Drugs that could make you into a morning person or help shift workers to concentrate at night could become a reality thanks to fresh insights into how the body clock works at a cellular level.
It’s all to do with circadian rhythms – the variation in our body’s biological processes over a 24-hour period. The most obvious of these is the sleep-wake cycle, but most other physiological processes also oscillate over this time.
Up until about a decade ago, scientists believed that these cycles were controlled by one body clock, located in a part of the brain called the suprachiasmatic nucleus, but subsequent research revealed that every cell in our body contains a clock that regulates the timing of cellular activity.
Now, investigations funded by the European Research Council (ERC) into how these cellular clocks work, and the relationship between them and the ‘master’ body clock in the brain, are yielding fresh insights into how our bodies keep time and what happens when things go wrong.
‘Normally we have 24-hour clocks in our bodies,’ said Dr Akhilesh Reddy from the University of Cambridge, UK, who is investigating the timing of cellular clocks as part of the METACLOCK project. ‘But we know that some people have slightly longer clocks or shorter clocks and that can interfere with your relationship with the outside world.
‘We’re designing drug molecules to adjust the clockwork – to make it faster or slower or beat harder, essentially.’
Dr Akhilesh Reddy, University of Cambridge, UK
‘If you’re a morning person, you tend to have a slightly faster clock, on average, compared to an evening person. One thing that’s come out from what we’re doing is actually to design drug molecules that we can use to change how the clock oscillates.’
The potential for drug treatment has arisen because METACLOCK researchers have found a new explanation for the rhythmic behaviour of cells. Previously it was thought that the control mechanism lay in genes, but Dr Reddy’s team has discovered that red blood cells, which don’t contain a nucleus or any genetic material, also demonstrate rhythmic behaviour.
Their new explanation, that cellular clocks are controlled by biochemical rather than genetic processes, has opened up a new area of research that could one day enable people such as shift workers to tweak their body clocks. It could also have important implications for people who suffer from sleep disorders because their body’s natural oscillations only vary slightly between day and night.
‘It’s the first time we can actually get a different window on the timing mechanism to try and manipulate it with drug molecules,’ said Dr Reddy. ‘That’s what we’re doing at the moment. We’re designing drug molecules to adjust the clockwork – to make it faster or slower or beat harder, essentially.’
It’s not only internal mechanisms that keep our clocks running on time. The environment also plays a vital role. The master body clock in the brain uses light cues to determine when it’s day and when it’s night and keep to a 24-hour cycle.
However, researchers are finding out that our cellular clocks respond to different environmental cues, such as eating. Dr Gad Asher, at the Weizmann Institute of Science in Israel, is examining the relationship between metabolism and cellular clocks within the METACYCLES project.
Dr Asher’s team has found a strong link between the timing of meals and how well cells metabolise food. In an experiment earlier this year researchers discovered that if you let a mouse eat at any time then the level of fat that builds up in the liver is twice the amount than if you restrict the mouse’s food intake to the night time, its natural period of activity.
‘This has major implications clinically because it suggests that it is not only the composition of the food which is important but also the time of the meals,’ said Dr Asher. While this experiment has not yet been reproduced in humans, he says that it could have knock-on effects when it comes to understanding and treating diseases such as fatty liver disease, obesity and other metabolic disorders.
Anticipation and separation
Circadian rhythms play two important roles in the body, according to Professor Ulrich Schibler at the University of Geneva, Switzerland. They allow your body to anticipate and prepare for events such as mealtimes and sleep, and they make sure chemically incompatible processes don’t occur at the same time.
For this to happen it is important not only that each cell runs on time, but that cells throughout the body are synchronised with each other. ‘It is logical that if you have a clock shop and every clock is a different time, it is difficult to orient yourself,’ said Prof. Schibler. ‘In the body it’s a little bit the same.’
Prof. Schibler leads the TIMESIGNAL project, which is investigating how the cellular clocks in liver and other tissues interact with the master clock in the brain. ‘We would like to know what signalling pathways are directed by the suprachiasmatic nucleus, either directly or indirectly, that then synchronise these clocks,’ he said.
His team has used its grant from the ERC to develop a way of testing which factors are important in synchronisation. So far the list includes signalling proteins in the blood, hormones, feeding time and body temperature, with feeding time appearing to be the dominant factor.
‘The knowledge about the clock is important because, in the long term, desynchronisation, in shift work for example, causes all sorts of problems,’ said Prof. Schibler.
He said that a greater understanding of circadian rhythms – particularly how the level of detoxification enzymes rises and falls in the liver – could also help doctors advise people on the best time of day to take medicine.
‘Detoxification enzymes also inactivate or activate, for example, cancer drugs or any other medication,’ he said. ‘So it makes sense to give them when they are most potent and the side effects are smallest.
‘The knowledge about circadian rhythms is already being used in the clinic to design chemotherapy that is given at the best time. Not enough people are doing that. I think we have to do more work to convince people to use all this knowledge.’
The promise of personalised medicine is not only that it could increase cure rates, but also that it could save people from undergoing treatment when there is no hope of it working, according to Dr Daniela Thorwarth from the University of Tübingen, Germany.
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