IMPERIAL COLLEGE LONDON

UKRI Gateway to Research · FY 2024 · 2024-11

The reliance of the human race on plastic materials has now resulted in a global pandemic where billions of ton of plastic waste have been deposited. As this degrades, micro-plastic particles (MPs) are generated that have now become ubiquitous in the environment, being found in water sources, food chains, air and dust. In addition, everyday objects such as textiles and plastic bottles and kettles have been shown to shed MPs. Numerous studies have shown that MPs in the oceans negatively impact the health of fish and estimates suggested 70% of the fish consumed by humans contains MPs. While the health impact of MPs on humans has yet to be established, we are now exposed to MPs on a daily basis and recent landmark studies have now identified MPs in human tissues, blood and thrombi surgically removed from patients. The exact significance of this is unknown, however studies using commercial polystyrene beads have showed interaction with vascular components highlighting the potential for MPs to interfere with normal vascular and haemostatic function and a study in mice suggested that MPs promoted the risk of cardiovascular disease (CVD). It is therefore likely that MPs will play a causative role in the pathogenesis of human CVD. To investigate this we have prepared MPs more closely resembling those in nature and found that they enhanced thrombus and fibrin clot formation in vitro and could activate the endothelial cells that line the blood vessels making them more pro-inflammatory and pro-thrombotic. In this proposed study we will generate microplastic particles and subject them to weather and chemical modification processes mimicking those found in the environment. We will then investigate the impact of these on components of the haemostatic and vascular system; endothelial cells, platelets and coagulation factors and use physiological assays to determine how MPs affect thrombosis, coagulation and inflammation at gene, protein and functional levels. The results obtained from this study will give the first systematic insight into how MPs can affect key parts of the vascular system and will provide invaluable insight into the vascular health implications of bioavailable plastic. This is turn will lead to better understanding of a growing problem which has the potential to significantly affect human health for the current and future generations. We also anticipate that our date will improve public awareness of plastic usage and direct manufactures and key policy makers to avoid plastics that can lead to long term cardiovascular health issues.

UKRI Gateway to Research · FY 2024 · 2024-11

ComeInCell will establish a novel integrated Synthetic Cell platform to provide cost- and resource-efficient, environmentally friendly, widely applicable and quantitative model systems to elucidate key cellular mechanisms of health and disease based on the integration of condensate and membrane models. Understanding membrane-condensate interactions is vital for deciphering their functional roles in cellular processes. Our consortium employs synthetic vesicles as model systems to explore these interactions. These tailor-made mimics of cellular compartments offer a platform for studying membrane dynamics and the impact of compartmentalization on the activity of reaction networks and the assembly of complex machinery. We will design synthetic cells as life-science prototyping tools to decipher the role of membrane-associated condensates in essential cellular processes linked to membrane transport, membrane transformation, metabolic networks, and repair. The network will confront global challenges, providing solutions in drug development, therapeutics, green-related issues, and synthetic biology. Our goal is to equip junior scientists with cross-disciplinary expertise for developing integrated synthetic cellular testbeds encompassing condensates and membranes, revolutionizing prototyping systems. We will train the next generation of biophysicists, biochemists and bioengineers in rigorous quantitative and mechanistic thinking, while establishing strong ties to young and emerging European SMEs in the health sector for efficient dissemination towards new therapies

UKRI Gateway to Research · FY 2024 · 2024-11

Molecular chirality plays an important role in chemical reactivity, has direct implications throughout the pharmaceutical and agrochemical industries, and is rapidly becoming an important asset for nanotechnology. But our ability to trigger different chemical reactions in the left and right enantiomers of a chiral molecule using light is extremely limited. The goal of this proposal is to leverage modern light sources to achieve potentially disruptive breakthroughs as well as to improve our fundamental understanding of highly enantioselective photochemistry. Multiphoton coherent control promises a plausible route towards this goal and pioneering experiments using microwaves to drive rotational transitions have taken important steps in this direction. But rotational excitations do not lead to the nuclear rearrangement required for photochemistry and the method cannot be scaled to liquid samples, where applications are most relevant. Thus, photochemistry requires replacing rotational transitions by electronic transitions, which in turn requries bridging a monumental gap in terms of energy scales and complexity, going from ~0.0001 eV to ~10 eV and from rigid rotors to complex multielectron polyatomic systems. Recent results show that this transition is far from trivial and taking into account variations of the field as a function of position is crucial. The first general objective of this proposal is to provide a theoretical demonstration of all- optical highly enantioselective photochemistry using realistic fields. The second general objective of this proposal is to explore the possibilities offered by approaching enantioselective photochemistry from the time-domain perspective (enantioselective charge migration) taking advantage of intense and ultrashort X-ray sources (XFELs).

UKRI Gateway to Research · FY 2024 · 2024-11

The principal objective of DANIO-ReCODE is to provide world-class doctoral training to a new generation of early-career researchers interested in understanding the complex and multilayered process of tissue regeneration. DANIO-ReCODE will combine the multidisciplinary expertise of 15 research laboratories at renowned EU and UK scientific institutions to unravel the regulatory mechanisms of heart, brain, and eye regeneration by employing the unique and highly tractable zebrafish model system. Unlike humans, teleosts can repair damaged tissues or even regrow entire appendages. In mammals, regeneration is rare, limited to skin, liver, and toes. Regenerative medicine, however, promises to restore tissue function via the use of stem cells, tissue engineering, and the production of artificial organs, with its importance being recognised as one of the EU strategic missions. A fundamental gap of knowledge is the understanding of the shared and distinct regulatory mechanisms defining regeneration in highly regenerative species and those with lower regeneration potential such as mammals. Since the vertebrate gene complement is highly conserved, applying the knowledge of regeneration mechanisms from non-mammalian models such as zebrafish could identify genetic underpinnings, which when manipulated in mammals, could strongly boost the mammalian regenerative potential. DANIO-ReCODE will thus nurture a cohort of exceptional doctoral candidates and turn them into interdisciplinary experts in computational and developmental biology, providing comprehensive training that spans experimental work, bioinformatics, visualisation, and industry applications. Through the integration of state-of-the-art genomics, computational, and data visualisation techniques, DANIO-ReCODE will result in an enhanced understanding of molecular determinants implicated in vertebrate regenerative processes while providing new avenues for the repair or replacement of damaged or diseased tissues and organs.

UKRI Gateway to Research · FY 2024 · 2024-11

Liver disease is one of the leading causes of premature death, accounting for 3.7% of total mortality and over 10,000 lives in the UK each year. A small but significant proportion of these deaths are due to inherited genetic defects in metabolic genes whose expression is restricted to the liver's main cell type, the hepatocyte. This group of diseases is known as the "inherited metabolic disorders" of the liver or IMDs. Despite progress in advanced therapeutics such as gene therapy, the only curative option for these patients remains a liver transplant. Unfortunately, the demand for liver transplantation is still far greater than the number of available donor livers and many patients, often children, do not find a donor in time. An alternative approach currently under development involves transplantation of cells instead of whole organs. Hepatocytes isolated from healthy donor tissue (primary human hepatocytes; PHH) successfully repopulate the livers of IMD patients as well as non-human disease models. Unfortunately, as with whole organ transplantation, donor scarcity prevents wider use of PHH in routine clinical practice. Pluripotent stem cell-derived hepatocytes (PSC-Heps) represent an exciting new approach to address this problem since they can be potentially produced in unlimited quantities and used in all patients without the need for harmful immunosuppression. We previously developed a robust methodology for generating hepatocytes from clinical grade induced (iPSC) and embryonic (ESC) pluripotent stem cells but unlike PHH, PSC-Heps did not work in our non-human models and are therefore unlikely to work in patients. Why is this the case? PHH transplants used in patients turn out to be a mixture of mature, highly functional hepatocytes and specific extracellular molecules. Our overarching hypothesis is that iPSC-Hep therapy is therefore failing right now due to (1) a lack of essential extracellular components and (2) the sub-optimal maturity of the hepatocytes being produced. Together, these factors prevent donor iPSC-Heps repopulating the host liver as non-cancerous entities and their downstream use in humans. Our objective in this project is to apply advances we have made in both the domains of biomechanical engineering and hepatocyte maturation to study extracellular and intracellular mechanisms regulating donor cell repopulation in vivo. It is hoped that the outcomes from these experiments will generate the critical preclinical data needed to move iPSC-Heps towards the clinic. The primary beneficiaries of this project will accordingly be patients with IMDs and researchers in cell therapy.

UKRI Gateway to Research · FY 2024 · 2024-11

A swine influenza virus caused the 2009 pandemic. Among all influenza viruses, swine influenza viruses are those considered to have greatest chance of causing the next pandemic, particularly one strain called 'Eurasian avian-like swine influenza virus H1N1' , EAH1N1. EAH1N1 originally jumped from birds into pigs in the late 1970s where it has circulated ever since. EAH1N1 is among the most prevalent swine influenza viruses in Europe and China, where it circulates alongside descendants of the 2009 pandemic influenza virus (pH1N1) - which jumped back into pigs shortly after 2009. In many places EAH1N1 and pH1N1 have exchanged genes generating viruses that may have even higher pandemic potential. In this proposal we aim to better understand how influenza viruses jump into, and adapt to new hosts, using EAH1N1 as a specific example. Additionally, we will risk assess different EAH1N1 viruses from around the world to determine if certain strains may be more likely to become future pandemics. Finally, we want to identify host proteins that these viruses rely on to efficiently infect their host, with the long-term strategy of using these identified proteins to generate gene-edited animals which are resistant to influenza virus. This work will be undertaken using a mix of phylogenetics and bioinformatics to choose relevant current strains to test, and to identify mutations in circulating viruses associated with mammalian adaptation. We will generate recombinant viruses for a comprehensively risk assessment and to validate if the mutations that we identified enhance replication in swine or human cells. This work will involve studies in primary cells and transmission studies in pigs, or in ferrets which are the gold standard model for airborne transmissibility of influenza viruses in humans. We will also perform large scale screens using technology such as CRISPR to identify proteins in pigs which are responsible for efficient virus replication or adaptation. Identification of these proteins will pave the way to future strategies for controlling these viruses in pigs, for example by using targeted gene-editing technology to generate pigs which are resistant to influenza infection. This UK/China collaboration brings together scientists from two of the biggest pig producers in the world (China and Europe), which both have high levels of circulating swine influenza viruses to work on a global problem with a timely and comprehensive approach. This will allow for a globally relevant risk assessment to be undertaken, and proper comparisons of viruses from the different continents to be made. This work will be valuable to both the agricultural industry, but also public health bodies and those preparing for future pandemics.

UKRI Gateway to Research · FY 2024 · 2024-11

Every single cell in our body displays on its surface a layer of sugars (glycans) that mediate interactions with pathogens, the immune system, and neighbouring cells. Glycans are commonly linked to proteins as their most abundant and complex modification. Thereby, glycans change the physical and biological properties of proteins and "fine-tune" their function in our body. Unsurprisingly, slight dysfunctions in the machinery that makes glycans can lead to severe disease. In contrast to other biomolecules, sugars are not directly encoded in the genome. Instead, they are synthesized by molecular machines called enzymes from simple building blocks. Hundreds of enzymes work together to manifest glycans in the right composition for a cell to function, usually as glycan "trees" with multiple building blocks being linked to each other. Among the manifold glycan types, so-called O-mannosyl (O-Man) glycans are perhaps the least understood type despite being of critical importance in physiology. O-Man glycans appear to be especially prevalent in the brain and other neuronal tissues, which suggests a special function in neurobiology. Dysfunctions in the biosynthesis of O-Man glycans are strongly linked to neuronal disorders such as abnormal brain development and muscular dystrophies. However, it is largely unclear how neuronal processes are conferred by these glycans because of a lack of suitable methods to investigate them. For instance, it is currently very challenging to understand how different parts of the same protein can carry O-Man glycans with different "trees" from different enzymatic processes. We know that three enzymes called POMGNT1, POMGNT2 and MGAT5B are important for decision-making of the right glycan "tree". But we do not know how these enzymes compete or collaborate with each other as well as with the hundreds of other enzymes in the cell. We also lack understanding on how individual, physiologically relevant glycan attachment sites are chosen by each enzyme. To understand how POMGNT1, POMGNT2 and MGAT5B function, we will develop chemical reporter tools that are specifically used by one of the enzymes. In our design, we will engineer each of the enzymes to transfer a sugar modified with a chemical tag to target proteins. The tag is amenable to bioorthogonal or "Click" chemistry, a concept that has been awarded the 2022 Nobel Prize in Chemistry. Using the bioorthogonal tag, we can adorn the sugars with a moiety that can be easily tracked or isolated, for instance a fluorescent molecule or a handle for glycoprotein enrichment. This tactic allows us to study which positions on which proteins are modified by which of the enzymes by employing cutting-edge instrumentation in mass spectrometry. Chemical tools are thus used to gain essential understanding in physiology. In an international collaboration, our work will establish a map of the fine details of O-Man glycans, with future applications in patient-relevant cells and organoids to probe which substrates these enzymes modify in a disease context. We have only in recent years gained the know-how needed to deliver on this project, underpinning the timeliness of our work. The project exactly matches the BBSRC scope to develop tools and technology underpinning biological research, and the scope to unravel some of the untapped potential of the glycosciences fits in the context of frontier bioscience to understand the rules of life. The postholders will be embedded in a diverse, supportive lab environment and experience outstanding multidisciplinary training opportunities.

UKRI Gateway to Research · FY 2024 · 2024-11

This funding application is for a 2-year extension to the MRC CARP (MR/V037315/1) project. This project aims to understand more about how transplanted lungs are damaged by infection. Survival following lung transplant is low compared to liver/kidney transplants. The most common causes of death are infection and chronic lung allograft dysfunction (CLAD). CLAD is often called "organ rejection". It is now understood however that this is an over-simplification. Infection can cause CLAD. Infection is far more common in transplanted lungs than in other transplanted organs because lungs are exposed to the air. It is a major reason why survival rates are lower in lung transplant patients. Some lung transplant patients live healthily for many years without developing CLAD. Other patients seem much more likely to develop CLAD. Doctors do not know why this is. Some patients develop CLAD in response to infection, but others do not. Limited understanding of the causes of CLAD makes it very difficult to treat. The immune system of the body produces immune cells. These cells can fight infection and reject transplanted organs. The original project used state-of-the-art techniques to measure over 2000 immune cell markers in blood samples and lung washings from lung transplant patients. It found important differences in how immune cells respond in patients who have CLAD or infection and those who do not. These early results strongly suggest it will be possible to predict who will develop CLAD and, importantly, identify if the cause is due to infection. This is potentially game changing. However, these initial results need to be confirmed. An additional two years of funding will allow this to be done. The plan is then to set up a large UK multi-centre trial. This will tell us if predictive immune tests for CLAD can be developed for clinical use. The second important finding from the original project involves a group of immune cells called B cells. B cells can produce antibodies which may damage transplanted organs. They may also protect transplanted organs. Data from the original project suggests a new and unexplored link between lung infection and CLAD and B cells. A 2-year extension to the project will allow us to explore this link in much more detail. It is hoped that this will tell us what these B cells are doing and whether their roles are protective or damaging to the lung. This could lead to new forms of treatment. There are many different drug and cell therapies that are already used to treat B cell disorders. Understanding the roles of B cells in organ rejection may allow repurposing of existing medicines. This means that treatments for other conditions might be used to help transplant patients. It is likely that lessons learned from this project will have far reaching implications for other forms of solid organ transplant and infectious diseases.

UKRI Gateway to Research · FY 2024 · 2024-11

This grant supports the IRIS Federation deliver compute to its science activities by placing hardwar at GridPP sites.

UKRI Gateway to Research · FY 2024 · 2024-11

This project aims to pioneer the Silicon Brain Cube, a groundbreaking hardware architecture with a three-dimensional implementation capable of enhancing energy efficiency of demanding AI workloads while supporting trustworthy processing. We will carry out joint research based on the expertise in energy-efficient deep learning models and in three-dimensional hardware architecture of the Japanese team, and in trustworthy AI design and in multi-level static and dynamic optimization and tools of the UK team. We will innovate an AI model that enables implementations to best achieve user-defined trade-offs between performance, resources required, energy efficiency, predictive accuracy, and level of uncertainty for trustworthy AI. More than an order of magnitude improvement in energy efficiency would be obtained by novel strategies for reducing memory accesses and irregular/sparse processing on a wired-logic and in-memory reconfigurable computing fabric. To promote research and practice of the Silicon Brain Cube beyond the end of the project, an open-source repository will be developed containing documented designs and tools, as well as online tutorials and application studies.

UKRI Gateway to Research · FY 2024 · 2024-11

Collectively, infectious diseases are the leading cause of death in the world, and in the UK alone, infectious diseases account for annual costs of £ 30 billion. To control disease spread, immunisation programmes have been the most effective public health intervention; but progress in this area has been deterred by the emergence of new virus variants, zoonotic transmission and vaccine manufacturing costs. Contributing to the failure in controlling infectious diseases, viruses can also rapidly evolve to circumvent our immune defences, allowing them to persist and cause disease. Despite considerable progress in our understanding of the immune response to viral infections, mechanisms underlying viral immune evasion remain inadequately understood. Live-attenuated virus vaccines offer a great way to provide immunity since they mimic the morphology and antigen repertoire of natural infections, eliciting protective immune responses while having little or no side effects during immunisation. However, strategies for the rational design of live-attenuated vaccines are scarce and poorly understood. Recent advancements in DNA synthesis have fuelled a new wave of vaccines generated by the introduction of numerous synonymous mutations in viral genomes. This type of vaccine can be quickly generated and is robust and stable. One such strategy involves the introduction of CpG dinucleotides, i.e. a cytosine followed by a guanine, in viral genomes rendering viruses extremely sensitive to immune defences. However, I have recently discovered that certain arrangements of CpGs are resistance to attenuation and, surprisingly, can circumvent innate immune defences by inducing their degradation. It is likely that certain human viruses with high CpG content may use this strategy to evade immune responses. This has exposed an Achilles' heel in the efficaciousness of CpG-derived live-attenuated vaccines that needs to be urgently addressed. The overall aim of this project is to discover how certain CpG arrangements in virus RNA are sensed by human cells and how that triggers the degradation of immune defences. Specific aims include: - To understand how currently circulating viruses may use CpG patterns to evade immune responses - To identify genes involved in the detection of CpG dinucleotides in virus RNA - To understand which arrangements of CpGs cause the degradation of innate immune defences - To devise a novel vaccine design strategy that preserves attenuation without degrading immune defences The main application of this research lies on the development of a novel vaccine design strategy that is safe to use and can be applied to all viruses. This project will also identify novel gene targets for therapeutic intervention. The benefits of such technology will greatly impact the economy, as new vaccines using this design can then be manufactured, protecting society from emerging diseases. The need for rapid vaccine development in face of novel infectious disease is likely to increase in the near future, as the permanent change to the climate in the UK is likely to attract animal species that are vectors for numerous viral diseases. The implementation of adequate technologies and infrastructures will protect the UK population from future zoonotic virus transmissions.

UKRI Gateway to Research · FY 2024 · 2024-11

Bowel cancer is the second leading cause of cancer-related deaths in the UK, which is an unacceptable outcome as over half of these cases are preventable. My fellowship focuses on enzymes, which are proteins that chop up molecules. Too much chopping results in damage to the bowel that can over activate the bodies defences, our immune system. My goal is to find ways to stop these enzymes from overacting, potentially using drugs. In the long term, I will explore how diet can reduce the activity of these enzymes in the gut to promote a healthy balance. There are several risk factors for bowel cancer, such as being overweight, having a poor diet, and having a long-term inflammatory condition, like inflammatory bowel disease. In fact, eating too little fibre causes 28% of bowel cancer cases in the UK (CRUK). The reason diet is important is because it affects the health of the bowel, which is the part of the intestine where bowel cancer develops. The bowel is home to trillions of organisms that you need a microscope to see, called microbes. What we eat influences these microbes and can cause inflammation. Normally, the bowel acts as a protective barrier between our immune system and the microbes. But if this barrier gets disrupted, it can lead to inflammation against the microbes and create an environment that promotes cancer development. Hydrolytic enzymes also called hydrolase, are important for a healthy bowel and for digestion. However, when there is too much activity of these enzymes, it leads to inflammation and cancer. In the bowel, hydrolases are released from human cells and microbes into the gut space and collected by passing faeces-like content. By analysing these bowel contents from cancer patients, I have found that the tumour environment has specific profile of active hydrolases. I have also developed a micro-model of human bowel cancer made from patient cells. Using this model, I have shown that by blocking the activity of hydrolases, I protect the bowel barrier from damage caused by its contents. The main goal of my Future Leaders Fellowship is to identify the specific hydrolases that are causing this damage, determine their role in bowel cancer, and find new ways to stop them. This will involve developing new drugs and designing specific diets to inhibit these enzymes. Ultimately, my aim is to reduce the impact of colorectal cancer and improve the outcomes for patients.

UKRI Gateway to Research · FY 2024 · 2024-11

Fungal infections are a growing problem, now killing more people than tuberculosis or malaria globally. Unfortunately fungi are also becoming resistant to the main anti fungal drugs we use to treat them. We have show that this is due to mass use of antifungals in agriculture. These are needed because fungi are the main pathogens that destroy crops. Furthermore global warming is increasing the threat of fungi across plant, animal and human health. To combat this, new types of antifungal therapies are coming into medical use, however we are already seeing equivalent antifungals being used in agriculture, known as "dual-use". We urgently need a holistic framework to ensure that we don't lose the efficacy of anti fungal drugs, both as medicines and as fungicides, whilst ensuring that we can continue to ensure that our food supplies are protected. In order to address the issue of antifungal resistance we have developed a Fungal One Health and Antimicrobial Resistance Network. One health refers to approaches that seek to balance and optimise the health of people, animals and ecosystems. The key challenges we face our to be able to understand the specific reasons why emergence of anti fungal resistance occurs within a one health context, to develop early warning systems that allow us to know when resistance in occurring or spreading, to identify the key hot-spots in the environment where anti fungal resistance is occurring, and have better understanding of where antifungals are being used most across one health. This will allow us to identify appropriate countermeasures that allow us to deliver judicious stewardship of antifungals so they can be used appropriately to enable food security and animal and human health, whilst ensuring that the risk of anti fungal resistance is minimised. In order to address these challenges and deliver appropriate countermeasures we have brought together a diverse range of scientists from across the relevant disciplines, as well as key stakeholders from relevant government departments, healthcare, agrochemical and pharmaceutical industries and end users such as farmers and patients. They will contribute to 4 working groups that focus on 1: the underlying causes of dual use anti fungal resistance, 2: surveillance of anti fungal resistance, 3: understanding the role of agricultural waste streams and water as hotspots for antifungal resistance, and 4: developing countermeasures such as anti fungal stewardship and other interventions to mitigate the risk of antifungal resistance. Our key aims will be to advance our knowledge of the underlying drivers of dual use antifungal resistance, how this occurs within the ecosystem, to develop surveillance systems and antifungal stewardship toolkits. We will develop policy documents and white papers, undertake outreach with end users, the public, governmental bodies and NGOs. The Network will train the next generation of multidisciplinary researchers in this area and develop pragmatic research proposals to enable us to fight the spread of anti-fungal resistance.

UKRI Gateway to Research · FY 2024 · 2024-10

Almost all of us have experienced our phone getting hot when we use it for too long. This is because the resistance of materials like silicon causes energy to be lost to heat, a key challenge preventing progress in electronics and energy conservation. A revolutionary recent discovery in condensed matter physics promises to solve this problem by providing a mechanism for stabilising desirable material properties against microscopic imperfections. This mechanism is called topological robustness, and it can be compared to a recipe that consistently produces a pleasing meal even if the ingredients are not all quite right. Topological robustness can give rise to perfect conductivity without the energy losses that plague common materials. In addition to highly efficient electronics, topological robustness also enables a wealth of breakthrough applications ranging from ultra-precise measurement tools to quantum computing. Nevertheless, finding materials that display topological robustness at room temperature has turned out to be immensely challenging, both in the lab and in computer simulations. With the support of the Future Leaders Fellowship, I will tackle this problem from a fresh perspective: I will generalise topological robustness beyond its current focus on non-interacting electrons - i.e., electrons that do not "talk to each other" - in low-temperature materials. I plan to achieve this by building a framework that predicts new topologically robust properties not only in natural materials composed of interacting electrons, but also in artificial metamaterials with nonlinear behaviour, meaning that their response to incoming light is not proportional to the light's intensity. Shifting paradigms even further, I will search for topological robustness in the dynamics of open quantum systems that constantly exchange energy and particles with their environment. My research will result in new mechanisms for topological robustness across a significantly wider range of scenarios than allowed by existing theories. This research will pave the way for ground-breaking applications in fields as diverse as quantum computing, optoelectronics, sensing, and photovoltaics.

UKRI Gateway to Research · FY 2024 · 2024-10

Peptide based drugs are one of the most important classes of new medicines. Peptides each containing a sequence of amino acids, the number and order of the amino acids in the peptide gives it unique biochemical properties. More than 7000 naturally occurring human peptides have been identified, and these often have crucial roles in human physiology, including actions as hormones, neurotransmitters, growth factors, ion channel ligands, or anti-infectives chemicals. The past 5 years has seen a rapid growth of new peptide drugs for diabetes which mimic a natural hormone called GLP. These new commercial drugs include Trulicity (Eli Lilly) and Ozempic(Novo-Nordisk) have become major drugs for managing type 2 diabetes. However, it has become clear in the past 12 months that these same drugs have major roles for controlling both obesity and heart disease, meaning that the demand and usage of these GLP mimics is likely to grow dramatically. However, the affordability of these new drugs is a serious issue, with annual costs for a patient is the USA using Trulicity is $10k. One significant factor in the cost of these peptide drugs is the complex process for their chemical synthesis which is specifically true for all therapeutic peptides than contain between 30 and 50 amino acids. The main method for synthesising peptide drugs is called the Merrifield Synthesis, which is commonly described also as solid phase peptide synthesis, and resulted in the awarding of the 1963 Nobel prize to Professor Merrifield. This technique has been improved incrementally over the past 60 years, but in remains unchanged at its core. The sequential growth, by chain elongation one amino acid at a time, of a peptide anchored to a solid resin particle. At the end of the synthesis, the final peptide is cleaved from the solid state media. It suffers from three primary disadvantages- it is not possible to synthesis peptides which are longer than 15 amino acids, the reaction process produces larges amounts waste chemicals, and it is not possible to synthesis non-linear peptides directly using this approach. The first two disadvantages directly contribute to expensive manufacturing costs, whilst the third disadvantage limited the ability of researchers to develop new non-linear peptide structures. The project will delivery key research data demonstrating a major advance in peptide synthesis developed by a UK university research group. We have developed a comprehensive improvement to the Merrifield synthesis approach, which we call Merrifield 2.0. This new method allows us to synthesis peptides of up to 50 amino acids directly using solid phase peptide synthesis and the method is much more sustainable; we anticipate reductions of up to 90% in waste products produced. These improvements will decrease manufacturing costs and also improve the sustainability of the entire peptide manufacturing process. In addition, this new synthetic approach allows us to synthesise for the first time a range of complex peptide structures, both linear and non-linear, which were not possible with the traditional Merrifield approach. This development in turn will open up new possibilities for pharmaceutical companies to develop new classes of peptide therapeutics, especially for oral delivery which is currently very difficult. The data generated in this project will allow us to quantify the process performance of our new manufacturing method, as well as confirming the purity and yield of the peptides we can manufacture. These data sets will be compared with data we will obtain using traditional synthesis methods. We will synthesis peptide materials at scales of 10 gm which to allow us to gain important industrial process data relevant to potential future scale up of our new manufacturing approach. In addition, we will demonstrate our ability to manufacture new peptide structures not currently possible using traditional synthesis approaches.

UKRI Gateway to Research · FY 2024 · 2024-10

Stroke is the second most common cause of death and morbidity worldwide affecting over 100,000 people each year causing 38,000 deaths and considerable disability, with an estimated annual cost to UK society of £26 billion. One of the major causes of stroke as well as other thromboses (blood clots) is antiphospholipid syndrome (APS); an autoimmune disease characterised by the constant presence of autoantibodies called antiphospholipid antibodies in the blood. Approximately 13.5% of thromboses causing stroke (up to 1/3 in patients <50 years2) and 11% of heart attacks, are attributable to APS. APS affects both sexes and all ethnic groups. In health, the lining of blood vessels (endothelium) helps to prevent blood clots and to break down those that do begin to form. We know that antiphospholipid antibodies can bind to the endothelium and cause inflammation which tends to reverse its protective effect against thrombosis. Current drugs to prevent blood clots (anticoagulants) are targeted at proteins and cells in the blood which create blood clots but not the endothelium. New anticoagulants (DOACs) target the blood enzymes factor Xa or thrombin and have proven equally successful as the traditional anticoagulant warfarin in some forms of thrombosis but are much less effective in patients with APS4,5. Although warfarin is therefore the oral anticoagulant of choice for APS, the risk of recurrent thrombosis in APS is still unacceptably high at 30% in 10 years. Therefore, identifying alternative ways that drugs can prevent recurrent stroke, without excess bleeding, is a vital and urgent need. Understanding how the differences in efficacy between different anticoagulants arise from their different mechanisms of action is an important step towards to this goal. In my current CARP award, I hypothesised that the difference in efficacy between warfarin and DOACs, arise from differences in their effects on the endothelium and the on endothelium's response to inflammation. My work so far confirms that they do indeed have significant but different effects on endothelium but also suggests that this is not the complete explanation. I now propose to explore these initial findings further and to extend the study to investigate the effects of anticoagulants on platelets (blood cell fragments essential for clotting). Finally I will study whether combining anticoagulants with the immunomodulatory drug hydroxychloroquine (HCQ) will have additional beneficial effects on endothelium. In summary I will: 1) Determine the effects of oral anticoagulants on platelet function. This is plausible because platelets are sensitive to thrombin and a to protein called Gas6 which is reduced by warfarin. 2) Determine the effects of warfarin and DOACs on the ability of endothelium to capture and activate blood cells (neutrophils) and platelets. 3) Determine the effects of anticoagulants on the ability of endothelium to break down blood clots (fibrinolysis). Fibrinolysis is known to be impaired in APS. 4). Determine the effects of combining anticoagulants and HCQ in reducing the endothelial prothrombotic response to aPL and inflammation. This work will provide better understanding of the differences between the current anticoagulants and the importance of the endothelium as a treatment target to prevent thrombosis. Using the immunomodulatory agent HCQ in combination with anticoagulants will begin to translate this understanding into new therapeutic approaches for patients with stroke and APS without increasing risk of bleeding.

UKRI Gateway to Research · FY 2024 · 2024-10

Preeclampsia, a multisystem disorder characterised by hypertension and organ dysfunction, remains a leading cause of maternal and fetal morbidity and mortality worldwide, complicating 3-5% of all pregnancies1. There are two types of preeclampsia based on when symptoms arise: early-onset (before 34 weeks of pregnancy) and late-onset (after 34 weeks)2. Early-onset preeclampsia, though less common (about 12% of cases), poses a much higher risk of severe health problems and fetal mortality3. Early detection of women at risk of early-onset preeclampsia is crucial to enable timely interventions like low-dose aspirin treatment, ideally before 16 weeks of pregnancy4,5. Unfortunately, current methods for identifying preeclampsiarisk during this time frame based solely on clinical risk factors are not very sensitive6. More advanced risk prediction models are available, including biomarker and ultrasound assessment of placental blood flow, but these are costly and labour-intensive, and not widely available. Additionally, even the advanced clinical models do not fully capture the entirety of preeclampsia risk. Therefore, there is a need to explore additional ways of screening for preeclampsia to enable timely, individualised preventive strategies aimed at improving outcomes for pregnant women and their babies. This project aims to evaluate, improve and further understand how genomics can help improve preeclampsia prediction. Initial experiments will evaluate available polygenic risk scores for preeclampsia in a cohort of approximately 6,000 women of multi-ethnic background from the Fetal Medicine Foundation (FMF) cohort. This will involve evaluating the improvement in prediction achieved by addition of polygenic scores to 'traditional' clinical models as well as the 'advanced' prediction model including biomarker and ultrasound assessment of placental blood flow. Subsequently the performance of the scores in women of African ancestry will be explored, and will be facilitated by the fact that the FMF cohort includes a higher number of women of African ancestry compared to any previous genetic study of preeclampsia. Specifically investigating genetic risk in this cohort is important because it is recognised that preeclampsia risk is higher among women of African ancestry7, but this cohort remains remain strongly underrepresented in genetic studies8. Thus, I will then aim to recalibrate available polygenic scores to make prediction more accurate for this ethnic group. Third, we will perform genotyping on a set of previously collected fetal chorionic villous samples that are paired to mothers in the biobank, with the aim of further understanding the contributions of both maternal and fetal genome in determining preeclampsia risk. We aim to then perform genome-wide association studies on both maternal and fetal genomes and meta-analyse these with all currently available data sources to create the largest up to date resource exploring both maternal and fetal genetic determinants of preeclampsia. Finally, a proteome- and transcriptome-wide Mendelian randomization analysis will be used to understand causal biological pathways.

UKRI Gateway to Research · FY 2024 · 2024-09

Context: Menopausal symptoms have a marked impact on women's lives with approximately 50% suffering from low sexual desire (LSD) with a large proportion distressed by this and seeking medical help. Indeed, the WHO strongly recognises the crucial positive influences of fulfilling sexual experiences on well-being throughout life. In the UK, menopause has been placed at the forefront of the healthcare agenda by the Department of Health following its publication of the Women's Health Strategy in 2022. This identified research into menopause treatments and psychosexual wellbeing as a key priority. Collectively, this aligns with priority 5.1 of the UKRI Strategy: 'Securing better health, ageing and wellbeing'. Challenge: Despite the high global health and social burden of menopausal LSD, the available therapeutic approaches are unsatisfactory due to their very limited efficacy and side-effect profiles. Crucially, a significant number of women suffer with persistent LSD despite first-line hormone replacement therapy (HRT), which only consistently improves pain during sex, but not sexual desire and arousal. Taken together, there is a significant unmet need to identify novel, safer, and more effective treatments to address the considerable burden of LSD in postmenopausal women. Kisspeptin and our pilot data: We have recently shown that administration of the reproductive neuropeptide kisspeptin to men and premenopausal women with LSD robustly modulates sexual brain processing with associated improvements in sexual desire/arousal (independent of downstream sex-steroids). To explore the potential benefit of kisspeptin in postmenopausal women with LSD (despite HRT) and provide mechanistic insight, we have undertaken an in vivo pilot study in ovariectomised (OVX) female mice with oestradiol (E2) replacement (as a rodent model to mimic the postmenopausal state on HRT treatment). This demonstrated that whereas E2 alone does not restore sexual motivation (akin to human sexual desire) in OVX mice, the addition of kisspeptin fully restored sexual motivation. Collectively, this pilot data in animals and our previous clinical findings suggests that kisspeptin administration may augment sexual behaviour in postmenopausal women with LSD and so serves as the timely research theme for this application.

UKRI Gateway to Research · FY 2024 · 2024-09

This project will develop advanced plasma-facing materials that may enable improvements in the efficiency and operating lifetime of future energy-producing fusion reactors. Such energy-demonstrating reactors may include the European Demonstration Power Plant (EU-DEMO) and the Spherical Tokamak for Energy Production (UK STEP). In all fusion tokamak configurations, the plasma-facing material (PFM) is exposed to an intense flux of particles of deuterium, tritium, helium and neutrons, which will degrade its performance. This leads to contamination of the reactor and consequently limit the reactor's operation. Baseline tungsten PFMs have already been identified for experimental (i.e. non-electricity producing) reactors, but the development of advanced tungsten-based alloys with improved thermal-mechanical performance and irradiation damage tolerance remains a vital concern for the future. In this research, I will develop a fundamental understanding of how W-based high entropy alloys (HEAs) degrade in extreme fusion reactor environments. Recently, these alloys have been proposed as having unrivalled resistance to neutron fluxes. However, to date their thermophysical properties and plasma-facing performance remain poorly understood. The goal of this work is the development of advanced tungsten-based HEAs via two interlinked work-packages: First, I will process new W-based HEAs and study their fundamental thermal and mechanical properties. Second, I will study their behaviour under fusion relevant plasma conditions including fluxes of heavy ions and hydrogen. By interlinking the microstructure, the fundamental materials properties, and the damage tolerance, my project will guide the development of materials with improved performance that are vital for commercial reactor operation.

UKRI Gateway to Research · FY 2024 · 2024-09

This grant award is for the purchase of eInfrastructure (CPU, storage and networking) as part of the IRIS consortium. IRIS supports STFC Science Projects, including the National Facilities and Science Programmes.

UKRI Gateway to Research · FY 2024 · 2024-09

Mathematics can be viewed as a game with precise rules -- everything is black and white. Computers are nowadays getting very good at such games. Computers can routinely beat the best humans at chess, and with the recent new developments by Deep Mind they can now beat us at the oriental board game Go. Indeed, computer scientists now consider board games to be essentially "solved" -- computers play them better than humans. But mathematics is different -- it is inherently infinite. For this and other reasons, computers are currently nowhere near "beating" humans at the game of proving new mathematical theorems. However, what is currently within scope is that computers could be used to *help* mathematicians with their research, doing things from checking messy lemmas automatically to suggesting results which may be helpful in a given situation. Perhaps surprisingly, the main obstacle to this sort of progress is that too few mathematicians are engaged with this kind of software, and hence computer proof assistants simply do not know most of the *definitions* of the objects which mathematicians use in their research, let alone the main theorems about these definitions. Computer scientists have already designed tools which can analyse databases of theorems and make suggestions or apply them automatically -- the problem is that the databases do not yet exist. The proposed research intends to change this. The resolution by Wiles and Taylor-Wiles of Fermat's Last Theorem in 1994 was a highlight of 20th century mathematics, and the tools used (automorphic forms, Galois representations) are still central objects of study in number theory today. My proposal is to fully formalise much of the mathematics involved in a modern proof of FLT in the Lean computer proof assistant, thus reducing the (gigantic) task of fully formalising a proof of Fermat's Last Theorem to the task of fully formalising various results from the 1980s. Such a project will enable Lean to understand many of the basic definitions in modern number theory and arithmetic geometry, meaning that it will be possible to start stating modern mathematical conjectures and theorems in number theory and arithmetic geometry which use such machinery. Ultimately the outcomes of the project will be that a computer will be able to understand some proofs from late 20th century mathematics, but also many statements of theorems of 21st century mathematics. In particular, this project enables humanity to start thinking about creating formalised databases of modern results in number theory. One could envisage a computer-formalised version of the services such as Math Reviews which summarise modern mathematical research papers for humans, or databases of results in algebraic and arithmetic geometry which can be mined by AI researchers.

UKRI Gateway to Research · FY 2024 · 2024-09

The UKRI AI CDT in Digital Healthcare (DigitalHealth CDT) will build on our established track record of research training to create a world-leading centre for PhD training of the next-generation innovators in AI applied to Digital Healthcare. Using AI in healthcare will provide more accurate medical decisions faster while reducing suffering, waiting times and costs across society, helping to address the pressing unmet health & care needs. AI for digital healthcare contains all the challenges that make AI generally a hard problem, yet to apply AI to healthcare effectively, we cannot use off-the-shelf AI but have to develop methods that are patient-ready and which address the challenges particular to the ethical, legal and regulatory requirements for healthcare. For example, the NHS requires 10,000 data & AI experts over the next five years as part of their recruitment strategy. Thus there is a pressing need for patient-ready AI specialists that can apply their skills, lead efforts and multidisciplinary teams in this heavily regulated domain. To address this need, our CDT and industrial and NHS partners propose training 121 PhD students including clinicians and allied NHS healthcare professions in five cohorts of 24+ students. Our PhD student journey is structured into multiple phases; in the first year-long phase, students will start their research and learn the technical aspects of AI and their specific application to healthcare. We broaden their training bespoke CDT advanced courses and hands-on training that only make sense for vast research cohorts such as ours to introduce them to the complex healthcare sector. These offerings, the academic and technical scope, comprise studies in AI ethics, healthcare practice and regulation, as well as hands-on software carpentry for vast NHS primary care (SAIL) and hospital databases (London SDE), as well as biobanking (UK BioBank) know-how on the technical end such as deep learning, federated machine learning and foundation models. Including these training aspects are key due to the immediate impact that our NHS and industry-aligned projects in the AI in Digital Health Centre for doctoral training can have on the life and health of citizens. Core to our approach is thus not only bespoke cohort-based training but also cohort-lead activities, such as funds for regular international speakers, seminars, hackathons and work-social events, as well as co-location that will keep these cohorts engaged and developing together. Therefore, our cohorts will endeavour to offer a rich mix of students from mathematics, computer science, engineering, physics, physiology, psychology, medical, and non-clinical professionals such as therapists and pharmacists. Our training offering is enhanced through co-created content by our industry partners that can help catalyse spin-offs (Scalespace), regulatory training (MHRA, HRA, BSI), data access (SAIL, LondonSDE, UK Biobank), as well as NHS trusts. Our graduating PhDs research will represent a new generation of diverse AI researchers with backgrounds ranging from computer science to design engineering and clinical medicine that can develop and deploy AI seamlessly across disciplinary boundaries to deliver health and care. We have teamed up with 3 NHS Trusts and clinical institutions to enable direct clinical involvement and impact - promoting on-site research & development of our students' projects and more than doubled the total number of UKRI studentships with studentships contributed by the UK's vibrant Digital Health industry and institutions. Our focus on AI for Digital Healthcare is not only addressing a pressing need but has also been recognised by our 44 partners and institution, which enabled us to multiple the requested UKRI investment three times (3X), evidence of the importance of this CDT.

UKRI Gateway to Research · FY 2024 · 2024-09

Delivery of Nucleic Acid Therapeutics to desired organs has become the current challenge of biotechnological applications. Advancements on the chemical synthesis or targeting ligands, formulation of complex lipid systems, and their bioassays are essential to establish new gene therapies. Therefore, the main aim of NATPRIME DN is to establish a multidisciplinary training network on the emerging topic of nanoparticle-based adjuvants to deliver nucleic acid therapeutics (NAT). In the last decade, great efforts have been spent on the development of synthetic strategies for the creation of RNA based therapies/vaccines, and these efforts have been acknowledged by the Nobel committee in 2023. The next important step is targeted delivery, which is to carry NATs to the desired tissue. For this purpose, various nanoassemblies, i.e lipid nanoparticles, polyplexes, liposomes, that are modified with targeting ligands will be utilised to encapsulate NATS. Antibodies, peptides, glycans, and glycopolymers open up greater possibilities in the precise targeting of nanoparticles to desired organs/tissues/cells. The combined molecular toolbox of targeting ligands, charged lipids, helper lipids and PEG-replacement lipids need a high-throughput formulation-screening to ensure increased uptake of such particles in the desired organs. 15 interdisciplinary researchers will be trained on the design, synthesis, and characterisation of such complex targeting ligands, their formulation in nanoparticles, and their utilisation in the nucleic acid based treatments. Last but not least, biophysical understanding of molecular interactions of formulation components will bridge the gap between fundamental and applied research while broadening the horizon of ESRs from an academic lab to good manufacturing practice (GMP) synthesis facilities that can positively impact the well-being of future generations.

UKRI Gateway to Research · FY 2024 · 2024-09

Passive surgical implants, those that do not include electronic components, are a cornerstone of modern medicine for the treatment of trauma and disease. Examples include joint replacements, fracture plates/screws, spine fusion devices, dental implants, and sports medicine soft-tissue anchors. In the UK, one out of every ten surgical procedures involve a passive implant. For the half million orthopaedic implant procedures undertaken in the UK each year, the treatment is open loop: patients receive an implant, are screened postoperatively for any anomalies, and then discharged home. Demand is increasing as the population ages, with these statistics mirrored worldwide. There are unmet clinical needs for: 1) Faster recovery, getting people back to work, recreational activities or independent living sooner. 2) Reducing revision burden, for better patient outcomes and a more financially sustainable healthcare provision. 3) Digital triaging, for more efficient workflows that give peace of mind to the majority and ensuring timely care for those in need. Active implants, with embedded electromechanical systems, could meet these needs. The implant could stimulate tissue growth into and around implants (meets need 1), provide a non-invasive therapy to avoid loosening or enhance infection treatment (meets need 2), and provide meaningful implant data to underpin digital triaging workflows (meets need 3). Innovation is needed to develop such technology, focusing on low-cost solutions suitable for high volume use. The aim of this fellowship is to develop controllable active therapies that can be delivered by an orthopaedic implant. The research will explore the functionalisation of implants with miniature low-cost electromechanical systems. The objectives are to: 1) Analyse the effects of implant design on deliverable stimulus. 2) Investigate how bone structure affects the apparent stimulus experienced by cells. 3) Research how bone cells respond to stimulus. 4) Develop a mechanistic understanding of how human bone responds to stimulus. 5) Explore how stimulus can be used to disrupt biofilm. If successful, this fellowship will lead the transition from passive to active implants, defining future goals for the wider field. A future where active implant therapies are tuned for individual patients to shorten their recovery time. Non-invasive therapies will become possible for those at risk of implant failure, and a reduced revision burden and digital triaging will enable more financially sustainable healthcare systems.

UKRI Gateway to Research · FY 2024 · 2024-09

Chemical biology is spearheading the development & translation of novel molecular tools and technologies to study biology and develop biomedical understanding. Dovetailing these platforms with industry 4.0/5.0 breakthroughs in automation & robotics, artificial intelligence & machine learning, the CDT will unlock the Lab of the Future paradigm. This will redefine the state of the art with respect to making, measuring, modelling & manipulating molecular interactions in biological systems, leading to novel R&D workflows, promoting efficient design-test cycles and driving sustainability. These molecular technologies will (i) enable biological & medical research, (ii) revolutionise understanding of disease & (iii) create novel diagnostics, drugs & therapies, focusing increasingly on individual patient outcomes. They will also impact the agri-tech sector which faces huge demand to increase productivity by unlocking strategies to e.g. track agrochemicals in plants/soil, understand modes of action & drive precision farming. Similarly, advances in personal care industrial processes are critically dependent on development of molecular technologies to gain insight into structured product design. The application of novel molecular tools/technologies, Lab of the Future strategies & their commercialisation through the instrumentation science sector is thus critical to the UK economy, supporting >4,500 healthcare, personal care, agri-science & biotech companies. This will transform (i) therapeutic, agrochemical & personal care product discovery (ii) med-tech/biotech/healthcare instrumentation R&D pipelines & (iii) stimulate creation of SMEs. Working closely with civic partners including Hammersmith & Fulham Council and the NHS, the CDT's talent & research pipeline will act as a growth engine for one of the most rapidly expanding Life Science ecosystems in Europe, the White City Innovation District. Given the importance of Chemical Biology to UK plc there is great demand but short supply of Chemical Biology PhD graduates able to match the pace of innovation across the physical/life science interface, at a time when industry & health sectors need these skills to accelerate productivity. The CDT in Chemical Biology: Empowering UK BioTech innovation with its unique 5 year programme: 1 year MRes + 3 year PhD + 1 year ELEVATE Fellowship directly addresses this skills gap by training a new generation of career-ready graduates, able to embrace the Lab of the Future concept and unlock its potential by fusing innovative molecular tools & tech with industry 4.0 & 5.0 advances to study molecular interactions & develop applications in the life science, agriscience & personal care sectors. CDT students will benefit from a research and training programme created with >100 industry/external stakeholders designed to meet future employer's needs. Our cohort-based programme with EDI at its heart, will allow students to contextualise their work within wider CDT activities & find novel solutions to their research, supported by one of the world's largest Chemical Biology communities: the Institute of Chemical Biology (>165) research groups. Students will be trained in multidisciplinary blue skies/translational research, lean innovation, scale fast/fail fast approaches, creating scientists able to understand molecular technologies, sustainable product design, early-stage commercialisation, & industry's pace of change. To support this, our training includes Future Lab & HackEDU courses (prototyping training), a drug screening programme, Biz-Catalyst (entrepreneurial training), InnovaLab (SME accelerator), a Data Science course, Human Centred Design, Science Communication (with BBC) & Bioethics/RRI/Sustainability/Policy courses. Following PhD completion, students can enter the ELEVATE fellowship programme, bridging the gap between PhD & industry/academia, offering training, personalised workplace opportunities & enable students to kickstart new companies.