Warwick Integrative Synthetic Biology Centre

Lead Research Organisation: University of Warwick
Department Name: School of Life Sciences

Abstract

Synthetic biology is seen as a way to develop biology beyond naturally evolved biological systems to the benefit of mankind. It is a new type of engineering in which either existing parts of living cells are modified, or completely new parts are generated, in order to produce useful technologies and products. The function of the Warwick Integrative Synthetic Biology Centre (WISB) will be to establish a community of researchers from a range of relevant disciplines that will pursue the aims of synthetic biology following responsible procedures that are informed by considerations of ethical, legal and societal aspects. Our work will create products and technologies that will be valuable to multiple sectors, including biotechnology, health, food security and the environment. We will work in partnership with a wide range of companies that have interests in this area.

At the core of WISB will be an underpinning commitment to developing synthetic biology technologies and knowhow that will both be useful to the wider community and will also enable progress in the applied projects that will be pursued in the Centre. This core activity is called Predictive Biosystems Engineering because the idea is to find ways of developing synthetic biological systems that behave in predictable ways. The benefit of this would be that predictable components can be assembled into more complex systems that also behave in predictable ways - this is a principle of fundamental importance in classical engineering.

There are also three areas of more applied research:

Engineering Biosynthetic Pathways is about building tailor-made and controllable pathways in living cells that direct the assembly of useful products, e.g. antimicrobials and anti-cancer drugs. Engineering principles will be applied with the objective of optimizing the productivity of these intracellular drug production lines.

Engineering Microbial Communities is a research area in which we assemble different species of microbial organism that can be used in a range of biotechnological and biomedical applications. For example, synthetic communities of this type will be able to degrade noxious and toxic compounds from the environment, or could be utilized to treat diseases of the skin or gut.

Engineering Microbial Effector Systems research will take advantage of the fascinating interplay between plants and microbial species with which they interact in Nature, for example in the soil. Such microorganisms use a range of molecules, called effectors, to modify the genetic and metabolic systems of plant cells. By re-engineering these interactions, we will be able to enhance the properties of plants, thus contributing to food security.

In parallel to the above activities, WISB will perform research on the ethical, legal and societal aspects of synthetic biology and follow principles of responsible research and innovation. We will engage in a wide range of outreach activities in order to communicate our research philosophy and findings to the wider community. A special feature of this outreach will involve work and presentations on the relationships between technology, design and art.

Finally, WISB will be fully committed to education and training in synthetic biology, thus ensuring that we contribute strongly to the training of future generations of synthetic biology researchers.

Technical Summary

The proposed Warwick Integrative Synthetic Biology Centre (WISB) will utilise state-of-the-art principles of computational design and control engineering to optimise the development and application of novel synthetic biology tools. This Predictive Biosystems Engineering strategy will underpin three further areas of applied research based on integrated computational/experimental approaches.

In the core Predictive Biosystems Engineering theme we will adopt a dual approach in order to balance relatively rapid progress in improving current synthetic biotool predictability against longer-term development of new types of tools. In the former, we will address the causative factors that undermine the predictability and scalability of synthetic gene circuitry. In the latter, we will explore the use of posttranscriptional layers of biomolecular circuitry, specifically RNA and protein components, as a way of expanding the capabilities of current SGC tools, and also with the ultimate objective of building new types of circuitry.

Our work on Engineering Biosynthetic Pathways will combine computational design, rate control engineering and high resolution analytical chemistry with de novo synthesis/assembly of entire pathways in Streptomyces. The Theme on Engineering Microbial Communities will pursue rational engineering of synthetic microbial communities that are rendered robust and functional through metabolic, genetic and physical interdependencies/interactions. The third applied Theme will be Engineering Microbial Effector Systems in Plants, in which we will build a new type of synthetic control system based on microbial effector molecules (synEffectors). The synEffectors will be used to re-engineer signalling pathways with the objective of developing desired properties in the plants.

There will also be research on ethical, legal and societal aspects of synthetic biology that will feed into the strategy and other activities of WISB.

Planned Impact

The Warwick Centre for Integrative Synthetic Biology (WISB) will work with key stakeholders from academia, industry, government departments, and the public, across a broad range of disciplines, to bring together researchers in the field of Synthetic Biology (SB) for the formation of a skilled, global-leading SB community, with a hub in the UK. WISB will provide state-of-art training and research infrastructure, promote awareness of the societal and ethical implications of SB, and enable and embed public engagement; to ensure the activities delivered through its national and international networks realise the potential of SB to have a significant impact to the UK's Economy and Society, Research Communities, and Education and Knowledge Programmes.

WISB will:
1. Accelerate the route to market for innovative SB research;
2. Develop and sustain an internationally competitive research programme with a strong collaborative culture and a supporting physical environment to drive advancement and lead development in the field of SB;
3. Facilitate adoption and uptake of novel SB approaches and make these available to the wider community;
4. Contribute to and accelerate growth in the SB UK network and offer outreach and exchange opportunities;
5. Practise responsible innovation and research at all stages.

Industrial impact will be maximised by:
(i) Engaging actively with the industrial members of the Advisory Board (AB) to promote dialogue as to research progress and potential applications;
(ii) Reviewing progress annually with our technology transfer office, Warwick Ventures (WV) to look for opportunities to develop commercial opportunities such as patents and licensing;
(iii) Seeking industrial engagement opportunities through our AB;
(iv) Engaging actively with the EPSRC-funded Innovation and Knowledge Centre (IKC) in SB.

International impact will be maximised by:
(i) Engaging with internationally leading research groups including Prof. Michael Elowitz (Caltech), Prof. Jim Collins (Boston University), Prof. Mark Bedau (Reed College), and Prof. Sibylle Gaisser (University of Ansbach)) who have agreed to serve on our AB;
(ii) Building on our existing partnerships with the SB Centre at Boston University (CoSBi), the University of São Paulo Biomass Systems and Synthetic Biology Center (BSSB), the University of Pompeu Fabra and the CSIC Institute in Madrid;
(iii) Extending our academic interactions to include additional key institutions in the EU, US and China;
(iv) Promoting a strong collaboration culture in which WISB researchers are encouraged to form cross-disciplinary teams.

Societal impact will be maximised by:
(i) Exploiting and exploring paths to society such as briefings to Government Departments and engaging with regulatory authorities;
(ii) Exploring the role of arts and design, both in the scientific development of SB and its engagement with the public via our formal relationship with our Artist-in-Residence;
(iii) Publishing in a range of popular science communication outlets;
(iv) Developing a publicly accessible web site for the tools and technologies that result from WISB research;
(v) Using social media and ways of online communication tools to enhance impact.

Impact to the UK's Synthetic Biology network will be maximised by:
(i) Actively engaging with the growing SB research community in the UK, through our SB Centre for Doctoral Training (joint with Oxford and Bristol), our membership of the SB IKC, and our many joint SB projects with collaborators from other UK Universities;
(ii) Organising an annual meeting and secondments with the scientific members of the AB to promote dialogue on scientific progress and potential collaborations;
(iii)Taking a leadership role in the UK in engaging with the broader base of stakeholders in the SB landscape, including environmental and other lobby groups, government departments, and the general public;
(iv) Training future leaders in SB.

Publications

10 25 50

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Zerfaß C (2019) Interrogating metabolism as an electron flow system. in Current opinion in systems biology

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Tiberi S (2018) Bayesian inference on stochastic gene transcription from flow cytometry data. in Bioinformatics (Oxford, England)

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Stratford J (2019) Electrically induced bacterial membrane-potential dynamics correspond to cellular proliferation capacity in Proceedings of the National Academy of Sciences

 
Description WISB has now entered its second year of existence. So far, we have been making progress in five main areas:
1. Predictive Biosystems Engineering - here we develop novel synthetic biomolecular circuitry for use in prokaryotic and eukaryotic hosts, try to improve system predictability, scalability and robustness by engineering stochasticity and circuit-host interactions, and develop advanced computer design tools. Progress is being made in all of these areas. Examples include: the development of novel regulatory modules for yeast based on the mammalian translational regulator Iron Regulatory Protein 1, noise reduction in yeast and mammalian cells, ribozyme-mediated signalling, development of computer-aided design tools based on DNA strand displacement in collaboration with Microsoft Research
2. Engineering Biosynthetic Pathways - computational design tools and yeast mediated recombination are being applied to build refactored biosynthetic gene clusters for structurally complex bioactive natural products with applications in medicine and agriculture. In parallel, and in collaboration with Syngenta, engineered transcriptional repressors are being developed that respond to non-natural ligands and operator sequences, with a view to fine-tuning of the refactored biosynthetic gene clusters. Progress is being made in all of these areas. Biosynthetic pathways currently being explored include those generating: eponomycin, epoxomicin, methylenomycin A, streptorubin B and deschlororoseophilin/prodigiosin R1. A more recent project in collaboration with Ingenza is focusing on the optimisation of synthetic pathways of cellulose-degrading enzymes.
3. Engineering Microbial Communities - we are applying synthetic biology at the level of heterogeneous and homogenous cell communities. This involves engineering synthetic microbial communities from bottom-up using (multiple) defined species that are functionally interlinked using metabolic, genetic and physical interactions, and reengineering existing communities using rational manipulations at the species and community level. On the former front, our work focuses on (i) engineering a three-species system involving a phototroph and aimed at conversion of light into final, high value chemicals in a closed ecosystem, and (ii) developing a spatially organised community for degradation of chlorinated compounds. On the latter front, we work on reengineering of gut communities towards reducing production of TMAO, which is a by-product of a high-meat diet that has been shown to increase the risk of atherosclerosis in humans.
4. Engineering Microbial Effector Systems in Plants - this theme exploits the mechanisms underpinning interactions between plants and microbial pathogens and mutualists. Natural microbial effectors are targeted to bespoke pathways within plants in order to engineer (orthogonal) temporal and spatial control of bespoke plant responses, thus paving the way for the development of plants with enhanced resistance to stress and microbial attack. Progress in being made in all of these areas. Examples include: identification of effectors derived by pathogenic and beneficial microbes that control developmental (senescence), immunity and abiotic stress (drought, high light) pathways. Particular emphasis is given to mechanisms that can uncouple growth and immunity - pathways that typically act antagonistically.
5. Ethical, Legal and Societal Aspects of SynBio. Here, we have been making strong progress in understanding cognitive processes related to human relationships with new technologies. In addition, in collaboration with the University of Copenhagen, we have developed an exciting new aural communication platform for SynBio called AURATOR.
Exploitation Route There will be many opportunities for others to take advantage of the tools and strategies that we develop.
Sectors Agriculture, Food and Drink,Chemicals,Digital/Communication/Information Technologies (including Software),Environment,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description Aurator is being disseminated to various groupings in the UK and will then be shared with partners abroad.
First Year Of Impact 2017
Sector Education
Impact Types Cultural

 
Description BARCELONA 
Organisation Pompeu Fabra University
Country Spain 
Sector Academic/University 
PI Contribution We are working jointly with Pompeu Fabra (Dept of Experimental & Health Sciences) on an ERANET grant application in synthetic biology. McCarthy has led an EU2020 Marie Sklodowska-Curie Doctoral Programme application involving this partner.
Collaborator Contribution Groups at Pompeu Fabra have contributed preliminary data and ideas to the development of the ERANET proposal and will contribute to training events for any PhD students on a joint PhD programme.
Impact These are indicated above.
Start Year 2015
 
Description BU 
Organisation Boston University
Country United States 
Sector Academic/University 
PI Contribution WISB is partnered with the Biological Design Centre at BU. McCarthy has been PI on a joint BBSRC/NSF grant proposal with Khalil at the Biological Design Centre. Bates has been Co-I on a successful joint NSF/BBSRC proposal with Densmore at the Biological Design Centre.
Collaborator Contribution As described above.
Impact Grant proposals and ongoing research collaboration as described above.
Start Year 2014
 
Description COPENHAGEN 
Organisation University of Copenhagen
Country Denmark 
Sector Academic/University 
PI Contribution We have collaborated with Uni Copenhagen on the development of a novel tool for communication on the subject of SynBio, called AURATOR. WISB has part-funded this project.
Collaborator Contribution Commitment of the time of Britt Wray.
Impact Creation of the new communications software called AURATOR.
Start Year 2015
 
Description FIOCRUZ Curitiba 
Organisation Oswaldo Cruz Foundation (Fiocruz)
Country Brazil 
Sector Public 
PI Contribution We work closely with the research group of Dr Nilson Zanchin at the FIOCRUZ institute in Curitiba, Parana, Brazil. Together with Prof Alex Breeze and Prof Andy Wilson at Leeds University, we are performing detailed molecular investigations on proteins from trypanosomatid parasites. As described in the original grant application, this involves the use of multiple biophysical methods, including microscope thermophoresis, SPR, ITC, NMR and X-ray crystallography, as well as screening assays.
Collaborator Contribution The Brazilian partners are performing in vivo studies on the trypanosomatid translation machinery, thus complementing the molecular work being performed by us.
Impact Collectively, we have already generated recombinant proteins corresponding to seven of the trypanosomatid translation factors, and have already analysed many of them using SPR, macroscale thermophoresis, SPR, and ITC. Two 15N-labelled proteins are now being analysed using NMR, and we have started crystallisation trials on three of the proteins.
Start Year 2016
 
Description SAOPAULO 
Organisation University of Sao Paulo
Country Brazil 
Sector Academic/University 
PI Contribution With BBSRC support, we have organised a joint workshop together with colleagues at Sao Paulo in 2014. This has resulted in joint FAPESP-BBSRC and GCRF research proposals and an exchange training programme for PhD students and postdocs working in the area of synthetic biology.
Collaborator Contribution Support for the above activities has been mutual.
Impact Two joint research proposals so far, with further ones planned.
Start Year 2014
 
Description SYNMIKRO 
Organisation Philipp University of Marburg
Country Germany 
Sector Academic/University 
PI Contribution SYNMIKRO is a national centre of excellence in synthetic biology at the University of Marburg in Germany. Working together with the Director, Prof Anke Becker, and her colleagues, we have established a partnership that supports researcher exchange and joint training activities.
Collaborator Contribution SYNMIKRO will provide most of the funding for a joint summer school on synthetic biology in 2018.
Impact This partnership is multidisciplinary, involving biosciences, computer science, chemistry, physics and maths. We have already submitted a joint ERANET proposal on developing new synthetic biology tools.
Start Year 2016
 
Description TARTU 
Organisation University of Tartu
Country Estonia 
Sector Academic/University 
PI Contribution The Synthetic Biology centre at Tartu is a partner on our joint ERANET research proposal on synthetic biology tools. McCarthy has led an EU2020 Marie Sklodowska-Curie Doctoral Programme application involving this partner, and is External Advisor to the Tartu SynBio Centre.
Collaborator Contribution The Tartu SynBio centre has contributed to the joint ERANET proposal and will be involved in a further proposal to the EU.
Impact Progress on joint research proposals.
Start Year 2016
 
Description COVENTRY FABLAB 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact WISB funded and ran a two-day practical event for schoolchildren at the Coventry Fablab.
Year(s) Of Engagement Activity 2016
 
Description Parliamentary and Science Committee workshop: How Safe is Pathogen Research? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact John McCarthy gave a presentation to the Parliamentary and Scientific Committee (PSC) in Westminster on the potential for Synthetic Biology to contribute to the development of dangerous pathogens and related potential security issues. There was a long discussion after the talk and also at the formal PSC dinner later that evening.
Year(s) Of Engagement Activity 2016
URL http://www.scienceinparliament.org.uk
 
Description Public Lecture and Debate on Synthetic Biology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I was a plenary speaker at a session on Synthetic Biology at the Cheltenham Science Festival. My remit was to explain the nature and objectives of Synthetic Biology and to encourage lively debate with the audience.
Year(s) Of Engagement Activity 2009
 
Description Seminar at Alleyns School, Dulwich, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk on Synthetic Biology and Systems Biology. This stimulated a lively discussion with pupils and teachers as well as interest in these subject areas among the pupils. Part of the discussion was about ethical, legal and societal aspects.
Year(s) Of Engagement Activity 2014
URL http://www.alleyns.org.uk/alleyn/documents/Newsletters/Advent_newsletter
 
Description Seminar by John McCarthy at Withington School, Manchester: How can we engineer living organisms? 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Approximately 60 pupils attended this interactive talk on Synthetic Biology. This was followed by a lengthy question and answer session.
Year(s) Of Engagement Activity 2015
 
Description SfAM 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Lecture by McCarthy at the Royal Society on the risks of Synthetic Biology in relation to pathogenic organisms.
Year(s) Of Engagement Activity 2017