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Characterizing cellular diversity in the nervous system of humans and other mammals to study disease, evolution and brain function
Goals and Approach
The Human Cell Types team team at the Allen Institute for Brain Science aims to characterize the diverse cell types of the mammalian brain and to build foundational open-access cell type classifications. This team applies cutting-edge single cell molecular genetic approaches to measure the gene expression signatures of hundreds of thousands or even millions of individual brain cells. They then apply computational approaches to identify cell type clusters and compare these cell types across individuals and species to understand how they change in health and disease and across evolutionary scale.
Additional focuses for this team are: defining the shapes, electrical properties and local connections of neuronal cell types in the same contexts, and creating viral genetic tools that allow observation and manipulation of specific brain cell populations to facilitate cell type characterization across species and to create new AAV therapeutics.
The Human Cell Types team is creating single cell transcriptomic and multiomic atlases of precisely defined anatomic structures spanning the human brain and non-human primate brain. In combination with spatial transcriptomics, these atlases define baseline gene properties and spatial locations of brain cell types that can be compared between individuals and across species, and to which additional properties (such as cell morphology or physiology) can be assigned. Much of this work is part of the multi-institute Human and Mammalian Brain Atlas (HMBA) funded as part of BICAN.
The Human Cell Types team is applying novel computational approaches to multiomic datasets from diverse mammals to characterize cellular diversity in the brain. Recent work compares cell types in motor circuits across species to find gene expression patterns that may contribute to conserved and species-specialized traits. Their goal is to use cutting-edge machine learning models to identify gene regulatory sequences that are active in specific cell types. This will enable targeting and perturbation of cell populations in the nervous system to study circuit function and to treat disease.
The Human Cell Types team is working to generate unified structural ontology, parcellation criteria and 2-D/3D anatomical atlases across mammalian brains to support accurate and consistent brain region sampling, anatomical mapping of cell types, and correlation and integration of multimodal data. They are using a combined approach to ensure accurate parcellation of brain structures across species, which mainly include human, non-human primates, and rodents. This approach combines anatomical topography, cytoarchitecture, molecular signature and connectional patterns as well as comparative aspects of these features. They are also applying this approach to parcellating developing and abnormal brains.
The Human Cell Types team is working to explain diversity in the shape (morphology) and electrical properties (physiology) of mammalian brain cells in terms of transcriptomic cell types/diversity. In doing so they are able to gain insights into the function of cell types and how that function differs across mammalian species including mouse, macaque, and human. To accomplish these goals, they are using a method called patch-seq, which enables morphology, physiology and transcriptomes to be assayed from the same neuron in living brain tissue. In some rare cases they can obtain human neurosurgical tissues from brain regions that contain rare or specialized cell types. For example, they have successfully obtained single neuron recordings from cell types that are not found in rodent brains such as von Economo neurons (VENs), fork cells, and Betz cells, thus providing new clues about the possible functional roles of these fascinating cell types in the human brain.
The Human Cell Types team is seeking to understand the cellular and molecular changes that underlie Alzheimer’s disease initiation and progressive cognitive decline, with the ultimate goal of identifying targets for therapeutic intervention. To accomplish this, they are integrating single-cell profiling technologies with quantitative neuropathology and deep clinical phenotyping to create a multifaceted open data resource. This work is part of the Seattle Alzheimer’s Disease Brain Cell Atlas (SEA-AD) consortium, a collaboration with the University of Washington Alzheimer’s Disease Research Center (ADRC) and Kaiser Permanente Washington Health Research Institute (KPWHRI), that extends a previous collaboration focused on aging, dementia, and traumatic brain injury.
The Human Cell Types team is leveraging genomics data from mouse, macaque, and human to discover novel cell type-specific enhancers and then clone them into Adeno-associated virus (AAV) vectors that can be used to deliver transgenes of interest (e.g., fluorescent proteins, Cre recombinase, etc.) into the brain. They are optimizing these enhancer AAV tools for diverse experimental applications including functional perturbation experiments in vivo. A major advantage of viral labeling approaches is the ability to apply such tools to target genetically defined cell types across diverse mammalian species, which greatly facilitates detailed analysis of homologous cell types. These tools are characterized systematically to determine cell type specificity of labeling and ultimately widely distributed to the external scientific community to fuel neuroscience discovery efforts.
The Applied gene therapy group seeks to apply emerging enhancer-AAV tools to develop gene therapy vectors to combat human neurological diseases. This group is devoted to characterizing the natural history of diseases in animal models, to building and optimizing AAV vectors, testing vectors for safety and efficacy, and validating routes of administration in non-human primate models. They are engaged in internal projects and partnerships with academic collaborators and commercial entities like BioMarin Pharmaceutical. The Applied gene therapy group is committed to leveraging single cell and spatial omics data, tools and knowledge produced by the Allen Institute to develop first-in-class precision therapeutics to address major unmet medical needs.