Central Theme
There are rare moments in time when a field of inquiry begins to accumulate the critical number and type of experimental observations necessary to develop an overarching conceptual framework that provides a unifying mechanistic basis for apparently diverse phenomena. This point in the development of a scientific field is marked by the beginning of predictive mechanistic principles which often emerge from a fusion of ideas derived from different intellectual disciplines. Our group believes that the field of adaptive immunity is at one of these critical tipping points.

Higher organisms, like humans, have an adaptive immune system that enables them to combat pathogens that they have not encountered before. But the adaptive immune system can also go awry, and many diseases are the direct consequence of the immune system failing to discriminate between “self” and “non-self”. Examples of such autoimmune disorders include multiple sclerosis and type I diabetes, The desire to combat infectious diseases and the untold suffering caused by autoimmune disorders has led to a great deal of experimental research whose ultimate aim is to develop new therapies. This research has focused on the pathogenesis of diseases as well as the underlying cellular and molecular origins. These studies have led to some spectacular discoveries, and new experimental techniques are providing a wealth of data with an unprecedented level of detail. Yet, in spite of these advances, a predictive mechanistic understanding of the principles that govern the emergence of an immune response or autoimmune diseases has proven elusive.

A principal reason for this is that activation of the adaptive immune response is the result of cooperative dynamic events that involve a multitude of components and span molecular, cellular, and tissue-scale processes. Molecular components in cells must act in concert to mediate collective cellular behavior, which then can influence the tissue environment. The tissue environment, in turn, can regulate cellular and molecular processes. It is this hierarchically organized cooperativity, with feedback, that makes it difficult to intuit underlying mechanisms from experimental observations alone. The focus of our research group is to confront and overcome this challenge by bringing together approaches that have traditionally been “stove-piped” in different disciplines.

Our work is focused on synergistic use of theoretical and computational approaches (that have proven useful in understanding cooperative processes in the physical and engineering sciences) and genetic, biochemical and imaging experiments.

The theoretical and computational work is rooted in statistical mechanics. The experimental work is carried out by key collaborators, who are leading immunologists. We have ongoing collaborations with many immunologist, including Prof. Paul Allen (Washington University Medical School), Prof. Mark Davis (Stanford Medical School), Prof. Michael Dustin (NYU Medical School), Prof. Herman Eisen (MIT), Prof. Hidde Ploegh (MIT), Prof. Andrey Shaw (Washington University Medical School), Prof. Arthur Weiss (UCSF Medical School), and Prof. Kai Wucherpfennig (Harvard Medical School). With these collaborators, we work on questions that pertain to the following broad areas of inquiry.

T cell activation in response to pathogens
T cell-mediated autoimmunity