Small molecule drugs (e.g. antibiotics) have traditionally been the mainstay of treatments and therapies in man, however in the last 10-20 years protein based drugs (e.g. herceptin, which is often used to treat breast cancer) have developed to such a point that these now constitute a significant section of the pharmaceutical market. There are several categories of protein based drugs, one of which, monoclonal antibodies, constitutes the largest number of protein molecules in a class either in use or in clinical trials. Many protein based drugs are challenging to produce because they (a) require particular helper proteins to fold and assemble into their final active state and (b) are decorated on their surfaces by sugars and other molecules that are essential to their bioactivity. Due to the high precision required to produce biotherapeutics, such protein based drugs for the treatment of diseases are usually produced by cells kept in culture under defined conditions. One problem with this is that the cells we use to make proteins for therapeutic uses are not as efficient as we would like them to be and the cells respond to small changes in the environment in which they are grown. This can affect the consistency and quality of the final drug-substance or protein drug. As a consequence, we may not be able to produce enough of these drugs and/or the cost of producing them is too high. This proposal sets out to address a key area that underpins recombinant protein synthesis yields from mammalian cells in culture, the role of trace metals (e.g. magnesium, manganese, iron, zinc, copper, nickel, colbalt) in, and their influence upon, mammalian cell growth and therapeutic recombinant protein (rP) production. The concentrations of such trace metals in the solution in which cells are grown can impact upon the therapeutic protein drug quality (particularly how these impact upon safety and efficacy of the drug substance and batch-to-batch variation/reproducibility of the process used to manufacture it) and heterogeneity. During this project we will build upon the synergistic expertise of the applicants to develop and deliver new understanding of key metal biology related to the cellular processes that ultimately determine recombinant protein heterogeneity and yield from Chinese hamster ovary (CHO) cells. CHO cells are the current gold standard mammalian cell line used in industry to produce therapeutic recombinant proteins. The studies will, for the first time, investigate the role of metal biology extra- and intra-cellularly (both total metal ion concentrations and free/buffered when the metal is bound to proteins) in underpinning the phenotype of recombinant CHO cell lines and determine how metal concentrations, cellular flux, and metal transporters may be manipulated to provide culture processes with better process control (e.g. which metal ions to monitor when screening raw materials). This will lead to more consistent drug substance production, improved safety, efficacy and reduced costs/improved security of the supply chain and longer term with cell lines with enhanced industrial phenotypes e.g. increased and prolonged growth, reduced rP heterogeneity, improved glycosylation profiles. Without improved process control and expression systems the biotechnology/pharmaceutical industries will lack the capability to produce large enough amounts of these valuable and effective drugs to meet the demand at a price that is affordable for health care providers.

The engineering paradigm of measure, model, manipulate and manufacture underpins the design of products, processes and structures with reliable, predictable performance. The design process requires a detailed knowledge of what the interacting components are, how they interact and the forces (rules) that govern those interactions. This is why it was possible to send a man to the moon in 1969 (i.e. to predict functional performance based on known physical interactions) but not to cure cancer (unpredictability deriving from complex, unknown components and interactions). Accordingly, as we enter a new age of biological engineering, the extent to which it will be possible to engineer complex biological systems for human benefit will ultimately depend upon the extent of our knowledge of those systems - the rules that govern how the complex biological system functions - or malfunctions in the case of disease. To engineer any biological system effectively we need a basic blueprint - knowledge (or design principles) that helps us to understand specifically how that organism is functionally equipped. For biological engineers this primary information is an organism's complete DNA sequence (it's genome). For simple organisms such as bacteria the genome is relatively simple - only about 6000 genes (functional genetic units) in Escherichia coli for example. In human cells there are over 30,000 genes and a large amount of 'non-coding' DNA involved in regulation of these genes. Using microbial genome sequence information, bioengineers can for the first time truly engage in the engineering design process. New ways of measuring and modelling the complexity of simple bacterial systems have emerged (this is 'systems biology') which enables us to (genetically) manipulate cells and manufacture novel products and processes using new tools (this is 'synthetic biology'). Importantly, bioengineers can now predict the functional capability of simple bacteria growing in vitro using computer models. Similar approaches are now being developed for inherently more complex mammalian cells. This project is designed to provide a much needed genomic resource for academic and industrial bioscientists and bioengineers in the UK concerned with the production of a new generation of recombinant DNA derived medicines made by made by genetically engineered cells in culture - biopharmaceuticals. Biopharmaceuticals are proving to be revolutionary treatments for many serious diseases such as rheumatoid arthritis and a range of cancers. We want to determine the genome sequence of an extremely important type of 'cell factory' that is used to make these bio-medicines; the Chinese hamster ovary (CHO) cell. Most (60-70%) biophamaceuticals are currently made by genetically engineered CHO cells in culture as well as the vast majority of those in development. However, despite the huge industrial and scientific importance of this cell type, we still do not have the CHO cell's genome sequence: The fundamental informatic resource necessary to utilise new systems and synthetic biology tools to understand and engineer the function of this cell factory. To address this problem we have formed a consortium of the UK's leading academic groups involved in research into CHO cell based manufacturing systems based at the Universities of Kent, Manchester and Sheffield, and four key industrial partners involved in biopharmaceutical manufacturing in the UK. In this project we will utilise the most advanced DNA sequencing technology available to rapidly sequence, assemble and annotate the CHO cell genome. We will establish a network to disseminate this information and to determine how we might most effectively harness this resource for future engineering strategies to improve CHO-cell based production processes. This project is necessary for, and will lead to, cutting-edge applied research underpinning new biopharmaceutical manufacturing technology.

The broad theme of the research training addresses the most rapidly developing parts of the bio-centred pharmaceutical and healthcare biotech industry. It meets specific training needs defined by the industry-led bioProcessUK and the Association of British Pharmaceutical Industry. The Centre proposal aligns with the EPSRC Delivery Plan 2008/9 to 2010/11, which notes pharmaceuticals as one of the UK's most dynamic industries. The EPSRC Next-Generation Healthcare theme is to link appropriate engineering and physical science research to the work of healthcare partners for improved translation of research output into clinical products and services. We address this directly. The bio-centred pharmaceutical sector is composed of three parts which the Centre will address:- More selective small molecule drugs produced using biocatalysis integrated with chemistry;- Biopharmaceutical therapeutic proteins and vaccines;- Human cell-based therapies.In each case new bioprocessing challenges are now being posed by the use of extensive molecular engineering to enhance the clinical outcome and the training proposed addresses the new challenges. Though one of the UK's most research intensive industries, pharmaceuticals is under intense strain due to:- Increasing global competition from lower cost countries;- The greater difficulty of bringing through increasingly complex medicines, for many of which the process of production is more difficult; - Pressure by governments to reduce the price paid by easing entry of generic copies and reducing drug reimbursement levels. These developments demand constant innovation and the Industrial Doctorate Training Centre will address the intellectual development and rigorous training of those who will lead on bioprocessing aspects. The activity will be conducted alongside the EPSRC Innovative Manufacturing Research Centre for Bioprocessing which an international review concluded leads the world in its approach to an increasingly important area .

Regenerative medicine (RM) is a convergence of conventional pharmaceutical sciences, medical devices and surgical intervention employing novel cell and biomaterial based therapies. RM products replace or regenerate damaged or defective tissues such as skin, bone, and even more complex organs, to restore or establish normal function. They can also be used to improve drug testing and disease modelling. RM is an emerging industry with a unique opportunity to contribute to the health and wealth of the UK. It is a high value science-based manufacturing industry whose products will reduce the economic and social impact of an aging population and increasing chronic disease.The clinical and product opportunities for RM have become clear and a broad portfolio of products have now entered the translational pipeline from the science bench to commercialisation and clinical application. The primary current focus for firms introducing these products is first in man studies; however, success at this stage is followed by a requirement for a rapid expansion of delivery capability - the 'one-to-many' translation process. This demands increasing attention to regulatory pathways, product reimbursement and refinement of the business model, a point emphasised by recent regulatory decisions demanding more clarity in the criteria that define product performance, and regulator initiatives to improve control of manufacturing quality. The IMRC will reduce the attrition of businesses at this critical point in product development through an industry facing portfolio of business driven research activities focussed on these translational challenges. The IMRC will consist of a platform activity and two related research themes. The platform activity will incorporate studies designed to influence public policy, regulation and the value system; to explore highly speculative and high value ideas (particularly clinically driven studies); and manufacturing-led feasibility and pilot studies using state of the art production platforms and control. The research themes will focus on areas identified as particular bottlenecks in RM product translation. The first theme will explore the delivery, manufacturing and supply processes i.e. the end to end production of an RM product. Specifically this theme will explore using novel pharmaceutical technology to control the packaged environment of a living RM product during shipping, and the design of a modular solution for manufacturing different cell based therapies to the required quality in a clinical setting. The second research theme will apply quality by design methods to characterise the quality of highly complex RM products incorporating cells and carrier materials. In particular it will consider optical methods for non-invasive process and product quality control and physicochemical methods for process monitoring.The IMRC will be proactively managed under the direction of a Board and Liaison Group consisting of leading industrialists to ensure that the Centre delivers maximum value to the requirements of the business model and assisting the growth of this emerging industry.