Frontiers in Chemistry and Chemical Engineering

All multicellular systems studied to date, from bacterial colonies to vertebrate brains, deposit and dynamically regulate molecular assemblies in the spaces between their cells. This extracellular matrix (ECM) is essential to nearly every process that involves cellular cooperation, from mechanical actuation to immunological defense.

As molecular and cell biology accelerate their progression from cultured monolayers to tissues, the ECM will need to be incorporated into conceptual frameworks and therapeutic strategies. Extracellular biology, however, has lagged behind its intracellular counterpart, due largely to challenges which arise directly from core properties of extracellular biomolecules: they cannot be predictably modulated with genetics and are resistant to sequencing. In my talk, I will make the argument that chemical biology and advanced imaging are poised to dramatically accelerate the study of ECM physiology and pathology. The majority of my presentation will focus on two projects. The first involves development and testing of a cell-impermeable small molecule fluorophore that turns on and red shifts upon binding glycans, enabling nonperturbative visualization of total ECM structure in systems ranging from in vitro substrates to in vivo mouse mammary tumors. The second reports a Ru(II)-based carbohydrate-directed electron microscopy stain for visualization of ECM, and its use for discovery of hitherto unseen intercellular linkages in kidney glomerulus. Time permitting, I will conclude with a discussion of the ECM's influence on diffusion of extracellular calcium and the challenges and opportunities presented by cryo-electron microscopy-based approaches for structural interrogation of extracellular complexes.