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. Last Updated: 07/27/2016

Research Unwinds the 'Human Clock'

For millennia, human engineers have tinkered with instruments for measuring time: from sundials, sandglasses, water clocks, pendulum-driven and spring-loaded clocks, to the electronic timepieces of the late 20th century. Now researchers believe they have begun to uncover the basic mechanisms of perhaps the most important clock of them all -- the internal biological clock that accurately ticks away time inside nearly all living creatures.


Scientists have long known that the biological clock, also called the "circadian pacemaker," precisely orchestrates cycles of sleeping and waking and controls crucial biological functions, causing body temperature, hormonal levels and heart rate to rise and fall with a precise daily rhythm. The symptoms of jet lag result from a temporary disruption of these rhythms. But while the functions and importance of the clock have been clear, exactly how this timekeeper works has remained a mystery.


Now, however, three independent research groups studying fruit flies have discovered a gene called "timeless" that may be the critical component of the circadian clock. The gene carries instructions for the production of a light-sensitive protein that the biological "oscillator," which forms the core of the clock, uses to keep accurate time. The clock apparently marks time by carrying out a predictable and elaborate process of synthesizing and destroying molecules within living cells.


Because the basic technology of the clock most likely evolved very early in the history of life, nearly all higher organisms -- including humans -- may use similar components to run their clocks.


"My bet," says Michael Young, a geneticist at Rockefeller University in New York who led one of the groups involved in the new research, "is that all organisms are using this strategy to build their circadian clocks."


To probe the inner workings of the clock, Young and his colleagues systematically plunged thousands of fruit flies into darkness, and then analyzed each fly's circadian rhythm. Although flies never exactly lie down and cuddle, they do become almost completely inactive at night, drifting into a state that closely resembles sleep. One indication of a sleep-like state in some insects is that the antennae, which are notably erect during the day, can sag at night -- a phenomenon known as "antennal drooping." And although flies have no eyelids, the light receptors in their compound eyes can become almost completely insensitive to light during sleep. "In a sense," Young says, "insects may just shut down the sensitivity of their eyes in a way that's roughly comparable to our closing our eyelids."


After being bombarded with chemicals that made random changes, or mutations, in their genes, each fly was placed in a small glass tube just big enough for the fly to turn around in. "The flies tend to be restless when they're awake and in these tubes," Young says. An infrared beam was pumped across each tube in the otherwise dark room, and when the flies were awake, their frequent movements interrupted the beam, registering a signal which was sent to a computer. During sleep, the flies barely twitch a wing and rarely disturb the beam.


Using this technique, Young's group identified flies whose sleep patterns were disrupted, indicating that they had suffered damage to a circadian clock gene. Some flies had unusually short sleep patterns; others were unusually long. Still others had no rhythm at all, walking around and sleeping at apparently random times of day and night. So the timeless gene is clearly important in running the fly's clock.


Unlike mechanical clocks, which are completely blind to their surroundings, a biological clock gets reset every day by the sun. In complete darkness, the circadian clock still continues to tick vigorously. But without the sun to reset it, the clock will "free-run" and cycle, in humans, about every 24 hours. The clock will maintain this schedule faithfully for weeks or months, though the schedule will soon have little to do with the rising and setting sun.


Remarkably, the timeless protein seems to act as a light sensor, linking the sun's cycle with the rhythm of the fly's body. The researchers discovered that the "timeless" protein is abundant at night and virtually undetectable during the day. But like a single gear in a mechanical clock, timeless cannot keep good time all by itself. One protein in particular, called "period" or "per," which is produced by another gene active in the pacemaker, serves as the timeless protein's vital partner.


The researchers found that the early morning sun normally causes the light-sensitive timeless protein, which is produced in specific pacemaker cells of the fly's brain, to degrade. When timeless is degraded, its partner per, becomes unstable and also degrades. For new proteins to be made, the DNA of the timeless gene must first, in a process called "transcription," make a different version of itself within the cell's nucleus. This version, called RNA, is then shipped out of the nucleus into the cell cytoplasm, where its information is translated to make timeless protein.


Between early morning, when the timeless protein is destroyed, and the late evening, when protein levels rise again, these molecular reactions tick away the hours with uncanny precision. When the timeless and per proteins finally become abundant in the late evening, they become tightly bound to one another. Then, together, the proteins travel back into the nucleus and shut off the very machinery necessary for making more protein. By early morning, per and timeless levels are once again very low, and the circadian cycle begins a new day. If the flies are outside, the rising sun will destroy whatever timeless protein is left, tightly synchronizing the oscillator with the solar day.


This process, in which per and timeless slowly build up during the day and then shut off their own production in the late evening, is important because different levels of per and timeless have different effects on the fly. High and low levels of per and timeless probably dictate the fly's biological rhythms by activating or suppressing the production of other molecules, such as hormones, which directly affect the fly's sleep-wake cycle. This scenario, Young believes, "explains how per-timeless interactions can act as an on-off switch for the circadian rhythm."


Martin Moore-Ede, a professor at Harvard Medical School who studies human circadian rhythms, believes the work on timeless has "answered a fundamental part of the puzzle" about how circadian clocks operate. Mutations with almost identical effects are also known in mice and hamsters, and circadian clock malfunctions in humans are associated with forms of depression. The human circadian oscillator could tick much like the fly's: by timing the synthesis of RNA and protein from specific genes.