New novel mass spectrometry technique enhances detection of low-abundance molecules
Researchers at Cold Spring Harbor Laboratory have developed a segmented ion accumulation method that significantly improves the sensitivity and dynamic range of mass spectrometry. The innovation, termed HDR-MS1, addresses a fundamental limitation in proteomics research by preventing abundant molecules from overwhelming rare analytes during analysis.
Cold Spring Harbor Laboratory scientists have unveiled a new mass spectrometry technique that could substantially improve drug discovery and biomarker identification by enhancing detection of low-abundance molecules in complex biological samples.
The method, published in Analytical Chemistry on 6 January 2026, challenges conventional assumptions about mass spectrometer performance. Whilst speed has traditionally been considered the primary determinant of sensitivity, the research demonstrates that dynamic range limitations during initial scanning represent an equally critical bottleneck.
Addressing the ‘blinding’ problem
“A mass spectrometer is essentially a very precise scale,” explains Research Associate Professor Paolo Cifani, who leads the Mass Spectrometry facility at Cold Spring Harbor Laboratory. “Imagine a bucket full of different molecules. Using mass spectrometry, you can figure out what molecules and how many are in that bucket.”
However, conventional approaches face a significant challenge. “Potentially interesting molecules can be overlooked because they’re not seen in the snapshot, as the spectrometer gets ‘blinded’ by more abundant ions,” Cifani notes. “Our new technique looks to remedy that.”
Segmented accumulation strategy
The innovation centres on dividing mass spectrometry scans into discrete “bins” rather than measuring all ions simultaneously. As the authors describe in their paper, the technique uses “quadrupolar isolation windows used to segment the MS1 scan range” that “are designed to transmit, on average, an equal number of charges.”
Cifani likens the approach to a sorting system: “Rather than measuring everything in the chamber at once, the Cifani lab breaks scans down into bins. If there’s a molecule at much higher levels, it only fills one bin, not the others.”
This segmentation prevents abundant ions from monopolising the instrument’s ion accumulation capacity, thereby improving detection of rare analytes.
Clinical and research implications
The enhanced sensitivity offers particular advantages for comparative studies. “Our method is much better at measuring differences in concentration,” Cifani observes. “That’s very important when studying a drug versus a placebo.”
The technique also promises improved tumour characterisation. Weight measurements can “reveal what tumours are made of, potentially influencing treatment options,” according to the research team.
The authors report that HDR-MS1 resulted in “a higher number of peptides and protein identifications under identical MS2 parameters, less redundant precursor ion sampling, and a higher rate of quantified precursor ions.”
Importantly, the method integrates seamlessly with existing workflows. The generated data files “can be analysed using any software for peptide-spectral matching and quantification,” ensuring broad accessibility.
“This is a proof of concept,” Cifani concludes. “We’re ready to inspire discovery, worldwide.”
Reference:
Ye, S., Kim, J.-S., Kim, M., et. al. (2025). MUTE-Seq: An ultrasensitive method for detecting low-frequency mutations in cfDNA with engineered advanced-fidelity FnCas9. Advanced Materials, 37(47), e2505208. https://doi.org/10.1002/adma.202505208
