Jan. 14, 1999 BOSTON -- January 11, 1999 -- The study of biological clocks is a field whose time has come -- and with breath-taking speed. Now a team of Massachusetts General Hospital (MGH) scientists has discovered that the same genetic machinery that controls the inner movements of the clock may drive the basic rhythms of the body -- the rise and fall of body temperature, blood pressure, hormones and the sleep -- wake cycle. The findings appear in the January 8 Cell.
"We think this is the first example of an output of the biological clock that we understand at a molecular level -- that is, how a bodily rhythm is controlled from the core clock loop," says Steven Reppert, professor of pediatrics at MGH and Harvard Medical School. Xiaowei Jin and Lauren Shearman, who are both research fellows in pediatrics at MGH, are lead authors on the Cell paper.
The discovery is also significant because it sheds further light on a biologically unique phenomenon, Reppert says. "We're talking about a time domain that is unusual in biology. We're talking about a cell being able to keep 24-hour time rather than millisecond or second-by-second time. That's what I think is so unusual. Feedback loops are very common in biology, but this sort of time domain is what makes this loop special," he says.
Ultimately, it may be possible to correct defects in the clock or harness it to improve the function of the body's daily, or circadian, rhythms. "Understanding the clock may allow us to manipulate sleep or at least to understand abnormalities of sleep in patients based on aberration of their central clock," he says.
A better understanding of how the clock mechanism drives bodily rhythms could also lead to more efficacious treatments of disease. For example, heart and asthma attacks are more likely to occur at certain times of day. And certain medications have greater efficiency and lower toxicity depending on what hour they are given. "It's a whole area of circadian biology that is coming into its own," Reppert says.
For 25 years, scientists knew a master timepiece was lodged behind the eyes, in a structure called the suprachiasmatic nucleus (SCN), but they knew little about the molecular workings of the clock -- the genes and proteins that make the clock tick on a 24-hour basis. Over the past eighteen months, they have discovered that the clock consists of at least six proteins that engage in a series of elegant and precisely timed pas de deux that result in genes being switched on and off over a 24-hour cycle.
They also suspected the clock might drive bodily rhythms through the release of peptides, hormones, and neurotransmitters but were mystified as to how genes for these substances were turned on and off. Reppert and his colleagues have discovered that the gene for arginine vasopressin, a peptide that is released rhythmically in specific brain regions over the course of the day, contains the same on switch as one of the six genes in the central clock mechanism. And the switch for this output gene appears to be turned on and off by the same proteins, or transcription factors, that control the central clock genes.
Reppert believes the device may be found on a number of output genes, such as those for proteins controlling blood pressure, sleep onset, and other circadian rhythms. "We think this is one way the transcription machinery of the central clock directs output genes in a variety of directions to ultimately get control of rhythms in physiology and behavior," says Reppert. "This is probably not the only way to control output from the SCN. There are probably others that are just waiting to be discovered."
This work was funded by the National Institutes of Health.
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