| Publications about 'retroactivity' |
| Articles in journal or book chapters |
| This paper describes a potential pitfall of perturbation-based approaches to network inference It is shows experimentally, and then explained mathematically, how even in the simplest signaling systems, perturbation methods may lead to paradoxical conclusions: for any given pair of two components X and Y, and depending upon the specific intervention on Y, either an activation or a repression of X could be inferred. The experiments are performed in an in vitro minimal system, thus isolating the effect and showing that it cannot be explained by feedbacks due to unknown intermediates; this system utilizes proteins from a pathway in mammalian (and other eukaryotic) cells that play a central role in proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis and is a perturbation target of contemporary therapies for various types of cancers. The results show that the simplistic view of intracellular signaling networks being made up of activation and repression links is seriously misleading, and call for a fundamental rethinking of signaling network analysis and inference methods. |
| This paper studies the direction of change of steady states to parameter perturbations in chemical reaction networks, and, in particular, to changes in conserved quantities. Theoretical considerations lead to the formulation of a computational procedure that provides a set of possible signs of such sensitivities. The procedure is purely algebraic and combinatorial, only using information on stoichiometry, and is independent of the values of kinetic constants. Two examples of important intracellular signal transduction models are worked out as an illustration. In these examples, the set of signs found is minimal, but there is no general guarantee that the set found will always be minimal in other examples. The paper also briefly discusses the relationship of the sign problem to the question of uniqueness of steady states in stoichiometry classes. |
| 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. |
| 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. |
| 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. |
| Conference articles |
| Summarized conference version of ``Modularity, retroactivity, and structural identification''. |
| Internal reports |
| 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. |
| 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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