CONTEXT OF THE RESEARCH: An ability to deliver biologically active molecules (drugs, DNA and proteins) to specified cells either in the lab or the body would impact on many branches of biology and medicine. Imagine being able to selectively find and destroy diseased cells; or "simply" to test the effectiveness of a new drug inside a range of cells before animal and human trials? Unfortunately, there is no general solution to this problem of delivering bioactive molecules within cells, and even bespoke true solutions are few and far between. The problem is not straightforward, and is best illustrated by how biology has evolved viruses to do this. Viruses are astonishing natural nanoscale packages, usually termed virions. Though they come in many types, all virions perform three functions: (1) they recognise often specific cell types, which they do by presenting molecules on their surfaces to recognize molecules on the target cells; (2) they penetrate the outer barriers of the cell; and (3) they deliver a payload, which is the genetic information to make more virus in the host cell. Functions (1) and (2) are performed by the viral coats, or capsids. Not surprisingly, many people have tried to mimic these structures to deliver payloads other than RNA and DNA. AIMS, OBJECTIVES AND ASPIRATIONS OF THE RESEARCH: The overall ambition of the proposed work is to produce hollow, cage-like particles that have the diameter of about one hundredth the width of a human hair, so-called SAGE particles. We will do this in a modular way, using small versions of proteins called peptides. Each peptide module will have a specific function to mimic one the properties of virions: one set will be made to recognize specific cell types; another will be used to construct the casing of the particles; and the third set will carry the biologically active payloads. On their own, these modules would not be useful at all. However, if combined correctly they could assemble into virus-like particles, but without the (deadly) RNA and DNA cargo, instead they would contain drugs or useful proteins. To do this we will build on a multidisciplinary team of chemists, biochemists, cell biologists and molecular modellers that has delivered the SAGE particles. The physical scientists will work together to design and make the assemblies of molecules, and then work with the biologists to test and visualise how they interact with cells and deliver their payloads. POTENTIAL APPLICATIONS AND BENEFITS: Throughout the research, we will work with a company, Syntaxin, interested in targeting and killing particular diseased cell types in the body. As well as providing reagents and know-how, this partnership will encourage real-life applications, and thus clear and practical end points for our research. In this way, we will explore both the fundamentals of SAGE assembly and engineering, and potential applications of functional SAGEs in cell biology and medicine. Broadly speaking, this modular and systematic approach to constructing complex biological molecules, assemblies and systems is called "synthetic biology". The aim and spirit of synthetic biology is to make the engineering of biological systems easier (that is, systematic, quick, and predictable) and ultimately to make useful functions and products. For example, synthetic biology is being recognised as increasingly important to generate new medicines, biofuels and fine chemicals. It is being invested in by Government and Research Councils, with the aim of developing the field sufficiently to be of direct benefit to the UK (biotech) industry and economy. One of the key aspects of our proposal is that it fits with this spirit and these aspirations: we aim to make a toolkit of different modules for each of the above three properties; in this way, modules could be combined rapidly, reliably and with predictable outcomes to generate different particles for targeting and tackling different cells and diseases.

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.

In the 1980s it began to be possible to produce potentially unlimited quantities of human proteins by placing the gene defining them in a simple organism such as yeast. From this grew a new kind of medicine capable of treating conditions such as severe arthritis, haemophilia, growth deficiency, and some cancers that previously had no satisfactory treatments. As well as having great clinical value the resulting technology has become the basis of a new and fastest growing part of the pharmaceutical industry, described as biopharmaceuticals. Because the molecules involved are proteins, they are orders of magnitude larger and more complex than conventional drugs such as aspirin and their processing is much more demanding. They are also so complex that they cannot in general be characterised with precision except in relation to the methods by which they are made. That means the capacity to precisely define such processes is critical to clinical safety and commercial success. Full scale trials of the processes are so costly they can only be conducted once clinical promise is established but, given the number of factors governing processing of even first generation products, there have often been hold-ups so extensive as to delay availability to patients. UCL has pioneered micro scale methods that are sufficiently good at predicting efficient conditions for large scale performance that far fewer and better focussed large scale trials suffice. That resolves part of the problem but an even greater challenge is now emerging. The early biopharmaceuticals were in general the easiest ones to produce. The final scales were also relatively modest. Now, the next generation of biopharmaceuticals are more complex materials and with rising demand the scales are far larger so that processes push the boundaries of the possible. The combined complexity of the product and the process with so many variables to consider means that the managers need better systematic means of supporting their decisions. Already the cost of developing a single biopharmaceutical can exceed 0.7 billion and take 10 years. With more advanced biopharmaceuticals these figures tend to rise and yet the world's governments are facing a healthcare cost crisis with more older people. They therefore exert pressure on companies to reduce prices. Because the public wishes to have medicines that do not pose risks, regulations become ever more stringent so they are a major factor in defining the bioprocess. This also adds to the need for managers to have sector-specific decisional-support aids well grounded in the detailed engineering of the processes. Finally, it is now possible to apply molecular engineering to proteins and vaccines to enhance their therapeutic properties but this can also cause serious bioprocessing problems. The research vision developed with detailed input from UK industry experts will apply these methods as the foundation for another step change whereby much faster and lower cost information can be gathered and integrated with advanced decisional techniques to give managers a better foundation on which to base their policies. The academic team from leading UK universities provides the necessary continuum of skills needed to assess the ease of manufacture of novel drugs, the costs of processing and of delivery to patients. We will work with companies to test the outcomes to ensure they are well proven prior to use on new biopharmaceuticals. This will cut costs so that all the patients who might benefit can receive them and at the earliest possible date achieved within the severely restricted budgets now available to the NHS.