Turned-Off Genes

Despite the great variety of cells present in any living organism, each one contains the same number and kinds of genes, the heredity-bearing components that determine the nature of the cell. But since the genes are identical in all the cells, why do some of the cells form hair, while others go to make up heart, liver, brain and so forth?

A possible answer was provided in 1961, when French Biologists Francois Jacob and Jacques Monod hypothesized that only a few genes in any cell were active in controlling the production of enzymes that gave the cell its characteristics. The remaining genes, they proposed, were deactivated --turned off by mysterious represser substances produced by other genes. Thus, the genes that are active in a hair cell may be turned off in a liver cell, where a different combination of genes is active.

Lactose Tracer. Although the brilliant concept of Jacob and Monod had become generally accepted by 1965, when it helped to win for them the Nobel Prize in Medicine, no one had ever been able to provide direct laboratory proof that their concept was correct. Now the evidence has begun to come in. Harvard University scientists have succeeded in isolating and analyzing two of the Hitherto theoretical substances that repress gene activity.

To isolate the represser, Biophysicist Walter Gilbert and Biochemist Benno Muller-Hill decided to work with a species of simple bacteria called Escherichia coli, which have a healthy appetite for lactose, a sugar found in milk. The scientists knew that when lactose was available, the bacteria cells produced an enzyme that broke the sugar down into two simpler sugars that the cells could use. When only other nutrients were present, however, the amount of this enzyme was drastically reduced; a repressor apparently turned off the gene that controlled its production.

The Harvard scientists devised their experiment on the premise that the lactose must have prevented the represser from turning off the appropriate gene --probably because it was attracted by the represser and combined with it chemically. With a sophisticated technique, they allowed radioactive lactose-like molecules that served as tracers to be attracted by a concentrate of bacteria cell material. Isolating and analyzing the substance that had combined with the tracer molecules, they discovered that it was a large protein molecule -- their long-sought "lactose represser."

Bursting Bacteria. In an equally complex experiment with the same type of bacteria cells, Harvard Molecular Biologist Mark Ptashne discovered a second represser -- a smaller protein molecule that prevents the bacteria from bursting when they are attacked by viruses. Ptashne's experiment also indicated that the represser turned off the appropriate cell genes by binding itself tightly to them, somehow preventing the production of an enzyme in the process.

The two discoveries, says Biophysicist Gilbert, confirm that cells of E. coli are controlled by gene-repressing agents and effectively demonstrate how simple cell mechanisms work. They may bring closer the day when scientists will be capable of genetic control of human beings, determining their characteristics and correcting metabolic defects by turning the proper genes on and off.

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