This proposal bids for £4.5M to both evolve and renew the Loughborough, Nottingham and Keele EPSRC CDT in Regenerative Medicine. The proposal falls within the 'Healthcare Technologies' theme and 'Regenerative Medicine' priority of the EPSRC call. This unique CDT is fully integrated across three leading UK Universities with complementary research profiles and a long track record of successful collaboration delivering fundamental and translational research. Cohorts of students will be trained in the core scientific, transferable, and translational skills needed to work in this emerging healthcare industry. Students will be engaged in strategic and high quality research programmes designed to address the major clinical and industrial challenges in the field. The CDT will deliver the necessary people and enabling technologies for the UK to continue to lead in this emerging worldwide industry.The multidisciplinary nature of Regenerative Medicine is fully captured in our proposal combining engineering, biology and healthcare thereby spanning the remits of the BBSRC and MRC, in addition to meeting EPSRC's priority area.

By 2025 targeted biological medicines, personalised and stratified, will transform the precision of healthcare prescription, improve patient care and quality of life. Novel manufacturing solutions have to be created if this is to happen. This is the unique challenge we shall tackle. The current "one-size-fits-all" approach to drug development is being challenged by the growing ability to target therapies to only those patients most likely to respond well (stratified medicines), and to even create therapies for each individual (personalised medicines). Over the last ten years our understanding of the nature of disease has been transformed by revolutionary advances in genetics and molecular biology. Increasingly, treatment with drugs that are targeted to specific biomarkers, will be given only to patient populations identified as having those biomarkers, using companion diagnostic or genetic screening tests; thus enabling stratified medicine. For some indications, engineered cell and gene therapies are offering the promise of truly personalised medicine, where the therapy itself is derived at least partly from the individual patient. In the future the need will be to supply many more drug products, each targeted to relatively small patient populations. Presently there is a lack of existing technology and infrastructure to do this, and current methods will be unsustainable. These and other emerging advanced therapies will have a critical role in a new era of precision targeted-medicines. All will have to be made economically for healthcare systems under extreme financial pressure. The implications for health and UK society well-being are profound There are already a small number of targeted therapies on the market including Herceptin for breast cancer patients with the HER2 receptor and engineered T-cell therapies for acute lymphoblastic leukaemia. A much greater number of targeted therapies will be developed in the next decade, with some addressing diseases for which there is not currently a cure. To cope, the industry will need to create smarter systems for production and supply to increasingly fragmented markets, and to learn from other sectors. Concepts will need to address specific challenges presented by complex products, of processes and facilities capable of manufacture at smaller scales, and supply chains with the agility to cope with fluctuating demands and high levels of uncertainty. Innovative bioprocessing modes, not currently feasible for large-scale manufacturing, could potentially replace traditional manufacturing routes for stratified medicines, while simultaneously reducing process development time. Pressure to reduce development costs and time, to improve manufacturing efficiency, and to control the costs of supply, will be significant and will likely become the differentiating factor for commercialisation. We will create the technologies, skill-sets and trained personnel needed to enable UK manufacturers to deliver the promise of advanced medical precision and patient screening. The Future Targeted Healthcare Manufacturing Hub and its research and translational spokes will network with industrial users to create and apply the necessary novel methods of process development and manufacture. Hub tools will transform supply chain economics for targeted healthcare, and novel manufacturing, formulation and control technologies for stratified and personalised medicines. The Hub will herald a shift in manufacturing practice, provide the engineering infrastructure needed for sustainable healthcare. The UK economy and Society Wellbeing will gain from enhanced international competitiveness.

The ability to reprogram a cell to direct the packaging of specific molecules into discrete membrane envelopes is a major objective for synthetic biology. This controlled packaging into membrane vesicles will allow biologists to create a plethora of new technologies, which could be applied in both biotechnology and medical industries. These include the generation of novel metabolic factories within a cell for energy production; for rapidly packaging toxic proteins into contained environments before they have a chance to harm any normal metabolic activities, so they can be purified for use in subsequent pharmaceutical applications; the creation of protective packages filled with difficult to isolate biomolecules, which can be kept in stable environment to allow their storage and purification; and also generate simple vehicles for delivery of drugs and vaccines to the patient. Here, we provide a simple and cost effective solution to the problem. We have discovered a method to program a simple cell to create membrane packages which can be filled with different molecules of interest. We have not only discovered a way to fine-tune the shape of the membrane package (e.g. into long tubular matrices or spherical vesicles), but we have also devised controllable mechanisms that either keep the package within, or secrete the package out of the cell. Thus we have therefore made a landmark breakthrough in synthetic biology research. A major aim of this BBSRC key strategic area is to design from new and improve on natural systems and exploit these for the production of commercially important chemicals and biotherapeutics, which is what we have achieved here. Our overall aim in this project is to make use of these exciting discoveries to modify cells, making them capable of creating membrane bound packages filled with any protein of interest, which can then either be secreted from the cell and isolated from the culture media using a simple one step filtration technique, or stored within the cell where it can be made to act as a metabolic micro-factories, producing useful and/or valuable molecules without intoxicating the cells. In this way we hope to develop new ways to produce fine and platform chemicals as well as biotherapeutics. Through the research described in this application we are certain that we will be able to contribute to the development of new sustainable approaches for generating biotherapeutics, which will be assimilated into production techniques by diverse bio-industries.

Biological drugs (e.g. monoclonal antibodies, MAbs) based on recombinant DNA technology have transformed the treatment of life-limiting diseases including cancer, haemophilia and rheumatoid arthritis. The recent explosive growth in the biologics sector looks set to continue, with growing applications in precision medicine and personalised healthcare, and there are many new complex biologics in the drug discovery pipeline (e.g. bispecific, trispecific, and conjugated MAbs). The intrinsic complexity of these life-saving drugs is too challenging for synthesis by simple chemistry and requires the utilisation of living cells. Forcing cells to produce proteins that they do not naturally express is complex, and often requires a long period of trial and error cell manipulation, making the bio-manufacturing process time-consuming and very expensive and directly impacting on the delivery of transformative medicines to patients. With the recent remarkable development of powerful tools for editing mammalian genomes, new methods and automation for the synthesis of large numbers of DNA constructs, and the context provided by systems biology, the time is now right for using Synthetic Biology to establish a new paradigm for cost-effective manufacture of biologic drugs. In turn this will have a major impact on medicine and the health related industries, and make the biopharmaceutical value chain more cost-efficient. The scale of the economic opportunity associated with this project is enormous. The UK has one of the most dynamic and innovative healthcare industries in the world and has developed over 20% of the world's top 100 selling drugs. The medical technology sector in the UK consists of around 2,800 companies, employing 52,000 people and generating around £10.6bn of turnover annually. An increasing portion of all medicines, currently estimated at 20%, are biopharmaceuticals. The global biologics market was valued at an estimated $251.5 billion in 2018 and is predicted to reach $319 billion by 2021. The CHO cell is the most widely used industrial expression system, which generates ~70% of approved and marketed therapeutic recombinant proteins, including multiple monoclonal antibodies (mAbs), so any enhancement of production efficiency and quality has a huge economic impact. The vision of this prosperity partnership is to utilise state of the art investigational tools and synthetic biology approaches to both elucidate the intricacies of the CHO cell manufacturing platform and engineer it to be more predictive, effective, cost-efficient, and competitive for the production of biotherapeutics in the UK.

The bioprocess industry manufactures novel macromolecular drugs, proteins, to address a broad range of chronic and debilitating human diseases. The complexity of these protein-based drugs brings them significant potential in terms of potency against disease, but they are also much more labile and challenging to manufacture than traditional chemical drugs. This challenge is continuing to increase rapidly as novel technologies emerge and make their way into new therapies, such as proteins conjugated to chemical drug entities, DNA, RNA or lipids, or fusions of multiple proteins, which increase their potency and targeted delivery in patients. The UK holds a leading position in developing and manufacturing new therapies by virtue of its science base and has unique university capabilities underpinning the sector. Whilst revenues are large, ~£110bn in 2009 on a worldwide basis, there are huge pressures on the industry for change if demands for healthcare cost reduction and waste minimisation are to be met, and populations are to benefit from the most potent drugs becoming available. A sea change in manufacturing will be needed over the next decade if the potential of modern drugs are to make their way through to widespread distribution. Moreover there is a widely accepted skills shortage of individuals with fundamental "blue-skies" thinking capability, yet also with the manufacturing research training needed for the sector. The proposed EPSRC CDT will deliver a national capability for training the next generation of highly skilled future leaders and bioprocess manufacturing researchers for the UK biopharmaceutical sector. They will be capable of translating new scientific advances both in manufacturing technologies and new classes of macromolecular products into safely produced, more selective, therapies for currently intractable conditions at affordable costs. This is seen as essential where the rapid evolution of biopharmaceuticals and their manufacturing will have major implications for future medicine. The CDT will be a national resource linked to the EPSRC Centre for Innovative Manufacturing (CIM) in Emergent Macromolecular Therapies (EP/I033270/1), which aims to tackle new process engineering, product stability, and product analysis challenges that arise when manufacturing complex therapies based on radically new chemistry and molecular biology. The CDT will embed PhD students into the vibrant research community of the top UK Institutions, with collaborations overseen by the EPSRC CIM, to enable exploration of new process engineering, modelling, analysis, formulation and drug delivery techniques, and novel therapies (e.g. fusion proteins, and chemical drugs conjugated to antibodies), as they emerge from the international science and engineering community. Alignment to the EPSRC CIM will ensure projects strategically address key bioprocess manufacturing challenges identified by the industrial user group, while providing a cohort-based training environment that draws on the research excellence of the ESPRC CIM to maximise impact and knowledge transfer from collaborative partners to research led companies.