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Joined: 19 Jul 2006
|Posted: Wed Jul 19, 2006 12:40 pm Post subject:
A New Take on the Body Clock
Some drug companies developing treatments for jet lag, insomnia, and
depression might be on the wrong track.
A new study suggests that we may have to reverse our current
understanding of the mechanism underlying circadian rhythms -- the
internal body clock that regulates everything from our wake cycles to
hormone production and heart rate.
If correct, this would have profound implications for any drugs being
developed on the basis of our previous understanding. "They are going
to be effective in the opposite direction," says David Virshup, who
carried out the study together with colleagues at the University of
Utah's Huntsman Cancer Institute and the University of Michigan, in Ann
It's the latest twist in a story that began in Oregon in 1988, with the
chance discovery of a mutant hamster that appeared to run on a 20-hour
cycle -- four hours less than of a normal hamster's day. The hamster's
unusual circadian rhythm was traced to what has become known as the tau
Previous research indicated that the tau mutation targeted a particular
gene, called casein kinase 1 epsilon (or CK1), which resulted in an 85
percent reduction in the activity of an enzyme produced by this gene.
And this reduction in activity was thought to be the reason why the
hamster had such a short day. But it now turns out the tau mutation has
the opposite effect: it increases the hamster's activity, says Virshup.
Gaining a better understanding of these mechanisms is relevant to far
more than just sleep disorders. Disruption of the circadian rhythm can
affect everything from stress hormones to cell division, and has been
linked to various diseases, including cancer, diabetes, and depression.
The new study was a collaboration between Virshup's laboratory and
Daniel Forger, a mathematician who specializes in biological
applications at the University of Michigan. Forger had already created
a detailed mathematical model of the core genetic pathways involved in
hamster circadian rhythms at the cellular level. "He developed a
totally mathematical model of the clock," says Virshup.
This model made it possible to put the prevailing theory to the test.
Surprisingly, the researchers found that a decrease in CK1 activity
actually extended the hamster's day, while an increase in CK1 activity
caused the shortened cycle observed in hamsters with the tau mutation.
In the latest collaborative research, Virshup's group reproduced
Forger's model in cultured mouse cells. They focused on a particular
protein, called PER, which is known to play a role in resetting the
clock cycle. Forger's mathematical model predicted that the tau
mutation would cause PER to degrade more quickly. The old model
predicted the opposite.
Publishing their findings in the current issue of the Proceedings of
the National Academy of Sciences, Virshup's group showed that cells
with mutant CK1 genes introduced into them did make the PER protein
disappear more quickly. Because of this, the clock ticked faster. "We
never would have looked for it if it weren't for this mathematician,"
"What this means is we now have a much clearer understanding of how the
clock works," says Andrew Loudon an animal biologist at the University
of Manchester in England.
Others are less convinced. "They could be right, but it's far from
conclusive," says Liz Maywood at the University of Cambridge's
Department of Physiology, Development and Neuroscience, in England.
What is not clear, she says, is whether this effect has been caused by
the mutation or whether it's due to the cells entering a particularly
active phase of their natural clock cycle. "Some drugs can shift the
phase of the clock," she says.
Virshup is dismissive of this, arguing that phase effects of the cells
were unlikely to have influenced the experiments because of the
conditions under which the cells were grown. "There are effects of
circadian rhythms on cell cycles, but not the other way around," he
"Knowing what we now know, anyone setting out to develop drugs would be
having a devil of a time," says Loudon. To the best of his knowledge,
Virshup says, there are no drug therapies on the market based on the
previous understanding of the tau mutation. But, he adds, at least two
companies have been working on drugs based on our prevailing
understanding of these CK1 mechanisms. "That may be why we haven't seen
any approved drugs on the market yet," he says.