How the Invisible Becomes Visible: the Fascination of Electron Microscopy

(a) rod-shaped tobacco mosaic viruses contrasted with heavy metal set (b) ultrathin section of E. coli cells embedded in epoxy resin (c) purified protein complex frozen in liquid nitrogen, microscopized under liquid nitrogen temperatures.
Katharina placing the sample into the electron microscope
Katharina placing the sample into the electron microscope

"The details you can see by electron microscopy, things you would otherwise never see in the minuscule sample – I find them incredibly fascinating," enthuses Katharina Hipp, looking at a copper-colored three-millimeter grid lying on the table in front of her. Even if you look closely, you can't make out anything with the bare eye. But it is precisely on this grid that she has just frozen a protein sample, which she now wants to look at more closely in an electron microscope under constant cooling with liquid nitrogen.

Dr. habil. Katharina Hipp has been head of the Electron Microscopy (EM) Facility at the Max Planck Institute for Biology Tübingen since 2016. A lecture on electron microscopy during her studies in technical biology at the University of Stuttgart first sparked in her an enthusiasm that has stayed with her to this day. A few months ago, she completed her habilitation in molecular biology at the University of Stuttgart.

In Katharina's daily work, she supports the researchers at the institute who want to see more in their biological samples than is technically possible with a light microscope. In meetings with the scientists, Katharina clarifies the research question and what they want to visualize with the help of electron microscopy.

At the same time, Katharina continuously educates herself on the scientific background of the individual projects. This allows her to better evaluate and understand how the sample must be prepared for the electron microscope in order to visualize targeted cell or protein structures. The methods of sample preparation are very complex, which is why only specialized personnel can carry out these steps. In addition to Katharina Hipp, these are Brigitte Sailer and Iris Koch at the Max Planck Institute for Biology in Tübingen.

The images, which make objects observable down to the nanometer scale, are compared with the research hypotheses of the scientists. "If you can actually see something, it's much easier to understand it. With a suitable visualization from electron microscopy, a scientific statement can be clearly supported," Katharina explains the importance for science. Moreover, with the help of electron cryomicroscopy, it is now possible to determine protein structures with up to atomic resolution.

Katharina, who is also Vice Chair of the German Electron Microscopy Society, looks into the future with an unquenchable thirst for knowledge: "You can't stay at a status quo, the field is always evolving, but I enjoy that a lot. The question is how to further improve methods and develop new techniques to uncover previously hidden issues."

Since this year, in addition to managing the EM Facility at the Max Planck Institute and a family with two children, Katharina has also been giving regular lectures at the University of Stuttgart. And when she talks about electron microscopy there with the same enthusiasm, she will fascinate students with her excitement just as the fire for this discipline was once kindled in her.

The science behind

The images from an electron microscope are two-dimensional. Obtaining them only works in vacuum. Samples of objects like cells, bacteria or purified proteins are fixed onto a small grid about three millimeters in size.  Using 50-100 nanometer (1 nanometer = 0.000001 millimeter) thin sections of the sample, the smallest objects can be made visible in the electron microscope. The difficulty lies in cutting the sample in the right place and making these sections very thin, which requires a lot of practice and experience. If, for example, a bacterium with a size of 1 µm (=0.001 millimeter) is prepared, then 10-20 different sections, and thus as many different images, of a single bacterium can be made. In electron cryomicroscopy, the frozen samples are imaged under constant cooling using liquid nitrogen, and image processing is used to determine the 3D structure of the proteins.

Fun fact

Probably the most famous result from an electron microscope at present is the image of the coronavirus published in the news. Viruses are very small, 20-400 nanometers, and were first made visible with the invention of the electron microscope in 1931.

Fixed samples on the grid, prepared for the electron microscope
Fixed samples on the grid, prepared for the electron microscope
Katharina analyzing the images from the electron microscope
Katharina analyzing the images from the electron microscope
Grid collection with already microscoped samples
Grid collection with already microscoped samples