September 24, 2004

New findings have circadian clock research ticking along

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Martin Egli, Ph.D., and colleagues including Carl H. Johnson, Ph.D., recently solved the structure (shown on screen) of a biological clock protein in a blue-green algae. Photo by Daniel Dubois

New findings have circadian clock research ticking along

If you’ve ever suffered jet lag while traveling, you can blame your circadian clock. These molecular timepieces synchronize our sleep-wake cycles — and a host of other physiological routines — with the external environment’s daily rhythm.

Out-of-sync clocks cause jet lag, make shift work difficult, and have been linked to sleep disorders, some forms of depression, and even cancer.

A flurry of recent research findings is now advancing our understanding of circadian clocks and could ultimately lead to novel treatments for clock-related disorders. Vanderbilt investigators Martin Egli, Ph.D., associate professor of Biochemistry, and Carl H. Johnson, Ph.D., professor of Biological Sciences, teamed to solve the structure of a clock protein in cyanobacteria, more commonly known as blue-green algae.

Blue-green algae are the simplest organism known to have biological clocks. As in higher organisms, like human beings, the clocks in cyanobacteria regulate gene expression, cyclically turning genes on and off. Three proteins — KaiA, KaiB, and KaiC, named after the Japanese word for cycle — are the key components of the cyanobacterial clock; without any one of them, the clock does not keep time.

Egli and Johnson published the crystal structure — a kind of molecular “snapshot” — of KaiC last month in Molecular Cell and reported additional features of the protein this week in the Proceedings of the National Academy of Sciences.

Though the proteins that make up the gears and springs of the circadian clock in cyanobacteria differ from those that form the human clock, the fundamental biochemistry of clock function may be conserved, the investigators said.

“Hopefully some of the basic principles that we uncover at the biochemical level [in cyanobacteria] will guide the research in the mammalian systems,” Johnson said.

Other investigators have published structures of KaiA and KaiB in recent months, putting the field in a position to tackle complex questions of clock function, Egli said. “There’s been this culmination of five years worth of work, all in a matter of months. It’s a really exciting time.”

The KaiC structure is already providing hints to its biochemical operations, but the investigators stressed that the work is still in an early stage.

“Even though we’ve learned things from the structure,” Egli said, “the big question still is: what are the underlying biochemical mechanisms that allow organisms to control their rhythms so precisely?”

Six KaiC molecules appear to group together, into a ring-like structure that looks something like a mechanical gear — oddly appropriate, given its function as the core of the timepiece. KaiA and KaiB associate with the KaiC ring depending on a biochemical reaction called phosphorylation. Egli and Johnson’s work has identified three phosphorylation sites on KaiC; mutation of any of these sites turns off the clock.

The KaiC structure reveals unexpected evolutionary relationships to proteins that manufacture the energy molecule ATP and to DNA pumps. What these similarities mean is still anyone’s best guess, Egli said. But armed with the structures of all three Kai proteins, investigators are poised to make progress at solving how the cyanobacterial clock keeps time.

“I think there must be some unusual mechanism,” Egli said.

In addition to potentially offering new avenues for treating some sleep disorders and forms of depression, clock research raises questions about timing of medication dosing. There may be optimum times of day for hitting a particular target, depending on the cycling of genes on and off. Other groups are investigating whether the timing of chemotherapy, for example, can reduce side effects and enhance efficacy, Egli said.

Circadian clocks, the researchers said, are increasingly being recognized as fundamental to biology.

“The emerging idea is that the organism is basically a clock shop — that everything is oscillating,” Johnson said. “The function of the brain then, specifically certain parts of the brain, is to keep all of that organized and synchronized. The brain acts as a pacemaker for all of the other clocks in all of the other cells in the body, even in your big toe.”

The research was supported by the National Institutes of Health, the National Science Foundation, and a VUMC Intramural Discovery Grant.

Nurses studied in new phase of circadian clock research

by Heather L. Hall

Could circadian clock genes play a key role in determining which time shift best suits each individual nurse?

Vanderbilt researchers think so, and they hope to prove that theory in a new study involving nurses from across the Medical Center.

Carl H. Johnson, Ph.D., Douglas McMahon, Ph.D., professor of Biological Sciences, Nancy Wells, D.N.S, and a number of nursing students will study clock genes in the largest population of shift workers at Vanderbilt — the nursing staff.

“We know from lower organism research that genes determine your biological clock,” said Johnson, professor of Biological Sciences. “That’s very likely to be the case in humans, but at this stage in the research it is not known.”

The researchers hope to determine who is going to have trouble adjusting to shift work based on their biological or circadian clock genes.

“The knowledge we gain will be in learning what genes may be related to poor shift work in the rhythm of nurses,” said Wells, director of Nursing Research and research professor of Nursing. “In the long run, the more we know about how people vary in terms of ability to shift rhythms, the better able we will be to help them either make job choices that fit with their genetics or learn strategies that will help them go against the grain,” she said.

Johnson said clock genes have been linked to problems like insomnia and certain cancers, as well as to the way a person responds to certain medications. Long term research like this could lead to tailor-made therapies that compensate for those genetic predispositions, he said.

“This may allow us to design therapies based on genetics that might be targeted therapy for people who have trouble with treatments, cancer treatments, sleep disorders and jet lag,” he said.

The researchers hope to study 400 nurses. Participants will take a 10-minute survey about their sleep-wake habits, how they adapt to shift work, and other related questions, and have their blood drawn.

At this time, only nurses who work at VUMC and are over the age of 21 are eligible for enrollment in the study. Information gathered will be strictly confidential. Participants can opt to find out what is learned about their circadian clock genes in the study. For more information, or to participate in this research, call Wells’ office at 322-6184.