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Results

The ethical governance of Artificial Intelligence health research in Higher Education Institutions 26 Jul 2018

Artificial Intelligence (AI) is increasingly being used in health research in areas such as genomics, medical imaging/screening, and health prediction of epidemics and disease outbreaks [1-6]. AI research has the potential to improve health outcomes but raises urgent, complex moral questions, including issues of AI design bias; AI's black-box nature and inherent lack of transparency; and the ownership of algorithms used in AI and the data they produce [6-12]. Such ethical issues challenge Higher Education Institution (HEI) ethical governance systems, which traditionally focus on notions of risk, consent and privacy in human participant research [13]. To preliminarily explore how we can move towards making these governance systems more appropriate for HEI AI health research, this project employs empirical methods to map one aspect of the AI research area, and explore the views, experiences and understandings of relevant scholars on: the usefulness of current HEI governance systems to oversee the types of ethical decisions they make during AI research; collaborating with the private sector and associated ethical concerns; their responsibility towards post-research/implementation issues associated with AI; and the need for specific ‘health research’ ethics governance. The goal is to make/disseminate preliminary recommendations to improve HEI ethical governance for AI health research.

Amount: £84,751
Funder: The Wellcome Trust
Recipient: King's College London

Public data, private collaborator: Will machine learning relocate medical knowledge? 26 Jul 2018

This study focuses on the transformations in the creation and ownership of medical knowledge that result from applications of machine learning (ML). In medical image recognition, ML applications are currently being developed and tested to assist in diagnostics. These developments are often carried out as collaborations between public and private sectors, with public medical institutions providing data and medical domain knowledge, and private technology companies providing ML expertise. However, the algorithms implemented in these tools are typically proprietary, trade secrets that underlie the competitive advantage of the companies that develop and operate them. There consequently limited transparency into and access to the medical knowledge that they generate. This knowledge is thus privatised in the sense that it is encapsulated within closed software that forms part of the IPR of a private company. This study analyses such risks of privatisation and the role of open data in medical research. By comparing cases of ML applications in Ophthalmology, by conducting semi-structured interviews with stakeholders and organising two participatory workshops, the project will examine the role of data ownership and explore measures that allow medical knowledge to be kept in the public realm while still attracting private collaborations for ML applications.

Amount: £57,307
Funder: The Wellcome Trust
Recipient: King's College London

Biomedical Research and the Politics of the Human 30 Jul 2018

The human is a primary reference point for the aims of contemporary biomedical research along with its ethical and political groundings. This project asks: what and who constitutes that human? Despite the many assumptions we may hold about what and who is human, no study has delivered fine-grained empirical research about how scientists, policymakers and regulators approach and define the human across the levels of cells, tissues, and organisms. A series of changes—in biomedicine and in the scholarship on science and society—signal that it is a crucial time to reconsider the meaning and function of the human in the life sciences. Using an inductive qualitative approach, this project offers an ambitious plan for an empirical reorientation with the human in relation to two domains of biomedicine that constitute the project’s work packages: 1) Kidney Organoids: miniature organs grown in petri dishes. 2) Interspecies Mammalian Chimera: injecting human cells into developing pig embryos Based on a theoretical framework that draws together insights from science and technology studies, sociology and legal and political studies, the project is built on detailed empirical observation of the two research domains covering four national case studies in the UK, Spain, Germany and USA.

Amount: £629,823
Funder: The Wellcome Trust
Recipient: King's College London

Senior Fellowship (WHO Placement & Global Health Justice Research) 30 Sep 2017

This proposal seeks support for an 18-month senior fellowship. The fellowship enables (1) placement at WHO GHE unit to help develop an ethical framework for ageing policies (‘just global ageing policies’) through a global, collaborative and comprehensive multi-stakeholder and multi-sectoral process, and incorporating WHO policy related documents. The framework would be informed by the fellow's (Venkatapuram) expertise in health justice philosophy and the capabilities approach previously cited by the WHO in the 2015 World Report on Ageing and Health. An ethical framework for addressing the needs of a specific social group (elderly) would be a distinctly new type of output for bioethics and the WHO compared to ethical guidelines for specific disease interventions or events (epidemics). The fellowship also enables (2) philosophical research on global health justice. Venkatapuram seeks to extend his argument for a human right to the capability to be healthy (CH)--presented in Health Justice (Polity, 2011) and in the WT funded project Population Level Bioethics and CA (WT 094245))--to global health governance and institutions. The research outputs will include two journal articles, short commentaries, lectures, and a monograph. The monograph proposal is being developed with Harvard University Press. 40% of time will be spent on this research.

Amount: £151,279
Funder: The Wellcome Trust
Recipient: King's College London

3i outreach - disseminating data, methods, analyses and knowledge 05 Dec 2016

An essential goal of the 3i Strategic Award is the provision of "high-end" data in open-access format. The approved plan was to send all data to the Wellcome Trust Sanger Institute (WTSI) and the European Bioinformatics Institute (EBI) who run the website of the International Mouse Phenotyping Consortium (IMPC). However, WTSI discontinued public data display in favour of contributing to the IMPC site (www.mousephenotype.org). Therefore, WTSI’s change in policy jeopardises our capacity to achieve an essential goal. Addressing this, we have allocated IT resources to establish a 3i website (www.immunophenotype.org), enabling users to search and appropriately analyse 3i data. This proposal will address the outlined issues by making sure both websites are updated with fast turnaround times, use the same statistics, score the same hits, use the same graphs, display flow data at different levels of complexity, and each offer optimal query options for their respective target groups, immunologists (3i) and a wider scientific community (IMPC), respectively.

Amount: £200,808
Funder: The Wellcome Trust
Recipient: King's College London

Imaging visuomotor transformations in the brain 30 Nov 2016

A central goal of sensory neuroscience is to understand how the brain builds internal representations of the external world and how these representations guide decision making and behaviour. For example, what patterns of activity in the brain allow an animal to distinguish prey from predator and how does this activity trigger the appropriate behavioural response? To address this fundamental problem we will use the optic tectum of larval zebrafish which converts visual information from the retina into hunting and escape behaviours. Thus, the tectum must generate distinct visual representations, prey vs predator, which biases a decision between mutually exclusive responses - move toward or away. To understand how the tectum does this we will combine high speed functional imaging of every neuron in the tectum with video recording of eye and tail movements. These approaches will allow us to describe how visual information is encoded in the tectum and to define the activity patterns that drive eye and tail movements associated with either approach or avoidance behaviours. Our project will generate new insights into how the brain enocdes visual information and the nature of sensory representations that drive behaviour.

Amount: £1,600,547
Funder: The Wellcome Trust
Recipient: King's College London

The genetic control of collective cell migration: insights from the neural crest 12 May 2017

Collective cell migration refers to the movement of a cell population that acquires directionality through cell-cell interactions. All cells of the group may be capable of reading directional cues, or they may divide their labour with front cells, ‘leaders’, indicating the path to rest of the group. The precise molecular signals that control cell identities and behaviour in the context of collective cell migration remain unclear. We have studied this process in Neural Crest (NC) cells, a highly migratory population that arise early during embryogenesis. Our recent work has demonstrated that zebrafish trunk NC (TNC) migrate collectively and present non-exchangeable leader and follower identities. The firm allocation of TNC identities strongly suggests these are transcriptionally regulated. In this project, we will generate new NC zebrafish reporter lines that will allow the specific labelling of TNC populations by photo-conversion (leader, follower or premigratory). Labelled cells will be then isolated and processed for RNA-Seq. These data sets will allow us to characterize leader, follower and premigratory cells transcriptomic signatures. This is an essential step towards the elucidation of the genetic networks controlling TNC identities and behaviour.

Amount: £99,939
Funder: The Wellcome Trust
Recipient: King's College London

How does nonsense-mediated decay contribute to gene regulation in developing neurons? 31 May 2018

Nonsense mediated decay (NMD) is a quality control mechanism used by eukaryotic cells to destroy messenger RNAs containing incorrectly positioned translation termination codons [1]. NMD, in combination with alternative RNA splicing (AS), also provides a potent mechanism for natural changes in gene expression in developing brain [2-5]. The main goal of my summer project will be to test the hypothesis that progressive down-regulation of an RNA-binding protein called PTBP1 during mammalian neurogenesis promotes neuronal identity by changing AS patterns and triggering NMD of multiple neural precursor-specific transcripts. I will first follow up on the RNA sequencing screen carried out in the Makeyev lab and validate bioinformatically predicted AS-NMD targets using Reverse Transcription PCR and quantitative PCR analyses of developing nervous system samples and embryonic stem cells undergoing neuronal differentiation in vitro. I will then analyse AS-MND regulation for one example showing the most robust regulation. This will be achieved by designing minigene and CRISPR-Cas constructs specific for AS-NMD promoting exons and testing these reagents in mouse ES cells undergoing neuronal differentiation or treated with siRNA against PTBP1. The results of this work should improve our understanding of the AS-NMD pathway and evaluate its contribution to neuronal differentiation.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Elucidating allosteric processes in immunoglobulin E 31 May 2018

Immunoglobulin E (IgE) is thought to be the first line of defence against parasitic pathogens, mediating immune reactions by binding to either of its two receptors, either the high-affinity FcepsilonRI receptor or the low-affinity CD23 receptors. While the IgE molecule was previously thought to exist in a primarily acutely bent conformation in solution, Drinkwater et al. (2014) found that IgE was able to exist in a fully extended conformation while Davies et al (2017) showed that omalizumab (XolairTM by Novartis) trapped IgE in a partially bent state to block its action on its FcepsilonRI receptors. The McDonnell Laboratory has derived a series of anti-IgE antibody Fab fragments, selected for their ability to affect IgE’s overall structure and dynamics and consequently to allosterically affect the binding to IgE’s receptors. In this proposed study, we will investigate how observed ligand-mediated changes in conformational dynamics manifest themselves as entropically-driven allosteric modulation. As a complement to NMR studies of ligand-mediated changes in protein dynamics, currently ongoing in the McDonnell Laboratory, direct measurements of the thermodynamic parameters of ligand binding will be performed using isothermal titration calorimetry.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London
Amount: £20,750
Funder: The Wellcome Trust
Recipient: King's College London

Impact of missense mutations in recessive Mendelian disease: insight from ciliopathies 10 Apr 2018

Background: Over 1,800 autosomal recessive (AR) Mendelian-disease genes have been identified. Missense mutations account for 59% of protein coding region mutations, yet their precise functional effects remain largely uncharacterized. Two important questions in human genetics aim to explain interindividual variation in phenotypic severity and assign pathogenic mechanisms to different disease phenotypes (including independent phenotypes within the same syndrome). For AR disorders, it is thought that many missense mutations cause protein instability. For these hypomorphic mutations, disease phenotypes are defined according to quantitative genetic threshold effects within a protein interaction network. Project: We will focus on a subset of AR ciliopathies which are strongly enriched for missense mutations, where complete gene knockout is thought to be lethal (see Rationale-below). We will use gene-editing and quantitative protein-protein interaction analyses to systematically compare the phenotypic effects of frameshift (likely knockout/null) and missense mutations. We will test our hypothesis that these missense mutations disrupt only a subset of gene functions/protein interactions, using phenomics algorithms we have developed and unbiased phenotyping in cell lines and mouse models, allowing us to assign pathogenic mechanisms to disease phenotypes. In future, this approach could be extended to the estimated 10-20% of > 3,000 Mendelian-disorders enriched for missense mutations.

Amount: £206,112
Funder: The Wellcome Trust
Recipient: King's College London

Regulation of CD25 expression and IBD risk 31 May 2018

The inflammatory bowel diseases (IBD) Crohn’s disease (CD) and ulcerative colitis (UC) are chronic disorders of the gastrointestinal tract affecting 1 in 400 people in the UK. Both have a complex aetiology involving genetic predisposition and environmental triggers which is not yet fully understood, but may result in persistent bacterial infection, defective mucosal barrier, or a dysregulated immune response. Genome-wide association scans (GWAS) have identified over 200 IBD-associated loci (Lui et al 2015). One locus encompasses the gene encoding the IL-2 receptor alpha chain (CD25). CD25 is expressed by activated T cells and important in signalling pathways that regulate the immune response. Our fine-mapping data (Huang et al 2017) show that the GWAS signal at IL2RA/CD25 is due to a single SNP associated with CD, in intron 1 of the gene and co-localising with a super enhancer that regulates expression (Fahr et al 2015). This SNP is also associated with Type 1 diabetes and multiple other autoimmune disorders. In this study we will identify additional recently recruited IBD patients who are homozygous for the CD risk allele at this SNP by genotyping and investigate alteration in the expression of IL2RA by qPCR in flow-sorted regulatory and effector T cells.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Modelling Monogenic Diabetes using induced Pluripotent Stem Cells (iPSCs) 30 Sep 2018

Diabetes is characterized by the body's inability to regulate blood glucose. Pancreatic beta-cells regulate glucose through insulin release. Monogenic Diabetes is a rare type of diabetes caused by single gene germline mutations that make beta-cells dysfunctional. Diagnosis with Monogenic diabetes is done through genetic testing. However, similar mutations can have different phenotypes and penetrance in families, underlying the need to address the pathophysiology of the mutations ex vivo. During my PhD project, I will analyse the data available for induced Pluripotent Stem Cells (iPSCs) derived from patients with Monogenic Diabetes banked through the Human Induced Pluripotent Stem Cells Initiative (HipSci). Mutant and healthy iPSCs lines will be differentiated towards pancreatic progenitors and beta-like cells, to determine their effect on pancreas development and beta-cell function. CRISPR-Cas9 will be employed to correct the mutations. The mechanism of action of the mutants will be investigated in vitro. The function of the corrected and mutant iPSCs differentiated towards beta-like cells will be addressed in vivo. This study should contribute towards understanding the heterogeneity of Monogenic Diabetes phenotypes. In the long-term, it could help towards a more accurate detection of Monogenic Diabetes and personalized treatment.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Bridging the glial scar in spinal cord injury with a stem-cell based CNS graft 30 Sep 2018

Spinal cord injury leads to paralysis of motor function as well as internal organ dysfunction. No current treatments are capable of restoring function reliably, if at all. We aim to construct a stem-cell based graft with therapeutic genes to bridge the gap produced during contusion injury. We will use mouse embryonic stem cells to derive specific neuronal populations involved in locomotion to treat spinal cord injury in a mouse model. The graft will be supplemented with therapeutic genes that will enhance neuronal survival, integration and functioning when transplanted. This will be measured several weeks after transplantation. Behavioural tests will be performed to evaluate motor function recovery. The study will help to advance in cellular therapies for spinal cord injury by using a combination of techniques that address previous failures in animal studies and clinical trials.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Do antipsychotics affect white matter? 31 May 2018

Converging evidence from post-mortem studies of human brain tissue and in vivo neuroimaging suggest that white matter integrity is negatively affected across several psychiatric disorders, including schizophrenia. Antipsychotics are the first-line treatment for but a key gap in our knowledge is the precise impact of these drugs on white matter integrity and pathology. Recent evidence suggests that antipsychotic drugs may be pro-myelinating. We aim to address this question using a rodent model of Maternal Immune Activation (MIA), an established epidemiological risk factor for several psychiatric disorders. Our goal is to determine the effect of chronic exposure to the antipsychotic haloperidol on white matter integrity in the MIA model. Existing tissue samples from animals treated in four experimental conditions (Saline – vehicle, Saline –Haloperidol, MIA-vehicle, MIA- Haloperidol) will be stained for myelin basic protein and neurofilament to assess the effects of MIA, haloperidol and their interaction, on white matter. We expect that the MIA model will exhibit a loss of white matter integrity and hypothesize that haloperidol will rescue this. This research may increase understanding of the development and treatment of psychopathology, both of which are poorly understood and affect millions of people around the world.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Imaging Focal Epilepsy in Children: A Developmental Perspective 31 May 2017

Focal cortical dysplasias are common causes of treatment-resistant epilepsy in childhood, but are persistently difficult to detect on clinical magnetic resonance imaging (MRI) scans by routine visual inspection. This is especially true in children, where pathology may be masked by the dynamically changing background of the developing brain. My fellowship will investigate focal epilepsy in the context of the developing human brain. I will build analytical tools from clinical MRI data to better detect subtle MRI lesions and, using quantitative MRI (qMRI), translate these tools so they can be applied across clinical sites and in other neurodevelopmental and neurological disorders. I propose to build a continuous time-space model of brain development using large population MRI data from typically developing children. Using this model, I will test the specificity of abnormality maps in individual patients to confirmed epileptic pathology in a training- and test-dataset from two large epilepsy neurosurgery programmes. To generalise this model to standard clinical sequences, I will collect qMRI and synthesise scanner-independent MR images to tailor this growth model to any local protocol. Finally, I will extend these structural findings to identify networks associated with focal epilepsies, and investigate whether they can predict a successful outcome from surgery.

Amount: £995,096
Funder: The Wellcome Trust
Recipient: King's College London

Associations between late-life depression and dementia: A large retrospective cohort study 27 Apr 2017

Aims This project aims to investigate factors that might contribute to the development of dementia in patients presenting with late-life depression. Specific objectives are to investigate depression severity, and which demographic factors, co-prescribed medications (as different antidepressant types), co-morbid conditions, and function and symptom clusters are predictive of dementia development. Methods Data for this study will be obtained via the South London and Maudsley NHS Foundation Trust (SLaM) Clinical Record Interactive Search (CRIS) application, providing anonymised access to electronic health records. CRIS contains records on over 270,000 patients, 17,000 with dementia and 6,500 with late-life depression. Following a retrospective cohort study design, diagnosis of late-life depression will define the cohort. Development of dementia and models of cognitive decline will serve as outcomes, which will be studied in relation to an unprecedented range of predictors. Expected Outcomes This study will provide more clarity on factors predicting transition from late-life depression, and in particular severe/psychotic depression, to dementia. The identified predictors will provide valuable potential targets for intervention. This project will result in publication in peer reviewed journals and presentation at old age psychiatry conferences, but also wider guidance on management of late-life depression for patients, carers, clinicians, and policy makers.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Automated single-cell microscopy of insulin-to-insulin regulation in C. elegans 27 Apr 2017

Insulin-like peptides (ILPs) play evolutionarily conserved roles in many physiological processes, including development, ageing, and neural function. Humans and other species possess multiple ILPs, and cross-regulation between ILPs is important for biological function. Here we exploit the stereotyped anatomy of C. elegans to dissect the regulation between two ILPs: ins-3 and ins-6. ins-3 negatively regulates ins-6 expression during the control of larval development. ins-3 is expressed in three identified neurons, while ins-6 is expressed in two identified neurons. Our key goal is to map out the regulatory connections from ins-3 neurons to ins-6 neurons. We will determine in which neurons is ins-6 affected in an ins-3 knock-out mutant using an ins-6::mCherry transcriptional reporter. We will next determine from which neurons ins-3 acts from, by examining ins-6 expression in a set of ins-3 mutant strains where wild-type ins-3 is selectively restored to each of its three neurons. All of the above strains have been made and will be analysed with an automated system for fluorescence microscopy to measure ins-6 reporter expression. This work will provide insights into cross-regulation between ILPs at single-cell level, and show how ILPs mediate communication in the nervous system.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Role of TRPC4 in regulating human myometrium contractions in vitro 27 Apr 2017

An estimated 15 million preterm births occur worldwide every year, associated with over a million neonatal deaths and a high incidence of physical and neurodevelopmental disability amongst surviving infants throughout their life course. In the ‘Born too Soon’ Global Action Report (2012), the World Health Organisation concluded that ‘much more knowledge is needed to address the solution and reach a point where preterm birth is prevented’. This vacation studentship focuses on understanding how pregnant human uterine smooth muscle functions in order to inform the development of tocolytic therapies for the prevention of spontaneous preterm labour and hence preterm birth. Specifically, the project will assess the contribution of TRPC4 channels (non selective cation channels that are implicated in store operated calcium entry) to the regulation of spontaneous and oxytocin induced contractile activity in human myometrium. Hypothesis and aims It is hypothesised that TRPC4 augments human myometrial contraction amplitude and frequency. The overall goal is to assess the actions of two TRPC4 channel inhibitors on spontaneously and oxytocin stimulated pregnant human myometrium obtained at the time of caesarean section. The results will help confirms or refute the hypothesis and described the role of TRPC4 in human myometrium.

Amount: £0
Funder: The Wellcome Trust
Recipient: King's College London

Discovery and development of novel small molecule inhibitors of the human Hyperpolarization activated Cyclic Nucleotide-gated 2 (HCN2) ion channel for the treatment of inflammatory and neuropathic pain 30 Jul 2016

Treatments for inflammatory pain (IP) and neuropathic pain (NP) are frequently ineffective and have many side effects. Scientists in Professor Peter McNaughton's laboratory at the University of Cambridge have discovered that both IP and NP are abolished in mice when an ion channel is genetically deleted. This suggests that drugs blocking this ion channel will have value as novel analgesics. IP is associated with injury, infection or chronic conditions such as arthritis; and NP is caused by nerve damage in conditions such as post-herpetic neuralgia and diabetic neuropathy. Both IP and NP can impose major limitations on lifestyle and working patterns and currently available treatments have major drawbacks. For example, non-steroidal anti-inflammatories cause gastric and renal damage; and opioids cause constipation and problems with tolerance and addiction. The team aims to develop selective ion channel blockers, which avoid those that play essential roles in the heart and brain, and test them in animal models of IP and NP. In separate parallel studies they will use a known non-selective blocker to carry out proof-of-principle studies in human NP.

Amount: £861,620
Funder: The Wellcome Trust
Recipient: King's College London