Modeling and Analyzing Biological Oscillations in Molecular Networks Techniques based on dynamical and control theories, for representing the synchronization of signals between cells, can be used to reduce the complexity of modeling biological systems.

One of the major challenges for postgenomic biology is to understand how genes, proteins, and small mole- cules dynamically interact to form molecular networks which facilitate sophisticated biological functions. In this paper, we present a survey on recent developments on modelling mole- cular networks and analyzing synchronization of bio-oscillators in multicellular systems from the viewpoint of systems biology. Attention will be focused on deriving general theoretical results to understand the dynamical behaviors of biological systems based on nonlinear dynamical and control theory. Specifically, we first describe the stochastic and deterministic approaches to model molecular networks and give a brief comparison between them. Then, we explain how to construct a molecular network, in particular, a gene regulatory network with specific functions, e.g., switches and oscillators, in individual cells at the molecular level by using feedback systems, and how to model a general multicellular system with the consideration of external fluctuations and intercellular coupling to study the general cooperative behaviors for a population of bio-oscillators. Finally, as an illustrative example, a synthetic multicellular system is designed to show how synchronization is effectively achieved and how dynamics of individual cells is efficiently controlled. Some recent developments and perspectives of analysis on biological oscillations in future are also discussed.

[1]  David Angeli,et al.  Monotone control systems , 2003, IEEE Trans. Autom. Control..

[2]  Sato Honma,et al.  Diversity in the circadian periods of single neurons of the rat suprachiasmatic nucleus depends on nuclear structure and intrinsic period , 2004, Neuroscience Letters.

[3]  C. Rao,et al.  Stochastic chemical kinetics and the quasi-steady-state assumption: Application to the Gillespie algorithm , 2003 .

[4]  Linda R. Petzold,et al.  Improved leap-size selection for accelerated stochastic simulation , 2003 .

[5]  E. Andrianantoandro,et al.  Synthetic biology: new engineering rules for an emerging discipline , 2006, Molecular systems biology.

[6]  S. Bernard,et al.  Spontaneous synchronization of coupled circadian oscillators. , 2005, Biophysical journal.

[7]  A. Winfree The geometry of biological time , 1991 .

[8]  K. Aihara,et al.  Chaos and phase locking in normal squid axons , 1987 .

[9]  R. Milo,et al.  Network motifs in integrated cellular networks of transcription-regulation and protein-protein interaction. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Liao,et al.  A synthetic gene–metabolic oscillator , 2005, Nature.

[11]  V. Hakim,et al.  Design of genetic networks with specified functions by evolution in silico. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[12]  K. Aihara,et al.  Molecular communication through stochastic synchronization induced by extracellular fluctuations. , 2005, Physical review letters.

[13]  Kazuyuki Aihara,et al.  Stability of Genetic Networks With SUM Regulatory Logic: Lur'e System and LMI Approach , 2006, IEEE Transactions on Circuits and Systems I: Regular Papers.

[14]  G. Sell,et al.  Systems of Differential Delay Equations: Floquet Multipliers and Discrete Lyapunov Functions , 1996 .

[15]  K. Aihara,et al.  Stability of genetic regulatory networks with time delay , 2002 .

[16]  Luonan Chen,et al.  Modelling periodic oscillation in gene regulatory networks by cyclic feedback systems , 2005, Bulletin of mathematical biology.

[17]  D. Gillespie Approximate accelerated stochastic simulation of chemically reacting systems , 2001 .

[18]  Luonan Chen,et al.  Analysis on multi-domain cooperation for predicting protein-protein interactions , 2007, BMC Bioinformatics.

[19]  B. Bassler,et al.  Quorum sensing in bacteria. , 2001, Annual review of microbiology.

[20]  Michael A Henson,et al.  Modeling the synchronization of yeast respiratory oscillations. , 2004, Journal of theoretical biology.

[21]  Arthur T. Winfree,et al.  The timing of biological clocks , 1986 .

[22]  Kazuyuki Aihara,et al.  Dynamics of gene regulatory networks with cell division cycle. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[23]  N. Kampen,et al.  Stochastic processes in physics and chemistry , 1981 .

[24]  S. Shen-Orr,et al.  Network motifs: simple building blocks of complex networks. , 2002, Science.

[25]  D. Gillespie Exact Stochastic Simulation of Coupled Chemical Reactions , 1977 .

[26]  J. Kurths,et al.  Coherence Resonance in a Noise-Driven Excitable System , 1997 .

[27]  Giles Auchmuty,et al.  Global bifurcations of phase-locked oscillators , 1986 .

[28]  Yi Tao,et al.  Intrinsic and external noise in an auto-regulatory genetic network. , 2004, Journal of theoretical biology.

[29]  M. Thattai,et al.  Intrinsic noise in gene regulatory networks , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[30]  Kaplan,et al.  Subthreshold dynamics in periodically stimulated squid giant axons. , 1996, Physical review letters.

[31]  L. Glass Synchronization and rhythmic processes in physiology , 2001, Nature.

[32]  Reinhart Heinrich,et al.  Transduction of intracellular and intercellular dynamics in yeast glycolytic oscillations. , 2000, Biophysical journal.

[33]  Hal L. Smith,et al.  Monotone Dynamical Systems: An Introduction To The Theory Of Competitive And Cooperative Systems (Mathematical Surveys And Monographs) By Hal L. Smith , 1995 .

[34]  S. Leibler,et al.  Mechanisms of noise-resistance in genetic oscillators , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Sandeep Krishna,et al.  Oscillation patterns in negative feedback loops , 2006, Proceedings of the National Academy of Sciences.

[36]  Nancy Kopell,et al.  Synchrony in a Population of Hysteresis-Based Genetic Oscillators , 2004, SIAM J. Appl. Math..

[37]  Kazuyuki Aihara,et al.  Construction of genetic oscillators with interlocked feedback networks. , 2006, Journal of theoretical biology.

[38]  M. Elowitz,et al.  A synthetic oscillatory network of transcriptional regulators , 2000, Nature.

[39]  T Höfer,et al.  Model of intercellular calcium oscillations in hepatocytes: synchronization of heterogeneous cells. , 1999, Biophysical journal.

[40]  A. Goldbeter A model for circadian oscillations in the Drosophila period protein (PER) , 1995, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[41]  K. Aihara,et al.  A model of periodic oscillation for genetic regulatory systems , 2002 .

[42]  J. Hasty,et al.  Synchronizing genetic relaxation oscillators by intercell signaling , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Kenzo Hirose,et al.  Intercellular coupling mechanism for synchronized and noise-resistant circadian oscillators. , 2002, Journal of theoretical biology.

[44]  J. Teramae,et al.  Robustness of the noise-induced phase synchronization in a general class of limit cycle oscillators. , 2004, Physical review letters.

[45]  L Schimansky-Geier,et al.  Macroscopic limit cycle via pure noise-induced phase transitions. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[46]  B. Bassler,et al.  Bacterial social engagements. , 2004, Trends in cell biology.

[47]  Mukund Thattai,et al.  Metabolic switching in the sugar phosphotransferase system of Escherichia coli. , 2003, Biophysical journal.

[48]  H. Risken Fokker-Planck Equation , 1984 .

[49]  A. Goldbeter,et al.  A Model for Circadian Rhythms in Drosophila Incorporating the Formation of a Complex between the PER and TIM Proteins , 1998, Journal of biological rhythms.

[50]  J. Hasty,et al.  Synthetic gene network for entraining and amplifying cellular oscillations. , 2002, Physical review letters.

[51]  Pablo A. Iglesias,et al.  Quantifying robustness of biochemical network models , 2002, BMC Bioinformatics.

[52]  Michael A. Gibson,et al.  Efficient Exact Stochastic Simulation of Chemical Systems with Many Species and Many Channels , 2000 .

[53]  Bernard Perbal,et al.  Communication is the key , 2003, Cell Communication and Signaling.

[54]  Kazuyuki Aihara,et al.  Stochastic Stability of Genetic Networks With Disturbance Attenuation , 2007, IEEE Transactions on Circuits and Systems II: Express Briefs.

[55]  Chunguang Li,et al.  Noise-induced dynamics in the mixed-feedback-loop network motif. , 2008, Physical review. E, Statistical, nonlinear, and soft matter physics.

[56]  Zhonghuai Hou,et al.  Internal noise stochastic resonance of synthetic gene network , 2005 .

[57]  Yiannis N. Kaznessis,et al.  Multi-scale models for gene network engineering , 2006 .

[58]  P. Gaspard,et al.  Biochemical Clocks and Molecular Noise: Theoretical Study of Robustness Factors , 2002 .

[59]  Van den Broeck C,et al.  Noise-induced nonequilibrium phase transition. , 1994, Physical review letters.

[60]  Melvin K. Simmons,et al.  Hybrid simulation of cellular behavior , 2004, Bioinform..

[61]  A. Winfree Biological rhythms and the behavior of populations of coupled oscillators. , 1967, Journal of theoretical biology.

[62]  Matthias Reuss,et al.  Cell population modelling of yeast glycolytic oscillations. , 2002, The Biochemical journal.

[63]  R Thomas,et al.  Dynamical behaviour of biological regulatory networks--I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state. , 1995, Bulletin of mathematical biology.

[64]  Mauricio Barahona,et al.  Perfect sampling of the master equation for gene regulatory networks. , 2006, Biophysical journal.

[65]  Eduardo D. Sontag,et al.  Molecular Systems Biology and Control , 2005, Eur. J. Control.

[66]  J. Hasty,et al.  Noise-based switches and amplifiers for gene expression. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[67]  S. Basu,et al.  A synthetic multicellular system for programmed pattern formation , 2005, Nature.

[68]  A. Goldbeter,et al.  Toward a detailed computational model for the mammalian circadian clock , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[69]  M. Ehrenberg,et al.  Stochastic focusing: fluctuation-enhanced sensitivity of intracellular regulation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[70]  Michal Linial,et al.  Using Bayesian Networks to Analyze Expression Data , 2000, J. Comput. Biol..

[71]  A. Goldbeter,et al.  Chaos and birhythmicity in a model for circadian oscillations of the PER and TIM proteins in drosophila , 1999, Journal of theoretical biology.

[72]  L. Arnold Stochastic Differential Equations: Theory and Applications , 1992 .

[73]  Kazuyuki Aihara,et al.  Stochastic synchronization of genetic oscillator networks , 2007, BMC Systems Biology.

[74]  Mayara MA Silva,et al.  Light-dark cycle synchronization of circadian rhythm in blind primates , 2005, Journal of circadian rhythms.

[75]  Jesper Tegnér,et al.  Reverse engineering gene networks using singular value decomposition and robust regression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[76]  Kazuyuki Aihara,et al.  Detection of cellular rhythms and global stability within interlocked feedback systems. , 2007, Mathematical biosciences.

[77]  Luonan Chen,et al.  Discovering functions and revealing mechanisms at molecular level from biological networks , 2007, Proteomics.

[78]  I. Birol,et al.  Metabolic control analysis under uncertainty: framework development and case studies. , 2004, Biophysical journal.

[79]  K. Aihara,et al.  A Systems Biology Perspective on Signal Processing in Genetic Network Motifs [Life Sciences] , 2007, IEEE Signal Processing Magazine.

[80]  K. Aihara,et al.  Synchronization of coupled nonidentical genetic oscillators , 2006, Physical biology.

[81]  Luonan Chen,et al.  Inferring transcriptional regulatory networks from high-throughput data , 2007, Bioinform..

[82]  Ting Chen,et al.  Modeling Gene Expression with Differential Equations , 1998, Pacific Symposium on Biocomputing.

[83]  S. Daan,et al.  Accuracy of Circadian Entrainment under Fluctuating Light Conditions: Contributions of Phase and Period Responses , 1999, Journal of biological rhythms.

[84]  M. Elowitz,et al.  Modeling a synthetic multicellular clock: repressilators coupled by quorum sensing. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[85]  Julian Lewis Autoinhibition with Transcriptional Delay A Simple Mechanism for the Zebrafish Somitogenesis Oscillator , 2003, Current Biology.

[86]  R. Novick Autoinduction and signal transduction in the regulation of staphylococcal virulence , 2003, Molecular microbiology.

[87]  Xiang-Sun Zhang,et al.  Hubs with Network Motifs Organize Modularity Dynamically in the Protein-Protein Interaction Network of Yeast , 2007, PloS one.

[88]  J. Goutsias Classical versus stochastic kinetics modeling of biochemical reaction systems. , 2007, Biophysical journal.

[89]  J. Dunlap Molecular Bases for Circadian Clocks , 1999, Cell.

[90]  R. Weiss,et al.  Programmed population control by cell–cell communication and regulated killing , 2004, Nature.

[91]  Stuart A. Kauffman,et al.  The origins of order , 1993 .

[92]  Tao Yang,et al.  In: Impulsive control theory , 2001 .

[93]  Hidde de Jong,et al.  Modeling and Simulation of Genetic Regulatory Systems: A Literature Review , 2002, J. Comput. Biol..

[94]  R. Thomas,et al.  The role of feedback circuits: Positive feedback circuits are a necessary condition for positive real eigenvalues of the Jacobian matrix , 1994 .

[95]  Luonan Chen,et al.  Synchronizing Genetic Oscillators by Signaling Molecules , 2005, Journal of biological rhythms.

[96]  P. Swain,et al.  Stochastic Gene Expression in a Single Cell , 2002, Science.

[97]  Kazuyuki Aihara,et al.  Noise-induced cooperative behavior in a multicell system , 2005, Bioinform..

[98]  Luonan Chen,et al.  Designing Gene Regulatory Networks With Specified Functions , 2006, IEEE Transactions on Circuits and Systems I: Regular Papers.

[99]  Jean-Jacques Meister,et al.  Ca2+ dynamics in a population of smooth muscle cells: modeling the recruitment and synchronization. , 2004, Biophysical journal.

[100]  A. Kierzek,et al.  Bridging the gap between stochastic and deterministic regimes in the kinetic simulations of the biochemical reaction networks. , 2004, Biophysical journal.

[101]  Luonan Chen,et al.  Inferring protein interactions from experimental data by association probabilistic method , 2006, Proteins.

[102]  S. Basu,et al.  Spatiotemporal control of gene expression with pulse-generating networks. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[103]  S. Yamaguchi,et al.  Synchronization of Cellular Clocks in the Suprachiasmatic Nucleus , 2003, Science.

[104]  J. Collins,et al.  Programmable cells: interfacing natural and engineered gene networks. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[105]  J. Hopfield,et al.  From molecular to modular cell biology , 1999, Nature.

[106]  G. Sell,et al.  THE POINCARE-BENDIXSON THEOREM FOR MONOTONE CYCLIC FEEDBACK SYSTEMS WITH DELAY , 1996 .

[107]  J. Collins,et al.  Construction of a genetic toggle switch in Escherichia coli , 2000, Nature.

[108]  M. Yčas,et al.  A model for binary logic in biochemical systems. , 1967, Journal of theoretical biology.

[109]  Yiannis N Kaznessis,et al.  An equation-free probabilistic steady-state approximation: dynamic application to the stochastic simulation of biochemical reaction networks. , 2005, The Journal of chemical physics.

[110]  Kazuyuki Aihara,et al.  Synchronizing a multicellular system by external input: an artificial control strategy , 2006, Bioinform..

[111]  Bonnie L Bassler,et al.  Chemical communication among bacteria , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[112]  Ruiqi Wang,et al.  Modelling periodic oscillation of biological systems with multiple timescale networks. , 2004, Systems biology.

[113]  D. Gillespie A rigorous derivation of the chemical master equation , 1992 .

[114]  D. Gillespie A General Method for Numerically Simulating the Stochastic Time Evolution of Coupled Chemical Reactions , 1976 .

[115]  Jürgen Kurths,et al.  Synchronization - A Universal Concept in Nonlinear Sciences , 2001, Cambridge Nonlinear Science Series.

[116]  Kazuyuki Aihara,et al.  Transient Resetting: A Novel Mechanism for Synchrony and Its Biological Examples , 2006, PLoS Comput. Biol..

[117]  Ertugrul M. Ozbudak,et al.  Predicting stochastic gene expression dynamics in single cells. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[118]  Eduardo Sontag,et al.  Untangling the wires: A strategy to trace functional interactions in signaling and gene networks , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[119]  J. T. Enright Temporal precision in circadian systems: a reliable neuronal clock from unreliable components? , 1980, Science.

[120]  Reinhart Heinrich,et al.  Dynamics of two-component biochemical systems in interacting cells; synchronization and desynchronization of oscillations and multiple steady states. , 1997, Bio Systems.

[121]  Thilo Gross,et al.  Structural kinetic modeling of metabolic networks , 2006, Proceedings of the National Academy of Sciences.

[122]  B. Spencer,et al.  New Insights on the Application of Moment Closure Methods to Nonlinear Stochastic Systems , 1996 .

[123]  G. Gerisch,et al.  Cell communication by periodic cyclic-AMP pulses. , 1975, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.