NIHRDataInsights/HRCSData huggingface dataset:
Title: Leveraging genealogies for powerful inference of evolutionary processes driving human genetic diversity
Funder: Wellcome Trust

Abstract: I will develop powerful statistical methods that leverage estimated genealogies to reveal the key processes driving human genetic diversity and how these have evolved over time. Genealogies have the potential to transform how we analyze genomes, by providing a single framework for addressing a broad range of population and statistical genetics questions, and by substantially increasing power compared to conventional approaches. I have four key research aims that will impact distinct areas. Firstly, I will develop a novel method for uncovering how genetic structure changes through time and along the genome. This method can uncover unknown ancestral groups; for example, I will characterize previously-reported deeply diverged ancestry of unknown origin in the genomes of modern Africans. Secondly, I will develop a framework for incorporating ancient genomes of diverse ages and data quality into genealogies of modern individuals, enabling the direct study of how ancient and modern genomes interrelate. Thirdly, I will study the evolution of complex human traits through time under various modes of selection, to explain genetic architectures observed in genome-wide association studies. Fourthly, I will investigate the evolution of the molecular mechanisms of recombination, a key driver of human genetic diversity and hybrid incompatibility.

Lay abstract: Our DNA is rich in information about human history, from key migrations in a nation’s recent past to the earliest days of our species. My research focuses on creating powerful new statistical techniques that can extract this subtle information from our DNA. We do this by using the genomes of people sampled world-wide to reconstruct the genealogical trees relating all humans. These have long been sought as the best achievable record of our shared genetic past, and the large-scale data resources now make this feasible. In my DPhil, I developed RELATE, which for the first time enables genealogy inference for the many thousands of available human genomes and for those of many other species. In this fellowship, I will leverage this technological breakthrough to address questions that were previously unattainable, pushing the envelope of our understanding of how our genomes have evolved and better equipping us to combat disease.

Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular mechanisms actin(g) on endosomal sorting
Funder: Wellcome Trust

Abstract: The process of endosomal sorting, where internalised transmembrane proteins (cargoes) are sorted for lysosomal degradation or recycled back to the cell surface, maintains and regulates the cell surface proteome. Thus, endosomal sorting regulates numerous cellular processes including cell signalling. A fine-tuned amount of endosomal branched actin is required for recycling of cargoes from endosomes to the cell surface. Yet the mechanistic roles of endosomal actin in this process are not understood. Moreover, cargo such as the beta-2 adrenergic receptor (&beta;2-AR), signal in actin-decorated endosomal recycling domains, suggesting that endosomal actin plays a role in both endosomal recycling and signalling. My project aims to determine the mechanistic and physiological roles of endosomal actin. I will focus on the major endosomal actin polymerisation machinery – the Arp2/3 activating Wiskott–Aldrich syndrome protein and SCAR homolog (WASH) complex. I will investigate the intrinsic regulation of the WASH complex and how external factors it recruits, cumulatively regulate polymerisation of endosomal actin. Furthermore, I will develop new tools including blocking nanobodies and in vitro reconstitution. In combination, these multi-disciplinary approaches will establish a mechanistic and quantitative model of the role of endosomal actin in sorting and signalling. This will further our mechanistic understanding of endosomal recycling.

Lay abstract: Cells sense and respond to their environments through proteins present at the cell surface. The cell surface proteome is constantly remodelled through internalisation of transmembrane proteins into endosomes, where proteins are sorted for degradation or recycled back to the cell surface. Defects in endosomal recycling alters the cell surface proteome, thus affecting processes such as signalling, nutrient uptake and cell migration. Branched endosomal actin is required for endosomal recycling of proteins. The amount of endosomal actin is crucial - too little or too much perturbs protein recycling. I aim to understand how the amount of endosomal actin is regulated and what the mechanistic and physiological role of endosomal actin is. I will use a multi-disciplinary approach, spanning structural, in vitro reconstitution and live cell microscopy approaches. This study will provide mechanistic insight into endosomal recycling, a process increasingly associated with neurodegeneration.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Defining stem cell states competent to self-organize morphogen signalling centres in human neural tube organoids
Funder: Wellcome Trust

Abstract: Groups of cells called 'organizers' release signals to induce cell fates during development. Remarkably, organizers can undergo ‘self-organization’ in 3D organoids. Understanding this phenomenon has profound implications for engineering and regenerating patterned tissues with bonafide cell-type complexity and 3D-architecture. Mouse pluripotent stem cells (PSCs) can form neural-tube (NT) organoids. Timely retanoic acid (RA) addition induces scattered precursors that self-organize into a floorplate organizer, which drives ventral-dorsal patterning. I will create cognate human (h)NT organoids from single naïve hPSCs. Exploiting advanced bioengineering technologies, I will isolate organoids from confounding inter-organoid communication and promote robust self-organisation. This interdisciplinary approach will enable me to probe previously inaccessible questions regarding complex mechanisms. Using this system, I will study how cellular competence to express morphogens is subject to strict temporal regulation. Why is there a restricted window-of-competence for RA response, and how does this trigger self-organization? I will molecularly profile the transient competent state, functionally define the gene-regulatory basis for competence restriction, and investigate how molecular changes at this time serve as the basis for long-range self-organizing behaviour. This will provide a 3D model for critical stages of human nervous system formation, and reveal how self-organization processes are adapted for human-specific developmental size and timing.

Lay abstract: During development, groups of cells called ‘organizers’ release signals to induce pattern formation and morphogenesis in the surrounding tissues. This is crucial for formation of a coherent body plan. In the developing spinal cord, a key organizer is the floorplate, which secretes the morphogen Sonic Hedgehog to guide neuronal positioning along the ventral-dorsal axis. I will recapitulate this in vitro, harnessing stem cell self-organization properties to instate a floorplate in human neural tube organoids. I will use sophisticated microengineering technologies to recapitulate physiological microenvironments and impose conditions for reproducible organoid patterning. This will enable me to investigate the mechanistic link between early molecular events and subsequent floorplate self-organisation, with profound biomedical implications for engineering and regenerating patterned tissues with correct cell-type complexity and 3D architecture. This will provide a model for inaccessible stages of human nervous system development, and a source of functional human spinal cord for future biomedical applications.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Rapid spatial imaging of subcellular dynamics
Funder: Wellcome Trust

Abstract: Dynamic cell biological processes such as trafficking and signalling are characterized by weak and transient interactions, which occur in an intrinsically noisy biochemical environment. State-of-the-art live cell imaging equipment is therefore essential for robust localization and tracking of key regulators, allowing temporal relationships and causal mechanisms to be established. To this end, we are seeking funds for an Andor Dragonfly series 500, which enables high speed and high sensitivity imaging in several modes: Spinning Disc confocal, TIRF, HILO and laser widefield. The novel spinning disc design of the Dragonfly has been created for maximum efficiency and speed of imaging on both live and fixed samples, at a wide range of size scales from single cells to tissue sections. For high temporal resolution in all imaging modes, the Dragonfly employs two-colour simultaneous detection with the latest sCMOS camera technology. Another important feature of the Dragonfly is the near infrared illumination. This will allow us to image with newly developed fluorescent probes and/or labeling strategies such as SNAP and CLIP-tag to extend the number of components in a given pathway that can be simultaneously tracked.

Lay abstract: Even the largest cell in the human body, the egg cell, is barely visible to the human eye. Microscopes are thus an essential tool for looking inside cells, allowing us to determine how they work normally and what goes wrong in disease. Cells are crammed full of different compartments that act as mini-organs (termed organelles). Each organelle has a specific role for normal cell health, and also interacts with other organelles in very dynamic manner. We therefore need microscopes that can provide sensitive and rapid imaging of these events inside cells. We particularly need this new microscope to understand: the cellular transport machinery that mediates movement of protein cargo between these different compartments (Robinson and Owen); cellular recycling and the role of molecular motors in such processes (Buss); how protein signals are relayed between cells (Sharpe); and how specific cell types such as immune cells adapt these fundamental processes (Griffiths).

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Ethics and British public health law, 1920-2020
Funder: Wellcome Trust

Abstract: This research will investigate the ethics of British public health over the period 1920-2020, through the lens of public health law. In so doing, it will develop the ‘public health humanities’ as a mode of designing and implementing interdisciplinary research in public health. My goals are to discover how the implicit and explicit ethical frameworks of public health law have changed over the period in question; to analyse how and why these changes came about; and to explore methods for investigating public health ethics from interdisciplinary perspectives. I will use documentary and archival sources to locate and interrogate moments of morally inflected controversy in public health law, and will work collaboratively with public health practitioners and researchers to explore novel methods of data generation and analysis. Attention to ethics and public health law in Britain 1920-2020 disrupts assumptions that ethics in this time and place has been neutral and unchanging, and examines relationships between shifting ethical frameworks and factors including the post-war welfare state and its subsequent roll-back, decolonisation, migration, epidemiology, HIV/AIDS, and bioethics. The project will historicise ethics, connect past and present, and provoke cross-disciplinary interrogation and integration, for the benefit of the humanities and public health alike.

Lay abstract: Public health, encompassing collective organised efforts to prevent disease, prolong life, and promote health, employs distinctive and often controversial methods of surveillance, compulsion, coercion, and wide-ranging state intervention. Debate about these in terms of morality, justice, or fairness and the decisions reached contribute to the ethical frameworks through which public health operates. How have the ethics of public health changed, over time and in relation to different publics, problems, and politics? This project places public health ethics in historical context. It focuses on public health law to ask how and why the implicit and explicit ethical frameworks of public health in Britain have changed, from interwar ‘social medicine’ to the era of Covid-19. Working collaboratively with public health practitioners and scientists, it also explores the potential of much closer interactions between the humanities and public health, for the benefit of both fields.

Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: The 100 million Brazilian linked data and datacentre
Funder: Wellcome Trust

Abstract: The proposed biomedical resource will be built around “CADASTRO-UNICO” a database of electronic records of over 100 million applicants to social protection programmes in Brazil. Records consist of detailed individual information on housing conditions, education and income, organized by household and by individuals. Our proposal is to link the individual social and benefits records to electronic health records including: births, deaths, hospitalizations, infectious disease notification and others. The size of the population will enable research on the interrelationships between social factors and health and on the impact of social protection policies on a large range of health outcomes on a degree of detail never done before. The datacentre will be high-powered, secure and have a public interface. This project is possible because Brazil has high quality records and an open, modern attitude towards use of data for research and policy, supported by a rigorous but enabling legal framework. We will create a unique international resource that will allow researchers and policy-makers to address questions that currently cannot be answered. The resource will serve as a beacon for methodological development and training. Our proposed resource has already attracted substantial interest from national and international scientists and policy makers.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE
Title: Advanced protein crystallography imaging system
Funder: Wellcome Trust

Abstract: Protein crystallisation continues to play a central role in structural biology as the foundation for determining the atomic structures of macromolecules, understanding disease mechanisms, vaccine design and drug discovery. Several challenges remain, including crystallisation of multiprotein complexes, membrane proteins and time-resolved studies from systems directly engaged in catalysis, cell signalling, and ion movement. Studying different levels of structural complexity and dynamics is essential to understand protein function in health and disease. Technical developments are contributing to progress in these areas, including X-Ray Free Electron Lasers (XFELs) and Serial Synchrotron (SFX) data collection, coupled with advances in crystal imaging, which enable researchers to identify microcrystals that were previously not detectable with older instrumentation. This proposal builds on these advances through the acquisition of cutting-edge instrumentation for protein crystallisation, including advanced UV and multi fluorescence imaging optics and lipid cubic phase fluorescence after photobleaching (LCP FRAP) systems, which will provide access to, and development of, novel methods to detect and grow protein crystals of challenging multiprotein systems. A new multiuser protein crystallisation facility, centred in Oxford Biochemistry, but incorporating several stakeholders from across the wider University research community, will provide access and training.

Lay abstract: Medical advances, including vaccine design and targeted drug discovery for human diseases, rely on scientists from many different disciplines understanding how proteins in the body function at the molecular level. To achieve this level of detail requires researchers to image molecules, using either protein crystallography or single-particle cryo-EM. Our proposal seeks support for the former method, which continues to play a major role in drug discovery and vaccine design efforts globally. We aim to develop recent imaging technology to tackle the most challenging questions in structural biology, including how chromosomes segregate during cell division, how enzymes function to sense oxygen in our body, how neurons grow and drugs transported into the body. Our researchers and graduates are at the forefront of efforts to provide structural insights into complex proteins that will help researchers globally understand and tackle human diseases.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Light sheet microscope for imaging of cell and developmental biology in health and disease
Funder: Wellcome Trust

Abstract: The ability to image cells in 3 dimensions as they migrate, differentiate, form multicellular structures and tissues, and interact with their environments is a cornerstone of modern cell and developmental biology. Our ability to perform such experiments has been transformed by advances in molecular genetics, biological and chemical engineering of new fluorescent probes, and perhaps most dramatically by advances in our ability to image samples, dynamically over long time frames with high spatial and temporal resolution. This is perhaps most clearly demonstrated by the development of light sheet microscopy for long-term imaging of cells, tissues, and model organisms. This instrument has been top of the Bioimaging Facility “wish list” for several years. The opportunities provided by the system for imaging of larger specimens, with reduced phototoxicity, over long time frames led to it being named as Nature Methods’ “Method of the Year 2014”. The key advantage of the lateral illumination path compared to other modes with vertical illumination is reduced photodamage. This enables imaging over tens of hours to track cell movements in development and during pathological processes such as cancer, inflammation, and wound healing. In future it would also enable imaging of cleared brain samples for advanced neuroscience applications.

Lay abstract: The ability to image cells in 3 dimensions over time is central to modern cell and developmental biology research. The ability to watch cells as they migrate, differentiate, form tissues, and interact with their environments gives us great insight into both the normal healthy state of cells and tissues as well as and in disease. Our ability to perform such experiments has been transformed, perhaps most dramatically, by advances in our ability to image samples, dynamically over long time frames with high spatial and temporal resolution. Light sheet microscopy, the technology requested in this bid, enables longer-term imaging of cells, tissues, and model organisms with reduced damage opening possibilities for experiments that have not been possible before. The work that will be enabled by this new technology has direct application to many pathological states including cancer, inflammation, and regeneration of various tissues from heart to skin and skeleton.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE
Title: Human rights human remains: forensic humanitarianism and the politics of the grave
Funder: Wellcome Trust

Abstract: This project advances a pioneering analysis of the ‘forensic turn’ in humanitarianism. This denotes the effort to establish forensically the identities and causes of death of the mass victims of atrocities such as enforced disappearance, torture, genocide and war crimes. It has flourished in diverse settings such as Argentina, Guatemala, Mexico, Rwanda, South Africa, Bosnia-Herzegovina, Spain and Libya. In such contexts exhumations and forensic identification carry enormous social force. They represent a powerful way of establishing ‘the truth’ about what happened. Yet forensic identification is a social act. It interacts with legal, political and humanitarian imperatives which include facilitating accountability, combatting political and cultural denial, and returning the dead to families to assist psychological ‘closure’. The project examines the emergence, social complications and implications of forensic investigations of atrocity. It provides the first (global) history of the forensic turn in humanitarianism, investigates challenges to, and innovations in, the forensics field via an original analysis of the case of Mexico, and explores the hypothesis that as a result of the forensic turn we can now argue that the dead have human rights. In so doing, the project aims to change the way we think about forensic action and about human rights.

Lay abstract: No Data Entered

Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE
Title: Molecular mechanisms of cell fate decisions in gastrulation and early organogenesis
Funder: Wellcome Trust

Abstract: The cell fate decisions that accompany exit from pluripotency and entry into gastrulation and early organogenesis establish the vertebrate body plan. Recent advances in single-cell multiomics have allowed transcriptomes and epigenomes to be mapped at single cell resolution during mouse embryogenesis. These studies suggest that cell fate decisions can be made autonomously, where cell fate derives from an intrinsic regulatory programme, or signalling-based, in which fate is determined by the reception of local extrinsic cues. The potency of precursors is progressively restricted as fate is allocated, but separate developmental routes can lead to convergent cell fates. To understand the fundamental principles of these cell fate determination processes, we will combine in vivo mechanistic studies and quantitative mechanistic modelling. We will integrate cell lineage relationships with spatial information and single cell multi-omics, using (epi)genome editing to perturb cell fate decisions in vivo. By comparing early organogenesis across the three germ layers, we will seek to understand the shared and unique features of the mechanisms that establish the underlying fate map.

Lay abstract: During the development of embryos in animals and humans from a fertilised egg, specialised cell types emerge to form all organs in the body during a process called gastrulation. This process is critically important for the normal functioning of these organs and hence for a healthy adult life. However gastrulation can go wrong, potentially leading to malformations and childhood diseases. Some of the principles of how cells in early embryos specialise have been discovered, but the process is not well understood in its entirety. For our understanding of gastrulation to be taken to another level, we are measuring the molecular behaviour of each individual cell so that we can see how decisions about cell specialisation are taken. This information will be useful in developing new strategies for using stem cells in regenerative medicine applications, and for a better understanding of childhood diseases.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE