NEW YORK – Members of the Human Cell Atlas (HCA) consortium have released dozens of new papers en route to their goal of producing a first draft of the cellular components, interactions, and dynamics found across 18 biological systems — from tissues and organ systems to organoid models — in the coming years.
"The Human Cell Atlas is a reference for all studies of human biology and disease and serves as a reference for organoid and in vitro systems and model organ systems," HCA Cofounder Sarah Teichmann, a researcher with the Cambridge Stem Cell Institute at the University of Cambridge who was previously affiliated with the Wellcome Sanger Institute, said in an online press briefing on Tuesday.
"In addition to advancing scientific understanding, it's equipping health professionals, drug developers, and others with high-resolution knowledge of the human body as a reference for how it's perturbed in disease," she explained.
Adding to the suite of studies that have emerged from the HCA consortium since it launched in 2016, the new collection of papers — published in Nature and other Nature family journals on Wednesday — represents work from HCA teams around the world. The studies are focused on everything from human tissue development to large-scale data integration within specific systems to ethics and equity to the computational tools that are being developed to bring together a range of data types.
"This collection represents just a fraction of the accomplishments of the consortium in its first seven years," Teichmann said, noting that the work "demonstrates the many experimental and computational advances that will provide the foundation for the first draft of the Human Cell Atlas" and represents "a major milestone that marks a great leap in our understanding of the human body."
The scientist-led HCA consortium currently includes more than 3,500 members from more than 100 countries, Genentech researcher and HCA consortium co-chair Aviv Regev added, noting that it has placed an emphasis on genetic and geographic diversity.
"The collection of papers that is released this week demonstrates both the value of the approach and the feasibility of meeting our ultimate goal of a full atlas," Regev told reporters on Tuesday. "But it is not yet the full atlas. It is not even the full first draft. It's a crucial component of that first draft."
For her part, HCA consortium member Alexandra-Chloe Villani, a researcher at the Broad Institute, Harvard Medical School, and Massachusetts General Hospital, discussed the need for analytical methods to make sense of the vast amounts of data. "Building the Human Cell Atlas resource requires developing the computational tools and methods that are needed to use the atlas in a coherent and consistent way," she said.
So far, data for roughly 100 million cells from more than 10,000 individuals have been assessed, she noted, and the cell atlas collections are expected to eventually encompass globally representative samples made up of billions of cells.
The latest studies provide additional resolution for the 18 biological systems being analyzed through the HCA. Last month, European investigators working within the HCA published a Nature paper focused on cell types involved in skin formation and wound healing during human development, for example, while a set of studies published in Science in 2023 revealed cellular features found in the human brain. Still other published work from HCA members have explored human skeletal muscle, blood and immune system development, and inflammatory skin conditions.
In one of the new papers published in Nature on Wednesday, Teichmann and co-senior author Rasa Elmentaite led an international team that brought together 25 single-cell RNA sequencing datasets spanning some 1.6 million cells from 385 human gastrointestinal samples to explore gastrointestinal tract development and inflammatory gut conditions such as ulcerative colitis, Crohn's disease, celiac disease, and gastrointestinal cancer.
"Overall, we describe inflammation-induced changes in stem cells that alter mucosal tissue architecture and promote further inflammation," the authors reported, "a concept applicable to other tissues and diseases."
With the single-cell gene expression and spatial data compiled in the Gut Cell Atlas, the team was able to characterize the cell types found in the gastrointestinal tract under normal or disease conditions, unearthing an inflammatory role for metaplastic cells previously implicated in stomach lining healing in IBD-affected individuals.
"As the integrated atlas contains such a large amount of data, from people with and without gut conditions, we were able to uncover a pathogenic cell type that may play a role in some chronic conditions and could be a target for intervention in the future," Elmentaite, a researcher at Ensocell Therapeutics who was formerly based at the Wellcome Sanger Institute, said in a statement.
Because it included samples from embryonic, fetal, or preterm donors, the gastrointestinal tract study made it possible to delve into processes related to human development — a theme that HCA investigators also explored in a single-cell, spatial transcriptomic study of the human thymus and in multiomic analyses of cells involved in placental development during pregnancy and skeletal development in human embryos.
"Understanding human development is going to be very important to understanding developmental disorders, which begin early in life, and also … infant and childhood diseases that also have an origin from prenatal stages," coauthor Muzlifah Haniffa, an HCA consortium researcher affiliated with the Wellcome Sanger Institute, Newcastle University, and the Newcastle Hospitals NHS Foundation Trust, said during the press briefing.
"What we've discovered from studies of the human cell atlas [is that] some of these developmental programs are also relevant and co-opted in adult-onset diseases, both inflammation and cancer," she added, noting that "really understanding the cellular and molecular regulators of this is going to have a huge impact in terms of diagnostics, in terms of management of those patients, and also new therapeutic strategies."
In an effort to optimize accurate model systems to study human brain development and other processes, meanwhile, investigators from Switzerland, Germany, and the US analyzed 1.8 million cells from the human neural organoid cell atlas (HNOCA), produced in vitro from pluripotent stem cell using 26 distinct protocols at 15 labs around the world.
By comparing single-cell transcript profiles from the organoid cells to data on developing brain cells, the team not only got a look at the cell types represented by the organoid collection but also explored variation linked to the organoid production protocols used.
"The human neural organoid cell atlas will be useful to assess organoid fidelity, characterize perturbed and disease states, and facilitate protocol development," the study authors explained, noting that their current results suggest that "the atlas can be used as a diverse control cohort to annotate and compare organoid models of neural disease, identifying genes and pathways that may underlie pathological mechanisms with the neural models."
Other HCA consortium members shared their views on ethical considerations related to the large-scale effort, including a team from McGill University and centers in Spain, the US, Argentina, and Japan that penned a perspectives paper in Nature Communications on the ethics of data sharing within HCA. Meanwhile, yet other researchers discussed computational tools being used in the HCA effort — from cell type-labeling tools to AI and machine-learning methods.
In the latter paper, Teichmann, Regev, and their coauthors discussed computational methods being used to integrate data from HCA, while highlighting current and future applications of the cross-system cell atlas collections.
"We are well on our way to developing an atlas, and this atlas will have really far-reaching implications for how we diagnose disease, how we discover and develop new medicines, and also how we deliver these medicines with precision to patients," Regev told reporters.
In addition, she noted that the HCA's focus on data sharing and open access has bolstered the development of artificial intelligence and other computational tools needed to create foundational models for understanding cells in the human body — from relationships between cells in a given system to their functional behavior over space and time and in response to various perturbations related to the presence of genetic mutations, environmental effects, or disease states.
"Several more [atlases] are expected within the next two years," Regev said, adding that the first draft of the full HCA is expected in 2026, with subsequent work anticipated to continue fleshing out the effort.