0090-6964/98 $10.50 1 .00 Copyright © 1998 Biomedical Engineering Society
Annals of Biomedical Engineering, Vol. 26, pp. 911–913, 1998 Printed in the USA. All rights reserved.
The Microcirculation Physiome Project A. S. POPEL,* A. S. GREENE,† C. G. ELLIS,‡ K. F. LEY,§ T. C. SKALAK,§ AND P. J. TONELLATO] *Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD, †Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, ‡Department of Medical Biophysics, University of Western Ontario, London, Canada, §Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, and ]Department of Mathematics, Statistics and Computer Science, Marquette University, Milwaukee, WI (Received 3 August 1998; accepted 12 August 1998)
Abstract—Presented is a discussion of steps towards the creation of a database of the microcirculation encompassing anatomical and functional experimental data, and conceptual and computational models. The discussion includes issues of database utility, organization, data deposition, and linkage to other databases. The database will span levels from gene to tissue and will serve both research and educational purposes. © 1998 Biomedical Engineering Society. @S0090-6964~98!01706-8#
A group of approximately 100 life scientists, including physiologists, biomedical engineers and bioinformatics specialists, met in San Francisco on April 16–17, 1998, in conjunction with the Microcirculatory Society and Experimental Biology annual meetings, to discuss possibilities of creating a database of experimental data and theoretical models in the area of microcirculation. The meeting was organized by Andrew S. Greene, Medical College of Wisconsin, and Aleksander S. Popel, Johns Hopkins University, and served as the inauguration of a working group of the Microcirculation Physiome Project. The goal of the project is to create a World Wide Web accessible database of the microcirculation that encompasses anatomical and functional data, spanning levels from the gene to the tissue, with mathematical models, computational engines, and tools for integration. The proposed database will include information on microcirculations in the heart, brain, skeletal muscle, lung, kidney, liver, pancreas, spleen, bone, eye, and other organs in health and disease. Information on biological systems continues to amass at a rapid rate. While attempts to integrate this information have begun, most of the effort has been aimed at collection of genetic sequence information. As the task
of compiling this information nears completion we must begin to layer functional data onto these databases. One attempt at organizing functional information is the Physiome Project. The Physiome Project is an integrated program whose mission is to archive and disseminate quantitative data and models of the functional behavior of biological molecules, cells, tissues, organs, and organisms. Several organ-based efforts, such as the Cardiome, have begun to develop. The working group is now proposing that a functional system such as the microcirculation is a logical extension of the organ-based approaches, since much of its structure and function are common between organs, and because its hemodynamic and transport function provides an important coupling between cells, tissues, and organs. In July 1997 a workshop entitled ‘‘On Designing the Physiome Project’’ ~http://www.physiome.org! was held near St. Petersburg, Russia, as a satellite meeting of the International Union of Physiological Sciences Congress. Thirty-four participants represented a broad range of international academic institutions, pharmaceutical industry, and the US Health and Human Services. Recommendations of this group included microcirculation as a focus area and an important system for integration since its role spans many tissues, organs, and diseases. It was noted that research in the area of microcirculation spans all of the NIH institutes. A quantitative understanding of the structure and functional properties of the microcirculation is also crucial for the emerging area of tissue engineering where it is necessary to engineer not only parenchymal cell constructs but also microvascular networks. Based upon the recommendations arising from the St. Petersburg group, the organizers of the San Francisco meeting identified three specific goals to be addressed:
Address correspondence to Dr. Aleksander S. Popel, Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21205. Electronic
[email protected]
~1! to discuss concepts of the project; ~2! to discuss standards for the curation and reporting of data and models to the microcirculation databases;
Keywords—Physiological database, Computational model, Conceptual ~pathway! model.
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~3! to explore mechanisms for publicizing and expanding access to the database; to produce an action report summarizing the meeting and its recommendations. The following issues were discussed at the meeting: ~1! How would the scientific community benefit from the resource? ~2! What should its content be, and how would it be used? ~3! How should the information be organized ~taxonomy issues: by species, by disease, by structural level, by function!? ~4! How could it be searchable ~e.g., by molecule, process, disease, cell type, vessel type!? ~5! How should the information be deposited—directly by scientists and/or curated by an editorial board? How can data quality be ensured? ~6! How should the information be linked to other databases? ~7! How would search engines be designed? ~8! How can preservation of intellectual property rights and copyright be ensured? The program consisted of presentation sessions followed by small group discussions. A. S. Popel in his introduction proposed that the database should consist of three parts: experimental data, conceptual models, and quantitative mathematical/computational models. Conceptual models are essentially physiological hypotheses expressed in the form of connections ~pathways, flow charts! between different structural and functional elements of the system. Making such models available would facilitate further development of complex physiological hypotheses; mechanisms should be in place that ensure that proper credits be given to the authors of previous models or versions of the models. Conceptual models could have many depth levels ~e.g., a link may reveal detailed biochemical reactions and those, in turn, lead to appropriate information in protein databases!. The conceptual models would serve as a foundation for mathematical/computational models, with additional structural, biophysical, and physiological information. J. B. Bassingthwaighte, University of Washington, who conceived the physiome concept and its name, presented general concepts of the Physiome Project. The project is described as an integrated multicentric program to design, develop, implement, test and document, archive and disseminate quantitative information and integrative models of the functional behavior of organelles, cells, tissues, organs, and organisms. The long-range goal is on the human organism, its physiology and pathophysiology, but much or most of what must be learned will come from other species. The project aims toward providing models that summarize information on physi-
ological systems, integrating the observations from many laboratories into quantitative, self-consistent, comprehensive descriptions. The goal of the project is to provide functional descriptions of human biological systems in health and disease. A. D. McCulloch, University of California at San Diego, discussed challenges of the Cardiome project, probably the most advanced effort within the Physiome Project. K. H. Fasman, then at the Whitehead/MIT Center for Genome Research and currently at Astra AB, presented his thoughts about building a public biological database based on his experience with the Human Genome Database. P. D. Karp of Pangea Systems, Inc. gave an overview of the E. coli Metabolic Pathways database. P. J. Tonellato, Marquette University and Medical College of Wisconsin, and A. S. Greene, Medical College of Wisconsin, discussed a genomic/ physiological database created for a ‘‘high-throughput physiology’’ project on hypertension. T. C. Skalak, University of Virginia, described issues of quantitative description of microvascular networks and their remodeling. His colleague, K. F. Ley, discussed how studies and database developments in functional genomics are relevant to microcirculation. Finally, two scientists from the San Diego Supercomputing Center, P. E. Bourne and D. Sutton, gave examples of biological and nonbiological databases and visualization tools developed by the Center. These presentations were followed by small discussion group sessions; summaries were subsequently presented to and discussed by the entire group. Below is a summary of major recommendations of the group. The proposed database would contain numerical records, text, and images describing spatial and temporal ~3D and 4D! anatomical, biophysical, and physiological characteristics. The database will be a tremendous resource for overview and further development of concepts, generation of new hypotheses, mathematical and computational modeling, particularly integrative models. It will benefit both suppliers and users of the information and will facilitate collaborations. The database will serve research communities in microcirculation and physiology and beyond, such as biotechnology and pharmaceutical industries. The database should use modern multimedia technology to be useful as an educational resource for students from K–12 to undergraduate and graduate. Specific, well focused projects were recommended as starting points. Examples include microvascular ~or even organ! network structure and hemodynamics, leukocyte– endothelium interactions, gas exchange ~skeletal muscle, heart, brain, lung!, angiogenesis with applications to cancer, diabetes, and arteriosclerosis. It would be important to link the emerging databases to existing genomic, proteomic, and pathway ~e.g., metabolic, signaling! databases. ‘‘User groups’’ for pilot projects should be initiated. More specifically, for the microvascular networks project~s! the following tissues were identified as pos-
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sible targets: skeletal muscle, heart, brain, intestine, mesentery, kidney, lung, tumors, retina, inner ear. Coordinating centers would be useful for integration and providing the necessary infrastructure for the project ~e.g., Center for Computational Medicine and Biology at the Johns Hopkins University, the BioNOME Resource at the San Diego Supercomputing Center, Informatics Research Center at the Medical College of Wisconsin, National Simulation Resource for Circulatory Mass Transport and Exchange at the University of Washington!. For data submission, several mechanisms could be considered such as: direct submission without curation, submission with continuous public review/comments, and curation of data by a board of experts. Funding mechanisms should be identified. Scientific societies should be surveyed that would sponsor the project. International cooperation should be developed that would
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enable different groups be funded by different national and international sources. Intellectual property rights for the database material would have to be established. Incentives for submitting data to the database have been discussed; e.g., major journals might require that data be deposited as a condition for publication. Guidelines for database use would have to be determined. Access might be different for educational, nonprofit research, and commercial use. Subscription fees might be necessary to support database maintenance and development. The working group expressed an interest in holding further meetings dealing with the Microcirculation Physiome Project. It recommended to start on-line discussions and survey the resources currently available. Further information about the project will be presented at www.bme.jhu.edu/news/microphys/.