Tick tock: body clock

It’s one of the banes of modern life – the feeling of being ruled by the clock. Off goes the alarm, then it’s up and out to work, returning home and grabbing some sleep before doing it all over again.

In a Nutshell

Life on Earth follows a daily rhythm, with activity following a 24-hour cycle. Its origin appears obvious: the rising and setting of the Sun each day. Yet experiments have shown that such ‘circadian’ rhythms have their roots in living organisms themselves: plants and animals kept in the dark still manage a roughly 24-hour cycle of activity. Recent research has identified genes within cells that drive biochemical reactions which ebb and flow on a daily basis. These ‘cellular clocks’ work perfectly well without outside input. But precisely how they are synchronised and why they evolved in the first place is a mystery.

At least we’re not alone. From buffalo to bacteria, oaks to algae, all life follows the same relentless 24-hour cycle, driven by the rising and setting of the Sun.

Or is it? Over 250 years ago, a French scientist performed a simple experiment that blew apart the idea that all life on Earth does the bidding of the Sun. Intrigued by the way plants open and close their leaves each day, Jean Jacques de Mairan put a heliotrope in a dark room and observed the effect. He was expecting the plant, robbed of sunlight, to cease its daily routine. To his astonishment, its leaves continued to open and close as if in response to some invisible timekeeper.

It was the first sign that the real timekeeper is ticking away inside us. But what – and where – is it? And how does it achieve such astonishing regularity? These are the mysteries now at the forefront of chronobiology, the study of the effect of time in living organisms.

The search for answers is about more than just tying up some scientific loose ends. We may curse the clock on the wall, but the clocks in our bodies can cause us a lot more trouble. When knocked out of synch through shift-work or long-haul flights, they can leave us utterly unable to think or act. Yet even when they work correctly, the natural rhythms of alertness they generate can catch us out: accident statistics show two deadly peaks, at 4am and again 12 hours later, when we are at our least alert.

During the 1970s, best-selling books began to emerge claiming such phenomena were manifestations of so-called biorhythms, a set of three cycles governing physical, emotional and intellectual traits. Said to start from the moment of birth and repeat every 23, 28 and 33 days respectively, they were supposed to lead to ‘critical days’ when one or more cycle led to sub-optimal performance, with unfortunate consequences.

Scientists have long dismissed biorhythms as pseudoscience, insisting the existence of the three cycles has no basis in fact. In 1998, Dr Terence Hines of Pace University, New York State, published the most comprehensive study of the claims made for biorhythms, reviewing the results of over 130 investigations. He found that three-quarters of them failed to provide any support for biorhythms. Most of the remainder contained blunders ranging from faulty mathematics to basic errors in statistics, while the handful of positive studies were explicable as flukes.

Free runners

But while biorhythms are given little credence by scientists, there is no doubting the existence of 24-hour biological cycles – or, rather, ones roughly 24 hours long. Following de Mairan’s pioneering work, other researchers found that when deprived of the cues provided by sunlight, organisms settle down to ‘free-running’ cycles that are close to, but rarely exactly, 24 hours. In the case of humans, experiments in which people are deprived of access to daylight have shown that the free running cycle is typically around 24.5 hours long. This is the so-called ‘circadian’ cycle (from the Latin meaning ‘about a day’), the length of which is generated by our internal timekeeper – whatever it is.

During the late 1960s, chronobiologists believed they had found it, in the form of the suprachiasmatic nucleus (SCN), a collection of nerve cells in a region of the brain known as the hypothalamus. Linked to photosensitive cells in the eye, the SCN senses daylight and triggers the release of hormones like melatonin, which keep body functions in synch with the time of day.

For years the SCN and its sensitivity to daylight was regarded as the ultimate pacemaker – at least in higher organisms such as humans. But in 1971 scientists at the California Institute of Technology working with fruit flies found evidence for something truly amazing. Fruit flies appeared to have genes affecting the daily rhythm of their behaviour – suggesting that there are ‘clocks’ inside each of their cells. Further evidence for this emerged in 1995, when researchers at Massachusetts General Hospital isolated nerve cells from the SCN, and found they could maintain a circadian rhythm without help from daylight. Finally, in 1997, scientists at Northwestern University, Illinois, found a gene that regulates the daily rhythms of cellular activity in mammals.

Wake-up call

How body temperature affects alertness

During a 24 hour period, our temperature rises and falls according to our level of alertness, and reaches its lowest level when we are deeply asleep. Two dips in alertness occur around 4am and 4pm. Less well known are two alertness peaks, when we’re very unlikely to fall asleep. These peaks occur a few hours after dips in our body temperature.

Clock watching

The details of how this gene, known as CLOCK, actually works are still being calculated, but they could lead to better ways of coping with shift-work and jet-lag. “When we want to synchronise our bodies, we have more than just the SCN in the brain to worry about,” says Professor Joseph Takahashi, who led the research. “With the new knowledge that circadian clocks exist throughout our bodies, we need new strategies and therapeutics to reset all of our cells.”

The discovery that living organisms have biochemical clocks ticking inside their cells raises two questions: how do they all stay in synch – and why did organisms bother to acquire a link with sunlight? So far, no-one knows, though there are several theories. For example, sunlight might be useful in keeping the myriad cellular clocks in lockstep. “We are far from understanding how circadian clocks evolved,” says Professor Carl Johnson of Vanderbilt University, Tennessee. “We have not identified the selective pressures that led to the evolution of these timekeepers, and in most cases, the significance of the rhythms is not known.”

In the search for answers, researchers are studying the behaviour of a microbe called cyanobacterium. In 2005, a team at Nagoya University, Japan, showed that chemical reactions between three proteins produced by this bacterium ebbed and flowed on a 24-hour cycle. Cyanobacterium is the oldest form of life on Earth, so this suggests that cellular clocks have existed for over three billion years.

All subsequent organisms have followed suit, says Johnson. “Bacteria, fungi, plants and animals all appear to have evolved clock systems independently from each other.”

Quite why is unknown. But one thing is clear: the daily routine of life is certainly not a modern invention.

Popping pills

Does it matter what time of day you take medicines?

The ebb and flow of our daily circadian rhythm is most obvious in our changing levels of alertness. But it manifests itself in other ways that are no less important – including the way we react to medicine.

In 1985, the prestigious journal Science published a study of how the effectiveness of drugs is influenced by the time at which they are given to patients. Animal experiments had already suggested that anticancer drugs became far more toxic if given at certain times of the day. William Hrushesky of the University of South Carolina, US, wondered if the same effect could be observed in humans. To find out, he recruited 31 patients with advanced ovarian cancer and gave them two standard drugs – cisplatin and adriamycin – either at 6am or 6pm, with the other being administered exactly 12 hours later. The results showed that those given cisplatin in the morning followed by adriamycin in the evening suffered a much higher rate of toxic reaction than those receiving the same drugs in reverse order.

Similar findings have been discovered by other researchers. Yet despite the implications for patients, such research has so far had minimal impact on hospital practice. “It has not taken off because it complicates medical practice,” says Hrushesky. He adds, however, that he gets a steady stream of calls from individual physicians who have learned of the research, and want to put it to use in treating their cancer patients.

That said, the long-standing belief that food eaten late at night is more likely to lead to weight gain does seem to be a myth. In 2003, scientists at Oregon Health & Science University in the US reported that tests on monkeys failed to find any connection between weight gain and when the animals ate.

Follow Science Focus onTwitter,Facebook, Instagramand Flipboard