The gene team

PUBLISHED : Sunday, 23 March, 2008, 12:00am
UPDATED : Sunday, 23 March, 2008, 12:00am

The 11-storey Zhonghe Building is a sparkling new structure with a hi-tech glass facade and wall cladding the colour of gun metal. From the top floor on a clear day, Shenzhen's eastern suburb of Imtin can be seen sprawling southwest through 5km of hazy seafront to the Hong Kong border at Sha Tau Kok. Nearby, to the south, hulking cranes hoist containers from cargo ships berthed at the Yantian docks.

Inside the building, in Shenzhen's Beishan Industrial Zone, another kind of unloading is going on, albeit on a scale that is paradoxically both far smaller and much, much larger. Row after row of bespectacled technicians, squeezed into an air-conditioned room, are hunched over flickering monitors - trying to determine what it is to be Chinese. They are analysing reams of data piped

up through cables from a supercomputer in the building's basement. As their manager, Fang Lin, explains, there's a lot of it.

'Our mainframe is now processing more than 300,000 gigabytes,' he says. 'All of this data has come from an analysis we are doing of the DNA of a single Chinese person.'

Fang and his team of more than 100 bioinformatics experts are working at China's newest, largest and most dynamic centre for genetic research. Called the Beijing Genomics Institute, Shenzhen (BGI-Shenzhen), the facility opened last April and is dedicated to the fastest developing area of genetic science: medical genomics. Its discoveries should herald nothing less than a revolution in health care for people of Chinese ethnicity.

BGI-Shenzhen announced its first significant result just six months into operations; the sequencing of the entire genome of an anonymous Han Chinese man. This was only the third time, following successes by American geneticists James Watson and Craig Venter, an individual human genome had been sequenced.

The achievement was the first step in the Yanhuang Project, named after two mythical kings from whom all Chinese are said to have descended, and which the mainland media has compared to the national space programme. In the next few years, Fang will lead an effort to crack the genetic code of

100 more individuals, to piece together a detailed 'map of the Chinese genome'.

A wall display points to why someone might want to do this. If the 6 billion chemical units of a sequenced human genome could be rendered as a bar code that stretched from Hong Kong to Delhi, in India, a 30-metre-long chart plastered up in the company's reception area is a scrunched-down representation of it. Here and there, individual genes have been picked out by the lightning calculations of the computer downstairs. MSH6 in chromosome 2, for example, has been identified as influencing the onset of lung cancer. A gene called ACVR2B in chromosome 3 is related to diabetes.

Shenzhen's geneticists are trying to find out how genes affect a person's health. They want to know how we inherit resistance against, or weakness for, disease and how genes shape our responses to treatment. The target is 'personalised medicine', based on a full genetic profile of everyone who goes to see a doctor. Such a profile would help doctors anticipate health problems and treat them before they took root. For patients already afflicted, the profile would act as a guide, telling a doctor which medicines would work and which would have the least damaging side-effects.

'Today's spread of humanity started with a migration out of Africa that took place between 100,000 and 150,000 years ago,' explains Professor Li Songgang, an associate director at BGI-Shenzhen. 'Since then, different tribes have encountered epidemics and environmental influences that have steered them on separate evolutionary courses. These influences have given them different genetic profiles, with associated levels of susceptibility to different diseases.'

The world's biggest tribe is the Han, which makes up 95 per cent of the Chinese population. It's well known that Chinese contract hepatitis B more easily than westerners do and some 130 million people in the mainland have the virus. Much of the time, this infection ends in cirrhosis or cancer of the liver and an excruciating death. No genes have yet been pinpointed as being responsible but scientists are homing in on the causes. They are pretty sure most of them come from variations in a narrow area of chromosome 21. A full investigation will make up a large chunk of BGI-Shenzhen's future work.

Hepatitis B is not alone. In the United States, for example, the Food and Drug Administration (FDA) has approved more than 1,500 genes as reliable indicators of susceptibility to particular diseases. In China, however, less than 40 of these are used, because disease-causing genes rarely act alone. Most of the time, they work in conjunction with other, often unidentified, genes or environmental factors. These may be absent in a typical Chinese and his or her surroundings, and this is where a 'reference map' of the Chinese genome would be of great use. 'China can't rely on foreign standards,' says Li. 'We have to do our own research.'

The side-effects of drugs are an enormous problem for the pharmaceutical industry. In the course of researching and developing drugs, many promising substances have to be thrown out because they produce adverse reactions in a small number of subjects. Sometimes those side-effects vary along the lines of ethnicity.

The world's No 1 influenza drug, Tamiflu, for example, has been found to cause depression and even suicide among Japanese. By finding the genes responsible in such cases, the institute's research promises more effective treatment tailored to Chinese patients, or even individuals who test positive for a given gene.

The emergence of genomics - and hence Shenzhen's status as a national centre for research - has in large part been due to a dramatic technological breakthrough. 'Massively parallel sequencing', developed over the past few years, increases by 10 times the speed at which scientists can sequence an individual's chromosomes while reducing the cost a hundredfold.

It works by taking whole genomes, smashing them into millions of pieces then determining the DNA order - or 'sequencing' - of each of those pieces simultaneously. BGI-Shenzhen has 12 American- and Swiss-made 'next-generation' machines that use this technology; metallic boxes humming away in a hermetically sealed clean room in the interior of the building.

Once each fragment of a shattered genome has been sequenced, it's the job of a supercomputer to line them up in their original order. After this, a bioinformatics expert will use statistical methods to identify, or 'annotate', the genome's 24,000-odd genes.

Two months after sequencing Yanhuang No1, in early January, BGI-Shenzhen announced it was starting on Yanhuang No2. A second anonymous Han volunteer had been found for sequencing.

The next 100-odd sequencings in the project should become progressively cheaper and faster given the rapid pace at which genomics technology is developing. After this will come the hard part. The institute's scientists will use clinical data to work out which of the thousands of genes that they have identified has medical importance and what they do. This will take years.

Although genomics is at a very early stage, BGI-Shenzhen is wasting no time in striking out on new initiatives. In late January, it launched the 1,000 Genomes Project. Together with the most important centres of genomics research in Europe and the US, the institute has committed to analysing DNA from hundreds of humans, from countries as diverse as Mexico, Kenya, Nigeria and Japan. The purpose is to work out medically important genetic differences between humanity's three largest sub-species: black, white and yellow.

Last month, BGI-Shenzhen launched a project to sequence the genome of the giant panda. The institute has also started selling its services internationally. A biotechnology firm in Massachusetts, in the US, called Knome offers whole-genome sequencing services to private individuals for US$350,000. In January, a millionaire living in Switzerland became the first to sign up. Under an agreement with Knome, BGI-Shenzhen's sequencing machines will do much of the heavy lifting.

The central government did not support the Beijing Genomics Institute in its earliest days and, unusually for the mainland, the project was given impetus by the initiative of three scientists. Yang Huanming, Yu Jun and Wang Jian had studied and worked in the US and Europe before returning home in the 1990s. They set up the Human Genome Centre of the State Council's Chinese Academy of Sciences (CAS) in 1998.

A year later they broke away to establish a private company - Beijing Huada Genomics Research Centre - in an industrial park just outside Beijing's Capital Airport. The local government of the municipal county of Shunyi donated the land for their enterprise. Most of the start-up money was supplied by Wang, who was running a successful company developing and selling diagnostic test kits for Aids.

Yang is a talented networker, who, after months of lobbying, won a 1 per cent share of the international Human Genome Project (HGP). Beijing Huada went on to sequence its allotted section of human chromosome 3 ahead of time and in a cost-effective way.

The State Council did not support Beijing Huada, mainly because it could see no point in contributing to a US$3 billion first-world project, the results of which would be made freely available to all countries anyway. Not until two months after work had started did the CAS give its official approval. This elevated the company's participation in the HGP to the status of a national project.

President Jiang Zemin visited Shunyi to honour this success. Since then, the Beijing Genomics Institute, as it is now called, has mapped the genomes of the rice plant and silk worm, and collaborated with laboratories in other countries to do the same for the chicken and pig. When Sars struck in 2003, the institute worked quickly to sequence the virus and develop a diagnostic test. For this, it was rewarded with a visit from President Hu Jintao.

BGI has branches in Hangzhou, Lhasa and Xishuangbanna, in the southern province of Yunnan. It chose Shenzhen for its flagship laboratory for four reasons. First, the mainland's richest city has the infrastructure - a reliable power supply together with the good air and road links needed for transporting perishable chemical reagents - to support such a world-class facility. To a visitor used to the mainland's grimy, communist-built universities and research facilities, the differences at BGI-Shenzhen are immediately apparent: the odour of the building's toilets cannot be detected as soon as you walk in the front door and the lifts are obviously cleaned regularly.

Proximity to Hong Kong, a major world transport hub with conference facilities to match, also went in Shenzhen's favour. Then there was the help being offered by the Yantian district government. BGI-Shenzhen is enjoying two years of rent-free lab space and construction is under way on a permanent home for 500 scientists on land donated to the company a stone's throw to the west. The new site has less seismic activity than is present in the dock area; fewer container trucks pass by to disturb sensitive gene sequencing machinery.

Most importantly, there is Shenzhen's status as a special economic zone. Although Chinese company law contains no provisions for non-profit organisations, Shenzhen has the autonomy to grant special privileges. BGI-Shenzhen is not a subsidiary of the original BGI but a stand-alone non-profit organisation dedicated to scientific research. It is the first of its kind in China.

Funding has come from government agencies on a project-by-project basis - the US$2 million needed for Yanhuang No1, for example, was stumped up by the CAS, the National Development and Reform Commission, the Ministry of Science and Technology and the National Natural Science Foundation - but the institute has made it clear it hopes for more support from private philanthropists and would like to benefit from a Chinese Paul Allen; the co-founder of Microsoft donated US$100 million in 2003 to a project to map the genes controlling human brain development.

In fact, it may already have found one. Last November, reports in the mainland press speculated that the DNA donor for Yanhuang No2 was going to be Shenzhen property magnate Wang Shi. Wang, who has climbed Mount Everest, and Yang share a friendship built around mountaineering. As chairman of China Vanke and one of the country's richest men, he also has the wherewithal. The press report said he had made a monetary donation to the institute, although it didn't say how much. BGI-Shenzhen will neither confirm nor deny the rumour.

A global race is underway to bring sequencing costs down low enough for a 'US$1,000 genome'. Li concedes that a developing country such as the mainland cannot hope to make advances in the main technologies underlying the science. (Most of the sequencing machines he uses were developed in Britain.) He's optimistic, however, that BGI-Shenzhen can contribute to the international effort through improvements in computer software and laboratory processes.

There's another reason why BGI-Shenzhen's work should catch the imagination of the public. Analysing the genome of a species or sub-species sheds a great deal of light on that organism's origins and evolutionary path. BGI-Shenzhen has collaborated with Britain's top centre of genetic research, the Wellcome Trust Sanger Institute, to develop software tracing the evolution of every living creature back to yeast.

For a people as conscious of their national identity as the Chinese, this 'genetic archaeology' is a powerful idea. The name 'Yanhuang' comes from Yandi and Huangdi, two chieftains of the Huaxia tribe who lived many thousands of years ago. Mythology has it that they gave birth to the entire Chinese people. Through presenting its work as some kind of quest to find the source of the nation, BGI-Shenzhen is tapping into powerful nationalist sentiments.

But is it a good idea to mix fairytales with hard science? Anthropologist Jared Diamond, for example, has opined that the Han are not one but two distinct races: the tall people of the north and their shorter fellow countrymen in the south.

And human beings are not the only Chinese creatures to have had their genome mapped. Three years ago, scientists at the National Cancer Institute in Maryland, in the US, collected tissue samples from around Asia for a study into the origins of the world's five sub-species of tiger. They found that the Chinese sub-species - called the South China tiger - was genetically identical

to the Indochinese tiger, which is indigenous to Myanmar, Laos, Cambodia, Thailand and Vietnam. Given the long history of rivalry between China and Vietnam, it's not surprising that many Chinese angrily rejected this discovery.

The genomic research taking place at BGI-Shenzhen should make for some surprising, if unpalatable, discoveries.

 

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