Redefining the cryo-transmission electron microscope

The past decade has seen two revolutions in electron microscopy. In materials science, hardware correctors for optical aberration have broken the Angstrom barrier to sub-atomic resolution. In life science, new camera technologies have transformed our insights to the structure of biological macromolecules preserved cryogenically in their native, fully hydrated state; this is the realm of "cryo-EM". The two fields took diverging paths, with materials science largely moving from wide-field imaging to the scanned-probe mode known as scanning transmission EM, or STEM, and life science developing increasingly complex pipelines for image processing to compensate for optical aberrations and specimen instabilities. We have been forging a third path, exploring the use of STEM for cryo-EM at the interface with life science. We look at the microscope afresh as a diffraction projector, by which the flexible arrangement of detectors can optimize the sensitivity to different features of the sample. For example, we can optimize for tomography of thick cellular samples, or for sensitivity to heavy elements such as calcium or zinc, or most recently for crystallography. Our goal overall is to broaden the focus of cryo-EM from molecular resolution per se to the triad of resolution, composition, and volume.