BY CARlOS OTTERY

CHINA'S GENE DREAM

BY CARlOS OTTERY

How China is changing the world of genomics

從參與人類基因圖譜的繪制開始，中國(guó)在基因科技的路上越行越遠(yuǎn)，欲罷不能

It took 16 years and billions of dollars, but in June, 2000, to great fanfare, the then American President Bill Clinton and the British Prime Minister Tony Blair announced in a joint statement that the world's largest ever collaborative biological project had been a resounding success; the Human Genome Project, a rough draft of it at least, had been mapped. As ever, Clinton's words were dazzling; Crick and Watson, the founding fathers of DNA, were invoked, as were Galileo, and, of course, God. Both Clinton and Blair were also quick to make a very particular point of thanking China for their contribution to the massive ground-breaking project.

Up to this point, the Chinese government had shown little interest in sequencing human genes, and though the Chinese contribution to the Human Genome Project was small (about one percent of the whole), the words of Clinton and Blair were game changers, putting China fi rmly on the genomics map. On hearing Clinton's words, Chinese President Jiang Zemin reportedly set about funding Chinese genomics immediately; the nation was about to embark on a journey that would put them at the very forefront of the world of genomics.

Today BGI (formerly Beijing Genomics Institute) in Shenzhen, Guangdong Province in southern China is the largest genetic sequencing center in the world, employing over 4,000 scientists. BGIhas mapped the genomes of over 60,000 people, not to mention the fi rst sequencing of an Asian human and an ancient human, as well as the genomes of giant pandas (naturally), rice, cucumbers, pigs, chickens, tigers, fl eas, silkworms, lizards, and sea slugs. If it lives, plant or animal, BGI have either mapped its genome or are on the way to doing so. BGI maps more genomic data than anywhere in the world, by some estimates over 25 percent of all gene data sequenced in the world. The amount of data involved in sequencing just a single human genome is mindboggling, containing over three billion base pairs—a remarkable undertaking. But BGI has very big plans indeed and its Three Million Genomes Project will sequence the DNA of one million people, one million microorganisms, and one million plants and animals. A single BGI supercomputer currently processes 10 terabytes of raw sequencing data every 24 hours.

NOBODY lS PREClSElY SURE OF THE FUll EXTENT OF THE VAlUE OF GENE SEQUENClNG, BUT THE VAST MAJORlTY OF THE SClENTlFlC COMMUNlTY THlNKS lT COUlD BE VERY FAR REACHlNG lNDEED

Whereas it cost billions of dollars and over a decade of work to map a single human genome for the fi rst time, advances in technology mean that today it costs as little as 1,000 USD and takes as little as two hours to map a single human genome. The price is falling fast, with some predicting it may fall to a few hundred dollars. Dealing with big data on such a huge scale causes its own raft ofproblems, and BGI is partly dealing with these issues by doing something many of its critics thought it would never do: sharing. For instance, for World Hunger Day it made 13 terabytes of rice genome data available to the public. This enables scientists the world over to do their own research, eventually allowing them into the secrets needed to develop strains of rice with higher yields. In 2011 a particular dangerous strain of E. coli, spread throughout Europe killing dozens. BGI were able to take a sample of the bacteria and sequence the bacterial genome, giving the data to the public. Soon researchers throughout the world were publishing reports analyzing the disease and its resistances, which ultimately helped to contain the outbreak. BGI's openness saved lives.

Dr. Beichang Yang is BGI's director of communications and public engagement and has been at the company for nearly six years. She speaks with passion and zeal about BGI's potential to change the world in a variety of ways: “I think BGI is in the leading group doing genetic sequencing in the world, but I would not say we are the most advanced—that would be a bit bold. Some US and UK groups are also very advanced, and we do a lot of collaboration with them,” she says. Regarding BGI's rare openness, especially rare for a Chinese company, she explains that to deal with such monumental amounts of information, BGI launched its own online journal,Gigasciencean open-data publication to help publish its vast reserves of data.

The scale of the data involved was so huge that they chose to base the journal's servers in Hong Kong where internet speeds are faster and cheaper. To Yang,Gigasciencewas an obvious choice: “There are drawbacks if we hold the data. It wastes a lot of time and resources. The idea of launchingGigasciencewas to accelerate research by releasing the data before the research stage. In the traditional publishing research model, you have to run your tests, do your numbers, write your papers, and then publish, which other researchers then pick up on.Gigascienceallows us to publish data before papers, research, and conclusions. That way, other groups can use the data to generate new research and studies.”

Nobody is precisely sure of the full extent of the value of gene sequencing, but the vast majority of the scientif i c community thinks it could be very far reaching indeed, and key, but not limited to, developments in unlocking the secrets behind human evolution, resolving world famines, increasing IQs, curing hereditary diseases, and increasing life spans; to the layman, this is the stuff of miracles.

In the spring of 2013, BGI announced it was establishing a partnership with a Middle Eastern biotech fi rm to introduce a non-invasive fetal trisomy (NIFTY). The NIFTY test detects fetal chromosomal abnormalities using fetal DNA in the maternal blood to detect Down's Syndrome with an accuracy of 99.9 percent at as early as 12 weeks of pregnancy. This is the fi rst time non-invasive tests have been possible at such an early stage.

The scale of BGI's international collaboration, much like BGI itself, is huge. They are working in the Philippines to develop new rice crops, doing projects in Mexico on maize, teaching scientists in Nairobi how to use their sophisticated sequencing machines, and perhaps one of the biggest feathers in the their cap is the close work they started with the Bill and Melinda Gates Foundation in September 2012. A memoriamof understanding was signed, which will focus on agricultural organisms, infectious diseases, and crops in Africa. It is hoped to achieve the goal of signif i cantly reducing poverty and/or improving health in the developing world. The scope of BGI'S plans sometimes seem almost too audacious.“The future development is fi rst related to personal healthcare. Genomics sequencing technology has been more and more applied in the clinical fi eld of hereditary disease testing, so we can better prevent some birth defects. Also, we can better predict or diagnose cancers and diseases such as diabetes and obesity. In maybe fi ve to 10 years, we can use technology to better predict and develop personalized treatments for those diseases,”says Yang.

And, of course, as with anything this size, some people seem to be running a little scared. Despite the fact that most of the science can be typif i ed as “good works”, BGI has been criticized for the sheer size and scale of it partnerships, hiring, purchasing power, business divisions, fi nancial muscle, and data collation. In short, some in the West fear China is fast approaching genomic hegemony.

In 2010 BGI secured a 10-year loan of 1.5 billion USD from state-owned China Development Bank and went on to purchase American genomics hardware fi rm Complete Genomics for about 118 million dollars, in what was the fi rst ever acquisition of a US listed public company by a Chinese fi rm. The move was seen as China gaining the edge in producing and providing its own sequencing machines, when previously they had simply been purchasing them from America. Complete Genomics' biggest rival, Illumina, were furious at the deal and attempted to block the purchase on the basis that the deal posed a threat to national security. Illumina's concerns were rejected out of hand, and the deal went ahead. Illumina's CEO Jay Flatley's fears seemed jingoistic and he repeatedly told journalists that the purchase would be equivalent to selling China the “formula for Coke”.

HE WENT ON TO EXPlAlN HOW HE BEllEVED CHlNA HAD BEEN EXPERlMENTlNG WlTH EUGENlCS FOR 30 YEARS

He hammered his point home in an interview with Xconomy, “There's risk they could build very large databases, and get access to the genomes of lots of Americans. They could bring them back to China. There are lots of nefarious ways you could use the information. There are theoretical bad things you could do with those kinds of databases if they aren't regulated by the law of the United States. So we were concerned about BGI's aff i liation with the Chinese government.” Though itsounded like the sour grapes of a nationalistic businessman soundly beaten, he continued to argue that in China the state has deep inf l uence into all spheres of daily life, and this was bad news when it came to storing so much biometric data.

“It is paranoia,” says Yang. “We bought Complete Genomics for one reason: BGI recognized the power of its technology. Complete Genomics business strategy was not doing what it was supposed to do and this was causing them fi nancial problems, but the technology itself had lots of potential. After buying them we went to try and develop the technology so it could be applied in a larger fi eld.”

There are other areas of BGI work that have caused controversy. Every year high-brow leaning online magazineEdge, which aims to “seek out the most complex and sophisticated minds, [and] put them in a room together”, asks its annual question so as to stir debate amongst the intellectuals, scientists, great thinkers, and assorted artists of the day. In 2013 their question was the simple but provocative: “What should we be worried about?”

Geoffrey Miller, an evolutionary psychologist at the University of New Mexico, was particularly alarmist, answering, “Chinese Eugenics.” He went on to explain how he believed China had been experimenting with eugenics for 30 years, citing the controversial 1995 Maternal and Infant Health Law, which tried to prevent people with heritable defects from marrying and promoted the scanning of fetal ultrasounds to check for birth defects. Interestingly, Miller was not remotely criticizing eugenics as an idea (if anything he seemed to imply the West should join in), but instead pointing out that BGI with their purchase of Complete Genomics were leaving the West behind, going on suggest that BGI's ongoing cognition project, a project to which he himself had donated his own DNA, was going to identify alleles within DNA that were predictors of IQ: “[They] will probably be used mostly in China, for China. Potentially, the results would allow all Chinese couples to maximize the intelligence of their offspring by selecting among their own fertilized eggs for the one or two that include the highest likelihood of the highest intelligence,” he said. “This method of ‘pre-implantation embryo selection' might allow IQ within every Chinese family to increase by fi ve to 15 IQ points per generation. After a couple of generations, it would be game over for Western global competitiveness.”

Miller was of course theorizing, and offered no hard evidence that BGI were intending to use theircognition project in this way at all. In fact the nature of IQ being in any way a real and valid measure of intelligence is hotly disputed and questioned by any number of scientists. Although, there are many in the scientif i c community who don't think using science in this way is problematic at all. Indeed, many see it as positive. Who wouldn't want babies that were more intelligent, right?

lT lS HOPED THAT BY CAREFUl SlFTlNG THROUGH THlS DNA, ClUES Wlll BE SPOTTED FOR WHAT lS THE GENETlC BASlS OF lNTElllGENCE

There is no doubt that the scientif i c community in China is hindered less by ethical concerns than the Western scientif i c community. Accordingly, some things are pushed through in China, where in the West they are delayed, such as stem cell research. Chris Chang, a visiting scholar at BGI who is working on their cognition project, toldTheNew Yorkerwhen discussing intelligence research: “There are ethical concerns about research in China too…But it is just not the career killing project it would be in the United States.”

Regardless of its ethical implications, BGI believe their cognition project is a potentially inf l uential one. The idea is to compare the DNA of about 2,100 people, all with high IQs (including Miller's), 1,600 of them taken from a previous study of those with exceptionally high IQs (over 150), against the genomes of thousands of people among the general population. It is hoped that by careful sifting through this DNA, clues will be spotted for what is the genetic basis of intelligence. Many, however, are skeptical. Firstly, it has been pointed out that, for a genetics study, 2,000 or so is an incredibly small sample size—sample sizes of tens of thousands are usually used for studies of this nature. Secondly, many argue that there isn't very much of a genetic basis for IQs anyway and that intelligence is more likely something acquired. Dr. Yang agrees and doesn't think the cognition project is going to yield quite the results that some claim: “I don't think this is feasible or possible; cognition is a very complex issue. A lot of other factors inf l uence this, not just genetics: environment, education all leads to IQ, so I think some of the press exaggerate the future potential outside of this. Cognition is a very small part of what we do.”

Aside from the potentialBrave New Worldaspects of genomics and where it could potentially go, one of the biggest fears regarding BGI, simply, is that it is Chinese. Of course there will always be those that criticize the storage of such vast amounts of human biometric data, but there is something about China itself that makes people nervous. It is true that the Chinese government is able to intrude into the superstructures and structures of society in a way that few other governments can or do, and it would not be unreasonable to think the Chinese authorities do not have at least some inf l uence on BGI. One and half billion dollar loans usually come with a few strings after all. BGI's relationship with the government has not been an easy one; part of the reason BGI relocated from Beijing to Shenzhen was because the central government was not giving them the support they deserved. On being asked if BGI gets support from the government, Yang said, “Yes, especially the local government. They support us more than the central government. The Shenzhen government gives us lots of support because they understand what we do—maybe other governments don't.”

In its early days, BGI was non-prof i t, and later it was aff i liated with the Chinese Academy of Sciences, but, ultimately, they were thrown out and had to set up as a private venture in Shenzhen. It was only their work on the Human Genome project that got them noticed. BGI almost has a slightly bad-boy image in China and has its own way of doing things. It gives scientists vast responsibility from an early age and notably even employs students who “dropped out” or failed to graduate. It's an image that has permeated the whole company, as if lying on the border town of Shenzhen, so far from the seat of government, they are outliers in some way. Yang certainly takes some small pride in the idea,“Interestingly, in China we are a troublemaker; we have a reputation for not following the rules. In some ways BGI is unique and not a typical Chinese-style organization.”

There is little doubt that, thanks to BGI, in China, genomes are being sequenced at remarkable magnitudes. And, as to the signif i cance of it all? The truth is nobody knows. Designer babies, eugenics, and totalitarian states using all the biometric data in the world for shadowy Orwellian purposes are the nightmares of the fi ercest critics of the gene dream. Unlocking the key to who we are, ending disease, feeding the world, and, who knows, perhaps even immortality are the promises of the scientists who dare to believe. But one thing is sure: however it pans out, the bad boys in Shenzhen with a passion for DNA sequencing will have a part to play. We can only hope they play their cards right.