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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
    Polizzi KM, Freemont PS, 2016,

    Synthetic biology biosensors for healthcare and industrial biotechnology applications

  • 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
    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., 2015,

    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.

  • 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
    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
  • 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
  • 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
    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
    Hancock E, Stan G-B, Arpino J, Papachristodoulou Aet al., 2015,

    Simplified mechanistic models of gene regulation for analysis and design

    , Journal of the Royal Society Interface, Vol: 12, ISSN: 1742-5689

    Simplified mechanistic models of gene regulation are fundamental to systems biology and essential for synthetic biology. However, conventional simplified models typically have outputs that are not directly measurable and are based on assumptions that do not often hold under experimental conditions. To resolve these issues, we propose a ‘model reduction’ methodology and simplified kinetic models of total mRNA and total protein concentration, which link measurements, models and biochemical mechanisms. The proposed approach is based on assumptions that hold generally and include typical cases in systems and synthetic biology where conventional models do not hold. We use novel assumptions regarding the ‘speed of reactions’, which are required for the methodology to be consistent with experimental data. We also apply the methodology to propose simplified models of gene regulation in the presence of multiple protein binding sites, providing both biological insights and an illustration of the generality of the methodology. Lastly, we show that modelling total protein concentration allows us to address key questions on gene regulation, such as efficiency, burden, competition and modularity.

  • Journal article
    Ceroni F, Algar R, Stan G-B, Ellis Tet al., 2015,

    Quantifying cellular capacity identifies gene expression designs with reduced burden

    , Nature Methods, Vol: 12, Pages: 415-418, ISSN: 1548-7105

    Heterologous gene expression can be a significant burden forcells. Here we describe an in vivo monitor that tracks changesin the capacity of Escherichia coli in real time and can be usedto assay the burden imposed by synthetic constructs and theirparts. We identify construct designs with reduced burden thatpredictably outperformed less efficient designs, despite havingequivalent output.

  • 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

    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.

  • Journal article
    Wright O, Delmans M, Stan G-B, Elis Tet al., 2015,

    Gene Guard: A Modular Plasnnid System Designed for Biosafety

    , ACS SYNTHETIC BIOLOGY, Vol: 4, Pages: 307-316, ISSN: 2161-5063
  • Journal article
    Kelwick R, Kopniczky M, Bower I, Chi W, Chin MHW, Fan S, Pilcher J, Strutt J, Webb AJ, Jensen K, Stan G-B, Kitney R, Freemont Pet al., 2015,

    A Forward-Design Approach to Increase the Production of Poly-3-Hydroxybutyrate in Genetically Engineered Escherichia coli

    , PLOS ONE, Vol: 10, ISSN: 1932-6203
  • Journal article
    Pan W, Yuan Y, Ljung L, Goncalves J, Stan G-Bet al., 2015,

    Identifying Biochemical Reaction Networks From Heterogeneous Datasets

    , 2015 54TH IEEE CONFERENCE ON DECISION AND CONTROL (CDC), Pages: 2525-2530, ISSN: 0743-1546
  • Journal article
    Rivadeneira PS, Moog CH, Stan G-B, Brunet C, Raffi F, Ferré V, Costanza V, Mhawej MJ, Biafore F, Ouattara DA, Ernst D, Fonteneau R, Xia Xet al., 2014,

    Mathematical Modeling of HIV Dynamics After Antiretroviral Therapy Initiation: A Review.

    , Biores Open Access, Vol: 3, Pages: 233-241, ISSN: 2164-7844

    This review shows the potential ground-breaking impact that mathematical tools may have in the analysis and the understanding of the HIV dynamics. In the first part, early diagnosis of immunological failure is inferred from the estimation of certain parameters of a mathematical model of the HIV infection dynamics. This method is supported by clinical research results from an original clinical trial: data just after 1 month following therapy initiation are used to carry out the model identification. The diagnosis is shown to be consistent with results from monitoring of the patients after 6 months. In the second part of this review, prospective research results are given for the design of individual anti-HIV treatments optimizing the recovery of the immune system and minimizing side effects. In this respect, two methods are discussed. The first one combines HIV population dynamics with pharmacokinetics and pharmacodynamics models to generate drug treatments using impulsive control systems. The second one is based on optimal control theory and uses a recently published differential equation to model the side effects produced by highly active antiretroviral therapy therapies. The main advantage of these revisited methods is that the drug treatment is computed directly in amounts of drugs, which is easier to interpret by physicians and patients.

  • Journal article
    Rivadeneira PS, Moog CH, Stan G-B, Costanza V, Brunet C, Raffi F, Ferre V, Mhawej M-J, Biafore F, Ouattara DA, Ernst D, Fonteneau R, Xia Xet al., 2014,

    Mathematical Modeling of HIV Dynamics After Antiretroviral Therapy Initiation: A Clinical Research Study

    , AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol: 30, Pages: 831-834, ISSN: 0889-2229
  • Journal article
    Casini A, Christodoulou G, Freemont PS, Baldwin GS, Ellis T, MacDonald JTet al., 2014,

    R2oDNA Designer: Computational Design of Biologically Neutral Synthetic DNA Sequences

    , ACS SYNTHETIC BIOLOGY, Vol: 3, Pages: 525-528, ISSN: 2161-5063

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