Nov. 24, 1998 WALTHAM, Mass. -- For the first time, scientists have identified a protein that uses natural light to set circadian rhythms -- and the protein, found in species ranging from microbes to fruit flies to humans, isn't one that most researchers had expected to play a role in programming organisms' internal clockwork. The findings, reported by Brandeis University biologists Michael Rosbash and Jeffrey Hall in this week's issue of the journal Cell, answer a key question about circadian rhythms by pinpointing the first molecular window through which external light can reset internal biological clocks.
"A functional biological clock has three components: input from the outside world to set the clock, the timekeeping mechanism itself, and genetic machinery that allows the clock to regulate expression of a variety of genes," says Hall, a professor of biology. "We now have a pretty good idea of how the first of these three parts works."
Rosbash and Hall fingered the clock-setting cryptochrome protein and its affiliated gene, cry, in work with fruit flies that slumber 12 to 16 hours a day, but both the gene and the protein have been remarkably well-conserved by evolution. There are two known cryptochromes in humans, Rosbash says; it's possible that these may work in concert with other photoreceptors to reset our biological clocks and those of our closest evolutionary brethren.
Hall says cryptochrome is almost certainly not the sole photoreceptor at work in setting circadian rhythms. "Cryptochrome harnesses the energy of incoming blue light, but other molecules are probably needed to absorb light of other colors," he says. Cryptochrome's penchant for blue light suggests it resets biological clocks at dawn and dusk's dimmest hours, when blue light is most abundant.
Cryptochrome hasn't been high on most researchers' lists of suspected circadian photoreceptors. In the world of circadian rhythms research, this light-sensitive protein -- better known in its plant-based incarnation -- has generally taken a back seat to rhodopsin, a photosensitive family of proteins found in the eyes of mammals. "Most researchers in the field have expected that the key light sensor for circadian rhythms would be rhodopsin, which appears to function in mammalian circadian rhythms," says Rosbash, a professor of biology and Howard Hughes Medical Institute investigator.
Cryptochrome evidently works on the front lines of circadian rhythms, which operate somewhat like a genetic chain letter linking a plethora of genes that are cyclical in their activity. When it detects light, cryptochrome begins to regulate a few choice clock genes, such as period and timeless, each of which in turn regulates a few more genes, and so on. Eventually, researchers suspect that many additional genes are affected by this orderly wave of activity.
It now appears that our bodies house not just one headquarters for maintaining circadian rhythms, says Hall, but rather a number of biological clocks scattered throughout the body. These clocks -- which, left unfettered, mete out a daily rhythm of about 24.5 hours -- need daily resetting to accurately regulate many rhythmic functions within the body.
The two biologists authored back-to-back papers in the Nov. 25 issue of Cell. The Rosbash lab's paper principally characterizes the wild-type form of the cry gene, while the Hall lab's examines its mutant variation. The two were joined in the research by Bonnie Beretta, Patrick Emery, Maki Kaneko, W. Venus So, and Ralf Stanewsky at Brandeis and by Steve A. Kay and Karen Wager-Smith at the Scripps Research Institute. The work was supported by the National Institutes of Health, the National Science Foundation's Center for Biological Timing, and the Swiss National Science Foundation.
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