Scientists know the functions of only a fraction of the proteins in a cell, and this project will systematically investigate 135 completely unstudied proteins that are shared across species from yeast to humans. This matters because biology has a blind spot: researchers overwhelmingly study the same well-known genes, leaving thousands of others uncharacterised. The project, called OFFBEAT, focuses on proteins that appear to influence aging in non-dividing, quiescent cells—cells that have stopped dividing but remain alive, like many cells in the human body. Without knowing what these proteins do, we cannot fully understand how cells age or why they eventually fail. The research is fundamental science. It will first map the functions of all 135 proteins in fission yeast using genetic, metabolic, and lifespan assays, then use machine learning to predict their roles. Targeted experiments will follow in both yeast and the short-lived turquoise killifish to test whether these proteins control aging-related processes. If successful, OFFBEAT could uncover entirely new biological pathways that govern cellular aging. Such discoveries have historically opened unexpected doors—for example, studies of yeast aging genes later revealed mechanisms relevant to human neurodegenerative diseases and cancer.
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Biological researchers concentrate their efforts on studying genes that are already known and function in established processes. While this focus on model genes is rewarding, we must also study genes whose functions remain uncharacterized. Progress with such unknown genes is astonishingly slow even in well-studied model organisms, presenting a limitation and challenge for research. We need to know what all parts do to fully understand how cells work. I propose a concerted, cohesive effort to investigate the cellular functions of all 135 'priority unstudied' proteins that are widely conserved from fission yeast to humans but have not been directly studied in any organism. Our findings indicate that many of these proteins exert aging-related functions in non-dividing, quiescent cells. We will broadly characterize these unknown proteins in fission yeast by applying multi-dimensional approaches, both unbiased and targeted, including assays for metabolic profiles, genetic interactions, chronological lifespan, and bulk mapping of quantitative trait loci linked to cellular aging. We will leverage these results with existing phenomics and other large-scale data for functional predictions using machine learning. We will actively disseminate the rich functional information and engage experts for specialized follow-on research. Using our predictions, we will apply targeted experiments in yeast to deeply characterize selected proteins with roles in cellular quiescence and aging, including any novel biological processes. In complementary analyses, we will study conserved roles of aging-associated proteins in the short-lived turquoise killifish. This project, OFFBEAT, breaks new ground by devoting resolute efforts to important but hitherto neglected proteins, a key blind spot for biological research. OFFBEAT offers vital groundwork to understand the roles of unknown proteins in quiescent cells and beyond, with the potential for discovering new aging biology.
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