Sensors permeate our society, measurement underpins quantitative action and standardized accurate measurements are a foundation of all commerce. The ability to measure parameters and sense phenomena with increasing precision has always led to dramatic advances in science and in technology - for example X-ray imaging, magnetic resonance imaging (MRI), interferometry and the scanning-tunneling microscope. Our rapidly growing understanding of how to engineer and control quantum systems vastly expands the limits of measurement and of sensing, opening up opportunities in radically alternative methods to the current state of the art in sensing. Through the developments proposed in this Fellowship, I aim to deliver sensors enhanced by the harnessing of unique quantum mechanical phenomena and principles inspired by insights into quantum physics to develop a series of prototypes with end-users. I plan to provide alternative approaches to the state of the art, to potentially reduce overall cost and dramatically increase capability, to reach new limits of precision measurement and to develop this technology for commercialization. Light is an excellent probe for sensing and measurement. Unique wavelength dependent absorption, and reemission of photons by atoms enable the properties of matter to be measured and the identification of constituent components. Interferometers provide ultra-sensitive measurement of optical path length changes on the nanometer-scale, translating to physical changes in distance, material expansion or sample density for example. However, for any canonical optical sensor, quantum mechanics predicts a fundamental limit of how much noise in such experiment can be suppressed - this is the so-called shot noise and is routinely observed as a noise floor when using a laser, the canonical "clean" source of radiation. By harnessing the quantum properties of light, it is possible reach precision beyond shot noise, enabling a new paradigm of precision sensors to be realized. Such quantum-enhanced sensors can use less light in the optical probe to gain the same level of precision in a conventional optical sensor. This enables, for example: the reduction of detrimental absorption in biological samples that can alter sample properties or damage it; the resolution of weak signals in trace gas detection; reduction of photon pressure in interferometry that can alter the measurement outcome; increase in precision when a limit of optical laser input is reached. Quantum-enhanced techniques are being used by the Laser Interferometer Gravitational Wave Observatory (LIGO) scientific collaboration to reach sub-shot noise precision interferometry of gravitational wave detection in kilometer-scale Michelson interferometers (GEO600). However, there is otherwise a distinct lack of practical devices that prove the potential of quantum-enhanced sensing as a disruptive technology for healthcare, precision manufacture, national security and commerce. For quantum-enhanced sensors to become small-scale, portable and therefore practical for an increased range of applications outside of the specialized quantum optics laboratory, it is clear that there is an urgent need to engineer an integrated optics platform, tailored to the needs of quantum-enhanced sensing. Requirements include robustness, miniaturization inherent phase stability and greater efficiency. Lithographic fabrication of much of the platform offers repeatable and affordable manufacture. My Fellowship proposal aims to bring together revolutionary quantum-enhanced sensing capabilities and photonic chip scale architectures. This will enable capabilities beyond the limits of classical physics for: absorbance spectroscopy, lab-on-chip interferometry and process tomography (revealing an unknown quantum process with fewer measurements and fewer probe photons).

Fibrosis of the lung is the gradual replacement of alveolar of air sacs with scar tissue that prevents the organ from carrying out efficient gas exchange and currently has no cure. Lung fibrosis can occur as a result of chronic disease such as idiopathic pulmonary fibrosis (IPF) or severe epithelial injury during respiratory infection. There are 6000 new cases of IPF each year in the UK, it is increasing in incidence and survival is only 3-5 years after diagnosis. Fibrosis remains one of the largest threats to health after recovery from COVID-19 and influenza. There is an urgent and unmet need to develop new therapies that can alter the progression of fibrosis. Repeated lung injury and an inability to repair properly play a central role in lung fibrosis, suggesting that repair processes could be important targets for therapy. Epithelial basal cells (BCs) are adult stem cells of the lung that can self-renew or differentiate to all types of lung epithelium after injury. They normally function to repair lungs efficiently, however recent studies suggest that basal cell function might be impaired in fibrosis. Further investigation is required to understand whether these cells can be manipulated to control how they function. Growth factors play an essential role in coordinating growth and regeneration of lung tissue. Fibroblast growth factor 7 (FGF7) binds specifically to FGF receptor 2-IIIb (FGFR2b) expressed only on epithelial cells including BCs to promote growth and differentiation. FGF7 has been shown to be dysregulated in lung fibrosis, as a result there is interest in supplementing FGF7 to promote repair and reduce fibrosis in the lung for disease modifying therapy. Delivery of FGF7 protein after lung injury in human and animal models has demonstrated its powerful influence on lung repair but it's use has been hindered because it must be delivered by intravenous injection which results in rapid elimination from the body, poor distribution to the lung and high toxicity. Synthetic messenger RNA (mRNA) is an emerging technology that instructs the body's own cells to produce a specific protein with transformative potential for how growth factors are applied clinically. Growth factors encoded by mRNA are being tested for heart and skin repair in humans but has never been attempted for the lung, partly due to challenges in delivery. We have previously developed materials to protect synthetic mRNA and facilitate its delivery into lung cells following nebulised delivery. This proposal will bring together our experience in mRNA delivery, with expertise in lung repair and fibrosis to investigate mRNA encoded growth factors as a novel strategy to guide lung repair after injury. In order to achieve our goal, we aim to address three key questions: 1. What is the influence of FGF7 mRNA on survival, proliferation and migration of human basal cells from normal and IPF lungs? 2. Can FGF7 mRNA promote differentiation of basal epithelial cells in human lung organoids? 3. Does local delivery of FGF7 mRNA reduce fibrosis and improve lung function following injury in a murine model? The outcomes of our research will be instrumental for the application of synthetic mRNA as a platform for protein production in the lung that could be broadly applied to different protein targets and will bring this pioneering technology closer to improving human health.

Chemistry is a dynamic subject that is at the centre of many different scientific advances. Organic chemistry is concerned with the reactivity of carbon in all its different forms and can be viewed as the chemistry taking place within living things. Chemists are constantly looking for new ways of designing and building molecules (synthetic chemistry is molecular architecture) and this proposal describes a short and powerful new way of making valuable molecules using a new type of catalyst. The molecules at the heart of the proposal are compounds containing a carbon-oxygen double bond (a carbonyl group) which have special properties and are the building blocks of many known pharmaceutical agents. The novel chemistry proposed here will provide a new, efficient and powerful way of making carbonyl compounds using catalysis to control all aspects of the structures of the products formed: this will be of great benefit to both academia and industry who will be able to make interesting molecules (some that were otherwise inaccessible) in new ways. Plans have also been made to screen the compounds that we make for a wide range of biological activity. Given all of the above, it is imperative that we have novel, efficient and powerful methods for making new carbonyl containing compounds so that we can study and use them. In addition, the development and application of new catalysts and catalytic systems is also important because catalysis makes chemical reactions run faster, and become cleaner with less waste: this is clearly a good thing for industry and also for the environment. The Fellowship aspect of this proposal is designed to allow the principal investigator the time to study and develop a new research direction. Plans have been made to interact and collaborate with other academics who can provide specialist knowlege and also with two project partners (one a multi-national pharmaceutical company and the other a leading academic in the United States of America) so that industrial problems and mechanistic details can be identified and addressed at all stages of the project. Three post-doctoral assistants will be employed to carry out the exprimental work, and the project will provide a thorough and comprehensive training in science and the attendant areas of communication/ presentation and creativity. This will equip them very well for the job market afterwards.

Cancer is a disease caused by accumulation of mutations that change the cancer cells in ways that allow them to avoid the normal restraints on their growth, survival and proliferation. Despite this simple truth understanding how mutations give cancer cells an advantage can be difficult to address yet is critical to creating strategies to kill cancer cells selectively. The major problems arise from the fact there are many changes in cancer cells that are merely reactions to the key driving events and actually make no difference to cancer progression. This project aims to understand how loss of a gene that normally resists cancer (PTEN) and is very commonly a key causal event in prostate cancer gives cancer cells an advantage. We have assembled a large amount of unpublished data using a combination of new genetic strategies to dissect signalling inside normal and cancerous mouse prostate cells. This work has revealed a totally unappreciated mechanism by which loss of PTEN can give prostate (or potentially other cell types in which PTEN is lost) new properties that help them avoid normal restraints on their growth, survival and proliferation. The mechanisms work like an in-built growth accelerator that partially bypasses the need for the driver to push on the gas pedal. We propose to do this work using a mouse model of cancer, and cultured cells derived from them, where it is possible to make single mutations and study their impacts in isolation from many other mutations and changes that have accumulated in human cancers. We will test if genetically removing the molecules that constitute the in-built accelerator mechanism slows cancer progression. Through this strategy we can build a detailed understanding of the key events causing or enabling cancer progression and hence focus efforts into creating new therapeutics into right places.

This application aims to catalyse and sustain a new dimension in UK research capability in physical organic chemistry. Our strategic alliance in physical organic chemistry will provide a unique continuum of expertise to tackle research opportunities in areas as diverse as materials chemistry, synthesis methodologies and pharmaceutical discovery and development. It will have the capability to address issues from solid-state to solution and gas-phase, from small molecules to biopolymers, and from nanoscale to pilot plant. We focus on topics of international significance to industry worldwide as well as to academic chemistry, that will help to (i) drive the creation of 21st-century electronic materials, devices and technologies (ii) understand and exploit methodologies for assisting chemical reactions with the potential to revolutionise energy use in chemicals and pharmaceuticals industries (iii) provide new and more effective medicines through understanding molecular recognition in pharmaceutical systems including drug-receptor, drug-drug and drug-carrier complexes. Its importance is underlined by the initial substantial support from diverse sectors of the chemicals and pharmaceuticals industry that we have so far put in place. It will initially lead to 26 new appointments, and we look forward to even more dynamic growth as the program unfolds.