The Runners-Up

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Science  18 Dec 1998:
Vol. 282, Issue 5397, pp. 2157-2161
DOI: 10.1126/science.282.5397.2157

Science recognizes nine discoveries that transform our ideas about the natural world and also offer potential benefits to society

Nineteenth-century philosophers proposed that God was a clockmaker who created the world and then let it run. Modern biologists might in part agree, for it's clear that evolution has carefully crafted clocks that allow almost all organisms to follow the rhythm of the sun. In 1998, a volley of rapid-fire discoveries revealed the stunning universality of the clock workings: Across the tree of life, from bacteria to humans, clocks use oscillating levels of proteins in feedback loops to keep time. Perhaps more amazing, fruit flies and mice—separated by nearly 700 million years of evolution—share the very same timekeeping proteins. Now that they better understand the cellular clock, scientists can begin to manipulate it, with applications from curing jet lag to brightening winter depression.

Lighting up.

Clock genes glow in the cells of a fruit fly.


Clocks made the Runner-Up list in 1997 too, after researchers identified the first two mammalian clock genes, Clock and per. This year a prodigious amount of work from the clock research community filled out the story dramatically. For example, work in fruit flies showed that during the morning hours, CLOCK binds to a protein partner and together they turn on genes for proteins called PER and TIM (Timeless). These two proteins eventually shut down their own genes.

But to keep the proteins on a 24-hour cycle, PER and TIM's turnoff must be delayed. This year researchers found the cause of that delay in flies: a protein called DOUBLETIME (DBT) that destabilizes PER, keeping its levels low until enough TIM accumulates to pair with PER and shield it from DBT. Only then do PER and TIM enter the nucleus to turn off their genes, causing levels of the two proteins to wane until morning, when CLOCK and its partner turn on the genes once again.

Discovering all this in one organism would be breakthrough enough, but researchers found the same proteins or close variants playing the same roles in mice, too. As reported in June, a negative feedback mechanism appears to power plant clocks as well, albeit with different genes. And in September, a Japanese team showed that the single-celled cyanobacteria's clock is based on the same theme.

Despite this elegant molecular machinery, circadian clocks are imperfect timekeepers: Left on their own, their daily cycles run longer or shorter than 24 hours. Light keeps them in line, like a daily adjustment of a watch. In July researchers showed how: Light causes the rapid destruction of TIM, at least in flies.

Researchers thought that, in mammals, eyes are required for the light signal to reach the clock. But in January a U.S. team made the shocking discovery that light shone on, of all places, the back of the knees seems to reset the clock in humans; several groups have now repeated that finding.

Capping a year of dramatic discoveries, in November researchers fingered three plant pigments that capture light and pass its signal to the clock; one seems to play the same role in animals. For clock researchers already pleased with the pace of findings in 1997, this year's double-quick barrage of discoveries has exceeded all expectations.

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