2 Americans Win Nobel in Chemistry for Work on How Humans Sense the World

美國兩位科學家分享諾貝爾化學獎

KENNETH CHANG 2012年10月15日

兩位美國人分享了今年的諾貝爾化學獎，他們破解了人體通訊系統的秘密，即身體如何感知外部世界，並向細胞發送信息，例如在危險臨近時會加速心跳。這項成果有助於新藥物的開發。

這兩位諾貝爾獎得主，一位是北卡羅來納州杜克大學醫學中心 (Duke University Medical Center)教授、69歲的羅伯特·J·萊夫科維茨(Robert J. Lefkowitz)博士，另一位是加州斯坦福大學醫學院教授、57歲的布萊恩·K·科比爾卡(Brian K. Kobilka)博士。他們的研究填補了細胞如何運作並對外界信號作出反應方面認識上的空白。

• 檢視大圖
  Left, Duke University; right, Stanford University
  羅伯特·J·萊夫科維茨博士（左）和布萊恩·K·科比爾卡博士在本周三贏得了諾貝爾化學獎。

科學家們此前已經知道，應激激素，例如腎上腺素，會引發人體的戰逃反應，使視域縮小，呼吸加快，減少不太迫切的身體器官如消化道的血液供應。但是腎上腺素並不進入細胞。

“有某種受體參與了此過程，這種假說是正確的。”諾貝爾化學獎評審委員會成員斯文·利丁(Sven Lidin)本周三在新聞發佈會上說，“但是這種受體是何種性質，及其如何進行反應，長期以來一直是個謎。”

萊夫科維茨博士說，儘管細胞受體的概念可以追溯到一個多世 紀以前，“但當我在20世紀70年代早期開始這一領域的研究時，學術界對是否存在受體仍有許多懷疑。”通過將放射性的碘同位素附着在一個激素上，萊夫科維 茨博士能夠追蹤激素的運動，並探索這些受體的行為。經過多年的研究，他已能夠提取受體蛋白質，並證明它們是一些特定的分子。

在20世紀80年代，他的團隊尋找並發現了生產一種這類蛋 白質受體的基因，那時的科比爾卡博士是該團隊中的一名博士後研究員。該基因的藍圖顯示，這種蛋白質呈螺旋狀，迂迴穿過細胞壁七次。與此同時，其他研究人員 在細胞內發現了一個新的蛋白質家族——G蛋白質。當這種蛋白質被激活時，將會引發一系列分子的魯布·哥德堡式的連鎖反應（Rube Goldberg cascade，指一個精密的機械聯動系統，譯註）。

受體是最後一個缺失環節。“如果身體釋放腎上腺素之類物質，激素達到細胞，轉動鑰匙，改變受體的形狀；受體改變了形狀之後，就可以觸發G蛋白質。” 萊夫科維茨博士說。

萊夫科維茨博士說，他意識到他研究的受體與已經在人體其他部位發現的另種一受體——視網膜上的感光體視紫紅質——一樣。那一刻，他靈機一動。“當時，我們想，‘等一下，或許與G蛋白質偶聯的那東西看起來也是這樣子，’”他說。

在一年之內，他們又破解了其他幾個類似受體的基因藍圖。他們想對了。

目前已知有約1000種這類受體，被稱為G蛋白偶聯受體(G protein-coupled receptor)，它們駐留在細胞表面，對激素和神經遞質的宿主作出反應。

瑞典皇家科學院(Royal Swedish Academy of Sciences)的利丁博士說，事實證明，半數的藥物都是針對這些受體起作用的。

科比爾卡博士搬到斯坦福大學後，開始了確定受體三維結構的研究，這需要構建一個蛋白質的晶型模型，並通過X射線反射研究其結構。去年，他和他的研究小組在受體把細胞外信號傳遞給細胞內蛋白質的那個瞬間，發現了受體的機構。

知道了不同受體的形狀，就可以改進藥物的設計。現在，很多藥劑分子不僅附着在細胞的預定目標上，也會附着其他受體，從而產生副作用。

“我們希望，通過了解其三維模型結構，我們可以開發更具選擇性的藥物，以及更有效的藥物。” 科比爾卡博士說。

翻譯：林蒙克

2 Americans Win Nobel in Chemistry for Work on How Humans Sense the World

By KENNETH CHANG October 15, 2012

Two Americans shared this year’s Nobel Prize in Chemistry for deciphering the communication system that the human body uses to sense the outside world and send messages to cells — for example, speeding the heart when danger approaches. The understanding is aiding the development of new drugs.

The winners, Dr. Robert J. Lefkowitz, 69, a professor at Duke University Medical Center in Durham, N.C., and a Howard Hughes Medical Institute researcher, and Dr. Brian K. Kobilka, 57, a professor at the Stanford University School of Medicine in California, filled in a major gap in the understanding how cells work and respond to outside signals.

• 檢視大圖
  Left, Duke University; right, Stanford University
  Dr. Robert J. Lefkowitz, left, and Dr. Brian K. Kobilka won the Nobel Prize in Chemistry on Wednesday.

Scientists already knew, for example, that stress hormones like adrenaline trigger the body’s fight-or-flight reflex — focusing vision, quickening breathing, diverting blood away from less urgent body systems like the digestive tract — but adrenaline never enters the cells.

“A receptor was correctly assumed to be involved,” said Sven Lidin, a member of the Nobel Prize committee for chemistry during a news conference on Wednesday, “but the nature of this receptor and how it reacted remained a mystery for a long time.”

Dr. Lefkowitz said that although the notion of cell receptors went back more than a century, “when I kind of started my work in the area in the early ’70s, there was still a lot of skepticism as to whether there really was such a thing.” By attaching radioactive iodine to a hormone, Dr. Lefkowitz was able to track the movement of the hormone and explore the behavior of these receptors. Over the years, he was able to pull out the receptor proteins and show they were specific molecules.

In the 1980s, his group, which included Dr. Kobilka as a postdoctoral researcher, searched for and found the gene that produced one of these protein receptors. The genetic blueprint indicated that the shape of the protein included long spirals that wove through the cell membrane seven times. Meanwhile, other researchers had discovered a class of proteins, called G proteins, inside the cell that, when activated, set off a Rube Goldberg cascade of molecular machinery.

The receptor was the last missing piece. “If you have something like adrenaline, it sticks in there, turns the key, changes the shape of the receptor, and now the receptor, having changed shape, is able to tickle the G protein,” Dr. Lefkowitz said.

There was a “eureka moment,” Dr. Lefkowitz said, when he realized that his receptor was the same as another receptor that had been found in another part of the body — the light receptor rhodopsin in the retina. “We said, ‘Well, wait a moment, maybe anything which couples to a G protein looks like this,’ ” he said.

Within a year, they were able to decode the genetic blueprints for several other similar receptors, and they were right.

About 1,000 of these receptors, known as G protein-coupled receptors, are now known, residing on the surface of cells and reacting to a host of hormones and neurotransmitters.

Dr. Lidin of the Royal Swedish Academy said that it turned out that half of all drugs target such receptors.

Dr. Kobilka, who moved to Stanford, then set out to determine the three-dimensional structure of the receptor, which requires building a crystal out of the proteins and then deducing the structure by bouncing X-rays off it. Last year, he and his research group were able to get an image of a receptor at the moment it was transferring a signal from the outside of the cell to a protein on the inside.

Knowledge about the shapes of different receptors could refine drug design. Many drug molecules attach to cells not only at the intended target but also to other receptors, causing side effects.

“We hope by knowing the three-dimensional structure we might be able to develop more selective drugs and more effective drugs,” Dr. Kobilka said.