CAREER: Network-based Inference of Complex Biological Interactions

Molecules in our cells and genes in our genome do not function in isolation. Instead, they operate collectively and under the influence of environmental factors. Despite the growing success of network models capturing single factor and pairwise effects, higher-order interactions between multiple genetic and environmental factors remain poorly understood. While elementary interactions in physics have been adequately captured at the pairwise level, higher-order interactions play a critical role in complex systems, requiring new approaches. Such higher-order interactions are also decisive for most types of cancer and complex diseases, triggered by the interplay of multiple factors. This knowledge gap prevents us from linking genotype to phenotype, systematically identifying therapeutic biomarkers, or designing efficacious drug combinations. The overarching goal of this CAREER award is to break down the existing conceptual and computational barriers, thereby deepening our understanding of higher-order interactions and insights into complex systems. Specifically, the Principal Investigator (PI) will develop a systematic framework to predict how biological fitness in eukaryotic model systems is influenced by combinations of mutations and environmental factors, including genetic, chemical-genetic, and drug-drug interactions. This will be achieved by creating a versatile hypergraph framework that models both pairwise and higher-order interactions, leveraging advanced methods from statistical physics and graph theory. In collaboration with experimental partners, this project will extend recent progress in network models of pairwise interactions to encompass interactions involving three or more components. In synergy with the research objectives, the PI will expand the lab’s High School outreach activities and will lead a community effort to organize art exhibits showcasing the captivating aesthetic beauty and hidden patterns of biological networks. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.