  Single-particle cryo-electron microscopy (cryo-EM) has recently joined X-ray
crystallography and NMR spectroscopy as a high-resolution structural method to
resolve biological macromolecules. In a cryo-EM experiment, the microscope
produces images called micrographs. Projections of the molecule of interest are
embedded in the micrographs at unknown locations, and under unknown viewing
directions. Standard imaging techniques first locate these projections
(detection) and then reconstruct the 3-D structure from them. Unfortunately,
high noise levels hinder detection. When reliable detection is rendered
impossible, the standard techniques fail. This is a problem, especially for
small molecules. In this paper, we pursue a radically different approach: we
contend that the structure could, in principle, be reconstructed directly from
the micrographs, without intermediate detection. The aim is to bring small
molecules within reach for cryo-EM. To this end, we design an autocorrelation
analysis technique that allows to go directly from the micrographs to the
sought structures. This involves only one pass over the micrographs, allowing
online, streaming processing for large experiments. We show numerical results
and discuss challenges that lay ahead to turn this proof-of-concept into a
complementary approach to state-of-the-art algorithms.
