生物学 1961

蛋白质合成中的遗传调控机制

弗朗索瓦·雅各布与雅克·莫诺

基因能彼此开关——细胞有选择地读取自己的 DNA。

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In depth · the introduction

你身上的每一个细胞都携带着相同的 DNA——那为什么神经细胞和皮肤细胞如此不同？因为基因能彼此开关。

核心想法

雅各布与莫诺琢磨的，是一个朴素的问题：细菌怎么知道，只有在周围真的有奶糖时，才去制造消化奶糖的酶？答案，原来是一种直接嵌在 DNA 里的分子开关。

他们证明，有些基因根本不是蛋白质的蓝图——而是控制器。一个「调节」基因，会造出一个小小的蛋白质，即阻遏蛋白；它会坐到 DNA 上一段叫作操纵基因的区段上，就像一只手按在开关上。只要它坐在那儿，旁边的基因就被压住、噤声。可一旦合适的信号分子出现，它便抓住阻遏蛋白、把它拉开——基因于是骤然活跃起来。这一整个被控制的基因簇，他们命名为操纵子。

它是如何诞生的

在巴黎的巴斯德研究所，弗朗索瓦·雅各布与雅克·莫诺一直在追逐两个看似毫不相干的谜题——细菌为何会突然开始制造一种消化酶，以及一种潜伏在细菌体内的休眠病毒，如何决定何时苏醒。经过多年精巧的遗传杂交，往往还有同事阿瑟·帕迪的参与，他们意识到：两者其实是同一个故事——一个阻遏蛋白把基因关着，直到一个信号把它释放。

他们 1961 年的这篇综述，把这一切汇成一个优雅的模型。它还作出一个大胆的旁证预言：基因并不直接造蛋白质，而是先誊出一份短命的工作副本——也就是我们今天所说的信使 RNA——再由细胞的蛋白质工厂去读它。这两个想法都成了奠基之论；1965 年，雅各布、莫诺与安德烈·勒沃夫，分享了诺贝尔奖。

它为何重要

在此之前，基因被想象成一份静态的指令清单。雅各布与莫诺却表明：这份清单同时也是一套程序——细胞时时刻刻都在决定，该去读哪些指令。仅此一个转变，就解释了：为什么一枚受精卵、只带着一套基因组，却能长成一个拥有数百种细胞类型的生命体，而每一种细胞都在读着不同的一页。这是我们理解「发育」的概念之根，也是理解「一个癌细胞，是一套出了错的控制系统」的根。

一个可以想象的画面

把操纵子想象成一盏由人体感应器控制的灯。灯（结构基因）只想在有人进屋时才亮起来。阻遏蛋白，就是一块贴在开关上的盖子，把它按在「关」上。信号分子——对细菌来说，就是奶糖——则是那个走进来的人：它把盖子掀开，灯就亮了。人一走出去，盖子又落回原处，灯随之熄灭。细胞，绝不为自己用不上的酶白费一分气力。

它的位置

这项工作站在 DNA 结构（沃森与克里克，也在本馆）之上——它追问的是：细胞拿这份信息做什么。它给了生物学「信使 RNA」这个概念，那个携带基因信息的分子，数十年后成了 mRNA 疫苗的基础。它还推开了后续一切的门：人们发现，人类的基因，是由远为繁复的机器来开关的；它也通向合成生物学——今天，科学家正用雅各布与莫诺所命名的那些零件，亲手搭建自己的遗传开关。

The original document

Original source text

摘要——一种双重的遗传控制

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.

导言——越过结构基因

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.

操纵基因与操纵子

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.

总论——一套协调的程序

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