1. 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.




2. 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. Keyword(s): systems biology, biochemical networks, synthetic biology, futile cycles, singular perturbations, modularity.



3. D. Del Vecchio, A.J. Ninfa, and E.D. Sontag. Modular Cell Biology: Retroactivity and Insulation. Nature Molecular Systems Biology, 4:161, 2008. [PDF] Keyword(s): 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.

1. E.D. Sontag. Remarks on structural identification, modularity, and retroactivity. In Proc. IEEE Conf. Decision and Control, Atlanta, Dec. 2010, pages ThA23.1, 2010. Keyword(s): modularity, retroactivity, identification. Abstract:

   Summarized conference version of ``Modularity, retroactivity, and structural identification''.




2. 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. Keyword(s): systems biology, biochemical networks, synthetic biology, futile cycles, singular perturbations, modularity.

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