CAREER: Physical and Evolutionary Constraints on Adaptive Immunity

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One remarkable feature of complex life is the ability to survive invasions of threatening microorganisms – a vast and changing variety of them. This relies on the possession of an adaptive immune system that learns from past encounters for future protection. Fast advancing data acquisition techniques have revealed that naturally occurring immune responses are limited in speed, efficacy and capacity to adapt to new challenges, but the origin of which remains poorly understood. This research project will investigate organizing principles behind the emergence of an effective immune response in the presence of functional constraints. By accounting for features unique to native microenvironments, this project will provide a predictive framework for how physical extraction of molecular information at cell-cell interfaces shape the evolutionary driving forces of adaptive immunity, advancing our understanding of molecular recognition in living organisms. In this project, the Principal Investigator (PI) will combine theory and experimental data to explain and predict how antibody repertoires respond to related antigens, providing key insights for developing universal vaccines against rapidly evolving pathogens. The proposed research activities will be closely integrated with education and outreach efforts to provide opportunities for exploring the physics of living systems. A core element is an active engagement of young students with quantitative approaches that span multiple traditional fields. Through a partnership with the UCLA Center X Science Project, the PI will develop interactive online learning modules to engage high-school students and teachers in under served school districts with computational modeling of complex systems. To provide first-hand research experience in her lab, the PI will continue to mentor and recruit underrepresented college students through the Science Exchange program at UCLA. To create a sense of community for young scientists, the PI will host biophysics researchers at various stages of their career to speak at the Center for Biological Physics Seminar series. The PI will engage the public via a workshop at the Institute for Pure and Applied Mathematics and a booth at the Exploring Your Universe event on campus. Major advances of experimental techniques in the past decade has revealed two sources of constraints -- physical and evolutionary – on rapid emergence of an effective immune response in organisms of varying complexity. But until recently we still lack a quantitative framework to determine the functional impact of these constraints and the extent to which cells can control and harness them for adaptation. In this project, the PI will couple theoretical and computational modeling with analysis of biophysical and mutagenesis data to elucidate the limit and potential of immune adaptation to complex antigenic environments. Two focuses are (i) developing first-principles predictions for why immune cells use active processes to physically extract antigen from other cell surface; and (ii) extending theoretical frameworks from statistical physics to characterize evolutionary pathways and adaptive capacity of immune repertoires under diverse and dynamic selection pressure. Theoretical predictions will be tested by collaborating groups probing physical and evolutionary constraints, respectively. Through development of a scale-bridging model framework, this study will provide a first demonstration of the role played by intracellular force generation in modulating natural selection of cell populations, laying the ground for a comprehensive understating of evolution of molecular recognition. Over the course of this project, the PI will construct and validate new measures for detecting the rich structure of epistatic landscapes and explore its evolutionary consequences, in order to bridge the gap between theory and experiment of evolutionary dynamics on rugged fitness landscapes. This understanding will in turn guide the design of mutagenesis and directed evolution experiment. Our study of adaptation to diverse and changing environments will derive general principles that apply broadly to biological search for adaptable solutions in genotype, phenotype, and real space.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.