NEW YORK (GenomeWeb) – Researchers hope to soon generate a Pediatric Cell Atlas that will provide single-cell profiles of gene expression across human tissues and organs in children.
The nascent endeavor involves participants from at least a dozen institutions, including the Children's Hospital of Philadelphia and Cincinnati Children's Hospital Medical Center, and those involved say coordinated efforts across centers and securing appropriate funding for the new project will be crucial.
Researchers were compelled to draw up plans for such an atlas given both clinical need and the emergence of single-cell gene expression profiling technologies, which they view as essential to the effort.
"This is something that there is a lot of consensus around in the pediatric community," said Deanne Taylor, director of bioinformatics in the department of biomedical and health informatics at CHOP, and lead author on the paper. "Kids' physiology has always been a little bit of a mystery, even to the pediatricians."
As described in the paper, the envisioned PCA will be part of the HCA, a three-year-old effort to harness single-cell profiling technologies to develop an atlas of all human cell types. The Chan Zuckerberg Initiative poured $15 million into the HCA last year, agreeing to fund multiple projects. The HCA aims to publish a first draft by 2022.
Taylor said she brought up the idea of expanding the HCA into pediatric tissues early on, in part because funding for pediatric research tends to trail adult health research, meaning that clinical advancements reach adults before they reach children.
At the same time, diseases, symptoms, and responses to therapies are often age-dependent. As noted in the paper, responses to anesthesia and medications can differ in pediatric cases compared to adult cases. Children's reactions to environmental influences, injuries, and surgery also diverge according to age, yet the factors behind these differences are poorly understood.
The authors also note in the paper that there is little known about the effects of genomic variants, environmental factors, and how their interaction might alter cellular development and function, or therapeutic efficacy in children.
Another added benefit would be the creation of an atlas that tracked development in children over time, while also providing insight into how chronic diseases, such as diabetes or asthma, present in children.
The researchers therefore believe that the PCA could serve as a reference tool for future pediatric research. Their hope is that the availability of such data will support insights into birth defects, developmental delay, metabolic problems, and pediatric cancers, and guide future treatments.
The effort has been inspired in part by innovation in single-cell profiling technologies. While single-cell sequencing is the most obvious workhorse for such a project, the authors were quick to note that they would not be wedded to any particular approach, but rather would use a variety of techniques to generate the atlas.
"I think a lot of this is driven by technology development," said Kai Tan, an associate professor of pediatrics at CHOP and coauthor on the paper. "I don't think that's surprising," he added. "Single-cell analysis is a collection of many different technologies and we are at the point of using these technologies to address many different questions."
Taylor said the PCA would include "multiple levels" of measurements. "We won't get one picture from doing RNAseq," she said. "We will get some information out of that, but there's proteomics, signaling molecules, [and] other techniques," she said. "We won't throw all our chips in one hat."
Taylor also noted that as technology develops and is implemented in the project researchers will need to establish standards, so that they can move with ease between platforms.
"No one can promise that doing single-cell biology is going to give us all the answers, just like we couldn't promise that microarrays or whole-genome sequencing is going to give us every answer for every disease," said Taylor. "But getting closer and closer at the molecular level of what biology is doing should hopefully get us a better platform with which to calculate what's going on."
The effort to generate the data will be pan-institution, and Taylor said that there is no principal investigator on the PCA project. Moreover, she believes that researchers must collaborate to accomplish the PCA, as pediatric diseases are often rare, and sourcing pediatric tissue will require input from many centers to get the sample sizes needed. "It will have to be across multiple different centers and investigators," she said. "It should never be one particular center. It would never work."
As outlined in the paper, data generated for the PCA would be made accessible via the HCA's Data Coordination Platform, which supports the "ingestion of rich and extensible metadata." The platform is still in development but includes an "ingestion service" for data submission, synchronized data storage across multiple clouds, standardized pipelines for analyzing sequencing and imaging data, and portals for data access, tertiary analysis, and visualization.
The researchers involved in the PCA project also will seek to address some of the unique ethical challenges of working with pediatric samples through the HCA's Ethics Working Group.
"There are a lot of considerations that will go into this, sometimes even more than you would have to go through with adults, because children don't have their own agency, except through their parents," noted Taylor. "We don't want to compromise privacy, we want to allow children, once they reach their majority, to be able to withdraw their samples," she said. "They should be able to do that."
Researchers involved in the PCA already have sketched out pilot projects to drive the effort, detailing plans for profiling tissues and organs in the brain and nervous system, gut, heart, hematopoietic and immune systems, kidneys, liver, lung, placenta, and skeletal muscle.
Getting there, though, will require both organization and funding.
"To realize the potential, we need to get everyone on the same page, figure out how to synergize data, get experimental technologies set up and sample collections all done in ways that ensure the data can be most comparable across different labs, projects, and places," said Bruce Aronow, co-director of the Computational Medicine Center at Cincinnati Children's Hospital Medical Center and a co-author on the paper.
Taylor noted that researchers involved in the PCA might establish their own working group within the HCA.
According to Aronow, funding is also an issue. Financial support for such efforts to date has been "fractional," he noted, while lauding US National Institutes of Health support and Chan Zuckerberg's "tremendous investment." Obtaining greater resources to realize the PCA is therefore a main objective at the moment, and Taylor noted that the effort is "actively looking" for funding.
"How do you fund this effort at the scale necessary to really leverage the opportunity is a big question," noted Aronow.
CHOP's Tan similarly called funding a "critical issue" for the PCA. "We need to think about how to get the first funding so the pilot projects can be launched," he said. "A similar situation happened with the HCA," Tan noted. "They really took off after they secured the Chan Zuckerberg funding."