The Body Clock Revisited

By Jason Socrates Bardi

In Shakespeare's Hamlet, the troubled young prince says longingly of sleep, "Tis a consummation devoutly to be wished."

Sleep, for Hamlet, signifies more than just sleep, but his lamentation still rings true to anyone who has suffered from lack of sleep. People who are jet lagged after a long plane flight or who are feeling wiped out after working a night shift know what it feels like to wish devoutly for sleep. Their bodies cry: Something is rotten in Denmark.

Shift workers and world travelers suffer because the body follows a daily cycle known as a circadian rhythm. Humans, mice, and other organisms have internal body "clocks" to keep track of time and coordinate biological processes to the rhythm of day and night. For instance, our blood pressure fluctuates daily, rising and falling at predictable times of the day or night.

Our bodies accomplish this through receptors that detect light, but scientists did not know which receptors were responsible for this until recently. Some scientists had speculated that the key receptor would be rhodopsin, the light-capturing protein present in rods and cones of the eye that are responsible for vision. However, certain people who were born blind because they lacked rods and cones could still maintain their circadian balance.

In recent months, scientists from The Scripps Research Institute (TSRI) and the Genomics Institute of the Novartis Research Foundation (GNF) have demonstrated that a gene called Opn4, which codes for a protein receptor called melanopsin, is responsible for keeping circadian rhythms entrained to a 24-hour day—like a tiny key that winds a grandfather clock.

A study by the TSRI and GNF team that appeared in Science last December demonstrated melanopsin is responsible for keeping the body in sync with the day. In the Science study the TSRI and GNF team knocked out the Opn4 gene in mice and showed that in its absence, the mice could not reset their clocks.

Now another Science article by the same team tests the role of melanopsin in visually blind mice. The TSRI and GNF team created a model with no visual photoreceptors and no melanopsin. Then they looked at how the sleep–wake cycle was affected. Not surprisingly, they found that these models cannot adjust their body clocks to the day–night cycle—their body clocks run like a runaway train. However, the controls who were visually blind but did have melanopsin had no such problems. This research demonstrates how critical melanopsin is for maintaining circadian rhythms, and it may help in the development of strategies for correcting sleep disorders, many of which are related to circadian rhythms. Furthermore, understanding the protein that resets the body's clock should help in research aimed at countering the most common circadian problems including jet-lag and night shifts.

The article, "Melanopsin is Required for Non-Image Forming Responses in Blind Mice," will be published by the journal Science and will appear on its rapid electronic publication web site on June 26, 2003. The article will appear in print later this year.



Micrographs of melanopsin in neuronal cells. Top panel shows a single fluorescently-labeled melanopsin-producing neuron. The middle panel shows a network of such neurons, and the bottom panel shows a close-up of this network. Images courtesy Satchidananda Panda, GNF.