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Cryo-OrbiSIMS – label-free biomolecular imaging in the native state

NPL, in collaboration with the Francis Crick Institute, The University of Nottingham and the National Institute for Biological Standards and Control have launched the Cryo-OrbiSIMS with two landmark papers.

The Cryo-OrbiSIMS is a cryogenic version of the OrbiSIMS, a chemical imaging instrument pioneered by Ian Gilmore, Senior Fellow and Head of Science at NPL. The instrument uses the technique of secondary ion mass spectrometry (SIMS). Since the OrbiSIMS was launched at NPL in 2016, it has revolutionised label-free imaging of metabolites and sub-cellular resolution. There are now a growing number of these powerful instruments (Hybrid SIMS, IONTOF GmbH) around the world, providing ground-breaking insights in biology and advanced materials.

To achieve this high-spatial resolution the sample is analysed in a vacuum chamber, like Electron Microscopy (EM). Biological samples must therefore be dehydrated for analysis and consequently are not in their native state. Inspired by the pioneering advances in cryo-EM, the team have developed and adapted the EM cryogenic techniques and methods to be compatible with mass spectrometry. The Cryo-OrbiSIMS now enables ultra-precise imaging of biomolecules in cells and tissue in the native hydrated state.

Ian Gilmore, Senior NPL Fellow, stated: “Cryo-OrbiSIMS can map the chemical composition of tissues more comprehensively and more accurately than before and this has led us to some surprising findings."

In a collaboration with the Francis Crick Institute (Alex Gould, Physiology and Metabolism Laboratory), they have published a paper in the journal Angewandte Chemie showing that the new cryogenic technique increases the range of different biomolecules that can be imaged, including semi-volatiles. As a proof-of-principle they imaged lipids and other molecules in human fingerprints, plant leaves and also in a popular genetic model organism, the fruit fly, Drosophila. “By testing Cryo-OrbiSIMS using diverse types of tissue samples, we’ve shown how it could be useful for a large number of research and industrial applications” says Clare Newell, first author of the paper and a PhD student jointly at NPL and the Crick.

Alex Gould, Senior Group Leader and Wellcome Trust Investigator at the Francis Crick Institute, stated: “This technique has the potential to answer fundamental questions about human biology and health that were previously very challenging to address. The ability to map accurately the sites where semi-volatile biomolecules accumulate within tissues and cells now opens up many new avenues of biomedical research.”

In another collaboration with the University of Nottingham (Kim Hardie, Paul Williams and Morgan Alexander) and the National Institute for Biological Standards and Control (Kirsty MacLellan-Gibson) they report in Analytical Chemistry the metrology and development of a comprehensive workflow to preserve biological samples in their native state (without ice formation) using high-pressure freezing. The performance is demonstrated by imaging a challenging sample (>90% water) of a mature Pseudomonas aeruginosa (bacterium) biofilm in its native state. It was discovered that analysis in the frozen-hydrated state yields a 10,000 fold increase in signal intensity for polar molecules, such as amino acid, which has important implications for imaging of metabolites and pharmaceuticals.

Junting Zhang, Higher Research Scientist at NPL and lead author on the paper says, “This method provides an opportunity to ‘see’ the close-to-native state distribution of different metabolites simultaneously in biological samples. With higher sensitivity, cryo-OrbiSIMS will improve the applications in the life science.”

Mark Richardson, CEO National Biofilm Innovation Centre, comments: “Across out NBIC research community of 52 UK universities and established national centres such as NPL, there is a wealth of expertise and capability. This is exemplified by partners such as NPL and the University Nottingham who are at the very leading edge of developing label free high resolution imaging techniques as demonstrated in these recent publications. We know from our Industrial partners that the ability to assess biofilms label free and to study drug or other interventions in the native state has been until now a huge unmet need. I feel certain this technique will disseminate widely and be of high commercial relevance.”



17 Aug 2020