Feature: Timing is everything
11 September 2006. By Chrissie Giles.
The Earth moves on a 24-hour cycle and so do we. Our body clocks synchronise us to our environment, and even to the seasons' changing day lengths.
For this we can thank circadian rhythms - temporal programmes of around 24 hours (hence circadian, from the Latin circa diem, 'about a day') found in virtually all living things. Their most obvious signature is our sleep–wake cycles. But research on a wide range of organisms is revealing many clocks, working at levels from the cellular to the whole-animal.
Entraining time
If previously free-living animals are kept in constant darkness, they continue to have active and quiet periods, but these gradually cease to coincide with natural day–night cycles. The so-called free-running or endogenous period is not exactly 24 hours long. In humans, it is about 20 minutes longer than a day.
Normally, our internal clocks are reset every day. The environmental signals that synchronise or entrain circadian clocks are called zeitgebers ('time-givers'). As well as light, temperature, social cues and hormones can also act as zeitgebers.
But what's behind the running of these rhythms? A key moment was the discovery of the naturally occurring tau mutation in the Syrian desert hamster, which gives animals a shortened circadian cycle. At the time, researchers were not able to identify the gene involved, but they did discover much about the physiology of the circadian system.
The most significant finding was that the body's main circadian pacemaker is found within the suprachiasmatic nuclei (SCN) of the hypothalamus. SCN receive input directly from the retina.
Interestingly, it is not rods or cones, the image-forming cells of the retina, that entrain the SCN clock but a recently discovered class of photoreceptors not involved in image generation. Even blind people lacking functional rods and cones can still respond to light signals. The light-entraining photoreceptors contain the light-sensitive pigment melanopsin.
From its position in the heart of the brain, the SCN master clock orchestrates a wide range of neural and hormonal signals, which drive a multitude of cyclical responses around the body.
One part of the SCN contains an endogenous 24-hour clock, which continues to tick even in complete darkness. The molecular mechanism of this is now well understood – thanks to work on organisms as diverse as fruit flies, mice, fungi (Neurospora makes spores on a 22-hour cycle even in darkness), plants and cyanobacteria (Synechococcus carries out incompatible biochemical processes – photosynthesis and nitrogen fixation - at different times of day).
Researchers looking at the circadian clock long suspected it had a genetic basis, but it wasn't until the 1970s that the first 'clock gene' was identified: Period (Per) in fruit flies.
The genetic approach has since helped scientists unravel many aspects of clock function. The main mammalian clock genes are summarised in the table. Central to all clocks are endogenous oscillators – gene-based systems that cycle with an intrinsic regular period, like a pendulum. Since isolated cells show cyclical behaviour, endogenous oscillators must operate at an intracellular level.
A typical clock is based on autoregulatory feedback pathways, which at their simplest could involve just one gene (see diagram below). In 2005, a Japanese group created an oscillating system in a test-tube using just four molecules from Synechococcus. However, their system continued to oscillate in constant darkness, when cyclical gene activity had disappeared, hinting at greater complexity. Indeed, clocks are turning out to be highly sophisticated molecular devices.
Clocks use a wide range of mechanisms. As well as cyclical gene activity, the level of messenger RNAs is finely controlled, and the activity of clock proteins is regulated by modifications such as phosphorylation (addition of phosphate groups) and by degradation. Control by phosphorylation provides flexibility, allowing multiple signalling systems to feed into circadian rhythm generation in the cell.
Because endogenous oscillators are self-contained systems, more than one clock can operate in the same cell. Within the body, peripheral clocks lag around three to nine hours behind that of the SCN. The peripheral oscillators allow specific tissues to tailor their responses to particular environmental signals.
Intriguingly, clock effects are even involved in communication, at least in fruit flies and honeybees. Pheromones cyclically released by one individual can affect the activity of circadian genes in another - helping to coordinate behaviour across a colony, say.
Human rhythms
Although we all show similar sleep patterns, we exhibit different chronotypes. 'Morning' and 'evening' people really do exist. Recent research from Dr Simon Archer and colleagues at the University of Surrey, funded by the Wellcome Trust, suggests that there is a genetic contribution to sleep patterns, possibly variation in a human version of the PER gene.
In extreme cases, genetics can play havoc with sleep patterns. In advanced sleep phase syndrome people fall asleep early in the evening and wake very early in the morning. Often more problematic is delayed sleep phase syndrome, where people wake up abnormally late. People with this syndrome - associated with a polymorphism in PER3 - may struggle with regular '9 to 5' jobs.
Shift work and jet lag have usually been thought of as nuisances, but the discordance between natural body rhythms and daily activities can cause disordered sleep patterns, mood disorders and other medical problems. In shift work, the risk of accidental injury is significantly increased.
Perhaps more disturbing is a recent report that women who worked rotating night shifts for over 20 years had an increased risk of breast cancer; the same may be true of air hostesses. Some suggest that disruptions to our endogenous clock caused by extensive exposure to night-time light may be contributing to the increased incidence of breast cancer in the industrialised world. Indeed, destruction of the SCN renders mice more susceptible to experimentally induced cancers.
Circadian rhythms are also disturbed in depression, bipolar disorder and schizophrenia - though it is unclear which is cause and which effect. Light therapy is used to treat seasonal affective disorder and may have potential in other psychiatric disorders.
The hormone melatonin is a zeitgeber for the circadian clock and is sometimes used by travellers keen to avoid jet lag. It is not licensed in the UK, however, as its full range of effects is unclear.
Its potential role in cancer and mood disorders is currently being studied. A new agent, agomelatine, that mimics the action of melatonin in rodents, has been submitted to the European Regulatory Agency as an antidepressant in humans.
Treatment can also benefit from an understanding of circadian rhythms. The power of pain-relievers such as morphine varies through the day. In the emerging field of chronotherapy, doctors administer treatments such as chemotherapy and radiotherapy at particular times of the day, when healthy tissues are most resilient to treatment, and cancer cells most susceptible.
References
Lowrey PL, Takahashi JS. Mammalian circadian biology: elucidating genome-wide levels of temporal organization. Annu Rev Genomics Hum Genet 2004;5:407–41.
Merrow M et al. The circadian cycle: daily rhythms from behaviour to genes. EMBO Rep 2005;6(10):930–5.
Klerman EB. Clinical aspects of human circadian rhythms. J Biol Rhythms 2005;20(4):375–86.
Bell-Pedersen D et al. Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nat Rev Genet 2005;6(7):544–56.