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Updated 10:00 AM October 12, 2009

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Biological clock discoveryoverturns long-held theory

University mathematicians and their British colleagues say they have identified the signal that the brain sends to the rest of the body to control biological rhythms, a finding that overturns a long-held theory about our internal clock.

Understanding how the human biological clock works is an essential step toward correcting sleep problems like insomnia and jet lag. New insights about the body's central pacemaker also might, someday, advance efforts to treat diseases influenced by the internal clock, including cancer, Alzheimer's disease and mood disorders, says mathematician Daniel Forger.

"Knowing what the signal is will help us learn how to adjust it, in order to help people," says Forger, an associate professor of mathematics and a member of the Center for Computational Medicine and Bioinformatics. "We have cracked the code, and the information could have a tremendous impact on all sorts of diseases that are affected by the clock."

The body's main time-keeper resides in a region of the central brain called the suprachiasmatic nuclei, or SCN. For decades, researchers have believed that it is the rate at which SCN cells fire electrical pulses — fast during the day and slow at night — that controls time-keeping throughout the body.

Imagine a metronome in the brain that ticks quickly throughout the day, then slows its pace at night. The rest of the body hears the ticking and adjusts its daily rhythms, also known as circadian rhythms, accordingly.

That's the idea that has prevailed for more than two decades. But new evidence compiled by Forger and his colleagues shows that "the old model is, frankly, wrong," Forger says.

The true signaling mechanism is very different: The timing signal sent from the SCN is encoded in a complex firing pattern that had previously been overlooked, the researchers concluded. Forger and graduate student Casey Diekman, along with Dr. Mino Belle and Hugh Piggins of the University of Manchester in England, report their findings in the Oct. 9 edition of Science.

To test predictions made by Forger and Diekman's mathematical model, the British scientists collected data on firing patterns from more than 400 mouse SCN cells. The U-M scientists then plugged the experimental results into their model and found that "the experimental data were almost exactly what the model had predicted," Forger says.

Though the experiments were done with mice, Forger says it's likely the same mechanism is at work in humans.

The SCN contains both clock cells (which express a gene call per1) and non-clock cells. For years, circadian-biology researchers have been recording electrical signals from a mix of both types of cells. That led to a misleading picture of the clock's inner workings.

But Forger's British colleagues were able to separate clock cells from non-clock cells by zeroing in on the ones that expressed the per1 gene. Then they recorded electrical signals produced exclusively by those clock cells. The pattern that emerged bolstered the audacious new theory.

Diekman is a doctoral student in bioinformatics, as well as industrial and operations engineering. He is a National Science Foundation Graduate Research Fellow. Forger is an Air Force Office of Scientific Research Young Investigator.

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