生物谷按：王曉東作為華人中的杰出代表，在細(xì)胞凋亡，以及近來(lái)在RNAi領(lǐng)域作出了一系列驚人的發(fā)現(xiàn)，從而獲得了美國(guó)科學(xué)院了院士這一榮譽(yù)稱號(hào)！本文將從多個(gè)方面重點(diǎn)綜述一下他的驕人成績(jī)，同時(shí)也會(huì)發(fā)表一系列相關(guān)的評(píng)論，希望更多的人能從這里獲得有益的啟示。

生物谷新聞快報(bào)

生物谷報(bào)道：據(jù)北京時(shí)間今天凌晨1點(diǎn)，美國(guó)科學(xué)院宣布，美籍華裔科學(xué)家王曉東當(dāng)選美國(guó)科學(xué)院院士，成為美國(guó)科學(xué)院*年輕的院士，年僅41歲。

　　今年41歲的王曉東教授，是近20年來(lái)，我國(guó)出國(guó)留學(xué)人員中當(dāng)選美國(guó)科學(xué)院的**位院士。1985年，王曉東畢業(yè)于北京師范大學(xué)，曾經(jīng)考取了北京師大薛少白教授的碩士生，但因獲得美國(guó)的留學(xué)簽證而未在國(guó)內(nèi)深造。1991年獲美國(guó)德州大學(xué)西南醫(yī)學(xué)中心博士學(xué)位?，F(xiàn)在在德州大學(xué)西南醫(yī)學(xué)中心任終身教授，并在有名的霍華德·休斯研究所擔(dān)任研究員。

　　王嘵東主要從事生命科學(xué)前沿領(lǐng)域細(xì)胞調(diào)亡規(guī)律的研究，這項(xiàng)研究可以為揭示生物生長(zhǎng)與死亡的規(guī)律，為人類癌癥及傳染病等疑難雜癥的**提供重要的理論依據(jù)。近年來(lái)在RNAi研究方面也取得一系列突破，引人注目。

　　美國(guó)科學(xué)院院士是美國(guó)科學(xué)界的*高榮譽(yù)，當(dāng)選者均是在科技和工程方面取得杰出成就的科學(xué)家和工程師。美國(guó)科學(xué)院現(xiàn)有院士2300多名。

王曉東相關(guān)論文

王曉東博士論文一般只發(fā)表在cell,Nature,science等**刊物上，而且許多研究都是開創(chuàng)性的研究，以下他本人近年來(lái)的代表性論文，僅列舉這一些便可見其成就大小了。

1 Li P, Nijhawan D, Wang X.Mitochondrial activation of apoptosis. Cell. 2004 Jan 23;116(2 Suppl):S57-9, 2 p following S59 2 Du C, Fang M, Li Y, Li L, Wang X.Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000 Jul 7;102(1):33-42. 3 Li K, Li Y, Shelton JM, Richardson JA, Spencer E, Chen ZJ, Wang X, Williams RS.Cytochrome c deficiency causes embryonic lethality and attenuates stress-induced apoptosis. Cell. 2000 May 12;101(4):389-99. 4 Luo X, Budihardjo I, Zou H, Slaughter C, Wang X.Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surfAce death receptors. Cell. 1998 Aug 21;94(4):481-90. 5 Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X.Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997 Nov 14;91(4):479-89. 6 Zou H, Henzel WJ, Liu X, Lutschg A, Wang X.Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell. 1997 Aug 8;90(3):405-13. 7 Liu X, Zou H, Slaughter C, Wang X.DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. Cell. 1997 Apr 18;89(2):175-84. 8 Liu X, Kim CN, Yang J, Jemmerson R, Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996 Jul 12;86(1):147-57. 9 Wang X, Sato R, Brown MS, Hua X, Goldstein JL.SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell. 1994 Apr 8;77(1):53-62. 10 Li LY, Luo X, Wang X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature. 2001 Jul 5;412(6842):95-9. 11 Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y. Structural basis of IAP recognition by Smac/DIABLO. Nature. 2000 Dec 21-28;408(6815):1008-12. 12 Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y. Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature. 2000 Aug 24;406(6798):855-62. 13 Liu Q, Rand TA, Kalidas S, Du F, Kim HE, Smith DP, Wang X.R2D2, a bridge between the initiation and effector steps of the Drosophila RNAi pathway. Science. 2003 Sep 26;301(5641):1921-5. 14 Jiang X, Kim HE, Shu H, Zhao Y, Zhang H, Kofron J, Donnelly J, Burns D, Ng SC, Rosenberg S, Wang X. Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science. 2003 Jan 10;299(5604):223-6. 15 Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X.Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science. 1997 Feb 21;275(5303):1129-32.

科學(xué)趣事：王曉東他們發(fā)現(xiàn)SMAC的趣事

生物谷按：這一過程主要說明研究工作的緊迫性，也為研究工作者提個(gè)醒。

IAP: Antagonizing the Antagonist
Two different routes find the mammalian enemies of apoptosis inhibitors

By Laura DeFrancesco

For this article, Laura DeFrancesco interviewed David Vaux, principal research fellow, Walter and Eliza Hall Institute, Melbourne, Australia. Data from the Web of Science show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age.

A.M. Verhagen et al., "Identification of DIABLO, a mammalian protein that promotes apoptosis by binding to and antagonizing IAP proteins," Cell, 102: 43-53, July 7, 2000. (Cited in 176 papers)

Apoptosis, or programmed cell death, provides organisms a way to remove unwanted cells, such as during morphogenesis, or to defend against viral infection. Of course, certain molecules exist to prohibit apoptosis. One of these proteins, aptly named Inhibitor of Apoptosis Protein (IAP), was first found in viruses, which use them to keep host cells alive while the virus replicates and propagates. These IAPs interfere with key effectors of apoptosis, the family of proteases known as caspases, which, when activated, literally digest the cell from the inside out.
But the story doesn't end there: antagonists exist to antagonize the IAPs; these molecules send the cell back down the apoptosis pathway. For example, three IAP antagonists, Reaper, Grim and HID, have been identified in Drosophila. These proteins promote cell death by binding to the IAPs, keeping them from suppressing caspase activity. However, no similar IAP antagonists had been identified in mammals until the labs of David Vaux, Xiaodong Wang, and the editors of Cell crossed paths.

Vaux's lab was one of the first to identify mammalian homologs of the baculoviral IAPs (XIAP, cIAP1 and cIAP2). Vaux, principal research fellow at the Walter and Eliza Hall Institute, Melbourne, Australia, hypothesized that, like their Drosophila counterparts, these IAPs could be controlled by pro-apoptotic proteins. When homologs for Reaper, Grim or HID couldn't be found by searching genomic databases, researchers took a different approach. Anne Verhagen, a postdoc in Vaux's lab, expressed XIAP in mammalian cells and immunoprecipitated it from cell lysates along with associated proteins. Several novel proteins were found by running the coimmunoprecipitated proteins on two-dimensional gels. Using nanoelectrospray tandem mass spectrometry, Lisa Connolly, a research assistant in the lab of Vaux's collaborator, Richard Simpson, obtained amino acid sequences on four IAP binding proteins, one of which was named DIABLO (for Direct IAP binding protein of low Pi) and another HtrA2 (also known as Omi).

?2002 Cell Press

Localizing DIABLO: The N-terminal 53 amino acids of DIABLO were fused to GFP, and the fusion protein was expressed in 293T cells (left) or NT2cells (right). Yellow indicates co-localization of mitotracker red and GFP fluorescence.

Working independently on apoptosis in HeLa cell lysates, Wang, a Howard Hughes Medical Institute investigator at the University of Texas Southwestern Medical Center at Dallas, identified several components of the cell death mechanism (including Apaf-1, caspase 9, cytochrome c, and DFF) using a classical biochemical approach. He found an additional activity in cell lysates that promoted efficient caspase activation. Purifying this activity led his team to identify a protein they termed Smac (for second mitochondrial activator of cell death), so-called because the protein had a mitochondrial targeting sequence, and antibodies showed it localized to the mitochondria in healthy cells.

The two groups independently submitted papers to Cell. The reviewers requested revisions, and then asked for more work because they still weren't satisfied. However, in an unusual move, the editors suggested that the two labs exchange their papers to see, with each other's help, if they could reach solutions.

In doing so, the two groups realized that they had purified the same protein. Wang hadn't determined how Smac promotes apoptosis, but after learning that Vaux had found that it was an IAP binding protein, he looked for and confirmed IAP binding activity by Smac. And while Vaux's group knew that DIABLO was processed, they didn't know this occurred in the mitochondria. Using antibody provided by Wang, they confirmed its presence in the mitochondria of healthy cells, but released into the cytosol by UV irradiation, an apoptotic inducer.

Vaux remembers, "Wang was surprised and delighted to learn from our paper that DIABLO/Smac functioned by binding to IAPs. From reading his paper we were blown away to learn that the reason DIABLO/Smac is processed is that it is targeted to the mitochondria, where its amino-terminus is removed."

Laura DeFrancesco (defrancesco1@earthlink.net) is a freelance writer in Pasadena, Calif.

1. C. Du et al., "Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition," Cell, 102:33-42, July 7, 2000.

評(píng)論：王曉東以后,留學(xué)生里誰(shuí)可能做美國(guó)科學(xué)院院士

這是一位網(wǎng)友的提名，這些人都是華人在美的精英！他們?cè)诟髯圆煌念I(lǐng)域中做出了巨大貢獻(xiàn)！

生物：哈佛大學(xué)袁鈞英，普林斯頓大學(xué)錢卓,斯坦福大學(xué)駱利群,華盛頓大學(xué)饒毅, 耶魯大學(xué)許田,克羅拉多大學(xué)韓民,密西根大學(xué)管坤良,耶魯大學(xué)鄧興旺,普林斯頓大學(xué)施一公

數(shù)學(xué)：普林斯頓大學(xué)田剛，西北大學(xué)夏志宏,斯坦福大學(xué)李駿

化學(xué)：哈佛大學(xué)謝曉亮,霍普金斯大學(xué)劉鈞

二十一項(xiàng)值得獲諾貝爾生理或醫(yī)學(xué)獎(jiǎng)的工作及科學(xué)家

饒毅

又到十月，是諾貝爾獎(jiǎng)宣布獲獎(jiǎng)人的季節(jié)。2002年諾貝爾生理或醫(yī)學(xué)獎(jiǎng)將在明天（10月7日）宣布。雖然評(píng)選委員會(huì)以外的人不能預(yù)計(jì)誰(shuí)當(dāng)年會(huì)得獎(jiǎng)，一般來(lái)說，有相當(dāng)一些人自己有判斷，哪些人及其工作值得獲獎(jiǎng)。就諾貝爾生理或醫(yī)學(xué)獎(jiǎng)來(lái)說，醫(yī)學(xué)常有一些和臨床有關(guān)的不容易預(yù)計(jì)，基礎(chǔ)的多半大家公認(rèn)，但是有時(shí)也出大家意外的，所以只可以列一個(gè)不**的單子，這些人和工作在2002年10月6日前已經(jīng)值得得獎(jiǎng)，但是還沒有得，由這個(gè)名單的長(zhǎng)度也可以知道，因?yàn)檫@些突出工作的數(shù)量也就決定了他們不可能都得獎(jiǎng)。后面幾個(gè)工作，第19,20項(xiàng)可能因?yàn)闀r(shí)間過去而得不到，第21項(xiàng)很可能過一些時(shí)間再給（比如等十年也不算久）。如果明天的名單里有以下科學(xué)家，也不會(huì)奇怪。我還要說明一下，這樣的預(yù)計(jì)不是特別難，能做這樣預(yù)計(jì)的人成百上千，因?yàn)檫@是評(píng)價(jià)已經(jīng)做出的研究。而預(yù)計(jì)未來(lái)研究領(lǐng)域和方向，則難。

1. Mario Capecchi〔美國(guó)尤他大學(xué)U. Utah〕，發(fā)明基因剔除技術(shù)，肯定值得得獎(jiǎng)，可能和其他1,2個(gè)做基因剔除(Oliver Smithies)或轉(zhuǎn)基因動(dòng)物的人合得，也有可能和**個(gè)做出鼠胚胎干細(xì)胞的Gail Martin〔美國(guó)舊金山加州大學(xué)UCSF〕合得。

2. Bob Horvitz 〔美國(guó)麻省理工學(xué)院MIT〕，細(xì)胞凋亡的遺傳機(jī)理，可能合得者是：AH Wylie或JFR Kerr其中之一（細(xì)胞凋亡的概念和電子顯微鏡下形態(tài)變化特征），Susanne Cory或Stanley Korsmeyer之一（Bcl-2在細(xì)胞凋亡中的作用）。得州大學(xué)西南醫(yī)學(xué)中心的王曉東也有可能（細(xì)胞凋亡的生物化學(xué)機(jī)理）。另外如果不以細(xì)胞凋亡來(lái)看，而以線立體新的功能來(lái)看，王曉東和Korsmeyer（甚至La Jolla癌癥研究所John Reed）也是一個(gè)可能組合。


3. Mark Ptashne 〔美國(guó)紐約凱特菱癌癥研究中心Sloan Kettering〕,基因調(diào)控的機(jī)理，發(fā)現(xiàn)**個(gè)轉(zhuǎn)錄因子：原核細(xì)胞（**）的lamda抑制子?？梢詥为?dú)，也可和Bob Tjian 〔錢澤南，UC Berkeley〕合得。Ptashne做真核細(xì)胞轉(zhuǎn)錄調(diào)控的研究中，有北大留學(xué)生馬俊的工作。

4. Elizabeth Blackburn 〔美國(guó)舊金山加州大學(xué)UCSF〕和Carol Greider 〔美國(guó)霍普金斯大學(xué)Johns Hopkins〕，端粒子和端粒酶，Blackburn主要發(fā)現(xiàn)在UC Berkeley做，Greider那時(shí)是她的學(xué)生。另外有復(fù)旦的留學(xué)生于國(guó)良在他實(shí)驗(yàn)室做過早期一些工作。

5. Roderick MacKinnon 〔美國(guó)洛克菲勒大學(xué)Rockefeller〕，鉀離子通道的結(jié)構(gòu)，可以單獨(dú)，也可以合得 （不確定合得者，如果就鉀通道而言，舊金山加州大學(xué)UCSF的Lily Jan葉公杼和YN Jan詹裕農(nóng)有可能；如果廣義地給離子通道，美國(guó)西雅圖華盛頓大學(xué)University of Washington的Bertil Hille有可能）。

6. Y. W. Kan 簡(jiǎn)悅威 〔美國(guó)舊金山加州大學(xué)UCSF〕，**個(gè)提出可以用限制性內(nèi)切酶片斷多態(tài)性跟蹤人類基因變異，使人類遺傳學(xué)進(jìn)入新時(shí)代，可以合得，也可以單獨(dú)。

7. Eric Lander 〔美國(guó)麻省理工學(xué)院MIT〕，John Sulston 〔英國(guó)劍橋Cambridge,UK〕，Bob Wasterson 〔美國(guó)圣路易斯華盛頓大學(xué)Washington University〕，基因組研究。

8. Roger Y. Tsien 錢永健〔美國(guó)圣跌哥加州大學(xué)UCSD〕和 Douglas C. Prasher〔美國(guó)農(nóng)業(yè)部麻州Otis植物保護(hù)中心〕，發(fā)明測(cè)定活細(xì)胞內(nèi)分子的新方法。Tsien發(fā)明鈣染料，Prasher發(fā)現(xiàn)綠色熒光旦白GFP。

9. Afred G. Knudson 〔美國(guó)費(fèi)城Fox Chase癌癥中心〕，腫瘤抑制基因，可能和Janet D. Rowley〔美國(guó)芝加哥大學(xué)University of Chicago〕和Bob Weinberg 〔麻省理工學(xué)院MIT〕合得，華裔李文華〔得州大學(xué)生物工程研究所〕和Weinberg工作很近，有爭(zhēng)議誰(shuí)**，Weinberg可能容易得，他以前因?yàn)榘┗蝈e(cuò)過一次和Bishop和Varmus合得的機(jī)會(huì)。

10. John Gordon〔英國(guó)劍橋Cambridge，UK〕和 Ian Wilmut 〔英國(guó)愛爾蘭Roslin研究所〕，核轉(zhuǎn)移，Gordon是60年代**個(gè)用成體細(xì)胞核成功克隆動(dòng)物（蛙），Wilmut是九十**個(gè)用類似方法克隆哺乳動(dòng)物。

11. Pamela Bjorkman 〔美國(guó)加州理工學(xué)院Caltech〕，Jack Strominger 〔美國(guó)哈佛大學(xué)Harvard〕和Emil Unanue 〔美國(guó)圣路易斯華盛頓大學(xué)Washington University〕，前二者發(fā)現(xiàn)MHC（主要組織相容性抗原復(fù)合體）結(jié)構(gòu)，后者發(fā)現(xiàn)抗原呈現(xiàn)細(xì)胞。Bjorkman是和Don Wiley做研究生時(shí)的工作，Wiley如果不去世，應(yīng)該得。

12. Yasutomi Nishizuka〔日本〕和Michael Berridge 〔英國(guó)〕，細(xì)胞內(nèi)信號(hào)轉(zhuǎn)導(dǎo)分子，前者發(fā)現(xiàn)旦白激酶C，后者發(fā)現(xiàn)磷酸肌醇。

13. Aaron Ciechanover 〔以色列工學(xué)院Technion〕，Avram Hershko 〔以色列工學(xué)院Technion〕，Alexander Varshavsky 〔美國(guó)加州理工學(xué)院Caltech〕，發(fā)現(xiàn)蛋白質(zhì)降解的生物化學(xué)機(jī)理。

14. Judah Folkman〔哈佛大學(xué)醫(yī)學(xué)院〕發(fā)現(xiàn)調(diào)節(jié)血管形成的分子。

15. Sydney Brenner 和 Seymour Benzer 〔美國(guó)加州理工學(xué)院Caltech〕，用遺傳學(xué)方法研究發(fā)育，神經(jīng)和行為。Brenner提出用c elegans研究發(fā)育和神經(jīng)，Benzer提出用果蠅做神經(jīng)和行為。

16. Marc Raichle 〔美國(guó)圣路易斯華盛頓大學(xué)Washington University〕,用正電子掃描（PET scan）做活體人影像檢測(cè)，可能和發(fā)明改進(jìn)fMRI（“功能性核磁共振”，或稱“功能性磁共振影像”）的人合得。 他們的工作是生物醫(yī)學(xué)影像的重要發(fā)展。

17. Luc Montagnier〔法國(guó)〕Robert C. Gallo（美國(guó)），發(fā)現(xiàn)愛滋病毒。

18. Tim Bliss〔英國(guó)〕和Terje Lomo 〔挪威〕，發(fā)現(xiàn)長(zhǎng)期性增強(qiáng)作用（LTP）,推動(dòng)高等動(dòng)物學(xué)習(xí)記憶研究。這項(xiàng)獎(jiǎng)，受Eric Kandel近年剛因?yàn)檠芯康偷葎?dòng)物（海兔）學(xué)習(xí)記憶得獎(jiǎng)而可能推后。

19. Herbert Boyer 〔美國(guó)舊金山加州大學(xué)UCSF〕和Stanley Cohen 〔美國(guó)斯坦福大學(xué)Stanford〕，發(fā)明重組DNA技術(shù)，開創(chuàng)生物工程時(shí)代。

20. Avaram Goldstein 〔美國(guó)斯坦福大學(xué)Stanford〕，Solomon Snyder 〔美國(guó)霍普金斯大學(xué)Johns Hopkins〕, John Hughes 〔英國(guó)帝國(guó)理工學(xué)院Imperial College of Science and Technology〕, 發(fā)現(xiàn)痛覺的分子機(jī)理。Goldstein提出證明**受體的方法，Snyder實(shí)驗(yàn)室的Candace Pert，紐約大學(xué)的Eric Simon和瑞典的Lars Terenius用Goldstein的方法發(fā)現(xiàn)**受體，在英國(guó)蘇格蘭Aberdeen工作的John Hughes和導(dǎo)師Hans Kosterlitz發(fā)現(xiàn)**個(gè)內(nèi)源性**肽。Kosterlitz已經(jīng)去世。嚴(yán)格地說，李卓浩〔Choh H Li， UC Berkeley〕是**個(gè)發(fā)現(xiàn)有鎮(zhèn)痛作用的蛋白質(zhì)，他在1964年發(fā)現(xiàn)B-Lipotropin 而且知道有鎮(zhèn)痛作用，但未提出內(nèi)源性的**樣物質(zhì)概念，而且他已經(jīng)去世多年了。

21. RNA干擾，不一定會(huì)在近年發(fā)獎(jiǎng)，可能等機(jī)理進(jìn)一步搞清，但是發(fā)獎(jiǎng)時(shí)會(huì)包括發(fā)現(xiàn)RNA干擾現(xiàn)象的人，有三個(gè)重要的候選人，如果不包括機(jī)理，就是他們，如果包括機(jī)理，那么只能在這三個(gè)里面選一倆個(gè)加上以后發(fā)現(xiàn)RNAi機(jī)理*重要的人。Ken Kemphues〔美國(guó)康乃爾大學(xué)Cornell〕，Andy Fire 〔美國(guó)卡內(nèi)磯研究所Carnegie〕，Craig Mello〔美國(guó)麻州大學(xué)University of Massachusetts〕。Kemphues的工作是復(fù)旦留美學(xué)生郭蘇做的。

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