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Feedback loops
How genomes mark time
Edward R. Winstead

The story of biological clocks has grown steadily more complex since the discovery of a gene in fruit flies that disrupts their normal sleep-wake cycle when mutated. That discovery was thirty years ago. This week, researchers propose a model for the core mechanism of the mammalian biological clock that suggests the most sophisticated molecular timepiece yet.

Mice have clocks that run on two biochemical "gears" that involve the interactions of seven genes and proteins, researchers write in the current issue of Science. Last year, a similar discovery was made in the fruit fly, but the mammalian clock was thought to run on a single gear, or feedback loop, that regulates the activity of certain genes throughout the day. Fluctuations in gene activity trigger a chain of events that results in physiological changes we call circadian rhythms.

This study takes a close look at a complicated set of gears. "The new thing here is taking these seven genes and trying to construct a picture of how molecular clocks work," says Steven M. Reppert of Harvard Medical School, who led the research. The mouse biological clock is widely thought to be a good model for the human version.

Indeed, the feedback loop appears to be a common feature of biological clocks in plants, bread mold, fruit flies, and mammals. And versions of the same clock genes have been identified in a variety of organisms, but the division of labor of these genes varies depending upon the genome. For instance, Reppert explains, the mouse clock uses the same collection of genes as the fruit fly but in different ways.

By further characterizing the feedback loops, the researchers hope to determine exactly what each gene does, making it feasible to attempt repairs on the human clock. "Some of these genes are potential drug targets," says Reppert. "By activating or inhibiting genes at various points in the loop, it may be possible to stop the clock and start it quickly."

In time, perhaps. Certainly many interesting questions about clocks remain. This study looked for the activity of clock genes outside the brain, where the master clock mechanism resides. To their surprise, the researchers found that many clock genes are expressed throughout the mouse. Why these peripheral oscillators exist is a mystery.

Beyond the genes in the feedback loops are others that help produce daily rhythms, including genes involved in resetting clocks and genes that transmit signals, letting other cells know what time it is. Reppert, for one, wouldn't be surprised to discover more genes that affect the core clock mechanism: "The more we look at this the more complex the story becomes."

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Shearman, L.P. et al. Interacting molecular loops in the mammalian circadian clock. Science 288, 1013-1019 (May 12, 2000).

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