The Human Cell Atlas (HCA) is a global effort to create a reference map of all cell types in the healthy human body in order to generate a fundamental reference for biomedical research and improve our understanding of health and disease. Progress over the past several years has resulted in advancement toward first drafts of many organs systems and tissues. However, gaps have emerged in reference data for tissues from ancestrally diverse donors across all atlas building efforts, including the HCA. This has introduced significant biases and limited utility for finding treatments for large classes of disease for segments of the population.
This Request for Applications (RFA) is intended to bring together teams of experts to 1) ethically and appropriately generate data derived from tissues from people whose ancestral groups are historically understudied and thereby expand the ancestral diversity of single-cell data that is available via the HCA, and 2) utilize best practices and build up systems to enable long-term engagement of potential participants and donors from diverse communities to contribute to the current and future drafts of the HCA. This work will help provide insights into the contribution of genetic ancestry to disease now and in the future, resulting in an atlas that may be more generalizable and representative of the diversity found in the global human population.
This funding opportunity supports the continued growth of the HCA, with the aim of filling potential gaps in the first draft of the healthy reference atlas around ancestral groups that have been historically understudied in the biomedical sciences. While there are no specific quotas for this RFA, it is expected that all of the tissue will be from understudied populations. This RFA seeks to attract a new set of grantees primed to answer questions related to commonalities and potential differences in ancestry at the cellular level, as well as grantees with experience in community engagement and building diverse cohorts, and/or access to ancestrally diverse donors and tissue.
This Ancestry Network should collectively generate new tools, open source analysis methods, and openly available data from ancestrally diverse donors across multiple tissue types that provide valuable contributions to the HCA community. Applications should focus on healthy human tissues that will contribute to the reference atlas. Community resources arising from the teams funded by this RFA must be accessible for rapid and open sharing via repositories such as protocols.io, Addgene, GitHub, bioRxiv, or other open repositories. Samples must be collected in an ethical, equitable, and respectful manner in keeping with the customs, norms, and expectations of the donor communities. Raw sequencing data should be submitted to an archive that ensures maximum accessibility while being respectful of privacy, ethical, and cultural considerations of donors, particularly of marginalized populations.
The overarching scientific goals of this RFA are:
- Generate and share data that will contribute to healthy references for organs and tissues and will clarify potential differences across ancestry at the cellular level and with the potential for utility to understand differences in disease across ancestries;
- Increase diverse ancestral representation in datasets to generate references that will promote understanding of disease in populations and communities with increased incidence and disparities;
- Build international collaborations that promote coordinated and cohesive progress and contribute to the Human Cell Atlas;
- Identify and address shared methodological, computational, or infrastructural challenges to data generation, analysis, and incorporation into a global reference atlas;
- Collect and share biospecimens, in particular promoting solutions for challenges associated with ensuring ancestral diversity, engagement with understudied communities, and tissue storage for subsequent single-cell analysis; and
Specific project examples may include, but are not limited to:
- Focused data generation on single organs, tissues, or multiple organs from single donors from multiple or a single ancestral group/s;
- Opportunities to develop and share tissue resources that will support standards, protocols, and tissue access to researchers;
- Extending and improving ancestry ontologies standards;
- Developing experimental methods to efficiently capture genetic ancestry at the single-cell level;
- Benchmarking studies, systematic power analysis, or developing statistical methods and standards for confidently measuring and interpreting ancestral differences at the cellular level; and
- Scaling, dissemination, or expansion of community engagement or donor recruitment programs/models.
Definition of Understudied Population
Underrepresentation in clinical research can vary regionally and is greatly affected by local demographics. However, there are clear historical trends in biomedical research and genomics studies in particular that can be used to inform researchers as to which ancestries are not well represented in the corpus of biomedical literature and data. Applicants should provide a justification for why the particular ancestral group(s) they have selected falls into the category of understudied or is of particular interest. Which ancestral groups and organ/tissue to focus on should be driven by the scientific questions and a clear rationale for the importance and relevance to the HCA in filling in basic knowledge gaps in our understanding of the healthy human body. This RFA will not fund the acquisition and analysis of diseased tissue; however, priority will be given to applications in which the generation of healthy single-cell data has the potential to also inform our understanding of diseases that are neglected, understudied, underfunded, or have high prevalence or disparities in understudied populations. Access to a particular cohort or tissue source is an important factor but should not be the exclusive justification.
There are many challenges around patient/donor recruitment, and in particular, of racial/ethnic groups that are a minority of the population in some localities. Patient and community engagement is critical for building trust and sustainable diverse donor pools. A community engagement plan is required. Applicants are strongly encouraged to develop and incorporate institutional-, departmental-, or laboratory-level patient/community engagement strategies to increase engagement of patients/donors from understudied racial, ethnic, and/or ancestral groups. The proposed strategies should be based on current best practices and include a plan for long-term sustainability after the grant period.
Applicants are encouraged to engage with their institutional core(s)/office(s) of community/patient engagement or outreach, if such offices exist, and obtain letters of support, if applicable. Partnering with non-institutional community-based organizations that interface with understudied communities is also allowed and encouraged. We also strongly encourage the inclusion of Co-PIs with expertise in community engagement and community-based participatory research. There is the expectation that appropriate levels of funding will be allocated to partners involved in the community engagement aspects of the work, demonstrating a commitment to true partnership.
This RFA aims to support collaborative teams of researchers that:
- Have access to established resources and protocols that are ready to be extended and scaled.
- Established team and new collaborations that will benefit from the experience of existing teams while bringing complementary and differentiated perspectives and resources.
- Will make contributions to the larger community via regular engagement and sharing of learnings, data, samples, and other resources.
Teams should consist of at least three principal investigators (PIs), including at least one computational biologist or data scientist and at least one single-cell biology expert. We strongly encourage that teams include community-engaged/community-based participatory researchers from any relevant discipline as Co-PI(s) to ensure that the research is sensitive to the needs of and connected with the participating donor communities. The engagement researchers are incorporated into this opportunity to help provide, promote, and build culturally competent connections with the research participants and members of their community in such a manner that they are empowered to participate in the Ancestry Networks research and also benefit from potential findings. As such, we strongly encourage the engagement researcher to act in the role of the Coordinating PI.
Because there are many different individual HCA projects and consortia supported by various funders, the HCA has organized into biological networks that coordinate organ/tissue specific projects. Teams are encouraged to reach out to the HCA biological network(s) that have relevance to their proposed project to learn about existing projects and potential collaborations. Applicants are also encouraged to register their interest in contributing to the HCA.
One of the most direct ways to ensure that tissue donors are from diverse backgrounds is to support research groups that have team members located in ancestrally diverse geographies that have established tissue resources and cohorts of the local population. For this reason, investigators from the Global South with populations that have historically been underrepresented in biomedical research are encouraged to apply. In particular, international collaborations between investigators in the Global North and South that leverage regional and technological expertise and strengths are encouraged.
Collaboration and Open Science
All projects will be evaluated based on their potential for scientific output (productivity), tool and resource dissemination (reach), inclusion of representative donors and communities, and collaboration among the team. We are looking for investigators and groups who will enthusiastically contribute to and benefit from a collaborative, dynamic, and interdisciplinary approach. For examples of evidence of productivity, reach, and collaboration, please see the CZI statement of values.
- In addition to providing funding, CZI functions as a scientific partner to investigators to help build the HCA. Investigators will have the opportunity to learn from, collaborate with, and interact with the community of investigators and groups across all Networks, as well as with CZI computational biologists and software engineers.
- CZI supports collaboration. All Principal Investigators listed on the application are expected to participate in meetings, reports, and other events. Networks should be genuine collaborative projects with responsibility and participation distributed across participating research groups. Members of funded labs with key roles in the project such as students, postdocs, and staff will also participate in scientific meetings, hackathons, and other activities.
- CZI’s mission is at the interface of technology and science. Working in collaboration with, and guided by, other grantees in the Network and the wider HCA community, we aim to develop technology-based tools and approaches to support and accelerate the scope and impact of tissue atlases and the HCA community.
- CZI supports open science values and principles. To accelerate scientific discovery and collaboration, CZI supports a consent, sharing, and publication policy for open and rapid dissemination of research results and a policy for software development that maximizes accessibility, reuse, and shared development.