A major increase in mass spectrometry sensitivity could change how researchers study intact proteins, protein complexes, and the molecular forms that shape human biology.
During an interview at ASMS 2026, Neil Kelleher, Professor of Chemistry, Molecular Biosciences, and Medicine at Northwestern University, discusses the direct mass technology incorporated into the Thermo Scientific Orbitrap Tribrid Apex mass spectrometer. He described the advance as one of the most significant developments he has seen during his career in mass spectrometry.
Increasing Sensitivity for Intact Protein Analysis
According to Kelleher, the technology delivers a 1,000-fold increase in sensitivity for applications focused on proteins and large protein complexes. Researchers can therefore analyze targets using far lower sample concentrations than previous workflows required.
This shift has practical implications for laboratories working with scarce biological material or low-abundance proteins. The improved sensitivity has enabled Kelleher’s group to pursue several research targets within months rather than spending a year on the same work.
Lower concentration requirements could also help expand top-down proteomics, an approach that analyzes intact proteins rather than breaking them into smaller peptides before measurement. By preserving the complete protein structure, researchers can distinguish specific proteoforms and study combinations of sequence variation, processing, and post-translational modification.
Making Proteoforms More Accessible
Proteoforms represent the different molecular forms produced from a single gene. These forms arise through processes such as genetic variation, alternative splicing, and chemical modification. Kelleher has focused much of his career on understanding their role in health and disease.
He explains that proteoforms reflect the molecular forms that function within the body and may change during disease. This makes them important targets for research into disease mechanisms, biomarkers, and treatment response.
Kelleher believes the new platform could bring intact proteoform analysis closer to routine use for a wider range of cellular protein targets. Targets linked to neurodegeneration and oncology that remained difficult to measure one or two years ago may now become accessible.
That capability could help researchers move beyond identifying which genes or proteins are present. It could reveal the precise molecular forms involved in disease pathways and biological regulation.
Building a More Complete View of Human Biology
The human genome contains about 20,300 genes, but the number of proteoforms produced from those genes remains unknown. Kelleher highlights the Human Proteoform Project, an initiative designed to identify and characterize the proteoforms present in human biology.
He compares the effort with the Human Genome Project and links its progress to full-length, or long-read, proteomics.
Reaching that goal will require instruments that can detect intact proteins with greater sensitivity, resolution, and throughput. Kelleher sees direct mass technology as an important step toward that broader objective.
By making more intact proteins and proteoforms measurable, the technology could support a more complete view of biology at the protein level and open new research opportunities across neurodegeneration, oncology, and other disease areas.
