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 am, 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 code for clock 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; the protein and chemicals that make up the clock itself; and components that help the clock control the activity of other genes.

In the last few decades, scientists have discovered the genes that control internal clocks: period (per), clock (clk), cycle (cyc), timeless (tim), frequency (frq), doubletime (dbt) and others. Clock genes have been found in organisms ranging from people to mice, fish, fruit flies, plants, molds, and even single-celled cyanobacteria.

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 outside of an animal's brain.

The SCN is believed to synchronize "local" clocks that sit in organs and tissues throughout the body, either through hormones or changes in body temperature. Local 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 a local clock 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.

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. Biological clocks keep working even when organisms are removed from natural light. Without daylight, the biological clock will continue 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.

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

Clock genes are sets of instructions that code for clock proteins. The genes and proteins interact with each other to produce daily fluctuations in protein levels. The central player is the per gene, which codes for PER protein. PER levels are highest during early evening and lowest early in the day.

In fruit flies, the clk and cyc gene products 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 codes for 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, codes for 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.

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. Clock genes normally keep us awake during the day and asleep at night. But this clock gene is altered in a way that disrupts the normal sleep cycle.

This inherited sleep pattern, known as "familial advanced sleep phase syndrome" (FASPS), has been linked to a variation in the hPer2 gene. People with FASPs are "morning larks" who usually get sleepy by 7 pm and wake up around 2 am. 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 a variation in 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.

Sunlight resets the internal biological clock every day, keeping it 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 because it is not exactly 24 hours long, your cycle 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.

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 affect 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.

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.

Plants use their circadian clocks to detect the length of days. When their clocks sense shorter fall days, they signal the plant to produce seeds and drop their leaves. When the clocks sense longer days in the spring, the plants 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. Genes have been identified that code for proteins that detect sunlight, send day-length information to the plant's internal clock, and delay flowering until days grow long enough.

By learning to manipulate the genetic clock in plants, scientists may be able to make crops more productive, more resistant to stressful conditions, and better able to grow in a wider range of environments.