Ten years ago, the Chinese National Human Genome Center at Shanghai (South Center, hereafter) was establishedin 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 forthis special issue. We hope that this effort may draw the attention of the Chinese life science research workersto collectively recall the short but fruitful history of human genome project and coordinately explore the trendand 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 isalso known as the 863 Program, funded the scientists of Fudan University (in Shanghai) to construct DNAjumping library for human genetic disease related physical mapping. It was probably the very first human genomerelated research project supported by a national funding agency. After 1991, Fudan University, RuijinHospital and the Cancer Research Institute in Shanghai were all funded by the 863 Program in succession, todevelop genomics technology by means of molecular genetics, and to study genetic diseases including cancerby 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 asNot I and Sfi I to facilitate the analysis of large DNA fragments of human genome, aiming at physical mapconstruction. These early efforts and progress became truly "the spark of a fire" and the human genomeresearch was thus initiated.
In the early 1990s, focusing on the total sequencing and annotation of the complete human genome as itscore mission, the Human Genome Project (HGP) was initiated under the leadership of the U.S.A. However, theinitial response in China was, instead, to participate in the International Rice Genome Project led by Japan. Thereasons behind were obvious. First of all, for China, the largest developing country of the world, food securityis of the primary concern and rice is the major staple food for Chinese people. Second, rice, a diploid crop, withits relatively small genome size (about 400 Mb), is a nice model of the monocotyledon plants. Third, over theyears, the Chinese scientists had accumulated a great deal of experiences in the basic and applied research ofrice, 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 governmentssupported the DNA sequencing expert HONG Guo-Fan, who just returned back to China from Sanger'slaboratory, to initiate the rice genome project in 1992 and the Chinese efforts in rice genome sequencing andresearch were thus, set out on its long journey.
Meanwhile, the far-sighted Chinese medical geneticists were still promoting the initiation of a humangenome 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 initiatesome major projects for human genome research. His efforts were supported by the academician LIANGDong-Cai, Deputy Director of the NSFC Committee and of the Department of Life Sciences, and thus, the firstmajor 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 theconcept of genomics, and by applying the genomics technology, they carried out a series of research and madesignificant breakthroughs in the study and identification of disease associated genes, particularly the cloningand identification of genes related to leukemia, solid tumors (including liver cancer, colorectal cancer and nasopharyngealcancer) and genetic diseases (such as deaf). Furthermore, substantial progresses were made in thedevelopment of technologies for human genome genotyping and genetic polymorphism detection, as well as forexpressed sequence tag (EST) and full-length cDNA cloning and sequencing. All these achievements greatlystrengthened the Chinese scientists' confidence and encouraged them to further explore the human genome. Onthe other hand, they made people perceive and appreciate the Chinese human genetic resources, for their abundancein 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 beable to and obligatory to make great contributions to the course of human health, especially to the oriental peoplefor the medical purpose.
With this scientific and historical background, in July 1997, the academician TAN Jia-Zhen petitioned thecentral government, appealing for the protection of the Chinese genetic resources, and proposed to establish thenational human genome center to speed up the human genome research in China. This petition attracted greatattention from the Party Central Committee and the State Council. JIANG Ze-Min, the General Secretary of theParty 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 HumanGenome 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 foundedon March 4, 1998. On October 20, 1998, the center was officially inaugurated as the Chinese National HumanGenome Center at Shanghai (abbreviated as the South Center), thus becoming the first national research centerlocated in the Zhangjiang Hi-Tech Park of Pudong District. The academician CHEN Zhu has served as the directorof 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 thesupport of the Ministry of Science and Technology and Beijing Municipal Government, and the academicianQIANG Bo-Qin served as the director. The "Huada" (Chinese Giant/Wash U) Genome Center, directed byYANG Huan-Ming, was also established by the Institute of Genetics, CAS. Together with the previously establishedNational Gene Research Center, which was established by the joint efforts of both CAS and the ShanghaiMunicipality 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 genomeproject and the rice genome project was greatly promoted, which eventually facilitated the success of therice genome project.
The 9th National Five-Year Plan (1996-2000) witnessed the rise, the struggle and the success of the Chinesegenomic research. In the early stage of the 9th Five-Year Plan, the scientific committee of the 863 Programthoroughly 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". Thecommittee 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 nationalhuman genome research centers for more efficient implementation. After acquiring the "one percent" share ofhuman genome sequencing, the committee, together with CAS, promptly reinforced the support for the sequencingproject. Coordinately, the National Key Basic Research Program, known as the 973 Program, starteda disease genomics project in 1998 led by the academicians CHEN Zhu and QIANG Bo-Qin. The 973 Programcontinued 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 theproject design, besides the above-mentioned "two one percent", it reinforced the research upon diseasegenomics and focused on the establishment of the disease sample/information collecting network along withthe continuous efforts in cloning and identification of disease related genes by employing human geneticresources from China and abroad. The human health oriented functional genomics research, includingbioinformatics, transcriptomics, proteomics, structural genomics and other technology platforms, such as modelanimals, biochip constructions, etc., were all developed along with the human genomic sequencing project inthe late 1990s. Making full use of the technology and resource advantages of the human genome researchhelped 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 wasregistered in and released from a public bioinformatics database (http://biodb.sgst.cn) . operated by theShanghai Bioinformation Technology Development Center, for sharing with the international Schistosomamansoni consortium. This action indicated that genomic information analysis technology had set out animportant step forward in merging with the international GeneBank. In summary, although China started late ingenomic sequencing, it has caught up with the international wave in functional genomics, and the achievementsof 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 internationalmodel 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, variouskinds of operation models for those genome centers were explored in order to encourage all sections of thegovernmental institutions to offer as much as possible funds through various channels. By adopting these multiplefunding patterns under the guidance of the national projects, the Chinese scientists mobilized as much enthusiasmfrom the society as possible and efficiently integrated the national and local, the governmental andsocial 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 andnational key genome projects, the original mixed research team of the center was tempered, and the abilities ofthe team members were improved. Meanwhile, influenced by the center, an array of "omics" and systems biomedicineresearch centers were gradually set up in the Zhangjiang HiTech Park of Shanghai. Collaborating withthese research centers, the South Center has been accomplishing its transformation from a platform technologycenter focusing on sequencing and genotyping services to a research center engaged in the cutting-edge innovationon molecular targets identification and characterization for human health and diseases and the translationalresearch on genomics, molecular genetics and systems biomedicine. Meanwhile, through the constant improvementof its comprehensive competitiveness in science and technology innovation, the service function ofthis systems biology research platform is becoming more substantial, and the center continues to promote theformation 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 developmentin terms of scale, quality, interdisciplinarity, organization and international collaboration. The genomicsresearch of human and rice, the two national major scientific projects, together with a series of genomicsequencing and functional genomics analyses, constitutes an unprecedented development in life science researchand 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 inthe 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 rapiddevelopment. The chemical synthesis and 3D structure determination of bovine insulin and the chemicalsynthesis 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 geneticsand molecular biology, i.e., studying DNA/RNA and the flow of genetic information (central dogma), whereasin China these disciplines were severely hampered, with few scientists such as Prof. TAN Jia-Zhen to be theonly leading scientist to defend Morgan's theory for a long time. That should be one of the reasons why China'slife science was largely behind the world development trend for decades. However, in the early 1990s, with theincoming "scientific spring", Chinese life scientists grasped the historical opportunity of HGP to catch up withthe 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 communitythanks to HGP. The "big sciences" are grand scientific research programs guided with a comprehensive andlong-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 aidof multi-disciplinary studies and integrated technologies. A strong link between big and small sciences was setup, in that in the genomic era, no body doing small science related to molecular biology, biochemistry and cellbiology won't benefit from the dataset generated by human (and other) genomic studies. For instance, just inShanghai, 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" furtherstrengthened the linkage of "big science" and "small science". For such a tremendous impact of this linkageupon 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 inChina. The rise of genomics relied on its integration with other academic disciplines, particularly in the followingthree areas. First, the integration with technology science has caused several rounds of revolution inDNA sequencing technology in the past 40 years, which directly led the first sequencing trial of 4 bases of theλ phage cos to the current program of sequencing the genomes of a thousand individuals. Second, the integrationwith computational science and computer technology brought about bioinformatics, which supported thesystem of data collection, administration, annotation, distribution, and services for genome researches; and thetechnology platform for data analysis was also thus established. Third, the integration with mathematics andstatistics led to the rise of computational biology, which makes full use of the genomic data and the data generatedby other "omics" and then, analyzes them with various kinds of biological data. It provides experimentalscientists with hypotheses/models for systems biology research. Actually, mainly promoted by bioinformaticsand 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 dynamicsof development, facilitated, in an extraordinary way, the domestic and international collaboration. HGP inChina set a good example for "liberation of mind" in the life science fields. It makes the Chinese biologists tounderstand 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 theinternational collaboration and competition. What's more, it teaches the Chinese biologists how to organizescientific teams for major scientific research projects and how to efficiently coordinate the nation-wide researchefforts. In the early 1990s, in the mind of the leaders of Chinese human genome research, a consensus had beenreached, that is, "In the next century, China will be one of the leading countries in genomics and life science. Ifwe do not start the genomics program today, we are going to lose the right of voice in 10 years. Though we startfrom small, we shall harvest huge." To be honest, with ten years of persistent struggle and hard working, wekeep 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 sequencingand the HapMap project, the international HGP has entered an assault-fortified position aiming at studyingthe genetic mechanisms of human diseases and other phenotypes. The initiation of HGP is due to the lessonlearnt from the failure of the cancer project in the Kennedy era of the 1960s, while the success of HGP also dependson its influence upon tackling cancer and other complex human diseases. Meanwhile, facilitated by thestrategic plan of big sciences, the innovation of science and technology and their industrialization, as well asthe fast progress in interdisciplinary studies such as bioinformatics, have prepared the ground for a new "greatfrogleap". Some of the minireviews published in this issue analyze the future trend of genomics research and itsscientific 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 theHGP with respect to liver cancer (hepatocarcinoma), immunology, and medical, environmental and industrialmicrobiology. These reviews reflect the progress we have achieved, showing that, compared with the situationten years ago, our research capability, technology experience, and academic intelligence have all been significantlyimproved. Meanwhile, we are confronted with more difficult challenges than ten years ago. If we canlearn from the past experience, focus on a correct direction, move forward bravely but with caution, carefullyorganize and integrate the research teams, improve the management with both democracy and discipline, andwork 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 ofinnovation, it is possible that we may miss the good opportunities, as said in this old Chinese proverb, "Ninetymiles 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, forever". The past glories are the momentum for our new journey, while the lessons of the past may teach us to besmarter. China, a developing socialist country rising from a hundred years of weakness and poverty, needs genomicsto make historic contributions to the rejuvenation of the nation.
Source: Science in China Press