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Cheaper cryo-EM on the horizon

Thermo Fisher hopes $1 million microscope could broaden access to microscopy method used to determine protein structures

by Mark Peplow, special to C&EN
November 20, 2020

Structure of the GABAA receptor.
Credit: Radu Aricescu, MRC LMB; Dimple Karia and Abhay Kotecha, Thermo Fisher Scientific
The new cryo-EM machine can visualize key structural features in the GABAA receptor, a common drug target.

Cryogenic electron microscopy (cryo-EM) is a vital tool for visualizing the structures of proteins and other biomolecules, but the enormous cost of buying and running the microscopes means that few labs are able to afford one of their own.

Instrument maker Thermo Fisher Scientific says that is all about to change, with the launch of a smaller, cheaper cryo-electron microscope: the Tundra. “I think this is a major advance for getting the technology in the hands of more scientists,” says Namandjé N. Bumpus, a pharmacologist who works on drug discovery at Johns Hopkins University, who was speaking during a panel discussion following the Tundra’s launch on Nov. 18.

The Tundra cryo-electron microscope.
Credit: Thermo Fisher Scientific
A new Thermo Fisher cryo-electron microscope promises to reveal the structures of proteins and other molecules at a much lower cost.

The past decade has seen rapid improvements in the quality of cryo-EM structures. The technique is particularly useful for proteins that refuse to crystallize, and it has played an important role in studying the SARS-CoV-2 virus, for example.

Unlike X-ray crystallography, which is the most common method for determining protein structures, cryo-EM can image flash-frozen molecules. A sensitive detector records how a beam of electrons scatters off atoms in the sample, revealing the shape and structure of the molecules.

Earlier this year, researchers achieved record-breaking 1.2 Å-resolution cryo-EM images of a protein called apoferritin, marking it the first time that the technique has picked out individual hydrogen atoms in a protein. That effort relied on the field’s flagship instrument, the Titan/Krios, also made by Thermo Fisher. But a Krios can cost more than $6 million, and at 4 m tall it needs an inconveniently large lab. Because it accelerates electrons to 300 keV, this machine requires large, expensive magnets to focus the beams as well as pricey safety equipment.

In contrast, the new Tundra is about 2.3 m high and should fit into a standard lab. It also operates at a gentler 100 keV, which has helped to lower its price tag to around $1 million. Results presented at the launch showed that the Tundra could produce a 3.0 Å resolution structure of apoferritin, and a 4.3 Å structure of the GABAA receptor, an important target for many drugs.

Although individual atoms blur together into blobs at these resolutions, the Tundra can clearly discern key structural features such as helical turns along a protein’s backbone. Bumpus says this resolution should be good enough to help drug discovery groups study proteins and optimize drug candidates. During the panel discussion, Bridget Carragher, codirector of the Simons Electron Microscopy Center at the New York Structural Biology Center, added that the Tundra will also be useful for screening samples before they are sent for analysis on heftier microscopes at specialist cryo-EM centers.

Christopher J. Russo, a cryo-EM expert at the MRC Laboratory of Molecular Biology (LMB), tells C&EN the Tundra is a welcome step in the right direction. He and his LMB colleague Richard Henderson—who won a share of the 2017 Nobel Prize in Chemistry for his pioneering cryo-EM work—have spent years pushing manufacturers like Thermo Fisher to produce cheaper, lower-voltage cryo-electron microscopes, and the Tundra is the first of its kind to reach the market.

But Russo notes that the Tundra’s electron detector is not optimized for a 100 keV beam, which limits the resolution the microscope can offer. “That is the technological bottleneck at this point, and that is the thing that Thermo Fisher has not solved yet with this new product launch,” he told C&EN. Russo and Henderson are continuing to develop their own 100 keV cryo-electron microscope, as part of a £25 million Wellcome-funded project.

Thermo Fisher points out that the Tundra also includes a range of features that aim to make cryo-EM more accessible to non-expert users, such as automated sample handling and an artificial intelligence system that tweaks various parameters of the microscope to improve the quality of its data. It will also be cheaper to service and maintain than pricier rivals. “Lowering that maintenance contract is absolutely key,” Carragher says. “Even though universities can often raise money for these big pieces of hardware, it’s very difficult to keep raising huge amounts every year just to keep them turned on.”

Thermo Fisher will start offering demonstrations of the Tundra in the second quarter of 2021, with the first commercial units shipping towards the end of that year.



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