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
    Blount BA, Weenink T, Ellis T, 2012,

    Construction of synthetic regulatory networks in yeast

    , FEBS LETTERS, Vol: 586, Pages: 2112-2121, ISSN: 0014-5793
  • Journal article
    Kitney R, Freemont P, 2012,

    Synthetic biology - the state of play

    , FEBS LETTERS, Vol: 586, Pages: 2029-2036, ISSN: 0014-5793
  • Journal article
    Anderson J, Strelkowa N, Stan G-B, Douglas T, Savulescu J, Barahona M, Papachristodoulou Aet al., 2012,

    Engineering and ethical perspectives in synthetic biology

    , EMBO Reports, Vol: 13, Pages: 584-590, ISSN: 1469-221X

    Synthetic biology has emerged as an exciting and promising new research field, garnering significant attention from both the scientific community and the general public. This interest results from a variety of striking features: synthetic biology is a truly interdisciplinary field that engages biologists, mathematicians, physicists and engineers; its research focus is applied; and it has enormous potential to harness the power of biology to provide scientific and engineering solutions to a wide range of problems and challenges that plague humanity. However, the power of synthetic biology to engineer organisms with custom‐made functionality requires that researchers and society use this power safely and responsibly, in particular when it comes to releasing organisms into the environment. This creates new challenges for both the design of such organisms and the regulatory process governing their creation and use.
  • Book
    Kitney RI, 2012,

    Synthetic Biology - A Primer

    , Publisher: Imperial College Press London
  • Journal article
    Weston DJ, Adams NM, Russell RA, Stephens DA, Freemont PSet al., 2012,

    Analysis of spatial point patterns in nuclear biology

    , PLoS ONE, Vol: 7, ISSN: 1932-6203

    There is considerable interest in cell biology in determining whether, and to what extent, the spatial arrangement of nuclear objects affects nuclear function. A common approach to address this issue involves analyzing a collection of images produced using some form of fluorescence microscopy. We assume that these images have been successfully pre-processed and a spatial point pattern representation of the objects of interest within the nuclear boundary is available. Typically in these scenarios, the number of objects per nucleus is low, which has consequences on the ability of standard analysis procedures to demonstrate the existence of spatial preference in the pattern. There are broadly two common approaches to look for structure in these spatial point patterns. First a spatial point pattern for each image is analyzed individually, or second a simple normalization is performed and the patterns are aggregated. In this paper we demonstrate using synthetic spatial point patterns drawn from predefined point processes how difficult it is to distinguish a pattern from complete spatial randomness using these techniques and hence how easy it is to miss interesting spatial preferences in the arrangement of nuclear objects. The impact of this problem is also illustrated on data related to the configuration of PML nuclear bodies in mammalian fibroblast cells.
  • Journal article
    Parker KH, Alastruey J, Stan G-B, 2012,

    Arterial reservoir-excess pressure and ventricular work

    , MEDICAL & BIOLOGICAL ENGINEERING & COMPUTING, Vol: 50, Pages: 419-424, ISSN: 0140-0118
  • Journal article
    Blount BA, Weenink T, Vasylechko S, Ellis Tet al., 2012,

    Rational Diversification of a Promoter Providing Fine-Tuned Expression and Orthogonal Regulation for Synthetic Biology

    , PLOS ONE, Vol: 7, ISSN: 1932-6203
  • Journal article
    Niwa H, Ewens CA, Tsang C, Yeung HO, Zhang X, Freemont PSet al., 2012,

    The Role of the N-Domain in the ATPase Activity of the Mammalian AAA ATPase p97/VCP

    , JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 287, Pages: 8561-8570
  • Journal article
    Silhan J, Nagorska K, Zhao Q, Jensen K, Freemont PS, Tang CM, Baldwin GSet al., 2012,

    Specialization of an Exonuclease III family enzyme in the repair of 3' DNA lesions during base excision repair in the human pathogen Neisseria meningitidis

    , Nucleic Acids Research, Vol: 40, Pages: 2065-2075, ISSN: 1362-4962

    We have previously demonstrated that the twoExonuclease III (Xth) family members presentwithin the obligate human pathogen Neisseriameningitidis, NApe and NExo, are important forsurvival under conditions of oxidative stress. Ofthese, only NApe possesses AP endonucleaseactivity, while the primary function of NExoremained unclear. We now reveal further functionalspecialization at the level of 30-PO4 processing forNExo. We demonstrate that the bi-functional meningococcalglycosylases Nth and MutM can performstrand incisions at abasic sites in addition to NApe.However, no such functional redundancy existsfor the 30-phosphatase activity of NExo, and thecytotoxicity of 30-blocking lesions is reflectedin the marked sensitivity of a mutant lackingNExo to oxidative stress, compared to strainsdeficient in other base excision repair enzymes. Ahistidine residue within NExo that is responsiblefor its lack of AP endonuclease activity isalso important for its 30-phosphatase activity,demonstrating an evolutionary trade off in enzymefunction at the single amino acid level. This specializationof two Xth enzymes for the 30-end processingand strand-incision reactions has notpreviously been observed and provides a newparadigm within the prokaryotic world for separationof these critical functions during baseexcision repair.
  • Journal article
    Nagorska K, Silhan J, Li Y, Pelicic V, Freemont PS, Baldwin GS, Tang CMet al., 2012,

    A network of enzymes involved in repair of oxidative DNA damage in Neisseria meningitidis.

    , Mol Microbiol, Vol: 83, Pages: 1064-1079

    Although oxidative stress is a key aspect of innate immunity, little is known about how host-restricted pathogens successfully repair DNA damage. Base excision repair is responsible for correcting nucleobases damaged by oxidative stress, and is essential for bloodstream infection caused by the human pathogen, Neisseria meningitidis. We have characterized meningococcal base excision repair enzymes involved in the recognition and removal of damaged nucleobases, and incision of the DNA backbone. We demonstrate that the bi-functional glycosylase/lyases Nth and MutM share several overlapping activities and functional redundancy. However, MutM and other members of the GO system, which deal with 8-oxoG, a common lesion of oxidative damage, are not required for survival of N. meningitidis under oxidative stress. Instead, the mismatch repair pathway provides back-up for the GO system, while the lyase activity of Nth can substitute for the meningococcal AP endonuclease, NApe. Our genetic and biochemical evidence shows that DNA repair is achieved through a robust network of enzymes that provides a flexible system of DNA repair. This network is likely to reflect successful adaptation to the human nasopharynx, and might provide a paradigm for DNA repair in other prokaryotes.
  • Journal article
    Bebeacua C, Förster A, McKeown C, Meyer HH, Zhang X, Freemont PSet al., 2012,

    Distinct conformations of the protein complex p97-Ufd1-Npl4 revealed by electron cryomicroscopy.

    , Proc Natl Acad Sci U S A, Vol: 109, Pages: 1098-1103

    p97 is a key regulator of numerous cellular pathways and associates with ubiquitin-binding adaptors to remodel ubiquitin-modified substrate proteins. How adaptor binding to p97 is coordinated and how adaptors contribute to substrate remodeling is unclear. Here we present the 3D electron cryomicroscopy reconstructions of the major Ufd1-Npl4 adaptor in complex with p97. Our reconstructions show that p97-Ufd1-Npl4 is highly dynamic and that Ufd1-Npl4 assumes distinct positions relative to the p97 ring upon addition of nucleotide. Our results suggest a model for substrate remodeling by p97 and also explains how p97-Ufd1-Npl4 could form other complexes in a hierarchical model of p97-cofactor assembly.
  • Journal article
    Kloppsteck P, Ewens CA, Foerster A, Zhang X, Freemont PSet al., 2012,

    Regulation of p97 in the ubiquitin-proteasome system by the UBX protein-family

    , BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH, Vol: 1823, Pages: 125-129, ISSN: 0167-4889
  • Journal article
    Yuan Y, Stan G-B, Warnick S, Goncalves Jet al., 2012,

    Minimal realization of the dynamical structure function and its application to network reconstruction

    Network reconstruction, i.e., obtaining network structure from data, is acentral theme in systems biology, economics and engineering. In some previouswork, we introduced dynamical structure functions as a tool for posing andsolving the problem of network reconstruction between measured states. Whilerecovering the network structure between hidden states is not possible sincethey are not measured, in many situations it is important to estimate theminimal number of hidden states in order to understand the complexity of thenetwork under investigation and help identify potential targets formeasurements. Estimating the minimal number of hidden states is also crucial toobtain the simplest state-space model that captures the network structure andis coherent with the measured data. This paper characterizes minimal orderstate-space realizations that are consistent with a given dynamical structurefunction by exploring properties of dynamical structure functions anddeveloping an algorithm to explicitly obtain such a minimal realization.
  • Journal article
    Pan W, Yuan Y, Goncalves J, Stan G-Bet al., 2012,

    Reconstruction of Arbitrary Biochemical Reaction Networks: A Compressive Sensing Approach

    , 2012 IEEE 51ST ANNUAL CONFERENCE ON DECISION AND CONTROL (CDC), Pages: 2334-2339, ISSN: 0743-1546
  • Journal article
    Batty EC, Jensen K, Freemont PS, 2012,

    PML NUCLEAR BODIES AND OTHER TRIM-DEFINED SUBCELLULAR COMPARTMENTS

    , TRIM/RBCC PROTEINS, Vol: 770, Pages: 39-58, ISSN: 0065-2598
  • Journal article
    Oyarzún DA, Stan GB, 2012,

    Synthetic gene circuits for metabolic control: design tradeoffs and constraints

    , Journal of the Royal Society Interface, Vol: 10
  • Journal article
    Lossi NS, Dajani R, Freemont P, Filloux Aet al., 2011,

    Structure-function analysis of HsiF, a gp25-like component of the type VI secretion system, in Pseudomonas aeruginosa

    , MICROBIOLOGY-SGM, Vol: 157, Pages: 3292-3305, ISSN: 1350-0872
  • Journal article
    Zhang H-T, Chen MZQ, Stan G-B, 2011,

    Fast Consensus Via Predictive Pinning Control

    , IEEE TRANSACTIONS ON CIRCUITS AND SYSTEMS I-REGULAR PAPERS, Vol: 58, Pages: 2247-2258, ISSN: 1549-8328
  • Journal article
    Dalchau N, Baek SJ, Briggs HM, Robertson FC, Dodd AN, Gardner MJ, Stancombe MA, Haydon MJ, Stan G-B, Goncalves JM, Webb AARet al., 2011,

    The circadian oscillator gene GIGANTEA mediates a long-term response of the Arabidopsis thaliana circadian clock to sucrose

    , PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 108, Pages: 5104-5109, ISSN: 0027-8424
  • Journal article
    Peccoud J, Anderson JC, Chandran D, Densmore D, Galdzicki M, Lux MW, Rodriguez CA, Stan G-B, Sauro HMet al., 2011,

    Essential information for synthetic DNA sequences

    , NATURE BIOTECHNOLOGY, Vol: 29, Pages: 22-22, ISSN: 1087-0156

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