Making Progress on Childhood Diseases
By: Chan Zuckerberg Science Initiative
Tags: Biology, Technology, Disease, Pediatrics, Philanthropy

Making Progress on Childhood Diseases

We are all familiar with changes early in life — those that are easily seen and others that are more difficult to detect or pinpoint. Growth charts show our bones getting longer, our immune system is trained via vaccination or exposure to diseases like chickenpox, many of us have allergies that then mysteriously subside as we grow, and puberty induces changes in our hormones and with it, changes in many organ systems. The processes are clear, as well as many diseases associated with them, but the cell types and how these cell types arise and change throughout these processes are not. We have so much to learn.

One thing we know for sure is that diseases — including most rare diseases — do not arise randomly distributed across our lifespan. Most diseases start in childhood or old age, underscoring the importance of understanding not only the normal state of adult health, but also how our health develops before and after birth, and then how it is maintained or degenerates as we grow older. That’s why we’re launching a new funding opportunity that aims to help teams of researchers and pediatricians map healthy cells in samples from pediatric tissues and in turn, help to better understand, prevent, and treat childhood diseases.

Why Pediatrics?

Early life is a scientifically fascinating period of time in the brain, lungs, skin, and the immune system. These and many other organs and systems are associated with diseases such as epilepsies, allergy, asthma, and a wide variety of rare diseases. In fact, half of rare disease patients are children, and 30% of these kids will not live to see their fifth birthday. Understanding the unique characteristics of healthy cells in organs, and how these cells mature during early childhood, is an important first step in clarifying many childhood — and potentially adult — diseases. By understanding traits of healthy pediatric cells, we can learn what goes wrong when disease strikes and potentially prevent it in the future.

Children are not simply smaller adults. Their physiology, cell types, response to drugs, and many other factors are distinct and poorly understood. This limits the ability of pediatricians to diagnose and treat many childhood diseases and also slows, or is not accounted for, during drug development. From infancy through puberty, cellular composition and maturation remain underexplored, if not totally unexplored, in most current research efforts. And most drugs never get tested on children, despite the impact these drugs could have, or if they are tested, are much delayed. For example, children were not included in the initial clinical trials for COVID-19 vaccines. While researchers have gained some foundational knowledge about prenatal organ systems development, there is more work to be done to build off of these discoveries.

Single-cell biology is a key tool that is helping researchers advance our understanding of how childhood diseases arise and progress at a cellular level. Recognizing the unique power of single-cell measurements, the international Human Cell Atlas (HCA) community is employing these new technologies to create shared and foundational references of all cell types in the healthy human body that will accelerate many scientific studies of health and disease. As we progress towards a first draft of the HCA, including samples from pediatric donors will help fill critical gaps in our understanding of the cellular mechanisms of diseases that arise in childhood, and also help improve diagnostics, therapeutics, and scientific research tailored to pediatrics. International experts have come together to highlight the opportunity of a dedicated effort to create a Pediatric Cell Atlas.

Recognizing Progress and Gaps

Together, we believe single-cell technologies and the Human Cell Atlas represent a unique opportunity to accelerate scientific knowledge of all organ systems and provide a powerful reference to understand the cellular mechanisms of all diseases. It is an exciting time in the field as researchers continue to innovate and refine methods while simultaneously applying them to an ever broader set of organisms and tissue types.

CZI has supported the HCA since its early days, initially with a focus on helping the community develop experimental and analytical single-cell methods. This work framed opportunities to begin to apply these methods at scale and contribute data to a first draft of the HCA. We have also started to support investigators that are using the HCA and single-cell methods to understand diseases. Single-cell methods are poised to help identify common cellular mechanisms or behavior across classes of complex diseases, such as neurodegeneration or inflammation.

The need to specifically support single-cell research on pediatrics — and the launch of our new pediatrics single-cell RFA — came out of our meetings and interactions with the HCA community and leading pediatric researchers over the past year. CZI also supports research on rare disease through its Rare As One Project, and gaining a deeper understanding of pediatric cell development could advance progress on these diseases.

CZI-funded investigators, as well as labs supported by other funders, have demonstrated the importance of single-cell references for understanding diverse diseases. Some of these include modalities of single-cell analysis, or the importance of scale, while others highlight opportunities to make scientific references more inclusive, and ultimately, more broadly useful. Often, scientific questions about disease arise during specific periods of life (e.g. childhood or old age), with different frequencies across global populations. In these cases, reference data from healthy adults is helpful, but is also likely to miss important differences across age and ancestry at the cellular level. We’re eager to continue to support and work with the single-cell biology field to build off past and present progress to bring additional diversity and utility to all researchers.

Pediatric Networks for the Human Cell Atlas RFA

The Pediatric Networks for the Human Cell Atlas RFA will support collaborative networks of researchers to contribute healthy pediatric single-cell reference data to the global Human Cell Atlas as a foundation for understanding how cells and organs progress and relate to disease onset in children. Teams should consist of at least three and up to 10 principal investigators, including at least one computational biologist or data scientist, one pediatrician actively engaged in direct patient care, and one expert in single-cell biology. Community-engaged researchers should be involved in the collaboration to ensure that the research is attuned to the needs of and connected with the participating communities providing pediatric tissue samples. Projects will be funded for three years. Learn more and apply.

Challenges of Studying Childhood Diseases

Specific challenges surface with building pediatric atlases that are not present when working with adult samples. While this new funding opportunity will not solve all of these challenges, we aim to support accelerated research progress and cohesion among the HCA community. In particular, the formation of multidisciplinary teams that bring together combined expertise in patient care, computational biology, and single-cell data generation is foundational to success. Newly formed teams will make important contributions to ongoing efforts and benefit from past progress.

In addition to these collaborators, we recognize that community engagement is central to pediatrics. Engagement with participating children, their families, and their communities requires cultural competency that is crucial to successful scientific projects. Community engagement is an emerging area of importance for CZI because of the connections that are formed between patients, community leaders, clinicians, and researchers. A key goal of this RFA is to encourage ancestral representation in datasets to generate references that will promote understanding of disease in populations and communities with increased incidence through childhood. All sample generation will adhere to key ethical considerations, including attention to privacy and consent protections specific to pediatric populations.

A final challenge is focus. Pediatrics covers a wide and diverse range of developmental stages, from neonatal to infancy, juvenile, and several distinct periods of adolescence. Each of these represents important age windows with relevance to different diseases. While this first funding opportunity centers on establishing reference data from healthy donors under the age of 18, applicants will be asked to state the rationale for the specific time window(s) they will focus on based on the incidence of disease or other factors. This foresight from potential teams will maximize the impact of initial work, while also underscoring that this research is a starting point from which to develop a scaffold that can be filled in and connected over time.

More Information

Pediatric Networks for the Human Cell Atlas Request for Applications

CZI Single-Cell Biology Program