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The Bedrock of BGI: Huanming Yang


The charismatic founder of the world’s largest genome center on short-term economic challenges and the long-term mission.

By Kevin Davies

September 27, 2011 | Earlier this year, the staff of BGI Americas, the U.S. subsidiary of the Chinese genomics institute formerly known as the Beijing Genomics Institute, held a first anniversary party in Boston, in a club situated above the famous Cheers pub.

Dozens of guests and BGI clients from medical schools, universities, and big pharma companies including Pfizer, Lilly and Novartis, were treated to a variety of entertainment, including an illusionist and a sand painter who chronicled the evolution of life on earth from the Big Bang to the birth of BGI itself.

But pride of place belonged to Yang Huanming, 58, the founder and chairman of BGI, who has guided BGI’s remarkable growth from a bit player in the Human Genome Project (HGP) to the world’s largest sequencing center and arguably the premier genomics outsourcing facility in the world (see, “Sequencing, Sequencing, Sequencing,” Bio•IT World, November 2009).

In a lengthy conversation with Bio•IT World, Yang, who punctuates his excellent English (honed during his Ph.D. at the University of Copenhagen in Denmark) with flashes of dry humor, talked candidly about BGI’s past, present and future.

Xq Boy

“My nickname was ‘Xq boy when I was a Ph.D. student,’” jokes Yang, a geneticist by training, harking back to life in the 1980s. His group in University of Copenhagen mapped many disease genes to the X chromosome using cytogenetics.

As the HGP geared up, Yang heard former U.S. Department of Energy executive Ari Patrinos argue that the project must be an international collaboration. “I was so impressed,” says Yang. “I asked [University of Washington geneticist] Maynard Olson whether our act could be a small part of the HGP.”

At the time, Yang was based at the Institute of Genetics at the Chinese Academy of Sciences (CAS). Yang lobbied the HGP leadership to convince them that China’s participation would “improve the international image of the HGP. There was also specific significance for China, as a representative nation from developing countries. I convinced [NHGRI director Francis Collins] that participation of China was very special.”

By August 1999, Yang had pledged to sequence 500,000 reads. There was just one problem: “We didn’t have a single machine! Half-a-million reads—it would be a miracle!” Yang bought a plaque for his partner, Wang Jian, which reads: Never give up. “It was really a Mission Impossible,” he says. Even with assistance from the Chinese government, it was not enough.

“But then the open-minded director of the Institute of Genetics, Shouyi Chen, said ‘Just do it.’ That’s the reason BGI was founded as a non-governmental, independent research institute.” In honor of China’s fascination with numerology, BGI was officially born at “9 seconds past 9 minutes past the 9th hour of the 9th day of the 9th month [September] of the 99th year of that century.”

BGI quickly expanded to more than 100 staff. “For half a year, it was really difficult, but we did the job, we did it very well,” says Yang. The institute duly completed its half-a-million reads, producing 64 megabases of raw sequence data, sequencing a segment of human chromosome 3 provided by Richard Gibbs.

China’s inclusion in the international HGP consortium was a major boost to the country’s scientific prestige. “At that time, China was regarded as a country still developing its science,” says Yang. He recalls with palpable pride the White House ceremony in June 2000. “President Bill Clinton, I really love him. Tony Blair appeared via satellite. Suddenly, it was not only their scientists but also China.”

After the Genome

After the genome project, BGI nearly fell victim to its own success. “After the Genome Project, we were waiting to die!” says Yang. “We had about 350 people to complete that portion of the genome. How to survive? We could not get any funding after HGP.”

When BGI’s first request for funding did not come through, Yang borrowed RMB4.2 million (about $657,000) from young members of staff. “I received a call from one of their parents, saying, ‘How can you try to ‘borrow’ money from my son? He is just graduating!’ Then we explained, ‘It’s just to borrow!’”

A lifeline emerged when the Hangzhou Municipal Government offered to lend RMB60 million ($9.3 million), on condition that the institute was relocated to Hangzhou “and did something big.” Something like the rice genome, for example, which graced the cover of Science in 2002. “Science met all our requests—cover story, poster, review, full column of data,” says Yang.

In 2003, BGI made news again, rapidly sequencing the first of four strains of the SARS virus, and developing an ELISA detection kit within three days. Yang hosted a visit from the president, Chairman Hu Jintao, who promised to designate BGI as an official institute in the CAS. But BGI’s staff was more than CAS could physically support. With permission and support from the president of CAS, BGI left CAS and set up shop in the booming economic development district in Shenzhen. Six months later, BGI publicly announced the sequencing of the first Asian Genome (see, “Who is Y.H.?”).

In January 2010, BGI catapulted the ranks of the world’s largest genome centers when it agreed to buy 128 Illumina HiSeq 2000 machines. Yang says such a massive spend was essential, and yet he remains surprisingly cautious about the institute’s long-term success. “We still have to wait another two years to validate whether our decision at that time was correct,” he says. “For BGI to survive, whether for a long or short period, we must be the biggest, to take advantage from the ‘scale effect,’ to do something others are unable or unwilling to do. That was the first step.”

Yang draws parallels with the airline industry. “How can Chinese airlines earn money when American airlines cannot? All of the planes are made by Uncle Sam or Uncle Europe. Maintenance, fuel, and salaries of Chinese workers are terrible. Now most U.S. airlines lose money, there is a problem. The market is so big that to survive on a small margin, BGI must be the biggest in the world.”

And it must be prepared to stay there. “If you buy, buy the most, the biggest number and be ready for the next generation, otherwise you’re looking to die. That’s the reason we announced a credit line of RMB10 billion [about $1.5 billion]… If Complete Genomics or Helicos would have better machines, we would buy even more. If PacBio can help, we’ll buy again.”

Twin Threats

Yang points to two potential threats facing BGI. “First, the machines are immediately out of date. Then we will die, replaced by Complete Genomics, etc. We’ll throw all the machines into the Pacific Ocean!” He worries that some customers might hedge if it appears a new machine is nearing the market where the cost to sequence is almost zero.

“Second, somebody else could do it better than us, on a larger scale with more innovative software.” Yang says BGI’s future—he actually uses the term “survival”—hinges on technology climate change.

“Only an idiot like me would think that sequencing as a service or as a collaboration could make money! Economically, the machine isn’t made by us. The reagents aren’t made by us. So how can we make money?”

Yang recognizes that no customer will relish sending samples to Hong Kong, where the bulk of BGI’s sequencers are based. One of the reasons to expand by setting up global subsidiaries—BGI Europe in Copenhagen and BGI Americas in Boston—is because of BGI’s experience. “Genomics cannot be done alone, it is international,” he says. “Only Broad can do it alone, only U.S. can do it alone.”

Yang says BGI’s two major advantages are scale and software. Thanks to Chinese government priorities, 100,000 computer programmers graduate each year. More than 25% of BGI’s 1,000 new recruits each year are programmers. They enter a rigorous, 7-month long training program in “the Temple.” There are 150 trainees at BGI at any given moment, with more than 500 computers ready for them on the floor.

“We’re going to share our capacity with our innovative software. That’s our open strategy—to stimulate global genomics. That’s why we worked on the Arabian camel, the reason we have a close collaboration in Scandinavia, the reason we initiated one big project after another,” such as the Genome 10K Project, billed as a “genomic zoo” of 101 vertebrate species

The next two years will be critical for BGI. “If in two years, we still keep our position as the biggest institute, and our young people win the reputation and trust of our partners, if we do that, it’s OK.”

Looking for Partners

Yang dismisses the idea that BGI is engaged in marketing (he pronounces the term “mah-keting” in a decent Boston accent). “We’re looking for partners,” he says. A close partnership exists with Eric Lander’s Broad Institute—Yang says they are twin organizations.

“Our relationship is better than brothers or sisters, so we should change the name from sister centers to twin centers! Eric had been my mentor. After joining the HGP, we were hosted by him in his big friendly house.” (So big, in fact, Yang says he got lost somewhere between the football pitch and the basketball court.)

Yang says he would like to build 50 labs around the world, although the cost of setting up labs abroad is considerable. Establishing BGI Europe in Denmark with his old friends was relatively easy. “Any international collaboration is based on personal friendship and mutual trust—more important than governmental or official or commercial contracts.” BGI has embarked on the biggest life sciences project in Denmark’s history, costing DKK170 million ($32.8 million). “This is the reason we put 5-10 machines there. It is convenient for them.”

Much of BGI’s service business is coming from big pharma, notably a 5-year agreement with Merck. “First, we emphasize quality. Second, our prices must be the most competitive in the market,” says Yang. “Third is turnaround time.” As for future opportunities, Yang highlights early diagnostics, including as pre-implantation genetic diagnosis and pre-symptomatic testing.  

Much effort will be in sequencing and studying plant and animal genomes. Yang says there are three main purposes for sequencing plant genomes: food and biofuels; environmental conservation; and identifying metabolic pathways for synthetic biology. “We are confident the rice genome sequence will lay foundation for future research and applications, not just because of the publication of the paper, but the free sharing of the database.” 

“For vertebrates, metabolic pathways are rather simple—there are only a few hundred. But each plant has a specific metabolic pathway that is essential to synthetic biology.” And there are opportunities in microbial sequencing and metagenomics. “Genomics is the foundation for the future of the biotech economy,” says Yang. “That’s the reason we estimate the market is huge, even if the margin benefit is very small.”  

On the software side, BGI has launched many bioinformatics/NGS tools, including BGI Cloud (see, “BGI Cloud on the Horizon,” Bio•IT World, Jan 2011). It’s not just about analyzing data, but also sharing data, says Yang. “We cannot over emphasize that the HGP has set up a brilliant example for international collaboration and sharing of basic data. But to share data, you have to share the cost. We try to convince our colleagues writing scientific publications to release the data. But we also respect our partners who don’t want to release their data right way.”

Yang says BGI is considering building a large genomics database, one of the biggest in the world after NCBI and Japan. “But we’re hesitating. It’s easy to announce a free lunch, but how can you sustain it? People will just complain if the service is not good enough.”

As for Yang’s own future, he hints that he may be winding down. “I’m old,” he says. “I’m psychologically very strong and scientifically very strong, but I’m not physically very strong anymore.”

BGI has strength in its numbers of young talented scientists, but it will need Yang’s experience going forward. BGI does not have a specified successor, he says unprompted. “I’m proud to have learned so much from so many mentors and teachers. I have so many students, they have more reason to be proud, because of their ‘grandfather.’

“I’m very proud of the young generation. We have more young people, but we’re in bad need of instruction from skilful, experienced people.”  

Who is Y.H.?

In 2007, BGI announced that it had sequenced the first Asian genome, an anonymous individual known only by the initials, Y.H.

“I cannot say it’s me,” says Yang. “If somebody says it is me, it’s a rumor. The rumor is reasonable but it will never be officially confirmed until I give the sequence—and they’re the same.”

The reason to remain coy revolves in part around the bioethics of personal lives and genome ownership. “In the past, if I wanted to take a drop of blood, I’d give you a form of informed consent. If your genome is sequenced and released, you know half the genome is the same as one of your kids. Then half of his genome is the genome of your wife! Have you got informed consent from them?” 

 

This article also appeared in the 2011 September-October issue of Bio-IT World magazine.

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