Key Laboratory of Systems Biomedicine (KLSB), Ministry of Education, was initiated in July, 2005 and has been reviewed and accredited by the Ministry of Education in the early 2009. It is based mainly on the Shanghai Center for Systems Biomedicine (SCSB) at Shanghai Jiao Tong University.
KLSB is located on the Minhang campus of Shanghai Jiao Tong University and will soon move into the new Shanghai Center for Systems Biomedicine Research Building. The total investment of SCSB is over 230,000,000 yuan or $33 million. The building, with a total area of 22,000 square meters, houses research laboratories, joint centers, core technology platforms, common facilities, bio-technology development core, teaching laboratories and a lecture hall, with an independently affiliated building specifically designed for Center of Experimental Animal Model Organisms.
Shanghai Center for Systems Biomedicine Research Building
The KLSB is established on the principle of interdisciplinary research, actively pursuing basic research in systems biology, and encouraging its application in biomedical research and clinical medicine. This new key laboratory has attracted many talented young investigators from overseas in diverse disciplines, and has made major efforts to integrate academic and clinical research with an explicit focus on major human diseases. Currently, the Laboratory employs 24 principal investigators and 30 researchers, and has completed 66 class-hour of graduate teaching. More than 80 graduate students are pursuing their degrees under the guidance of our investigators. To date, the laboratory has undertaken 34 externally funded research projects, including national "863" and "973" projects. In addition, the Laboratory also encourages technological developments and emphasizes its role in supporting joint research projects with its common core facilities and platforms. The Laboratory has already established a number of core facilities, including metabolomics, biotechnology, bio-nanotechnology, single-cell analysis, bioinformatics, protein arrays, multi-dimensional high resolution single molecule imaging, chemical biology, clinical resources and a tissue bank.
The administration of the University has given the KLSB a great deal of support, from the allocation of graduate students to the recruitment of young talents. Such support has been crucial to the rapid development of the KLSB.
Director: Professor Shao Zhifeng
Executive Deputy Director: Wu Qiang
Deputy Director: Ping Ao, Yihuang Wang
Honorary Chairman: Professor Chen Zhu, Academician of CAS
Chairman: Professor Yang Shengli, Academician of CAE
Deputy Chairmen: Professor Shao Zhifeng, Professor Lisa X.
Chen Zhu, Chen Saijuan, Academicians, Distinguished Professors, molecular genetics, pathogenesis of leukemia.
Shao Zhifeng, KC Wong, Chair Professors, molecular biophysics, methodological development in functional genomics, biotechnology.
Ao Ping, Cheung Kong Distinguished Professor, theoretical framework and mathematical models in systems biology, theory of biological evolution.
Gong Bing (SUNY and Beijing Normal), adjunct Cheung Kong Distinguished Professor, macromolecules, nanomaterials and organic chemistry.
Jia Wei (UNC), adjunct Distinguished Professor, metabolomics.
Hu Jun (CAS), adjunct Cheung Kong Distinguished Professor, nanobiology and nano-bio-engineering.
Li Yixue (CAS), adjunct professor,bioinformatics and computational biology.
Liang Jie (UIC), adjunct distinguished professor, computational biology and bioinformatics.
Liang Shoudan (MD Anderson), adjunct professor, bioinformatics.
Lin Zongli (UVA), adjunct Cheung Kong Distinguished Professor,electrical engineering and engineering cybernetics.
Liu Bingya, Professor, gastrointestinal cancer research and gene therapy.
Shen Yumei, Professor, chemical biology and organic chemistry.
Tao Shengce, Professor, biochips and proteomics.
Wu Fang, Professor, drug design and discovery, cell biology.
Wu Qiang, Distinguished Professor, Molecular Biology, Neurobiology, Developmental Biology.
Xu Lisa X., Cheung Kong Distinguished Professor, mechanism of comprehensive cancer treatment.
Xu Yuhong, Distinguished Professor, targeted drug delivery, systems, nanotechnology in pharmaceutical formulations.
Yuan Bo, Professor, Computer science and bioinformatics.
Zhang Yan, Professor, tumor-associated glycoprotein.
Zhao Liping, Professor, metagenomics.
Zhao Xiaodong, Professor, functional genomics and high throughput sequencing.
Since its establishment, investigators at the KLSB have made significant progress in a number of areas in the field of systems biology. For example, Prof. Jia Wei's group has developed a method using metabonomical approaches to evaluate the overall efficacy of Traditional Chinese Medicine in vivo (Nature Review Drug Discovery 6: 506, 2007); Prof. Zhao Liping's group has examined the relationship between gut flora and the metabolism disease, and is developing approaches for gut microbiota-targeted healthy monitoring and preventive medicine (Proc Natl Acad Sci USA 105: 2117, 2008); Prof. Xu Lisa's group has found that local thermal treatment of tumor has induced a global response that might inhibit the development of metastasized tumors, a finding that may have important applications; Prof. Zhang Yan's group has focused on functional glycobiology and has developed a new high-throughput technique to discover O-glycosylated proteins; Prof. Ao Ping's group has developed a novel stochastic dynamic approach for systems biology and has solved the robustness question of the phage lambda genetic switch, which has now been applied to complex diseases such as cancers (Med Hypothesis 70: 678, 2008); Prof. Li Yixue's group for the first time developed a novel method to search for functional similarities of small molecules based on both transcriptome data and function module analyses and has applied this method on the research and development for new drugs (Nucleic Acids Res. 36: e137, 2008). The following are several recent discoveries of the KLSB discussed in detail.
Two drugs in clinical use for APL, arsenic trioxide (As2O3) and all-trans retinoic acid (ATRA), both act by promoting degradation of PML-RARa. When used as a combination therapy, these drugs lead to durable remission of APL. The molecular pharmacology of ATRA is relatively clear, and is through direct binding RAR receptor located within the RARa side of PML-RARa. However, the molecular mechanism of the arsenic has not been elucidated. Therefore, finding arsenical drug targets directly will be an important step toward the understanding of the molecular pharmacology of the arsenic and the molecular mechanism in its combined therapy with ATRA in the treatment of APL.
Our research has found that the arsenic binds directly to cysteine residues in zinc fingers (ZFs) located within the RBCC domain of PML-RARa and PML. Results show that the arsenic binds to cysteines in the ZFs of the PML RBCC domains either intramolecularly or by forming cross-links between the two RBCC molecules in the homodimer. The resulting conformational changes may facilitate further oligomerization of PML-RARa or PML and promote SUMOylation of these proteins through enhanced interaction of PML with the enzymes that catalyze this modification (such as UBC9) or through enhanced exposure of the modification sites. Ultimately, this would lead to enhanced ubiquitination and degradation of PML and the PML-RARa oncoprotein (Science 328: 240, 2010)
Pentameric IgM, a potent activator of complement C1q, plays an important role in natural immunity, but its structure has not been solved. The typical planar illustration found in many textbooks is largely based upon the crystallographic structure of IgG, lacking a major immunoglobulin fold (Ig) domain in its Fc region which is present in IgM. Here, based on homology modeling using the recently structure of the IgE Fc, which has this additional Ig domain, and direct cryo-AFM images of individual IgM molecules, we describe a novel model of the pentameric IgM. In contrast to the planar model, this new model presents a non-planar, mushroom-shaped architecture, with the central portion formed by the C-terminal domains protruding out of the plane formed by the Fab domains. Further analysis of this model with free energy calculations of out-of-plane Fab domain rotations reveals a pronounced asymmetry favoring flexions towards the central protrusion, which provides a mechanistic explanation for the well known table-like structure of IgM with its C1q binding sites fully exposed to solution. Using this model of IgM, we further constructed a structural model of IgM and the malarial protein, PfEMP1. The model of this complex clearly reveals the key residues and surfaces involved in the interaction, providing possible sites as drug targets. In addition, the particular orientation of the IgM on the surface of infected erythrocytes that result from this interaction suggests possible further investigations of malarial immune evasion, in which IgM is known to play a central role (Proc Natl Acad Sci USA 106: 14960, 2009)
The human brain contains billions of neurons with trillions of synaptic connections. Protocadherins (Pcdhs) are a large family of cadherin-like cell adhesion genes that are mainly expressed in the brain and play important roles in synaptic development and neuronal connectivity. Interneurons are extremely diverse in the mammalian brain and provide an essential balance for functional neural circuitry. Aberrant interneuron development and function have been implicated in major neural diseases including seizures, autism spectrum disorders, schizophrenia, and anxiety disorders. The vast majority of murine cortical interneurons is generated in the subpallium and migrates tangentially over a long distance to acquire their final positions. By using gene-targeting mice, we found that the protocadherin Celsr3 gene is crucial for interneuron migration in the developing mouse forebrain. Specifically, in Celsr3 knockout mice, calretinin-positive interneurons are reduced in the developing neocortex, accumulated in the corticostriatal boundary, and increased in the striatum. In addition, the laminar distribution of cortical calbindin-positive cells is altered. These results demonstrate that the protocadherin Celsr3 gene is essential for both tangential and radial interneuron migrations in a class-specific manner (Mol Cell Biol 29: 3045, 2009).
Defects of interneuron migration without the Pcdh Celsr3 gene
UDP-glucuronosyltransferases (Ugts) are a supergene family of phase II drug-metabolizing enzymes that catalyze the conjugation of numerous hydrophobic small molecules with the UDP-glucuronic acid, converting them into hydrophilic molecules. We previously found that the mouse Ugt gene cluster contains multiple highly-similar variable exons organized in a tandem array followed by a single set of constant exons, similar to that of the protocadherin gene clusters (Genome Research 14:79-89). We recently found that the zebrafish genome contains 45 Ugt genes that can be divided into three families: Ugt1, Ugt2, and Ugt5. Both Ugt1 and Ugt2 have two unlinked clusters: a and b. The Ugt1a, Ugt1b, Ugt2a, and Ugt2b clusters each contain variable and constant regions. Cloning the full-length coding sequences confirmed that each of the variable exons is separately spliced to the set of constant exons within each zebrafish Ugt cluster. Comparative analyses showed that both a and b clusters of the zebrafish Ugt1 and Ugt2 genes have orthologs in other teleosts, suggesting that they may be resulted from the "fish-specific" whole-genome duplication event. These findings have interesting implications regarding the molecular evolution of genes with diversified variable exons in vertebrate genomes (PLoS One 5:e9144, 2010).
Proteome chips have a high-throughput and even global analysis capability. Its power is far beyond the traditional approaches. We can use proteome chip to address some very important biological questions through high-speed screening, to identify highly promising candidate proteins. Combined with comprehensive traditional biological validation of these candidates, it may sharply increase the chance of making important new discovery.
The Tao group and international collaborators took advantage of the high-throughput and parallel analysis capability of yeast proteome chip, by performing a limit number of chip experiments; they've successfully identified 406 new glycoproteins from budding yeast. Forty five of them were successfully validated by glycosidase treatment combined mobility shift experiments. Furthermore, functional analysis revealed the localization of two proteins in mitochondria is highly related to their glycosylation status. (Mol Syst Biol. 5: 308, 2009)
Glycoprotein discovery using two types of yeast proteome chips
The SCSB that hosts the KLSB has been designated as a National Center for International Research (NCIR) by the Bureau of Foreign Experts Affairs, and the Chinese Ministry of Science and Technology. This designation has laid a solid foundation for the KLSB to establish robust and deep collaborations with institutions abroad. Together with the SCSB, with the endowment of Professor Tony Leggett, a Nobel Prize Winner, a "Tony Leggett Graduate Award" program has already been established to encourage creative research and scientific advance by graduate students supervised by KLSB investigators. In addition, KLSB/SCSB has also initiated exchange programs with University of Virginia (UVA), Japan's National Institute of Advanced Industrial Science and Technology (AIST) and Hong Kong Baptist University (BU).
The KLSB has established close relationships with many leading institutions in systems biology. These have included the Institute of Systems Biology in Seattle, led by the "father of systems biology", Professor Leroy Hood, a US Academy member, and the Department of Biochemistry at the Imperial College, led by the "metabonomics pioneer" Professor Jeremy Nicholson, the Department of Human Genetics at University of Utah, led by Nobel Laureate Professor Mario Capecchi, Japan National Institute of Advanced Industrial Science and Technology, led by Professor Hisashi Narimatsu, a well-known authority in glycobiology. Of worth noting is the recently approved joint program "Novel early diagnosis technologies in liver carcinoma based on glycan bio-markers" by NEDO, Japan, a solid step toward establishing a joint research laboratory between the two institutions in this area.