Timing is everything
Besides the one in the brain, biological clocks have been found all over the human body
The human body is a master timekeeper. It knows when to spur us to eat, sleep, or gear up for activity. It has predictable daily, or circadian, rhythms that make sure all its parts are doing the right thing at the right time.
There was once nearly universal consensus that controlling such a complicated function could only be a job for the brain. But in recent years, scientists have drastically changed their ideas about how our bodies tell time.
"We now know that there are clocks all over the body," said Dr. Steven Reppert, a neurobiologist at the University of Massachusetts Medical School. "They're widespread."
The master clock in the brain is now increasingly seen not as the body's only clock, but as the conductor of a seemingly limitless number of peripheral clocks, including those found in heart, liver, lung, and retina cells. Though research into these clocks is still in its infancy, it could have profound implications for human health.
Data show that daily patterns can affect both diseases and their treatments. The symptoms of conditions ranging from asthma to cancer vary by time of day, as does the effectiveness of medical interventions -- though research into peripheral clocks is too preliminary to know whether they play an active role in disease.
"People are starting to realize how important timing is to all aspects of life," said Michael Rosbash, a molecular geneticist and chronobiologist at Brandeis University. "You could pick up a paper and find that something you never thought of as being circadian has these rhythms. The field is starting to penetrate medicine and physiology in a way it never has before."
Recent studies indicate that destroying circadian rhythms entirely can severely compromise health. Animals with no functioning clocks display many physiological problems, including infertility, high cholesterol, and conditions that resemble diabetes, obesity, and metabolic disorders.
"That doesn't mean that there are necessarily any humans walking around with these problems caused by their clocks," said Dr. Charles Weitz, a neurobiologist at Harvard Medical School. "But we can certainly learn a lot about the related pathways and processes."
The body's master clock is set by light. When light hits the retinas in the morning, for instance, the eyes communicate this information to the master clock, which then sends messages out to the rest of the body telling it to prepare for activity.
The location of this master clock was pinpointed in 1972, in a network of neurons in the hypothalamus called the superchiasmatic nuclei, or SCN. It was considered the body's only important clock until the mid-1990s when advances in molecular genetics allowed scientists to search for the genes that governed circadian rhythms at the cellular level. Rather than having to look for evidence of circadian rhythms in organism-wide hormonal and behavioral changes, scientists could actually study circadian gene expression, watching daily patterns of certain genes turning on and off. This advance allowed them to take their search for biological clocks to the level of the individual cell.
In 1996, researchers found that cells taken from the retina exhibited predictable rhythms over the course of a day. Shortly thereafter, scientists discovered that fibroblasts, cells in body tissues such as tendons, could be induced to act the same way.
"These organs, in isolation from the rest of the animal, have circadian rhythms that you can measure," Weitz said. "And they go for weeks."
Since peripheral clocks can't detect light directly, they rely on the master clock to synchronize their activity, though scientists still don't know exactly how. Research has shown that if liver cells, for instance, are cut off from signals from the SCN, the individual cells maintain their rhythms, but lose synchrony with one another.
"What the SCN is doing is keeping all the liver cells together," Reppert said. "The SCN is the orchestra leader."
But having clocks distributed in many cells, tissues, and organs throughout the body, does not mean that the body operates on one unified schedule. Clocks in the organs can run hours behind the master clock, peaking in their production of certain proteins long after the SCN.
Though peripheral clocks seem unable to directly detect light, research has shown that they respond to food, altering their rhythms to fit the body's feeding schedule. This finding, Weitz speculates, could indicate that the function of these clocks is to prepare the body for alternating periods of eating and fasting throughout a 24-hour period.
"You have these two extreme states, but they're not coming at random," Weitz said. "It could turn out to be able to be very important for organs to be able to anticipate when nutrients are going to be available."
Interestingly, the master clock seems impervious to altered feeding schedules and maintains its normal rhythms, said David Weaver, a neurobiologist at the University of Massachusetts Medical School. When animals eat regularly at times when they are supposed to be inactive, the result, he said, is "internal desynchrony. Organs don't maintain their normal temporal relationships" to the brain clock.
Experimentally shifting an animal's usual light-dark cycle, which mimics phenomena like shift work or jet lag in humans, can also disrupt the normal relationships between clocks. "The brain clock shifts over quite rapidly to the new schedule," said Fred Davis, a neurobiologist at Northeastern University. But "the peripheral oscillators may require weeks before they switch over. The consequences for the health and well-being of the animal are not clear."
Scientists are still trying to untangle the specific functions of the peripheral clocks. Weitz, for instance, has genetically engineered mice to have no clocks. When he restored circadian rhythms in their livers, Weitz was able to reverse their abnormal cholesterol and lipid levels.
He is also conducting experiments using the reverse approach, selectively knocking out individual clocks -- either in the liver, ovaries, pancreas, or retinas. A paper on his findings in mice without retina clocks will be published in the journal Cell this week. The research is still preliminary, but already shows that knocking out any one of these individual clocks results in observable changes in the rodents.
"There's some really important information in here about something," he said, "but we don't know exactly what." 