James E. Rothman, Randy W. Schekman and Thomas C. Südhof: The 2013 Nobel Prize in Physiology or Medicine

2013諾貝爾生理學與醫學獎授予3名美德科學家

北京新浪網 (2013-10-07 19:39)

2013諾貝爾生理學或醫學獎得主

　　新浪科技訊 北京時間10月7日消息，據諾貝爾獎官方網站報導，2013諾貝爾生理學或醫學獎今日公布，得主為James E. Rothman, Randy W. Schekman & Thomas C. S?dhof，得獎原因為他們發現了細胞內的運輸機制之謎。

翻譯: 原文參考附文

    生物體內每一個細胞都是一個生產和輸出分子的工廠。比如，胰島素在這裏被製造出來並釋放進入血液當中，神經傳遞素從一個神經細胞傳導至另一個細胞。這些分子在細胞內都是以「小包」的形式傳遞的，這就是「細胞囊泡」。這三位獲獎科學家發現了這些「小包」是如何被在正確的時間輸運至正確地點的分子機制。

　　Randy Schekman發現了一系列與細胞囊泡輸運機制有關的基因；James Rothman發現了讓這些囊泡得以與其目標相融合的蛋白質機制，從而可以實現對所運「貨物」的傳遞；Thomas S?dhof則揭示了信號是如何實現對囊泡的控制，使其得以精確分配其所載「貨物」。

　　在這項發現過程中，三位科學家：Rothman, Schekman 和S?dhof揭示了細胞內輸運體系的精細結構和控制機制。這一系統的失穩將導致有害結果，如神經系統疾病，糖尿病或免疫系統紊亂。

　　細胞內物質輸運是如何實現的？

　　正如在一個繁忙的大型港口，你必須要有一套體系來確保你的貨物會在規定的時間被配送到規定的位置，細胞也是一樣。細胞內有各種複雜的細胞器，它們面臨的問題是相似的：細胞會產生出各種不同的分子，如荷爾蒙，神經傳遞素，細胞活素以及?，它們必須被傳遞至細胞內不同的位置上，或者需要被精確地在正確的時間轉運至細胞外部。在這一過程中，時間和地點的正確是最關鍵的。這就要依賴於囊泡的作用，這是一些微小的小泡結構，外部有膜包裹，它們負責在各細胞器之間運輸細胞內部的「貨物」，或是通過與細胞膜的融合從而向細胞外部釋放細胞內產生的物質。這一機制至關重要，如它控制著神經傳遞素的傳遞，後者是激發生物體神經系統反應的觸發開關；又或者在新陳代謝方面，它控制著荷爾蒙的分配傳遞。那麼這些囊泡結構究竟是如何能確保運輸的時間和地點正確性的呢？

　　交通堵塞背後的基因控制機制

　　早在上世紀的1970年代，Randy Schekman便被細胞如何調節其內部輸運機制深深吸引並投身此項研究，並試圖利用酵母菌作為模型樣本來研究其背後的基因機制。在基因篩選中，他找到一些顯示出輸運機制缺陷的酵母菌細胞，其表現就像是一個缺乏指揮協調而一片混亂的公共交通系統，其內部囊泡堆積在細胞內的部分區域。他發現造成這種囊泡發生「交通堵塞」的原因是基因層面的，並據此順藤摸瓜找到了其背後的基因機制。他找到了3組不同的基因對這一細胞運輸機制產生作用，從而改變並大大加深了我們對細胞如何規範其內部輸運系統的認識。

　　精確對接

　　James Rothman同樣對細胞輸運機制感到好奇。在上世界80~90年代期間，Rothman正開展對哺乳動物細胞囊泡輸運機制的研究，他發現一種蛋白質可以讓囊泡實現與其目標細胞膜的對接和融合。在融合過程中，囊泡上的蛋白質和細胞膜上的蛋白質相互結合，就像分開的拉鏈相互咬合一樣。這類蛋白質有很多種，並且只有當合適的配對出現時才會發生融合，這就確保了「貨物」只會被運輸到設定的位置上而不會出現錯誤。這一機制不管是在內部細胞器之間的運輸，還是向外的運輸過程中都會起作用。

　　隨後的研究發現，Schekman在酵母菌細胞內所發現的部分基因正是產生Rothman在哺乳動物細胞內發現的蛋白質的背後機制，這揭示了一項細胞輸運體系內古老的進化起源。至此，這兩位科學家的研究工作描繪了細胞輸運體系的關鍵環節。

　　時間就是一切

　　Thomas S?dhof對大腦內神經細胞是如何相互之間進行溝通感興趣。這種傳遞信息的物質被稱為神經傳遞素，這種特殊分子正是由囊泡負責運輸至神經細胞的細胞膜上並藉助融合機制向外釋放的。這正是Rothman 和Schekman所發現的機制。然而這些囊泡只有在其所在的神經細胞向其「鄰居」發送信號之後才會被允許釋放它們運載的「貨物」。這種精確的時機把握究竟是如何實現的？

　　科學家們此前便已經知道鈣離子參与了這一過程，在上世紀90年代，S?dhof便開始在神經細胞中尋找對鈣離子敏感的蛋白質。最終他識別出一種分子機制，其會對注入的鈣離子做出反應，並控制鄰近的蛋白質迅速讓囊泡與神經細胞的外部細胞膜相結合。於是「拉鏈」打開了，信號物質被釋放出去。S?dhof的發現解釋了這種細胞傳輸的時間精確性是如何實現的，以及囊泡中的物質是如何實現受控地釋放。

　　囊泡輸運機制與疾病過程

　　今年的3位諾獎獲獎科學家發現了細胞生理學過程中的一項關鍵過程。他們的工作揭示了細胞內部和外部的輸運體系是如何達成時間與位置上的精確性的。在細胞中，不管是酵母菌還是人類，不管高等生物還是低等生物，它們體內的囊泡輸運以及細胞膜融合機制都遵循相同的基本原理。這一體系對於一系列的生理過程而言都至關重要，從大腦信號的傳遞，到荷爾蒙的釋放，再到免疫細胞活素。但當發生疾病時，細胞內的囊泡輸運機制會出現問題，這當中包括一些神經系統和免疫系統疾病。離開這一堪稱完美的控制機制，細胞將陷於混亂。

　　獲獎科學家簡歷：

　　James E. Rothman，1950年出生於美國馬薩諸塞州Haverhill，他於1976年在哈佛大學醫學院獲得博士學位，隨後在麻省理工學院做博士后研究工作。1978年Rothman前往加州的斯坦福大學，並在那裡開始進行針對細胞囊泡的研究工作。Rothman還曾經在普林斯頓大學以及紀念斯隆-凱特林癌症研究所和哥倫比亞大學工作過。2008年，他開始在耶魯大學任職，目前是耶魯大學細胞生物學繫系主任和教授。

　　Randy W. Schekman，1948年生於美國明尼蘇達州St Paul，曾先後在加州大學洛杉磯分校以及斯坦福大學求學，並於1974年獲得博士學位，指導老師為Arthur Kornberg，後者是1959年度諾貝爾獎獲得者。1976年，Schekman前往加州大學伯克利分校任職，目前他仍然是該校分子與細胞生物學系教授。同時Schekman也是霍華德休斯醫學研究所研究員。

　　Thomas C. S?dhof，1955年生於德國哥廷根。他在哥廷根大學求學並於1982年獲得碩士學位，同年獲得該校神經化學博士學位。1983年他前往美國達拉斯的德州大學西南醫學研究中心開展博士后研究，其導師是Michael Brown和Joseph GOLdstein，他們是1985年度諾貝爾生理學與醫學獎得主。S?dhof在1991年成為霍華德休斯醫學研究所研究員，並在2008年開始擔任斯坦福大學分子與細胞生理學教授。(晨風)

　　原文：http://www.nobelprize.org/nobel_prizes/medicine/laureates/2013/press.html

Press Release

2013-10-07

The Nobel Assembly at Karolinska Institutet has today decided to award

The 2013 Nobel Prize in Physiology or Medicine

jointly to

James E. Rothman, Randy W. Schekman
and Thomas C. Südhof

for their discoveries of machinery regulating vesicle traffic,
a major transport system in our cells

Summary

The 2013 Nobel Prize honours three scientists who have solved the mystery of how the cell organizes its transport system. Each cell is a factory that produces and exports molecules. For instance, insulin is manufactured and released into the blood and chemical signals called neurotransmitters are sent from one nerve cell to another. These molecules are transported around the cell in small packages called vesicles. The three Nobel Laureates have discovered the molecular principles that govern how this cargo is delivered to the right place at the right time in the cell.
Randy Schekman discovered a set of genes that were required for vesicle traffic. James Rothman  unravelled protein machinery that allows vesicles to fuse with their targets to permit transfer of cargo. Thomas Südhof revealed how signals instruct vesicles to release their cargo with precision.
Through their discoveries, Rothman, Schekman and Südhof have revealed the exquisitely precise control system for the transport and delivery of cellular cargo. Disturbances in this system have deleterious effects and contribute to conditions such as neurological diseases, diabetes, and immunological disorders.

How cargo is transported in the cell

In a large and busy port, systems are required to ensure that the correct cargo is shipped to the correct destination at the right time. The cell, with its different compartments called organelles, faces a similar problem: cells produce molecules such as hormones, neurotransmitters, cytokines and enzymes that have to be delivered to other places inside the cell, or exported out of the cell, at exactly the right moment. Timing and location are everything. Miniature bubble-like vesicles, surrounded by membranes, shuttle the cargo between organelles or fuse with the outer membrane of the cell and release their cargo to the outside. This is of major importance, as it triggers nerve activation in the case of transmitter substances, or controls metabolism in the case of hormones. How do these vesicles know where and when to deliver their cargo?

Traffic congestion reveals genetic controllers

Randy Schekman was fascinated by how the cell organizes its transport system and in the 1970s decided to study its genetic basis by using yeast as a model system. In a genetic screen, he identified yeast cells with defective transport machinery, giving rise to a situation resembling a poorly planned public transport system. Vesicles piled up in certain parts of the cell. He found that the cause of this congestion was genetic and went on to identify the mutated genes. Schekman identified three classes of genes that control different facets of the cell´s transport system, thereby providing new insights into the tightly regulated machinery that mediates vesicle transport in the cell.

Docking with precision

James Rothman was also intrigued by the nature of the cell´s transport system. When studying vesicle transport in mammalian cells in the 1980s and 1990s, Rothman discovered that a protein complex enables vesicles to dock and fuse with their target membranes. In the fusion process, proteins on the vesicles and target membranes bind to each other like the two sides of a zipper. The fact that there are many such proteins and that they bind only in specific combinations ensures that cargo is delivered to a precise location. The same principle operates inside the cell and when a vesicle binds to the cell´s outer membrane to release its contents.
It turned out that some of the genes Schekman had discovered in yeast coded for proteins corresponding to those Rothman identified in mammals, revealing an ancient evolutionary origin of the transport system. Collectively, they mapped critical components of the cell´s transport machinery.

Timing is everything

Thomas Südhof was interested in how nerve cells communicate with one another in the brain. The signalling molecules, neurotransmitters, are released from vesicles that fuse with the outer membrane of nerve cells by using the machinery discovered by Rothman and Schekman. But these vesicles are only allowed to release their contents when the nerve cell signals to its neighbours. How is this release controlled in such a precise manner? Calcium ions were known to be involved in this process and in the 1990s, Südhof searched for calcium sensitive proteins in nerve cells. He identified molecular machinery that responds to an influx of calcium ions and directs neighbour proteins rapidly to bind vesicles to the outer membrane of the nerve cell. The zipper opens up and signal substances are released. Südhof´s discovery explained how temporal precision is achieved and how vesicles´ contents can be released on command.

Vesicle transport gives insight into disease processes

The three Nobel Laureates have discovered a fundamental process in cell physiology. These discoveries have had a major impact on our understanding of how cargo is delivered with timing and precision within and outside the cell.  Vesicle transport and fusion operate, with the same general principles, in organisms as different as yeast and man. The system is critical for a variety of physiological processes in which vesicle fusion must be controlled, ranging from signalling in the brain to release of hormones and immune cytokines. Defective vesicle transport occurs in a variety of diseases including a number of neurological and immunological disorders, as well as in diabetes. Without this wonderfully precise organization, the cell would lapse into chaos.

James E. Rothman was born 1950 in Haverhill, Massachusetts, USA. He received his PhD from Harvard Medical School in 1976, was a postdoctoral fellow at Massachusetts Institute of Technology, and moved in 1978 to Stanford University in California, where he started his research on the vesicles of the cell. Rothman has also worked at Princeton University, Memorial Sloan-Kettering Cancer Institute and Columbia University. In 2008, he joined the faculty of Yale University in New Haven, Connecticut, USA, where he is currently Professor and Chairman in the Department of Cell Biology.
Randy W. Schekman was born 1948 in St Paul, Minnesota, USA, studied at the University of California in Los Angeles and at Stanford University, where he obtained his PhD in 1974 under the supervision of Arthur Kornberg (Nobel Prize 1959) and in the same department that Rothman joined a few years later. In 1976, Schekman joined the faculty of the University of California at Berkeley, where he is currently Professor in the Department of Molecular and Cell biology. Schekman is also an investigator of Howard Hughes Medical Institute.
Thomas C. Südhof was born in 1955 in Göttingen, Germany. He studied at the Georg-August-Universität in Göttingen, where he received an MD in 1982 and a Doctorate in neurochemistry the same year. In 1983, he moved to the University of Texas Southwestern Medical Center in Dallas, Texas, USA, as a postdoctoral fellow with Michael Brown and Joseph Goldstein (who shared the 1985 Nobel Prize in Physiology or Medicine). Südhof became an investigator of Howard Hughes Medical Institute in 1991 and was appointed Professor of Molecular and Cellular Physiology at Stanford University in 2008.

Key publications:

Novick P, Schekman R: Secretion and cell-surface growth are blocked in a temperature-sensitive mutant of Saccharomyces cerevisiae. Proc Natl Acad Sci USA 1979; 76:1858-1862.

Balch WE, Dunphy WG, Braell WA, Rothman JE: Reconstitution of the transport of protein between successive compartments of the Golgi measured by the coupled incorporation of N-acetylglucosamine. Cell 1984; 39:405-416.

Kaiser CA, Schekman R: Distinct sets of SEC genes govern transport vesicle formation and fusion early in the secretory pathway. Cell 1990; 61:723-733.

Perin MS, Fried VA, Mignery GA, Jahn R, Südhof TC: Phospholipid binding by a synaptic vesicle protein homologous to the regulatory region of protein kinase C. Nature 1990; 345:260-263.

Sollner T, Whiteheart W, Brunner M, Erdjument-Bromage H, Geromanos S, Tempst P, Rothman JE: SNAP receptor implicated in vesicle targeting and fusion. Nature 1993; 362:318-324.

Hata Y, Slaughter CA, Südhof TC: Synaptic vesicle fusion complex contains unc-18 homologue bound to syntaxin. Nature 1993; 366:347-351.