Spatial biology’s technological advances over the past few years have deepened researchers’ ability to ask biological questions. However, limitations remain. For example, methods are lacking for the molecular analysis of large biological specimens imaged in 3D.

Now, a novel spatial technique, DISCO-MS, combines whole-organ/whole-organism clearing and imaging, deep-learning-based image analysis, robotic tissue extraction, and ultra-high-sensitivity mass spectrometry to enable unbiased proteome analysis of preclinical and clinical tissues after unbiased imaging of entire specimens in 3D.

DISCO-MS is the first spatial-omics technology in intact 3D volumes. Because it works with preclinical and clinical tissues, it may enable the study of diseases at their earliest stages and, subsequently, the development of potential new therapeutics.

This work is published in Cell, in the paper, “Spatial proteomics in three-dimensional intact specimens.

DISCO-MS starts with DISCO tissue clearing, which renders the mouse body or human organs transparent—making them accessible to imaging. Thereby, fluorescently-labeled cells can be readily identified in intact tissues of specific sites using high-resolution three-dimensional microscopy. Once the regions of interest have been identified, they are isolated using the robotics technology called DISCO-bot. The robot-assisted extracted tissues are processed for their proteome analysis using advanced mass spectrometry (MS) methods. This high-tech approach allows molecular characterization of any desired tissue region identified in 3D in whole mouse bodies or human organs.

Researchers applied DISCO-MS to an Alzheimer’s disease (AD) mouse model and to atherosclerotic plaques in the human heart. In the tissue samples of the AD model, the team applied artificial intelligence (AI) to identify the typical AD plaques at the early stages of the disease, which had been difficult to detect by any other method.

More specifically, DISCO-MS investigated “microglia activation along axonal tracts after brain injury and characterized early- and late-stage individual amyloid-beta plaques in a mouse model of Alzheimer’s disease.”

In addition, DISCO-bot robotic sample extraction enabled the team to study the regional heterogeneity of immune cells in intact mouse bodies and aortic plaques in a complete human heart. Subsequent proteomics analyses of the plaques provided an unbiased and large-scale study of proteins affected in AD, revealing new molecular players that could be biomarkers for Alzheimer’s disease.

In the human heart, the researchers were interested in the composition of the tissues around atherosclerotic plaques. AI detection and robotics extraction of the tissues again allowed the identification of dysregulated molecular pathways in human heart cells related to aortic plaques.

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