Life inhabits a 24-hour world, and to stay tuned to it, plants and animals live to a 24-hour beat. Leaves open in the day, harvesting sunlight, and close at night to retain water. We are active in the day, with elevated body temperature and heart rate, but withdraw from the world to sleep in the cocoon of night, our temperature and heart rate at baseline. But are these dramatic and regular cycles simply a response to the world? Does the leaf wait until dawn before it moves?

In 1962, Michel Siffre isolated himself in a cavern, and for several weeks monitored his bodily rhythms. He discovered that they did not stop but continued running in the absence of external time cues. He concluded that an internal timer must drive them: a ‘body clock’. Like all things biological our clock is approximate, hence is termed circadian (circa – approximate; diem – day), running between 23.8 and 24.5 hours, depending on the person. Dawn and dusk light correct any slight error, keeping us exactly in synch with the world.

Laboratory studies show that this clock governs everything measurable: alertness of mind, secretion of stress hormones and detoxification of drugs. What our body and brain can do in the daytime is very different from what our clock equips them to do at night. We should think of ourselves as 24-hour biological machines. Evolution has favoured clocks because, by anticipating the demands of day and night, they make the machine more efficient.

A more general awareness of our internal gearing arises with flight between time zones, or shiftwork. The discomfort, fatigue and confusion are commonly attributed to lack of sleep, but they have a deeper origin: the scrambling of our internal daily programme. Indeed, the drive to 24/7 living is becoming a major health issue. A working life spent on rotating shifts increases the risks of cancer and cardiovascular diseases, and shortens life expectancy by several years. Circadian control over our attentional abilities can also have devastating consequences. The disasters of Bhopal, Chernobyl, Three Mile Island and Exxon Valdez share a common feature: operator error crept in when the operator was working in the circadian ‘attentional dip’.

So where is the clock? It is a pair of pinhead-sized clusters of about 10,000 nerve cells at the base of the brain: the suprachiasmatic nuclei, or SCN for short. The SCN are keeping you awake now. A direct nervous connection from the eyes keeps them in synch with the light/dark cycle. In turn, their circadian time signals, a biological equivalent of Big Ben’s chimes, are encoded as a daily rhythm in electrical activity: high activity marks day and low marks night. Nervous and hormonal pathways relay these chimes throughout the body, orchestrating our daily life.

An astonishing property of SCN cells is that they sustain their rhythm of electrical activity when they are isolated in a dish: a ‘ticking’ body clock in a test-tube. But how can individual cells tell the time? The answer lies in ‘clock genes’. A landmark breakthrough was the identification of the genes that make up our clockwork and the biochemical mechanism of how they define time. Clock genes and the proteins they encode are entwined within a negative feedback loop: the activation of the genes produces proteins, which accumulate in the cell and then inactivate the genes. The cycle can only restart once the proteins have been degraded, re-releasing the genes from negative feedback.

Biochemical delays between the various stages mean that the whole loop takes approximately 24 hours to complete, but this varies between people. In early risers with ‘lark-like’ habits the proteins are less stable and the cycle runs faster. The extreme is Familial Advanced Sleep Phase Syndrome, in which people with a 22 hour clock awake in the small hours but cannot resist falling asleep around 5 pm. In contrast, ‘night owls’ have slow clocks because their proteins take longer to clear. Differences in clock genes can also make people more or less susceptible to the negative effects of sleep deprivation.

Identification of clock genes led to an even more revolutionary discovery: the circadian mechanism is active throughout the body. The heart has a local circadian clock, as do the lungs, liver, and ovaries; even human skin cells can be cultured and shown to carry this clockwork. No longer do we see our inner clockwork as a hierarchical, top-down process with the omnipotent SCN directing every detail of our circadian lives. Rather, our bodies contain myriad clock cells, each keeping its local time, but synchronised to all the other clocks by the ‘chimes’ of the SCN.

This breakthrough offers unprecedented insights into disease. For example, clocks control the time of day when a cell can divide. If the cell misses that open door today, it must wait until tomorrow for the door to re-open before it divides. In this way the clock slows down cell division, and hence is a natural suppressor of cancer. In cells or animals with disturbed clocks, cell division and the growth of tumours is accelerated. The epidemiological data showing more cancer in shift workers suddenly starts to make more sense, and the aim now is to develop treatments that enhance the oncostatic role of the clock. Local clocks are also important in metabolic diseases – mice and hamsters with defective clock genes are more prone to severe obesity and cardiovascular disease. If we can find out how local clocks boost fat metabolism or keep heart rate low at night, we can alleviate diseases by boosting these circadian changes, developing ‘circadian-savvy’ medicines.

And what of the ultimate rhythm, sleep? The SCN controls when we can sleep and when we can be awake. But what happens in sleep? Recent studies emphasise the role of sleep, especially the non-dreaming state, in the formation of new memories and restoration of older ones. The riot of new experiences that occurs during the day has to be sorted against existing memory, filtered for relevance and, where necessary, encoded into our brain circuitry. A brain region called the hippocampus is critical for this process, and its local clock controls biochemical activity necessary for learning. For us to learn effectively, therefore, all areas of the brain have to work in unison, running to the same clock time. This temporal coherence delivers the cognitive and emotional restoration of a good night’s sleep. In contrast, mismatch perturbs the brain’s machinery, disturbing memory formation and mood.

We are 24-hour beasts. We live better and for longer if our lives run in tune with our inner clockwork, synched to the solar day outside. Having discovered the genes and biochemistry that make up our countless body clocks, we can now look to exploit that knowledge to target diseases when their circadian variation makes them most vulnerable. We can also optimise lifestyles and work schedules to mitigate the worst consequences of circadian misalignment. As for Varsity life, it is good to work hard and play hard, but be kind to your clocks: keep to a regular beat!

Dr Michael Hastings is a Cambridge neuroscientist, based at the MRC Laboratory of Molecular Biology, specialising in the molecular neurobiology of circadian body clocks.

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