How it Works: Cryo-Electron Microscopy


An introduction to one of science's most advanced techniques


Electron microscopes function on the basic principle that electron wavelengths are shorter than photons’, and thus generally are able to pick up more detail. Photons are the basic particles of light and everything we see around us is the result of these particles reflecting off of objects and into our eyes. However some objects are smaller than the wavelength of photons, so they don’t really interact and our eyes just can’t see them.
But never fear: because their wavelength is so minute, electrons can interact with tiny objects. So by using electron rather than light microscopes, we can delve even deeper into cellular and molecular structures – about 5,000 times deeper to be precise. Cryo-electron microscopy, or cryo-EM, is exactly what it sounds like: using this method under really cold conditions, at -200 °C using liquid nitrogen. This amazing technique can help us to uncover even more about the minute, hidden elements in matter, leading to advancements in medicine, bio-engineering, and our fundamental understanding of the world around us.

What is it?

Electrons are the tiny charged particles that make up the outside of atoms, and they’re able to help us see minute components of matter like cells, microorganisms, molecules, and the up-close structure of materials.
Electron microscopes work by generating a beam of electrons. Electromagnetic lenses are used to focus the beam, which is then fired at a sample. The electrons then interact with nano-scale components, allowing us to investigate and visualise samples in astonishing detail.
There are different varieties of electron microscopy, and cryo-EM is a relatively new field. Regular electron microscopy requires samples to be prepared in complex ways – techniques include coating samples in substances that protect them from radiation, sectioning them into tiny slices, or dehydrating them to prevent the interaction between electrons and water molecules.
But with cryo-EM, samples don’t require this sort of preparation – they can simply be frozen and then studied in their normal state. This means that scientists can see biological elements as a whole and in an active state. Furthermore, rather than studying individual components of a sample and piecing a wider picture together, cryo-EM enables scientists to look at big, complex biological systems.
Cryo-EM isn’t perfect. It produces lower resolution images than some other techniques, like X-ray crystallography. But the real strength of cryo-EM lies in its versatility. The technique allows scientists to study objects that – because of their size, complexity, or sheer awkwardness – would be virtually impossible to scrutinise with other techniques. It’s quick and flexible; and when used in tandem with other techniques, cryo-EM is a supremely powerful tool.

The History

The first microscope was invented in the 1600s, but the first electron microscope wasn’t developed until about 300 years later, and cryo-electron microscopes are even newer than that – they’ve only been about since the 1980s.
When the first commercial electron microscope became available in the 1930s, electron microscopy wasn’t immediately popular as a scientific technique. People recognised their potential to be more powerful than a standard light microscope, but the electron microscopes tended to seriously damage samples. To solve the problem, scientists began treating and preparing their samples to protect them prior to experiments – this development suddenly made electron microscopy much more useful, and it shot onto the scientific scene.
In the 1980s scientists began working on an entirely new approach to counteract the sample-destruction challenge. In 1984, a European team discovered a method of carefully cooling samples without compromising their structure or usability. This was the birth of cryo-EM, and from here, the technique grew and grew. There are now cryo-EM facilities all over the world – and that’s where Diamond comes in.
Artist's impression of Diamond's new I14/Cryo EM facility

Cryo-electron microscopy at Diamond

Cryo-EM is an amazing technique with the power to add an entirely new level of insight to biological science, but the infrastructure to support the latest generation of electron microscopes can be prohibitively expensive. Cryo-EM requires specialist equipment, advanced software, and scientific staff who have specialised as electron microscopists, so it makes sense for facilities to be centralised at places like Diamond experienced in running very valuable equipment 24 hours a day.

At Diamond, scientists can access state-of-the-art cryo-EM facilities through the electron Bio-Imaging Centre (eBIC). An onsite cryo-electron microscope is currently being used by scientists to study everything, from complex virus structures, to never before seen proteins. It will soon be joined by a second microscope to serve the growing needs of the science community: a development that will further augment Diamond’s ability to support advances in medicine and healthcare.
Cryo-EM has real potential as a tool for the biological sciences. Its ability to quickly and simply illuminate large and complex components makes it a profoundly useful addition to the arsenal of techniques that scientists use to explore the world and generate advances. With cryo-EM behind us, we can study more comprehensively, see more deeply, and come to understand more fully.

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