François Jacob

The study of these mutants would further lead to the realization that, in bacteria, genetic material is organized into functional units known as operons, which are often more complex than the gene, which is typically considered the basic unit of function. In fact, the lactose system of E. coli comprises three known proteins, and the three genes governing the structure of these proteins are adjacent on a small segment of the chromosome, with the operator located at one end of this segment. However, constitutive mutations—whether due to damage to the regulatory gene or to the operator—always exhibit the remarkable property of being pleiotropic, meaning that they simultaneously affect the production of all three proteins to the same degree. It therefore followed that the regulatory circuit must act on an integral structure containing the information that specifies the structure of the three proteins. This structure could only be the DNA itself, or a messenger common to all three genes. This concept was further supported by the properties observed in mutations affecting the structural genes of the lactose system. While some of these mutations follow Beadle and Tatum’s “one gene, one enzyme” rule—in that they abolish only one of the three biochemical activities—other mutations, on the contrary, violate this rule because they affect the expression not of a single gene, but of several at once.

The concept of the operon—a cluster of adjacent structural genes whose regulation is controlled by a common operator—explained why genes governing enzymes in the same biochemical pathway tend to remain clustered in bacteria, as Demerec and Hartman had observed. It also accounted for the coordinated production of enzymes already observed in certain biosynthetic pathways. While the concept of the operon was originally based exclusively on genetic criteria, it is now supplemented by biochemical criteria. Indeed, there are numerous experimental arguments, both genetic and biochemical, suggesting that an operon produces a single messenger RNA molecule that binds to ribosomes to form the series of peptide chains determined by the various structural genes of the operon.

Thus, we can conceptualize the activity of the E. coli genome as follows. The expression of genetic material requires a continuous flow of unstable mRNAs that dictate to the ribosomal machinery the specific proteins to be produced. The genetic material consists of operons containing one or more genes, with each operon forming a single mRNA. Messenger production by the operon is, in one way or another, inhibited by regulatory loops consisting of three elements: regulatory gene—repressor—operator. It is at the level of these loops that specific metabolites act as signals: in inducible systems, to inactivate the repressor, thereby allowing the production of messenger RNA and, consequently, proteins; in repressible systems, to activate the repressor, thereby inhibiting the production of messenger RNA and proteins. According to this model, only a fraction of the cell’s genes can be expressed at any given time, while the rest remain repressed. It is a network of specific, genetically determined circuits that selects, at any given moment, which segments of DNA are to be transcribed into messenger RNA—and thus translated into proteins—based on chemical signals from the cytoplasm and the environment.

---

Excerpts from the Nobel Lecture delivered on December 11, 1965
(Copyright © The Nobel Foundation)

Source: article excerpted from *The Collège de France Newsletter* No. 35