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Synthetic Biology underpins advances in the bioeconomy

Biological systems - including the simplest cells - exhibit a broad range of functions to thrive in their environment. Research in the Imperial College Centre for Synthetic Biology is focused on the possibility of engineering the underlying biochemical processes to solve many of the challenges facing society, from healthcare to sustainable energy. In particular, we model, analyse, design and build biological and biochemical systems in living cells and/or in cell extracts, both exploring and enhancing the engineering potential of biology. 

As part of our research we develop novel methods to accelerate the celebrated Design-Build-Test-Learn synthetic biology cycle. As such research in the Centre for Synthetic Biology highly multi- and interdisciplinary covering computational modelling and machine learning approaches; automated platform development and genetic circuit engineering ; multi-cellular and multi-organismal interactions, including gene drive and genome engineering; metabolic engineering; in vitro/cell-free synthetic biology; engineered phages and directed evolution; and biomimetics, biomaterials and biological engineering.

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  • Conference paper
    Rutten PJ, Kitney RI, 2016,

    Design and characterisation of new to nature inducible promoters

  • Conference paper
    Reynolds CR, Exley K, Bultelle MA, De Murieta IS, Kitney RIet al., 2016,

    Business process management of synthetic biology workflows

  • Conference paper
    Kitney RI, 2016,

    Information and communication technology in biodesign and component characterisation

  • Conference paper
    De Murieta IS, Bultelle M, Kitney RI, 2016,

    Information standards supporting the characterisation of bioparts in synthetic biology

  • Journal article
    Hammond A, Galizi R, Kyrou K, Simoni A, Siniscalchi C, Katsanos D, Gribble M, Baker D, Marois E, Russell S, Burt A, Windbichler N, Crisanti A, Nolan Tet al., 2016,

    A CRISPR-Cas9 gene drive system-targeting female reproduction in the malaria mosquito vector Anopheles gambiae

    , Nature Biotechnology, Vol: 34, Pages: 78-83, ISSN: 1087-0156

    Gene drive systems that enable super-Mendelian inheritance of a transgene have the potential to modify insect populations over a timeframe of a few years. We describe CRISPR-Cas9 endonuclease constructs that function as gene drive systems in Anopheles gambiae, the main vector for malaria. We identified three genes (AGAP005958, AGAP011377 and AGAP007280) that confer a recessive female-sterility phenotype upon disruption, and inserted into each locus CRISPR-Cas9 gene drive constructs designed to target and edit each gene. For each targeted locus we observed a strong gene drive at the molecular level, with transmission rates to progeny of 91.4 to 99.6%. Population modeling and cage experiments indicate that a CRISPR-Cas9 construct targeting one of these loci, AGAP007280, meets the minimum requirement for a gene drive targeting female reproduction in an insect population. These findings could expedite the development of gene drives to suppress mosquito populations to levels that do not support malaria transmission.

  • Conference paper
    De Murieta IS, Bultelle M, Kitney RI, 2016,

    A data model for biopart datasheets

  • Journal article
    Sootla A, Oyarzun DA, Angeli D, Stan GBet al., 2016,

    Shaping Pulses to Control Bistable Systems: Analysis, Computation and Counterexamples

    , Automatica, Vol: 63, Pages: 254-264, ISSN: 1873-2836

    In this paper we study how to shape temporal pulses to switch a bistable system between its stable steady states. Our motivation forpulse-based control comes from applications in synthetic biology, where it is generally difficult to implement real-time feedback controlsystems due to technical limitations in sensors and actuators. We show that for monotone bistable systems, the estimation of the set ofall pulses that switch the system reduces to the computation of one non-increasing curve. We provide an efficient algorithm to computethis curve and illustrate the results with a genetic bistable system commonly used in synthetic biology. We also extend these results tomodels with parametric uncertainty and provide a number of examples and counterexamples that demonstrate the power and limitationsof the current theory. In order to show the full potential of the framework, we consider the problem of inducing oscillations in a monotonebiochemical system using a combination of temporal pulses and event-based control. Our results provide an insight into the dynamics ofbistable systems under external inputs and open up numerous directions for future investigation.

  • Journal article
    Pan W, Yuan Y, Goncalves J, Stan G-Bet al., 2015,

    A Sparse Bayesian Approach to the Identification of Nonlinear State-Space Systems

    , IEEE Transactions on Automatic Control, Vol: 61, Pages: 182-187, ISSN: 1558-2523

    This technical note considers the identification ofnonlinear discrete-time systems with additive process noise butwithout measurement noise. In particular, we propose a methodand its associated algorithm to identify the system nonlinear functionalforms and their associated parameters from a limited numberof time-series data points. For this, we cast this identificationproblem as a sparse linear regression problem and take a Bayesianviewpoint to solve it. As such, this approach typically leads tononconvex optimizations. We propose a convexification procedurerelying on an efficient iterative re-weighted 1-minimization algorithmthat uses general sparsity inducing priors on the parametersof the system and marginal likelihood maximisation. Using thisapproach, we also show how convex constraints on the parameterscan be easily added to the proposed iterative re-weighted1-minimization algorithm. In the supplementary material availableonline (arXiv:1408.3549), we illustrate the effectiveness of theproposed identification method on two classical systems in biologyand physics, namely, a genetic repressilator network and a largescale network of interconnected Kuramoto oscillators.

  • Journal article
    Oyarzun DA, Chaves M, 2015,

    Design of a bistable switch to control cellular uptake

    , Journal of the Royal Society Interface, Vol: 20150618, ISSN: 1742-5689
  • Journal article
    Trusch F, Matena A, Vuk M, Koerver L, Knaevelsrud H, Freemont PS, Meyer H, Bayer Pet al., 2015,

    The N-terminal region of the ubiquitin regulatory x (UBX) domain-containing Protein 1 (UBXD1) modulates interdomain communication within the valosin-containing Protein p97

    , Journal of Biological Chemistry, Vol: 290, Pages: 29414-29427, ISSN: 1083-351X
  • Journal article
    Quinn JY, Cox RS, Adler A, Beal J, Bhatia S, Cai Y, Chen J, Clancy K, Galdzicki M, Hillson NJ, Le Novère N, Maheshwari AJ, McLaughlin JA, Myers CJ P U, Pocock M, Rodriguez C, Soldatova L, Stan GB, Swainston N, Wipat A, Sauro HMet al., 2015,

    SBOL Visual: A Graphical Language for Genetic Designs.

    , PLOS Biology, Vol: 13, ISSN: 1545-7885

    Synthetic Biology Open Language (SBOL) Visual is a graphical standard for genetic engineering. It consists of symbols representing DNA subsequences, including regulatory elements and DNA assembly features. These symbols can be used to draw illustrations for communication and instruction, and as image assets for computer-aided design. SBOL Visual is a community standard, freely available for personal, academic, and commercial use (Creative Commons CC0 license). We provide prototypical symbol images that have been used in scientific publications and software tools. We encourage users to use and modify them freely, and to join the SBOL Visual community: http://www.sbolstandard.org/visual.

  • Journal article
    Yuan Y, Rai A, Yeung E, Stan G-B, Warnick S, Goncalves Jet al., 2015,

    A Minimal Realization Technique for the Dynamical Structure Function of a Class of LTI Systems

    , IEEE TRANSACTIONS ON CONTROL OF NETWORK SYSTEMS, Vol: 4, Pages: 301-311, ISSN: 2325-5870

    The dynamical structure function of a linear time invariant (LTI) system reveals causal dependencies among manifest variables without specifying any particular relationships among the unmeasured states of the system. As such, it is a useful representation for complex networks where a coarse description of global system structure is desired without detailing the intricacies of a full state realization. In this paper, we consider the problem of finding a minimal state realization for a given dynamical structure function. Interestingly, some dynamical structure functions require uncontrollable modes in their state realizations to deliver the desired input-output behavior while respecting a specified system structure. As a result, the minimal order necessary to realize a particular dynamical structure function may be greater than that necessary to realize its associated transfer function. Although finding a minimal realization for a given dynamical structure function is difficult in general, we present a straightforward procedure here that works for a simplified class of systems.

  • Journal article
    Kopniczky M, moore S, freemont P, 2015,

    Multilevel regulation and translational switches in synthetic biology

    , IEEE Transactions on Biomedical Circuits and Systems, Vol: 9, Pages: 485-496, ISSN: 1940-9990

    In contrast to the versatility of regulatory mechanisms in natural systems, synthetic genetic circuits have been so far predominantly composed of transcriptionally regulated modules. This is about to change as the repertoire of foundational tools for post-transcriptional regulation is quickly expanding. We provide an overview of the different types of translational regulators: protein, small molecule and RNA responsive and we describe the new emerging circuit designs utilizing these tools. There are several advantages of achieving multilevel regulation via translational switches and it is likely that such designs will have the greatest and earliest impact in mammalian synthetic biology for regenerative medicine and gene therapy applications.

  • Journal article
    Ceroni F, Carbonell P, François JM, Haynes KAet al., 2015,

    Editorial - Synthetic Biology: Engineering Complexity and Refactoring Cell Capabilities.

    , Frontiers in Bioengineering and Biotechnology, Vol: 3, ISSN: 2296-4185
  • Journal article
    Storch M, Casini A, Mackrow B, Fleming T, Trewhitt H, Ellis T, Baldwin GSet al., 2015,

    BASIC: a new Biopart Assembly Standard for Idempotent Cloning provides accurate, single-tier DNA assembly for synthetic biology

    , ACS Synthetic Biology, Vol: 4, Pages: 781-787, ISSN: 2161-5063

    The ability to quickly and reliably assemble DNA constructs is one of the key enabling technologies for synthetic biology. Here we define a new Biopart Assembly Standard for Idempotent Cloning (BASIC), which exploits the principle of orthogonal linker based DNA assembly to define a new physical standard for DNA parts. Further, we demonstrate a new robust method for assembly, based on type IIs restriction cleavage and ligation of oligonucleotides with single stranded overhangs that determine the assembly order. It allows for efficient, parallel assembly with great accuracy: 4 part assemblies achieved 93% accuracy with single antibiotic selection and 99.7% accuracy with double antibiotic selection, while 7 part assemblies achieved 90% accuracy with double antibiotic selection. The linkers themselves may also be used as composable parts for RBS tuning or the creation of fusion proteins. The standard has one forbidden restriction site and provides for an idempotent, single tier organisation, allowing all parts and composite constructs to be maintained in the same format. This makes the BASIC standard conceptually simple at both the design and experimental levels.

  • Conference paper
    Sootla A, Oyarzun DA, Angeli D, Stan GBet al., 2015,

    Shaping Pulses to Control Bi-Stable Biological Systems

    , American Control Conference 2015, Publisher: IEEE, Pages: 3138-3143

    In this paper, we present a framework for shaping pulses to control biological systems, and specifically systems in synthetic biology. By shaping we mean computing the magnitude and the length of a pulse, application of which results in reaching the desired control objective. Hence the control signals have only two parameters, which makes these signals amenable to wetlab implementations. We focus on the problem of switching between steady states in a bistable system. We show how to estimate the set of the switching pulses, if the trajectories of the controlled system can be bounded from above and below by the trajectories of monotone systems. We then generalise this result to systems with parametric uncertainty under some mild assumptions on the set of admissible parameters, thus providing some robustness guarantees. We illustrate the results on some example genetic circuits.

  • Journal article
    Kopniczky M, freemont P, Moore S,

    Multilevel regulation and translational switches in synthetic biology

    , IEEE Transactions on Biomedical Circuits and Systems, ISSN: 1940-9990

    In contrast to the versatility of regulatory mechanisms in natural systems, synthetic genetic circuits have been so far predominantly composed of transcriptionally regulated modules. This is about to change as the repertoire of foundational tools for post-transcriptional regulation is quickly expanding. We provide an overview of the different types of translational regulators: protein, small molecule and RNA responsive and we describe the new emerging circuit designs utilizing these tools. There are several advantages of achieving multilevel regulation via translational switches and it is likely that such designs will have the greatest and earliest impact in mammalian synthetic biology for regenerative medicine and gene therapy applications.

  • Journal article
    Kopniczky M, freemont P, moore S, 2015,

    Multilevel regulation and translational switches in synthetic biology

    , IEEE Transactions on Biomedical Circuits and Systems, ISSN: 1940-9990
  • Journal article
    Casini A, Storch M, Baldwin GS, Ellis Tet al., 2015,

    Bricks and blueprints: methods and standards for DNA assembly

    , Nature Reviews Molecular Cell Biology, Vol: 16, Pages: 568-576, ISSN: 1471-0080

    DNA assembly is a key part of constructing gene expression systems and even whole chromosomes. In the past decade, a plethora of powerful new DNA assembly methods — including Gibson Assembly, Golden Gate and ligase cycling reaction (LCR) — have been developed. In this Innovation article, we discuss these methods as well as standards such as the modular cloning (MoClo) system, GoldenBraid, modular overlap-directed assembly with linkers (MODAL) and PaperClip, which have been developed to facilitate a streamlined assembly workflow, to aid the exchange of material between research groups and to create modular reusable DNA parts.

  • Journal article
    Wong A, Wang H, Poh CL, Kitney RIet al., 2015,

    Layering genetic circuits to build a single cell, bacterial half adder

    , BMC Biology, Vol: 13, ISSN: 1741-7007

    Background: Gene regulation in biological systems is impacted by the cellular and genetic context-dependenteffects of the biological parts which comprise the circuit. Here, we have sought to elucidate the limitations ofengineering biology from an architectural point of view, with the aim of compiling a set of engineering solutionsfor overcoming failure modes during the development of complex, synthetic genetic circuits.Results: Using a synthetic biology approach that is supported by computational modelling and rigorouscharacterisation, AND, OR and NOT biological logic gates were layered in both parallel and serial arrangements togenerate a repertoire of Boolean operations that include NIMPLY, XOR, half adder and half subtractor logics in asingle cell. Subsequent evaluation of these near-digital biological systems revealed critical design pitfalls thattriggered genetic context-dependent effects, including 5′ UTR interferences and uncontrolled switch-on behaviourof the supercoiled σ54 promoter. In particular, the presence of seven consecutive hairpins immediately downstreamof the promoter transcription start site severely impeded gene expression.Conclusions: As synthetic biology moves forward with greater focus on scaling the complexity of engineeredgenetic circuits, studies which thoroughly evaluate failure modes and engineering solutions will serve as importantreferences for future design and development of synthetic biological systems. This work describes a representativecase study for the debugging of genetic context-dependent effects through principles elucidated herein, therebyproviding a rational design framework to integrate multiple genetic circuits in a single prokaryotic cell.

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