The rendering shown below is known around the world as a visual representation of SARS-CoV-2, the virus that causes COVID-19. How did scientists know what the virus actually looked like? They were able to create a visual design of the virus’s protein structure thanks to cryo-electron microscopy (cryo-EM) – a structural biology technique that was considered “niche” as recent as five years ago.
Without cryo-EM, the world wouldn’t have witnessed the authorization of a COVID-19 vaccine less than one year after scientists determined the virus’s structure. Even before the pandemic, cryo-EM has been making significant advancements in research and discovery to treat numerous illnesses impacting millions of lives around the globe.
The cryo-EM technique—in which protein samples are flash-frozen and hit with electrons to help visualize the structure of individual molecules—advanced the ongoing study of other viral pathogens and their vaccine candidates, including
HIV, influenza, Ebola, and Zika.
In 2016, Nature named cryo-EM the 2015 Method of the Year.
Such recognition from one of the world’s most cited scientific journals resulted in
an echo of excitement across the biology community as they witnessed the end
of “blobology”—a term used up until this point to describe the study of vague,
blob-like shapes previously produced by electron microscopy—as well as continued advancements made on what was deemed a resolution revolution
As a structure-determination technique, cryo-EM has played second fiddle to the then higher-resolution approaches of X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy. This is rapidly changing, however, thanks to recent technical advances that now allow near-atomic-resolution structures to be solved using cryo-EM. – Nature, 2016
Though the technique had been around for decades, it wasn’t until the integration of new technologies into Thermo Scientific microscopes, including the direct electron detector, that made structure determination of proteins at never-before-seen resolution possible. The powerful view enabled by such technology has been compared to the ability to read the lettering of a tennis ball on Earth, from the moon.
In scientific terms, these microscopes enable us to see molecules at less than three Angstroms (or one hundred-millionth of a centimeter.) With this level of detail, researchers can determine the structure and function of proteins, including where drugs and therapeutics bind.
With the increasing ability to view individual proteins with extreme clarity, especially those previously difficult or impossible to determine by other methods, scientists gained a broader picture of how proteins function and contribute to disease, driving new research projects and discoveries to improve drug design.
In 2017, researchers Jacques Dubochet, Joachim Frank, and Richard Henderson won The Nobel Prize in Chemistry for the development of cryo-EM, catapulting biochemistry and the imaging of biomolecules into a new era.
Then, in early November 2020, a never-before-seen image of a protein determined by Thermo Fisher Scientific technology at only 1.2 Angstrom resolution engulfed the cover of Nature. The headline read, “ATOMS IN FOCUS. Single-particle cryo-EM powers protein imaging at atomic resolution.”
The world was, for the first time, seeing individual atoms in all their glory.
Up until this point, the resolution revolution was presented to the world as an unprecedented view into the molecular world with the enablement of ‘near-atomic resolution,’ meaning structures of approximately 1.5-2 Angstrom that allow for the view of a distinguished protein chain, but not quite the individual atom.
In the study that produced this cover-worthy shot, scientists from Thermo Fisher Scientific collaborated with the Medical Research Council Laboratory of Molecular Biology to determine the structure of iron-storing protein apoferritin at 1.22 Angstroms—the first to dip below that ‘near-atomic’ level. They did so with impressive new cryo-EM technology, including the Thermo Scientific Selectris X Imaging Filter, released just that year, in combination with the powerful Thermo Scientific Krios Cryo-Transmission Electron Microscope (TEM).
Their findings proved the
potential impact of technological advancements in cryo-EM and
the need for wider adoption by researchers, especially in the
realm of drug discovery.
This breakthrough also earned cryo-EM a coveted spot on Nature’s end-of-year list of scientific events that “shaped the year.”
Since 2020, researchers have used these state-of-the-art solutions to further investigate the protein structures of SARS-CoV-2, ion channels, human membrane proteins, HIV and tau filaments.
Most proteins of interest as drug targets are large, asymmetric, and form complex groupings. Yet x-ray crystallography, a longstanding technique for structure determination, is made difficult when trying to determine larger proteins. The determination of some protein complexes can take years to crystallize, while others never crystallize at all.
Cryo-EM, on the other hand, enables high-resolution imaging of large protein complexes without crystallization, providing key information on drug targets and disease mechanisms.
With a recent influx of creative collaborations, enhanced technology, software, and techniques, including the specialized cryo-electron tomography (cryo-ET) technique, cryo-EM is now entering an entirely new dimension—one breaking records in impact and speed, driving a first-of-its-kind and much desired high-throughput revolution. In other words, thanks to cryo-EM, we are and will continue to see a faster time-to-data, and therefore, time-to-market, from structure determination to drug discovery, design, and distribution.
While cryo-EM has come a long way in a relatively short time, realizing its full potential will require a far greater level of adoption. Whether it be new diseases and viruses or changing environments, far more scientists, especially those in pharmaceuticals, need access to cryo-EM technologies.
At Thermo Fisher, our priorities are focused on access, technological excellence and expertise, and constant collaboration with the scientists doing the work every single day to ensure they have what they need to succeed.
We’re on a journey to both increase accessibility of cryo-EM by helping make in-house adoption of technology and technique attainable, and to work hand-in-hand with research teams around the world on innovating for the future.
Together, we’ll drastically expand the everyday use of cryo-EM—from sample prep to data analysis and action—and advance specialized cryo-EM methods of increasing demand, including cryo-ET, offering biological insights like never before.
Ultimately, such continuous innovation will help researchers gain a better understanding, at unprecedented resolution, of how proteins work in health and disease to catapult the design of more advanced and effective therapeutics.