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Publications about 'biochemical networks'
Articles in journal or book chapters
  1. J. K. Kim and E.D. Sontag. Reduction of multiscale stochastic biochemical reaction networks using exact moment derivation. PLoS Computational Biology, 13:13(6): e1005571, 2017. [PDF] Keyword(s): systems biology, biochemical networks, stochastic systems, Chemical Master Equation, chemical reaction networks, moments, molecular networks, complex-balanced networks.
    Abstract:
    Biochemical reaction networks in cells frequently consist of reactions with disparate timescales. Stochastic simulations of such multiscale BRNs are prohibitively slow due to the high computational cost incurred in the simulations of fast reactions. One way to resolve this problem is to replace fast species by their stationary conditional expectation values conditioned on slow species. While various approximations schemes for this quasi-steady state approximation have been developed, they often lead to considerable errors. This paper considers two classes of multiscale BRNs which can be reduced by through an exact QSS rather than approximations. Specifically, we assume that fast species constitute either a feedforward network or a complex balanced network. Exact reductions for various examples are derived, and the computational advantages of this approach are illustrated through simulations.


  2. E.V. Nikolaev, S.J. Rahi, and E.D. Sontag. Chaos in simple periodically-forced biological models. 2017. Note: Submitted. Preprint: biorxiv 10.1101/145201.[PDF] Keyword(s): chaos, entrainment, systems biology, periodic inputs, subharmonic responses, biochemical systems, forced oscillations.
    Abstract:
    What complicated dynamics can arise in the simplest biochemical systems, in response to a periodic input? This paper discusses two models that commonly appear as components of larger sensing and signal transduction pathways in systems biology: a simple two-species negative feedback loop, and a prototype nonlinear integral feedback. These systems have globally attracting steady states when unforced, yet, when subject to a periodic excitation, subharmonic responses and strange attractors can arise via period-doubling cascades. These behaviors are similar to those exhibited by classical forced nonlinear oscillators such as those described by van der Pol or Duffing equations. The lack of entrainment to external oscillations, in even the simplest biochemical networks, represents a level of additional complexity in molecular biology.


  3. S. J. Rahi, J. Larsch, K. Pecani, N. Mansouri, A. Y. Katsov, K. Tsaneva-Atanasova, E. D. Sontag, and F. R. Cross. Oscillatory stimuli differentiate adapting circuit topologies. Nature Methods, 14:1010-1016, 2017. [PDF] Keyword(s): biochemical networks, periodic behaviors, monotone systems, entrainment, oscillations.
    Abstract:
    Elucidating the structure of biological intracellular networks from experimental data remains a major challenge. This paper studies two types of ``response signatures'' to identify specific circuit motifs, from the observed response to periodic inputs. In particular, the objective is to distinguish negative feedback loops (NFLs) from incoherent feedforward loops (IFFLs), which are two types of circuits capable of producing exact adaptation. The theory of monotone systems with inputs is used to show that ``period skipping'' (non-harmonic responses) is ruled out in IFFL's, and a notion called ``refractory period stabilization'' is also analyzed. The approach is then applied to identify a circuit dominating cell cycle timing in yeast, and to uncover a calcium-mediated NFL circuit in \emph{C.elegans} olfactory sensory neurons.


  4. E.D. Sontag and A. Singh. Exact moment dynamics for feedforward nonlinear chemical reaction networks. IEEE Life Sciences Letters, 1:26-29, 2015. [PDF] Keyword(s): systems biology, biochemical networks, stochastic systems, Chemical Master Equation, chemical reaction networks.
    Abstract:
    Chemical systems are inherently stochastic, as reactions depend on random (thermal) motion. This motivates the study of stochastic models, and specifically the Chemical Master Equation (CME), a discrete-space continuous-time Markov process that describes stochastic chemical kinetics. Exact studies using the CME are difficult, and several moment closure tools related to "mass fluctuation kinetics" and "fluctuation-dissipation" formulas can be used to obtain approximations of moments. This paper, in contrast, introduces a class of nonlinear chemical reaction networks for which exact computation is possible, by means of finite-dimensional linear differential equations. This class allows second and higher order reactions, but only under special assumptions on structure and/or conservation laws.


  5. J. Barton and E.D. Sontag. The energy costs of insulators in biochemical networks. Biophysical Journal, 104:1390-1380, 2013. [PDF]
    Abstract:
    Complex networks of biochemical reactions, such as intracellular protein signaling pathways and genetic networks, are often conceptualized in terms of ``modules,'' semi-independent collections of components that perform a well-defined function and which may be incorporated in multiple pathways. However, due to sequestration of molecular messengers during interactions and other effects, collectively referred to as retroactivity, real biochemical systems do not exhibit perfect modularity. Biochemical signaling pathways can be insulated from impedance and competition effects, which inhibit modularity, through enzymatic ``futile cycles'' which consume energy, typically in the form of ATP. We hypothesize that better insulation necessarily requires higher energy consumption. We test this hypothesis through a combined theoretical and computational analysis of a simplified physical model of covalent cycles, using two innovative measures of insulation, as well as a new way to characterize optimal insulation through the balancing of these two measures in a Pareto sense. Our results indicate that indeed better insulation requires more energy. While insulation may facilitate evolution by enabling a modular ``plug and play'' interconnection architecture, allowing for the creation of new behaviors by adding targets to existing pathways, our work suggests that this potential benefit must be balanced against the metabolic costs of insulation necessarily incurred in not affecting the behavior of existing processes.


  6. G. Craciun, C. Pantea, and E.D. Sontag. Graph-theoretic analysis of multistability and monotonicity for biochemical reaction networks. In H. Koeppl, G. Setti, M. di Bernardo, and D. Densmore, editors, Design and Analysis of Biomolecular Circuits, pages 63-72. Springer-Verlag, 2011. [PDF] Keyword(s): biochemical networks, monotone systems.
    Abstract:
    This is a short expository article describing how the species-reaction graph (SR graph) can be used to analyze both multistability and monotonicity of biochemical networks.


  7. E.D. Sontag. Modularity, retroactivity, and structural identification. In H. Koeppl, G. Setti, M. di Bernardo, and D. Densmore, editors, Design and Analysis of Biomolecular Circuits, pages 183-202. Springer-Verlag, 2011. [PDF] Keyword(s): modularity, retroactivity, identification.
    Abstract:
    Many reverse-engineering techniques in systems biology rely upon data on steady-state (or dynamic) perturbations --obtained from siRNA, gene knock-down or overexpression, kinase and phosphatase inhibitors, or other interventions-- in order to understand the interactions between different ``modules'' in a network. This paper first reviews one such popular such technique, introduced by the author and collaborators, and focuses on why conclusions drawn from its use may be misleading due to ``retroactivity'' (impedance or load) effects. A theoretical result characterizing stoichiometric-induced steady-state retroactivity effects is given for a class of biochemical networks.


  8. D. Angeli, P. de Leenheer, and E.D. Sontag. Persistence results for chemical reaction networks with time-dependent kinetics and no global conservation laws. SIAM Journal on Applied Mathematics, 71:128-146, 2011. [PDF] Keyword(s): biochemical networks, fluxes, Petri nets, persistence, biochemical networks with inputs.
    Abstract:
    New checkable criteria for persistence of chemical reaction networks are proposed, which extend and complement existing ones. The new results allow the consideration of reaction rates which are time-varying, thus incorporating the effects of external signals, and also relax the assumption of existence of global conservation laws, thus allowing for inflows (production) and outflows (degradation). For time-invariant networks parameter-dependent conditions for persistence of certain classes of networks are provided. As an illustration, two networks arising in the systems biology literature are analyzed, namely a hypoxia and an apoptosis network.


  9. A.C. Jiang, A. C. Ventura, E. D. Sontag, S. D. Merajver, A. J. Ninfa, and D. Del Vecchio. Load-induced modulation of signal transduction networks. Science Signaling, 4, issue 194:ra67, 2011. [PDF] Keyword(s): systems biology, biochemical networks, synthetic biology, futile cycles, singular perturbations, modularity.
    Abstract:
    Biological signal transduction networks are commonly viewed as circuits that pass along in the process amplifying signals, enhancing sensitivity, or performing other signal-processing to transcriptional and other components. Here, we report on a "reverse-causality" phenomenon, which we call load-induced modulation. Through a combination of analytical and experimental tools, we discovered that signaling was modulated, in a surprising way, by downstream targets that receive the signal and, in doing so, apply what in physics is called a load. Specifically, we found that non-intuitive changes in response dynamics occurred for a covalent modification cycle when load was present. Loading altered the response time of a system, depending on whether the activity of one of the enzymes was maximal and the other was operating at its minimal rate or whether both enzymes were operating at submaximal rates. These two conditions, which we call "limit regime" and "intermediate regime," were associated with increased or decreased response times, respectively. The bandwidth, the range of frequency in which the system can process information, decreased in the presence of load, suggesting that downstream targets participate in establishing a balance between noise-filtering capabilities and a s ability to process high-frequency stimulation. Nodes in a signaling network are not independent relay devices, but rather are modulated by their downstream targets


  10. R. Albert, B. Dasgupta, and E.D. Sontag. Inference of signal transduction networks from double causal evidence. In David Feny÷, editor, Computational Biology, Methods in Molecular Biology vol. 673, pages 239-251. Springer, 2010. [PDF] Keyword(s): systems biology, biochemical networks, algorithms, signal transduction networks, graph algorithms.
    Abstract:
    We present a novel computational method, and related software, to synthesize signal transduction networks from single and double causal evidence.


  11. D. Angeli, P. de Leenheer, and E.D. Sontag. Graph-theoretic characterizations of monotonicity of chemical networks in reaction coordinates. J. Mathematical Biology, 61:581-616, 2010. [PDF] Keyword(s): biochemical networks, fluxes, monotone systems, reaction cordinates, Petri nets, persistence, futile cycles.
    Abstract:
    This paper derives new results for certain classes of chemical reaction networks, linking structural to dynamical properties. In particular, it investigates their monotonicity and convergence without making assumptions on the form of the kinetics (e.g., mass-action) of the dynamical equations involved, and relying only on stoichiometric constraints. The key idea is to find an alternative representation under which the resulting system is monotone. As a simple example, the paper shows that a phosphorylation/dephosphorylation process, which is involved in many signaling cascades, has a global stability property.


  12. G. Russo, M. di Bernardo, and E.D. Sontag. Global entrainment of transcriptional systems to periodic inputs. PLoS Computational Biology, 6:e1000739, 2010. [PDF] Keyword(s): contractive systems, contractions, systems biology, biochemical networks, gene and protein networks.
    Abstract:
    This paper addresses the problem of giving conditions for transcriptional systems to be globally entrained to external periodic inputs. By using contraction theory, a powerful tool from dynamical systems theory, it is shown that certain systems driven by external periodic signals have the property that all solutions converge to fixed limit cycles. General results are proved, and the properties are verified in the specific case of some models of transcriptional systems.


  13. L. Scardovi, M. Arcak, and E.D. Sontag. Synchronization of interconnected systems with applications to biochemical networks: an input-output approach. IEEE Transactions Autom. Control, 55:1367-1379, 2010. [PDF]
    Abstract:
    This paper provides synchronization conditions for networks of nonlinear systems, where each component of the network itself consists of subsystems represented as operators in the extended L2 space. The synchronization conditions are provided by combining the input-output properties of the subsystems with information about the structure of network. The paper also explores results for state-space models as well as biochemical applications. The work is motivated by cellular networks where signaling occurs both internally, through interactions of species, and externally, through intercellular signaling.


  14. E.D. Sontag and D. Zeilberger. A symbolic computation approach to a problem involving multivariate Poisson distributions. Advances in Applied Mathematics, 44:359-377, 2010. Note: There are a few typos in the published version. Please see this file for corrections: https://drive.google.com/file/d/0BzWFHczJF2INUlEtVkFJOUJiUFU/view. [PDF] Keyword(s): probability theory, stochastic systems, systems biology, biochemical networks, Chemical Master Equation.
    Abstract:
    Multivariate Poisson random variables subject to linear integer constraints arise in several application areas, such as queuing and biomolecular networks. This note shows how to compute conditional statistics in this context, by employing WZ Theory and associated algorithms. A symbolic computation package has been developed and is made freely available. A discussion of motivating biomolecular problems is also provided.


  15. D. Angeli and E.D. Sontag. Graphs and the Dynamics of Biochemical Networks. In B.P. Ingalls and P. Iglesias, editors, Control Theory in Systems Biology, pages 125-142. MIT Press, 2009.
    Abstract:
    This is an expository paper about graph-theoretical properties of biochemical networks, discussing two approaches, one based on bipartite graphs and Petri net concepts, and another based on decompositions into order-preserving subsystems. Other papers on this website contain basically the same material.


  16. D. Angeli, P. de Leenheer, and E.D. Sontag. Chemical networks with inflows and outflows: A positive linear differential inclusions approach. Biotechnology Progress, 25:632-642, 2009. [PDF] Keyword(s): biochemical networks, fluxes, differential inclusions, positive systems, Petri nets, persistence, switched systems.
    Abstract:
    Certain mass-action kinetics models of biochemical reaction networks, although described by nonlinear differential equations, may be partially viewed as state-dependent linear time-varying systems, which in turn may be modeled by convex compact valued positive linear differential inclusions. A result is provided on asymptotic stability of such inclusions, and applied to biochemical reaction networks with inflows and outflows. Included is also a characterization of exponential stability of general homogeneous switched systems


  17. A. Dayarian, M. Chaves, E.D. Sontag, and A. M. Sengupta. Shape, Size and Robustness: Feasible Regions in the Parameter Space of Biochemical Networks. PLoS Computational Biology, 5:e10000256, 2009. [PDF]
    Abstract:
    The concept of robustness of regulatory networks has received much attention in the last decade. One measure of robustness has been associated with the volume of the feasible region, namely, the region in the parameter space in which the system is functional. In recent work, we emphasized that topology and geometry matter, as well as volume. In this paper, and using the segment polarity gene network to illustrate our approach, we show that random walks in parameter space and how they exit the feasible region provide a rich perspective on the different modes of failure of a model. In particular, for the segment polarity network, we found that, between two alternative ways of activating Wingless, one is more robust. Our method provides a more complete measure of robustness to parameter variation. As a general modeling strategy, our approach is an interesting alternative to Boolean representation of biochemical networks.


  18. D. Del Vecchio and E.D. Sontag. Engineering Principles in Bio-Molecular Systems: From Retroactivity to Modularity. European Journal of Control, 15:389-397, 2009. Note: Preliminary version appeared as paper MoB2.2 in Proceedings of the European Control Conference 2009, August 23-26, 2009, Budapest. [PDF] Keyword(s): systems biology, biochemical networks, synthetic biology, futile cycles, singular perturbations, modularity.


  19. M. Arcak and E.D. Sontag. Passivity-based Stability of Interconnection Structures. In V. Blondel, S. Boyd, and H. Kimura, editors, Recent Advances in Learning and Control, volume Volume 371, pages 195-204. Springer-Verlag, NY, 2008. [PDF] [doi:10.1007/978-1-84800-155-8_14] Keyword(s): passive systems, secant condition, biochemical networks.
    Abstract:
    In this expository paper, we provide a streamlined version of the key lemma on stability of interconnections due to Vidyasagar and Moylan and Hill, and then show how it its hypotheses may be verified for network structures of great interest in biology.


  20. R. Albert, B. Dasgupta, R. Dondi, and E.D. Sontag. Inferring (biological) signal transduction networks via transitive reductions of directed graphs. Algorithmica, 51:129-159, 2008. [PDF] [doi:10.1007/s00453-007-9055-0] Keyword(s): systems biology, biochemical networks, algorithms, signal transduction networks, graph algorithms.
    Abstract:
    The transitive reduction problem is that of inferring a sparsest possible biological signal transduction network consistent with a set of experimental observations, with a goal to minimize false positive inferences even if risking false negatives. This paper provides computational complexity results as well as approximation algorithms with guaranteed performance.


  21. D. Angeli and E.D. Sontag. Oscillations in I/O monotone systems. IEEE Transactions on Circuits and Systems, Special Issue on Systems Biology, 55:166-176, 2008. Note: Preprint version in arXiv q-bio.QM/0701018, 14 Jan 2007. [PDF] Keyword(s): monotone systems, hopf bifurcations, circadian rhythms, tridiagonal systems, nonlinear dynamics, systems biology, biochemical networks, oscillations, periodic behavior.
    Abstract:
    In this note, we show how certain properties of Goldbeter's 1995 model for circadian oscillations can be proved mathematically, using techniques from the recently developed theory of monotone systems with inputs and outputs. The theory establishes global asymptotic stability, and in particular no oscillations, if the rate of transcription is somewhat smaller than that assumed by Goldbeter, based on the application of a tight small gain condition. This stability persists even under arbitrary delays in the feedback loop. On the other hand, when the condition is violated a Poincare'-Bendixson result allows to conclude existence of oscillations, for sufficiently high delays.


  22. D. Angeli and E.D. Sontag. Translation-invariant monotone systems, and a global convergence result for enzymatic futile cycles. Nonlinear Analysis Series B: Real World Applications, 9:128-140, 2008. [PDF] [doi:10.1016/j.nonrwa.2006.09.006] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    Strongly monotone systems of ordinary differential equations which have a certain translation-invariance property are shown to have the property that all projected solutions converge to a unique equilibrium. This result may be seen as a dual of a well-known theorem of Mierczynski for systems that satisfy a conservation law. As an application, it is shown that enzymatic futile cycles have a global convergence property.


  23. M. Arcak and E.D. Sontag. A passivity-based stability criterion for a class of interconnected systems and applications to biochemical reaction networks. Mathematical Biosciences and Engineering, 5:1-19, 2008. Note: Also, preprint: arxiv0705.3188v1 [q-bio], May 2007. [PDF] Keyword(s): systems biology, biochemical networks, cyclic feedback systems, secant condition, nonlinear stability, dynamical systems.
    Abstract:
    This paper presents a stability test for a class of interconnected nonlinear systems motivated by biochemical reaction networks. One of the main results determines global asymptotic stability of the network from the diagonal stability of a "dissipativity matrix" which incorporates information about the passivity properties of the subsystems, the interconnection structure of the network, and the signs of the interconnection terms. This stability test encompasses the "secant criterion" for cyclic networks presented in our previous paper, and extends it to a general interconnection structure represented by a graph. A second main result allows one to accommodate state products. This extension makes the new stability criterion applicable to a broader class of models, even in the case of cyclic systems. The new stability test is illustrated on a mitogen activated protein kinase (MAPK) cascade model, and on a branched interconnection structure motivated by metabolic networks. Finally, another result addresses the robustness of stability in the presence of diffusion terms in a compartmental system made out of identical systems.


  24. D. Del Vecchio, A.J. Ninfa, and E.D. Sontag. Modular Cell Biology: Retroactivity and Insulation. Molecular Systems Biology, 4:161, 2008. [PDF] Keyword(s): retroactivity, systems biology, biochemical networks, synthetic biology, futile cycles, singular perturbations, modularity.
    Abstract:
    Modularity plays a fundamental role in the prediction of the behavior of a system from the behavior of its components, guaranteeing that the properties of individual components do not change upon interconnection. Just as electrical, hydraulic, and other physical systems often do not display modularity, nor do many biochemical systems, and specifically, genetic networks. Here, we study the effect of interconnections on the input/output dynamic characteristics of transcriptional components, focusing on a property, which we call "retroactivity," that plays a role analogous to non-zero output impedance in electrical systems. In transcriptional networks, retroactivity is large when the amount of transcription factor is comparable to, or smaller than, the amount of promoter binding sites, or when the affinity of such binding sites is high. In order to attenuate the effect of retroactivity, we propose a feedback mechanism inspired by the design of amplifiers in electronics. We introduce, in particular, a mechanism based on a phosphorylation/dephosphorylation cycle. This mechanism enjoys a remarkable insulation property, due to the fast time scales of the phosphorylation and dephosphorylation reactions. Such a mechanism, when viewed as a signal transduction system, has thus an inherent capacity to provide insulation and hence to increase the modularity of the system in which it is placed.


  25. M.R. Jovanovic, M. Arcak, and E.D. Sontag. A passivity-based approach to stability of spatially distributed systems with a cyclic interconnection structure. IEEE Transactions on Circuits and Systems, Special Issue on Systems Biology, 55:75-86, 2008. Note: Preprint: also arXiv math.OC/0701622, 22 January 2007.[PDF] Keyword(s): MAPK cascades, systems biology, biochemical networks, nonlinear stability, nonlinear dynamics, diffusion, secant condition, cyclic feedback systems.
    Abstract:
    A class of distributed systems with a cyclic interconnection structure is considered. These systems arise in several biochemical applications and they can undergo diffusion driven instability which leads to a formation of spatially heterogeneous patterns. In this paper, a class of cyclic systems in which addition of diffusion does not have a destabilizing effect is identified. For these systems global stability results hold if the "secant" criterion is satisfied. In the linear case, it is shown that the secant condition is necessary and sufficient for the existence of a decoupled quadratic Lyapunov function, which extends a recent diagonal stability result to partial differential equations. For reaction-diffusion equations with nondecreasing coupling nonlinearities global asymptotic stability of the origin is established. All of the derived results remain true for both linear and nonlinear positive diffusion terms. Similar results are shown for compartmental systems.


  26. S. Kachalo, R. Zhang, E.D. Sontag, R. Albert, and B. Dasgupta. NET-SYNTHESIS: A software for synthesis, inference and simplification of signal transduction networks. Bioinformatics, 24:293 - 295, 2008. [PDF] Keyword(s): systems biology, biochemical networks, algorithms, signal transduction networks, graph algorithms.
    Abstract:
    This paper presents a software tool for inference and simplification of signal transduction networks. The method relies on the representation of observed indirect causal relationships as network paths, using techniques from combinatorial optimization to find the sparsest graph consistent with all experimental observations. We illustrate the biological usability of our software by applying it to a previously published signal transduction network and by using it to synthesize and simplify a novel network corresponding to activation-induced cell death in large granular lymphocyte leukemia.


  27. E.D. Sontag. Network reconstruction based on steady-state data. Essays in Biochemistry, 45:161-176, 2008. [PDF] Keyword(s): systems biology, biochemical networks, gene and protein networks, reverse engineering, systems identification.
    Abstract:
    The ``reverse engineering problem'' in systems biology is that of unraveling of the web of interactions among the components of protein and gene regulatory networks, so as to map out the direct or local interactions among components. These direct interactions capture the topology of the functional network. An intrinsic difficulty in capturing these direct interactions, at least in intact cells, is that any perturbation to a particular gene or signaling component may rapidly propagate throughout the network, thus causing global changes which cannot be easily distinguished from direct effects. Thus, a major goal in reverse engineering is to use these observed global responses - such as steady-state changes in concentrations of active proteins, mRNA levels, or transcription rates - in order to infer the local interactions between individual nodes. One approach to solving this global-to-local problem is the ``Modular Response Analysis'' (MRA) method proposed in work of the author with Kholodenko et. al. (PNAS, 2002) and further elaborated in other papers. The basic method deals only with steady-state data. However, recently, quasi-steady state MRA has been used by Santos et. al. (Nature Cell Biology, 2007) for quantifying positive and negative feedback effects in the Raf/Mek/Erk MAPK network in rat adrenal pheochromocytoma (PC-12) cells. This paper presents an overview of the MRA technique, as well as a generalization of the algorithm to that quasi-steady state case.


  28. L. Wang and E.D. Sontag. On the number of steady states in a multiple futile cycle. Journal of Mathematical Biology, 57:29-52, 2008. [PDF] Keyword(s): singular perturbations, futile cycles, MAPK cascades, systems biology, biochemical networks, multistability.
    Abstract:
    This note studies the number of positive steady states in biomolecular reactions consisting of activation/deactivation futile cycles, such as those arising from phosphorylations and dephosphorylations at each level of a MAPK cascade. It is shown that: (1) for some parameter ranges, there are at least n+1 (if n is even) or n (if n is odd) steady states; (2) there never are more than 2n-1 steady states (so, for n=2, there are no more than 3 steady states); (3) for parameters near the standard Michaelis-Menten quasi-steady state conditions, there are at most n+1 steady states; and (4) for parameters far from the standard Michaelis-Menten quasi-steady state conditions, there is at most one steady state.


  29. L. Wang and E.D. Sontag. Singularly perturbed monotone systems and an application to double phosphorylation cycles. J. Nonlinear Science, 18:527-550, 2008. [PDF] Keyword(s): singular perturbations, futile cycles, MAPK cascades, systems biology, biochemical networks, nonlinear stability, nonlinear dynamics, multistability, monotone systems.
    Abstract:
    The theory of monotone dynamical systems has been found very useful in the modeling of some gene, protein, and signaling networks. In monotone systems, every net feedback loop is positive. On the other hand, negative feedback loops are important features of many systems, since they are required for adaptation and precision. This paper shows that, provided that these negative loops act at a comparatively fast time scale, the main dynamical property of (strongly) monotone systems, convergence to steady states, is still valid. An application is worked out to a double-phosphorylation "futile cycle" motif which plays a central role in eukaryotic cell signaling.


  30. R. Albert, B. DasGupta, R. Dondi, S. Kachalo, E.D. Sontag, A. Zelikovsky, and K. Westbrooks. A novel method for signal transduction network inference from indirect experimental evidence. In R. Giancarlo and S. Hannenhalli, editors, 7th Workshop on Algorithms in Bioinformatics (WABI), volume 14, pages 407-419. Springer-Verlag, Berlin, 2007. Note: Conference version of journal paper with same title. Keyword(s): systems biology, biochemical networks, algorithms, signal transduction networks, graph algorithms.


  31. E.D. Sontag. Monotone and near-monotone systems. In I. Queinnec, S. Tarbouriech, G. Garcia, and S-I. Niculescu, editors, Biology and Control Theory: Current Challenges (Lecture Notes in Control and Information Sciences Volume 357), pages 79-122. Springer-Verlag, Berlin, 2007. Note: Conference version of ``Monotone and near-monotone biochemical networks,'' basically the same paper.Keyword(s): systems biology, biochemical networks, monotone systems, Ising spin models, nonlinear stability, dynamical systems, consistent graphs, gene networks.
    Abstract:
    See abstract and pdf for ``Monotone and near-monotone biochemical networks''.


  32. R. Albert, B. DasGupta, R. Dondi, S. Kachalo, E.D. Sontag, A. Zelikovsky, and K. Westbrooks. A novel method for signal transduction network inference from indirect experimental evidence. Journal of Computational Biology, 14:927-949, 2007. [PDF] Keyword(s): systems biology, biochemical networks, algorithms, signal transduction networks, graph algorithms.
    Abstract:
    This paper introduces a new method of combined synthesis and inference of biological signal transduction networks. The main idea lies in representing observed causal relationships as network paths, and using techniques from combinatorial optimization to find the sparsest graph consistent with all experimental observations. The paper formalizes the approach, studies its computational complexity, proves new results for exact and approximate solutions of the computationally hard transitive reduction substep of the approach, validates the biological applicability by applying it to a previously published signal transduction network by Li et al., and shows that the algorithm for the transitive reduction substep performs well on graphs with a structure similar to those observed in transcriptional regulatory and signal transduction networks.


  33. D. Angeli, P. de Leenheer, and E.D. Sontag. A Petri net approach to the study of persistence in chemical reaction networks. Mathematical Biosciences, 210:598-618, 2007. Note: Please look at the paper ``A Petri net approach to persistence analysis in chemical reaction networks'' for additional results, not included in the journal paper due to lack of space. See also the preprint: arXiv q-bio.MN/068019v2, 10 Aug 2006. [PDF] Keyword(s): Petri nets, systems biology, biochemical networks, nonlinear stability, dynamical systems, futile cycles.
    Abstract:
    Persistency is the property, for differential equations in Rn, that solutions starting in the positive orthant do not approach the boundary. For chemical reactions and population models, this translates into the non-extinction property: provided that every species is present at the start of the reaction, no species will tend to be eliminated in the course of the reaction. This paper provides checkable conditions for persistence of chemical species in reaction networks, using concepts and tools from Petri net theory, and verifies these conditions on various systems which arise in the modeling of cell signaling pathways.


  34. P. Berman, B. Dasgupta, and E.D. Sontag. Algorithmic issues in reverse engineering of protein and gene networks via the modular response analysis method. Annals of the NY Academy of Sciences, 1115:132-141, 2007. [PDF] Keyword(s): systems biology, biochemical networks, gene and protein networks, reverse engineering, systems identification, graph algorithms.
    Abstract:
    This paper studies a computational problem motivated by the modular response analysis method for reverse engineering of protein and gene networks. This set-cover problem is hard to solve exactly for large networks, but efficient approximation algorithms are given and their complexity is analyzed.


  35. P. Berman, B. Dasgupta, and E.D. Sontag. Randomized approximation algorithms for set multicover problems with applications to reverse engineering of protein and gene networks. Discrete Applied Mathematics Special Series on Computational Molecular Biology, 155:733-749, 2007. [PDF] Keyword(s): systems biology, biochemical networks, gene and protein networks, systems identification, reverse engineering.
    Abstract:
    This paper investigates computational complexity aspects of a combinatorial problem that arises in the reverse engineering of protein and gene networks, showing relations to an appropriate set multicover problem with large "coverage" factor, and providing a non-trivial analysis of a simple randomized polynomial-time approximation algorithm for the problem.


  36. B. DasGupta, G.A. Enciso, E.D. Sontag, and Y. Zhang. Algorithmic and complexity aspects of decompositions of biological networks into monotone subsystems. BioSystems, 90:161-178, 2007. [PDF] [doi:http://dx.doi.org/10.1016/j.biosystems.2006.08.001] Keyword(s): monotone systems, systems biology, biochemical networks.
    Abstract:
    A useful approach to the mathematical analysis of large-scale biological networks is based upon their decompositions into monotone dynamical systems. This paper deals with two computational problems associated to finding decompositions which are optimal in an appropriate sense. In graph-theoretic language, the problems can be recast in terms of maximal sign-consistent subgraphs. The theoretical results include polynomial-time approximation algorithms as well as constant-ratio inapproximability results. One of the algorithms, which has a worst-case guarantee of 87.9% from optimality, is based on the semidefinite programming relaxation approach of Goemans-Williamson. The algorithm was implemented and tested on a Drosophila segmentation network and an Epidermal Growth Factor Receptor pathway model.


  37. T. Gedeon and E.D. Sontag. Oscillations in multi-stable monotone systems with slowly varying feedback. J. of Differential Equations, 239:273-295, 2007. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    This paper gives a theorem showing that a slow feedback adaptation, acting entirely analogously to the role of negative feedback for ordinary relaxation oscillations, leads to periodic orbits for bistable monotone systems. The proof is based upon a combination of i/o monotone systems theory and Conley Index theory.


  38. E.D. Sontag. Monotone and near-monotone biochemical networks. Systems and Synthetic Biology, 1:59-87, 2007. [PDF] [doi:10.1007/s11693-007-9005-9] Keyword(s): systems biology, biochemical networks, monotone systems, Ising spin models, nonlinear stability, dynamical systems, consistent graphs, gene networks.
    Abstract:
    This paper provides an expository introduction to monotone and near-monotone biochemical network structures. Monotone systems respond in a predictable fashion to perturbations, and have very robust dynamical characteristics. This makes them reliable components of more complex networks, and suggests that natural biological systems may have evolved to be, if not monotone, at least close to monotone. In addition, interconnections of monotone systems may be fruitfully analyzed using tools from control theory.


  39. P. de Leenheer, D. Angeli, and E.D. Sontag. Monotone chemical reaction networks. J. Math Chemistry, 41:295-314, 2007. [PDF] [doi:10.1007/s10910-006-9075-z] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    We analyze certain chemical reaction networks and show that every solution converges to some steady state. The reaction kinetics are assumed to be monotone but otherwise arbitrary. When diffusion effects are taken into account, the conclusions remain unchanged. The main tools used in our analysis come from the theory of monotone dynamical systems. We review some of the features of this theory and provide a self-contained proof of a particular attractivity result which is used in proving our main result.


  40. B. Dasgupta, P. Berman, and E.D. Sontag. Computational complexities of combinatorial problems with applications to reverse engineering of biological networks. In D. Liu and F-Y. Wan, editors, Advances in Computational Intelligence: Theory & Applications, pages 303-316. World Scientific, Hackensack, 2006. Keyword(s): systems biology, biochemical networks, gene and protein networks, reverse engineering, systems identification, theory of computing and complexity.


  41. B. Dasgupta, G.A. Enciso, E.D. Sontag, and Y. Zhang. Algorithmic and complexity results for decompositions of biological networks into monotone subsystems. In C. └lvarez and M. Serna, editors, Lecture Notes in Computer Science: Experimental Algorithms: 5th International Workshop, WEA 2006, pages 253-264. Springer-Verlag, 2006. Note: (Cala Galdana, Menorca, Spain, May 24-27, 2006). Keyword(s): systems biology, biochemical networks, monotone systems, theory of computing and complexity.


  42. M. Arcak and E.D. Sontag. Diagonal stability of a class of cyclic systems and its connection with the secant criterion. Automatica, 42:1531-1537, 2006. [PDF] Keyword(s): passive systems, systems biology, biochemical networks, cyclic feedback systems, secant condition, nonlinear stability, dynamical systems.
    Abstract:
    This paper considers a class of systems with a cyclic structure that arises, among other examples, in dynamic models for certain biochemical reactions. We first show that a criterion for local stability, derived earlier in the literature, is in fact a necessary and sufficient condition for diagonal stability of the corresponding class of matrices. We then revisit a recent generalization of this criterion to output strictly passive systems, and recover the same stability condition using our diagonal stability result as a tool for constructing a Lyapunov function. Using this procedure for Lyapunov construction we exhibit classes of cyclic systems with sector nonlinearities and characterize their global stability properties.


  43. M. Chaves and E.D. Sontag. Exact computation of amplification for a class of nonlinear systems arising from cellular signaling pathways. Automatica, 42:1987-1992, 2006. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems.
    Abstract:
    A commonly employed measure of the signal amplification properties of an input/output system is its induced L2 norm, sometimes also known as H-infinity gain. In general, however, it is extremely difficult to compute the numerical value for this norm, or even to check that it is finite, unless the system being studied is linear. This paper describes a class of systems for which it is possible to reduce this computation to that of finding the norm of an associated linear system. In contrast to linearization approaches, a precise value, not an estimate, is obtained for the full nonlinear model. The class of systems that we study arose from the modeling of certain biological intracellular signaling cascades, but the results should be of wider applicability.


  44. M. Chaves, E.D. Sontag, and R. Albert. Methods of robustness analysis for Boolean models of gene control networks. IET Systems Biology, 153:154-167, 2006. [PDF] Keyword(s): systems biology, biochemical networks, boolean systems, gene and protein networks, hybrid systems.
    Abstract:
    As a discrete approach to genetic regulatory networks, Boolean models provide an essential qualitative description of the structure of interactions among genes and proteins. Boolean models generally assume only two possible states (expressed or not expressed) for each gene or protein in the network as well as a high level of synchronization among the various regulatory processes. In this paper, we discuss and compare two possible methods of adapting qualitative models to incorporate the continuous-time character of regulatory networks. The first method consists of introducing asynchronous updates in the Boolean model. In the second method, we adopt the approach introduced by L. Glass to obtain a set of piecewise linear differential equations which continuously describe the states of each gene or protein in the network. We apply both methods to a particular example: a Boolean model of the segment polarity gene network of Drosophila melanogaster. We analyze the dynamics of the model, and provide a theoretical characterization of the model's gene pattern prediction as a function of the timescales of the various processes.


  45. G.A. Enciso and E.D. Sontag. Global attractivity, I/O monotone small-gain theorems, and biological delay systems. Discrete Contin. Dyn. Syst., 14(3):549-578, 2006. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    This paper further develops a method, originally introduced in a paper by Angeli and Sontag, for proving global attractivity of steady states in certain classes of dynamical systems. In this aproach, one views the given system as a negative feedback loop of a monotone controlled system. An auxiliary discrete system, whose global attractivity implies that of the original system, plays a key role in the theory, which is presented in a general Banach space setting. Applications are given to delay systems, as well as to systems with multiple inputs and outputs, and the question of expressing a given system in the required negative feedback form is addressed.


  46. E.D. Sontag. Passivity gains and the ``secant condition'' for stability. Systems Control Lett., 55(3):177-183, 2006. [PDF] Keyword(s): cyclic feedback systems, systems biology, biochemical networks, nonlinear stability, dynamical systems, passive systems, secant condition, biochemical networks.
    Abstract:
    A generalization of the classical secant condition for the stability of cascades of scalar linear systems is provided for passive systems. The key is the introduction of a quantity that combines gain and phase information for each system in the cascade. For linear one-dimensional systems, the known result is recovered exactly.


  47. P. de Leenheer, D. Angeli, and E.D. Sontag. Crowding effects promote coexistence in the chemostat. Journal of Mathematical Analysis and Applications, 319:48-60, 2006. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    We provide an almost-global stability result for a particular chemostat model, in which crowding effects are taken into consideration. The model can be rewritten as a negative feedback interconnection of two monotone i/o systems with well-defined characteristics, which allows the use of a small-gain theorem for feedback interconnections of monotone systems. This leads to a sufficient condition for almost-global stability, and we show that coexistence occurs in this model if the crowding effects are large enough.


  48. P. de Leenheer, S.A. Levin, E.D. Sontag, and C.A. Klausmeier. Global stability in a chemostat with multiple nutrients. J. Mathematical Biology, 52:419-438, 2006. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    We study a single species in a chemostat, limited by two nutrients, and separate nutrient uptake from growth. For a broad class of uptake and growth functions it is proved that a nontrivial equilibrium may exist. Moreover, if it exists it is unique and globally stable, generalizing a previous result by Legovic and Cruzado.


  49. N.A.W. van Riel and E.D. Sontag. Parameter estimation in models combining signal transduction and metabolic pathways: The dependent input approach. IET Systems Biology, 153:263-274, 2006. [PDF] Keyword(s): systems biology, biochemical networks, parameter identification.
    Abstract:
    Biological complexity and limited quantitative measurements impose severe challenges to standard engineering methodologies for systems identification. This paper presents an approach, justified by the theory of universal inputs for distinguishability, based on replacing unmodeled dynamics by fictitious `dependent inputs'. The approach is particularly useful in validation experiments, because it allows one to fit model parameters to experimental data generated by a reference (wild-type) organism and then testing this model on data generated by a variation (mutant), so long as the mutations only affect the unmodeled dynamics that produce the dependent inputs. As a case study, this paper addresses the pathways that control the nitrogen uptake fluxes in baker's yeast Saccharomyces cerevisiae enabling it to optimally respond to changes in nitrogen availability. Well-defined perturbation experiments were performed on cells growing in steady-state. Time-series data of extracellular and intracellular metabolites were obtained, as well as mRNA levels. A nonlinear model was proposed, and shown to be structurally identifiable given input/output data. The identified model correctly predicted the responses of different yeast strains and different perturbations.


  50. M. Andrec, B.N. Kholodenko, R.M. Levy, and E.D. Sontag. Inference of signaling and gene regulatory networks by steady-state perturbation experiments: structure and accuracy. J. Theoret. Biol., 232(3):427-441, 2005. Note: Supplementary materials are here: http://www.math.rutgers.edu/(tilde)sontag/FTPDIR/andrec-kholodenko-levy-sontag-JTB04-supplementary.pdf. [PDF] Keyword(s): systems biology, biochemical networks, gene and protein networks, systems identification, reverse engineering.
    Abstract:
    One of the fundamental problems of cell biology is the understanding of complex regulatory networks. Such networks are ubiquitous in cells, and knowledge of their properties is essential for the understanding of cellular behavior. This paper studies the effect of experimental uncertainty on the accuracy of the inferred structure of the networks determined using the method in "Untangling the wires: a novel strategy to trace functional interactions in signaling and gene networks".


  51. M. Chaves, R. Albert, and E.D. Sontag. Robustness and fragility of Boolean models for genetic regulatory networks. J. Theoret. Biol., 235(3):431-449, 2005. [PDF] Keyword(s): systems biology, biochemical networks, boolean systems, gene and protein networks.
    Abstract:
    Interactions between genes and gene products give rise to complex circuits that enable cells to process information and respond to external signals. Theoretical studies often describe these interactions using continuous, stochastic, or logical approaches. Here we propose a framework for gene regulatory networks that combines the intuitive appeal of a qualitative description of gene states with a high flexibility in incorporating stochasticity in the duration of cellular processes. We apply our methods to the regulatory network of the segment polarity genes, thus gaining novel insights into the development of gene expression patterns. For example, we show that very short synthesis and decay times can perturb the wild type pattern. On the other hand, separation of timescales between pre- and post-translational processes and a minimal prepattern ensure convergence to the wild type expression pattern regardless of fluctuations.


  52. G.A. Enciso and E.D. Sontag. Monotone systems under positive feedback: multistability and a reduction theorem. Systems Control Lett., 54(2):159-168, 2005. [PDF] Keyword(s): multistability, systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    For feedback loops involving single input, single output monotone systems with well-defined I/O characteristics, a previous paper provided an approach to determining the location and stability of steady states. A result on global convergence for multistable systems followed as a consequence of the technique. The present paper extends the approach to multiple inputs and outputs. A key idea is the introduction of a reduced system which preserves local stability properties. New results characterizing strong monotonicity of feedback loops involving cascades are also presented.


  53. E.D. Sontag. Molecular systems biology and control. Eur. J. Control, 11(4-5):396-435, 2005. [PDF] Keyword(s): cell biology, systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems, molecular biology, systems biology, cellular signaling.
    Abstract:
    This paper, prepared for a tutorial at the 2005 IEEE Conference on Decision and Control, presents an introduction to molecular systems biology and some associated problems in control theory. It provides an introduction to basic biological concepts, describes several questions in dynamics and control that arise in the field, and argues that new theoretical problems arise naturally in this context. A final section focuses on the combined use of graph-theoretic, qualitative knowledge about monotone building-blocks and steady-state step responses for components.


  54. P. de Leenheer, D. Angeli, and E.D. Sontag. On predator-prey systems and small-gain theorems. Math. Biosci. Eng., 2(1):25-42, 2005. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    This paper deals with an almost global attractivity result for Lotka-Volterra systems with predator-prey interactions. These systems can be written as (negative) feedback systems. The subsystems of the feedback loop are monotone control systems, possessing particular input-output properties. We use a small-gain theorem, adapted to a context of systems with multiple equilibrium points to obtain the desired almost global attractivity result. It provides sufficient conditions to rule out oscillatory or more complicated behavior which is often observed in predator-prey systems.


  55. D. Angeli and E.D. Sontag. Interconnections of monotone systems with steady-state characteristics. In Optimal control, stabilization and nonsmooth analysis, volume 301 of Lecture Notes in Control and Inform. Sci., pages 135-154. Springer, Berlin, 2004. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    One of the key ideas in control theory is that of viewing a complex dynamical system as an interconnection of simpler subsystems, thus deriving conclusions regarding the complete system from properties of its building blocks. Following this paradigm, and motivated by questions in molecular biology modeling, the authors have recently developed an approach based on components which are monotone systems with respect to partial orders in state and signal spaces. This paper presents a brief exposition of recent results, with an emphasis on small gain theorems for negative feedback, and the emergence of multi-stability and associated hysteresis effects under positive feedback.


  56. D. Angeli, J. E. Ferrell, and E.D. Sontag. Detection of multistability, bifurcations, and hysteresis in a large class of biological positive-feedback systems.. Proc Natl Acad Sci USA, 101(7):1822-1827, 2004. Note: A revision of Suppl. Fig. 7(b) is here: http://www.math.rutgers.edu/(tilde)sontag/FTPDIR/nullclines-f-g-REV.jpg; and typos can be found here: http://www.math.rutgers.edu/(tilde)sontag/FTPDIR/angeli-ferrell-sontag-pnas04-errata.txt. [WWW] [PDF] [doi:10.1073/pnas.0308265100] Keyword(s): multistability, systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    Multistability is an important recurring theme in cell signaling, of particular relevance to biological systems that switch between discrete states, generate oscillatory responses, or "remember" transitory stimuli. Standard mathematical methods allow the detection of bistability in some very simple feedback systems (systems with one or two proteins or genes that either activate each other or inhibit each other), but realistic depictions of signal transduction networks are invariably much more complex than this. Here we show that for a class of feedback systems of arbitrary order, the stability properties of the system can be deduced mathematically from how the system behaves when feedback is blocked. Provided that this "open loop," feedback-blocked system is monotone and possesses a sigmoidal characteristic, the system is guaranteed to be bistable for some range of feedback strengths. We present a simple graphical method for deducing the stability behavior and bifurcation diagrams for such systems, and illustrate the method with two examples taken from recent experimental studies of bistable systems: a two-variable Cdc2/Wee1 system and a more complicated five-variable MAPK cascade.


  57. D. Angeli and E.D. Sontag. Multi-stability in monotone input/output systems. Systems Control Lett., 51(3-4):185-202, 2004. [PDF] Keyword(s): multistability, systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    This paper studies the emergence of multi-stability and hysteresis in those systems that arise, under positive feedback, from monotone systems with well-defined steady-state responses. Such feedback configurations appear routinely in several fields of application, and especially in biology. The results are stated in terms of directly checkable conditions which do not involve explicit knowledge of basins of attractions of each equilibria.


  58. D. Angeli, P. de Leenheer, and E.D. Sontag. A small-gain theorem for almost global convergence of monotone systems. Systems Control Lett., 52(5):407-414, 2004. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    A small-gain theorem is presented for almost global stability of monotone control systems which are open-loop almost globally stable, when constant inputs are applied. The theorem assumes "negative feedback" interconnections. This typically destroys the monotonicity of the original flow and potentially destabilizes the resulting closed-loop system.


  59. M. Chaves, R.J. Dinerstein, and E.D. Sontag. Optimal length and signal amplification in weakly activated signal transduction cascades. J. Physical Chemistry, 108:15311-15320, 2004. [PDF] Keyword(s): systems biology, biochemical networks, dynamical systems.
    Abstract:
    Weakly activated signaling cascades can be modeled as linear systems. The input-to-output transfer function and the internal gain of a linear system, provide natural measures for the propagation of the input signal down the cascade and for the characterization of the final outcome. The most efficient design of a cascade for generating sharp signals, is obtained by choosing all the off rates equal, and a "universal" finite optimal length.


  60. M. Chaves, E.D. Sontag, and R. J. Dinerstein. Steady-states of receptor-ligand dynamics: A theoretical framework. J. Theoret. Biol., 227(3):413-428, 2004. [PDF] Keyword(s): zero-deficiency networks, systems biology, biochemical networks, receptor-ligand models, dynamical systems.
    Abstract:
    This paper studies aspects of the dynamics of a conventional mechanism of ligand-receptor interactions, with a focus on the stability and location of steady-states. A theoretical framework is developed, and, as an application, a minimal parametrization is provided for models for two- or multi-state receptor interaction with ligand. In addition, an "affinity quotient" is introduced, which allows an elegant classification of ligands into agonists, neutral agonists, and inverse agonists.


  61. G.A. Enciso and E.D. Sontag. On the stability of a model of testosterone dynamics. J. Math. Biol., 49(6):627-634, 2004. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    We prove the global asymptotic stability of a well-known delayed negative-feedback model of testosterone dynamics, which has been proposed as a model of oscillatory behavior. We establish stability (and hence the impossibility of oscillations) even in the presence of delays of arbitrary length.


  62. E.D. Sontag. Some new directions in control theory inspired by systems biology. IET Systems Biology, 1:9-18, 2004. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems, cellular signaling.
    Abstract:
    This paper, addressed primarily to engineers and mathematicians with an interest in control theory, argues that entirely new theoretical problems arise naturally when addressing questions in the field of systems biology. Examples from the author's recent work are used to illustrate this point.


  63. E.D. Sontag, A. Kiyatkin, and B.N. Kholodenko. Inferring dynamic architecture of cellular networks using time series of gene expression, protein and metabolite data. Bioinformatics, 20(12):1877-1886, 2004. Note: Supplementary materials are here: http://www.math.rutgers.edu/(tilde)sontag/FTPDIR/sontag-kiyatkin-kholodenko-informatics04-supplement.pdf. [PDF] [doi:http://dx.doi.org/10.1093/bioinformatics/bth173] Keyword(s): systems biology, biochemical networks, systems identification, gene and protein networks, reverse engineering.
    Abstract:
    High-throughput technologies have facilitated the acquisition of large genomics and proteomics data sets. However, these data provide snapshots of cellular behavior, rather than help us reveal causal relations. Here, we propose how these technologies can be utilized to infer the topology and strengths of connections among genes, proteins, and metabolites by monitoring time-dependent responses of cellular networks to experimental interventions. We show that all connections leading to a given network node, e.g., to a particular gene, can be deduced from responses to perturbations none of which directly influences that node, e.g., using strains with knock-outs to other genes. To infer all interactions from stationary data, each node should be perturbed separately or in combination with other nodes. Monitoring time series provides richer information and does not require perturbations to all nodes.


  64. P. de Leenheer, D. Angeli, and E.D. Sontag. A feedback perspective for chemostat models with crowding effects. In Positive systems (Rome, 2003), volume 294 of Lecture Notes in Control and Inform. Sci., pages 167-174. Springer, Berlin, 2003. Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.


  65. P. de Leenheer, D. Angeli, and E.D. Sontag. Small-gain theorems for predator-prey systems. In Positive systems (Rome, 2003), volume 294 of Lecture Notes in Control and Inform. Sci., pages 191-198. Springer, Berlin, 2003. Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.


  66. D. Angeli and E.D. Sontag. Monotone control systems. IEEE Trans. Automat. Control, 48(10):1684-1698, 2003. Note: Errata are here: http://www.math.rutgers.edu/(tilde)sontag/FTPDIR/angeli-sontag-monotone-TAC03-typos.txt. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    Monotone systems constitute one of the most important classes of dynamical systems used in mathematical biology modeling. The objective of this paper is to extend the notion of monotonicity to systems with inputs and outputs, a necessary first step in trying to understand interconnections, especially including feedback loops, built up out of monotone components. Basic definitions and theorems are provided, as well as an application to the study of a model of one of the cell's most important subsystems.


  67. J. R. Pomerening, E.D. Sontag, and J. E. Ferrell. Building a cell cycle oscillator: hysteresis and bistability in the activation of Cdc2. Nature Cell Biology, 5(4):346-351, 2003. Note: Supplementary materials 2-4 are here: http://www.math.rutgers.edu/(tilde)sontag/FTPDIR/pomerening-sontag-ferrell-additional.pdf. [WWW] [PDF] [doi:10.1038/ncb954] Keyword(s): systems biology, biochemical networks, oscillations, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    In the early embryonic cell cycle, Cdc2-cyclin B functions like an autonomous oscillator, at whose core is a negative feedback loop: cyclins accumulate and produce active mitotic Cdc2-cyclin B Cdc2 activates the anaphase-promoting complex (APC); the APC then promotes cyclin degradation and resets Cdc2 to its inactive, interphase state. Cdc2 regulation also involves positive feedback4, with active Cdc2-cyclin B stimulating its activator Cdc25 and inactivating its inhibitors Wee1 and Myt1. Under the correct circumstances, these positive feedback loops could function as a bistable trigger for mitosis, and oscillators with bistable triggers may be particularly relevant to biological applications such as cell cycle regulation. This paper examined whether Cdc2 activation is bistable, confirming that the response of Cdc2 to non-degradable cyclin B is temporally abrupt and switchlike, as would be expected if Cdc2 activation were bistable. It is also shown that Cdc2 activation exhibits hysteresis, a property of bistable systems with particular relevance to biochemical oscillators. These findings help establish the basic systems-level logic of the mitotic oscillator.


  68. M. Chaves and E.D. Sontag. State-Estimators for chemical reaction networks of Feinberg-Horn-Jackson zero deficiency type. European J. Control, 8:343-359, 2002. [PDF] Keyword(s): observability, zero-deficiency networks, systems biology, biochemical networks, observers, nonlinear stability, dynamical systems.
    Abstract:
    This paper provides a necessary and sufficient condition for detectability, and an explicit construction of observers when this condition is satisfied, for chemical reaction networks of the Feinberg-Horn-Jackson zero deficiency type.


  69. B.N. Kholodenko, A. Kiyatkin, F.J. Bruggeman, E.D. Sontag, H.V. Westerhoff, and J. Hoek. Untangling the wires: a novel strategy to trace functional interactions in signaling and gene networks. Proceedings of the National Academy of Sciences USA, 99:12841-12846, 2002. [PDF] Keyword(s): systems biology, biochemical networks, reverse engineering, gene and protein networks, protein networks, gene networks, systems identification.
    Abstract:
    Emerging technologies have enabled the acquisition of large genomics and proteomics data sets. This paper proposes a novel quantitative method for determining functional interactions in cellular signaling and gene networks. It can be used to explore cell systems at a mechanistic level, or applied within a modular framework, which dramatically decreases the number of variables to be assayed. The topology and strength of network connections are retrieved from experimentally measured network responses to successive perturbations of all modules. In addition, the method can reveal functional interactions even when the components of the system are not all known, in which case some connections retrieved by the analysis will not be direct but correspond to the interaction routes through unidentified elements. The method is tested and illustrated using computer-generated responses of a modeled MAPK cascade and gene network.


  70. E.D. Sontag. Correction to: ``Structure and stability of certain chemical networks and applications to the kinetic proofreading model of T-cell receptor signal transduction'' [IEEE Trans. Automat. Control 46 (2001), no. 7, 1028--1047; MR1842137 (2002e:92006)]. IEEE Trans. Automat. Control, 47(4):705, 2002. [PDF] Keyword(s): zero-deficiency networks, systems biology, biochemical networks, nonlinear stability, dynamical systems.
    Abstract:
    errata for Structure and stability of certain chemical networks and applications to the kinetic proofreading model of T-cell receptor signal transduction


  71. E.D. Sontag. For differential equations with r parameters, 2r+1 experiments are enough for identification. J. Nonlinear Sci., 12(6):553-583, 2002. [PDF] Keyword(s): identifiability, observability, systems biology, biochemical networks, parameter identification.
    Abstract:
    Given a set of differential equations whose description involves unknown parameters, such as reaction constants in chemical kinetics, and supposing that one may at any time measure the values of some of the variables and possibly apply external inputs to help excite the system, how many experiments are sufficient in order to obtain all the information that is potentially available about the parameters? This paper shows that the best possible answer (assuming exact measurements) is 2r+1 experiments, where r is the number of parameters.


  72. E.D. Sontag. Structure and stability of certain chemical networks and applications to the kinetic proofreading model of T-cell receptor signal transduction. IEEE Trans. Automat. Control, 46(7):1028-1047, 2001. [PDF] Keyword(s): zero-deficiency networks, systems biology, biochemical networks, nonlinear stability, dynamical systems.
    Abstract:
    This paper deals with the theory of structure, stability, robustness, and stabilization for an appealing class of nonlinear systems which arises in the analysis of chemical networks. The results given here extend, but are also heavily based upon, certain previous work by Feinberg, Horn, and Jackson, of which a self-contained and streamlined exposition is included. The theoretical conclusions are illustrated through an application to the kinetic proofreading model proposed by McKeithan for T-cell receptor signal transduction.


Conference articles
  1. Y. Shafi, Z. Aminzare, M. Arcak, and E.D. Sontag. Spatial uniformity in diffusively-coupled systems using weighted L2 norm contractions. In Proc. American Control Conference, pages 5639-5644, 2013. [PDF] Keyword(s): contractions, contractive systems, matrix measures, logarithmic norms, Turing instabilities, diffusion, partial differential equations, synchronization.
    Abstract:
    We present conditions that guarantee spatial uniformity in diffusively-coupled systems. Diffusive coupling is a ubiquitous form of local interaction, arising in diverse areas including multiagent coordination and pattern formation in biochemical networks. The conditions we derive make use of the Jacobian matrix and Neumann eigenvalues of elliptic operators, and generalize and unify existing theory about asymptotic convergence of trajectories of reaction-diffusion partial differential equations as well as compartmental ordinary differential equations. We present numerical tests making use of linear matrix inequalities that may be used to certify these conditions. We discuss an example pertaining to electromechanical oscillators. The paper's main contributions are unified verifiable relaxed conditions that guarantee synchrony.


  2. G. Russo, M. di Bernardo, and E.D. Sontag. Stability of networked systems: a multi-scale approach using contraction. In Proc. IEEE Conf. Decision and Control, Atlanta, Dec. 2010, pages FrB14.3, 2010. Keyword(s): contractive systems, contractions, systems biology, biochemical networks, synchronization.
    Abstract:
    Preliminary conference version of ''A contraction approach to the hierarchical analysis and design of networked systems''.


  3. D. Angeli, P. de Leenheer, and E.D. Sontag. On persistence of chemical reaction networks with time-dependent kinetics and no global conservation laws. In Proc. IEEE Conf. Decision and Control, Shanhai, Dec. 2009, pages 4559-4564, 2009. [PDF] Keyword(s): biochemical networks, fluxes, Petri nets, persistence, biochemical networks with inputs.
    Abstract:
    This is a very summarized version ofthe first part of the paper "Persistence results for chemical reaction networks with time-dependent kinetics and no global conservation laws".


  4. L. Scardovi, M. Arcak, and E.D. Sontag. Synchronization of interconnected systems with an input-output approach. Part I: Main results. In Proc. IEEE Conf. Decision and Control, Shanhai, Dec. 2009, pages 609-614, 2009. Note: First part of conference version of journal paper.Keyword(s): passive systems, secant condition, biochemical networks, systems biology.
    Abstract:
    See abstract and link to pdf in entry for Journal paper.


  5. L. Scardovi, M. Arcak, and E.D. Sontag. Synchronization of interconnected systems with an input-output approach. Part II: State-Space result and application to biochemical networks. In Proc. IEEE Conf. Decision and Control, Shanhai, Dec. 2009, pages 615-620, 2009. Note: Second part of conference version of journal paper.Keyword(s): passive systems, secant condition, biochemical networks, systems biology.
    Abstract:
    See abstract and link to pdf in entry for Journal paper.


  6. D. Del Vecchio, A.J. Ninfa, and E.D. Sontag. A Systems Theory with Retroactivity: Application to Transcriptional Modules. In Proceedings of the 2008 American Control Conference, Seattle, June 2008, pages Paper WeC04.1, 2008. [PDF] Keyword(s): retroactivity, systems biology, biochemical networks, synthetic biology, futile cycles, singular perturbations, modularity.


  7. D. Angeli, P. de Leenheer, and E.D. Sontag. Petri nets tools for the analysis of persistence in chemical networks. In Proc. 7th IFAC Symposium on Nonlinear Control Systems (NOLCOS 2007), Pretoria, South Africa, 22-24 August, 2007, 2007. Keyword(s): Petri nets, systems biology, biochemical networks, nonlinear stability, dynamical systems, futile cycles.


  8. M. Arcak and E.D. Sontag. A passivity-based stability criterion for a class of interconnected systems and applications to biochemical reaction networks. In Proc. IEEE Conf. Decision and Control, New Orleans, Dec. 2007, pages 4477-4482, 2007. Note: Conference version of journal paper with same title. Keyword(s): systems biology, biochemical networks, cyclic feedback systems, secant condition, nonlinear stability, dynamical systems.


  9. D. Del Vecchio and E.D. Sontag. Dynamics and control of synthetic bio-molecular networks. In Proceedings American Control Conf., New York, July 2007, pages 1577-1588, 2007. Keyword(s): systems biology, biochemical networks, synthetic biology.
    Abstract:
    This tutorial paper presents an introduction to systems and synthetic molecular biology. It provides an introduction to basic biological concepts, and describes some of the techniques as well as challenges in the analysis and design of biomolecular networks.


  10. M.R. Jovanovic, M. Arcak, and E.D. Sontag. Remarks on the stability of spatially distributed systems with a cyclic interconnection structure. In Proceedings American Control Conf., New York, July 2007, pages 2696-2701, 2007. Keyword(s): systems biology, biochemical networks, cyclic feedback systems, spatially distributed systems, secant condition.
    Abstract:
    For distributed systems with a cyclic interconnection structure, a global stability result is shown to hold if the secant criterion is satisfied.


  11. L. Wang and E.D. Sontag. Further results on singularly perturbed monotone systems, with an application to double phosphorylation cycles. In Proc. IEEE Conf. Decision and Control, New Orleans, Dec. 2007, pages 627-632, 2007. Note: Conference version of Singularly perturbed monotone systems and an application to double phosphorylation cycles.Keyword(s): singular perturbations, futile cycles, MAPK cascades, systems biology, biochemical networks, nonlinear stability, nonlinear dynamics, multistability, monotone systems.


  12. D. Angeli and E.D. Sontag. A note on monotone systems with positive translation invariance. In Control and Automation, 2006. MED '06. 14th Mediterranean Conference on, 28-30 June 2006, pages 1-6, 2006. IEEE. Note: Available from ieeexplore.ieee.org. [PDF] [doi:10.1109/MED.2006.3287822B2B2B2B2B2B] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    Strongly monotone systems of ordinary differential equations which have a certain translation-invariance property are shown to have the property that all projected solutions converge to a unique equilibrium. This result may be seen as a dual of a well-known theorem of Mierczynski for systems that satisfy a conservation law. As an application, it is shown that enzymatic futile cycles have a global convergence property.


  13. D. Angeli, P. de Leenheer, and E.D. Sontag. On the structural monotonicity of chemical reaction networks. In Proc. IEEE Conf. Decision and Control, San Diego, Dec. 2006, pages 7-12, 2006. IEEE. [PDF] Keyword(s): monotone systems, systems biology, biochemical networks, nonlinear stability, dynamical systems.
    Abstract:
    This paper derives new results for certain classes of chemical reaction networks, linking structural to dynamical properties. In particular, it investigates their monotonicity and convergence without making assumptions on the structure (e.g., mass-action kinetics) of the dynamical equations involved, and relying only on stoichiometric constraints. The key idea is to find a suitable set of coordinates under which the resulting system is cooperative. As a simple example, the paper shows that a phosphorylation/dephosphorylation process, which is involved in many signaling cascades, has a global stability property.


  14. M. Arcak and E.D. Sontag. Connections between diagonal stability and the secant condition for cyclic systems. In Proc. American Control Conference, Minneapolis, June 2006, pages 1493-1498, 2006. Keyword(s): systems biology, biochemical networks, cyclic feedback systems, secant condition, nonlinear stability, dynamical systems.


  15. L. Wang and E.D. Sontag. A remark on singular perturbations of strongly monotone systems. In Proc. IEEE Conf. Decision and Control, San Diego, Dec. 2006, pages 989-994, 2006. IEEE. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, singular perturbations, monotone systems.
    Abstract:
    This paper deals with global convergence to equilibria, and in particular Hirsch's generic convergence theorem for strongly monotone systems, for singular perturbations of monotone systems.


  16. L. Wang and E.D. Sontag. Almost global convergence in singular perturbations of strongly monotone systems. In C. Commault and N. Marchand, editors, Positive Systems, pages 415-422, 2006. Springer-Verlag, Berlin/Heidelberg. Note: (Lecture Notes in Control and Information Sciences Volume 341, Proceedings of the second Multidisciplinary International Symposium on Positive Systems: Theory and Applications (POSTA 06) Grenoble, France). [PDF] [doi:10.1007/3-540-34774-7] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, singular perturbations, monotone systems.
    Abstract:
    This paper deals with global convergence to equilibria, and in particular Hirsch's generic convergence theorem for strongly monotone systems, for singular perturbations of monotone systems.


  17. G.A. Enciso and E.D. Sontag. A remark on multistability for monotone systems II. In Proc. IEEE Conf. Decision and Control, Seville, Dec. 2005, IEEE Publications, pages 2957-2962, 2005. Keyword(s): multistability, systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.


  18. E.D. Sontag and M. Chaves. Computation of amplification for systems arising from cellular signaling pathways. In Proc. 16th IFAC World Congress, Prague, July 2005, 2005. Keyword(s): systems biology, biochemical networks, dynamical systems.


  19. D. Angeli and E.D. Sontag. An analysis of a circadian model using the small-gain approach to monotone systems. In Proc. IEEE Conf. Decision and Control, Paradise Island, Bahamas, Dec. 2004, IEEE Publications, pages 575-578, 2004. [PDF] Keyword(s): circadian rhythms, tridiagonal systems, nonlinear dynamics, systems biology, biochemical networks, oscillations, periodic behavior, monotone systems.
    Abstract:
    We show how certain properties of Goldbeter's original 1995 model for circadian oscillations can be proved mathematically. We establish global asymptotic stability, and in particular no oscillations, if the rate of transcription is somewhat smaller than that assumed by Goldbeter, but, on the other hand, this stability persists even under arbitrary delays in the feedback loop. We are mainly interested in illustrating certain mathematical techniques, including the use of theorems concerning tridiagonal cooperative systems and the recently developed theory of monotone systems with inputs and outputs.


  20. D. Angeli, P. de Leenheer, and E.D. Sontag. A tutorial on monotone systems- with an application to chemical reaction networks. In Proc. 16th Int. Symp. Mathematical Theory of Networks and Systems (MTNS 2004), CD-ROM, WP9.1, Katholieke Universiteit Leuven, 2004. [PDF] Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.
    Abstract:
    Monotone systems are dynamical systems for which the flow preserves a partial order. Some applications will be briefly reviewed in this paper. Much of the appeal of the class of monotone systems stems from the fact that roughly, most solutions converge to the set of equilibria. However, this usually requires a stronger monotonicity property which is not always satisfied or easy to check in applications. Following work of J.F. Jiang, we show that monotonicity is enough to conclude global attractivity if there is a unique equilibrium and if the state space satisfies a particular condition. The proof given here is self-contained and does not require the use of any of the results from the theory of monotone systems. We will illustrate it on a class of chemical reaction networks with monotone, but otherwise arbitrary, reaction kinetics.


  21. D. Angeli, P. de Leenheer, and E.D. Sontag. Remarks on monotonicity and convergence in chemical reaction networks. In Proc. IEEE Conf. Decision and Control, Paradise Island, Bahamas, Dec. 2004, IEEE Publications, pages 243-248, 2004. Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.


  22. M. Chaves, E.D. Sontag, and R.J. Dinerstein. Gains and optimal design in signaling pathways. In Proc. IEEE Conf. Decision and Control, Paradise Island, Bahamas, Dec. 2004, IEEE Publications, pages 596-601, 2004. Keyword(s): systems biology, biochemical networks, dynamical systems.


  23. G.A. Enciso and E.D. Sontag. A remark on multistability for monotone systems. In Proc. IEEE Conf. Decision and Control, Paradise Island, Bahamas, Dec. 2004, IEEE Publications, pages 249-254, 2004. Keyword(s): multistability, systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.


  24. D. Angeli and E.D. Sontag. A note on multistability and monotone I/O systems. In Proc. IEEE Conf. Decision and Control, Maui, Dec. 2003, IEEE Publications, 2003, pages 67-72, 2003. Keyword(s): systems biology, biochemical networks, nonlinear stability, dynamical systems, monotone systems.


  25. M. Chaves and E.D. Sontag. An alternative observer for zero deficiency chemical networks. In Proc. Nonlinear Control System Design Symposium, St. Petersburg, July 2001, pages 575-578, 2001. Keyword(s): observability, observers, zero-deficiency networks, systems biology, biochemical networks, nonlinear stability, dynamical systems.


  26. M. Chaves and E.D. Sontag. Observers for certain chemical reaction networks. In Proc. 2001 European Control Conf., Sep. 2001, pages 3715-3720, 2001. Keyword(s): zero-deficiency networks, systems biology, biochemical networks, nonlinear stability, dynamical systems, observability, observers.


Internal reports
  1. E.D. Sontag. Examples of computation of exact moment dynamics for chemical reaction networks. Technical report, arXiv:1612.02393, 2016. [PDF] Keyword(s): systems biology, biochemical networks, stochastic systems, Chemical Master Equation, chemical reaction networks, moments, molecular networks, complex-balanced networks.
    Abstract:
    We review in a unified way results for two types of stochastic chemical reaction systems for which moments can be effectively computed: feedforward networks and complex-balanced networks.


  2. J. Barton and E.D. Sontag. Remarks on the energy costs of insulators in enzymatic cascades. Technical report, http://arxiv.org/abs/1412.8065, December 2014. [PDF] Keyword(s): retroactivity, systems biology, biochemical networks, futile cycles, singular perturbations, modularity.
    Abstract:
    The connection between optimal biological function and energy use, measured for example by the rate of metabolite consumption, is a current topic of interest in the systems biology literature which has been explored in several different contexts. In [J. P. Barton and E. D. Sontag, Biophys. J. 104, 6 (2013)], we related the metabolic cost of enzymatic futile cycles with their capacity to act as insulators which facilitate modular interconnections in biochemical networks. There we analyzed a simple model system in which a signal molecule regulates the transcription of one or more target proteins by interacting with their promoters. In this note, we consider the case of a protein with an active and an inactive form, and whose activation is controlled by the signal molecule. As in the original case, higher rates of energy consumption are required for better insulator performance.


  3. J. Barton and E.D. Sontag. The energy costs of biological insulators. Technical report, http://arxiv.org/abs/1210.3809, October 2012. Keyword(s): retroactivity, systems biology, biochemical networks, futile cycles, singular perturbations, modularity.
    Abstract:
    Biochemical signaling pathways can be insulated from impedance and competition effects through enzymatic "futile cycles" which consume energy, typically in the form of ATP. We hypothesize that better insulation necessarily requires higher energy consumption, and provide evidence, through the computational analysis of a simplified physical model, to support this hypothesis.



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