Plasma proteomics: harnessing cutting-edge technologies for unprecedented depth and throughput

Význam tématu

Plasma proteomics combined with liquid chromatography–mass spectrometry (LC-MS) offers unparalleled sensitivity and specificity for protein identification, enabling real-time insights into disease mechanisms and biomarker discovery. Unbiased, high-throughput analysis of the plasma proteome is critical for advancing translational research across oncology, neurology, and even spaceflight biology.

Cíle a přehled studie

This case study evaluates the integration of Seer’s Proteograph™ XT Assay and Thermo Fisher Scientific’s Orbitrap Astral Mass Spectrometer to achieve deep, rapid, and scalable plasma proteomics. Objectives include demonstrating enhanced proteome coverage, throughput, and quantification accuracy, and applying the workflow to non-small cell lung cancer (NSCLC), Alzheimer’s disease (AD), and astronaut plasma studies.

Použitá metodika a instrumentace

• Sample preparation via engineered nanoparticles forming a stable protein corona in plasma, followed by on-particle digestion and peptide cleanup using the SP100 Automation Instrument.
• LC-MS analysis on the Orbitrap Astral Mass Spectrometer for synchronized quadrupole, Orbitrap, and Astral™ analyzers.
• Complementary studies employed Orbitrap Fusion Lumos Tribrid and Orbitrap Exploris 480 instruments.
• Data processing with the Proteograph Analysis Suite using library-free, data-independent acquisition (DIA) methods.

Hlavní výsledky a diskuse

• Combined workflow achieved identification of over 6 000 protein groups and 70 000 unique peptides in under one hour of LC-MS, with median CV ≤12.1 %.
• Study 1 (NSCLC): Peptide-level analysis revealed splice-variant biomarkers (e.g., BMP1, COL18A1, VWF, ITH2) undetected at protein level, improving disease characterization.
• Study 2 (AD): Analysis of 1 790 plasma samples identified >5 000 proteins per sample; classification model discriminated dementia versus controls with AUC = 0.81.
• Study 3 (Astronauts): Expanded from ~3 000 to over 7 500 protein groups across 37 samples, uncovering pathways related to immune response, stress adaptation, and protein translation during spaceflight.

Přínosy a praktické využití metody

The synergistic workflow enables large-cohort studies with enhanced statistical power, rapid biomarker discovery, and deep insight into low-abundance proteins. Applications span early cancer detection, neurodegenerative disease monitoring, and personalized health assessments in extreme environments.

Budoucí trendy a možnosti využití

• Integration with clinical diagnostics and point-of-care testing for real-time biomarker monitoring.
• Advanced automation and microfluidic sample handling to further increase throughput.
• AI-driven data analysis and machine learning for predictive biomarker panels.
• Expansion to tissue proteomics and single-cell applications for comprehensive systems biology.

Závěr

The Proteograph XT Assay coupled with the Orbitrap Astral Mass Spectrometer establishes a new paradigm for plasma proteomics, enabling unprecedented depth, speed, and reproducibility. This workflow paves the way for transformative discoveries in human health and disease.

Reference

• Seer Inc Large-scale plasma proteomics with the Proteograph XT workflow. 2023.
• Schwenk J et al J Proteome Res 2017;16(12):4299–4310.
• Donovan MKR et al PLoS ONE 2023;18(3):e0282821.
• Lacar B et al bioRxiv 2024.01.05.574446.