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Spatial components of molecular tissue biology


Methods for profiling RNA and protein expression in a spatially resolved manner are rapidly evolving, making it possible to comprehensively characterize cells and tissues in health and disease. To maximize the biological insights obtained using these techniques, it is critical to both clearly articulate the key biological questions in spatial analysis of tissues and develop the requisite computational tools to address them. Developers of analytical tools need to decide on the intrinsic molecular features of each cell that need to be considered, and how cell shape and morphological features are incorporated into the analysis. Also, optimal ways to compare different tissue samples at various length scales are still being sought. Grouping these biological problems and related computational algorithms into classes across length scales, thus characterizing common issues that need to be addressed, will facilitate further progress in spatial transcriptomics and proteomics.

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Fig. 1: Components of variation in spatial profiling assays.
Fig. 2: Trajectory inference in new dimensions.
Fig. 3: Analytical challenges and opportunities of spatial molecular data.


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We thank A. Hupalowska for help with figure graphics and J. Rood for useful comments and suggestions that greatly improved the paper. G.P. is supported by the Helmholtz Association under the joint research school ‘Munich School for Data Science-MUDS’. F.J.T. acknowledges support by the BMBF (grant nos. 01IS18036B and 01IS18053A) and by the Helmholtz Association’s Initiative and Networking Fund through Helmholtz AI (grant no. ZT-I-PF-5-01) and sparse2big (grant no. ZT-I-0007). A.R. was an Investigator of the Howard Hughes Medical Institute. D.S.F. acknowledges support from a German Research Foundation (DFG) fellowship through the Graduate School of Quantitative Biosciences Munich (grant no. GSC 1006 to D.S.F.). G.P. and D.S.F. acknowledge support by the Joachim Herz Stiftung.

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F.J.T. reports receiving consulting fees from Immunai and ownership interest in Dermagnostix GmbH and Cellarity. A.R. is a founder of and equity holder in Celsius Therapeutics, is an equity holder in Immunitas Therapeutics, and was a scientific advisory board member for ThermoFisher Scientific, Syros Pharmaceuticals and Neogene Therapeutics until 1 August, 2020. Since 1 August, 2020, A.R. has been an employee of Genentech. A.R. is a named inventor on several patents and patent applications filed by the Broad Institute in the area of single-cell and spatial genomics.

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Palla, G., Fischer, D.S., Regev, A. et al. Spatial components of molecular tissue biology. Nat Biotechnol 40, 308–318 (2022).

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