January 27, 2005

Human Biological Clock Sensor Uses Fly Eye 'Technology'

Salk News

Human Biological Clock Sensor Uses Fly Eye ‘Technology’

La Jolla, CA – Scientists working for the Genomics Institute of the Novartis Research Foundation (GNF) and the Salk Institute for Biological Studies have discovered the chemical basis of our sixth sense – the mysterious switch that resets our biological clocks as we cross time zones. The finding brings closer to reality medications to treat so-called circadian disorders such as severe jet lag and seasonal depression, as well as improve the lives of shift workers.

In a bizarre twist, a GNF team led by Satchin Panda, now an assistant professor at the Salk Institute, and Tim Jegla, a group leader at GNF, has shown that the photosensory system that resets the biological clock in people works in the same way as the visual systems of lower animals such as flies. Their findings were published in Science on January 28, 2005.

The biological, or circadian, clock in humans resides in a small network of nerve cells in the suprachiasmatic nucleus of the brain that fires rhythmically to control our sleep/wake cycles. When time zones or seasons change, a light sensor in our eyes resets the clock to the new light:dark regime, a process called photoentrainment. Impaired photoentrainment prolongs jet lag and can lead to depression and metabolic disorders in shift workers and people living at high latitudes.

Interestingly, some blind people without rods and cones, which are responsible for conscious vision, still retain this light sensor, while individuals who are born without eyes lose all ability to photoentrain. This led scientists to believe that a novel photosensory system, distinct from the ‘regular’ visual system, exists in the eye and functions as a sixth sense.

The prime suspect for the elusive photosensor is currently a group of a few hundred specialized nerve cells in the retina called retinal ganglion cells that are sensitive to light, connect directly to the SCN clock, and contain a new type of photopigment called melanopsin.

Panda and Jegla have now confirmed that melanopsin can absorb light and trigger chemical changes that can reset the biological clock. Their elegant series of experiments used a combination of genetic, pharmacological and micro-electrical tools. By injecting the mouse melanopsin gene into frog eggs, they showed that when light hits these eggs, melanopsin can convert the light information into an electrical signal. They went further to demonstrate that the mechanism by which melanopsin generates this electrical signal is very different from that of normal human visual photopigments such as rhodopsin. “In fact, the melanopsin photoresponse is akin that of lower animals such as insects,” said Jegla. “We should be able to tap into years of research on fly vision for more clues to how melanopsin signals our biological clock.”

Panda and Jegla also demonstrated that melanopsin is most sensitive to cyan blue light, the same wavelength of light known to be best at resetting the clock in humans. The study holds out hope for medicines that are able to reset the clock without affecting the visual system.

“If photoentrainment involved the normal visual pigments of the eye, you couldn’t interfere with that because it would affect your vision as well,” said Panda. “Since melanopsin signals in a very different way, we have the potential to tweak the process and treat jet lag, seasonal affective disorders or shift workers much better.”

For example, Panda envisions travelers taking drugs that either block melanopsin (antagonists) or imitate melanopsin agonists). “Depending on whether you are flying east or west, you could take a melanopsin agonist or an antagonist,” said Panda.

The Genomics Institute of the Novartis Research Foundation (GNF) founded in 1999 focuses on paradigm-shifting technologies, making possible new approaches to complex biomedical problems. Pioneering technology platforms in genomics, proteomics, chemistry, structural biology, computational biology and engineering have been established as part of an integrated, multidisciplinary approach to biomedical research and drug discovery. The mission is to combine technology and discoveries in molecular, cellular and organismal model systems to identify novel biological processes to modulate pathways of human disease. The Institute is funded through the Novartis Research Foundation.

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine all but eradicated the crippling disease poliomyelitis in 1955, opened the Institute in 1965 with a gift of land from the City of San Diego and the financial support of the March of Dimes.

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