Cryo-electron microscopy (cryo-EM) is a powerful emerging technology which enables high-resolution imaging of proteins, nucleic acids and other biomolecules, an area where traditional methods such as TEM, x-ray crystallography and NMR spectroscopy have been somewhat limited. In TEM, biomolecules are not compatible with the intense electron beams and high-vacuum environment, resulting in damaged or destroyed samples. X-ray crystallography, which requires the crystallization of molecules as part of the sample preparation process, yields altered molecules, rendering them unsuitable for study. Moreover, there are many proteins and other molecules that cannot be crystallized easily or even at all. NMR, while useful for small molecules, is severely limited in its ability to image large or membrane-bound biomolecules.

Cryo-EM overcomes these challenges by using frozen samples, less-intense electron beams and advanced image processing tools, resulting in a new method for the imaging of proteins and other larger biological molecular structures. In cryo-EM, samples are prepared using a rapid freezing process to ensure that water does not form a crystalline ice lattice, which is necessary to preserve the biological sample’s structural integrity. Like traditional EM, in cryo-EM, an electron beam is used to interact with the sample, thus leaving traces that are detected and used to construct many 2D images. These 2D image constructs are further processed in order to generate a high resolution (3 Å–10 Å limit) 3D structural image of the sample.

The applications of cryo-EM are numerous due to the vast library of biomolecules that can be imaged using the technology. The understanding of the structure, function and interaction of biological molecules is paramount to the field of biochemistry, which provides potential significant advances in the understanding of disease, immune interactions, and ultimately the development of better therapeutics and medical treatments. In fact, the 2017 Nobel prize in chemistry was awarded to scientists “for developing cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution,” further validating its potential for high-impact scientific research.

The current end-user market for cryo-EM is primarily in academia. In 2016, University of Texas Southwestern Medical Center opened a new $17 million cryo-EM center containing three new cryo systems. As the technology continues to mature and be adopted, it is migrating into the pharmaceutical and biotechnology sectors as well. AstraZeneca recently announced its investment in a Thermo Fisher Scientific Titan Krios G2 cryo-EM by its discovery sciences team, which the team has already used to define the world’s first protein structures for human ataxia telangiectasia mutated (ATM), a prime therapeutic target in cancer.

Current vendors in the cryo-EM market include Thermo Fisher Scientific, JEOL and Hitachi High-Technologies. Thermo Scientific is currently in a leadership position following its $4.2 billion acquisition of FEI (see IBO 5/31/16), offering three cryo-based models: the Glacios Cryo-TEM, Krios G3i-TEM and Talos Arctica. As the commercial cryo-EM market continues to develop, more vendors will surely be entering this space as well. The market is expected to grow in the high single digits going forward.

Cryo-EM at a Glance:

Leading Vendors

• Thermo Fisher Scientific
• JEOL
• Hitachi High-Technologies

Largest Markets

• Academia
• Pharmaceutical
• Biotechnology

Instrument Cost

• $3–$5 Million