Bold Move

It took a leap of faith for Tian Xu to move from Shanghai to Harlem in 1983, but he says the biggest risk he has taken during his career was switching a decade ago from fruit flies to mice as model organisms to study gene functions.

Xu had made his name at Yale and later as a postdoc at HHMI Vice President Gerald M. (Gerry) Rubin's lab at the University of California, Berkeley, for his Drosophila research— conducting large-scale analyses of mutant flies to decipher the roles of key genes and the biochemical pathways related to cancer cell growth and metastasis.

But when Xu applied for an HHMI investigator position in 1996, he made a bold proposal: he would discover a way to create mutant mouse strains as easily as developing mutant flies. That would represent a big step forward in genetic screening of mice, about 99 percent of whose genes have direct equivalents in the human genome.

“It was risky because I had a lot to learn about mouse genetics,” Xu recalls, describing the years of complex and often frustrating research that it took for him to come up with the deceptively simple breakthrough: using a moth transposon (“jumping gene”) called piggyBac. Inserted into the mouse genome, the tiny segment of DNA causes random mutations when the animal breeds, disabling one gene per mouse and creating an efficient way to create knockout mutants.

“Geneticists had been searching for decades to find a system like this for mammals—an efficient tool for transgenesis and mutagenesis,” says Xu, who displays a framed cover of the August 2005 issue of the journal Cell that featured his piggyBac report. “Now we have the tool and we need to produce the mutant mice strains for scientists to use in their research.”

With the new technique, scientists can produce the mutant mouse strains about 100 times faster and cheaper than they could with previous methods. And Xu says the Institute of Developmental Biology and Molecular Medicine at Fudan University in Shanghai, which he coestablished at the urging of Chinese officials, is able to produce such strains at a lower cost than a similar facility in the United States.

At the Fudan institute, which already houses 25,000 mouse cages, Xu and his researchers so far have produced about 5,000 strains of knockout mice. The goal is to produce 100,000 mutant strains by the end of 2010, among which scientists hope to eventually identify knockout equivalents for nearly all of the 25,000 or so genes in the mouse genome.

“I wanted to accomplish things with a real impact on society,” says Xu. “To do that, you need to take some risks along the way.”

- Robert Koenig
HHMI Bulletin, February 2010

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