Nature reports:

For a few weeks in 2017, Wanda Kukulski found herself binge-watching an unusual kind of film: videos of the insides of cells. They were made using a technique called cryo-electron tomography (cryo-ET) that allows researchers to view the proteins in cells at high resolution. In these videos, she could see all kinds of striking things, such as the inner workings of cells and the compartments inside them, in unprecedented detail. “I was so overwhelmed by the beauty and the complexity that in the evenings I would just watch them like I would watch a documentary,” recalls Kukulski, a biochemist at the University of Bern, Switzerland.

In recent years, imaging techniques such as cryo-ET have started to enable scientists to see biological molecules in their native environments. Unlike older methods that take individual proteins out of their niches to study them, these techniques provide a holistic view of proteins and other molecules together with the cellular landscape. Although they still have limitations — some researchers say that the resolution of cryo-ET, for example, is too low for molecules to be identified with certainty — the techniques are increasing in popularity and sophistication. Researchers who turn to them are not only mesmerized by the beautiful images, but also blown away by some of the secrets that are being revealed — such as the tricks bacteria use to infect cells or how mutated proteins drive neurodegenerative diseases such as Parkinson’s.

Every peek through the microscope is another chance to explore uncharted cellular terrain, says Grant Jensen, a structural biologist at the California Institute of Technology in Pasadena. “There’s definitely a great joy in being able to see something for the first time,” he says.

Other researchers share his delight. Elizabeth Villa, a biophysicist at the University of California, San Diego, recalls her overwhelming excitement the first time she saw cell structures with cryo-ET. “It felt as if all of a sudden, we were paparazzi with access we never had before,” Villa says.

For decades, researchers have relied on a technique called X-ray crystallography to visualize proteins, viruses and other biological entities. The method involves coaxing molecules into forming static, well-ordered crystals and then bombarding the samples with intense X-ray beams. It enabled the discovery of the helical nature of DNA and the structure of more than 100,000 proteins, but it has its limitations: crystallizing molecules is difficult and tedious, and not always possible.

Scientists have overcome these drawbacks using cryo-electron microscopy (cryo-EM), a technique that reveals the structure of biomolecules that have been isolated from their surroundings and then frozen. In cryo-EM, the samples are showered with beams of electrons. Although the technique was initially ridiculed as ‘blobology’, owing to the blurry images it produced, advances in sample preparation and image processing have increased its resolution enough to visualize individual atoms (around 1.2 ångströms or 1.2 × 10–10 m in size).

As this ‘resolution revolution’ started to sweep through cryo-EM, around 2013, scientists flocked to the method. So far, researchers have used it to solve the structures of more than 10,000 biological molecules. Proteins found in cell membranes, in particular, have been of interest, because many of them are important for understanding disease and developing drugs. The advance “opened the door for some of those really talented people to then look for the next richest, most ripe field for big impact advances”, says Jensen. That area happened to be cryo-ET. [Continue reading…]