Mapping the path of genetics

Twenty-seven years ago, in a resort town high in Utah's Wasatch Mountains, David Botstein had a simple idea that would change the course of genetics.

Botstein, then a professor at MIT, was in town for an informal meeting of University of Utah researchers. Listening to a graduate student discuss genetic markers of disease, he had a striking thought.

He knew that natural variations in individuals' DNA sequences were already used to study diseases such as sickle cell anemia. But if these inherited variations were studied throughout the entire genome, he thought, a scientist could do more than mark abnormal genes. With a little patience and some large families, a complete chart could be made, predicting the locations of many genes through their correlation with the variants.

In other words, the human genome could be mapped.

This insight, published in 1980, was a milestone in genetics. It laid the foundation for one of the most important scientific undertakings in recent history: the Human Genome Project. It also established Botstein — now director of Princeton's Lewis-Sigler Institute for Integrative Genomics — as a pioneer in genetics.

"It was an 'aha' moment," Botstein said. "As soon as it was out of my mouth, I knew that it would work, that you can map any gene. I still don't understand why nobody thought of it before."

Botstein, who came to the University in 2003, has been at the forefront of genetics ever since. In addition to creating techniques for genetic mapping, he helped sequence the yeast genome and pioneered microarray technology, which allows scientists to assess the behavior of many genes at once.

"He is a towering intellect in the field of molecular genetics," said President Tilghman, who has known Botstein for 25 years and recruited him to the University. "He's one of a handful of the greatest living geneticists."

Botstein, a member of the National Academy of Sciences and the Institute of Medicine, has won numerous awards, including the prestigious Genetics Prize of the Peter Gruber Foundation.

In addition to his research, Botstein has recently taken on a new task: preparing students for the post-genome era. And it is in this role that he has already left his mark at the University, just two years after arriving.

In his leadership of the Lewis-Sigler Institute, and his creation of an "absolutely revolutionary curriculum for freshmen and sophomores," Botstein has been "every bit as amazing as I knew he would be," Tilghman said. "I knew exactly what Princeton was going to get, and he has not disappointed me at all."

Background for discovery

Though he has always been interested in science, Botstein didn't start out as a geneticist. At Harvard in the early 1960s, he was a physics major first, and then switched to biochemistry. It was only when he left college that he became interested in the burgeoning field of molecular genetics.

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Genetics "looked like more fun," Botstein said, because unlike physics, it didn't make him feel like "a small cog in a large machine."

After pursuing a doctorate in human genetics at the University of Michigan, Botstein returned to the East Coast, where he rose through the ranks at MIT from lecturer to professor.

In 1987, after 20 years in academia, Botstein was ready for something new. He joined the private sector and became vice president of science at the biotechnology firm Genentech.

Botstein remains a consultant for the firm to this day, but left his position within three years to become chair of the genetics department at Stanford. "I didn't enjoy managing 500 people," he said.

But his time in industry remains a defining experience in his life. "I would recommend to every serious scientist the idea of spending some fraction of your time thinking about what's important for health, for society," he said. "[Working in industry] is as good a way as I can think of."

"Directly or indirectly, I had a small part in producing a number of drugs that make a big difference," he added. "There's a big reward for that. [It's] different than having your name on a paper."

Today, Botstein remains an active researcher and still publishes regularly. Like much of his work, his new discoveries could have implications for curing diseases, particularly cancer.

Asked to choose the most fundamental contribution he's made over his 40-year career, Botstein couldn't answer. "It's like having to choose among your children," he said.

A Princeton education

The most fundamental contribution Botstein has made at Princeton, however, is clear: the formation of an Institute — and a curriculum — unique in the country.

The Lewis-Sigler Institute is about the "interface of biology with physics and computation," Botstein said. Instead of isolating the science departments, the Institute hopes to encourage collaboration, so that scientists can pool their expertise to solve previously unapproachable questions.

"The idea is that the genome sequences have really put us in a position to do a kind of science that was only a dream just 15 to 20 years ago," Botstein said. "In order to take advantage of all the technological advances ... we have to educate ourselves and the students differently."

To this end, Botstein worked with a team of faculty to develop an integrated science sequence for freshmen and sophomores, which was first offered last year. Instead of taking chemistry, computer science, molecular biology and physics separately, students in the sequence take one two-year course that combines all of the fields. Botstein hopes the sequence will prepare students for post-genome era research.

"It's been a long time since anyone's looked from the ground up at what's important, and what's merely traditional," Botstein said. "So far, I've been happy with how it's gone."

Tilghman has, too. "What makes [Botstein] so unique is that he comes with a passion for undergraduate education," she said. "He's committed to inspiring students to love science the way he's loved science his whole life. Not as a set of dry facts in a textbook that you've got to memorize, but as a dynamic, living set of questions whose answers will really matter to the way we think about the natural world."