Cellular and Molecular Life Sciences

, Volume 70, Issue 6, pp 1035–1053 | Cite as

Systems biology for molecular life sciences and its impact in biomedicine



Modern systems biology is already contributing to a radical transformation of molecular life sciences and biomedicine, and it is expected to have a real impact in the clinical setting in the next years. In this review, the emergence of systems biology is contextualized with a historic overview, and its present state is depicted. The present and expected future contribution of systems biology to the development of molecular medicine is underscored. Concerning the present situation, this review includes a reflection on the “inflation” of biological data and the urgent need for tools and procedures to make hidden information emerge. Descriptions of the impact of networks and models and the available resources and tools for applying them in systems biology approaches to molecular medicine are provided as well. The actual current impact of systems biology in molecular medicine is illustrated, reviewing two cases, namely, those of systems pharmacology and cancer systems biology. Finally, some of the expected contributions of systems biology to the immediate future of molecular medicine are commented.


Complexity Disease-ome Holism Network Reductionism Systems biology 

Supplementary material

18_2012_1109_MOESM1_ESM.docx (51 kb)
Supplementary material 1 (DOCX 50 kb)


  1. 1.
    Chuang HY, Hofree M, Ideker T (2010) A decade of systems biology. Annu Rev Cell Dev Biol 26:721–744PubMedGoogle Scholar
  2. 2.
    Loeb J (1912) The mechanistic conception of life. Bellknap Press, CambridgeGoogle Scholar
  3. 3.
    Smuts JC (1926) Holism and evolution. Viking Press, New YorkGoogle Scholar
  4. 4.
    Corning P (2002) The re-emergence of “emergence”. A venerable concept in search of a theory. Complexity 7:18–30Google Scholar
  5. 5.
    Vernadsky V (1926) The Biosphere [in Russian]. Nauch, St. PetersburgGoogle Scholar
  6. 6.
    Williams RJ (1956) Biochemical Individuality: the Key for the Genotrophic Concept. Wiley, New YorkGoogle Scholar
  7. 7.
    La Jacob F (1970) Logique du Vivant. Gallimard, ParisGoogle Scholar
  8. 8.
    Polanyi M (1968) Life’s irreducible structure. Live mechanisms and information in DNA are boundary conditions with a sequence of boundaries above them. Science 160:1308–1312PubMedGoogle Scholar
  9. 9.
    Von Bertalanffy L (1950) The theory of open systems in physics and biology. Science 111:23–29Google Scholar
  10. 10.
    Von Bertalanffy L (1968) General systems theory: foundations, development, applications. George Braziller, New YorkGoogle Scholar
  11. 11.
    Kitano H (2002) Systems biology: a brief overview. Science 295:1662–1664PubMedGoogle Scholar
  12. 12.
    Hartwell LH, Hopfield JJ, Leibler S, Murray AW (1999) From molecular to modular cell biology. Nature 402:C47–C52PubMedGoogle Scholar
  13. 13.
    Ideker T, Galitski T, Hood L (2001) A new approach to decoding life: systems biology. Annu Rev Genomics Hum Genet 2:343–372PubMedGoogle Scholar
  14. 14.
    Ranea JA, Morilla I, Lees JG, Reid AJ, Yeats C, Clegg AB, Sánchez-Jiménez F, Orengo C (2010) Finding the “dark matter” in human and yeast protein network prediction and modelling. PLoS Comput Biol 6:e1000945Google Scholar
  15. 15.
    Barabasi AL (2002) Linked: the new science of networks. Basic Books, New YorkGoogle Scholar
  16. 16.
    Jeong H, Tombor B, Albert R, Oltvai ZN, Barabasi AL (2000) The large-scale organization of metabolic networks. Nature 407:651–654PubMedGoogle Scholar
  17. 17.
    Rodríguez-Caso C, Medina MA, Solé RV (2005) Topology, tinkering and evolution of the human transcription factor network. FEBS J 272:6423–6434PubMedGoogle Scholar
  18. 18.
    Han JD, Bertin N, Hao T, Goldberg DS, Berriz GF, Zhang LV, Dupuy D, Walhout AJ, Cusick ME, Roth FP, Vidal M (2004) Evidence for dynamically organized modularity in the yeast protein–protein interaction network. Nature 430:88–93PubMedGoogle Scholar
  19. 19.
    Watts DJ, Strogatz SH (1998) Collective dynamics of ‘small-world’ networks. Nature 393:440–442PubMedGoogle Scholar
  20. 20.
    Li S, Armstrong CM, Bertin N, Ge H, Milstein S, Boxem M, Vidalain PO, Han JD, Chesneau A, Hao T, Goldberg DS, Li N, Martinez M, Rual JF, Lamesch P, Xu L, Tewari M, Wong SL, Zhang LV, Berriz GF, Jacotot L, Vaglio P, Reboul J, Hirozane-Kishikawa T, Li Q, Gabel HW, Elewa A, Baumgartner B, Rose DJ, Yu H, Bosak S, Sequerra R, Fraser A, Mango SE, Saxton WM, Strome S, Van Den Heuvel S, Piano F, Vandenhaute J, Sardet C, Gerstein M, Doucette-Stamm L, Gunsalus KC, Harper JW, Cusick ME, Roth FP, Hill DE, Vidal M (2004) A map of the interactome network of the metazoan C. elegans. Science 303:540–543PubMedGoogle Scholar
  21. 21.
    Cusick ME, Klitgord N, Vidal M, Hill DE (2005) Interactome: gateway into systems biology. Hum Mol Genet 14 Spec No. 2:R171–181Google Scholar
  22. 22.
    Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksoz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE (2005) A human protein–protein interaction network: a resource for annotating the proteome. Cell 122:957–968PubMedGoogle Scholar
  23. 23.
    Warner GJ, Adeleye YA, Ideker T (2006) Interactome networks: the state of the science. Genome Biol 7:301PubMedGoogle Scholar
  24. 24.
    Figeys D (2008) Mapping the human protein interactome. Cell Res 18:716–724PubMedGoogle Scholar
  25. 25.
    Venkatesan K, Rual JF, Vazquez A, Stelzl U, Lemmens I, Hirozane-Kishikawa T, Hao T, Zenkner M, Xin X, Goh KI, Yildirim MA, Simonis N, Heinzmann K, Gebreab F, Sahalie JM, Cevik S, Simon C, de Smet AS, Dann E, Smolyar A, Vinayagam A, Yu H, Szeto D, Borick H, Dricot A, Klitgord N, Murray RR, Lin C, Lalowski M, Timm J, Rau K, Boone C, Braun P, Cusick ME, Roth FP, Hill DE, Tavernier J, Wanker EE, Barabasi AL, Vidal M (2009) An empirical framework for binary interactome mapping. Nat Methods 6:83–90PubMedGoogle Scholar
  26. 26.
    Walhout AJ, Reboul J, Shtanko O, Bertin N, Vaglio P, Ge H, Lee H, Doucette-Stamm L, Gunsalus KC, Schetter AJ, Morton DG, Kemphues KJ, Reinke V, Kim SK, Piano F, Vidal M (2002) Integrating interactome, phenome, and transcriptome mapping data for the C. elegans germline. Curr Biol 12:1952–1958PubMedGoogle Scholar
  27. 27.
    Lage K, Karlberg EO, Storling ZM, Olason PI, Pedersen AG, Rigina O, Hinsby AM, Tumer Z, Pociot F, Tommerup N, Moreau Y, Brunak S (2007) A human phenome-interactome network of protein complexes implicated in genetic disorders. Nat Biotechnol 25:309–316PubMedGoogle Scholar
  28. 28.
    Yao C, Li H, Zhou C, Zhang L, Zou J, Guo Z (2010) Multi-level reproducibility of signature hubs in human interactome for breast cancer metastasis. BMC Syst Biol 4:151PubMedGoogle Scholar
  29. 29.
    Shutt TE, Shadel GS (2007) Expanding the mitochondrial interactome. Genome Biol 8:203PubMedGoogle Scholar
  30. 30.
    Reja R, Venkatakrishnan AJ, Lee J, Kim BC, Ryu JW, Gong S, Bhak J, Park D (2009) MitoInteractome: mitochondrial protein interactome database, and its application in ‘aging network’ analysis. BMC Genomics 10(Suppl 3):S20PubMedGoogle Scholar
  31. 31.
    Bandyopadhyay S, Chiang CY, Srivastava J, Gersten M, White S, Bell R, Kurschner C, Martin CH, Smoot M, Sahasrabudhe S, Barber DL, Chanda SK, Ideker T (2010) A human MAP kinase interactome. Nat Methods 7:801–805PubMedGoogle Scholar
  32. 32.
    Eden G, Archinti M, Furlan F, Murphy R, Degryse B (2011) The urokinase receptor interactome. Curr Pharm Des 17:1874–1889PubMedGoogle Scholar
  33. 33.
    Tieri P, Termanini A, Bellavista E, Salvioli S, Capri M, Franceschi C (2012) Charting the NF-kappaB pathway interactome map. PLoS ONE 7:e32678PubMedGoogle Scholar
  34. 34.
    Tarassov K, Messier V, Landry CR, Radinovic S, Serna Molina MM, Shames I, Malitskaya Y, Vogel J, Bussey H, Michnick SW (2008) An in vivo map of the yeast protein interactome. Science 320:1465–1470PubMedGoogle Scholar
  35. 35.
    Kast J (2008) Making connections for life: an in vivo map of the yeast interactome. HFSP J 2:244–250PubMedGoogle Scholar
  36. 36.
    Przytycka TM, Singh M, Slonim DK (2010) Toward the dynamic interactome: it’s about time. Brief Bioinform 11:15–29PubMedGoogle Scholar
  37. 37.
    Gallego O, Betts MJ, Gvozdenovic-Jeremic J, Maeda K, Matetzki C, Aguilar-Gurrieri C, Beltran-Alvarez P, Bonn S, Fernandez-Tornero C, Jensen LJ, Kuhn M, Trott J, Rybin V, Muller CW, Bork P, Kaksonen M, Russell RB, Gavin AC (2010) A systematic screen for protein-lipid interactions in Saccharomyces cerevisiae. Mol Syst Biol 6:430PubMedGoogle Scholar
  38. 38.
    Kohler S, Bauer S, Horn D, Robinson PN (2008) Walking the interactome for prioritization of candidate disease genes. Am J Hum Genet 82:949–958PubMedGoogle Scholar
  39. 39.
    Coulombe B (2011) Mapping the disease protein interactome: toward a molecular medicine GPS to accelerate drug and biomarker discovery. J Proteome Res 10:120–125PubMedGoogle Scholar
  40. 40.
    Kahle JJ, Gulbahce N, Shaw CA, Lim J, Hill DE, Barabasi AL, Zoghbi HY (2011) Comparison of an expanded ataxia interactome with patient medical records reveals a relationship between macular degeneration and ataxia. Hum Mol Genet 20:510–527PubMedGoogle Scholar
  41. 41.
    Soler-Lopez M, Zanzoni A, Lluis R, Stelzl U, Aloy P (2011) Interactome mapping suggests new mechanistic details underlying Alzheimer’s disease. Genome Res 21:364–376PubMedGoogle Scholar
  42. 42.
    Vidal M, Cusick ME, Barabasi AL (2011) Interactome networks and human disease. Cell 144:986–998PubMedGoogle Scholar
  43. 43.
    Simonis N, Rual JF, Lemmens I, Boxus M, Hirozane-Kishikawa T, Gatot JS, Dricot A, Hao T, Vertommen D, Legros S, Daakour S, Klitgord N, Martin M, Willaert JF, Dequiedt F, Navratil V, Cusick ME, Burny A, Van Lint C, Hill DE, Tavernier J, Kettmann R, Vidal M, Twizere JC (2012) Host-pathogen interactome mapping for HTLV-1 and 2 retroviruses. Retrovirology 9:26PubMedGoogle Scholar
  44. 44.
    Hernandez-Toro J, Prieto C, De las Rivas J (2007) APID2NET: unified interactome graphic analyzer. Bioinformatics 23:2495–2497PubMedGoogle Scholar
  45. 45.
    Cline MS, Smoot M, Cerami E, Kuchinsky A, Landys N, Workman C, Christmas R, Avila-Campilo I, Creech M, Gross B, Hanspers K, Isserlin R, Kelley R, Killcoyne S, Lotia S, Maere S, Morris J, Ono K, Pavlovic V, Pico AR, Vailaya A, Wang PL, Adler A, Conklin BR, Hood L, Kuiper M, Sander C, Schmulevich I, Schwikowski B, Warner GJ, Ideker T, Bader GD (2007) Integration of biological networks and gene expression data using Cytoscape. Nat Protoc 2:2366–2382PubMedGoogle Scholar
  46. 46.
    Smoot ME, Ono K, Ruscheinski J, Wang PL, Ideker T (2011) Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics 27:431–432PubMedGoogle Scholar
  47. 47.
    Montañez R, Sánchez-Jiménez F, Quesada AR, Medina MA (2011) Exploring and challenging the network of angiogenesis. Sci Rep 1:61PubMedGoogle Scholar
  48. 48.
    Kravchenko-Balasha N, Levitzki A, Goldstein A, Rotter V, Gross A, Remacle F, Levine RD (2012) On a fundamental structure of gene networks in living cells. Proc Natl Acad Sci USA 109:4702–4707PubMedGoogle Scholar
  49. 49.
    Westerhoff HV, Winder C, Messiha H, Simeonidis E, Adamczyk M, Verma M, Bruggeman FJ, Dunn W (2009) Systems biology: the elements and principles of life. FEBS Lett 583:3882–3890PubMedGoogle Scholar
  50. 50.
    Wilson EO (1999) Consilience: the Unity of Knowledge. Vintage Books, New YorkGoogle Scholar
  51. 51.
    (1999) Consilience, complexity, and communication: three challenges at the start of the new century. Bioessays 21:983–984Google Scholar
  52. 52.
    Rodríguez-Caso C, Montañez R, Cascante M, Sánchez-Jiménez F, Medina MA (2006) Mathematical modeling of polyamine metabolism in mammals. J Biol Chem 281:21799–21812PubMedGoogle Scholar
  53. 53.
    Li C, Courtot M, Le Novere N, Laibe C (2010) BioModels.net Web Services, a free and integrated toolkit for computational modelling software. Brief Bioinform 11:270–277PubMedGoogle Scholar
  54. 54.
    Reyes-Palomares A, Montañez R, Sánchez-Jiménez F, Medina MA (2012) A combined model of hepatic polyamine and sulfur amino acid metabolism to analyze S-adenosyl methionine availability. Amino Acids 42:597–610PubMedGoogle Scholar
  55. 55.
    Savageau MA (1969) Biochemical systems analysis. II. The steady-state solutions for an n-pool system using a power-law approximation. J Theor Biol 25:370–379PubMedGoogle Scholar
  56. 56.
    Savageau MA (1969) Biochemical systems analysis. I. Some mathematical properties of the rate law for the component enzymatic reactions. J Theor Biol 25:365–369PubMedGoogle Scholar
  57. 57.
    Savageau MA (1970) Biochemical systems analysis. 3. Dynamic solutions using a power-law approximation. J Theor Biol 26:215–226PubMedGoogle Scholar
  58. 58.
    Voit EO (2000) Computational analysis of biochemical systems. Cambridge University Press, CambridgeGoogle Scholar
  59. 59.
    Kanehisa M, Goto S (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28:27–30PubMedGoogle Scholar
  60. 60.
    Mendes P, Hoops S, Sahle S, Gauges R, Dada J, Kummer U (2009) Computational modeling of biochemical networks using COPASI. Methods Mol Biol 500:17–59PubMedGoogle Scholar
  61. 61.
    Reyes-Palomares A, Montañez R, Real-Chicharro A, Chniber O, Kerzazi A, Navas-Delgado I, Medina MA, Aldana-Montes JF, Sánchez-Jiménez F (2009) Systems biology metabolic modeling assistant: an ontology-based tool for the integration of metabolic data in kinetic modeling. Bioinformatics 25:834–835PubMedGoogle Scholar
  62. 62.
    Cvijovic M, Olivares-Hernandez R, Agren R, Dahr N, Vongsangnak W, Nookaew I, Patil KR, Nielsen J (2010) BioMet Toolbox: genome-wide analysis of metabolism. Nucleic Acids Res 38:W144–W149PubMedGoogle Scholar
  63. 63.
    Schellenberger J, Que R, Fleming RM, Thiele I, Orth JD, Feist AM, Zielinski DC, Bordbar A, Lewis NE, Rahmanian S, Kang J, Hyduke DR, Palsson BO (2011) Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox v2.0. Nat Protoc 6:1290–1307PubMedGoogle Scholar
  64. 64.
    Voit EO, Radivoyevitch T (2000) Biochemical systems analysis of genome-wide expression data. Bioinformatics 16:1023–1037PubMedGoogle Scholar
  65. 65.
    Ma H, Sorokin A, Mazein A, Selkov A, Selkov E, Demin O, Goryanin I (2007) The Edinburgh human metabolic network reconstruction and its functional analysis. Mol Syst Biol 3:135PubMedGoogle Scholar
  66. 66.
    Duarte NC, Becker SA, Jamshidi N, Thiele I, Mo ML, Vo TD, Srivas R, Palsson BO (2007) Global reconstruction of the human metabolic network based on genomic and bibliomic data. Proc Natl Acad Sci USA 104:1777–1782PubMedGoogle Scholar
  67. 67.
    Terzer M, Maynard ND, Covert MW, Stelling J (2009) Genome-scale metabolic networks. Wiley Interdiscip Rev Syst Biol Med 1:285–297PubMedGoogle Scholar
  68. 68.
    Edwards JS, Palsson BO (2000) Metabolic flux balance analysis and the in silico analysis of Escherichia coli K-12 gene deletions. BMC Bioinformatics 1:1PubMedGoogle Scholar
  69. 69.
    Kauffman KJ, Prakash P, Edwards JS (2003) Advances in flux balance analysis. Curr Opin Biotechnol 14:491–496PubMedGoogle Scholar
  70. 70.
    Lee JM, Gianchandani EP, Papin JA (2006) Flux balance analysis in the era of metabolomics. Brief Bioinform 7:140–150PubMedGoogle Scholar
  71. 71.
    Raman K, Chandra N (2009) Flux balance analysis of biological systems: applications and challenges. Brief Bioinform 10:435–449PubMedGoogle Scholar
  72. 72.
    Murabito E, Simeonidis E, Smallbone K, Swinton J (2009) Capturing the essence of a metabolic network: a flux balance analysis approach. J Theor Biol 260:445–452PubMedGoogle Scholar
  73. 73.
    Orth JD, Thiele I, Palsson BO (2010) What is flux balance analysis? Nat Biotechnol 28:245–248PubMedGoogle Scholar
  74. 74.
    Gianchandani EP, Chavali AK, Papin JA (2010) The application of flux balance analysis in systems biology. Wiley Interdiscip Rev Syst Biol Med 2:372–382PubMedGoogle Scholar
  75. 75.
    Li Z, Wang RS, Zhang XS (2011) Two-stage flux balance analysis of metabolic networks for drug target identification. BMC Syst Biol 5(Suppl 1):S11Google Scholar
  76. 76.
    Tiger CF, Krause F, Cedersund G, Palmer R, Klipp E, Hohmann S, Kitano H, Krantz M (2012) A framework for mapping, visualisation and automatic model creation of signal-transduction networks. Mol Syst Biol 8:578PubMedGoogle Scholar
  77. 77.
    Wild DJ, Ding Y, Sheth AP, Harland L, Gifford EM, Lajiness MS (2012) Systems chemical biology and the Semantic Web: what they mean for the future of drug discovery research. Drug Discov Today 17:469–474PubMedGoogle Scholar
  78. 78.
    Ekins S, Nikolsky Y, Nikolskaya T (2005) Techniques: application of systems biology to absorption, distribution, metabolism, excretion and toxicity. Trends Pharmacol Sci 26:202–209PubMedGoogle Scholar
  79. 79.
    Hoeng J, Deehan R, Pratt D, Martin F, Sewer A, Thomson TM, Drubin DA, Waters CA, de Graaf D, Peitsch MC (2012) A network-based approach to quantifying the impact of biologically active substances. Drug Discov Today 17:413–418PubMedGoogle Scholar
  80. 80.
    Quesada AR, Muñoz-Chápuli R, Medina MA (2006) Anti-angiogenic drugs: from bench to clinical trials. Med Res Rev 26:483–530PubMedGoogle Scholar
  81. 81.
    Medina MA, Muñoz-Chápuli R, Quesada AR (2007) Challenges of antiangiogenic cancer therapy: trials and errors, and renewed hope. J Cell Mol Med 11:374–382PubMedGoogle Scholar
  82. 82.
    Quesada AR, Medina MA, Muñoz-Cáapuli R, Ponce AL (2010) Do not say ever never more: the ins and outs of antiangiogenic therapies. Curr Pharm Des 16:3932–3957PubMedGoogle Scholar
  83. 83.
    Quesada AR, Medina MA, Alba E (2007) Playing only one instrument may be not enough: limitations and future of the antiangiogenic treatment of cancer. BioEssays 29:1159–1168PubMedGoogle Scholar
  84. 84.
    Lehar J, Krueger AS, Avery W, Heilbut AM, Johansen LM, Price ER, Rickles RJ, Short GF 3rd, Staunton JE, Jin X, Lee MS, Zimmermann GR, Borisy AA (2009) Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat Biotechnol 27:659–666PubMedGoogle Scholar
  85. 85.
    Kummar S, Chen HX, Wright J, Holbeck S, Millin MD, Tomaszewski J, Zweibel J, Collins J, Doroshow JH (2010) Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements. Nat Rev Drug Discov 9:843–856PubMedGoogle Scholar
  86. 86.
    Cokol M, Chua HN, Tasan M, Mutlu B, Weinstein ZB, Suzuki Y, Nergiz ME, Costanzo M, Baryshnikova A, Giaever G, Nislow C, Myers CL, Andrews BJ, Boone C, Roth FP (2011) Systematic exploration of synergistic drug pairs. Mol Syst Biol 7:544PubMedGoogle Scholar
  87. 87.
    Wagner H (2011) Synergy research: approaching a new generation of phytopharmaceuticals. Fitoterapia 82:34–37PubMedGoogle Scholar
  88. 88.
    Hopkins AL (2007) Network pharmacology. Nat Biotechnol 25:1110–1111PubMedGoogle Scholar
  89. 89.
    Hopkins AL (2008) Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 4:682–690PubMedGoogle Scholar
  90. 90.
    Berger SI, Iyengar R (2009) Network analyses in systems pharmacology. Bioinformatics 25:2466–2472PubMedGoogle Scholar
  91. 91.
    Hansen J, Zhao S, Iyengar R (2011) Systems pharmacology of complex diseases. Ann N Y Acad Sci 1245:E1–E5PubMedGoogle Scholar
  92. 92.
    Zhao S, Iyengar R (2012) Systems pharmacology: network analysis to identify multiscale mechanisms of drug action. Annu Rev Pharmacol Toxicol 52:505–521PubMedGoogle Scholar
  93. 93.
    Edelman LB, Eddy JA, Price ND (2010) In silico models of cancer. Wiley Interdiscip Rev Syst Biol Med 2:438–459PubMedGoogle Scholar
  94. 94.
    Abbod MF, Hamdy FC, Linkens DA, Catto JW (2009) Predictive modeling in cancer: where systems biology meets the stock market. Expert Rev Anticancer Ther 9:867–870PubMedGoogle Scholar
  95. 95.
    Deisboeck TS, Zhang L, Yoon J, Costa J (2009) In silico cancer modeling: is it ready for prime time? Nat Clin Pract Oncol 6:34–42PubMedGoogle Scholar
  96. 96.
    Alarcon T, Byrne HM, Maini PK (2004) A mathematical model of the effects of hypoxia on the cell-cycle of normal and cancer cells. J Theor Biol 229:395–411PubMedGoogle Scholar
  97. 97.
    Spencer SL, Berryman MJ, Garcia JA, Abbott D (2004) An ordinary differential equation model for the multistep transformation to cancer. J Theor Biol 231:515–524PubMedGoogle Scholar
  98. 98.
    Kohandel M, Sivaloganathan S, Oza A (2006) Mathematical modeling of ovarian cancer treatments: sequencing of surgery and chemotherapy. J Theor Biol 242:62–68PubMedGoogle Scholar
  99. 99.
    Ostby I, Oyehaug L, Steen HB (2006) A stochastic model of cancer initiation including a bystander effect. J Theor Biol 241:751–764PubMedGoogle Scholar
  100. 100.
    d’Onofrio A, Tomlinson IP (2007) A nonlinear mathematical model of cell turnover, differentiation and tumorigenesis in the intestinal crypt. J Theor Biol 244:367–374PubMedGoogle Scholar
  101. 101.
    Verschraegen C, Vinh-Hung V, Cserni G, Gordon R, Royce ME, Vlastos G, Tai P, Storme G (2005) Modeling the effect of tumor size in early breast cancer. Ann Surg 241:309–318PubMedGoogle Scholar
  102. 102.
    Bearer EL, Lowengrub JS, Frieboes HB, Chuang YL, Jin F, Wise SM, Ferrari M, Agus DB, Cristini V (2009) Multiparameter computational modeling of tumor invasion. Cancer Res 69:4493–4501PubMedGoogle Scholar
  103. 103.
    McDougall SR, Anderson AR, Chaplain MA (2006) Mathematical modelling of dynamic adaptive tumour-induced angiogenesis: clinical implications and therapeutic targeting strategies. J Theor Biol 241:564–589PubMedGoogle Scholar
  104. 104.
    Bauer AL, Jackson TL, Jiang Y (2007) A cell-based model exhibiting branching and anastomosis during tumor-induced angiogenesis. Biophys J 92:3105–3121PubMedGoogle Scholar
  105. 105.
    Khalil IG, Hill C (2005) Systems biology for cancer. Curr Opin Oncol 17:44–48PubMedGoogle Scholar
  106. 106.
    Hornberg JJ, Bruggeman FJ, Westerhoff HV, Lankelma J (2006) Cancer: a systems biology disease. Biosystems 83:81–90PubMedGoogle Scholar
  107. 107.
    Rosenfeld S, Kapetanovic I (2008) Systems biology and cancer prevention: all options on the table. Gene Regul Syst Bio 2:307–319PubMedGoogle Scholar
  108. 108.
    Laubenbacher R, Hower V, Jarrah A, Torti SV, Shulaev V, Mendes P, Torti FM, Akman S (2009) A systems biology view of cancer. Biochim Biophys Acta 1796:129–139PubMedGoogle Scholar
  109. 109.
    Baker SG, Kramer BS (2011) Systems biology and cancer: promises and perils. Prog Biophys Mol Biol 106:410–413PubMedGoogle Scholar
  110. 110.
    Bizzarri M, Giuliani A, Cucina A, D’Anselmi F, Soto AM, Sonnenschein C (2011) Fractal analysis in a systems biology approach to cancer. Semin Cancer Biol 21:175–182PubMedGoogle Scholar
  111. 111.
    Gentles AJ, Gallahan D (2011) Systems biology: confronting the complexity of cancer. Cancer Res 71:5961–5964PubMedGoogle Scholar
  112. 112.
    Price ND, Foltz G, Madan A, Hood L, Tian Q (2008) Systems biology and cancer stem cells. J Cell Mol Med 12:97–110PubMedGoogle Scholar
  113. 113.
    Faratian D, Goltsov A, Lebedeva G, Sorokin A, Moodie S, Mullen P, Kay C, Um IH, Langdon S, Goryanin I, Harrison DJ (2009) Systems biology reveals new strategies for personalizing cancer medicine and confirms the role of PTEN in resistance to trastuzumab. Cancer Res 69:6713–6720PubMedGoogle Scholar
  114. 114.
    Goldberger NE, Hunter KW (2009) A systems biology approach to defining metastatic biomarkers and signaling pathways. Wiley Interdiscip Rev Syst Biol Med 1:89–96PubMedGoogle Scholar
  115. 115.
    Enderling H, Hahnfeldt P, Hlatky L, Almog N (2012) Systems biology of tumor dormancy: linking biology and mathematics on multiple scales to improve cancer therapy. Cancer ResGoogle Scholar
  116. 116.
    Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, Greninger P, Thompson IR, Luo X, Soares J, Liu Q, Iorio F, Surdez D, Chen L, Milano RJ, Bignell GR, Tam AT, Davies H, Stevenson JA, Barthorpe S, Lutz SR, Kogera F, Lawrence K, McLaren-Douglas A, Mitropoulos X, Mironenko T, Thi H, Richardson L, Zhou W, Jewitt F, Zhang T, O’Brien P, Boisvert JL, Price S, Hur W, Yang W, Deng X, Butler A, Choi HG, Chang JW, Baselga J, Stamenkovic I, Engelman JA, Sharma SV, Delattre O, Saez-Rodriguez J, Gray NS, Settleman J, Futreal PA, Haber DA, Stratton MR, Ramaswamy S, McDermott U, Benes CH (2012) Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 483:570–575PubMedGoogle Scholar
  117. 117.
    Wang E, Lenferink A, O’Connor-McCourt M (2007) Cancer systems biology: exploring cancer-associated genes on cellular networks. Cell Mol Life Sci 64:1752–1762PubMedGoogle Scholar
  118. 118.
    Kreeger PK, Lauffenburger DA (2010) Cancer systems biology: a network modeling perspective. Carcinogenesis 31:2–8PubMedGoogle Scholar
  119. 119.
    Cui Q, Ma Y, Jaramillo M, Bari H, Awan A, Yang S, Zhang S, Liu L, Lu M, O’Connor-McCourt M, Purisima EO, Wang E (2007) A map of human cancer signaling. Mol Syst Biol 3:152PubMedGoogle Scholar
  120. 120.
    Flores RJ, Li Y, Yu A, Shen J, Rao PH, Lau SS, Vannucci M, Lau CC, Man TK (2012) A systems biology approach reveals common metastatic pathways in osteosarcoma. BMC Syst Biol 6:50PubMedGoogle Scholar
  121. 121.
    Li J, Lenferink AE, Deng Y, Collins C, Cui Q, Purisima EO, O’Connor-McCourt MD, Wang E (2010) Identification of high-quality cancer prognostic markers and metastasis network modules. Nat Commun 1:34PubMedGoogle Scholar
  122. 122.
    Winter C, Kristiansen G, Kersting S, Roy J, Aust D, Knosel T, Rummele P, Jahnke B, Hentrich V, Ruckert F, Niedergethmann M, Weichert W, Bahra M, Schlitt HJ, Settmacher U, Friess H, Buchler M, Saeger HD, Schroeder M, Pilarsky C, Grutzmann R (2012) Google goes cancer: improving outcome prediction for cancer patients by network-based ranking of marker genes. PLoS Comput Biol 8:e1002511PubMedGoogle Scholar
  123. 123.
    Camacho DF, Pienta KJ (2012) Disrupting the networks of cancer. Clin Cancer Res 18:2801–2808PubMedGoogle Scholar
  124. 124.
    Lee MJ, Ye AS, Gardino AK, Heijink AM, Sorger PK, Macbeath G, Yaffe MB (2012) Sequential application of anticancer drugs enhances cell death by rewiring apoptotic signaling networks. Cell 149:780–794PubMedGoogle Scholar
  125. 125.
    Erler JT, Linding R (2012) Network medicine strikes a blow against breast cancer. Cell 149:731–733PubMedGoogle Scholar
  126. 126.
    Nevins JR, Potti A (2007) Mining gene expression profiles: expression signatures as cancer phenotypes. Nat Rev Genet 8:601–609PubMedGoogle Scholar
  127. 127.
    Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274PubMedGoogle Scholar
  128. 128.
    Chen HY, Yu SL, Chen CH, Chang GC, Chen CY, Yuan A, Cheng CL, Wang CH, Terng HJ, Kao SF, Chan WK, Li HN, Liu CC, Singh S, Chen WJ, Chen JJ, Yang PC (2007) A five-gene signature and clinical outcome in non-small-cell lung cancer. N Engl J Med 356:11–20PubMedGoogle Scholar
  129. 129.
    Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A, Hong SM, Fu B, Lin MT, Calhoun ES, Kamiyama M, Walter K, Nikolskaya T, Nikolsky Y, Hartigan J, Smith DR, Hidalgo M, Leach SD, Klein AP, Jaffee EM, Goggins M, Maitra A, Iacobuzio-Donahue C, Eshleman JR, Kern SE, Hruban RH, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806PubMedGoogle Scholar
  130. 130.
    Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812PubMedGoogle Scholar
  131. 131.
    Pawson T, Linding R (2008) Network medicine. FEBS Lett 582:1266–1270PubMedGoogle Scholar
  132. 132.
    Antman E, Weiss S, Loscalzo J (2012) Systems pharmacology, pharmacogenetics, and clinical trial design in network medicine. Wiley Interdiscip Rev Syst Biol Med 4:367–383Google Scholar
  133. 133.
    Barabasi AL (2007) Network medicine–from obesity to the “diseasome”. N Engl J Med 357:404–407PubMedGoogle Scholar
  134. 134.
    Zanzoni A, Soler-Lopez M, Aloy P (2009) A network medicine approach to human disease. FEBS Lett 583:1759–1765PubMedGoogle Scholar
  135. 135.
    Ghosh S, Basu A (2012) Network medicine in drug design: implications for neuroinflammation. Drug Discov Today 17:600–607PubMedGoogle Scholar
  136. 136.
    Loscalzo J, Barabasi AL (2011) Systems biology and the future of medicine. Wiley Interdiscip Rev Syst Biol Med 3:619–627PubMedGoogle Scholar
  137. 137.
    Goh KI, Cusick ME, Valle D, Childs B, Vidal M, Barabasi AL (2007) The human disease network. Proc Natl Acad Sci USA 104:8685–8690PubMedGoogle Scholar
  138. 138.
    Lee DS, Park J, Kay KA, Christakis NA, Oltvai ZN, Barabasi AL (2008) The implications of human metabolic network topology for disease comorbidity. Proc Natl Acad Sci USA 105:9880–9885PubMedGoogle Scholar
  139. 139.
    Hidalgo CA, Blumm N, Barabasi AL, Christakis NA (2009) A dynamic network approach for the study of human phenotypes. PLoS Comput Biol 5:e1000353PubMedGoogle Scholar
  140. 140.
    Zhang M, Zhu C, Jacomy A, Lu LJ, Jegga AG (2011) The orphan disease networks. Am J Hum Genet 88:755–766PubMedGoogle Scholar
  141. 141.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70PubMedGoogle Scholar
  142. 142.
    Karr JR, Sanghvi JC, Macklin DN, Gutschow MV, Jacobs JM, Bolivar B Jr, Assad-García N, Glass JI, Covert MW (2012) A whole-cell computational model predicts phenotype from genotype. Cell 150:389–401PubMedGoogle Scholar
  143. 143.
    Freddolino PL, Tavazoie S (2012) The dawn of virtual cell biology. Cell 150:248–250PubMedGoogle Scholar

Copyright information

© Springer Basel AG 2012

Authors and Affiliations

  1. 1.Department of Molecular Biology and BiochemistryUniversity of MálagaMalagaSpain
  2. 2.CIBER de Enfermedades Raras (CIBERER)MálagaSpain
  3. 3.Departamento de Biología Molecular y Bioquímica, Facultad de CienciasUniversidad de MálagaMálagaSpain

Personalised recommendations