Corporate Story

Atom by Atom, Cryo-Electron Microscopy is Revolutionizing Drug Discovery and Treatments



Humans Are Made Up of 7 Octillion Atoms.
Now We Can See Every Single One.





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.

Cryo-electron tomography image of SARS-CoV-2. Courtesy of Sai Li. Yao, C. Molecular Architecture of the SARS-CoV-2 Virus, Cell, 183: 730-739, 2020. Zimmer, Carl. “The Coronavirus Unveiled,” New York Times 2020.

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.


Cryo-EM structure of mature Zika virus at 3.1Å resolution. The three envelope glycoproteins are colored yellow, blue and red. (Purdue University photo/Madhumati Sevvana)

Cryo-EM also is now making incredible headway in structural determination and drug discovery for debilitating neurodegenerative disorders like Alzheimer’s, Parkinson’s, and Huntington’s diseases, as well as in cancer research and highly targeted drug treatments for gene mutations.


2015 Method of the Year

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
in 2014.  

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.

 

(2016) Composite image of beta-galactosidase showing how cryo-EM’s resolution has improved dramatically in recent years. Older images to the left, more recent to the right. Credit: Veronica Falconieri, Subramaniam Lab, National Cancer Institute

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.


3D reconstruction of a GABA receptor membrane protein in a nanodisk, bound to the drug Ro-15-4513 at resolution 2.75 Angstroms. Images Courtesy of Simonas Masiulis, Radu Aricescu, MRC-LMB Cambridge and Evgenia Pechnikova, Abhay Kotecha, Thermo Fisher Scientific via GABAA receptor signaling mechanisms revealed by structural pharmacology. Nature 565.
 

Reaching atomic resolution for the very first time.

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.
 


Entering a high-throughput revolution.

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.


Quotation marks
“The field is developing so fast that it’s very exciting to be a part of it. A few years ago, we would have never thought these kinds of projects would be possible. Now, we’re able to see small membrane proteins at high resolution. We can analyze more difficult samples . . . We can even think about doing drug discovery with cryo-EM.”

Stephen Brohawn
Assistant Professor
UC Berkeley

Seeking biological insights we never knew possible.

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.


Quotation marks
“Without knowing the shape and form and how macromolecular machines work, we do not understand how life works.”

Alessandro Vannini
Head of the Structural Biology Research Center
Human Technopole

Human Technopole Cryo-EM Facility & Centre for Structural Biology



Case Studies

High-throughput cryo-EM epitope mapping of SARS-CoV-2 spike protein antibodies using EPU Multigrid: a case study with Takeda Pharmaceuticals and Utrecht University

Thermo Fisher Scientific, Takeda Pharmaceuticals and the University of Utrecht collaborated to explore how cryo-EM can be used for high throughput mapping of epitopes—the parts of a molecule to which an antibody attaches itself. The research focused on the implications of this technique on studying fast-moving SARS-CoV-2 variants and accelerating decision-making in selecting antibody combinations that target mutations.

An expedited gene-to-drug approach using Thermo Scientific Cryo-EM and the Schrödinger Platform: a case study with Schrödinger

To demonstrate the potential of drug design using cryo-EM, Thermo Fisher Scientific collaborated with Schrödinger to showcase an expedited gene-to-drug approach, finding drug target hits in only three months. 

Max Planck Institute of Molecular Physiology in Dortmund and the potential of cryo-ET