» Issue 3: Autumn 2005

Born free but controlled by a biological clock

‘The 24-hour variation in our performance is increasingly at odds with the demands of a 24/7 life-style’, says Professor Russell Foster. In a recent book he examined the biological clocks controlling the daily lives of every living thing.

WE ARE ruled by time and we need to know the time to tell us what to do. But the clocks that instruct us to wake, eat and go to bed are unnatural. Indeed, many groups within our society are expected to perform with equal efficiency throughout the 24-hour day. In these groups, sleep is regarded as an illness which needs to be cured.

In our modern world, we are being driven by the energy states of an electron in the caesium atom and use machines to hack our day into hours, minutes and seconds. Yet despite the atomic clock, our bodies answer to another more persistent beat which probably started to tick shortly after life evolved. Embedded within our genes, 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 across multiple time zones, we were largely unaware of these internal clocks.

Yet the striking impairment of our abilities at 4am soon reminds us that we are slaves to our biology. Our ability to perform mathematical calculations or other intellectual tasks between 4 and 6am is worse than if we had consumed several shots of whisky and would be classified as legally drunk.

Welcome to the world of circadian rhythms, those near 24-hour rhythms which persist when we are isolated from all environmental time signals, such as change in light or temperature.

Human volunteers have gone deep underground and stayed in a constantly lit environment for weeks. 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 around midday and rising at around 8pm. After about a month they were back, more or less, in synchrony with the outside world, before drifting off again. Our circadian rhythms under such 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 changing conditions. Body temperature drops, blood pressure decreases, tiredness increases in anticipation of going to bed. Before dawn metabolism is geared-up, anticipating 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 (drosophila) and mouse.

The understanding of the molecular basis of circadian rhythms is one of the first succeses arising from the genome sequencing projects. It is currently 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 a structure known as the suprachiasmatic nuclei (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, then we lose our 24-hour patterns of sleep/ wake, and all other 24-hour rhythms.

The finding that individual SCN neurones, isolated from all other cells, show near 24-hour rhythms in electrical activity demonstrated that the basic mechanisms that generate this internal clock must be due to the molecular interactions within a single cell. So far, approximately 12 genes have been linked to the generation of this 24-hour rhythm of life. At the heart of the mechanism is a ‘negative feedback loop’. The so-called ‘clock genes’ located in the mass of DNA in the nucleus of the cell are transcribed and produce a message (mRNA). This mRNA is translated into its protein in the cytoplasm. Then the protein moves into the nucleus to turn-off the transcription of its own mRNA. The clock protein in the nucleus in then degraded, and the gene is once more free to make mRNA, more protein, and so the cycle continues. This negative feedback loop generates a near 24 hour rhythm of protein production and degradation which ultimately acts as a signal to regulate the whole body.

Tiny changes in these clock genes can have a profound effect upon our behaviour. One family studied by researchers at Utah University included a grandmother, daughter and grandchild all with the same sleep disturbance. Regardless of work or social pressures, they cannot stay up much later than 7.30pm and they tend to wake up around 3am. A small mutation was identified in one of the clock genes. One commentator 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 the health care systems billions. Schizophrenics, and people with 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. These sensory cells are independent of the rod and cone receptors that we use to see. Indeed, some people can lack any sense of conscious vision, due to genetic disease of the rod and cone photoreceptors, but 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 shift their circadian rhythm in response to the demands of working at night. Metabolism, along with alertness and performance, are still high during the day when the night-shift worker is trying to sleep, and low at night when the individual is trying to work.

A misaligned physiology, along with poor sleep, in night-shift workers has been associated with increased cardiovascular mortality and an eight-fold higher incidence of peptic ulcers. Other physical problems include chronic fatigue, excessive sleepiness, difficulty sleeping, higher rates of substance abuse and depression. Finally, shiftworkers are also vulnerable when driving home after a night shift, especially on quiet monotonous roads. There is a 50% increase in the risk of a single vehicle crash at 3am after four successive night shifts.

So why don’t shift-workers shift their clocks? After all, if we travel across multiple time zones, we do recover from jet-lag and adjust to local time. If night shift-workers hide from bright natural light during the day, they can shift their body clock to the night.

It seems that the mechanism that adjusts our clock is fairly insensitive to light. The 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. At noon, natural light can be 500 to a 1000 times brighter – even in Britain. Exposure to strong natural light to and from work, and perhaps during the day, normally prevents the night-shift worker from shifting.

Space is the most extreme shiftworking environment. Crews on space missions sleep poorly. On some missions up to half the crew take sleeping pills and, overall, nearly half 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 – a problem that will have to be solved before the manned flight to Mars. Many big 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, at 12.15am.

The search is on to create the ‘metabolically dominant soldier’ – a generation of warriors who can fight 24 hours a day, seven days 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. Soldiers, sailors and aircrew have to make instant decisions based on incomplete information. Even a slight drop in cognitive performance makes all the difference between life and death.

British troops used stimulants to keep them awake during the Falklands conflict and USAF aircrews took amphetamines during the Libyan air strikes. But a range of side effects from agitation, irritability and nausea to impotence are associated with amphetamine use.

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 inside Iraq during the first Gulf War.

There are great hopes for Modafinil among the US military which is allegedly spending $100 million on research on the rationale that soldiers who sleep less will give the US a military edge.

Professor Michel Jouvet, an authority on sleep, claimed during an international defence meeting 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 the many millions in our 24-hour society who might also be tempted to take Modafinil.

Based upon our increasing understanding of the mechanisms that generate circadian rhythms and sleep, it is not too farfetched 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. The choice, as ever, is not completely free but it is one that we are going to have to make.