Multi-tissue cell atlases lead to leap of understanding of immunity and disease

The Human Cell Atlas goal of mapping every cell type in the human body to transform our knowledge of biology, infection and disease is a milestone step closer with four studies published in Science today (13th May).

Researchers with the international Human Cell Atlas (HCA) consortium have created highly detailed maps of more than a million individual cells across 33 organs and systems across the human body, giving new biological insights into human health and disease, including the immune system.

These complementary multi-tissue cell atlases will contribute towards a single Human Cell Atlas and have many therapeutic implications including informing our understanding of common and rare diseases, vaccine development, anti-tumour immunology and regenerative medicine.

Until now, the HCA has mostly focused on gaining a deep cellular understanding of individual organs, tissues or small subsets of tissues.  Now, four major collaborative studies by researchers at the Wellcome Sanger Institute, UK; the Broad Institute of MIT and Harvard, USA; The Chan Zuckerberg Biohub, USA; and their international collaborators, have developed methods and created the most comprehensive, cross-tissue atlases to date.

Openly available, the atlases allow researchers to compare specific cell types across the body in fine detail, revealing novel cell functions and shedding light on health and disease. 

Deep dive into the immune system across tissues

Historically our understanding of the human immune system has been mainly limited to the role of cells circulating in blood, however immune cells within tissues play a key role in maintaining health and combating infection. In one of the Science papers^§, researchers from the Wellcome Sanger Institute, the University of Cambridge and their collaborators sequenced RNA from 330,000 single immune cells from across the adult body to understand the function of immune cells in different tissues.

After creating a curated catalogue of immune cells within the human body, the team developed a machine-learning tool – CellTypist - to automate cell type identification. Using this tool, they identified about a hundred distinct types of immune cells, including specific macrophages, T cells and B cells and their distribution across different tissues.

Dr Sarah Teichmann, Co-Chair of the Human Cell Atlas Organising Committee, Head of Cellular Genetics at the Wellcome Sanger Institute, and a senior author on the paper, said: “A detailed understanding of cells through the Human Cell Atlas will help explain many aspects of human health and disease. By comparing particular immune cells in multiple tissues from the same donors we identified different flavours of memory T cells in different areas of the body, which could have great implications in managing infections. Our openly available data will contribute to the Human Cell Atlas and could serve as a framework for designing vaccines, or to improve the design of immune therapies to attack cancers.”

A second study^§§ from the Sanger Institute, the University of Cambridge and their collaborators appears online in Science today, which created a comprehensive atlas of the developing human immune system across organs, revealing tissues involved in the formation of blood and immune cells and enhancing our understanding of immune disorders. It also reveals cell types that are lost as we grow up, to inform in-vitro cell engineering and regenerative medicine research.

An atlas from frozen tissues sheds light on rare and common disease genes    

One of the promises of single cell atlases is to help map the specific cell types in which disease genes – from those causing rare diseases like muscular dystrophy or contributing to the risk of common diseases like heart disease – act across the human body. It needs all cell types to be profiled, including cells from skeletal muscle, fat cells and neurons which are hard to capture. Cells from larger numbers of individuals are also vital, requiring scientists to collect and freeze tissues before analysis.

In one of the new papers in Science*, researchers from the Broad Institute and their collaborators reveal how they optimised single-nucleus RNA sequencing to overcome the challenge of using frozen cells, and then created a cross-tissue atlas to analyse 200,000 cells from multiple banked frozen tissues focusing on rare and common disease genes. Using novel machine learning algorithms, the team then systematically associated the cells in the atlas with 6,000 single-gene diseases and 2,000 complex genetic diseases and traits to identify cell types and gene programs that could be involved in disease, revealing multiple novel starting points for new studies into health and disease.

Dr Aviv Regev, Co-Chair of the Human Cell Atlas and Faculty on Leave from the Broad Institute and MIT, who is now Head of Genentech Research and Early Development, and a senior author on the paper, said: “Our single-nucleus Human Cell Atlas study demonstrates a powerful large-scale way to analyse cells from frozen tissue samples across the body with deep-learning computational advances, and opens the way to studies of tissues from entire patient cohorts at the single cell level. We were able to create a new roadmap for multiple diseases, by directly relating cells to human disease biology and disease-risk genes across tissues.  We anticipate this work will lead to many new studies and enable the ongoing efforts of the human cell atlas to build a reference map of all human cells.”
 

The Tabula Sapiens: broad cross-tissue cell atlas

The final paper in this set describes a very large cross-tissue study** by researchers from the Chan Zuckerberg Biohub and their collaborators. The team used single cell RNA sequencing of live cells to analyse many organs from the same donor, which enabled cross-tissue comparisons controlled for genetic background, age and environmental effects. The collection of nearly half a million cells provides a uniquely broad cross-tissue atlas from live cells, and has created a data set the researchers call ‘The Tabula Sapiens’.

The Tabula Sapiens data allowed detailed characterisation of more than 400 specific cell types, their distribution and variation in gene expression across the tissues. In addition, by analysing live cells, their data also enabled the first large-scale analysis of alternative gene splicing in a single cell atlas. The study provides researchers with a huge research resource of human expert annotated cell types which will give major new insights into fundamental biology and disease.

Professor Stephen Quake, President of the CZ Biohub Network, and Lee Otterson Professor of Bioengineering and Professor of Applied Physics at Stanford University, and a senior author on the paper, said: "The Tabula Sapiens is a reference atlas that provides a molecular definition of hundreds of cell types across 24 organs in the human body. It represents the efforts of more than 150 authors across several institutions; the scientific community will be discovering new insights into human biology from this resource for many years to come."

HCA cross-tissue data and tools are openly available

The HCA is an international collaborative consortium that charts the cell types in the healthy body, providing an unprecedented resource for studying health and disease. An open, cutting-edge, scientist-led consortium, HCA is a collaborative effort of researchers, institutes, and funders worldwide, with more than 2,300 members from 83 countries across the globe. 

With commitments to open access, ethics and global equity, HCA data is openly available to benefit people everywhere. The data from these and other studies are freely available on the HCA Data Portals, which researchers worldwide can access through the HCA Data Coordination Platform as well as through the Cambridge Cell Atlas, the Broad Single Cell Portal, and the UCSC Cell Browser.

Professor Sten Linnarsson, from Karolinska Institutet in Sweden, and a member of the HCA Organizing Committee, said: “The Human Cell Atlas is transforming our understanding of biology and disease. These cross-tissue studies represent a milestone for the HCA and single cell biology by enabling systematic, in-depth comparison of the same cell types across development and adulthood. They are a great step forwards to generating a Human Cell Atlas of all cell types in the human body, laying a foundation for a new era of diagnosis, healthcare and precision medicine.”

ENDS

Notes to editors:

The Human Cell Atlas (HCA)

The Human Cell Atlas (HCA) is an international collaborative consortium which is creating comprehensive reference maps of all human cells—the fundamental units of life—as a basis for understanding human health and for diagnosing, monitoring, and treating disease. The HCA is likely to impact every aspect of biology and medicine, propelling translational discoveries and applications and ultimately leading to a new era of precision medicine.

The HCA was co-founded in 2016 by Dr Sarah Teichmann at the Wellcome Sanger Institute (UK) and Dr Aviv Regev, then at the Broad Institute of MIT and Harvard (USA). A truly global initiative, there are now more than 2,300 HCA members, from 83 countries around the world. https://www.humancellatlas.org
 

Publications:

^§ C. Domínguez Conde, C Xu, LB Jarvis, DB Rainbow, SB Wells et al. ‘Cross-tissue immune cell analysis reveals tissue-specific adaptations and clonal architecture in humans.’ (2022) Science. DOI: 10.1126/science.abl5197

^§§ Chenqu Suo and Emma Dann et al. ‘Mapping the developing human immune system across organs’ (2022) Science. DOI: 10.1126/10.1126/science.abo0510

* Gokcen Eraslan and Eugene Drokhlyansky et al. ‘Single-nucleus cross-tissue molecular reference maps towards understanding disease gene function.’ (2022) Science. DOI: 10.1126/science.abl4290

** The Tabula Sapiens Consortium. ‘The Tabula Sapiens: a multiple organ single cell transcriptomic atlas of humans.’  (2022) Science. DOI: 10.1126/science.abl4896
 

Funding:
Funders for the papers included the Chan Zuckerberg Initiative, Wellcome, U.S. National Institutes of Health, European Research Council, the Manton Foundation, Klarman Family Foundation and HHMI. Please see the papers for full funding information.

Data portals: 
Annotated data from these studies can be accessed and visualised on the HCA Data Portals including Cambridge Cell Atlas, Broad Single Cell Portal, Tabula Sapiens, UCSC Portal, Developmental Cell Atlas, and on the Genotype Tissue Expression Project Portal.

The HCA has also built a Data Coordination Platform (DCP), which is a cloud-based platform where scientists from around the world can share, organise and access single-cell data from the HCA.

Tools:
CellTypist is publicly available, with user-friendly documentation for automatically annotating immune cells in single cell transcriptomics datasets.

cellxgene enables scientists to annotate, publish, find, download, explore and analyze single cell datasets.

Selected websites:

The Wellcome Sanger Institute
The Wellcome Sanger Institute is a world leading genomics research centre. We undertake large-scale research that forms the foundations of knowledge in biology and medicine. We are open and collaborative; our data, results, tools and technologies are shared across the globe to advance science. Our ambition is vast – we take on projects that are not possible anywhere else. We use the power of genome sequencing to understand and harness the information in DNA. Funded by Wellcome, we have the freedom and support to push the boundaries of genomics. Our findings are used to improve health and to understand life on Earth. Find out more at www.sanger.ac.uk or follow us on Twitter, Facebook, LinkedIn and on our Blog.

About Broad Institute of MIT and Harvard
Broad Institute of MIT and Harvard was launched in 2004 to empower this generation of creative scientists to transform medicine. The Broad Institute seeks to describe the molecular components of life and their connections; discover the molecular basis of major human diseases; develop effective new approaches to diagnostics and therapeutics; and disseminate discoveries, tools, methods and data openly to the entire scientific community.
Founded by MIT, Harvard, Harvard-affiliated hospitals, and the visionary Los Angeles philanthropists Eli and Edythe L. Broad, the Broad Institute includes faculty, professional staff and students from throughout the MIT and Harvard biomedical research communities and beyond, with collaborations spanning over a hundred private and public institutions in more than 40 countries worldwide.

About Chan Zuckerberg Biohub 
The Chan Zuckerberg Biohub is a nonprofit research center that brings together physicians, scientists, and engineers from Stanford University; the University of California, Berkeley; and the University of California, San Francisco. Working at CZ Biohub are some of the brightest, boldest engineers, data scientists, and biomedical researchers, who together with our partner universities seek to understand the fundamental mechanisms underlying disease and develop new technologies that will lead to actionable diagnostics and effective therapies. For more information, please visit czbiohub.org.

About the Chan Zuckerberg Initiative
The Chan Zuckerberg Initiative was founded in 2015 to help solve some of society’s toughest challenges — from eradicating disease and improving education, to addressing the needs of our local communities. Our mission is to build a more inclusive, just, and healthy future for everyone. For more information, please visit chanzuckerberg.com.

About Wellcome
Wellcome supports science to solve the urgent health challenges facing everyone. We support discovery research into life, health and wellbeing, and we’re taking on three worldwide health challenges: mental health, global heating and infectious diseases. https://wellcome.org/