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QA: Nobel Laureate: “Keep Hoping the Future Will Save You”

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Lee Hartwell, president and director of the Fred Hutchinson Cancer Research Center in Seattle, was honored this year with the Nobel Prize in physiology or medicine for his studies of cell cycle behavior. By studying yeast, he first proved that the cell cycle is genetically controlled and later showed that the cycle has developmental checkpoints. Through the career that established him as a pioneer in genetics and genomics, Hartwell has pursued extensive cancer research and in 1996 co-founded Rosetta Inpharmatics with Stephen Friend and Leroy Hood. He recently took time to speak with GT’s Meredith Salisbury about his accomplishments and the state of the industry.

 

What did you do when you heard you won the Nobel Prize?

HARTWELL: It was about three o’clock in the morning when we found out, so it was a pretty hectic day in terms of news conferences. The center had a huge reception in the afternoon, and [there was] a reception at the University of Washington. We’ve had a couple of very nice celebrations.

 

What was your feeling when you were studying the cell cycle in yeast? What did you learn from it?

HARTWELL: Taking on something as complex as cell behavior was probably foolish at the time. But I think it just emphasizes the fact that it sometimes is worthwhile taking on something that is not technically possible at the time you begin it, and that technology and other advances catch up with you. We could not have imagined DNA cloning coming along at the time we started the project. You just keep hoping the future will save you.

Is your work in genomics or genetics?

HARTWELL: Genomics is really in concept an attempt to be comprehensive. It has its roots in genetics: any time one does a genetic search for mutants, you’re doing genomics because you’re letting the cell tell you what genes you’re looking for. There were very important roots to the current genomic technology from the very beginning — geneticists are approaching biology from a systematic and comprehensive way.

 

What are the latest projects you’re involved with?

HARTWELL: The thing that I’m interested in now is genomic diversity. The human population is outbred and has all this diversity — so my lab, small as it is, is beginning to work in this area of genetic diversity. Most of the model organisms that we deal with in the labs — yeast, worms, flies, zebrafish — are all highly inbred so we can see a discrete phenotype. We have this whole mentality of a very precise phenotype for a gene and function for a gene, but when you start comparing you often get very different phenotypes. This whole concept really had the rug pulled out from under it. I think we just have not coped with the complexity of the genotype-phenotype relationship.

 

What made Rosetta a worthwhile genomics venture to you? Have you invested in or explored any other such opportunities?

HARTWELL: My main interest was in using yeast as a model for drug discovery and the potential power of transcript arrays to reveal the target of a drug. So with yeast we could compare a gene deletion with a drug-treated cell, and the idea was that if the patterns were the same that meant that the drug was acting on that gene very cleanly.

That was my only acquaintance with companies. In fact I never did have much of a role in it; I was in a scientific advisory role until it was sold to Merck.

 

And is the Fred Hutchinson center working with the Institute for Systems Biology?

HARTWELL: Lee Hood’s institute is fairly new. There are certainly scientific collaborations going on between scientists at the two institutions, and we are talking about more a formal affiliation agreement.

 

You’ve been especially interested for some time now in cancer research. From your work in the cell cycle and cancer fields during the past 30 years and what you’ve seen, where do we stand?

HARTWELL: Where we’re at, I think, is that a tremendous amount of work in model organisms and genetic approaches has created a pretty good catalog of gene function in cells and development. We have a fundamental insight into what cancer is: the mutation of a half a dozen genes in the human genome that affect cell behavior — cell cycle, angiogenesis, these kinds of things. We’re at that stage where we know what a lot of the players are, and the pathways that are often affected. We know that there are a relatively small number of changes. But with that insight, we’re now faced with tremendous complexity. There are more than a hundred types of cancer; that would be much too great a complexity to deal with by past technologies. The hope is that genomic technologies will take us to the next level because they allow us to deal with the complexity. Having that information will be very important not only in molecular therapeutics, but also [for] major advances [in] sensitive diagnostic techniques, earlier detection, and prevention.

 

Some critics contended that the people in charge of sequencing the human genome were motivated more by the Nobel Prize than by scientific ardor. What’s your feeling, and do they deserve the prize?

HARTWELL: Well, I haven’t heard that allegation. I have no idea what people’s motives are, nor do I have any insight into what criteria are used to award the prize. I do feel myself that the prize is used to point out major accomplishments in a field. I think the human genome certainly deserves that recognition. I am being recognized with my colleagues for the whole field of yeast genetics, and I certainly think it would be worth recognizing the ability to deal with genome information with the prize, though I don’t know who would be the appropriate people.

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