发信人: rkong (wrong), 信区: Biology
标 题: Beijing Genomics Institute: From Standing Start..
发信站: The unknown SPACE (Thu Apr 4 21:21:38 2002), 站内信件

(FROM SCIENCE)
THE RICE GENOME:
Beijing Genomics Institute: From Standing Start to Sequencing Superpower
Dennis Normile*
Good timing and determination have helped geneticist Yang Huanming create an
institute that has catapulted China into the front ranks of sequencing
BEIJING AND HANGZHOU--In August 1998, geneticist Yang Huanming led a skeptic
al crowd of scientists from around the world through a new, two-story brick
building in the northern reaches of Beijing. As the scientists trooped throu
gh the empty building, their footsteps echoing off bare walls, Yang explaine
d that it would soon become a world-class sequencing facility. He said that
employees and sequencing machines were on the way, neglecting to mention tha
t he didn't yet have the money for either. His colleagues were polite but du
bious.
"The building had a nice double helix on the brick facade," recalls Maynard
Olson, a geneticist at the University of Washington, Seattle. "But that was
the only indication that this was a genome center as opposed to an empty war
ehouse. I really wondered if they could get the support to become an interna
tionally competitive group."
Olson wonders no more. Today, visitors to the Beijing Genomics Institute (BG
I) see 92 of the latest-model automated sequencing machines, four of the fas
test supercomputers in China, and a staff of 500 that grows by a dozen or so
every month. The sequencing center has moved from that tiny brick building
to a spacious, modern industrial park and has spread to a second campus in t
he southern city of Hangzhou. And its science--including the shotgun sequenc
ing of the indica rice genome reported on page 79--is certainly internationa
lly competitive.
Olson says he always had confidence in the scientific capabilities of the gr
oup. His sequencing center has trained many BGI scientists, engineers, and t
echnicians, and two of the four lead authors on the paper, Yu Jun and Wong G
ane Ka-Shu, are on the staff of the University of Washington Genome Center i
n Seattle. But "it's pretty startling," Olson admits. "When you think of bei
ng a support center for a scientific program in a developing country, you do
n't expect them to become 10 times bigger than you are, in less than 4 years
, and to start publishing papers in Science."
Such accomplishments no longer surprise fellow University of Washington gene
ticist Mary-Claire King. "The Beijing Genomics Institute would be a miracle,
" she says, "except that the BGI guys make genomic miracles routine."
Young and restless
The Ferrari-like acceleration from standing start to joining the global fron
t-runners in genomic sequencing is a tale of timing, determination, and hust
le. It also demonstrates Yang's ability to translate his vision into reality
by tapping the increasingly diversified sources of support in a reform-mind
ed China.
Yang, 50, is a spark plug of a man. The fact that he's considerably shorter
than most of his staff would be obvious if he ever stood still. Likewise, hi
s nonstop discourses jump from topic to topic. He sprinkles Chinese proverbs
into his conversation, reciting them in Chinese and then looking around for
a translator.
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Rising son. Institute director Yang Huanming has made China a sequencing pow
erhouse using domestic computers from Dawning.
CREDIT: D. NORMILE
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Born in Yueqing, Zhejiang Province, Yang earned his Ph.D. in genetics at the
University of Copenhagen, Denmark. Over the next 6 years, he focused on map
ping genes on the X chromosome during stints at the CNRS Immunology Center i
n Marseilles, France, Harvard Medical School in Boston, and the University o
f California, Los Angeles. In 1994 Yang returned to China with the idea of a
dapting to sequencing the large-scale, high-efficiency, low-cost techniques
that have boosted the country's manufacturing capacity. "[Sequencing] is whe
re a developing country can compete in big science," he says.
His target was the human genome sequencing effort that was already under way
, and his intended vehicle was the Human Genome Center, a part of the Chines
e Academy of Sciences' (CAS's) Institute of Genetics. But he and his colleag
ues realized that the academy's rules and traditions would prevent them from
ramping up fast enough to join the rest of the world, and the center--the b
rick building the visiting scientists toured--never really got off the groun
d.
Instead, Yang and three colleagues who had worked with Olson at the Universi
ty of Washington took advantage of new laws, and in spring 1999 they set up
BGI as a private, nonprofit research organization. Seed money came from CAS,
the Institute of Genetics, and even Yang's hometown municipal government, a
long with loans from employees, family, and friends. CAS also designated BGI
as its Genomics and Bioinformatics Institute, although fewer than 10 member
s of BGI are actually CAS employees.
BGI bought its first batch of sequencing machines on an installment plan and
trained its staff on Thermoanaerobacter tengcongensis, a thermophilic bacte
rium isolated from a hot spring in Tengcong, China. In September of that yea
r, Yang made his pitch to be a global player at the 5th International Strate
gy Meeting on Human Genome Sequencing in Hinxton, U.K. There was only one qu
estion that stumped him: "Do you have the money?" "I lied," he now admits. "
We didn't have the money, but I was sure we would get it."
Four months later he did. CAS agreed to fund three Chinese sequencing center
s to tackle 1% of the human genome, and BGI received slightly more than half
the total award. China completed its share of the draft on time and has rec
ently closed the gaps and corrected the errors in the draft sequence.
Although the Western press barely mentioned China's participation, Chinese a
ccounts emphasized the nation's role in this historic endeavor and its statu
s as the only developing country in the global partnership. That participati
on helped Yang convince Hangzhou municipal officials to provide a rent-free
building and enough money for BGI to set up and equip a sister center, the H
angzhou Genomics Institute. In return, city officials hope the institute wil
l attract foreign high-tech investment.
The mood in the two labs is akin to that in a U.S. high school before the bi
g game against its archrival. Posters in every room in Beijing remind employ
ees that "Discovery can't wait!" and "Speed! Speed! Speed!" In a nod to the
scientific task at hand, other posters proclaim "High throughput is everythi
ng!" The Hangzhou group prefers symbolic reminders of its mission, including
a rusty hoe propped in a corner of the computer room "to remind us that we'
re data miners," says bioinformaticist Zhou Yan.
The youthful enthusiasm is no act. Excluding the dozen or so senior scientis
ts, the average age of the 100 authors on the Science paper is in the mid-20
s. Wang Jun, who leads 150 programmers and computer scientists in the bioinf
ormatics department, entered Beijing University at 16 and is now 26. "This i
s a new field," he says, "so I don't think I'm too young for this job."
The head of the lab's 100-person sample preparation and sequencing group is
29-year-old Deng Yajun. A forensic investigator for the police department in
her hometown of Xi'an, Deng began working part-time at BGI while studying f
or her Ph.D. in forensic medicine. "The policewoman," as her colleagues call
her, quickly mastered the techniques and took charge of the group.
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Team leaders. Deng Yajun (top) preaches speed and economy in sample preparat
ion and sequencing; bioinformatics chief Wang Jun (bottom, at left) works wi
th his mentor, Li Songgang, on shotgun assembly.
CREDITS: D. NORMILE
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Yang likes to brag about BGI's parsimony. When BGI first started, it importe
d the 96-well plates used to hold the DNA samples during preparation for $2.
54 apiece. Then Deng found a local glassmaker who could make them for just 3
6 cents. The same cost advantages apply to reagents used in sample preparati
on and to salaries. "The key to driving down costs is to scale up so we can
negotiate better prices with suppliers," says Deng.
Shotgun success
Yang says his "addiction to sequencing" has helped the institute achieve tha
t economy of scale. With work on the human genome sequence well under way, Y
ang landed two major sequencing jobs in 2000 that broadened the center's sco
pe. In April 2000, he convinced CAS to support sequencing indica (Science, 5
May 2000, p. 795). Then in October, BGI reached an agreement with the Danis
h Pig Genome Consortium, a joint public-private endeavor, to sequence the pi
g (Science, 3 November 2000, p. 913).
For both projects, BGI chose a sequencing technique known as the whole-genom
e shotgun. Traditionally, sequencing has required mapping the genome, then d
eveloping a library of clones, or relatively short strings of DNA, tied to a
known location, which are then sequenced. In the shotgun approach, the enti
re genome is broken into pieces and sequenced. Then powerful computers and s
ophisticated software sort the pieces into the proper order.
Shotgunning appealed to BGI officials because the maps and clones needed for
the traditional method were not available for indica and would have taken y
ears to prepare. Just as importantly, "we felt that mastering the shotgun te
chnique would be the next step in our development," says Liu Bin, BGI's chie
f of research and collaborations.
The BGI scientists faced a big challenge in developing the computer expertis
e to pull off the whole-genome shotgun. Initially barred from acquiring U.S.
supercomputers because of security-related export restrictions, BGI became
one of the best customers of Dawning, a homegrown supercomputer maker. Parti
cularly critical was the so-called assembler, which pieces together the data
from the sequenced fragments. Whereas the pig project can use the human gen
ome as something of a template, rice required its own assembler. "The assemb
ler was our biggest worry," Yang says.
Rather than starting completely from scratch, BGI decided to modify the asse
mbly program used in the public Human Genome Project, called phrap. A key st
ep was developing a subroutine that would identify and temporarily mask repe
titive strings, which make up 40% of the rice genome. By temporarily ignorin
g such repetitive sequences, the BGI assembler reduced the chance of making
mistakes in stringing together sequence data and dramatically cut the comput
ing time required. Li Songgang, a professor of bioinformatics at Beijing Uni
versity and senior adviser to BGI, developed an algorithm to search for such
strings, and the BGI group tested it against virtually all the sequence dat
a for all organisms publicly available. The effort took nearly a year.
Once the group was convinced that it would work, BGI pulled out all the stop
s to beat the competition. In particular, Yang was taking aim at Syngenta Co
rp., which had announced that it had completed a draft of the rice genome se
quence in early 2001 but had never made the data public. Starting last July,
the sequencing team was split into two, 12-hour shifts. That allowed BGI to
keep the machines running 24 hours a day for the 74 days needed to complete
the actual sequencing. Then came the analysis team, working practically aro
und the clock. "It was like going into battle," says bioinformatics head Wan
g.
Most of the Beijing staff lives in a housing development barely a kilometer
down the road from the center. But to save commuting time, mattresses and sl
eeping bags were spread out in the halls. And some people didn't even make i
t that far. "I just slept in my chair," says Han Yujun. Ping-Pong was the on
ly diversion from the data crunching. On 8 October the paper was sent off to
Science.
The completion of the draft is certain to put BGI on the sequencing map. Ols
on calls it "a major accomplishment." Adds plant geneticist Jeff Bennetzen o
f Purdue University in West Lafayette, Indiana, "the Chinese showed how quic
kly you can do this if you take a modern approach."
Yang has drawn up a long list of organisms he thinks should be sequenced, an
d the institute has already dipped its toe into proteomics and drug discover
y, including a project to isolate the active compounds in the herbs used in
traditional Chinese medicine. "Diversification is a challenge all of the seq
uencing centers must face," says Olson.
So is finding money to take the next step. Chen Zhu, CAS vice president for
life sciences, says BGI is free to compete for project grants but that "we t
hink the big genome sequencing projects should depend on international coope
ration." Yang isn't saying where he plans to get the institute's next round
of funding. But after going from an empty building to a paper in Science in
40 months, Yang is confident that he hasn't run out of miracles.
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With reporting by Ding Yimin and Elizabeth Pennisi.
Ding Yimin writes for China Features in Beijing.


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