This web page was produced as an assignment for an undergraduate course at Davidson College
CIRCADIAN RHYTHM
The how and why of sleeping and waking
The background:
Most living things have a daily cycle that reflects the rising and setting of the sun. The term used to describe this coincidental cycle is circadian rhythm, which comes from the Latin circa diem -- literally 'about a day'. In January 2001, scientists from Howard Hughes Medical Institute led by Louis J. Ptacek found a mutation within the newly discovered human gene, hPer 2, which leads to a condition called familial advanced sleep phase syndrome. The gene was found to be homologous both to Drosophila and three murine genes named respectively, per and mper1, mper2 and mper3. Click on the respective links to learn more about their discovery or find the abstract of their report in Science.
A recent article in USA Today highlighted one of the most recent discoveries also published in Science on April 13, 2001. The article concentrates on "night owl" and "morning lark" syndromes -- and the potential this research could have in identifying the genetics basis for these common behavioral patterns. The USA Today article focuses its audience on the applicability and possible effects of this research on their lives. It's very common to say, "Oh, I'm a morning person" or "I work better at night." Now, scientists are coming up with biological explanations.
Research shows that the human "master clock" is located in the hypothalmus of the brain. From there, it sends signals (probably based on light cues) to other parts of the body that, in effect, reset "peripheral clocks" daily. People end up with different body clocks -- different circadian rhythms -- because of difference in the genes that code for these "clock genes." In some cases, the genetics differences are so extreme, that it severely affects sleep patterns and daily functioning. The journalists also emphasized the oscillating effects of many genes at work. Although it's easy to imply genetic differences, it turns out that establishing circadian rhythm is dependent upon many biological factors working together.
Interestingly enough, as an article
in an online newspaper, Cosmiverse,
describes, there is evidence to suggest that circadian clocks can be "turned
on" as early as egg fertilization in some fish. A similar article published
by an ABC
News Science reports that, although it was previously believed that circadian
rhythm was dependent upon the brain, this new study begins to cloud the waters.
Although the importance of circadian rhythm seems clear, how the body "turns
on" these genes so early is still a mystery. Yet, as the articles states,
it is clear that, "... these ‘clock genes’ create circadian
rhythms in the body and control the timing of a variety of biological changes,
including hormone production, blood pressure, and the metabolism's slowdown
during sleep."
The science:
Most current research demonstrates a high degree of conservation (genetics similarity between different species) between all of the genes responsible for maintaining circadian rhythm, which implies exceptional evolutionary importance of circadian rhythm. Naturally, it makes sense that most living organisms' daily functions reflect a key universal component -- sunlight. Yet, rarely do we stop to consider how, on the cellular level, an organism can regulate activity dependent on such a critical component like sunlight.
Recent discoveries published in Nature by Schibler 1998, have focused on the negative-feedback loops responsible for controlling circadian rhythm in Drosophila melanogaster. Two genes, per and tim work together to repress their own expression and activation that are dependent on the heterodimers of two other genes, Clk and BMAL1(respective proteins Clock and Cyc). The story is complicated, but essentially relies upon varying levels of each gene's respective proteins to modulate the others. More specifically, the promoter regions of both per and tim contain E-boxes which are bound by both Clock and Cyc. Messenger RNA of per and tim is synthesized until concentrations of their protein products, Per and Tim, reach a certain level. At that point, these protein products inactivate Clk and Cyc which prevents mRNA synthesis of per and tim. Transcription is prevented until Per and Tim decay, protein levels drop, and synthesis is once again activated.
Diagram of fluctuation mRNA levels during the sleep and wake cycle:
Explanation of per/tim cycle without Clk and Cyc interaction. Permission requested from Rockefeller Institute for Medical Research. To view the article from which this diagram was taken click here.
Between the eye and the sleepiness:
The feedback loop that regulates the expression of these circadian rhythm genes is fascinating. The complex simplicity is marvelous. Yet, how, exactly, does the body communicate between visual cues and cellular responses? Naturally, there are other genes. Blue-light receptors called crypotchormes in Drosophila, are encoded by the gene cry (Whitemore et al.) . Light input received by these cryptochromes (within the body and not through the eyes) somehow signals the per/tim system because per/tim levels will remain constant in the absence of light or a functional gene copy. As Scibler (2000) describes, the mammalian system has a slightly more complicated pathway. Light information is sent from the eyes to the suprachiasmatic nucleus in the brain and subsequently sent to the rest of the body. However, the mechanisms for these systems remain undiscovered.
Recently, Yamaguchi et al. were able to monitor the expression of mPer1 in a living mouse. Their dtechnique demonstrate in vivo the acutal flucuation of mRNA expression as light varied. This experiment, they report, is the first time that real-time monitoring of the circadian rhythm genes has been possible in a mammal. This advancement, of course, presents exciting possibilities for future research in behavioral genetic studies.
A recent review article by Clayton et al. published in Nature in January 2001 summarizes the current understanding of feedback loops within Drosophila, mouse and human systems. The human homologues are the most recently discovered, yet, posits Clayton, will be the most quickly advancing given the completion of the human genome project. The system is a fascinating model for the burgeoning field of genomics because of the complexity of the system and its regulatory mechanisms.
The per protein:
A structure for the per protein has not yet been identified. However, there is a great deal of homology studies amongst different species. Some areas such as the PAS region are highly conserved whereas others seem somewhat more flexible. To read more on per homology, check out the OMIM listing below.
Informative links:
References:
Clayton, J.D., C.P. Kyriacou and S.M. Reppert. Keeping time with the human genome. Nature 409,829-830 (2001).
Schibler, U. Heartfelt enlightenment. Nature 404, 25-28 (2000).
Schibler, U. New cogwheels in the clockworks. Nature 393, 620-621 (1998).
Whitmore, D. et al. Light acts directly on organs and cells in culture to set the vertebrate circadian clock. Nature 404, 87-91 (2000).
Yamaguchi, S. et al. View of a mouse clock gene ticking. Nature 409, 684 (2000).
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Email me at: amhartman@davidson.edu