Challenges ahead Electron Microscopy for Structural Biology from the Image Processing point of view

Since the introduction of Direct Electron Detectors (DEDs), the resolution and range of macromolecules amenable to this technique has significantly widened, generating a broad interest that explains the well over a dozen reviews in top journal in the last two years. Similarly, the number of job offers to lead EM groups and/or coordinate EM facilities has exploded, and FEI (the main microscope manufacturer for Life Sciences) has received more than 100 orders of high-end electron microscopes by summer 2016. Strategic corporate movements are also happening, with very big players entering the market through key acquisitions (Thermo Fisher has recently bought FEI for \$4.2B), partly attracted by new Pharma interest in the field, now perceived to be in a position to impact structure-based drug design. The scientific perspectives are indeed extremely positive but, in these moments of well-founded generalized optimists, we want to make a reflection on some of the hurdles ahead us, since they certainly exist and they indeed limit the informational content of cryoEM projects. Here we focus on image processing aspects, particularly in the so-called area of Single Particle Analysis, discussing some of the current resolution and high-throughput limiting factors.