Toward Full-Stack <i>In Silico</i> Synthetic Biology: Integrating Model Specification, Simulation, Verification, and Biological Compilation

Konur, Savas; Mierlă, Laurenţiu; Fellermann, Harold; Ladroue, Christophe; Brown, Bradley; Wipat, Anil; Twycross, Jamie; Dun, Boyang Peter; Kalvala, Sara; Gheorghe, Marian; Krasnogor, Natalio

doi:10.1021/acssynbio.1c00143

Cited by 17 publications

(20 citation statements)

References 72 publications

(105 reference statements)

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“…8,9 The rise in tools for specific tasks has led to their integration into pipelines and repositories like SynBioHub, 10 Galaxy SynBioCAD, 11 and Infobiotics. 12 SynBioHub is a platform that facilitates the integration of software and data for synthetic biological designs so that users can easily share and reproduce system designs in a standardized format. Similarly, an end-toend metabolic design portal called Galaxy SynBioCAD chains tools together into various workflows for common design and analysis tasks such as genetic design, flux balance analysis, and pathway benchmarking.…”

Section: ■ Introductionmentioning

confidence: 99%

“…A software suite that claims to integrate modeling, simulation, and verification for synthetic biological circuits was recently presented, called the Infobiotics Workbench. 12 Infobiotics develops a domain-specific language for synthetic biology circuits to write specifications and provides a Java-based GUI platform for modeling and analyses. It is clear from these recent efforts that, for scalable biological circuit design, there is a need for open-source, user-friendly, and easyto-access modeling and analysis pipelines that work alongside experimental data in a design-build-test-learn cycle.…”

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of Integrase and Excisionase Activity in a Cell-Free Protein Expression System Using a Modeling and Analysis Pipeline

Pandey

Rodriguez

Poole³

et al. 2023

ACS Synth. Biol.

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We present a full-stack modeling, analysis, and parameter identification pipeline to guide the modeling and design of biological systems starting from specifications to circuit implementations and parametrizations. We demonstrate this pipeline by characterizing the integrase and excisionase activity in a cell-free protein expression system. We build on existing Python tools� BioCRNpyler, AutoReduce, and Bioscrape�to create this pipeline. For enzyme-mediated DNA recombination in a cell-free system, we create detailed chemical reaction network models from simple highlevel descriptions of the biological circuits and their context using BioCRNpyler. We use Bioscrape to show that the output of the detailed model is sensitive to many parameters. However, parameter identification is infeasible for this high-dimensional model; hence, we use AutoReduce to automatically obtain reduced models that have fewer parameters. This results in a hierarchy of reduced models under different assumptions to finally arrive at a minimal ODE model for each circuit. Then, we run sensitivity analysis-guided Bayesian inference using Bioscrape for each circuit to identify the model parameters. This process allows us to quantify integrase and excisionase activity in cell extracts enabling complex-circuit designs that depend on accurate control over protein expression levels through DNA recombination. The automated pipeline presented in this paper opens up a new approach to complex circuit design, modeling, reduction, and parametrization.

show abstract

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Characterization of Integrase and Excisionase Activity in a Cell-Free Protein Expression System Using a Modeling and Analysis Pipeline

Pandey

Rodriguez

Poole³

et al. 2023

ACS Synth. Biol.

View full text Add to dashboard Cite

show abstract

“…SBOL can now encode complex genetic circuits, metabolic pathways, vectors, and plasmids. Complying with SBML and SBOL standards a suite of in silico genetic circuit design tools was recently proposed 6 .…”

Section: Introductionmentioning

confidence: 99%

The automated Galaxy-SynBioCAD pipeline for synthetic biology design and engineering

Hérisson

Duigou

et al. 2022

Nat Commun

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Here we introduce the Galaxy-SynBioCAD portal, a toolshed for synthetic biology, metabolic engineering, and industrial biotechnology. The tools and workflows currently shared on the portal enables one to build libraries of strains producing desired chemical targets covering an end-to-end metabolic pathway design and engineering process from the selection of strains and targets, the design of DNA parts to be assembled, to the generation of scripts driving liquid handlers for plasmid assembly and strain transformations. Standard formats like SBML and SBOL are used throughout to enforce the compatibility of the tools. In a study carried out at four different sites, we illustrate the link between pathway design and engineering with the building of a library of E. coli lycopene-producing strains. We also benchmark our workflows on literature and expert validated pathways. Overall, we find an 83% success rate in retrieving the validated pathways among the top 10 pathways generated by the workflows.

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“…8,9 The rise in tools for specific tasks has led to their integration into pipelines and repositories like SynBioHub, 10 Galaxy SynBioCAD, 11 and Infobiotics. 12 SynBioHub is a platform that facilitates the integration of software and data for synthetic biological designs so that users can easily share and reproduce system designs in a standardized format. Similarly, an end-to-end metabolic design portal called Galaxy SynBioCAD chains tools together into various workflows for common design and analysis tasks such as genetic design, flux balance analysis, and pathway benchmarking.…”

Section: Introductionmentioning

confidence: 99%

“…A software suite that claims to integrate modeling, simulation, and verification for synthetic biological circuits was recently presented, called the Infobiotics Workbench. 12 Infobiotics develops a domain-specific language for synthetic biology circuits to write specifications and provides a Java-based GUI platform for modeling and analyses. It is clear from these recent efforts that, for scalable biological circuit design, there is a need for open-source, user-friendly, and easy-to-access modeling and analysis pipelines that work alongside experimental data in a design-build-test-learn cycle.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Integrase and Excisionase Activity in Cell-free Protein Expression System Using a Modeling and Analysis Pipeline

Pandey

Rodriguez

Poole

et al. 2022

Preprint

View full text Add to dashboard Cite

We present a full-stack modeling, analysis, and parameter identification pipeline to guide the modeling and design of biological systems starting from specifications to circuit implementations and parameterizations. We demonstrate this pipeline by characterizing the integrase and excisionase activity in cell-free protein expression system. We build on existing Python tools --- BioCRNpyler, AutoReduce, and Bioscrape --- to create this pipeline. For enzyme-mediated DNA recombination in cell-free system, we create detailed chemical reaction network models from simple high-level descriptions of the biological circuits and their context using BioCRNpyler. We use Bioscrape to show that the output of the detailed model is sensitive to many parameters. However, parameter identification is infeasible for this high-dimensional model, hence, we use AutoReduce to automatically obtain reduced models that have fewer parameters. This results in a hierarchy of reduced models under different assumptions to finally arrive at a minimal ODE model for each circuit. Then, we run sensitivity analysis-guided Bayesian inference using Bioscrape for each circuit to identify the model parameters. This process allows us to quantify integrase and excisionase activity in cell extracts enabling complex-circuit designs that depend on accurate control over protein expression levels through DNA recombination. The automated pipeline presented in this paper opens up a new approach to complex circuit design, modeling, reduction, and parameterization.

show abstract

Toward Full-Stack In Silico Synthetic Biology: Integrating Model Specification, Simulation, Verification, and Biological Compilation

Cited by 17 publications

References 72 publications

Characterization of Integrase and Excisionase Activity in a Cell-Free Protein Expression System Using a Modeling and Analysis Pipeline

Characterization of Integrase and Excisionase Activity in a Cell-Free Protein Expression System Using a Modeling and Analysis Pipeline

The automated Galaxy-SynBioCAD pipeline for synthetic biology design and engineering

Characterization of Integrase and Excisionase Activity in Cell-free Protein Expression System Using a Modeling and Analysis Pipeline

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