Where is our body clock? The supra-chiasmatic nuclei (SCN) sit at the base of the human brain (circled, left). Each contains about 10,000 ‘clock’ cells or neurons that can be identified by the clock proteins they contain, here seen in a mouse brain (centre). These neurons can act as individual time-keepers, conveying time signals to other parts of the brain via long thin connections, imaged here at high magnification in a living clock neuron (right).
Dr Michael Hastings, Dr Elizabeth Maywood
Stunning images of the body's internal clock ticking away in brain tissue are providing further insights into the molecular genetic basis of our biological or circadian rhythms. The images are the work of the Medical Research Council's Laboratory of Molecular Biology and are throwing light on those daily cycles of physiology and behaviour that persist even when we are isolated from the external world. 'The most obvious function controlled by our internal body clock is sleep,' says Michael Hastings. 'But we are beginning to discover a whole host of functions controlled in this way, including control of the cycle of cell division, the starting point for cancer.'
It is only recently that the genetic process that controls our circadian rhythms has been identified. Michael explains, 'Clock genes are activated at the start of our day and gradually produce mRNA the genetic output from DNA. This mRNA is slowly translated into clock proteins outside the cell nucleus. These proteins bind together to protect themselves from degradation and can therefore move into the nucleus of the cell where they start to turn off the clock gene activity a negative feedback loop. The production of mRNA stops as the clock moves into its early night phase. The proteins are then progressively degraded over the course of the night so that by the new dawn, the proteins are gone and clock genes are ready to turn on again. Hey presto! A 24-hour cycle.' This molecular clockwork appears to be present in almost all cells of our body, ticking away in unison to regulate our rhythms in brain function, growth and even the fight against illness.
Michael and his team use the production of proteins that naturally fluoresce to image the action of these clock genes. The production of the fluorescent protein is controlled by the period gene, an essential part of the body's internal clockwork. As the clock goes through its daily cycle of activation and inactivation of the gene so the fluorescent emission waxes and wanes. 'Using time lapse photography we see the brain's clock ticking away in a test tube,' says Michael.
Michael and others work to unpick the genetic control of circadian rhythms is throwing light on cancer, sleep disorders, and jet lag. 'Cancer is a disregulation of cell division and survival', says Michael. 'Normally the body clock controls cell division but in mice with mutations in their clock genes this regulation is lost, cell division increases and they are prone to more cancers. This could be the reason for the observed incidence of cancer in long term shift workers.' Mutations of the clock genes or the genes that influence them can also lead to disrupted cycles. In humans this can cause Advanced Sleep Phase Syndrome a condition where the individual wakes at 4am and then sleeps again at 8pm, basically their whole day is shifted forward.
There is also hope for new treatments. Chronotherapy promises treatments specifically timed to provide optimum benefits. In cancer there may be specific points in the cell cycle that make the tumour cells more susceptible to drugs. In addition, lower doses of drugs could be used, leading to fewer side effects, if the rhythmic cycle of drug clearance by the liver were better understood.