DISCO-MS: Proteomics of spatially identified tissues in whole organs and organisms

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Spatial molecular profiling of complex tissues is essential to investigate cellular function in physiological and pathological states. However, methods for molecular analysis of biological specimens imaged in 3D as a whole are lacking. Here, we present DISCO-MS, a technology combining whole-organ/ism imaging, deep learning-based image analysis, robotic tissue extraction and ultra-high sensitivity mass spectrometry. DISCO-MS yielded qualitative and quantitative proteomics data indistinguishable from uncleared samples in both rodent and human tissues. Using DISCO-MS, we investigated microglia activation along axonal tracts after brain injury and characterized early and late-stage individual amyloid-beta plaques in Alzheimer's disease mouse model. Furthermore, aided by DISCO-bot robotic extraction we studied regional proteomics heterogeneity of immune cells in intact mouse bodies and aortic plaques in whole human heart. Overall, DISCO-MS enables unbiased proteome analysis of pre-clinical and clinical tissues after unbiased imaging of entire specimens in 3D, providing new diagnostic and therapeutic opportunities for complex diseases.