Proteins control almost all biochemical processes in the human body. These biological macromolecules are encoded in our DNA, which is first transcribed to mRNA and subsequently translated to proteins. Traditional small molecule pharmaceuticals are designed to selectively bind to a target protein in order to modulate its function. While this approach has proven very powerful, there are numerous diseases which are difficult or not possible to treat in this manner. In recent years, a new class of drug molecules called nucleic acid therapeutics (NATs) have emerged which offer a potentially versatile approach for the treatment of a wide range of genetic disorders and diseases. These molecules are short modified DNA sequences which are designed to bind to mRNA and directly modulate the production of disease related proteins. Existing methods of producing NATs rely on chemical synthesis, which requires large excesses of expensive reagents, huge volumes of organic solvent (1 ton of acetonitrile per Kg of product) and deliver the final products with low yield and modest (~90%) purity. Reactions are performed on solid supports or columns, which limits the process scalability meaning that these methods are only suitable for producing oligonucleotides in <10 Kg batches. These limitations have not been a major problem for the manufacture of NATs currently on the market, as these have been limited to the treatment of rare diseases and are therefore produced in low volumes. However, a large volume cholesterol lowering drug called Inclisarin was recently approved and there are several hundred NATs under evaluation in clinical trials for the treatment of common diseases. As current chemical methods are not suitable for the large (tonne) scale synthesis of NATs, it is now essential that we develop new, sustainable, scalable and versatile manufacturing strategies for their production. In this application, we will develop a green, cost-efficient and truly versatile biocatalytic platform for manufacturing NATs and their nucleotide triphosphate (NTP) building blocks. Biocatalysis is an exciting technology which is widely used across the chemical industry, whereby enzymes (nature's own catalysts) are used to convert starting materials into high-value products. Compared to natural DNA, NATs contain chemical modifications which are designed to improve their efficacy, selectivity and metabolic stability. These chemical modifications are not well tolerated by natural enzymes, however using a technology called directed evolution we are able to quickly engineer enzymes to modify their functions and optimise their properties making them suitable for practical applications. We will use combinations of different engineered enzymes to firstly access NTP building blocks, which will be used in subsequent biocatalytic reactions to produce NATs. We will then compare NATs produced using our approaches to those produced with standard chemical approaches, using state of the art analytical techniques combined with biological validation assays. The technologies developed will allow efficient, sustainable and cost-effective manufacturing of NATs in high purity, thus allowing this important new drug modality to realise its full potential for the treatment of a wide-range of diseases.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

In spite of its challenging properties, the utilization of graphene for technical applications still demands considerable efforts in developing dedicated processing methods, which have a potential to be adapted and finally utilized for industrial scale device manufacturing. Among the processes which have been investigated so far, chemical vapour deposition of graphene on copper, where copper acts as a catalyst to facilitate the growth of single layered graphene - appears to be one the most promising approaches. Although extensively studied, there are issues with this process related to quality, reproducibility and yield, which are connected to the lack of control of the interface between copper and graphene. Within the process, which we will be able to tackle these issues in a more controllable way by a combined in-situ deposition system, where copper and other possible metals are deposited within one vacuum system together with the graphene CVD, i.e without exposing the sample to an ambient environment. Like for 2D Ga-Al-As semiconductor heterostructures, the control of the interfaces on an atomic length scale by means of an in-situ multilayer deposition process is expected to be the pathway which will enable the ultilization of graphene's unqiue properties within manufacturable device structures. In spite of this potential, we feel the full integration of graphene into CMOS technology, although being extremely challenging on the long term - still has a very long way to go and may even be impossible without fundamentally different processing approaches. However, sensor technologies as a whole are mostly based on hybrid solutions, where the sensor itself - even chip based in some cases - is still separated from the CMOS digital electronic by flip chip, wire bonding or simple by conventional wiring. A widely used example of high indutrial impact are piezoelectric sensors, where the high processing temperature of the lead-zirconium-titanate ceramics are incompatible with CMOS processing conditions. Based on this philosophy, we believe that the in-situ growing approach for metal-graphene multilayers, as envisaged to be developed within this project, will enable a significant improvement of existing sensor concepts and the realization and manufacturing of new sensor concepts. Based on the expertise of our scientific partners within Imperial College and NPL and our associated partners from industry, we will focus on biosensor applications, where graphene - as carbon based material - is particularly challenging as bio-interface. As - from the point of view of process technology -the most simple approach, graphene coated copper electrodes will have a potential for radiofrequency - microwave - terahertz biosensor, where copper will outperform gold due to lower conduction losses and graphene provides the interface to the biomolecules and cells. As a second step on a scale of increasing complexity of process technology, we believe that a sacrificial layer process for arbitrary shaped free standing graphene membranes and (sub)micro scale flexural beam is a realistic development goal. This technology will enable the development of arrays of nanomechanical sensors, based on the exceptional mechanical properties of graphene. Apart from sensor applications, graphene- based NEMS structures are challenging objects for the refinement and exploration of metrology for nanotechnology and biology, as being pursued by our collaborators from NPL. The recently discovered confined plasmon-polariton excitations - originating from the unique electronic properties of graphene - are currently one of the hottest topic within the graphene research community. We believe, that the tailored free standing structures we will be able to manufacture with this deposition kit, will pave the way to explore and finally utilize this unique optical - infrared properties of graphene for novel sensor applications.

We propose to use recently developed technologies and sequence information to create and trial a novel transcriptomics-based resource for the wheat community. This resource, which will be fully upgradable without further cost to the community, will consist of a wheat array capable of monitoring the expression of up to 90,000 different homoeolog and paralog transcripts. This approach will remove many of the seen and unseen problems associated with the existing GeneChip and EST-based platforms and will be a valuable source of new and novel information on the formation of Triteace polyploids and the differential expression of the three different genomes that make up allohexaploid wheat. We propose to open up this resource to the entire wheat community as an unencumbered facility free of MTAs and follow on IP agreements.

The last decade has seen a significant shift in the way computers are designed. Up to the turn of the millennium advances in performance were achieved by making a single processor, which could execute a single program at a time, go faster, usually by increasing the frequency of its clock signal. But shortly after the turn of the millennium it became clear that this approach was running into a brick wall - the faster clock meant the processor got hotter, and the amount of heat that can be dissipated in a silicon chip before it fails is limited; that limit was approaching rapidly! Quite suddenly several high-profile projects were cancelled and the industry found a new approach to higher performance. Instead of making one processor go ever faster, the number of processor cores could be increased. Multi-core processors had arrived: first dual core, then quad-core, and so on. As microchip manufacturing capability continues to increase the number of transistors that can be integrated on a single chip, the number of cores continues to rise, and now multi-core is giving way to many-core systems - processors with 10s of cores, running 10s of programs at the same time. This all seems fine at the hardware level - more transistors means more cores - but this change from one to many programs running at the same time has caused many difficulties for the programmers who develop applications for these new systems. Writing a program that runs on a single core is much better understood than writing a program that is actually 10s of programs running at the same time, interacting with each other in complex and hard-to-predict ways. To make life for the programmer even harder, with many-core systems it is often best not to make all the cores identical; instead, heterogeneous many-core systems offer the promise of much higher efficiency with specialised cores handling specialised parts of the overall program, but this is even harder for the programmer to manage. The Programme of projects we plan to undertake will bring the most advanced techniques in computer science to bear on this complex problem, focussing particularly on how we can optimise the hardware and software configurations together to address the important application domain of 3D scene understanding. This will enable a future smart phone fitted with a camera to scan a scene and not only to store the picture it sees, but also to understand that the scene includes a house, a tree, and a moving car. In the course of addressing this application we expect to learn a lot about optimising many-core systems that will have wider applicability too, and the prospect of making future electronic products more efficient, more capable, and more useful.