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Biological Clocks No Longer Found Only in the Brain

La Jolla, CA, November 28, 1997 -- A recent discovery by a team of scientists at The Scripps Research Institute (TSRI) and Brandeis University challenges the strongly-held belief that 24-hour rhythms, or biological clocks, are centrally controlled from the brain. Using the fruit fly as a genetic model system to study circadian rhythms, the researchers, led by Steve Kay, Ph.D., Professor, Department of Cell Biology, TSRI, sought to determine if individual body parts would respond to changes in the light/dark cycle without any help from the head. As reported in the November 28 issue of Science, in each separately cultured segment, so-called clock genes turned on and off in unison, according to rhythms set by environmental light manipulations.

These findings demonstrate that time-keeping genes may be running in tissues all over the body and controlled locally in the flies and therefore possibly in mammals, as well. The scientists hope that understanding the location of such clocks in tissues and cells, as well as identifying which genes and proteins make up the biological process, will yield insights into human circadian rhythms that could lead to new strategies for the treatment of disorders associated with jet lag, shift work and seasonal depression.

According to Kay, "Our findings confirm that body clocks run independently in many tissues outside the brain and are reset by light, implying that cells harbor novel photoreceptors that aren't involved in vision."

To measure one of the genes that control clocks switching on and off in animals, called per for "period," the researchers borrowed some tricks from the world of bioluminescent organisms. They fused the fruit flies' per gene DNA to "glow" genes either from jellyfish or fireflies, to make glow-in-the-dark fruit flies. The researchers engineered a transgenic strain of flies that expressed luciferase the enzyme in fireflies that glows a greenish color in the presence of luciferin whenever the per gene was expressed. To reveal where the gene was expressed, fruit flies were altered to express the gene from jellyfish that produces Green Fluorescent Protein as a marker of per sites.

Kay commented, "We found that all these tissues we cultured from the whole animal were glowing on and off, demonstrating that lots of clocks are running throughout the fly, independently of the brain."

Under normal light/dark conditions, the clock genes rhythmically luminesced in each of the cultured segments head, thorax and abdomen. The researchers noted that the waveform and phase of the rhythms from all three segments was nearly identical.

The tagged per genes were especially conspicuous in chemosensory cells at the base of hairs on the legs and wings and on the antennae and proboscis. These clocks also ebbed and flowed autonomously in response to light, suggesting that circadian rhythms likely regulate a fruit fly's sense of smell, much as they influence light and pain sensitivity in mammals.

While the authors raise the possibility that this evidence of multiple oscillators challenges the current notions about the role of the brain as the seat of a "master oscillator" that coordinates rhythms throughout the organism, they acknowledge that the brain still retains a certain distinction, even in a fruit fly. In the prolonged absence of light, the head was the only organ in which the per genes remained in sync. "The exciting questions now are, why is this gene expressed all over? And are these biological rhythms in fact controlled locally?" adds Jeffrey C. Hall, Ph.D., professor of biology at Brandeis University.

A mammalian variant of the Drosophila's per gene recently was identified, along with another rhythm-related gene (Clock), both found throughout the body of mice; both per and Clock make their products in many different mouse tissues. According to Kay, the discovery of many non-brain clocks in fruit flies could well be true for humans. He suggests that, "In this case it might mean that our skin, liver or other peripheral tissues have their own clocks to control these local functions."

Also participating in the research were Jeffrey D. Plautz, Department of Cell Biology, TSRI, University of Virginia, and NSF Center for Biological Timing; and Maki Kaneko of the Department of Biology and NSF Center for Biological Timing, Brandeis University.

The study was funded by the National Institute of Mental Health of the National Institutes of Health, and the National Science Foundation.

Color images are available at http://www.scripps.edu/~jplautz/images.html


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