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, in our first draft atlas we are focusing on tissues 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. Each of these tissues, organs, organ systems or focus areas is the subject of an HCA Biological Network. Contact information for the coordinators of each network is included in the network descriptions below.
The goals of this seminar series are:
The seminar format will be as follows:
The HCA Biological Network Seminar Series is made possible through the generous support of the Chan Zuckerberg Initiative.
A list of current and past seminars are available here.
The 2021 HCA General Meeting was focused on Biological Networks, and many of them had an opportunity to brainstorm and discuss recent findings, challenges, and future directions in concurrent breakout sessions.
These sessions were not recorded, but you can read the summaries here.
Adipose tissue, commonly known as fat, serves as the primary repository for excess calories. In addition, adipose tissue plays an important role in functions as diverse as insulation, immunity, blood pressure control, and regulation of tissue growth and repair. Adipocytes, the parenchymal cells of adipose tissue, are specialized cells with the ability to store large lipid droplets in the cytoplasm. Hormonal signals produced by adipocytes regulate a wide spectrum of metabolic functions including appetite and insulin sensitivity. Humans possess several different types of adipocytes, which appear in different amounts in the many fat depots throughout the body. In addition to adipocytes, there are a wide variety of immune, vascular, and stromal cells that interact with one another to coordinate the development and function of adipose tissue. Obesity is associated with aberrations of these interactions and of adipocyte function, and this is believed to underlie many of the comorbidities of weight gain.
The Adipose Biological Network will establish an atlas of the cells that populate adipose tissues in various states of health and disease. This will help us to understand the interplay between cell types in the fat pad as well as between the fat pad and other organs, and will enable us to develop new strategies to combat chronic diseases associated with overnutrition.
The human breast consists of a glandular epithelial network embedded into an adipose-rich tissue that connects the milk-producing lobular units through an intricate network of ducts to the nipple to enable breastfeeding of infants after pregnancy. Histopathological studies have identified around 10 major cell types that are spatially organized into three major areas of the breast: ductal and lobular epithelium, adipose regions, and interconnective tissues.
The central goal of the Breast Biological Network of the Human Cell Atlas is to build a spatially resolved atlas of cell types and states using a combination of multi-modal single cell genomics as well as in situ transcriptomics and proteomics approaches. This international project currently involves the collaboration between multiple groups in the US and the UK. We aim to analyze samples from hundreds of women to reconstruct the natural variation and life cycle of this organ by integrating individual metadata such as age, breast size/density, ethnicity, body-mass index (BMI), pregnancy/parity status as well as menstrual cycle or menopausal stage. In addition to single cell RNA sequencing, we will include single cell epigenomic profiling, spatially-resolved genomic and proteomic technologies, and perform functional validation of paracrine cell type interactions using primary human organoid systems. The breast cell atlas will serve as an unprecedented reference for studying diseases such as breast cancer, mastitis and lactation failure.
During development, controlled differentiation programmes give rise to a broad repertoire of cells with highly specialised functions and tissue locations. The Human Developmental Cell Atlas (HDCA) aims to generate a comprehensive profile of these cell types and states present during development. This detailed study of development will be critical for understanding congenital and childhood disorders, as well as ageing. Furthermore, since malignant cells exploit developmental programmes for their survival and growth, a deeper understanding of development will have impact in cancer research.
Visual disorders affect approximately 440 million people worldwide, and understanding the visual system is critical to treating these disorders. The visual system is composed of both structural parts, such as the cornea and lens, and light-sensing parts, the retina. The retina, made up of seven neuron classes, processes the light signal into an electric signal that is relayed to the visual cortex in the brain. Notably, the retina is part of the central nervous system and shares neuron organization patterns and vascular structure with the brain, but is much more accessible than other CNS tissues. This allows it to provide direct insights into the human brain.
The eye biological network will establish a comprehensive molecular and spatial atlas of the cells in the visual system across age and ethnicity groups. This resource will serve the foundation for further dissection of the function, interaction, and involvement of subtypes of cells in the visual function and diseases.
The composition and molecular properties of human cells within complex tissues are highly variable, influenced by genetics, age, sex, and environment. These factors also influence risk of contracting and suffering harm from diseases and individual response to treatments. However, most human genetic studies are focused on individuals with European ancestry.
Given the high levels of genetic, phenotypic and environmental diversity among human populations, the Genetic Diversity Network aims to characterize the impact of genes and environment on molecular traits in cells from ethnically diverse individuals across the globe. By characterizing differences within and across human populations, this resource will help us understand variation in disease risk and treatment response, and thus lay a foundation for more effective medical and public health interventions.
The intestine is one of the most complex organs in the human body and serves a wide range of functions, including the digestion and absorption of nutrients and a major site of immune interactions. Different anatomical sections of the gut play specific roles in the digestive process, which are performed by different tissue compositions or cell types in each section that communicate with each other in myriad ways. Interactions with trillions of nearby microbes add further complexity.
The Gut Biological Network of the Human Cell Atlas aims to generate a detailed map of the cells forming the intestinal tube, thereby providing critical information that will allow us to further unravel the complex networks that operate in health. Importantly, understanding the healthy gut provides the starting point for interrogating related diseases such as bowel cancer and inflammatory bowel diseases, which affect an increasing number of patients.
The human heart is composed of four chambers: right and left atrium and right and left ventricle, which together facilitate the circulation of blood. During a heartbeat, biophysical stimuli in each chamber vary dramatically due to large blood pressure differences. These differences influence muscle development and function in adulthood via changes in gene expression. However, little is known about the exact cellular composition and molecular architecture of individual cells in the different regions and how each cell works in a symphony to maintain the heartbeat - 100,000 of which occur every day in the body to keep the blood flowing.
The Heart and Vascular Biological Network uses cell atlas technologies to unravel the full range of cardiac and vascular cells. With new methods to understand gene activity, this network can identify regional differences in the tissues that pump and transport blood to the body. Implementing approaches to reconstruct cellular networks in 3D is also a crucial aim of the network. Understanding the healthy heart cell by cell and in 3D space will help to understand interactions between cell types and cell states that can allow lifelong function and how these differ in diseases. Ultimately, these fundamental insights may suggest specific targets that can lead to individualized therapies in the future, creating personalized medicine for heart disease and improving the effectiveness of treatments for each patient.
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.
Progressive kidney diseases affect over 800 million people worldwide, and their prevalence continues to grow. A fundamental challenge to curing these diseases is understanding the great cellular and spatial complexity of the human kidney, and the molecular pathways and circuits that regulate kidney homeostasis and are disrupted in disease.
The Kidney Biological Network aims to generate a comprehensive reference atlas of normal human kidney across lifespan, sex and ancestry. The atlas will determine the cellular composition and transcriptome of fetal and adult kidneys, and how they change with normal human development and aging, as well as examine sex and ancestry differences that may underlie well-established differences in susceptibility to kidney disease. This Kidney Cell Atlas will provide a comprehensive foundational resource open to the scientific community.
The human liver is a central coordinator of metabolism, an immune system hub, and the primary site of drug processing in the body. Diseases of the liver are a major and increasing burden worldwide, affecting over a billion people, due to conditions including obesity, chronic infection, autoimmune disease, drug toxicity and alcohol use disorder. The current treatments for many chronic liver diseases are of limited effect, and once chronic injury progresses to end stage liver disease, transplantation is the only effective therapy.
The Liver Biological Network seeks to spatially, structurally, and genomically map the normal liver at single cell resolution, from early development to childhood and adulthood across diverse ethnicities, races, and sexes. Ultimately, comprehensive single cell maps of the healthy and diseased liver will provide a foundation to develop new therapies for liver disease and the basis for evaluation of the liver’s response to these treatments.
The lung is the organ essential for gas exchange, which is facilitated by a highly specialized anatomy involving distinct epithelial and endothelial cell populations, supported by various mesenchymal cell types providing structural support. In addition, the lung is an essential part of the mucosal immune system, harbouring a rich variety of specialized tissue-resident immune cells. The high cellular complexity of lung tissue has resulted in the description of at least 60 different cell types to date. Regional differences in the molecular states of these cells as these occur along the various gradients and axes of the lung further adds to the cellular heterogeneity in this intricate tissue.
The Lung Biological Network of the HCA aims to establish a complete atlas of the healthy human lung. This atlas will sample the entire coordinate framework of the lung, both macro- and micro-anatomically to capture the natural variation of cellular states present within the healthy population, as outlined in this paper. This effort will generate a comprehensive map that describes the lung cells and their molecular phenotypes, the transitions between different cell states and their location in the tissue relative to each other and to anatomical landmarks.
The Human Lung Cell Atlas will serve as a reference for the analysis of diseased lung tissue at single-cell resolution and will allow identification of the shifts in cellular repertoire, the changes in cellular states and phenotypes, and the altered cell-cell interactions that disrupt normal lung homeostasis and constitute disease.
The musculoskeletal system is a diverse organ system principally composed of the bony skeleton, muscles and connective tissues such as ligaments (connecting bone to bone) and tendons (connecting muscle to bone). It also incorporates joints; where two or more bones meet with their ends covered in a highly specialised tissue called cartilage which allows almost frictionless movement between the bones. Some of these joints are surrounded by synovial tissue, which secretes lubricating fluid and filters waste products from the joint. All of these tissues act in concert to enable locomotion and fine movement whilst providing shape, support and protection to the body.
The musculoskeletal system also includes fibroblast, immune and endothelial cells which have different functions and expression profiles depending on the tissue type in which they reside. These cells help orchestrate development, homeostasis and repair and have key roles in regulating the production and turnover of the rich extracellular matrix of musculoskeletal tissues.
At present, a complete, high resolution, landscape of cell types and their functions within each musculoskeletal tissue remains to be defined.
The Musculoskeletal Biological Network aims to coordinate clinical and non-clinical researchers to define the distinct cell types and cell states present within musculoskeletal tissues across development and adulthood. Our overarching goal is to provide a comprehensive reference dataset of the musculoskeletal system in health and disease. This resource will deliver unparalleled insight and inform delivery of efficacious strategies targeted at revolutionizing our treatments for a wealth of common and debilitating musculoskeletal system diseases.
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 the Allen Brain Atlas, which has spatially mapped gene expression across the human brain, and the NIH’s BRAIN 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.
Oral and craniofacial tissues are incredibly diverse, including tongue, teeth, gums and glands. Each of these is supported by epithelia, cartilage, bone, ligaments, muscles, adipose tissue, blood and lymphatic vessels, and nerves; and all of these tissues are harmoniously integrated into the vital functions of communication, feeding, breathing, defense, sensing, and early digestion. These tissues are intimately interconnected with the nervous, immune and endocrine systems, as well as with microbes. Oral and craniofacial tissues are affected in many disorders and diseases that can decrease quality of life and cause deleterious psychosocial issues, emphasizing the need for effective, precise, and aesthetic strategies for the regeneration of craniofacial tissues.
The HCA Oral & Craniofacial Biological Network aims to create comprehensive and integrated cell atlases to understand the common and unique cell types that support these niches in health and uncover which cell types and networks are affected in disease. This level of cell annotation and integration will be critical for understanding oral and craniofacial diseases across the lifespan. In tandem, due to the growing body of literature displaying interconnected roles for oral and systemic health, findings from this network will be critical to future meta-analyses with other tissue and organ atlases for precision diagnostics and treatments.
The Human Cell Atlas data provides the “recipe” for tissue engineering, including organoids. Human organoids – three-dimensional structures of cells that recapitulate organ development in vitro – hold tremendous potential for biomedical applications. They provide tractable models of human physiology and pathology, thereby enabling interventional studies that are difficult or impossible to conduct in human subjects, and reducing the need for animal experiments. Moreover, they can provide patient-specific “avatars” for drug development and personalized therapies, and they help advance regenerative medicine, with the ultimate goal of aiming towards regenerative medicine, and producing functional biological structures that can be transplanted into patients.
Single-cell epigenome/transcriptome sequencing and spatial profiling can provide a comprehensive assessment of cell composition and cell states within organoids, enabling a comparison to matched primary tissue samples. These comparisons can catalyse the development of better organoid protocols. The Organoid Cell Atlas will foster the production, quality control, dissemination, and utilization of single-cell data for human organoids, and it will connect such datasets with the comprehensive profiles of primary tissue that are being generated within the HCA.
The human pancreas is a physiologically unique organ that is both an exocrine and endocrine gland. It is involved in the secretion of several hormones, including insulin for blood sugar regulation and enzymes for the digestive system. Dysregulation of the physiological functions of the pancreas can result in diseases such as pancreatic ductal adenocarcinoma or diabetes mellitus. Unfortunately, the pancreas' high autolytic activity makes it challenging to study.
The Pancreas Biological Network will integrate molecular transcriptome data from millions of single cells with epigenomics profiles, tissue spatial transcriptomics and proteomics from all regions of the pancreas (head, body, tail and islets) to identify cell types and/or states and their phenotypes in healthy adults and in disease. Further, it will complement the Developmental Cell Atlas by characterizing the molecular and cellular landscape of the developing human pancreas in the prenatal and postnatal period.
The reproductive system is the system of organs involved in producing offspring. Alterations of the physiological functions of the reproductive system can result in diseases such as infertility or cancer.
The Reproductive Network of the Human Cell Atlas aims to generate a detailed, dynamic map of the cells forming reproductive tissues across the lifespan. To do so, we are combining single-cell genomics with spatial transcriptomics and proteomics tools to disentangle tissue organisation and cell signalling within the tissue compartments. This detailed study of the reproductive tissues will be critical for understanding many understudied reproductive disorders, as well as cancer. Furthermore, the single-cell multi-omics roadmap for reproductive tissues will be used as a blueprint for the improvement and development of new in vitro models to recapitulate cell behaviour in physiological and pathological conditions.
The skin is a readily accessible organ, with a defined spatial organisation, and is affected in many diseases.
The Skin Biological Network, building on a well-integrated international network of clinical and non-clinical researchers who study skin and a large body of existing information about skin cells from human and mouse experimental models, aims to answer several outstanding questions about the skin through constructing an atlas. These include how many distinct cell types and states are present in healthy adult human skin; how body site, gender, age, ethnicity and sun exposure cause variation in these cells; and how cellular composition of the skin changes in disease. Ultimately, a comprehensive reference map of skin cells will provide new insights into the properties of the tissue in health and disease.