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The State Of: The Human Cell Atlas Initiative

Announced in 2016, the Human Cell Atlas initiative aims to characterise all cell types in the human body. Led by Aviv Regev and Sarah Teichmann, the project comprises hundreds of researchers from all over the world.

Using genomics, proteomics, transcriptomics, metabolomics and more, the initiative aims to provide a thorough atlas of every human cell, from skin to blood to brain. In this feature, we look at the past, present and future of the project, so that you can get a comprehensive overview of the research landscape.

The past

Following the completion of the Human Genome Project in the early 2000s, the potential of genomics, and other biological research fields, massively expanded. With continued growth over the years and the advent of technologies such as single-cell sequencing and spatial transcriptomics, alongside powerful new computational and lab-based methodologies, what was once only a dream began to become reality.

The Human Cell Atlas initiative was first proposed by a group of scientists spearheaded by Aviv Regev and Sarah Teichmann in 2016, aiming to characterise every cell type in the human body to understand disease, development and evolution thanks to the growth of various omics technologies. The initiative is described by some as a ‘periodic table’ of human cells. The project was launched in 2017 at a convention held in Israel and the consortium initially involved over 130 scientists from across the globe. The project took advantage of the swathes of new technology that had been, and continued to be, developed during the 2010s.  Many scientists involved in the project also worked to develop their own tools to characterise cells, making these available to other researchers in order to speed up the process. A significant aspect of the project is ensuring safe and efficient data sharing and standardisation techniques in order to enhance the abilities of collaborators.

Over the last six years, a variety of omics technologies have been used to characterise millions of cells and, by 2018, the number of researchers involved in the project had more than tripled. Some of the first publications linked to the project involved a deep dive into the molecular architecture of the mouse nervous system, single-cell RNA sequencing of the human liver and the characterisation of plasma cell heterogeneity in myeloma patients. Significant research has also gone into characterising the cells of the human lung and the consequences of disease on these cells. Researchers have also gained a comprehensive understanding of fetal development.

The Present

There have been over 150 publications associated with the Human Cell Atlas initiative, which have come in quick succession over the last six years. Below, we describe some of the biggest stories from the last 12 months.

Single-nucleotide variant calling in single-cell sequencing data with Monopogen: One of the latest peer-reviewed papers linked to the Human Cell Atlas, this publication describes the development of a computational tool, Monopogen, that detects single-nucleotide variants in single-cell data to better understand how transcriptional and epigenetic characteristics rely on the cell’s genetic background (Dou et al., 2023).

An integrated atlas of the lung in health and disease: This study from June 2023 describes the development of a single-cell atlas describing the cells of the human lung. It consists of over 2.4 million cells from approximately 480 donors. It is an excellent example of data integration, merging cells from 49 different datasets (Sikkema et al., 2023).

A spatially resolved single-cell genomic atlas of the adult human breast: Using single-cell and spatial technologies, researchers developed an atlas of the adult human breast, profiling over 700,000 cells and charactering major cell types and over 50 biological cell states. The work will contribute to breast cancer research but will also aid in furthering our understanding of processes such as lactation (Kumar et al., 2023).

An atlas of healthy and injured cell states and niches in the human kidney: Single-cell and single-nucleus assays were used in this study to define the cell types and states of healthy and diseased kidneys, in order to assist our understanding of kidney disease and the molecular mechanisms at play (Lake et al., 2023).

A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates: Published in December 2022, this paper describes the development of a fetal lung cell atlas that identified 144 cell types, including previously uncharacterized progenitor cell states, transition populations and a neuroendocrine cell subtype that could be linked to the development of human small-cell lung cancer (He et al., 2022).

Spatial multiomics map of trophoblast development in early pregnancy: This study used a spatial multiomics approach to map trophoblast development and differentiation in early pregnancy, defects in which can lead to dangerous health conditions such as pre-eclampsia and even miscarriage (Arutyunyan et al., 2023).

Dandelion uses the single-cell adaptive immune receptor repertoire to explore lymphocyte developmental origins: This publication from April 2023 details the development of Dandelion, a computational pipeline for single-cell adaptive immune receptor sequencing (scVDJ-seq) to map immune cell development. The work facilitates better understanding of the origins of immune cells and the impacts of disease (Suo et al., 2023).

Single-cell atlas of common variable immunodeficiency shows germinal center-associated epigenetic dysregulation in B-cell responses: This paper adds an epigenetic component to the single-cell mapping of naïve to mature B cells in common variable immunodeficiency in a pair of monozygotic twins (Rodríguez-Ubreva et al., 2022).

In the spotlight:

Below, we take a look at some crucial recent research that is deserving of being in the spotlight.

Yolk sac cell atlas reveals multiorgan functions during human early development” – Goh et al., 2023.

In this study, researchers profiled the yolk sac, a structure crucial for embryonic development that assists in a number of critical processes and provides sustenance to the developing fetus. The human yolk sac has been historically understudied, but advances in single-cell sequencing technologies have made it possible to assess the yolk sac in unprecedented detail.

Using a combination of scRNA-seq, CITE-seq and imaging methods like light-sheet microscopy, the team developed an atlas of yolk sac cells derived from 10 samples from 4-8 weeks of conception. They uncovered previously unknown details about how the yolk sac performs its vital functions and highlighted different cellular differentiation pathways after conception. They revealed that the yolk sac initially plays the role of various different organs before they have a chance to develop, acting as an ‘extraembryonic organ’ in its own right.

Figure 1: Graphical abstract detailing the study methodology and results. Taken from Goh et al., 2023.

The future

The Human Cell Atlas initiative has recently surpassed the milestone of having over 3,000 members, highlighting the growing interest, and need, for accessible large-scale databases in this field. With so many cell types and states remaining unknown and unexplored, there is much to still be done.

The individual atlases described as part of the overarching initiative each serve their own purpose for furthering our understanding of human health. For example, the adult breast atlas will provide valuable insights into cancer whilst maps of immune cells will allow us better insights into immune disorders, allergies, wound healing and much more. Beyond this, the atlases will provide invaluable insight into human evolution.

The leaders of the initiative recognise that there are still challenges associated with the project. For example, in ensuring benefits for all, scientists must not only profile healthy cells but also diseased cells. With so many diseases leading to distinct cell states, this remains a significant challenge. Thankfully, vast efforts are being made to address the need for more efficient technology and processes to make this dream a reality. Data-sharing legislation also has to address the need for more efficient and secure open access databases.

Ultimately, the project has already led to the development of significant new technologies that, in turn, further the progression of the initiative. This has already proved invaluable in the research of diseases such as COVID-19. There is no doubt that the continuation of the project will see more diseases addressed in time, with novel treatments stemming from the work of the thousands of scientists involved.

Want to read more about the Human Cell Atlas initiative’s goals? Check out this recent article that describes the vision for the future of the project, and details successes and upcoming challenges. Additionally, see this video for a comprehensive overview of the current state of the project presented by Aviv Regev at the recent Human Cell Atlas General Meeting.