Unwinding the Body Clock
Your body, if you pay attention to the way it ticks, may be your best timekeeper. At dawn, your blood pressure has its sharpest rise, allowing you to safely assume a vertical position. Around lunchtime, your liver enzymes kick into full gear in anticipation of food. In the evening, the pineal gland in the base of your brain begins producing the hormone melatonin, which makes you feel sleepy. As you sleep, your body temperature drops. In the morning, as the sun comes up and light hits your retinas, your body stops making melatonin and your temperature rises, revving up your metabolism for the day ahead.
© 2004 James Collins
External cues keep the body in sync.
Many basic biological functions follow a 24-hour cycle. These rhythms—called circadian, Latin for "about a day"—are hardwired, controlled by a master clock, a cluster of specialized nerve cells in the hypothalamus, and other subservient clocks in the tissues of the body—the liver, for example. Still, cues like the sun or an alarm clock are crucial for keeping these internal clocks in sync with the external world.
While researchers know that the clock in the hypothalamus is in charge, they're not sure how it works with the millions of other clocks in the cells of the brain and body. "Biological timing is even more complicated than we thought five years ago," biologist Gene Block told attendees at the 2004 Penn State Lectures on the Frontiers of Science. Most of the research today is at the molecular level, using genes and proteins from fruit flies and mice to tease apart clock mechanisms, he added. But the more researchers learn, the more complicated the body's timekeeping system seems.
Sleep bunkers and zeitgebers
Early circadian rhythm experiments were a little simpler and usually involved tracking the sleep patterns of people, Block noted. Groundbreaking work took place in the late 1960s and early 1970s, when dozens of volunteers spent weeks in underground bunkers at the Max Planck Institute near Munich, Germany. The volunteers—mostly students looking for extra money and a quiet place to study for exams—lived in isolation, with no exposure to daylight, no clocks, and no way to measure the passage of time. Researchers monitored their sleep patterns, body temperature, and a host of other rhythms.
Over the course of the experiment, almost all of the people settled into a 25-hour cycle, gradually falling out of sync with above-ground dwellers on a standard 24-hour cycle. Interestingly, a small percentage of them developed a cycle that was closer to 48-hours, often staying awake and active for very long stretches of time. However, their body temperatures still fluctuated on cycle that was close to 25 hours.
© 2004 Courtesy of Gene Block
Gene Block
These "sleep bunker" experiments, said Block, told researchers that body clocks are somewhat independent from the 24-hour clock the world runs on. Exposure to light and other external cues - zeitgebers, as the German researchers called them—is necessary to reset internal clocks and keep people in sync with the natural cycles of day and night. The experiments also demonstrated that some people—those 48-hour folks, for example—have their own unique rhythms.
Clock genes
Around the time these sleep experiments were taking place at the Max Planck Institute, researchers were beginning to explore the genetic basis for biological rhythms. In 1971, the first clock gene was discovered in the common fruit fly, Drosophila melanogaster. Advances in genetic and molecular techniques over the last decade have led to an explosion in the number of clock genes discovered, most of them in more complex animals like mice. Today, researchers are still identifying new clock genes and proteins, but they're also trying to understand how all of these timekeeping components work together.
A clock within a cell is really just a simple chemical loop. For example, the clock genes period (per) and timeless (tim) switch on early in the night and begin making their corresponding proteins, PER and TIM. When the proteins reach a certain concentration in the cell, they bind together, move into the nucleus, and block the cell's protein-making mechanism, shutting down the work of the genes. After a while, the protein structure falls apart and the genes switch on again. When normal copies of the genes are present in the cell, this chemical loop plays out over a roughly 24-hour period. You can actually observe the cycle in a Petri dish, said Block. "The cells are outside of the brain, in culture, and they're still generating electrical activity in cycles." That 24-hour electrical rhythm is generated by the genes switching on and off as they make the proteins.
The bigger question, said Block, is how all of the clocks in the cells throughout the brain and body stay calibrated and running smoothly. And what happens if someone has a sleep disorder, or works the night shift, or travels across multiple time zones? Researchers at several labs, including the Center for Biological Timing at the University of Virginia, which Block directs, are tackling the question of clock coordination. In one experiment, Block and his team exposed different cells from mice to changing cycles of light and dark, meant to represent time zone changes travelers might experience. While the master clock cells adjusted rapidly to each new "time zone," clock cells from other parts of the brain and body took much longer to adjust.
Understanding body clocks at the molecular level could help researchers develop drugs that will help people whose clocks are out of sync, said Block. But, that's not an easy task. To be successful, a drug would have to do more than target just the master clock. "The reason you feel terrible is because all of the clocks are out of sync. It's a system problem."
