Molecular biology professor David Botstein awarded $3 million prize

Molecular biology professor David Botstein was awarded a $3 million Breakthrough Prize in Life Sciences Feb. 20 for his work in developing a technique to map genes causing inherited diseases on the human genome. The award recognized 11 scientists who have made groundbreaking achievements in fighting disease and prolonging human life.

The $3 million prize has the largest purse of any academic award for medicine or biology, awarding more than twice the Nobel Prize. According to the prize’s website, it aims not only to recognize the achievements of the winners but also to create a splash big enough to make these scientists household names and make science visible at a broader level. The founders have pledged to award five prizes annually.

Eric Lander ’78 was also a recipient for his role as a leader of the Human Genome Project. Lander graduated as valedictorian, and he is the founding director and current president of the Broad Institute of MIT and Harvard.

The Breakthrough Prize was founded by some of the biggest names in genomics and technology, including Facebook CEO Mark Zuckerberg, Google co-founder Sergey Brin, chairman of Apple Inc. and former CEO of Genentech Art Levinson, Yuri Milner, Anne Wojcicki and Priscilla Chan. It follows on the heels of a similar award in fundamental physics, headed by Milner and Steven Weinberg.

The prize’s guidelines do not stipulate how the money should be spent, and it is awarded specifically to the individual scientists. At present, Botstein said he has not decided how to use the money, though he hopes to put it to good use.

A novel method to map the human genome

In 1980, Botstein and his colleagues published his prize-winning technique, which systematically maps the human genome according to DNA polymorphisms.

Prior to his discovery, geneticists understood that some genes controlling different traits don’t get inherited independently, as Gregor Mendel had found, but are sometimes linked in inheritance because they reside near each other on the same chromosome. During reproduction, these genes could be separated by “crossing over” during the formation of eggs and sperm.

In 1913, Alfred Sturtevant showed that the frequency of crossing over can be used as a measure of distance between parent genes, and genetic mapping became possible in all kinds of organisms. This method relied on being able to make experimental crosses between organisms at will, and to collect the progeny and analyze them over several generations. Before Botstein and his colleagues published their paper in 1980, there was no way to do this with humans.

Botstein said that during a discussion with his colleagues, he had the idea to use DNA polymorphisms — sequence differences in the same species’ DNA across populations — to detect these crossing-over locations, measure their frequency of recombination and to begin to map out the human genome without having to perform experimental crosses.

“We had an epiphany that there was a way to do this retrospectively in human families,” Botstein explained. He and his colleagues proposed to use the many polymorphisms, or differences, in individual sequences of DNA as identifying flags on each chromosome, just as the FBI might do today to identify a person.

“With just a few hundred of these [polymorphisms], you could guarantee that any gene that is inherited and that causes a disease will be near one or more of these signposts,” he explained.

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Botstein’s technique has been applied extensively to the study of inherited diseases, including Huntington’s disease and cystic fibrosis. It was this technique that first made possible the tracking of genetic disease.

At U., a leading scientist-professor

Botstein’s work as a scientist has evolved with advances in technology. Post-Human Genome Project, Botstein runs a genomics lab at Princeton that works with yeast. He studies genes as an interactive system throughout their life cycle in metabolic homeostasis, and as they evolve. He has been a leading figure in several stages of progress in genomics and molecular biology, as well as in Princeton’s Integrated Science Curriculum.

Botstein is also the director of the Lewis-Sigler Institute for Integrative Genomics and teaches in the ISC.

According to his students, Botstein is known for advocating for the appreciation of undergraduates in the lab.

“He’s really enthusiastic about getting undergraduates working in labs early,” said Krysta Dummit ’15, who worked in Botstein’s lab this past summer. Dummit said Botstein encouraged her to give weekly presentations of her research, though most students only present their work at the beginning and the end of the term, which she said challenged her to understand the logic in the methodology of her research.

“He expected you to remember what you’ve already learned, which I think is the sign of a really good teacher — that he still cared after a class that you remembered what he already taught you,” said Dummit.

While Botstein is currently on sabbatical, he taught ISC courses and graduate seminar MOL 515: Method and Logic in Quantitative Biology in the fall of 2012. His co-teacher in that course, molecular biology professor and Associate Director of the Lewis-Sigler Institute Ned Wingreen, said he admires Botstein for his “energy” and sense of humor.

“All the students feel [his energy] and it kind of builds on itself,” Wingreen said. “One of the things that I’ve tried to learn from him is that sense of sharpening the question and figuring out what is the critical experiment to do. David is really masterful at that.”

Wingreen explained that Botstein holds high expectations for both his colleagues and students. “He is really an egalitarian,” Wingreen said. “It’s also wonderful in the classroom to have David talk about things because he has been there and done that. He demystifies things, and he explains why things were done a certain way. He really brings the logic to life.”

According to the rules of the prize, Botstein and this year’s 11 other laureates will sit on the committee that decides next year’s winners. Botstein says he’ll look at the impact of a candidate’s discoveries in thinking about next year’s recipients.

“Success in science means that the entire learned world thought about some subject in a particular way, and now through the efforts of you and your collaborators, they’re obliged to think about it differently,” Botstein said. “Now, nothing I did was of that great a magnitude, but that’s the idea.”