Transmission electron microscopy of frozen-hydrated specimens (cryo-EM) enabled atomic-resolution reconstruction of biological macromolecules. However, thin soft matter specimens are almost transparent to the electron beam and are extremely sensitive to radiation damage. This hinders the reconstruction of protein complexes that are either too small or too structurally heterogeneous to be readily discerned in electron micrographs. The visibility of biological macromolecules in cryo-EM images can be improved via electron interferometry, similarly to Zernike phase contrast in optical microscopy. We develop laser-based electron interferometry tools to enable Zernike phase contrast in electron microscopy. Laser coherent control of electron beams holds the promise of expanding the class of protein complexes amenable to cryo-EM reconstruction. Initial demonstration experiments are currently underway.
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