Modular Analysis of Biological Networks

  • Hans-Michael KaltenbachEmail author
  • Jörg StellingEmail author
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 736)


The analysis of complex biological networks has traditionally relied on decomposition into smaller, semi-autonomous units such as individual signaling pathways. With the increased scope of systems biology (models), rational approaches to modularization have become an important topic. With increasing acceptance of de facto modularity in biology, widely different definitions of what constitutes a module have sparked controversies. Here, we therefore review prominent classes of modular approaches based on formal network representations. Despite some promising research directions, several important theoretical challenges remain open on the way to formal, function-centered modular decompositions for dynamic biological networks.


Metabolic Network Biological Network Community Detection Network Motif Modular Analysis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Financial support by the EU FP7 project UNICELLSYS is gratefully acknowledged.


  1. 1.
    Alexander RP, Kim PM, Emonet T, Gerstein MB (2009) Understanding modularity in molecular networks requires dynamics. Sci Signal 2(81):44CrossRefGoogle Scholar
  2. 2.
    Alon U (2007) Network motifs: theory and experimental approaches. Nat Rev Genet 8(6): 450–461PubMedCrossRefGoogle Scholar
  3. 3.
    Bruggeman FJ, Snoep JL, Westerhoff HV (2008) Control, responses and modularity of cellular regulatory networks: A control analysis perspective. IET Syst Biol 2(6):397–410PubMedCrossRefGoogle Scholar
  4. 4.
    Bruggeman FJ, Westerhoff HV, Hoek JB, Kholodenko BN (2002) Modular response analysis of cellular regulatory networks. J Theor Biol 218(4):507–520.PubMedGoogle Scholar
  5. 5.
    Chen WW, Schoeberl B, Jasper PJ, Niepel M, Nielsen UB, Lauffenburger DA, Sorger PK (2009) Input–output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data. Mol Syst Biol 5:239PubMedGoogle Scholar
  6. 6.
    Consortium, TGO (2000) Gene ontology: tool for the unification of biology. Nat Genet 25(1):25–29CrossRefGoogle Scholar
  7. 7.
    Csete M, Doyle J (2002) Reverse engineering of biological complexity. Science 295: 1664–1669PubMedCrossRefGoogle Scholar
  8. 8.
    DasGupta B, Enciso GA, Sontag E, Zhang Y (2007) Algorithmic and complexity results for decompositions of biological networks into monotone subsystems. Biosystems 90(1):161–178PubMedCrossRefGoogle Scholar
  9. 9.
    Dong J, Horvath S (2007) Understanding network concepts in modules. BMC Syst Biol 1:24PubMedCrossRefGoogle Scholar
  10. 10.
    Ederer M, Sauter T, Bullinger E, Gilles ED, Allgower F (2003) An Approach for Dividing Models of Biological Reaction Networks into Functional Units. Simulation 79(12):703–716CrossRefGoogle Scholar
  11. 11.
    Fortunato S (2010) Community detection in graphs. Phys Rep 486(3–5):175–174Google Scholar
  12. 12.
    Francis B, Wonham W (1976) The internal model principle of control theory. Automatica 12:457–465CrossRefGoogle Scholar
  13. 13.
    Gagneur J, Jackson DB, Casari G (2003) Hierarchical analysis of dependency in metabolic networks. Bioinformatics 19(8):1027–1034PubMedCrossRefGoogle Scholar
  14. 14.
    Hartwell L, Hopfield J, Leibler S, Murray A (1999) From molecular to modular cell biology. Nature 402 (Suppl.):C47–C52Google Scholar
  15. 15.
    Hirsch M, Smith H (2006) Monotone dynamical systems. Handbook Differen Equat Ord Differen Equat 2:239–357CrossRefGoogle Scholar
  16. 16.
    Ingram P, Stumpf M, Stark J (2006) Network motifs: structure does not determine function. BMC Genom 7(1):108CrossRefGoogle Scholar
  17. 17.
    Kholodenko BN, Kiyatkin A, Bruggeman FJ, Sontag ED, Westerhoff HV, Hoek JB (2002) Untangling the wires: A strategy to trace functional interactions in signaling and gene networks. Proc Natl Acad Sci USA 99(20):12841–12846PubMedCrossRefGoogle Scholar
  18. 18.
    Kitano H (2002) Systems biology: a brief overview. Science 295:1662–1664PubMedCrossRefGoogle Scholar
  19. 19.
    Klamt S, Haus UU, Theis F (2009) Hypergraphs and cellular networks. PLoS Comput Biol 5(5):e1000385PubMedCrossRefGoogle Scholar
  20. 20.
    Klamt S, Stelling J (2002) Combinatorial complexity of pathway analysis in metabolic networks. Mol Biol Rep 29:233–236PubMedCrossRefGoogle Scholar
  21. 21.
    Koonin EV, Wolf YI, Karev GP, Almaas E, Barabasi A.L (2006) Power laws in biological networks. In: Power Laws, Scale-Free Networks and Genome Biology, Molecular Biology Intelligence Unit, Springer USA, 1–11Google Scholar
  22. 22.
    Lauffenburger DA (2000) Cell signaling pathways as control modules: complexity for simplicity? Proc Natl Acad Sci USA 97(10):5031–5033PubMedCrossRefGoogle Scholar
  23. 23.
    Marchisio MA, Stelling J (2008) Computational design of synthetic gene circuits with composable parts. Bioinformatics 24(17):1903–1910PubMedCrossRefGoogle Scholar
  24. 24.
    Montanez R, Medina MA, Sole RV, Rodrigues-Caso C (2010) When metabolism meets topology: Reconciling metaboltie and reaction networks. BioEssays 32:246–256PubMedCrossRefGoogle Scholar
  25. 25.
    Nurse P (2003) Understanding cells. Nature 424:883CrossRefGoogle Scholar
  26. 26.
    Pfeiffer T, Sanchez-Valdenebro I, Nuno J, Montero F, Schuster S (1999) METATOOL: For studying metabolic networks. Bioinformatics 15:251–257PubMedCrossRefGoogle Scholar
  27. 27.
    Pinkert S, Schultz J, Reichardt J (2010) Protein interaction networks – More than mere modules. PLoS Comput Biol 6(1):e1000659PubMedCrossRefGoogle Scholar
  28. 28.
    Poolman MG, Sebu C, Pidcock MK, Fell DA (2007) Modular decomposition of metabolic systems via null-space analysis. J Theor Biol 249(4):691–705PubMedCrossRefGoogle Scholar
  29. 29.
    Przulj N (2007) Biological network comparison using graphlet degree distribution. Bioinformatics 23(2):e177–e183PubMedCrossRefGoogle Scholar
  30. 30.
    Reder, C (1988) Metabolic control theory: A structural approach. J Theor Biol 135:175–201PubMedCrossRefGoogle Scholar
  31. 31.
    Saez-Rodriguez J, Gayer S, Ginkel M, Gilles E.D (2008) Automatic decomposition of kinetic models of signaling networks minimizing the retroactivity among modules. Bioinformatics 24(16):i213–i219PubMedCrossRefGoogle Scholar
  32. 32.
    Seebacher J, Gavin AC (2011) SnapShot: Protein–protein interaction networks. Cell 144(6):1000.e1Google Scholar
  33. 33.
    Shen-Orr SS, Milo R, Mangan S, Alon U (2002) Network motifs in the transcriptional regulation network of Escherichia coli. Nat Genet 31(1): 64–68Google Scholar
  34. 34.
    Sontag E (2007) Monotone and near-monotone biochemical networks. Lecture Notes in Control and Information Sciences, vol. 357, pp. 79–122CrossRefGoogle Scholar
  35. 35.
    Sontag ED (2003) Adaptation and regulation with signal detection implies internal model. Syst Contr Lett 50(2):119–126CrossRefGoogle Scholar
  36. 36.
    Sontag ED (2004) Some new directions in control theory inspired by systems biology. Syst Biol 1(1):9–18CrossRefGoogle Scholar
  37. 37.
    Soranzo N, Ramezani F, Iacono G, Altafini C (2010) Graph-theoretical decompositions of large-scale biological networks. Automatica, conditionally accepted.Google Scholar
  38. 38.
    Stelling J, Kremling A, Ginkel M, Bettenbrock K, Gilles E (2001) Towards a Virtual Biological Laboratory. In: Kitano H (ed) Foundations of Systems Biology, MIT Press, Cambridge, MA, pp. 189–212Google Scholar
  39. 39.
    Terzer M, Maynard ND, Covert, MW, Stelling J (2009) Genome-scale metabolic networks. Wiley Interdiscip Rev Syst Biol Med 1(3):285–297PubMedCrossRefGoogle Scholar
  40. 40.
    Tyson JJ, Chen KC, Novak B (2003) Sniffers, buzzers, toggles, and blinkers: Dynamics of regulatory and signaling pathways in the cell. Curr Opin Cell Biol 15(2):221–231PubMedCrossRefGoogle Scholar
  41. 41.
    Tyson JJ, Novák B (2010) Functional motifs in biochemical reaction networks. Annu Rev Phys Chem 61:219–240PubMedCrossRefGoogle Scholar
  42. 42.
    Vecchio DD, Ninfa AJ, Sontag ED (2008) Modular cell biology: retroactivity and insulation. Mol Syst Biol 4:161PubMedGoogle Scholar
  43. 43.
    Wagner GP, Pavlicev M, Cheverud JM (2007) The road to modularity. Nat Rev Genet 8(12):921–931PubMedCrossRefGoogle Scholar
  44. 44.
    Wang Z, Zhang J (2007) In search of the biological significance of modular structures in protein networks. PLoS Comput Biol 3(6):e107PubMedCrossRefGoogle Scholar
  45. 45.
    Westerhoff HV, Kolodkin A, Conradie R., Wilkinson SJ, Bruggeman FJ, Krab K, van Schuppen JH, Hardin H, Bakker BM, Moné MJ, Rybakova KN, Eijken M, van Leeuwen HJP, Snoep JL (2009) Systems biology towards life in silico: Mathematics of the control of living cells. J Math Biol 58(1–2):7–34PubMedCrossRefGoogle Scholar
  46. 46.
    Yi TM, Huang Y, Simon MI, Doyle J (2000) Robust perfect adaptation in bacterial chemotaxis through integral feedback control. Proc Natl Acad Sci USA 97(9):4649–4653PubMedCrossRefGoogle Scholar
  47. 47.
    Yoon J, Si Y, Nolan R, Lee K (2007) Modular decomposition of metabolic reaction networks based on flux analysis and pathway projection. Bioinformatics 23(18):2433–2440PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Biosystems Science and EngineeringETH ZurichBaselSwitzerland

Personalised recommendations