Development of Nano-Biology with Atomic Force Microscopy

The first observation of double-stranded DNA by atomic force microscopy in the late 1980’s greatly encouraged many biological researchers to jump into the nano-world. Here we briefly review the history of how AFM has been utilized to reveal nanometer-scale structures of DNA-protein complexes, and we highlight key technical developments that have accelerated applications of AFM to molecular biology, physiology, biophysics, and cell biology. Biology is a visual science. Understanding the ‘biological events’ around us through visualization and observation has always been a fundamental part of biological scientific inquiry. Since the early days in the 17th century, biological investigations of the fundamental components of biological systems have relied on microscopes, the resolution of which is limited to one half the wavelength of light. Electron microscopy (EM), invented in the 1920-1930’s, brought a hundred times greater resolution than the light microscope, and it continues to enable us to visualize biological materials in the nanometer range [1]. However, EM requires special specimen preparation and operational constraints, e.g., coating the sample with a fine layer of gold and observing it under vacuum. These limitations were in large part circumvented in the 1980’s by an altogether new concept. Shortly after Binnig invented atomic force microscopy (AFM) [2], Hansma [3] proposed many possible uses for AFM in biology [3]. However it took almost 20 years for it to become an indispensable technique in biological research that allows observations in solution without fixation of the specimen. Commercially available instruments equipped with a scanning method known as the tapping mode [4,5], have yielded unprecedented views of biological materials such as DNA and proteins in their native state. The subsequent invention of high-speed AFM [6], which can scan biological samples in solution with sub-second temporal resolution, was a landmark accomplishment that has contributed greatly to the establishment of nanobiology as a major field in bioscience [7].