The TV crew, from an Italian network, was in the San Francisco Bay area last fall filming a show on venture capital. When the 2007 Nobel Prize in Physiology or Medicine was announced, they detoured to the University of Utah to interview Italian-born Capecchi, an HHMI investigator who shared the prize with Oliver Smithies (at the University of North Carolina at Chapel Hill) and Sir Martin Evans (at Cardiff University in the United Kingdom) for developing techniques that enabled the creation of “knockout mice.”

The OCD mouse is just one example. After Capecchi and then-student Joy Greer knocked out a gene called Hoxb8 in a mouse embryonic stem cell line, the mice derived from these cells engaged in compulsive grooming of themselves and neighbors. Though Hox genes are best known for regulating development, this experiment showed they could also control behaviors in adults.

When scientists want to understand what a gene does, one of the first things they do is create a mouse knockout. “I think it is the most powerful method we have for understanding the function of mammalian genes,” says Francis S. Collins, director of the National Human Genome Research Institute at the National Institutes of Health (NIH). Students today take for granted that knockout technology has always been around, he says.

When Capecchi was an undergrad at Ohio's Antioch College, molecular biology was a new field; he studied physics and chemistry. However, after a couple of obligatory work-study semesters in biology labs at the Massachusetts Institute of Technology, Capecchi knew he wanted to be a molecular biologist. During an interview at Harvard University, he asked James Watson where he should go for graduate school. Watson told him “here,” and that's where Capecchi went.

“He has probably told you about Jim Watson's advice, `Don't waste time on small questions,' which he took to heart, much better than most of us did,” says Ray Gesteland, a geneticist in Watson's lab at the same time and now a colleague at the University of Utah. “As a graduate student, Mario was clearly unique,” recalls Gesteland. “His experiments were always more elegant. They were designed better, and they worked better.”

When Capecchi was ready to leave Watson's lab, he got an offer from Harvard Medical School to stay and start one of his own. By the early 1970s, however, Capecchi was no longer happy at Harvard. “What they do there is hire a bunch of people all doing similar kinds of things and then watch Darwinian principles at play,” he says, observing that this created an incentive for scientists to work on short-term projects. Capecchi preferred the long term.

When the University of Utah came calling, promising him freedom to focus on big questions without having to justify his existence every couple of months, he had some qualms—one doesn't leave Harvard lightly. So, again, he asked Watson for advice. “He said you can do good work anywhere,” Capecchi recalls. With four students and their families, he picked up his lab and caravanned across the country.

Photo: Ramin Rahimian

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