Community Page The Human Brain Online: An Open Resource for Advancing Brain Research Sara Ball*, Terri L. Gilbert, Caroline C. Overly Allen Institute for Brain Science, Seattle, Washington, United States of America Introduction comparative evolutionary studies and hu- number of new methods were developed man genetics. The Allen Human Brain to deal specifically with human tissue in With an estimated 86 billion neurons Atlas is a multimodal atlas of gene this high-throughput setting. After tissue [1] and about a trillion synapses per cubic expression and anatomy comprising a procurement—which involves obtaining centimeter of cortex [2], the human brain comprehensive ‘‘all genes, all structures’’ consent, tissue dissection, MRI, and diffu- is arguably the most complex system in the array-based dataset of gene expression and sion tensor (DTI) imaging, slabbing, and human body, and it is the seat of diseases complementary in situ hybridization (ISH) freezing of the tissue all within a very short and disorders that affect an estimated one studies targeting selected genes in specific window of time—rigorous steps are taken billion people worldwide [3]. Yet the brain regions. All data are publicly for sample inclusion, such as assessment of human brain remains poorly understood. available online (www.brain-map.org) tissue/RNA quality, gross and microneur- Model systems are essential to progress in along with a suite of integrated data opathology, toxicology, and medical his- neuroscience, but a true understanding of visualization and mining tools that enable tory research. New workflows allowed for the human brain and the diseases and scientists to uncover connections between sampling of specific anatomic regions for disorders that affect it ultimately requires structure, function, and the brain’s under- microarray analysis and mapping those analyses of the human brain itself. Human lying biochemistry. locations back into the 3-D brain space brain tissue is a rare commodity and In developing the earlier Allen Mouse determined by the MRI. Detailed descrip- therefore inadequately explored. Pub- Brain Atlas, a genome-wide, high-resolu- tions of scientific and informatics methods lished studies point to the scarcity of tion atlas of gene expression throughout are available in the whitepapers under the high-quality postmortem human brain the adult mouse brain [6], the Allen Documentation tab of the online atlas. tissue, particularly disease-free control Institute for Brain Science created the brains [4]; the largest brain bank in the infrastructure to handle high-throughput Data and Tools United States reported last year that only ISH, microscopy, and data processing. 40–50 control brains become available The Allen Human Brain Atlas includes This expertise enabled the Allen Institute genome-wide microarray data for approx- each year [5]. Further hindrance lies in the to tackle high-throughput processing of fragmented nature of data from studies imately 500 discrete anatomic regions per human tissue and to systematically create hemisphere of the adult human brain, with human brain tissue. Brain banks an atlas of spatially mapped gene expres- along with ISH data covering select genes typically subdivide the brain into small sion in the human brain. In addition to in specific brain regions and complemen- blocks to distribute among a variety of decisions concerning level of resolution tary anatomic data. With more than 100 researchers, thus precluding holistic anal- and project scope [7], a major challenge million microarray expression data points yses, and data derived from such studies was to define processes for systematic from three brains and over 46,000 ISH are focused on diverse and often nonpar- dismantling and sequential partitioning of images to date, the depth and breadth of allel hypotheses and experimental the brain to enable gathering multiple data transcend the resources available to approaches. types of data from a single brain and allow traditional laboratories, allowing scientists Here we describe an open online reassembly of those data into a unified 3-D to easily explore beyond the streetlamp resource, the Allen Human Brain Atlas, framework. From initial tissue procure- and into the shadows. The entire data- which puts comprehensive, standardized ment and processing at the front end to set—including MRI, DTI, histology, im- data from multiple entire human brains data integration at the other end, a munohistochemistry, ISH, transcriptome into the hands of the global research community, along with tools for mining Citation: Ball S, Gilbert TL, Overly CC (2012) The Human Brain Online: An Open Resource for Advancing Brain and making sense of that data. This Research. PLoS Biol 10(12): e1001453. doi:10.1371/journal.pbio.1001453 resource opens new avenues for advancing Published December 27, 2012 research programs across disciplines that share an interest in the human brain— Copyright: ß 2012 Ball et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, from neuroscience research programs provided the original author and source are credited. based on functional MRI (fMRI) or Funding: A complete list of funders can be found here: http://help.brain-map.org/download/attachments/ neuropharmacology, for example, to 2818165/Acknowledgments_funders.pdf?version=1&modificationDate=1338492307010. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. The Community Page is a forum for organizations and societies to highlight their efforts to enhance Abbreviations: DTI, diffusion tensor imaging; GWAS, genome-wide association studies; fMRI, functional the dissemination and value of scientific knowledge. magnetic resonance imaging; ISH, in situ hybridization; MRI, magnetic resonance imaging. * E-mail: [email protected] PLOS Biology | www.plosbiology.org 1 December 2012 | Volume 10 | Issue 12 | e1001453 data from microarray, and anatomic profiles, highlighting interest in a certain Institute offers both Web-based and in- annotation—is viewable online and down- region of the brain. Detailed gene expres- person training sessions, as well as video loadable for offline use and analysis. The sion information for that region provides a tutorials, to help researchers become more associated Web application includes path to a more complete understanding of adept at using these resources. Addition- unique search and visualization tools its underlying biochemistry, potentially ally, the Allen Human Brain Atlas has providing multiple entry points into the revealing what distinguishes it from other been designed to facilitate cross-referenc- data, accompanied by an interactive 3-D brain areas and helping to elucidate the ing with other Allen Brain Atlas resources viewer that allows you to spin, slice, and biological processes that relate to the for comparative studies among species and search each entire brain in the virtual phenotype of interest. Further, a recent across development. A growing hub for world (Figure 1). With more brains in the review points to the potential of fMRI extensive, systematically generated data- pipeline and a large ISH study of neuro- studies to speed the drug discovery process sets and sophisticated data mining and transmitter system genes underway, new for central nervous system diseases, par- visualization tools, the Allen Brain Atlas data will be added to the Atlas into 2013. ticularly via use of brain imaging biomark- portal provides public access to a collec- Initially launched online in May 2010, the ers [12]. The Atlas can take this proposed tion of resources for exploring the central Allen Human Brain Atlas is already a process a step further by revealing associ- nervous system. These include gene ex- widely used resource with approximately ations between regions or imaging bio- pression atlases of the adult and develop- 7,000 unique visitors each month world- markers of interest and genes at work in ing mouse brain, mouse spinal cord, adult wide. those areas. and developing human brain and the The Allen Human Brain Atlas database As most work in neuroscience is con- rhesus macaque brain, as well as a recently and associated Web application were ducted in model systems, the Atlas also launched mouse brain connectivity atlas. designed as a bridging resource, with provides a platform to help verify and The entire suite of Allen Brain Atlas multiple data types offering multiple entry translate such work into a human context. resources, with embedded crosslinks to points for researchers coming from differ- A recent paper scratches the surface of the related data and global search across all ent areas of expertise with different types of comparisons that can be made datasets, is available at http://www.brain- questions. Whether accessing the Allen between the mouse and human brain map.org. Human Brain Atlas from a gene-centric using publicly available online data. Furthermore, there is a growing num- perspective or a structural or functional Among other observations, the study ber of other online resources that can be point of view, the variety of data— points to a 79% similarity in expression used synergistically with the Allen Human histology, annotation, genomics, and of approximately 1,000 genes in the visual MRI—provides a launchpad