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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.
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Journal articleTrusch F, Matena A, Vuk M, et al., 2015,
The N-terminal region of the ubiquitin regulatory x (UBX) domain-containing Protein 1 (UBXD1) modulates interdomain communication within the valosin-containing Protein p97
, Journal of Biological Chemistry, Vol: 290, Pages: 29414-29427, ISSN: 1083-351X -
Journal articleQuinn JY, Cox RS, Adler A, et al., 2015,
SBOL Visual: A Graphical Language for Genetic Designs.
, PLOS Biology, Vol: 13, ISSN: 1545-7885Synthetic Biology Open Language (SBOL) Visual is a graphical standard for genetic engineering. It consists of symbols representing DNA subsequences, including regulatory elements and DNA assembly features. These symbols can be used to draw illustrations for communication and instruction, and as image assets for computer-aided design. SBOL Visual is a community standard, freely available for personal, academic, and commercial use (Creative Commons CC0 license). We provide prototypical symbol images that have been used in scientific publications and software tools. We encourage users to use and modify them freely, and to join the SBOL Visual community: http://www.sbolstandard.org/visual.
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Journal articleYuan Y, Rai A, Yeung E, et al., 2015,
A Minimal Realization Technique for the Dynamical Structure Function of a Class of LTI Systems
, IEEE TRANSACTIONS ON CONTROL OF NETWORK SYSTEMS, Vol: 4, Pages: 301-311, ISSN: 2325-5870The dynamical structure function of a linear time invariant (LTI) system reveals causal dependencies among manifest variables without specifying any particular relationships among the unmeasured states of the system. As such, it is a useful representation for complex networks where a coarse description of global system structure is desired without detailing the intricacies of a full state realization. In this paper, we consider the problem of finding a minimal state realization for a given dynamical structure function. Interestingly, some dynamical structure functions require uncontrollable modes in their state realizations to deliver the desired input-output behavior while respecting a specified system structure. As a result, the minimal order necessary to realize a particular dynamical structure function may be greater than that necessary to realize its associated transfer function. Although finding a minimal realization for a given dynamical structure function is difficult in general, we present a straightforward procedure here that works for a simplified class of systems.
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Journal articleKopniczky M, moore S, freemont P, 2015,
Multilevel regulation and translational switches in synthetic biology
, IEEE Transactions on Biomedical Circuits and Systems, Vol: 9, Pages: 485-496, ISSN: 1940-9990In contrast to the versatility of regulatory mechanisms in natural systems, synthetic genetic circuits have been so far predominantly composed of transcriptionally regulated modules. This is about to change as the repertoire of foundational tools for post-transcriptional regulation is quickly expanding. We provide an overview of the different types of translational regulators: protein, small molecule and RNA responsive and we describe the new emerging circuit designs utilizing these tools. There are several advantages of achieving multilevel regulation via translational switches and it is likely that such designs will have the greatest and earliest impact in mammalian synthetic biology for regenerative medicine and gene therapy applications.
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Journal articleKopniczky M, freemont P, moore S, 2015,
Multilevel regulation and translational switches in synthetic biology
, IEEE Transactions on Biomedical Circuits and Systems, ISSN: 1940-9990 -
Journal articleCeroni F, Carbonell P, François JM, et al., 2015,
Editorial - Synthetic Biology: Engineering Complexity and Refactoring Cell Capabilities.
, Frontiers in Bioengineering and Biotechnology, Vol: 3, ISSN: 2296-4185 -
Journal articleStorch M, Casini A, Mackrow B, et al., 2015,
BASIC: a new Biopart Assembly Standard for Idempotent Cloning provides accurate, single-tier DNA assembly for synthetic biology
, ACS Synthetic Biology, Vol: 4, Pages: 781-787, ISSN: 2161-5063The ability to quickly and reliably assemble DNA constructs is one of the key enabling technologies for synthetic biology. Here we define a new Biopart Assembly Standard for Idempotent Cloning (BASIC), which exploits the principle of orthogonal linker based DNA assembly to define a new physical standard for DNA parts. Further, we demonstrate a new robust method for assembly, based on type IIs restriction cleavage and ligation of oligonucleotides with single stranded overhangs that determine the assembly order. It allows for efficient, parallel assembly with great accuracy: 4 part assemblies achieved 93% accuracy with single antibiotic selection and 99.7% accuracy with double antibiotic selection, while 7 part assemblies achieved 90% accuracy with double antibiotic selection. The linkers themselves may also be used as composable parts for RBS tuning or the creation of fusion proteins. The standard has one forbidden restriction site and provides for an idempotent, single tier organisation, allowing all parts and composite constructs to be maintained in the same format. This makes the BASIC standard conceptually simple at both the design and experimental levels.
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Conference paperSootla A, Oyarzun DA, Angeli D, et al., 2015,
Shaping Pulses to Control Bi-Stable Biological Systems
, American Control Conference 2015, Publisher: IEEE, Pages: 3138-3143In this paper, we present a framework for shaping pulses to control biological systems, and specifically systems in synthetic biology. By shaping we mean computing the magnitude and the length of a pulse, application of which results in reaching the desired control objective. Hence the control signals have only two parameters, which makes these signals amenable to wetlab implementations. We focus on the problem of switching between steady states in a bistable system. We show how to estimate the set of the switching pulses, if the trajectories of the controlled system can be bounded from above and below by the trajectories of monotone systems. We then generalise this result to systems with parametric uncertainty under some mild assumptions on the set of admissible parameters, thus providing some robustness guarantees. We illustrate the results on some example genetic circuits.
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Journal articleKopniczky M, freemont P, Moore S,
Multilevel regulation and translational switches in synthetic biology
, IEEE Transactions on Biomedical Circuits and Systems, ISSN: 1940-9990In contrast to the versatility of regulatory mechanisms in natural systems, synthetic genetic circuits have been so far predominantly composed of transcriptionally regulated modules. This is about to change as the repertoire of foundational tools for post-transcriptional regulation is quickly expanding. We provide an overview of the different types of translational regulators: protein, small molecule and RNA responsive and we describe the new emerging circuit designs utilizing these tools. There are several advantages of achieving multilevel regulation via translational switches and it is likely that such designs will have the greatest and earliest impact in mammalian synthetic biology for regenerative medicine and gene therapy applications.
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Journal articleCasini A, Storch M, Baldwin GS, et al., 2015,
Bricks and blueprints: methods and standards for DNA assembly
, Nature Reviews Molecular Cell Biology, Vol: 16, Pages: 568-576, ISSN: 1471-0080DNA assembly is a key part of constructing gene expression systems and even whole chromosomes. In the past decade, a plethora of powerful new DNA assembly methods — including Gibson Assembly, Golden Gate and ligase cycling reaction (LCR) — have been developed. In this Innovation article, we discuss these methods as well as standards such as the modular cloning (MoClo) system, GoldenBraid, modular overlap-directed assembly with linkers (MODAL) and PaperClip, which have been developed to facilitate a streamlined assembly workflow, to aid the exchange of material between research groups and to create modular reusable DNA parts.
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Journal articleWong A, Wang H, Poh CL, et al., 2015,
Layering genetic circuits to build a single cell, bacterial half adder
, BMC Biology, Vol: 13, ISSN: 1741-7007Background: Gene regulation in biological systems is impacted by the cellular and genetic context-dependenteffects of the biological parts which comprise the circuit. Here, we have sought to elucidate the limitations ofengineering biology from an architectural point of view, with the aim of compiling a set of engineering solutionsfor overcoming failure modes during the development of complex, synthetic genetic circuits.Results: Using a synthetic biology approach that is supported by computational modelling and rigorouscharacterisation, AND, OR and NOT biological logic gates were layered in both parallel and serial arrangements togenerate a repertoire of Boolean operations that include NIMPLY, XOR, half adder and half subtractor logics in asingle cell. Subsequent evaluation of these near-digital biological systems revealed critical design pitfalls thattriggered genetic context-dependent effects, including 5′ UTR interferences and uncontrolled switch-on behaviourof the supercoiled σ54 promoter. In particular, the presence of seven consecutive hairpins immediately downstreamof the promoter transcription start site severely impeded gene expression.Conclusions: As synthetic biology moves forward with greater focus on scaling the complexity of engineeredgenetic circuits, studies which thoroughly evaluate failure modes and engineering solutions will serve as importantreferences for future design and development of synthetic biological systems. This work describes a representativecase study for the debugging of genetic context-dependent effects through principles elucidated herein, therebyproviding a rational design framework to integrate multiple genetic circuits in a single prokaryotic cell.
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Journal articleHancock E, Stan G-B, Arpino J, et al., 2015,
Simplified mechanistic models of gene regulation for analysis and design
, Journal of the Royal Society Interface, Vol: 12, ISSN: 1742-5689Simplified 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.
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Journal articleTay D, Poh CL, Van Reeth E, et 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- Author Web Link
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- Citations: 8
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Journal articleCeroni F, Algar R, Stan G-B, et al., 2015,
Quantifying cellular capacity identifies gene expression designs with reduced burden
, Nature Methods, Vol: 12, Pages: 415-418, ISSN: 1548-7105Heterologous 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.
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Conference paperSainz de Murieta Fuentes I, bultelle M, kitney, 2015,
A DICOM Extension Supporting Data Acquisition in Synthetic Biology
, Synthetic Biology: Engineering, Evolution & Design (SEED) -
Conference paperbultelle, Sainz de Murieta Fuentes I, kitney RI, 2015,
Introducing Synbis – the Synthetic Biology Information System
, Synthetic Biology: Engineering, Evolution & Design (SEED) -
Journal articleTay 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- Author Web Link
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- Citations: 15
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Journal articleWeston DJ, Russell RA, Batty E, et 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 articleWright O, Delmans M, Stan G-B, et al., 2015,
Gene Guard: A Modular Plasnnid System Designed for Biosafety
, ACS SYNTHETIC BIOLOGY, Vol: 4, Pages: 307-316, ISSN: 2161-5063- Author Web Link
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- Citations: 74
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Journal articleKelwick R, Kopniczky M, Bower I, et al., 2015,
A Forward-Design Approach to Increase the Production of Poly-3-Hydroxybutyrate in Genetically Engineered <i>Escherichia coli</i>
, PLOS ONE, Vol: 10, ISSN: 1932-6203- Author Web Link
- Open Access Link
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- Citations: 8
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Work in the IC-CSynB is supported by a wide range of Research Councils, Learned Societies, Charities and more.
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