NanoSIMS: from imagination to imaging at the sub cellular level

Tuesday, 1 December 2015

What if you could follow target engagement of a new compound at a sub-cellular level instead of testing qualified theories in endless in-vivo models? For a long time, this idea has been nothing but science fiction for pharmaceutical research scientists. But through a novel agreement between Swedish academia and AstraZeneca Gothenburg, it’s become a real possibility. Let us share why we are excited and what we hope to achieve through the NanoSIMS imaging collaboration.

NanoSIMS, which is a top notch mass spectrometry platform available in only a handful of locations worldwide, is now the cornerstone of a unique new collaboration between Gothenburg University/Chalmers University of Technology, AstraZeneca and the funding institution Knut and Alice Wallenberg foundation (KAW).

The NanoSIMS is located at the AstraZeneca BioVenture Hub in Gothenburg, Sweden and accessible for use by scientists from all partner organisations.

The objective of the collaboration is to enable identification of new areas of research where the NanoSIMS technology platform can be applied to deliver innovative solutions and a greater understanding of the quantitative distribution of drug compounds and target engagement at a sub-cellular level.

Cameca NanoSIMS 50L installed at the AstraZeneca BioVenture Hub in Gothenburg.

What is NanoSIMS imaging?

Mass spectrometry imaging (MSI) technology is one of the most versatile tools for profiling individual cells and cell structures and visualise the spatial distribution of compounds, biomarkers, peptides or proteins by their molecular mass. Promising technologies in the field of MSI are matrix assisted laser desorption ionization (MALDI) imaging and secondary ion mass spectrometry imaging (SIMS). These imaging techniques can deliver spatial resolutions at 20-0.2 µm level and are frequently used in studies of chemical composition of tissue structures.

SIMS imaging is based on mass spectrometry (MS) of secondary ions emitted from a surface of a sample of interest, e.g. a tissue section, during bombardment with primary ion beam. Due to collisions between primary ions and the sample, a variety of particles such as electrons, molecules or ions are released from the surface of the sample and secondary ions are detected by the SIMS instrument (see figure below).

Schematic of the NanoSIMS instrument, showing the focused primary ion beam and the collection and detection of secondary ion signals. A: A Cs+ or O− beam is used to bombard the surface of a sample (e.g., a tissue section), and secondary ions are released from the surface. B: The secondary ions from the surface of the sample pass through a secondary ion column and are analyzed by a mass analyzer, which detects secondary ions with high sensitivity and high mass resolution. Haibo Jiang et al. J. Lipid Res. 2014; 55:2156-2166

Nanoscale SIMS (NanoSIMS) is a further evolution of MSI-SIMS technology and enables quantitative molecular imaging at sub-cellular resolution using stable isotope labeled compounds. The super resolution obtained by NanoSIMS is comparable to the Stimulated Emission Depletion (STED) microscopy that received the 2014 Nobel Prize in Chemistry and emphasizes the significance of imaging with super resolution at a nm scale.

NanoSIMS imaging of mouse tissues using stable isotope labelled lipids.

Mice were given stable isotope-enriched fatty acids by gavage or injected with stable isotope-enriched triglyceride-rich lipoproteins. Tissues were harvested, fixed, dehydrated, resin embedded and sectioned. A tissue section is transferred to a NanoSIMS instrument, which generates images at up to 50 nm lateral resolution. NanoSIMS imaging provides high-resolution chemical information based on the distribution of stable isotopes within the sample. Shown here are 12C14N− and 13C/12C NanoSIMS images of brown adipose tissue (BAT) from a wild-type mouse that had been fed 13C fatty acids for 4 days. In the 12C14N− image, an erythrocyte within the lumen of a capillary is white (reflecting a high 14N content), whereas the cytosolic lipid droplets of adipocytes are black (reflecting a low 14N content). In the 13C/12C ratio image, the lipid droplets are orange, reflecting enrichment with 13C.

The field of imaging has a pivotal role to play in drug discovery today and NanoSIMS imaging will provide a step change by enabling ultra-high spatial resolution required to answer the question of molecule localisation within single cells.