Jet lag drug still years away

A “body clock pill” could cure both jet lag and manic depression, according to The Daily Telegraph. The newspaper reports that a new study has identified a drug that can “slow down, kick-start and reset the body clocks of mice”.

The lead researcher is quoted as follows: “It's possible to use drugs to synchronise the body clock of a mouse and so it may also be possible to use similar drugs to treat a whole range of health problems associated with disruptions of [the body clock]”. He suggests that these could include serious conditions such as bipolar disorder.

This was well-conducted research into a complex area. The study and its findings pave the way for further research into this field and into the application of this new drug to human health. However, the news reports are perhaps overly optimistic given the early stage of this research as there is a long way to go before the full potential of this new drug is realised. It is certainly too soon to proclaim this as a new cure for anything.

Where did the story come from?

The study was carried out by researchers from the University of Manchester, the Medical Research Council and the Pfizer pharmaceutical company. The research was funded by the Biotechnology and Biological Sciences Research Council and the Medical Research Council in the UK. It was published in the peer-reviewed medical journal, Proceedings of the National Academy of Sciences (USA).

Generally the media has reported the story accurately, although headlines suggesting that scientists have found “cures” for human health problems are premature. This may be misleading for readers; while very important in the development of new drugs, animal studies are the preliminary stages in a long chain of research that may eventually establish the effects of drugs in humans. Animal studies cannot prove efficacy in humans. The Daily Mail only makes it clear that this was a study in mice several paragraphs into its article.

What kind of research was this?

This was a laboratory study in mice investigating the workings of “circadian rhythms”, the biological clock, in greater detail. Previous studies have shown that mutations in particular genes that make a protein called “casein kinase 1” (CK1) can affect the biological clock, but the exact mechanism behind this phenomenon is not yet known. There are two different forms of the CK1 protein, delta and epsilon, and researchers tried drug-based methods to block each of these proteins to determine their function in mice.

What did the research involve?

The circadian rhythm is a complex process, involving the production of different proteins that act to repress the activity of others. Two proteins are known to be important to the processes, CK1 delta and epsilon, although CK1 delta is more critical. A small region of the brain called the suprachiasmatic nucleus is known to set the pace of the biological clock, and in this study researchers determined how manipulating CK1 affected this pacemaker function.

There were several phases to the study, with initial laboratory studies testing lung tissue from mice to establish how the cells responded to different doses of drugs. The two drugs tested were PF-670462, which inhibits the action of CK1 delta, and PF-4800567, which inhibits CK1 epsilon. When researchers used drugs to block the activity of CK1 delta they found that the circadian rhythms in mice lengthened (slowed down) and that this was associated with a concentration of a particular protein, called PER2 protein, in the nuclei of cells.

Further experiments then examined the effects of this chemical inhibition on the brain’s biological pacemaker. Live animals that were injected with the drugs at particular points in their circadian cycles and the effects on their body clocks were assessed. The researchers also investigated what effect the drugs had on the concentration of PER2 protein in their cells.

In the next set of experiments, which provided the findings that most newspapers highlighted, brain slices from mice with compromised brain pacemakers (i.e. with poor or no circadian rhythm) were cultured with the CK1 delta inhibitor drug to see what effect the drug could have on the biological clock of the cells. The drug was then tested in live mice. The mice were conditioned to a light-dark cycle for 7-10 days before being transferred to constant darkness and given daily injections of the CK1 delta inhibitor. The researchers repeated the experiment after transferring the mice from constant light conditions.

What were the basic results?

The researchers found that the activity of the CK1 protein was necessary for the progression of the circadian pacemaker (i.e. the cycle in the physiological processes). This was particularly evident when CK1 delta was inhibited with PF-670462 in lung cells, and less so when PF-4800567 inhibited CK1 epsilon.

Using the PF-670462 drug to inhibit the CK1 delta protein reactivated the pace-making function in the isolated brain cells. This also occurred in the brains of live mice that had a faulty suprachiasmatic nucleus (which normally functions as the pacemaker of the biological clock), restoring the circadian rhythm in these mice.

How did the researchers interpret the results

The researchers say that they have shown that selective inhibition of CK1 delta can restore the circadian rhythms in animals where this is disturbed. This highlights this enzyme as “an important therapeutic target for regulation of disturbed sleep and other circadian disorders”, they say. They add that in humans a large number of “disease states” are thought to be underpinned by disrupted circadian rhythms and they say that targeting CK1 delta may offer a “promising therapeutic avenue”, particularly for conditions that involved circadian disruptions, e.g. shift working and circadian sleep disorders.

Conclusion

This is a well-conducted and well-reported animal study that has demonstrated the effects of inhibition of particular proteins on the functioning of the biological clock, both in mouse cells and in living mice. It paves the way for future research into this area, revealing more about how the brain’s pacemaker works.

However, it is too soon to claim that the study has found a cure for anything. Animal studies are one of the early steps it the drug development pathway, an important step, but one that must be followed by replication by other researchers and ultimately research in humans to establish whether these findings apply to humans and that the drug is safe.

Until such research is undertaken, the implications of the new drug, currently known as PF-670462, are far from clear. Therefore it is far too soon to claim that this is a cure for jet lag, bipolar disorder or any other diseases in humans.