All Wound Up

Our body wants to eat, sleep and work at specific times. Scientists now know what makes the biological clock tick, writes T.V. Jayan

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All living organisms — humans are no exception — are controlled by a master clock. This biological timepiece, located in the brain, aligns an organism’s biological, behavioural and physiological activities with the day and night cycle. Its tick tock wakes us up in the morning, reminds us to eat at regular intervals and tells us when to go to bed.

But what sets this internal timekeeping, known as the circadian rhythm, has remained a mystery for long. This, despite scientists having had clues about its existence for more than a century.

The puzzle is slowly unfolding, thanks to advances in modern biology that offer a better insight into genes and their workings. Scientists now know the exact location of the master pacemaker and how is it regulated.

Research has also shown the circadian rhythm shares a reciprocal relationship with metabolism. In other words, while the circadian rhythm can influence metabolic activity, food intake can also modulate the functioning of the biological clock.

The mechanism by which feeding modulates the components of the clock machinery was discovered last month by a team of researchers led by Gad Asher of the University of Geneva. The paper, which appeared in the latest issue of Cell, shows that a protein called PARP-1 is at play here. The scientists found that mice that lack the gene that secretes PARP-1 fail to give the correct food intake cues to the circadian clock, thereby disrupting the synchronisation.

“This is an important finding,” says Raga Krishnakumar, a University of California San Francisco University researcher who, together with her former mentor W. Lee Kraus, showed early this year that PARP-1 is a multi-faceted protein that also regulates the expression of another protein which plays a vital role in aging, apart from helping contain DNA damage.

Scientists believe disruptions in the synchronisation between the circadian rhythm and metabolism play a key role in triggering many disorders that plague the modern world such as obesity, diabetes and cardiovascular diseases.

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The master clock occupies a tiny area in the hypothalamus region of the brain. Called the suprachiasmatic nucleus (SCN), this brain region — the size of a grain of rice — contains a cluster of nearly 20,000 neurons. These neurons, in response to light signals received from the retina, send signals to other parts of the brain as well as the rest of the body to control a host of bodily functions such as sleep, metabolism, body temperature and hormone production.

As per the cues received through these neurons from the master clock, the cellular clocks in the tissues in different body organs are reset on a daily basis. The operation of these cellular clocks is controlled by the co-ordinated action of a limited number of core clock genes.

The year 1994 was a watershed year in research on the circadian rhythm. American Japanese scientist Joseph Takahashi, working at Northwestern University in the US, discovered the genetic basis for the mammalian circadian clock. The gene his team discovered was named CLOCK in 1997. Subsequently, scientists discovered several other genes associated with the timekeeping function such as BMAL1, PER and CRY, which are also involved in the working of the main SCN clock machinery as well as subsidiary clocks in other parts of the body.

The cues received from the master clock are important. Based on them, various genes in the cells change their expression rhythmically over a 24-hour period. It times the production of various body chemicals such as enzymes and hormones so that the body can function in an optimal fashion.

In the normal course, the body follows the master clock in setting its physiological and psychological conditions for optimal performance. While the 24-hour solar cycle is the main cue for resetting the master clock — just like a wall-mounted clock resets after a 24-hour cycle — there are other time cues as well: food intake, social activity, temperature and so on. “Unlike geophysical time, the biological clock does not follow an exact 24-hour cycle on its own. Various external and internal time cues that it receives play a vital role in bringing the periodicity close to 24 hours,” says Vijay Kumar Sharma of the Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, who has been studying the circadian rhythm for years.

However , modern society often imposes deviations from the regular work-rest cycle. “Basically, mammals including humans are diurnal (active during the day rather than at night). Whatever be the external compulsions (night shifts or partying late), the inner mechanisms of the body follow a diurnal pattern,” says Sharma. “It is bound to be out of sync if we deviate from the routine.”

“A major consequence of modern lifestyle is the disruption of the circadian rhythm. This leads to a number of pathological conditions, including sleep disturbances, depression, metabolic disorders and cancer. Studies reveal the risk of breast cancer is significantly higher in industrialised societies, and that the risk increases as developing countries become more and more westernised. Moreover, a moderate increase in the incidence of breast cancer is reported in women working nightshifts,” says Sourabh Sahar, a researcher working on the circadian rhythm at the University of California, Irvine.

Need more proof that the body has a mind of its own?

Source: The Telegraph (Kolkata, India)

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