Molecular microscopy: Theoretical possibilities and experimental realities

Abstract

It is interesting to imagine a world in which microscopy had never been invented. What techniques would scientists use to study cell structure? Lack of microscopy would not prevent research.... instead scientists would study cells using indirect means; e.g. by homogenizing, filtering, and centrifuging cells. After much work, they would be able to demonstrate that cells are surrounded by membranes, and contain nuclei carrying genetic information. All aspects of cell structure could be studied in this indirect way.Biomedical researchers would not feel particularly handicapped by the lack of microscopy. Rather they would compete for access to the newest and most ingenious filtering devices. In this hypothetical world, it would not be readily apparent that instrument technology was a crucial medical/scientific issue.It is arguably the case that we live in a similar world, and that (from a clinical perspective) we need a microscope technology that can image 3D biomolecular structure with the subangstrom spatial resolution that is required for the rational design of drugs and vaccines.The highest-resolution techniques for determining 3D molecular structure are x-ray crystallography and mutidimensional NMR analysis. However, neither of these techniques can properly be called “microscopy”.