今年的诺贝尔化学奖又一次奖给了生命大分子的研究者：美国生物学家罗伯特 • 莱夫科维茨（ Robert J. Lefkowitz ）和布莱恩 • 克比尔卡（ Brian K. Kobilka ），因为他们发现了生命大分子 G 蛋白偶联受体。 G 蛋白偶联受体是生物的生命活动中一类极其重要的生物大分子，也是人类治疗各种疾病的主要药物靶点。诺贝尔评奖委员会为什么把 G 蛋白偶联受体的发现奖奖给了化学而没有奖给生理学或医学？其实你把历史上的化学奖细数一下就会发现诺贝尔奖委员会自从 1901 年颁发第一个奖以来，几近一半的化学奖是奖给了研究生命分子和现象的化学家和生物学家，近年来更是频繁地把化学奖奖给生命大分子的研究。这是为什么？难道是化学领域已经没有自己的科学难题需要被解答、科学原理需要被发现？ 物理、化学、生物是自然科学的三大基本学科，它们研究的都是物质和物质的相互关系、相互作用和运动规律。 物理学是“研究物质结构、物质相互作用和运动规律”； 化学是“研究物质的组成、结构、性质、以及变化规律”； 生物学是“研究生物的结构、功能、发生和发展的规律” （百度语）。 物质有大有小。物质往小里研究就是物理学研究的原子、电子、中子、质子、夸克、“上帝粒子”……，往大里研究就是生命科学的氨基酸、核苷酸、蛋白质、核酸、基因、细胞……。如果我们只在地球上做研究，把三门学科总结一下就是物理研究小物质，往“小”里研究；化学是研究中物质，在“中”间研究；生物是研究大物质，往“大”里研究。如果我们往地球以外做研究，那又是物理的事了：天体物理。 搞化学的人称化学为“中心科学”，说的明白点就是上有生物、下有物理，是夹在物理和生物中间的一门学问和学科。因此，化学是夹缝中的科学。 夹缝中的化学，应该向哪里突破？近年来的化学诺贝尔化学奖给化学指出了一个方向：向生命科学突破。生命现象是地球上最复杂的一个自然现象。生命现象中还有千千万万的新物质等待我们去发现，还有万万千千的生物难题等待我们去解决。生命科学需要化学，需要化学的逻辑和工具。化学需要往横向突破去解决方法和工具的问题，需要往上突破去发现新的生物大分子和解决生物大分子中的化学问题。 于是就有了一门新兴的化学和生物学的交叉学科：化学生物学——用化学的逻辑、方法和工具去解决生物学问题。 化学家们：诺贝尔生命化学奖在向你们招手。
最新一期Nature Chemical Biology发表了系列Commentary文章，其中The challenges of integrating multi-omic data sets 一文明确指出：多组学数据的集成、挖掘所需投入的资源可能高于数据的采集，这对从事计算生物学建模的学者无疑是极大地鼓励： The capability to generate multi-omic data sets raises the issue of resource allocation for data generation versus data curation and integration. The initial experience of researchers shows that the effort required for the latter can be much greater than that for the former. 当组学数据的类型增加，例如mRNAs数据与microRNAs的集成分析时，上述趋势更加明显。 上述资源的理解，似可包括人力、物力、经费。 作者还指出： （1） 之所以上述情况现在还没有发生，部分因为人们发现难于找到合适的人从事多种组学数据的处理和集成，因为 这项工作需要对数据产生的过程有深入的技术知识； （2） 同时，实验设计时的预谋预筹很重要，组学数据往往由于技术背景的人掌管，而试图测试一切（参数）。此时，深厚的生命科学背景显得尤为重要。总之，生物医学、信息科学的多学科背景是解决多组学数据集成的重要素质，因为任何一个数据集成方案的背后，都实际上代表了你对这个问题的理解，即modeling。 原文链接： http://www.nature.com/nchembio/journal/v6/n11/full/nchembio.462.html
刚参加完美国化学会普林斯顿分会的有机化学年度学术报告会。【1a】报告人包括一位默克的（前）副总裁，1位MIT和2位Harvard 的教授。最著名的是晚餐之后的讲演者，哈佛的Stuart Schreiber，他上一次在这里做报告是20年前的事。【1b] 他的名字和化学生物学连在一起，和波士顿地区好几个生物技术公司连在一起，也是一本书里面的重要人物。【2】当普林斯顿大学的David MacMillan教授介绍他时，开玩笑说他参考了wikipedia【3】才得到全面的数据。 考虑到正在忙着过生日的祖国依旧禁止wikipedia登陆，为了帮助读者了解他的工作和化学生物学，后面拷贝wikipedia的内容。 他的一些讲课录像可以在何士刚曾经担任过研究员的HHMI网站找到。这是个非常重要的领域，值得感兴趣的读者参考。【4】 如果哪天化学生物学这一领域被瑞典人选中发奖，他应该是接到电话的那个人。 参考资料 【1a】 http://www.pacsfocs.org/ 【1 b] http://www.pacsfocs.org/history 【2】 http://www.amazon.com/Billion-Dollar-Molecule-Companys-Perfect/dp/0671510576 【3】 http://en.wikipedia.org/wiki/Stuart_Schreiber 【4】 http://www.hhmi.org/biointeractive/genomics/lectures.html Stuart Schreiber From Wikipedia, the free encyclopedia Jump to: navigation , search Stuart L. Schreiber (born 6 February 1956) is a scientist at Harvard University and the Broad Institute . He has been a pioneer in a field of research named chemical biology for over 20 years. His name is closely associated with the increasingly common use of small molecules as probes of biology and medicine. Small molecules are the molecules of life most associated with dynamic information flow; these work in concert with the macromolecules (DNA, RNA, proteins) that are the basis for inherited information flow. During the 1980s and '90s, he provided dramatic advances in biology using this approach, and, in the past ten years, his systematization efforts have made this one of the fastest growing areas of life-science research. Contents 1 Education and Training 2 Key discoveries, 1980s and 1990s 3 Advancing chemical biology through the 1990s and 2000s 4 Selected Awards 5 External links 6 Notes and references // Education and Training Schreiber obtained a Bachelor of Science degree in Chemistry from the University of Virginia, after which he entered Harvard University as a Graduate Student in Chemistry. He joined the research group of Robert B. Woodward and after Woodward's death continued his studies under the supervision of Yoshito Kishi . In 1980 he joined the faculty of Yale University as an Assistant Professor in Chemistry. Key discoveries, 1980s and 1990s Schreiber started his research work in Organic Synthesis, pioneering concepts such as the use of photocycloaddition to establish stereochemistry in complex molecules, the fragmentation of hydroperoxides to produce macrolides, ancillary stereocontrol, group selectivity and two-directional synthesis. Notable accomplishments include the total syntheses of complex natural products such as talaromycin B, asteltoxin, avenaciolide, gloeosporone, hikizimicin, mycoticin A, epoxydictymene and the immunosuppressant FK-506 . Following his co-discovery of the FK506-binding protein FKBP12 in 1988, Schreiber reported that the small molecules FK506 and ciclosporin inhibit the activity of the phosphatase calcineurin by forming the ternary complexes FKBP12-FK506-calcineurin and cyclophilin-ciclosporin-calcineurin. This work, together with work by Gerald Crabtree at Stanford University concerning the NFAT proteins, led to the elucidation of the calcium-calcineurin-NFAT signaling pathway. This landmark discovery, an early example of defining an entire cellular signaling pathway from the cell surface to the nucleus, can be appreciated when it is considered that the Ras-Raf-MAPK pathway was not elucidated for another year. In 1993 Schreiber and Crabtree developed small-molecule dimerizers, which provide small-molecule activation over numerous signaling molecules and pathways (e.g., the Fas, insulin, TGF and T-cell receptors ) through proximity effects. Schreiber and Crabtree demonstrated that small molecules could activate a signaling pathway in an animal with temporal and spatial control. Dimerizer kits have been distributed freely to (as of February, 2005) 898 laboratories at 395 different institutions worldwide, resulting thus far in over 250 peer-reviewed publications from the scientific community. Its promise in gene therapy has been highlighted by the ability of a small molecule to induce production of erythropoeitin (EPO) in primates without diminution over, thus far, a six-year period, and more recently in phase II human clinical trials for treatment of graft-vs-host disease (ARIAD Pharmaceuticals, Inc.). In 1994, Schreiber discovered that the small molecule rapamycin simultaneously binds FKBP12 and mTOR (originally named FKBP12-rapamycin binding protein, FRAP). Using diversity-oriented synthesis and small-molecule screening, Schreiber helped illuminate the nutrient-response signaling network involving TOR proteins in yeast and mTOR in mammalian cells. Small molecules such as uretupamine and rapamycin were shown to be particularly effective in revealing the ability of proteins such as mTOR, Tor1p, Tor2p, and Ure2p to receive multiple inputs and to process them appropriately towards multiple outputs (in analogy to multi-channel processors). Several pharmaceutical companies are now targeting the nutrient-signaling network for the treatment of several forms of cancer, including solid tumors. In 1996 Schreiber used the small molecules trapoxin and depudecin to characterize molecularly the histone deacetylases (HDACs). Prior to Schreibers work in this area, the HDAC proteins had not been isolated despite many attempts by others in the field who had been inspired by Allfrey's detection of the enzymatic activity in cell extracts over 30 years earlier. Coincident with the HDAC discovery, David Allis and colleagues reported their discovery of the histone acetyltransferases (HATs). These two contributions catalyzed much research in this area, eventually leading to the characterization of numerous histone-modifying enzymes, their resulting histone marks, and numerous proteins that bind to these marks. By taking a global approach to understanding chromatin function, Schreiber proposed a signaling network model of chromatin and compared it to an alternative view, the histone code hypothesis presented by Strahl and Allis. The work by chromatin researchers has shined a bright light on chromatin as a key regulatory element rather than simply a structural element. Advancing chemical biology through the 1990s and 2000s During the past 10 years, Schreiber has attempted to systematize the application of small molecules to biology through the development of diversity-oriented synthesis (DOS), chemical genetics, and ChemBank . Schreiber has shown that DOS can produce small molecules distributed in defined ways in chemical space by virtue of their different skeletons and stereochemistry, and that it can provide chemical handles on products anticipating the need for follow-up chemistry using, for example, combinatorial synthesis and the so-called Build/Couple/Pair strategy of modular chemical synthesis. DOS pathways and new techniques for small-molecule screening provided many new, potentially disruptive insights into biology. For example, Schreiber and collaborator Tim Mitchison used cytoblot screening to discover monastrol the first small-molecule inhibitor of mitosis that does not target tubulin . Monastrol was shown to inhibit kinesin-5 , a motor protein and was used to gain new insights into the functions of kinesin-5. This work led pharmaceutical company Merck, among others, to pursue anti-cancer drugs that target human kinesin-5. Small-molecule probes of histone and tubulin deacetylases, transcription factors, cytoplasmic anchoring proteins, developmental signaling proteins (e.g., histacin, tubacin, haptamide, uretupamine, concentramide, and calmodulophilin), among many others, have been discovered in the Schreiber lab using diversity-oriented synthesis and chemical genetics. Multidimensional screening was introduced in 2002 and has provided insights into tumorigenesis, cell polarity, and chemical space, among others. More than 100 laboratories from over 30 institutions have performed small-molecule screens at the screening center he developed ( Broad Chemical Biology (BCB), formerly the Harvard ICCB), leading to many small-molecule probes (81 probes were reported in the 2004 literature alone) and insights into biology. To facilitate the open sharing of small-molecule-based insights, Schreiber pioneered the development of the assay-data repository and analysis environment named ChemBank, which was launched on the Internet in 2003. A complete rework of ChemBank (v2.0) , which makes accessible to the public results and analyses from 1,209 small-molecule screens that have yielded 87 million measurements, was re-launched in March 2006. Schreibers laboratory has served as a focal point for the field of chemical biology, first by the ad hoc use of small molecules to study three specific areas of biology, and then through the more general application of small molecules in biomedical research. As a principal architect of chemical biology, he has influenced the public and private research communities. Academic screening centers have been created that emulate the Broad Institute Chemical Biology Program; in the U.S., there has been a nationwide effort to expand this capability via the government-sponsored NIH Road Map. Chemistry departments have changed their names to include the term chemical biology and new journals have been introduced ( Chemistry Biology , ChemBioChem , Nature Chemical Biology , ACS Chemical Biology ) to cover the field. Schreiber has been involved in the founding of three biopharmaceutical companies based on chemical biology principles: Vertex Pharmaceuticals, Inc. (VRTX), Ariad Pharmaceuticals, Inc. (ARIA), and Infinity Pharmaceuticals, Inc (INFI). These companies have produced new medicines in several areas of disease, including AIDS and cancer. Selected Awards Award in Pure Chemistry, ACS (1989). For pioneering investigations into the synthesis and mode of action of natural products. Ciba-Geigy Drew Award for Biomedical Research: Molecular Basis for Immune Regulation (1992). For the discovery of immunophilins and for his role in elucidating the calcium-calcineurin-NFAT signaling pathway. Leo Hendrik Baekeland Award, North Jersey Section of ACS (1993). For outstanding achievement in creative chemistry. Eli Lilly Award in Biological Chemistry, ACS (1993). For fundamental research in biological chemistry. American Chemical Society Award in Synthetic Organic Chemistry (1994). For creative accomplishments at the interface of organic synthesis, molecular biology, and cell biology as exemplified by landmark discoveries in the immunophilin area. George Ledlie Prize (Harvard University) (1994). For his research which has profoundly influenced out understanding of the chemistry of cell biology and illuminated fundamental processes of molecular recognition and signaling in cell biology. Harrison Howe Award (1995). In recognition of accomplishments in the synthesis of complex organic molecules, progress in understanding the immunosuppressant action of FK506, and innovation in molecular recognition and its role in intracellular signaling. Warren Triennial Award (shared with Leland Hartwell) (1995). For creating a new field in organic chemistry, what Phil Sharp has coined 'chemical cell biology.' In these studies, small molecules have been synthesized and used to understand and control signal transduction pathways. Schreiber has made it possible to generalize the use of small molecules to study protein function in analogy to the use of mutations in genetics. This approach has illuminated fundamental processes in cell biology and has great promise in medicine. Tetrahedron Prize for Creativity in Organic Chemistry (1997). For his fundamental contributions to chemical synthesis with biological and medicinal implications. ACS Award for Bioorganic Chemistry (2000). For his development of the field of chemical genetics, where small molecules are used to dissect the circuitry of cells using genetic-like screens. William H. Nichols Medal (2001). For contributions toward understanding the chemistry of intracellular signaling. Chiron Corporation Biotechnology Research Award, American Academy of Microbiology (2001). For the development of systematic approaches to biology using small molecules. Society for Biomolecular Screening Achievement Award (2004). In recognition of the advances made in the field of chemical biology through the development and application of tools that enable the systematic use of small molecules to elucidate fundamental biological pathways. American Association of Cancer Institutes (2004). For his development of the field of chemical biology, which has resulted in a new approach to the treatment of cancer. External links Broad Institute of Harvard and MIT, Chemical Biology Program Schreiber lab, Harvard University HHMI Genomics Chemical Genetics, Video Lecture ChemBank Notes and references ^ Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL (August 1991). Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66 (4): 80715. doi : 10.1016/0092-8674(91)90124-H . PMID 1715244 . ^ Schreiber SL, Crabtree GR (1995). Immunophilins, ligands, and the control of signal transduction. Harvey Lectures 91 : 99114. PMID 9127988 . ^ Yang J, Symes K, Mercola M, Schreiber SL (January 1998). Small-molecule control of insulin and PDGF receptor signaling and the role of membrane attachment. Current Biology 8 (1): 118. doi : 10.1016/S0960-9822(98)70015-6 . PMID 9427627 . ^ Stockwell BR, Schreiber SL (June 1998). Probing the role of homomeric and heteromeric receptor interactions in TGF-beta signaling using small molecule dimerizers. Current Biology 8 (13): 76170. doi : 10.1016/S0960-9822(98)70299-4 . PMID 9651680 . ^ Functional Analysis of Fas Signaling in vivo Using Synthetic Dimerizers David Spencer, Pete Belshaw, Lei Chen, Steffan Ho, Filippo Randazzo, Gerald R. Crabtree, Stuart L. Schreiber Curr. Biol . 1996 , 6, 839-848. ^ Brown EJ, Albers MW, Shin TB, et al. (June 1994). A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369 (6483): 7568. doi : 10.1038/369756a0 . PMID 8008069 . ^ Dissection of a glucose-sensitive pathway of the nutrient-response network using diversity-oriented synthesis and small molecule microarrays Finny G. Kuruvilla, Alykhan F. Shamji, Scott M. Sternson, Paul J. Hergenrother, Stuart L. Schreiber, Nature , 2002 , 416, 653-656. ^ Shamji AF, Nghiem P, Schreiber SL (August 2003). Integration of growth factor and nutrient signaling: implications for cancer biology. Molecular Cell 12 (2): 27180. doi : 10.1016/j.molcel.2003.08.016 . PMID 14536067 . ^ Taunton J, Hassig CA, Schreiber SL (April 1996). A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272 (5260): 40811. doi : 10.1126/science.272.5260.408 . PMID 8602529 . ^ Schreiber SL, Bernstein BE (December 2002). Signaling network model of chromatin. Cell 111 (6): 7718. doi : 10.1016/S0092-8674(02)01196-0 . PMID 12526804 . ^ (a) Schreiber SL (March 2000). Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287 (5460): 19649. doi : 10.1126/science.287.5460.1964 . PMID 10720315 . (b) Burke MD, Berger EM, Schreiber SL (October 2003). Generating diverse skeletons of small molecules combinatorially. Science 302 (5645): 6138. doi : 10.1126/science.1089946 . PMID 14576427 . (c) Burke MD, Schreiber SL (January 2004). A planning strategy for diversity-oriented synthesis. Angewandte Chemie 43 (1): 4658. doi : 10.1002/anie.200300626 . PMID 14694470 . ^ The small-molecule approach to biology: Chemical genetics and diversity-oriented organic synthesis make possible the systematic exploration of biology, S L Schreiber, CE News , 2003 , 81, 51-61. ^ Strausberg RL, Schreiber SL (April 2003). From knowing to controlling: a path from genomics to drugs using small molecule probes. Science 300 (5617): 2945. doi : 10.1126/science.1083395 . PMID 12690189 . ^ Stockwell BR, Haggarty SJ, Schreiber SL (February 1999). High-throughput screening of small molecules in miniaturized mammalian cell-based assays involving post-translational modifications. Chemistry Biology 6 (2): 7183. doi : 10.1016/S1074-5521(99)80004-0 . PMID 10021420 . ^ Printing Small Molecules as Microarrays and Detecting Protein-Ligand Interactions en Masse Gavin MacBeath, Angela N. Koehler, Stuart L. Schreiber J. Am. Chem. Soc. 1999 , 121, 7967-7968. ^ MacBeath G, Schreiber SL (September 2000). Printing proteins as microarrays for high-throughput function determination . Science 289 (5485): 17603. PMID 10976071 . http://www.sciencemag.org/cgi/pmidlookup?view=longpmid=10976071 . ^ Mayer TU, Kapoor TM, Haggarty SJ, King RW, Schreiber SL, Mitchison TJ (October 1999). Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 286 (5441): 9714. doi : 10.1126/science.286.5441.971 . PMID 10542155 . ^ Schreiber SL (July 2005). Small molecules: the missing link in the central dogma. Nature Chemical Biology 1 (2): 646. doi : 10.1038/nchembio0705-64 . PMID 16407997 .
详细信息见 http://f1000biology.com/browse/CHEMBIOL/cell 国际生物学专家按F1000 Factor评出的细胞化学生物学国际优秀论文，你可以选择查阅近一周至近五年发表的优秀论文。 可按以下分类进行检索查阅： Chemical Biology Biocatalysis Bioinorganic Chemistry Biomimetic Chemistry Chemical Biology of the Cell Directed Molecular Evolution Macromolecular Chemistry Protein Chemistry Proteomics Small Molecule Chemistry
2008年的化学生物学最高级别会议在海德堡的欧洲分子生物学实验室举行，大会对于对于化学生物学的定义也进行了探讨，最后得到了一个基本认同的定义：an ad hoc chemical synthesis to tackle a biological problem，就是专门用化学合成的方法解决生物问题。这只是一个基本的定义，它所涵盖的范围比这个定义的范围要广得多。 做与化学生物学相关的都是一些化学家，化学家才能进行化学合成，合成出来的化合物用于解决生物问题。这里就有一个问题了。化学家的这种做法是否被生物学家所认可，生物学家已经建立了一套解决生物问题的行之有效的方法，现在化学家跑来说要帮他们解决他们自己的问题，生物学家当然不欢迎的。不过化学生物学家还是用小分子探针解决了一些问题，更为重要的这些小分子探针可以成为药物开发的先导。 遗传学家在研究某个蛋白的功能的时候，他们会把对应的基因敲除掉，然后看看会带来什么表观变化，这样就找到蛋白的功能。化学生物学家第一步工作是把小分子探针送进细胞，组织或生物体，看看带来了什么表型变化，然后再用他们建立的方法找到和这个探针分子结合的蛋白，同样也知道了蛋白的功能。化学生物学家用这种方法，会找到一些已知的蛋白，但他们却发现蛋白的新功能。 老板说我们实验室就是做化学生物学。国内已经有化学生物学这个专业了，北京大学的研究生有这个专业，最近好像看到厦门大学本科就有这个专业了。我觉得这个专业主要还是学好化学，毕竟化学合成是这个学科的立足之本。
标签: 化学生物学
