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 articleGilbert C, Howarth M, Harwood CR, et al., 2017,
Extracellular self-assembly of functional and tunable protein conjugates from Bacillus subtilis
, ACS Synthetic Biology, Vol: 6, Pages: 957-967, ISSN: 2161-5063The ability to stably and specifically conjugate recombinant proteins to one another is a powerful approach for engineering multifunctional enzymes, protein therapeutics, and novel biological materials. While many of these applications have been illustrated through in vitro and in vivo intracellular protein conjugation methods, extracellular self-assembly of protein conjugates offers unique advantages: simplifying purification, reducing toxicity and burden, and enabling tunability. Exploiting the recently described SpyTag-SpyCatcher system, we describe here how enzymes and structural proteins can be genetically encoded to covalently conjugate in culture media following programmable secretion from Bacillus subtilis. Using this approach, we demonstrate how self-conjugation of a secreted industrial enzyme, XynA, dramatically increases its resilience to boiling, and we show that cellular consortia can be engineered to self-assemble functional protein–protein conjugates with tunable composition. This novel genetically encoded modular system provides a flexible strategy for protein conjugation harnessing the substantial advantages of extracellular self-assembly.
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Journal articleWebb AJ, Kelwick R, Freemont PS, 2017,
Opportunities for applying whole-cell bioreporters towards parasite detection
, Microbial Biotechnology, Vol: 10, Pages: 244-249, ISSN: 1751-7915 -
Journal articleHazel P, Kroll SH, Bondke A, et al., 2017,
Inhibitor selectivity for cyclin-dependent kinase 7: a structural, thermodynamic, and modelling study
, Chemmedchem, Vol: 12, Pages: 372-380, ISSN: 1860-7187Deregulation of the cell cycle by mechanisms that lead to elevated activities of cyclin-dependent kinases (CDK) is a feature of many human diseases, cancer in particular. We identified small-molecule inhibitors that selectively inhibit CDK7, the kinase that phosphorylates cell-cycle CDKs to promote their activities. To investigate the selectivity of these inhibitors we used a combination of structural, biophysical, and modelling approaches. We determined the crystal structures of the CDK7-selective compounds ICEC0942 and ICEC0943 bound to CDK2, and used these to build models of inhibitor binding to CDK7. Molecular dynamics (MD) simulations of inhibitors bound to CDK2 and CDK7 generated possible models of inhibitor binding. To experimentally validate these models, we gathered isothermal titration calorimetry (ITC) binding data for recombinant wild-type and binding site mutants of CDK7 and CDK2. We identified specific residues of CDK7, notably Asp155, that are involved in determining inhibitor selectivity. Our MD simulations also show that the flexibility of the G-rich and activation loops of CDK7 is likely an important determinant of inhibitor specificity similar to CDK2.
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Conference paperFoo M, Sawlekar R, Kim J, et al., 2017,
Biomolecular implementation of nonlinear system theoretic operators
, European Control Conference (ECC), Publisher: IEEE, Pages: 1824-1831Synthesis of biomolecular circuits for controlling molecular-scale processes is an important goal of synthetic biology with a wide range of in vitro and in vivo applications, including biomass maximization, nanoscale drug delivery, and many others. In this paper, we present new results on how abstract chemical reactions can be used to implement commonly used system theoretic operators such as the polynomial functions, rational functions and Hill-type nonlinearity. We first describe how idealised versions of multi-molecular reactions, catalysis, annihilation, and degradation can be combined to implement these operators. We then show how such chemical reactions can be implemented using enzyme-free, entropy-driven DNA reactions. Our results are illustrated through three applications: (1) implementation of a Stan-Sepulchre oscillator, (2) the computation of the ratio of two signals, and (3) a PI+antiwindup controller for regulating the output of a static nonlinear plant.
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Conference paperPan W, Menolascina F, Stan G, 2016,
Online Model Selection for Synthetic Gene Networks
, IEEE Conference on Decision and Control, Publisher: IEEEControl algorithms combined with microfluidicdevices and microscopy have enabled in vivo real-time controlof protein expression in synthetic gene networks. Most controlalgorithms rely on the a priori availability of mathematicalmodels of the gene networks to be controlled. These modelsare typically black/grey box models, which can be obtainedthrough the use of data-driven techniques developed in thecontext of systems identification. Data-driven inference of bothmodel structure and parameters is the main focus of thispaper. There are two main challenges associated with theinference of dynamical models for real-time control of generegulatory networks in living cells. Since biological systemsare typically evolving over time, the first challenge stemsfrom the fact that model selection needs to be done online,which prevents the application of computationally expensiveidentification algorithms iterating through large amounts ofstreaming data. The second challenge consists in performingnonlinear model selection, which is typically too burdensomefor Kalman filtering related techniques due the heterogeneityand nonlinearity of the candidate models. In this paper,we combine sparse Bayesian techniques with classic Kalmanfiltering techniques to tackle these challenges
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Journal articleKuntz J, Ottobre M, Stan G-B, et al., 2016,
Bounding stationary averages of polynomial diffusions via semidefinite programming
, SIAM Journal on Scientific Computing, Vol: 38, Pages: A3891-A3920, ISSN: 1095-7197We introduce an algorithm based on semidefinite programming that yields increasing (resp.decreasing) sequences of lower (resp. upper) bounds on polynomial stationary averages of diffusionswith polynomial drift vector and diffusion coefficients. The bounds are obtained byoptimising an objective, determined by the stationary average of interest, over the set of realvectors defined by certain linear equalities and semidefinite inequalities which are satisfied bythe moments of any stationary measure of the diffusion. We exemplify the use of the approachthrough several applications: a Bayesian inference problem; the computation of Lyapunov exponentsof linear ordinary differential equations perturbed by multiplicative white noise; and areliability problem from structural mechanics. Additionally, we prove that the bounds convergeto the infimum and supremum of the set of stationary averages for certain SDEs associated withthe computation of the Lyapunov exponents, and we provide numerical evidence of convergencein more general settings.
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Journal articleSenthivel V, Sturrock M, Piedrafita G, et al., 2016,
Identifying ultrasensitive HGF dose-response functions in a 3D mammalian system for synthetic morphogenesis
, Scientific Reports, Vol: 6, ISSN: 2045-2322Nonlinearresponses to signalsarewidespread natural phenomenathat affect various cellular processes. Nonlinearitycan bea desirable characteristic for engineering living organismsbecause it can lead to more switch-like responses, similar to those underlying the wiring inelectronics. Steeperfunctions are described as ultrasensitive, and can be applied in synthetic biologyby using various techniquesincludingreceptor decoys, multiple co-operative binding sites, and sequentialpositive feedbacks. Here, we explore the inherent non-linearity of a biological signaling system to identify functions that can potentially be exploited using cell genome engineering.For this,we performed genome-wide transcription profilingto identify genes with ultrasensitiveresponse functionsto Hepatocyte Growth Factor (HGF). Weidentified3,527genesthat react to increasing concentrations of HGF, in Madin-Darby canine kidney (MDCK) cells,grown as cystsin 3D collagen cell culture. By fitting a generic Hill function to the dose-responsesof these genes we obtained ameasure of the ultrasensitivityofHGF-responsive genes, identifying a subset with higher apparent Hill coefficients (e.g. MMP1, TIMP1,SNORD75, SNORD86 andERRFI1). The regulatory regions of these genes are potential candidates for future engineering of synthetic mammalian gene circuits requiring nonlinear responses to HGF signalling.
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Journal articleBroedel AK, Jaramillo A, Isalan M, 2016,
Engineering orthogonal dual transcription factors for multi-input synthetic promoters
, Nature Communications, Vol: 7, Pages: 1-9, ISSN: 2041-1723Synthetic biology has seen an explosive growth in the capability of engineering artificial gene circuits from transcription factors (TFs), particularly in bacteria. However, most artificial networks still employ the same core set of TFs (for example LacI, TetR and cI). The TFs mostly function via repression and it is difficult to integrate multiple inputs in promoter logic. Here we present to our knowledge the first set of dual activator-repressor switches for orthogonal logic gates, based on bacteriophage λ cI variants and multi-input promoter architectures. Our toolkit contains 12 TFs, flexibly operating as activators, repressors, dual activator–repressors or dual repressor–repressors, on up to 270 synthetic promoters. To engineer non cross-reacting cI variants, we design a new M13 phagemid-based system for the directed evolution of biomolecules. Because cI is used in so many synthetic biology projects, the new set of variants will easily slot into the existing projects of other groups, greatly expanding current engineering capacities.
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Journal articleToczek M, Kutryb-Zajac B, Zukowska P, et al., 2016,
Changes in cardiac nucleotide metabolism in Huntington’s disease
, Nucleosides, Nucleotides and Nucleic Acids, Vol: 35, Pages: 707-712, ISSN: 1525-7770Huntington’s disease (HD) is a monogenic neurodegenerative disorder with a significant peripheralcomponent to the disease pathology. This includes an HD-related cardiomyopathy, with an unknownpathological mechanism. In this study, we aimed to define changes in the metabolism of cardiacnucleotides using the well-established R6/2 mouse model. In particular, we focused on measuring theactivity of enzymes that control ATP and other adenine nucleotides in the cardiac pool, includingeNTPD, AMPD, e5'NT, ADA and PNP. We employed HPLC to assay the activities of these enzymes bymeasuring the concentrations of adenine nucleotide catabolites in the hearts of symptomatic R6/2 mice.We found a reduced activity of AMPD (12.9 ± 1.9 nmol/min/mg protein in control; 7.5 ± 0.5nmol/min/mg protein in R6/2) and e5'NT (11.9 ± 1.7 nmol/min/mg protein in control; 6.7 ± 0.7nmol/min/mg protein in R6/2). Moreover, we detected an increased activity of ADA (1.3 ± 0.2nmol/min/mg protein in control; 5.2 ± 0.5 nmol/min/mg protein in R6/2), while no changes in eNTPDand PNP activities were detected. Analysis of cardiac adenine nucleotide catabolite levels revealed anincreased inosine level (0.7 ± 0.01 nmol/mg dry tissue in control; 2.7 ±0.8 nmol/mg dry tissue in R6/2)and a reduced concentration of cardiac adenosine (0.9 ± 0.2 nmol/mg dry tissue in control; 0.2 ± 0.08nmol/mg dry tissue in R6/2). This study highlights a decreased rate of degradation of cardiac nucleotidesin HD mouse model hearts, and an increased capacity for adenosine deamination, that may alteradenosine signaling.
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Journal articleMoore SJ, lai H-E, Kelwick R, et al., 2016,
EcoFlex - a multifunctional MoClo kit for E. coli synthetic biology
, ACS Synthetic Biology, Vol: 5, Pages: 1059-1069, ISSN: 2161-5063Golden Gate cloning is a prominent DNA assembly tool in synthetic biology for the assembly of plasmid constructs often used in combinatorial pathway optimisation, with a number of assembly kits developed specifically for yeast and plant-based expression. However, its use for synthetic biology in commonly used bacterial systems such as Escherichia coli, has surprisingly been overlooked. Here, we introduce EcoFlex a simplified modular package of DNA parts for a variety of applications in E. coli, cell-free protein synthesis, protein purification and hierarchical assembly of transcription units based on the MoClo assembly standard. The kit features a library of constitutive promoters, T7 expression, RBS strength variants, synthetic terminators, protein purification tags and fluorescence proteins. We validate EcoFlex by assembling a 68-part containing (20 genes) plasmid (31 kb), characterise in vivo and in vitro library parts, and perform combinatorial pathway assembly, using pooled libraries of either fluorescent proteins or the biosynthetic genes for the antimicrobial pigment violacein as a proof-of-concept. To minimise pathway screening, we also introduce a secondary module design site to simplify MoClo pathway optimisation. In summary, EcoFlex provides a standardised and multifunctional kit for a variety of applications in E. coli synthetic biology.
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Journal articleEllis T, Cai Y, 2016,
Synthetic Biology in Europe
, ACS SYNTHETIC BIOLOGY, Vol: 5, Pages: 1033-1033, ISSN: 2161-5063 -
Journal articleKelly CL, Liu Z, Yoshihara A, et al., 2016,
Synthetic Chemical Inducers and Genetic Decoupling Enable Orthogonal Control of the rhaBAD Promoter.
, ACS Synth Biol, Vol: 5, Pages: 1136-1145External control of gene expression is crucial in synthetic biology and biotechnology research and applications, and is commonly achieved using inducible promoter systems. The E. coli rhamnose-inducible rhaBAD promoter has properties superior to more commonly used inducible expression systems, but is marred by transient expression caused by degradation of the native inducer, l-rhamnose. To address this problem, 35 analogues of l-rhamnose were screened for induction of the rhaBAD promoter, but no strong inducers were identified. In the native configuration, an inducer must bind and activate two transcriptional activators, RhaR and RhaS. Therefore, the expression system was reconfigured to decouple the rhaBAD promoter from the native rhaSR regulatory cascade so that candidate inducers need only activate the terminal transcription factor RhaS. Rescreening the 35 compounds using the modified rhaBAD expression system revealed several promising inducers. These were characterized further to determine the strength, kinetics, and concentration-dependence of induction; whether the inducer was used as a carbon source by E. coli; and the modality (distribution) of induction among populations of cells. l-Mannose was found to be the most useful orthogonal inducer, providing an even greater range of induction than the native inducer l-rhamnose, and crucially, allowing sustained induction instead of transient induction. These findings address the key limitation of the rhaBAD expression system and suggest it may now be the most suitable system for many applications.
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Journal articleMacDonald J, Freemont PS, 2016,
Computational protein design with backbone plasticity
, Biochemical Society Transactions, Vol: 44, Pages: 1523-1529, ISSN: 1470-8752The computational algorithms used in the design of artificial proteins have become increasingly sophisticated in recent years, producing a series of remarkable successes. The most dramatic of these is the de novo design of artificial enzymes. The majority of these designs have reused naturally occurring protein structures as ‘scaffolds’ onto which novel functionality can be grafted without having to redesign the backbone structure. The incorporation of backbone flexibility into protein design is a much more computationally challenging problem due to the greatly increased search space, but promises to remove the limitations of reusing natural protein scaffolds. In this review, we outline the principles of computational protein design methods and discuss recent efforts to consider backbone plasticity in the design process.
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Journal articleClarke LJ, Kitney RI, 2016,
Synthetic biology in the UK – An outline of plans and progress
, Synthetic and Systems Biotechnology, Vol: 1, Pages: 243-257, ISSN: 2405-805XSynthetic biology is capable of delivering new solutions to key challenges spanning the bioeconomy, both nationally and internationally. Recognising this significant potential and the associated need to facilitate its translation and commercialisation the UK government commissioned the production of a national Synthetic Biology Roadmap in 2011, and subsequently provided crucial support to assist its implementation.Critical infrastructural investments have been made, and important strides made towards the development of an effectively connected community of practitioners and interest groups. A number of Synthetic Biology Research Centres, DNA Synthesis Foundries, a Centre for Doctoral Training, and an Innovation Knowledge Centre have been established, creating a nationally distributed and integrated network of complementary facilities and expertise.The UK Synthetic Biology Leadership Council published a UK Synthetic Biology Strategic Plan in 2016, increasing focus on the processes of translation and commercialisation. Over 50 start-ups, SMEs and larger companies are actively engaged in synthetic biology in the UK, and inward investments are starting to flow.Together these initiatives provide an important foundation for stimulating innovation, actively contributing to international research and development partnerships, and helping deliver useful benefits from synthetic biology in response to local and global needs and challenges.
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Journal articleKelwick RJR, Webb AJ, MacDonald JT, et al., 2016,
Development of a Bacillus subtilis cell-free transcription-translation system for prototyping regulatory elements
, Metabolic Engineering, Vol: 38, Pages: 370-381, ISSN: 1096-7184Cell-free transcription-translation systems were originally applied towards in vitro protein production. More recently, synthetic biology is enabling these systems to be used within a systematic design context for prototyping DNA regulatory elements, genetic logic circuits and biosynthetic pathways. The Gram-positive soil bacterium, Bacillus subtilis, is an established model organism of industrial importance. To this end, we developed several B. subtilis-based cell-free systems. Our improved B. subtilis WB800N-based system was capable of producing 0.8 µM GFP, which gave a ~72x fold-improvement when compared with a B. subtilis 168 cell-free system. Our improved system was applied towards the prototyping of a B. subtilis promoter library in which we engineered several promoters, derived from the wild-type Pgrac (σA) promoter, that display a range of comparable in vitro and in vivo transcriptional activities. Additionally, we demonstrate the cell-free characterisation of an inducible expression system, and the activity of a model enzyme - renilla luciferase.
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Journal articleStorch M, Casini A, Mackrow B, et al., 2016,
BASIC: A Simple and Accurate Modular DNA Assembly Method.
, Methods Mol Biol, Vol: 1472, Pages: 79-91Biopart Assembly Standard for Idempotent Cloning (BASIC) is a simple, accurate, and robust DNA assembly method. The method is based on linker-mediated DNA assembly and provides highly accurate DNA assembly with 99 % correct assemblies for four parts and 90 % correct assemblies for seven parts [1]. The BASIC standard defines a single entry vector for all parts flanked by the same prefix and suffix sequences and its idempotent nature means that the assembled construct is returned in the same format. Once a part has been adapted into the BASIC format it can be placed at any position within a BASIC assembly without the need for reformatting. This allows laboratories to grow comprehensive and universal part libraries and to share them efficiently. The modularity within the BASIC framework is further extended by the possibility of encoding ribosomal binding sites (RBS) and peptide linker sequences directly on the linkers used for assembly. This makes BASIC a highly versatile library construction method for combinatorial part assembly including the construction of promoter, RBS, gene variant, and protein-tag libraries. In comparison with other DNA assembly standards and methods, BASIC offers a simple robust protocol; it relies on a single entry vector, provides for easy hierarchical assembly, and is highly accurate for up to seven parts per assembly round [2].
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Journal articleAwan A, Blount B, Bell D, et al., 2016,
Biosynthesis of the Antibiotic Nonribosomal Peptide Penicillin in Baker’s Yeast
, BiorxivAbstract Fungi are a valuable source of enzymatic diversity and therapeutic natural products including antibiotics. By taking genes from a filamentous fungus and directing their efficient expression and subcellular localisation, we here engineer the baker’s yeast Saccharomyces cerevisiae to produce and secrete the antibiotic penicillin, a beta-lactam nonribosomal peptide. Using synthetic biology tools combined with long-read DNA sequencing, we optimise productivity by 50-fold to produce bioactive yields that allow spent S. cerevisiae growth media to have antibacterial action against Streptococcus bacteria. This work demonstrates that S. cerevisiae can be engineered to perform the complex biosynthesis of multicellular fungi, opening up the possibility of using yeast to accelerate rational engineering of nonribosomal peptide antibiotics.
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Journal articleMacDonald JT, Kabasakal BV, Godding D, et al., 2016,
Synthetic beta-solenoid proteins with the fragment-free computational design of a beta-hairpin extension
, Proceedings of the National Academy of Sciences of the United States of America, Vol: 113, Pages: 10346-10351, ISSN: 1091-6490The ability to design and construct structures with atomic level precisionis one of the key goals of nanotechnology. Proteins offer anattractive target for atomic design, as they can be synthesized chemicallyor biologically, and can self-assemble. However the generalizedprotein folding and design problem is unsolved. One approach tosimplifying the problem is to use a repetitive protein as a scaffold.Repeat proteins are intrinsically modular, and their folding and structuresare better understood than large globular domains. Here, wehave developed a new class of synthetic repeat protein, based onthe pentapeptide repeat family of beta-solenoid proteins. We haveconstructed length variants of the basic scaffold, and computationallydesigned de novo loops projecting from the scaffold core. Theexperimentally solved 3.56 ˚A resolution crystal structure of one designedloop matches closely the designed hairpin structure, showingthe computational design of a backbone extension onto a syntheticprotein core without the use of backbone fragments from knownstructures. Two other loop designs were not clearly resolved in thecrystal structures and one loop appeared to be in an incorrect conformation.We have also shown that the repeat unit can accommodatewhole domain insertions by inserting a domain into one of the designedloops.
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Journal articleAgustín-Pavón C, Mielcarek M, Garriga-Canut M, et al., 2016,
Deimmunization for gene therapy: host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice
, Molecular Neurodegeneration, Vol: 11, Pages: 1-16, ISSN: 1750-1326Background: Synthetic zinc finger (ZF) proteins can be targeted to desired DNA sequencesand are useful tools for gene therapy. We recently developed a ZF transcription repressor (ZFKOX1)able to bind to expanded DNA CAG-repeats in the huntingtin (HTT) gene, which arefound in Huntington’s disease (HD). This ZF acutely repressed mutant HTT expression in amouse model of HD and delayed neurological symptoms (clasping) for up to 3 weeks. In thepresent work, we sought to develop a long-term single-injection gene therapy approach in thebrain.Method: Since non-self proteins can elicit immune and inflammatory responses, we designed ahost-matched analogue of ZF-KOX1 (called mZF-KRAB), to treat mice more safely incombination with rAAV vector delivery. We also tested a neuron-specific enolase promoter(pNSE), which has been reported as enabling long-term transgene expression, to see whetherHTT repression could be observed for up to 6 months after AAV injection in the brain.Results: After rAAV vector delivery, we found that non-self proteins induce significantinflammatory responses in the brain, in agreement with previous studies. Specifically, microglialcells were activated at 4 and 6 weeks after treatment with non-host-matched ZF-KOX1 or GFP,respectively, and this was accompanied by a moderate neuronal loss. In contrast, the hostmatchedmZF-KRAB did not provoke these effects. Nonetheless, we found that using a pCAGpromoter (CMV early enhancer element and the chicken β-actin promoter) led to a strongreduction in ZF expression by 6 weeks after injection. We therefore tested a new non-viralpromoter to see whether the host-adapted ZF expression could be sustained for a longer time.Vectorising mZF-KRAB with a promoter-enhancer from neuron-specific enolase (Eno2, rat)resulted in up to 77% repression of mutant HTT in whole brain, 3 weeks after bilateralintraventricular injection of 1010 virions. Importantly, repressions of 48% and 23% were stilldetected after 12 and 24 weeks
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Journal articleToczek M, Zielonka D, Zukowska P, et al., 2016,
An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy
, BBA - Molecular Basis of Disease, Vol: 1862, Pages: 2147-2157, ISSN: 0925-4439Huntington's disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies havedemonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed anincreased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentiallyinvolve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energyphosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathyin pre-clinical and clinical settings. We found that HD mouse models developed a profound deteriorationin cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by areduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion ofadenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolitessuch as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be causedlocally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation.Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plusan inhibition of re-synthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction toameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscledysfunction in both pre-clinical and clinical HD settings.
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