Science: Are you ticking comfortably?

It's that old chemistry: new discoveries may show how the body clock works, and identify those sexy pheromones. By Steve Connor

Tick, tock. Something is happening inside our bodies. All day and all night, our internal clocks measure the march of time. They tell us it's time to sleep, time to wake up, time to feel hungry, time to visit the bathroom. Although scientists have identified some of the key components of the body clock, its most mysterious mechanism has until now eluded their inquiry - how does it set itself to local time?

As most people know, the human bioclock runs on a circadian cycle that is slightly longer than the 24 hours of a full night and a day. This means that it must constantly have to reset itself to the local hours of daylight, otherwise it will continue to run slower and slower until it ends up expecting someone to sleep for eight hours during the day and be awake during the night. For 30 years, scientists have known that this resetting to local time involves the eyes. Blind mice, and people who have lost the sight of their eyes, are almost always incapable of resetting their circadian rhythm.

Recent lines of research have thrown the spotlight on a set of chemicals called cryptochromes, found in both animals and plants. Could these substances be the timer that keeps the human clock in check? This question is no mere exercise in academic curiosity. Understanding the human bioclock promises to help shift workers who have trouble sleeping, business travellers who experience jet lag, and sufferers of debilitating sleep disorders. Experts point out that some of the worst industrial accidents in history (Chernobyl, Three Mile Island and Bhopal) have occurred in the wee hours when our body clocks are striving to shut down brain activity. Knowing how to override the body clock's natural tendencies may save lives.

Several elements of the bioclock are already well understood. Practically every living thing appears to have an internal clock, and biologists are convinced that whatever controls the human circadian cycle must share its evolutionary origins with the clocks of other organisms. In humans, scientists have shown that melatonin, the hormone secreted at night by the pineal gland, plays a crucial role in the cycle. They have also determined that the suprachiasmic nucleus - a group of cells deep within the brain - acts as a sort of biological pacemaker, sending orders to the pineal gland on how to regulate its melatonin production.

The clock seems to go awry as people grow older. Beyond a certain age, many people find it difficult to keep to their usual patterns of activity and rest. Animal studies have shown that transplanting cells from the suprachiasmic nucleus of a foetus to an older animal restores the youthful vigour of the bioclock.

Light plays a role in influencing the pacemaker within the suprachiasmic nucleus. Bright light has been used to reset the clock of people with jet lag and some scientists believe it can avert the psychological depression associated with long winter nights - called seasonally affected disorder (SAD). What could be the mechanism that converts daylight into a physical signal to influence the pacemaker cycle of the suprachiasmic nucleus?

The blind mice research focused attention on the eyes, particularly the light-sensitive cells in the retina known as rods and cones. These contain a group of chemicals called the opsins, which are the crucial photosensitive substances used in vision. Do the opsins also act as the vital chemical timer that resets the circadian clock each day?

Russell Foster, of Imperial College of Science and Technology, led a team that tested the idea by studying another group of mice that lacked both rods and cones but whose eyes were otherwise intact. As they reported in the last issue of the journal Science, they found that these mice behave much like normal mice - exposure to light resets their clock and suppresses the production of melatonin, the nocturnal clock hormone. The research suggested that something else in the eye acts as the timer.

A team of Dutch scientists, working in collaboration with a group in Japan, was dabbling in the chemistry of DNA repair when they stumbled on something quite different. "We weren't really working on the biological clock," explains Jan Hoeijmakers, professor of molecular genetics at Erasmus University in Rotterdam. "But now we are."

Professor Hoeijmakers and his colleagues were studying cryptochromes - which in some animals are able to convert light into a form of chemical energy that is then used to repair damage to DNA. They found evidence of cryptochromes in human DNA, but became puzzled because no one had come across any evidence that these chemicals are active in DNA repair. They decided to investigate what happened when the genes for two cryptochromes - cry1 and cry2 - were deleted in mice.

Mice are nocturnal animals. After a period of 12 hours in darkness and 12 hours in light, they will continue to show a circadian rhythm, resting for 12 hours and being active for 12, even when living in total darkness for the whole 24 hours. When mutant mice lacking both cry1 and cry2 were put on 12-hour cycles of light and darkness, they behaved just like normal mice. But when the same mice were put through total, 24-hour darkness, they ran around randomly at all times of day and night. They had lost the use of their bioclocks.

More intriguingly, Professor Hoeijmakers tested the effects of deleting just one of these two genes. The mouse missing the cry1 protein still had use of a clock during 24-hour darkness, but the clock was running an hour faster. The mouse missing the cry2 protein had a clock that ran about an hour slower. "The two proteins seem to be balancing each other out," Professor Hoeijmakers says. The difference in the way the two cryptochromes work could explain why some people are more alert in the morning and some more active late at night.

"The cryptochromes not only constantly adjust the clock to the period of daylight, in order to prepare the body for changes in the seasons of the year; they also form part of the clock itself. Without them, there is no clock," the Professor points out.

It appears that cryptochrome proteins, which are present in the eye as well as the cells of the brain's suprachiasmic nucleus, may be the crucial link between the stimulus of daylight and the constant resetting needed to adjust the internal bioclock. Although there are still several missing elements to the jigsaw puzzle of what makes the bioclock tick, one central mystery appears to have been resolved. Our internal clocks use proteins in the eye, known as cryptochromes, to adjust to local time.