Will Cryo-EM Take Over Structural Biology?

Posted by Jerry Carter on March 25th, 2022

According to \"Nature\", in recent years, the data submitted by laboratories to the Electron Microscopy Database (EMDB, established by the European Institute of Bioinformatics to meet the needs of the academic community for cryo-EM data) has increased exponentially, mainly because explosive growth in the number of cryo-EM in laboratories around the world. Although the database also accepts data from other electron microscopy structural analyses, the vast majority of these data are from cryo-EM.

cryo-EM generates microscopic images of individual molecules by snap-freezing proteins or other biomolecules and bombarding them with electrons. They are used to reconstruct the three-dimensional shape or structure of molecules. This helps reveal how proteins work, how they function in disease, and how to target them with drugs.

For decades, X-ray crystallography, a method favored by structural biologists, first crystallizes proteins, then hits them successively with X-rays and reconstructs their shapes from the signal patterns of diffracted light.

X-ray crystallography, while capable of producing high-quality molecular structures, is not readily available for all proteins, as some may take months or years to crystallize, and some may not crystallize at all.

This shows the advantages of cryo-EM, which does not require protein crystallization, but the technique also has limitations, such as it often generates low-resolution structures.

In 2012 and 2013, breakthroughs in hardware and software led to more sensitive electron microscopes and sophisticated software that can convert captured images into higher-resolution molecular structures.

“This paves the way for the rapid development of cryo-EM,” says Sjors Scheres, a structural biologist at the MRC Laboratory of Molecular Biology (LMB) in Cambridge, UK, an expert on the technique.

LMB structural biologist Richard Henderson, who won the 2017 Nobel Prize in Chemistry for his contributions to the development of cryo-EM technology, said that even after advances in the technology, initial growth was slow because there were only a few laboratory configurations the device. But when they started using cryo to draw detailed structural images of molecules, such as ribosomes, known as protein-making machines, the technique quickly caught the attention of other scientists, their institutions and funders.

\"All the people who invested in other research and made bad decisions, it took a year to catch up,\" Henderson said.

He predicts that by 2024, the number of protein structures determined by cryo-electron microscopy will surpass that of X-ray crystallography. cryo-EM has replaced X-ray crystallography as a tool of particular interest for scientists to study proteins embedded in cell membranes. Many membrane proteins are implicated in disease and provide targets for drugs.

In addition, Henderson believes that cryo-EM development will start to slow down at some point. One factor affecting its rapid growth, he said, was high cost, which could cost more than £5 million ( million) for such a powerful microscope. They also cost thousands of pounds a day to run and require specialized laboratories to house them to reduce vibration.

Henderson is trying to persuade companies to develop a better and cheaper cryo-EM to further promote the technology.