Francois Jacob

Francois Jacob and Jaques Monod[?] (circa 1961) originated the idea that control of enzyme levels in all cells happens through feedback on transcription. Their experiments and ideas gave rise to the large field of regulatory biology, and of transcriptional regulation in particular.

For many years it had been known that bacterial and other cells could respond to external conditions by regulating levels of their key metabolic enzymes, and/or the activity of these enzymes. For instance if a bacterium finds itself in a broth containing lactose, rather than the simpler sugar glucose, it has to adapt itself to the need to 1) import lactose, 2) cleave lactose to its constituents glucose and galactose, and 3) convert galactose to glucose. It was known that cells ramp up their production of the enzymes that do these steps when exposed to lactose, rather than wastefully producing these enzymes all the time. Studies of enzyme activity control were progressing through theories of the (allosteric) action of small molecules on the enzyme molecule itself (switching it on or off), but how the production of enzymes themselves were controlled was less easy to understand.

With the earlier determination of the structure and central importance of DNA, it became clear that all proteins were being produced in some way from its genetic code, and that this step might form a key control point. Jacob and Monod made key experimental and theoretical discoveries that demonstrated that in the case of the lactose system outlined above (in the bacterium E. coli), there are specific proteins that are devoted to repressing the transcription of the DNA to its product (RNA, which in turn is decoded into protein).

This repressor (the lac repressor) is made in all cells, binds directly to DNA at the genes it controls, and physically prevents the transcription apparatus from gaining access to the DNA. In the presence of lactose, this repressor binds lactose, making it no longer able to bind to DNA, and the transcriptional repression is lifted. In this way, a robust feedback loop is constructed that allows the set of lactose-digesting proteins products to be made only when they are needed.

Jacob and Monod somewhat recklessly extended this repressor model to all genes in all organisms, in their initial exuberance. The fact is that the regulation of gene activity has developed into a very large sub-discipline of molecular biology, and exhibits enormous variety in mechanism and many levels of complexity. Current researchers find regulatory events at every conceivable level of the processes that express genetic information. In the relatively simple genome of baker's yeast, (Saccharomyces cerevisiae), 405 of its 6,419 protein-encoding genes are directly involved in transcriptional control, compared to 1,938 that are enzymes.