Incentivizing More Representative Research

Supporting Tissue Diversity for the Human Cell Atlas

Researchers worldwide are working together to create a common reference map of all human cells that will allow us to better understand and treat disease: the Human Cell Atlas (HCA). The HCA is already making an impact — for example, researchers used initial cell atlas data from the nose and airway to identify cells that may be entry points for SARS-CoV2. Scientists have also used reference data from many organ systems to begin to clarify the complex pathology associated with COVID-19. Yet to be truly useful as a reference atlas for the human body, the HCA must be broadly representative of race, ethnicity, ancestry, and other determinants of health. A disease like COVID-19 highlights this: many understudied communities and populations are heavily impacted, and due to a myriad of factors, are more likely to contract the disease and experience more severe symptoms and outcomes.

The field of genomics overall has fallen short of generating and sharing data that is representative of the global population, leading scientists all over the world to call for more genetic diversity in studies and research. For example, our knowledge about some diseases is biased toward the mechanisms and genes that underlie these conditions primarily in populations of European ancestry. We know from other areas of genomics and biomedical research that studies based on a narrow slice of ancestral background are often not generalizable to all people. Extending this information and understanding to include individuals from across the globe strengthens our overall understanding of the pathways and genes associated with diseases in different populations.

Diseases often manifest differently across genetic backgrounds, meaning we need to have an understanding of how ancestry can impact disease severity, outcome, and treatment — including the effectiveness of treatments and the often-inequitable access to them. In examining disease prevalence, it’s also imperative to account for other major causes of racial health disparities, such as social determinants of health, systemic racism, inadequate access to quality healthcare, and mistrust in science by communities of color as a result of historical and discriminatory practices. These factors further highlight a critical need for broad representation in research.

Much like the majority of genomics research, most tissues and data included in the HCA to date come from individuals of European ancestry. If we don’t work as a community to learn from past shortcomings and actively seek to limit disparities in representation, the applicability of the HCA to understanding how diseases impact Black, Latinx, Asian, and Indigenous populations will be limited, and ultimately, will create major knowledge gaps in our understanding of basic human and cellular biology. We believe in the power and potential of the Human Cell Atlas and want to help ensure this important reference will accelerate the goal of curing, preventing, and managing all diseases for all people, not just those of European ancestry.

Researchers who study tissue samples from a diversity of populations for the HCA can help us learn and course correct historical systemic racism and bias in genomics — ultimately encouraging the nascent field of single-cell biology to emphasize the importance of studying samples from racially, ethnically, and ancestrally diverse participants.

Understanding the cellular map of fibroblast subpopulations in the knee of a patient with rheumatoid arthritis sheds light on the role they play in disease. Synovial lining fibroblasts (orange) break down the joint’s cartilage and erode bone. Synovial sub-lining fibroblasts (green) are important in contributing to inflammation in the joint. Blood vessels (red) and the mural cell marker CD146 (blue) are found in the sub-lining and provide the blood supply to the synovium. | Photo provided by Christopher Buckley, Universities of Birmingham and Oxford.

The Chan Zuckerberg Initiative (CZI) supports 38 collaborative teams — involving more than 200 research labs — to generate data and tools and develop methods to advance the HCA through the Seed Networks for a Human Cell Atlas. These groups bring together scientists, computational biologists, software engineers, and physicians to help accelerate progress toward a first version.

One of the Seed Networks’ goals is to help ensure that the first draft of the HCA is representative of the global population to increase its impact and utility for the global scientific community. True representation of human genetic ancestral diversity results in a broader application of the HCA to diseases that impact everyone, ultimately helping to build a more equitable and inclusive future for the field of single-cell biology and beyond.

That’s why we’re providing additional funding to current Seed Networks grantees to increase tissue diversity from understudied racial, ethnic, and ancestral populations in their funded projects. Increasing representation within the HCA, and scientific studies more generally, requires building relationships with historically understudied communities. This work takes time and requires dedicated commitment from all involved to gain common understanding of priorities and sensitivities. This effort is only the start of addressing diversity and equity in the HCA in the long term, and these projects will serve as an initial step to surface future opportunities to more deeply address these disparities in the future.

With these supplemental grants, we want to ensure that a minimum of 30 percent (around double the historical rate) of the total samples profiled by a Seed Network group of researchers represent ethnically and/or ancestrally understudied groups. CZI is providing $1.13 million to support 10 proposals. All selected proposals will expand the richness of the HCA data corpus by collecting and analyzing additional samples from donors belonging to understudied racial and ethnic backgrounds. Two of these groups will pilot patient engagement strategies to increase recruitment of ethnically underrepresented donors and to try to better understand the barriers to this recruitment. Eight new collaborators will join the Seed Networks through meaningful partnerships to expand tissue collection representative of the global population alongside community and patient engagement activities.

The selected proposals will collectively add transcriptomics data generated from races and ethnicities historically understudied across eight organ systems — including lung, kidney, and neural retinal system, among others. The coordinating PIs for the selected proposals are Alexander Misharin, Allon Klein, Benjamin Humphreys, Harikrishna Nakshatri, Jonathan Siedman, Peter Kharchenko, Rui Chen, Sarah Snelling, Sheng Zhong, and Shyam Prabhakar.

Dr. Zhen Chen and her lab team at Beckman Research Institute at City of Hope National Medical Center. Dr. Chen will work with co-principal investigator Dr. Sheng Zhong to expand the racial diversity of the endothelial cell atlas, focusing on samples from Black and Latinx donors in order to clarify how cardiovascular disease manifests differently among various populations. | Photo provided by Dr. Zhen Chen.

The Ancestry Networks for the Human Cell Atlas Request for Applications builds off of CZI’s experience supporting these 10 collaborative research teams. This new RFA will support collaborative networks of researchers for three-year projects. Teams should consist of at least three and up to 10 principal investigators, including at least one computational biologist or data scientist and one expert in single-cell biology. Community-based participatory researchers should be involved in the collaboration to ensure that the research is attuned to the needs of and connected with the participating donor communities.

The CZI Single-Cell Biology Program is committed to supporting tools and technology that will clarify cellular mechanisms of all disease. In order to do this, it’s imperative to increase the racial, ethnic, and ancestral diversity of the single-cell transcriptomics data used to construct the first draft of the HCA. We want to accelerate the creation of new collaborations, help implement systems that encourage and enable recruitment of understudied, racially, ethnically, and ancestrally diverse populations, and encourage a shift in the scientific culture towards valuing, incentivizing, rewarding, and replicating these activities.

Increasing the richness of the donor samples making up the HCA will help build a more inclusive, scientifically-relevant product that will have greater value and functionality to more researchers globally, and inform a wider array of disease states for patients across the globe.

More Information
Ancestry Networks for the Human Cell Atlas Request for Applications
Seed Networks for the Human Cell Atlas grantees
CZI Single-Cell Biology Program

Norbert Tavares, CZI Program Manager for Single-Cell Biology

Norbert is a microbiologist by training and manages CZI’s Single-Cell Biology programs, including those that support the Human Cell Atlas consortium. Previously, Dr. Tavares served at the National Cancer Institute, at the National Institutes of Health as an American Association for the Advancement of Science, Science & Technology Policy Fellow, where he managed interdisciplinary trans-institute/agency grant programs. He is particularly interested in increasing the representation of ethnically diverse individuals in biomedical research and bolstering the availability of ethnically and ancestrally diverse genetic and -omics data.

Supporting the science and technology that will make it possible to cure, prevent, or manage all diseases by the end of the century.

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