1. 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, reaction 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.




2. E.D. Sontag. Network reconstruction based on steady-state data. Essays in Biochemistry, 45:161-176, 2008. [PDF] Keyword(s): modular response analysis, systems biology, reaction networks, reverse engineering, gene and protein networks, protein networks, gene networks, systems identification, MAPK cascades. 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.




3. 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://sontaglab.org/FTPDIR/andrec-kholodenko-levy-sontag-JTB04-supplementary.pdf. [PDF] Keyword(s): systems biology, reaction networks, gene and protein networks, systems identification, reverse engineering, modular response analysis, systems biology, reaction networks, reverse engineering, gene and protein networks, protein networks, gene networks, systems identification. 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".




4. E.D. Sontag. Molecular systems biology and control. Eur. J. Control, 11(4-5):396-435, 2005. [PDF] Keyword(s): cell biology, systems biology, reaction 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.

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