Anatomical structures, cell types and biomarkers of the Human Reference Atlas

Katy Börner¹, Sarah A Teichmann², Ellen M Quardokus³, James C Gee⁴, Kristen Browne⁵, David Osumi-Sutherland⁶, Bruce W Herr 2nd³, Andreas Bueckle³, Hrishikesh Paul³, Muzlifah Haniffa⁷, Laura Jardine⁷, Amy Bernard⁸, Song-Lin Ding⁹, Jeremy A Miller⁹, Shin Lin¹⁰, Marc K Halushka¹¹, Avinash Boppana¹², Teri A Longacre¹³, John Hickey¹³, Yiing Lin¹⁴, M Todd Valerius¹⁵, Yongqun He¹⁶, Gloria Pryhuber¹⁷, Xin Sun¹⁸, Marda Jorgensen¹⁹, Andrea J Radtke²⁰, Clive Wasserfall¹⁹, Fiona Ginty²¹, Jonhan Ho²², Joel Sunshine²³, Rebecca T Beuschel²⁰, Maigan Brusko¹⁹, Sujin Lee²⁴, Rajeev Malhotra^{15

24}, Sanjay Jain^{25

26}, Griffin Weber²⁷

Affiliations

¹ Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA. katy@indiana.edu.
² Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
³ Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA.
⁴ Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Health and Human Services, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁶ European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Cambridge, UK.
⁷ Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
⁸ The Kavli Foundation, Los Angeles, CA, USA.
⁹ Allen Institute, Seattle, WA, USA.
¹⁰ Department of Medicine, University of Washington, Seattle, WA, USA.
¹¹ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Computer Science, Princeton University, Princeton, NJ, USA.
¹³ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁴ Department of Surgery, Washington University in St Louis, St Louis, MO, USA.
¹⁵ Harvard Institute of Medicine, Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Microbiology and Immunology, and Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
¹⁷ Department of Pediatrics, University of Rochester, Rochester, NY, USA.
¹⁸ Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
¹⁹ Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
²⁰ Center for Advanced Tissue Imaging, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA.
²¹ Biology and Applied Physics, General Electric Research, Niskayuna, NY, USA.
²² Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA.
²³ Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁴ Division of Vascular Surgery and Endovascular Therapy, Massachusetts General Hospital, Boston, MA, USA.
²⁵ Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
²⁶ Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
²⁷ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.

PMID: 34750582
PMCID: PMC10079270
DOI: 10.1038/s41556-021-00788-6

Review

Anatomical structures, cell types and biomarkers of the Human Reference Atlas

Katy Börner et al. Nat Cell Biol. 2021 Nov.

. 2021 Nov;23(11):1117-1128.

doi: 10.1038/s41556-021-00788-6. Epub 2021 Nov 8.

Authors

Affiliations

¹ Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA. katy@indiana.edu.
² Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
³ Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA.
⁴ Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.
⁵ Department of Health and Human Services, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁶ European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Cambridge, UK.
⁷ Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK.
⁸ The Kavli Foundation, Los Angeles, CA, USA.
⁹ Allen Institute, Seattle, WA, USA.
¹⁰ Department of Medicine, University of Washington, Seattle, WA, USA.
¹¹ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Department of Computer Science, Princeton University, Princeton, NJ, USA.
¹³ Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁴ Department of Surgery, Washington University in St Louis, St Louis, MO, USA.
¹⁵ Harvard Institute of Medicine, Harvard Medical School, Boston, MA, USA.
¹⁶ Department of Microbiology and Immunology, and Center for Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI, USA.
¹⁷ Department of Pediatrics, University of Rochester, Rochester, NY, USA.
¹⁸ Biological Sciences, University of California, San Diego, La Jolla, CA, USA.
¹⁹ Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
²⁰ Center for Advanced Tissue Imaging, Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, USA.
²¹ Biology and Applied Physics, General Electric Research, Niskayuna, NY, USA.
²² Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA.
²³ Department of Dermatology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
²⁴ Division of Vascular Surgery and Endovascular Therapy, Massachusetts General Hospital, Boston, MA, USA.
²⁵ Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
²⁶ Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
²⁷ Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.

PMID: 34750582
PMCID: PMC10079270
DOI: 10.1038/s41556-021-00788-6

Abstract

The Human Reference Atlas (HRA) aims to map all of the cells of the human body to advance biomedical research and clinical practice. This Perspective presents collaborative work by members of 16 international consortia on two essential and interlinked parts of the HRA: (1) three-dimensional representations of anatomy that are linked to (2) tables that name and interlink major anatomical structures, cell types, plus biomarkers (ASCT+B). We discuss four examples that demonstrate the practical utility of the HRA.

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Figures

**Fig. 1.**
a, Alphabetical listing of 16 human reference atlas construction efforts (left) linked to 30 human organs they study (right). See legend for color and size coding. The lung is studied by 10 consortia; see orange links. This review focuses on 10 organs (bolded) plus vasculature. b, 3D reference objects for major anatomical structures were jointly developed for 11 organs. c, Exemplary ASCT+B table showing all AS and CT and some B for the glomerulus in kidney; annotated with names of the three entity types (AS, CT, B) and four relationship types (in italics).

**Fig. 2.**
a, Registration and semantic annotation of tissue data (blue block) in 3D via collision detection in the Registration User Interface (RUI): A user sizes, positions, and rotates tissue blocks and saves results in JSON format. b, Semantically and spatially explicit search, browsing, and filtering of tissue data (white blocks in spleen and kidney) in the Exploration User Interface (EUI): RUI-registered tissue data can be explored semantically using the AS partonomy on left and spatially using the anatomy browser in middle; a filter in top left supports subsetting by sex, age, tissue provider, etc. Clicking on a tissue sample on the right links to the Vitessce image viewer.

**Fig. 3.**
a, HSCs migrate from liver to the thymus during embryonic and fetal development. The transcriptomic identity of these HSCs changes between the first and second trimester pregnancy, as shown by the maroon *versus* blue shading of the HSCs in the left (embryo) and right (fetal) part of the figure. The scRNAseq data in the UMAP plots are from; the top plot shows liver cells (blue) and thymus cells (orange) overlapping, labelled “lymphoid progenitor” in bottom plot. b, The nature of HSC subsets in adult blood shifts in health *versus* COVID-19. HSCs in the blood of COVID-19 patients (top-left) shows a megakaryocyte priming bias when compared to healthy (top-right). This is quantified in the histogram from of relative HSPC contributions for different donor/patient cohorts.

**Fig. 4.**
Kidney ASCT+B table linked to processes, disease, clinicopathologic information, and ontology data.

See this image and copyright information in PMC

References

1. International Human Genome Sequencing (IHGS) Consortium Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001). - PubMed
1. Venter JC et al. The sequence of the human genome. Science 291, 1304–1351 (2001). - PubMed
1. Regev A et al. The Human Cell Atlas. eLife 6, e27041 (2017). - PMC - PubMed
1. Rozenblatt-Rosen O, Stubbington MJT, Regev A & Teichmann SA The Human Cell Atlas: from vision to reality. Nature 574, 187–192 (2017). - PubMed
1. Ding SL et al. Comprehensive cellular-resolution atlas of the adult human brain. J Comp Neurol 524, 3127–3481 (2016). - PMC - PubMed

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Anatomical structures, cell types and biomarkers of the Human Reference Atlas

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Anatomical structures, cell types and biomarkers of the Human Reference Atlas

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