugs.   I mean, you basically have the three points that you, In it, there are basically three points where it is obvious to intervene with the reverse transcriptase or the integrase or the protease inhibitors, or in addition to the cell membrane at the point of infection and what have you.

Wong-Staal:                                Right.

Harden:                                              Now, this second diagram is from one of your papers. [Poeschla, E.M. and Wong-Staal, F. Gene Therapy for HIV Disease. In AIDS Clinical Review, 1995, 1-45.]

Wong-Staal:                Mm-hmm, yeah.                  Yes, I recognize it.

Harden:                       But it                        It has some similarities, but it’s a lot more sophisticated.  And what I...

Wong-Staal:                Much more sophisticated.

Harden:                       And what . What I want you to do is tell me what we’ve learned from here to here, and how people were between the two diagrams. What were people thinking in 1986 and what are people are thinking now about ways to intervene...?

Wong-Staal:                Right.

Harden:                       In it.

Wong-Staal:                I think                 Dr. Timen’s Temin’s scheme is really outlining outlines the different steps for the virus replication, and then imply this implies that each of these steps can be interfered with. In my scheme, I’m actually putting down what are the strategies that intervene with strategies can be used to intervene in some of these processes.

Harden:                       But                        In the paper, you walk them readers through it.

Wong-Staal:                                Right.   So, for For example, I put say here ribozymes and antisense can act at the time when the virus comes in because the genomic information is RNA.   So ribozymes essentially Ribozymes recognize the specific RNA by sequence complementarity and then inactivates inactivate it by cleaving it up.  So, and antisense Antisense at the same time hybridizes the RNA genome and then can prevent it from being utilized essentially.  _____ CD4 . The CD4 [cluster of differentiation 4] receptor acts as a competitor at the level of binding of the virus.   So those Those would be strategies to stop the infection event so you prevent the establishment virus at the point of infection.  And

I draw this line there [points] because that it separates the early events from the late events.   You can also have strategies that do not prevent infection per se, but would prevent expression of the virus.   So even though even though the cell is infected, it’s it would not be making more progeny, you know, more viruses.   And, again, the The ribozyme can work at this level as well because it can work on the level of the messenger RNA as well as the genomic RNA that needs to be repackaged into these progenies. Tar decoys, now I’ve progeny viruses.

We can also talk about TAR [Trans-Activation Response] decoys. 

I’ve mentioned that mentioned we discovered the gene tat [trans-activation of transcription], which is a critical gene for regulating virus expression.   And tar TAR is the RNA that binds to tat.   So for tat to work, it has to bind to that RNA on the virus genome.   Now tar decoys is Now a TAR decoy means that you express that RNA element as a decoy molecule, so it competes for the binding of the tat Tat protein, so it prevents, you know, pulling it which pulls it away from its normal function.  And people have used that, in fact, including

TAR decoys have been used, including by Gallo’s lab, these tar decoys for virus inhibition. Trans-dominant rev protein.  Rev, again, we Next, let’s talk about trans-dominant [a mutant form of the protein that effectively inhibits the function of the wild-type protein] Rev [regulator of expression] protein. We also did one of the earliest work demonstrating how rev it works in the cell.   And Gary Nable is using, Gary Nabel [Gary J. Nabel, M.D., Ph.D.] has a gene-therapy approach using trans-dominant revRev, which means that it’s a mutant form of revRev, which is not only inactive, but it, again, interferes with normal rev Rev function.   So, again, because rev Because Rev is critical for HIV replication, you can also inhibit virus that way. RE

An RRE [Rev Response Element] decoy is like the tar TAR decoy except now, instead of binding to tarTat, it binds to rev.  So, again, it prevents rev from working. So these--the rev gene Rev. It prevents Rev from working. The RRE decoy does not prevent transcription, but it prevents, it interferes it interferes with the processing nuclear transport of incompletely processed viral RNA and therefore utilization of a subset of the viral messenger RNA.   So it’s It is post-transcription of regulation in its interference at that point.

You Actually, that didn’t turn out‑‑some studies from George Pavlakis’s lab that have not been reproduced.  I won’t even talk about that. And then you can also use other strategies like the trans-dominant gag -dominant Gag [Group antigens] protein as a mutant gag Gag protein that prevents the assembly of the virus. And you You can also have transdominant trans-dominant envelopes, and, finally, what I would call envelope traps, is that, you know,  if you, envelope . An envelope protein binds to CD4, for example, that so if you can express intracellular CD4, you can trap the envelope inside the cell.   The alternative is you can also express antibodies to envelope, to express an antibody to the envelope protein, an intracellular single-chain antibody.   So, again, it It binds the virus envelope inside the cell so that it doesn’t, is not free to become incorporated to form the as a new virus .

Now, our approach is using ribozymes.  But I was--this is a review, I think...

Harden:                       This is a review, yes.

Wong-Staal:                So I was listing different approaches.

is formed.

Harden:                       So Harden:                       All the different ones. Now, with all these different ways to attack the virus, how come we haven’t inactivated it hasn’t yet been inactivated?

Wong-Staal:                Well, I think gene Staal:                Gene therapy has enormous potential, but there’s also there are a lot of technical hurdles, because having knowing the gene that will stop the virus is only the first step.   The next part is, how do you get the that gene in the right cell in sufficient amounts?   I think that’s the , you know, hurdle that we’re all trying to get over.

Harden:                       And the thing...                         I believe there was something in this week’s Science magazine, or one of the another recent onesissue, about the naked DNA, plasma DNA, that seems to look very promising.

Wong-Staal:                                Yes, yes.   But that’s really using gene...  I mean, it’s But that is a strategy to use gene therapy for vaccination, I mean, to stimulate the immune response.  So it’s the gene vaccine approach...

Harden:                       Okay.                         Rather than a therapy approach.

Wong-Staal:                                Right.   Because what What we’re doing here is trying to inhibit the virus rather than to stimulate the immunity, because for . For stimulating the immunity, you just need to get the gene in, some gene in, to a gene into a cell that will have some level of virus, of expression of that protein. 

But to inhibit the virus, we have to get it in at least the gene into a significant number of the functional target cells.

Harden:                                              And how which approach do you think --which approach is going to work?   The ribozymes ribozyme is what you’re putting in your...

Wong-Staal:                Yeah.  I mean, these                 These approaches are all sort of equivalent, except that we . We prefer the ribozymes for many, I mean, for ribozyme for a number of reasons, : because it’s it works with RNA, ; it’s not immunogenic, but also, ; it’s not tied to a single gene, because a ribozymethat is, you can design it a ribozyme to match any part of the virus genome.   So essentially, we We can have a dozen different ribozymes that recognize different parts of HIV and attack it.   And, you know; now we’re We’re all aware that you can probably never stop the virus with one drug because of resistance.   I’m also I’m also convinced that you can never stop the virus with by blocking the protein expressed by one gene because, for the same reason.   So with With ribozymes, you don’t have aren’t limited to one gene, you have many ribozymes targeting many different viral genes that you can link together because they’re really small molecules.  So that’s they will be transcribed into separate small RNA molecules. That’s why we go after that approach.

Harden:                                              Where do we stand at this point?   Are you still working at it at the laboratory level in vitro?   Or is it ready to move into trials, clinical trials?

Wong-Staal:                We have, we are doing...

Harden:                       You said Or is your approach ready to move into clinical trials? You said that you’ve had one clinical trial.

Wong-Staal:                Yeah                Yes.   We are doing a...  We’re gotten have introduced a gene into three patients.   But the design of the trial is not to treat patients per se.   It’s really to see whether the gene we’re putting in persists, first of all, and is expressed, and whether, you know, in the design of the experiment, we actually take the cells out of the patient, put in a vector that expressed the ribozyme gene, but we also put in a different population of cells, a vector that expressed the control, I mean, the vector alone, without a ribozyme.   So the idea is really to compare the two populations in the patient to see , because if the ribozyme is doing its job, it .  If it is, the cells would not be infected by HIV, and therefore it they should be around, persist longer than the control , because that population of cells which can be infected and then it can be killed.   Just Our goal is just to see if it’s the ribozyme gene is functional in that sense. And we, actually, we

We were not working under optimal conditions because our vector level, titer , is too low.   But even so, in one patient we can tell that the ribozyme is functioning, that it is being selectively expanded over the control vector _____ vector’s population of cells.   So that’s the first part. But the second part is really to increase the efficiency of gene transfer, and I think there are, you know, that progress is being made that can lead to that. The next problem, I mean, issue, is really the way of introducing the gene.  Right now, because of, againSo that’s the first part. The second part is to increase the efficiency of gene transfer. Right now, because of the vector’s low efficiency, we have to take the cells out to put in the vector and then put the cells back.   This is called ex vivo manipulation, which is very impractical, you know, especially for developing countries.

Harden:                       Yeah.

Wong-Staal:                You can never...

Hannaway:                  Try to do this on a large scale. Wong-Staal:                You can never do it on a large a large scale in , you know, countries that don’t have the necessary laboratory expertise particularly, and that’s, of course, , but those countries are where the greatest impact of the epidemic is. So we’re also working on getting , perhaps, vectors that can be directly injected into the patient that will to deliver the gene.   And, ironically, I think my personal and I think a lot of other people are thinking along the same direction, is that perhaps the best vector to do that is HIV itself, if you can turn HIV now into a vector for delivering the gene that would kill itself.

Harden:                       That’s                        That is indeed ironic, isn’t it.?

Wong-Staal:                                Yes.   I mean, it’s It’s sort of poetic justice.Hannaway:                  Killer virus kills virus.  Yes.

Wong-Staal:                Right, right.

Harden:                                              I’m smiling , though, as you’re talking , because what I keep thinking is that you were talking about the really exciting days referred to the “really exciting days” in ‘84, ‘85, ‘86, but I don’t think today is any less exciting, to as I watch you talk.

Wong-Staal:                                That’s true, that’s true.  But it’s just the pace of discovery is less.  I mean, before, this actually was easy because everything you do was discovery.  Right now it’s more challenging, but it’s no less exciting.  You’re right.  I think it’s...

Harden:                       And that’s it.

Wong-Staal:                Mm-hmm.

Harden:                       Okay.  Well, why don’t we go on to 31.

. But the pace of discovery is slower now. In the early years of the epidemic, everything we did was discovery. Right now it’s more challenging, but it’s no less exciting.

Hannaway:                  Hannaway:                  Yes, I think so.  You’ve mentioned the annual Gallo laboratory meeting on AIDS.   You Do you continue to participate in that.?

Wong-Staal:                Mm-hmm                Yes.

Hannaway:                                    Do you have any major collaboration going on with members of the Gallo Institute in Baltimore?

Wong-Staal:                                Not actively, although we have talked somewhat about collaborating somewhat.

Hannaway:                  Because they                   They also are interested in developing therapies, we understand.

Wong-Staal:                                Yes, yes.   And so So far, they have not had a major program on gene therapy, so they’re . They’re more interested in cytokines, chemokines, the small-molecule approach.

Hannaway:                  Mm-hmm, yes.

Wong-Staal:                Which is okay, you know.   I don’t need the competition.  There’s enough competition.

Hannaway:                  Now you have the right to want more competition.

Wong-Staal:                Rightthe competition. There’s enough competition.

Hannaway:                                    Do you have any collaboration with David Ho’s [David D. Ho, M.D.] group in New York?

Wong-Staal:                                We’ve had some, off and on in the past, but not really that much _____.   Again, I think we have sort of--we have taken different direction, I guess.Hannaway:                  Yesdirections.

Harden:                       We’ve more or less talked about what I had in order as the next questions, about the gene-therapy approaches that you’re working on.

Wong-Staal:                Right.

Harden:                       So maybe I’ll just                        I’d like to ask you one question that we have asked to everybody.  : If AIDS had appeared in 1955 instead of 1981, how would the scientific community have been able to approach it?

Wong-Staal:                                I think it would have been a disaster because, I mean, again, even after HTLV-1, there was a lot of resistance in to thinking that this new disease was a retrovirally transmitted disease.   I mean, there were still theories of antigen overload , you know, whatever, at that late stage.  So and whatever else for a long time. I think mentally, they would not make the connection, at least not as readily. The Also, the technology for growing T cells was not there, so that. . . .

Harden:                                              T cells were not even there—that is, in 1955, there was no ability to subdivide white cells.

Wong-Staal:                                Right, exactly.   You’re right.  So the The ability to isolate the virus was not available.   Reverse transcriptase was not there.

Harden:                       That’s right.

Wong-Staal:                So I think it would be unimaginable.   It probably would have killed off most of the human race, at least in Africa, I would say.Harden:                       Okay.

Hannaway:                  I mean, epidemiologists                   Epidemiologists might have some understanding of how it was transmitted.

Wong-Staal:                                Right.   That’s true.

Harden:                       Figured it out, that it                        And they would probably have figured out that the disease was sexually transmitted, blood-borne.

Wong-Staal:                                Right, right.   That’s true.  So So they might have taken action from a prevention point of view.  But   But by then, so many people would have been infected that...

Hannaway:                                    One policy question.   When you were at the NIH, you were associated with Sam Broder’s work on AZT, and you were familiar with NCI’s ongoing empirical work screening compounds for potential anti-cancer activity.  I’d like to ask, do ? What I’m getting at is the question: Do we know enough molecular biology to really hope for a rationally designed AIDS therapy in the near future?   Or is it going to be the long-term future?

Wong-Staal:                                I think there has been a lot of effort in rational drug design based on our knowledge of the virus.   For example, you know, linking, I mean, there is work on linking some of the decoys, what they call aptimersaptamers [oligonucleotide or peptide molecules that bind to a specific target molecule], for interfering with tat and rev and so on.   The problem with HIV is really, when I first _____, using a drug approach, because now, you know, it’s also as Tony Fauci’s recent studies .  A have shown, is that a person who’s infected probably needs to be treated forever.   The virus, once it’s established itself in the immunological reservoir; you , can never get rid of it.  And anytime be completely eliminated. Anytime you withdraw drugs, the virus comes back.   So you have to , you know, treat the patient for three decades maybe, you know, two or three decades or longer.   And to maintain a drug at that high a level for such a long time, first there are problems. First of all, you can have cumulative toxicity, . There is also the problem of resistance is...  You know, so that’s That’s why you also need not just need one drug , you need but three or four drugs, and . You also need to mix the regimen.   Very This is very difficult, I think.   You know, there There are also compliance issues.   It’s overwhelming now because it’s hard to juggle all the different drugs that are supposed to do different things at different times.   I think logistically, it would be just very difficult with a small drug approach.   I mean, that’s That’s why I personally came to gene therapy.   I mean, you You need something that’s just working all the time for you without worrying about it.

Harden:                                                  Can you project a time frame for gene therapy to be effective?

Wong-Staal:                                Well, unfortunately, I think that is the hard part.   It’s hard to say.   It certainly would not be in the next five to 10 years.   It may be beyond that.   So, in that sense, I think it’s good to have the drugs, at least to keep patients going for a while.

Harden:                       At this point.

Wong-Staal:                Right.

Harden:                                              How would you advise policymakers to think about this, about approaching...  ? They have to deal with constituents who are ill and constituents who don’t want to spend too much money on this or that.  open-ended research. How should they balance out the spending on basic molecular biology to come up with some sort of rational design, versus empirical, let’s try this, let’s try that.

Wong-Staal:                Right.  Well, I think, first of all, I think AIDS research...  You know, a                 A lot of people say, “Why should we support AIDS research when we can support basic research?”  ” But, in fact, AIDS research has been very beneficial to basic research.   I mean, from From this model, this system, you know, we gain gained a lot of insights on into basic molecular biology and virology and immunology.  So it’s not all just practical.  Now, but in terms of the sort of more practical, applied part of the research.  And then you have to think of it this way, is that this is

So it was not all just practical. You have to think of AIDS research as a window of opportunity.   I mean, this This is one of a few diseases or major diseases that for which we have a defined course.  I mean, the cancers, cause. For a lot of the cancers, we still don’t know what causes them.   Right?  But here But with AIDS you know that the virus cause themcauses it, and if you can stop the virus, you can stop the disease.   So, I mean, it’s It’s a defined target even though even though it’s a very slippery target.   I mean, it’s there.  So we We shouldn’t lose sight of that.

And the second part of that is that AIDS, you know, as you know, is-- the victims of AIDS are usually young, productive people, and because of that we are in fact losing a lot economically, I mean, losing a lot from this disease, while some of the other diseases may be targeting more the older population.  So there is, should be a motivation to keep this under control.  So hopefully, I think it’s that this is a temporary measure. You know, you don’t , we are losing a lot economically. This alone should be a strong motivation for policy makers to fund the effort to keep AIDS under control. Hopefully, they won’t need to make the investment forever.   Hopefully, something will come out of it.  But up Up to a point, I mean, some people may be right, is that putting more money in it into AIDS research may not make the process faster because there’s only so much one can try at the same time to see what works and what...  So a . A more coordinated, rational  rational approach is more important , rather than the trial-and-error type of approach.

Hannaway:                                    The sort of coordinated activity that you’re involved in currently.

Wong-Staal:                Right.  Yeah, yeah.  And then the                 Yes. The other part, of course, I think, you know, the vaccine program, is very important because prevention ultimately would be , you know, the most effective means , if not for education, which of stopping the epidemic. I’m still having trouble understanding why it’s public health education is not working as well as we hoped.   It has worked to some extent, I guess, but it’s not the final answer.   But a vaccine would be very important.halt the epidemic. But we also shouldn’t be under the impression that that’s a vaccine is all we have to worry about, that therapy is solved.   Therapy is not solved because of this problem.

Harden:                                              One question I forgot to ask earlier.   You’re now on the NIAID Board of Scientific Counselors.   How is the Board as a body advising NIAID to proceed on AIDS research intramurally?

Wong-Staal:                Yeah, intramurally.  Actually, we                 We have just been evaluating each lab within NIAID rather than taking a global policy approach.   But I think we We certainly endorse the vaccine effort, including the vaccine research center that’s supposed to be formed here.   I think there’s think there’s a lot of good work going on within NIAID, and it certainly should continue to be supported at a high level.   It may be useful if there’s more there can be more coordination in some parts of it, I think.  I think overall it has a good, the institute. But overall there’s good coordination.

Harden:                       Well, we’re winding down here, but I’d like to know if there’s                        Is there anything else, from start to finish, that you can think of that we haven’t touched on that you’d like to bring up.?

Wong-Staal:                                I think you’ve been very exhaustive.

Harden:                       We try, but...

Hannaway:                  And exhausting?

                       We want to thank you very much for speaking with us.

Wong-Staal:                I didn’t say that                You are welcome.

Harden:                       Well, we want to thank you very much for speaking with us.

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