The 2017 Nobel Prize in Chemistry Cryoelectron microscopy explained

Jacques Dubochet, Joachim Frank, and Richard Henderson have claimed this year’s Nobel Prize in Chemistry, taking biochemistry--and perhaps medicine--into a new era, according to the Nobel committee. The trio earned the prize for their work on cryo-electron microscopy, which is an imaging technique that lets researchers see proteins and other large biomolecules with atomic precision. Knowing where all the pockets and crevices are in a molecule helps chemists design drugs that fit into them, which makes imaging techniques vital to understanding and treating diseases and disorders. Researchers have had really powerful tools for imaging biomolecules for a while, particularly X-ray crystallography and nuclear magnetic resonance spectroscopy. In fact, lots of Nobel Prizes have already gone to researchers who have imaged the molecules that make life possible. So why another one? Well, even the most-decorated methods have shortcomings. NMR spectroscopy works best for smallish biomolecules--which is a drag if you want to know what a virus looks like, for example. And if you want to use x-ray crystallography, the biomolecule you’re interested in has to crystallize, which not all biomolecules do. Cryo-EM gets around these problems without sacrificing resolution. Generally speaking, electron microscopy uses an electron beam, rather than light, to magnify samples to atomic resolution. But plain old electron microscopy isn’t optimized for living things and their molecules. Hitting biomolecules with an electron beam can damage or destroy them. And electron microscopes work in vacuums--which can also damage or destroy biomolecules. Still, today we’re seeing viruses, proteins, and other subcellular structures like never before thanks to cryo-EM. Understanding how this is possible also sheds some light on why these three laureates were selected. In the late 1960s, Richard Henderson earned his Ph.D. imaging proteins using x-ray crystallography, so he was well-versed in the limitations of the technique. He decided to give electron microscopy a go to study bacteriorhodopsin, a protein that Archaea use to pump protons across cell membranes. Henderson kept the proteins snug in their membranes, then coated the samples with a glucose solution to protect them from the microscope’s vacuum. He also used a low-intensity electron beam, which would normally result in poor image quality. But because of how the protein secures itself inside the membrane, Henderson and his colleague were able to get enough signal out of the instrument to publish a rough model of bacteriorhodopsin in 1975. Over the next 15 years, researchers improved the technique and started cooling samples with liquid nitrogen. This better protected them from the hazards of electron microscopy--hence the cryo part of cryo-EM. In 1990, Henderson unveiled an atomic cryo-EM structure of bacteriorhodopsin with resolution on par with x-ray crystallography. But remember, this was one protein. In order for electron microscopy to be widely useful, it needed to work for more than bacteriorhodopsin, which meant, for one, researchers needed better ways to prepare arbitrary samples. Although freezing samples protected them inside an electron microscope, ice crystals actually interfered with imaging. Enter Jacques Dubochet and his team. In 1982, they found they could vitrify water by adding ethane that had been chilled by liquid nitrogen.Vitrified water is glass-like and randomly ordered rather than crystal-like and ordered so it wouldn’t interfere with the imaging. Another early obstacle for cryo-EM was image processing power. Shortly before Jacques Dubochet’s breakthrough, Joachim Frank had developed an algorithm that enabled computers to look at a bunch of fuzzy electron micrographs and average them into one sharp image. He then built on this software to create high-resolution 3-D micrographs from the 2-D images generated by microscopes. That takes us to the mid-80s,but it’d be decades before cryo-EM was ready for prime time. In the intervening years, computers got way better and, of course, researchers got better at using the technique. But there have also been big advances in the past five years to electron detector technology, which led to an avalanche of high-resolution cryo-EM structures.Cryo-EM’s tackled all sorts of complex proteins, the nuclear pore complex, even the Zika virus during the recent outbreak--all with atomic resolution. We’ve talked about biology, medicine and even a little bit of physics, but remember this was a chemistry prize. Here’s the president of the American Chemical Society, Allison Campbell, explaining why. Campbell: To me, this is all about chemistry because this enables us as scientists to look at molecules and the arrangement of atoms in molecules and the resulting structure. And that's all about chemistry. It doesn't really matter that it's a biomolecule. It's how that molecule is interacting with its environment or other molecules, which is important. To me, this is all about chemistry. You can look at a biological sample, you can look at a human biological sample, you can look at a microbial system, you might even be able to look at polymer samples or enzymatic materials that are used for industrial applications. So it's all about chemistry to me. Matt: Also, not to downplay the importance of this work to chemistry or medicine or anything, but cryo-EM has produced some really, really amazing images. We’ve got a collection of links in the description with some awesome structures revealed by cryo-EM. Let us know your favorites in the comments.

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