Scientists shed new light on the body’s internal clock

As mammals, our internal (circadian) clock is regulated by the patterns of light and dark we experience. But how that information is transmitted from the eye to the biological clock in the brain has been a matter of scientific debate. Scientists had suspected that a molecule called melanopsin, which is found in the retina, plays an important role.

Now researchers at Stanford University and Deltagen Inc. have confirmed that melanopsin does indeed transmit light information from the eye to the part of the brain that controls the internal clock. According to the researchers, melanopsin may be one of several photosensitive receptors that work redundantly to regulate the circadian system.

“This study clarifies the role of melanopsin in setting and maintaining the circadian clock,” said Bruce O’Hara, senior research scientist at Stanford and co-author of the study published in the Dec. 13 issue of the journal Science.

O’Hara noted that without a circadian clock many behavioral and physiological traits of mammals would be disturbed – including body temperature, activity levels and sleep.

“Instead of being able to sleep for extended periods of time, we would be at the mercy of unpredictable bursts of sleep and activity,” added Stanford senior research scientist Norman Ruby, lead author of the study.

Photoreceptors

For a circadian clock to function, it must be able to detect and respond to light. In mammals, the only cells specialized to do this are in the eyes, which means that our eyes not only allow us to see the world but also synchronize our body’s internal rhythms.

Photoreceptors are specialized cells that can detect light and send signals to the brain, which then processes and interprets the information – allowing us to see. Rods and cones, which are located in the retina, are the primary photoreceptors for vision. Researchers first thought that these molecules had dual roles in vision and setting the circadian clock. But experiments showed that animals lacking rods or cones could still modify their internal clocks in response to changing light conditions. This led scientists to hunt for an alternate photoreceptor that could regulate the circadian system.

Melanopsin, a molecule originally found in frog skin, was the most likely suspect. Scientists discovered that melanopsin molecules in frog skin cells sense and respond to light. The molecule later was found in frog and mouse retinas, and complementary studies determined that cells containing melanopsin send signals to different parts of the brain – further evidence of the molecule’s potential role in setting the circadian clock.

The only test that remained was to determine if the circadian clock could function without melanopsin. To accomplish that, Ruby and O’Hara teamed up with Deltagen Inc., a company based in Redwood City, Calif., that specializes in deleting specific genes from mice. Deltagen deleted (or “knocked out”) the melanopsin gene in mice. The Stanford group then used the knockout mice to determine the relative role of melanopsin in transmitting light information to the circadian system.

Lowered response

In their Science study, the researchers found that the circadian system in melanopsin-depleted knockout mice had a 40 percent decrease in their ability to respond to changes in light intensity compared with normal mice. This result led the scientists to conclude that, although melanopsin is important, it is not the only molecule involved in setting the circadian clock.

“Melanopsin is one of the key players, but it is not the only player,” Ruby and O’Hara explained, noting that the knockout mice, which lacked melanopsin, continued to respond to new light patterns, albeit less efficiently. The researchers concluded that the eye and the brain probably have redundant systems that contribute to regulating and resetting the circadian clock. Such redundancy would be evolutionarily advantageous, they added.

“Deltagen is very pleased with the work flowing from our collaboration with Stanford, and we commend the scientists involved in this study on their work to further elucidate the role of melanopsin in the sleep cycle,” said Mark Moore, chief scientific officer of Deltagen Inc. “We believe that our company’s high throughput gene knockout approach, coupled with our comprehensive systems biology analysis program, will continue to be instrumental in leading researchers to gene function – and ultimately to new pharmaceutical targets and drug candidates.”

While the Science study confirms that melanopsin can transmit information to the circadian clock, future studies will focus on identifying the relative contributions of other molecules to circadian clock maintenance, Ruby and O’Hara noted.

Other co-authors of the Science study are Thomas J. Brennan and Ximmin Xie of Deltagen, and Vinh Cao, Paul Franken and H. Craig Heller of the Department of Biological Sciences at Stanford. This project was funded by the National Institutes of Health and Deltagen.

Caroline Uhlik is a science-writing intern at the Stanford News Service.

By Caroline Uhlik

CONTACT: Mark Shwartz, News Service: 650-723-9296, mshwartz@stanford.edu

COMMENT: Bruce F O’Hara, Biological Sciences: (650) 725-6510, bfo@stanford.edu
Norman F. (“Bud”) Ruby, Biological Sciences: 650-725-6510, ruby@stanford.edu
Nina Ferrari, Deltagen: 650-569-5154, nferrari@deltagen.com

EDITORS: The study, “Role of Melanopsin in Circadian Responses to Light,” will be published in the Dec. 13 issue of Science. A copy of the study can be obtained by contacting the AAAS Office of Public Programs at 202-326-6440 or scipak@aaas.org.