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A U.S.-China odyssey: Building a better mouse map


SHANGHAI » Xu Tian embodies the American dream to an extent that many of his fellow Americans might well envy.

So what is he doing in China?

Part of the answer lies here, on the sprawling grounds of a former military airfield. It is the new campus of Fudan University in Shanghai, mammoth ersatz-Roman classroom buildings erupting from the flatland the way American land-grant universities sprouted classrooms in their salad days, 50 to 60 years ago. Here is a gigantic new law school. Over there is a hulking biosciences building.

And here, Xu said, are his two homes for lab rats.

"There are 20,000 cages here," he said, almost nonchalantly. "That one over there has 25,000. Each one holds a maximum of four or five animals."

Xu is a world-class geneticist, a Yale professor and one of roughly 340 American scientists endowed by the Howard Hughes Medical Institute to pursue their wildest research desires. He seeks a holy grail: the key to what makes a mouse tick, gene by gene by gene. The implications for human health are profound, as the mouse and human genomes are substantially the same.

At Yale, he devised a process that allows mass production of genetically altered mice, an important step toward decoding the genome. At Fudan, he perfected it, and he is putting it to work at laboratories that hold one of the world’s largest collections of test animals. Soon, the new campus will sprout another building in the neo-Classical style: the Fudan Institute of Developmental Biology and Molecular Medicine, of which Xu is a co-director.

The Chinese government built them all, gratis.

In a sense, Yale and the Hughes Institute have outsourced the genome project to a place where labs are built quicker and more cheaply — "China speed," Xu said, half-jokingly — and where talented young scientists work for a pittance.

"Realistically, with the flatlined budget in science, one can imagine he’d have to spend six times the money he’s spending in China" to duplicate the labs in the United States, said Jack E. Dixon, the Hughes Institute’s vice president and chief medical officer. "It’s probably just not possible in the United States to do that on the scale that he wants to do it."

Xu now leaves Yale for Shanghai about three months a year. Other American scientists of Chinese descent are moving for good, lured by a lavishly financed government campaign that offers foreign scientists ample money and a chance to make waves in what is still a small research pond.

But were money the only issue, Xu might not be here. For while he is a thoroughly naturalized American, Shanghai and Fudan are where he was born, and where he ultimately found his calling. He left China for the United States 27 years ago, chasing a dream he thought unattainable here.

Xu does not want China’s young scientists to be denied their dreams, and not every aspiring Chinese scientist is lucky enough to make it to Yale.

"This has made students realize it’s possible to do first-class research in China," he said in a long interview at his Spartan Fudan office, one wall covered by a scribble-filled whiteboard. "That’s a very important change in the mind-set. It makes them more willing to take on high-risk projects and ask big questions."

Xu’s own rise was a matter of luck — and boundless ambition. He was born in 1962 in Jiaxing, about 50 miles southwest of Shanghai, to a onetime college literature professor and his wife, a union leader at a silk factory. Reviled for his educated status during the Cultural Revolution, Xu’s father was sent to a labor camp; his mother was publicly persecuted. In middle school, Xu suffered daily criticism.

"I was really full of anger," he said. "The school principal would come to me and say: ‘How come you are in school? We aren’t supposed to educate people like you. You’re the kind we punish.’ " The principal had studied under Xu’s father in college.

When the Cultural Revolution ended, he enrolled at Fudan. Determined to avoid being labeled an elitist, he chose the most obscure major he could find. Fudan’s genetics department, the only one in China, was led by C.C. Tan, a brilliant scholar educated in the United States.

Xu became his protege, and he graduated with honors, eventually winning a stipend in 1983 to attend City College of New York. Broke and barely able to speak English, he lived with fellow students in an abandoned house on 140th Street in Harlem, subsisting on bread and bananas.

In his first week, Xu was mugged at knifepoint. "In the Cultural Revolution, I go through a lot of hardships, so that’s OK," he said.

But he quickly discovered that City College lacked money to finance his real love, laboratory research. So after fruitlessly scouring New York for another scholarship, he took a train to New Haven to plead his case at Yale, where he won a fellowship despite his poor English and lack of credentials, like graduate exam scores.

After postdoctoral work on fruit-fly genetics at the University of California in Berkeley, he returned to the Yale School of Medicine. In 1996, he pitched a radical idea to the Hughes Institute: breeding genetically altered mice with the ease that scientists produced mutations in fast-breeding fruit flies.

The first scientist who produced genetically altered mice won the 2007 Nobel Prize in Medicine. But breeding mutant mice was a laborious, one-mouse-at-a-time process. A decade of trial and error rewarded Xu with the jackpot: a butterfly gene, nicknamed piggyBac, that could insert itself into the mouse genome, randomly turning off one gene per mouse.

Until then, scientists had charted the mouse genome but had scant idea what each gene actually did. Xu’s innovation allowed them to find out by examining mouse genes on a vast scale.

In the five years since the piggyBac gene was disclosed, researchers worldwide have decoded more of the mouse genome than had been deciphered in the preceding 20 years. Xu and other scientists using his technique are now looking for genes that govern behavior, nutrition, instinct, predisposition to diseases and other basics. Just one discovery — a gene regulating the molecule that controls digestion in mice — potentially opens the door to simple treatments that could end not only obesity but malnutrition as well, he said.

The report of Xu’s achievement at Fudan, published in August 2005 in the prestigious scientific journal Cell, was the first time that China-based research had produced a cover story.

In that sense, Xu’s victory is a cautionary tale for American policy makers.

Robert J. Alpern, dean of Yale’s medical school, said that China leaped at the chance to host Xu’s project when the American scientific establishment, asked several times to finance Xu’s work, demurred.

"They were clearly trying to make an entrance into science, and they were excited by Tian and this project," Alpern said. "They felt Tian would lift China and science. And I think that’s true."

Science is not a zero-sum game — even when the competition is trying to poach your stars, said Dixon of the Hughes Institute. World-class research benefit all humanity, regardless of where it originates.

"Some Chinese labs are in fact very competitive with U.S. laboratories now," Dixon said. "And in a way, that’s what you hope to see — that they would excel. I don’t view this as an arms race of any sort."

Alpern agrees. "The key to success in the United States is strengthening the American enterprise, not trying to slow down another country," he said.

Xu goes a step further. His work at Fudan is a boon for the United States, he said, because it promotes the transparency and freedom from government interference that are hallmarks of American research.

And it takes a small step toward debunking the notion, widespread among ordinary Chinese and government officials alike, that the United States is bent on thwarting China’s ascension to global power.

"Chinese society is deeply suspicious of the West’s intentions," Xu said. "That’s why some behavior is ultranationalistic. To integrate China into the international society will be fantastic. It will be great for the world, great for China — great for everybody."


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