ARPA-H BIOGAMI program starts work to find and fix protein dysfunction at earliest stages 

Program-funded teams aim to stop neurodegenerative disease, like Alzheimer’s, by decoding proteins’ “biomolecular grammar” 

The Advanced Research Projects Agency for Health (ARPA-H), an agency within the U.S. Department of Health and Human Services (HHS), today announced the teams receiving awards for the BIOmolecular Grammar for protein Aggregation Modulation and Intervention (BIOGAMI) program. BIOGAMI teams will decode the “grammar” that guides how intrinsically disordered proteins (IDPs) behave and create new ways to steer misfolded or clumped (aggregated) proteins back into healthy shapes. The program focuses on the very earliest steps in the misfolding process — before proteins clump together and damage cells — especially in the brain and other vulnerable tissues. By acting early, BIOGAMI aims to stop neurodegenerative disease and other chronic diseases before they fully develop, instead of only treating symptoms after serious damage has occurred. 

“Proteins in our cells need to fold correctly to work,“ said BIOGAMI Program Manager Shannon Greene, Ph.D. “Some proteins have flexible segments called intrinsically disordered regions that can change shape in response to aging, inherited risk, and environmental factors. They can get pushed off course and fold the wrong way or stick together, forming clumps that damage cells and lead to Alzheimer’s disease, ALS, and other progressive and debilitating conditions. While we know this happens, we do not have the tools to intervene when the misfolding first starts, leaving many of these diseases ‘undruggable.’ This is where BIOGAMI comes in.” 

BIOGAMI teams’ efforts are two-fold: 1) develop an experimental and computational toolbox to design early detection capabilities and novel interventions for diseases of protein misfolding, and 2) design therapeutic and diagnostic solutions for neurodegenerative diseases. This work will inform the translation of BIOGAMI technologies to other diseases of protein misfolding, including cancer and diabetes. 

Performer teams are led by: 

Buck Institute for Research on Aging and Georgetown University: The team will build a scalable platform to map how intrinsically disordered region (IDR) sequence and biological context shape protein behavior across both a broad library of heterogeneous proteins and a depth of variants of a smaller group of aggregation-prone disease proteins. The team will leverage their computational platform to enable earlier detection and intervention in Alzheimer’s disease and other tauopathies (neurodegenerative disorders caused by the abnormal buildup of tau aggregates in the nervous system) and Ewing sarcoma, a rare and aggressive pediatric cancer that forms in bones or surrounding soft tissue. 

Johns Hopkins University: The team will develop a Dynamic Ensemble-to-Rescue (DETR) generalizable platform to predict IDR behavior from sequence, identify transient disease-relevant conformational states, and design interventions that block pathological conformations and restore protein function. DETR will predict whether an IDR will fold into dysfunctional shapes, aggregate, or differentially interact with molecules that help complete critical functions under different conditions; identify protein shapes for diagnostic and therapeutic applications; and design protein and cyclic peptide binders for Parkinson’s disease and other synucleinopathies (neurodegenerative disorders caused by the abnormal buildup and misfolding of alpha-synuclein protein aggregates in the nervous system) and rare Ewing sarcoma as initial clinical indications. 

Massachusetts Institute of Technology: The team will develop next-generation computational models that incorporate two key factors that are often overlooked in understanding how proteins function and dysfunction in disease: small molecules found in the body (metabolites) and cell membranes and similar surfaces (lipid interfaces). The goal is to establish these as first-class variables to accurately predict IDP aggregation across healthy and disease conditions. These include neurodegenerative diseases, diabetes, and cancer, which are linked to membrane trafficking dysfunction (when a cell’s delivery system is not working correctly). 

University of California, Berkeley: The team will develop a comprehensive IDR dataset encompassing diverse sequences spanning the human genome and across species, enabling the visualization of the behavior of a vast array of proteins at high resolution in living cells. The project will create a general foundation computational model of IDP behavior and interaction networks that could be leveraged for downstream therapeutic discovery against disease-associated proteins. 

University of California, San Francisco: The team will combine large-scale computational modeling with high-throughput cellular and animal studies to explore a novel hypothesis that stress-regulated IDRs enter mitochondria and contribute to neurodegenerative disease. The work builds on the established role for mitochondria in neurodegenerative disease and facilitating IDR misfolding and aggregation under cellular stress. 

University of North Carolina, Chapel Hill: The team will develop a first-in-class, closed-loop, computational-experimental pipeline to map the context-dependent IDR grammar. The work will first combine sequence to structure, function, condensation, aggregation, and binding partners; then refine the IDR atlas to design indicators and modulators of early protein aggregation in Alzheimer’s disease and idiopathic pulmonary fibrosis (a rare, uncurable chronic disease of the lung); and then move to preclinical studies to advance and validate candidates. 

BIOGAMI teams combine expertise in protein science with powerful computing tools to better understand and reshape molecular grammar. The agency’s commitment is up to $152 million over 4 years. Performer awards vary in funding amount per awardee and are contingent upon each team meeting aggressive and accelerated research milestones. 

Learn more about BIOGAMI on its program page.