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Thermo Fisher Sees Boost for Mass Spec/Cryo-EM Combo From NIH Funding, Instrument Release


NEW YORK (GenomeWeb) – Following a recent federal funding boost for cryo-electron microscopy research and the launch this week of its Q Exactive UHMR instrument, Thermo Fisher Scientific sees opportunities to expand adoption of these technologies for structural biology and protein research, according to company officials.

In an interview at this week's American Society for Mass Spectrometry annual meeting in San Diego, Ken Miller, Thermo Fisher's vice president of omics marketing, said the company sees the new Q Exactive as a "complement to our overall protein analysis and proteomic portfolio, and an excellent complement to the structural biology work being done by our cryo-EM colleagues."

In a separate interview last week, Michael Shafer, president of the company's materials and structural analysis division, said Thermo Fisher has seen a steady increase in customer interest to combine mass spec with cryo-EM since it acquired cryo-EM firm FEI for $4.2 billion in September 2016. Also, the launch of a $129.5 million effort by the National Institutes of Health in May to improve research access to cryo-EM and further the technology's development will likely accelerate demand for the technology, he noted.

In recent years, cryo-EM has become an important tool for structural biologists, emerging as an alternative and complement to X-ray crystallography, which, though the traditional gold standard and highest resolution technique, suffers from downsides such as the need for relatively large amounts of sample and the need to form crystals.

At the same time, researchers, including a number of leading proteomics labs, have published papers combining mass spectrometry data with cryo-EM data to characterize different proteins and protein complexes.

In 2014, for example, a team led by Swiss Federal Institute of Technology (ETH) Zurich researcher Ruedi Aebersold published a paper in Nature, combining mass spec with cryo-EM to determine the structure of the 39S large subunit of the mammalian mitochondrial ribosome.

In 2015, University of Victoria researcher Christoph Borchers co-authored a study in Nature with Max Planck Institute for Biophysical Chemistry researcher Patrick Cramer that used a combination of cryo-EM and mass spec to elucidate the structure of the RNA polymerase II-Mediator core initiation complex in yeast.

Also, In 2017, Albert Heck, professor of biomolecular mass spectrometry and proteomics at Utrecht University, led a study published in Science that used mass spec and cryo-EM to characterize the structure of the cyanobacterial circadian oscillator.

These approaches use techniques like crosslinking or hydrogen-deuterium exchange (HDX) to collect structural information via mass spec that can be combined with cryo-EM data to generate higher-resolution structures than would be possible with cryo-EM alone.

Mass spec can also "add complementary data that can help constrain [cryo-EM-based] models," Miller said. "When you go to fit the [cryo-EM] data to a model, using crosslinking constraints or intact top-down information can be very useful in terms of model building."

Shafer noted that mass spec has also become a tool for assessing samples before cryo-EM analysis to make sure they have suitable levels of purity or to determine, for instance, if a target complex is actually present in its intact form with the correct number of subunits.

As a leading provider of both cryo-EM and mass spec systems, Thermo Fisher has an obvious interest in promoting combined cryo-EM-mass spec research, and  sees the announced NIH funding as a potentially significant driver of such work, Shafer said.

He said that one major goal of the NIH program is increasing access to cryo-EM technology in hopes of producing more studies using the technique.

Another issue the NIH funding aims to address is the lack of expertise around cryo-EM, Shafer said.

"There is a limited community of researchers that are truly expert at doing cryo-electron microscopy," he said. "So they are trying to provide more access [to instrumentation], which will yield more people who learn to use the instruments and the development of future scientists using these instruments."

Named the Transformative High Resolution Cryo-Electron Microscopy program, the NIH initiative will create three national cryo-EM service centers to provide access to and training on the technology. The centers are slated to open in late 2018 and will be funded by six-year awards. They will be located at the New York Structural Biology Center, the Oregon Health & Science University in partnership with the Pacific Northwest National Laboratory, and the SLAC National Accelerator Laboratory at Stanford University.

The initiative has also awarded three-year grants to the California Institute of Technology, Yale University, the University of Utah, and Purdue University to create instructional materials and hands-on training programs in cryo-EM techniques.

Shafer said that Thermo Fisher is similarly working to increase the accessibility of the technology, with a focus on developing products to ease sample screening and sample prep and on providing lower price points for some applications.

"There's a lot of work we need to do in terms of innovating solutions to this problem," he said.

Last year, the company launched two new cryo-EM instruments, the Krios G31 and Glacios, aimed at streamlining use of the technology through increased automation and simplified user interfaces.

Improvements in mass spectrometry instrumentation also factor into the company's plans. To that end, this week's launch of the Q Exactive UHMR marks a step forward for Thermo Fisher's intact-protein mass spec capabilities.

The new system is "specifically designed to go after the native, intact [protein], structural biology, and biopharma market," Miller said, noting that the company had modified instrument components including the ion optics and the regulation of the gas pressure to optimize it for larger molecules.

With these modifications, the instrument is able to effectively analyze intact proteins or complexes as large as 80,000 m/z, he added.

This is a significant jump compared to previous Orbitrap instruments. In a study published in the journal Analyst in November 2017, a team led by Heck and Alexander Makarov, a professor at Utrecht University and director of global research at Thermo Fisher, detailed several of the modifications involved in the development of the UHMR instrument. The authors noted that existing Orbitraps topped out at around 20,000 m/z, and that analysis of ions of this size was hampered by low transmission levels and limited mass resolution.