Synthetic Biology is the engineering of biology. In this spirit, this Fellowship aims at combining control engineering methodology and expertise with synthetic biology current know-how to solve important real-world problems of high industrial and societal importance. Anticipated high-impact applications of synthetic biology range from cell-based diagnostics and therapies for treating human diseases, to efficiently transforming feedstocks into fuels or biochemicals, to biosensing, bioremediation or production of advanced biomaterials. Central to tackling these problems is the development of in-cell automatic feedback control mechanisms ensuring robust functionality and performance of engineered cells that need to operate under uncertain and changing environments. The availability of methods for designing and implementing feedback control mechanisms that yield improved robustness, efficiency and performance is one of the key factors behind the tremendous advances in engineering fields such as transportation, industrial production and energy. As in these and other engineering disciplines, systems and control engineering will accelerate the development of high-impact synthetic biology applications of societal, commercial and industrial importance. In particular, through this Fellowship, I propose a comprehensive engineering approach to push forward the robustness frontier in synthetic biology towards reliable cell-based biotechnology and biomedicine. This ambitious goal requires: (1) the development of feedback mechanisms to reduce the footprint of engineered metabolic pathways on their cell "chassis", (2) the development of system-level feedback mechanisms to robustly and efficiently manage one or more synthetic devices in the context of whole-cell fitness, and (3) the development of synthetic cell-based systems designed to restore and maintain the extra-cellular concentration of some biomolecules within tight homeostatic bounds. These three aspects define three work packages in my Fellowship. Each work package on its own tackles important synthetic biology challenges for real-world applications, while their combination in WP4 aims towards robust cell-based biotechnology and biomedicine. The corresponding work packages are: *WP1*: Automatic management of fluxes for robust and efficient metabolic pathways (through genetic-metabolic feedback control) *WP2*: Automatic management of cellular burden for robust and efficient whole-cell behaviour (through host-circuit feedback control) *WP3*: Automatic management of extra-cellular concentrations for robust homeostatic regulation of environmental conditions (through cell-environment feedback control) *WP4*: System integration and combination of the feedback control mechanisms developed in WP 1-3 The first two work packages address device robustness to cellular context, while the third addresses robust adaptation to and control of changing environmental conditions. WP4 will use and further develop the systems and control engineering framework developed in WP 1-3 to explore the synergistic combination of the proposed feedback control mechanisms. By providing systematic engineering solutions that endow engineered biosystems with robust functionalities, we will enable the enhancement of existing biotechnological processes and the reliable development of industrial applications to improve health and quality of life. Through the above, this Fellowship will foster strong and long-lasting economic and societal impact in the UK and globally and promote knowledge-based UK leadership.

Synthetic Biology is the underpinning discipline for advances in the UK bioeconomy, a sector currently worth ~£200Bn GVA globally. It is a technology base that is revolutionising methods of working in the biotechnology sector and has been the subject of important Government Roadmaps and supported by significant UKRI investments through the Synthetic Biology for Growth programme. This is now leading to a vibrant translational landscape with many start-ups taking advantage of the rapidly evolving technology landscape and traditional industries seeking to embed new working practices. We have sought evidence from key industry leaders within the emerging technology space and received a clear and consistent response that there is a significant deficit of suitably trained PhDs that can bridge the gap between biological understanding and data science. Our vision is a CDT with an integrative training programme that covers experimentation, coding, data science and entrepreneurship applied to the design, realisation and optimisation of novel biological systems for diverse applications: BioDesign Engineers. It directly addresses the priority area 'Engineering for the Bioeconomy' and has the potential to underpin growth across many sectors of the bioeconomy including pharmaceutical, healthcare, chemical, energy, and food. This CDT will bring together three world-leading academic institutions, Imperial College London (Imperial), University of Manchester (UoM) and University College London (UCL) with a wide portfolio of industrial partners to create an integrated approach to training the next generation of visionary BioDesign Engineers. Our CDT will focus on providing an optimal training environment together with a rigorous interdisciplinary program of cohort-based training and research, so that students are equipped to address complex questions at the cutting edge of the field. It will provide the highly-skilled workforce required by this emerging industry and establish a network of future UK Bioindustry leaders. The joint location of the CDT in London and Manchester will provide a strong dynamic link between the SE England biotech cluster and the Northern Powerhouse. Our vision, which brings together a BioDesign perspective with Engineering expertise, can only be delivered by an outstanding and proven grouping of internationally renowned researchers. We have a supervisor pool of 66 world class researchers that span the associated disciplines and have a demonstrated commitment to interdisciplinary research and training. Furthermore, students will work directly with the London and Manchester DNA Foundries, embedding the next generation bioscience technologies and automation in their training and working practices. Cohort training will be delivered through a common first year MRes at Imperial College London, with students following a 3-month taught programme and a 9-month research project at one of the 3 participating institutions. Cohort and industry stakeholder engagement will be ensured through bespoke training and CDT activities that will take place every 6 months during the entire 4-year span of the programme and include multi-year group hackathons, training in responsible research and innovation, PhD research symposia, industry research days, and entrepreneurial skills training. Through this ambitious cohort-based training, we will deliver PhD-level BioDesign Engineers that can bridge the gap between rigorous engineering, efficient model-based design, in-depth cellular and biomolecular knowledge, high throughput automation and data science for the realisation and exploitation of engineered biological systems. This unique cohort-based training platform will create the next generation of visionaries and leaders needed to accelerate growth of the UK bioeconomy.

The Covid-19 pandemic continues to take a huge toll - an estimated 6.3m people have died including 178,000 in the UK. Globally 1.6bn students have missed school, 250m people will be pushed into extreme poverty and economic losses are estimated at £12tr. History shows that epidemic and pandemic threats constantly emerge, whilst SARS-CoV-2 continues to mutate as it becomes endemic. It is clear that major losses could be prevented by sustained domestic investment in public health. Work undertaken within Vax-Hub1 on responsive technologies and accelerated quality control methods enabled rapid development and manufacture of the ChAdOx1 vectored vaccine against SARS-CoV-2 (licensed for emergency use in December 2020 via a non-profit partnership with AstraZeneca). Over 2.9bn doses have now been released in 180 countries. The UK had a leading role during the pandemic and the proposed Hub builds on this success to advance novel research on a broader range of technologies. Working closely with stakeholders, Vax-Hub will enable the UK to be better prepared for the next pandemic. This investment into The Future Vaccine Manufacturing Hub will enable our vision to make the UK the global centre for vaccine discovery, development and manufacture. The Vaccine Manufacturing Hub brings together a world-class multidisciplinary team with decades of cumulative experience in all aspects of vaccine design and manufacturing research. This Hub will bring academia, industry, not-for-profit organizations and policy makers together to propose radical change in vaccine development and manufacturing technologies, building on a technological innovation culture. The Hub will enhance future vaccine manufacturing through (i) de-risked manufacture of new vaccines by strategically innovating for a selected range of the most promising platform technologies (established and novel/disruptive); (ii) developing manufacturing options that improve the product quality and so immunogenicity; (iii) streamlined manufacturing process development with novel responsive solutions and advanced digitalisation strategies; (iii) a focus on enhancing stability and needle-free administration routes so they become a reality within the lifetime of the Hub. The proposed Hub would be the natural location for early-stage research before projects are transferred to a GMP manufacturing facility. The work focuses on development of improved vaccine platforms which can be flexible enough to be used for multiple product manufacture. These improved vaccine technologies are used as case studies to test rapid and responsive development tools to create a whole process mimicking vaccine manufacture, which could be easily and quickly deployed in case of epidemic/pandemic scenario. Finally the research focuses on standard and novel adjuvants to make mucosal delivery a reality, thus allowing alternative route to injection for mass administration. The Hub will establish the UK as the global centre for end-to-end vaccine research and manufacture. Additionally, vaccines should be considered a national security priority, as it is evident that diseases do not respect international boundaries, thus this work into capacity building and rapid response is a significant advantage. The impact of this Hub will be felt internationally, as the UK reaffirms its leadership in Global Health and works to ensure that the outputs of this Hub reach the global community and the most vulnerable, especially children.

The UK government recognises that 'our economy is driven by high levels of skills and creativity' and has prioritised investment in skills as a means to recovery rapidly from the current economic downturn (HM Government: New Industry, New Jobs, 2009). Bioprocessing skills underpin the controlled culture of cells and microorganisms and the design of safe, environmentally friendly and cost-effective bio-manufacturing processes. Such skills are generic and are increasingly being applied in the chemical, pharmaceutical and regenerative medicine sectors. Recent reports, however, highlight specific skills shortages that constrain the UK's capacity to capitalise on opportunities for wealth and job creation in these areas. They emphasise the need for bioprocessing skills related to the application of 'mathematical skills... to biological sciences', in core bioprocess operations such as 'fermentation' and 'downstream processing' and, for many engineering graduates 'inadequate practical experience'. UK companies have reported specific problems in 'finding creative people to work in fermentation and downstream processing' (ABPI: Sustaining the Skills Pipeline, 2005 & 2008) and in finding individuals capable of addressing 'challenges that arise with scaling-up production using biological materials' (Industrial Biotechnology Innovation and Growth Team report: Maximising UK Opportunities from Industrial Biotechnology, 2009). Bioprocessing skills are also scarce internationally. Many UK companies have noted 'the difficulties experienced in recruiting post-graduates and graduates conversant with bioprocessing skills is widespread and is further exaggerated by the pull from overseas (Bioscience Innovation and Growth Team report: Bioscience 2015, 2003 & 2009 update). The EPSRC Industrial Doctorate Centre (IDC) in Bioprocess Engineering Leadership has a successful track record of equipping graduate scientists and engineers with the bioprocessing skills needed by UK industry. It will deliver a 'whole bioprocess' training theme based around fermentation and downstream processing skills which will benefit from access to a superbly equipped £25M bioprocess pilot plant. The programme is designed to accelerate graduates into doctoral research and to build a multidisciplinary research cohort. Many of the advanced bioprocessing modules will be delivered via our MBI Training Programme which benefits from input by some 70 industry experts annually (www.ucl.ac.uk/biochemeng/industry/mbi). Research projects will be carried out in collaboration with many of the leading UK chemical and pharmaceutical companies. The IDC will also play an important role supporting research activities within biotechnology-based small to medium size enterprises (SMEs). The need for the IDC is evidenced by the fact that the vast majority of EngD graduates progress to relevant bioindustry careers upon graduation. This proposal will enable the IDC to train the next generation of bioindustry leaders capable of exploiting rapid progress in the underpinning biological sciences. Advances in Synthetic Biology in particular now enable the rational design of biological systems to utilise sustainable sources of raw materials and for improved manufacturing efficiency. These will lead to benefits in the production of chemicals and biofuels, in the synthesis of chemical and biological pharmaceuticals and in the culture of cells for therapy. The next generation of IDC graduates will also possess a better understand of the global context in which UK companies must now operate. This will be achieved by providing each EngD researcher with international placement opportunities and new training pathways either in bioprocess enterprise and innovation or in manufacturing excellence. In this way we will provide the best UK science and engineering graduates with internationally leading research and training opportunities and so contribute to the future success of the UK bioprocess industries.

The UK government's support for the Life Sciences Industry Strategy (Bell Report, 2017) recognises the importance of developing new medicines to facilitate UK economic growth. Examples include new antibody therapies for the treatment of cancer, new vaccines to control the spread of infectious diseases and the emergence of cell and gene therapies to cure previously untreatable conditions such as blindness and dementia. Bioprocessing skills underpin the safe, cost-effective and environmentally friendly manufacture of this next generation of complex biological products. They facilitate the rapid translation of life science discoveries into the new medicines that will benefit the patients that need them. Recent reports, however, highlight specific skills shortages that constrain the UK's capacity to capitalise on opportunities for wealth and job creation in these areas. They emphasise the need for 'more individuals trained in advanced manufacturing' and for individuals with bioprocessing skills who can address the 'challenges with scaling-up production using biological materials'. The UCL EPSRC CDT in Bioprocess Engineering Leadership has a successful track record of equipping graduate scientists and engineers with the bioprocessing skills needed by industry. It will deliver a 'whole bioprocess' training theme based around the core fermentation and downstream processing skills underpinning medicines manufacture. The programme is designed to accelerate graduates into doctoral research and to build a multidisciplinary research cohort; this will be enhanced through a partnership with the Synthesis and Solid State Pharmaceutical Centre (SSPC) and the National Institute for Bioprocess Research and Training (NIBRT) in Ireland. Research projects will be carried out in partnership with leading UK and international companies. The continued need for the CDT is evidenced by the fact that 96% of previous graduates have progressed to relevant bioindustry careers and many are now in senior leadership positions. The next generation of molecular or cellular medicines will be increasingly complex and hence difficult to characterise. This means they will be considerably more difficult to manufacture at large scale making it harder to ensure they are not only safe but also cost-effective. This proposal will enable the CDT to train future bioindustry leaders who possess the theoretical knowledge and practical and commercial skills necessary to manufacture this next generation of complex biological medicines. This will be achieved by aligning each researcher with internationally leading research teams and developing individual training and career development programmes. In this way the CDT will contribute to the future success of the UK's bioprocess-using industries.