We study how cells sense and respond to changes in their surroundings using protein engineering and synthetic biological techniques. Our projects can be categorized into two synergistic themes:

(1) Notch Signaling and Synthetic Mechanobiology

(2) Strategies for Imaging and Engineering the Central Dogma 

(1) Synthetic Mechanobiology--programming how cells sense force.

A primary aim of our research program is to understand how cells sense and interpret mechanical information–a goal that we are pursuing through the development and implementation of new molecular tools. Ultimately, we aim to achieve a “multi-scale” understanding of mechanotransduction in which atomistic insights regarding the structure and biophysics of force-sensitive proteins is integrated with observations regarding the “mechanical landscape” of cells. A “holy grail” of these efforts is to gain a comprehensive appreciation of the molecular logic underlying natural mechanical signaling networks, with the ambition of applying such knowledge to engineer customized networks for application in biotechnology and cell-based medicine. In other words, we aim to enable, and realize “synthetic mechanobiolgy,” in which one is able to precisely program how cells sense and respond to mechanical forces. In this presentation I will describe our efforts toward this end, focusing on the development and implementation of tunable and modular mechanoreceptors based on the mammalian signaling protein Notch and its synthetic derivatives (‘SynNotch’). By combing structure-guided protein engineering with biophysical and cellular analyses, we have engineered a set of SynNotch proteins with whichwe have used to program human cells that are able to activate customized genetic programs in response to defined tensional cues.

(2) Strategies for Imaging and Engineering the Central Dogma 

In addition to Notch studies, we create technologies in order to visualize how molecules are organized within and between cells, with the goal of understanding how changes in organization give rise to dynamic biological processes. In pursuit of this goal, we develop genetically encoded probes and chemical methods in order to dissect and control when and where proteins exist, and to track and manipulate the interactions they make with other biomolecules. Our work draws upon principles from chemistry, biophysics, and evolution.