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New Mass Spectrometry Technologies: A Greater Vantage Point for Research

Advancements in mass spectrometry technologies have enabled an ever-broadening view of the research landscape – from small molecule metabolomics to large-scale proteomics and beyond.

This year, many interesting developments entered the mass spectrometry field. As the year draws to a close, it’s time to take a closer look at a few examples and note their impact in helping research attain a even greater vantage point than before.

The upward climb of mass spectrometry-based proteomics

A number of instrument platforms have recently entered the clinical space, with either Class 1 Medical Device or FDA-approved IVD status. There are, however, significant roadblocks to gaining greater traction on the complex clinical terrain. Biomarker discovery and validation, as an example, has been hindered by challenging biomarker workflows and low-throughput limitations.

Notable advancements promise to increased the quality, depth, and speed of proteomic data generation. These in turn may support higher levels of achievement for research and clinical MS applications.

PASEF enhances mass spectrometry data acquisition

A difficulty in LC-MS based proteomics involves the coelution of many precursor peptides from the LC column at the same time. Data-dependent analyses is limited by the sampling rate, which can lead to significant losses of sample and data. Orthogonal multi-dimensional analytic approaches are needed to effectively parse information-rich samples from complex protein-rich biofluids.

The recently pioneered technique of parallel accumulation-serial fragmentation (PASEF) allows precursor ions to accumulate in parallel, and be released sequentially as a function of their ion mobility. Instead of the quadrupole selecting a single precursor ion, sub-millisecond switching allows selection and fragmentation of multiple precursors in a single 50 ms scan. Early estimates showed ~10-fold gain in sequencing speed by PASEF without a decrease in sensitivity – ideal for complex high-throughput proteomics.

timsTOF increases data quality and protein identification

With this new ability to capture multiple ions in parallel with LC-MS analysis, several formats for the ion mobility dimension were considered. Trapped ion mobility spectrometry (TIMS) was selected in initial investigations, enabling the observation of 100 fragmentations per second and more than 800,000 fragmentation spectra in a standard 120 LC run. The result of online PASEF on an LC-TOF instrument was over 2,900 protein identifications in a 30 min run of only 10 ng HeLa digest.

Bruker commercialized its revolutionary timsTOF in 2016 as a solution for next-generation proteomics. The most recent timsTOF pro, released this year and showcased at ASMS, offers four dimensions (4D) of separation (using dual TIMS) in a unique nano LC-TIMS-MS/MS instrument. The instrument is optimized for high-throughput shotgun proteomics, with >100 Hz sequencing speed and the ability to select low abundant peptides for multiple scans, thus increasing spectral quality. The platform is compatible with software for protein ID, label-free quantitation, and tandem mass tag (TMT) workflows.

Next-generation bottom-up proteomics and biomarker discovery

Systems such as the timsTOF Pro are part of the large theme of next-generation bottom-up proteomics. From a research perspective, these platforms may help address fundamental concerns -- What information am I missing? How to I obtain higher quality data? Where are the biomarkers?

The latter is the most clinically relevant question, and new technologies may prove to accelerate biomarker discovery in the challenging landscape of complex backgrounds, sample variability, low abundance detection, and other complicating factors.

Next-generation top-down proteomics and biomarker validation

Fourier-transform mass spectrometry (FT-MS) has been a sentinel technology for ultrahigh resolution intact protein identification in complex samples. This year saw the introduction of a new technology meant to remove bottlenecks of existing platforms and help drive even higher resolution and accuracy for top-down proteomics.

Magnetic Resonance Mass Spectrometry (MRMS)

Commercialized by Bruker and introduced at ASMS this year, MRMS is designed to deliver a new benchmark in mass-resolution (>20,000,000), without the need for liquid cryogens and the excess space requirements of FT-MS devices.

Performance-wise, the scimaX MRMS platform allows isotopic fine structure (IFS) analysis to easily determine exact elemental compounds in complex biofluids. In a biomarker context, advanced native protein identification and label-free quantitation can be performed. Ultrahigh resolution (>20 M) and mass accuracy (600 ppb) equate to high-fidelity biomarker quantitation direct from biological samples. The ability to swap sources (ESI, MALDI, and ETD) provides greater flexibility and broader sample coverage. The novel flow injection analysis (FIA) enables large cohort, high-throughput analyses.

Future trends in proteomics

New technologies such as those described above may serve a significant role in shortening the path from biomarker discovery to validation. The advancements in technologies will also enable faster more complete protein sequencing, identification, and quantitation for applications such as biopharmaceutical development and diagnostics.

The new year will undoubtedly bring new discoveries and further validation of these technologies. Innovative mass spectrometry solutions will continue to provide research with an ever-greater vantage point towards molecular medicine and beyond.