Cryo-EM is such a powerful and important tool in biochemistry that any advancement is bound to have significant impacts. Its difficult to overstate how powerful a tool this is and how widely used it is to understand protein structures. Essentially, it let's you see what proteins look like, with some significant advantages over previous techniques like xray crystallography for many use cases. The technique won the 2017 chemistry nobel and was method of the year for nature in 2016, even without atomic resolution.<p><a href="https://www.nature.com/articles/nmeth.4115" rel="nofollow">https://www.nature.com/articles/nmeth.4115</a>
When I was in grad school I was a TA for a biochemistry class and the prof asked me to deliver the lecture on crystallography while he was on vaca. Part of the lecture was about how electron microscopy was easier but pretty inaccurate compared to x-ray crystallography. But the slides were 10 years out of date, the accuracy of EM was still not as good but the gap was much smaller. So I updated them with more recent EM results from the same labs.<p>When the prof came back he spent the first 5m of the next lecture "correcting" me, explaining that EM sucked, x-ray was the only good technique. I realized that he had basically made up his mind decades earlier and no matter what changed in the technology he wasn't going to change his opinion. Science has its own politics, similar to actual politics in that conclusions drive observations, but instead of being about minimum wage or housing supply it's about arcane scientific techniques.
Some readers here might be interested in the history of the technology that has enabled cryo-EM. One of the key innovations was the development of CMOS direct detection devices that are able to detect electrons with extremely high signal to noise ratio, operating very close to the thermal limit of the DDD itself. I think it is an excellent example of the fundamental interdependence of cutting edge research and cutting edge engineering. Some (maybe most?) of the initial research and development [0, 1] on the cameras was done in my grandadvisor's lab. Another part of the story is related to the massive improvements in algorithms that in some cases have enabled nearly real time reconstruction and visualization of viruses from cryo-EM samples (I don't have links for these handy), and the work to increase the resolution of the reconstructions presented in the linked article.<p>0. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359769/" rel="nofollow">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359769/</a>
1. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210420/" rel="nofollow">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210420/</a>
FYI - This means they're able to image individual atoms, not that they're imagining WITHIN atoms as the title somewhat implies.<p>That is: atomic resolution, not sub-atomic resolution
Can I just say how amazingly well articulated this article was?<p>It was so clear, lacked fluff and explained enough of an extremely complex area of science to have basic grasp of the limitations, difficulties and gains that were made in the latest advancement.<p>I really wish more articles would be like this.
The progress of Cryo EM has been extremely impressive. I wouldn't have thought you could push it to actual atomic resolution. Even with X-Ray you don't achieve that for typical protein structures.<p>It'll be interesting to see if and how quickly these advances can be put into routine use.
The paper <i>Atomic-resolution protein structure determination by cryo-EM</i> [1]:<p>> Single-particle electron cryo-microscopy (cryo-EM) is a powerful method for solving the three-dimensional structures of biological macromolecules.<p>> At resolutions better than 4 Å, atomic model building starts to become possible, but the direct visualization of true atomic positions in protein structure determination requires much higher (better than 1.5 Å) resolution, which so far has not been attained by cryo-EM.<p>> Here we report a 1.25 Å-resolution structure of apoferritin obtained by cryo-EM with a newly developed electron microscope that provides, to our knowledge, unprecedented structural detail.<p>[1] <a href="https://www.nature.com/articles/s41586-020-2833-4" rel="nofollow">https://www.nature.com/articles/s41586-020-2833-4</a>
Since people might not be familiar with the unit Angstrom used in the article: it is a shorthand for 10^-10 m = 0.1 nm = 1 Å (Ångström).<p>Edit: Wikipedia entry: <a href="https://en.wikipedia.org/wiki/Angstrom" rel="nofollow">https://en.wikipedia.org/wiki/Angstrom</a>
The original paper:
<a href="https://www.nature.com/articles/s41586-020-2829-0" rel="nofollow">https://www.nature.com/articles/s41586-020-2829-0</a><p>Published: 21 October 2020<p>Single-particle cryo-EM at atomic resolution<p>Takanori Nakane, Abhay Kotecha, Andrija Sente, Greg McMullan, Simonas Masiulis, Patricia M. G. E. Brown, Ioana T. Grigoras, Lina Malinauskaite, Tomas Malinauskas, Jonas Miehling, Tomasz Uchański, Lingbo Yu, Dimple Karia, Evgeniya V. Pechnikova, Erwin de Jong, Jeroen Keizer, Maarten Bischoff, Jamie McCormack, Peter Tiemeijer, Steven W. Hardwick, Dimitri Y. Chirgadze, Garib Murshudov, A. Radu Aricescu & Sjors H. W. Scheres<p>Nature (2020)
Interesting to see the work being done to try to move structural biology towards a place where we can observe biological processes more easily. Crystal structures (Especially with ligands) were really useful to determine structure and function, but you sometimes get artifacts and it is hard to see exactly how things transition (Assuming you even get it to crystallized in the first place).<p>Techniques like cryo-EM and smFRET are definitely helping bridge this toolset gap to do better functional analysis of proteins and complexes. Definitely worth the Nobel Prize it won a few years back.
Sort of off-topic but I recall the first time I ran a scan on an atomic force microscope back in the early 90’s. I was totally blown away by the ability to “see” individual atoms.<p>The whole system was so high tech for its day; including the computer hardware which I think was a Sun workstation. It even had magneto optical drives for storing images and a high resolution color printer for printing images out. Given that I had only used DOS up to this time, it felt like to I had been teleported into the future.
Layman's question: if we know the precise shapes of two molecules, is that enough information for us to compute every interesting detail about how they'll interact?
<i>Next, researchers will strive to achieve similar sharp resolution with less rigid, large protein complexes, such as the spliceosome</i><p>Does this mean we don't currently have a good picture of what the spliceosome looks like? That seems important!