Biological structures exist across a vast range of scales. At one end are whole organisms, varying in size from bacteria only a few micrometers across to mammals measured in feet. These can be seen with the naked eye or with simple light microscopes, which have been in use since the mid-1600s. At the smaller end, however, are atoms, amino acids, and proteins, spanning angstroms to nanometers in size.
Observing molecules at this smaller scale allows us to untangle the finer mechanisms of life: how individual neurons connect and communicate, how the ribosomal machinery translates genetic code into proteins, or how viruses like HIV invade and hijack host cells. Resolving fine structures, whether the double membrane of a chloroplast, the protein shell of a bacteriophage, or the branching architecture of a synapse, provides the bridge between atomic detail and whole-organism physiology, taking us from form to function.
Neurons communicate via the release of excitatory (left) and inhibitory (right) neurotransmitters at the junction, or synapse, between two cells. This gap is roughly 20 nanometers wide. Credit: David Goodsell
The ability to explore and map such minute mechanisms eluded scientists until the invention of the electron microscope. Conceived in the 1930s, it promised theoretical resolutions on the order of angstroms, nearly a hundred times finer than the most advanced light microscope of that era. In 1931, Ernst Ruska and his advisor Max Knoll, working at the Technical University in Berlin, designed the first prototype by replacing glass lenses with electromagnetic coils to focus beams of electrons instead of light.
That first instrument barely outperformed a magnifying glass in terms of resolution. But over the next century, refinements in design, sample preparation, and computation transformed the electron microscope into an indispensable tool for modern biology.
By 1938, scientists used an electron microscope to take a photograph of a virus — the mouse ectromelia orthopoxvirus — for the first time. And today, modern cryo-electron microscopy, in which samples are frozen in liquid ethane prior to imaging, can resolve individual atoms within proteins. During the COVID-19 pandemic, cryo-electron microscopy revealed the spike protein in the SARS-CoV-2 virus, which directly influenced the development of COVID vaccines. The technique also revealed a protein receptor that senses heat and pain, demonstrating how it translates physical signals to our nervous system, a breakthrough discovery that earned the 2021 Nobel Prize in Physiology.
The 1938 article, penned in German, where Ruska and von Borries first shared their electron micrographs of Bacterium coli , Bacilli , and viruses.
Electron micrographs of the mouse ectromelia virus taken in 1938 by Ernst Ruska, Helmut Ruska, and Bodo von Borries. Source
Even as electron microscopes have allowed us to view ever smaller structures with clarity, challenges remain. One is that the images remain limited to static snapshots. Because samples must be imaged in a vacuum, it is impossible to directly observe the dynamism of live cells. In addition, specimens must be extremely thin to allow the electron beam to pass through, which prevents imaging of thick tissues. And finally, beyond these biological constraints, electron microscopes are physically large, can cost millions of dollars, and demand specialized facilities, training, and expertise to operate.
Despite these limitations, electron microscopy remains a powerful tool in biology, bridging the scales between molecular structure and living function. The story of its discovery is one of persistent ingenuity, involving a large cast of characters and numerous breakthroughs that helped make the modern electron microscope possible.
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