Is There a Clock in Your Head?

Internal clocks keep pace with the 24-hour cycle of day and night and light and dark, enabling organisms to adapt their behavior accordingly. Whether these daily—or circadian—rhythms help a single-celled organism anticipate the first rays of morning light or a rodent prepare for a busy night foraging for food, they are a universal feature of life on earth.

Circadian clocks govern many human activities. From sleep-starved students to active octogenarians, the body intrinsically observes a daily regimen of wakefulness and sleep. Our internal clocks keep us mentally alert during the day and prompt us to rest and recuperate during the night. The pattern continues even in the absence of external cues from the rising and setting sun. Research volunteers living in a bunker in constant dim light naturally maintain a roughly 24-hour cycle of activity and rest. Researchers have concluded that sunrise can reset the clock but that the clock does not depend on sunrise and sunset to keep time.

We generally take our biological clock for granted, but as anyone who has experienced the misery of jet lag or worked the night shift knows, disturbing our natural rhythms exacts a toll. In rare cases, severe disturbances in the body clock can be inherited, with problems affecting members of particular families. Individuals suffering from advanced phase sleep syndrome, for example, routinely fall asleep in the late afternoon or early evening, only to wake up in the middle of the night.

Despite a long-standing fascination with biological clocks, only in recent years have scientists made major progress in understanding the molecular mechanisms that regulate them. The circadian pacemaker, or control center, in humans is located in the brain's hypothalamus. A cluster of only several thousand neurons called the suprachiasmatic nucleus (SCN) governs a wide range of 24-hour physiological variations in our body, ranging from changes in hormonal levels and body temperature to susceptibility to disease. Understanding the detailed workings of the circadian clock may explain why heart attacks occur more often in the morning and why the incidence of asthma is more common at night, for example.

The breakthrough in unraveling the molecular basis of circadian rhythms came, as genetic advances so often have, using the fruit fly, Drosophila melanogaster. In the late 1960s, a student working in the laboratory of the famous Drosophila geneticist Seymour Benzer identified three mutant flies that exhibited abnormal patterns of circadian behavior. These mutant flies were named period or per mutants, and all of their circadian timekeeping problems were traced to different changes—mutations—in a single gene named per. It took some 20 years from the initial discovery to clone and determine the nucleotide sequence of the per gene, the first "clock gene."

Over the past five years, the pace of activity in circadian rhythm research has accelerated. Studies using cyanobacteria, fungi, fruit flies, mice, plants, and humans have identified a small but growing family of genes that control circadian rhythms. Many of the most important recent discoveries in this rapidly advancing field have come from the laboratories of this year's lecturers, Michael Rosbash and Joseph S. Takahashi. Their studies and those of their colleagues have unveiled the molecular choreography of circadian rhythms. The molecular players, with names like timeless, Clock, and cycle, share a remarkable degree of sequence similarity across different species. The emerging picture is of exquisitely sensitive molecular mechanisms in which the levels of specific circadian genes ebb and flow in harmony with daily light and dark cycles.

The significance of the latest research into circadian rhythms goes beyond our efforts to understand how fungi, fruit flies, and even humans track time or to devise effective new treatments for various sleep disorders. The flurry of new insights offers one of the best examples in modern biology of how complex patterns of behavior can be scripted by interactions at the molecular level. These insights are a portal into the fascinating world of genes and behavior.

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