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It’s small and furry and it can’t tell the time to save its life, but
this mutant mouse could teach scientists more about our mysterious internal
pacemakers and, ultimately, help with therapies for people whose biological
clocks are ‘out of sync’.

In last week’s issue of Science, a team led by Joseph Takahashi of Northwestern
University in Illinois describes a mouse whose circadian rhythms – the biological
clocks that nudge us to sleep and wake us again at appropriate times of
the day – are destroyed. The mouse carries a damaged gene that the team
has christened clock, for ‘circadian locomotor output cycles kaput’.

To find the mutant, Takahashi and his colleagues at Northwestern University
and the University of Wisconsin at Madison treated mice with a chemical
that introduced mistakes in the animals’ genetic codes. They then screened
the next generation of mice for altered rhythms by putting them in cages
with an exercise wheel and recording when the animals exercised during
the following weeks.

A normal animal exercises during the night and rests during the day,
in a 24-hour cycle. But a mouse with one copy of the clock mutation has
a daily rhythm lasting more than one hour longer. Mice with two copies of
clock do even worse: they start out with rhythms of 26 to 29 hours. Eventually
they subside into random, arrhythmic spurts of exercise and rest.

Jeffrey Hall, a geneticist at Brandeis University in Waltham, Massachusetts,
who has long had an interest in rhythms of behaviour, says researchers
are close to understanding the molecular basis of biological clocks. Å®ÉúСÊÓƵs
have found circadian rhythms in many species, including fungi, plants, animals
and certain bacteria, suggesting that clocks evolved early in the history
of life. The clocks continue to tick even when organisms are isolated in
total darkness, as measured for instance by an animal’s patterns of activity,
or fluctuations in its body temperature.

But while the phenomenon is well documented, the inner workings of these
clocks are a total mystery. And so, in an attempt to take the clock apart,
geneticists have searched for the genes that direct it, by damaging the
DNA of a variety of organisms, then looking for mutants that display abnormal
rhythms. Such efforts have led to the cloning of the gene called period
in the fruit fly (Drosophila melanogaster), and the gene called frequency
in the red bread mould Neurospora crassa. In both cases, destroying the
gene leads to total loss of rhythms. And in both cases, the proteins encoded
by the normal, undamaged genes appear to rise and fall in abundance inside
cells in a roughly 24-hour cycle.

Clock appears to sit near the middle of mouse chromosome 5 and Takahashi
and colleagues are busily working to narrow down the location. Once that
is done, they will be able to clone the gene and eventually test whether
clocks in mammals are similar to clocks in other species.

Takahashi says he has been deluged with calls from geneticists, all
hoping to learn what clock can tell them about human conditions such as
seasonal affective disorder, a depression that appears to be linked to disturbed
circadian clocks. Understanding the clock’s molecular workings might suggest
therapies for these conditions, as well as ways to alleviate jet lag and
the problems associated with shiftwork.