7.3 Molecular clocks: mastering time.

Self-sustaining clocks that regulate daily and seasonal rhythms are found in many biological systems, from fungi to humans. Imagine that you're locked in a room with no clocks and no windows. For most people, the cyclic patterns of sleeping, waking, activity and hunger will soon adopt a period of about 22-23 hours — evidently, the body 'knows' the length of the day, even in the absence of visual cues. Environmental signals, such as the day-night cycle, simply modify this biological rhythm to a slightly longer period of 24 hours.

In mammals, this internal clock controls rhythmic physiology and behaviour. The clock is composed of molecular gears in measuring time. But where is the clock? When does it start ticking? And how does it work?

What is the clock?

Until the 1930s, biological rhythms were studied only by botanists. In 1729, the French astronomer d'Ortous de Mairan reported that the leaves of a heliotrope plant could open and close following a day and night rhythm. Then, 100 years later, Augustin de Candolle showed that these leaves could also open in constant darkness, indicating that the cycle was independent of the light-dark rhythm.

Research has since broadened to include almost every organism with a nucleus (eukaryotes) as well as some bacteria, and we now know that the clock consists of three conceptual components. First, there is an input pathway that links the internal cycle to external light-dark patterns. Second is the autonomous pacemaker, which generates the daily (circadian) oscillation. Finally, there is an output pathway for the expression of the physiologically measurable rhythms. For many years it was thought that the control of such complex required tissue organization and high-level intercellu­lar communications. In fact, every cell in the pacemaker constitutes an autonomous clock, with its own oscillatory properties.

Where is the clock?

In many organisms, the clock is localized in specific areas of the central nervous system. The pineal gland of birds, reptiles and fish, for example, contains photosensitive cells that show pacemaker properties and direct the circadian production of hormones. In mammals the situation is more complicated. The centre of the clock is an area in the ante­rior hypothalamus of the brain, called the suprachiasmatic nucleus (SCN). The SCN contains about 10,000 densely packed neu­rons, which are among the smallest cells in the brain.

Perhaps there are various clocks for different physiological situations, residing in distinct anatomical structures, and such parallel clocks may overlap to regulate human physiology and behaviour.

7.4 A biological defect underlying obesity

Human appetite is thought to be regulated by a delicate chemical balance between the part of the brain that stimulates the basic feeding mechanism and the various chemicals that suppress it.

It has long been known that damage to hypothalamus results in obesity, suggesting that some biological defect underlying obesity might reside in the hypothalamus. Now this defect has been found.

Over the years of work researchers suggested that a nerve-regulating chemical in the brain, and especially in the hypothalamus might influence appetite regulation. It is called cholecystokinin (CCK). Scientists compared concentrations of immunoreactive CCK in brain extracts from obese mice and normal mice. CCK in the brain of the obese mice averaged one – fourth of that in the normal mice. These findings proved a causal relationship between diminished brain CCK content and the unrestrained appetite of the obese mice.

Can CCK injections help obese people lose weight? Some animal evidence suggests that it may. More than two decades ago researchers showed that injections of enterogastrone, a preparation rich in CCK, reduced food intake in mice.