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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.

Publications

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  • Journal article
    Brucoli F, Hawkins RM, James CH, Jackson PJM, Wells G, Jenkins TC, Ellis T, Kotecha M, Hochhauser D, Hartley JA, Howard PW, Thurston DEet al., 2013,

    An Extended Pyrrolobenzodiazepine-Polyamide Conjugate with Selectivity for a DNA Sequence Containing the ICB2 Transcription Factor Binding Site

    , JOURNAL OF MEDICINAL CHEMISTRY, Vol: 56, Pages: 6339-6351, ISSN: 0022-2623
  • Journal article
    Wright O, Stan G-B, Ellis T, 2013,

    Building-in biosafety for synthetic biology

    , MICROBIOLOGY-SGM, Vol: 159, Pages: 1221-1235, ISSN: 1350-0872
  • Journal article
    Arpino JAJ, Hancock EJ, Anderson J, Barahona M, Stan G-BV, Papachristodoulou A, Polizzi Ket al., 2013,

    Tuning the dials of Synthetic Biology

    , Microbiology-Sgm, Vol: 159, Pages: 1236-1253, ISSN: 1465-2080
  • Journal article
    Wu M, Su R-Q, Li X, Ellis T, Lai Y-C, Wang Xet al., 2013,

    Engineering of regulated stochastic cell fate determination

    , PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 10610-10615, ISSN: 0027-8424
  • Journal article
    MacDonald JT, Kelley LA, Freemont PS, 2013,

    Validating a Coarse-Grained Potential Energy Function through Protein Loop Modelling

    , PLOS One, Vol: 8, ISSN: 1932-6203

    Coarse-grained (CG) methods for sampling protein conformational space have the potential to increase computational efficiency by reducing the degrees of freedom. The gain in computational efficiency of CG methods often comes at the expense of non-protein like local conformational features. This could cause problems when transitioning to full atom models in a hierarchical framework. Here, a CG potential energy function was validated by applying it to the problem of loop prediction. A novel method to sample the conformational space of backbone atoms was benchmarked using a standard test set consisting of 351 distinct loops. This method used a sequence-independent CG potential energy function representing the protein using -carbon positions only and sampling conformations with a Monte Carlo simulated annealing based protocol. Backbone atoms were added using a method previously described and then gradient minimised in the Rosetta force field. Despite the CG potential energy function being sequence-independent, the method performed similarly to methods that explicitly use either fragments of known protein backbones with similar sequences or residue-specific /-maps to restrict the search space. The method was also able to predict with sub-Angstrom accuracy two out of seven loops from recently solved crystal structures of proteins with low sequence and structure similarity to previously deposited structures in the PDB. The ability to sample realistic loop conformations directly from a potential energy function enables the incorporation of additional geometric restraints and the use of more advanced sampling methods in a way that is not possible to do easily with fragment replacement methods and also enable multi-scale simulations for protein design and protein structure prediction. These restraints could be derived from experimental data or could be design restraints in the case of computational protein design. C++ source code is available for download from http://www.sbg.

  • Journal article
    Yuan Y, Stan G-B, Shi L, Barahona M, Goncalves Jet al., 2013,

    Decentralised minimum-time consensus

    , AUTOMATICA, Vol: 49, Pages: 1227-1235, ISSN: 0005-1098
  • Journal article
    Chappell J, Jensen K, Freemont PS, 2013,

    Validation of an entirely in vitro approach for rapid prototyping of DNA regulatory elements for synthetic biology

    , Nucleic Acids Research, Vol: 41, Pages: 3471-3481, ISSN: 0305-1048

    A bottleneck in our capacity to rationally and predictably engineer biological systems is the limited number of well-characterized genetic elements from which to build. Current characterization methods are tied to measurements in living systems, the transformation and culturing of which are inherently time-consuming. To address this, we have validated a completely in vitro approach for the characterization of DNA regulatory elements using Escherichia coli extract cell-free systems. Importantly, we demonstrate that characterization in cell-free systems correlates and is reflective of performance in vivo for the most frequently used DNA regulatory elements. Moreover, we devise a rapid and completely in vitro method to generate DNA templates for cell-free systems, bypassing the need for DNA template generation and amplification from living cells. This in vitro approach is significantly quicker than current characterization methods and is amenable to high-throughput techniques, providing a valuable tool for rapidly prototyping libraries of DNA regulatory elements for synthetic biology.

  • Journal article
    Cehovin A, Simpson PJ, McDowell MA, Brown DR, Noschese R, Pallett M, Brady J, Baldwin GS, Lea SM, Matthews SJ, Pelicic Vet al., 2013,

    Specific DNA recognition mediated by a type IV pilin.

    , Proc Natl Acad Sci U S A, Vol: 110, Pages: 3065-3070

    Natural transformation is a dominant force in bacterial evolution by promoting horizontal gene transfer. This process may have devastating consequences, such as the spread of antibiotic resistance or the emergence of highly virulent clones. However, uptake and recombination of foreign DNA are most often deleterious to competent species. Therefore, model naturally transformable gram-negative bacteria, including the human pathogen Neisseria meningitidis, have evolved means to preferentially take up homotypic DNA containing short and genus-specific sequence motifs. Despite decades of intense investigations, the DNA uptake sequence receptor in Neisseria species has remained elusive. We show here, using a multidisciplinary approach combining biochemistry, molecular genetics, and structural biology, that meningococcal type IV pili bind DNA through the minor pilin ComP via an electropositive stripe that is predicted to be exposed on the filaments surface and that ComP displays an exquisite binding preference for DNA uptake sequence. Our findings illuminate the earliest step in natural transformation, reveal an unconventional mechanism for DNA binding, and suggest that selective DNA uptake is more widespread than previously thought.

  • Journal article
    Papadimitriou KI, Stan G-B, Drakakis EM, 2013,

    Systematic computation of non-linear cellular and molecular dynamics with low-power cytomimetic circuits: A simulation study

    , PLoS ONE, Vol: 8, ISSN: 1932-6203

    This paper presents a novel method for the systematic implementation of low-power microelectronic circuits aimed at computing nonlinear cellular and molecular dynamics. The method proposed is based on the Nonlinear Bernoulli Cell Formalism (NBCF), an advanced mathematical framework stemming from the Bernoulli Cell Formalism (BCF) originally exploited for the modular synthesis and analysis of linear, time-invariant, high dynamic range, logarithmic filters. Our approach identifies and exploits the striking similarities existing between the NBCF and coupled nonlinear ordinary differential equations (ODEs) typically appearing in models of naturally encountered biochemical systems. The resulting continuous-time, continuous-value, low-power CytoMimetic electronic circuits succeed in simulating fast and with good accuracy cellular and molecular dynamics. The application of the method is illustrated by synthesising for the first time microelectronic CytoMimetic topologies which simulate successfully: 1) a nonlinear intracellular calcium oscillations model for several Hill coefficient values and 2) a gene-protein regulatory system model. The dynamic behaviours generated by the proposed CytoMimetic circuits are compared and found to be in very good agreement with their biological counterparts. The circuits exploit the exponential law codifying the low-power subthreshold operation regime and have been simulated with realistic parameters from a commercially available CMOS process. They occupy an area of a fraction of a square-millimetre, while consuming between 1 and 12 microwatts of power. Simulations of fabrication-related variability results are also presented.

  • Journal article
    Stan G-B, 2013,

    A century of revolution in bioengineering

    , BIOFUTUR, Pages: 38-39, ISSN: 0294-3506
  • Book chapter
    Goers L, Kylilis N, Tomazou M, Wen KY, Freemont P, Polizzi Ket al., 2013,

    Engineering Microbial Biosensors

    , MICROBIAL SYNTHETIC BIOLOGY, Editors: Harwood, Wipat, Publisher: ELSEVIER ACADEMIC PRESS INC, Pages: 119-156, ISBN: 978-0-12-417029-2
  • Journal article
    Kelay T, Kesavan S, Collins RE, Kyaw-Tun J, Cox B, Bello F, Kneebone RL, Sevdalis Net al., 2013,

    Techniques to aid the implementation of novel clinical information systems: A systematic review

    , INTERNATIONAL JOURNAL OF SURGERY, Vol: 11, Pages: 783-791, ISSN: 1743-9191
  • Journal article
    Boehm CR, Freemont PS, Ces O, 2013,

    Design of a prototype flow microreactor for synthetic biology in vitro

    , LAB ON A CHIP, Vol: 13, Pages: 3426-3432, ISSN: 1473-0197
  • Journal article
    Weenink T, Ellis T, 2013,

    Creation and characterization of component libraries for synthetic biology.

    , Methods Mol Biol, Vol: 1073, Pages: 51-60

    Large numbers of well-described components are essential for advanced synthetic biology and model-guided design of pathways and regulatory networks. Here a method is presented for the creation of libraries of novel control elements. From these libraries, parts with well-defined properties can be selected and used in construction of finely tuned synthetic systems. The example of the PFY1 promoter in S. cerevisiae is used to describe library creation using degenerate synthetic oligos and the circular polymerase extension cloning (CPEC) method. Additionally the workflow of screening the raw library for functional parts is included to provide a full overview of the process of creating and characterizing a component library for synthetic biology.

  • Journal article
    Chappell J, Freemont P, 2013,

    In vivo and in vitro characterization of σ70 constitutive promoters by real-time PCR and fluorescent measurements.

    , Methods Mol Biol, Vol: 1073, Pages: 61-74

    The characterization of DNA regulatory elements such as ribosome binding sites and transcriptional promoters is a fundamental aim of synthetic biology. Characterization of such DNA regulatory elements by monitoring the synthesis of fluorescent proteins is a commonly used technique to resolve the relative or absolute strengths. These measurements can be used in combination with mathematical models and computer simulation to rapidly assess performance of DNA regulatory elements both in isolation and in combination, to assist predictable and efficient engineering of complex novel biological devices and systems. Here we describe the construction and relative characterization of Escherichia coli (E. coli) σ(70) transcriptional promoters by monitoring the synthesis of green fluorescent protein (GFP) both in vivo in E. coli and in vitro in a E. coli cell-free transcription and translation reaction.

  • Conference paper
    Tay D, Poh CL, Goh C, Kitney RIet al., 2013,

    An Evolutionary Data-Conscious Artificial Immune Recognition System

    , 15th Genetic and Evolutionary Computation Conference (GECCO), Pages: 1101-1108
  • Journal article
    Odendall C, Rolhion N, Foerster A, Poh J, Lamont DJ, Liu M, Freemont PS, Catling AD, Holden DWet al., 2012,

    The Salmonella Kinase SteC Targets the MAP Kinase MEK to Regulate the Host Actin Cytoskeleton

    , CELL HOST & MICROBE, Vol: 12, Pages: 657-668, ISSN: 1931-3128
  • Journal article
    Lu D, Silhan J, MacDonald JT, Carpenter EP, Jensen K, Tang CM, Baldwin GS, Freemont PSet al., 2012,

    Structural basis for the recognition and cleavage of abasic DNA in Neisseria meningitidis

    , PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 109, Pages: 16852-16857, ISSN: 0027-8424
  • Journal article
    Lossi NS, Manoli E, Simpson P, Jones C, Hui K, Dajani R, Coulthurst SJ, Freemont P, Filloux Aet al., 2012,

    The archetype Pseudomonas aeruginosa proteins TssB and TagJ form a novel subcomplex in the bacterial type VI secretion system

    , MOLECULAR MICROBIOLOGY, Vol: 86, Pages: 437-456, ISSN: 0950-382X
  • Journal article
    Yang X, Han R, Guo Y, Bradley J, Cox B, Dickinson R, Kitney Ret al., 2012,

    Modelling and performance analysis of clinical pathways using the stochastic process algebra PEPA

    , Bmc Bioinformatics, Vol: 13, ISSN: 1471-2105

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