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Mapping the Human Body at Cellular Resolution -- The NIH Common Fund Human BioMolecular Atlas Program
Michael P Snyder, Shin Lin, Amanda Posgai, Mark Atkinson, Aviv Regev, Jennifer Rood, Orit Rosen, Leslie Gaffney, Anna Hupalowska, Rahul Satija, Nils Gehlenborg, Jay Shendure, Julia Laskin, Pehr Harbury, Nicholas A Nystrom, Ziv Bar-Joseph, Kun Zhang, Katy Börner, Yiing Lin, Richard Conroy, Dena Procaccini, Ananda L Roy, Ajay Pillai, Marishka Brown, Zorina S Galis
TL;DR
Comprehensive maps of cellular and molecular states across human tissues remain limited. HuBMAP proposes a multidisciplinary, spatially resolved single-cell atlas framework whose integrated multiomic compilation represents an important step toward comparing healthy and diseased tissues.
Problem
A comprehensive understanding of cellular and molecular states and interactive networks across human tissues and organs remains incomplete.
Method
HuBMAP combines multidisciplinary expertise to support technology development, data acquisition, and detailed spatial mapping at single-cell resolution.
Results
HuBMAP’s spatially resolved compilation of diverse multiomic information at single-cell level represents an important step toward a human cellular and molecular atlas.
Takeaways & Limitations
The resulting atlas framework may support comparative analyses of how cells and tissue structures vary across contexts.
Takeaways & Limitations
The program’s stated scope includes mapping the human body in health and various disease settings.
Abstract
from arXiv · showhide
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.
HuBMAP Integration, Visualization, and Engagement (HIVE) Collaboratory
The HIVE Collaboratory includes teams for tools, mapping, infrastructure, and collaboration, alongside the NIH HuBMAP Working Group. Participating institutions include Harvard Medical School, Indiana University Bloomington, University of Pittsburgh, and New York Genome Center.
- Tools Component: Harvard Medical School contributes the Tools Component through Nils Gehlenborg, Peter Kharchenko, Margaret Vella, and Chuck McCallum.
- Mapping Component: Indiana University Bloomington contributes the Mapping Component through Katy Börner, Leonard E. Cross, Samuel H. Friedman, Randy Heiland, Bruce Herr II, Paul Macklin, Ellen M. Quardokus, Lisel Record, James P. Sluka, and Griffin M. Weber.
- Infrastructure Component: The University of Pittsburgh contributes the Infrastructure Component through Nicholas A. Nystrom, Jonathan C. Silverstein, Philip D. Blood, Alexander J. Ropelewski, and William E. Shirey.
- Mapping Component: The New York Genome Center contributes the Mapping Component through Rahul Satija, John Marioni, Aviv Regev, Andrew Butler, Tim Stuart, Eyal Fisher, Shila Ghazanfar, Jennifer Rood, Leslie Gaffney, Gokcen Ersalan, and Tommaso Biancalani.
- NIH HuBMAP Working Group: The NIH HuBMAP Working Group includes Richard Conroy, Dena Procaccini, Ananda Roy, Ajay Pillai, Marishka Brown, Zorina Galis, Pothur Srinivas, Aaron Pawlyk, Salvatore Sechi, Elizabeth Wilder, and James Anderson.
Transformative technologies are enabling the construction of three dimensional (3D)
Transformative technologies are enabling 3D tissue maps with unprecedented spatial and molecular resolution. Over seven years, HuBMAP intends to develop a widely accessible framework for comprehensively mapping the human body at single-cell resolution through technology development and data acquisition.
- Transformative technologies enable 3D tissue maps with unprecedented spatial and molecular resolution.
- Over seven years, HuBMAP intends to develop a widely accessible framework for comprehensively mapping the human body at single-cell resolution.
- HuBMAP will support technology development and data acquisition to build this single-cell mapping framework.
detailed spatial mapping. HuBMAP will integrate its efforts with other funding agencies,
HuBMAP aims to advance a comprehensive, accessible 3D molecular and cellular atlas of the human body spanning health and various disease settings.
- HuBMAP’s vision is a comprehensive, accessible 3D molecular and cellular atlas of the human body.
- Together, these aims define an accessible atlas spanning molecular and cellular organization across human health and disease.
- The atlas is intended to represent the human body in health and various disease settings.
Introduction
Existing knowledge does not comprehensively explain the cellular and molecular states, interactions, and three-dimensional organization of human tissues and organs. HuBMAP aims to address this gap by developing open cellular-resolution mapping technologies and foundational tissue maps through spatially resolved, single-cell molecular mapping.
- Knowledge gap: Comprehensive understanding of cellular and molecular states, interactive tissue networks, and three-dimensional cell organization remains lacking.These features influence normal function, aging, tissue remodeling, and disease progression.
- Technological opportunity: New technologies now enable molecular characterization and spatial mapping of diverse cell types in complex tissues at unprecedented scale and single-cell resolution.These advances create an opportunity to build high-resolution three-dimensional maps of human tissues and organs.
- HuBMAP goals: HuBMAP seeks to develop an open framework and technologies for mapping the human body at cellular resolution and generate foundational maps from normal individuals across a wide age range.The program is NIH-sponsored and targets several tissues.
- Program scope: HuBMAP focuses on spatially resolved molecular maps at the single-cell level, using a more limited number of subjects than GTEx.GTEx examined DNA variants and bulk tissue expression patterns across approximately a thousand individuals.
- Collaboration: The HuBMAP Consortium will use openness and team science while collaborating with the Human Cell Atlas, Human Protein Atlas, LIfeTime, organ-specific consortia, and emerging programs.Named organ-focused initiatives include efforts involving brain, lungs, kidney, and genitourinary regions, alongside pre-cancer and tumor studies.
HuBMAP organization and approaches
HuBMAP brings together diverse biological, clinical, engineering, computational, and data-science expertise across three organizational components. Its program will expand tissue and technology coverage through synergistic funding opportunities, then use demonstration projects to engage researchers in analyzing HuBMAP data with other datasets.
- Consortium expertise: HuBMAP brings together expertise spanning molecular, cellular, developmental, computational, measurement, clinical, pathological, anatomical, engineering, and data-information sciences.The consortium includes molecular, cellular, developmental, and computational biologists; measurement experts; clinicians; pathologists; anatomists; biomedical and software engineers; and computer and data information scientists.
- Program organization: HuBMAP is organized into Tissue Mapping Centers, HuBMAP Integration, Visualization & Engagement, and Innovative Technologies Groups.The three components are Tissue Mapping Centers (TMCs), HuBMAP Integration, Visualization & Engagement (HIVE) collaborative components, and Innovative Technologies Groups (TTDs and RTIs).
- Program approaches: HuBMAP will expand the range of tissues and technologies studied through funding opportunities designed to work synergistically with other NIH and international efforts.The program will grow the tissues and technologies studied throughout its course using a series of funding opportunities.
- Program approaches: Later-stage demonstration projects will show the utility of HuBMAP resources and engage the wider research community in analyzing HuBMAP data with external or laboratory-generated data.Researchers will be encouraged to analyze HuBMAP data alongside data from other programs or their own labs.
Tissue and data generation
HuBMAP will collect diverse largely normal human tissues using protocols designed to preserve quality and enable open data sharing. Complementary single-cell profiling and multiplexed spatial imaging will generate integrated multi-omics maps of organs and cellular interactions.
- Tissue collection: TMCs will collect largely normal tissues across both sexes, different ethnicities, and ages spanning the adult lifespan, including organs, vasculature, and lymphatic organs.Collection will occur at precisely defined anatomical locations using established protocols that preserve tissue quality and minimize degradation.
- Data generation: A complementary two-step approach will combine massively parallel single-cell ‘omic assays with spatial measurements of RNA, proteins, metabolites, and lipids in tissue sections.Single-cell transcriptomic and chromatin-accessibility profiles will characterize molecular states and inform spatial assays.
- Spatial mapping: Imaging modalities including fluorescent microscopy, seqFISH, imaging mass spectrometry, and imaging mass cytometry will provide spatial information for up to hundreds of molecular targets.Computational registration will connect cell-specific epigenomic and transcriptomic profiles to cells on histologic slides and integrate information across imaging modes.
- Integration and quality: Single-cell profiling combined with multiplexed in situ imaging will support multi-omics spatial maps of human organs and their cellular interactions at molecular resolution.Benchmarking, QA/QC standards, SOPs, and standardized metadata annotations will promote rigor, reproducibility, and transparency.
Computational approaches for building an integrated tissue map across scales
HuBMAP will build computational infrastructure to integrate spatial and molecular data across scales and individuals into an accessible high-resolution 3D atlas. A common coordinate framework, interoperable portals, and extensible pipelines will support unified exploration, visualization, and comparative analysis.
- HuBMAP will develop analytical and visualization tools that bridge spatial and molecular relationships to generate an integrated, high-resolution 3D molecular atlas.These tools will collectively explore diverse anatomic, histologic, cellular, molecular, and genomic datasets.
- Open-source portals will use recognized standards and interoperability to support modular software, multi-platform access, and customized processing with other data sources.External developers will be able to apply code, applications, APIs, and data schemas to HuBMAP data.
- A common coordinate framework will define a 3D spatial representation and addressable scaffold for integrating HuBMAP data across individuals, technologies, labs, and scales.It will enable unified interactive exploration, visualization, and comparative analysis.
- HuBMAP will align and assemble an integrated reference using anatomical and tissue-organization landmarks, while also exploring ontology-based frameworks for multi-scale data.Medical imaging such as CT and MRI may support landmarking and construction of the common coordinate framework.
Technology development and implementation
HuBMAP will accelerate detailed tissue mapping by developing and multiplexing complementary technologies that improve molecular imaging across tissues. The program will also support new imaging methods and computational tools for integrating data across modalities.
- Technology development and implementation: No single technique currently fully addresses the challenge of quantitatively imaging diverse biomolecules in tissue with high spatial resolution, sensitivity, specificity, and throughput.Complementary capabilities therefore provide a promising approach for accelerating tissue mapping efforts.
- Technology development and implementation: HuBMAP Innovation Technologies groups will develop innovative approaches to address limitations of existing state-of-the-art techniques.The program will refine SABER, SeqFISH, and Lumiphore probes to improve multiplexing, sensitivity, and throughput for imaging RNA and proteins across multiple tissues.
- Technology development and implementation: New mass spectrometry imaging techniques will quantitatively map hundreds of lipids, metabolites, and proteins from the same tissue section with high spatial resolution and sensitivity.The program also has scope to develop and test new technologies.
- Technology development and implementation: Novel computational tools and machine learning algorithms will be optimized using pilot-phase data from a common tissue to integrate data across modalities.These computational efforts will benefit from the broader technology-development program.
Challenges
HuBMAP’s comprehensive, multimodal atlas introduces major challenges in tissue collection, biomolecule measurement, data integration, accessibility, and prioritization. Capturing rare cell types and structures will require adaptive power analyses using expanding datasets.
- Challenges: HuBMAP must optimize collection, preservation, and processing across diverse tissue types and multiple donors while generating high-resolution maps with varied assays.Previous programs such as GTEx5 have addressed some collection and processing challenges, but HuBMAP’s broader goals add complexity.
- Challenges: Sensitive, specific, and high-throughput assays are still lacking for some functionally important biomolecules, including ones not yet recognized.Developing these assays will require devoted attention.
- Challenges: Unprecedented dataset volume and diversity create challenges for comprehensive capture, management, mining, modelling, visualization, communication, and multimodal integration.Analysis and interactive visualization tools are needed to make the data and atlas widely accessible to the life-sciences community.
- Challenges: HuBMAP must prioritize tissues and technologies, sample across tissues and donors, synergize internationally, and determine sampling requirements for rare cell types and structures.Adaptive power analyses can leverage growing data from HuBMAP, other consortia, and individual groups.
Conclusions
HuBMAP aims to build a high-resolution, publicly accessible 3D atlas of key human organs that integrates spatially resolved single-cell multiomic data. The Consortium also seeks to develop analytical methods and a common coordinate framework enabling new views of tissues and future biomedical applications.
- Conclusions: HuBMAP will generate a high-resolution atlas of key normal human organs, capture inter-individual differences, and support contributions to tissue biology and cellular ecosystems.The Consortium will work closely with other initiatives and contribute to community efforts pursuing similar mapping goals.
- Conclusions: The Consortium emphasizes analytical methods for spatial molecular data and a common coordinate framework to integrate datasets.These efforts are intended to provide leadership in data analysis and integration across related initiatives.
- Conclusions: The project aims to establish a foundation for diagnostic interrogation, modeling, navigation, and targeted therapeutic interventions at unprecedented resolution.HuBMAP also seeks to catalyze new views of tissue organization, cellular expression patterns, phenotypes, and functional interactions.
- Conclusions: HuBMAP envisions an easily accessible public interface for visualizing single-cell molecular landscapes, pathways, networks, and spatial and temporal changes.Researchers will be able to browse, search, download, and analyze richly annotated datasets in standard formats.
- Conclusions: Spatially resolved single-cell multiomic information is envisioned as an important step toward advancing human biology and precision medicine.The data may redefine cell types and subtypes and their relationships within and between tissues beyond standard methods.
Figure Legends
HuBMAP will create an accessible, high-resolution 3D atlas linking specific histologic locations and individual cells to multiple molecular layers. It will combine reproducible specimen collection, imaging, omics, and mass spectrometry within a common coordinate framework.
- Atlas objective: HuBMAP aims to let users examine a specific histologic slide location and determine an individual cell’s genomic, epigenomic, transcriptomic, proteomic, and/or metabolomic contents.The atlas is designed to support multi-omic characterization at defined sites within organs.
- Atlas objective: Centers will apply imaging, omics, and mass spectrometry techniques to specimens collected reproducibly from specific sites in the body.These complementary measurements provide the inputs for spatial and molecular mapping.
- Map generation: Integrated data will produce a high-resolution, high-content 3D map for each tissue.The mapping process combines measurements across specimens and molecular modalities into a tissue-level representation.
- Map generation: A robust common coordinate framework will help prevent inter-individual differences from being confounded with collection heterogeneity.Standardized spatial coordinates are intended to support comparisons across collected specimens.