TheChinaConnection by supzero20102010



   are helping
         foSter    by robert Koenig
    innovation     illUStration by MiKe perry
 and revitalize
        in their
   native land.

                                                February 2o1o   |   hhmi bulletin   25
                                                         China—is also an innovative step toward        structure (see “Bold Move,” page 29)—a
                                                         closer collaboration with scientists in a      template that Xu says is needed to help
                                                         nation that lagged behind North Ameri-         spur innovation in China’s research.
                                                         can research for most of the 20th cen-             “China has a tremendous number of
                                                         tury and lost many of its talented young       smart young people who are interested in
                                                         researchers to the West.                       pursuing science, and its recent economic
                                                             Today, China is catching up, in part       growth has made it possible to invest heav-
                                                         by attracting expatriates like Xu who are      ily in science and technology research,”
                                                         willing to work at least part time to help     he says. “What China needs now are role
                                                         improve the quality of Chinese research.       models in innovative science.”
                                                         Their personal stories vary, but many share        Researchers and students who work
                                                         the feeling that it is time to “give back”     with him, both in China and in New
                                                         to their native land, which—after decades      Haven, describe Xu as such a model. “He
                                                         of stagnation—is poised to become a            is creative, highly focused, and a great
                                                         major international player in biomedical       mentor,” says Yale postdoc Sheng Ding,
                                                         research. As China expands its laboratories    who first studied under Xu in Shanghai.
                                         ian Xu taps     and begins to adopt successful templates           The story of how Xu became a role
          a button on his remote control and looks       of Western science, many experts see the       model is emblematic of the changing per-
          up at the 4-foot-wide screen on his office     potential for more synergy among biomed-       spectives of expatriate Chinese scientists
          wall at the Yale School of Medicine. The       ical researchers in the two countries.         over the last 30 years. The former “black
          image that flickers on—showing a desktop           “I see science as very much a global       sheep” of his Jiaxing high school has
          stacked with files and half-finished dia-      enterprise,” says HHMI President Robert        become an American mentor for a new
          grams—could be any scientist’s cubicle.        Tjian, a biochemist who left Hong Kong         generation of bright young science stu-
          Except that the scene is 7,400 miles away,     as a young child with his parents and, after   dents in a Chinese city that has become a
          in China.                                      a brief time in South America, has since       window to the West.
              Xu pokes at the control to swivel a        lived in the United States. “If the Ameri-
          distant webcam and focus on the face of        can style of science can be disseminated       FOllOwINg OppOrTuNITIEs AbrOAd
          a scientific collaborator, Xiaohui Wu, a       to other places, it can only be good—espe-     With an impish grin, Xu admits that he
          mouse researcher at Fudan University           cially in the field of medicine.”              spent his unhappy high school years in
          in Shanghai. “This is fantastic,” says the         The Fudan institute combines a West-       Jiaxing playing “Go”—a Chinese stra-
          bespectacled Xu, testing the sound level       ern model of research with a Chinese cost      tegic board game. “I liked the game
          as he prepares for a teleconference. “It’s
          like I’m sitting in Shanghai.”
              There’s good reason for Xu to be in
          Shanghai—both virtually and in person.
          In addition to his duties as an HHMI
          investigator in Yale’s department of genet-
          ics, he is a cofounder of the Institute of
          Developmental Biology and Molecular
          Medicine at Fudan, one of China’s lead-
          ing biomedical research universities. Xu’s
          work at those two laboratories, half a world
          apart, aims to give scientists valuable
          research tools to help reveal the genetic
          underpinnings of many human diseases.
                                                                                                                                                      Dustin Aksland

              The around-the-world arrangement—
          under which Xu spends about one of every
          four weeks teaching and researching in

26   hhmi bulle t in   | February 2o1o
                                                           because you win if you are good,” he says.        The Cultural Revolution was only the      to rural areas, destroying the careers of
                                                           “It doesn’t matter where your ancestors        latest blow to Chinese science, which        many promising scholars who might have
                                                           came from.”                                    had been damaged by the wars, political      pursued science.
                                                               Unlike the Go meritocracy, Xu’s privi-     upheavals, and social turmoil of the 1930s       If the severe academic disruption had
                                                           leged family history made him “a targeted      and 1940s and then restructured along        continued beyond 1978, Xu might never
                                                           kid” during the Cultural Revolution,           the Soviet model after the communist         have attended college. But his applica-
                                                           from 1966 to 1976, which was hard on           takeover in 1949. That ossified system—      tion to Fudan University coincided with
                                                           intellectual families like Xu’s. His father,   under which most research took place         China’s reform movement that restored
                                                           a teacher, was demoted to a labor camp;        in Academy of Science institutes rather      merit-based admissions to universities.
                                                           his mother was punished as a “capitalist       than at universities—became vulnerable       “Fudan really changed me,” says Xu.
                                                           roader”—someone with left-leaning politi-      to political favoritism, corruption, and     “The level of research was not high then,
                                                           cal views who bows to bourgeois pressures.     domination by seniority. Then, starting in   but the spirit of scientific exploration was
                                                           And Xu was mistreated by his school prin-      the late 1960s, Chairman Mao Zedong’s        tremendous.”
                                                           cipal because he came from a politically       “Down to the Countryside” campaign               That spirit may have been uplifting, but
                                                           tainted family.                                transplanted urban “young intellectuals”     Xu and other Chinese undergraduates dis-
                                                                                                                                                       covered that, to do first-rate science, they
                                                                       left page:                                                                      had to pursue their Ph.D.s abroad. After
                                                                  Yang Dan and                                                                         he met a visiting official from the City
                                                                 Mu-ming Poo,
                                                                   University of                                                                       College of New York, Xu was accepted
                                                            California, Berkeley                                                                       in the college’s graduate program in biol-
                                                                      right page:                                                                      ogy. In 1983, the young student—who
                                                                 (top) Tian Xu,
                                                                    Yale School                                                                        spoke virtually no English—arrived at a
                                                                   of Medicine;                                                                        ramshackle house in Harlem with $50 in
                                                                    (bottom, l-r)
                                                                                                                                                       his pocket and the challenge of living in
                                                               Xiaodong Wang,
                                                             University of Texas                                                                       New York for a school year on a stipend
                                                                  Southwestern                                                                         of $1,500.
                                                                Medical Center
                                                                        at Dallas;                                                                         Many Chinese expatriates share simi-
                                                            Min Han, University                                                                        lar stories. “At that time, China was not a
                                                                 of Colorado at
                                                                         Boulder                                                                       good place to study life sciences,” recalls
                                                                                                                                                       molecular biologist Min Han, a HHMI
                                                                                                                                                       investigator at the University of Colorado
                                                                                                                                                       at Boulder, who has been Xu’s main col-
                                                                                                                                                       laborator in establishing the new institute
                                                                                                                                                       at Fudan.
                                                                                                                                                           Sent to a farm during the Cultural Rev-
                                                                                                                                                       olution, Han majored in biology at Beijing
Xu: Chris Jones Wang: Matt Rainwaters Han: Carmel Zucker

                                                                                                                                                       (Peking) University and was recruited to
                                                                                                                                                       study in the United States—getting his
                                                                                                                                                       Ph.D. from the University of California,
                                                                                                                                                       Los Angeles—as part of a program created
                                                                                                                                                       by the late Ray Wu, a Cornell University
                                                                                                                                                       biologist who played a key role in recruit-
                                                                                                                                                       ing Chinese students to U.S. universities
                                                                                                                                                       during the 1980s and 1990s. Another
                                                                                                                                                       talented scientist recruited in the same
                                                                                                                                                       program was Xiaodong Wang, now an
                                                                                                                                                       HHMI investigator at the University of
                                                                                                                                                       Texas Southwestern Medical Center at

                                                                                                                                                                         February 2o1o   |   hhmi bulle t in   27
          Dallas. Wang recalls the “incredible cul-      a world power, its universities and bio-            One of the most influential U.S.-trained
          ture shock” of his move from Beijing to        medical research lagged behind Europe.          scientists who has announced plans to
          Texas in 1985.                                 Thousands of young Americans went to            return permanently to China is Wang,
              Even if they were not directly affected    Britain, Germany, and France for their          who plans to move to Beijing this summer
          by the Cultural Revolution, many younger       graduate or medical studies and to learn        as he begins his second stint—after 5 years
          Chinese science students also headed           the research techniques of the great Euro-      in a part-time, long-distance capacity—as
          to the United States because “you didn’t       pean masters.                                   the director of China’s National Insti-
          stay in China if you wanted a career in            Eventually, American university inno-       tute of Biological Sciences. The institute
          research,” says neuroscientist Yang Dan,       vators—including pathologist William H.         started from scratch a few years ago under
          an HHMI investigator at the University         Welch, who built the Johns Hopkins Uni-         a mostly Western model and now boasts
          of California, Berkeley. After she’d earned    versity School of Medicine into a research      23 labs and 500 scientists—nearly all its
          her initial degree in physics at Beijing       powerhouse, and Abraham Flexner, whose          principal investigators did their Ph.D.
          (Peking) University, Dan was restricted        1910 report led to fundamental reforms of       and/or postdoc work in the United States.
          by the rigid Chinese system from doing         U.S. medical schools—combined lessons               Wang says he has reached a point in
          graduate studies in another field, so she      from Europe with their own ideas to cre-        his life “when it’s time to give back” to his
          decided to pursue a life sciences Ph.D.        ate what has become the world’s leading         native country. “And there are great oppor-
          program at Columbia University in New          biomedical research complex.                    tunities in China today.” Xu expresses
          York, where she had to work hard to catch          “Like America in those years, China is      similar sentiments about his inner need to
          up on basic biology and related courses        on the cusp of great advances in science        help young scientists in China—especially
          that she had missed in Beijing.                and technology,” says Xu. “One of my            out of gratitude to his early inspiration to
              Despite the sometimes difficult transi-    dreams is to set up a new university in         professors at Fudan, who “opened up a
          tions, many of those students succeeded        China that would teach innovation and           new world of science for me.”
          with the help of talent, hard work, and        would be modeled on some of the most                For her part, Dan has become involved
          American mentors. “We were nurtured            effective research institutions in the West.”   in the past 5 years in research collabora-
          and cultivated by our professors,” recalls         Before that happens in China, however,      tions with neuroscientists in Shanghai
          Xu, who landed a fellowship at Yale within     plenty of work needs to be done. In the         and has been mentoring young scientists
          a year of his arrival in New York and was      meantime, numerous initiatives are under        there and at Berkeley. “A lot of really good
          soon using fruit flies as a model organism     way to deepen scientific ties between           expatriate scientists are trying to revamp
          to decipher the roles of genes in neural       China and America. After China began            the research structure at Chinese uni-
          development.                                   to reform its economy, the nation stepped       versities,” she says. “The idea is to more
              Excited by his early success, Xu called    up its efforts to convince top expatriate       strongly link teaching and research.”
          his mother in China and explained that         scientists to return home. In 1998, the             In addition to university reforms, similar
          he was making a name for himself in            education ministry’s Changjiang Scholars        efforts are being made to bolster Chinese
          America by studying flies. After a long        Program started offering incentives for         Academy research, including an inno-
          pause, she said: “Son, we have lots of flies   expatriates to do research and to teach at      vative initiative led by Dan’s husband,
          right here in our hometown.”                   universities in China. After many targeted      neuroscientist Mu-ming Poo, who is also
                                                         researchers in the United States said they      based at University of California, Berkeley.
          EmulATINg THE wEsT                             had little interest in returning to China       Born in China, Poo began his university
          On the corner of Xu’s desk sits a stack        full time, the program was altered in 2006      studies in Taiwan and later excelled in the
          of books about famous American medi-           to include some senior scientists on a part-    United States. Asked by Academy officials
          cal innovators. “I want to see how this        time basis.                                     to assess neuroscience research in China,
          country built up biomedical research,” he          In 2009, China’s central government         he advised them in 1999 to create an
          says, looking for a template for potential     started an ambitious program called             entirely new institute to avoid “the flawed
          reforms in China.                              Qianren Jihua, or the Thousand-Person           mechanism of managing China’s estab-
             In the field of medical research, Xu        Plan. The goal is to recruit as many as         lished scientific institutions … [which] left
          sees parallels between pre-World War I         2,000 top Chinese-born scientists, finan-       little room for innovation.” Poo became
          America and today’s China. A century ago,      cial experts, and entrepreneurs back to         the founding director of the Chinese Acad-
          while the United States was becoming           China over the next decade.                     emy’s Institute of Neurosciences, which

28   hhmi bulle t in   | February 2o1o
bOld mOvE
It took a leap of faith for Tian Xu to move from                        gene per mouse and creating an efficient way to create
Shanghai to Harlem in 1983, but he says the biggest                     knockout mutants. ¶ “Geneticists had been searching
risk he has taken during his career was switching a                     for decades to find a system like this for mammals—an
decade ago from fruit flies to mice as model organisms                  efficient tool for transgenesis and mutagenesis,” says Xu,
to study gene functions. ¶ Xu had made his name at                      who displays a framed cover of the August 2005 issue of
Yale and later as a postdoc at HHMI Vice President                      the journal Cell that featured his piggyBac report. “Now
Gerald M. (Gerry) Rubin’s lab at the University of                      we have the tool and we need to produce the mutant
California, Berkeley, for his Drosophila research—                      mice strains for scientists to use in their research.”
conducting large-scale analyses of mutant flies to                      ¶ With the new technique, scientists can produce
decipher the roles of key genes and the biochemical                     the mutant mouse strains about 100 times faster and
pathways related to cancer cell growth and metastasis.                  cheaper than they could with previous methods. And
¶ But when Xu applied for an HHMI investigator                          Xu says the Institute of Developmental Biology and
position in 1996, he made a bold proposal: he would                     Molecular Medicine at Fudan University in Shanghai,
discover a way to create mutant mouse strains as easily                 which he coestablished at the urging of Chinese
as developing mutant flies. That would represent a                      officials, is able to produce such strains at a lower cost
big step forward in genetic screening of mice, about                    than a similar facility in the United States. ¶ At the
99 percent of whose genes have direct equivalents in                    Fudan institute, which already houses 25,000 mouse
the human genome. ¶ “It was risky because I had a lot                   cages, Xu and his researchers so far have produced
to learn about mouse genetics,” Xu recalls, describing                  about 5,000 strains of knockout mice. The goal is to
the years of complex and often frustrating research that                produce 100,000 mutant strains by the end of 2010,
it took for him to come up with the deceptively simple                  among which scientists hope to eventually identify
breakthrough: using a moth transposon (“jumping                         knockout equivalents for nearly all of the 25,000 or so
gene”) called piggyBac. Inserted into the mouse                         genes in the mouse genome. ¶ “I wanted to accomplish
genome, the tiny segment of DNA causes random                           things with a real impact on society,” says Xu. “To do
mutations when the animal breeds, disabling one                         that, you need to take some risks along the way.” —R.K.

is producing high-quality research. He               Xu says he didn’t really want to start a   number of Chinese science students are
receives no salary and “works only on            new institute at Fudan but was convinced       placing heavy burdens on faculty. “Every
scientific aspects” of the institute, while      to proceed because “it was a priority for      lab tends to have way too many students.
retaining his faculty and research position      the Chinese. I like it because the research    And there are serious ethics problems that
at Berkeley.                                     is connected with a university, which is       result from the pressure to produce lots
    “I think it’s a very positive trend,” says   unusual for China.” With the advent of         of papers.”
HHMI’s Tjian. “These scientists have a           teleconferencing and high-speed Internet           Wang is optimistic as he prepares for
sense of responsibility to their native coun-    in China, he finds that he can “accom-         his move to Beijing, saying that China’s
try and it’s clear that China is progressively   plish our goals with fewer trips back and      economic success is freeing up tremen-
expanding its scientific presence.”              forth” between New Haven and Shanghai.         dous resources for research. “Young
                                                     Like his Fudan institute colleague,        people have an easier time getting grants
ENgAgINg A COmmON gOAl                           Han opted—for family as well as profes-        in China today than in the U.S.,” he
While the current trends in Chinese              sional reasons—to limit his China com-         says. Also, those students “treat scientific
science are mostly headed in the right           mitment, despite entreaties from Chinese       research as a privilege. If a merit-based
direction, expats say it will take time—as       officials to move back. “I regard the U.S.     system takes root, these young people will
well as a continued government commit-           as my main base for research,” he says,        get great opportunities and excel.”
ment to reform the research system—to            “but that doesn’t mean that you can’t              Poo agrees that, “as more scientists
reach the nation’s potential. In the mean-       make contributions to Chinese science.”        return to China after successful post-
time, many of the older generation of                Han says, “I see changes in both direc-    docs in the U.S., the quality of Chinese
China-born scientists prefer to keep their       tions—good and bad” in Chinese science.        research will continue to improve.” But
research bases in the United States.             For example, the dramatic increases in the                         (continued on page 48)

                                                                                                                  February 2o1o   |   hhmi bulle t in   29
     CO N T I N U E d F R O M pAg E 2 9
                                                     tists rarely happens, and the outcome of the    live connection to his colleague in Shang-
     ( T H E C H I N A Co N N E C T I o N )
                                                     reviews, if they were carried out, rarely has   hai. They are discussing how to expand
     he cautions that “the new traditions of         any consequence.”                               the Fudan institute’s research and offer its
     high-quality science have yet to become             While Xu believes that far more progress    unique mouse mutants to scientists world-
     established at most of the Chinese research     needs to be made, he is generally optimis-      wide who are trying to understand and find
     institutes. My concern is that most institu-    tic about China’s “tremendous potential”        cures for diseases.
     tions need to move more quickly in the          in science. “Scientific interaction is one of       “This is a site where East meets West,” he
     direction of merit-based resource alloca-       the best ways to deepen the understanding       says. “We are engaged in a common goal: to
     tion and promotion. Rigorous review of the      between China and America,” he says, look-      develop knowledge as a way to improve the
     research performance of individual scien-       ing up at his teleconference screen with its    well-being of humankind.” W

     CO N T I N U E d F R O M pAg E 3 3
                                                     that branch off them. With crippled mito-       since mtDNA defects are associated with
     ( A M AT T E R o F E q u I L I B R I u M )
                                                     chondrial fusion machinery, the arbor of        additional pathological conditions.
         For other diseases, though, the culprit     fibers was reduced to short stumps.                  On a computer screen, when membrane
     is the equilibrium between the fission              Looking closer at the mitochondrial         fission and fusion are slowed down, they
     and fusion of a different organelle: the        membranes, Chan saw fragmented organ-           appear to be straightforward processes. Press
     mitochondrion.                                  elles, not the interconnected network that      play and the membranes move. The merging
         Mitochondria, energy-generating organ-      ought to be there. Furthermore, mitochon-       of membranes looks fluid and natural, like it
     elles, snake throughout the insides of cells    dria usually contain their own DNA—             requires no molecular machinery at all. After
     in an interconnected network. “People often     mtDNA. “But in this fragmented mutant,          all, two soap bubbles can join together without
     think of mitochondria as static organelles      only a fraction of them have mtDNA,”            the help of proteins. But inside the cell, as
     that work alone,” says HHMI investiga-          Chan says. The observation of missing DNA       these researchers have shown, taking away a
     tor David Chan, “but they constantly fuse       explains why fragmented mitochondria            piece of the membrane’s control mechanisms
     and divide. No one really understood why        can’t produce energy—they lack the DNA          leads to a messy jumble of membranes, or a
     these events happen, or how, until the last     that encodes proteins controlling energy        stand-still in vesicle creation—and both prob-
     10 years.”                                      generation. Neurons may be particularly         lems have unmistakable links to disease. W
         Chan, at the California Institute of        sensitive to these defects, because the cells
     Technology, studies how the cell achieves       are among the most energy demanding.                W E b E x t r A : To learn what happens when vesicles arrive

     a balance in its mitochondria network.          His lab is pursuing the link between mito-          at their targets and how structural biology is illuminating
                                                                                                         the biology of vesicles, visit
     If fusion overwhelms fission, the mito-         chondrial fission and fusion and mtDNA,
     chondria become excessively long and
     connected, eventually “collapsing into a
     messy jumble,” says Chan. And if fission
     overwhelms fusion, the organelles are dra-
                                                                                                 Knowledge Discovery Research Education
     matically fragmented and less efficient at
                                                                                                 These four key components of HHMI’s
     producing energy. It’s a delicate balance.
                                                                                                 work also guide and define the mission
         When geneticists at Duke University                                                     of the Institute’s quarterly magazine,
     linked a mitochondrial fusion gene to a                                                     the HHMI Bulletin.
     neurological disease, Chan wondered how                                                     Subscribing is fast, easy and free. Visit
     a defect in mitochondrial fusion might lead                                        and follow the
                                                                                                 instructions there to subscribe online.
     to peripheral neuropathy, which causes
     numbness and weakness in the hands and                                                      While you’re online, read the Web edition
                                                                                                 of the Bulletin.
     feet. Chan engineered mice that lacked
     the implicated fusion gene, mitofusin2.
     He found defects in the mitochondria of                                                     HHMI          BULLETIN

     the Purkinje cells, a class of neurons in the
     brain known for the dramatic fan of fibers

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48   hhmi bulle t in        | February 2o1o

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