Provided by the National Institute of Mental Health
Anyone who has traveled has experienced jet
lag—that groggy realization that while your day is beginning in Washington, DC,
the night you just left in San Francisco is hardly over. Jet lag is an
inconvenient reminder that the body is set to a 24-hour clock, known by
scientists as circadian rhythms, from the Latin circa dies, "about one day." An
internal biological clock is fundamental to all living organisms, influencing
hormones that play a role in sleep and wakefulness, metabolic rate, and body
temperature.
Disruption of circadian rhythms not only affects sleep patterns but also has
been found to precipitate mania in people with bipolar disorder
(manic-depressive illness).1 Other types of illnesses also are affected by
circadian rhythms; for example, heart attacks occur more frequently in the
morning while asthma attacks occur more often at night.2,3
Although biological clocks have been the focus of intensive research over the
past four decades, only recently have the tools needed to examine the molecular
basis of circadian rhythms become available. Early studies pointed to an area of
the brain, the hypothalamus, as the location of the circadian pacemaker in
mammals.4 More recent findings show proteins called cryptochromes, located
throughout the body, are also involved in detecting changes in light and setting
the body's clock.5
Genes that code for the clock protein, PER, glow in the head and other body
parts of a fruit fly. Researchers made the clocks glow by engineering transgenic
strains of flies in which the same genes that illuminate a jellyfish and a
firefly's tail are attached to PER. The gene for luciferase, the enzyme that
glows intermittently in fireflies, was expressed along with PER to reveal when
the clock protein was being produced. Flies were also molecularly altered to
brightly mark the clock sites with Green Fluorescent Protein, which glows
constantly in jellyfish. Source: Jeffrey Plautz, Ph.D., Stanford University;
Steve Kay, Ph.D., The Scripps Research Institute.6
The first circadian gene was discovered in 1971 in the fruit fly;7 a second
circadian gene was detected 13 years later.8,9 Following these discoveries,
however, the search for clock genes in other organisms faltered. Not until 1997
was the first circadian gene found in a mammalian model, the mouse.10 This
discovery immediately accelerated the search for other clock genes, and findings
in higher order animals are yielding a consistent picture of the role and
function of circadian rhythms in organisms from bacteria to plants to mammals.11
Today, we know the most about the workings of the biological clock in the fruit
fly and a peek inside its mechanisms illustrates the complex elegance of the
rhythms of life.12 The fly's clock consists of a core system of four regulatory
proteins that interact to give the clock periodicity. The cycle begins when two
of these proteins, CLOCK and CYCLE, bind together and increase the production of
two other proteins, PER and TIM, the levels of which slowly accumulate over
time. When enough PER and TIM are made, they inactivate the CLOCK-CYCLE complex,
slowing their own production and signaling the end of the cycle.
Fruit fly clock cycle—Interaction of four regulatory proteins, entrained by
light, creates the daily rhythm of the fruit fly's clock. The binding of CYCLE
and CLOCK turns on genes that make PER and TIM, which accumulate over several
hours until they reach levels that turn off CYCLE and CLOCK. This, in turn,
slows down the production of PER and TIM, which begins the cycle all over again.
Source: Steve Kay, Ph.D., and Karen Wager-Smith, Ph.D., The Scripps Research
Institute.12
Although parts of the puzzle still are missing, discoveries stimulated by this
progress are yielding intriguing findings. Proteins such as DBT ("Double-Time")
that act to fine tune the mechanism have been identified.13 Recently, variations
have been found in the human Clock gene, which may predispose people to be
"early birds" or "night owls."14 Other research has linked academic and behavior
problems in adolescents to irregular sleep patterns.15
Researchers have found that imposing too early school start times on children
requires unrealistic bedtimes to allow adequate time for sleeping.16 Early
school start times for adolescents are frequently associated with significant
sleep deprivation, which can lead to academic, behavioral, and psychological
problems, as well as increased risk for accidents and injuries, especially for
teenage drivers. Completing our understanding of biological clockworks will lead
to better treatments for diseases affected by circadian rhythm, as well as to
methods of coping with disrupted sleep patterns.
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