Challenges at the interface of control engineering and synthetic biology

Synthetic biology is a rapidly expanding field at the interface of the engineering and biological sciences which aims to apply rational design principles in biological contexts. Many natural processes utilise regulatory architectures that parallel those found in control and electrical engineering, which has motivated their implementation as part of synthetic biological constructs. Tools based upon control theoretical concepts can be used to design such systems, as well as to guide their experimental realisation. In this paper we provide examples of biological implementations of negative feedback systems, and discuss progress made toward realisation of other feedback and control architectures. We then outline major challenges posed by the design of such systems, particularly focusing on those which are specific to biological contexts and on which feedback control can have a significant impact. We explore future directions for work in the field, including new approaches for theoretical design of biological control systems, the utilisation of novel components for their implementation, and the potential for application of automation and machine-learning approaches to accelerate synthetic biological research.

[1]  Kang Wu,et al.  A modular positive feedback-based gene amplifier , 2010, Journal of biological engineering.

[2]  Ankit Gupta,et al.  Antithetic Integral Feedback Ensures Robust Perfect Adaptation in Noisy Biomolecular Networks. , 2014, Cell systems.

[3]  T. Lu,et al.  Synthetic recombinase-based state machines in living cells , 2016, Science.

[4]  Heinz Koeppl,et al.  Sensitivity estimation for stochastic models of biochemical reaction networks in the presence of extrinsic variability. , 2017, The Journal of chemical physics.

[5]  H. Westerhoff,et al.  Synthetic biology and regulatory networks: where metabolic systems biology meets control engineering , 2016, Journal of The Royal Society Interface.

[6]  J. Keasling,et al.  Microbial engineering for the production of advanced biofuels , 2012, Nature.

[7]  K. Burrage,et al.  Stochastic models for regulatory networks of the genetic toggle switch. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[8]  A. Arkin,et al.  Contextualizing context for synthetic biology – identifying causes of failure of synthetic biological systems , 2012, Biotechnology journal.

[9]  J. Collins,et al.  Construction of a genetic toggle switch in Escherichia coli , 2000, Nature.

[10]  A. Oudenaarden,et al.  Cellular Decision Making and Biological Noise: From Microbes to Mammals , 2011, Cell.

[11]  Mauricio Barahona,et al.  Engineering modular and tunable genetic amplifiers for scaling transcriptional signals in cascaded gene networks , 2014, Nucleic acids research.

[12]  Naira Hovakimyan,et al.  Load capacity improvements in nucleic acid based systems using partially open feedback control. , 2014, ACS synthetic biology.

[13]  Eduardo Sontag,et al.  Modular cell biology: retroactivity and insulation , 2008, Molecular systems biology.

[14]  P. Swain,et al.  Intrinsic and extrinsic contributions to stochasticity in gene expression , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Juan F. Poyatos,et al.  Genetic Redundancies Enhance Information Transfer in Noisy Regulatory Circuits , 2016, bioRxiv.

[16]  Andrew D Ellington,et al.  Synthetic DNA Synthesis and Assembly: Putting the Synthetic in Synthetic Biology. , 2017, Cold Spring Harbor perspectives in biology.

[17]  D. Endy,et al.  Refinement and standardization of synthetic biological parts and devices , 2008, Nature Biotechnology.

[18]  D Thirumalai,et al.  Gene regulation by riboswitches with and without negative feedback loop. , 2012, Biophysical journal.

[19]  M. Omar Din,et al.  Synchronized cycles of bacterial lysis for in vivo delivery , 2016, Nature.

[20]  M. Khammash,et al.  Automated optogenetic feedback control for precise and robust regulation of gene expression and cell growth , 2016, Nature Communications.

[21]  David Yu Zhang,et al.  Towards Domain-Based Sequence Design for DNA Strand Displacement Reactions , 2010, DNA.

[22]  Deepak Mishra,et al.  A load driver device for engineering modularity in biological networks , 2014, Nature Biotechnology.

[23]  Mustafa Khammash,et al.  Design of a synthetic integral feedback circuit: dynamic analysis and DNA implementation , 2016, ACS synthetic biology.

[24]  Nicola J. Rinaldi,et al.  Transcriptional Regulatory Networks in Saccharomyces cerevisiae , 2002, Science.

[25]  Hieu Bui,et al.  Analog Computation by DNA Strand Displacement Circuits. , 2016, ACS synthetic biology.

[26]  L. You,et al.  Emergent bistability by a growth-modulating positive feedback circuit. , 2009, Nature chemical biology.

[27]  Nicolas E. Buchler,et al.  On schemes of combinatorial transcription logic , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[28]  J. Doyle,et al.  Robust perfect adaptation in bacterial chemotaxis through integral feedback control. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Baojun Wang,et al.  Tools and Principles for Microbial Gene Circuit Engineering. , 2016, Journal of molecular biology.

[30]  Christopher A. Voigt,et al.  Advances in genetic circuit design: novel biochemistries, deep part mining, and precision gene expression. , 2013, Current opinion in chemical biology.

[31]  G. Balázsi,et al.  Negative autoregulation linearizes the dose–response and suppresses the heterogeneity of gene expression , 2009, Proceedings of the National Academy of Sciences.

[32]  D. Pincus,et al.  In silico feedback for in vivo regulation of a gene expression circuit , 2011, Nature Biotechnology.

[33]  M. Elowitz,et al.  Synthetic Biology: Integrated Gene Circuits , 2011, Science.

[34]  Antonis Papachristodoulou,et al.  A single phosphatase can convert a robust step response into a graded, tunable or adaptive response. , 2013, Microbiology.

[35]  James Chappell,et al.  Creating small transcription activating RNAs. , 2015, Nature chemical biology.

[36]  J. Collins,et al.  Synthetic Biology Moving into the Clinic , 2011, Science.

[37]  Pu Qian,et al.  Development of SimCells as a novel chassis for functional biosensors , 2017, Scientific Reports.

[38]  Drew Endy,et al.  Precise and reliable gene expression via standard transcription and translation initiation elements , 2013, Nature Methods.

[39]  L. Serrano,et al.  Engineering stability in gene networks by autoregulation , 2000, Nature.

[40]  Douglas Densmore,et al.  Design Automation in Synthetic Biology. , 2017, Cold Spring Harbor perspectives in biology.

[41]  Lydia M Contreras,et al.  Rational Modular RNA Engineering Based on In Vivo Profiling of Structural Accessibility. , 2017, ACS synthetic biology.

[42]  J. Chin,et al.  Synthesis of orthogonal transcription-translation networks , 2009, Proceedings of the National Academy of Sciences.

[43]  Richard M. Murray,et al.  Synthetic circuit for exact adaptation and fold-change detection , 2014, Nucleic acids research.

[44]  L. MacNeil,et al.  Gene regulatory networks and the role of robustness and stochasticity in the control of gene expression. , 2011, Genome research.

[45]  H. Westerhoff,et al.  Protein burden in Zymomonas mobilis: negative flux and growth control due to overproduction of glycolytic enzymes , 1995 .

[46]  Timothy K Lu,et al.  Synthetic circuits integrating logic and memory in living cells , 2013, Nature Biotechnology.

[47]  D. G. Gibson,et al.  Design and synthesis of a minimal bacterial genome , 2016, Science.

[48]  Rahul Sarpeshkar,et al.  Synthetic analog computation in living cells , 2013, Nature.

[49]  T Drengstig,et al.  A basic set of homeostatic controller motifs. , 2012, Biophysical journal.

[50]  Richard M. Murray,et al.  A population-based temporal logic gate for timing and recording chemical events , 2015, bioRxiv.

[51]  D. Vecchio,et al.  Biomolecular Feedback Systems , 2014 .

[52]  J. Collins,et al.  Toehold Switches: De-Novo-Designed Regulators of Gene Expression , 2014, Cell.

[53]  Ting Ni,et al.  Oscillatory stress stimulation uncovers an Achilles ’ heel of the yeast MAPK signaling network , 2016 .

[54]  U. Alon,et al.  The incoherent feedforward loop can provide fold-change detection in gene regulation. , 2009, Molecular cell.

[55]  Julio R. Banga,et al.  Exploring Design Principles of Gene Regulatory Networks via Pareto Optimality , 2016 .

[56]  Hana El-Samad,et al.  Building robust functionality in synthetic circuits using engineered feedback regulation. , 2013, Current opinion in biotechnology.

[57]  M. Elowitz,et al.  Regulatory activity revealed by dynamic correlations in gene expression noise , 2008, Nature Genetics.

[58]  Mario di Bernardo,et al.  In-Vivo Real-Time Control of Protein Expression from Endogenous and Synthetic Gene Networks , 2014, PLoS Comput. Biol..

[59]  Antonis Papachristodoulou,et al.  Ribo-attenuators: novel elements for reliable and modular riboswitch engineering , 2017 .

[60]  Paul R Jaschke,et al.  Wet Lab Accelerator: A Web-Based Application Democratizing Laboratory Automation for Synthetic Biology. , 2017, ACS synthetic biology.

[61]  Richard M. Murray,et al.  Negative autoregulation matches production and demand in synthetic transcriptional networks , 2013 .

[62]  Domitilla Del Vecchio,et al.  Integral action with time scale separation: A mechanism for modularity in biological systems , 2014, 53rd IEEE Conference on Decision and Control.

[63]  W. Lim,et al.  Defining Network Topologies that Can Achieve Biochemical Adaptation , 2009, Cell.

[64]  Casim A. Sarkar,et al.  Robust Network Topologies for Generating Switch-Like Cellular Responses , 2011, PLoS Comput. Biol..

[65]  Domitilla Del Vecchio,et al.  Modularity, context-dependence, and insulation in engineered biological circuits , 2015 .

[66]  Matthew R. Lakin,et al.  Supervised Learning in Adaptive DNA Strand Displacement Networks. , 2016, ACS synthetic biology.

[67]  Mario di Bernardo,et al.  In-Silico Analysis and Implementation of a Multicellular Feedback Control Strategy in a Synthetic Bacterial Consortium. , 2017, ACS synthetic biology.

[68]  Antonis Papachristodoulou,et al.  Designing Genetic Feedback Controllers , 2015, IEEE Transactions on Biomedical Circuits and Systems.

[69]  A. Oudenaarden,et al.  A Systems-Level Analysis of Perfect Adaptation in Yeast Osmoregulation , 2009, Cell.

[70]  Konstantinos Michalodimitrakis,et al.  Noise in transcription negative feedback loops: simulation and experimental analysis , 2006, Molecular systems biology.

[71]  Christopher A. Voigt,et al.  Realizing the potential of synthetic biology , 2014, Nature Reviews Molecular Cell Biology.

[72]  G. Seelig,et al.  Dynamic DNA nanotechnology using strand-displacement reactions. , 2011, Nature chemistry.

[73]  Drew Endy,et al.  Amplifying Genetic Logic Gates , 2013, Science.

[74]  S. Mangan,et al.  Structure and function of the feed-forward loop network motif , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[75]  Antonis Papachristodoulou,et al.  Engineering a Genetic Oscillator Using Delayed Feedback , 2014 .

[76]  V. Kulkarni,et al.  Computational design of nucleic acid feedback control circuits. , 2014, ACS synthetic biology.

[77]  M. Bennett,et al.  A fast, robust, and tunable synthetic gene oscillator , 2008, Nature.

[78]  Domitilla Del Vecchio,et al.  Mitigation of ribosome competition through distributed sRNA feedback , 2016, 2016 IEEE 55th Conference on Decision and Control (CDC).

[79]  Antonis Papachristodoulou,et al.  Design Constraints for Biological Systems That Achieve Adaptation and Disturbance Rejection , 2018, IEEE Transactions on Control of Network Systems.

[80]  Hiroaki Kitano,et al.  Biological robustness , 2008, Nature Reviews Genetics.

[81]  K Oishi,et al.  Biomolecular implementation of linear I/O systems. , 2011, IET systems biology.

[82]  Mustafa Khammash,et al.  A molecular implementation of the least mean squares estimator , 2016, 2016 IEEE 55th Conference on Decision and Control (CDC).

[83]  G. Storz,et al.  Bacterial small RNA regulators: versatile roles and rapidly evolving variations. , 2011, Cold Spring Harbor perspectives in biology.

[84]  Matthias Heinemann,et al.  Molecular Systems Biology Peer Review Process File Bacterial Persistence Is an Active Σ S Stress Response to Metabolic Flux Limitation Transaction Report , 2022 .

[85]  M. Jewett,et al.  Cell-free synthetic biology: thinking outside the cell. , 2012, Metabolic engineering.

[86]  J. Keasling,et al.  Engineering Cellular Metabolism , 2016, Cell.

[87]  Pablo Carbonell,et al.  Semisupervised Gaussian Process for Automated Enzyme Search. , 2016, ACS synthetic biology.

[88]  T. Lu,et al.  Digital and analog gene circuits for biotechnology , 2014, Biotechnology journal.

[89]  Mauricio Barahona,et al.  Tuning the dials of Synthetic Biology , 2013, Microbiology.

[90]  Kunihiko Kaneko,et al.  Fold-change detection and scale invariance of cell–cell signaling in social amoeba , 2017, Proceedings of the National Academy of Sciences.

[91]  J. Park,et al.  Metabolic engineering of Escherichia coli using synthetic small regulatory RNAs , 2013, Nature Biotechnology.

[92]  H. Berg,et al.  Chemotaxis in Escherichia coli analysed by Three-dimensional Tracking , 1972, Nature.

[93]  Phillip M. Rivera,et al.  Synthetic tunable amplifying buffer circuit in E. coli. , 2015, ACS synthetic biology.

[94]  Anirban Mukhopadhyay,et al.  An improved method for identification of small non-coding RNAs in bacteria using support vector machine , 2017, Scientific Reports.

[95]  Antonis Papachristodoulou,et al.  Frequency domain analysis of small non-coding RNAs shows summing junction-like behaviour , 2017, 2017 IEEE 56th Annual Conference on Decision and Control (CDC).

[96]  M. Elowitz,et al.  A synthetic oscillatory network of transcriptional regulators , 2000, Nature.

[97]  Georg Seelig,et al.  Molecular circuits for dynamic noise filtering , 2016, Proceedings of the National Academy of Sciences.

[98]  J. Keasling,et al.  Design of a dynamic sensor-regulator system for production of chemicals and fuels derived from fatty acids , 2012, Nature Biotechnology.

[99]  Jordan Ang,et al.  Physical constraints on biological integral control design for homeostasis and sensory adaptation. , 2013, Biophysical journal.

[100]  Ron Weiss,et al.  Isocost Lines Describe the Cellular Economy of Genetic Circuits , 2015, Biophysical journal.

[101]  Wei Su,et al.  Perfect adaptation of general nonlinear systems , 2015, Journal of Systems Science and Complexity.

[102]  Erik Winfree,et al.  DNA as a universal substrate for chemical kinetics , 2009, Proceedings of the National Academy of Sciences.

[103]  M. Khammash An engineering viewpoint on biological robustness , 2016, BMC Biology.

[104]  Melody Bomgardner,et al.  Start-ups with robots seek to scale up synthetic biology , 2016 .

[105]  P. Swain,et al.  Stochastic Gene Expression in a Single Cell , 2002, Science.

[106]  Michael Eisenstein,et al.  Living factories of the future , 2016, Nature.

[107]  Ahmad S. Khalil,et al.  Synthetic biology: applications come of age , 2010, Nature Reviews Genetics.

[108]  Domitilla Del Vecchio,et al.  Modular Composition of Gene Transcription Networks , 2014, PLoS computational biology.

[109]  Thomas P. Prescott,et al.  A Synthetic Recombinase-Based Feedback Loop Results in Robust Expression. , 2017, ACS synthetic biology.

[110]  Young Je Lee,et al.  Robust, tunable genetic memory from protein sequestration combined with positive feedback , 2015, Nucleic acids research.

[111]  Wei Su Topologies needed for perfect adaptation , 2011, Proceedings of the 30th Chinese Control Conference.

[112]  S. Forst,et al.  Signal transduction by the EnvZ-OmpR phosphotransfer system in bacteria. , 1994, Research in microbiology.

[113]  G. Vinnicombe,et al.  Synchronous long-term oscillations in a synthetic gene circuit , 2016, Nature.

[114]  J. Vogel,et al.  Small RNA-based feedforward loop with AND-gate logic regulates extrachromosomal DNA transfer in Salmonella , 2015, Proceedings of the National Academy of Sciences.

[115]  Timothy K Lu,et al.  Synthetic analog and digital circuits for cellular computation and memory. , 2014, Current opinion in biotechnology.

[116]  Antonis Papachristodoulou,et al.  Designing Conservation Relations in Layered Synthetic Biomolecular Networks , 2015, IEEE Transactions on Biomedical Circuits and Systems.

[117]  Christopher A. Voigt,et al.  Genetic circuit design automation , 2016, Science.

[118]  Syed Mansoor Raza,et al.  A Review of Computational Methods for Finding Non-Coding RNA Genes , 2016, Genes.

[119]  Antonis Papachristodoulou,et al.  The autorepressor: A case study of the importance of model selection , 2017, 2017 IEEE 56th Annual Conference on Decision and Control (CDC).

[120]  N. Grindley,et al.  Mechanisms of site-specific recombination. , 2003, Annual review of biochemistry.

[121]  Mustafa Khammash,et al.  A synthetic integral feedback controller for robust tunable regulation in bacteria , 2017, bioRxiv.

[122]  U. Alon,et al.  Negative autoregulation speeds the response times of transcription networks. , 2002, Journal of molecular biology.

[123]  Baojun Wang,et al.  Engineering modular and orthogonal genetic logic gates for robust digital-like synthetic biology , 2011, Nature communications.