Physiol. Genomics 30: 209-212, 2007.
First published May 8, 2007; doi:10.1152/physiolgenomics.00002.2007
1094-8341/07 $8.00
Received 2 January 2007;
accepted in final form 27 April 2007.
Physiological Genomics 30:209-212 (2007)
1094-8341/07 $8.00 © 2007 American Physiological Society
Perspectives
Integrative pathway knowledge bases as a tool for systems molecular medicine
Mingyu Liang
Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin
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ABSTRACT
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There exists a sense of urgency to begin to generate a cohesive assembly of biomedical knowledge as the pace of knowledge accumulation accelerates. The urgency is in part driven by the emergence of systems molecular medicine that emphasizes the combination of systems analysis and molecular dissection in the future of medical practice and research. A potentially powerful approach is to build integrative pathway knowledge bases that link organ systems function with molecules.
bioinformatics; translational research; systems biology; database; physiology
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INTRODUCTION
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BIOMEDICAL SCIENTISTS TYPICALLY work on a component or a segment of a regulatory network in their daily research. The size of the portion that can be worked on at any given time has increased in the genomic/postgenomic era, and the need for biomedical scientists to think in an integrative manner is increasingly obvious. Clinicians have always been taught to think in an integrative, multiscale manner as they evaluate and treat patients. Fragmentation of knowledge, however, limits the dimensionality of their thinking. As fragments of knowledge accumulate at an accelerating pace, there is a sense of urgency to begin generating a cohesive assembly of biological and medical knowledge. One of the approaches toward generating such an assembly is to build organized and digitized knowledge bases of pathways and networks of pathways.
This brief article examines the concept of biological pathways, introduces integrative functional pathway knowledge bases, and discusses the significance of integrative functional pathway knowledge bases in the emerging field of systems molecular medicine.
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UNDERSTANDING BIOLOGICAL REGULATION AS NETWORKS OF PATHWAYS
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The concept of "pathway" is widely used in biomedical research and clinical medicine. It refers to a group of biological entities and their sequential (or mainly sequential) relationship that contains a flow of biological information. In a cellular metabolic pathway, the relationship is mainly that of a conversion as substance A is converted to substance B, often catalyzed by an enzyme (Fig. 1A). Substance B can be converted to another substance catalyzed by a different enzyme, and the sequence of events continues to form a pathway. A typical example is the glycolysis pathway where glucose is converted to glucose-6-phosphate when catalyzed by hexokinase and glucose-6-phosphate is then converted to fructose-6-phosphate, etc.
A pathway becomes an amplifying cascade when substance B, the product of a conversion reaction, acts as a catalyst or facilitator of another conversion reaction (Fig. 1B). The cAMP pathway is a typical example of this type of signal transduction pathway. Activated adenylate cyclase, converted from inactive adenylate cyclase by an activated G protein subunit, catalyzes the conversion of ATP to cAMP. cAMP, in turn, facilitates downstream reactions.
The integrative function of an organ system or an organism is often mediated or controlled by interactions between biochemical entities (molecules, reactions) and biophysical elements (force, movement, dimension, etc.) within certain anatomical structures. These interactions form integrative functional pathways that manifest over time and within the context of specific biological states (Fig. 1C). For example, the regulation of arterial blood pressure is most appropriately illustrated by a pathway beginning with biophysical terms indicating the fact that arterial blood pressure at any given moment is determined by cardiac output and peripheral vascular resistance. The control of each of the two determinants can then be illustrated by a series of biophysical and biochemical pathways. Abnormalities can be presented in the context of integrative functional pathways to explain complex diseases such as hypertension.
Biological pathways in a human body do not exist in isolation. Boundaries of pathways are often arbitrarily defined. A seemingly self-contained pathway can be easily considered a segment of a larger pathway. An element in a pathway, either the final product or an intermediate, could be part of another pathway. A downstream element or pathway could affect upstream events through feedback control mechanisms. All of this gives rise to the concept of a regulatory network that highlights the interconnectivity and interdependence of various parts and pathways in a human body.
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METABOLIC AND SIGNALING PATHWAY KNOWLEDGE BASES
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Several dozen knowledge bases containing large collections of biological pathways have been built over the last few years. A fairly complete list of currently available pathway knowledge bases is available at http://www.pathguide.org/, although one could argue that many databases on the list, such as protein interaction databases, do not contain an explicit flow of information and, therefore, differ from conventional pathways. Several examples of publicly available pathway knowledge bases and their URLs, home institutions, and main contents are listed in Table 1. In addition to free, publicly available knowledge bases, several pathway knowledge bases are available for purchase or subscription. Notable examples include Ingenuity Pathways created by Ingenuity Systems (http://www.ingenuity.com/) and the Connections Map in the Signal Transduction Knowledge Environment hosted by Science (http://stke.sciencemag.org/cm/).
As one can see from Table 1, the overwhelming emphases of existing pathway knowledge bases are metabolic and signaling pathways. Some of the knowledge bases, such as KEGG Pathway, GenMAPP, and BioCarta, provide some but limited information about disease and integrative pathways.
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SiMAP AS AN EXAMPLE OF AN INTEGRATIVE FUNCTIONAL PATHWAY KNOWLEDGE BASE
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Knowledge bases of metabolic and signaling pathways, together with numerous databases containing information of genomes, genes, proteins, and small molecules, provide a valuable cell and molecular basis for understanding biology. A major challenge for bioinformaticians, bench experimentalists, and clinicians alike, however, is how to integrate all of the above into a cohesive picture of the function of organ systems and the human body as a whole. How do genes and other molecules work together to control the function of a human heart? How do abnormalities in a signal transduction pathway lead to the development of high blood pressure? Information needed to answer important questions such as these is abundant in the literature. However, it is often a challenge for molecular biologists or geneticists to fully access the known physiological and clinical context of the relationships among individual molecules and for physiologists and clinicians to grasp all the cell and molecular intricacies of a complex disease. One solution is to build integrative functional pathways that allow scientists and clinicians to navigate with ease from organ systems physiology and medicine to cell and molecular biology and back.
Integrative functional pathways are the explicit emphasis of a new pathway knowledge base at an early stage of development, Systems and Integrative Molecular Atlas of Physiology (SiMAP, http://simap.mcw.edu) (3). The concept of SiMAP clearly emphasizes the integration of biochemical, biophysical, and anatomical information ranging from the molecular level to organ systems physiology and common diseases (Fig. 2A). Accordingly, SiMAP is explicitly presented as networks consisting of pathways that are extensively linked with each other both vertically from organ systems to molecules and horizontally across parallel mechanisms. The layered structure allows users to navigate from clinical diseases and organ systems physiology to molecules or the other way around. Links to literature references, molecular annotations, and outside pathway knowledge bases are provided. By integrating cell and molecular information into organ systems function and complex diseases, SiMAP fills a significant gap in bioinformatics (Fig. 2B).
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Fig. 2. Systems and Integrative Molecular Atlas of Physiology (SiMAP) as an example of an integrative functional pathway knowledge base. A: SiMAP emphasizes the integration of organ systems physiology with cell and molecular mechanisms. SiMAP consists of a relational database and a network of pathway diagrams. B: SiMAP fills a significant gap in bioinformatics.
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INTEGRATIVE PATHWAY KNOWLEDGE BASES AS A TOOL FOR SYSTEMS MOLECULAR MEDICINE
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An obvious benefit of representing biological regulation in the form of pathway diagram is in the schematic visualization itself. Schematics, compared with text, are easier for human brains to memorize, process, and understand. The popularity of tools such as GenMAPP and Ingenuity Pathways in representing large-scale gene expression data is an example of the power of schematic diagrams in facilitating the understanding and interpretation of biological regulation. In addition, pathway knowledge bases can serve as an excellent basis on which the rich information from databases of genomes, genes, proteins, and small molecules can be placed to illustrate or reveal the biological and functional relevance of the molecules.
An exciting, yet largely unrealized, value of an integrative pathway knowledge base such as SiMAP is facilitating systems analysis of human function and disease. The last few years have witnessed a renewed recognition that biology is best understood when one takes a multidimensional integrative approach that has been made more feasible than ever by recent progress in genomics and high-throughput technologies (7). However, if the concept of systems biology (1) is to fully realize its potential, it will have to be applied to human function, disease, and medicine.
The concept of "systems molecular medicine" highlights the application of a combination of systems analysis and molecular dissection in the future of medical research and practice. The enormous complexity, compared with simpler model organisms, makes human physiology and disease a particularly appropriate, although challenging, subject for such a systems molecular approach.
Tools such as SiMAP could be highly valuable to systems molecular medicine. An integrative pathway knowledge base such as SiMAP will greatly facilitate the navigation through the vast quantity of biological and medical knowledge by both clinicians and biomedical scientists. Clinicians and biomedical scientists often think about a disease, a treatment, or a scientific question using a small system containing a small number of elements and relationships, especially when decisions or judgments have to be made within a short time frame. This is, in many cases, by necessity, not by choice, because it is simply beyond the human brain's capability to simultaneously process a large number of elements and their complex relationships. An integrative pathway knowledge base such as SiMAP allows visualization of complex regulatory relationships with a few clicks of a mouse. The ease will make it more feasible and, thereby, encourage clinicians and biomedical scientists to think more often in an integrative systems manner that is necessary for truly understanding human physiology and complex diseases.
A scientifically more exciting possibility is that an integrative pathway knowledge base such as SiMAP may help to reveal properties of, and identify missing links in, the regulatory network of normal and diseased human function. Such an effort to utilize pathway knowledge bases as a discovery tool in systems molecular medicine is in a very early stage. One possibility is to use pathway knowledge bases for qualitative modeling to reveal qualitative network properties or identify missing relationships or gaps in the current knowledge.
Another possibility is to use integrative functional pathway knowledge bases as a framework for large-scale, quantitative systems modeling. While a qualitative description of a defined pathway is often used as a starting point for quantitative modeling of a specific biological process, larger-scale modeling will require a more extensive qualitative framework. It is conceivable that an integrative functional pathway knowledge base such as SiMAP will facilitate quantitative modeling that aims for integrating various aspects of biological regulation ranging from the molecular level to whole human body. Quantitative models of a specific biological process can be built beginning from the qualitative description of the process in SiMAP. SiMAP can then assist the assembly of quantitative models of related processes into a larger, cohesive model. The qualitative framework in SiMAP will be gradually and, ultimately, completely replaced by quantitative models as the framework guides the growth of quantitative models. In this regard, it is interesting to note that many models in the Physiome Project (http://www.physiome.org.nz), a project aimed for mathematically modeling all physiological processes (4), contain schematic representations of pathways that appear to be fundamental to the quantitative modeling efforts.
The value of an integrative pathway knowledge base is clear. It is an area where interdisciplinary collaboration among clinicians, biomedical scientists, and computer scientists will likely bear fruit.
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GRANTS
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This work is supported in part by National Heart, Lung, and Blood Institute Grant R01HL-077263.
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FOOTNOTES
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Address for reprint requests and other correspondence: M. Liang, Dept. of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (e-mail: mliang{at}mcw.edu)
Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).
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Copyright © 2007 by the American Physiological Society.
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ABSTRACT
INTRODUCTION
