Crossing the body's time zones
By Shannon Montgomery

OTTAWA — Hotel front desk clerk Devon Gignac has been working nights for the past five years, and says it’s now his way of life.

“It’s not so bad on me, because I work steady nights, but I find it hard to reset my clock on the weekend,” he says.

He says that Sunday nights are difficult because he’s gets back into sleeping nights over Friday and Saturday so he can do things like grocery shop during the daytime hours. But besides the occasional fatigue and the 15 pounds he’s lost since starting the graveyard shift, Gignac says he hasn’t noticed any ill health effects from his shift work.

People working shiftwork can have a much higher incidence of breast cancer, diabetes, cardiovascular disease, among other things.

A new field of research shows that Gignac’s internal clock may not be faring as well as he thinks, with a constantly shifting definition of “day."

Genes that can be considered little clocks are peppered in cells throughout the human body. From the brain to the skin to the while blood cells, research has shown that many of the parts of the body contain cells that oscillate to the rhythm of the solar cycle.

And scientists are beginning to realize that when these clocks begin to lose time, they can have an effect on conditions as diverse as cancer, diabetes and depression.

“If you do mess with a circadian clock, you do get sick,” says Michael Antle, a psychology professor and circadian expert at the University of Calgary.

"There’s a study that came out of Harvard a number of years ago, they were tracking nurses who did shift work. And they had a much higher incidence of breast cancer, diabetes, cardiovascular disease and a number of other things (as compared to nurses who worked regular daytime hours)," he says.

20,000 clock genes are clustered in your brain to make a master clock that responds to light to keep you in sync with the cycle of light and dark.

A cell is considered a clock or circadian cell if it has a steady rotational pattern that lasts around 24 hours. This pattern starts when clock genes in these cells code for proteins that slowly build in the system. Once these proteins have reached a certain level, they activate a process that works to turn the original genes off. The level of the proteins then diminish until they have reached a low enough level that the genes are switched back on and recommence protein synthesis. This process is called gene oscillation and it takes one day in a properly functioning cell.

Around 20,000 of these clock cells are clustered in the brain to create a “master clock”, called the suprachiasmatic nucleus (SCN). The SCN is located in the hypothalamus. The SCN then absorbs light, uses it to calculate a proper rhythm, and communicates the time to a number of smaller, “peripheral clocks” located throughout the body.

“Some of these tissues in the body can oscillate on their own, but they sort of need the boss, up in the SCN to tell them how to oscillate, and tell them when to work,” says Antle.

Clock genes and cancer

The entire system is extraordinarily complicated and takes place in most of the systems in the body. This gives many scientists reason to believe that circadian clocks developed early in the evolutionary process.

“We see that the circadian clock is present even in the single-celled bacteria,” says Loning Fu, an assistant professor at the Baylor College of Medicine in Texas.

“Some of these bacteria existed at least four billion years ago on the earth. So the circadian clock is kind of an ancient part of our bodies.”

Fu and her colleagues theorize that this oscillation could have started to protect organisms from harmful UV rays that hit the earth billions of years ago at a much more powerful level than they do today, because the ozone layer had not yet formed.

Early in its history, the "earth’s surface was naked, it wasn’t really covered. So the UV radiation from sunlight could be lethal for any organism. But if an organism could develop a circadian rhythm, a clock that could gage all sorts of biological processes, DNA replication could happen at night and then the organism could acquire an evolutionary advantage,” she says.

This power that clock genes hold over the rate of DNA replication has led Fu and other researchers to stunning findings about the ways in which cancer forms.

“A previous finding states that in the mammalian body, the cell cycle proliferation — the cell dividing from one into two — takes about 24 hours,” she says.

“If you talk about cancer connection, cancer is a process of uncontrolled cell proliferation. And how the clock can inhibit cancer formation, can prevent cancer formation, is that the clock gene can directly regulate cell cycle genes.”

Fu’s lab proved this point, showing that if mice lacked one of the key clock genes, called Period 2 (per2), they are more prone to developing cancer.

She says that this clock gene also helped protect against cancer by activating the pathway that causes cells that have DNA damage to die, keeping them from mutating — as DNA-damaged cells often do — into cancerous cells. When per2 was removed, this pathway wasn’t activated, which meant that many more cells that suffered DNA damage weren’t destroyed and became cancerous.

These two findings provide insight into how cancer can be prevented from occurring in the first place, Fu says, and they also suggest a better way to treat cancer that already exists.

As cancerous cells are not properly using their internal clocks, they proliferate much more quickly than normal cells, says Fu. This means that it’s possible to target the cancerous cells with radiation or chemotherapy at times when they will suffer the most damage and normal cells the least, based on the clock cycles of both types of cells.

“Today’s cancer treatment, you just go to cancer treatment when the doctor’s available, it’s not that you go to treatment when your body is best fit to the therapy,” she says.

“So it would be important in the future to look at the patient and the tumour biology, and their normal tissue to see the difference. If you apply the drug when the tumour is more sensitive to the drug, it can improve the treatment efficiency, and also at the same time can reduce the side-effects.”

A delicate balance

Research is also beginning to show that it’s not only disturbing the individual clocks that can do damage to the body. The body’s peripheral clocks have a delicate balance in their co-ordination both with each other and the master clock, and disrupting this balance can cause just as many problems as disrupting an individual clock.

At times this can be adaptive, says Atler.

“Part of the idea is that you don’t need to do the same thing all day long. So you can parcel you behaviours and your physiological processes into special little temporal niches, or times of the day,” he says.

If the body's peripheral clocks fall out of sync with the master clock people end up feeling sick. A mild form of this is experienced as jet lag.

“You eat meals at certain times of the day and your digestive system needs to be active at those times and you sleep at other times, and you engage in physical activities at other times. So by sort of coordinating the systems, you can be ready to do the things you need at certain times.”

Shimon Amir, a psychology professor at Concordia University, has studied what happens when these clocks go out of sync.

“A good example of this is what happens when you travel across time zones. For example, when you travel to France from here, the clock has to advance the phase by six hours because it’s earlier here than there. Now, when that happens, the master clock tries to catch up with the new local time, those other clocks have to catch up as well,” he says.

The clocks become desynchronized as a result, as the master clock can reorient to new light cues fairly quickly while all of the peripheral clocks take longer to reset.

“What you experience as jet lag is really the result of desynchronization of clocks. All those gastrointestinal disturbances, emotional disturbances that you suffer — lousy mood, all kinds of disturbances in appetite. They are all the result of desynchronization of circadian clocks in the body,” he says.

Amir says this research has yielded several interesting tidbits, like it’s easier to adjust to having your clock delayed than advanced.

“Even in animals, we see when the phase of the clock is delayed — say we simulate travel from Montreal to Vancouver — the clocks catch up much faster than if we put the animal in an airplane and send the animal to Europe.”

This kind of research could yield better shifts for people who have rotational hours to ensure they are always moving in the direction that is easiest for them to adjust to.

He says his research has also shown that it’s possible to throw the peripheral clocks out of sync from the master clock by only targeting them, and not by changing the master clock at all.

He did this by stressing animals, or inducing fear. These findings could account for the fact that people with mental disorders also have disrupted sleep schedules.

“We know, for example that when you’re stressed, your circadian rhythms are disturbed, you suffer from sleep disruption,” he says.

“Or people who suffer from depression have severe disturbances in their sleep schedules, they suffer from what is called advanced sleep onset syndrome — they go to bed very early and they get up really, really early.”

Not only in rats

Although most of the research done on clock genes has been done on animals to this point, it’s slowly becoming possible to look at these genes in humans.

Nicolas Cermakian at McGill University is one of the first people to look at these genes in humans, as part of the Center for Study and Treatment of Circadian Rhythms. He says his work, with the centre’s director, Diane Boivin, is “unique in Canada.”

As opposed to his usual work, where he still works with animals, at this lab the information about the clock genes come from a more readily available source.

“In the blood, some of these genes have an oscillation rhythm,” he says.

Francine James, a PhD candidate working with both Cermakian and Boivin, says it’s not as easy to study these genes in humans.

“It’s actually pretty hard to start to get clock genes dosed in humans, because the advantage of working in animals is you can go right into the brain and dose the genes, dose the proteins directly from the clock in the brain, but you can’t really do that in humans, at least not live ones,” she says.

But she says any drawbacks to not being able to peer directly into the master clock are easily made up for.

“The interesting part of humans is that you can have humans do stuff that you can’t have animals do, like simulate jet lag, or stay awake for 36, 48 hours. Or have them live on a sleep-wake schedule that isn’t a normal sleep-wake schedule. So instead of going to sleep every 24 hours, they’d go to sleep every 40 hours,” she says.

“So then, you can start to look at more than one thing at the same time. Mostly the interest with humans is that you can ask a human whereas you can’t ask an animal ‘How do you feel?’ after 24-hours of sleep deprivation, which is nice to know if you’re a pilot, or if you’re a long-haul truck driver.”

The lab began combining clock gene research with traditional research about five years ago, says James. But much of that time has been spent making sure the genes in white blood cells really do oscillate.

'We know, for example that when you’re stressed, your circadian rhythms are disturbed, you suffer from sleep disruption.'

The first full-scale human experiment at the lab to look at clock genes is currently underway — participants in the experiment are undergoing sleep deprivation.

Right now, the field of circadian genes and rhythms is still a new one with a lot of questions and not many answers.

But the results of these different studies could end up revolutionizing the way we think about sleep.

For example, pills that can whisk away jet lag in an instant may seem like fantasy, but the University of Calgary’s Antle says he’s going to begin working on a serotonin/light combination that seems to reset the body’s clock by eight hours in one go.

And he says that he’s been constantly surprised by how complicated all the genes’ interactions are, making the field full of research that needs to be done simply to understand it all. For example, he’s recently shown that the master clock cells — once considered all the same type of cell — are actually very diverse with complex communication patterns in themselves, even before beginning to talk to the peripheral clocks.

Laughing, he says, “It’s one of those things that make it so much fun, though.”