The ability to visualize an object is the first step to understanding it.

This generalization holds true especially for what is microscopic. So, when the electron microscope was invented in 1931 by physicist Ernst Ruska and electrical engineer Max Knoll, it was considered one of the most significant early advances in the field of molecular biology.

Electron microscopes allowed for magnifications greater than 100,000 times, almost 100 times more than the typical light microscopes. However, because living organisms cannot typically withstand the strength of an electron beam, electron microscopes were only useful in imaging dead matter. If the beam was weakened, the image would begin to lose its contrast, which led to the conviction that electron microscopy would never be able to examine living, organic material.

This conviction was challenged by three scientists: Jacques Dubochet, Joachim Frank and Richard Henderson. On Oct. 4 they were awarded the 2017 Nobel Prize Award in Chemistry for their contributions towards the development of a technique that creates three-dimensional visualizations of complex and microscopic biomolecules, cryo-electron microscopy.

The contributions of the three Laureates lie in their ingenuity in modifying the procedure of electron microscopy.

Between 1975 and 1986, German biophysicist Joachim Frank developed a method to create an accurate model of a biomolecule to determine its overall structure. He weakened the strength of the electron beam to avoid destroying the biomolecule and took thousands of images captured from a different angle each. A computer then calculated how these 2D images related to each other and merged them to create a 3D structure of the molecule.

However, because Frank was forced to use a low-energy electron beam to avoid destroying the biomolecule, the images produced using his method at the time were in low-resolution.

In the 1980s, Swiss biophysicist Jacques Dubochet proposed a solution to this problem. Freezing the biomolecule prior to imaging would shield it from the high-energy electrons. The typical freezing process would not work in this situation, as ice crystals tend to form on the specimen, interfering with the path of the electron and consequently distorting the image. Dubochet instead developed a method to vitrify the molecules by cooling trem so rapidly that the specimen freezes without the formation of any ice crystals.

The developments of these two techniques set the stage for the cryo-EM procedure. Scottish molecular biologist and biophysicist Richard Henderson combined electron microscopy with the imaging technique from Frank and the molecule vitrification technique developed by Dubochet. In 1990, he succeeded in producing the first detailed three-dimensional model of the protein called bacteriorhodopsin. This demonstrated that it was possible to obtain high-resolution images of biomolecules using an electron microscope.

Thanks to the contributions and techniques developed by these researchers, it is now possible to model the structure of almost any biomolecule. This technology has become widespread and is routinely used by researchers nowadays.

This method has allowed humans to deepen their understanding of the microscopic world, which has implications in many fields such as medicine. For example, it allows us to identify the protein receptor molecules viruses use to bind to cells and develop antiviral drugs that target those receptors, preventing them from infecting human cells. In fact, this method was used in response to the Zika virus outbreak in 2015, as scientists were able to identify unique proteins on the pathogen’s outer surface and develop vaccines that target those proteins.

There still remain several limitations of this method. For instance, even with the quality cryo-EM provides, we are unable to observe microscopic processes as they occur , as the specimen must first be frozen.

Nevertheless, cryo-EM has become a major tool in structural biology and becomes more sophisticated as more modifications are added. To continue progressing, scientists must continue to build upon each others’ discoveries, just as the three Laureates, and the many that preceded them, have done in the past.