BioEd Online

Society celebrates its early birds, but for an unlucky few, the internal alarm clock goes off much too early. Now, studies of early-rising mice have led researchers to change their view of how biological clocks tell time, and could ultimately lead to new treatments for people with sleep disorders.

Variation in sleep cycles is normal, says Louis Ptcek, a geneticist at the University of California at San Francisco. "In the general population, there's a huge spectrum between people who habitually wake up without an alarm clock or coffee at 6 am, and those who would sleep until two in the afternoon if they didn't have any other responsibilities," says Ptcek.

But at the far reaches of normal behaviour are individuals whose internal curfews are set much earlier or later than those of the rest of the population. People who have familial advanced sleep phase syndrome which Ptcek estimates affects only 0.3% of the population usually wake up around 4 in the morning, and go to bed around 7 at night.

"The time that most people are most awake is around dinnertime," says Ptcek. "But that's when these people are so sleepy that their face could fall into a bowl of soup."

Ptcek and his colleagues previously showed that some people with the condition carried a mutation in a gene called period 2 (PER2), and levels of PER2 proteins are often critically low.

Researchers previously thought that the mutation associated with this syndrome caused PER2 proteins to degrade. But now, this team's work with affected mice shows that the mutated gene simply makes less protein in the first place.

That's a complete reversal in thinking says David Virshup, a biochemist at the University of Utah in Salt Lake City. "It all made perfect sense to us then, and it all makes perfect sense now, but in the opposite direction."

The result, published in Cell¹, should have implications for those trying to manipulate the body-clock system, perhaps even with a simple pill. Such treatments could be used for many disorders, from serious sleep problems to simple jetlag.

Wake me up

The overall picture of body-clock regulation has also become more complicated through this research. The team found that the PER2 gene has two sites that can be modified by a well-known chemical trigger, which is in turn activated by another gene.

Only one of these sites is implicated in familial advanced sleep phase syndrome. At this site, the chemical trigger normally increases expression of PER2. But in those with a mutation, the trigger is ineffectual, and PER2 levels start to decline. At the second site, the trigger does the opposite it degrades the protein.

There is no known human condition associated with a mutation at this second site. But the researchers think that it probably plays a part in the normal body clock, with some unknown regulation system moderating the interactions between the two. "It's sort of a yin-yang type of relationship," says Steve Kay, a body-clock researcher at the Scripps Research Institute in La Jolla, California. "The two sites have to balance each other out to produce the tight clock regulation that we see."

Researchers are now chasing down that new regulatory component in the hope that it could one day be used to derive a treatment for people with sleep disorders.

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