Development of an untargeted spatial omics approach with molecular spatial resolution

Ziel

The next frontier in the life sciences is to map not only the composition but also the spatial organization of entire transcriptomes, genomes, and proteomes at molecular resolution. Existing approaches either achieve high resolution without scalability, scalability without resolution, or breadth without unbiased detection. Targeted methods such as MERFISH, seqFISH+, or FLASH-PAINT rely on affinity reagents and remain blind to unknown molecules, while untargeted approaches such as Light-Seq or DBiT-Seq require complex hardware, are diffraction-limited, and are restricted to nucleic acids.

The Molecular Atlas Project (MAP) will overcome these barriers by developing the first untargeted, scalable, and super-resolved spatial omics strategy. MAP introduces randomized DNA barcodes that are assembled directly on molecules in situ and read out by sequential imaging with FLASH-PAINT. This strategy enables unique labeling of every RNA or DNA molecule in a sample, with subsequent identification by sequencing and correlation with spatial imaging data. In parallel, FLASH-RESI will achieve Ångström-level resolution in a single imaging round, enabling barcoded imaging even in dense molecular environments. Finally, MAP will pioneer the extension of this strategy to proteins by attaching DNA barcodes to protein functional groups and reading them out by nanopore-based protein fingerprinting. This objective will establish, for the first time, a route to unbiased spatial proteomics with molecular precision.

By combining accessibility (compatible with standard microscopes and sequencing platforms) with disruptive conceptual advances, MAP will transform spatial biology from targeted imaging into truly comprehensive, untargeted spatial omics, catalyzing discovery across cancer biology, neuroscience, microbiology, immunology, and medicine.