Why Did Eric Betzig Pivot From Super-resolution?

Eric Betzig pivoted from super-resolution because chemical fixation makes nanoscale structure artificial. Regular optical resolution can tolerate the damage. Super-resolution shows artificiality.

Betzig starts with cultured cells because they are the easiest, and palm is where the work had to start. Super-resolution began on single culture, and at first on dead cells chemically fixed so they are not wiggling. The techniques were slow at first and remain slow in many cases today, so a sample wiggling and moving fast blurs. The cell is chemically locked in place and then imaged. The fixation protocols started with electron microscopy and are incredibly perturbative to the ultrastructure at the nanoscale.

Electron microscopy has known the problem for years, and Betzig names the damage as one reason he pivoted. The gold standard is not chemical fixation. High-pressure freezing locks the structure in milliseconds into vitreous ice, not crystalline ice.