Hi everyone! Welcome to our third article. This time, I’ll talk about a very important technique that has revolutionized the study of biological processes: cryogenic electron microscopy (Cryo-EM). Sorry not sorry for the cheesy title ;).
By now, most of us have probably seen pretty pictures of biological molecules like these ones:
(Source: https://pdb101.rcsb.org/motm/motm-about)
Although the artificial colors added to these structures suggest that they were made up by a talented artist, many of these “pictures” were actually“taken” by scientists. Do you want to know more about how these beautiful images were obtained? More importantly, do you want to know what important insights scientists can learn from them? Keep reading.
When I started to study biology, many of my teachers would draw the enzymes that carry out many amazing processes in the cell (like making an exact copy of the genome every time a cell divides). I was always perplexed by the shapes that these drawings had. At first, I thought that these drawings were the result of my very imaginative teachers. As I learned more biology, however, I realized that many of these drawings were actually based on real structures seen by scientists.
Why is Cryo-EM so important?
Cryo-EM is a technique that allows us to obtain high-resolution structures of biological molecules or larger biological complexes (i.e. groups of biological molecules). Before Cryo-EM, other techniques that had been around for quite some time allowed biologists to learn a lot about biomolecules. Nevertheless, these preceding techniques had important experimental complications that limited the number of biomolecules that we could observe. Cryo-EM overcame many of these limitations, drastically expanding the number of biomolecules that we can obtain structures from. This is why Jacques Dubochet, Joachim Frank, and Richard Henderson were awarded the 2017 Nobel Prize in Chemistry for the development of Cryo-EM.
How does Cryo-EM work?
I spent quite some time thinking whether to go into more detail into how Cryo-EM structures are actually obtained. In the end, I decided not to because I thought I might start to drift away from our “science for everyone” motto. Nonetheless, for those of you who are interested, I found this nice explanation of a basic Cryo-EM experiment:
But what are these pretty pictures useful for?
In addition to delighting the eyes of big nerds like me and artists alike, the structures of biological molecules are extremely useful to biological and biomedical research. In particular, obtaining the structure of biological molecules can help us understand their function (i.e. what a biomolecule does in a cell) and to understand the effect of disease mutations on their function. For instance, having the structure of a protein can help us map the location of mutations that occur in a disease. In turn, this helps us to better understand how mutations might affect different cellular processes. Additionally, having the structure of a protein that malfunctions in disease (like cancer, for instance) can help us more easily develop drugs that will deactivate the faulty protein.
Seeing is believing?
I must say that having the structure of a biomolecule is not absolutely necessary to understand its function (so in a sense, seeing is not necessarily believing). Indeed, without any structural information, scientists all over the world have learned a lot about what biomolecules do. However, there’s something quite special about seeing the structure of the biological molecules that you work with. On a daily basis, doing biological research involves a lot of pipetting clear liquids into other clear liquids. However, visualizing these structures in my head helps me bring my research into life.
What’s next?
The resolution (the level of detail of a structure) of Cryo-EM has been getting better and better every year due to the hard work of scientists all over the world. In fact, at the end of 2020, a truly important milestone was achieved: two Cryo-EM structures were obtained in which we could map the individual atoms of a protein (if you want, you can read more about this very exciting achievement here: https://www.nature.com/articles/d41586-020-02924-y
One of the limitations of Cryo-EM is that it only shows a snapshot of a biological process (like last birthday’s pictures). Nevertheless, current developments of this technique have allowed biologists to take several snapshots of a biological process with higher and higher time resolution. This means that we can essentially take movies of biological processes. The current time resolutions are not fast enough to allow us to see very fast molecular processes. However, very recently, scientists have been able to reconstruct molecular motions from Cryo-EM images using machine learning. This has allowed us to generate little “videos” of proteins in action. Pretty cool, right? You can learn more about it here:
All in all, Cryo-EM techniques have improved exponentially in the past decade. At this pace, it may not be too far-fetched to think that these beautiful high-resolution images will one day become beautiful high-resolution movies. I can’t wait! Already buying popcorn.
I hope that you found this article useful and that the next time that you see a biomolecular structure in the news, you think about all the cool things that we can learn from them. Please don’t hesitate to email us if you have any questions. See you next time!
P.S.: Nerding out with Daniel:
If you like these structures like me, you should check out a repository called the Protein Data Bank. This repository contains the structures of biomolecules solved by structural biologists all over the world. Once a month, they feature an important protein or protein complex month in a short article called “Protein of the Month” (https://pdb101.rcsb.org/motm/motm-about). These short articles always have a beautiful render of the protein structure made by the very talented scientist and artist Dr. David Goodsell. I often look at the beautiful images that we have been fortunate enough to observe thanks to Cryo-EM and other structural techniques.