July 08, 2006

IN 1729, a French astronomer by the name of Jean Jacques de Marion was intrigued by a plant in his garden, which opened its leaves in the morning and closed them in the evening. He wondered if the widely held belief that this was triggered by the appearance and disappearance of sunlight was correct.

To test this, he transferred the plant to a dark room. The plant continued to open and close its leaves at exactly the same time! This proved that there was a sensitive timing mechanism within the plant, which operated independently of the sunlight.

In 1737, a Swedish botanist, Carolus Linnaeus, made a similar observation. He noticed that the flowers of different plants opened at different times and this process was so accurate that one could even tell the time of the day! It seemed as if the plants had internal clocks!

More than 200 years passed before scientists discovered that the internal clocks are indeed present and found not only in plants but also in all animals. This led to the birth of a whole new science of biology, known as chronobiology, which is essentially a study of body functions in relationship to time.

Chronobiologists first concentrated their attention on finding the location of the so-called internal clock or clocks. Many animals were used for this purpose, but the fruit fly (Drosophila iticlatiognster) was the most useful, as it was easy to breed in large numbers and had a sleep-wake cycle like that in the higher animals, which is presumably controlled by an internal clock.

It was discovered that animals had two types of internal clocks — a central clock in the brain and peripheral clocks in other organs of the body. These clocks work in unison. The destruction of the central clock makes the peripheral clocks inoperative, but the destruction of the peripheral clocks did not impair the working of the central clock.

The genome of the fruit fly has recently been sequenced and the gene responsible for the programming of the clocks has been identified. The same “clock gene” is found in all mammals and in humans, which means that it is a highly conserved gene, and important for the survival of all animal species.

We now know that the central clock in mammals and in humans is located in a group of cells in the hypothalamus just above the optic chiasma (the crossing of the optic nerves at the base of the brain), and called the suprachiasmatic nucleus (SCN). The light sensors found in the retina have a pathway to the SCN.

The retinal cells convey the information about the ambient light to SCN which interprets it as day or night. SCN then sends the information via the spinal cord to the pineal gland (so named because it resembles a pine cone). The pineal gland secretes a hormone called melatonin in response to the message.

If it is night, melatonin secretion rises and sleep is induced. If it is day, melatonin secretion decreases and the person wakes up. In one of the most exciting discoveries in the field of chronobiology, the light sensors in the retina have recently been identified by David Berson of the Brown University.

Dr Berson said that a deeper understanding of the light sensors might lead to a novel treatment for disturbances of the body’s internal clock. It may turn out that the people who have defective light sensors could suffer from “time blindness” (similar to colour blindness), causing sleep problems.

The sleep-awake cycle varies a great deal from animal to animal. For instance, in giraffes the sleep time is estimated to be only 1.9 hours, while in bats it is about 19.9 hours. In humans it is 8 hours. During sleep, the body temperature, urine production and the secretion of various hormones all drop under the influence of internal clocks.

The jet lag that occurs during air travel is because it creates a disharmony between SCN timing and the light cue which it receives from the retina, the passenger being in a different time zone. It may take a few days for the SCN to get reset to the new timing, but before that happens the sleep pattern becomes very irregular. Administration of melatonin has been shown to hasten the resetting of the SCN.

SCN also needs resetting during seasonal changes from summer to winter and vice versa. This is especially true in countries where the seasonal variation is very marked in terms of light and darkness. Individuals, in whom resetting has not occurred, may develop a form of depression during winter, known as Seasonal Affective Disorder (SAD).

SAD patients may complain of lack of energy, overeating, excessive sleeping, weight gain, and a craving for carbohydrates and sweets. SAD can be treated by bright light therapy, in which the patient is exposed to bright light (1000 lux intensity) for 30 minutes each morning.

The light helps in resetting SCN and the symptoms of SAD abate or disappear. Light is therefore the dominant stimulus which affects the SCN, and as the Earth rotates on its axis producing alternating day and night, a rhythmic activity results. This is known as the circadian rhythm, from circa, meaning “about” and diem meaning “day”, as the circadian rhythm controlled by SCN is approximately 24 hours.

In January of 1998, scientists from the Laboratory of Human Chronobiology at Cornell University in New York discovered that by shining a bright light for three hours on the back of the knees, they could reset the SCN by a few hours. This may turn out to be a useful technique for overcoming the jet lag and future airplanes may provide a light source placed under the passenger seats for this purpose!

It is common knowledge that some individuals are alert and productive at midnight, while others can’t keep their eyes open at this time. This could be connected to our gene, as some findings have shown. Recently, a female patient came to the University of Utah, in Salt Lake City, USA, complaining that she falls asleep at 7.30pm and wakes up around 4.30am. All members of the family have the same problem.

All of them were suffering from a condition known as familial advanced sleep phase syndrome (FASPS). Later studies on this family, done at the Howard Hughes Medical Institute, revealed that all its members had a mutation in one of their genes. This mutation set the SCN a few hours earlier than the normal.

The aging process adversely affects SCN functioning as some of the neurons in SCN degenerate. As a result, melatonin production decreases. The elderly (over 65) are therefore more likely to suffer from sleep disorders. The problems include frequent daytime naps, less total nighttime sleep and a phase shift causing them to go to bed early and get up earlier, as in FASPS.

The internal clocks regulate the reproductive cycle in many animals. In a series of remarkable experiments, male hamsters were shown to change their testicular size, and thus their reproductive capability, in response to the length of the day.

Hamsters breed and bear their young during spring and summer, when the days are long, so that the newly born are able to move around and find food. As the days shorten, the male hamster’s testes shrink and spermatogenesis stops. The cessation of reproduction occurs at the time of the year when the survival of the young could be jeopardised by unfavourable weather conditions and difficulty in finding food. So, when Tennyson wrote, “In the spring a young man’s fancy lightly turns to thoughts of love,” he was not imagining and making things up.

Research now reveals that the administration of medicine at the right time makes them more effective because disease manifestations are also controlled by internal clocks. Medications for asthma, cancer, epilepsy, cardiovascular disease and allergies all have shown better results, if administered at the right time.

The right time is the time when the drug is most needed. For example, the blood pressure is at its highest in the morning, which is why heart attacks are most likely to occur early in the day. A constant dose of medication will push the blood pressure lower than needed during the night, without sufficiently reducing it during early morning.

Similarly, many of the asthma patients suffer most at about 4am, so the appropriate time for medication would be 3am to prevent an attack, rather than at 8pm, which is usually the case.

Rheumatoid arthritis hurts most in the morning hours, when the body’s natural anti-inflammatory agents appear to be low. This would therefore be the best time to take aspirin or other painkilling drugs.

We have come a long way from de Marion’s observations made on plants in 1729. We now know the location of most of the internal clocks in humans and we also know that they have a profound effect on virtually all physiological activities.

However, we still do not know how to reset the clocks. For instance, if we are able to reset the clocks responsible for aging we may not only be able to extend our lifespan but also overcome many age-related diseases. There is no doubt that chronobilogy has the potential of bringing great benefit to mankind and many new discoveries are waiting to be made.

Published with permission from World Scientific, the publishers of Prof Zaman’s book Life sciences for the non-scientist

 

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