Paul O’Maille

Dr. Paul O’Maille is Program Director for Biocomplexity Sciences in SRI’s Biosciences Division, where he leads multidisciplinary research spanning biodefense, precision medicine, biotechnology, and artificial intelligence. His work integrates protein engineering, molecular evolution, structural biology, biophysics, bioinformatics, systems biology, metabolism, and microbiology to address complex biological problems.

A central theme of Dr. O’Maille’s research is genotype-to-phenotype prediction: understanding how genetic variation alters molecular function across biological scales and ultimately produces biochemical, cellular, and organismal traits. This work has broad practical implications, including anticipating viral adaptation and emerging biological threats, predicting individual susceptibility to cardiac disease and adverse drug responses, and elucidating the evolution of chemical communication in plants and insects.

Dr. O’Maille currently serves as co-principal investigator of a Defense Threat Reduction Agency program developing an integrated, AI-enabled platform to identify broad-spectrum host-directed therapeutic targets for hemorrhagic fever virus infections. The program combines computational prediction with biophysical analysis of host-virus protein interactions and experimental validation in cellular and animal models. As part of this effort, Dr. O’Maille co-led research revealing how the Rift Valley fever virus virulence protein NSs exploits a short linear motif to bind human LC3-family proteins and inhibit antiviral autophagy. This work identified a specific residue, phenylalanine 261, as critical to the interaction and provided a potential mechanistic basis for developing host-directed antiviral strategies.

His broader SRI portfolio has included leading projects for DARPA and IARPA in human performance and resilience, biological threat assessment, genome-engineering detection, and AI-based prediction of gene function. He led SRI’s contribution to DARPA’s Measuring Biological Aptitude program, which integrated molecular biomarkers, predictive models, and wearable sensors to characterize human performance and resilience. His precision-medicine research also contributed to a patented platform using patient-derived cardiomyocytes carrying genetic variants to model cardiac disease and drug response. Additional programs funded by NSF, NIH, and BBSRC have addressed viral host mimicry, metabolic pathway analysis, chemical ecology, protein evolution, and synthetic biology.

Dr. O’Maille earned his Ph.D. in biochemistry from The Ohio State University, where he was an NIH Chemistry-Biology Interface Fellow. He subsequently trained at the Salk Institute for Biological Studies as an NIH postdoctoral fellow and Howard Hughes Medical Institute research associate. Before joining SRI, he led research groups at the John Innes Centre and Institute of Food Research (Quadram Institute) in the United Kingdom, where his laboratory investigated the molecular evolution of terpene biosynthesis and the emergence of chemical diversity used by organisms for defense, communication, and environmental adaptation. He has delivered more than 40 invited lectures worldwide and has published across structural biology, molecular evolution, virology, bioinformatics, metabolism, and biotechnology.