Many of the outstanding questions in biology and medicine are difficult to address because there is no way to directly look at the complex molecular machines responsible for life. We work on developing new instruments and methods for imaging biological molecules, (DNA, RNA and proteins), at atomic resolution. The primary instrument that enables atomic resolution imaging is the electron microscope. We aim to improve cryo-preparation and imaging methods to the point where we can use the electron microscope to image the atomic resolution structure of purified macromolecular complexes, and the sub-nanometer resolution structure of any biological specimen. We plan to accomplish this by first studying the physical principles underlying the current resolution limits and then reengineering the critical components in the imaging system to improve resolving power. We draw on recent advances in nanoscience, solid-state physics, surface chemistry, electrical engineering and materials science to achieve these improvements. Using this new technology, we study the detailed mechanisms of biomolecules to understand how they function.