Toward mapping the human body at a cellular resolution (original) (raw)
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Mapping the Human Body at Cellular Resolution – The NIH Common Fund Human BioMolecular Atlas Program
2019
Transformative technologies are enabling the construction of three dimensional (3D) maps of tissues with unprecedented spatial and molecular resolution. Over the next seven years, the NIH Common Fund Human Biomolecular Atlas Program (HuBMAP) intends to develop a widely accessible framework for comprehensively mapping the human body at single-cell resolution by supporting technology development, data acquisition, and detailed spatial mapping. HuBMAP will integrate its efforts with other funding agencies, programs, consortia, and the biomedical research community at large towards the shared vision of a comprehensive, accessible 3D molecular and cellular atlas of the human body, in health and various disease settings.
The human body at cellular resolution: the NIH Human Biomolecular Atlas Program
Nature
Transformative technologies are enabling the construction of three-dimensional maps of tissues with unprecedented spatial and molecular resolution. Over the next seven years, the NIH Common Fund Human Biomolecular Atlas Program (HuBMAP) intends to develop a widely accessible framework for comprehensively mapping the human body at single-cell resolution by supporting technology development, data acquisition, and detailed spatial mapping. HuBMAP will integrate its efforts with other funding agencies, programs, consortia, and the biomedical research community at large towards the shared vision of a comprehensive, accessible three-dimensional molecular and cellular atlas of the human body, in health and under various disease conditions.
2017
The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body, by undertaking a Human Cell Atlas Project as an international collaborative effort. The aim would be to define all human cell types in terms of distinctive molecular profiles (e.g., gene expression) and connect this information with classical cellular descriptions (e.g., location and morphology). A comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic study of physiological states, developmental trajectories, regulatory circuitry and interactions of cells, as well as provide a framework for understanding cellular dysregulation in human disease. Here we describe the idea, its potential utility, early proofs-of-concept, and some design considerations for the Human Cell Atlas.
Advances and prospects for the Human BioMolecular Atlas Program (HuBMAP)
Nature Cell Biology
The Human BioMolecular Atlas Program (HuBMAP) aims to create a multi-scale spatial atlas of the healthy human body at single-cell resolution by applying advanced technologies and disseminating resources to the community. As the HuBMAP moves past its first phase, creating ontologies, protocols and pipelines, this Perspective introduces the production phase: the generation of reference spatial maps of functional tissue units across many organs from diverse populations and the creation of mapping tools and infrastructure to advance biomedical research. HuBMAP was founded with the goal of establishing state-of-the-art frameworks for building spatial multiomic maps of non-diseased human organs at single-cell resolution 1. During the first phase (2018-2022), the priorities of the project included the validation and development of assay platforms; workflows for data processing, management, exploration and visualization; and the establishment of protocols, quality control standards and standard operating procedures. Extensive infrastructure was established through a coordinated effort among the various HuB-MAP integration, visualization and engagement teams, tissue-mapping centres, technology and tools development and rapid technology implementation teams and working groups 1. Single-cell maps, predominantly consisting of two-dimensional (2D) spatial data as well as data from dissociated cells, were generated for several organs. The HuBMAP Data Portal (https://portal.hubmapconsortium.org) was established for open access to experimental tissue data and reference atlas data. The infrastructure was augmented with software tools for tissue data registration, processing, annotation, visualization, cell segmentation and automated annotation of cell types and cellular neighbourhoods from spatial data. Computational methods were developed for integrating multiple data types across scales and interpretation 2. Standard reference terminology and a common coordinate framework spanning anatomical to biomolecular scales were established to ensure interoperability across organs, research groups and consortia 3. Guidelines to capture high-quality multiplexed spatial data 4 were established including validated panels of cell-and structure-specific antibodies 5. The first phase produced a large number of manuscripts (https://commonfund.nih.gov/ publications?pid=43) including spatially resolved single-cell maps 6-11. The production phase of HuBMAP was launched in the autumn of 2022. The focus is on scaling data production spanning diverse biological variables (for example, age and ethnicity) and deployment and enhancement of analytical, visualization and navigational tools to generate high-resolution 3D accessible maps of major functional tissue units from more than 20 organs. This phase involves over 60 institutions and 400 researchers with opportunities for active intra-and inter-consortia collaborations and building a foundational resource for new biological insights and precision medicine. Below, we summarize major accomplishments and challenges encountered from the first phase of HuBMAP and describe the future roadmap of HuBMAP in the production phase and beyond. Key resources and insights from the first phase of HuBMAP Data types, organs and technologies Since the second quarter of 2023, HuBMAP datasets using 18 different analytical technologies or assay types have been publicly available
Proteomics. Tissue-based map of the human proteome
Science (New York, N.Y.), 2015
Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body.
A Quantitative Proteome Map of the Human Body
Determining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes that control protein levels. We quantified the relative protein levels from 12,627 genes across 32 normal human tissue types prepared by the GTEx project. We found 5,499 tissue specific or enriched proteins including known and new ones. Tissue-specificity at the RNA level and at the protein level does not always mirror each other: tissue specific or enriched RNAs may be ubiquitously expressed as proteins, while many ubiquitous transcripts are found to encode tissue enriched proteins. Such discordance in the sites of RNA expression and protein detection revealed potential sites of synthesis and action of protein signalling molecules. Examination of tissue specific proteins provided potential insights into human biology and in several cases, a molecular explanation for the underlying defects in disease. Overall, these d...
The Human Cell Atlas White Paper
2019
We thank HCA Organizing Committee members Dana Pe'er, Gary Bader and Henk Stunnenberg for multiple critical readings of the entire white paper and their insightful comments.
A global view of protein expression in human cells, tissues, and organs
2009
Defining the protein profiles of tissues and organs is critical to understanding the unique characteristics of the various cell types in the human body. In this study, we report on an anatomically comprehensive analysis of 4842 protein profiles in 48 human tissues and 45 human cell lines. A detailed analysis of over 2 million manually annotated, high-resolution, immunohistochemistry-based images showed a high fraction (465%) of expressed proteins in most cells and tissues, with very few proteins (o2%) detected in any single cell type. Similarly, confocal microscopy in three human cell lines detected expression of more than 70% of the analyzed proteins. Despite this ubiquitous expression, hierarchical clustering analysis, based on global protein expression patterns, shows that the analyzed cells can be still subdivided into groups according to the current concepts of histology and cellular differentiation. This study suggests that tissue specificity is achieved by precise regulation of protein levels in space and time, and that different tissues in the body acquire their unique characteristics by controlling not which proteins are expressed but how much of each is produced.
A subcellular cookie cutter for spatial genomics in human tissue
Intracellular heterogeneity contributes significantly to cellular physiology and, in a number of debilitating diseases, cellular pathophysiology. This is greatly influenced by distinct organelle populations and to understand the aetiology of disease it is important to have tools able to isolate and differentially analyse organelles from precise location within tissues. Here we report the development of a subcellular biopsy technology that facilitates the isolation of organelles, such as mitochondria, from human tissue. We compared the subcellular biopsy technology to laser capture microdissection (LCM) that is the state of art technique for the isolation of cells from their surrounding tissues. We demonstrate an operational limit of (>20μm) for LCM and then, for the first time in human tissue, show that subcellular biopsy can be used to isolate mitochondria beyond this limit.
Anatomical structures, cell types and biomarkers of the Human Reference Atlas
Nature Cell Biology
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.