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Molecular Biology 1961

Genetic Regulatory Mechanisms in the Synthesis of Proteins

François Jacob & Jacques Monod

A gene can be switched off — a repressor sits on an 'operator' and silences a whole block of genes at once.

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In depth · the introduction

Why does a cell carry thousands of genes but switch most of them off? In 1961, two scientists in Paris worked out how the switch is built — from a sugar and a sleeping virus.

The idea

A cell doesn't read all its genes at once. It keeps most of them off and turns on only the ones it needs right now. Jacob and Monod found the mechanism: a special protein called a repressor parks on a spot of DNA — the operator — like a hand held over a switch, keeping a nearby group of genes silent.

When the cell needs those genes, a small signal molecule sticks to the repressor and pulls its hand off the switch. The genes — a whole block of them, controlled together — come on at once. They called that block an operon. Turning genes on, in this picture, is really just stopping the thing that was keeping them off.

How it came about

At the Institut Pasteur, François Jacob and Jacques Monod were chasing two mysteries that seemed unrelated. One: the gut bacterium E. coli makes the enzyme to digest milk-sugar only when milk-sugar is around. The other: a virus can hide inside a bacterium for generations, silent, then suddenly wake up. Jacob and Monod had a hunch they were the same trick — a gene held shut, then let go.

A clever experiment (now nicknamed PaJaMo, after Pardee, Jacob and Monod) showed that the 'off' signal was a substance already floating in the cell, made by one gene to govern others. From a wall of genetic crosses, the two of them reasoned out the whole circuit — repressor, operator, operon — years before anyone could hold those molecules in their hands. Monod liked to say that what is true for the humble E. coli is true for the elephant: the same logic, scaled up.

Why it mattered

Before this paper, nobody knew how a cell chooses which genes to use. After it, gene regulation had a vocabulary and a mechanism, and it was beautifully simple: genes are wired to switches, and switches respond to signals. Every cell in your body carries the same DNA, yet a brain cell and a skin cell are utterly different — because each reads a different subset of genes. The operon was the first clear picture of how that choosing works.

An analogy

Think of a row of lights wired to one switch, and a security guard standing on that switch with his foot, holding it off. That guard is the repressor; the switch is the operator; the lights are the operon's genes. Now someone hands the guard a cup of coffee (the inducer). He reaches for it, lifts his foot — and the whole row of lights comes on together. Take the coffee away and his foot drops back: lights off. The cell turns genes on not by pressing a button, but by distracting the guard who was holding the button down.

A diagram of the lac operon with a slider for the inducer; turning it up lifts the repressor off the operator and switches the three genes on together, while a readout shows how strongly the genes are being expressed.

Where it sits

It picks up where the genetic code leaves off. Watson and Crick (1953) showed how DNA is structured; Crick (1958) set out how a gene's sequence becomes a protein. But a recipe book is not a meal — something must decide which recipes get cooked, and when. Jacob and Monod supplied that missing layer, and in the same year helped pin down the messenger RNA that carries each order to the kitchen. The control circuits they sketched are the ancestors of today's synthetic biology, where engineers wire repressors together to build switches and clocks inside living cells.

The original document
Original source text
F. Jacob & J. Monod · Journal of Molecular Biology 3 (1961), 318–356 · Services de Biochimie Cellulaire et de Génétique Microbienne, Institut Pasteur, Paris
Structural genes and regulator genes
The review opens by splitting the genome's labour in two. Some genes — the structural genes — carry the sequence of a protein: in the lactose system of E. coli these are z, y and a, specifying β-galactosidase, a galactoside permease and a transacetylase. Other genes do nothing but govern: a regulator gene makes a diffusible product whose only function is to control whether the structural genes are read.
The repressor and the operator
That regulatory product is named the repressor. In the absence of an inducer it keeps the structural genes silent — not by acting on each gene, but by binding a single controlling site on the DNA, the operator, that sits at one end of the cluster. Genetics had already pointed the way: operator-constitutive mutants escape control and express the genes whatever the conditions, and they act only on the genes physically next to them on the same chromosome.
The operon
The operator together with the block of structural genes it commands is proposed as a single unit of coordinated expression — christened the operon. Because the whole block is governed through one operator, its genes are switched on and off together; this is why the three lactose enzymes rise and fall in concert.
Induction as derepression
Induction, the paper argues, is simply the lifting of repression. The inducer is a small molecule that combines with the repressor and inactivates it; with the repressor disabled, the operator is freed and the operon is read. The logic is a double negative — the inducer represses the repressor — and it unifies enzyme induction with the mirror-image case of repression, where a small molecule instead activates a repressor to switch a pathway off.
The messenger
For the scheme to work, the structural genes' instructions must reach the protein-making machinery quickly and transiently. Jacob and Monod propose an unstable intermediate — a short-lived 'messenger' RNA, copied from the structural genes and carried to the comparatively stable ribosomes, present only while the operon is on. (The messenger was demonstrated experimentally the same year.)
[ … ]
What is left open
The review is candid that the chemical nature of the repressor is unknown, and that the model is built largely from genetics rather than from isolated molecules. It does not settle how the operator is recognised, nor prove that any of these objects could be purified — questions it hands, explicitly, to the experiments it provokes.
Institut Pasteur, Paris · 1961