DOI: 10.1126/science.1073374 , 1551 (2002); 297Science et al.E. Ravasz,NetworksHierarchical Organization of Modularity in Metabolic www.sciencemag.org (this information is current as of December 21, 2007 ):The following resources related to this article are available online at http://www.sciencemag.org/cgi/content/full/297/5586/1551version of this article at: including high-resolution figures, can be found in the onlineUpdated information and services, http://www.sciencemag.org/cgi/content/full/297/5586/1551/DC1 can be found at: Supporting Online Material http://www.sciencemag.org/cgi/content/full/297/5586/1551#otherarticles, 9 of which can be accessed for free: cites 26 articlesThis article 493 article(s) on the ISI Web of Science. cited byThis article has been http://www.sciencemag.org/cgi/content/full/297/5586/1551#otherarticles 85 articles hosted by HighWire Press; see: cited byThis article has been http://www.sciencemag.org/cgi/collection/cell_biolCell Biology : subject collectionsThis article appears in the following http://www.sciencemag.org/about/permissions.dtl in whole or in part can be found at: this articlepermission to reproduce of this article or about obtaining reprintsInformation about obtaining registered trademark of AAAS. is aScience2002 by the American Association for the Advancement of Science; all rights reserved. The title CopyrightAmerican Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by theScience on December 21, 2007 www.sciencemag.orgDownloaded from9. M. L. Rosenzweig, Species Diversity in Space and Time(Cambridge Univ. Press, Cambridge, 1995).10. R. E. Ricklefs, D. Schluter, in Species Diversity in Ecolog-ical Communities, R. E. Ricklefs, D. Schluter, Eds. (Chica-go Univ. Press, Chicago, 1993) , pp. 350–363.11. C. Rahbek, G. R. Graves, Proc. Natl. Acad. Sci. U.S.A.98, 4534 (2001).12. R. K. Colwell, D. C. Lees, Trends Ecol. Evol. 15, 70 (2000).13. D. C. Lees, C. Kremen, L. Andriamampianina, Biol. J.Linn. Soc. 67, 529 (1999).14. W. Jetz, C. Rahbek, Proc. Natl. Acad. Sci. U.S.A. 98,5661 (2001).15. Materials and methods are available as supportingmaterial on Science Online.16. N. A. C. Cressie, Statistics for Spatial Data ( Wiley,New York, 1993).17. 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Wint, and S. Hay forGeographic Information Systems advice and discus-sions; I. Woodward for providing productivity data; L. A.Hansen for assistance with access to the African birddatabase on behalf of the Zoological Museum Univer-sity of Copenhagen ( ZMUC); and E. Baker, N. Baker, F.Dowsett-Lemaire, R. Dowsett, J. Fjeldså, M. E. Gartshore,H. M. de Klerk, M. Languy, R. B. Payn, COC/BirdLifeCameroon, and BirdLife International for providing datafor the ZMUC database. The manuscript benefited tre-mendously from discussions with R. K. Colwell andcomments from J. Brown, J. Fjeldså, R. Freckleton, K.Gaston, N. J. Gotelli, G. R. Graves, P. Harvey, R. Lande, O.Lewis, R. May, I. Owens, and D. Rogers. W.J. was sup-ported by Natural Environment Research Council andGerman Scholarship Foundation studentships; C.R. wassupported by the Danish National Science Foundation(grant J. nr. 21-01-0547).Supporting Online Materialwww.sciencemag.org/cgi/content/full/297/5586/1548/DC1Materials and MethodsSupporting TextTables S1 to S311 April 2002; accepted 25 July 2002Hierarchical Organization ofModularity in MetabolicNetworksE. Ravasz,1A. L. Somera,2D. A. Mongru,2Z. N. Oltvai,2*A.-L. Baraba´si1*Spatially or chemically isolated functional modules composed of several cellularcomponents and carrying discrete functions are considered fundamental build-ing blocks of cellular organization, but their presence in highly integratedbiochemical networks lacks quantitative support. Here, we show that themetabolic networks of 43 distinct organisms are organized into many small,highly connected topologic modules that combine in a hierarchical manner intolarger, less cohesive units, with their number and degree of clustering followinga power law. Within Escherichia coli, the uncovered hierarchical modularityclosely overlaps with known metabolic functions. The identified network ar-chitecture may be generic to system-level cellular organization.The identification and characterization ofsystem-level features of biological organiza-tion is a key issue of postgenomic biology(1–3). The concept of modularity assumesthat cellular functionality can be seamlesslypartitioned into a collection of modules. Eachmodule is a discrete entity of several elemen-tary components and performs an identifiabletask, separable from the functions of othermodules (1, 4–8). Spatially and chemicallyisolated molecular machines or protein com-plexes (such as ribosomes and flagella) areprominent examples of such functional units,but more extended modules, such as thoseachieving their isolation through the initialbinding of a signaling molecule (9), are alsoapparent.Simultaneously, it is recognized that thethousands of components of a living cell aredynamically interconnected, so that the cell’sfunctional properties are ultimately encodedinto a complex intracellular web of molecularinteractions (2–6, 8). This is perhaps mostevident with cellular metabolism, a fully con-nected biochemical network in which hun-dreds of metabolic substrates are densely in-tegrated through biochemical reactions.Within this network, however, modular