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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
    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
    Tay D, Poh CL, Van Reeth E, Kitney RIet al., 2015,

    The Effect of Sample Age and Prediction Resolution on Myocardial Infarction Risk Prediction

    , IEEE JOURNAL OF BIOMEDICAL AND HEALTH INFORMATICS, Vol: 19, Pages: 1178-1185, ISSN: 2168-2194
  • 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
    Tay D, Poh CL, Kitney RI, 2015,

    A novel neural-inspired learning algorithm with application to clinical risk prediction

    , JOURNAL OF BIOMEDICAL INFORMATICS, Vol: 54, Pages: 305-314, ISSN: 1532-0464
  • Conference paper
    bultelle, Sainz de Murieta Fuentes I, kitney RI, 2015,

    Introducing Synbis – the Synthetic Biology Information System

    , Synthetic Biology: Engineering, Evolution & Design (SEED)
  • Conference paper
    Sainz de Murieta Fuentes I, bultelle M, kitney, 2015,

    A DICOM Extension Supporting Data Acquisition in Synthetic Biology

    , Synthetic Biology: Engineering, Evolution & Design (SEED)
  • Journal article
    Weston DJ, Russell RA, Batty E, Jensen K, Stephens DA, Adams NM, Freemont PSet al., 2015,

    New quantitative approaches reveal the spatial preference of nuclear compartments in mammalian fibroblasts

    , JOURNAL OF THE ROYAL SOCIETY INTERFACE, Vol: 12, ISSN: 1742-5689
  • 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
    Elani Y, Law R, Ces O,

    Vesicle-based artificial cells: recent developments and prospects for drug delivery

    , Therapeutic delivery, ISSN: 2041-6008
  • Journal article
    Campeotto I, Zhang Y, Mladenov MG, Freemont PS, Grundling Aet al., 2015,

    Complex Structure and Biochemical Characterization of the Staphylococcus aureus Cyclic Diadenylate Monophosphate (c-di-AMP)-binding Protein PstA, the Founding Member of a New Signal Transduction Protein Family

    , Journal of Biological Chemistry, Vol: 290, Pages: 2888-2901, ISSN: 1083-351X

    Signaling nucleotides are integral parts of signal transductionsystems allowing bacteria to cope with and rapidly respond tochanges in the environment. The Staphylococcus aureus PII-likesignal transduction protein PstA was recently identified as acyclic diadenylate monophosphate (c-di-AMP)-binding protein.Here, we present the crystal structures of the apo- and c-diAMP-boundPstA protein, which is trimeric in solution as wellas in the crystals. The structures combined with detailed bioinformaticsanalysis revealed that the protein belongs to a newfamily of proteins with a similar core fold but with distinct featuresto classical PII proteins, which usually function in nitrogenmetabolism pathways in bacteria. The complex structurerevealed three identical c-di-AMP-binding sites per trimer witheach binding site at a monomer-monomer interface. Althoughdistinctly different from other cyclic-di-nucleotide-bindingsites, as the half-binding sites are not symmetrical, the complexstructure also highlighted common features for c-di-AMPbindingsites. A comparison between the apo and complexstructures revealed a series of conformational changes thatresult in the ordering of two anti-parallel !-strands that protrudefrom each monomer and allowed us to propose a mechanismon how the PstA protein functions as a signaling transductionprotein.

  • Conference paper
    Bricio C, Liu X, Li X, Rehak M, Ellis T, Smith Cet al., 2015,

    High-throughput picodroplet-based analysis of biosynthetic libraries

    , Pages: 709-710
  • Journal article
    Pothoulakis G, Ellis T, 2015,

    Using Spinach Aptamer to Correlate mRNA and Protein Levels in Escherichia coli

    , RIBOSWITCHES AS TARGETS AND TOOLS, Vol: 550, Pages: 173-185, ISSN: 0076-6879
  • 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
    Lu M, Williamson N, Boschetti C, Ellis T, Yoshimi T, Tunnacliffe Aet al., 2015,

    Expression-level dependent perturbation of cell proteostasis and nuclear morphology by aggregation-prone polyglutamine proteins

    , Biotechnol. Bioeng., Pages: n/a-n/a, ISSN: 1097-0290

    We describe a gene expression system for use in mammalian cells that yields reproducible, inducible gene expression that can be modulated within the physiological range. A synthetic promoter library was generated from which representatives were selected that gave weak, intermediate-strength or strong promoter activity. Each promoter resulted in a tight expression range when used to drive single-copy reporter genes integrated at the same genome location in stable cell lines, in contrast to the broad range of expression typical of transiently transfected cells. To test this new expression system in neurodegenerative disease models, we used each promoter type to generate cell lines carrying single-copy genes encoding polyglutamine-containing proteins. Expression over a period of up to three months resulted in a proportion of cells developing juxtanuclear aggresomes whose rate of formation, penetrance and morphology were expression-level dependent. At the highest expression levels, fibrillar aggregates deposit close to the nuclear envelope, indicating that cell proteostasis is overwhelmed by misfolded protein species. We also observed expression-level dependent, abnormal nuclear morphology in cells containing aggresomes, with up to ∼80% of cells affected. This system constitutes a valuable tool in gene regulation at different levels and allows the quantitative assessment of gene expression effects when developing disease models or investigating cell function through the introduction of gene constructs. This article is protected by copyright. All rights reserved

  • Journal article
    Kelwick R, MacDonald JT, Webb AJ, Freemont Pet al., 2014,

    Developments in the Tools and Methodologies of Synthetic Biology

    , Frontiers in Bioengineering and Biotechnology, Vol: 2
  • Journal article
    Foerster A, Planamente S, Manoli E, Lossi NS, Freemont PS, Filloux Aet al., 2014,

    Coevolution of the ATPase ClpV, the Sheath Proteins TssB and TssC, and the Accessory Protein TagJ/HsiE1 Distinguishes Type VI Secretion Classes

    , JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 289
  • Journal article
    Robinson T, Valluri P, Kennedy G, Sardini A, Dunsby C, Neil MAA, Baldwin GS, French PMW, de Mello AJet al., 2014,

    Analysis of DNA Binding and Nucleotide Flipping Kinetics Using Two-Color Two-Photon Fluorescence Lifetime Imaging Microscopy

    , Analytical Chemistry, Vol: 86, Pages: 10732-10740, ISSN: 0003-2700

    Uracil DNA glycosylase plays a key role in DNA maintenance via base excision repair. Its role is to bind to DNA, locate unwanted uracil, and remove it using a base flipping mechanism. To date, kinetic analysis of this complex process has been achieved using stopped-flow analysis but, due to limitations in instrumental dead-times, discrimination of the “binding” and “base flipping” steps is compromised. Herein we present a novel approach for analyzing base flipping using a microfluidic mixer and two-color two-photon (2c2p) fluorescence lifetime imaging microscopy (FLIM). We demonstrate that 2c2p FLIM can simultaneously monitor binding and base flipping kinetics within the continuous flow microfluidic mixer, with results showing good agreement with computational fluid dynamics simulations.

  • Journal article
    Campeotto I, Percy MG, MacDonald JT, Foerster A, Freemont PS, Gruendling Aet al., 2014,

    Structural and Mechanistic Insight into the Listeria monocytogenes Two-enzyme Lipoteichoic Acid Synthesis System

    , Journal of Biological Chemistry, Vol: 289, Pages: 28054-28069, ISSN: 0021-9258

    Lipoteichoic acid (LTA) is an important cell wall componentrequired for proper cell growth in many Gram-positive bacteria.In Listeria monocytogenes, two enzymes are required for the synthesisof this polyglycerolphosphate polymer. The LTA primaseLtaPLm initiates LTA synthesis by transferring the first glycerolphosphate(GroP) subunit onto the glycolipid anchor and theLTA synthase LtaSLm extends the polymer by the repeated additionof GroP subunits to the tip of the growing chain. Here, wepresent the crystal structures of the enzymatic domains ofLtaPLm and LtaSLm. Although the enzymes share the same fold,substantial differences in the cavity of the catalytic site andsurface charge distribution contribute to enzyme specialization.The eLtaSLm structure was also determined in complexwith GroP revealing a second GroP binding site. Mutationalanalysis confirmed an essential function for this binding siteand allowed us to propose a model for the binding of thegrowing chain.

  • 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.

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