Robert Yarchoan '71 Transcription
I want to thank the college and thank everyone who came out here this morning and particularly the kids who managed to get up in time to get out here. I know this is a bit early for your schedules….
I want to talk a bit about this story of my research in AIDS over the years, going back….It’s best to start with the time when I was graduating high school, and [at that] time there was a substantial optimism in the country that infectious diseases were really a thing of the past. A number of vaccines had been developed. In fact, the surgeon general at the time declared victory against the threat of infectious diseases and suggested our nation turn its resources towards the more important threat of chronic disease. I went to college, where I was … a biophysics major. I did my work with Peter Offenhartz and actually did some computer modeling … of compounds, thinking very far from any sort of diseases at the time; went to medical school at Penn; did some work in internal medicine; and went to the NIH, where there is a lot of interest in immunology.
One of the things I really should say is that the science training that I got at Amherst really was key in terms of the work that I did later on. Not so much the specifics of what I did, although there are some resonances, but more in terms of the scientific approach. I learned some in medical school, but it was really the training … that helped me, and—at least until tomorrow—I had never got a formal Ph.D.
So I joined a group that was studied in immunodeficiency diseases and mostly genetic immunodeficiency diseases—children that are born with some failure of their immune system. And we used to see patients that would come that had weird immunodeficiencies, and around 1981 we saw a patient from New York that had this severe immunodeficiency, and we could not figure what was going on with him, and he actually soon died. At about that time, the Centers for Disease Control reported a group of mostly gay men from the West Coast that had pneumocystis…. Soon after, a report came out about Kaposi’s sarcoma among homosexual men. This is a skin cancer that was very rare that had been seen in people living around the Mediterranean and was known to exist in Africa, and suddenly this was occurring in the same population that was getting pneumocystis and, in some cases, were getting both, and people were starting to connect the dots that is was a new disease.
Now one of the things that we lose track of is that when AIDS first came on the scene, it didn’t explode. This was a report from The New York Times, sort of buried on the later pages … reporting progress on this disease, and people really didn’t perceive right on that it was anything more than what it was … in contrast to, for example, you may all remember the Legionella epidemic that appeared at the Legionairres’ convention in Philadelphia in 1976 that just exploded on the scene … this is a front page from the L.A. Times at the time….
Actually, even by the end of 1983, when it was clear that this disease was sort of expanding and seemed to be pretty [audio fails] relentless … a number of gay men had other manifestations that might be pre-AIDS but maybe weren’t pre-AIDS, and people weren’t sure. It was still considered a rare disease: at this time, there had been 3,000 cases and about 1,200 deaths, but it really wasn’t appreciated as what an extensive disease it was. About that time, the Cancer Institute was given in part the charge of looking at—actually, at the NIH, the number of institutes that all have missions, and to a certain extent AIDS falls under one of the other institutes which deals with infectious diseases, but a lot of the developments came to the Cancer Institute, particularly Kaposi’s sarcoma, and I joined the group of two other people as shown here, Sam Broder and [Hiroaki] Mitsuya, were given charge to develop some sort of therapy for AIDS. For a while we worked on a related virus that caused a kind of immunodeficiency in Japan, a retrovirus, and we were trying to figure out a good way to approach this.
At about that time, two scientists, Luc Montagnier and Bob Gallo, did work in which [they] did find the virus that caused AIDS and showed that this was really the cause of AIDS. Luc Montagnier and his group really were the first to identify the virus, but Bob Gallo and his group at the NCI really, in a series of four papers, showed pretty definitely that this was the cause of AIDS, and people could start working on the virus at that time.
So, I remember we got a pre-print of these papers before they came out. I remember, at the time, reading them and got this insight that I think very few people appreciated at the time. This was part of one of those core papers, as I mentioned, from Bob Gallo’s group. What they had done: they developed a blood test, a way of measuring antibodies to the virus, and then tested people either with AIDS or who were at risk for AIDS. As you can see here, the people with AIDS were 87 percent positive—it wasn’t a perfect test, and it wasn’t really 100 percent—but they then looked at groups of people that were at risk for AIDS. You can see the intravenous blood users were 60 percent positive, gay men had 26 percent positive. I knew the population that they’d studied; it was a group that one of the other immunologists at the NIH had pulled together of roughly monogamous gay men. They were studying their immunologic interactions … [audio fails]… and in this population, there is about 26 percent positive, and doing some back-of-the-envelope calculations, it became clear that there were at least half a million people in the United States that were infected with this virus.
At that time there was no cure, and there is a sense that the pre-AIDS [patients] would go on to develop AIDS and that this would lead to death. And it was clear, at least in my reading of it, really without realizing it, this virus weaved its way through the population and infected half a million people, who now essentially had a death sentence. This was quite frightening. At the time that the virus was identified, based on some of the work we had done with other viruses, there was all this enthusiasm about a vaccine—that now we can get a vaccine. In fact, when it was announced, Margaret Heckler, who was then Secretary of Health and Human Services, made a big press conference and stated that this would lead to a vaccine very soon, which was a prophecy that has not quite … as you probably know, there is no vaccine even now for HIV.
We took a different approach and thought—and I was impressed with the number of people infected with it—and we felt we really had to do something to treat the disease, and we would let other people work on the vaccine. There was a lot of pessimism to do anything, but we thought the way to the disease was to go to attack the virus. This HIV is a retrovirus, and there had been a lot of work on other retroviruses; many of these go and cause cancers, and it was known somewhat about the steps. This is more specific for HIV, but these basic steps had been known for other retroviruses: The virus binds to a surface receptor on the cell, fuses the genetic material in a retrovirus as RNA, and it’s unique in that it’s got an enzyme that gets the information from RNA into DNA. The DNA then can go and insert itself in the DNA of the infected cell, which is one of things that makes curing it so difficult, because you’ve got cells have a little slips of DNA of the virus. It then gets activated and produces proteins, they get cleaved, and it forms a virus.
The one enzyme that really stood out as being unique that we knew something about was reverse transcriptase. Other retroviruses have reverse transcriptase and there had been some work done in ways of inhibiting them, because it is a bit of a unique virus, and we thought that that was a good approach to try to attack.
I should say a lot of people thought we were nuts at the time. There was a lot of reason to think that one would not be able to develop therapy for this. First of all, HIV integrated into the cell of the DNA, and therefore they felt it would not be amenable to treatment. Our thought was: Since it seems to have to move from cell to cell, it was still potentially attackable. The other thing is that the whole field of nanoviral therapy was really new at the time. About the only drug that was really used at the time was acyclovir, and the idea of jumping in and getting an antiviral drug for this new disease was considered pretty far-fetched. Also, HIV, unlike a herpes virus that acyclovir works on, only had nine genes, so there were relatively few unique targets to attack. And then there’s this whole idea that there are so few infected cells that most of the destruction of the immune system has to happen by indirect mechanisms, and even if you could stop the virus you wouldn’t be able to do anything. Finally there was this pessimism that the immunological damage would not be reversible. We thought it would still be worth a shot, and tried it. We sort of teamed up. Mitsuya started working on an assay to test the drugs, and he developed an assay [in] which he got a T cell line that he was doing for some other purposes that was infected with another virus, that actually turned out to be very susceptible to being killed by the AIDS virus. And since we’re in the same institute as Gallo’s group, we were able to go across the street, get the virus, bring over the vial and start using it. When he threw it in—this is a picture with a regular camera looking up at the bottom of a test tube in which [there are] these cells, and you can see the size of the pellet of cells. This isn’t through a microscope. This is sort of our initial primitive assay, and you can see without the drug, cells are growing quite happily, and without a virus. When you add HIV, the cells are getting destroyed. When you add AZT, the cells are not destroyed, and the cells are also very happy with AZT by itself, and this is another drug that we developed.
In terms of getting the drugs: we looked at all the literature, all the work had been done with the other retroviruses, and also went around to drug companies see if they had anything that might work. We teamed up with the Burroughs Wellcome company, who had actually developed acyclovir, had expertise in antiviral drugs and had started a program themselves trying to look at drugs to treat HIV. But they had no ability to use HIV and no interest in using HIV. So we had a very nice relationship with them. They had some drugs and medicinal chemistry, we had the assay, we had the patients, and we teamed up together, and they give us AZT, and it worked very nicely.
We also got some drugs based on some literature in mouse retroviruses, and one of them was ddI, as seen here, and that was also quite active. We actually found fairly soon a series compounds that all had one characteristic … these are all nucleosides, they are sort of the building blocks of DNA, and they have one modification in that the OH group here is replaced by some other group so they can’t form further chains. So they are either replaced by hydrogen or, in the case of AZT, an azido group, and so on. And all of these are now AIDS drugs—all of these compounds. The long names come from the chemical names of these drugs.
The first one that we put in the trial was AZT. The reason was because we had a pharmaceutical company, they had done some animal toxicity, and in fact they were developing it as an antibacterial drug, and it was ready to go into humans. So, we could very quickly get this into human trials. And, just to give you a sense of the timeline here, the virus was discovered in May of 1984, we found that AZT had activity in February of the following year, and we put it into the first patient in July of 1985, which is just about 13 months after the virus was discovered. If any of you are aware of drug development these days, this is sort of an indoor track record.
This is the first patient that got AZT: a gay man who had very few CD4 cells, as seen here—and we really didn’t have any way of measuring the virus at the time, so we can only look at these indirect things like CD4 count. What we found is that there is actually a very nice increase in the CD4 count, and the total T cell count, and the patient had been in inergic—in other words: if you do a skin test, with TB, the patient didn’t react. Although he had been exposed to TB, when we tested him a few weeks later, he now had a very strong skin response. We had a sense that something was going on with the patient. We then continued to test further patients and sort of gave increasing doses of it, first intravenously, and then orally. I think one of these patients lived in Aberdeen, Maryland, which is about 40 miles from the NIH and would drive down every day to get his AZT and drive back home again—it was really quite remarkable—until we were able to get him an oral form of it.
The FDA really worked with us at that time to try to expedite amending the protocol and sort of keeping things going as quickly as possible. And what we found by the time we’re treated about 12 patients or so was that pretty much every patient had an initial increase in the CD4 count, and actually it was statistically significant … the CD4 counts tend to bounce around a lot, and for us this was huge—that we were actually seeing some sort of pretty consistent increase in the immunologic parameter … and we thought we had something.
And some of the patients were also feeling better. There was one lady who was a nurse who [had] gotten HIV through a needle stick who had a fungus infection of her fingernails, and suddenly the fungus infection cleared itself, and her normal nails started growing back.
Very soon after this phase 1 trial was finished, Burroughs Wellcome then organized what’s called a placebo-controlled trial. They got a number of people with AIDS or with severe AIDS-related complex—sort of pre-AIDS. Half of them got AZT, and half of them got placebo. And then they followed them for a period of time. There was a lot of controversy about whether this was ethical. But [by] the same token, if they hadn’t done that, there’s a sense that the approval of the drug would have been delayed fairly substantially. This is the quickest way to get things going: they realized, if it was working from this trial, everyone was given AZT. But as you can see [from] the blue line, the people who got placebo, there was a series of AIDS-related events, and the arrows are those that died. The red line: of those that got AZT, there was only one death and very few events. It was highly statistically significant. Everyone was given AZT, AZT was made available to patients all over the country on an expanded access program, and it was approved in 1987 by the FDA, which is only 25 months after the demonstration of its in vitro activity and less than three years after the virus was first discovered. So we were very pleased about that.
The government was pleased. President Reagan, who had had never uttered the name of AIDS before that, he came to visit the NIH—my kids probably don’t want me to show you this—but this is me at the time, shaking hands with Reagan. You can see that I was terrified about doing anything that would get the Secret Service people activated. My other hand is held very reluctantly in the back.
I should also say the Secret Service agents were terrified to come into our lab where we were dealing with AIDS virus. They made us clean it up. And also take out take down all the Far Side cartoons, which we were very displeased about. [Laughter] But anyway, he then went and acknowledged that there was AIDS, and people were very happy with the work that we had done.
Although the patients still realized that this was not a cure. A year or two later, their fear and their concern bubbled up into a protest at the NIH. They stormed the NIH, as you can see: 10 years, $1 billion, one drug. Here they are at the NIH campus. The administrators who were around at that time, too—if you mention “pink smoke,” they still get nervous about it. We understood from actually talking to them privately, we felt that we shared a common cause in this. And we continued to develop these other drugs.
Unlike AZT, in which we had a drug company as a partner, ddC and ddI were actually first developed here in the Cancer Institute and then licensed out to other drug companies. ddI was the next drug approved, and then ddC, which we discovered first and put in trial first, but didn’t think it was good, was approved a bit later. So [at] this point we had three drugs that were working. I should say that the patent on these two were patents from the government, and we licensed them out to drug companies. Our group at the Cancer Institute has actually grown a profit since the beginning of the AIDS epidemic on royalties from the drug. So in terms of government efficiency, we were very proud of that.
The other thing is that when we started having two drugs, we could start combining them. One of the problems with giving AZT was that the increases in CD4 counts were relatively transient. They would only last a few months, and the virus would get resistant. We started being able to combine them, and this was where [we did] the first trials of combination therapy. As you can see, for several years now, people were having increases in CD4 counts when we used the drugs together rather than using them in an alternating way.
The other thing is that the drug companies initially were very reluctant to get involved in AIDS drugs. They had the sense that this is an orphan disease, there are not enough cases, it’s not worth it financially. We went around and gave little pep talks at various drug companies trying to get them interested. Burroughs, to their credit, was the only one that seemed to be interested at all in the early days.
And then, after AZT was marketed and they realized it wasn’t just people with AIDS but all these people who had pre-AIDS, that there’s actually a big market for this, other companies started getting involved. Actually, since that time there’ve been a number of drugs approved. You can count them in various ways. I think it’s fair to say there are about 26 drugs. A number of them are in this class of nucleoside inverse transcriptase inhibitors in yellow here; others are other chemicals that hit the same enzyme, in green; and then the protease, which cleaves some of the proteins of HIV, are in blue; and there are some other targets that people have hit. One of the things that I’ve been amused by is that now that people are developing drugs, they take HIV protease, and this is a structure of it here, and try to get compounds that bind to a cleft inside and block the action of it. What they’ll do is they will do crystallography … you get the structure of the protease, and then [they] will model it with different drugs. They use modeling programs that try to find the lowest energy to figure out which confirmation they’re going to take—actually, the same sort of approach that I was working on [in] my thesis has now been taken over to do this sort of modeling, so I’ve been sort of amused by that.
Once protease inhibitors were developed, one had two classes of drugs and a series of drugs, and one could start to combine three drugs. It became apparent that one of the big problems with HIV is that reverse transcriptase makes a lot of mistakes, and so it can develop resistance really quickly. There are some drugs which can develop resistance if they’re used by [themselves] in as little as eight weeks. And that’s obviously a big problem. What they learned is that if you give three drugs, you can block the virus to the point that it doesn’t replicate enough to develop resistance, and so you can knock the viral application down to essentially zero, and it doesn’t mutate and develop resistance, and you can get long-term therapy. These are the cocktails that [have] gone under the name of highly active antiretroviral therapy (HART).
This first really happened in 1996 when protease [inhibitors] were marketed. Trials were done, and people got some guidance in how to use them. The introduction of these had a dramatic effect on the course of HIV. Once HART was introduced, the number of deaths from HIV, which is shown in blue here, went down fairly dramatically, and also the number of people that crossed the line into AIDS (because these were given to people before they developed AIDS), also went down. So this was actually very encouraging.
In fact, Newsweek sort of jumped the gun a little bit and had a cover saying “The End of AIDS.” But really it made a dramatic effect and converted AIDS from essentially a death sentence to a manageable disease that one could treat over a period of time. And it’s now estimated that, or least a few years ago it was estimated, in the United States there are 3 million years of life have been saved as a result of these sorts of treatments. And worldwide it’s estimated to have been about 14 million life years that have been saved as a result of this sort of therapy.
The other thing: periodically people ask, “Why are we treating AIDS at the Cancer Institute?” One of the things that the ability to treat the virus did is to reduce the development of the sort of cancers, like Kaposi’s sarcoma, which tend to occur in people whose immune systems are really depleted by the AIDS virus. What you saw was a fairly dramatic drop in the number of what are called AIDS-defining cancers, and these are Kaposi’s sarcoma, certain kinds of lymphoma and cervical cancer that tend to occur in people whose immune systems are quite depleted. This was quite encouraging.
I’m going to talk a bit about some of the cancers associated with AIDS, because I’ve been focusing more of my career on that. There’s sort of this tail onto the story that is worth hearing. Many people don’t really, unless you are in the field, know about this. So one of the questions that many people wondered was, “Why is it that the cancers that develop in AIDS patients aren’t all cancers but these very particular cancers?” Kaposi’s sarcoma just exploded on the scene and had been a really rare tumor before that. It was one of those cancers that you got all the med students in to see. It really wasn’t clear what was going on there. In Kaposi’s sarcoma, it was interesting, because certain groups of AIDS patients tended to get it. Gay men tended to get it; intravenous drug users didn’t tend to get it. People that got AIDS from a transfusion did not get it. People had a sense that there was some other virus involved. And for years people looked for and could not find it. Finally the team of Pat Moore and Yuan Chang, a husband-wife team who were at the time working in Columbia, discovered a new virus that they called “Kaposi’s-sarcoma-associated herpes virus”—it’s sort of in the same family as Epstein-Barr virus that causes mono—and that this was the cause of Kaposi’s sarcoma. If you had this virus and you had HIV, you could get Kaposi’s sarcoma. With that observation, it became clear that most of the diseases, most of the cancers that are really highly associated with HIV, are caused by other viruses. The ones in the orange here are these sort of AIDS-defining cancers; they are caused either by Epstein-Barr virus, KSHV or papilloma virus. These are some other cancers that are associated with AIDS that the CDC did not call AIDS-defining, but many of these are also associated with other viruses.
What we were thinking of, in a broad sense, is what is going on is poor immunologic control. Some of these [are] chronic viruses that we all live with—for example, I would bet that almost everyone in this room is infected with EBV. Maybe we got mono, maybe we didn’t, but we live with the virus for the rest of our lives. When the immune system goes, the virus starts replicating more … the virus does some things to cells in order to survive. They tend to push the cells towards cancer cells, and then get a nudge and become cancer cells, and a cancer develops. So this is sort of the main thing. There some other cancers that develop that we don’t know why. Lymphomas, for example—we have no [idea] why they develop. And one of the other things is that these other cancers are continuing to be a problem.
The other thing that has happened is that people have this idea that AIDS has gone away or not become an issue anymore. This is some data from the CDC showing the number of people living with AIDS in the United States. This is 1996, when HART came out, and, as you can see, the population of people with AIDS has not dropped. In fact, it continues to grow in this country. It has essentially doubled since the highly active antiretroviral therapy was developed. And what has happened is the number of people infected with the AIDS virus every year has been pretty constant—at about 40[,000] to 50,000—but they’re living longer.
In addition, a number of them are living for years and are getting older. The yellow and the orange and red is the age of the patient. As you can see, in the earlier days of the epidemic, it was mostly a disease of young people. Now the population is increasing, and it’s becoming an older population. This [is] actually a lot more HIV transmission in the older population, which is something that I really don’t want to go into at this point.
One of the other things that happened is that although [the rate of] AIDS-defining cancers—the three that I mentioned: Kaposi’s sarcoma, lymphoma and cervical cancer—has gone down, these non-AIDS-defining cancers have increased. Now, some of this is cancers that people get particularly in the upper years of life anyway—colon cancers and so on—but a lot of this is some of these cancers that are associated with viruses that can still take years to develop. Cancers like anal cancer, hepatocellular carcinoma, nasopharyngeal carcinoma. Lung cancer has increased radically, and we don’t know really why that is, to what extent—whether there’s another virus evolved or there’s more smoking in this population—so there [are] still some things that we need to tease out.
In fact, if we look at the number of cancers overall, the cancers reached a nadir about 1997 and have actually been increasing since then, with most of it being these non-AIDS-defining cancers, but a still stronger representation from some of these AIDS-defining cancers that still develop in this population. And this is some data from France where they have catchment areas. … [A]bout a third of the deaths of HIV have been due to cancer, and cancer has now become the most frequent cause of death in AIDS patients. So this is sort of the new emerging problem in the AIDS population.
A lot of our work in the Cancer Institute and my group has switched over to addressing these other cancers. It seems to me that with the development of the initial drugs and the fact that companies could make a lot of money selling them, to a large part, companies have taken over the development of AIDS drugs.
These cancers tend to be sort of orphan diseases, as there are many of them and are not [enough patients(?)] of them to get a strong industrial support, and we’ve been working with trying to develop therapies for them. These are some of the clinical trials that we’ve done either on regimens to treat cancers or other drugs. In some cases these were drugs that were developed for Kaposi’s sarcoma. In other cases, for example, we show that Taxol [inaudible] drugs that have been shown to work on other tumors and showed that they were active in Kaposi’s sarcoma.
In recent years we’ve been focusing on a disease called Castleman’s disease, which is sort of a very interesting tumor that develops … basically some cells that are infected with the same virus that causes Kaposi’s sarcoma but [inaudible] cells start increasing. They produced [what] were called cytokines, which rev up the immune system and make patients incredibly sick—basically the same sort of symptoms as if they had rip-roaring set sepsis infections. And patients used to die of this. We had noticed that some people with Kaposi’s seemed to get better when they were given high levels of AZT, and we always wondered if there was some interaction between AZT and this other virus. In fact, as people started understanding this virus in the enzymes, they discovered that one of the proteins in this virus, in KSHV, actually activated AZT to a different form—it put phosphate groups on it, which is the form that works against HIV, but it’s also toxic to cells. In fact, what we guessed was that enough of this might happen that cells that were infected with the virus might, if we give them high doses of AZT, might get toxic, and then we could selectively kill the cancer cells. We recently have been doing a trial with this, and we found that, in fact, most people with Castleman’s disease—these are two parameters of disease activity, C-reactive protein and interleukin 6—both of them got better fairly dramatically. We used a combination of AZT and another antiviral drug that is also active. So it’s been interesting to see a drug that we worked with early in the AIDS epidemic now having this different use and being helpful to this disease that, at least until a few years ago, had been quite fatal.
Just to give you a sense of what my career has been doing: One of the other things is, about six or seven years ago, the Cancer Institute asked me to lead a group that was coordinating the AIDS and AIDS Cancer Program throughout the Institute. I get a lot of the questions when I run into people in Bethesda: … “Why is the Cancer Institute still involved?” Because, as you can see, there’s a lot of problems in the cancers associated with HIV; that’s really a major problem.
Perhaps not so much in this country, but worldwide, as you can see here, the AIDS epidemic is really a major problem in other parts of the world. This is the estimated [number of] cases in North America. But the real epicenter is Sub-Saharan Africa, where you now have an estimated 22 million people infected. There’s sort of an epidemic in Russia right now, India has some, but Sub-Saharan Africa is really where most of the infection of HIV is in the world right now. And the other thing about Africa is that even before the AIDS epidemic appeared, this has been an area where TSHV which is a virus which actually evolved with the human species, was quite prevalent. It’s not known why it’s prevalent in some populations and not others, but as you can see, it was highly prevalent in Africa. This is HIV, and this is really the epicenter of Kaposi’s sarcoma, [which,] in some of these countries, is the most common cancer overall. Kaposi’s is often very, very aggressive in Africa.
And Harold Varmus [’61], who is now the NCI director, is also in Amherst graduate. He’s been very interested in doing global health … been interested in the AIDS epidemic around the world. So one of the things our office has been doing has been to start doing research in the diseases in Africa and also to do trials to try and figure out the best way of preventing and treating these diseases in low-income countries where you don’t have all the medical sophistication that you do in the United States. This is been an interesting phase of my career, while I continue to do some other work in the lab. For instance, Castleman’s disease isn’t reported in Africa. Given all the incidence of KSHV, it has to be very common there, and we’re trying to figure out why these cases are being missed and what to do about them.
So I thank you for your attention. I do want to give a few thanks here, and these are not usually the ones that I give in talks, but first of all, my parents, [who gave] me a good start. My wife, Giovanna, who’s been a colleague of mine—she’s also a principal investigator in the Cancer Institute and collaborated; we talk science a lot. My two sons, who are both here in the back—they’re both in college and have been an inspiration and entertain any questions…. I want to thank the college for my good start in science; my thesis advisor, Peter Offenhartz; my other mentors; my colleagues of the NIH. I really should thank the Cancer Institute for providing an environment and the American taxpayers for funding the research. That really made it all possible. And finally the patients who volunteered for our trials.