Enabled by Single-Cell Genomics, International Team Launches Human Cell Atlas Initiative

GenomeWeb - A new effort has laid the framework for creating an atlas of all human cell types, using single-cell genomics approaches to produce 3D maps of how different cells function together, and how changes in these networks can lead to disease.

The project, called the Human Cell Atlas Initiative, held its first meeting earlier this month in London, and was convened by researchers from the Broad Institute and the Wellcome Trust Sanger Institute. As a result of the meeting, which was attended by roughly 100 scientists, the initiative has formulated a vision for the HCA, available on its new website, as well as outlined a series of pilot projects that could lead to the generation of a full atlas.

At the core of the effort are various single-cell genomics approaches, which should produce information that could ultimately be used to diagnose, monitor, and treat disease, according to Mike Stubbington, principal staff scientist at the Sanger Institute.

The "driving motivations behind the HCA have been important for a long time but, until recently, the technology hasn't been available to sequence the genomes from individual cells," Stubbington told GenomeWeb. "Now, advances in single-cell genomic analysis of cells and tissues have made this possible."

The amount of funding it will take to complete the atlas is unclear, according to Stubbington, and its completion is about a decade off, he predicted. "It will have significant costs and will need a range of funding from governments, charities, and research organizations," said Stubbington. "We hope to have useful data from pilot projects within the next couple of years," he added.

Stubbington said the creation of such an atlas would have "immediate, tangible, and transformative benefits" for research. It could provide a reference map for comparing related cells, identifying new cell types, interpreting genetic variants, distinguishing disease from healthy states, defining markers and signatures for pathology, and sorting cells, he said.

The HCA could also serve to redefine cell types, states, and transitions, provide a direct view of human biology in vivo, identify the regulatory codes that control cell differentiation and cell-cell interactions, as well as drive the creation of new technologies, he said.

"A human cell atlas would likely impact almost every aspect of biology and medicine, leading to a richer understanding of life's most fundamental units and principles," Stubbington noted.

Aviv Regev, a core member of the Broad and an associate professor of biology at the Massachusetts Institute of Technology, told GenomeWeb that the HCA has been in discussion for years, though the recent meeting was the first time that scientists from various backgrounds, including genomics, biology, informatics, and technology development sat down to set plans for fulfilling that vision.  

"The need for a human cell atlas is very clear," said Regev. "We cannot deeply understand how biology works without a more detailed understanding of its most basic functional units," she said. "We don't even know how many cell types there are in the human body, much less what they all do and how their activities influence health and disease."

According to Stubbington, single-cell genomics will be "crucial" in enabling the HCA Initiative.

"We could not achieve this without single-cell approaches," he said. In terms of data types, he said the initiative will at first generate a "comprehensive set of single-cell transcriptomic data." The initiative will also seek to analyze gene expression within the spatial context of tissues and combine the resulting data with the gene expression analyses from disaggregated cells.

"We will also explore single-cell epigenomic analyses along with methods that detect expression at the level of proteins instead of RNA," said Stubbington.

Regev agreed that single-cell RNA sequencing will "obviously play a major role," in the project but suggested that other technologies, including mass cytometry, single-cell epigenomics, and multiplexed error-robust fluorescence in situ hybridization (MERFISH), a single-cell imaging approach, are also being discussed within the initiative.

Sten Linnarsson, a professor of molecular systems biology at the Karolinska Institute in Sweden, who took part in the discussions earlier this month, said that single-cell RNA sequencing will likely be the "workhorse of the project, because it is the most mature and scalable technology for cell-type discovery."

Spatial methods such as RNA FISH, MERFISH, in situ sequencing, or microarray-based spatial transcriptomics could prove to be complementary platforms as the atlas is assembled, helping to define every cell type and place them in space and time, Linnarsson told GenomeWeb. To learn more about the function and regulation of cell types, Linnarsson said that his group will study chromatin, methylation, protein expression, and electrophysiology in more focused experiments.

Piero Carninci, director of the division of genomic technologies at the Riken Center for Life Science Technologies in Japan, who also took part in the first HCA meeting, said that his group will likely use its in house-developed cap analysis of gene expression (CAGE) technology as part of the project. Carninci and colleagues developed CAGE in the 1990s and have applied it to next-generation sequencing platforms sold by Illumina and others to identify various promoters, enhancers, and long non-coding RNAs.

"Accordingly, also in the HCA initiative, we will identify these elements at the single-cell level to pave the way to understand transcriptional regulation at the single-cell level for all cell types and states," Carninci told GenomeWeb. "Being in Japan, we will also ensure that samples with Asian genetic backgrounds will also be included, which ... influence gene expression," he added.

Pilot projects

According to Regev, the HCA Initiative has outlined four areas of focus for potential pilot projects that could not only reveal interesting biology, but inform future strategies for a full-scale cell atlas effort. The projects should also encourage the formation of international networks. Areas of interest include the immune system, the brain and central nervous system, epithelial tissue, and cancer.

"We expect these pilots will teach us a great deal about how to expand to a full-scale atlas over the next decade," said Regev.

On its website, the HCA Initiative said it intends to work with the Immunological Genome Project, an international effort that has analyzed gene expression and its regulation across the immune system of the mouse, to extend its methods to the human immune system at a extreme level of resolution" using single-cell profiling to ultimately "resolve the hundreds of finely differentiated cell types that compose all facets of the immune system, and the genomic signatures that define them."

In terms of the brain and nervous system, the initiative will reach out to the Allen Brain Atlas as well as the US National Institute of Health's BRAIN Initiative in order to catalog cell types and subtypes of the human brain and nervous system. They noted that the BRAIN Initiative has supported projects to characterize brain cells using single-cell genomics, and that they also aim to use such methods to study epithelial tissue in a third pilot project.

Linnarsson said that his team at Karolinska aims to work on the nervous system pilot project, and is particularly interested in development, or embryogenesis. "We are also ready to serve as a large-scale data production center, but the exact roles of participants remain to be defined," he added.

Cancer is the fourth pilot project for the HCA Initiative. On the website, the researchers noted that current methods of analyzing cancer genomes are based on analysis of large populations of cells, and provide an averaged view of the tumor's profile. They believe that single-cell profiling approaches, such as single-cell RNA sequencing could potentially "unlock the interactions between different types of cells in tumors and monitor how these interactions change over time."

According to Stubbington, these projects will be managed by research partners worldwide. They should also result in a white paper detailing steps to create a full Human Cell Atlas, he noted.

Image citation: Nissim Benvenisty / Vojtech.dostal, CC BY 2.5

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