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PORTLAND, Maine � , and , have earned a five-year, $9.6 million from the National Institutes of Health to answer a set of questions that could fundamentally transform our understanding of health and disease: If you were born multiple times under the exact same circumstances, would you turn out to be the same person each time? And if not, what implications could the differences have for your health?

Although it may sound like science fiction, the answers could revolutionize our understanding of how “probabilistic� variation influences health before birth and throughout life � and provide insights into new strategies for combating cancer, obesity and a host of other health concerns and diseases.

This groundbreaking research is made possible by a Transformative Research Award, part of the NIH Common Fund’s High-Risk, High-Reward Research Program. The award promotes cross-cutting, interdisciplinary approaches to projects that have potential to create new paradigms or challenge existing ones, according to NIH.

“In some ways, our health is like a game of dice in which chance, or ‘variation,� plays a major role. We want to understand exactly how variation defines our health and how we can leverage it to combat disease,� Pospisilik said. “As scientists, we’re trained to see variation as ‘error,� but we believe that it is actually a necessary and vital biological regulatory process. We are grateful to the National Institutes of Health Common Fund for its support of this exciting project. These high-risk, high-reward funding mechanisms from the NIH are a rare opportunity to peek into the unknown � to remind ourselves how little we actually know.�

Variation is built into every species on earth and is thought to promote resilience against threats such as disease and environmental shifts. However, the genetic and epigenetic regulators that control variation have been difficult to identify and even more challenging to directly link to clinical outcomes.

“Our genes and our environment are just 50% of what makes us who we are,� Nadeau said. “We want to understand what that other 50% is so that someday we may be able to predict whether early medical interventions or lifestyle changes could improve our chances for a healthy life.�

Now, thanks to advances in technology and technique, Pospisilik, Nadeau and their collaborators will be able to detect and analyze the genetic and epigenetic factors that control variation patterns and link them to their effects.

To do so, they will leverage tools created by Nadeau and MMCRI’s , (also a collaborator on the award) that allow scientists to identify molecular regulators of variation. Another team at VAI, led by , will support this effort to push current methodologies beyond their current limitations. Finally, teams lead by , of the Icahn School of Medicine at Mount Sinai, , of Weis Center for Research at Geisinger, , of Singapore Institute for Clinical Sciences and , of Singapore Institute for Clinical Sciences and University of Auckland will help place Pospisilik and Nadeau’s novel discoveries into real-world, clinical context.
By the end of the study, the team hopes to identify new sets of disease-related genes, delineate subtypes of disease, and better understand how the complex interaction between genetics and epigenetics impacts health.

Research reported in this publication was supported by the Office of the Director of the National Institutes of Health under award no.1R01HG012444 (Pospisilik and Nadeau). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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ABOUT MAINE MEDICAL CENTER
Maine Medical Center (MMC), recognized as a Best Regional Hospital by U.S. News and World Report for 2021-2022, is a complete health care resource for the people of Greater Portland and the entire state, as well as northern New England. Incorporated in 1868, MMC is the state’s largest medical center, licensed for 637 beds and employing more than 9,600 people. MMC's unique role as both a community hospital and a referral center requires an unparalleled depth and breadth of services, including an active educational program and a world-class biomedical research center. As a nonprofit institution, Maine Medical Center provides nearly 23 percent of all the charity care delivered in Maine. MMC is part of the AOAÌåÓýƽ̨ system, a growing family of health care services in northern New England. For more information, visit www.mmc.org.

ABOUT VAN ANDEL INSTITUTE
(VAI) is committed to improving the health and enhancing the lives of current and future generations through cutting edge biomedical research and innovative educational offerings. Established in Grand Rapids, Michigan, in 1996 by the Van Andel family, VAI is now home to nearly 500 scientists, educators and support staff, who work with a growing number of national and international collaborators to foster discovery. The Institute’s scientists study the origins of cancer, Parkinson’s and other diseases and translate their findings into breakthrough prevention and treatment strategies. Our educators develop inquiry-based approaches for K-12 education to help students and teachers prepare the next generation of problem-solvers, while our Graduate School offers a rigorous, research-intensive Ph.D. program in molecular and cellular biology. Learn more at .