Once the technology has Impact Objectives been introduced, the main goal of ELY4OFF • Develop new engineering methods and tools is the development and • Apply them to solve foundational and applied problems in synthetic biology demonstration of an autonomous off-grid electrolysis system linked to renewable energy sources

Project Insights Engineering biology

FUNDING This project has received funding from Dr Guy-Bart Stan leads a diverse research group of scientists and engineers working on introducing control the Fuel Cells and Hydrogen 2 Joint engineering in synthetic biology. Here, he introduces himself and his team, outlines the nature of their work, Undertaking under grant agreement and highlights the importance of working across disciplines and with industry no. 700359 of renewable energy sources. ‘PEMWE Following this, a new iteration of the business PARTNERS To begin, can you and regulatory mechanisms governing Our group strives to engage with industry to Aragon Hydrogen Foundation (Spain) has showed capabilities in the emerging development plan will be organised by share a little about genetic circuits in order to describe their understand which technological innovations • ITM Power (UK) • INYCOM (Spain) • hydrogen scenarios to be a valid alternative to September 2018, six months prior to the EPIC POWER (Spain) • CEA TECH (France) your own research operation in terms of rigorous mathematical will have the most practical and beneficial previously developed technologies, especially project’s conclusion. interests and and computational models as is done impact on society. As an example, we are considering the dynamic and versatile CONTACT background? for example in electronics for complex currently running a project for the optimised operation expected of hydrogen production In addition, over the remaining months of Pedro Casero circuits. We then use these models to production of high-value recombinant methods when integrated with renewable the project, the researchers will spend time Project Head I am fascinated rigorously analyse, design, optimise and proteins in bacterial hosts for which the energy sources,’ Casero elaborates. ‘Off-grid investigating current regulations, codes and by the possibility of engineering biology implement novel biological systems in initial project formulation was pieced electrolysis and hydrogen storage have the standards, with an aim to identifying barriers T: +34 974215258 in a way akin to what has happened for living cells (e.g. gene regulatory networks, together after consultation with a leading E: [email protected] key advantage of being able to manage both to be overcome. The ELY4OFF team will also highly complex physical systems in other metabolic pathways, whole-cell biosensors, UK-based synthetic biology company. W: http://ely4off.eu/ the long- and short-term transient variations devote time to designing system capabilities engineering fields, such as aeronautics, biomolecular feedback systems). We in renewable supply, whereas batteries cannot to run off-grid and studying business information technology or advanced are also interested in characterising and Finally, how do you disseminate and share BIO manage the seasonal variations unless very cases and scenarios for where the off-grid Pedro Casero holds an MSc in Mechanical robotics. I started my career as an electronic predicting the interactions between cells and the results from your work? large battery stores are specified.’ electrolysis system could be an enabler. Engineering from the University of engineer. I then spent some time as an the engineered genetic systems they host. Zaragoza, Spain. He has more than 15 applied mathematician, with a PhD focused One of the most effective methods of Electrolysis enables excess renewable energies RENEWABLE RESEARCH years of experience in the field of R&D on complex systems. After a stint at Philips Can you talk a little about the sharing the group’s work is through to be transformed into hydrogen and stored. According to Casero, the ELY4OFF project is in the energy sector while working in the Applied Technologies in Belgium, where I interdisciplinary nature of your research and scientific collaborations and publications. This means that when there is a deficit of progressing well. ‘Technical partners have R&D Department in the Puertollano IGCC worked as Senior Digital Signal Processing why this is an important approach? We collaborate with different research Demo Plant, where he developed projects renewable energies, it can be converted developed their parts in their premises based on Engineer, I returned to academic research, groups wherever possible. This is not only in the field of CO2 capture, H2 production, into electricity to cover this demand. A key the specifications agreed at the beginning of the biomass gasification and process first as a Postdoctoral Research Associate Our group is composed of researchers with vital for strengthening our interdisciplinarity, advantage of hydrogen in this context is that it project – for example, power electronics by EPIC optimisation. He joined Aragon Hydrogen in the Control Group of the Department of expertise ranging from biological sciences, but also helps in opening our research to has a higher energy density, which means it can POWER and an electrolyser by ITM Power,’ he Foundation in 2016 and is currently the Engineering at the University of Cambridge, such as molecular biology and biochemistry, the wider scientific community, either accumulate much more energy in less space. elaborates. ‘In Spring 2018, transport to the Innovation Area Manager where projects and then as Principal Investigator and to engineering, computer science and through joint projects, publications, or demonstration site at Huesca and integration based on bringing hydrogen technologies permanent member of staff in the applied mathematics. Each researcher academic/general audience events. We ROADMAP TO SUCCESS with the peripheral elements developed by closer to the market are developed. Department of Bioengineering at Imperial brings a unique perspective and a different also maintain a strong presence at broad The project recently created its first business FHA are expected. Finally, the control and College London. My return to academia was skillset on how to approach the scientific audience events; this in turn helps people development plan, which provides a clear communication system developed by INYCOM motivated by my urge to apply my systems questions and bioengineering challenges from a variety of backgrounds to become roadmap to follow over the next few months. will take control of the whole system.’ and control engineering knowledge to one we are facing. This mix of educational familiar with our research. For example, The initial stage is defining the scope of the of the biggest engineering challenges of backgrounds and problem-solving skills one talk was at the Mathematical project, which will be followed by a raw cost The team believes that the solution being our time: biology. produces a very stimulating and creative Biosciences Institute at Ohio State analysis of materials. Subsequently, market implemented in the ELY4OFF project will environment for everyone, which allows University, USA, in October 2017, where research will be performed, involving four be market ready in 2020. From there, it can You head the Control Engineering Synthetic us to undertake complex and ambitious we presented our recent efforts to engineer or five potential customers comprising be implemented as an off-grid storage Biology group at Imperial College London. multidisciplinary projects. living E. coli cells that exhibit improved renewable energy manufacturers, public system coupled to renewable energy, What are its key aims? robustness and performance during authorities, chemical plants, countries with becoming an enabler for increased Do you collaborate with industry in your synthetic network operations (you can watch isolated areas, owners and end users, and renewable energy penetration in member One of our chief aims is obtaining a work? How do you ensure the outcomes the talk at: https://mbi.osu.edu/video/ off-grid installation operators and services. states to the European Commission. thorough understanding of the dynamics have practical application? player/?id=4377).

76 www.impact.pub www.impact.pub 77 Designing and controlling synthetic biology systems

In the Centre for Synthetic Biology at Imperial College London, the Control Engineering Synthetic Biology group is working to produce solutions to some of the most important challenges of our time

In essence, synthetic biology aims to engineer BIOTECHNICAL SYSTEMS implementing novel control mechanisms that biology. Similar to how classic engineering It is with the above in mind that the Control aim to automatically regulate the behaviour disciplines such as mechanical and electrical Engineering Synthetic Biology group was of a genetic system to meet our design engineering employ knowledge from maths established. Led by Dr Guy-Bart Stan and objectives.’ These novel control mechanisms and physics to rationally design, model and based at Imperial College London, UK, the can be thought of as similar to a thermostat; build mechanical and electronic systems, group’s research focuses on exploring the just as a thermostat can detect discrepancies synthetic biology aims to rationally design modelling, analysis and design of biotechnical between the desired temperature and and implement novel biological systems in systems, and developing engineering methods the actual temperature, a genetic control living cells. As such, its development and that will enable the design, control, mechanism can be designed to sense the progression rely on researchers from a wide optimisation and easy implementation of deviation between the desired and actual levels range of disciplines coming together in an novel biological systems in living cells. of a protein of interest. From there, the system effort to solve some of the most important can automatically downregulate or upregulate challenges facing the world today. The Stan The work of the group falls within three major its expression to minimise the error. group is working at the frontier between categories. First, they want to understand the control engineering and synthetic biology dynamics and regulatory mechanisms that Another major challenge centres around to create new bioengineering methods and govern genetic expression by describing their the pressing need for mathematical and tools that will help the development of operation through rigorous mathematical and computational tools to describe and design applications in the medical, pharma, energy, computational models. Second, they want synthetic genetic regulatory networks that need bio-remediation and bio-production sectors. to characterise and predict the interactions to operate within a specific context. ‘While between cells and the engineered genetic biological organisms have evolved networks The importance of synthetic biology is illustrated networks they host. And third, they are of impressive complexity, we are trying to by the significant increase in investments the expanding current state-of-the-art results identify and parametrise only what is essential field receives from around the world. In the in biocontrol theory to facilitate the design to adequately capture the behaviour of a given USA in 2016, more than $1 billion was invested and experimental realisation of predictable, system through abstract models,’ explains Stan. in synthetic biology companies, of which controllable and robust genetic systems. ‘We use these coarse-grained models to capture there were more than 400 (rising from 88 in rigorously observed biological phenomena 2001). Meanwhile, in the UK, there has been However, given the relative youth of the field and dynamic behaviours and, based on their significant investment in the field by the public and its inherent complexity, the group’s mathematical analysis, to optimise our designs.’ research councils. It is hoped that, by pooling aims are not without their challenges. ‘Some a community of experts from many different of the most important barriers are due to TOOLS, TECHNOLOGIES, FRAMEWORKS disciplines, the potential of this relatively new stochastic gene expression, cross talks Many of the projects that are currently field can be realised sooner rather than later – between native and non-native genetic parts, ongoing within the group’s laboratory are thereby accelerating growth across many sectors and burden due to limited shared cellular laying the groundwork for the future of of the bioeconomy, such as the pharmaceutical, resources,’ explains Stan. ‘In our work we are biological engineering by the development of healthcare, chemical, energy and food sectors. addressing these challenges by designing and genetic tools, foundational technologies and

78 www.impact.pub Through our collaborations, we develop cutting-edge biomolecular engineering methods and tools necessary to come up with solutions to the current challenges faced by the synthetic biology community

conceptual frameworks. One project is focused The complexity of living organisms realising on the development of predictable and robust the goals of the group as outlined above design methods for the engineering of complex requires a multitude of expertises to come Project Insights genetic systems (such as robust genetic together and work harmoniously. This is why FUNDING oscillators whose oscillation properties, such as the members of the group come from various UK Engineering and Physical Sciences amplitude and frequency, can be independently backgrounds like life sciences, engineering, Research Council (EPSRC) projects controlled). Another project is centred on maths and chemistry. The emergent outcome EP/M002187/1, EP/P009352/1 developing breakthrough technologies that of this interdisciplinary mix is what generates and EP/P02596X/1 • EU H2020- will take synthetic biology to the next level by novel possibilities for engineering biology in FETOPEN-2016-2017 project 766840 engineering biological functions and dynamic ways that could not be imagined before. behaviours at the multicellular level. And yet ADCADEMIC PARTNERS Massachusetts Institute of Technology another is concerned with creating whole-cell The group also collaborates with undergraduate- (USA) • Boston University (USA) • ETH Designing and controlling mathematical models that will improve the led research teams to great success. The Zurich (Switzerland) • University of Oxford predictability of genetic designs by considering International Genetically Engineered Machine (UK) • University College London (UK) • the interplay between synthetic circuits and (iGEM) competition is the largest undergraduate University of Edinburgh (UK) • University synthetic biology systems their host cells. synthetic biology competition globally, with of Manchester (UK) more than 300 teams from around the world In addition, the group is also conducting showcasing innovative ideas and projects INDUSTRIAL PARTNERS Microsoft Research (UK) • Lonza research that focuses on the practical covering a diverse range of societal challenges. In the Centre for Synthetic Biology at Imperial College London, the Control Engineering Synthetic Biology (Switzerland) • Synthace (UK) applications of synthetic biology – such as the In 2016, Imperial’s iGEM team, led by Stan, group is working to produce solutions to some of the most important challenges of our time investigation of methodologies that optimise pursued a foundational project tackling some of CONTACT the production of valuable recombinant the current core challenges facing the synthetic Dr Guy-Bart Stan In essence, synthetic biology aims to engineer BIOTECHNICAL SYSTEMS implementing novel control mechanisms that proteins in bacterial cells, and the combination biology community, and ultimately emerged Head of the Control Engineering biology. Similar to how classic engineering It is with the above in mind that the Control aim to automatically regulate the behaviour of 3D printing and synthetic biology to create victorious. ‘The undergraduate students Synthetic Biology group, Department of disciplines such as mechanical and electrical Engineering Synthetic Biology group was of a genetic system to meet our design novel 3D biosynthetic printing methods for identified a problem – namely that researchers Bioengineering, Imperial College London, South Kensington Campus, SW7 2AZ, engineering employ knowledge from maths established. Led by Dr Guy-Bart Stan and objectives.’ These novel control mechanisms manufacturing applications. in our Centre for Synthetic Biology had London, UK and physics to rationally design, model and based at Imperial College London, UK, the can be thought of as similar to a thermostat; difficulties maintaining stable co-cultures – build mechanical and electronic systems, group’s research focuses on exploring the just as a thermostat can detect discrepancies NOVEL POSSIBILITIES and proposed a solution, called ‘E.colibrium’ T: +44 2075946375 synthetic biology aims to rationally design modelling, analysis and design of biotechnical between the desired temperature and Given that the group’s vision is to bring (http://2016.igem.org/Team:Imperial_College), E: [email protected] and implement novel biological systems in systems, and developing engineering methods the actual temperature, a genetic control systems and control engineering principles to that involved creating a circuit that could W: http://www.bg.ic.ac.uk/research/ living cells. As such, its development and that will enable the design, control, mechanism can be designed to sense the the field of biology, it follows that they actively maintain two bacterial populations at a g.stan/group/ progression rely on researchers from a wide optimisation and easy implementation of deviation between the desired and actual levels collaborate with multiple research groups, both specific ratio,’ recalls Stan. ‘Our lab now BIO range of disciplines coming together in an novel biological systems in living cells. of a protein of interest. From there, the system within Imperial College London and around the continues to develop this idea of expanding Dr Guy-Bart Stan is a permanent can automatically downregulate or upregulate synthetic biology to microbial consortia and effort to solve some of the most important world. ‘Building relationships with academic academic member of staff and Co-Director challenges facing the world today. The Stan The work of the group falls within three major its expression to minimise the error. groups gives us the chance to use engineering we are currently looking into different ways of Research in the Department of group is working at the frontier between categories. First, they want to understand the concepts and develop novel bioengineering of building stable co-cultures and synthetic Bioengineering at Imperial College control engineering and synthetic biology dynamics and regulatory mechanisms that Another major challenge centres around methods aimed at efficiently building more ecosystems for a multitude of applications.’ London; the Head of the Control to create new bioengineering methods and govern genetic expression by describing their the pressing need for mathematical and reliable, robust and predictable systems,’ Engineering Synthetic Biology group; and tools that will help the development of operation through rigorous mathematical and computational tools to describe and design explains Stan. ‘Through our collaborations, we OPTIMISING ENGINEERED the Co-Director of the Imperial College Centre for Synthetic Biology (IC-CSynB). applications in the medical, pharma, energy, computational models. Second, they want synthetic genetic regulatory networks that need develop cutting-edge biomolecular engineering BIOLOGICAL SYSTEMS bio-remediation and bio-production sectors. to characterise and predict the interactions to operate within a specific context. ‘While methods and tools necessary to come up As it stands, synthetic biologists spend between cells and the engineered genetic biological organisms have evolved networks with solutions to the current challenges faced significant amounts of time and resources The importance of synthetic biology is illustrated networks they host. And third, they are of impressive complexity, we are trying to by the synthetic biology community.’ growing cell cultures and carefully engineering by the significant increase in investments the expanding current state-of-the-art results identify and parametrise only what is essential them to perform desired tasks. This can often field receives from around the world. In the in biocontrol theory to facilitate the design to adequately capture the behaviour of a given be a painstaking process, where systematic USA in 2016, more than $1 billion was invested and experimental realisation of predictable, system through abstract models,’ explains Stan. and exhaustive testing of numerous variables in synthetic biology companies, of which controllable and robust genetic systems. ‘We use these coarse-grained models to capture is required because of the lack of predictive there were more than 400 (rising from 88 in rigorously observed biological phenomena models which would allow them to accelerate 2001). Meanwhile, in the UK, there has been However, given the relative youth of the field and dynamic behaviours and, based on their and systematically explore the design space. By significant investment in the field by the public and its inherent complexity, the group’s mathematical analysis, to optimise our designs.’ bringing together biological and biomolecular research councils. It is hoped that, by pooling aims are not without their challenges. ‘Some engineering, rigorous characterisation and a community of experts from many different of the most important barriers are due to TOOLS, TECHNOLOGIES, FRAMEWORKS quantification of biology, and theoretical disciplines, the potential of this relatively new stochastic gene expression, cross talks Many of the projects that are currently and computational modelling, the Control field can be realised sooner rather than later – between native and non-native genetic parts, ongoing within the group’s laboratory are Engineering Synthetic Biology group strives thereby accelerating growth across many sectors and burden due to limited shared cellular laying the groundwork for the future of to accelerate the design-build-test-learn of the bioeconomy, such as the pharmaceutical, resources,’ explains Stan. ‘In our work we are biological engineering by the development of cycle for the realisation of optimally healthcare, chemical, energy and food sectors. addressing these challenges by designing and genetic tools, foundational technologies and Image courtesy of Ella Maru Studio engineered biological systems.

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