Chronic pain is a global health problem which affects approximately 30% of all adults. Current therapies have limitations in their effectiveness or side effects therefore there is an urgent need to develop more precise and effective forms of medication for individual pain causing conditions. The search for new drugs has been hampered by the lack of methods to translate early identification of promising molecules into clinically effective treatments - for example, to date much of the research needed to show drug effectiveness has been carried out in animal models which don't always show the same pain response as humans. We will address this problem by establishing and validating a laboratory model of pain causing mechanisms that was developed by Pfizer before its withdrawal from the pain treatment market and the UK as a whole. This model was developed by one of the other co-applicants on this proposal (James Bilsland) and uses nerve cells made from induced pluripotent stem cells that were themselves generated from patients who suffer from a rare but debilitating pain condition called erythromelalgia. The nerve cells that detect pain in these patients are hypersensitive - that is they produce signals that the brain interprets as pain much more easily than those of normal people. We call this phenomenon "hyperexcitability" and our aim is to identify chemical compounds which can reduce the rate ease with which erythromelalgia derived nerve cells can produce pain signals. Naturally this would be extremely valuable for erythromelalgia patients but identifying compounds to stop hyperexcitability could be much more important since there is a lot of evidence that this phenomenon contributes significantly to a lot of other pain causing conditions. In short, if we find pain killing drugs using our proposed method, they are likely to be effective against pain of many types.

Many existing challenges, from personalized health care to energy production and storage, require the design and manufacture of new molecules. However, identifying new molecules with desired properties is difficult and time-consuming. We aim at accelerating this process by exploiting advances in data availability, computing power, and AI. We will create generative models of molecules that operate by placing atoms in 3D space. These are more realistic and can produce better predictions than alternative approaches based on molecular graphs. Our models will guarantee that the generated molecules are synthetically accessible upfront. This will be achieved by mirroring realistic real-world processes for molecule generation where reactants are first selected, and then combined into more complex molecules via chemical reactions. Additionally, our methods will be reliable, by accounting for uncertainty in parameter estimation, and data-efficient, by jointly learning from different data sources. Our contributions will have a broad impact on materials science, leading to more effective flow batteries, solar cell components, and organic light-emitting diodes. We will also contribute to accelerate the drug discovery process, leading to more economic and effective drugs that can significantly improve the health and lifestyle of millions.

Vaccines are the most successful public health initiative of the 20th century. They save millions of lives annually, add billions to the global economy and extended life expectancy by an average of 30 years. Even so, the UN estimates that globally 6 million children each year die before their 5th birthday. While vaccines do exist to prevent these deaths, it is limitations in manufacturing capacity, technology, costs and logistics that prevent us for reaching the most vulnerable. The UK is a world leader in vaccine research and has played a significant leadership role in several public health emergencies, most notably the Swine Flu pandemic in 2009 and the recent Ebola outbreak in West Africa. While major investment has been made into early vaccine discovery - this has not been matched in the manufacturing sciences or capacity. Consequently, leading UK scientists are forced to turn overseas to commercialise their products. Therefore, this investment into The Future Vaccine Manufacturing Hub will enable our vision to make the UK the global centre for vaccine discovery, development and manufacture. We will create a vaccine manufacturing hub that brings together a world-class multidisciplinary team with decades of cumulative experience in all aspects of vaccine design and manufacturing research. This Hub will bring academia, industry and policy makers together to propose radical change in vaccine development and manufacturing technologies, such that the outputs are suitable for Low and Middle Income Countries. The vaccine manufacturing challenges faced by the industry are to (i) decrease time to market, (ii) guarantee long lasting supply - especially of older, legacy vaccine, (iii) reduce the risk of failure in moving between different vaccine types, scales of manufacture and locations, (iv) mitigating costs and (v) responding to threats and future epidemics or pandemics. This work is further complicated as there is no generic vaccine type or manufacturing approach suitable for all diseases and scenarios. Therefore this manufacturing Hub will research generic tools and technologies that are widely applicable to a range of existing and future vaccines. The work will focus on two main research themes (A) Tools and Technologies to de-risk scale-up and enable rapid response, and (B) Economic and Operational Tools for uninterrupted, low cost supply of vaccines. The first research theme seeks to create devices that can predict if a vaccine can be scaled-up for commercial manufacture before committing resources for development. It will include funds to study highly efficient purification systems, to drive costs down and use genetic tools to increase vaccine titres. Work in novel thermo-stable formulations will minimise vaccine wastage and ensure that vaccines survive the distribution chain. The second research theme will aim to demystify the economics of vaccine development and distribution and allow the identification of critical cost bottlenecks to drive research priorities. It will also assess the impact of the advances made in the first research theme to ensure that the final cost of the vaccine is suitable for the developing world. The Hub will be a boon for the UK, as this research into generic tools and technologies will be applicable for medical products intended for the UK and ensure that prices remain accessible for the NHS. It will establish the UK as the international centre for end-to-end vaccine research and manufacture. Additionally, vaccines should be considered a national security priority, as diseases do not respect international boundaries, thus this work into capacity building and rapid response is a significant advantage. The impact of this Hub will be felt internationally, as the UK reaffirms its leadership in Global Health and works to ensure that the outputs of this Hub reach the most vulnerable, especially children.

Over the next few decades, quantum computing (QC) will transform the way we design new materials, plan complex logistics and solve a wide range of problems that conventional computers cannot address. The Hub for Quantum Computing via Integrated and Interconnected Implementations (QCI3) brings together >50 investigators across 20 universities to address key challenges, and deliver applications across diverse areas of engineering and science. We will work with 27 industrial partners, the National Quantum Computing Centre, the National Physical Laboratory, academia, regulators, Government and the wider community to achieve our goals. The Hub will focus on where collaborative academic research can make transformative progress across three interconnected themes: (T1) developing integrated quantum computers, (T2) connecting quantum computers, and (T3) developing applications for them. Objectives for each are outlined below. (T1) Developing integrated quantum computing systems, with a goal of creating quantum processors that will show real utility for specific problem examples. Objectives: OB1.1: Demonstrate quantum advantage in analogue platforms with neutral atoms and photons OB1.2: Make neutral atom quantum simulation platforms available in the cloud OB1.3: Develop new applications for these and other near-term systems (T2) A key challenge of building the million qubit machines of the future is that of 'wiring' together the quantum processors that will create such a machine. The Hub will develop technologies that help achieve this and develop models to understand how such machines will scale. Objectives : OB2.1: Develop interconnect technologies for quantum processors OB2.2: Demonstrate blind computing and multi-component networks with trapped ion quantum computers OB2.3: Demonstrate transduction and networking of superconducting processors (T3) Developing applications in science and engineering, including materials design, chemistry and fluid dynamics. Objectives: OB3.1: Develop new methods for materials and chemical system modelling and design, fluid dynamics, and quantum machine learning OB3.2: Identify the nearest routes to quantum advantage for these application areas OB3.3: Develop implementations of these algorithms on T1 and T2 Hardware These will be supported by work in overarching tools (T4) that can be used across the themes of the Hub, including error correction, digital twins, verification and software stack optimisation. Skills and training Hub partners will work with end-users, our students and researchers, and partners across the UK National Quantum Technologies Programme (UKNQTP) to ensure members of the Hub have the skills they need. Specific objectives include: Provide training in innovation, commercialisation and IP, Equality, Diversity and Inclusion and Responsible Research and Innovation (RRI) to Hub partners Provide reports and training to end-users, working in partnership with the NQCC and others Continue to provide advocacy and advice to policy makers, through work in such areas as RRI Exploitation and Engagement: The Hub will build on the strong engagement activities of the UK programme, further developing the technology pipeline. We will play a key role in strengthening and expanding the UK ecosystem through events, networking and education. Specific goals are to: Broaden the partnership of the Hub, bringing new academic, government and industrial partners into the Hub network Contribute to regulation and governance through programmes of work in standards and RRI, and close collaboration with UKNQTP partners Support the generation and protection of intellectual property within the Hub, and its exploitation Develop Hub and cross-Hub outreach initiatives, working with the RRI team, to help ensure the potential of quantum computing for societal benefit can be realised

Lung diseases are a major global health burden. 300 million people live with asthma worldwide and it is predicted that chronic obstructive pulmonary disease will become the third-leading cause of death by 2020. The inhalation of therapeutic aerosols is a familiar medical strategy to treat lung diseases. Aerosol therapy can also achieve high antibiotic concentrations in the lung to treat infections. When aerosols are targeted into the deep lung, inhaled therapy also provides a means to achieve systemic concentrations of active pharmaceutical ingredients and avoid the need for injections of drugs that are destroyed in the gastrointestinal tract, such as insulin. Despite its potential, many patients fail to gain the full benefits of inhaled therapies in treating lung disease, and systemic drug delivery has failed to achieve the market break-through it deserves. Some of the ineffectiveness arises from the inability of patients to use their therapy correctly. However, achieving aerosol deposition in the lungs is a major challenge even for those patients with good inhaler technique. The challenge is to produce a portable dosage form containing components that can be redispersed by a patient. Redispersion must be achieved with uniformity of a dose in the form of an aerosol with the properties required for lung penetration. Turning potentially inhalable particles into formulated products that can be manufactured reproducibly, and that achieve consistent aerosolization performance between different patients poses many challenges that are poorly-solved. Consensus meetings of industrial, academic and regulatory experts in the field of inhaled medicine have identified the need to improve control and consistency of drug deposition performance. Additionally there is a need to improve our understanding of how and why the characteristics of starting materials interact with the manufacturing conditions to lead to inter-batch and inter-patient variability in aerosol characteristics. At the heart of the challenge is the fact that the very property of the particles that makes them suitable for inhalation (their small size which, at less than 5 microns, is less than the diameter of a human hair) also causes them to clump together as agglomerates. Theme 1 of the project will employ synthonic engineering (a computer modelling technique based on the molecular structures of pharmaceutical ingredients) to achieve new abilities to predict agglomeration behaviour early in development, and the interactions of agglomerate materials with inactive ingredients in the formulation. Theme 2 will use new measurement techniques that image how agglomerates interact with each other in powders to develop an understanding and characterize how the agglomerate phase in a formulation leads to inter-patient or inter-batch variability of product performance. Theme 3 will underpin the knowledge gained from powder imaging to assess the underlying causes of agglomeration. Better, integrated experimental measurement techniques will be developed to characterize the material properties that regulate the extent and strength of interactions between particles. Theme 4 focuses on developing new computational models to characterize the behaviour of agglomerated powders during the mechanical processes occurring when a patient breathes through an inhaler, and when powders are processed during manufacturing. The final component of the project is to integrate the knowledge gained in Themes 1-4 to engineer quality into a range of test products selected by an advisory panel. This will be achieved by using the prediction and measurement techniques to inform formulation scientists, device designers and process engineers of the steps that are appropriate to mitigate the effects of agglomeration on product performance. The ultimate goal is to use the techniques developed to translate the therapeutic benefits for patients using inhaled medicines from molecules to manufactured products.