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Tinkering with biological time

OTTAWA — Brittni Laframboise looks like the typical university student as she totes her canary-yellow book bag and chats about midterms. The faint dark circles under her eyes are the only indication the 22-year-old hasn’t been getting enough sleep.


Brittni Laframoise's biological clock is out of sync
Brittni Laframboise has an internal clock that can't keep time.

But Laframboise's lack of shut-eye isn't because she's been staying out too late. Her biological clock has been ticking out of sync for the past six years.

"I get tired but still don't fall asleep," she says. "It's extremely frustrating."

Even a slight change in her routine can throw her internal clock off track. Falling asleep at 6 a.m. to wake up at 3 p.m. is not out of the ordinary, says Laframboise.

After trying therapy, sleeping pills, natural supplements and relaxation techniques, she says it's still very hard for her body to follow a regular schedule.

Laframboise is exactly the kind of person researcher Mary Cheng is trying to help.

Cheng, a neuroscientist and professor at the University of Ottawa, is figuring out how the mammalian clock works.

More specifically, she is trying to show how a few short strands of tiny molecules in the brain influence the speed at which the internal clock reacts to light. And light, says Cheng, can reset the biological clock.

"By understanding what's going on, we can look at more effective treatments for those with screwed up biological clocks," she says, adding she plans to publish the results of her work this summer.

It is known that most mammals have a set of regular circadian rhythms or daily cycles of activity, but how these occur at a cellular level is not clear.

"I'd like to know how the clock ticks and I'd like to figure out the genes that make it tick," says Cheng.

Mapping the genetics

The equivalent of a swinging pendulum in our brain is its master timekeeping centre, the suprachiasmatic nucleus (SCN).

Thirty-four-year-old Cheng is zeroing in on microRNA present in the SCN which influence the genes that help our bodies keep time.

By exploring how these strands instruct genes in the body's clock, Cheng says she is laying the groundwork to help scientists and eventually clinicians better understand and treat problems related to biological time.

"It's not only cool to know how the molecules are working, it actually has some clinical relevance," she says. "It's going to help a lot of scientists down the road."

Cheng employs genetically modified mice with magnified versions of the microRNA being studied, to conduct her experiments.

Mary Cheng and her graduate student are mapping the genetics of the biological clock
Mary Cheng (right) and her graduate student, Matias Alvarez-Saavedra, are trying to understand what makes us tick.

She has found the genes the light-related microRNAs target to bring about behavioral changes as the body goes through its daily rhythms.

"We're really trying to go from genes to behavior and everything else in between," says Cheng.

Aziz Sancar is an example of someone who could use Cheng's results in his own work.

Sancar, a biochemist and professor at the North Carolina School of Medicine, studies the circadian rhythmns of cancerous cells in mice.

His most recent work found that the ability of DNA repair differs greatly between day and night. Consequently, chemotherapy can be more effective if conducted when the ability of a cancer cell to repair itself is at its lowest in the body's time cycle, says Sancar.

But, not enough is known yet about the mechanics of mammalian clocks, he says.

"We know we have to sync our functions with the daily light-dark cycle, but how do we do it?" asks Sancar. "What is the molecular mechanism that makes a 24 hour cycle?"

Until recently, chronotherapy-treatment administered at specific times in a body's 24 hour cycle-had not been taken serious by the medical community, he says.

Mapping the genetic components which control the mammalian clock is giving scientists new ways to link research with clinical use, says Sancar.

Blending science with medicine

Therapists working with patients complaining of irregular sleep-wake patterns keep an eye out for work which sheds light on the biological clock, says Wendy-Lee Caldwell, a therapist and sleep counselor.

Caldwell, who has run her own counseling centre in Ottawa for 17 years, says chronobiology is still a relatively young field of study.

"I built all my programs based on research," she says of the treatment options she offers her patients. "I'm constantly reading up on new material."

According to Caldwell, studies on biological clocks have grown in number and depth over the past four years, creating more options for clinicians.

Peek into the lab

Cheng lab Mary Cheng showcases her state-of-the-art workspace.
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"Before the research was just baseline," she says. "Now we've got more foundational research to substantiate the things we've basically expected."

As Cheng returns to her mice, and Caldwell recommends new forms of chronotherapy, Laframboise shops around for another short-term remedy which might ease her sleepless nights.

Talk of Cheng's research makes her sit up straighter. She says she would volunteer as a test subject when the research graduates to clinical experimentation, even though that might not be for a few years.

"All this takes a toll mentally and physically," she says. "I'm willing to try anything."

Front page courtesy of Anti Aging Treatments

Related Links

More on microRNAs

Mary Cheng details her work

Aziz Sancar explains his studies



The genetic breakdown

DNA is the molecule containing the blueprint for any organism.

RNA are molecular strands which follow DNA instructions on how to make proteins.

MicroRNAs are recently discovered shorter strands of RNA which direct the activity of genes by acting like the director of a film — delegating instructions but not taking part.


MicroRNA magic

The term MicroRNA came into existence in 2001.

Before this, microRNAs were considered strands of "junk DNA."

MicroRNAs never get converted into protein. Instead, they regulate gene expression.

Links have been suggested between microRNAs and viral disease, neurodevelopment, and cancer.

This regulatory role makes them interesting drug targets as scientists work to learn more about this understudied genetic character.

There are hundreds of different types of MicroRNAs with new ones still being discovered.

Source: Ambion applied biosystems



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