Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

This proposal requests funding to purchase a sample probe and superconducting magnet to be used for a magnetic resonance spectrometry at the University of Birmingham for scientific research by a broad range of users from across the United Kingdom. This probe and magnet will be used to characterize the structures and interactions of animal, plant and microbial proteins and metabolites. This information will be used to understand the functions of these molecules in solutions similar to those in the interior of a living organism or cell. In order to obtain such information, very weak electromagnetic signals originating from the hydrogen, nitrogen and carbon atoms of the protein must be detected. The requested probe offers the highest possible level of sensitivity for these experiments, allowing researchers to observe molecules that are rare, difficult or expensive to produce, or insufficiently soluble or stable at the high concentrations required for NMR analysis. The cryogenic probe allows one to either lower the concentration of the sample or reduce the time required to obtain NMR spectra of proteins. New experiments that are otherwise precluded by sensitivity requirements can be used, allowing larger proteins and rare small molecules to be detected and data to be collected more quickly. The requested magnet offers the latest in superconducting technology at a magnetic field strength of 14 Tesla. This magnet offers excellent separation of the hydrogen, nitrogen and carbon signals, and represents the state-of-the-art standard for metabolomics and ligand discovery research. In addition this magnet is actively cooled and actively shielded, meaning that it recycles helium and does not require weekly maintenance, thus reducing manpower costs in an environmentally friendly manner. The research that would be enabled by this probe focuses on proteins and biochemical systems which are involved in regulation of cell growth, and the control of the metabolic and signalling pathways within several organisms. The organisms to be studied include food-borne pathogenic bacteria, models for genomics such as Dictyostelium, aphids and the Arabidopsis plant, zebrafish, and mammalian tissues including the human brain. The availability of this probe and magnet would be a major draw for new users, allowing more experiments to be performed, better quality data to be collected, and new projects initiated and supported within a new national facility used for internationally competitive research in the post-genomic sciences.

Miniaturisation of electronic devices has been matched in recent years by a drive to create miniature Lab-on-Chip systems that can handle and analyse chemical and biological materials in tiny volumes. Ultrasonic standing-wave fields are a promising technology that can potentially achieve many of the functions required for Lab-on-Chip systems, including: pumping, mixing, cell lysis, cell sorting, and sonoporation (opening pores in cell walls to allow drugs or genetic material to enter). Most importantly, by establishing and shaping the acoustic field bacteria and other biological cells can be manipulated and levitated within fluidic devices. In contrast to other technologies, it is possible to manipulate thousands of cells at once without harming them. However, controlling these various functions and preventing interactions in the confines of a microfluidic system is challenging and prevents wider uptake of these technologies. Research is required to better understand how secondary effects interfere with the primary functions. One example is the disruption of manipulation by acoustic streaming (a movement of the fluid itself induced by the ultrasound). Using novel techniques such as surface structuring I will enable the streaming flows to be controlled, and put to practical use (e.g. to enhance diffusion for cell perfusion, and analyte diffusion in sensor systems). Initial modelling suggests that this approach could enhance streaming by a factor of 10, leading to applications in other domains such as micro-cooling systems. I will be researching several other key areas: The mechanical stimulation of cells with acoustic forces to direct the development of mechanically responsive cells such as stem cells; the integration of ultrasonic arrays into microfluidic devices for enhanced flexibility of manipulation; and ways to integrate multiple acoustic functions within a single disposable device. The fundamental research will both enable and be driven by the second focus of the fellowship, applications. Two applications that each have the potential to transform existing technologies will be developed: 1) Bacterial detection in drinking water: My team has recently proven that bacteria (who typically experience forces 1000x smaller than human cells) can be successfully concentrated in flow-through ultrasonic devices. As part of a European project we have used this to concentrate the bacteria in samples of water to enhance the detection efficiency. However, I believe that we could deliver around a 100-fold increase in sensitivity by using the ultrasound to drive bacteria directly towards an antibody coated sensor surface where they will be captured and optically detected. Deploying such devices widely would be very beneficial for detecting contamination of drinking waters, rivers, and industrial waste streams. 2) Drug screening system: I will create a system that forms arrays of tiny clusters of human cells. Cells cultured in this 3D environment behave more naturally than those grown on a petri dish. The cells will be held in place by acoustic forces, both levitated away from contaminating surfaces, and also held against a steady flow of nutrients over a period of several days. Drugs will be introduced into the flow, and an integrated laser based detection system will monitor the resulting metabolites produced by the cells. The advantage of this is that large numbers of drugs can be tested in parallel, identifying those that could be further developed. A strong motivation for this application is that by providing a representative model of human tissues it could reduce the number of animal experiments required for drug testing. Given the huge potential impacts of these and other related systems I will work closely with industrial companies that have experience of creating detection and analytical systems to bring our technologies into widespread use.

In the UK, one in two people will be diagnosed with cancer during their lifetime and of those who survive, 41% can attribute their cure to a treatment including radiotherapy. Radiotherapy is very cost effective, accounting for only 6% of the total cost of cancer care in the UK. In radiotherapy the way the radiation dose is delivered and conformed to the tumour uses a treatment plan, which is based around a CT scan of the patient and their tumour. The treatment plan uses beams of radiation at different angles, to maximise the dose (and damage) to the tumour and to minimise the damage to the surrounding healthy tissue. Constraints are also applied for "organs at risk" which are often more sensitive to radiation and so require the dose to be as low as possible. Radiotherapy is normally delivered in fractions, with a fraction being typically 1-2 Gy. A course of radiotherapy is typically 1 fraction every week-day over a period of 4-6 weeks. Radiotherapy seeks to maximise the damage to the tumour (to sterilise it) while minimising the damage to the surrounding healthy tissue (to reduce side effects). In recent years radiotherapy has developed rapidly with the development of new machines and methodologies. These in turn, have resulted in better imaging, treatment planning and dosimetry, which enable the dose to be more accurately delivered and conformed to the tumour. This has resulted in better cancer survival and reduced side effects for patients. However, to maintain this rate of advancement and deliver even better treatments for patients we require innovation and solutions to the challenges, which still confront advanced RT. This is exactly where the STFC community can make an enormous impact, working in partnership with the clinical community, as they together they have exactly the skill set which is needed to effectively tackle these new challenges as they arise. In addition, the latest developments in radiotherapy - such as MR-linacs and proton therapy - evidence the need for the STFC community to work in partnership with the clinical community and commercial partners. If the UK is to remain competitive and deliver even better treatments for patients, and produce income and impact for the UK economy, it can no longer rely on serendipitous partnerships. This is what this Advanced Radiotherapy Network + (ARN+) seeks to address. Working actively with the clinical community through the National Cancer Research Institute (NCRI) Clinical and Translational working group on Radiotherapy (CTRad) it has been able to establish a new community drawn from across STFC with clinicians and clinical scientists from the NHS. This application is an extension of an existing successful ARN + and is aimed at both consolidating the success of the ARN+ and taking it one step further by developing a global dimension for its activities by working with the IAEA. It also seeks to showcase its activities to industry and develop a pipeline of innovation to the clinic. Finally it looks to work with STFC within the framework of UK Research and Innovation to build a national consensus, research roadmap and funding strategy in the field of Advanced Radiotherapy.

Synthetic biology accelerates the research and development of new biotechnologies by rigorously applying engineering design principles to the way we work with biological systems. The most prominent application of synthetic biology is the rational modification and redesign of living organisms like microbes for new efficient use in sectors such as energy production, biomaterials, biomedicine, drug production and food technology. Crucial to developing and applying synthetic biology is the rigorous quantification, modelling and analysis of synthetic biology designs. By using this engineering framework researchers aim to predict how engineered biological systems will operate. Despite many successes, it is still difficult to predict how engineered cells behave when new synthetic genetic information is added to these host cells. Key to the high failure rates in forward engineering in synthetic biology is the lack of high-quality data available on parts and devices. Without a holistic dataset reporting on performance of a biological part in its host cell, it is difficult to predict how it will behave when included in complex designs. The work proposed in this project seeks to address this by developing a novel workflow to obtain a richer-dataset on thousands of different parts and devices as they are implemented in bacterial host cells. To achieve this goal, a screening workflow will be established, that for the first time incorporates in vitro prototyping, with in vivo assaying and mass-spectrometry profiling to simultaneously capture how synthetic biology device design affects gene expression, expression load and host cell health, energy and growth. Measuring these multiple parameters in parallel will greatly enrich predictive models and ideally will lead to robust in silico predictions on performance characteristics such as growth rate and mutation likelihood. In this project, modelling will be developed specifically for this task and mass spectrometry will also be introduced as a state-of-the-art measurement tool. Both are new frontiers for synthetic biology. While this research will have a very wide impact and accelerate the many different future applications of synthetic biology, in this project it will be specifically used to tackle a high-value biomaterials application that would be unlikely to succeed without the strong engineering foundations this work provides. For this part of the project, predictions of gene expression and growth will be used to express a library of different functional proteins in engineered microbes and microbial consortia that can then be polymerised together to generate polyprotein biomaterials with programmable catalytic and material properties. For example, by combining silk proteins with lipase enzymes in biological polymers, advanced materials such as self-cleaning fabrics can be realised. While this materials work is intended as a showcase for the foundational methods developed in this project, it will no doubt lead to many future exciting applications and new industries in a rich variety of commercial, engineering and research sectors, from fashion and manufacturing to medicine.