Michelle Taylor

I love when things come full circle. It’s always nice to tie a bow on something. In this case, I experienced a “full circle moment” while writing two articles in July—this month’s cover story, and one on tau filaments for our website.

When I write about Pittcon—the lab industry’s largest event of the year—I usually point out that it “sets the stage” for the rest of the year. Meaning, the research trends and goals established at Pittcon tend to reverberate throughout the industry for the next 365 days, until the next meeting. Of course, this year is no exception.

In my April editorial, you may remember I identified three specific trends that came out of Pittcon 2017. One was electron microscopy—and it’s already making waves in the industry.

This month’s cover article tells the story of David Muller and Sol Gruner, two Cornell scientists who developed a custom detector for electron microscopes. It’s so novel that multiple laboratory equipment manufacturers approached the physicists to commercialize the device. Muller and Gruner decided to work with FEI Co., one of the largest companies in the EM space. That was in summer 2016. In September 2016, Thermo Fisher Scientific acquired FEI for $4.2 billion.

Immediately following the acquisition, Thermo Fisher created an entirely new department—the Materials & Structural Analysis Division.
At the Pittcon press conference, Dan Shine, Thermo’s senior vice president, analytical instruments group, confirmed that electron microscopy was a new focus for the company. And Mike Shafer, president of the new materials division, reaffirmed the belief that EM is moving beyond the life sciences into structural biology.

So, in the span of a few months, Muller and Gruner went from having the backing of FEI, to working with an $18 billion company that is looking to focus on exactly what the researchers have developed. Good timing.

In a second instance of EM technology playing an important role, I spoke with two researchers from the Medical Research Council (UK) who recently used cryo-EM to reveal, for the first time, the atomic structure of tau filaments, the protein linked to a variety of neurodegenerative diseases including Alzheimer’s and CTE.

“Cryo-EM was essential for this project,” study author Sjors Scheres told me. “Alternative structure determination techniques are X-ray crystallography and nuclear magnetic resonance. For crystallography, you need 3-D crystals, which are very hard, if not impossible to obtain for these types of samples. For NMR you need isotope-labeled samples, which precludes working with samples from human tissues. Both techniques require much larger amounts of protein than cryo-EM. Cryo-EM was therefore in a unique position to work with the small amounts of unlabeled protein one can purify out of a human brain.”

That being said, cryo-EM presented its own set of unique challenges. Amyloid reconstructions are notoriously difficult to image since they are helical structures that are smooth along the helical axis—making it hard to superimpose noisy cryo-EM images at the atomic level.
Thus, Scheres’ team had to rely on a software he created called RELION (REgularised LIkelihood OtimisatioN), which implements a statistical approach. The approach infers parameters about signal and noise from cryo-EM data, thereby replacing decisions from expert users in alternative software solutions.

According to Scheres, it has proven to be highly efficient at separating images from many different 3-D conformational states, and in this research, RELION managed to complete amyloid cryo-EM reconstructions to resolutions sufficient for atomic model building.

“[The software] has contributed to the rapid uptake of the resolution revolution in cryo-EM by many labs new to electron microscopy,” Scheres said. “We have used collaborations with various groups to work on cryo-EM samples that were challenging to existing methods in order to drive methods development forward, while also learning exciting new things about biology.”