Back in the Day

The feverish pace of technological evolution during the twentieth century must have been mind-boggling. My grandparents (one born in the nineteenth century and the others born slightly after the start of the twentieth century) had front row seats to witness the transition from horse carts to automobiles, from hot air balloons to trans-oceanic flights, from communicating via telegrams to watching television and using phones, and from cooking over a wood-burning stove to using microwaves. My grandparents and parents also witnessed the emergence of computers, and people walking on the moon. Compared to the last century, technology may not appear to be evolving as rapidly, but it does.

In structural biology, the long time gold standards for obtaining high resolution structures were crystallography and nuclear magnetic resonance. Each technique had its strengths and weaknesses. When it came to studying large macromolecules, the size of the target threw a monkey wrench into the works for both techniques. To solve a high-resolution structure of a large and very important macromolecule, such as the ribosome, and accomplish what many thought was impossible instantly started speculations of Nobel prizes.

While the two techniques dominated the structural biology scene, another technique, cryo-electron microscopy (cryo-EM), started emerging as another viable imaging tool, with many advantages and a few disadvantages. Unlike crystallography, the macromolecules do not need to be coerced into a crystal. Also, cryo-EM eliminates the whole “phase” problem that involves taking diffraction spots and converting them into a meaningful structure. This technique, however, was limited to very large macromolecules, and the resulting structure typically looked like a balloon animal.

In what seems like a recent blink of an eye, the cryo-EM technology has improved considerably. No longer resembling blobs from a 50’s B-movie, the resulting structures now rival those generated from crystallography. Also, the technique is becoming more applicable to smaller molecules (about 5% the size of a eukaryotic ribosome), and it may be possible to go even smaller. If this happens, it is conceivable that cryo-EM could become the predominant means for determining the structure of proteins, RNA, and protein-nucleic acid complexes.

What changed?

The technology improved for both the equipment and the software to compensate for the poor contrast that occurs when the sample is irradiated while the image is taken. In capturing images of the molecules in a super-chilled solution, the process of taking images switched from static snapshots to movies. The new software compiles all the movie frames together to render a high-resolution structure.

As the technology continues to improve, it is possible cryo-EM could become the prevailing technique for solving structures. It’s exciting to realize we are potentially witnessing one of those momentous technological transitions. Before long, our descendants will be pondering our front row seats during this amazing technological age.


Kuhlbrandt, W. (2014). Cryo-EM enters a new era. Elife, 3, e03678. doi:10.7554/eLife.03678