Introduction to Human Cell Atlas
In London on 13 and 14 October, 2016, a collaborative community of world-leading scientists met and discussed how to build a Human Cell Atlas—a collection of maps that will describe and define the cellular basis of health and disease.
Cells are the most fundamental unit of life, yet we know surprisingly little about them. They vary enormously within the body, and express different sets of genes. Without maps of different cell types and where they are located in the body, we cannot describe all their functions and understand the biological networks that direct their activities.
A complete Human Cell Atlas would give us a unique ID card for each cell type, a three-dimensional map of how cell types work together to form tissues, knowledge of how all body systems are connected, and insights into how changes in the map underlie health and disease. It would allow us to identify which genes associated with disease are active in our bodies and where, and analyze the regulatory mechanisms that govern the production of different cell types.
This has been a key challenge in biology for more than 150 years. New tools such as single-cell genomics have put it within reach. It is an ambitious but achievable goal, and requires an international community of biologists, clinicians, technologists, physicists, computational scientists, software engineers, and mathematicians.
Human Cell Atlas - Areas of Focus
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.
1) 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.
2) 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.
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.
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.
Organizing terabytes of data for billions of cells
The Human Cell Atlas will be organizing and standardizing terabytes of data for billions of cells, across multiple modalities, generated by hundreds of labs around the world. We want to make this data open and easily accessible to all researchers, enabling the scientific community to innovate rapidly without barriers to data access. We also want to make it easy for computational researchers to develop and share new analysis approaches. To do this, we intend to design and build a modern, cloud-based, modular architecture for organizing and sharing data for the Human Cell Atlas. All software will be developed in the open and made available as open source.
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