Human genomics in China

Ten years ago, the Chinese National Human Genome Center at Shanghai (South Center, hereafter) was established in the Zhangjiang HiTech Park of Pudong District in Shanghai. To commemorate this important event, which marks the beginning of the Genomics Era in China, we specially organize a series of mini-reviews for this special issue. We hope that this effort may draw the attention of the Chinese life science research workers to collectively recall the short but fruitful history of human genome project and coordinately explore the trend and goal of the future development of this academic discipline in China.

As early as in the late 1980s, the Chinese High Technology Research and Development Program, which is also known as the 863 Program, funded the scientists of Fudan University (in Shanghai) to construct DNA jumping library for human genetic disease related physical mapping. It was probably the very first human genome related research project supported by a national funding agency. After 1991, Fudan University, Ruijin Hospital and the Cancer Research Institute in Shanghai were all funded by the 863 Program in succession, to develop genomics technology by means of molecular genetics, and to study genetic diseases including cancer by means of medical genetics. Meanwhile, Beijing scientists such as those in the Institute of Basic Medicine, Chinese Academy of Medical Sciences also independently developed the rare cutter restriction enzymes such as Not I and Sfi I to facilitate the analysis of large DNA fragments of human genome, aiming at physical map construction. These early efforts and progress became truly "the spark of a fire" and the human genome research was thus initiated.

In the early 1990s, focusing on the total sequencing and annotation of the complete human genome as its core mission, the Human Genome Project (HGP) was initiated under the leadership of the U.S.A. However, the initial response in China was, instead, to participate in the International Rice Genome Project led by Japan. The reasons behind were obvious. First of all, for China, the largest developing country of the world, food security is of the primary concern and rice is the major staple food for Chinese people. Second, rice, a diploid crop, with its relatively small genome size (about 400 Mb), is a nice model of the monocotyledon plants. Third, over the years, the Chinese scientists had accumulated a great deal of experiences in the basic and applied research of rice, and achieved significant progress in rice breeding and physiology studies, particularly, for the hybrid rice, a model of "Green Revolution". Inspired by these ideas, both the central and the Shanghai municipal governments supported the DNA sequencing expert HONG Guo-Fan, who just returned back to China from Sanger's laboratory, to initiate the rice genome project in 1992 and the Chinese efforts in rice genome sequencing and research were thus, set out on its long journey.

Meanwhile, the far-sighted Chinese medical geneticists were still promoting the initiation of a human genome project in China. Academician WU Min, at that time, the director of the Department of Life Sciences, National Natural Science Foundation of China (NSFC), strongly recommended the NSFC committee to initiate some major projects for human genome research. His efforts were supported by the academician LIANG Dong-Cai, Deputy Director of the NSFC Committee and of the Department of Life Sciences, and thus, the first major human genome project in China was funded to study the genetic variations among the 56 Chinese nationalities. Meanwhile, the Chinese scientists working in the field of medical genetics gradually accepted the concept of genomics, and by applying the genomics technology, they carried out a series of research and made significant breakthroughs in the study and identification of disease associated genes, particularly the cloning and identification of genes related to leukemia, solid tumors (including liver cancer, colorectal cancer and nasopharyngeal cancer) and genetic diseases (such as deaf). Furthermore, substantial progresses were made in the development of technologies for human genome genotyping and genetic polymorphism detection, as well as for expressed sequence tag (EST) and full-length cDNA cloning and sequencing. All these achievements greatly strengthened the Chinese scientists' confidence and encouraged them to further explore the human genome. On the other hand, they made people perceive and appreciate the Chinese human genetic resources, for their abundance in population (more than 1 billion) with 56 nationalities and numerous relatively isolated ethnic groups. If we actively collect and utilize the resources with intelligence in research, along with the HGP, we will be able to and obligatory to make great contributions to the course of human health, especially to the oriental people for the medical purpose.

With this scientific and historical background, in July 1997, the academician TAN Jia-Zhen petitioned the central government, appealing for the protection of the Chinese genetic resources, and proposed to establish the national human genome center to speed up the human genome research in China. This petition attracted great attention from the Party Central Committee and the State Council. JIANG Ze-Min, the General Secretary of the Party and the President of the People's Republic of China, wrote: "One, who did not think far enough ahead, inevitably may have trouble right-a-way. We have to cherish our genetic resources." Thus, the Shanghai Human Genome Research Center, co-sponsored by the Ministry of Science and Technology, Shanghai Municipal Government, Pudong District, Zhangjiang High-Tech Park, and six research institutions in Shanghai, was founded on March 4, 1998. On October 20, 1998, the center was officially inaugurated as the Chinese National Human Genome Center at Shanghai (abbreviated as the South Center), thus becoming the first national research center located in the Zhangjiang Hi-Tech Park of Pudong District. The academician CHEN Zhu has served as the director of the center ever since, while ZHAO Guo-Ping acted as the executive director of the center after 2002. At the same time, the National Human Genome Center at Beijing (the North Center) was established with the support of the Ministry of Science and Technology and Beijing Municipal Government, and the academician QIANG Bo-Qin served as the director. The "Huada" (Chinese Giant/Wash U) Genome Center, directed by YANG Huan-Ming, was also established by the Institute of Genetics, CAS. Together with the previously established National Gene Research Center, which was established by the joint efforts of both CAS and the Shanghai Municipality for rice genome research, a basic genomics sequencing and research framework formed in China, with Beijing and Shanghai each equipped with two genome centers. The connection between the human genome project and the rice genome project was greatly promoted, which eventually facilitated the success of the rice genome project.

The 9th National Five-Year Plan (1996-2000) witnessed the rise, the struggle and the success of the Chinese genomic research. In the early stage of the 9th Five-Year Plan, the scientific committee of the 863 Program thoroughly assessed the international trend of research related to human health and diseases and promptly de- termined to set up a "key project" for human genome research, and soon upgraded it as a "major project". The committee set up a "two 1%" goal with respect to the genomic sequencing and the full-length cDNA identification, respectively, and coordinated the efforts of Shanghai and Beijing local government to set up the national human genome research centers for more efficient implementation. After acquiring the "one percent" share of human genome sequencing, the committee, together with CAS, promptly reinforced the support for the sequencing project. Coordinately, the National Key Basic Research Program, known as the 973 Program, started a disease genomics project in 1998 led by the academicians CHEN Zhu and QIANG Bo-Qin. The 973 Program continued to fund the project in 2004 under the title of "Systems Biology for the Multi-gene Complex Diseases" coordinated by CHEN Zhu.

The Chinese human genome project fully exemplified the "Chinese characteristics". With respect to the project design, besides the above-mentioned "two one percent", it reinforced the research upon disease genomics and focused on the establishment of the disease sample/information collecting network along with the continuous efforts in cloning and identification of disease related genes by employing human genetic resources from China and abroad. The human health oriented functional genomics research, including bioinformatics, transcriptomics, proteomics, structural genomics and other technology platforms, such as model animals, biochip constructions, etc., were all developed along with the human genomic sequencing project in the late 1990s. Making full use of the technology and resource advantages of the human genome research helped to extend the genomic sequencing and related research to plants other than rice, microorganisms (pathologens for medicine and agriculture or important industry bacteria), insects (silkworm) and parasites (Schistosoma japonicum). In 2006, the original and assembled genomic sequence data of S. japonicum was registered in and released from a public bioinformatics database (http://biodb.sgst.cn) . operated by the Shanghai Bioinformation Technology Development Center, for sharing with the international Schistosoma mansoni consortium. This action indicated that genomic information analysis technology had set out an important step forward in merging with the international GeneBank. In summary, although China started late in genomic sequencing, it has caught up with the international wave in functional genomics, and the achievements of which effectively enhanced the life science research and biotechnology development in China.

With respect to funding policy and the establishment of platform centers, China adopted the international model initially — organizing grand scientific program/projects and establishing genome centers for implementation. On the other hand, based on the characteristics of funding and administration systems in China, various kinds of operation models for those genome centers were explored in order to encourage all sections of the governmental institutions to offer as much as possible funds through various channels. By adopting these multiple funding patterns under the guidance of the national projects, the Chinese scientists mobilized as much enthusiasm from the society as possible and efficiently integrated the national and local, the governmental and social resources and secured the development of the projects and centers. Take the South Center as an example. During the ten years period since its establishment, in the process of completing a series of international and national key genome projects, the original mixed research team of the center was tempered, and the abilities of the team members were improved. Meanwhile, influenced by the center, an array of "omics" and systems biomedicine research centers were gradually set up in the Zhangjiang HiTech Park of Shanghai. Collaborating with these research centers, the South Center has been accomplishing its transformation from a platform technology center focusing on sequencing and genotyping services to a research center engaged in the cutting-edge innovation on molecular targets identification and characterization for human health and diseases and the translational research on genomics, molecular genetics and systems biomedicine. Meanwhile, through the constant improvement of its comprehensive competitiveness in science and technology innovation, the service function of this systems biology research platform is becoming more substantial, and the center continues to promote the formation and transformation of intellectual property based on the biomedicine research achievements.

As a matter of fact, within the past ten years, the progress of genomics in China was a sort of frogleap development in terms of scale, quality, interdisciplinarity, organization and international collaboration. The genomics research of human and rice, the two national major scientific projects, together with a series of genomic sequencing and functional genomics analyses, constitutes an unprecedented development in life science research and biotechnology development in China. For decades, particularly from the early 1950s to the 1970s, genetics and molecular genetics were sort of lagging in China, largely due to the influences of Lysenkonism in the 1950-1960s and then the hit by "culture revolution" in the 1960-1970s. Fortunately, in this difficult period, with the cooperation of Chinese biologists and chemists, protein and nucleic acid chemistry gained a rapid development. The chemical synthesis and 3D structure determination of bovine insulin and the chemical synthesis of yeast alanine-tRNA were land marker achievements recorded in the scientific history.

In contrast to the situation in China, from the 1960s to the 1980s, life science worldwide was led by genetics and molecular biology, i.e., studying DNA/RNA and the flow of genetic information (central dogma), whereas in China these disciplines were severely hampered, with few scientists such as Prof. TAN Jia-Zhen to be the only leading scientist to defend Morgan's theory for a long time. That should be one of the reasons why China's life science was largely behind the world development trend for decades. However, in the early 1990s, with the incoming "scientific spring", Chinese life scientists grasped the historical opportunity of HGP to catch up with the world cutting-edge life science and realized a frogleap forward.

For the first time, the concept of "big science" was introduced into the Chinese life science community thanks to HGP. The "big sciences" are grand scientific research programs guided with a comprehensive and long-term objective to tackle the major scientific problems related to the development of human and human society. They aimed to gather important scientific data and to make significant scientific discoveries with the aid of multi-disciplinary studies and integrated technologies. A strong link between big and small sciences was set up, in that in the genomic era, no body doing small science related to molecular biology, biochemistry and cell biology won't benefit from the dataset generated by human (and other) genomic studies. For instance, just in Shanghai, biologists engaging in molecular biology studies of mammalian reproductive system, signal transduction, immunology, microbiology, central nerve system, genetic evolution, leukemia pathogenesis and so on, were all somehow involved in genomics work to certain extent. The rise of other molecular "omics" further strengthened the linkage of "big science" and "small science". For such a tremendous impact of this linkage upon life science research and the development of biotechnology, it is truly a revolution.

Human genome study in China initiated a new phase of interdisciplinarity in the history of life science in China. The rise of genomics relied on its integration with other academic disciplines, particularly in the following three areas. First, the integration with technology science has caused several rounds of revolution in DNA sequencing technology in the past 40 years, which directly led the first sequencing trial of 4 bases of the λ phage cos to the current program of sequencing the genomes of a thousand individuals. Second, the integration with computational science and computer technology brought about bioinformatics, which supported the system of data collection, administration, annotation, distribution, and services for genome researches; and the technology platform for data analysis was also thus established. Third, the integration with mathematics and statistics led to the rise of computational biology, which makes full use of the genomic data and the data generated by other "omics" and then, analyzes them with various kinds of biological data. It provides experimental scientists with hypotheses/models for systems biology research. Actually, mainly promoted by bioinformatics and computational biology, laws of a complex life system can now be deciphered and understood.

Human genomic research, with the magnitude of "big science "and "big project" and unprecedented dynamics of development, facilitated, in an extraordinary way, the domestic and international collaboration. HGP in China set a good example for "liberation of mind" in the life science fields. It makes the Chinese biologists to understand what the meaning of "leading the scientific frontier" is and what the "national strategic demand" is. It also inspired the Chinese biologists to challenge the important scientific problems and to participate in the international collaboration and competition. What's more, it teaches the Chinese biologists how to organize scientific teams for major scientific research projects and how to efficiently coordinate the nation-wide research efforts. In the early 1990s, in the mind of the leaders of Chinese human genome research, a consensus had been reached, that is, "In the next century, China will be one of the leading countries in genomics and life science. If we do not start the genomics program today, we are going to lose the right of voice in 10 years. Though we start from small, we shall harvest huge." To be honest, with ten years of persistent struggle and hard working, we keep our words and have mostly realized these objectives.

To recall the history is for a better development in the future. After the completion of the genomic sequencing and the HapMap project, the international HGP has entered an assault-fortified position aiming at studying the genetic mechanisms of human diseases and other phenotypes. The initiation of HGP is due to the lesson learnt from the failure of the cancer project in the Kennedy era of the 1960s, while the success of HGP also depends on its influence upon tackling cancer and other complex human diseases. Meanwhile, facilitated by the strategic plan of big sciences, the innovation of science and technology and their industrialization, as well as the fast progress in interdisciplinary studies such as bioinformatics, have prepared the ground for a new "great frogleap". Some of the minireviews published in this issue analyze the future trend of genomics research and its scientific impact based on the technical perspectives of genomic sequencing, genotyping and functional genomics. While the others present the significant change of research strategy and technology brought in by the HGP with respect to liver cancer (hepatocarcinoma), immunology, and medical, environmental and industrial microbiology. These reviews reflect the progress we have achieved, showing that, compared with the situation ten years ago, our research capability, technology experience, and academic intelligence have all been significantly improved. Meanwhile, we are confronted with more difficult challenges than ten years ago. If we can learn from the past experience, focus on a correct direction, move forward bravely but with caution, carefully organize and integrate the research teams, improve the management with both democracy and discipline, and work hard to explore the scientific truth, we shall be able to make faster and greater progress. On the other hand, if we arrogantly enjoy the past but ignore the new challenge, or underestimate our capabilities and feel afraid of innovation, it is possible that we may miss the good opportunities, as said in this old Chinese proverb, "Ninety miles is only half way of a hundred-mile journey".

Confucius once said: "The passage of time is just like the flow of the River, which goes on day and night, for ever". The past glories are the momentum for our new journey, while the lessons of the past may teach us to be smarter. China, a developing socialist country rising from a hundred years of weakness and poverty, needs genomics to make historic contributions to the rejuvenation of the nation.

Source : Science in China Press