在协助完成人类基因排序之后，中国生物学家正在讨论如何进一步推进成为生物领域的强国。

中国把参加国际人类基因组计划（HGP）作为一种荣耀。上个月，当国际人类基因组计划协会在自然杂志公布人类基因的排序时，中国的研究院也成为人们关注的热点。

北京基因组研究所所长Yang Huanming 说：“现在中国人都知道人类基因组了，中国人为参加这项国际合作而感到自豪。”

1998年，中国科学界的领导不顾来自国际人类基因组计划成员，甚至许多自身研究人员的怀疑，坚持参加基因组计划，成为承担基因排序任务的唯一的发展中国家。科技部成立了中国国家人类基因组研究中心，下设北京和上海两个分支机构。一年后，中国科学院成立了北京基因研究所。这些研究机构承担了已公布的1％的排序任务，这是非常了不起的成就。

以自己的在人类基因排序中的勇气和早期在植物转基因方面的成功经验，中国进一步集中所有必需的条件形成在生物学和生物技术领域的中坚力量。在政府的大力支持下，研究人员展开了庞大的研究计划，从茎细胞研究到大力探索蛋白质结构的决定机制，再到搜寻人类疾病基因的人口研究，甚至讨论克隆濒危动物大熊猫。

由于研究人员是从海外学成归来，他们的步伐是惊人的。虽然中国大多数生物学家仍然工作在破旧的房子里，但实验室里的新设备格外显眼。许多研究所正计划扩充他们的设备－－这仅仅是转变中国城市风景的建筑变化的一部分。上海第二医科大学的分子遗传学家Zhu-Gang Wang说，在纽约the Memorial Sloan-Kettering Cancer Center （癌症研究中心）三年后回到上海，都快不认识这个城市了。并且，他惊奇的发现，他需要的试剂隔夜可取，而在以前需要几个月的时间。

但是，在快速发展中，一些研究人员警告说，与已形成的研究力量相配套，我们还有许多工作要做。中国生物学家认为，要在扩充DNA排序的力量和投资功能遗传和医学遗传之间寻找平衡点。他们要求更多的协调，最好对各种不同的已考虑的计划进行同等的价值判断。另一些研究人员担心，尽管中国在向市场经济转变，但还是缺乏培育凸起的生物技术工业所需要的真正的竞争环境。

原文：

A great leap forward

DAVID CYRANOSKI

David Cyranoski is Nature's Asian-Pacific correspondent.

After helping to sequence the human genome, Chinese scientists are debating how best to continue the push towards becoming a world power in biology. David Cyranoski reports.

China wears its participation in the international Human Genome Project (HGP) like a badge of honour. Last month, when the HGP published its sequence of the human genome in Nature¹, Chinese institutes were among those sharing the spotlight.

"Now everyone in China knows what the human genome is," says Huanming Yang, director of the Beijing Genomics Institute (BGI). "Chinese people are so proud to be part of this international effort."

In 1998, China's scientific leaders overcame scepticism from some members of the HGP — and from many of their own researchers — to become the only developing country to take a role in sequencing the human genome. The Ministry of Science and Technology launched its Chinese National Human Genome Center (CHGC), with branches in Beijing and Shanghai. A year later the Chinese Academy of Sciences opened the BGI. These institutes contributed 1% of the published sequence — an achievement that is of huge symbolic importance.

Having now proven its mettle in sequencing, and following earlier successes in plant transgenics, China is now taking a leap towards assembling all the elements needed to become a major force in biology and biotechnology. With strong government support, researchers are setting up programmes in everything from stem-cell research, through large-scale efforts to determine protein structures, to population studies to hunt for human disease genes. There is even talk of trying to clone the endangered giant panda.

For researchers returning from positions abroad, the pace of change is striking. Although most of China's biologists still work in run-down buildings, these labs are starting to bulge with gleaming new equipment. And many institutes are planning to expand their facilities — just part of the construction upheaval that is currently transforming China's cityscapes. Returning after three years at the Memorial Sloan-Kettering Cancer Center in New York to Shanghai, a city he "no longer recognized", molecular geneticist Zhu-Gang Wang of Shanghai Second Medical University was startled to find that reagents could now be acquired overnight, rather than in the months that he remembered.

But amid this rapid growth, some researchers are warning that there is more to be done than simply matching the spending of the established powers. As Chinese biologists debate the optimal balance between building more capacity for DNA sequencing against investing in areas such as functional genomics and medical genetics, there are calls for more coordination, and better peer review to judge the relative merits of the various programmes being considered. Other researchers are concerned that, despite moves towards a market economy, China still lacks the genuinely competitive environment needed to nurture a vibrant biotechnology industry.

A valuable lesson
Although many Chinese researchers originally questioned the value of a Chinese contribution to the HGP, there is now little doubt that the work has provided a springboard for the development of Chinese biology. "We learned large-scale sequencing, how to coordinate many centres, and how to do bioinformatics," says Zhu Chen, director of the Shanghai CHGC and vice-president of the Chinese Academy of Sciences.

Now, those who led China's contribution to the HGP are debating how to strike a balance between building on these strengths and exploring other frontiers. At the BGI, Yang is pressing on with sequencing. In late January, he opened a new sequencing facility in Hangzhou, south of Shanghai. This will work on two main complete genome sequencing projects: the pig — a collaboration with Danish scientists — and the parent strains of China's 'superhybrid' rice, a productive variety that accounts for 60% of the country's rice harvest.

"Some people say, 'sequencing is not everything'," says Yang, "but I believe that it is the best place to start." However, Yang feels he is losing a tug-of-war over central government funding to those who are switching to functional genomics, research that aims to identify the biological role played by the newly sequenced genes. To open the Hangzhou facility, Yang had to borrow US$6 million from the city government.

Although Chen's Shanghai CHGC was responsible for about a quarter of China's HGP contribution, he is now more excited by the possibilities offered by the hundreds of full-length complementary DNAs sequenced as part of China's involvement in the project. These represent the sequences of expressed genes, and can be engineered into cells which are then cultured to mass-produce proteins so that their structures can be determined.

Like the Shanghai CHGC, the Beijing branch is turning increasingly to functional studies. The two centres have several joint projects, focusing on genes related to liver cancer, nasopharyngeal cancer, oesophageal cancer and leukaemia.

But there is one major point of convergence in the research strategies of the BGI and the CHGC: both are using their sequencing machines to identify single-nucleotide polymorphisms (SNPs) from Chinese populations. These markers of genetic variability should aid the search for the genes that predispose humans to complex diseases such as cancer and psychiatric disorders. Some critics argue that the Chinese SNP projects will largely duplicate the efforts of the international SNP Consortium, a collaborative effort uniting leading Western genome centres and drugs companies. But Chen argues that about 30% of the SNPs in Chinese populations will be different from those found elsewhere — twice as many as has previously been thought.

Whether or not a separate Chinese SNP effort is required, there is widespread agreement that China has a lot to offer geneticists. The country's array of isolated, relatively homogeneous sub-populations from 56 different ethnic groups represents a unique resource for disease gene searches. Inbreeding has produced a homogeneous genetic make-up within each population, and the lack of emigration or immigration means that it is easy to construct large family pedigrees. These features have made Iceland and Finland hotspots for mapping the chromosomal location of genes predisposing to disease. "We have several Icelands and several Finlands," says Lin He of Shanghai Jiao Tong University, who coordinates a bank for blood, tumour and cerebrospinal fluid samples collected from populations across China.

The search for genes that underlie diseases, and for ways to block their effects, is a national priority. "With an estimated population of 1.6 billion by 2030 and an ageing society brought on by the one-child policy, we will need medical breakthroughs," says Xu Zhi-Hong, president of Peking University. "This is our challenge."

It is a challenge that both the government and researchers are taking on. In 1998, the government set up a programme alongside the HGP sequencing effort, which has established banks of blood samples and associated information about family pedigrees in Hunan, Guanzhuo, Beijing and Shanghai. Independent scientists have been working in parallel. Yunnan University recently announced that it has assembled the largest biological sample collection in the world in terms of ethnic diversity. At Shanghai Jiao Tong University, meanwhile, He claims to have compiled the world's largest sample bank related to neuropsychiatric disease, in a joint project with the Shanghai Institutes of Biological Sciences.

Studies of samples taken from Chinese populations are already yielding advances. The first success came in 1998, when a team led by Jia-hui Xia of the National Laboratory of Medical Genetics of China in Changsha, Hunan province, identified a gene for a form of neurological deafness². Then, last year, researchers led by He mapped the gene for brachydactyly type A-1 — a disease in which joints of the figures are missing, misplaced or disfigured — to a small region of chromosome 2 (ref. 3). He and his colleagues say they have now isolated the gene, beating competition from several groups around the world, and have submitted the results for publication. "We just had good samples with good pedigrees," He says.

And the pace looks set to pick up. Last month, researchers led by Yan Shen of the Institute of Basic Medical Sciences in Beijing revealed the genetic basis of another disease, dentinogenesis imperfecta Shields type II, in which the teeth are discoloured and chip easily⁴. From their studies of large pedigrees in the Jiangsu province, north of Shanghai, the team showed that a mutation in a gene called DSPP is responsible. Alongside this paper, researchers led by Xiangyin Kong of the Shanghai Research Center of Biotechnology reported, from their studies of three extended families from the same region, that mutations in DSPP can also cause hearing loss⁵.

But there are obstacles to progress. Some Chinese people are unwilling to take part in studies for fear that discovery of a genetic disease could lead to discrimination. And in the longer term, China's one-child policy, and the increasing population mobility being promoted by the country's economic development, will pare down the number of large pedigrees and lead to genetic mixing between populations.

Commercial breaks?
To capitalize on the discovery of disease genes, biotechnology and pharmaceutical companies will have to take the lead. This is the weakest link in the chain, although with generous government support, universities are launching large numbers of spin-off companies. Peking University is the leader, boasting a portfolio of eight biotech firms.

"China's system for allowing professors to engage in industry is much more flexible than most others," says Jing Cheng, one of China's best-known biotech entrepreneurs, who runs a DNA microarray company spun off from Tsinghua University in Beijing. Indeed, compared with Pacific Rim neighbours such as Japan, there seems to be little or no restriction on university researchers trying their hand at business.

But unlike the situation in its capitalist neighbours, China's government retains a large chunk of any company, and may even fund its research. Some researchers argue that this is holding the sector back. "With generous government grants, people do not worry about making profits. Even if something is developed, it will sit on the shelf because no one will make the effort to commercialize," says one researcher working at an institute of the Chinese Academy of Sciences. "Many researchers seem just to use public funds freely to do research while claiming to set up their own company," says a senior executive of a Hong Kong-based biotech company.

Reliance on the government is "the greatest problem for biotech in China", agrees Yu-Min Mao, a geneticist at Fudan University in Shanghai. Venture capital is not well established, so would-be entrepreneurs have few other places to turn. But Mao is showing that it is possible to break the mould. In three short years, his United Gene Holdings has become China's biggest biotechnology company. It now covers a wide range of genomic science services such as gene cloning and sequencing, and claims to have identified 5,000 novel complementary DNAs.

Mao and his business partner, Yi Xie, invented their own venture capital format to encourage investment: they stipulate that, with any investment, one-third goes towards buying stock and two-thirds go towards a low-interest, long-term loan to the company. "There are few investment banks in China, but the principle is the same," says Mao. "We just borrow from individual investors instead of investment banks." For the investors, this lowers the financial risk, should the company fail. "Normally they would lose their entire investment, and we would only lose our technology. Now, they would only lose one-third of their investment, and we would still owe them the rest," says Mao. "It shows that we are confident in our products."

Apart from the struggle to generate a favourable climate for biotech investment, the other main obstacle to China's development in biology is the eccentricity of funding decisions, which are often based on political leverage rather than peer review. The result, critics claim, is a proliferation of uncoordinated projects. "Everybody is just trying to jump on the genomics bandwagon, but very few know where they are going," says Ming-Wei Wang, formerly chief executive officer of a Shanghai-based biotech company. "In China, everything is decided in backrooms, and then just announced," says one researcher with the Chinese Academy of Sciences. Genomics research in China is an uncoordinated "bunch of loose ends", complains another.

But others are optimistic that China will begin to apply more rigorous, open and accountable methods of decision-making. If so, its future as a leading international player in biology should be secure. Li Jin, formerly of Fudan University's Institute of Genetics, and now based at the University of Texas at Houston, is one of those predicting a bright future. "With increasing funding and by taking advantage of its unique resources, China will soon become a serious contender on the world stage," he says.

[返回上一页] [打 印]