1993 Invited entry for McGraw Hill Scientific Encyclopedia 8th Edition 1997
(deleted and replaced)

Biological clocks:

Living organisms of almost all kinds show fluctuations of leaf movement, of cell division, of
stomatal opening and closing, of alertness, of cell division, of serum composition, and so on.
These are called circadian ('roughly daily') rhythms. In the absence of environmental cues (in
'temporal isolation') these activities repeat at intervals close to 24 hours (different in
different species and in mutants of a given species) with hardly any change of period at different
temperatures. In an outdoor environment the interval is adjusted daily through a sensitivity to
visible light, with the result that rhythms keeps pace with the day/night cycle. In no instance
has the underlying mechanism --- the 'biological clock' --- yet been deciphered. There may be
multiple mechanisms: diverse organs and tissues often have distinct autonomous rhythms but
they mutually synchronize or one tissue dominates. In some insects the left and right optic lobes
of the brain dominate; in others, cells of the 'pars intercerebralis'. Transferring brains
between individuals whose clocks were removed or set to different time zones transfers the
behavioral phase setting. In birds of different species the pineal gland and/or the
suprachiasmatic nuclei (SCN) of the brain's hypothalamus dominate. In mammals the SCN
dominates. In primates including man, internal circadian rhythms originate both from the
brain's two SCN, patches of about 50,000 cells of several types in a 1/4 mm3 volume. The SCN
mechanism is photosensitive through the eyes, specifically through nerve fibers from ganglion
cells in the retina which enter the SCN near the optic chiasm. Neural activity in the SCN has
natural period about 25 hours; at each peak it suppresses the pineal gland's secretion of a
hormone called melatonin, which regulates sleep. Another indicator of body clock phase is core
body temperature, which waxes and wanes within a range of one degree C (to which additional
variations are added if the subject exercises, eats ice cream, etc., but without effect on the
timing and amplitude of the underlying clock.) Other physiological rhythms driven by 'clock'
tissues include plasma cortisol concentration and (less directly) the tide of sleepiness and of
waking.

See Nervous System (Invertebrate); Nervous System (Vertebrate).

Though the physiological mechanism of circadian clocks remains to be deciphered,
something of apparently universal scope is now known about how it works. This experimentally
proven principle is strangely un"clock"like, but it has direct applications, even to control of
human jet lag by sunlight. If any stimulus (e.g., an hour of sunlight) fleetingly disturbs any
cycling mechanism in a way that resets its phase, then its new phase will depend on the size of the
stimulus and on the initial phase of the clock. The dependance reveals something about the
underlying mechanism. A smooth biochemical oscillator, for example, typically resets to a new
phase that varies smoothly with the initial phase, and with the amount of some chemical added in
a resetting pulse in the pattern represented qualitatively in the accompanying figure and formula.
The figure is a contour map: at any combination of initial phase (on the cylinder's circular axis)
and stimulus size (on its downward long axis) you read the resulting new phase by following a
nearby contour line back to the circular phase axis. Contours are sampled only at 4-hour
intervals to minimize clutter. You might think of the cylinder as being colored: red along one
contour, orange along the next, yellow, green, blue, violet, and red again. The colors grade
smoothly between contours. Each phase of the clock is thus coded by hue and you read the new,
reset phase by the cylinder's hue at any stimulus timing and size. The conspicuous feature of this
pattern is its 'singularity' where all contours converge at a unique combination of stimulus size
(1) and initial phase (0). This combination resets the phase ambiguously: hues merge to hueless
white. No such pattern could possibly result from perturbing the speed of a clock which executes
a fixed cycle of changes at rates that depend on time of day and exposure to resetting cues... as in
some postulated mechanisms of circadian clocks. This discriminating test was applied to a
representative sampling of circadian clocks, resetting them by a variable dose of visible light or
of some metabolically active drug applied at various times in the cycle: a clock governing the
timing of metamorphosis in fruitflies, one revealed in the timing of mosquito flight and feeding
activity, one controlling the nocturnal bioluminescence of 'red tide' organisms in sea water, one
revealed in the diurnal opening and closing of a flower. In every case the results are nicely
summarized by a diagram resembling this figure. Following the singular pulse, flies hatch at
random times, mosquitoes become insomniacs, seawater ceases ever to glow, and the flower
thereafter stays closed.

The familiar discomfort of 'jet lag' stems from some combination of (a)'the' clock remaining set to
your home time zone while activities are required on a different schedule, and (b) possible loss of
synchrony among body rhythms while each adjusts toward the new time zone at its own rate (even
in opposite directions, one advancing 9 hours, another delaying 15 hours, for example.)
Adjustment to a shifted time zone typically takes several days during which phase advances
and/or delays accumulate during each exposure to sunlight brightness, especially if such
exposures are badly timed. The measured phase reset depends on timing and magnitude of each
exposure, as in the Figure: .

Caption: --------------------------

On the 25-hour circular horizontal axis, New York night-time phases are on the frontside:
sunset is on the left, sunrise on the right, and zero represents a phase in the wee hours of a
typical day/night cycle. Choose a phase of a travelling New Yorker's biological clock when she
will take sunlight, e.g., A: when it is evening at home. Descend to B at the magnitude of intended
sunlight exposure (in arbitrary units here, as a generic figure typifying diverse animal and
plant species). Follow the contour line through B back up to the circular phase scale and read
the new phase to which her clock will thus be instantly reset: C, a quarter-cycle delay back to a
phase typical of mid-afternoon, optimal for places 6 time zones westward. Were A on the right
side of 0 (before sunrise at home), the effect would be an advance, larger for more light. Were
A during daytime at home, the phase change would be slight (contours near vertical on backside
of cylinder). The dotted phase scale above the cylinder compares the 6-hour earlier phase of
airport personnel in Hawaii with that of fresh arrivals from New York (the shaded scale atop
the cylinder). New Yorkers need a quarter-cycle delay and can get it at A during New York's
evening = Hawaiian mid-afternoon, resetting to C = the mid-afternoon phase of people adjusted
to the local local light/dark cycle. Notice the origin of all contours at the singular phase in the
wee hours (early evening in Hawaii for a traveller from New York) when a unit dose can reset
the clock to any new phase, depending delicately on the exact timing and dose. Any smaller dose
leaves the clock near the same new phase contour as a zero dose; any larger dose sets it near the
opposite phase. Exposures near the singularity extinguish the clock's amplitude. From
amplitude 0 any later exposure restarts the rhythm at a phase opposite to 0, viz. appropriate to
early afternoon; so it should be taken at that local time. This is the pattern for all circadian
clocks probed to date with strong stimuli. Its quantitative expression was first derived from
non-linear dynamics a quarter-century ago in the form: