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The human circadian clock is a powerful device. Buried deep in the brain,
it tells us when to wake and when to sleep, regulating the temperatures
of our bodies and the release of hormones accordingly. It is also a stubborn
device. Jet lag and the chronic fatigue suffered by many night workers are
proof enough of that. What controls the clock, and hence the body rhythms
it sets, is a puzzle that has kept a branch of physiology known as chronobiology
in business for more than two decades. Only now are researchers getting
to grips with its most important environmental timekeeper: daylight.

Chronobiologists have long known that seasonal changes in day length
influence the biological rhythms of animals. Since the mid-1980s, we have
also known about so-called ‘seasonal affective disorder’ (SAD) in humans
– a mild form of depression most commonly diagnosed in winter. Initially
greeted with scepticism by the medical profession, SAD is now listed in
the official compendium of mental illnesses published each year by the US
National Institutes of Health. Yet controversy persists over exactly what
causes it, how many people it affects (some studies claim as many as 1 in
20) and how best to treat it.

The favoured theory blames disrupted circadian rhythms, set by a body
clock whose timing is thrown out of kilter in autumn by the sudden shortening
of the day. Circum-stantial evidence abounds: many psychia-trists, for example,
claim people with SAD respond favourably to ‘doses’ of bright artificial
light. Until recently, however, concrete evidence of a direct link between
light and the timing of our body clock was lacking.

That changed earlier this year when bio-logists at Harvard University
in the US succeeded in using artifical light to reset the clock. Their study
not only shows that light can affect biological rhythms quite dramatically
on a day-to-day basis, but adds weight to the idea of using light as a therapy,
both for seasonal depression and for jet lag. It also bolsters the intuitively
appealing notion of the night-day cycle being the circadian clock’s most
important timekeeper. Yet it would be a mistake to view the cycle as the
only timekeeper – the reality is more complex.

Left to its own devices, the body clock completes its cycle over a period
of about, but not exactly, 24 hours – hence the term circadian (circa, about;
diem, day). In this free-running state, all that drives the clock is the
activity of its constituent nerve cells. In everyday life, we never experience
the rhythms of this state because the clock is always entrained by time
cues in the environment. These cues, which chronobiologists call ‘zeitgebers’
(the German word meaning ‘time givers’), synchronise the clock with the
daily solar cycle.

Daylight is only one of a multitude of potential zeitgebers. Others
include physical activity, diet and social cues, though exactly how much
these influence the circadian clock is still unknown. Unravelling each of
their effects is made all the more difficult by their interdependence. For
example, our regular cycle of sleep and activity affects the times we eat,
our social interactions and exposure to daylight. So even if it was discovered
that our circadian rhythms are influenced by how much we sleep, this would
not in itself prove sleep acts as a zeitgeber: it might act instead by influencing
the impact of daylight.

Humans are not alone in possessing a circadian clock. For centuries
people have noted daily rhythms in the behaviour and physiology of animals
and plants. Many unicellular organisms, such as the alga Gonyaulax, have
biological clocks. Their widespread occurrence suggests that they confer
a key evolutionary advantage. With a clock, you can not only react to daily
events, such as the onset of darkness, but anticipate them. The clock behaves
as an internal predictor of daily environmental change.

We all experience this kind of anticipation when we stay up all night.
In the evening, the circadian clock tells the body to step up heat loss
and reduce heat production. So body temperature falls and we become slightly
befuddled. Inthe early morning, by contrast, the clock prepares us for the
rigours of a new day by increasing our body temperature and making us feel
more alert. The result is a clear rhythm in our body temperature which peaks
during mid-afternoon and bottoms out during the night.

But not all the body’s rhythms peak during the day. The concentration
in the bloodstream of some hormones, such as prolactin, peak at night. Exactly
why is unclear, but one possibility is that the hormones contribute in some
way to the recuperation of the body during sleep. Another hormone, cortisol,
peaks as we wake up. The belief here is that cortisol acts in some unknown
way to guard our bodies against the stress of waking. Of all hormones whose
release is timed by the circadian clock, melatonin is the best known. It
is released by the pineal gland, whose activity is closely linked to that
of the body clock, late in the evening and at night (‘A gland for all seasons’,
¿ìè¶ÌÊÓƵ, 25 July 1985).

About 15 years ago melatonin provided one of the first clues that light
influences biological rhythms. Several teams of researchers discovered that
the daily duration of its secretion from the pineal glands in a variety
of mammals varies during the course of the year, reflecting the changing
length of the night. We have since learnt that this variation in secretion
is linked to seasonal reproductive activity .

Around the same time, researchers began to master the art of studying
the human circadian clock. The first hurdle was to prove that humans possess
an internal, self-sustaining clock and do not simply adjust their behaviour
in response to environmental time cues. The obvious solution was to create
a ‘time-free’ environment. The first experiments of this kind were carried
out in the late 1970s and early 1980s by groups in Europe and the US, and
involved volunteers living in bunkers for months at a time. These days we
use purpose-built isolation chambers, where a subject can live in relative
comfort for extended periods, often a month or more. The subject chooses
when he or she eats and sleeps, but is given no information about time –
no television or radio, no social contacts and, of course, no clock.

It soon emerged that subjects placed in such an environment do not slip
into random habits but maintain a routine: powerful evidence for the existence
of an internal body clock. Yet critics argued that the result simply reflected
habit repetition. Even without a body clock, they said, rhythms might continue
in a time-free environment if the subjects are very methodical. This view
fails under scrutiny, however, because boredom would tend to collapse self-imposed
routines. All of the subjects in the experiments, regardless of whether
they were interested in what they were doing, tended to wake up at regular
times.

A key result from the isolation chamber experiments was that the circadian
clock runs slow, taking about 25 hours to complete its cycle. Obviously,
a 25-hour body clock would be quite useless as a predictor of daily environmental
change, and so the search for zeitgebers began. The importance of light
to the circadian cycles of animals made it an obvious candidate to test.
The first breakthough came in 1985, when Rutger Wever of the Max Planck
Institute in Andechs, Germany, looked at the effect of the light-dark cycle
on the body’s temperature rhythm. Wever placed his subjects in an isolation
chamber in which he created artifical light-dark cycles running over 21
or 28 hours rather than 24. When he then exposed his subjects to pulses
of bright light, their temperature rhythms rapidly adjusted to the abnormal
light-dark cycles. Intriguingly, light of normal intensity had no such effect.

Further evidence came in 1987, when Al Lewy and his colleagues at the
Oregon Health Sciences University in the US exposed people suffering from
SAD to pulses of bright light, of an intensity about equal to that found
one hour after sunrise. The treatment appeared not only to alleviate the
subjects’ depression, but to shift their melatonin rhythms, suggesting (though
not proving) a causal relationship between the two.

Lewy’s work attracted much publicity. It also sparked controversy and
a series of follow-up studies on both sides of the Atlantic. Although these
supported the original observation, they did not circumvent what many see
as the key problem: the lack of a placebo treatment for bright light. At
the same time, a vital piece of the puzzle was missing – namely, whether
the timing of a pulse of light affects its influence on the body clock.
If natural light really does act as a zeitgeber, then the potency of a pulse
of light should depend on when it is given in the circadian cycle. In theory,
pulses given at times corresponding to the very end of the dark period of
the cycle – dawn – should be the most potent.

Temperature trough

It was exactly this point which Charles Czeisler and his colleagues
at Harvard University addressed earlier this year. In their study, volunteers
who were exposed to a pulse of bright light each day for three days experienced
dramatic shifts in the phases of their body clocks. Each pulse was five
hours long and timed to coincide with a particular point in the subjects’
temperature cycle. As a marker for the phase of the body clock, the researchers
used the temperature trough, which normally occurs between 4 am and 5 am.
And to ensure temperature rhythms were not distorted by activity or meals,
the subjects were asked to stay awake for at least 30 hours, resting in
bed and taking regular snacks.

The researchers’ crucial finding was that the amount and direction of
the shift in the subjects’ circadian clocks depended on the timing of the
daily pulses. The critical period was around the temperature trough, near
5 am. Exposure just after the trough advanced the clock, while exposure
just before delayed it. Pulses of light given when the body temperature
is near its peak (between 4 pm and 5 pm) had little effect. Recently, my
colleagues and I at the University of Manchester and the University Clinic
of Psychiatry at Basel produced similar, but less pronounced, shifts with
just one daily pulse instead of three.

The results are entirely consistent with daylight being a zeitgeber.
The circadian clock’s natural tendency is to run slow. So, in the absence
of an environmental timekeeper, the timing of the body temperature minimum
would slip backwards from 5 am, into the morning. The human response to
artificial light, however, suggests that early-morning daylight would block
this shift by advancing the body clock.

How light interacts with the circadian clock is not completely clear,
but evidence for two routes is emerging. In the first, light adjusts the
clock directly by exploiting a nerve that connects it with the retina. In
the second, light acts indirectly by suppressing the secretion of melatonin
in the early morning (Lewy’s 1987 study had shown that bright artificial
light suppresses the release of melatonin). Melatonin appears to shift the
phase of the body clock in the opposite direction to light: its continued
secretion in the morning would therefore delay the body clock.

All this raises a puzzle, however. Humans are exposed to artificial
lighting at odd times of day and are often shielded from daylight. So what
sets our body clocks during our working lives, particularly in the winter
when we see little natural light? This question alone points to the existence
of other influences, such as activity, sleep and social interactions. Indeed,
studies have already shown that for animals light is not the only zeitgeber.
Female rodents, for example, can adjust the circadian clocks of their offspring:
foster mothers with abnormal sleep-activity cycles are able to reset the
cycles of their young, presumably through social contact.

What are the prospects of using light as a therapy for jet lag? Jet
lag arises because the body clock adjusts only slowly to changes in routine.
Normally this is an advantage. It ensures that a brief break in our routine,
a daytime nap or a foray to the larder during the night, does not disturb
our body rhythms. For night workers, however, the sluggishness can cause
serious problems. Sleeping every day and staying up every night can lead
to continual jet lag. In susceptible people, the result is often chronic
health problems involving cardio-vascular disorders and ulcers.

Light therapy for jet lag was first tried in 1984 by Serge Daan, of
the University of Groningen in the Netherlands, working with Lewy, when
the clock-shifting effects of light in humans were still purely hypothetical.
The researchers tested the notion that travellers might adjust more quickly
to a new time zone if they avoid natural light at certain times, while seeking
it at others. The two subjects tested seemed to benefit from such a regime.

Since then, researchers have concentrated on therapies based on bright
artifical light. The idea is to strengthen the abnormal light-dark cycle
experienced by night workers in the hope of resetting their body clocks.
A study completed last year by Czeisler and his colleagues provides the
best evidence so far that exposure to bright light at night and virtual
darkness during the day does indeed make people better nightbirds.

For four consecutive nights, the researchers exposed a group of volunteers
to an array of bright lights. During the day, the volunteers were asked
to spend exactly eight hours sleeping (or at least trying to) in a specially
darkened bedroom. The result was striking: a shift of about eight hours
in the circadian rhythm of body temperature and similar shifts in the rhythms
of urine flow and cortisol in the bloodstream. There were also improvements
in mental performance and alertness at night. None of these effects was
evident in a group of control subjects, who worked at night in light of
normal intensity and slept when they wanted to in unmodified rooms.

On the face of it the interpretation is obvious: strengthening the light-dark
cycle does help the body clock to adjust to an inverted sleep-activity cycle.
But there are some caveats. Is it safe to exclude a placebo effect, for
example? After all, the experimenters were going to a great deal of trouble
to help the volunteers adjust to night work. And what of the impact of other
potential influences, such as the sleep-activity cycle itself? Volunteers
in the experimental group tended to sleep longer than those in the control
group, and were also more alert at night. This would have strengthened their
sleep-activity cycle, which in turn could have contributed to the shift
in phase of the volunteers’ body clocks.

Further insights come from research done in the Antarctic by a team
led by Josephine Arendt of the University of Surrey. The prolonged darkness
of the Antarctic winter makes it ideal for field studies of the effects
of light. In a recent study, the team gave pulses of bright light to people
whose body clocks had been disrupted by the unremitting darkness of winter.
Two pulses, each one hour long, in the morning and late afternoon, helped
to shift the melatonin rhythms of the subjects back to the timing associated
with summer.

Reducing fatigue

Of course, bright light is not the only therapy that could be used for
body-clock disorders. Other researchers continue to investigate the use
of melatonin as a kind of chemical ‘dark pulse’. Several studies have shown
that melatonin capsules taken in the evening (local time) reduce fatigue,
one of the major symptoms of jet lag, and their use during night work seems
to promote daytime sleep.

By contrast, there are still question marks against physical exercise
and diet as regulators of the body clock. In hamsters, several lines of
evidence indicate that physical activity acts as a zeitgeber. Early on in
the animal’s activity cycle, extra activity advances the clock and vice
versa. A new exercise wheel, a potential mate or a dose of a benzodiazepine
drug (which in hamsters increases activity) are all sufficient to shift
the phase of the hamster’s body clock. In humans, however, physical exercise
has been little studied.

Similarly, there is little hard information about the usefulness of
special dietary regimens. Much attention has focused on the role of amino
acids. The rhythmic firing of neurons in the body clock depends on neurotransmitters
derived from amino acids. So perhaps one could alter this rhythm by timing
the flow of amino acids to the brain. This idea has triggered a series of
widely publicised claims about the merits of using dietary supplements containing
amino acids to combat jet lag. As yet, however, none of the claims has been
properly substantiated and research on animals casts doubt on the idea.
Using dietary supplements to manipulate the concentration of neurotransmitter
precursors in blood, or even the timing of neurotransmitter synthesis, is
one thing; regulating the release of neurotransmitters by the neurons inside
the body clock is quite another.

Another possibility is benzodiazepine drugs. The body clock is packed
with receptors for such compounds. Yet while the sleep-inducing effects
of benzodiazepines are well known, their direct effects on the human body
clock are uncertain. These could prove difficult to measure, because any
disruption of the sleep-activity cycle will also modify the body’s exposure
to other zeitgebers, perhaps obscuring the effect of the drug on the body
clock. A very recent study on humans claims one type of benzodiazepine can
reduce jet lag, apparently without altering the body clock.

The discovery that light acts as a day-to-day regulator of circadian
rhythms opens the door to remedying body clock disorders – not just winter
depression, but jet lag and the malaise suffered by night workers, too.
Even so, it seems prudent at present to regard bright light as an important,
but by no means our only, weapon against some of the unpleasant consequences
of our modern lifestyle.

James Waterhouse is a reader in the School of Biological Sciences at
the University of Manchester