Nobel Prize in Physiology or Medicine: François Jacob with André Lwoff and Jacques Monod in 1965
Notes de la rédaction
Excerpts from the Nobel Lecture delivered on 11 December 1965
Copyright © The Nobel Foundation
Source: La lettre, no. 35, December 2012
1Having thus constructed the requisite genetic tool for our analysis, we set out to isolate under different conditions a whole series of mutants constitutive for the lactose system, in order to subject them to functional analysis. These mutants proved to belong to two quite distinct groups, which possessed the predicted properties for the transmitter and the receiver, respectively. Many of these mutations were found to be “recessive” with respect to the wild-type allele. They allowed a definition of the transmitter, that is, of the regulatory gene.
2In the second group, the mutations turned out to be “dominant” over the wild-type allele, and only those genes which were located on the same chromosome, that is, in cis position, were expressed constitutively. With these mutations, it was possible to define the receptor of the repressor, termed the operator.
3The study of these mutants led, furthermore, to the notion that in bacteria the genetic material is organized into units of activity called operons, which are often more complex than the gene considered as the unit of function. In fact, the lactose system of E. coli contains three known proteins, and the three genes governing their structure are adjacent to one another on a small segment of the chromosome with the operator at one end. Constitutive mutations, whether due to the alteration of the regulatory gene or of the operator, always display the remarkable property of being pleiotropic; that is, they affect simultaneously, and to the same extent, the production of the three proteins. The regulatory circuit therefore had to act on one integral structure containing the information which specifies the amino acid sequences of the three proteins. This structure could only be either the DNA itself or a messenger common to the three genes. This idea was further supported by the properties observed in mutations affecting the structural genes of the lactose system. Whereas some of these mutations obey Beadle and Tatum’s “one gene-one enzyme” rule in the sense that they abolish only one of the three biochemical activities, others violate this rule by affecting the expression of several genes at a time.
4The notion of the operon, a grouping of adjacent structural genes controlled by a common operator, explained why the genes controlling the enzymes of the same biochemical pathway tend to remain clustered in bacteria, as observed by Demerec and Hartman. Similarly, it accounted for the coordinate production of enzymes already found in certain biochemical pathways. Although at first the operon concept was based exclusively on genetic criteria, it now includes biochemical criteria as well. There are, in fact, a number of experimental arguments, both genetics and biochemical, in support of the inference that an operon produces a single messenger, which binds to ribosomes to form the series of peptide chains determined by the different structural genes of the operon.
5We can therefore envision the activity of the genome of E. coli as follows. The expression of the genetic material requires a continuous flow of unstable messengers which dictate to the ribosomal machinery the specificity of the proteins to be made. The genetic material consists of operons containing one or more genes, each operon giving rise to one messenger. The production of messenger by the operon is, in one way or another, inhibited by regulatory loops composed of three elements: regulatory gene, repressor, operator. Specific metabolites intervene at the level of these loops to play their role as signals: in inducible systems, to inactivate the repressor and hence allow production of messenger and ultimately of proteins; in repressible systems, to activate the repressor, and hence inhibit production of messenger and of proteins. According to this scheme, only a fraction of the genes of the cell can be expressed at any moment, while the others remain repressed. The network of specific, genetically determined circuits selects at any given time the segments of DNA that are to be transcribed into messenger and consequently translated into proteins, as a function of the chemical signals coming from the cytoplasm and from the environment.
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