The building blocks of life fall into four categories: polynucleotides, proteins, lipids, and glycans. Each of these exhibits properties which are useful for cells, as well as bioengineers. DNA/RNA base pairing enables data storage and amplification. Strings of amino acids adopt exquisite three-dimensional folds, creating pockets for catalysis and shapes that bind one another. Lipids self-organize into micelles which are the basis for cellular compartmentalization. But what properties have made glycans essential to all cells, from archaea to neurons? How can we leverage those properties for new approaches in basic and translational research?

Electron micrograph of cell surface glycans, collectively termed the glycocalyx (G), of a starfish (British Library).

Broadly, three characteristics are responsible for the challenges inherent in studying glycans, as well as the opportunities they present to biotechnologists. First, glycans are biosynthesized from 9 monomeric carbohydrate units (in humans), but are not done so based on sequence templates encoded in the genome. Rather, glycans are highly dynamic products of combinatorial enzymatic pathways that react nimbly to cell state and external stimuli. Second, monosaccharide units are linked together in a multitude of branching arrangements, resulting in extraordinary structural heterogeneity, which is elaborated further by post-synthetic modifications. Third, glycans and glycoconjugates commonly form intercellular supramolecular assemblies and signal through multivalent interactions. These properties render glycans critical to cell-cell and cell-matrix interactions, where they are key determinants of both biophysical and biochemical signals.

Overview of glycan biosynthesis.

Our lab develops tools rooted in chemical biology, protein engineering, and microscopy that leverage the unique properties of glycans to deepen our understanding of cellular functioning and pathology. As glycans exert their chief influence at cellular interfaces, we aim our technologies at the study of multicellular systems, and are especially curious about the roles glycans play in modulating ultrastructure and signaling in the brain. For example, we and others have observed microheterogeneity in the distributions of glycans on cell surfaces— what is the precise organization of these structured, densely-glycosylated cell surface domains and how do they influence neuronal/glial function? How does the tissue-level distribution of glycans in the brain influence communication among cell populations? How are these processes regulated over the course of development?

Chemical structure of a biantennary N-glycan. Red text highlights the regio- and stereochemistry of glycosidic linkages. Blue text highlights examples of post-synthetic modifications.

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