For Release: February 13, 2009
Contact: dms.communications@dartmouth.edu, 603-650-1492
Research sheds new light on fascinating rhythms of biological clock
A light box to treat jet-lag and reset the clock uses blue, the peak wave length of light to reset the circadian clock.
Hanover, N.H.—Scientists have long known that interrupting the 24-hour daily rhythm plays havoc with the lives and health of medical, military and airline personnel, factory employees and travelers. Now, a Dartmouth Medical School research team has uncovered a potential target that could be exploited to help ameliorate the effects of jet lag and shift work.
Their study, in the February 24 Current Biology, sheds new light on cellular timing systems and focuses on a key gene that seems to regulate the response of the circadian clock to light signals. The authors include Drs. Jay Dunlap, professor and chair of genetics; Jennifer Loros, professor of biochemistry; Mark Israel, professor of pediatrics and genetics, and director of the Norris Cotton Cancer Center (NCCC), and Giles Duffield, former instructor at DMS and NCCC, now assistant professor at the University of Notre Dame.
"The circadian clock is the lens through which the environment modulates our physiology. Control of bodily functions by the internal circadian clock is an overarching aspect of physiological control in humans: the light dark cycle sets the clock and the clock directly or indirectly controls body temperature, alertness, sleep/wake, and a host of other functions," Dunlap said. "Understanding how the light/dark cycle sets the clock may provide the basis for understanding and correcting a wide variety of metabolic and psychological disorders ranging from obesity to depression."
Duffield, lead author, noted, "For example, the human sleep-wake cycle is a very obvious rhythm and tightly gated to the night, while perhaps less obvious is that virtually all hormones oscillate with a 24-hour rhythm, and up to 10 percent of genes in each cell are rhythmically controlled."
An estimated 16 percent of the U.S. working population is involved in rotational shift work, and a significant population is affected by jet lag and related sleep-wake disorders. The impact of the large shifts in the body's internal clock that these individuals experience can be profound, contributing to increased accident rates, medical errors and the development of particular illnesses.
The circadian clock is the lens through which the environment modulates our physiology.
—Dr. Jay Dunlap
"Both the Three Mile Island accident in 1979 and the Chernobyl disaster in 1986 occurred late at night or early in the morning," Duffield said. "Most traffic accidents occur around 2 a.m. Incidents of cancer and cardiovascular disease are elevated in transatlantic airline staff and in shift workers."
The master circadian clock in humans resides within the suprachiasmatic nucleus in the hypothalamus, at the base of the brain. It receives direct input from the retina (eye) though which it can be reset or synchronized on a daily basis to the prevailing light-dark cycle. This provides both time of day and time of year information to the brain and body. Things can go wrong with the internal clocks when either the clock system or its light input pathway is disrupted.
Using DNA microarray techniques, the researchers identified an important gene called Inhibitor of DNA-binding 2 (Id2) and found that the gene is rhythmically expressed in various tissues including the suprachiasmatic nucleus.
The collaboration with Duffield built on the joint interests of the Dunlap-Loros laboratories that focus on the molecular biology of the circadian clock and the Israel lab that studies the role of Id genes in development.
"In conjunction with Mark Israel and colleagues at the Norris Cotton Cancer Center, we produced a knockout mouse that does not express the Id2 gene and is thus null for the functional Id2 protein. By exposing these mice to a time-zone change in their light-dark cycle, we were able to examine the effect of artificial jet lag. We altered the light-dark conditions for these mice to produce an effect that was the equivalent of a person flying from Athens, Greece, to Los Angeles, a 10 hour delay of their cycle.
"We discovered that the knockout mice took only one or two days to recover from jet lag, while unaltered mice required the normal longer four or five days to fully adjust. It's like we removed the hand brake on their molecular machinery."
The experimental results have important implications for understanding the development and function of the circadian clock in the brain and peripheral tissues such as the liver and heart. It turns out that many cells throughout the body have an intrinsic circadian clock mechanism; jet lag and shift work can produce internal asynchrony between each of the tissue clocks systems.
Our brains, on a daily basis, generate the hormonal and neuronal signals that influence the cellular clocks in the peripheral tissues. If this communication line is disrupted, the liver, for example, ends up on one time zone, and the brain on another.
These peripheral clocks in the body's organ systems cannot themselves receive light information directly. To know what time of day it is in relation to the external environment, these tissues depend on signals originating in the suprachiasmatic nucleus: every day the brain sends signals that inform the peripheral cells to adjust the phase of their rhythms, like the pin of a wrist watch being moved a little bit forward or backward.
"If we could somehow tinker with this system in the adult human, it might be possible to ameliorate the effects of jet lag and shift work by rapidly adjusting our internal clock." says Duffield.
The work was funded by the Royal Society, the Wellcome Trust, the Theodora B. Betz Foundation and grants from the National Institute of General Medical Sciences, the National Institute of Mental Health, the National Cancer Institute, the Norris Cotton Cancer Center, and University of Notre Dame.
-DMS-