Cool microscopy: Nobel chemistry

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  • Published: Oct 15, 2017
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Cool microscopy: Nobel chemistry

Chilled approach

 Over the last few years, researchers have published atomic structures of numerous complicated protein complexes. a. A protein complex that governs the circadian rhythm. b. A sensor of the type that reads pressure changes in the ear and allows us to hear. c. The Zika virus. (Credit: Nobel Foundation)

The development of cryo-electron microscopy has led to this year's Nobel Prize for Chemistry been awarded to Jacques Dubochet of the University of Lausanne, Switzerland, Joachim Frank of Columbia University, New York, USA, and Richard Henderson of the Medical research Council Laboratory of Molecular Biology (MRC-LMB) in Cambridge, UK.

The technique is used for the high-resolution determination of biomolecular structures in solution and is often used alongside or instead of X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy especially in situations where those otherwise powerful techniques cannot obtain a structure.

A picture paints a thousand words, as the old cliché goes. But, when it comes to molecular structure this is never truer. A picture of a molecule helps us understand the properties and behaviour of the molecule. Of course, in the realm of biological macromolecules, X-ray crystallography has reigned supreme for decades. Unfortunately, as we know and the name suggests, it requires crystals of the compound of interest and these are not always available especially when it comes to the myriad proteins that reside in the membranes of cells. NMR spectroscopy has had many successes where XRD has failed. But, it is not always the easiest approach to structure determination even though it can work with dynamic molecules in solution as well as the solid state. Cryo-electron microscopy can often fill the gap, bridge the divide between solution spectroscopy and crystallography as it were. With the "cryo", researchers can now freeze biomolecules in mid-motion and visualise processes that they have not seen before. This become decisive in improving our basic understanding of basic life chemistry and thence informs the development of synthetic molecules that we know as pharmaceuticals that can modulate those processes to fix them when they go awry in disease.

3D

Conventionally, electron microscopy was suitable only for imaging dead matter. Not only did a sample require preparation, such as coating with a noble metal, to make it visible to the electrons, but even if no coating was required in modern approaches, the energy of the electron beam destroys tissue quickly, often too quickly for a detailed image to be obtained. In 1990, of course, one of this year's three Nobel Laureates, Henderson, succeeded in using electron microscopy to generate a three-dimensional image of a protein with atomic resolution; a breakthrough that demonstrated the great potential of this technology.

Frank had meanwhile, during the period 1975 to 1986 developed an image processing method for electron microscopy that could overlay its generally fuzzy two-dimensional images and merge them to reveal a better than pin-sharp three-dimensional structure.

Convergence

Dubochet added water to electron microscopy. While liquid water obviously quickly evaporates in the vacuum chamber of the electron microscope leading to the collapse of biomolecules supported by the water molecules, Dubochet realized in the 1980s that it would be possible to circumvent this evaporation problem by "vitrifying" water. This was achieved by cooling it to very low temperature so rapidly that it was trapped in essentially the liquid state around a biological sample without the biomolecules ever getting the chance to lose their natural shape even in the microscope's vacuum chamber.

These three parallel efforts converged as electron microscopy was optimized over the years until it was eventually possible in 2013 to use the chilled approach to obtain atomic resolution imaging of a biomolecule. This is almost a routine procedure today and has been used to routinely obtain three-dimensional structures of many biological macromolecules, such as proteins that endow bacteria with antibiotic resistance and even the surface of viruses, such as the emergent Zika. Intriguingly, the structure of a protein involved in governing circadian rhythms has also been analysed with cryo-electron microscopy. Circadian rhythms were the subject of the Nobel Prize for Physiology or Medicine this year.

Related Links

Nobel Foundation 2017, online: "Scientific Background: The development of cryo-electron microscopy (PDF)"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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