Cheaper Microscope Could Bring Protein Mapping Technique To the Masses

A team of researchers at the Medical Research Council's Laboratory of Molecular Biology has developed a prototype cryo-electron microscopy (cryo-EM) microscope that, despite being significantly cheaper than high-end machines, has successfully solved protein structures with near-atomic resolution. The findings have been published in the journal Proceedings of the National Academy of Sciences. Science Magazine reports: [MB physicist Chris Russo] wants a manufacturer to commercialize his team's design, which he believes could be built and sold for $500,000. That's within reach of a new hire's startup package, or one of the regular equipment grants offered by the National Institutes of Health (NIH) or National Science Foundation, says Bridget Carragher, founding technical director of the Chan Zuckerberg Imaging Institute. 'It would be a marvelous machine,' she says. 'Everyone who wants to do structural biology could do it.' One of the team's key insights was that the electron beam does not need the energies typically used in high-end cryo-EM microscopes. Levels of 100 kiloelectronvolts (KeV) -- one-third as high -- suffice to reveal molecular structure, and they reduce costs by eliminating the need for a regulated gas, sulfur hexafluoride, to snuff out sparks. The team also saw room for improvement in the system of lenses that focuses the electrons and the detector that captures them after they probe the sample.

With the resulting prototype, the LMB group determined the structure of 11 diverse proteins. One was the iron-storing protein apoferritin, which has become a benchmark for cryo-EM resolution records. The LMB researchers mapped it at 2.6 angstroms -- 2.6 times the diameter of a hydrogen atom. That's not as high as the record cryo-EM resolution of 1.2 angstroms, but plenty good enough to make an atomic model, Russo says. And the process was fast. Because the microscope sat in the same lab as the freezing stage, the team could quickly check that its samples were good enough, rather than waiting weeks for results from a high-end machine. 'Every single structure was done in less than a day,' Russo says. Thermo Fisher Scientific, which makes a top-end machine, says it is already expanding the cryo-EM market. In 2020, it began to sell a lower cost option, called Tundra, that operates at 100 KeV. 'I would say that there are universities that probably never believed they could own cryo-EM that now have the tools,' says Trisha Rice, a vice president who heads the company's cryo-EM business. Indeed, Rajan's university just ordered one for $1.5 million.

Russo says Tundra is a step in the right direction, but his team's innovations could make cryo-EM even cheaper. For example, he says, Tundra dials back the energy on a simplified version of the costly electron source used in top-end microscopes, whereas the electron gun on the LMB prototype was designed for 100 KeV from scratch. But he understands that commercializing his team's design would require large investments by potential manufacturers. 'We're talking to all of them,' Russo says. 'But at the end of the day, it's up to them.'

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