Skip to main content
Premium Trial:

Request an Annual Quote

Thermo Fisher Targets Structural Biology Space With Mass Spec, Cryo-EM Offerings


NEW YORK (GenomeWeb) – Since its acquisition last year of electron microscopy firm FEI, Thermo Fisher Scientific has moved to expand its footprint in the structural biology space.

The purchase gave Thermo Fisher access to FEI's cryo-EM technology, which in recent years a number of researchers, including leading proteomics scientists, have been exploring in combination with mass spectrometry as an approach to characterizing the structures of proteins and protein complexes.

Thermo Fisher purchased FEI in September 2016 for $4.2 billion. Last week, on the company's Q1 2017 earnings call, President and CEO Marc Casper discussed the deal and where Thermo Fisher aims to apply the technology, highlighting in particular the recent opening of a new customer demo lab at China's Tsinghua University.

At the lab, Thermo Fisher is "sponsoring research and educating students through hands-on cryo-EM courses," Casper said, adding that "understanding the structure of proteins in our blood is a key to advancing precision medicine. And our cryo-EM and Orbitrap platforms are essential to this research."

X-ray crystallography has traditionally been the gold standard for structural biology research, and it still provides the highest resolution structural information. However, the technique has its downsides. For instance, a major limitation is the large amount of sample required, which makes it impractical in cases where it is difficult to generate large, highly pure quantities of the target molecules.

In recent years, cryo-EM has emerged as an alternative to crystallography, with many structural biologists adding the technique to their repertoires. A seminal moment for the field came in 2013 with the publication of a paper in Nature by University of California, San Francisco researchers, describing the structure of the TRPV1 ion channel as characterized by cryo-EM, said Jeffrey Lengyel, principal scientist at Thermo Fisher and formerly technical lead for structural biology at FEI.

"That showed that cryo-EM could address what we consider smaller, sub-500 kilodalton proteins that were very difficult to crystallize," he said. "And this was a mammalian ion channel and also a pain receptor, so it was biomedically quite interesting. So it was basically a message to all crystallographers that they need to start adopting this technology."

Around the same time, papers began to emerge from several top proteomics labs using cryo-EM in combination with mass spectrometry to characterize various proteins and protein complexes.

For instance, in 2014, 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. 

This year, 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 enable the generation of higher-resolution structures than would be possible with cryo-EM alone.

Cross-linking chemistry uses molecules to link proteins together at different points, with mass spec then used to generate structural information based on the position of these linkages. HDX works similarly by labeling the amides in protein backbones with deuterium. Amides from the regions involved in binding will, in theory, be less accessible to labeling than those from other regions, and this can be detected using mass spec to provide structural information.

Putting together mass spec and cryo-EM data, researchers are able to generate a picture of both the overall shape of a protein or protein complex as well as an understanding of the arrangement and orientation of individual proteins within the structure.

With both cryo-EM and mass spec technologies in house, Thermo Fisher has an opportunity to capitalize on and broaden this trend. As Casper noted on the Q1 call, one of the company's "key strategic objectives in acquiring FEI is to use our leadership in life sciences to drive adoption of this technology with those [existing] customers."

"I think there are going to be interesting applications [using cryo-EM and mass spec]," Lengyel said. "Particularly looking at different structural states with this sort of analysis."

He noted as well that mass spec is useful on the front end for characterizing what is in a sample before putting it through cryo-EM analysis.

"Cryo-EM can potentially address a wide range of structural problems that could not be assessed previously," he said. "And some of these are very complex protein complexes that oftentimes have dynamic on- and off-rates, and many subunits, many components. And so it's really critical to understand what you're actually analyzing before you go into cryo-EM, to assess purity and what is the ratio of subunits or if it is actually an intact complex. You have to make sure you have the right sample, because these can be very difficult to handle biochemically."

"And so I think that as the range of problems that scientists are addressing becomes more and more complex, a lot of issues will be handled with things like a mass spectrometer [for] sample prep and actual data collection with cryo-EM," Lengyel said. "And there's very clear synergy with this."

He noted that FEI, which posted revenues of $930 million in 2015, the last full year prior to being acquired, has large footprints in the electronics and semiconductor market as well as in materials science.

"But for the last couple of years, the life science group was the fastest growing group at FEI," he said. "And this is principally due to the explosion of cryo-EM in structural biology."

Lengyel estimated that FEI has around 95 percent of the structural biology cryo-EM market. The bulk of these customers are academic researchers, he said, though pharmaceutical companies are becoming interested in the technology, as well.

Genentech recently purchased cryo-EM instrumentation from Thermo Fisher, which will be installed later this year, he said. The company also runs a pharmaceutical consortium out of Cambridge, England where five drugmakers split time on its instruments, which, Lengyel said, run in the range of $5 million to $6 million each.

Casper echoed this assessment on the company's Q1 call, citing "excellent interest" from the academic community as well as "the beginning of interest in the pharmaceutical community."

Lengyel noted the company is now working to develop methods for improving image contrast, which "has allowed us to look at smaller and smaller proteins and also different conformation states."

"I think there's a lot of potential in the future," he said.