In 1975 Dr. David Baltimore shared a Nobel Prize in Medicine for his discovery of the reverse transcriptase enzyme, which allows a retrovirus to convert its genetic information from RNA to DNA inside a healthy cell. Here, Baltimore, who was the first chair of the National Institutes of Health's AIDS Vaccine Research Committee, and who will end his term as president of California Institute of Technology in June 2006 in order to pursue AIDS research, talks about his discovery and why he was surprised to learn a retrovirus was the cause of AIDS. He also talks about the state of AIDS vaccine research -- why HIV has proved such an elusive target and his unique vaccine approach using genetic therapy to instruct, rather than elicit, an immune system response. "The problem is that HIV is insidious and that it has protected itself against almost everything that we can think of doing, so we need to think of new things to do," he says. "That's been the block, is to think of new things to do." This is the edited transcript of an interview conducted on Dec. 8, 2004.
- Some highlights from this interview
- The history of vaccine development
- How HIV "hides" from the body's defenses
- Reflections on 25 years of AIDS
- His response to denialists who don't think HIV causes AIDS
How did you first hear about or encounter AIDS?
I heard about gay men dying with a new kind of syndrome back in the early 1980s, and heard about Michael Gottlieb, who was the first one to put it all together and say there's something going on. Then the question was, what? We all speculated about what it might be.
There was a lot of crazy speculation at the time, since they were all gay men, about sperm and this and that and the other thing. But it looked like an infectious disease, and the question was, what did it? It never occurred to me that it was going to turn out to be a retrovirus, because there had been no retrovirus associated with human disease. Actually, HTLV1 was the first one, with a T-cell lymphoma, but not an infectious disease in the general population like this. Then, actually thanks to the work that [Baltimore's co-winner of the 1975 Nobel Prize for Medicine] Howard Temin and I had done in 1970, it was identified as a retrovirus, and that was a huge surprise.
Tell us, how did the work that you two had done actually feed into the discovery?
Howard Temin, working actually first as a student at Caltech -- and you can find it in his thesis -- suggested that there was something really odd about cancer-inducing RNA viruses. What was odd was that they were able to induce cancer, because cancer is permanent change in cells, and viruses generally transiently associate themselves, and the immune system gets rid of them, and they're gone. They transiently associate with people, and so the idea that they could cause cancer seemed strange.
But we knew that DNA-containing viruses could cause cancer. ... Howard made the remarkable leap to suggest that RNA, which is generally a trenchant molecule in cells and doesn't do things permanently, would have to have been transmuted in some way into DNA, which was known to be the stable source of hereditary information.
That seemed like a bizarre idea. It violated the central dogma of biology, which is that DNA makes RNA makes protein, and biochemically it had never been seen. For 10 years that notion sat there. Howard tried to prove it, had great difficulty finding an experiment that would prove it.
In 1970, it occurred to me that I knew how to do this, because I had been working on synthesis of DNA and RNA for a long time, and maybe the machinery to do this was in the virus particle itself. If it was in the virus particle itself, it was going to be very easy, because you just have to go get a lot of virus concentrated and use it like a biochemical reagent. I did that and found the reverse transcriptase. Actually, a guy in Howard's lab did it at the same time, and so we jointly published and jointly received the Nobel Prize some five years after we made the discovery, which is a short time in such things, and largely because the discovery had already opened up cancer research.
We thought that was going to be the major application of it -- within cancer research. We pretty soon showed that not only was the virus capable of transmuting RNA into DNA in the virus, but you could isolate the enzyme and make it do it in a test tube with RNA that you gave it, so that actually was one of the things that started the biotechnology industry. We already knew it was more potent than we had originally seen.
But then came along HIV, and the way that [virologist Robert] Gallo and [virologist Luc] Montagnier found HIV as the cause of AIDS was by using the ... reverse transcriptase reaction, the ability of viruses to copy RNA into DNA. That was the key. This thing which we had found because of an interest in cancer turned out to be the key to uncovering the nature of AIDS really as a viral disease. Once we knew it was a viral disease, then we imagined -- and this in fact happened -- that the whole panoply of things that we knew already that we could apply to viruses would apply to HIV.
However, HIV turned out to be a much smarter virus than we ever imagined it to be. We knew about other retroviruses, and they were not particularly smart. They had a few structural proteins and an enzyme in them, and they sort of forced the cell to make more of themselves, but HIV made a whole series of little proteins that would modify cells in ways that we'd never seen before.
People have accused biological engineers of making HIV. No biological engineer could have made HIV because none of us had ever seen these capabilities before. We not only hadn't seen them in a virus; in many cases, they affected processes that we didn't even know were going on in cells at that time. We've learned a lot about cells by following what HIV is capable of doing, and we're still uncovering mechanisms that HIV has. This is now 20 years later. So the obscurity of these things is very hard to imagine, the obscurity to the scientific community of these capabilities, but we now understand them a lot better.
... The scientific community always has its contrarians, people who try to make a reputation for themselves and often are deep believers in notions which are counter to the general trend of knowledge. The scientific community is careful, I think, not to be too hard on these people, because you never know when it's going to turn out that they had something important to say.
The area that people who denied that HIV causes AIDS, it was very hard to see that they had anything important to say, since the evidence that HIV caused AIDS was just overwhelmingly clear; in particular, the ability to inhibit HIV with the drugs allowed people to bounce back from their immune deficiency, so there was a clear proof at the human level [that] HIV caused AIDS. It wasn't just extrapolating from animals or anything else.
I guess there are still people who deny that. I at times feel that they're murderers, that they're people who are giving false hope to individuals that they don't need to protect themselves from HIV transmission. Probably the worst case is the president of South Africa [Thabo Mbeki], who to this day, I know, refuses to forcefully say, "HIV causes AIDS, and we have to prevent the transmission of HIV." People are dying as a consequence of that. There's absolutely no question about it.
How do you bridge that gap between scientific truth and politics?
You try very hard, as a scientist, to tell people what it is you believe is true, what it is in many cases that you absolutely know is true. You try to tell them in lots of different ways. You try to be patient.
But there are always people who for their own political reasons will deny the truth. It's very hard to get the press, for instance, to completely understand that, because the press always says: "Well, there are perfectly reputable human beings saying the opposite. We have to include that in our articles." They intend to include it 50 percent on one side, 50 percent on the other side, even if the actuality of it is 99 percent on one side and 1 percent on the other. That's frustrating to science, but it is a political reality. We just have to keep fighting it, and you can't give up. But sometimes, particularly in the case of HIV, it's heart-wrenching to see what happens when a clear truth is denied for political ends.
Are there U.S. examples of that?
Peter Duesberg, a professor at Berkeley, old friend of mine, a very respected virologist, member of the National Academy of Sciences, has gotten it [in] his head that HIV doesn't cause AIDS. He goes around the country saying that, and people give him lots of money to give talks about it. He's very funny and [an] attractive sort of human being, self-deprecatory and all of that, so he comes across very well.
He's a disaster. Now, I must say I haven't heard much from him now in the last couple of years, but in his heyday, there were a lot of people walking around saying: "Peter Duesberg says it doesn't. I can go out and do what I want. I'm not going to get infected." And they were infected. ...
[Tell me about the Institute of Medicine committee you chaired in the mid-'80s and the report you released.]
We had a period of real political frustration in the 1980s, because the administration in Washington, the Reagan administration, really did not want to admit that this was an important problem. That required admitting that gay men in particular were important to care about, and they didn't want that. They didn't want to have to deal with that. ...
We needed the president to get up and say that people had to protect themselves, because when we don't have a vaccine -- and we still don't have a vaccine -- the only thing you can do to prevent HIV transmission is to protect yourself, and we know how to protect people, or how people can protect themselves. It's not that difficult, but it does require commitment, and we could not get the administration to do anything.
So the Institute of Medicine and the National Academy of Science[s] came together and used their own money ... to fund a study of what should be the American response to this developing epidemic. This is 1986. They asked me and a physician ... at Tufts, Sheldon Wolff, if we would co-chair a commission, and we did that. We brought in some of the very best people who understood the virus, who understood the disease, who understood the history, and they gave testimony, and we wrote up [a report]. Frank Press, who was then head of the National Academy of Science[s], said to me just last summer, he said to me this was the most important thing ever done by the National Academy in terms of a report. It sold more copies or more copies have been printed than anything else they've ever done there, and it had an influence.
I remember, as we came to the end of it, I said, "Look, this has great importance politically as well as scientifically, and politically they're going to ask how much money is it going to take, so we need a number in there." Numbers like that are projections into the future, very hard to be precise about, particularly since we didn't know what kind of research was needed, and we just know we needed a focus on it.
We said $1 billion, and so we published $1 billion. That was a lot of money in those days. Now we throw around billions, but that was a big billion. We said we needed a $1 billion program of research. To the credit of the government, by about three years from then, we were spending $1 billion. They ramped up a program very quickly, and that program has its strengths and deficiencies like all government programs do. But they were now spending money on a scale that could uncover the nature of the virus, the nature of these very strange little proteins that the virus makes, give us the lay of the land so we could figure out how to attack the virus.
In fact, we could attack the virus, and the drugs that were developed were drugs that focused first on the reverse transcriptase, which we knew was there from the very beginning, and later on protease, [which] we didn't know much about initially but learned about through this process of research. We also learned about the variety of viruses, and we learned about the spread of viruses, and we learned about all those things that we had wanted to know through this government-funded program. The United States at that point was spending a lot more money on HIV than any other country in the world. Still does, for that matter. ...
Vaccines started with [Edward] Jenner at the end of the 18th century. He is supposed to have noticed that milkmaids didn't get smallpox and figured that they were being protected by a cowpox virus, and had the idea that you could actually vaccinate people with an attenuated virus that would, although he didn't know it in that time, retain the immunologic properties of the virus, not the pathologic properties of the virus. So it's the separation of the immunogenicity from pathogenicity that was really the paradigm for vaccine development over many, many, many years.
What does "attenuated" mean?
You can separate the immunogenicity from the pathogenicity in two ways. You can kill the virus, and if you kill it in the right way so you keep its antigenicity but you get rid of its ability to grow at all, then it can't be a pathogen; it can't cause disease, but it can stimulate the immune system. A simple way is formaldehyde will do it. That's how, in fact, [Jonas] Salk made the Salk vaccine [against polio], with formaldehyde.
The other way to do it is do it biologically. You get the virus to mutate the genes that cause disease, and it turns out one way to do that is just grow the virus in a laboratory for a long time, and the virus adapts itself to laboratory and no longer cares about the pathogenetic mechanisms because they're not playing any role in its life, and so it begins to mutate those away. That's an attenuated virus.
You can biologically attenuate it, or you can just kill it. So there are two kinds of vaccines. There are attenuated vaccines, and there are killed vaccines. Salk's vaccine was a killed vaccine, and [Albert] Sabin's [polio] vaccine was an attenuated vaccine.
When HIV came along, people said, "Well, let's make a vaccine against it." That was the first thing. [Reagan's Secretary of Health and Human Services] Margaret Heckler, when she announced that Bob Gallo had discovered the virus [and] said, "We should now have a vaccine in two years," she couldn't have been more wrong. But she was not wrong about the history of virology, because once we knew viruses caused diseases, we often then could develop vaccines for them. What she didn't know or what she couldn't understand at that time, and I must say those of us out in the field did understand, was that this was a different kind of virus, and that it wasn't going to be so easy to make a vaccine.
But people started trying to make either a killed vaccine or a live attenuated vaccine, or now a sub-unit vaccine, because a third way of making vaccines had come about from molecular biology, where you could just make the protein that stimulates the immune system, and you'd get rid of the virus entirely, and now you have something totally safe and actually very easy to manipulate and very easy to store. It's good stuff if you can make a vaccine.
What's an example of an early sub-unit vaccine?
The best sub-unit vaccines that we've made actually come from bacteria and involve the surface constituents in bacteria. There are a few sub-unit vaccines for viruses. Hepatitis B is one in particular that's made in yeast, in fact.
Those who were working on the hepatitis vaccine adapted that to AIDS when they made the gp120 [vaccine. Can you explain what happened?]
People tried to make vaccines either by taking the surface protein, the gp120 from HIV, and using that as a vaccine, or using intact virus particles that had been killed in some way, although we always worry that you don't know how to totally kill HIV. But none of it worked.
None of it worked, because HIV has somehow figured out how to hide most of its surface behind a layer of sugar. We call it a sugar-coated virus, and the sugars are actually self-constituents of the body, and therefore the immune system doesn't react to them because they're not foreign. The immune system is looking for things that are foreign. The foreign parts of HIV, which are the proteins, are all hidden behind this sugar.
Now, there have to be some places on the surface of the virus that are open. And there are some places. You'd think, well, just those places would suffice. But the virus has figured out how to get around that problem, too, by hiding things in deep crevices, by using a two-step mechanism for binding to the cell so it binds first in one place and then in another, and that second place doesn't open up until the first place has been bound to, and so the virus is now protected in that way.
That virus is amazing in the number of ways that it has found to protect itself against our immune defenses. That's why it is what it is. If it wasn't for that, our bodies would just take care of it, and it would be like any other virus. You might get a little sick from it, but then you'd get better. We'd annihilate the virus, and life would go on.
But we can't do that. Our bodies are unable to find any crevice in that virus that we can attack and kill it. We have two arms of our immune system. We have the antibodies which are in the blood, and we have T-cells which are also in the blood but carry their specificity determinants on their surface, the thing that allows it to see the virus. HIV has found ways around both of them. Some of it is mutations -- you know, just staying ahead of the game -- but a lot of it is this hiding the critical parts of the virus.
What kind of adversary are we fighting against?
We're fighting against an adversary that has taken advantage of a long evolutionary history to become the stealth agent, and it's that stealthiness that makes HIV so different than other viruses. Other viruses are somehow more overt. But HIV, by its [being] hidden behind its sugar, gets in through holes in our immune defenses that no other virus has ever found. ...
In the search for an AIDS vaccine, what's the optimal relationship between government, academia and private industry?
To my mind, the search for an AIDS vaccine is a program that is pretty well defined, not absolutely defined. It involves areas of immunology that are still obscure. It needs a combination of some basic research and lots of applied research, and applied research is much better done in an organized fashion than in a haphazard fashion, as any drug company knows.
One of the answers might be, well, the drug companies should develop the vaccines. But the drug companies don't have the incentives to develop the vaccine, and they also know that it's very hard. We actually have had now 20 years of experience and then still don't have a vaccine, so we know that it's a tough, tough problem. And the pharmaceutical companies don't like tough problems. They like easier problems for good and sufficient reason: They don't want to do a lot of basic research. They want to get in there and make a drug or make a vaccine, and you can't do that with HIV now in the vaccine.
We need some kind of hybrid structures, institutional structures to do this, either coming out of universities or coming out of research institutes or coming out of some union of pharmaceutical companies and research institutes. We haven't been particularly good about evolving these things. ...
People are now trying to do this. But I don't [think] you can expect the pharmaceutical companies to do all the work. Merck has been a very forward-looking company in putting a lot of resources into the development of a vaccine, and they're having a hard time. They've proved how difficult it is. They've put a lot of energy, for instance, into DNA-based vaccines, and now they pretty well stopped that because they just found that the immune response that can be elicited by DNA is not strong enough to give the kind of protection in humans that seems to be necessary to protect against HIV. They've gone more over to andovirus-based systems.
Of the vaccines that are in trial now, are there any particular ones that you have more hopes for than others?
The vaccines that are under trial now, I don't know of any of them that have the obvious potential to be a useful preventative. I wish that there were a lot of them. There are lots of people trying from various points of view, but there are certain kinds of commonalities to everybody's approach which I think doom them all.
What do you mean?
Well, they're focused on T-cell responses, for instance, a lot of them, and the T-cell response against HIV is strong. It's strong already, so you don't necessarily have to make it better. And it's not totally sufficient to prevent the virus from maintaining itself; otherwise we wouldn't have AIDS. The ability to go one better than the natural response is what I haven't really seen the potential for in any vaccine.
But you have an idea.
Well, I'm trying to do something different, which is to program the immune system using genetic therapy methods to try to free us from having to depend on what the normal immune system would do. I think if we could be instructive to the immune system rather than just trying to elicit its responses that we could do better. We are trying to take a new approach to development first of therapy, actually, because using this in a protective mode requires the development of a whole new kind of technology of very simple gene therapy. I can imagine it happening. I can see how it might happen, but it's going to take years. Who knows [how] many years? I don't know how many years. ...
When I'm asked about when we're going to have a vaccine, what I have said from the 1986 report to today is it's going to be at least 10 years. That's never changed over the last 20 years.
Because we haven't made any kind of progress that says it's going to be less than 10 years.
Some people have said we'll never have an effective vaccine because you can't inoculate against human nature.
Sure you can inoculate against human nature. We just have an HPV [human papillomavirus] vaccine coming along which prevents a sexually transmitted disease, the papillomavirus that causes cervical cancer. We have vaccines against hepatitis, which is transmitted perinatally through inoculation as well as sexually.
You can protect against human nature. When we protect against polio, we protect against transmission of virus mostly by kids actually when they play. That's human nature.
No, all vaccines are about protecting against human nature in a sense. We can do that perfectly well. That's not the problem. The problem is that HIV is insidious and that it has protected itself against almost everything that we can think of doing, so we need to think of new things to do. That's been the block, is to think of new things to do.
Looking back over 25 years of the epidemic is the saddest thing to do in the world, because we have watched [as] what exactly we knew would happen has happened. We saw it in the early '80s that this thing was being transmitted: It was being transmitted sexually, it was being transmitted perinatally, and we said nothing's going to stop this unless we can intervene.
We have not found an intervention that's effective. Certain countries' education has been effective. I think in the United States education has been effective, although not totally so. We still have 40,000 cases a year in the United States of transmission. Education has began to lower the rate of transmission in countries like Uganda and Thailand, so you can do something with education. But since that's the only thing we have actually, today we ought to be doing a lot more.
We ought to be trying lots of new models. We ought to be working very closely with the rest of the world to try to get people to understand that they transmit this virus in a variety of natural ways and that they have to intervene; they have to protect themselves.
You can only be devastated by seeing the 40 million people that are affected around the world today, and know that there could be a lot less than that. It could be a lot less than that.
The title of this series is The Age of AIDS, and that is because Supreme Court Justice Stephen Breyer was sitting next to me at a dinner, and when I told him what I was doing professionally, he said, "People think of this as the nuclear age or the information age, but I think when we look back we will realize, because of all the different levels, that this was the age of AIDS." Do you agree? Disagree?
This is not the age of AIDS, because the developed world, which is driving forward technology, which is driving forward the quality of culture, is increasingly less affected by AIDS. There was a moment in which it was the dominant thing and which really came together with the recognition of how widespread homosexuality was.
In the less developed world, AIDS is the most important thing going on, because it is cutting down the productivity of these countries; it's cutting down the life span of people; it's making it very difficult to carry out development projects. To that extent in those populations, probably AIDS is the dominant force in the world.
But if you look at the world overall, the growth of Asia is the biggest thing going on today, and they so far have not been terribly affected by AIDS. Will they be? Yes, they're going to be more and more affected by AIDS, but I think they can control it, and I think countries like China have the will to control it. The will is the big thing.
All right. I'll try one more quote on you. [Evolutionary biologist] Stephen [Jay] Gould said that evolutionarily, AIDS is a drop in the bucket. If 40 million, 60 million, 100 million died, that's evolution at work.
Yeah, any disease is evolution at work. The influenza epidemic of 1918 may have killed more people than HIV has killed yet, so we do see big, devastating infections sometimes concentrated, sometimes spread over time. But they are defining characteristics of evolution itself, and we need to evolve, in a sense, to protection against HIV.
Oddly enough, some people have. There's populations, particularly coming out of Scandinavia, that have a high rate of mutation of a key gene. That mutation protects them against HIV, so we could see evolution taking a hold here. I'd hate to wait for it. It's a slow process. But I think in the history of development of the parts of the world that still need to come into a much more modern age that AIDS is going to be seen as a really devastating disease, and I would not minimize that. That's important. It may not be the most important thing going on in the world, but it's important.