Research

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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
    Tay D, Poh CL, Goh C, Kitney RIet al., 2014,

    A biological continuum based approach for efficient clinical classification

    , JOURNAL OF BIOMEDICAL INFORMATICS, Vol: 47, Pages: 28-38, ISSN: 1532-0464
  • Journal article
    Reeve B, Hargest T, Gilbert C, Ellis Tet al., 2014,

    Predicting translation initiation rates for designing synthetic biology.

    , Frontiers in Bioengineering and Biotechnology, Vol: 2, Pages: 1-1, ISSN: 2296-4185

    In synthetic biology, precise control over protein expression is required in order to construct functional biological systems. A core principle of the synthetic biology approach is a model-guided design and based on the biological understanding of the process, models of prokaryotic protein production have been described. Translation initiation rate is a rate-limiting step in protein production from mRNA and is dependent on the sequence of the 5'-untranslated region and the start of the coding sequence. Translation rate calculators are programs that estimate protein translation rates based on the sequence of these regions of an mRNA, and as protein expression is proportional to the rate of translation initiation, such calculators have been shown to give good approximations of protein expression levels. In this review, three currently available translation rate calculators developed for synthetic biology are considered, with limitations and possible future progress discussed.
  • Journal article
    Pan W, Sootla A, Stan G-B, 2014,

    Distributed Reconstruction of Nonlinear Networks: An ADMM Approach

    , IFAC PAPERSONLINE, Vol: 47, Pages: 3208-3213, ISSN: 2405-8963
  • Journal article
    Dickinson RJ, Kitney RI, 2014,

    Information driven care pathways and procedures

    , IFMBE Proceedings, Vol: 41, Pages: 1322-1325, ISSN: 1680-0737

    The paper addresses the issue of the implementation of care pathways in electronic form. Within the National Health Service (NHS) of England, Care Pathways are becoming increasingly important. These are typically provided by the Department of Health. The Pathways provided are in the form of paper-based schema. They either have to be implemented via paper forms or, as presented here, in electronic form. In addition, care pathways must be seen in the context of the TModel of health care which comprises the care continuum and the biological continuum. The two care pathways which had been chosen as exemplars are myocardial infarction and stroke. However, the objective of the paper is not to discuss the specific care pathways in detail, but, rather, to describe technology which has been developed for their electronic implementation. The result of this implementation is that all the data and information acquired from the implementation of the care pathway is stored in a single clinical information system (CIS), which has incorporated in it the SQL database. Another important element of the system which has been developed is the ability to display data and information in terms of two dashboards (i.e. single screens which show the most important information). The two dashboards display clinical information (the point of care dashboard) and management information (the management dashboard). © Springer International Publishing Switzerland 2014.
  • Conference paper
    Algar RJR, Ellis T, Stan G-B, 2014,

    Modelling essential interactions between synthetic genes and their chassis cell

    , 53rd IEEE Annual Conference on Decision and Control (CDC), Publisher: IEEE, Pages: 5437-5444, ISSN: 0743-1546
  • Journal article
    Reeve B, Sanderson T, Ellis T, Freemont Pet al., 2014,

    How Synthetic Biology Will Reconsider Natural Bioluminescence and Its Applications

    , BIOLUMINESCENCE: FUNDAMENTALS AND APPLICATIONS IN BIOTECHNOLOGY, VOL 2, Vol: 145, Pages: 3-30, ISSN: 0724-6145
  • Journal article
    Casini A, MacDonald JT, De Jonghe J, Christodoulou G, Freemont PS, Baldwin GS, Ellis Tet al., 2013,

    One-pot DNA construction for synthetic biology: the Modular Overlap-Directed Assembly with Linkers (MODAL) strategy

    , Nucleic Acids Research, Vol: 42, ISSN: 1362-4962

    Overlap-directed DNA assembly methods allowmultiple DNA parts to be assembled together inone reaction. These methods, which rely onsequence homology between the ends of DNAparts, have become widely adopted in syntheticbiology, despite being incompatible with a key principleof engineering: modularity. To answer this, wepresent MODAL: a Modular Overlap-DirectedAssembly with Linkers strategy that brings modularityto overlap-directed methods, allowing assemblyof an initial set of DNA parts into a variety ofarrangements in one-pot reactions. MODAL isaccompanied by a custom software tool thatdesigns overlap linkers to guide assembly,allowing parts to be assembled in any specifiedorder and orientation. The in silico design of syntheticorthogonal overlapping junctions allows formuch greater efficiency in DNA assembly for avariety of different methods compared with usingnon-designed sequence. In tests with three differentassembly technologies, the MODAL strategy givesassembly of both yeast and bacterial plasmids,composed of up to five DNA parts in the kilobaserange with efficiencies of between 75 and 100%.It also seamlessly allows mutagenesis to beperformed on any specified DNA parts duringthe process, allowing the one-step creation of constructlibraries valuable for synthetic biologyapplications.
  • Journal article
    O'Clery N, Yuan Y, Stan G-B, Barahona Met al., 2013,

    Observability and coarse graining of consensus dynamics through the external equitable partition

    , PHYSICAL REVIEW E, Vol: 88, ISSN: 1539-3755
  • 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
    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
    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
    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

    , PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 110, Pages: 3065-3070, ISSN: 0027-8424
  • 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
  • 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
    Chappell J, Freemont P, 2013,

    In Vivo and In Vitro Characterization of σ<SUP>70</SUP> Constitutive Promoters by Real-Time PCR and Fluorescent Measurements

    , SYNTHETI C BIOLOGY, Vol: 1073, Pages: 61-74, ISSN: 1064-3745

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