The clock ticks as life follows its own rhythm

February 27, 2004

We may be on the threshold of developing drugs that allow us to work at peak levels for 22 hours at a time. Society needs to decide whether to embrace or reject this option, says Russell Foster.

We are ruled by time, but the clocks that instruct us to wake, eat and go to bed are unnatural. Our bodies answer to another, more persistent beat that probably started to tick shortly after life evolved.

Embedded within the genes of humans (and almost all life on earth) are the instructions for a biological clock that marks the passage of approximately 24 hours.

Until we turned our nights into days and began to travel in aircraft across multiple time zones, we were largely unaware of these internal clocks. Yet the striking impairment of our abilities at 4am in the morning soon reminds us that we are slaves to our biology. Our ability to perform mathematical calculations or other intellectual tasks between 4am and 6am is worse than if we had consumed several shots of whisky and were legally over the limit.

Welcome to the world of circadian rhythms, those near 24-hour rhythms that persist when we are isolated from all environmental time signals, such as changes in light or temperature. Human volunteers have gone deep underground and stayed in a constant light environment for weeks on end. With no way of knowing day from night, their body rhythms started to drift out of synchronisation with the outside world. After about a fortnight they were going to bed about what was, in fact, midday and rising at about 8pm. After a month they were back, more or less, in synchrony with the outside world. Our circadian rhythms under such constant conditions are not exactly 24 hours, but a little longer, on average 24 hours and 11 minutes.

Biological clocks drive or alter our sleep patterns, alertness, mood, physical strength, blood pressure and every other aspect of our physiology and behaviour. Under normal conditions, we experience a 24-hour pattern of light and dark, and our clock uses this signal to align biological time to the day and night. The clock is then used to anticipate the differing demands of the 24-hour day and "fine-tune" physiology and behaviour in advance of the changing conditions. Body temperature drops, blood pressure decreases and tiredness increases in anticipation of going to bed, and before dawn our metabolism is geared up in anticipation of increased activity when we wake.

The past decade has witnessed remarkable progress in the understanding of circadian rhythms in many different organisms. Much of what we know of the molecules that make up our biological clockwork has been learnt from the fruit fly and the mouse. The understanding of the molecular basis of circadian rhythms is one of the first success stories arising from the genome-sequencing projects and is one of the best examples we have of how genes and their protein products give rise to complex behaviours.

At the base of our brain in the anterior hypothalamus is the suprachiasmatic nucleus (SCN). Its 20,000 nerve cells form our "master" biological clock and coordinate 24-hour rhythmicity in every cell of the body. If this region of the brain is damaged or destroyed by a tumour, we lose our 24-hour patterns of sleep/wake and all other 24-hour rhythms.

Life's activities become randomly distributed about the day and night. So far, about 12 genes have been linked to the generation of this 24-hour rhythm of life, generating a near 24-hour rhythm of protein production and degradation that ultimately acts as a signal to regulate the whole body.

Tiny changes in these genes can have a profound effect on our behaviour.

One family studied by researchers at the University of Utah included a mother, daughter and grandchild, all with the same sleep disturbance.

Regardless of work schedules or social pressures, they cannot stay up much later than 7.30pm and they tend to wake up at about 3.30am. By studying the family relationships, a small mutation was identified in one of the "clock genes". One commentator on this study said: "By their contribution to our genes, our parents are still telling us what time to go to bed."

This "delayed sleep-phase syndrome" is exceedingly rare, but there is growing evidence that circadian malfunctions may be involved in depressive illnesses, a condition that will affect a significant percentage of the population and costs healthcare systems billions. People with schizophrenia or bipolar disorder have difficulties with timing activities, and this may be a symptom related to a circadian defect rather than dysfunctional behaviour.

A clock is not a clock unless it can be set to local time, and the near-24-hour molecular rhythm in the SCN is normally adjusted by daily exposure to darkness and light. Studying these light-detecting mechanisms led to the discovery of a previously unrecognised light-sensing mechanism within the eye, independent of the rod and cone receptors we use to see.

Some people lack any sense of conscious vision because of genetic disease of the rod and cone photoreceptors, but they are still able to use their eyes to regulate their circadian clock using novel receptors.

The strong effect of light on our biological clock presents a problem for night-shift workers. Even after 20 years of night-shift work, individuals will not normally adjust their circadian rhythm in response to the demands of working at night. This has been linked to increased cardiovascular mortality and an eightfold higher incidence of peptic ulcers compared with the normal population. Other physical problems include chronic fatigue, excessive sleepiness, difficulty sleeping, higher rates of substance abuse and depression. Finally, shift-workers are also vulnerable when driving home after a night shift, especially on quiet, monotonous roads. There is a 50 per cent increase in the risk of a single vehicle crash at 3am after four successive night shifts.

Moreover, many of the big maritime and industrial accidents have happened at night. The nuclear accident at Three Mile Island began at 4am, Chernobyl at 1.23am and the explosion at the Union Carbide plant in Bhopal, India, at 12.15am.

So why don't shift-workers adjust their clocks? After all, if we travel across multiple time zones we do recover from jet lag and adjust to local time. It seems that the mechanism that adjusts our clock will always respond to bright natural sunlight in preference to the dim artificial lights commonly found in the workplace. But in the absence of any natural light, the clock will eventually respond to man-made light. It is not immediately obvious, but shortly after dawn natural light is some 50 times brighter than normal office lighting, and at noon natural light can be 500 to 1,000 times brighter, even in Britain. Exposure to strong natural light on the journey to and from work, and perhaps during the day, normally prevents the night-shift worker from adjusting.

Space is the most extreme shift-working environment. The crews on space missions sleep poorly. On some space shuttle missions, up to half the crew take sleeping pills and, overall, nearly half of all medication used in orbit is intended to help astronauts sleep. Even so, astronauts average about two hours less sleep each night in space than they do on the ground.

This is a problem that will have to be solved before the manned flight to Mars - a round trip that will take more than two years.

The search is on to create the "metabolically dominant soldier" - a warrior who can fight 24 hours a day, seven days a week without rest. Eliminating the need for sleep while maintaining a high level of mental and physical performance is considered to be the way forward in modern warfare. A slight drop in cognitive performance can make the difference between life and death.

British troops used stimulants to keep them awake during the Falklands conflict, and US air crews took amphetamines during the Libyan air strikes.

But a range of side-effects ranging from agitation, irritability and nausea to impotence are associated with amphetamine use. Also, when the drug wears off it can lead to a rebound effect that causes extreme fatigue or depression. By contrast, modafinil is a so-called eugeroic ("good arousal") drug. The French government admitted that its crack corps, the Foreign Legion, used modafinil during covert operations in Iraq during the first Gulf war. There are great hopes for it among the US military, which is allegedly spending $100 million (£54 million) on research.

Michel Jouvet, an authority on sleep, claimed during an international defence meeting in Paris that "modafinil could keep an army on its feet and fighting for three days and nights with no major side-effects". Police, hospital staff, pilots, people who work all night and even students taking exams are among those in our 24-hour society who might also be tempted to use the drug.

Based on our increasing understanding of the mechanisms that generate circadian rhythms and sleep, it is not too far-fetched to imagine that in the next few years we will develop a whole range of drugs that could be used to manipulate our rhythms. We could develop a world in which we sleep only two hours a night and perform at peak levels throughout the other 22 hours.

We have to make choices. We could manage the continued development of the 24-hour society and, if necessary, use pharmacological intervention to counteract the biological downside of working around the clock; or we can reject the trend and use what we know about the clock to embrace biological time.

Russell Foster is professor of molecular neuroscience at Imperial College London. His book Rhythms of Life is published this week by Profile Books, £20.00, and he will speak at the British Library on March 15.

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