The mechanism behind jet lag, insomnia and other disorders that rely on an inner body clock is not what it seems, scientists announced today.

The effect of a mutation in a key gene involved in the regulation of sleep and wake cycles in mammals works in the opposite way from what was previously thought.

The finding, detailed in the July 3rd issue of the journal for the Proceedings of the National Academy of Sciences, means drug makers will have to change their approach when concocting new drugs to treat disorders that involve a malfunctioning body clock.

How we number our days

The bodies of humans and other mammals know what time it is by constantly measuring the concentration of a protein called PER in the body.

Drug companies are currently working on ways to manipulate the level of PER in the body to treat disorders caused by disruptions to the body's clock, or circadian rhythm.

The degradation of PER is regulated by another protein, called CK1e, whose production is controlled by the gene casein kinase 1, or CK1.

A mutation called "tau" in CK1 was previously thought to lead to the production of defective CK1e proteins that break down PER more slowly than is normal, causing the protein to accumulate in the body.

The buildup of PER, it was thought, sped up a mammal's internal clock, causing it to have shorter days.

However, the new study finds that actually the opposite occurs: The tau mutation doesn't slow down PER degradation — it speeds it up.

Thus, it is not excess PER that leads to shorter days in affected animals, but not enough PER.

Just a mathematician

One of the early hints that the conventional wisdom about the tau mutation was wrong came from a computer model of the mammalian biological clock developed by Daniel Forger, a mathematician at the University of Michigan.

Hamsters with the tau mutation have short 20-hour days, instead of the usual 24.

Forger's simulation suggested this could only occur if the activity of CK1e was sped up by the mutation, not slowed down.

"I had this prediction for a year or two," Forger said. "Basically, people said this is ridiculous, you're a mathematician, what do you know?"

While giving a talk at the University of Utah, Forger met David Virshup, researcher at the university's Huntsman Cancer Institute.

The results from experiments conducted by Virshup's team also suggested that the tau mutation increased rather than decreased CK1e activity.

Virshup's team found that rat cell cultures with the tau mutation degraded PER in only a few hours, compared to the 8 to 10 hours that it normally takes.

The results proved Forger's prediction: The circadian rhythm within the rat cells sped up because the mutated CK1 gene was more active, not less.

The finding will affect new drugs currently in development for the treatment of disorders that are influenced by our circadian rhythms, including depression, insomnia and even some forms of cancer.

"If the working model is wrong, drugs will have the opposite effect," Virshup said.

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