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ASMS 2022 Sees Imaging Mass Spectrometry Take Center Stage


NEW YORK – Tracking with the growing interest in spatial biology more generally, imaging mass spectrometry was a hot topic at the American Society for Mass Spectrometry annual meeting held this week in Minneapolis.

Vendors including Thermo Fisher Scientific, Bruker, Shimadzu, and Waters either introduced or highlighted instruments intended for imaging work, and while many of these platforms are currently focused on small molecules and metabolites, mass spec firms are also keeping an eye on the high-plex spatial proteomics market currently occupied by companies like Akoya Biosciences, Standard BioTools, Ionpath, NanoString Technologies, and others.

Bruker, in fact, recently entered this market via a strategic partnership with Watertown, Massachusetts-based reagents firm AmberGen, which has developed a set of imaging reagents for MALDI mass spectrometry-based immunohistochemistry. Called Miralys Spatial Biology Imaging Reagents, they use peptide code photocleavable mass tags to enable high levels of multiplexing (up to roughly 100 proteins per experiment) across fresh frozen and formalin-fixed paraffin-embedded tissue sections as large as 25 mm by 75 mm. The reagents are conceptually similar to the metal conjugated antibodies used for spatial proteomic analyses by mass cytometry firms like Ionpath and Standard BioTools.

At this week's ASMS meeting, Bruker announced several new features of what it is calling its MALDI HiPLEX-IHC mass spec imaging system, which combines protein imaging using the Miralys reagents with direct MALDI imaging of small molecules including glycans, lipids, metabolites, and drugs, allowing researchers to collect data on all of these molecule types from the same tissue section.

The system includes Bruker's microgrid technology, which the company said helps eliminate image artifacts, as well as its SCiLS Lab 2023a software, which allows researchers to use collisional cross-section data for molecule identification and aids in combining imaging data from different molecule types.

Thermo Fisher also announced a move this week aimed at mass spec imaging, an area where the firm has not previously focused. The company said it had entered a comarketing agreement with TransMIT Center for Mass Spectrometric Developments at Justus Liebig University Giessen to promote a mass spectrometry imaging platform that combines its Orbitrap instruments with TransMIT's scanning microprobe matrix-assisted laser desorption/ionization (SMALDI) and 3D-surface technology. The system will allow researchers to perform spatial analyses of various analytes including metabolites, peptides, and enzymatically digested proteins.

The TransMIT device will let users convert their existing Orbitraps to MALDI imaging instruments, giving "customers a very affordable way to do spatial imaging," said Andreas Huhmer, global marketing director for mass spectrometry solutions at Thermo Fisher. "I think it is going to allow a lot of laboratories that may not be able to commit to a full MALDI system to think about either upgrading one of their existing Orbitrap Explorer or adding another Orbitrap Explorer at a very affordable price point."

Thermo Fisher announced another release this week that, while not focused on mass spec imaging, could prove an interesting technology for that purpose. The company has added what it is calling direct mass technology to its Q Exactive UHMR instrument, giving that platform the ability to do charge detection mass spec, a form of mass spectrometry in which the instrument determines the mass of hundreds to thousands of different ions, allowing for high-resolution analysis of large molecules and complexes like intact proteins, antibody-based drugs, and protein complexes.

While charge detection mass spec has been around for decades, the technique has seen a recent uptick in commercial activity. In February, Waters announced it had acquired charge detection technology from Indiana University spinout Megadalton Solutions, and at last year's ASMS meeting, Manchester, UK-based mass spec firm TrueMass launched what it said was the first commercial charge detection instrument.

Huhmer said that recent interest in the technology has been driven in large part by biopharma, where it could be useful for analyzing antibodies and oligonucleotide drugs. However, Northwestern University researcher Neil Kelleher, who collaborated with Thermo Fisher to develop the capability on the Q Exactive UHMR, said that he sees a role for the technology in spatial proteomics.

In a BioRxiv preprint published last year, Kelleher and colleagues combined nano-desorption electrospray ionization (nano-DESI) with the Q Exactive's direct mass technology to image intact proteoforms of up to 70 kDa at a spatial resolution of better than 80 µm. In a spatial top-down proteomic analysis of kidney tissue, the researchers identified 169 proteoforms using the technique.

Proteoform imaging "is probably one of the most exciting things that we have used the technology to do," said Kelleher, who is a leader in top-down proteomics and a longtime proponent of the need to analyze the proteome at the level of proteoforms. Last year, he and other top-down researchers proposed the Human Proteoform Project, through which they hope to generate a catalog of the different protein forms, including genetic variants and post-translationally modified forms, present in various mammalian cell lines and human cells.

"The [charge detection] technology really is a game-changer," Kelleher said. "It allows us to do direct, off-tissue proteoform imaging and identification."

Shimadzu also introduced a new imaging mass spec platform, its iMScope QT, which combines an optical microscope with MALDI and LC-MS capabilities. The instrument is the latest of the company's iMScope platforms and is an improvement over the previous systems in that its MALDI source features a more powerful laser and it uses a Q-TOF analyzer as opposed to an ion trap TOF, said Nazim Boutaghou, a Shimadzu product manager.

Boutaghou said the company has seen uptake for the instruments for drug discovery applications like biomarker discovery and pharmacokinetics work, with most of this focused on small molecule analysis. He said the company had no immediate plans to pursue high-plex proteomics on the platform but that it was closely following developments in the field.

Shimadzu also previewed plans to make an imaging option available on its benchtop MALDI systems, which Boutaghou said it planned to target at academic labs and smaller CROs that might not have the budget for more expensive mass spec imaging systems.

Waters, meanwhile, this week released a version of its Select Series MRT instrument with an electrospray ionization source, making it compatible with liquid chromatography. The company launched the MRT platform at last year's ASMS meeting but only as an imaging instrument featuring both a MALDI and DESI source.

Emmanuelle Claude, principal scientist at Waters, said the company has seen uptake of the MRT imaging instruments within core labs and by some leading mass spec imaging researchers, including Malcolm Clench, professor of mass spectrometry at Sheffield Hallam University, who Claude said has been using the system for analysis of peptides prepared via on-tissue digestion.

She said Waters has also collaborated on research projects with Standard BioTools to explore combining analysis by its mass spec imaging platform with Standard BioTools mass cytometry systems. She noted that the fact that DESI is nondestructive makes it ideal for researchers who want to combine analyses on the same tissue — for instance using DESI to look at small molecules and then some sort of antibody staining technique to look at proteins.

Claude said that Waters was also keeping an eye on the development of the market for high-plex spatial proteomics tools, noting that "it's not something that we can ignore."

Aside from imaging

Vendors introduced a number of non-imaging instruments and applications, as well. Sciex released a new data-independent acquisition workflow for use on its ZenoTOF 7600 instrument, which it launched at the 2021 ASMS meeting. Called Zeno Swath DIA, the approach makes use of the instrument's Zeno trap to accumulate ions within a particular m/z window and then release them as the instrument cycles through that particular window.

According to Jose Castro-Perez, senior director of accurate mass at Sciex, the method provides between a sixfold and tenfold improvement in raw sensitivity compared to previous Swath workflows, which he noted translates into deeper coverage and faster experiments.

"What the method effectively does is accumulates ions so that you can make use of the instrument measurement time more effectively," said Markus Ralser, a group leader at the Francis Crick Institute.

In April, Ralser and Sciex researchers published a BioRxiv preprint on the technique showing that the Zeno Swath approach boosted protein identifications by fivefold to tenfold compared to current Swath methods, and that it identified nearly 5,000 proteins in 2 µg of human cell lysate using a five-minute analytical flow LC separation.

Bruker introduced a new version of its timsTOF platform, the timsTOF HT, which the company said offers greater dynamic range and improved proteome coverage, enabling identification of more than 100,000 tryptic peptides in low microgram sample sizes using 60-minute LC gradients.

The company also announced this week that its timsTOF SCP instrument, which is targeted to single-cell proteomics experiments, is available for purchase with Scienion's CellenOne F1.4 instrument for dispensing single cells and its proteoChip platform for automated single-cell proteomics sample preparing, providing an end-to-end system for single-cell proteomics.

Thermo Fisher, meanwhile, released an automated proteomics sample prep system. Called AccelerOme, the system uses pre-established methods and kitted reagents along with tools for monitoring LC-MS performance to largely automate mass spec-based proteomic analyses. The system also includes experimental design software to help researchers ensure their experiments have sufficient statistical power, Huhmer said.

"We've tried to make it as easy as possible to really drive the democratization of proteomics," he said. "Anyone who can operate an espresso machine can operate this instrument."