AMHERST, Mass. — It is well known that our body’s circadian clock runs on a 24-hour cycle and regulates everything from our sleep patterns to our appetites, hormones and body temperature. But a team of researchers led by the University of Massachusetts Amherst, in collaboration with Boston Children’s Hospital, suspects that a single, centralized 24-hour clock can’t, on its own, keep the schedule for all of the brain’s energy-intensive work—and that a second, still-undiscovered clock helps do the job. To find out, the W.M. Keck Foundation, among the most selective supporters of scientific research in the U.S., has just awarded the three-person team $1.3 million.
“Think of the circadian clock as the federal government,” says Margaret Stratton , associate professor of biochemistry and molecular biology at UMass Amherst. “It sets the body’s schedule from the center, on a broad, 24-hour cycle.”
“But we think there’s another clock,” Stratton continues, “more like a local government—working close to where the demand is and responding to it in the moment.” The team believes this second clock is comprised of only three proteins and regulates the energy-intensive work that happens over shorter time periods.
A three-protein clock has deep evolutionary precedent. The oldest known biological clock, found in ancient cyanobacteria, also keeps time using just three proteins and runs entirely outside the genetic, 24-hour machinery of the circadian clock. If the team is right, our own brains may depend on a similar three-component timekeeper.
“We think this protein clock is what links neurobiological brain function, including memory formation, to the body’s circadian clock,” says Eric Strieter , professor of chemistry at UMass Amherst. “When it, or any of the three proteins of which it’s composed, malfunctions, the results can be devastating.”
Stratton and Strieter have each devoted their careers to understanding two of the three proteins and cellular pathways that make up their hypothesized clock, but it took collaboration with Jonathan Lipton , a neurologist at Boston Children’s Hospital who studies sleep and the circadian clock, which relies on the third protein, to complete the team.
Lipton had discovered that his protein interacts with Stratton’s, and he reached out to share his findings and learn more. Meanwhile, Stratton and Strieter had been working closely together for more than a decade to understand how their proteins worked together.
“We were all freely sharing and discussing our unpublished work with each other,” says Strieter, “and we realized that our three proteins are doing something that no one has observed before.”
“This three-protein clock is similar to the ancient protein-based clocks of algae,” says Lipton, “and it’s remarkable that single-celled organisms and mammalian synapses could have evolved similar strategies for circadian timekeeping. What is perhaps most important is that each of the three proteins we have connected are—when disrupted—responsible for neurodevelopmental disorders. This creates some urgency to our collaboration because there is a realistic possibility that disruption of timekeeping could directly contribute to human disease.”
When the team realized that they may have found something that fundamentally changes how we understand the body’s function, they approached the W.M. Keck Foundation, which is known for backing early stage, novel projects rooted in basic science that are typically too high-risk or too interdisciplinary for more traditional funding sources.
With the W.M. Keck Foundation’s support, Stratton, Strieter and Lipton will spend the next three years mapping the structures of each protein in great detail, learning how they communicate with one another, how they come together to form the new clock, where in the brain this new clock forms and how it works alongside the central circadian one.
This research is a foundational step toward not just understanding how our body works, but treating it when it malfunctions. Their research is also a step in potentially developing new tools—a protein-based timer engineered into biosensors, molecular switches or chronotherapeutics timed to the body’s clock—that could help keep us healthy.
Contacts:
Eric Strieter, estrieter@umass.edu
Margaret Stratton, mstratton@umass.edu
Daegan Miller, drmiller@umass.edu
About the University of Massachusetts Amherst
The flagship of the commonwealth, the University of Massachusetts Amherst is a nationally ranked public land-grant research university that seeks to expand educational access, fuel innovation and creativity and share and use its knowledge for the common good. Founded in 1863, UMass Amherst sits on nearly 1,450-acres in scenic Western Massachusetts and boasts state-of-the-art facilities for teaching, research, scholarship and creative activity. The institution advances a diverse, equitable, and inclusive community where everyone feels connected and valued—and thrives, and offers a full range of undergraduate, graduate and professional degrees across 10 schools and colleges and 100 undergraduate majors.
About the W. M. Keck Foundation
The W. M. Keck Foundation was established in 1954 in Los Angeles by William Myron Keck, founder of The Superior Oil Company. One of the nation's largest philanthropic organizations, the W. M. Keck Foundation supports outstanding science, engineering and medical research. The Foundation also supports undergraduate education and maintains a program within Southern California to support arts and culture, education, health and community service projects.