Three individuals were accorded the Nobel Prize for Chemistry – Joachim Frank, Richard Henderson and Jacques Dubochet – at this year's Nobel Prize. The prestigious accolade was for their ground-breaking discovery of a technique called cryo-electron microscopy, which can be used to visualise biological molecules. The discovery was termed a “revolution in biochemistry” by the Nobel Prize Committee.

Cryo-electron microscopy represents an improvement on conventional imaging techniques, due to its ability to showcase molecules in greater detail. Samples are frozen to abysmally low temperatures such as -180 degrees Celcius, which enables the detailed illumination of atomic structure. This is particularly useful in the development of pharmaceutical therapies, as molecular and protein structures can now be examined and targeted more specifically. Claudio Ciferri, a scientist for structural biology at Genentech, comments that this technique “speeds up the way in which you can start experiments and start addressing diseases.”

Cryo-electron microscopy: Biological samples not required to be dehydrated

In standard electron microscopy, samples are treated with dehydrating agents, which compromises the quality and detail of the sample. In cryo-electron microscopy, samples are frozen within their surrounding liquid medium using vitreous ice. Vitreous ice essentially preserves and freezes the liquid molecules in their original form, without the ordered lattice formation that occurs in standard crystallisation, which can disrupt molecular structure.

As molecules can now be viewed in greater detail, drugs targeting specific binding sites on proteins can be designed. This can be helpful in the treatment of cancer and targeting the expression of viral proteins.

The development of cryo-electron microscopy: The final technical hurdle was overcome in 2013, when a new type of electron detector came into use. Photo credit: Guardian
The development of cryo-electron microscopy: The final technical hurdle was overcome in 2013, when a new type of electron detector came into use. Photo credit: Guardian

Previous imaging techniques had various shortcomings addressed by cryo-electron microscopy

Crystallography is another pioneering technique which involves crystallising the protein of interest. Whilst this is relatively straightforward for smaller proteins with simple structures, larger proteins may take years before they can be appropriately crystallised and visualised. This is another shortcoming that is addressed by cryo-electron microscopy, which facilitates efficient viewing of larger protein structures. Crystallography also requires proteins to be studied in a rigid form, which limits the scope for observing protein interactions and movement.

Conventional electron microscopy also requires the samples to be non-living, as the specimens are inevitably killed by the electron beams. The study of dead specimens is invariably not reflective of what occurs in living specimens, and therefore can limit the application of information obtained to real-life scenarios.

Pharmaceutical, healthcare and biology sectors weigh in

Professor Magdalena Zernicka-Goetz, a professor of stem cell biology at the University of Cambridge comments on the technique, expressing that “a visual image is the essential component to understanding, often the first one to open our eyes, and so our minds, to a scientific breakthrough.”

The Medical Research Council Laboratory in Cambridge has also implemented this technique in cancer research to study the structure of abnormal proteins in malignant states and the formation of new cells. Pfizer, a pharmaceutical company, has used cryo-electron microscopy in the development of new vaccines. The company also utilises the technique to facilitate more specific drug designing, which therefore allows drugs to be more quickly approved for clinical trials.

Cryo-electron microscopy also has potential for widespread clinical use. For instance, the technique was used to unveil the structure of the Zika virus in the viral epidemic that afflicted many countries last year. The technique’s potential to design more specific therapies may revolutionise the way we treat viral infections, cancer and other common medical conditions. MIMS

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