Biological Rhythms Health Article

Physiology of biological clocks

The physiological location of biological clocks has been studied in a number of animal systems, including humans. In most vertebrates other than mammals—sparrows, for example—the primary biological clock has been located in the pineal gland. This gland is located at the base of the brain and is responsible for the production of melatonin, a hormone produced in high levels at night and low levels during the day.

In mammals, additional cells responsible for biological clock functions were located in the hypothalamus, in two clusters of nerve cells called the suprachiasmatic nuclei (SCN). Light receptors in the retina are connected by nerves to the SCN. The SCN and the mammalian pineal gland are linked, by both nervous connections and by the presence of melatonin receptors on SCN cells. Thus, light is detected by the eye, which passes this information on to the SCN, which in turn passes the information on to the pineal gland, controlling melatonin production.

The exact function of melatonin in mammals is not completely understood. Scientists believe this hormone is likely involved in many aspects of biology, including the wake-sleep cycle, body temperature control, and (particularly with mammals that have seasonal mating) sexual maturity and reproduction.

Genetic control of biological clocks

The molecular basis for the control of circadian rhythms has been studied extensively in the fruit fly insect model, where the first genetic mutants that affected circadian rhythms were discovered. Because homologs to the fruit fly genes (genes which have a similar structure, and therefore likely have a similar function) have been discovered in mammals, including mice and humans, scientists strongly suspect that similar control mechanisms have been conserved in mammals.

In fruit flies, five genes are believed responsible for the baseline oscillation of the circadian rhythms: period (per), timeless (tim), clock (clk), cycle (cyc), and double-time (dbt). The protein products of these genes work together to produce a negative feedback loop that allows the concentration of the period and timeless proteins to build in concentration slowly over the 12-hour day. Both clock and cycle are positive transcription elements. These proteins work together to result in the production of the period and timeless proteins.

When the period protein is produced, the doubletime protein modifies it, marking it with a phosphate molecule for quick destruction by the cell if not paired with the timeless protein. Thus, the period protein will be degraded until the concentration of timeless protein is high enough so that period and timeless dimers form. The destruction resulting from the phosphate modification delays the formation of the dimers, stretching out the process over the 12-hour evening.

Eventually, dimers of period and timeless are present in high enough concentrations to interact with clock and cycle proteins to turn off production of both period and timeless proteins, closing the feedback loop. At dawn, the highly light-sensitive timeless protein is degraded, leaving the phosphorylated period protein unpaired and vulnerable to degradation as well. In this way, light resets the feedback loop to start again, making it the Zeitgeber for this biological clock.

In early 2001, studies of the molecular basis of biological rhythms were extended to humans, with the report of the first known human gene homologous to the fruit fly genes. The gene is called hPer2 and is homologous to the period gene. A mutation in this gene is present in a Utah family and results in an advanced sleep phase syndrome. The mutation maps to the location where the period gene is marked with a phosphate, suggesting that the mutant protein would be not be phosphorylated. The details of the mutation fit the proposed function of the protein and the problems seen by those having the mutation. Lack of phosphorylation would cause the mutant protein to be degraded more slowly, speeding up the circadian rhythms of the person having the mutation.

Role in human health

The exact role of biological rhythms and biological clocks in human health is not fully understood. However, it is clear that humans are subject to biological clocks in a number of physiological areas, most notably hormone secretion and wake-sleep cycles. A well-functioning biological clock is important for falling asleep and getting enough of the various stages of normal sleep. This affects, in turn, alertness, job performance, interpersonal relationships, and day-to-day safety issues. Well-functioning circadian rhythms may also play a role in psychological health, particularly for persons living in areas with decreased light in the winter months.