Light-sheet microscopy, owing to its selective illumination and highly-parallelized detection, enables time-lapse imaging with minimal photobleaching or phototoxicity. However, most light-sheet microscopes capable of high-resolution 3D imaging with single-molecule sensitivity can only operate over small fields-of-view (~20 microns), limiting observation to thin adherent cells or only the most superficial cells in a developing organism. We addressed this issue and developed several light-sheet microscopes that deliver a unique combination of isotropic 300 nm resolution, single-molecule sensitivity, field of view (160 x 160 x 100 microns), imaging speed (from 1 to 14 Hz volumetric), 3D parallelization, and aberration compensation, depending upon the mode of operation. Furthermore, we developed a universal framework that allows us to generate any light-sheet and tailor it to the specific biological application. We quantitatively compared our new approach to lattice light-sheet microscopy and confirmed identical optical performance. Today, ongoing efforts in the lab combine these microscopes with computer vision, optical biosensors, and genome engineering to evaluate a diverse set of cell biological questions, including clathrin-mediated endocytosis, vesicular trafficking, and cell-matrix adhesions and migration in tissue-like extracellular environments.

Three-dimensional imaging with high-spatiotemporal resolution

2019 Spring National Meeting

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