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 Arbor.
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 mutation.
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,” says Virshup.
“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 says.
“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.
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