In the game of baseball, a pinch-hitter is a player at bat put in place of a player scheduled to bat - especially when a hit is badly needed. In the great game of bioscience research, a mouse is the pinch-hitting animal model when a relief pitcher for a human being is needed.

Considering their enormous differences in size and lifestyle, substituting mouse for man (and woman) comes on as something of a stretch. Yet the two species have traits in common that span all mammalian life on earth. This highest class of living organisms embraces virtually all vertebrates. Mammals suckle their young, grow hair and give birth to living infants rather than eggs.

Mammals are designed by evolution to sleep by day and prowl by night. Mice stick close to this age-old biological clock, but modern humans have tinkered with that mechanism. "In mammals," explained molecular geneticist Steve Kay, at the Scripps Research Institute in La Jolla, Calif., "all of the light-of-day information is coming through the retina of the eye. The probable reason is that early on in their evolution, all mammals were nocturnal. So they actually see each day only a little bit of daylight at twilight, when they emerge from their burrows and hiding places.

"The fact that we humans have these internal 24-hour clocks," Kay noted, "means that there's a number of pathologies associated with them. Some are due to our present lifestyles, such as night-shift work and jet lag. They cause severe economic problems in people adjusting quickly to a new regimen of sleeping and resting.

"One issue with mammals," Kay continued, "is that all of the light information that mice use to bump the hands of their clock each day comes through the retina. And our human internal clock isn't set exactly for every 24 hours."

Melanopsin - A New Player At Bat

A key messenger in transmitting this light perception is the hormone melatonin, which is linked to both the sleep/wakefulness and light/dark cycles of circadian (round the clock) rhythms. "Earlier this year," Kay recounted, "a colleague, Ignacio Provencio, discovered a new photopigment in the mammalian retinas. And because he first found it in melanocytes, he named it melanopsin. This was all very intriguing, but there was no proof yet whether it was the key photopigment sending light signals to the clocks. So we did the obvious thing - knock out the gene that expresses melanopsin in mice, to see how they responded in the absence of this pigment."

Kay is senior author of an article in Science dated Dec. 13, 2002. It's titled: "Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting."

"What we found in our paper," he told BioWorld Today, "was that under normal cycles of bright light and darkness, without melanopsin, some light signaling is clearly going on to the clock, because in our in vivo experiments melanopsin-minus mice could adjust to an external bright light/dark cycle. So then we tested how well the clock perceives daylight, by giving the animals a brief flash of light, and seeing whether that bumps the hands of their clock. When we did that experiment, we found that the mouse clock was severely defective in receiving light signals of low intensities.

"We looked at a mouse's circadian control of behavior, such as humans have. We put the animals in a cage with a running wheel, and just before dusk every day the mouse woke up, hopped into the wheel and ran like crazy all night. They could run more than five miles before dawn. Of course mice don't have running wheels when they're living in your basement. But they're doing two things nocturnally - foraging for food and for mates. The running wheel simply represented a way of measuring mouse activity.

"Next we started in the lab to emulate the onset of winter. Each day we made the lights go off sooner, like winter coming on. And we found that by shortening the day, the hands of the clock were being bumped daily by the light signal. That way, the mice could anticipate each day - even though its duration was changing. As we went into winter, the animals were still waking up at dusk and running.

"That's why we humans have a clock in every cell of our body," Kay pointed out, "to enable us to adjust our metabolism and behavior to take advantage of this phenomenon. A huge amount of our physiology - such as almost anything to do with cholesterol metabolism or blood-pressure fluctuation, for example - is clock-regulated. All of this results in the timing of heart attacks and stroke that cluster very much around a particular time of day.

"That's the thing about circadian clocks; they can run in the absence of these environmental tuning signals," Kay said. "By flashing a pulse of light on the mice, we've learned from them how we suggest that people with sleep disorders or jet lag get treated. That is, we flash a mouse or a human with light in the early part of the evening. That gives delays of the clock. It's like pushing the hands of a grandfather clock back by an hour or so."

Pushing The Hands Of Your Body Clock

"If you give the light flashes just before morning," Kay added, "then you advance the clock. You get delays in the early evening and advances in the early morning. In fact, our knowledge of how clocks respond to light can be used quite effectively to treat jet lag. If, for example, you fly from the U.S. East Coast to London you've got a five-hour time difference; they're ahead. So what you want to do is delay your clock. The best thing you can do when you get to London is give yourself some bright artificial sunlight when it's early evening in Boston. And that will help you adjust much more rapidly to your time schedule.

"The important next step in our work," Kay observed, "is to find out in these specialized retinal ganglion cells exactly how the biochemistry of melanopsin operates. If it has unique signaling capabilities, can we manipulate those with small molecules? In other words, we're looking for a pill - eventually. And that," Kay concluded, "takes a long, long time."