Human Cell Atlas

Areas of Impact

Where do we start?

Studying all the cells in the human body is an enormous endeavor—current estimates suggest that an average human being is made of at least 37.2 trillion cells. To take on this bold task, we are conducting preliminary pilot projects that will not only reveal interesting biology, but also inform us about efficient and effective sampling and analysis strategies for a full-scale cell atlas effort. These pilot projects will also begin to build the collaborative international network that is essential for the cell atlas’s success. A few examples are:

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    The Immune System

    In partnership with the Immunological Genome Project (immgenH).
    Immune cells are found throughout the body and are the primary responders to changes in our environment, from the presence of pathogens to our nutrition and even our mental state. The immune system is composed of many different cell lineages, which use innate or adaptive receptors to sense antigens or other body perturbations. The immune system includes primary immune organs, such as the thymus and bone marrow, where immunocytes differentiate; secondary immune organs like the lymph nodes and spleen, where immunocytes identify foreign molecules and initiate responses against them, then radiating and patrolling through the body. Immunocytes also reside in front line tissues such as the gut, lung, or skin, where they orchestrate a carefully controlled balance between defense against pathogens and tolerance of food or commensal microbes.

    Pioneering efforts such as the Immunological Genome Project (immgenH) have systematically analyzed gene expression and its regulation across the immune system of the mouse. The Human Cell Atlas will build upon this foundation and, in partnership with the newly launched Human Immunological Genome Project (immgenH), extend it to the human immune system, at the extreme level of resolution allowed by single-cell profiling.

    This effort will combine deep knowledge of immunological lineages, clinical expertise and infrastructure needed to procure and process diverse samples, genomic and computational expertise to resolve the hundreds of finely differentiated cell-types that compose all facets of the immune system, and the genomic signatures that define them. Because the immune system patrols the whole body, all immune organs and body locations will be surveyed. Because the immune system only manifests its potential when challenged, many forms of infectious and inflammatory diseases will be analyzed to assess the states that immunocytes can be pushed to adopt. Because infectious and immunologic diseases vary with geography, the effort will involve partners worldwide. The results will provide a unique and illuminating perspective on the human immune system, in unprecedented breadth and detail. It should radically transform our knowledge of immune function and dysfunction in infectious diseases, autoimmune or inflammatory disorders, and the role of immunocytes in other diseases as diverse as cancer, type 2 diabetes, and psychiatric disease.

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    The Brain and Nervous System

    The brain and nervous system are some of the most complex tissues in the human body. For centuries, studying them has been a daunting prospect due to their relative inaccessibility and scale (there are more than 86 billion neurons in the brain alone).

    Recent large-scale efforts have launched a new generation of studies that aim to identify the molecular and cellular characteristics of the brain and how these translate into normal brain function—or, in the case of disease, dysfunction. These efforts include theAllen Brain Atlas, which has spatially mapped gene expression across the human brain, and the NIH’sBRAIN Initiative, which is accelerating the development and application of new technologies.

    The BRAIN Initiative has laid critical groundwork for a Human Cell Atlas by funding transformative initiatives that have developed next-generation technologies to explore the brain and nervous system. For example, the BRAIN Initiative supports a series of projects that are characterizing mammalian brain cell types using single-cell genomic analysis. These efforts and others will complement the Human Cell Atlas as we strive to complete a catalog of all of the cell types and sub types of the human brain and nervous system.

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    Epithelial tissue

    Epithelium is one of the basic types of animal tissue—but also one of the most versatile. It is found throughout our bodies, lining the inside and outside of our organs, serving as a protective layer in our blood vessels, lungs, skin, and more, and making up our glands in the kidney, gut, lung, and pancreas. Epithelial cells have diverse shapes and functions, such as secretion, absorption, protection, transport, and sensing.

    Epithelial organs can serve as a central hub where the host interacts with its environment, responds to it in a dynamic manner, and relays information throughout the body. A fascinating example is the gut, an organ that is intimately interconnected with the immune system, nervous system, and endocrine system, as well as commensal microbe ecosystems. It is a nexus that connects and integrates organ systems throughout the body, with far-reaching consequences in health and disease.

    To understand how epithelial organs interact with many parts of the body in both healthy and disease states, we will generate cellular maps of these organs to identify and categorize all the cell types present in the tissue and how they interact with each other, shedding light on both healthy and disease states.

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    Cancer

    Cancer can arise in almost any tissue in the human body. As a result, studying cancer can yield insights into not only the disease itself but also the normal functioning and development of healthy cells.

    Tumors are not found in isolation—they are surrounded by a heterogeneous ecosystem of malignant and nonmalignant cells (such as the immune cells that try to keep them in check and the blood cells that nourish them). Furthermore, the genetic and expression profiles of malignant cells vary within individual tumors, between tumors at different sites within the same patient, and among tumors from different patients. This variation may drive drug resistance and tumor recurrence.

    Current methods to analyze cancer genomes rely on large, “bulk” populations of cells and provide an average view of the tumor’s molecular profile—not the fine-resolution information necessary to understand the inherent variation in a tumor ecosystem. Now, however, cutting-edge single-cell profiling technologies such as single-cell RNA sequencing can overcome this problem. Studying cancer with single-cell technology will allow us to unlock the interactions between different types of cells in tumors—and monitor how these interactions change over time, affecting patients’ outcomes. Ultimately, this will help us predict responses to existing therapies and identify promising targets of new ones.

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    The Fetal Cell Atlas

    During fetal development, controlled differentiation programmes give rise to a broad repertoire of cells with highly specialised functions and tissue locations. The Human Fetal Cell Atlas (HFCA) aims to generate a comprehensive profile of these cell types and states present during the embryo formation. This detailed study of human development will be critical for understanding congenital and childhood disorders, as well as ageing. Furthermore, since malignant cells exploit early developmental programmes for their survival and growth, a deeper understanding of fetal development will have impact in cancer research.

    The HFCA programme is part of the Human Cell Atlas (HCA) initiative­, an ambitious global research effort that aims to generate a reference map of cells in the human body across all developmental stages. The HFCA will be coordinated by the Wellcome Trust Sanger Institute (WTSI) and Newcastle University in partnership with the Wellcome Trust- and MRC- funded Human Developmental Biological Resource (HDBR; www.hdbr.org). The success of this effort lies in its integration of multidisciplinary scientific expertise and knowledge.

    To achieve the goals of the HFCA, the HDBR team will provide direct access to human embryonic and fetal tissues up to 22 weeks of gestation. The experimental plan includes a fine-grained analysis of the different cell populations within these precious tissues using cutting-edge single-cell genomics methods. Moreover, integration of spatial transcriptomics will generate a three-dimensional atlas of tissues during early development.

    Data analysis and curation will be led by WTSI, with sharing of computational skills with Newcastle University.  There will be a strong focus on provision and dissemination of data to the wider research community and general public, in keeping with the HCA initiative and HDBR ethos on data sharing. We expect to generate extensive biological data that will benefit the broad scientific community, as well as develop new methodologies and tools that will pave the way for future -omics studies to benefit human health.

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