Retroviruses, engineering and the future of science

A conversation with Harold Varmus and David Baltimore

Editor’s Note:  Drs. Baltimore and Varmus were interviewed separately in 2003, and their responses were combined in a question-and-answer format.

Bill Snyder
Published: April, 2004

Two of the nation’s most prominent Nobel laureates discuss recent scientific advances, including the potential to “engineer” the immune system to prevent viral infections, as well as the changing roles of government and the private sector in advancing the research enterprise, and the need to improve the public’s “science literacy.”

David Baltimore, Ph.D., president emeritus and professor of Biology at the California Institute of Technology, is a former director of the Whitehead Institute of Biomedical Research at MIT and former president of Rockefeller University. He shared the 1975 Nobel Prize with Howard Temin for identifying reverse transcriptase, and with Renato Dulbecco for other virological research. The discovery of the enzyme opened up the genomes of retroviruses and then all genomes for investigation. It also was the opening salvo in the very successful attack on the nature of cancer that has taken place since 1970, and set the stage for the discovery of HIV.

Harold Varmus, M.D., is president of the Memorial Sloan-Kettering Cancer Center in New York City, and former director of the National Institutes of Health. He shared the 1989 Nobel Prize with Michael Bishop for their discovery that the oncogene of the Rous sarcoma virus was not a true viral gene but was a normal cellular gene, which the retrovirus had acquired during replication and carried along. This led to the identification of a large family of genes that control normal cell growth and division. Mutations in these “oncogenes” can transform normal cells into tumor cells, and can lead to cancer.

Editor’s note: Drs. Baltimore and Varmus were interviewed separately in 2003, and their responses were combined in a question-and-answer format.

Where is the field of virology headed?

Varmus: One thing that’s happened in the last 20 years that really was unprecedented was the development of drugs that worked to treat viral illness. The idea of using protease inhibitors to counter viral infections had the earliest success with HIV. Now there is reason to believe that people are hot on the trail of developing protease inhibitors for the treatment of hepatitis C. That would be a tremendous advance, because hepatitis C is a virus that is still very difficult to grow.

One of the (other) things we’ve learned is how to work with viruses that can’t even be grown in tissue culture. That seems paradoxical, but we know enough about how to study viral genomes, and pull them apart so we can understand how parts of them work without having to grow the whole genome.

Baltimore: It occurred to me many years ago that … if you could modify the genetic inheritance of the cell, you could put into the cell something which could in principle totally prevent a virus from growing.

There is not today on the market any such form of “intracellular immunization” against infectious agents (but) in the last couple of years a new method of potentially inhibiting virus growth has appeared, which is called interfering RNAs. They interfere with the growth of a virus in a very potent manner.

So we started to see whether we could adapt this to HIV, by targeting the receptor on the cell. We worked very closely with the laboratory at UCLA run by Irvin Chen. What I call this whole line of work at the moment is “engineering” the immune system. And it raises all the problems that any engineering effort does: How to you make it happen? How to you deliver it? How do you make it safe?

What are some of the forces that will drive biomedical research over the next 20 years?

Baltimore: I think a lot of discovery is going to come from wedding fields that have traditionally been separate. I think there’s a lot of biological engineering that’s going to be done and that’s going to come about from traditional engineers as well as people with nanotechnology skills applying their techniques to biological questions.

Systems biology is looking at biological problems in a holistic way rather than piece-by-piece. It has the strengths and weaknesses of any holistic approach, the strength being that you are looking at things in a new way, and the weakness being that it’s very hard to do controlled experimentation when you have that number of variables around.

But I wouldn’t count out traditional modes of carrying out molecular biological research. The human genome was sequenced and turned up lots of genes, the functions of which we know very little about. So there’s an awful lot of work to be done just to fill out the catalog. And that’s going to turn up some very important and very surprising things.

Varmus: There are incredibly high levels of discovery at the moment. Wherever you turn, the tools are so much more powerful than they were 15 or 20 years ago, thanks to genomics, computer science and the number of ways in which we can make use of models of disease in a variety of organisms. Just about every field is prospering.

I meet with computational people at least once a week and I didn’t used to do that. It’s because we’re using different kinds of tools … that present a density of data that none of us had before. But the basic experimental design is still for the most part unaltered. Sure we use arrays to look at (gene) expression patterns. It broadens our view, but the important work still gets done one gene at a time.

Do you support the NIH “Roadmap,” a reorganization of the National Institutes of Health that is being undertaken by NIH Director Elias Zerhouni?

Varmus: Many of the things in the roadmap are the attempt to bring the NIH together to work as a single institution, something which has always been difficult to do, given the way in which the NIH has grown, and the way in which it has been established by Congress as a very large collection of independent units, more like a confederacy than a real union.

There are advantages to confederacy. But the important thing is to recognize when appropriate that every institute at NIH has a stake in common technology development.

One example where I think the work is particularly important is the effort to develop centers for training and research in computational biology, where the issues of multidisciplinary investigation are already very alive. And if Elias is able to keep the team together, despite the fact that the NIH budget is not going to be rising in the years ahead the way it did over the last five years, this would be a big triumph because it’s very much needed.

Baltimore: I believe that what Dr. Zerhouni is saying is that research has reached a new level of sophistication that we haven’t seen before, and that at this level of sophistication, we have to be able to think more strategically than we have in the past. And I happen to think he’s right about that.

It involves us in doing things in new ways, and as such is a little scary. I think it’s good to be experimental. It’s a measure of the success of the biomedical enterprise that we can start thinking in new ways, and we should be excited by that kind of success, rather than saying, “All we need is more of the same.”

How is the Grand Challenges in Global Health, a $200 million initiative supported by the Bill & Melinda Gates Foundation, adding to the nation’s research enterprise?

Varmus (who chairs the initiative’s executive committee and scientific board):

I do believe that the NIH has a major responsibility to address diseases throughout the world, not just diseases that are prevalent in the U.S. (But) I certainly don’t believe that NIH should be funding all the research that gets done. There are lots of other outstanding sources of funding for research … and these other sources ought to be applauded and sustained.

The real appeal of the Grand Challenges comes from its unique aspects; that is, trying to focus on what we as a scientific board thought to be obstacles (to) making much more rapid progress in confronting diseases in developing countries. The initial request for ideas resulted in our receiving over 1,000 proposals from well over 70 countries. We won’t know for several years whether this really works, but every step so far has been very successful.

How well are we training the next generation of scientists?

Baltimore: We’re doing a good job in training; the problem is, we don’t have enough people. In particular, the number of engineers and physical scientists who are being trained is just simply too small.

What we’ve been doing is using immigrants in the place of training our own people, and that’s worked perfectly well. We have large numbers of immigrants coming in continually from countries where they are training people in engineering and science, and those people play a central role in the biomedical enterprise and the general research enterprise in the United States.

Varmus: I have concerns about the way in which we’re training people. One of those concerns is the need to learn computation at the same time that one learns biology. This is something that can only be rectified by new curricula for undergraduates, by generating centers in which people who are trained in computation or statistics or computer science are side by side with biologists training students to know both languages.

What attracted you to a career in science?

Baltimore: First of all, I found it easy, and so I followed my nose. My mother (Gertrude Baltimore) was a scientist, and nudged me at critical times in my life into directions that were very powerful and very effective.

She studied experimental psychology with the Gestalt psychologists at the New School for Social Research. She taught at the New School for many years, and then went to Sarah Lawrence College where she taught for the rest of her career. She was a great teacher, and anybody I’ve every run into who was touched by her at Sarah Lawrence told me how special she was.

Varmus: I spent most of my college career running away from science. I did the premed requirements, but one of the things that was most important to me when I was at college was my work as an English major studying Charles Dickens … Then I went to graduate school in literature for a while before going back into medicine.

I was not particularly interested in putting on a uniform and going to Vietnam ... Because I was a reasonable student at medical school, it wasn’t all that difficult for me to get into a government program that would allow me to do research, in this case at the NIH.

I ended up, despite an almost complete lack of research experience, in the laboratory of Ira Pastan. He was a terrific mentor, and got me excited about molecular biology. The serendipity factor for most people has a lot to do with who you run into and how they influence you.

Why did you get involved in administration?

Varmus: I never saw the NIH as an administrative job. What I found interesting were the policy issues. What is the direction medical research should be taking? How do we show the public the best side of science? How do we advertise our science? I saw this as a chance to do public service.

Baltimore: I discovered long ago about myself that I am interested in the institutions that make science happen. A very important part of the scientific enterprise is the maintenance of strong institutions, because all science takes place in institutions. That’s where all the money goes.

I never thought that I would do anything about this interest until I was offered the opportunity to start the Whitehead Institute (in 1982). I found it extremely rewarding to do that. But at the same time, I haven’t wanted to leave behind my science, and so I managed … to continue to run a large laboratory.

How do we encourage more young people to go into the sciences?

Baltimore: We need more mothers like my mother! I really don’t know the answer because it involves our whole society, the way it functions and what it honors.

Developing the capabilities to be a scientist is very hard, because it involves learning a lot of mathematics and science, generally when you’re very young.

We don’t have a society that honors people who work hard. We have a society that honors people who play hard, that is great athletes or great entertainers. But the people who are really driving our society are anonymous. They are the scientists and engineers who are making the discoveries and devising the gadgets that make our lives easier and better.

Varmus: For our society probably a more fundamental issue is: how do we make citizens who are more capable of thinking in an evidence-based way? That actually is one of the biggest problems we face as a country, that we don’t teach people to do that, yet we could.

We could be giving virtually all of our instruction in grade school in a way that emphasizes experiment (and) observation … as opposed to rote and ritual. We’d have a more informed electorate. An awful lot of political issues these days are based on questions that have scientific component.

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