CD美国著名华人教授介绍(7)--哈佛大学庄小威

普渡哥

庄小威，1972年生人。1987年，15岁时从苏州中学科大少年班预备班考入中国科技大学少年班。


哈佛大学双聘正教授
　庄小威2000年获美国卫生研究院（NIH）国家研究个人奖，03年获美国国家自然基金成就奖、Beckman青年科学家奖和Searle学者奖（后面2项奖励的奖金均为24万美金），另外她还摘获奖金高达50万美金的美国“天才奖”（Genius Awards），哈佛大学首页新闻对此进行了报道，中科院院长致信祝贺。


研究领域　庄小威的研究，是要探明生物体系中单个分子或单个粒子的运动表现。庄小威创造性地将荧光光谱和显微分析技术应用于单个分子，这种崭新的物理手段，使得实时揭示复杂生物过程中的分子个体及其运动步骤成为可能。
　　这要拜跨学科所赐的灵感。事实上，庄小威完全转入了另一领域的研究。她19岁在中国科大拿到本科学位，然后赴美，在加州大学伯克利分校拿到硕士和博士学位，这些学位都归属物理学。1997年之后，她在斯坦福大学师从诺贝尔物理学奖得主朱棣文进行博士后研究时，才偶然与化学、生物学科的合作伙伴一起开始做一些跟踪分子行为的实验，但几乎有整整一年时间只是在摸索试探，什么结果也没做出来。
　　她在单分子动力学、核酸与蛋白的相互作用、基因表达机制、细胞核病毒的相互作用等领域做出了杰出的贡献。近年来发明了突破光学衍射极限的STORM荧光成像技术，使得光学显微镜分辨能力接近纳米尺度，极大地推动了亚细胞微观结构的研究。她连续多年在Nature，Science，Cell，Nature Methods，Nature Biology，Neuron，PNAS等重要学术期刊上发表多篇文章，并获得MacArthur Fellowship，HHMI collaborative Innovation Award，TR Worlds Top 100 Young Innovators Award，Max Delbruck Prize in Biological Physics，Raymond & Beverly Sackler International Prize in Biophysics等著名奖项和荣誉。


从助教到“天才奖”得主2001年，庄小威被聘为哈佛大学助理教授。她的物理根底启发她将带荧光的分子标记物附在病毒上，当用激光照射时，标记物发射出特殊的彩色光。用这种方法，借助显微镜，她详实跟踪了单个病毒的行为，也跟踪了诸如蛋白质和核糖核酸（RNA）片断这样的单个分子行为。她拍摄到单个流感病毒的连续影像，这是世界上首次记录到病毒的各阶段过程。
　　50万美元的麦克阿瑟“天才奖”因此向她垂青。她是24个获奖者中最年轻的一位，而且是女性。


教授之路　美国艺术与科学文学院（FAS）的科比先生预见了庄的研究对病毒侵入细胞机制的深入了解和对传染病研究以及药物开发的意义。他说，庄的研究如此引人注目，很高兴麦克阿瑟基金会注意到了“她的天才”。中国科学院院长路甬祥也代表中科院给庄小威发去贺信。
　　2004年，美国著名的《科技评论》杂志从来自美国、加拿大、英国、中国、韩国、新加坡、印度等国600余提名者中，评选出在纳米技术、计算机与通信及生物技术领域从事前沿技术研究的、年龄在35岁以下的100名青年创新者，庄小威名列其中。
　　2005年3月，美国霍华德·休斯医学研究会（HHMI，一家为全美科学家提供资助的富有卓越声望的非盈利型研究机构）从全美300多位提名人中选出43位生命科学家（当选者称为HHMI研究员，基本代表了美国生命科学及其相关交叉学科领域最活跃、最富创新能力、最高水平的研究力量，迄今341位当选者中，10人是诺贝尔奖得主，100多人是美国国家科学院院士），在未来7年中向每位提供700万美元的资助。庄小威和科大校友骆利群榜上有名。
　　“在科研领域搭建关系网络并不是最重要的，在博士和博士后阶段更应该专注于课题研究，成功的研究成果一定会引起别人的关注，功到自然成。”庄小威这样解释她的“顺”----博士后结束时，她拿到美国七所大学（哈佛、麻省理工、耶鲁、普林斯顿、康奈尔、加州理工、加州大学洛杉矶分校）的 offer（录用通知书），而此后她总能顺利获得研究资金。
　　2006年初，庄小威晋升为哈佛正教授，34岁的正教授。她在哈佛大学建立了以自己名字命名的单分子生物物理实验室，带领21名博士、博士后研究流感、艾滋??ARS等病毒侵入宿主细胞的过程。在实验室团队的网页上，她着无袖红色恤衫，戴着墨镜眺望远方，极其舒展。朋友们这样说她： “在课题研究之外，庄小威是一个活泼的女青年。”


成功经验谈在庄小威的字典里，动力、眼界和深度思考是三个关键词。
　　“我从小喜欢科学。”庄小威的早期教育，是个性与顺其自然的结合，她顺着自己的心意和兴趣，保有了strong motivation（强烈的动力）。
　　庄小威的父母退休前都是中国科大教授，母亲朱仁芝提起女儿，心满意足：“她小时候在江苏如皋跟爷爷、奶奶生活了5年，到5岁多时我们才接回来。小威没有上过幼儿园，拼音识字是我们在工作之余教的。我们落实政策以后分到合肥中国科大，小威就直接上了科大附小二年级。”
　　庄小威自小聪明伶俐，勤奋好学。5岁多时，父母上班不在家，她自学了炒青菜、打扫卫生等家务活。初中时，年龄最小，但各门功课都拔尖，曾获得全国中学生数理化竞赛第一名。后被推荐到北京景山学校上了半年中国科大预备班，13岁转入离家较近的苏州中学科大预备班。以高考600多分的状元成绩考进少年班之后，她的成绩也一直名列前茅，数学、物理常拿满分。
　　少年班同学毛珺婕回想起19年前初见留着短发，热情爽朗的庄小威，觉得她不像苏州美女，却有几分枕霞旧友史湘云的神采。
　　“小威得天独厚，虽然读书无数，视力却是1.5。有时在宿舍里，大家都伏案用功，她躺在上铺的床上看书，还能看见我们书上的字。小威还有个一心两用的本领，一边听三国评书一边做原子物理作业，这些都让我们好生佩服。”
　　做科研是很辛苦的事，对自己的学问有热情，才有动力，保持动力是化解困难的秘诀。每当遇到梗阻，庄小威就勒令自己忘掉过去的成功和失败，一切从头开始，从不轻言放弃。在哈佛大学工作以来，她一周七天，每天都从早上10时工作到半夜12时。她说：“除了吃饭和睡觉，剩下的时间都在工作。”
　　“由于中国传统教育方式有其弱点，以致中国人的创造性思维不够活跃，华人学生在此方面应注意调整。只要科研做得好，就一定会被别人承认，性别、国籍都不是关键。”庄小威建议后晋同行挑选对社会产生影响、能使多数人受益的课题，在研究时，务必深思，杜绝肤浅。

Research Summary

The Zhuang research lab works on the forefront of single-molecule biology and bioimaging, developing and applying advanced optical imaging techniques to study the behavior of individual biological molecules and complexes in vitro and in live cells. Students in the Zhuang lab apply their diverse backgrounds in biology, chemistry, physics and engineering to develop new imaging methods and applying these methods to a variety of interesting biological systems. Our current research is focused on three major directions: (1) Developing super-resolution optical microscopy that allows cell and tissue imaging with nanoscopic scale resolution and applying this technology to cell biology and neurobiology, (2) investigating how biomolecules function, especially how proteins and nucleic acids interact, using single-molecule fluorescence imaging and spectroscopy; (3) developing live-cell imaging techniques for studying cellular dynamics, in particular virus-cell interactions.
Nanoscopic Optical Imaging
Single-molecule biology: Nucleic Acid - Protein Interactions
Single-virus tracking: Virus-cell Interactions

Nanoscopic Optical Imaging Optical microscopy is one of the most widely used imaging methods in biomedical research. Several advantages make light microscopy a particularly powerful tool for cell, tissue and animal imaging. These include the exquisite molecular specificity, the relatively fast time resolution and the non-invasive imaging nature. However, the spatial resolution of far-field optical microscopy, classically limited by the diffraction of light to a few hundred nanometers, is substantially larger than typical molecular length scales in cells. This limit leaves many biological problems beyond the reach of light microscopy. To overcome this limit, we have developed a new form of super- resolution light microscopy, stochastic optical reconstruction microscopy (STORM). STORM uses photo-switchable fluorescent probes to temporally separate the otherwise spatially overlapping images of individual molecules, allowing the construction of high-resolution images. Using this concept, we have achieved three-dimensional, multicolor fluorescence imaging of molecular complexes, cells, and tissues with ~20 nm lateral and ~50 nm axial resolutions. We hope to advance STORM capabilities to ultimately enable real-time imaging of cells and tissues with resolution at the true molecular length scale. This new form of fluorescence microscopy allows molecular interactions in cells and cell-cell interactions in tissues to be imaged at the nanometer scale. We are applying this new technology to cell biology and neurobiology.

Click here for a more detailed description of research in this direction.
Nature Method of the Year (2008)
Watch the movie here
STORM Workshop (August 2010)
Workshop Information
Selected recent publications:

1. B. Huang, H. Babcock, X. Zhuang, "Breaking the diffraction barrier: Super-resolution imaging of cells", Cell 143, 1047-1058 (2010)
   
2. A. Dani, B. Huang, J. Bergan, C. Dulac, X. Zhuang, "Super-resolution imaging of chemical synapses in the brain", Neuron 68, 843-856 (2010)
   
3. M. Wu, B. Huang, M. Graham, A. Raimondi, J.E. Heuser, X. Zhuang, P. De Camilli, "Coupling between clathrin-dependent endocytic budding and F-BAR-dependent tubulation in a cell-free system", Nature Cell Biology 12, 902-908 (2010)
   
4. B. Huang, W. Wang, M. Bates, X. Zhuang, "Three-dimensional Super-resolution Imaging by Stochastic Optical Reconstruction Microscopy", Science 319, 810-813 (2008)
   
5. M. Bates, B. Huang, G. T. Dempsey, X. Zhuang, "Multicolor Super-Resolution Imaging with Photo-Switchable Fluorescent Probes", Science 317, 1749-1753 (2007)
   
6. M. J. Rust, M. Bates, X. Zhuang, "Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM)", Nature Methods 3, 793-795 (2006)
   

Single-Molecule biology: Nucleic Acid - Protein Interactions We explore single-molecule fluorescence imaging and spectroscopy techniques to study complex biomolecular systems. An area of special interest to us is the interactions of proteins with nucleic acids. Many essential cellular reactions, such as DNA replication, transcription, messenger RNA editing, and protein synthesis, involve DNA-protein or RNA-protein complexes. Understanding nucleic acid-protein interactions is thus crucial for deciphering the molecular mechanisms underlying many important biological processes. Using single-molecule fluorescence imaging and spectroscopy methods, we directly visualize the assembly and function of these molecular complexes in real time. These experiments allow us to observe transient states and multiple kinetic paths that are difficult to detect by classical ensemble experiments, to probe the dynamic interactions between DNA, RNA and proteins, and to determine the relationship between the structural dynamics and function for these molecular complexes. From these quantitative data, we aim to formulate in-depth mechanistic understanding of these biomolecular processes. Using this approach, we are studying the assembly process, catalytic cycle, and structure-function relationship of several nucleic acid-interacting enzymes, including telomerase, HIV reverse transcriptase and chromatin remodeling enzymes.

Click here for a more detailed description of research in this direction.Selected recent publications:

1. T. Blosser, J. Yang, M. Stone, G. Narlikar, X. Zhuang, "Dynamics of Nucleosome Remodeling by Individual ACF Complexes", Nature 462, 1022-1027 (2009)
   
2. S. Liu, E. Abbondanzieri, J. W. Rausch, S. F. J. Le Grice, X. Zhuang, "Slide into action: dynamic shuttling of HIV reverse transcriptase on nucleic acid substrates", Science 322, 1092-1097 (2008)
   
3. E. Abbondanzieri, G. Bokinsky, J. W. Rausch, J. X. Zhang, S. F. J. Le Grice, X. Zhuang, "Dynamic binding orientations direct activity of HIV reverse transcriptase", Nature 453, 184-189 (2008)
   
4. M. D. Stone, M. Mihalusova, C. M. O'Connor, R. Prathapam, K. Collins, X. Zhuang, "Stepwise protein-mediated RNA folding directs assembly of telomerase ribonucleoprotein",Nature 446, 458-461 (2007)
   
5. S. Liu, G. Bokinsky, N. G. Walter, X. Zhuang, "Dissecting the multi-step reaction pathway of an RNA enzyme by single-molecule kinetic fingerprinting", Proc. Natl. Acad. Sci. USA 104, 12634-12639 (2007)
   
6. G. Bokinsky, D. Rueda, V. K. Misra, A. Gordus, M. M. Rhodes, H. P. Babcock, N. G. Walter, X. Zhuang, "Single-molecule transition-state analysis of RNA folding", Proc. Natl. Acad. Sci. USA 100 , 9302-9307 (2003)
   

Single-virus tracking: We are developing live cell imaging methods to allow direct visualization and quantitative analysis of cellular dynamics. Our research in this direction focuses on virus-cell interactions and related cellular trafficking pathways. Viruses must deliver their genome into cells to initiate infection. This entry process is a subject of fundamental importance as well as a therapeutic target for viral disease treatment. However, understanding viral entry mechanisms is challenging because of the involvement of multiple entry pathways and multiple steps in the pathway, each featuring interactions of the viruses with different cellular structures. What could be a better way to study viral trafficking than to take a ride with the virus particle on its journey into the cell? To realize this goal, we have developed real-time imaging methods to track individual virus particles in live cells. This approach allows us to follow the fate of individual viruses, to dissect the infection pathways into microscopic steps, and to determine the molecular mechanism of each step. By combining this approach with other biochemical methods, we have studied the entry mechanisms of influenza virus, poliovirus, dengue virus and non-viral gene delivery vectors. Our research also extends to the post entry trafficking, assembly and budding mechanisms of viruses.

Click here for a more detailed description of research in this direction.
Selected recent publications:

1. H.M. van der Schaar, M.J. Rust, C. Chen, H. van der Ende-Metselaar, J. Wilschut, X. Zhuang, J.M. Smit, "Dissecting the Cell Entry Pathway of Dengue Virus by Single-Particle Tracking in Living Cells", PLOS Pathogens 4, e1000244 (2008)
   
2. C. Chen, X. Zhuang, "Epsin1 is a cargo specific adaptor for the clathrin-mediated endocytosis of influenza virus", Proc. Natl. Acad. Sci. USA 105, 11790-11795 (2008)
   
3. B. Brandenburg, L. Y. Lee, M. Lakadamyali, M. J. Rust, X. Zhuang, J. M. Hogle, "Imaging poliovirus entry in live cells", PLoS Biol. 5, e183, 1543-1555 (2007)
   
4. B. Brandenburg, X. Zhuang, "Virus trafficking - learning from single-virus tracking", Nat. Rev. Microbiology 5, 197-208 (2007)
   
5. M. Lakadamyali, M. J. Rust, X. Zhuang, "Ligands for clathrin-mediated endocytosis are differentially sorted into distinct populations of early endosomes", Cell 124, 997-1009 (2006)
   
6. M. J. Rust, M. Lakadamyali, F. Zhang, X. Zhuang, "Assembly of endocytic machinery around individual influenza viruses during viral entry", Nature Struct. Mol. Biol. 11 , 567-573 (2004)