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Unit 7: Flossie Wong-Staal

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Flossie Wong-Staal is a pioneer in research on AIDS, a topic discussed in this unit. She is credited with being the first to clone the retrovirus HIV and map its genes. This work, carried out in the laboratory headed by Robert Gallo at the National Cancer Institute (NCI), paved the way for the development of more sensitive and reliable tests for the presence of HIV in blood. After growing up in Hong Kong, Dr. Wong-Staal moved to Los Angeles, where she received her B.A. in bacteriology and Ph.D. in molecular biology from UCLA. She went to the NCI after postdoctoral work at the University of California, San Diego. Back at UCSD since 1990, she is the codirector of the AIDS Research Institute and a professor of biology and medicine, holding the Florence Riford Chair in AIDS Research.

What led you to retroviruses?

My interest in retroviruses first came about because of their value as tools in molecular biology. When I was in graduate school, RNA tumor viruses (retroviruses that cause cancer in certain animals) were generating a lot of excitement, particularly the discovery of their reverse transcriptase, which offered a potential tool for gene cloning and analysis. The most fascinating thing about these RNA tumor viruses was that many of them had essentially cloned a cellular gene, which acted as an oncogene—cancer-causing gene—in the cells it infected. Later we learned that some RNA tumor viruses do not carry oncogenes but produce cancer in other ways. Anyway, I became very interested in RNA tumor viruses.

After postdoctoral work at UCSD, I joined Robert Gallo's group at the NCI. Not only were they studying retroviruses but they were interested in determining if retroviruses were involved in human disease.

Was this unusual? Weren't other labs also looking for human retroviruses?

In those days, many people didn't think retroviruses had any role in human disease. Yes, the Rous sarcoma virus caused cancer in chickens, and other RNA tumor viruses caused cancer in inbred lab mice, but these viruses were regarded as flukes (accidents of nature). Most scientists working on retroviruses thought of them mainly as convenient tools for doing molecular biology, not as important disease agents in the real world. Some people even referred to the viruses we were seeking as "human RNA rumor viruses" because they didn't believe such viruses existed. But our lab kept at it. We were encouraged by the appearance of evidence that retroviruses could cause leukemia in cats and cattle.

What were the results of this research?

The persistence of people in our group paid off with the discovery of the first human retrovirus, HTLV (human T cell leukemia virus), which causes a type of leukemia affecting the white blood cells called T cells. I was heading the molecular biology section of Gallo's group, and we immediately began to study HTLV. Soon it became clear that HTLV was unlike other known retroviruses in that it could turn on its own transcription in the cell—it was not solely dependent on cellular proteins.

It was now the late 1970s, and AIDS was becoming known as a specific disease that attacks the immune system. But what caused AIDS? Every causative agent imaginable was suggested, from chemicals to fungi. Bob Gallo and a few of his colleagues thought that a retrovirus might be involved. There are actually some parallels between AIDS and the leukemia caused by HTLV. Both diseases affect T cells, although leukemia causes T cell proliferation and AIDS causes T cell depletion; and both diseases are transmitted by blood or other body fluids and can be passed from mother to fetus. In addition, the feline leukemia virus was known occasionally to cause depletion of white blood cells.

People who thought that the cause of AIDS was likely to be a virus formed an international task force. There was a spirit of cooperation and frequent collaboration. We exchanged reagents, as well as tissue and blood samples from patients. This work finally led to the isolation of HIV in our lab and also in the lab of Luc Montagnier at the Pasteur Institute in France.

In light of the fact that the relationship between the Gallo group and the Montagnier group became contentious, what are your thoughts about collaboration and competition in science?

A certain level of competition is healthy, I think. It certainly spurs you on and hastens discoveries. A good example in the area of art occurred during the Renaissance. Why were so many masterpieces of art produced within such a short period? Part of the answer, I think, was competition. Artists saw what others were doing and wanted to outdo them. Competition contributes to higher aspirations and thus to greater achievements.

But competition can be overdone. Unlike art, science requires collaboration, especially these days. Research questions are often very complicated and also multidisciplinary. No single scientist can do it all. A virologist, for example, might need to collaborate with a structural biologist, a clinician, a statistician, a protein chemist, or a geneticist.

What motivates you as a researcher?

For me, as for most researchers, the main motivation is simply the satisfaction of making discoveries, finding things out that no one knew before. However, we are now at an interesting time, when there is no longer a clear dividing line between basic, "pure," research and applied research. The case of AIDS and HIV is an obvious example of how basic research can quickly lead to important practical developments, such as diagnostic tests and treatments. It adds to the joy of discovery to know that your work may make a difference in people's lives.

On the negative side, the potential for commercial application of a discovery can cause problems. The controversy surrounding the discovery of HIV was, I think, blown out of proportion because of the patent issue and the commercial implications of the discovery.

Why don't we have an AIDS vaccine yet?

Before AIDS emerged on the scene, there was a lot of optimism about conquering infectious diseases, to the point that some medical schools actually did away with infectious disease departments. It was thought that antibiotics and vaccines would quickly conquer all such diseases. And it was known that the immune system alone can overcome many infections.

A viral vaccine consists of inactivated ("dead") virus, viral proteins, or a mutant virus that isn't pathogenic. The vaccine primes the immune system without causing disease. Then, if the pathogenic virus comes along, the immune system destroys it.

Unfortunately, HIV differs in some major ways from most other viruses. First of all, as a retrovirus, it integrates its genetic information into the host's DNA and remains latent even when progeny viruses are not being made. This is a big problem for HIV patients undergoing drug treatment. You think the virus has completely gone away because there's no sign of any viral proteins. But, once you take away the drug, the virus can become rampant again.

The second problem is HIV's diversity. We're talking about millions of variations, which result from mutations. We would of course expect strains of the virus from different places to be different. But with HIV, even when we examine the viruses isolated from a single person at a single point in time, we see a very diverse population. The population continually changes in response to external factors. For instance, in the presence of a drug or antibodies produced by a vaccine, any viral variants that happen to be resistant will out replicate the others and come to predominate. So the virus is a moving target. Any weapon used against it has to be so broadly effective that the virus cannot mutate to escape its effects.

The third problem is that HIV attacks the immune system, the very system that's supposed to combat it. And not only does it demolish immune cells, but many of the chemical signals involved in the operation of the immune system actually help the virus replicate! So we have a serious problem: If we try to counter HIV by stimulating the immune system, we also stimulate the virus!

Finally, there is the practical problem of not having a good animal model. HIV doesn't infect rodents, and even with monkeys we have to use a related virus rather than HIV itself. Chimpanzees are infected by HIV, but they don't get sick.

Right now, many people think that a vaccine to block infection completely may not be feasible, but that it may be possible to develop a vaccine that lowers the amount of virus to a point that is too low to cause disease. That would also decrease the transmission of the virus.

For the time being, I think AIDS prevention by education is probably the most powerful way to stem the epidemic. There has been progress along this line in some developing countries. Thailand, for example, has had considerable success with education campaigns and other preventive measures, such as condom distribution. Ultimately, however, a vaccine would certainly be the cheapest and most effective way to combat AIDS around the world.

Besides a vaccine or drugs, are there other approaches to prevention or treatment?

One approach we're working on is gene therapy. It's not likely to be the answer in the near term because gene therapy is not yet a mature field; there are technical problems we just can't overcome right now. However, eventually gene therapy may be useful. The idea is simple: You introduce genes into the target cells of HIV to block infection. What might these introduced genes be? We are using synthetic genes whose transcripts are ribozymes that recognize and cut up HIV RNA, inactivating it. We have a lot of data showing that this method works at the cellular level; and, in collaboration with clinical researchers, we have even shown that it can work in T cells inside the body. But for the ribozyme genes to work in a patient for the long term, they would have to be put into stem cells and remain permanently active.

Another approach we are taking is to look for cellular genes that are essential for HIV replication. A treatment doesn't necessarily have to target the virus; instead, it could target cellular genes that are critically important for the virus but not for the cell. This approach won't immediately lead to anti-HIV drugs, but rather to the identification of molecular targets against which drugs might be developed.

What is your advice to undergraduates considering a career in medical research?

You need to have a passion for making discoveries because this is the most rewarding aspect of a scientific career. But you also have to realize that if you choose this career, you're in for a long haul. "Eureka" moments are few and far between. So before deciding, it's important to go into a research lab, both to get some experience with the scientific process and to see the kind of hard work that's required. It's also helpful to expose yourself to the passion and enthusiasm of outstanding scientists, by attending seminars, for instance. In this way, you can get a glimpse of the dedication that science requires and also the satisfaction it can provide.






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