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- BioSeek's approach to drug discovery featured in Nature Biotechnology issue on Systems Biology - Click for pdf |
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Systems Biology-what is it? Historically, much of the emphasis of biological research has been placed on identifying the function of the individual parts of the cell on a part-by-part basis. This, so called, "reductionist" approach was based on the assumption that by unraveling the function of all the different component parts the information gained could be used to piece together the maze of complex metabolic pathways and intermolecular relationships which form the basis of life itself, rather like a puzzle. This is a slow and exhaustive process that fails to adequately account for the true complexities of the systems under investigation and is of limited relevance to biological systems as a whole. Systems biology is the study of the ways in which the elements of biological systems including genes and proteins integrate and interact within an organism. It requires a broad interdisciplinary approach. In addition to molecular and cell biology and medicine, systems biology draws on the disciplines of chemistry, informatics, math, computing and engineering. It relies on the combination of hypothesis-driven perturbation and global capture of data and is a strategic iterative experimental approach focused heavily on quantitative, not qualitative, information. On a practical level, systems biology involves the systematic and precise manipulation of individual genetic and/or environmental factors and the subsequent global analysis of biological parameters that are altered. The analysis of this information in the global perspective of a network of molecules then allows the deciphering of molecular interactions and the recognition of a broad number of downstream biological effects. Systems biology and drug discovery Systems biology allows the systematic analysis of the changes that constitute the basis of a disease within the global cellular environment. This makes it possible to gain far more information concerning the identification of the major genes or proteins involved and therefore lead to improved means of targeting for therapeutics. More critically, it provides an early means of accurately distinguishing the efficacy of a drug in a physiologically relevant environment. This allows the early identification of drug activities with the potential to dramatically improve the rate of success, and reduce the time and cost of the drug development process. For further reading about systems biology please refer to selected articles below: Systems biology in drug discovery Eugene C Butcher, Ellen L Berg, and Eric J Kunkel Nature Biotechnology The hope of the rapid translation of 'genes to drugs' has foundered on the reality that disease biology is complex, and that drug development must be driven by insights into biological responses. Systems biology aims to describe and to understand the operation of complex biological systems and ultimately to develop predictive models of human disease. Although meaningful molecular level models of human cell and tissue function are a distant goal, systems biology efforts are already influencing drug discovery. Large-scale gene, protein and metabolite measurements ('omics') dramatically accelerate hypothesis generation and testing in disease models. Computer simulations integrating knowledge of organ and system-level responses help prioritize targets and design clinical trials. Automation of complex primary human cellÐbased assay systems designed to capture emergent properties can now integrate a broad range of disease-relevant human biology into the drug discovery process, informing target and compound validation, lead optimization, and clinical indication selection. These systems biology approaches promise to improve decision making in pharmaceutical development. Systems Biology Completes The Circle Jennifer Van Brunt Signals Magazine, June 21, 2003 Systems biology practitioners - at universities, government and non-profit labs and companies -- have been hard at work these last several years developing the technologies and computational tools they believe will allow them to actually study intact biological systems - such as human beings. They've created massive databases bursting with information - especially in genomics and proteomics. They've devised amazingly clever algorithms and bioinformatics capabilities to interpret these data. They've even modeled diseases in silico. But despite these advances - and the knowledge that the next scientific challenge is to integrate every piece of biological information into a cohesive whole -- the field is just now at the point where everyone understands exactly what it will take to accomplish this awesome feat. Biologists' New Approach: Do Not Shoot the Radio. Sharon Begley The Wall Street Journal, February 21, 2003. Sharon Begley provides an insightful layperson's account of the current inadequacies of biological research and introduces the new paradigm of Systems Biology, how it has developed and its promise for the future. Sharon uses a clever analogy by likening the efforts of current reductionist approaches to biologists trying to fix radios. They find it impossible because they spend all their time on a part-by-part approach and fail to view the radio as a system. They do not identify the interacting parts which make it work. Advancing Drug Discovery through Systems Biology Davidov et al Drug Discovery Today, February 2003. This article outlines how Systems Biology attempts to facilitate and alleviate many of the current drug discovery issues and problems. The systematic integration of technologies results in a superior output of data and information, which enhances the understanding of biological function, chemico-biological interactions and, ultimately, drug discovery. Systems Biology Alexandra Strikeman Technology Review, March 2002 This article outlines how the completion of the genome simply provides the "rule book" but systems biology is the "ball game." What systems biology is and how it stands to revolutionize the drug discovery/development process. Integrated genomic and proteomic analyses of a systematically perturbed metabolic network. Ideker T, et al Science 292, 4 May 2001 This important paper describes an integrated approach to build, test, and refine a model of a cellular pathway, in which perturbations to critical pathway components are analyzed using DNA microarrays, quantitative proteomics, and databases of known physical interactions. The biological model is established through further iterations of perturbation and global measurements, suggesting hypotheses about the regulation of galactose utilization and physical interactions between this and a variety of other metabolic pathways. BioSeek
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