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The Revolutionary Power of Single-Particle Cryo-EM

Joachim Frank

27 Sept 2023

Visualizing Reactions Between Biological Molecules with Nobel Laureate Joachim Frank

On September 27th, GEC Academy successfully hosted the Global Top Scientists Forum featuring an illuminating online open lecture delivered by Professor Joachim Frank, Nobel Laureate and Professor of Biochemistry and Molecular Biophysics and of Biological Sciences at Columbia University. The lecture on the theme of Visualizing Reactions Between Biomolecules by Single-Particle Cryo-EM drew a diverse audience comprised mostly of university students specializing in Physics, Biology, and Chemistry. It provided a comprehensive overview of the current hot topic of cryo-electron microscopy, delving into its recent developments, exploring its prospects in great depth, as well as shedding light on the capability of single-particle cryo-EM in visualizing biomolecular interactions, inspiring attendees to push the boundaries of biomolecular research and chart new courses in scientific discovery.


The development of cryo-electron microscopy is largely attributed to Professor Frank's groundbreaking work on image-processing techniques, for which he was granted the 2017 Nobel Prize in Chemistry. He was inducted into the American Academy of Arts and Sciences and the National Academy of Sciences in 2006, and he was elected a Fellow of the American Association for the Advancement of Science and the Biophysical Society in recognition of his outstanding contributions to the scientific community.  

Cryo-EM has shown itself to be an invaluable tool in the field of structural biology research, Professor Frank stated, the three-dimensional structure and biological interactions of biomolecules can be reconstructed with atomic resolution in a near-natural state. Therefore, cryo-electron microscopy has been widely used as an important tool to reveal the structure of biomolecules including viruses, ribosomes, proteins, and protein complexes. and Cryo-EM could be able to capture the transient structural states of functional macromolecules on a time scale of 1ms.

The necessity of cryo-EM for unraveling the reaction mechanisms of biological molecules.

Professor Frank gave a thorough overview of the three evolutionary steps that three-dimensional electron microscopy of biological molecules has taken, as well as the future paths that the field is expected to take. He noted that single-particle cryo-EM saw its first golden age after the first and second revolutions, when the exquisite structures of the ribosome, various hemocyanin forms, and the calcium release channel were obtained, revealing detail never seen, albeit at a relatively low resolution. Single-particle cryo-EM, which boasted structural resolutions as high as 2Å to 3Å, began its second golden era after the third revolution. In addition, Professor Frank emphasized the recent significant advancements in this field, such as time-resolved cryo-electron microscopy, mapping states in a continuum, and cyro-electron tomography representations of molecules in situ.

The First and Second Golden Age of Single-Particle Cryo-EM Introduction.

An innovation of Cryo-EM of PDMS-based microfluidic chip was highly emphasis by Professor Frank, which was designed by his student Dr. Xiangsong Feng. A high-efficiency mixer, SO2 coating preventing molecular adhesion, a 3D sprayer, and control of ice thickness were setup on Cryo-EM. The purpose of the microfluidic chip is to prepare biological samples that are more in line with the requirements of the experimental level. So, when compared to conventional methods, Feng proposed is more practical, more cost-effective, and more efficient. On the other hand, the topic of the combination of Cryo-EM and biochips will become one of the important development directions.

Innovations of PDMS-based microfluidic biochip.

At the end of the lecture, students had a heated discussion on the application of cryo-EM in medicine with professors Frank. Moreover, he pointed out that technological breakthroughs in single-particle cryo-electron microscopy have pushed structural biology into a new era. With the development of many new technologies, the field of cryo-electron microscopy also has many aspects that can continue to improve. Examples include optimizing image contrast, new sample preparation techniques, and even incorporating more physics, materials science, and computer science techniques.

Features comparison between conventional cryo-EM and time-resolved techniques.

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