The Time of Our Lives

Take the red-eye from California to New York, and you'll experience firsthand the effects of your body's internal clock. If you feel drowsy or 'jet lagged' after the flight, it's because there's been a disruption to your natural circadian rhythms. Your internal clock is saying it's 3 a.m., but outside, it's time for breakfast.

Living organisms evolved an internal biological clock, called the Circadian rhythm, to help their bodies adapt to the daily cycle of day and night (light and dark) as the Earth rotates every 24 hours. The term 'circadian' comes from the Latin words for about (circa) a day (diem).

Circadian rhythms are controlled by "clock genes" that carry the genetic instructions to produce proteins. The levels of these proteins rise and fall in rhythmic patterns. These oscillating biochemical signals control various functions, including when we sleep and rest, and when we are awake and active. Circadian rhythms also control body temperature, heart activity, hormone secretion, blood pressure, oxygen consumption, metabolism and many other functions.

Daily cycles also regulate the levels of substances in our blood, including red blood cells, blood sugar, gases and ions such as potassium and sodium. Our internal clocks may even influence our mood, particularly in the form of wintertime depression known as seasonal affective disorder (SAD).

A biological clock has three parts: a way to receive light, temperature or other input from the environment to set the clock; the clock itself, which is a chemical timekeeping mechanism; and genes that help the clock control the activity of other genes.

In the last few decades, scientists have discovered the genes responsible for running the internal clocks: period (per), clock (clk), cycle (cyc), timeless (tim), frequency (frq), doubletime (dbt) and others.

Genes that control circadian rhythms have been found in organisms ranging from people to mice, fish, fruit flies, plants, molds and even single-celled, blue-green algae known as cyanobacteria.

Where is the body's master clock?

The master circadian clock that regulates 24-hour cycles throughout our bodies is found in a region called the suprachiasmatic nuclei (SCN) in the hypothalamus of the brain. The SCN is made up of two tiny clusters of several thousand nerve cells that "tell time" based on external cues, such as light and darkness. The SCN regulates sleep, metabolism, and hormone production.

How important is the SCN? When a rat's SCN is removed, its daily cycle of activity and sleep is disrupted. The SCN still produces rhythmic chemical signals, even after it has been removed from an animal's brain.

The SCN is believed to synchronize "local" clocks in organs and tissues throughout the body, either through hormones or changes in body temperature. Gene-operated clocks independent of the brain's master pacemaker have been found in the liver, lung, testis, connective tissue and muscle.

One example of how a local clock works comes from fruit flies. Cells in their antennae display a circadian rhythm independent of the brain's master clock. The antennae oscillations correlate with sense of smell, which is more sensitive at night than during the day.

How many hours are in a biological clock?

The human circadian rhythm is not exactly 24 hours - it's actually 10 to 20 minutes longer. Other species have circadian rhythms ranging from 22 to 28 hours. The biological clock in living organisms keeps working even when the organism is removed from natural light. Without daylight, the biological clock will eventually start running on its own natural cycle. But as soon as morning light hits the eyes, the clock will reset to match the earth's 24-hour day.

Why aren't organisms' internal clocks exactly 24 hours long? A computer simulation suggests competition for food and other resources is most intense among species with 24-hour cycles. If you eat at the same time as everyone else, you're less likely to get your share. Our slightly out of sync internal clock may have evolved to help us survive the competition.

The circadian clock in the hamster brain signals a change in coat color according to season by releasing the melatonin hormone.

Biological clocks also play a role in longer cycles such as hibernation, bird migrations and even annual changes in the color of a hamster's coat. When the animal brain records longer days in the spring and shorter days in the fall, it triggers hormone secretion that influences these events.

How do clock genes work?

Clock genes send out instructions that dictate protein production. The genes interact with each other to produce daily fluctuations in the amount of proteins produced.

The central player is the per gene, which produces the PER protein. PER levels are highest during early evening and lowest early in the day.

In fruit flies, the clk and cyc genes work together to activate the per and tim genes so they produce proteins. Those proteins, PER and TIM, then combine and slowly accumulate in the cell nucleus, where they slow down the clk and cyc genes, which in turn deactivates per and tim and stops further production of the PER and TIM proteins. As PER and TIM diminish, clk and cyc kick into action again, starting a new daily cycle.

The cycle is a bit more complicated in mammals, in which clk works with a gene named Bmal1 instead of with cyc. Also, mammals have three versions of the Per gene.

Other clock genes also play a role. In the fruit fly, the dbt gene produces a protein that helps break down the per protein to keep it at just the right levels for the particular time of day. A gene named pdf for pigment-dispersing protein produces a protein that appears to tell the rest of the fly's body what time it is according to the master clock in its brain.

When were clock genes discovered?

Biological clocks have been recognized for almost 300 years in plants, but only in the 1950s did scientists verify their existence in animals. The first identified clock gene - per for period - was found in fruit flies in 1971, and the precise sequence of its genetic code was determined in 1984. Three versions of the clock gene have been identified. Mutations of these genes produce fruit flies that either lack circadian rhythms, or that have 19-hour or 29-hour cycles rather than the normal cycle of about 24 hours.

In 1988, scientists established the existence of the first clock gene in mammals when they discovered mutant hamsters with a 20-hour circadian rhythm. In 1997, the first mammalian clock gene was discovered in the mouse. Scientists pinpointed its location and decoded its DNA sequence. The gene was named Clock, for "circadian locomotor output cycles kaput." (Unlike other genes, clock genes in mammals are written with the first letter of the gene name capitalized: per in fruit flies, Per in mammals, or mPer in mice and hPer in humans.)

Other clock genes and their proteins have since been discovered. In Neurospora (a kind of bread mold), scientists found clock-controlling genes called frq, and proteins named wc-1 (White Collar-1) and wc-2 (White Collar-2) that turn on the frq gene.

In 2001, scientists at the University of Utah discovered the first human clock gene. They found it while studying a rare inherited disorder that makes people fall asleep early and wake spontaneously hours before dawn.

How do clock genes influence sleep?

Clock genes normally keep us awake during the day and asleep at night. But when a clock gene mutates, it can disrupt the normal sleep cycle.

A mutant hPer2 gene is responsible for an inherited sleep pattern known as "familial advanced sleep phase syndrome" (FASPS). People with FASPs are "morning larks" who usually get sleepy by 7 p.m. and wake up around 2 a.m. Another sleep condition, called "delayed sleep phase syndrome," has the opposite effect, turning people who have it into extreme night owls. They fall asleep very late and have trouble waking up in the morning. Delayed sleep phase syndrome has been linked to the hPer3 gene.

Any student who has studied during an "all-nighter" knows the circadian clock isn't the only sleep influencer. Our need for sleep also plays a role. When rats are awake and vigilant, their brain's master clock is more active. When rats are deprived of sleep, their master-clock doesn't respond normally during different times of day.

Sunlight resets the internal biological clock every day so it is synchronized with a 24-hour day. If you lived in an underground bunker under constant artificial light, you would continue to follow an approximately 24-hour sleep-wake pattern, but your cycles would slowly get out of phase with actual daytime and nighttime.

Air travel to a distant time zone can also disrupt normal cycles. The resulting jet lag is both a disconnect between local time and your body's time, and a disconnect between your brain's master clock and local clocks in tissues throughout your body. Once you arrive at your destination, the change in daylight hours will "entrain" or reset your internal clock, but it will take a few days to get rid of the jet lag.

What are the health implications of clock genes?

Understanding exactly how clock genes work may help scientists develop new medicines that adjust or reset the human biological clock to treat the ill effects of jet lag, night shift work or wintertime depression. Clock genes may also offer clues to sleep disorders such as narcolepsy, which makes people feel sleepy during the day.

Our internal clock controls hormone levels, which can effect the way our bodies respond to certain medications. Better knowledge of circadian rhythms may improve the effectiveness of medications by revealing the best times to take them.

Light is used to treat people with seasonal affective disorder, the form of depression that surfaces during the shorter days of winter. Some research indicates light therapy is more effective if it is synchronized with a patient's internal clock, which is why some patients are treated with exposure to bright light early in the morning. Bright light also has been used to help people adjust to jet lag and to changes in work shifts.

Clock genes may some day help scientists treat cancer. At least eight clock genes are known to coordinate normal functions such as cell proliferation (which is uncontrolled in cancer) and cell suicide (which fails to occur in tumor cells). One study found that without the mPer2 gene, mouse cells with damaged DNA become cancerous instead of committing cell suicide. If clock genes actually play a role in cancer, they could be a target for new drugs that might disrupt the "clock" to halt the cancer.

Aging may disrupt the synchronization of local clocks throughout the body and their synchronization with the brain's master timekeeper. One study found that electrical activity in the internal clocks of aging rats was not as regular as in younger rats, so the aging rats did what elderly people often do: they napped during the day.

Funding for this feature was provided by The R. Harold Burton Foundation and a Science Education Partnership Award (No. 1 R25 RR16291-01) from the National Center for Research Resources, a component of the National Institutes of Health.

Author: Lee J. Siegel, with additional contributions by Stephanie Watson.

How does light reset the biological clock?

Only in recent years have scientists begun to understand how the daily cycle of day and night is transmitted from the eye to the master clock in the brain.

Rods and cones in the retina of the eye detect light to form visual images. For many years, scientists believed our circadian clock was reset with the help of rhodopsin, a light-detecting protein in the rods and cones. But researchers recently found evidence for a separate light-detection system in the eye. They believe it gauges overall brightness to help reset our internal clock.

This newly discovered system may explain why some blind people and mice lacking rods and cones can still reset their internal clocks and regulate their biological rhythms. A protein named melanopsin - which is sensitive to blue light - is critical for the brightness-detection system. Scientists believe that a small fraction of the eye's light-sensitive "retinal ganglion cells" contain melanopsin and carry signals to the brain's master clock.

Several years ago, a study suggested that exposing the back of the knees to light might reset our sleep-wake cycle, but a later study found no evidence for that, supporting the notion that light must pass through our eyes to influence our internal clock.

What about clock genes in plants?

Plants use their circadian clocks to detect the length of days. When their clocks sense shorter fall days, they produce seeds and drop their leaves. Then they sense longer days in the spring, they grow flowers or fruit. Biological clocks also help plants prepare for sunrise by raising their leaves and getting ready to perform photosynthesis to convert sunlight into food. And internal clocks play a role in the opening and closing of leaf pores and the nighttime folding of leaves to prevent water loss.

Some researchers have found evidence that plants can have two internal clocks: one sensitive to light and the other sensitive to temperature changes. Genes have been identified that produce proteins to detect sunlight, send day-length information to the plant's internal clock and delay flowering until days grow long enough.

Scientists believe that by learning to manipulate the genetic clock in plants, they can make crops more productive, more resistant to stressful conditions and better able to grow in a wider range of environments.