A Tribute to Cryo-EM


This year’s Nobel Prize in Chemistry was recently awarded to Jacques Dubochet, Joachim Frank and Richard Henderson "for developing cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution".

The resolution of light microscopy images is restricted by diffraction limits. Because the wavelengths of electrons are up to 100,000 times shorter than those of visible photons, a resolution of 50 pm can be achieved using state-of-the-art electron microscopes. This results in a 10,000,000-fold higher magnification than that achievable by light microscopy.

Preparing a biological specimen for electron microscopy is not straightforward. For TEM (Transmission Electron Microscopy) extremely thin specimens (< 50 nm) must be obtained by sectioning or by adsorption to an electron transparent substrate. Conventional sample processing includes chemical fixation and/or resin embedding. Both of these steps lead to artifacts such as distorted cellular membranes, protein aggregation or severe loss of cellular content. Moreover, such sections need to be stained with heavy metal salts in order to increase image contrast, thereby hampering the acquisition of high-resolution data.

A major challenge is the observation of specimens in their hydrated, native state at high spatial resolution. This is where cryo-EM enters the scene. A sample for cryo-EM is frozen extremely fast using liquid ethane (± -182°C) – such that it forms a vitreous non-crystalline ice. Suppressing ice crystal nucleation and growth is crucial to prevent degradation of image quality as they diffract electrons more strongly or damage of the fragile contents of the cells.

The low contrast inherent to unstained specimens was believed to be a major limitation, however the introduction of phase plates enhanced image contrast and allowed the acquisition of in-focus data.

Cryo-EM is a particularly special case of technology development, given that it was the sample preparation technique, rather than the imaging method, that was key to its implementation. Jacques Dubochet receives the Nobel Prize for the development of methods for preparation of samples for cryo-EM studies of biomolecules in water.

In the five articles below, you can read about latest cryo-EM sample preparation techniques and how Leica Microsystems is actively engaged in delivering solutions for the cryo-EM community for over 30 years.

The Imaging Team




Immersion Freezing for Cryo-Transmission Electron Microscopy


Transmission electron microscopy of fully hydrated, unstained specimens at cryogenic temperatures (cryo-TEM) is a versatile tool in structural biology, cell biology, pharmacology and other branches of science. Ultra-fast freezing of the ...


New Insights into Cilia and Flagella by Cryo-EM


Cilia and flagella were the first organelles to be discovered and have been studied for centuries. However, their essential role in humans and how ciliary defects cause diseases are still not well understood. Cryo-EM has recently shed new ...




Towards Correlative Super-Resolution Fluorescence and Electron Cryo-Microscopy


This peer-reviewed scientific article is freely accessible after registration due to a friendly sponsoring by Leica Microsystems! The Leica EM GP allows plunge freezing of thin-blotted samples and blotting from one side of the specimen ...


Nanoscale Platelet Formation by Monounsaturated and Saturated Sophorolipids under Basic pH Conditions

This peer-reviewed scientific article is freely accessible after registration due to a friendly ...


Lipid-Conjugation of Endogenous Neuropeptides: Improved Biotherapy against Human Pancreatic Cancer

Wiley open access: In research on pancreatic cancer a Leica EM CPC was used to plunge-freeze ...


An Oscillating Cryo-knife Reduces Cutting-induced Deformation of Vitreous Ultrathin Sections

Wiley open access: In the context of developing a new cryo-knife for producing of vitreous ...


Compression and Crevasses in Vitreous Sections under Different Cutting Conditions

Wiley open access: A related research article, again with Jacques Dubochet in the authorship, ...




Cryo-EM Allows the Study of Biomolecules at Atomic Resolution Prepared under Cryogenic Conditions


Statement of Markus Lusser, President of Leica Microsystems for this year Nobel Prize in Chemistry: “We are pleased that this honor conferred by the Nobel Prize Committee once again highlights the enormous importance of microscopy ...




Leica EM Cryo CLEM - Correlating Samples in their Native State


The innovative Leica EM Cryo CLEM set for widefield light microscopy with the Leica DM6 FS represents the state-of-the art solution for analysis of cryo samples in the cryo light and electron microscope.


Leica EM ICE - A New Generation High Pressure Freezer

The Leica EM ICE is a versatile High Pressure Freezer that combines quality and innovation, ...


Leica EM VCM and Leica EM VCT500 - The Future is Connectivity

The Leica EM VCM enables users to easily put their cryogenic samples on holders under liquid ...


Leica EM ACE900: The Next Generation of Freeze Fracture System

Fully reproducible high class results with maximum resolution: The Leica EM ACE900 is a ...

Imaging & Microscopy Issue 2/2019

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