Making gene circuits sing

Prindle, Arthur; Hasty, Jeff

doi:10.1073/pnas.1214118109

Cited by 4 publications

(3 citation statements)

References 20 publications

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Section: Resultsmentioning

confidence: 99%

“…No modifications were made to the VEGF-MESA, which releases tTA. In the field of genetic circuit design, it is known that ideal circuit performance requires the output of upstream components to match the input requirements of downstream components. , For our application, we reasoned that level-matching requires that the amounts of TFs released from MESA upon ligand treatment match the amounts required for synergistic activation of the hybrid promoter. We hypothesized that level-matching could be achieved using a strategy in which we first identify the dose of each MESA required to activate the hybrid promoter in a ligand-inducible fashion when the complementary soluble TF is in excess.…”

Section: Resultsmentioning

confidence: 99%

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Multiplexing Engineered Receptors for Multiparametric Evaluation of Environmental Ligands

et al. 2017

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Engineered cell-based therapies comprise a promising, emerging biomedical technology. Broad utilization of this strategy will require new approaches for implementing sophisticated functional programs, such as sensing and responding to the environment in a defined fashion. Towards this goal, we investigated whether our self-contained receptor and signal transduction system (MESA) could be multiplexed to evaluate extracellular cues, with a focus on elucidating principles governing the integration of such engineered components. We first developed a set of hybrid promoters that exhibited AND gate activation by two transcription factors. We then evaluated these promoters when paired with two MESA receptors and various ligand combinations. Unexpectedly, although the multiplexed system exhibited distinct responses to ligands applied individually and in combination, the same synergy was not observed as when promoters were characterized with soluble transcription factors. Therefore, we developed a mechanistic computational model leveraging these observations, to both improve our understanding of how the receptors and promoters interface and to guide the design and implementation of future systems. Notably, the model explicitly accounts for the impact of intercellular variation on system characterization and performance. Model analysis identified key factors that affect the current receptors and promoters, and enabled an in silico exploration of potential modifications that inform the design of improved logic gates and their robustness to intercellular variation. Ultimately, this quantitative design-driven approach may guide the use and multiplexing of synthetic receptors for diverse custom biological functions beyond the case study considered here.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Multiplexing Engineered Receptors for Multiparametric Evaluation of Environmental Ligands

et al. 2017

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“…The second illustrates that although protein levels are usually on the order of thousands, the reliable transmission of more than a few levels is limited by the stochasticity in the system and parameters need to be carefully tuned to achieve it. In the particular case of the design of synthetic circuits, the need for proper impedance matching has already been noted [64], but the results of Tkačik et al show that the stochastic effects also need to be properly tuned.…”

Section: Information Content Of Gene Expressionmentioning

confidence: 99%

Noise, Information and Fitness in Changing Environments

Pedraza

Garcia

2018

Front. Phys.

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In this paper we discuss recent results regarding the question of adaptation to changing environments in intermediate timescales and the quantification of the amount of information a cell needs about its environment, connecting the theoretical approaches with relevant experimental results. We first show how advances in the study of noise in genetic circuits can inform a detailed description of intracellular information flow and allow for simplified descriptions of the phenotypic state of a cell. We then present the different types of strategies that cells can use to respond to changing environments, and what a quantitative description of this process implies about the long term fitness of the population. We present an early approach connecting the transmission of information to the average fitness, and then move on to a full model of the process. This model is then simplified to obtain analytical results for a few cases. We present the necessary notation but avoid technical detail as much as possible, as our goal is to emphasize the biological interpretation and significance of the mathematical results. We focus on how carefully constructed models can answer the long-standing objection to the use of information theory in biology based on decision-theoretic considerations of the difference between the amount of information and its fitness value.

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Weak Emergence Drives the Science, Epistemology, and Metaphysics of Synthetic Biology

Bedau

2013

Biol Theory

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Making gene circuits sing

Cited by 4 publications

References 20 publications

Multiplexing Engineered Receptors for Multiparametric Evaluation of Environmental Ligands

Multiplexing Engineered Receptors for Multiparametric Evaluation of Environmental Ligands

Noise, Information and Fitness in Changing Environments

Weak Emergence Drives the Science, Epistemology, and Metaphysics of Synthetic Biology

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