Contribution received to the FET Flagships consultation: A 4D Human Atlas: Charting Human Development and Ageing in Health and in Disease.

Ehud Shapiro, Department of Computer Science and Applied Math and Department of Biological Chemistry,Weizmann Institute of Science, Israel

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he grand S&T challenge is to construct a 4D Human Atlas that charts human development and ageing in time and in space at up to cellular (and at places even molecular) resolution, starting from the fertilized egg, through embryonic development, childhood, adolescence, adulthood and ageing, in health and in various diseases. The 4D Human Atlas would integrate an ever-increasing collection of 4D maps, each providing (a typically partial) description of the cellular dynamics of a particular individual that had particular conditions. The proposed approach to constructing this atlas is based on single-cell genomics— one of the fastest advancing branches of science today, an epitome of interdisciplinary research and the newest and most exciting frontier of biology. The key technology to enable the construction of the 4D Human Atlas is single-cell multi-omics, the integrated and simultaneous genomic, epigenomic, transcriptomic, and possibly also proteomic analysis of individual cells. Genomic analysis of individual cells obtained from a person, by biopsies, body fluid samples and/or autopsy, can uncover somatic mutations that endow each individual cell with a unique genomics signature.  Phylogenetic analysis of such cellular genomics signatures can reveal the lineage relations among the cells. Transcriptomic analysis of individual cells can reveal their types.  Complementing these analyses by epigenetic analysis further refines and improves cell lineage, cell type and state analysis. By applying multi-omics to single cells and analyzing the resulting data with appropriate algorithms, a mathematical entity encoding the 4D maps that comprise the 4D Human Atlas, termed 4D-labelled cell lineage tree, can be constructed. The leaves of the tree would represent the analysed cells, whereas the tree’s internal nodes would denote their ancestral cells. Types and 4D coordinates of the leaves (sampled cells) would be determined by experimental analysis, whereas those of their ancestral cells would be inferred computationally by various techniques, including machine learning. To allow comprehension of the 4D Human Atlas, it will be transformed by special software into a visually appealing 3D Virtual Reality application. Each 4D map in the Atlas would be transformed into a corresponding 3D VR scenario that could be traversed in time and in space by scientists and the public alike. By integrating multiple 4D maps across multiple conditions of health and disease, the navigable VR application would support navigation not only in time and in space but also under multiple health and disease conditions, serving as the ultimate tool for the research and learning of human biology and medicine.

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