Enhancing Boolean networks with continuous logical operators and edge tuning

Due to the scarcity of quantitative details about biological phenomena, quantitative modeling in systems biology can be compromised, especially at the subcellular scale. One way to get around this is qualitative modeling because it requires few to no quantitative information. One of the most popular qualitative modeling approaches is the Boolean network formalism. However, Boolean models allow variables to take only two values, which can be too simplistic in some cases. The present work proposes a modeling approach derived from Boolean networks where continuous logical operators are used and where edges can be tuned. Using continuous logical operators allows variables to be more finely valued while remaining qualitative. To consider that some biological interactions can be slower or weaker than other ones, edge states are also computed in order to modulate in speed and strength the signal they convey. The proposed formalism is illustrated on a toy network coming from the epidermal growth factor receptor signaling pathway. The obtained simulations show that continuous results are produced, thus allowing finer analysis. The simulations also show that modulating the signal conveyed by the edges allows to incorporate knowledge about the interactions they model. The goal is to provide enhancements in the ability of qualitative models to simulate the dynamics of biological networks while limiting the need of quantitative information.

[1]  Henning Hermjakob,et al.  The Reactome pathway knowledgebase , 2013, Nucleic Acids Res..

[2]  B. Matthews Device-Drug Combination Products , 2016 .

[3]  Henning Hermjakob,et al.  The Reactome pathway Knowledgebase , 2015, Nucleic acids research.

[4]  Sarah Filippi,et al.  Information theory and signal transduction systems: from molecular information processing to network inference. , 2014, Seminars in cell & developmental biology.

[5]  Kevin Burrage,et al.  Stochastic simulation in systems biology , 2014, Computational and structural biotechnology journal.

[6]  Réka Albert,et al.  Boolean modeling: a logic‐based dynamic approach for understanding signaling and regulatory networks and for making useful predictions , 2014, Wiley interdisciplinary reviews. Systems biology and medicine.

[7]  B. Haibe-Kains,et al.  Gene regulatory networks and their applications: understanding biological and medical problems in terms of networks , 2014, Front. Cell Dev. Biol..

[8]  Shigehiko Kanaya,et al.  Systems Biology in the Context of Big Data and Networks , 2014, BioMed research international.

[9]  Charles Auffray,et al.  Prediction of chronic lung allograft dysfunction: a systems medicine challenge , 2014, European Respiratory Journal.

[10]  T. Cleophas,et al.  Fuzzy Modeling, a Novel Approach to Studying Pharmacodynamics , 2014, American journal of therapeutics.

[11]  Olaf Wolkenhauer,et al.  Hybrid modeling of the crosstalk between signaling and transcriptional networks using ordinary differential equations and multi-valued logic. , 2014, Biochimica et biophysica acta.

[12]  Ulrik Brandes,et al.  Biological Networks , 2013, Handbook of Graph Drawing and Visualization.

[13]  Tim Beißbarth,et al.  Boolean ErbB network reconstructions and perturbation simulations reveal individual drug response in different breast cancer cell lines , 2014, BMC Systems Biology.

[14]  Luay Nakhleh,et al.  Modeling Integrated Cellular Machinery Using Hybrid Petri-Boolean Networks , 2013, PLoS Comput. Biol..

[15]  Hedi Peterson,et al.  Qualitative modeling identifies IL-11 as a novel regulator in maintaining self-renewal in human pluripotent stem cells , 2013, Front. Physiol..

[16]  Andrés Fernando González Barrios,et al.  Modeling of the hypothalamic-pituitary-adrenal axis-mediated interaction between the serotonin regulation pathway and the stress response using a Boolean approximation: a novel study of depression , 2013, Theoretical Biology and Medical Modelling.

[17]  Denis Thieffry,et al.  Integrative Modelling of the Influence of MAPK Network on Cancer Cell Fate Decision , 2013, PLoS Comput. Biol..

[18]  M. L. Martins,et al.  Boolean Network Model for Cancer Pathways: Predicting Carcinogenesis and Targeted Therapy Outcomes , 2013, PloS one.

[19]  Assieh Saadatpour,et al.  Boolean modeling of biological regulatory networks: a methodology tutorial. , 2013, Methods.

[20]  S. Klamt,et al.  Modeling approaches for qualitative and semi-quantitative analysis of cellular signaling networks , 2013, Cell Communication and Signaling.

[21]  Claudine Chaouiya,et al.  Logical Modelling of Regulatory Networks, Methods and Applications , 2013, Bulletin of Mathematical Biology.

[22]  Giuseppe Longo,et al.  Randomness and multilevel interactions in biology , 2011, Theory in Biosciences.

[23]  Tomas Tokar,et al.  Boolean network-based model of the Bcl-2 family mediated MOMP regulation , 2012, Theoretical Biology and Medical Modelling.

[24]  Tilo Beyer,et al.  Discrete, qualitative models of interaction networks. , 2013, Frontiers in bioscience.

[25]  Neo D. Martinez,et al.  Food webs: reconciling the structure and function of biodiversity. , 2012, Trends in ecology & evolution.

[26]  Michelle L. Wynn,et al.  Logic-based models in systems biology: a predictive and parameter-free network analysis method. , 2012, Integrative biology : quantitative biosciences from nano to macro.

[27]  R. Cheong,et al.  How Information Theory Handles Cell Signaling and Uncertainty , 2012, Science.

[28]  R. Altman,et al.  Pharmacogenomics Knowledge for Personalized Medicine , 2012, Clinical pharmacology and therapeutics.

[29]  Rui-Sheng Wang,et al.  Boolean modeling in systems biology: an overview of methodology and applications , 2012, Physical biology.

[30]  F. Mazzocchi Complexity and the reductionism–holism debate in systems biology , 2012, Wiley interdisciplinary reviews. Systems biology and medicine.

[31]  Melanie Boerries,et al.  Boolean approach to signalling pathway modelling in HGF-induced keratinocyte migration , 2012, Bioinform..

[32]  C. Koch Modular Biological Complexity , 2012, Science.

[33]  Andre Levchenko,et al.  The application of information theory to biochemical signaling systems , 2012, Physical biology.

[34]  M. Kanehisa,et al.  Using the KEGG Database Resource , 2005, Current protocols in bioinformatics.

[35]  P. Ghazal,et al.  Digital clocks: simple Boolean models can quantitatively describe circadian systems , 2012, Journal of The Royal Society Interface.

[36]  Luis Mendoza,et al.  A Boolean network model of the FA/BRCA pathway , 2012, Bioinform..

[37]  M. Turnea,et al.  Ordinary differential equations with applications in molecular biology. , 2012, Revista medico-chirurgicala a Societatii de Medici si Naturalisti din Iasi.

[38]  H. Kitano,et al.  Software for systems biology: from tools to integrated platforms , 2011, Nature Reviews Genetics.

[39]  Z. Bar-Joseph,et al.  Algorithms in nature: the convergence of systems biology and computational thinking , 2011, Molecular systems biology.

[40]  E. Klipp,et al.  Information theory based approaches to cellular signaling. , 2011, Biochimica et biophysica acta.

[41]  Ravi Iyengar,et al.  Systems Biology—Biomedical Modeling , 2011, Science Signaling.

[42]  R Albert,et al.  Exploring phospholipase C-coupled Ca(2+) signalling networks using Boolean modelling. , 2011, IET systems biology.

[43]  Julio Saez-Rodriguez,et al.  Training Signaling Pathway Maps to Biochemical Data with Constrained Fuzzy Logic: Quantitative Analysis of Liver Cell Responses to Inflammatory Stimuli , 2011, PLoS Comput. Biol..

[44]  Chuan Yi Tang,et al.  A genetic algorithm-based boolean delay model of intracellular signal transduction in inflammation , 2011, BMC Bioinformatics.

[45]  P. Mendes,et al.  Multi-scale modelling and simulation in systems biology. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[46]  Olaf Wolkenhauer,et al.  Stochastic approaches in systems biology , 2010, Wiley interdisciplinary reviews. Systems biology and medicine.

[47]  Jinde Cao,et al.  A New Approach to Dynamic Fuzzy Modeling of Genetic Regulatory Networks , 2010, IEEE Transactions on NanoBioscience.

[48]  Casey S Greene,et al.  Integrative systems biology for data-driven knowledge discovery. , 2010, Seminars in nephrology.

[49]  Aurélien Naldi,et al.  Diversity and Plasticity of Th Cell Types Predicted from Regulatory Network Modelling , 2010, PLoS Comput. Biol..

[50]  Thimo Rohlf,et al.  Receptor cross-talk in angiogenesis: mapping environmental cues to cell phenotype using a stochastic, Boolean signaling network model. , 2010, Journal of theoretical biology.

[51]  Reka Albert,et al.  Boolean models of within-host immune interactions. , 2010, Current opinion in microbiology.

[52]  Peter K. Sorger,et al.  Logic-Based Models for the Analysis of Cell Signaling Networks† , 2010, Biochemistry.

[53]  Oliver Sawodny,et al.  ON/OFF and Beyond - A Boolean Model of Apoptosis , 2009, PLoS Comput. Biol..

[54]  Yufei Xiao,et al.  A Tutorial on Analysis and Simulation of Boolean Gene Regulatory Network Models , 2009, Current genomics.

[55]  F. Gueyffier,et al.  Modeling and Medical Product R&D , 2009 .

[56]  Zhong Mai,et al.  Boolean network-based analysis of the apoptosis network: irreversible apoptosis and stable surviving. , 2009, Journal of theoretical biology.

[57]  Steffen Klamt,et al.  The Logic of EGFR/ErbB Signaling: Theoretical Properties and Analysis of High-Throughput Data , 2009, PLoS Comput. Biol..

[58]  Avi Ma’ayan Insights into the Organization of Biochemical Regulatory Networks Using Graph Theory Analyses* , 2009, Journal of Biological Chemistry.

[59]  Hao Ge,et al.  Boolean Network Approach to Negative Feedback Loops of the p53 Pathways: Synchronized Dynamics and Stochastic Limit Cycles , 2009, J. Comput. Biol..

[60]  Julio Saez-Rodriguez,et al.  Fuzzy Logic Analysis of Kinase Pathway Crosstalk in TNF/EGF/Insulin-Induced Signaling , 2007, PLoS Comput. Biol..

[61]  J. Bascompte,et al.  Ecological networks : beyond food webs Ecological networks – beyond food webs , 2008 .

[62]  Lotfi A. Zadeh,et al.  Fuzzy Logic , 2009, Encyclopedia of Complexity and Systems Science.

[63]  Zuyi Huang,et al.  Fuzzy modeling of signal transduction networks , 2009 .

[64]  Holger Fröhlich,et al.  Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance , 2009, BMC Systems Biology.

[65]  Gwenael Kervizic,et al.  Dynamical modeling of the cholesterol regulatory pathway with Boolean networks , 2008, BMC Systems Biology.

[66]  Song Li,et al.  Boolean network simulations for life scientists , 2008, Source Code for Biology and Medicine.

[67]  R. Albert,et al.  Network model of survival signaling in large granular lymphocyte leukemia , 2008, Proceedings of the National Academy of Sciences.

[68]  Avi Ma’ayan Network integration and graph analysis in mammalian molecular systems biology. , 2008, IET systems biology.

[69]  Guy Karlebach,et al.  Modelling and analysis of gene regulatory networks , 2008, Nature Reviews Molecular Cell Biology.

[70]  Stefan Bornholdt,et al.  Boolean network models of cellular regulation: prospects and limitations , 2008, Journal of The Royal Society Interface.

[71]  V. Shahrezaei,et al.  The stochastic nature of biochemical networks. , 2008, Current opinion in biotechnology.

[72]  A. Garg,et al.  Synchronous versus asynchronous modeling of gene regulatory networks , 2008, Bioinform..

[73]  Emmanuel Grenier,et al.  Modelling methodology in physiopathology. , 2008, Progress in biophysics and molecular biology.

[74]  P. Ghazal,et al.  Logic models of pathway biology. , 2008, Drug discovery today.

[75]  A. Levchenko,et al.  Wires in the soup: quantitative models of cell signaling. , 2008, Trends in cell biology.

[76]  C. Pipper,et al.  [''R"--project for statistical computing]. , 2008, Ugeskrift for laeger.

[77]  S. Bornholdt,et al.  Boolean Network Model Predicts Cell Cycle Sequence of Fission Yeast , 2007, PloS one.

[78]  George Boole,et al.  The Mathematical Analysis of Logic: Being an Essay Towards a Calculus of Deductive Reasoning , 2007 .

[79]  Robert Gentleman,et al.  Graphs in molecular biology , 2007, BMC Bioinformatics.

[80]  M. Gerstein,et al.  Getting connected: analysis and principles of biological networks. , 2007, Genes & development.

[81]  Ezequiel Franco-Lara,et al.  Application of fuzzy-logic models for metabolic control analysis. , 2007, Journal of theoretical biology.

[82]  S. Brahmachari,et al.  Boolean network analysis of a neurotransmitter signaling pathway. , 2007, Journal of theoretical biology.

[83]  O Mason,et al.  Graph theory and networks in Biology. , 2006, IET systems biology.

[84]  Barbara Di Ventura,et al.  From in vivo to in silico biology and back , 2006, Nature.

[85]  A. Mogilner,et al.  Quantitative modeling in cell biology: what is it good for? , 2006, Developmental cell.

[86]  Benno Schwikowski,et al.  Graph-based methods for analysing networks in cell biology , 2006, Briefings Bioinform..

[87]  Gene Expression Networks , 2006 .

[88]  Aurélien Naldi,et al.  Dynamical analysis of a generic Boolean model for the control of the mammalian cell cycle , 2006, ISMB.

[89]  Luis Mendoza,et al.  A network model for the control of the differentiation process in Th cells. , 2006, Bio Systems.

[90]  Jian Gong,et al.  Modeling gene expression networks using fuzzy logic , 2005, IEEE Transactions on Systems, Man, and Cybernetics, Part B (Cybernetics).

[91]  H. Kitano,et al.  A comprehensive pathway map of epidermal growth factor receptor signaling , 2005, Molecular systems biology.

[92]  Robert Longtin An integrated approach: systems biology seeks order in complexity. , 2005, Journal of the National Cancer Institute.

[93]  Alexei Kurakin,et al.  Stochastic Cell , 2005, IUBMB life.

[94]  A. Barabasi,et al.  Network biology: understanding the cell's functional organization , 2004, Nature Reviews Genetics.

[95]  D. Bonchev On the complexity of directed biological networks , 2003, SAR and QSAR in environmental research.

[96]  H. Kitano,et al.  Computational systems biology , 2002, Nature.

[97]  Albert-László Barabási,et al.  Life's Complexity Pyramid , 2002, Science.

[98]  H. Kitano Systems Biology: A Brief Overview , 2002, Science.

[99]  James S. Harris,et al.  Measurements and measurement errors , 2002 .

[100]  X. Chen,et al.  TTD: Therapeutic Target Database , 2002, Nucleic Acids Res..

[101]  S. Huang,et al.  Genomics, complexity and drug discovery: insights from Boolean network models of cellular regulation. , 2001, Pharmacogenomics.

[102]  C. E. SHANNON,et al.  A mathematical theory of communication , 1948, MOCO.

[103]  S. Huang,et al.  Shape-dependent control of cell growth, differentiation, and apoptosis: switching between attractors in cell regulatory networks. , 2000, Experimental cell research.

[104]  L. A. Zadeh,et al.  From computing with numbers to computing with words. manipulation of measurements to manipulation of perceptions , 1999, Proceedings of the Second International Conference on Intelligent Processing and Manufacturing of Materials. IPMM'99 (Cat. No.99EX296).

[105]  U. Bhalla,et al.  Complexity in biological signaling systems. , 1999, Science.

[106]  L. Zadeh Fuzzy sets as a basis for a theory of possibility , 1999 .

[107]  L Yang,et al.  Incorporating qualitative knowledge in enzyme kinetic models using fuzzy logic. , 1999, Biotechnology and bioengineering.

[108]  R Hofestädt,et al.  Quantitative modeling of biochemical networks , 1998, Silico Biol..

[109]  Lotfi A. Zadeh,et al.  Fuzzy logic = computing with words , 1996, IEEE Trans. Fuzzy Syst..

[110]  Reza Langari,et al.  Complex systems modeling via fuzzy logic , 1994, Proceedings of 1994 33rd IEEE Conference on Decision and Control.

[111]  Lotfi A. Zadeh,et al.  Fuzzy logic , 1988, Computer.

[112]  Herbert A. Simon,et al.  Why a Diagram is (Sometimes) Worth Ten Thousand Words , 1987, Cogn. Sci..

[113]  J. Dumont,et al.  Boolean analysis of cell regulation networks. , 1983, Journal of theoretical biology.

[114]  R. May Food webs. , 1983, Science.

[115]  L. Glass Classification of biological networks by their qualitative dynamics. , 1975, Journal of theoretical biology.

[116]  R. Thomas,et al.  Boolean formalization of genetic control circuits. , 1973, Journal of theoretical biology.

[117]  L. Glass,et al.  The logical analysis of continuous, non-linear biochemical control networks. , 1973, Journal of theoretical biology.

[118]  J. Brand,et al.  Functional Boolean models for systems with continuous variables. , 1973, Journal of theoretical biology.

[119]  S. Kauffman Metabolic stability and epigenesis in randomly constructed genetic nets. , 1969, Journal of theoretical biology.