FLY FAR ENOUGH FROM HOME and you become groggily aware of the clock inside your head. Suddenly, going to bed seems tempting at 2 p.m., or your eyelids may snap open and refuse to shut again at midnight. Then you know — not only does the body have an internal timekeeper, it's out of synch. Welcome to jet lag.

Humans and other organisms don't just have one clock inside their bodies: they have the makings of an entire clock shop. There are central clocks in the brain and multiple peripheral clocks both in the brain and elsewhere in the body. The clocks in this metaphorical shop are a strange lot:

• They can coordinate efforts, sometimes deciding time by consensus and sometimes bowing to the opinion of the central clock.
• They can keep time with the window shades in the clock shop drawn, free of any input from the outside world, such as sunlight. They can also alter their settings on the basis of clues like sunrise and sunset.
• Each clock is made up of "gears" that are themselves clocks: individual cells that contain a specialized group of proteins that react with each other in a cycle that regularly restarts itself over a particular length of time.

Insights into these clocks could fix more than just jet lag: They have implications for the treatment of sleep disorders, for fully understanding time-related factors that control the body's response to pharmaceuticals and increase the chances of heart attack, for dealing with potentially serious metabolic disorders and depression, and for control of fertility.

Time flies: The Taghert lab studies timing mechanisms in fly brain cells. Researchers monitor the activity of flies in chambers, above, over the course of several weeks. The Herzog lab focuses on the "master" circadian pacemaker in mammals — the suprachiasmatic nucleus (SCN), which regulates daily rhythms including sleep-wake, hormone release and body temperature.

THE STUDY OF THE CYCLES of these clocks — big and small, central and peripheral — is known as circadian biology. Washington University has an unusually diverse group of circadian biologists that meets monthly in a discussion group called the Clock Club (see sidebar at bottom of page).

Circadian researcher Paul H. Taghert, PhD, professor of anatomy and neurobiology, notes that he and his colleagues typically divide their field into three areas.

The first area, the clocks, includes both the groups of specialized cells at various parts of the body that track the passage of time and the individual clock cells or gears that compose those groups.

The second part, the inputs, refers to the factors like changes in the timing of sunlight that can lead to adjustments in the time kept by the internal clocks.

The final segment, the outputs, describes signals that go out from the clock cells to various parts of the body to turn a process on or off — for example, to begin warming up the body temperature in preparation for getting up from bed in the morning.

"We divide the system up this way, but you can't really talk about one part without talking about the other two," says Taghert. "For example, an output of one clock can feed back into another clock, becoming an input."

Given that caveat, Taghert cites outputs as the primary focus of his laboratory, where they work with the fruit fly, a classic model for circadian biologists because of the ease with which scientists can modify or delete genes and assess the effect. The trails Taghert's group follow begin in the fruit fly's brain, where they and other scientists have identified 150 of 10,000 brain cells as clock cells. From there, they track the metaphorical circuits of the clock systems in the twining of cell branches and the tumble of molecular signals from one cell to another.

"We look at where the cell branches go, what signals they release and when they release them, and who is listening," he says. "We're hoping that path doesn't get too complicated too fast by branching and feedback between the different clocks and other biological systems."

To the extent that his research can be pinned to an area of circadian biology, Erik D. Herzog, PhD, professor of biology in the School of Arts and Sciences, casts his lot with the clocks. One of his primary interests is understanding how different clocks consult each other to determine the time, like people with watches regularly interfacing to decide whose watch is the most accurate.

"We're thinking of it as a political system with many different individuals, each with an opinion about what time it is," he explains. "And they vote and influence the opinions of others."

Herzog modifies genes and removes brain cells, looking for effects on the activity schedules of the mice. Herzog's laboratory contains 100 small chambers where mice can be kept with computer-controlled, customizable exposures to light and dark periods. When a mouse wakes up to begin its day (which begins at the onset of what humans think of as nighttime) with a run on the activity wheel, that run is automatically recorded by a remote monitoring system.

Paul H. Taghert, PhD, and Weihua Li, PhD, view an activity monitor containing fruit flies.

TIMEKEEPING SYSTEMS have been highly conserved through evolution, notes Taghert. Clock mechanisms developed in early life forms passed down relatively unchanged to later, more complex organisms.

For example, fruit fly studies helped scientists identify Period, the first gene associated with circadian rhythms. Based on study of the fly Period gene, scientists were later able to identify three structurally and functionally similar genes in human DNA, now known as Periods 1 through 3. One of these genes is mutated in patients with advanced phase sleep syndrome, a condition that causes them to be sleepy at dinnertime but alert at 3 or 4 a.m.

"Our field has begun to recognize that clocks are involved in regulating everything from the cell cycle to sleep to metabolism to cognitive behavior," Herzog says. "And so now we recognize that when clocks go bad, the consequences can be dire."

Herzog and Taghert can cite multiple examples. Disruption of the clock system has been linked to fatal metabolic disorders and to depression. Heart attacks occur more frequently in the early morning hours, leading to suspicion that changes induced at that hour by the circadian system are increasing heart attack risk. Regular timing of ovulation likely plays an important role in fertility.

Better understanding of the circadian system also may help scientists find ways to treat very common conditions like jet lag, age-related sleep disruption and the symptoms experienced by people who work outside regular business hours.

"Medical staff, reporters, law enforcement — many of the symptoms they complain about are similar to what we'd describe as jet lag," Herzog explains. "What we learn now may one day help us seek new treatments for those conditions."

Other Washington University researchers with interests in circadian biology: Paul A. Gray, PhD, assistant professor of anatomy and neurobiology, studies the neural circuits that underlie basic behaviors. His lab has identified a group of neurons in rats that may be responsible for generating breathing rhythms in mammals. Louis Muglia, MD, PhD, director of pediatric endocrinology and associate professor of pediatrics, molecular biology and pharmacology, and of obstetrics and gynecology, is a clinician-scientist who specializes in endocrine regulation of behavior — the release of hormones that affect mood, energy and other characteristics. His lab recently found that resistance to circadian glucocorticoid action leads to depression. Paul J. Shaw, PhD, assistant professor of neurobiology and anatomy, studies sleep patterns in flies, looking for genes linked to the timing of sleep and probing how disruptions in the activity of these genes affect behavior when the subjects are awake. Shaw also uses mice to see if the fly genes he identifies have mammalian counterparts that affect sleep. Russell N. Van Gelder, MD, PhD, associate professor of ophthalmology and visual sciences and of molecular biology and pharmacology, is a clinician-scientist whose interests in degenerative eye disorders have led him to explore connections between the eye's retina and the master timekeeping cells in the brain's suprachiasmatic nucleus (SCN). Van Gelder's research is helping reveal how daylight detected by cells in the retina can reset or adjust the cycling of clock cells in the SCN.