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• Journal article
  Ellis T, 2019,

  Predicting how evolution will beat us

  , MICROBIAL BIOTECHNOLOGY, Vol: 12, Pages: 41-43, ISSN: 1751-7915
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  • Citations: 8
• Conference paper
  Tuza ZA, Stan G-B, 2019,

  An Automatic Sparse Model Estimation Method Guided by Constraints That Encode System Properties

  , 18th European Control Conference (ECC), Publisher: IEEE, Pages: 2171-2176
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• Book chapter
  Stopnitzky E, Still S, Ouldridge TE, Altenberg Let al., 2018,

  Physical Limitations of Work Extraction from Temporal Correlations

  , The Interplay of Thermodynamics and Computation in Both Natural and Artificial Systems, Publisher: SFI Press
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• Book chapter
  Ouldridge TE, Brittain R, ten Wolde PR, 2018,

  The power of being explicit: demystifying work, heat, and free energy in the physics of computation

  , The Interplay of Thermodynamics and Computation in Both Natural and Artificial Systems
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• Journal article
  Silhan J, Zhao Q, Boura E, Thomson H, Förster A, Tang CM, Freemont PS, Baldwin GSet al., 2018,

  Structural basis for recognition and repair of the 3'-phosphate by NExo, a base excision DNA repair nuclease from Neisseria meningitidis

  , Nucleic Acids Research, Vol: 46, Pages: 11980-11989, ISSN: 0305-1048

  NExo is an enzyme from Neisseria meningitidis that is specialized in the removal of the 3'-phosphate and other 3'-lesions, which are potential blocks for DNA repair. NExo is a highly active DNA 3'-phosphatase, and although it is from the class II AP family it lacks AP endonuclease activity. In contrast, the NExo homologue NApe, lacks 3'-phosphatase activity but is an efficient AP endonuclease. These enzymes act together to protect the meningococcus from DNA damage arising mainly from oxidative stress and spontaneous base loss. In this work, we present crystal structures of the specialized 3'-phosphatase NExo bound to DNA in the presence and absence of a 3'-phosphate lesion. We have outlined the reaction mechanism of NExo, and using point mutations we bring mechanistic insights into the specificity of the 3'-phosphatase activity of NExo. Our data provide further insight into the molecular origins of plasticity in substrate recognition for this class of enzymes. From this we hypothesize that these specialized enzymes lead to enhanced efficiency and accuracy of DNA repair and that this is important for the biological niche occupied by this bacterium.

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• Software
  Brittain R, Jones N, Ouldridge T, 2018,

  Biochemical Szilard engine for memory limited inference

  Code and data for figures in 'Biochemical Szilard engine for memory limited inference'

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• Journal article
  Kontoravdi K, Jimenez Del Val I, 2018,

  Computational tools for predicting and controlling the glycosylation of biopharmaceuticals

  , Current Opinion in Chemical Engineering, Vol: 22, Pages: 89-97, ISSN: 2211-3398

  Glycosylation is a critical quality attribute of biopharmaceuticals because it is a major source of structural variability that influences the in vivo safety and therapeutic efficacy of these products. Manufacturing process conditions are known to influence the monosaccharide composition and relative abundance of the complex carbohydrates bound to therapeutic proteins. Multiple computational tools have been developed to describe these process/product quality relationships in order to control and optimise the glycosylation of biopharmaceuticals. This review will provide a summary highlighting the strengths and weaknesses of each modelling strategy in their application towards cellular glycoengineering or bioprocess design and control. To conclude, potential unified glycosylation modelling approaches for biopharmaceutical quality assurance are proposed.

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• Journal article
  Larroude M, Rossignol T, Nicaud J-M, Ledesma Amaro Ret al., 2018,

  Synthetic biology tools for engineering Yarrowia lipolytica

  , Biotechnology Advances, Vol: 36, Pages: 2150-2164, ISSN: 0734-9750

  The non-conventional oleaginous yeast Yarrowia lipolytica shows great industrial promise. It naturally produces certain compounds of interest but can also artificially generate non-native metabolites, thanks to an engineering process made possible by the significant expansion of a dedicated genetic toolbox. In this review, we present recently developed synthetic biology tools that facilitate the manipulation of Y. lipolytica, including 1) DNA assembly techniques, 2) DNA parts for constructing expression cassettes, 3) genome-editing techniques, and 4) computational tools.

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• Conference paper
  Webb AJ, Allan F, Kelwick R, Jensen K, Templeton MR, Freemont Pet al., 2018,

  Protease-based bioreporters for the detection of schistosome cercariae

  , American Society of Tropical Medicine and Hygiene (ASTMH) 67th Annual Meeting, New Orleans, Louisiana, USA
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• Journal article
  Kyrou K, Hammond AM, Galizi R, Kranjc N, Burt A, Beaghton AK, Nolan T, Crisanti Aet al., 2018,

  A CRISPR-Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes

  , Nature Biotechnology, Vol: 36, Pages: 1062-1066, ISSN: 1087-0156

  In the human malaria vector Anopheles gambiae, the gene doublesex (Agdsx) encodes two alternatively spliced transcripts, dsx-female (AgdsxF) and dsx-male (AgdsxM), that control differentiation of the two sexes. The female transcript, unlike the male, contains an exon (exon 5) whose sequence is highly conserved in all Anopheles mosquitoes so far analyzed. We found that CRISPR–Cas9-targeted disruption of the intron 4–exon 5 boundary aimed at blocking the formation of functional AgdsxF did not affect male development or fertility, whereas females homozygous for the disrupted allele showed an intersex phenotype and complete sterility. A CRISPR–Cas9 gene drive construct targeting this same sequence spread rapidly in caged mosquitoes, reaching 100% prevalence within 7–11 generations while progressively reducing egg production to the point of total population collapse. Owing to functional constraint of the target sequence, no selection of alleles resistant to the gene drive occurred in these laboratory experiments. Cas9-resistant variants arose in each generation at the target site but did not block the spread of the drive.

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• Journal article
  Girvan P, Teng X, Brooks NJ, Baldwin GS, Ying Let al., 2018,

  Redox Kinetics of the Amyloid-β-Cu Complex and Its Biological Implications

  , BIOCHEMISTRY, Vol: 57, Pages: 6228-6233, ISSN: 0006-2960
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  • Citations: 7
• Journal article
  Ledesma-Amaro R, Jiménez A, Revuelta JL, 2018,

  Pathway Grafting for Polyunsaturated Fatty Acids Production in Ashbya gossypii through Golden Gate Rapid Assembly.

  , ACS Synthetic Biology, Vol: 7, Pages: 2340-2347, ISSN: 2161-5063

  Here we present a Golden Gate assembly system adapted for the rapid genomic engineering of the industrial fungus Ashbya gossypii. This biocatalyst is an excellent biotechnological chassis for synthetic biology applications and is currently used for the industrial production of riboflavin. Other bioprocesses such as the production of folic acid, nucleosides, amino acids and biolipids have been recently reported in A. gossypii. In this work, an efficient assembly system for the expression of heterologous complex pathways has been designed. The expression platform comprises interchangeable DNA modules, which provides flexibility for the use of different loci for integration, selection markers and regulatory sequences. The functionality of the system has been applied to engineer strains able to synthesize polyunsaturated fatty acids (up to 35% of total fatty acids). The production of the industrially relevant arachidonic, eicosapentanoic and docosahexanoic acids remarks the potential of A. gossypii to produce these functional lipids.

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• Journal article
  Hurault G, Schram M, Roekevisch E, Spuls P, Tanaka RJet al., 2018,

  Relationship and probabilistic stratification of EASI and oSCORAD severity scores for atopic dermatitis

  , British Journal of Dermatology, Vol: 179, Pages: 1003-1005, ISSN: 1365-2133

  The Harmonizing Outcome Measures for Eczema (HOME) recommended the Eczema Area and Severity Index (EASI) as the core outcome instrument for measuring the clinical signs of atopic dermatitis (AD). However, EASI may not have been used in previous clinical trials, and other scores, e.g. SCORAD (SCORing Atopic Dermatitis), the objective component of SCORAD (oSCORAD) and the Investigator Global Assessment (IGA), remain widely used. It is useful to establish a method to convert these scores into EASI to compare the results from different studies effectively. Indeed, EASI and oSCORAD have been found to be strongly correlated (rSpearman=0.92)7, suggesting a possibility to find a relationship between the two scores.

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• Journal article
  Kelly CL, Harris AWK, Steel H, Hancock EJ, Heap JT, Papachristodoulou Aet al., 2018,

  Synthetic negative feedback circuits using engineered small RNAs

  , Nucleic Acids Research, Vol: 46, Pages: 9875-9889, ISSN: 0305-1048

  Negative feedback is known to enable biological and man-made systems to perform reliably in the face of uncertainties and disturbances. To date, synthetic biological feedback circuits have primarily relied upon protein-based, transcriptional regulation to control circuit output. Small RNAs (sRNAs) are non-coding RNA molecules that can inhibit translation of target messenger RNAs (mRNAs). In this work, we modelled, built and validated two synthetic negative feedback circuits that use rationally-designed sRNAs for the first time. The first circuit builds upon the well characterised tet-based autorepressor, incorporating an externally-inducible sRNA to tune the effective feedback strength. This allows more precise fine-tuning of the circuit output in contrast to the sigmoidal, steep input-output response of the autorepressor alone. In the second circuit, the output is a transcription factor that induces expression of an sRNA, which inhibits translation of the mRNA encoding the output, creating direct, closed-loop, negative feedback. Analysis of the noise profiles of both circuits showed that the use of sRNAs did not result in large increases in noise. Stochastic and deterministic modelling of both circuits agreed well with experimental data. Finally, simulations using fitted parameters allowed dynamic attributes of each circuit such as response time and disturbance rejection to be investigated.

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• Journal article
  Gorochowski TE, Ellis T, 2018,

  Designing efficient translation

  , NATURE BIOTECHNOLOGY, Vol: 36, Pages: 934-935, ISSN: 1087-0156
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• Journal article
  Trantidou T, Dekker L, Polizzi K, Ces O, Elani Yet al., 2018,

  Functionalizing cell-mimetic giant vesicles with encapsulated bacterial biosensors

  , Interface Focus, Vol: 8, ISSN: 2042-8901

  The design of vesicle microsystems as artificial cells (bottom-up synthetic biology) has traditionally relied on the incorporation of molecular components to impart functionality. These cell mimics have reduced capabilities compared with their engineered biological counterparts (top-down synthetic biology), as they lack the powerful metabolic and regulatory pathways associated with living systems. There is increasing scope for using whole intact cellular components as functional modules within artificial cells, as a route to increase the capabilities of artificial cells. In this feasibility study, we design and embed genetically engineered microbes (Escherichia coli) in a vesicle-based cell mimic and use them as biosensing modules for real-time monitoring of lactate in the external environment. Using this conceptual framework, the functionality of other microbial devices can be conferred into vesicle microsystems in the future, bridging the gap between bottom-up and top-down synthetic biology.

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• Journal article
  Revuelta JL, Serrano-Amatriain C, Ledesma-Amaro R, Jiménez Aet al., 2018,

  Formation of folates by microorganisms: towards the biotechnological production of this vitamin

  , Applied Microbiology and Biotechnology, Vol: 102, Pages: 8613-8620, ISSN: 0175-7598

  Folates (vitamin B9) are essential micronutrients which function as cofactors in one-carbon transfer reactions involved in the synthesis of nucleotides and amino acids. Folate deficiency is associated with important diseases such as cancer, anemia, cardiovascular diseases, or neural tube defects. Epidemiological data show that folate deficiency is still highly prevalent in many populations. Hence, food fortification with synthetic folic acid (i.e., folic acid supplementation) has become mandatory in many developed countries. However, folate biofortification of staple crops and dairy products as well as folate bioproduction using metabolically engineered microorganisms are promising alternatives to folic acid supplementation. Here, we review the current strategies aimed at overproducing folates in microorganisms, in view to implement an economic feasible process for the biotechnological production of the vitamin.

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• Journal article
  Liu J, Li J, Liu Y, Shin H-D, Ledesma-Amaro R, Du G, Chen J, Liu Let al., 2018,

  Synergistic rewiring of carbon metabolism and redox metabolism in cytoplasm and mitochondria of aspergillus oryzae for increased l-Malate production

  , ACS Synthetic Biology, Vol: 7, Pages: 2139-2147, ISSN: 2161-5063

  l-Malate is an important platform chemical that has extensive applications in the food, feed, and wine industries. Here, we synergistically engineered the carbon metabolism and redox metabolism in the cytosol and mitochondria of a previously engineered Aspergillus oryzae to further improve the l-malate titer and decrease the byproduct succinate concentration. First, the accumulation of the intermediate pyruvate was eliminated by overexpressing a pyruvate carboxylase from Rhizopus oryzae in the cytosol and mitochondria of A. oryzae, and consequently, the l-malate titer increased 7.5%. Then, malate synthesis via glyoxylate bypass in the mitochondria was enhanced, and citrate synthase in the oxidative TCA cycle was downregulated by RNAi, enhancing the l-malate titer by 10.7%. Next, the exchange of byproducts (succinate and fumarate) between the cytosol and mitochondria was regulated by the expression of a dicarboxylate carrier Sfc1p from Saccharomyces cerevisiae in the mitochondria, which increased l-malate titer 3.5% and decreased succinate concentration 36.8%. Finally, an NADH oxidase from Lactococcus lactis was overexpressed to decrease the NADH/NAD+ ratio, and the engineered A. oryzae strain produced 117.2 g/L l-malate and 3.8 g/L succinate, with an l-malate yield of 0.9 g/g corn starch and a productivity of 1.17 g/L/h. Our results showed that synergistic engineering of the carbon and redox metabolisms in the cytosol and mitochondria of A. oryzae effectively increased the l-malate titer, while simultaneously decreasing the concentration of the byproduct succinate. The strategies used in our work may be useful for the metabolic engineering of fungi to produce other industrially important chemicals.

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• Journal article
  McFarlane C, Shah N, Kabasakal B, Cotton CAR, Bubeck D, Murray Jet al., 2018,

  Structural basis of light-induced redox regulation in the Calvin cycle

  , biorxiv

  Abstract In plants, carbon dioxide is fixed via the Calvin cycle in a tightly regulated process. Key to this regulation is the conditionally disordered protein CP12. CP12 forms a complex with two Calvin cycle enzymes, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoribulokinase (PRK), inhibiting their activities. The mode of CP12 action was unknown. By solving crystal structures of CP12 bound to GAPDH, and the ternary GAPDH-CP12-PRK complex by electron cryo-microscopy, we reveal that formation of the N-terminal disulfide pre-orders CP12 prior to binding the PRK active site. We find that CP12 binding to GAPDH influences substrate accessibility of all GAPDH active sites in the binary and ternary inhibited complexes. Our model explains how CP12 integrates responses from both redox state and nicotinamide dinucleotide availability to regulate carbon fixation. One Sentence Summary How plants turn off carbon fixation in the dark.

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• Journal article
  Trantidou T, Friddin M, Salehi-Reyhani S, Ces O, Elani Yet al., 2018,

  Droplet microfluidics for the construction of compartmentalised model membranes

  , Lab on a Chip, Vol: 18, Pages: 2488-2509, ISSN: 1473-0189

  The design of membrane-based constructs with multiple compartments is of increasing importance given their potential applications as microreactors, as artificial cells in synthetic-biology, as simplified cell models, and as drug delivery vehicles. The emergence of droplet microfluidics as a tool for their construction has allowed rapid scale-up in generation throughput, scale-down of size, and control over gross membrane architecture. This is true on several levels: size, level of compartmentalisation and connectivity of compartments can all be programmed to various degrees. This tutorial review explains and explores the reasons behind this. We discuss microfluidic strategies for the generation of a family of compartmentalised systems that have lipid membranes as the basic structural motifs, where droplets are either the fundamental building blocks, or are precursors to the membrane-bound compartments. We examine the key properties associated with these systems (including stability, yield, encapsulation efficiency), discuss relevant device fabrication technologies, and outline the technical challenges. In doing so, we critically review the state-of-play in this rapidly advancing field.

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