Professor Jeff Lichtman examines the development of imaging technologies from the days of Cajal to the development of the nanoscope.

The light microscope has arguably been the most powerful tool neurobiologists have had. The beginnings of the nervous systems study was the work of [Santiago] Ramon Cajal, a Spanish neurobiologist who used a stain called the Golgi stain to image nerve cells. And this stain was quite beautiful, but it was limited, in part by the fact that the resolution of the light microscope has been limited by the fundamental properties of light. Particularly something known as diffraction; the fact that no matter how hard you squeeze light and try to focus it, it can’t be focused any better than roughly to about half a wavelength of light. Objects that are smaller than that tend to be impossible to resolve. For the history of neurobiology in fact the history of all biologies from the time microscopes were invented until around the turn of the millennium, around the year 2000, this was sacrosanct that light microscopes are just not going to do any better then the diffraction limit of light. Then suddenly in many different places, all at the same time, from different sources of different scientists, a whole bunch of brand new technologies appeared that showed that there were clever ways one could get around the problems of diffraction and turn light microscopes into microscopes that have resolutions that compete with the resolution of electron microscopes. Electrons have wavelengths that are much, much smaller than light’s wavelength and that is why electron microscopes can see a few atoms, whereas light microscopes have a problem even seeing a synapse made up of millions of atoms. These new microscope techniques are all called nanoscopy, nano being smaller than micro. Microscopy is the standard technique, nano allows one to look at things not at the level of millionths of a meter, microns, which is what a microscope can do, but look at objects at the level of nanometers which is a thousandth of a micron, much, much smaller and these are what could be called nanometers, but people call these microscopes nanoscopes. Nanoscopy is the term for these new techniques and they have very exotic names like PALM, and STORM, STED, structure illumination are a bunch of the newer techniques. They’re quite amazing and they are allowing light microscopes to go in places they have never gone before. They are the tools that may allow us ultimately to see the function of a synapse at the level of resolution where the fine events occur, which right now are too blurry for us to see with standard techniques.

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