How Good Can Single-Particle Cryo-EM Become? What Remains Before It Approaches Its Physical Limits?

Impressive though the achievements of single-particle cryo-electron microscopy are today, a substantial gap still remains between what is currently accomplished and what is theoretically possible. As is reviewed here, twofold or more improvements are possible as regards (a) the detective quantum efficiency of cameras at high resolution, (b) converting phase modulations to intensity modulations in the image, and (c) recovering the full amount of high-resolution signal in the presence of beam-induced motion of the specimen. In addition, potential for improvement is reviewed for other topics such as optimal choice of electron energy, use of aberration correctors, and quantum metrology. With the help of such improvements, it does not seem to be too much to imagine that determining the structural basis for every aspect of catalytic control, signaling, and regulation, in any type of cell of interest, could easily be accelerated fivefold or more.