生物學 1961

蛋白質合成中的遺傳調控機制

弗朗索瓦·雅各布與雅克·莫諾

基因能彼此開關——細胞有選擇地讀取自己的 DNA。

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In depth · the introduction

你身上的每一個細胞都攜帶著相同的 DNA——那為什麼神經細胞和皮膚細胞如此不同？因為基因能彼此開關。

核心想法

雅各布與莫諾琢磨的，是一個樸素的問題：細菌怎麼知道，只有在周圍真的有奶糖時，才去製造消化奶糖的酶？答案，原來是一種直接嵌在 DNA 裡的分子開關。

他們證明，有些基因根本不是蛋白質的藍圖——而是控制器。一個「調節」基因，會造出一個小小的蛋白質，即阻遏蛋白；它會坐到 DNA 上一段叫作操縱基因的區段上，就像一隻手按在開關上。只要它坐在那兒，旁邊的基因就被壓住、噤聲。可一旦合適的信號分子出現，它便抓住阻遏蛋白、把它拉開——基因於是驟然活躍起來。這一整個被控制的基因簇，他們命名為操縱子。

它是如何誕生的

在巴黎的巴斯德研究所，弗朗索瓦·雅各布與雅克·莫諾一直在追逐兩個看似毫不相干的謎題——細菌為何會突然開始製造一種消化酶，以及一種潛伏在細菌體內的休眠病毒，如何決定何時甦醒。經過多年精巧的遺傳雜交，往往還有同事阿瑟·帕迪的參與，他們意識到：兩者其實是同一個故事——一個阻遏蛋白把基因關著，直到一個信號把它釋放。

他們 1961 年的這篇綜述，把這一切匯成一個優雅的模型。它還作出一個大膽的旁證預言：基因並不直接造蛋白質，而是先謄出一份短命的工作副本——也就是我們今天所說的信使 RNA——再由細胞的蛋白質工廠去讀它。這兩個想法都成了奠基之論；1965 年，雅各布、莫諾與安德烈·勒沃夫，分享了諾貝爾獎。

它為何重要

在此之前，基因被想像成一份靜態的指令清單。雅各布與莫諾卻表明：這份清單同時也是一套程序——細胞時時刻刻都在決定，該去讀哪些指令。僅此一個轉變，就解釋了：為什麼一枚受精卵、只帶著一套基因組，卻能長成一個擁有數百種細胞類型的生命體，而每一種細胞都在讀著不同的一頁。這是我們理解「發育」的概念之根，也是理解「一個癌細胞，是一套出了錯的控制系統」的根。

一個可以想像的畫面

把操縱子想像成一盞由人體感應器控制的燈。燈（結構基因）只想在有人進屋時才亮起來。阻遏蛋白，就是一塊貼在開關上的蓋子，把它按在「關」上。信號分子——對細菌來說，就是奶糖——則是那個走進來的人：它把蓋子掀開，燈就亮了。人一走出去，蓋子又落回原處，燈隨之熄滅。細胞，絕不為自己用不上的酶白費一分氣力。

它的位置

這項工作站在 DNA 結構（沃森與克里克，也在本館）之上——它追問的是：細胞拿這份信息做什麼。它給了生物學「信使 RNA」這個概念，那個攜帶基因信息的分子，數十年後成了 mRNA 疫苗的基礎。它還推開了後續一切的門：人們發現，人類的基因，是由遠為繁複的機器來開關的；它也通向合成生物學——今天，科學家正用雅各布與莫諾所命名的那些零件，親手搭建自己的遺傳開關。

The original document

Original source text

摘要——一種雙重的遺傳控制

François Jacob & Jacques Monod · J. Mol. Biol. 3 (1961): 318–356 · received 28 December 1960

The synthesis of enzymes in bacteria follows a double genetic control. The so-called structural genes determine the molecular organization of the proteins. Other, functionally specialized, genetic determinants, called regulator and operator genes, control the rate of protein synthesis through the intermediacy of cytoplasmic components or repressors.

The repressors can be either inactivated (induction) or activated (repression) by certain specific metabolites. This system of regulation appears to operate directly at the level of the synthesis by the gene of a short-lived intermediate, or messenger, which becomes associated with the ribosomes where protein synthesis takes place.

導言——越過結構基因

1. Introduction

According to its most widely accepted modern connotation, the word “gene” designates a DNA molecule whose specific self-replicating structure can, through mechanisms unknown, become translated into the specific structure of a polypeptide chain.

It has been known for a long time, however, that the synthesis of individual proteins may be provoked or suppressed within a cell, under the influence of specific external agents, and more generally that the relative rates at which different proteins are synthesized may be profoundly altered, depending on external conditions.

[ … ]

The elective effects of agents other than the structural gene itself in promoting or suppressing the synthesis of a protein must then be described as operations which control the rate of transfer of structural information from gene to protein.

操縱基因與操縱子

4. The Operator and the Operon

The specificity of operation of the repressor implies that it acts by forming a stereospecific combination with a constituent of the system possessing the proper (complementary) molecular configuration. … This controlling element we shall call the “operator” (Jacob & Monod, 1959).

This genetic unit of co-ordinate expression we shall call the “operon.”

It is clear that when an operator controls the expression of only a single structural cistron, the concept of the operon does not apply … It is tempting to predict that such proteins will often be found to be controlled by two (or more) adjacent and co-ordinated structural cistrons, forming an operon.

總論——一套協調的程序

6. Conclusion

The synthesis of the messenger by the structural gene is a sequential replicative process, which can be initiated only at certain points on the DNA strand, and the cytoplasmic transcription of several, linked, structural genes may depend upon a single initiating point or operator. The genes whose activity is thus co-ordinated form an operon.

The fundamental problem of chemical physiology and of embryology is to understand why tissue cells do not all express, all the time, all the potentialities inherent in their genome. The survival of the organism requires that many, and, in some tissues most, of these potentialities be unexpressed, that is to say repressed.

The discovery of regulator and operator genes, and of repressive regulation of the activity of structural genes, reveals that the genome contains not only a series of blue-prints, but a co-ordinated program of protein synthesis and the means of controlling its execution.

François Jacob & Jacques Monod · Institut Pasteur, Paris · received 28 December 1960