Chinese institute makes bold sequencing play.

China's BGI has become the largest next-generation genome sequencing center in the world after it purchased 128 new HiSeq 2000 genome sequencers from Illumina. The deal was announced in January by Jay Flatley, president and CEO of San Diego–based Illumina, at the 28th Annual J.P. Morgan Healthcare Conference in San Francisco (Box 1). The announcement comes amid a boom of scientific productivity in China centered around next-generation sequencing technology, which has resulted in the publication of three landmark papers by Chinese researchers in the past two months alone: the sequencing of the cucumber (Nat. Genet. 41, 1275–1281, 2009) and giant panda (Nature 463, 311–317, 2010) genomes and the human pan-genome (Nat. Biotechnol. 28, 57–63, 2010).

China's BGI, now in Shenzhen, has become Illumina's largest customer overnight.

BGI

BGI, which started life as the Beijing Genomics Institute but then moved to Shenzhen, China, will install most of the newly acquired Illumina sequencers at its new genome center at Hong Kong Science Park throughout 2010, says BGI executive director Jun Wang. “We will use these instruments to help build research and application platforms for sustainable development in agriculture, bioenergy, personalized health care and related fields in China.”

The emergence of BGI as a sequencing powerhouse could have a significant upside for Hong Kong's biotech sector. “Having the largest DNA sequencing facility in the world in Hong Kong will hopefully contribute towards attracting talent in genomics and bioinformatics and stimulate collaboration with other local research groups, such as those in the two medical schools,” says Dennis Lo, director of the Li Ka Shing Institute of Health Sciences (LiHS), a translational medicine research institute of The Chinese University of Hong Kong (CUHK).

Lo, who is also associate dean for research of the Faculty of Medicine at CUHK, adds that the facility's international visibility might also “trigger more investment from the Hong Kong government and the commercial sector to develop biotech in Hong Kong.” LiHS recently installed 10 Illumina Genome Analyzers, eight of which are part of a joint CUHK-BGI genome research center that intends to conduct collaborative “projects in the fields of cancer, diabetes and plant genomics,” he says.

BGI's vice president, Xiuqing Zhang, also points to a deliberate international agenda. “BGI's investment in Illumina's new HiSeq 2000 system is an important step in our effort to develop a premier sequencing facility that serves scientists globally,” he says. The HiSeq 2000 platform is capable of generating two billion paired-end reads and 200 gigabases of quality-filtered data in a single run, allowing researchers to obtain 30-fold coverage of two human genomes in a single run. “Our goal is to build partnerships and collaborations around the world that contribute to our global society,” says Zhang. “Creating solutions that enhance agriculture and food production, for example, are a key focus for us, [as are] more region-specific programs, such as the development of the personal genomics field in China.”

“[BGI's investment] aligns well with some of (China's) strategies in a number of areas, like reducing medical costs and improving plant- and animal-based industry,” says Charles Cantor, chief scientific officer of San Diego–based Sequenom. The company's technology is commonly used to follow up whole-genome studies to confirm newly discovered alleles and phenotypic associations, and Cantor expects China to be an important market. China has been “very successful” in efforts to develop genome analysis software, he adds.

BGI has also been establishing its own technical platforms based on large-scale genome sequencing, efficient bioinformatics analysis and innovative genetic healthcare initiatives, with these achievements having contributed considerably to the development of genomics in China and elsewhere.

BGI's Wang, who is also a professor in the Department of Biology at the University of Copenhagen, notes that genomic sequencing platforms would also open the door for further collaborative projects worldwide, including the 1,000 plant and animal reference project, to which BGI has pledged $100 million; the 10,000 microbial genomes project; and the Chinese Cancer Genome project.

BGI has already established itself as an important genome center on the world map. It successfully sequenced 1% of the human genome for the International Human Genome Project; contributed 10% of the International Human HapMap Project, with which CUHK was also involved; played a key role in the Sino-British Chicken Genome Project; completely sequenced the rice and silkworm genomes; and completed the first diploid human genome sequence of an Asian.

As reference genomes for certain organisms are now relatively common, “different strains are now being sequenced to discover the variations related to certain traits in those species,” says Wang, noting that “large-scale studies in exomics, metagenomics, epigenomics and transcriptomics” have suddenly all become realistic propositions.

In terms of applications, Lo's group at CUHK has pioneered the use of next-generation DNA sequencing as a molecular diagnostics tool, using noninvasive prenatal diagnosis as an example. CUHK researchers have also been involved in viral and bacterial genomic sequencing. For example, “my group was one of the first two Asian groups to report the complete sequencing of the SARS [severe acute respiratory syndrome] coronavirus and to use genomic information to research the molecular epidemiology and evolution of this virus,” says Lo.

In China, “the challenges are getting more resources, [especially] funding, samples, and collaborative agreements from various groups that study different subjects,” says Wang. “We also need more young talent to work in this field, in particular to analyze the data.” Finally, Wang stresses that although the Illumina deal may have made BGI the largest sequencing center in the world, “genomics cannot be done alone and must be performed on an international basis.”

One of the best examples concerns the 1000 Genomes Project, an international research effort to establish the most detailed catalog of human genetic variation by sequencing the genomes of at least 1,000 individuals from different ethnic backgrounds, in which BGI is collaborating with genome centers in Germany, the UK and the USA.

The size of China's population could be a boon to international efforts at unraveling how genome variations contribute to disease. Indeed, China has also made a commitment to cancer research. “They are doing work to describe such patients, and one can only expect it's going to accelerate as they become more sophisticated and [Chinese people] get better and better healthcare,” says Richard Cotton, who is head of the Genomics Disorders Research Centre at the University of Melbourne in Australia and convenor of the Human Variome Project, which focuses on collecting and curating human genetic variations that affect health.

Cotton's efforts have focused on single-gene disorders, and he is excited about the potential for new research to emerge from China's bulked-up resources. “I can see a renaissance in single gene disorder work because the sequencers can be put in there to find something useful for patients. There's no question in my mind that these sequencers will be put to work in the Chinese population,” adds Cotton.

But that won't necessarily be enough, he says. Healthcare infrastructure will also be critical. “They've got to (obtain) the material to put in them. Single gene disease research is not high-throughput. A patient comes in the door of a doctor's office and then leaves, but that rate is not very high. If they get themselves organized in China, they could get a lot of samples coming in,” adds Cotton.

Along with its continued strengthening of expertise in sequencing and analysis, “China is now producing more well-trained scientists than any other country,” says Cantor. As long as this trend continues, China's impact on progress in research and technology is likely to continue to rise proportionally. “It is inevitable,” he adds. And in terms of both investment (Nature 463, 282, 2010) and scientific output, China's genome centers are already beginning to rival some genome centers in Europe and North America, although today the emphasis is more on collaborative research between many international centers than on competition.

China's efforts could well spur development elsewhere. “I think there is a tremendous opportunity for any country or funding agency to really empower that discovery by making some investment. I assume that China understands that. They have a good group at BGI, which has a pretty good track record of making this kind of thing work,” says Richard Wilson, director of The Genome Center at the Washington University School of Medicine, St. Louis, Missouri. “If countries such as the US, or the UK, or anyone else sees that as a good reason to build up their own genetic sequencing infrastructure, I think that's a good thing. The more the better.”

The BGI deal represents Illumina's largest single order for sequencers so far and is estimated to be worth over $88 million, given that the retail list price of the HiSeq 2000 is $690,000, although BGI may have received a significant volume discount.

BGI signed an agreement last month with the China Development Bank under which BGI will receive $1.5 billion in 'collaborative funds' over the next ten years, which the institute plans to use for infrastructural development and to cover running costs.

However, BGI is not the only institute sequencing genes in China, so the country's overall annual equipment expenditure is likely to be in excess of $1 billion. “There are other scientists in China involved in gene sequencing,” says Jun Wang. “There are another three genome centers and more labs with [sequencing] instruments.”

Although the initial cost of the Illumina sequencers may be high, technical innovations “take the cost of sequencing a human genome below $10,000,” says Illumina's Jay Flatley, noting that just three years ago, sequencing a human genome cost $1 million, whereas the new HiSeq 2000 sequencing system could “recreate the International Human Genome Project in a week.”

According to the manufacturer, the HiSeq 2000 is capable of generating 200 gigabases of data per sequencing run and 25 gigabases of data per day. It uses two flow cells and an innovative dual-surface imaging method, enabling new levels of sequencing output as well as experimental flexibility. “With the rapid reduction in the costs associated with [gene] sequencing, this approach will soon be cost-effective enough to be used on a routine clinical basis,” Lo predicts. JF

Table 1

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Victoza (liraglutide [rDNA origin] injection)	Novo Nordisk (Copenhagen)	The US Food and Drug Administration approved the new drug application for Victoza, the first once-daily human glucagon-like peptide-1 (GLP-1) analog for type 2 diabetes. Victoza is indicated as an adjunct to diet and exercise to improve blood sugar control in adults with type-2 diabetes mellitus.
Xiaflex (collagenase clostridium histolyticum)	BioSpecifics Technologies (Lynbrook, New York) and Auxilium Pharmaceuticals (Malvern, Pennsylvania)	The US Food and Drug Administration approved Xiaflex for adults with Dupuytren's contracture with a palpable cord. Xiaflex consists of two microbial collagenases in a defined mass ratio, Collagenase AUX-1 and Collagenase AUX-II, which are isolated and purified from the fermentation of Clostridium histolyticum bacteria.