CAREER: Emergence of Functional Organization in the Adaptive Immune System

University Of Washington, Seattle WA

Investigators

Abstract

It takes decades for humans to reproduce, but our pathogens can reproduce in less than a day. How can we coexist with pathogens that can evolve more than 10,000 times faster than us? The answer lies in our adaptive immune system, which is a self-organized system of highly diverse immune cells that develop during the lifetime of an organism. The adaptive immune system incorporates all aspects of life, from molecular signaling to cellular evolution. The result is an information processing molecular organization with many interacting components, which can reliably sense and adaptively respond to diverse and evolving pathogens. The vast differences in immune repertoires between individuals suggest the existence of many molecular solutions to statistically similar pathogenic environments. The goal of this project is to use machine learning to derive a map from the diverse and high-dimensional space of receptor repertoire sequences to a lower dimensional space of immune functions that relates to biophysics of immune recognition. This effective functional representation of immune repertoires would allow construction of predictive models for immune responses to pathogens, and will shed light on functional organization of immune repertoires. To bridge the gap between physics and biology, the PI will introduce pre-college and undergraduate students to biophysics research, with particular emphasis on women and underrepresented minorities. The PI will create new teaching modules to introduce both the physics and the life-science undergraduate and graduate students to current progress in physics of living systems. In addition the PI will commit significant resources to mentor undergraduate and high school students during summers and the academic year to pursue biophysics research. The PI will invite biophysics researchers to the department’s “Frontiers of Physics Public Lecture Series”, to foster an appreciation and support among the community for the exciting developments in this field. The adaptive immune system develops during the lifetime of an organism and consists of highly diverse B-and T-cells, whose unique surface receptors are generated through genomic rearrangement, mutation, and selection. This diverse repertoire of receptors can mount specific responses against a multitude of evolving pathogens and keep a memory of past infections for future encounters. Pathogens in return, evolve to escape the immune challenge, forming a rapid co-evolutionary arms race during the life-time of an organism. Over the past decade, high throughput immune repertoire sequencing has been instrumental in characterizing the diversity of immune receptor sequences. However, we still lack an understating of how receptor sequence diversity translates to immune function. In this project, the PI will combine theoretical modeling with inference from molecular data to uncover the biophysical and evolutionary basis of the functional organization and encoding of pathogenic information in the adaptive immune system. The life-cycle of immune cells is defined by a continuum of selection stages leading to their functional specialization. The PI will develop biophysical inference techniques to leverage receptor repertoire data of distinct immune cell-types and use machine learning to derive sequence-determinants of immune function. In addition the PI will develop predictive fitness models to characterize how the short-and long-term dynamics of immune repertoires relate to functional responses to pathogens. By building upon recent advances in machine learning, the PI will infer a latent representation (i.e., a shape space) for immune receptors that reflects the relevant biophysics of immune recognition and function. The inferred immune shape space will allow to ask fundamental questions regarding the biophysical determinants of antigenic interactions, and self/non-self discrimination. Lastly, a theoretical framework to study how the co-evolutionary history of hosts and pathogens has shaped immune strategies, both at the individual-and the population-level will be developed. 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.