Researchers Show Mechanism And Similarities Of Biological Clocks

June 05, 1998

Scientists picking apart the inner workings of the biological clocks that govern the daily cycles of life have now identified several key cogs of the machinery and have shown that these main parts are remarkably similar between invertebrates and mammals.

In the June 5 issue of Science, one team describes the working parts that drive the clock in mice forward like a watch spring, and in another paper another team for the first time identifies the gene in fruit flies that corresponds to the mammalian Clock gene and shows how it can turn itself off again, enabling it to oscillate like a pendulum.

"We always thought that circadian clocks might work the same way in different organisms, but this is really the first evidence -- with the same genes playing the same role in flies and mice," says Joseph S. Takahashi, professor of neurobiology and physiology at Northwestern University, who is an author on both papers and last year was the first to clone the mammalian clock gene.

"We now have three different circadian clock genes that are conserved between insects and mammals," Takahashi said. "These genes define a surprisingly simple and elegant feedback loop of gene activation and inhibition that composes the core mechanism of the clock in animals."

In the first paper, Charles Weitz and coworkers at Harvard Medical School, with Takahashi's group at Northwestern, searched for and identified a protein molecule that can bind to the protein, CLOCK, produced by the mouse Clock gene. This protein molecule, called BMAL1, is produced at the same time and in the same regions of the brain as the CLOCK protein.

The CLOCK-BMAL1 pair, they showed, is capable of binding to and turning on a genetic switch that regulates another gene, which is called mper-1 because it is the mammalian version of the period gene, which is required for circadian rhythm in flies.

"We think this 'on' mechanism accounts for the positive component of the oscillation that drives the circadian rhythm," Takahashi said.

The backward swing of the pendulum -- an "off" genetic switch -- was found by a group tinkering with the clockwork in fruit flies. That team, headed by Steve A. Kay at Scripps Research Institute, in collaboration with Takahashi's and Weitz's laboratories, showed that the fly's CLOCK protein teams up with a fly version of BMAL to bind to the genetic switch and turn on production of the proteins PERIOD and TIMELESS. These latter two proteins, they showed, were an "off" switch that blocked the ability of the CLOCK-BMAL pair to activate the genes for PERIOD and TIMELESS production -- a finding that "closed the circadian loop," according to the authors, and accounted for the on-again/off-again genetic oscillation.

Circadian (Latin for "around the day") clocks regulate daily activities such as sleep and wakefulness. Difficulty in readjusting our clocks causes jet lag and shift work problems, as well as some types of sleep disorders. The clock may also explain why heart attacks occur more often in the morning and asthma flare-ups more often at night.

Some neurobiologists believe that higher species evolved more specialized mechanisms built around the ancient "core oscillator." These accessories would allow an organism to harness the clock to suit to its own needs and changing conditions of light or temperature.

Other authors on the two Science papers are Thomas K. Darlington, Karen Wager-Smith and M. Fernanda Geriani from Scripps; Nicholas Gekakis, David Staknis and Hubert B. Nguyen from Harvard; Fred C. Davis from Northeastern University; and Thomas D.L. Steeves, Lisa D. Wilsbacher and David P. King from Northwestern.

The research at Northwestern was funded by the NSF Center for Biological Timing and the National Institutes of Health. Takahashi is a researcher in the Howard Hughes Medical Institute.

Northwestern University

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