Mark H. Ellisman - Abstract and Bio
Abstract
MULTI-SCALE IMAGING OF THE NERVOUS SYSTEM: Including New Views of Astrocytes and Delineation of their Territories
Mark H. Ellisman, Ph.D.,
Professor, UCSD Departments of Neurosciences and Bioengineering; Director of the Biomedical Informatics Research Network Coordinating Center (BIRN-CC) (www.nbirn.net); and the National Center for Microscopy and Imaging Research (NCMIR) (http://www.ncmir.ucsd.edu/) - within the Center for Research in Biological Systems at the University of California San Diego at UCSD - La Jolla, California
The grand goal in neuroscience research is to understand how the interplay of structural, chemical and electrical signals in nervous tissue gives rise to behavior. Experimental advances of the past decades have given the individual neuroscientist an increasingly powerful arsenal for obtaining data, from the level of molecules to nervous systems. Scientists have begun the arduous and challenging process of adapting and assembling neuroscience data at all scales of resolution and across disciplines into computerized databases and other easily accessed sources. These databases will complement the vast structural and sequence databases created to catalogue, organize and analyze gene sequences and protein products. The general premise of the neuroscience goal is simple; namely that with "complete" knowledge of the genome and protein structures accruing rapidly we next need to assemble an infrastructure that will facilitate acquisition of an understanding for how functional complexes operate in their cell and tissue contexts. Our U.C. San Diego-based group is leading several interdisciplinary projects around this grand challenge. We are evolving a shared infrastructure that allows for mapping molecular and cellular brain anatomy in the context of a shared multi-scale mouse brain atlas system. The informatics framework is facilitating cooperative work by distributed teams of scientists engaged in focused collaborations aimed to deliver new fundamental understanding of structures on the scale of 1 nm to 10's of µm's, a dimensional range that encompasses macromolecular complexes, organelles, and multi-component structures like synapses and the cellular interactions in the context of the complex organization of the entire nervous system. This effort is providing multi-scale structural frameworks for construction of models that are now being used to test hypotheses using software tools that allow for simulation of microphysiological and network properties of nervous systems.
Since understanding of the structure function relationships in the nervous system must include careful consideration of its glial cells we have focused considerable attention on these cells. Most notably, the spatial interactions occurring between protoplasmic astrocytes in vivo are poorly understood. Previous attempts to characterize these interactions have relied on immunolabeling of glial fibrillary acidic protein (GFAP) and on assumptions based on a generalized view of these complex cells. We have approached this problem using a protocol that allows for the differential fluorescent labeling of cells in their entirety while preserving their natural morphologies. We have determined that traditional labeling of astrocytes via GFAP labeling greatly under represents the extent of the astrocyte by an astonishing 85%. Furthermore, we have determined that domains of astrocytes do not overlap; instead of interdigitating, astrocytes abut one another. Thus our main contribution to this area has been to correct previous estimates of astrocyte size and domains leading to a new model of astrocytic parcellation of neuropil. Furthermore, this technique allows one to subsequently label molecular elements of the tissue using immunohistochemistry or to photooxidize the injected dye and analyze the corresponding structures at the electron microscopic level.
Bio: Mark H. Ellisman, Ph.D.
Dr. Mark Ellisman is Professor of Neurosciences and Bioengineering at the University of California San Diego. After earning a Ph.D. in molecular, cellular, and developmental biology from the University of Colorado, Boulder, Ellisman began his tenure at UCSD in 1977.
In 1988, Ellisman established the National Center for Microscopy and Imaging Research (NCMIR) to achieve greater understanding of the structure and function of the nervous system by developing three-dimensional light and electron microscopy methods spanning dimensions from 1nm to 10's of µm's. Ellisman, also a founding fellow of the American Institute of Medical and Biological Engineering, has received numerous awards including the Jacob Javits Neuroscience Investigator Award from the National Institutes of Health (NIH) and the Creativity Award from the National Science Foundation (NSF).
Since 1996, he has been serving as the founding director of the UCSD Center for Research in Biological Systems (CRBS) and has received several teaching awards, including the Department of Neurosciences Award for Outstanding Teaching in 1987 and 1992, and was named the University Lecturer in Biomedicine in 2001. He is also the interdisciplinary coordinator for the National Partnership for Advanced Computing Infrastructure (NPACI) and leads NPACI's Neuroscience thrust, which involves integration of brain research and advanced computing and communications technologies.
In 2001, Ellisman founded the Biomedical Informatics Research Network (BIRN), a NIH initiative that provides a multiscale imaging infrastructure linking major neuroimaging centers around the country. The BIRN builds infrastructure and technologies to enable large-scale biomedical data mining and refinement. The following year, he was appointed to the National Advisory Council of the NIH National Center for Research Resources (NCRR) and to the Physics Division Review Committee of the Department of Energy, Los Alamos National Laboratory.
Dr. Ellisman is recognized nationally and internationally for helping to pioneer the development of new technologies that enhance neurobiological and clinical research. His laboratory is actively pursuing several research tracks that are yielding seminal contributions to neuroscience.
The first track focuses on the role of astrocytes in the cellular organization of the brain. Ellisman's laboratory is known in the international neurobiological community for its paradigm-shifting work on astrocytes, the most prevalent glial cell type in the mammalian nervous system. Through investigation of the dynamics of myelinated nerves and the maturation of astrocyte "spongiform" morphology, Ellisman and his colleagues were the first to observe and document that these cells establish individual domains of activity, with limited overlap occurring between the extents of neighboring astrocytes, a finding that fundamentally redefines our understanding of the cell as a unique domain.
On a second research track, Ellisman's lab is at the forefront of efforts to tackle the large-scale federation and integration of biomedical databases, leading to the creation of new infrastructures and thinking on how to meld information and assemble systems that allow scientists to navigate multiscale databases, and how to make new knowledge discoverable using neuroinformatics.
Instrument development and new technologies represents a third area of collaborative research in Ellisman's lab, as evidenced by the creation of a new electron microscope that permits unprecedented 3D imaging and accessibility for acquiring mesoscale neuroscientific data.
Employing advanced imaging and reconstruction methods developed at NCMIR, the Ellisman group continues to pursue new lines of inquiry regarding the structure and function of nerve amplifiers within the node of Ranvier. Using high-resolution 3D structures of the node's structures in microphysiological models is helping to advance knowledge about how aging and disease influence nerve transmission.
On a fifth research track, the Ellisman group has simulated a ganglion synapse and demonstrated ectopic activation. Through a collaborative effort with the Salk Institute and UCSD's Department of Biology, the team developed in silico experiments, using Monte Carlo simulations with high-resolution serial electron microscopic tomography, to identify a novel model synapse exhibiting ectopic neurotransmission. The group has found that simulated synaptic activity is consistent with experimental recordings of miniature excitatory postsynaptic currents only when ectopic transmission is included in the model, broadening the possibilities for mechanisms of neuronal communication.
Dr. Ellisman regularly engages in high-profile activities for the university and at the national and international levels. In addition to his CRBS directorship, he serves as Director of the Laboratory for Neurocytology (a core electron microscopy facility for UCSD), the BIRN Coordinating Center, and NCMIR. Further, he is former chair of the Executive Committee of the San Diego Super Computer Center and former leader of the "Neuroscience Thrust" of the National Partnership for Advanced Computational Infrastructure, a large-scale collaborative effort among 50 universities nationwide led by UCSD.
In addition to editorial activities for numerous first-tier specialty journals such as the Journal of Neurocytology and Journal of Neuroinformatics, Dr. Ellisman is a much sought-after lecturer and consultant to governmental agencies and foundations, in the United States and worldwide.
