A Nobel connection: CIFAR senior fellow tinkering with the circadian clock

by Juanita Bawagan Announcement Child & Brain Development 04.12.2017

Senior Fellow Joel Levine can remember the morning of October 2 vividly. It was not yet dawn as he drove to the University of Toronto, Mississauga campus. His quiet commute was interrupted when his sister called with exciting news: His mentor Jeffrey Hall had won the Nobel Prize.

“I screamed. I couldn’t believe it,” recalls Levine, who did his postdoc with Hall in Brandeis University’s biology department.

The 2017 Nobel Prize in Physiology or Medicine was awarded jointly to Hall, Michael Rosbash (Brandeis University) and Michael Young (Rockefeller University) for their discoveries of molecular mechanisms controlling the circadian rhythm.

“This was something that many of us knew might happen, but it’s been brewing for several years and there are so many deserving people in the world that you never know who’s going to get it,” Levine says.

“I was so happy for the three winners who I know. So it was a very intense moment for me.”

December 10 will be another memorable day. Levine will be one of the few people from Hall’s lab to accompany him to the Nobel ceremony in Stockholm, Sweden.

“Some people are happy that they’re going to Disneyland, but I’m going to Stockholm. Watching these guys get the award will be very, very gratifying,” Levine says.

Tapping into the body clock

In 1971, scientists identified mutant fruit flies whose behaviours tied to biological rhythms appeared to have been altered. Through mutagenesis, the scientists identified the “period” gene that controlled timekeeping.

Pictured L to R: Michael Young (The Rockefeller University), Tom Jessell (Columbia University), Jeffrey Ravetch (The Rockefeller University), Lorne Babiuk (University of Alberta), Michael Rosbash (Brandeis University), Brian Greenwood (London School of Hygiene and Tropical Medicine) and Jeff Hall (Brandeis University) at the 2012 Canada Gairdner Awards dinner. Young, Rosbash and Hall jointly won the 2017 Nobel Prize in Physiology or Medicine. (Photo credit: The Gairdner Foundation)

A decade later, Hall, Rosbash, and Young would unlock the inner workings of the circadian clock. They began by isolating the period gene and understanding its role. Young’s group found that it controlled the circadian rhythm by interacting with the “timeless” protein that cooperates with “period” as it builds up through the night and degrades during the day on a 24-hour cycle. They also identified connected protein components that were part of what the Nobel committee poetically described as the circadian “clockwork within the cell.”

“Some people are happy that they’re going to Disneyland, but I’m going to Stockholm. Watching these guys get the award will be very, very gratifying,”

“They did something that I don’t think had been done before. They could take an animal with a broken clock and give a normal copy of the gene to that animal and restore normal clock functions. It’s almost like gene therapy. The ability to fix and change behaviour and restore a normal behaviour to a fly that lacked that function was unprecedented,” Levine says.

This discovery had broad implications for human health and disease. Nearly every living organism has a body clock and this shapes when they eat, sleep and how their bodies heal. The three researchers had opened the door to many new biomedical questions and would further probe the gene’s interconnected role.

Life in Hall’s lab

“Jeff and Michael Rosbach were a team and the work that they got the prize for happened over a course of 10 to 15 years before I got to the lab… but they were still going full tilt when I got there,” Levine says. “It was crazy. I loved it.”

This time left a mark on Levine and his research. Today, he is still pursuing some of the ideas that he began exploring in Hall’s lab.

“They could take an animal with a broken clock and give a normal copy of the gene to that animal and restore normal clock functions. It’s almost like gene therapy.”

Levine’s first project in Hall’s lab focused on “peripheral clocks.” While most attention is focused on the body clock in the brain, there are similar mechanisms in other tissues. In his own lab, at the University of Toronto Mississauga, Levine and his co-workers looked at the cells that make pheromones and how their biological clocks work.

A second research question in Levine’s lab was focused on whether the biological clock plays a role in the social behaviour of fruit flies.

“[Hall] predicted that it would never work. I’m happy to say he was wrong and I think he was happy to say he was wrong,” Levine says.

In 2002, Levine and Hall published “Resetting the Circadian Clock by Social Experience in Drosophila melanogaster” in Science. Their paper showed that flies influence one another’s circadian clock functions and that their clocks act to synchronize social interactions.

From fruit flies to healthy kids

In 2003, Levine joined the University of Toronto Mississauga’s Department of Biology where he is a full professor and holds the Canada Research Chair in Mechanisms and Features of Social Behaviour. His lab focuses on the genetic basis of social interactions in fruit flies.

“The interest in social behaviour has helped me understand that our social world is a complicated environment. The social world influences individuals, but individuals are part of it. The individuals are changing and the environment they are part of is also changing,” Levine says.

“The relationship between individuals and their social group is exciting because part of this relationship is part of our inherited biological legacy. If we can understand the relationship between individuals and their group, we may find ways to improve how groups function from classrooms to board rooms, in surgical teams and in conflict resolution.”

Pictured L to R: Dr. Molly Zirkle, Program Co-Director Marla Sokolowski, Senior Fellow Joel Levine, Jeff Hall and Dr. Allen Sokolowski at the 2012 Canada Gairdner Awards dinner. Marla Sokolowski, Hall and Levine have maintained a longstanding friendship and professional association. (Photo credit: The Gairdner Foundation))

Levine’s research interests led to an invitation to CIFAR’s Child & Brain Development program (then known as Experience-based Brain & Biological Development). The program brings scientists from different backgrounds around the questions of how the world affects children and how to redress the issues that they face.

“It’s inspiring to be part of that group and it’s helped me frame research questions in ways that are meaningful. The ultimate goal will be to make a better world for kids,” Levine says.

Most recently, Levine with others in Child & Brain Development program have started two research projects through CIFAR’s Catalyst fund. These projects were encouraged by Program Co-Directors Marla Sokolowski and Tom Boyce as a sort of a challenge. The Catalyst fund designates money to help facilitate high-risk, interdisciplinary research collaborations across CIFAR’s membership. In one project, researchers are studying the effect of early life stress and adolescent sleep in different animals: mice, fruit flies, humans, and monkeys.

“If we can understand the relationship between individuals and their group, we may find ways to improve how groups function from classrooms to board rooms, in surgical teams and in conflict resolution.”

Levine’s second project bridges his program with the Learning in Machines & Brains program. The collaboration includes Senior Fellow and neurologist Takao Hensch, as well as CIFAR Azrieli Global Scholar Graham Taylor, who is a computer scientist and Jonathan Schneider, a post-doctoral fellow. Together, they are developing computational approaches to look at structures of social behaviour in fruit flies and mice.

One of Levine’s hopes is that similar to the shared biological clock mechanism, there might also be a shared mechanism for sociality across species.

“If we bring to light certain things about social structures that apply to human societies, it may help build a better workforce or identify autism or other types of pathologies at an earlier stage or suggest ways to treat them that would be incredibly gratifying. I don’t expect a quick fix but I think the work we’re doing right now will help get us there,” he says.

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