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Frontiers
Taking Apart the Body's Clock: How Do Molecules Tell Us the Time?

December 1996

Humans have always measured their existence with outward signs of the passage of time: day and night, sunrise and sunset, the ebb and flow of tides, and the change of seasons. And not surprisingly, our internal clocks, set to a 24-hour or circadian schedule, tend to match these natural cycles.

But today, the 24-hour workplace, frequent flights across time zones, and our inability to sleep on cue are forcing researchers to take a closer look at our biological clocks.

Biological clocks exist inside most of the world's organisms. The clock tells bears to hibernate, honeybees to deposit their nectar, and molds to discharge their spores.

In humans, the clock is more technically known as suprachiasmatic nucleus--a small cluster of about 10,000 brain cells located above the optic nerve in the hypothalamus. It governs our metabolism, digestion, and the sleep-wake cycle, and is resistant to abrupt changes in routine. Our clocks also regulate some lesser known daily cycles by which our sensitivity to drugs, our temperatures, our tolerance to pain, and our various hormone levels rise and fall with predictable regularity.

Yet, despite their significance, biological clocks of humans and other organisms are only beginning to be understood. How does the body set up the clock? What genes control it? How do the genes keep track of time, and how do they interact with the rest of the body?

Gaining control of this clock, researchers claim, could produce many benefits, including lowering blood pressure, improving drug metabolism, overcoming jet lag, and helping shift workers function efficiently.

FINDING THE GEARS AND SPRINGS

This is why Gene Block, Director of NSF's Science and Technology Center for Biological Timing at the University of Virginia in Charlottesville, hopes the public will become more familiar with the study of biological timing. The Center, which operates in conjunction with the University of Virginia, Northwestern University, The Rockefeller University, and Brandeis University, is investigating a field that covers everything from high-frequency oscillations within the nervous system, to the 24-hour clock, to much slower clocks, such as reproductive cycles.

"A primary focus of the Center," says Block, "is to understand the cellular and molecular mechanism of the biological clock."

Geneticist Michael Young has taken the Center a long way toward achieving that result. Young and his colleagues Michael Rosbash and Jeffrey Hall, both of Brandeis University, are working with fruit flies, who, like humans, have a 24-hour clock.

"Our data show the setting and running of the daily body clock comes from the delicate affinity of two proteins," says Young, who is also affiliated with The Rockefeller University. Young and his colleagues recently published four articles in the journal, Science, describing the internal mechanisms of a fruit fly's clock.

This information did not come easily. Over the last three decades, many researchers have looked for the clock's gears, springs, and controls.

The first breakthrough came in 1971, when investigators from California Institute of Technology discovered one of the genes involved. In 1984, the laboratories of Young and Rosbash succeeded in cloning it. Then in 1994, Young's group found the second gene, and more recently put the whole story together.

They identified the genes by mutating fruit flies. Certain mutations altered the flies' circadian characteristics. Using the genetic information from these mutations, the corresponding DNA was identified.

And when they found these genes, they named them. The labels were not impersonal numbers like those attached to human genes, but rather useful (and funny), job-identifying names. The first gene is called "per" for Period. The second is "timv for Timeless.

Consequently, when Rosbash and Hall found the proteins that the genes produce, they were named PER and TIM respectively.

And with that discovery, Young, Rosbash, and Hall finally had a key for describing the winding, setting, and daily running of the fruit fly's biological clock.

A DAY IN THE LIFE

The day starts in the fly's brain, Young says. Even though all of the cells in the fly have "per" and "tim" genes, the brain cells set the decisive pace.

About midday, the two genes become active, transcribing the genes' DNA code into "per" and "tim" RNA (ribonucleic acid) molecules.

At dusk, the production of "per" and "tim" RNA molecules peaks. Then the cell uses the stockpiles of RNA to produce proteins PER and TIM.

Until this moment, both genes have been working simultaneously, but independently. Now the two proteins meet.

"Part of the TIM protein binds to the PER protein," Young explains. "Once joined, the proteins enter the cell nucleus, a process that sets the time and duration of the circadian cycle."

The scientists hypothesize that about four hours before dawn, PER and TIM have reached their maximum levels and signal the nucleus to stop making RNA. Near dawn, the proteins disintegrate and the cycle begins again, with the "per" and "tim" genes producing new RNA.

Other mechanisms and as-yet-unidentified proteins may also influence the interaction between the PER and TIM proteins, which could determine timing, he says. Evidence in one of the Science articles suggests that the PER/TIM protein union is affected by light. More specifically, degradation of the TIM protein is induced by exposure to light, which might explain how our body clocks are reset after jet lag.

While all of Young's work is done on flies, he says it will help investigators searching for the genes of the human body clock.

"In general, the genes that control fundamental body mechanisms are passed on in evolution," Young reports. "Now that we know the mechanisms in the fly's body clock that produce the TIM and PER proteins, and the feedback loops involved, we expect to find a similar process in the body clocks of humans."

ILLUMINATING THE CLOCK

In the meantime, other researchers continue the investigation, and in the case of biologist Steve Kay and his colleagues, they're turning on lights.

Kay, who is formerly of the University of Virginia and currently a researcher at The Scripps Research Institute, is using an enzyme from fireflies, called luciferase, to watch the biological clock in action.

Kay's team transplanted the firefly's luciferase gene into the genome of Arabidopsis thalina, a plant in the mustard family. Before they inserted luciferase, however, they attached another piece of DNA which they knew was connected to the plant's biological clock. They hoped the piece of DNA would continue to glow in rhythm to the clock once it was reinserted in the plant.

It worked. The plant has a bioluminescent glow during the day and none at night. Kay and his colleagues are working to identify the plant genes similar to the fruit fly's "clock genes."

The implications for this kind of modification in plants are of enormous interest to the agricultural community. Scientists may now be able to change the value of plants as a food crop if they can modify their seasonal behavior.

Kay moved on to work on fruit flies, in collaboration with Brandeis' Jeffrey Hall. As with the plant, the firefly luciferase gene is joined to the biological clock gene -- in this case "per." The resulting flies grow brighter and dimmer as they pass through the rhythms of their daily cycle.

THE HUMAN FACTOR

These investigations are helping the Center refine its understanding of biological clocks, specifically human's own internal timepieces. "The outcome," says Gene Block, "will be the eventual ability to control both the period and phase of biological clocks."

That is, humans may find a way of controlling the body's 24-hour clock (that's the period) and the way that clock phases or synchronizes with other internal clocks (such as women's reproductive cycle) or external clocks (such as the sun) on different schedules.

This control could be very useful, Block says, giving the examples of people with sleep disorders or shift workers who need to remain alert while they work through the night.

The latter is the subject of another area of investigation. Center researchers are looking at the records of steel workers, many of whom work on a rotating day, evening, night schedule. The computer records include productivity, accident rate, and absenteeism as well as the shift schedules.

The investigators hope the data will explain which factors of shift work can lead to accidents and loss of work time.

Outside the Center, other researchers are examining such things as what time of day humans best endure pain, and when we metabolize drugs at the most efficient rate.

These pieces of information from the Center and others have the potential of being powerful tools for humankind. The research will eventually offer a way to coordinate the demands of our activities with our biological rhythms so that we can always be working at our peak capacity.


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