New dimension discovered in body clock rhythm

May 18 2008

Research on what makes the body clock tick has led Dr Michael Hastings of the MRC Laboratory of Molecular Biology in Cambridge to discover a new and unanticipated cog in the human body clock. A patent for the compound involved has been filed by MRC Technology. The results, published in Science, could lead to therapies for people whose sleep is disrupted by shift work or old age.

Circadian rhythms are cycles of body metabolism and behaviour that allow organisms to adapt to day and night. An example is the human cycle of sleep and wakefulness in which the brain adopts different states controlled by an internal clock.

By examining the molecular basis of body clock regulation in the brain, Dr Hastings and his team hope to learn how interruptions to circadian rhythms can have a negative effect on health.

''Disruption of our circadian programme through shift work, old age and neurological disease is a significant and growing cause of chronic illness. If we can identify ways to control the clockwork we may be able to learn how to reset it when it goes wrong,'' said Dr Hastings.

Circadian cycles are controlled from a part of the brain called the hypothalamus in a region known as the suprachiasmatic nuclei or SCN. In the SCN, individual neurones (brain cells) operate as self-sustained clocks. The cells of the SCN synchronise the body clock mechanisms that are present in the other major organs including the heart, lungs and liver, via their control over behaviour, the nervous system and secretion of hormones from other parts of the brain.

The circadian rhythm runs on negative feedback loops. Protein products of clock genes are synthesised at the start of the circadian day and then at the end of the day switch off the genes that originally produced them. The proteins are broken down during the circadian 'night' so that the cycle can begin afresh the next day.

In this study, the researchers found that the negative feedback loops that occur in the SCN are supported by signals sent by a small intracellular molecule c-AMP. Together, c-AMP and the circadian genes and proteins keep the body clock ticking. The effect of c-AMP cycle on the clockwork in the brain is mirrored in the body clock cells present in other organs too.

The study found that the negative feedback loops in which proteins are produced by genes and then switch those same genes off again drive the rhythm of c-AMP signalling. In turn, changes in the c-AMP cycle regulate the production of proteins involved in the negative feedback loop, creating a "super loop".

MRC Technology, the technology commercialisation arm of the MRC has filed a patent application to protect pharmacological methods of manipulating the cAMP pathway. It is hoped that drugs developed using these methods could lead to treatments for genetic sleep disorders or jet lag.

Dr Hasting explains: ''We have found that daily activation of c-AMP signals help to sustain progression of the body clock's rhythm. The output of the c-AMP cycle feeds into the protein production that kick starts the negative feedback loop cycle we already know about. This doesn't just happen in the brain cells that control the body clock but in all the other body clock cells in other organs.

''This is a new way of thinking about how the body clock ticks, the involvement of c-AMP shows that the control mechanism extends into areas of the cell we weren't aware of it working in before. This gives us a new way to control the body clock in all of our organs and tissues.''

Original research paper: cAMP-Dependent Signalling as a Core Component of the Mammalian Circadian Pacemaker is published in Science.

Web links

Michel Hasting's webpage: http://www2.mrc-lmb.cam.ac.uk/NB/Hastings_M/

The Body's Daily Clock: http://www2.mrc-lmb.cam.ac.uk/groups/mha/