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Electron Microscopy

Cryo-Electron Microscopy of Viruses

Virus research with cryo-EM, providing high resolution data on antibody antigen interaction.


Viruses are miniature, highly efficient gene delivery machines. These infectious agents come in a wide variety of shapes and sizes, with most having a diameter between ten and a few hundred nanometers. Due to their size, analytical techniques such as electron microscopy provide valuable insights for diagnosis, treatment, and vaccine development.

Transmission electron microscopy, for example, is routinely used for fast virus detection and identification in diagnostic settings. Beyond viral diagnoses, electron microscopy is also on the forefront of virology, as it is used in virus structure and pathogenesis studies, especially though near-atomic resolution instruments like cryo-electron microscopes (cryo-EM).

The power of cryo-EM in virology

Imaging with cryo-electron microscopy does not necessitate typical negative staining or chemical fixation, as the sample is instead flash frozen in its native state. Cryo-EM features several techniques that can image virus structure, viral proteins, and virus-antibody immune complexes in 3D. Single particle analysis is a cryo-EM technique capable of determining high-resolution structures of macromolecular complexes such as the "spike" protein of coronaviruses. The cryo-EM technique known as cryo-electron tomography provides structural information with broader cellular context, such as viral assembly within bacteria.

Preparing for the next major virus

Viruses will doubtlessly continue to evolve and affect our world in devastating ways. Minimizing their impact will rely on the development of treatments and preventative measures driven by highly detailed insight into the nature and structure of viruses. 

Cryo-EM has been used to study virus morphology for over 20 years, resolving the structure of viruses such as Zika, Ebola, HIV and coronaviruses. The near-atomic-resolution information provided by cryo-EM is critical for a better understanding of the molecular mechanisms behind antibody-antigen interactions. In fact, cryo-EM structures are increasingly used in protein epitope mapping, defining specific binding sites. These iterative studies aid the understanding of antibody mutations for faster discovery and development of more specific and effective vaccines or antiviral treatments.

SARS-CoV-2 virus particles imaged with TEM.
SARS-CoV-2 virus particles imaged with transmission electron microscopy. Note the spike protein, visible as protrusions on the surface of each particle. Image captured and pseudo-colored at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland.

Featured research

Battling the coronavirus at atomic scale with cryo-EM

As the global community fights against the COVID-19 pandemic, researchers have used electron microscopy, particularly cryo-EM, to increase our understanding of the SARS-CoV-2 virus. In January 2020, a Thermo Scientific 120kV TEM was first used to directly image the novel coronavirus in human cells at the National Institute for Viral Disease Control and Prevention (NIVDC), part of the China Centers for Disease Control in Beijing. In February, cryo-EM researchers determined the structure of the SARS-CoV-2 spike protein and its cellular receptor during infection using the Thermo Scientific Krios cryo-TEM. Researchers have made their cryo-EM structures publically available. By quickly solving the structure of the coronavirus spike protein, researchers used these results to develop a vaccine that entered phase 1 clinical trials in March 2020. Since then, more and more research groups around the world use cryo-EM to gain a detailed understanding of SARS-CoV-2 and to aid the development of vaccines, antivirals, and neutralizing antibodies.

Watch our webinar to learn more about the role of cryo-EM in coronavirus research ›

Learn more about how Thermo Fisher Scientific is aiding in the battle against the novel coronavirus ›

 

Below are some more examples of the successful application of cryo-EM in virology, highlighting the diversity of information that the technique can provide researchers.

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

Cryo-EM in Zika virus research

The Zika virus, while initially transmitted by mosquito or tick, is infamous for passing from mother to unborn child, leaving the infant with a range of developmental and neurological defects. Researchers at Purdue University used cryo-EM to determine the structure of the entire virus particle with a 3.1 Å resolution; this is vital as viruses in this family appear otherwise identical at lower resolutions. These observations helped contribute to two potential vaccines currently in human trials.

Learn more about how cryo-EM is driving Zika virus research ›

Ebola virus nucleocapsid like assembly structure produced with cryo-EM.
A 3D rendering of the viral nucleocapsid-like assembly produced with cryo-EM by researchers at OIST. The RNA and NP are colored in red and grey, respectively. A single NP molecule is highlighted in blue. Credit: Yukihiko Sugita, OIST.

Cryo-EM in Ebola virus research

Highly infectious and often fatal, outbreaks of the Ebola virus have imminently devastating consequences. Despite the danger it poses, there is still no effective treatment for this disease. Given the inherent danger of working with this virus, researchers are focused on studying viral components, which promise to accelerate the discovery of treatments and vaccines. For example, researchers at the Okinawa Institute of Science and Technology (OIST) determined the structure of the nucleocapsid-like assembly (which houses the genetic material of the virus) at near-atomic resolution. Understanding this component of the Ebola virus allows researchers to more accurately target the mechanism and spread of this deadly disease.

Learn more about how cryo-EM is impacting Ebola virus research ›

HIV nucleoprotein complex bound with preclinical compound, visualized with cryo EM.
HIV nucleoprotein complex bound with preclinical compound. Image courtesy of D. Lyumkis, Salk Institute.

Cryo-EM in HIV research

As a retrovirus, HIV introduces a copy of its genetic material into the DNA of the host, hijacking the machinery of the cell to produce further copies of itself. Research is focused on preventing the initial binding of the virus to the host cell and the integration of its genetic material into the host DNA. Researchers at Harvard Medical School employed cryo-EM to capture the structure of the fusion protein complex, which is believed to initiate the binding of the virus to the host cell. By fully understanding this structure, effective treatments that inhibit the binding mechanism can be produced.

Learn more about the impact cryo-EM has on HIV research by reading our blog ›


Media Gallery

Bacteriophage attached to cell wall; structure generated with virus EM (cryo electron tomography).
Structure of bacteriophage attached to salmonella cell wall, generated via cryo tomography (sub-tomogram averaging). 29.0 Å resolution. EMDB ID: 9010. Image generated with 3DBIONOTES.
Zika virus and antigen-antibody site generated with virus EM (3D single particle analysis).
3D single particle analysis reconstruction of the Zika virus and antigen-antibody target sites. Image courtesy of Sirohi et al., Purdue University
Human adenovirus 2 generated with virus EM (single particle analysis).
Human adenovirus 2 structure generated from single particle analysis data. 1.86 Å resolution. PDBe ID: 6E9D. Image generated with LiteMol.
HIV nucleoprotein complex bound with preclinical compound, visualized with cryo EM.
HIV nucleoprotein complex bound with preclinical compound. Image courtesy of D. Lyumkis, Salk Institute.
Zika virus structure produced with cryo-EM.
Cryo-EM structure of mature Zika virus at 3.1 Å resolution. The three envelope glycoproteins are colored yellow, blue and red. (Purdue University photo/Madhumati Sevvana)
Ebola virus nucleocapsid like assembly structure produced with cryo-EM.
A 3D rendering of the viral nucleocapsid-like assembly produced with cryo-EM by researchers at OIST. The RNA and NP are colored in red and grey, respectively. A single NP molecule is highlighted in blue. Credit: Yukihiko Sugita, OIST.

Prof. Erica Ollmann Saphire from La Jolla Institute for Immunology discusses how cryo-EM has been a winner to understand a range of virus structures from Ebola to SARS-CoV-2 leading to insights for drugs and vaccine development.

Prof. Jason McLellan answers questions about spike protein structure, cryo-EM and vaccine trials with collaborators at NIH. Filmed in March 2020, video courtesy of The University of Texas at Austin.

Cryo-electron microscopy (cryo-EM) is helping researchers determine the structure of coronavirus spike proteins—fueling strategies to prevent infections.


Peering inside SARS CoV-2 using high-resolution imaging

Register to watch our recorded webinar from Dr. Deborah Kelly, Penn State Center for Structural Oncology featured in our Reveal 2021 event.

Register now

Structure-guided design of SARS-CoV-2 antivirals

Register to watch our recorded webinar from Dr. Quan Wang of ShanghaiTech University and Dr. Renhong Yan of Westlake University on new cryo-EM studies of the structural basis of key molecular processes including RNA replication/transcription and receptor recognition.

Register now

Cryo-EM for virology and vaccine design

Register to watch our recorded webinar from Dr. Jeff Lengyel, Thermo Fisher Scientific, on how cryo-electron microscopy has been used against viruses even the recent COVID-19 outbreak. Cryo-EM protein structure-based research has led to applications in virology and vaccine design.

Register now

Using cryo-EM for designing next-gen therapeutics against HIV

Register to watch our recorded webinar from Prof. Dmitry Lyumkis, Salk Institute for Biological Studies, on how HIV’s ability to integrate its genome into host DNA is vulnerable to inhibition and how cryo-EM studies for structure-based drug design can help combat global HIV epidemic.

Register now

Bacteriophage attached to cell wall; structure generated with virus EM (cryo electron tomography).
Structure of bacteriophage attached to salmonella cell wall, generated via cryo tomography (sub-tomogram averaging). 29.0 Å resolution. EMDB ID: 9010. Image generated with 3DBIONOTES.
Zika virus and antigen-antibody site generated with virus EM (3D single particle analysis).
3D single particle analysis reconstruction of the Zika virus and antigen-antibody target sites. Image courtesy of Sirohi et al., Purdue University
Human adenovirus 2 generated with virus EM (single particle analysis).
Human adenovirus 2 structure generated from single particle analysis data. 1.86 Å resolution. PDBe ID: 6E9D. Image generated with LiteMol.
HIV nucleoprotein complex bound with preclinical compound, visualized with cryo EM.
HIV nucleoprotein complex bound with preclinical compound. Image courtesy of D. Lyumkis, Salk Institute.
Zika virus structure produced with cryo-EM.
Cryo-EM structure of mature Zika virus at 3.1 Å resolution. The three envelope glycoproteins are colored yellow, blue and red. (Purdue University photo/Madhumati Sevvana)
Ebola virus nucleocapsid like assembly structure produced with cryo-EM.
A 3D rendering of the viral nucleocapsid-like assembly produced with cryo-EM by researchers at OIST. The RNA and NP are colored in red and grey, respectively. A single NP molecule is highlighted in blue. Credit: Yukihiko Sugita, OIST.

Prof. Erica Ollmann Saphire from La Jolla Institute for Immunology discusses how cryo-EM has been a winner to understand a range of virus structures from Ebola to SARS-CoV-2 leading to insights for drugs and vaccine development.

Prof. Jason McLellan answers questions about spike protein structure, cryo-EM and vaccine trials with collaborators at NIH. Filmed in March 2020, video courtesy of The University of Texas at Austin.

Cryo-electron microscopy (cryo-EM) is helping researchers determine the structure of coronavirus spike proteins—fueling strategies to prevent infections.


Peering inside SARS CoV-2 using high-resolution imaging

Register to watch our recorded webinar from Dr. Deborah Kelly, Penn State Center for Structural Oncology featured in our Reveal 2021 event.

Register now

Structure-guided design of SARS-CoV-2 antivirals

Register to watch our recorded webinar from Dr. Quan Wang of ShanghaiTech University and Dr. Renhong Yan of Westlake University on new cryo-EM studies of the structural basis of key molecular processes including RNA replication/transcription and receptor recognition.

Register now

Cryo-EM for virology and vaccine design

Register to watch our recorded webinar from Dr. Jeff Lengyel, Thermo Fisher Scientific, on how cryo-electron microscopy has been used against viruses even the recent COVID-19 outbreak. Cryo-EM protein structure-based research has led to applications in virology and vaccine design.

Register now

Using cryo-EM for designing next-gen therapeutics against HIV

Register to watch our recorded webinar from Prof. Dmitry Lyumkis, Salk Institute for Biological Studies, on how HIV’s ability to integrate its genome into host DNA is vulnerable to inhibition and how cryo-EM studies for structure-based drug design can help combat global HIV epidemic.

Register now

Applications

Drug discovery

Drug Discovery

Learn how to take advantage of rational drug design for many major drug target classes, leading to best-in-class drugs.

Infectious disease research

Infectious Disease Research

Cryo-EM techniques enable multiscale observations of 3D biological structures in their near-native states, informing faster, more efficient development of therapeutics.

Structural biology research

Structural Biology Research

Cryo-electron microscopy enables the structural analysis of challenging biological targets such as large complexes, flexible species and membrane protein.

Pathology research

Pathology Research

Transmission electron microscopy (TEM) is used when the nature of the disease cannot be established via alternative methods. With nano-biological imaging, TEM provides accurate and reliable insight for certain pathologies.


Techniques

Single Particle Analysis

Single particle analysis (SPA) is a cryo-electron microscopy technique that enables structural characterization at near-atomic resolutions, unraveling dynamic biological processes and the structure of biomolecular complexes/assemblies.

Learn more ›

Cryo-Tomography

Cryo-electron tomography (cryo-ET) delivers both structural information about individual proteins as well as their spatial arrangements within the cell. This makes it a truly unique technique and also explains why the method has such an enormous potential for cell biology. Cryo-ET can bridge the gap between light microscopy and near-atomic-resolution techniques like single-particle analysis.

Learn more ›

Single Particle Analysis

Single particle analysis (SPA) is a cryo-electron microscopy technique that enables structural characterization at near-atomic resolutions, unraveling dynamic biological processes and the structure of biomolecular complexes/assemblies.

Learn more ›

Cryo-Tomography

Cryo-electron tomography (cryo-ET) delivers both structural information about individual proteins as well as their spatial arrangements within the cell. This makes it a truly unique technique and also explains why the method has such an enormous potential for cell biology. Cryo-ET can bridge the gap between light microscopy and near-atomic-resolution techniques like single-particle analysis.

Learn more ›

Products

Style Sheet for Instrument Cards Original

Krios Rx Cryo-TEM

  • Industry leading productivity and ease of use
  • Fixed 300 kV voltage for SPA only
  • Pharma-dedicated service package for guaranteed reliability

Krios G4 Cryo-TEM

  • Improved ergonomics
  • Fits more easily into new and existing labs
  • Maximized productivity and automation
  • Best image quality for high-resolution 3D reconstruction

Glacios Cryo-TEM

  • Flexible Accelerating Voltage 80-200 kV
  • Industry-leading Autoloader for cryogenic sample manipulation
  • Small footprint
  • Enhanced ease-of-use

Tundra Cryo-TEM

  • Structural information at biologically relevant resolution
  • Space efficient and cost effective
  • Easy, iterative sample optimization
  • Unique AI algorithms for streamlined data collection

Talos Arctica TEM

  • Increased data acquisition speed
  • High data with robotic sample handling & automated loading
  • Unattended platform operation and automated data acquisition
  • Low cost of ownership with remote diagnostics and preventive service

Talos F200C TEM

  • Flexible EDS analysis reveals chemical information
  • High-contrast, high-quality TEM and STEM imaging
  • Ceta 16 Mpixel CMOS camera provides large field of view and high read-out speed

Talos L120C TEM

  • Increased stability
  • 4k × 4K Ceta CMOS camera
  • TEM magnification range from 25–650 kX
  • Flexible EDS analysis reveals chemical information

Prisma E SEM

  • Entry-level SEM with excellent image quality
  • Easy and quick sample loading and navigation for multiple samples
  • Compatible with a wide range of materials thanks to dedicated vacuum modes

Quattro ESEM

  • Ultra-versatile high-resolution FEG SEM with unique environmental capability (ESEM)
  • Observe all information from all samples with simultaneous SE and BSE imaging in every mode of operation

Apreo 2 SEM

  • High-performance SEM for all-round nanometer or sub-nanometer resolution
  • In-column T1 backscatter detector for sensitive, TV-rate materials contrast
  • Excellent performance at long working distance (10 mm)

Verios 5 XHR SEM

  • Monochromated SEM for sub-nanometer resolution over the full 1 keV to 30 keV energy range
  • Easy access to beam landing energies as low as 20 eV
  • Excellent stability with piezo stage as standard

VolumeScope 2 SEM

  • Isotropic 3D data from large volumes
  • High contrast and resolution in high and low vacuum modes
  • Simple switch between normal SEM use and serial block-face imaging

Helios Hydra DualBeam

  • 4 fast switchable ion species (Xe, Ar, O, N) for optimized PFIB processing of a widest range of materials
  • Ga-free TEM sample preparation
  • Extreme high resolution SEM imaging

Scios 2 DualBeam

  • Full support of magnetic and non-conductive samples
  • High throughput subsurface and 3D characterization
  • Advanced ease of use and automation capabilities

Aquilos 2 Cryo-FIB

  • Automation enables production of multiple lamellas
  • Target and extract your structure of interest with lift-out nano-manipulator
  • 3D visualization for high-resolution tomography

Vitrobot System

  • Fully automated sample vitrification
  • Blotting device
  • Semi-automated grid transfer
  • High sample throughput

Selectris and Selectris X Imaging Filters

  • Designed for high stability and atomic resolution imaging
  • Straightforward operation
  • Paired with the latest generation Thermo Scientific Falcon 4 Direct Electron Detector

Ceta-D Camera

  • Optimum performance at any high tension (20–300 kV)
  • Compatible with post-column filters and spectrometers
  • Movie acquisition for dynamic studies

Falcon 4i Detector

  • High throughput for more images per hour
  • Unsurpassed imaging quality with high DQE
  • Lossless data compression with EER

Tomography 5
Software

  • Automated multi-site batch tomography
  • Automatic cassette mapping
  • Dose symmetric tilt scheme for optimal electron dose
  • Fully integrated with Selectris Imaging Filters

Maps Software

  • Acquire high-resolution images over large areas
  • Easily find regions of interest
  • Automate image acquisition process
  • Correlate data from different sources

Auto Slice and View 4.0 Software

  • Automated serial sectioning for DualBeam
  • Multi-modal data acquisition (SEM, EDS, EBSD)
  • On-the-fly editing capabilities
  • Edge based cut placement

Inspect 3D Software

  • Image processing tools and filters for cross-correlation
  • Feature tracking for image alignment
  • Algebraic reconstruction technique for iterative projection comparison

Amira Software
Life Sciences

  • Explore 2D-5D bioimaging data
  • Identify and understand structures
  • Obtain statistical information
  • Share reports and stunning animations

EPU 2 Software

  • Microscope-embedded solution for single particle acquisition
  • Optimized for high-throughput particle collection
  • Compatible with film, CCD cameras, and direct electron detectors

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