Research currently under way at Smith is investigating precisely where the sleep problems associated with age arise and how the youthful aspects of the human biological clock could be harnessed to help improve the lives of older people. Their findings in the scientific subfield of chronobiology promise to yield information valuable for treating people who can’t seem to get enough rest.

By Eric Goldscheider / Published October 5, 2011

What happens when the aging brain experiences sleep disruptions? That question is part of a research investigation that Tippit Professor in Life Sciences Mary Harrington is conducting in collaboration with Stephany Biello ’90, a psychology professor at the University of Glasgow in Scotland.

During their study they are artificially creating the conditions for mice to experience jetlag by disrupting their sleep cycles via methodically turning the lights on and off in their cages. Their findings in the scientific subfield of chronobiology promise to yield information valuable for treating people who can’t seem to get enough rest. If they can better understand the effect of aging on biological rhythms that influence the sleep cycle, pinpointing which cycles are more susceptible to deteriorating function, they will have gone a long way toward unlocking some of the mechanisms that make us tick.

They have been able to show in mice that exercise is beneficial to keeping the body’s rhythms on track. While this may be intuitively correct, their data is honing in on some of the underlying biological reasons for this.

“We know that among people over 65, one of the very top reasons they go to the doctor is because they are having sleep disruptions,” explains Biello. “As people age they don’t synchronize as well with the environment.” She has found evidence that one culprit might be the suprachiasmatic nucleus (SCN), a tiny region in the brain located near where the optic nerves cross. Most people know it simply as our “biological clock.” It uses the light of day and the dark of night to regularly update the cycles of the body and the mind.

Experiments show that without external cues, the sleep-wake cycles of the human biological clock, or circadian clock, run on cycles of approximately 24 1/2  hours. Hence the word “circadian,” Latin for “about a day.”

Harrington’s first reaction when Biello told her of this line of inquiry was, “That’s boring. Things just get worse with age, that’s just the way it is—and I don’t particularly want to do studies on that.” But when Biello pointed out the many aspects of SCN function that were unchanged in aged animals, Harrington was intrigued.

The two researchers decided to join forces to determine precisely where the sleep problems associated with age arise and how the youthful aspects of the SCN could be harnessed to help improve the lives of older people. Their findings “suggest the sleep disruption young mice experience following jetlag is similar to the state old mice are generally experiencing even without jetlag,” says Harrington. Their study extends to other clocks, distributed in cells around the body that might work independently of the SCN (which they also refer to as the body’s “pacemaker).”

Harrington and Biello are coming at the same puzzles from different angles. “Stephany is doing the electrophysiology; I’ll do the bioluminescence. We’ll divvy up the work according to the techniques that best address our questions,” says Harrington. The first technique amasses data based on the electrical signals emitted by the target cells and neurons in the young, middle-aged and older (over 2 years) mice they are studying.

The second technique uses mice that have had a firefly enzyme fused to a circadian clock protein added to their genomes. When she puts their cells under a special camera developed by astronomers to spot very dim stars, Harrington gathers information based on the timing of light emission. This gives her clues about how proteins associated with different phases of the circadian clocks are expressed in different cells in the body following jetlag.

“We saw in older animals that the process of the body catching up to the brain clock was worse, but the brain clock was shifting perfectly—it didn’t get worse with age,” says Harrington. “We were intrigued that maybe there is something really helpful we can do with this information.”

Their latest advances are in being able to show that “internal desynchrony,” or the condition in which environmental cues don’t mesh with an individual’s eating and sleeping patterns, is greater in older mice in the first few days after induced jetlag as compared with younger mice. Standardized measurements of how much the mice move around, or their “locomoter activity,” showed some interesting discrepancies.

“Activity and time of clocks in peripheral tissues such as the spleen and thymus lagged the clock in the brain in all mice, but this was especially so in old mice,” says Harrington. “Thus, the experience of jetlag may be longer lasting in old mice.”

Significantly, her and Biello’s work shows that the presence of an exercise wheel seems to benefit the old mice. “We are now analyzing data of the PER2 gene and rhythms in the firing rate expressed by cells in the clock in the brain (the SCN), and our preliminary results suggest that these rhythms also show benefits from being housed with a running wheel,” says Harrington. “Thus, it could be that exercise benefits circadian rhythms of old animals, and we may be able in future work to detail exactly how this works at the neurochemical level.”

Harrington and Biello brought in a third collaborator. Gurprit Lall, a lecturer in pharmacology and neurophysiology at the Medway School of Pharmacy in London, did his doctoral work under Biello’s supervision in Glasgow and some of his postdoctoral research with Harrington at Smith. His expertise in molecular biology and how the eye influences the circadian rhythm adds yet another approach to common questions.

Such collaboration is an increasingly important part of science today, Harrington notes. “The bar has been raised; it is harder to get funding or even to publish, so you need a multitude of techniques for people to be more confident in the results.”

Stephany Biello was pursuing an interest in politics and economics as a sophomore at Smith when she decided to take some psychology courses. She decided that she should learn something about behavior if she wanted to understand how people wield power and money. And besides, Smith encourages students to be well rounded in their studies and take classes outside their comfort zone.

That decision set Biello’s life and career on a new path when Mary Harrington, Tippit Professor in Life Sciences and at that time a new faculty member in the psychology department, turned her on to chronobiology. It is the study of the internal clocks, or circadian rhythms, that inform the lives of living organisms.

Today, Biello is the second woman ever to earn the rank of professor of psychology at the University of Glasgow, an achievement she attributes in no small part to what became a sustained collaboration and lifelong friendship with Harrington. “Mary inspired me as a role model as a woman in the sciences and she has mentored me through the years,” says Biello from her office in Scotland.

The two women published their first joint paper when Biello was still an undergraduate at Smith. That, coming on top of Harrington’s ability to place her student in a research position in England during a junior year abroad, set Biello in a direction that led to a doctorate in zoology at the University of Toronto and eventually to her current post. Along the way, she came back to Smith for a postdoctoral year, funded by the National Institutes of Mental Health, in her mentor’s lab.

Harrington says that it is not only gratifying to see a former student go on to become an academic peer and a valued collaborator, it is also instructive. “It is interesting to me to see the impact of the Smith education when people go on to very different places because often there are not that many women in senior positions,” she says. “I often have former students who touch base, and I think they are trying to get back to that sense of confidence they had at Smith when they hit those tough points along the road.”

Biello echoes those sentiments and more. As a slightly older (there are nine years between them) scientist, Harrington contributed greatly to Biello’s success as she came up through the ranks of academia. “Personally and professionally I couldn’t imagine having a better mentor or colleague,” says Biello of Harrington. “She has very strong ethics, very strong research practice and she’s an excellent teacher.” In some ways, Biello sees herself as having followed a path that she watched her mentor forge first. “It’s so useful to see somebody going through all the stages just a little before you.” Through this a friendship formed that blossomed to include family visits.

Whenever they talk, either by phone or in person, the conversations inevitably go beyond chronobiology. “I really enjoy having a relationship where you can switch between having really detailed neuroscientific discussions and then commenting on shoes, clothes, literature and art,” says Harrington. “It’s such a pleasure to collaborate with work, but also with every other aspect of life.”
Five years ago, when Biello’s second son was born, she asked Harrington to be his godmother, cementing a bond that will doubtless live beyond their respective careers.