Discovery: Experiments Confirm Novel Eye Pigment Controls Circadian Rhythm

November 19, 1998

CHAPEL HILL - New research by University of North Carolina at Chapel Hill scientists has proven that a light-sensitive pigment they discovered in the eye, the skin and part of the brain controls the body's internal clock.

Their initial discovery, published in May, was the first of its kind in more than a century. The work could lead to better treatment for depression and fewer accidents during night work shifts, researchers say.

"Because some investigators questioned how conclusive our earlier data was, we decided to create a mouse lacking the pigment to see what effect it had on the mouse," said Dr. Aziz Sancar, Kenan professor of biochemistry and biophysics at the UNC-CH School of Medicine. "Using what some people have called 'knock-out mouse technology,' we created animals that lacked the gene responsible for making the pigment."

The scientists found the pigment, called cryptochrome (CRY), drives mammals' circadian rhythm, the 24-hour biological timer that regulates numerous bodily functions, Sancar said. Those processes -- synchronized to light and dark by light at dawn -- range from body temperature and blood pressure regulation to intellectual performance, sleep and wakefulness.

A report on the findings appears in the Nov. 20 issue of Science. Besides Sancar, authors are Randy J. Thresher, Yasuhide Miyamoto, Aleksey Kazantsev, David S. Hsu, Claude Petit, Christopher P. Selby, Lala Dawut and Oliver Smithies, all of UNC-CH, and Martha Hotz Vitatarna and Joseph S. Takahashi of Northwestern University.

Experiments at UNC-CH showed that production of a protein known as "Period," which is controlled by light and helps regulate mammals' internal clock, was reduced by more than 50 percent in the mutant mice, Sancar said.

Complementary experiments at Northwestern that involved having the Carolina knockout mice running on treadmills and resting during simulated nights and days showed mutants to have abnormal response to light and abnormally long daily cycles lasting about an hour longer - 25 hours -- than they should.

"We are extremely excited about this fundamental discovery because it appears to be so central to mental and physiologic functioning," Sancar said. "Previously, it was assumed that the same pigment in the eye was responsible for vision and circadian synchronization, and now we know that's not true."

Discovered in 1877, pigments known as opsins, which are linked to vitamin A and located in the retina, enable mammals to see by absorbing light and transferring visual signals through the optic nerve to the brain. The newly discovered cryptochromes, which come in two forms called CRY 1 and CRY 2, are linked to vitamin B-2 and located in a different part of the retina. Cryptochromes enable animals and humans to synchronize their circadian clocks by absorbing blue light and transferring the light signal through the optic nerve to a different part of the brain from the center for vision.

Severing the optic nerve abolishes both vision and circadian photo-response, the scientist said. However, because pigments for vision and circadian clocks occur in different parts of the retina, some blind people who have lost the part of the retina containing opsins still retain the cryptochrome region and maintain normal circadian rhythm.

"Understanding how circadian rhythm works has many practical applications," said Sancar, a member of the UNC Lineberger Comprehensive Cancer Center. "First, individuals with a disease called seasonal affective disorder, or SAD, suffer serious depression during the winter months with short daylight. It may be that SAD patients have a defective gene that doesn't produce the pigment properly or simply suffer from a vitamin B-2 deficiency. Maybe we can treat some patients with vitamin B-2."

Second, industrial accidents such as those at Three Mile Island and Chernobyl often occur at night. American industry has collected data showing most accidents happen during the midnight shift.

"That's because people's circadian clocks have told them that it is time to slow down, and mistakes are more likely," Sancar said.

Jet lag follows the discrepancy between local time and a passenger's circadian time, which was in tune with the day and night cycle of the departure point. Also, breast cancer rates have climbed this century with some blaming long exposure to electric lights for disrupting normal hormone patterns.

Cancer experts want to know more about such rhythms because both beneficial and side effects of anti-cancer drugs can depend on what time of day they are administered, he said. He and colleagues found evidence of the new pigment widespread in body tissues including skin and brain.

Daily light-dark cycles regulate biologic functions in creatures as simple as bacteria and as complex as humans, Sancar said. Human Genome Project staff found the human CRY1 but not its function. He and his students discovered the CRY2 gene with Human Genome Sciences Inc. researchers. They have applied for a patent on the work, which was supported by NIH.
Note: Sancar can be reached at 919-962-0115.
Contact: David Williamson, 919-966-8596.

University of North Carolina at Chapel Hill

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