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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
    Jovicevic D, Blount BA, Ellis T, 2014,

    Total synthesis of a eukaryotic chromosome: Redesigning and SCRaMbLE-ing yeast

    , BIOESSAYS, Vol: 36, Pages: 855-860, ISSN: 0265-9247
  • 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
  • Conference paper
    Polizzi KM, Kylilis N, Lai HE, Freemont PSet al., 2014,

    Detecting protein biomarkers using engineered biosensors based on synthetic biology principles

    , 248th National Meeting of the American-Chemical-Society (ACS), Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727
  • 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
  • Journal article
    Goers L, Freemont P, Polizzi KM, 2014,

    Co-culture systems and technologies: taking synthetic biology to the next level

    , JOURNAL OF THE ROYAL SOCIETY INTERFACE, Vol: 11, ISSN: 1742-5689
  • Journal article
    Galdzicki M, Clancy KP, Oberortner E, Pocock M, Quinn JY, Rodriguez CA, Roehner N, Wilson ML, Adam L, Anderson JC, Bartley BA, Beal J, Chandran D, Chen J, Densmore D, Endy D, Gruenberg R, Hallinan J, Hillson NJ, Johnson JD, Kuchinsky A, Lux M, Misirli G, Peccoud J, Plahar HA, Sirin E, Stan G-B, Villalobos A, Wipat A, Gennari JH, Myers CJ, Sauro HMet al., 2014,

    The Synthetic Biology Open Language (SBOL) provides a community standard for communicating designs in synthetic biology

    , NATURE BIOTECHNOLOGY, Vol: 32, Pages: 545-550, ISSN: 1087-0156
  • Journal article
    Oyarzun DA, Lugagne J-B, Stan G-B, 2014,

    Noise propagation in synthetic gene circuits for metabolic control

    , ACS Synthetic Biology, Vol: 4, Pages: 116-125, ISSN: 2161-5063

    Dynamic control of enzyme expression can be an effective strategy to engineer robust metabolic pathways. It allows a synthetic pathway to self-regulate in response to changes in bioreactor conditions or the metabolic state of the host. The implementation of this regulatory strategy requires gene circuits that couple metabolic signals with the genetic machinery, which is known to be noisy and one of the main sources of cell-to-cell variability. One of the unexplored design aspects of these circuits is the propagation of biochemical noise between enzyme expression and pathway activity. In this article, we quantify the impact of a synthetic feedback circuit on the noise in a metabolic product in order to propose design criteria to reduce cell-to-cell variability. We consider a stochastic model of a catalytic reaction under negative feedback from the product to enzyme expression. On the basis of stochastic simulations and analysis, we show that, depending on the repression strength and promoter strength, transcriptional repression of enzyme expression can amplify or attenuate the noise in the number of product molecules. We obtain analytic estimates for the metabolic noise as a function of the model parameters and show that noise amplification/attenuation is a structural property of the model. We derive an analytic condition on the parameters that lead to attenuation of metabolic noise, suggesting that a higher promoter sensitivity enlarges the parameter design space. In the theoretical case of a switch-like promoter, our analysis reveals that the ability of the circuit to attenuate noise is subject to a trade-off between the repression strength and promoter strength.

  • Journal article
    Ewens CA, Panico S, Kloppsteck P, McKeown C, Ebong I-O, Robinson C, Zhang X, Freemont PSet al., 2014,

    The p97-FAF1 Protein Complex Reveals a Common Mode of p97 Adaptor Binding

    , JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 289, Pages: 12077-12084
  • Journal article
    Pothoulakis G, Ceroni F, Reeve B, Ellis Tet al., 2014,

    The spinach RNA aptamer as a characterization tool for synthetic biology

    , ACS Synthetic Biology, Vol: 3, Pages: 182-187, ISSN: 2161-5063

    Characterization of genetic control elements is essential for the predictable engineering of synthetic biology systems. The current standard for in vivo characterization of control elements is through the use of fluorescent reporter proteins such as green fluorescent protein (GFP). Gene expression, however, involves not only protein production but also the production of mRNA. Here, we present the use of the Spinach aptamer sequence, an RNA mimic of GFP, as a tool to characterize mRNA expression in Escherichia coli. We show how the aptamer can be incorporated into gene expression cassettes and how co-expressing it with a red fluorescent protein (mRFP1) allows, for the first time, simultaneous measurement of mRNA and protein levels from engineered constructs. Using flow cytometry, we apply this tool here to evaluate ribosome binding site sequences and promoters and use it to highlight the differences in the temporal behavior of transcription and translation.

  • Journal article
    Yeung HO, Foerster A, Bebeacua C, Niwa H, Ewens C, McKeown C, Zhang X, Freemont PSet al., 2014,

    Inter-ring rotations of AAA ATPase p97 revealed by electron cryomicroscopy

    , Open Biology, Vol: 4, ISSN: 2046-2441

    The type II AAA+ protein p97 is involved in numerous cellular activities, including endoplasmic reticulum-associated degradation, transcription activation, membrane fusion and cell-cycle control. These activities are at least in part regulated by the ubiquitin system, in which p97 is thought to target ubiquitylated protein substrates within macromolecular complexes and assist in their extraction or disassembly. Although ATPase activity is essential for p97 function, little is known about how ATP binding or hydrolysis is coupled with p97 conformational changes and substrate remodelling. Here, we have used single-particle electron cryomicroscopy (cryo-EM) to study the effect of nucleotides on p97 conformation. We have identified conformational heterogeneity within the cryo-EM datasets from which we have resolved two major p97 conformations. A comparison of conformations reveals inter-ring rotations upon nucleotide binding and hydrolysis that may be linked to the remodelling of target protein complexes.

  • Journal article
    Cai Y, Ellis T, 2014,

    The Sixth International Meeting on synthetic Biology (SB6.0) Special Issue Editorial

    , ACS SYNTHETIC BIOLOGY, Vol: 3, Pages: 107-107, ISSN: 2161-5063
  • Journal article
    Luboz V, Kyaw-Tun J, Sen S, Kneebone R, Dickinson R, Kitney R, Bello Fet al., 2014,

    Real-time stent and balloon simulation for stenosis treatment

    , VISUAL COMPUTER, Vol: 30, Pages: 341-349, ISSN: 0178-2789
  • 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
    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.

  • 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
  • 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
    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
    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

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