NEW YORK (GenomeWeb) – The Human Cell Atlas Consortium continues to move forward with its plans to create a comprehensive reference map of all human cells. Such an atlas could help investigators understand how genetic variants impact disease risk, define drug toxicities, improve therapies, and advance regenerative medicine.
The consortium recently outlined its strategy for creating the atlas in a white paper as well as a commentary in Nature. Both discuss the aims and structure of the initiative, which includes hundreds of participants and is led by an organizing committee of 27 scientists from 10 countries.
The project also said it will next month release single-cell RNA expression profiles of a million immune cells collected from the bone marrow and cord blood of healthy human donors, the first installment of what it hopes will be a catalog of up to 100 million cells representing multiple tissues and organs that will comprise the atlas's first draft.
The data release and publication of the white paper coincided with the initiative's annual meeting, which was held this month at the Weizmann Institute of Science in Rehovot, Israel.
"The white paper is crucial for sharing our plans with all scientific participants and funding partners and enables us to move to the next stage of starting to create a draft atlas of human cells," said Sarah Teichmann, head of cellular genetics at the Wellcome Trust Sanger Institute and a co-chair of the effort.
Aviv Regev, a core member of the Broad Institute of MIT and Harvard and co-chair of the consortium, said that the initiative has made progress since its first meeting in London last year, with follow-on events subsequently held at the Karolinska Institute in Sweden and Stanford University.
According to Regev, the project has since its launch brought on a number of financial backers and built an "enthusiastic and open community" around its aim of generating a reference catalog of all human cells, including their proportions, locations, and how they interact.
"The project will help propel translational discoveries and applications and could transform basic biological research and clinical practice," said Regev.
According to Regev, the consortium will initially set out to study and map between 30 million and 100 million cells from tissues and organs of choice. Single-cell RNA sequencing will be the main platform used in the project, while the initiative will rely on other technologies to characterize molecules, as well as spatial methods to map cell locations and interactions.
The "complex" workflow is laid out in depth in the HCA consortium's 107-page white paper, Regev noted. After tissue acquisition and processing, samples will be characterized through a "spatial branch" focused on cell mapping, as well as a "cellular branch" for characterizing the molecular fingerprint of single cells or nuclei, she said. The data will then be integrated computationally and made accessible via the group's data coordination platform.
"Our key principle has been to find ways to effectively handle a few key tradeoffs: between depth and cell numbers for the cellular branch, between genomic scale and spatial resolution for the spatial branch, between availability of tissues from healthy individuals versus from the entire body … and so on," said Regev. "We combine these by using samples from specimens in several modalities, and by iterating with a computational power analysis as we go from one set of methods to another."
Teichmann said the consortium aims to carry out this primary phase of the project based on this approach within the next five years. She noted that all the data from the first draft of the HCA will be released soon after it has been collected, meaning that researchers will not have to wait until the first draft of the HCA is published five years from now to access and use it.
However, even the completion of the first draft will just be a step towards fulfilling the vision of consortium members. Given the "ambition and scale" of the HCA, it is incumbent that it be built in stages, Teichmann said, increasing in "size, breadth, and resolution as technologies develop and understanding increases."
Ultimately, Teichmann said, the HCA would like to profile about 10 billion cells across all tissues, organs, and systems, from both healthy tissues as well as those affected by various diseases.
The initiative would also like to collect samples from various locations and age groups, to make the atlas as diverse as possible, she said, resulting in a reference that could be used for "comparison and … insight across disease areas, genetic diversity, environments, and ages."
Obtaining samples from diverse sources is certainly a priority for the project. Piero Carninci, deputy director of the Riken Center for Life Science Technologies in Yokohama, Japan, said that the institute and consortium member has been supporting the HCA there, working to both "create a broad consensus within the local community and involve local funding agencies."
"It is very important that the HCA will include many countries to collect a large variety of cells from different genetic backgrounds," Carninci noted.
Carninci added that Riken is also liaising with scientists in other Asian countries, including counterparts in India, Korea, and Singapore, and has organized HCA Diversity Meeting Series: Asia, which will take place in Okinawa at the end of November to discuss regional coordination.
According to Regev, the HCA is being funded through a variety of channels. The Chan-Zuckerberg Initiative has already decided to back the project, lending its support to the development of the data coordination platform, as well as some pilot projects. The US National Institutes of Health is another source of financing. According to the consortium, the NIH has awarded $200 million to HCA-related projects in the past two years. Other backers named so far include the Wellcome Trust, the Helmsley Charitable Trust, the Manton Foundation, and the Kavli Foundation.
"Leading participants of each country will have to identify their own funding," noted Carninci. "Additionally, local funding will ensure broad participation, development of technologies, and expertise," he said. "This is essential for the progress of the field globally."
'Powerful new microscope'
Technology development is a centerpiece of the HCA, with the availability of cost-effective single-cell RNA sequencing widely seen as one of the catalysts for the effort.
"Single-cell genomics represents one of the most powerful new microscope technologies ever developed," said Gary Bader, a computational biologist at the University of Toronto and a member of the consortium's organizing committee. "Using it, we can identify new cell types and dynamic states, and this can transform our understanding of how tissues work," he said.
The collective use of new technologies by the consortium should yield results, Bader noted, in the form of new cell maps for healthy and disease states. "Even the most preliminary glimpse of the human liver at single-cell genomic resolution has changed our view of how it works," noted Bader, signaling that there is a "vast potential for new discoveries."
To encourage the use of innovative technologies in the project, the consortium's white paper calls for the establishment of a technical forum devoted to developing new platforms and comparing existing ones. Bioinformatics is another component, as HCA members better coordinate how to upload, share, and analyze project data. The HCA also envisions an "analysis garden" where computational biologists can hone data mining and interpretation techniques.
All of this work should benefit the field of cell biology, according to organizers.
"We will see a larger number of technologies entering the field to broadly understand not only gene expression but chromatin, genome sequence, proteins, and most importantly, to put this in a 3D organization and later to understand how organs function," said Carninci, adding that some of his personal interests include the transcription of non-coding RNAs, including chromatin-bound RNAs.
The widespread adoption of these new approaches will also lead to their refinement and standardization, noted Orit Rozenblatt-Rosen, scientific director of the Klarman Cell Observatory and the lead scientist at the Broad for the HCA initiative.
"The [HCA] will need methods to address both the cellular and spatial branches of the atlas," said Rozenblatt-Rosen. These could include methods that perform single-cell molecular profiling of dissociated cells, such as measuring RNA, DNA, proteins and epigenetic features alone and in combination, as well as methods that "assess intact tissues in a spatially-resolved manner," by measuring proteins or RNA in both targeted and untargeted ways.
"Methods to do this already exist but we anticipate that the HCA will inspire technology development, refinement and importantly, dissemination, across all of these areas," said Rozenblatt-Rosen.
Mike Stubbington, a principal staff scientist at the Sanger who leads its HCA team, likened the effort to the Human Genome Project, noting that the latter "catalyzed a multi-decade period of innovation in sequencing technologies" that led the cost of sequencing a human genome to drop from $3 billion to under $1,000 in less than two decades.
"We hope that the same type of improvement in cost, availability and democratization of technology will occur for the methods that are used in the HCA," Stubbington said.
Together with Regev, Teichmann, and Rozenblatt-Rosen, Stubbington was a co-author on the Nature commentary, in which the organizers also discussed some of the challenges associated with building the HCA. While much of the consortium's focus is on how to generate the data for the envisioned reference map, attention has also been paid to ensure that it is an open and ethical project.
This means keeping the project open to all interested participants while implementing standards for protecting and sharing the resulting data as well as any new technologies and computational methods developed. The authors also wrote that they are concerned with getting appropriate consent agreements and maintaining public trust in the initiative. To that end, the HCA consortium will establish an ethics working group to determine the best ways to gain informed consent from sample donors and how to protect their privacy.
"Challenges are a key part of any important project," said Riken's Carninci. "In Japan, [we] mostly see the issue of involving hospitals, doctors, and informed consent, and the flow of samples," he said. "Particular attention has to be taken care to create consensus to meet both the requirement for individuals' protection and openness of the data."