Researchers Tap into the Rhythms of Life


by Brenda Patoine

September, 2007

Recent discoveries about circadian rhythms, the daily oscillations in biological function orchestrated by the brain’s internal clock, are driving new applications that range from better cancer treatment to helping future astronauts adapt to the length of a day on Mars.

The circadian system is best known for governing the sleep-wake cycle: It is the internal clock that makes some people morning larks and others night owls. When it is out of synch, as it is in some sleep disorders, jet lag, or shift work, sleep patterns are disrupted along with all sorts of sleep-dependent behaviors, including cognitive performance and overall functioning.

As it turns out, regulating sleep is only the tip of the circadian iceberg. It is now clear that signals emanating from the brain’s master timekeeper ultimately modulate fundamental physiological activity throughout the body, affecting how much we eat, how drugs affect our liver, and how tumors grow, among other things. That’s because clocks are now known to exist throughout the body.

“For a long time it was thought that the circadian clock was strictly a brain thing,” says Carla B. Green, who studies the circadian system at the University of Virginia. “It’s only fairly recently that we’ve understood that lots of different cells have clocks, including fibroblasts, intestinal cells, liver cells, skin cells, and even cancer cells. That was not appreciated before.”

These new understandings have far-reaching implications for disease prevention and treatment and are increasingly being applied to the design of therapeutic regimens that optimize drug delivery in accordance with circadian timing. In the latest twist, NASA is tapping the minds of circadian researchers to find a way for future space explorers to reset their body clocks in synchrony with the longer-than-24-hour Martian day. (See "Headed to Mars? Pack Bright Lights "). 

Synchronicity

Here on Earth, humans have evolved to survive in a light-dark cycle of 24 hours. Our biological rhythms resonate to that cycle, as do the rhythms of every other light-sensitive organism on the planet, from bacteria on up.

In humans, the central command station for the circadian system resides in a tiny cluster of brain cells called the suprachiasmatic nucleus, behind the eye sockets. These cells receive light cues directly from the retina via the optic nerve and in turn send signals to clocks in peripheral tissues, resetting them daily to resonate in time with the light-dark cycle.

Synchronicity between our internal clocks and the external environment is critical because our bodies do different things during the day than at night. The human circadian system is evolutionarily tuned to process food during daylight, whereas a nocturnal animal’s system is tuned to night feeding, for example.

“Every time you eat, you intoxicate yourself,” says Ueli Schibler, a molecular biologist at the University of Geneva who is internationally recognized in the field. Food introduces poisons into the body that have to be detoxified, he says.

The circadian system anticipates this, triggering higher concentrations of detoxifying enzymes in the liver and kidney around feeding times: “When you eat, you already have the enzymes present to save you from intoxication,” Schibler says.

The same enzymes that deal with “poisons” in our food also deal with toxic effects of medications, making drug metabolism highly time-dependent, he adds. In the case of some anti-cancer drugs, such as cyclophosphamide, the difference is dramatic.

“A certain dose of cyclophosphamide, if given at noon, kills most animals receiving it. But if the same dose is given at midnight, it rarely kills an animal,” Schibler says. “This is not a small effect.”

Chronotherapy

This observation raises the question of whether it is possible to pinpoint a precise time of day when cancer cells are highly vulnerable to attack by chemotherapy, or when normal cells are particularly resistant to the toxic effects of anti-cancer agents. What if it were possible to improve the effectiveness and reduce the side effects of virtually any drug, just by taking it at a different time?

That is the concept behind an emerging field of medicine known as chronotherapy, a treatment approach that tweaks medication dosing to capitalize on the daily rhythms of the body’s internal clock.

Chronotherapy appears to be particularly well suited for fighting cancer, a battleground where medicine’s primary weapons, chemotherapy and radiation, are notoriously toxic to healthy tissue. There is substantial evidence going back more than a decade that both the effectiveness and toxicity of several anti-cancer agents vary dramatically depending on when the drug is given—in other words, where in the circadian cycle the patient is. At some points of the day, the body is simply better equipped to efficiently use and metabolize drugs.

There is even evidence that the circadian clock itself acts as a sort of “tumor suppressor” in living tissue, according to work by Loning Fu at Baylor College of Medicine. With funding from the National Cancer Institute, Fu’s group has shown that knocking out one of the known circadian genes increases tumor development in laboratory mice, possibly by disrupting cellular safeguards for repairing DNA damage. His team is now trying to better understand how the circadian clock suppresses malignant growth.

Clinical research on chronotherapy is still in its infancy, but recent controlled clinical trials of “chronomodulated” cancer chemotherapy in metastatic colorectal cancer are promising. They offer tantalizing evidence that better timing of cancer drug administration can significantly reduce serious adverse effects, and, at least in men, modestly improve survival (an opposite survival effect was seen in women). The key seems to be a shift to nighttime dosing, though optimal timing depends on the drug, the tumor, and, to some extent, each patient’s unique circadian rhythm.

Despite the promise, there remain formidable barriers before chronotherapeutics see the light of day in routine clinical practice, including the healthcare system itself. “I think that a lot of people who work in the clinic have been a little bit resistant to this type of thing, because it complicates their life a lot,” Green says. “Often, nighttime turns out to be best, so they’ve got to arrange chemotherapy or drug treatment at 3 a.m. rather than the middle of the day when they are fully staffed.”

“A lot of this is very recent,” Green adds. “[Chronotherapy] hasn’t made it into the textbook-level general knowledge.”

What Makes Us Tick?

Green points out that it is only in the last few years that scientists have really begun to unravel the molecular machinery behind the circadian oscillator. A breakthrough occurred in 2005, when Takao Kondo and collaborators at Nagoya University in Japan reported in Science that they had reassembled in a test tube the circadian clock of cyanobacteria, a type of bacteria capable of photosynthesis.

Cyanobacteria, commonly referred to as blue-green algae, are believed to be the oldest oxygen-producing organisms on Earth and have long been important models for studying circadian mechanisms. The “clock in a tube” model has made it possible to tease apart the protein interactions underlying clock function in exquisite detail.

“This is the most exciting thing in circadian research right now,” Schibler says. “Once you can assemble the oscillator in vitro, then you know you’re going to be able to solve the problem of how it functions—to understand what makes it tick with the rhythm of 24 hours.”