Synthetic Tunable Amplifying Buffer Circuit in <i>E. coli</i>

Nilgiriwala, Kayzad; Jiménez, José I.; Rivera, Phillip M.; Vecchio, Domitilla Del

doi:10.1021/sb5002533

Cited by 46 publications

(57 citation statements)

References 43 publications

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“…A number of ways have been proposed to implement such a mechanism within an insulation device [94]. One implementation that was experimentally realized and validated uses a covalent modification cycle as shown in figure 6c [101]. Here, the input amplification G is realized by having a sufficiently large reservoir of inactive protein y in , which upon presentation of the input u is turned into the active output y.…”

Section: Explicit High-gain Negative Feedback To Design Insulation Dementioning

confidence: 99%

Control theory meets synthetic biology

Vecchio

Qian

2016

J. R. Soc. Interface.

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236

191

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The past several years have witnessed an increased presence of control theoretic concepts in synthetic biology. This review presents an organized summary of how these control design concepts have been applied to tackle a variety of problems faced when building synthetic biomolecular circuits in living cells. In particular, we describe success stories that demonstrate how simple or more elaborate control design methods can be used to make the behaviour of synthetic genetic circuits within a single cell or across a cell population more reliable, predictable and robust to perturbations. The description especially highlights technical challenges that uniquely arise from the need to implement control designs within a new hardware setting, along with implemented or proposed solutions. Some engineering solutions employing complex feedback control schemes are also described, which, however, still require a deeper theoretical analysis of stability, performance and robustness properties. Overall, this paper should help synthetic biologists become familiar with feedback control concepts as they can be used in their application area. At the same time, it should provide some domain knowledge to control theorists who wish to enter the rising and exciting field of synthetic biology.

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Section: Explicit High-gain Negative Feedback To Design Insulation Dementioning

confidence: 99%

Control theory meets synthetic biology

Vecchio

Qian

2016

J. R. Soc. Interface.

Self Cite

236

191

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“…The output is thus made independent of the presence of load; however, such a device slows down the dynamics of the input. This tradeoff was theoretically characterized in [9] and experimentally verified using a NRI-NRI * PD cycle [8]. The results of [10] suggest that this tradeoff may be overcome by using multiple stages of PD cycles.…”

Section: Introductionmentioning

confidence: 90%

“…A single phosphorylation-dephosphorylation (PD) cycle has been theoretically [6] and experimentally [7], [8] shown to behave as an insulation device due to a high-gain feedback mechanism. In these works, the total substrate and phosphatase concentration of the cycle is increased to attenuate the effect of retroactivity on the output due to the presence of load.…”

Section: Introductionmentioning

confidence: 99%

An N-stage cascade of phosphorylation cycles as an insulation device for synthetic biological circuits

Shah

Vecchio

2016

2016 European Control Conference (ECC)

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Single phosphorylation cycles have been found to have insulation device abilities, that is, they attenuate the effect of retroactivity applied by downstream systems and hence facilitate modular design in synthetic biology. It was recently discovered that this retroactivity attenuation property comes at the expense of an increased retroactivity to the input of the insulation device, wherein the device slows down the signal it receives from its upstream system. In this paper, we demonstrate that insulation devices built of cascaded phosphorylation cycles can break this tradeoff, allowing to attenuate the retroactivity applied by downstream systems while keeping a small retroactivity to the input. In particular, we show that there is an optimal number of cycles that maximally extends the linear operating region of the insulation device while keeping the desired retroactivity properties, when a common phosphatase is used. These findings provide optimal design strategies of insulation devices for synthetic biology applications.

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“…When the demand for the output protein y increases due to load, the large inlet flux quickly generates more y, while the large outlet flux guarantees that no more y than required to track the concentration of the input u is generated. This system has been implemented using the NRI/NRII TCS system of E. coli, in which the authors showed that increased phosphatase and substrate amounts make, as predicted from theory, the system's response independent of load [41]. However, the authors also showed that increasing these amounts make the temporal response of the device substantially slower.…”

Section: Modularity Of Functional Modules: the E↵ects Of Loadsmentioning

confidence: 99%

Modularity, context-dependence, and insulation in engineered biological circuits

Vecchio¹

2015

Trends in Biotechnology

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119

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Abstract. The ability of linking systems together such that they behave as predicted once interacting with each other is an essential requirement for the forward engineering of robust synthetic biological circuits. Unfortunately, because of context dependencies, parts and functional modules often behave unpredictably once interacting in the cellular environment. In this paper, we review some recent advances toward establishing a rigorous engineering framework for insulating parts and modules from their context to improve modularity. Overall, a synergy between engineering better parts and higher-level circuit design that overcome the physical limitations of available parts will be important to resolve the problem of context dependence. Modularity and context-dependence in engineered biological systemsSynthetic biology, that is, the use of molecular biology techniques to forward engineer cellular behavior, is a rising branch of biological research [1]. One aim of the field is to gather a better understanding of natural systems by re-wiring their subsystems and exporting them to new settings. The ability of re-designing living systems has especially potential in the biotechnology industry, promising a number of breakthroughs in human health and the environment. Designing living systems does not simply relay on the engineering of parts, such as proteins or genetic sequences. In contrast, it essentially requires the ability of linking parts together to create sophisticated functionalities. Linking parts together to achieve a predictable behavior is 1

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Synthetic Tunable Amplifying Buffer Circuit in E. coli

Cited by 46 publications

References 43 publications

Control theory meets synthetic biology

Control theory meets synthetic biology

An N-stage cascade of phosphorylation cycles as an insulation device for synthetic biological circuits

Modularity, context-dependence, and insulation in engineered biological circuits

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