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An Interview With Harold Varmus
Errol C. Friedberg Nature Reviews Molecular Cell Biology 9,502-503
July 2008

Author Affiliations

Department of Pathology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, Texas 75390-9072, USA.
Email: errol.friedberg@utsouthwestern.edu

Harold Varmus was born in 1939 and began his academic career by studying English literature at Amherst College and Harvard University, Massachusetts. After medical school at Columbia University and a residency at Columbia-Presbyterian Hospital, both in New York, and postdoctoral training at the National Institutes of Health (NIH), Bethesda, Maryland, he jointly received a Nobel Prize in 1989 for his research on retroviruses and oncogenes with J. Michael Bishop at the University of California, San Francisco.Four years later, Varmus became the first Nobel Laureate to be appointed Director of the NIH, where he guided the agency to unprecedented financial resources for biomedical research. In 2000 he was appointed the President and CEO of Memorial Sloan-Kettering Cancer Center in New York, where he also runs an active research laboratory.

Question: How has molecular biology changed since the 'golden age' in the second half of the twentieth century?
Answer: It can be difficult to define the 'golden age'. My own view is that the golden age of molecular biology started with gene cloning. That's when things really started to move. Perhaps my perspective on this is a little different from that of many others who grew up in that era. I
came to medical school from a background in English literature, entering with a primary interest in psychiatry and leaving headed for internal medicine - not basic research. During the Vietnam War, which I opposed, physicians were subject to the draft, so I was fortunate to obtain a Public Health Service commission to work in Ira Pastan's laboratory at the National Institutes of Health (NIH), Bethesda, Maryland, USA. When I was assigned to him in 1966, he was an endocrinologist and biochemist working on cyclic AMP (cAMP) in the thyroid, and he wasn't really doing molecular biology. But by the time I joined him in 1968, he had become interested in cAMP as a possible regulator of bacterial gene expression
and was teaching himself molecular biology.

Although I was coming to laboratory work relatively late (at the age of 28), with essentially no experience, it didn't take me long to sense the power and pleasure of combining genetics and biochemistry with molecular methods, like nucleic acid hybridization, to answer fundamental questions. Even so, before the era of gene cloning, molecular biology was painfully slow, because the tools available were very limited. For example, both in Ira's laboratory and in my subsequent work with proto-oncogenes, we were very dependent on transducing viruses, phage or retroviruses, which happened to carry interesting cellular genes. With molecular cloning, it now takes a student no more than a month to accomplish what would have taken several years in the late 1960s or early 1970s.

 ...it didn't take me long to sense the power and pleasure of combining genetics and biochemistry with molecular methods...

Q: Your career route was to get a medical degree first and then to go into the laboratory with minimal research experience. How do you think this compares with the combined M.D.-Ph.D. approach?

A: M.D.-Ph.D. programmes provide superb training, but at a very high price: the long M.D.-Ph.D. curriculum, followed by clinical residency and often clinical fellowship training, delays the time before young investigators are ready to take an independent job and apply for their first major research grant. My approach of going straight from medical school and
residency into the laboratory didn't exactly prepare me well for research. During the Vietnam War, physicians in the United States who were keen on doing biomedical research could fulfil their military obligation by becoming commissioned officers at the NIH. These
commissions were very competitive, but I managed to win one. In addition to working in a research laboratory, a diverse array of courses allowed one to learn biology at the same time. People typically took heavy course loads to learn what they had missed by not going to graduate school. But their careers then accelerated very quickly. So within a few years of leaving the NIH, still in my early thirties, I was a faculty member at the University of California, San Francisco (UCSF) and applying for grants. Of course I had recognized by then that I wasn't interested in practicing medicine, which cut down on the time I might
otherwise have spent on clinical training. But now, with the large number of people seeking academic positions, prolonged training periods may be important, or even necessary, especially for M.D. graduates, in order to be competitive for faculty positions.

In recent years I have become very interested in trying to identify college students or recent graduates who have already decided that they want to pursue careers in disease-orientated research, but don't want to practice medicine. Such people should not necessarily go to medical school. They should instead consider doing Ph.D. programmes that have heavy emphasis on understanding human disease. Unfortunately, there are few programmes of this type in the United States. At Memorial Sloan-Kettering Cancer Center we have recently begun such a programme, offering a Ph.D. in cancer biology. Our students are not only grounded in the principles of modern biology; they also have direct contact with outstanding physicians and with patients and become familiar with cancers as disease entities. So they come to understand not only cell signalling and genomic stability, but also radiotherapy, chemotherapy and targeted therapy. The programme has attracted enormous interest and
a large number of students apply each year.

Speeding up the educational process and ensuring that people can begin their research careers early is very important. When people are young, they have more energy and are free of other responsibilities, enabling them to immerse themselves more fully in science.

Q: Do graduate students need new or different skills to be successful in cutting-edge biomedical research?

A: It's always beneficial to have graduate students in the life sciences who have been trained in physics, chemistry and even mathematics. Drawing from my own experience, I believe that the two most important allied disciplines for the life sciences are computational biology and
chemistry. I think that we possibly undervalue engineering; those skills can lead to the development of new and important technologies and to new ways of understanding how cells work. After all, many of the proteins we study in my own field of cancer biology are components of complex molecular machines; understanding the principles of engineering can
provide important insights into those machines. Similarly, knowing sophisticated chemistry surely is important in understanding protein-protein and small-molecule interactions that are relevant to developing new therapeutics.

Has the current focus on biomedical science by large groups changed the practice of research?

A: Well, there's still a lot of small-group science going on. One of the major changes we have experienced is the enormous breadth of research opportunities in biomedicine, some of which justifiably call for very large groups. But at the end of the day, it boils down to trying to understand how individual genes and their products work. It may take a large group to screen the human genome for genes of interest, but once those are identified, their in-depth study usually progresses by traditional small-group research programmes.

Q: How should we address the problems associated with the crowding in biomedical science nowadays?

A: If by 'crowding' you mean that there are now more senior people still active in research compared with a time when retirement was mandatory, I am not convinced that this is a large problem. There is talk about unclogging the system at this level, but I suspect the number of those active in science beyond what used to be retirement age is still quite
small. Furthermore, I believe that the research enterprise should function as a strict meritocracy, regardless of age. So older people should be evaluated in exactly the same way that young investigators are, and people should not be allowed to dominate precious resources, such as money and space, at universities simply because they are senior
faculty members.

The real problem is that there are many more grant proposals that deserve funding than the funding systems can support. Research has become more complex and expensive. The doubling of the NIH budget in recent years allowed us to catch up from the serious resource
limitations we had prior to that doubling, but the budget has shrunk by 12% during the past four years, while the number of grant applications has increased dramatically. This has created a huge waiting list for grants that deserve support. Even though the NIH budget is very large relative to research budgets in most other countries, there are so many outstanding opportunities now that the lack of funding is limiting scientific progress. Besides, the NIH budget is very small relative to what we spend on health care. We need to continue to increase our investment in basic and applied research.

Q: Do you have any pet peeves about the system of peer review?

A: The aspect of peer review that troubles me most occurs not in journals, whether open access or traditional, but in the context of faculty appointments and promotions. To my mind, too much emphasis is being placed on publication in so-called high-profile journals. This is a 'disease' that has arisen, in large part, from the way in which many academic institutions evaluate their faculty members. Academic institutions tend to focus on where papers are published rather than on the absolute scientific value of what is in the papers. We need to change this. Taking a leaf from Howard Hughes Medical Institute procedures for the appointment and promotion of faculty members, at Memorial Sloan-Kettering Cancer Center we ask candidates who are up for promotion to identify what they consider to be their four or five best publications, regardless of where they were published, and to explain
why these papers are important. The names of journals should not be used as adjectives the way they are now. There's no such thing as a 'Nature paper' or a 'Science paper'. There are only papers that do or do not do a good job in advancing a particular field or idea. Of course, journals like Nature and Science publish a lot of good work. But good work is
also published in many other places!

Academic institutions tend to focus on where papers are published rather than on the absolute scientific value of what is in the papers. We need to change this.

Q: In which areas in biology can we expect to see the greatest advances in the next few decades?

A: Big things are happening in the neurosciences and also in the stem-cell field; I think that both of these areas of investigation will yield huge dividends in the near future. In oncology, my own field, we are identifying cancer genotypes at an impressive rate, and in some cases we
are identifying new therapeutic opportunities and occasionally seizing them successfully as well. As a result, there is likely to be a lot of progress in treating cancer in the next couple of decades. Advanced countries are facing a huge public health problem with Alzheimer's
disease and other forms of neurodegeneration, and I am cautiously optimistic that the neurosciences will make progress in these areas. But understanding consciousness, cognition and emotion in molecular terms seems very far off.