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Recipients:
Broadfield Primary School
University of Cambridge
Amounts:
£500 - £1,000
£50,000 - £100,000
£1,000,000 - £10,000,000
Award Year:
2017

Results

Principles of human development and germ cell program 28 Nov 2017

<p>Specification of human primordial germ cells (hPGCs)&nbsp;occurs around gastrulation, a critical juncture when the specification of the primary somatic lineages&nbsp;also occurs. In combination with human preimplantation embryos, in<em> vitro</em> models and hPGCs from aborted fetuses, our objective is to elucidate the origin and properties of the early human germline.</p> <p>For&nbsp;the mechanism of the hPGC fate, we will use experimental models that simulate early human development. We aim to investigate how cells gain competence for&nbsp;germ cell fate, and then respond to combinatorial effects of the critical transcription factors, which induce hPGC specification.&nbsp;Altogether, this study will&nbsp;reveal the organisation of the very early human embryo, and mechanisms of hPGC and somatic outcomes, which is essential for advances in regenerative&nbsp;medicine.</p> <p>Following hPGC specification, epigenetic resetting of the early human germline leads to extensive erasure of DNA methylation and epimutations&nbsp;in response to the critical regulators&nbsp;of chromatin organisation and nuclear architecture&nbsp;towards the epigenetic ground state. &nbsp;Some conserved resistant loci ('escapees') evade reprogramming. &nbsp;We will explore if some escapees have been exapted&nbsp;to function as&nbsp;regulatory elements. &nbsp;If so, this&nbsp;may have a crucial influence on&nbsp;human development, including brain development and neuronal diseases.</p> <p>&nbsp;</p> <p>&nbsp;</p>

Amount: £2,750,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

The chemical biology and function of natural modified DNA bases in genomes 28 Nov 2017

<p>I aim to elucidate the function of natural, chemically-modified DNA bases in the genomes of model organisms, using chemical&nbsp;biology and physical science approaches on genomic DNA. Modified bases are of fundamental importance to transcriptional programming and cell identity during and after development. The role of the cytosine derivative 5-formylcytosine and its influence on nucleosome formation, active enhancers, transcription and cell identity will be one area of focus to build mechanistic understanding, following on from hypotheses derived from our prior work. There will also be an investigation of 5-carboxycytosine&nbsp;and 5-hydroxymethyluridine and their potential links with transcription regulation.&nbsp; For other modified bases, such as N6-methyladenine, we will develop and use new chemical mapping/sequencing methods to elucidate their function in mammalian systems. The programme will include a systematic discovery of other&nbsp;natural DNA base modifications, building on and augmenting chemical methodologies I have developed to discover and profile modified bases in RNA.&nbsp; The function of newly identified base modifications will be investigated during the programme. The insights provided from these fundamental studies may have far-reaching consequences for normal biology and disease states.</p> <p>&nbsp;</p> <p>Keywords: chemical biology, nucleic acids, DNA, modified bases, epigenetics, sequencing</p>

Amount: £2,198,391
Funder: The Wellcome Trust
Recipient: University of Cambridge

Development of likelihood-based methods in structural biology 28 Nov 2017

<p>I propose to build on our development of new likelihood-based methods for structural biology, transposing approaches that have had great impact in macromolecular crystallography to the new area of cryo-EM.&nbsp; 1) In crystallography we will enable the solution of difficult structures (poor data or poor starting models) that still evade current methods.&nbsp; New statistical innovations will automate the clustering of alternative molecular replacement models into sensible ensembles representing different conformations. &nbsp;2) We will exploit a promising new approach to the determination of substructures for SAD phasing, based on our SAD likelihood function.&nbsp; 3) In cryo-EM we will investigate the propagation of errors in reconstructions, building on this understanding to devise improved likelihood-based methods to dock atomic models into cryo-EM maps, particularly those challenging cases determined at low resolution such as sub-tomogram averages.&nbsp; The implications of multi-variate cryo-EM likelihood targets will be explored, with potential applications in the angular deconvolution of cryo-EM maps.&nbsp; 4) Finally, we will develop a new approach to modelling macromolecular structures at low resolution, using interactive molecular dynamics flexible fitting to combine high-quality potential functions with likelihood targets.</p>

Amount: £1,916,285
Funder: The Wellcome Trust
Recipient: University of Cambridge

Molecular mechanisms of alternative splicing regulation 28 Nov 2017

<p>Alternative pre-mRNA splicing (AS) is a widespread regulatory mechanism enabling individual genes to generate multiple protein isoforms. We have investigated the mechanisms controlling AS events that are regulated during the transition of smooth muscle cells (SMCs) between contractile and proliferative phenotypes. We have shown how the widely-expressed RNA binding proteins (RBPs) PTBP1 and MBNL1 regulate SMC splicing events. Recently, we identified RBPMS as a potential &ldquo;master&rdquo; regulator of SMC AS. RBPMS is sufficient to switch AS events to the SMC pattern and its activity is strongly modulated by its own AS and by phosphorylation. Critically, RBPMS is sufficient to switch AS to the SMC pattern <em>in vitro</em>. This offers a unique opportunity to determine the molecular anatomy of regulated splicing complexes. We will carry out detailed mechanistic analyses of RBPMS-regulated splicing using a combination of biochemical, proteomic, single-molecule, and structural approaches including Cryo-EM. We will identify critical regulatory interactions between regulatory RBPs and core splicing factors, and test their importance by genome editing and mRNA-Seq. In a complementary aim, we will investigate how peptide-ligand interactions equip PTBP1 to regulate AS and a range of other post-transcriptional processes, and whether a family of such peptide-mediated interactions extends to related RBPs.</p>

Amount: £1,503,005
Funder: The Wellcome Trust
Recipient: University of Cambridge

A multi-disciplinary approach to understanding and improving hearing by cochlear implant users 28 Nov 2017

<p>Cochlear implants (CIs) restore hearing by electrically stimulating the auditory nerve. This allows many CI users to understand speech well in quiet, but even the most successful have poor pitch perception and struggle in noisy situations. We believe there are two main reasons for these limitations.(i) Although it is possible to elicit different pitches by stimulating different electrodes, the selectivity of this &quot;place-of-excitation&quot; cue is much worse than in normal hearing (NH). (ii) It is also possible to increase pitch by increasing the pulse rate applied to each electrode, but use of this temporal cue is also much worse than in NH.&nbsp; We will study both of these limitations by performing analogous experiments in cats and humans, using some of the same measures in the two species. This will allow us, for the first time, to link the limitations that occur perceptually to their underlying physiological bases, and to do so even for novel stimulation methods that are not possible with existing clinical CIs. The knowledge gained wiill allow us to propose and test modifications both to implant design and audiological practice.</p>

Amount: £1,727,476
Funder: The Wellcome Trust
Recipient: University of Cambridge

Fractionating the human frontoparietal cortex: combining meta-analytic and real-time optimization approaches 08 Nov 2017

<p>Disruptions in the same set of frontal and parietal brain regions are seen across a striking range of psychiatric and neurological conditions. This network of regions has been referred to as <em>multiple-demand</em> (MD) system and can be divided into at least two closely coupled subnetworks. However, despite extensive research efforts, the specific functional mechanism each subnetwork supports remains poorly understood using available neuroimaging technology.</p> <p>&nbsp;</p> <p>To overcome these limitations, I have recently developed a novel technique based on real-time neuroimaging&nbsp;and machine learning: Neuroadaptive Bayesian Optimization (NaBO).</p> <p>&nbsp;</p> <p>The key goal of this fellowship is to develop a complementary approach that leverages&nbsp;the strength of large-scale, automated meta-analyses and NaBO to obtain a fine-grained functional mapping between MD subnetworks and the cognitive processes they support. This approach will exploit&nbsp;the wealth of data generated by neuroimaging to date (meta-analysis) for defining a prior model of how cognitive functions relate to MD subnetworks and then refine this model in unprecedented detail (NaBO). The resulting model will be validated using behavioural assessment.</p> <p>&nbsp;</p> <p>Advancing our understanding of these subnetworks in normal brain function is an important first step for developing&nbsp;targeted clinical interventions and informing the design of sensitive diagnostic test batteries.</p>

Amount: £250,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Building and breaking epithelial integrity in the neural tube: an optogenetic approach 18 Oct 2017

<p>Using an innovative optogenetic approach within the zebrafish neural tube, I will directly explore <strong>how the polarity of individual cells drives the tissue organisation of a whole organ. </strong>In combination with 4D live imaging and functional abrogation, I will use light to specifically and reversibly manipulate apicobasal polarity, cleavage furrow formation and PI3K pathway signalling on a subcellular level. I will assess <strong>how apicobasal polarity and division are interrelated </strong>during morphogenesis of vertebrate epithelial tubes and how this relationship contributes to <strong>tissue integrity.</strong></p> <p>&nbsp;</p> <p>Early zebrafish neuroepithelial divisions are highly predictable and coincident with <em>de novo </em>apicobasal polarisation. This provides a tractable model to assess a potential <strong>feedback loop between apical protein localisation and cleavage furrow positioning</strong> during epithelial <em>establishment. </em>The PI3K pathway is likely key to integrating apicobasal polarity with division. Within <em>established</em> epithelia, PI3K pathway defects are prevalent in cancers. I will manipulate PI3K pathway signalling within individual cells or groups of cells within an otherwise normal zebrafish neural tube. This <em>in vivo</em> method for manipulating cancer-linked signalling will allow me to test whether<strong> apicobasal polarity dysregulation is a cause or consequence of tissue disruption</strong>, providing clues to the cellular mechanisms of disease initiation.</p>

Amount: £977,448
Funder: The Wellcome Trust
Recipient: University of Cambridge

Metabolic magnetic resonance imaging across the human heart 18 Oct 2017

<p>During my fellowship, I proved the feasibility of measuring cardiac energetics in volunteers and patients using ultra-high field (7T) MRI scanners. The sensitivity and the separation of signals from different metabolites both improved significantly compared to standard research scanners.</p> <p>I recently secured &pound;340k funding to fit a new phosphorus coil on the Oxford 7T scanner, which I am now testing in volunteers. Theory predicts that this coil will have several complementary technical advantages. These will enable mapping of cardiac energy metabolism across the whole heart, with sufficient spatial resolution to distinguish signals from healthy from diseased tissue. It will also enable quantification of cardiac energy metabolism with high precision to study single subjects rather than groups.</p> <p>I request funding to validate these new whole-heart methods, proving their value in three carefully-targeted groups of patients, <em>via</em> an extension of my fellowship. My goals are (A) to study patients in which the metabolic pattern is known by other means; (B)&nbsp;others where the metabolic pattern will reveal previously-inaccessible aspects of disease mechanism; and (C)&nbsp;to prove I can resolve metabolic changes in single patients.</p> <p>Success in each of these studies will give me the pilot data needed for competitive Senior Fellowship applications.</p>

Amount: £584,259
Funder: The Wellcome Trust
Recipient: University of Cambridge

Virus remodelling of host-cell endomembranes 18 Oct 2017

<p>Enveloped viruses appropriate host-cell membranes to assemble their progeny. Large DNA viruses achieve this by dramatically remodelling the host-cell endomembrane system. I work at the intersection of virology and membrane trafficking, exploiting the intimate connection between viruses and their host cells to gain insights into both virus biology and the dynamic regulation of cellular membranes. I will combine biophysics, biochemistry and cell-based infection assays to investigate the conserved mechanisms by which human herpesviruses change the composition and architecture of intracellular membranes, addressing two questions:</p> <ul> <li><strong>What is the role of ceramide transport in the biology of enveloped viruses?</strong> We have identified a direct interaction between a conserved herpesvirus protein and a cellular ceramide transporter. This suggests that herpesviruses actively modify the ceramide composition of intracellular membranes during infection, a new paradigm in virus:host interactions.</li> <li><strong>How do enveloped viruses bend membranes during assembly?</strong> We have identified a conserved protein complex that promotes herpesvirus membrane wrapping, potentially via palmitoylation-dependent sensing and/or stimulation of membrane curvature.</li> </ul> <p>A detailed molecular understanding of how viruses subvert host-cell membranes not only expands our knowledge of host and virus biology, but it provides the basic underpinning science for the next generation of vaccines and antiviral therapies.</p>

Amount: £599,947
Funder: The Wellcome Trust
Recipient: University of Cambridge

Institutional Translation Partnership Award (iTP A): University of Cambridge 30 Sep 2017

The University of Cambridge is committed to achieving excellence in research and scholarship and ensuring that our research contributes to the wellbeing of society. The Cambridge bioscience cluster is the largest outside of the US, and third largest in the world, which, together with our multidisciplinary research strengths indicates tremendous potential to further build on the translational biomedical research activity at the University. The aims in working with the Wellcome Trust iTPA are to stimulate the translatable ideas pipeline across the breadth of relevant research at the University of Cambridge, and enable the early collaborative partnerships (industry and/or clinical medicine) that are essential in successful delivery of translational biomedicine. There will be an initial focus on chemical biology and resource will be deployed to conduct translational workshops, provide Cambridge scientists with flexible support and access to medicinal chemistry experts and bring together cross disciplinary and cross sector groups via challenge-led workshops. This will be complemented by a proof of concept funding scheme which will focus on funding cross-disciplinary collaborative projects.

Amount: £1,000,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Dynamic neural remapping across the sleep-wake cycle: A mechanistic link between sensory re-organisation and GABA 05 Sep 2017

<p>Across a single day, we undergo behavioral, physiological and neurochemical changes, from vigilant wakefulness to unconscious sleep. Despite the loss of consciousness, sensory processing continues in sleep. Attempts to assess the degree to which sensory processing differs between wakefulness and sleep have yielded contradicting results with studies showing greater, smaller or comparable responses to the same stimuli when comparing the two states. Hence, it remains unclear <strong>precisely how sensory processing is modulated throughout the sleep-wake cycle</strong>.</p> <p>&nbsp;</p> <p>Most studies have focused on responses to specific stimuli, neglecting the relationship between different stimuli. We suggest a new comprehensive approach to elucidate how vigilance state dynamically shapes sensory processing, by combining electroencephalography (EEG), functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) together with state-of-the-art computational tools, measuring neural distances between stimuli to quantify <strong>sensory remapping</strong> across the sleep-wake cycle.</p> <p>&nbsp;</p> <p>We hypothesize that &gamma;-Aminobutyric Acid (GABA), an inhibitory neurotransmitter implicated in sleep regulation and correlated with sensory sensitivity, has a central role in sensory remapping. Thus, in this research proposal, the key goals are:(i) to elucidate the temporal and spatial dynamics of sensory remapping throughout the sleep-wake cycle, and (ii) to investigate whether sensory remapping across the sleep-wake cycle is GABA-dependent.</p>

Amount: £99,935
Funder: The Wellcome Trust
Recipient: University of Cambridge

Vacation Scholarships 2017 - University of Cambridge 16 Jun 2017

<p>Vacation Scholarships 2017 - University of Cambridge</p>

Amount: £21,500
Funder: The Wellcome Trust
Recipient: University of Cambridge

Master's Award in Humanities and Social Science 30 Jul 2017

<p>&nbsp; &nbsp; &nbsp; &nbsp; &nbsp; &nbsp;&nbsp;In my three essays, I will explore case studies of British biotechnology and bioethics since the 1960s. My first essay will investigate the history of organ donation regulation in the UK by focusing on two pieces of legislation: the Human Tissue Act of 1961 and the Human Organ Transplants Act of 1989, which aimed to regulate the procurement of cadaveric and live organ donors, respectively. Next, I will examine the British Biotech controversy of the 1990s. After exaggerating their production of marimastat for cancer treatment, the company lost accreditation and eventually dissolved. I will explore this public controversy using as a key source the episode in BBC2&rsquo;s series <em>Blood on the Carpet </em>that recorded the politics behind the company&rsquo;s downfall as a key source. Finally, I will examine the use of Foucauldian ideas in the rise of British bioethics in the 1960s. Focusing specifically on the emergence of what, following Ludwik Fleck, I call the bioethical thought collective, I hope to expand on Daniel Wilson&rsquo;s work by analyzing how the collective&rsquo;s philosophical ideals deployed and engaged with Foucault&rsquo;s concept of biopower. Pursuing these research topics will expand my understanding of current British bioethical debates and American-British policy differences.</p>

Amount: £28,440
Funder: The Wellcome Trust
Recipient: University of Cambridge

Exploring Disorganised Attachment: Unravelling Developmental Pathways and Outcomes using Data Mining 30 Jun 2017

<p>Disorganised attachment is an important assessment of infant mental health, introduced by Main and Solomon (1990). Disorganisation is thought to result from an infant having in some way experienced trauma within the context of the relationship with their caregiver (e.g. observing severe domestic violence). Infants classified as disorganised have an&nbsp;elevated risk of psychological problems, most notably conduct disorders (Fearon et al. 2012).</p> <p>&nbsp;</p> <p>The possibility of a finer-grained measure emerged out of archival research, under Duschinsky's New Investigator Award,&nbsp;on&nbsp;the original Berkeley dataset from which disorganised attachment was first identified.&nbsp;</p> <p>&nbsp;</p> <p>As a result of the significant stakes for research and clinical practice, we have been offered unprecedented access to a remarkable longitudinal dataset to explore a) how the finer-grained measure fares against the standard construct in predicting a range of negative outcomes, and b) whether particular forms of disorganisation have specific antecedents.&nbsp;Given that the goal is exploratory and the array of relevant measures is extensive, data mining will be used rather than hypothesis-testing. The research offers the prospect of a significant&nbsp;transformation of research in this area. Three focus groups with clinicians will be conducted to facilitate clinical input and translation.&nbsp;</p>

Amount: £25,976
Funder: The Wellcome Trust
Recipient: University of Cambridge

Amulets and the material culture of healing 25 May 2017

<p>The goal of this project is to investigate how amulets represent varying forms of value and power across differing chronologies. The Science Museum's collection will allow me to comprehensively examine a diverse range of objects, and research different forms of medical, magical and scientific worth and potency unavailable by studying textual sources alone. This project will ask three questions:&nbsp;How do objects with both similar and antithetical social values&ndash;from the rare to the quotidian, the expensive to the ubiquitous&ndash;represent differing forms of remedial power?&nbsp;In which different ways do these amulets represent the patients' experience of illness and healing and how can we as historians and museum curators afford these objects &lsquo;voices&rsquo; without being anachronistic and jeopardising their original power?&nbsp;Finally, what material features have led to certain objects being considered as curative, prophylactic or apotropaic, and to what extent do function and potency depend on manmade and natural materials? This project will use these amulets to help answer important questions about European healing practices from medieval period to present day. A direct, material analysis of the objects and collections will elucidate the historical importance of these objects, and what they can contribute to our knowledge of health and healing.</p>

Amount: £15,523
Funder: The Wellcome Trust
Recipient: University of Cambridge

ISA-InterMine: accelerating and rewarding data sharing 06 Jul 2017

<p>There is a growing recognition that research should be carried out in an open fashion, making data available early and in a reusable form to maximise worldwide research output. However, fulfilling this promise requires front-line researchers to comply with current data management standards as required by the data policies of funders and journals. These are additional burdens to research that will give them little immediate return.</p> <p>&nbsp;</p> <p>Thus we propose to create a cloud-based, open-source, extensible data collection and presentation platform that will provide scientists with: (1) immediate reward for their annotation efforts through sharable data visualisation, integration outputs and exploration tools; (2) standardised web services to facilitate script-based data manipulation and analysis; (3) an easy-to-use pipeline for preparing their data for publication; (4) incentives to improve data quality, accessibility, and machine-actionability at the appropriate level of granularity; and (5) allow institutions and other parties to host the platform to ensure its availability and reliability.</p> <p>&nbsp;</p> <p>We will do this by building on the success and complementarity of the ISA tools suite (Oxford) and the InterMine platform (Cambridge) to make it quicker and easier to generate rich integrated dynamic web sites at single paper/lab scale up to consortium scale.</p>

Amount: £670,410
Funder: The Wellcome Trust
Recipient: University of Cambridge

Virtual Fly Brain 06 Jul 2017

<p>Neuroscience is accelerating: the capability to generate circuit level hypotheses is now matched with the ability to visualise, manipulate and record from individual neurons, in vivo. Drosophila, with its complex adaptive behaviors, powerful genetic toolkit and small nervous system, for which we will soon have complete connectomes, is uniquely placed to contribute to this work.</p> <p>&nbsp;</p> <p>Virtual Fly Brain (VFB) is a unique resource for Drosophila neuroscience, integrating disparate, large-scale datasets and linking them to curated literature and other resources. VFB works with international data providers and bioinformatics resources to ensure efforts are complementary, non-redundant, and make best use of resources.</p> <p>&nbsp;</p> <p>VFB users browse and query curated information from many sources to understand structure, function and relationships in the brain. Critically, VFB provides the data to generate circuit hypotheses and identify research tools to test them. This proposal continues this vital service and extends it to incorporate rich new data types. We will incorporate synaptic resolution connectomic data, develop bridging registrations to make it bidirectionally queryable from light level data. We will add phenotypic and transcriptomic datasets and enhance tools that enable researchers to find reagents. We will enable users to upload, view and query their own 3D datasets.</p>

Amount: £996,004
Funder: The Wellcome Trust
Recipient: University of Cambridge

‘Pre-embryos’ Revisited: a historical sociology of translational biology 02 May 2017

<p>This project will revisit the debates on human fertilisation and embryology that took place after the release of the Warnock report in 1984 and ended with the enactment of the Human fertilisation and Embryology Act in 1990. Firstly, it will ask how developmental biologist Dame Anne McLaren (1927-2007) used the scientific concept of the &lsquo;pre-embryo&rsquo; as a rhetorical device in the debates to make the case for the continuation of research. McLaren&rsquo;s role as the only research scientist on the Warnock Committee, but also in public debate and in the scientific community offers insight into the translational dimensions of human embryo research. Secondly, the research will explore the legacy of the term &lsquo;pre-embryo&rsquo; by asking practicing developmental biologists conducting research that begs for an extended limit on in vitro research on human embryos, to reflect on the term in order to suggest which lessons about biological translation can be taken from the debates in the 1980s, and to assess the usefulness of new scientific terms and concepts when engaging lay-audiences in scientific debates.</p>

Amount: £135,903
Funder: The Wellcome Trust
Recipient: University of Cambridge

Diagnosing Diagnosis: a multidisciplinary perspective 17 Jul 2017

<p>Diagnosis is at the heart of the medical encounter, but many features of making, communicating and recording a diagnosis remain poorly understood and little researched. Without greater understanding, we cannot provide adequate guidance to clinicians about what information to share with patients or adequate advice to patients about what questions to ask, and policy incentives to address problems with &lsquo;overdiagnosis&rsquo; or &lsquo;misdiagnosis&rsquo; are at risk of unintended consequences.</p> <p><strong>Key goals:</strong></p> <ol> <li>To examine the process of making, communicating and recording a medical (differential) diagnosis in the acute care setting;</li> <li>To examine institutional influences on the diagnostic process;</li> <li>To examine ethical and philosophical influences on making and communicating diagnoses;</li> <li>To establish an empirically based, ethically grounded framework for making, communicating and recording a diagnosis to improve patient outcomes on both individual and societal levels.&nbsp;</li> </ol> <p><strong>Methodology:</strong></p> <p>Qualitative methods including ethnography and interviews will be combined with medical records analysis and quantification of the reach and permanence of diagnostic labelling between health care settings. Integrated with this empirical work, ethical analysis will explore how the interplay between responsibility, uncertainty and trust affects the process and communication of making a medical diagnosis. This is emphatically multidisciplinary research which &nbsp;benefits from combining different perspectives and methodologies.</p>

Amount: £647,257
Funder: The Wellcome Trust
Recipient: University of Cambridge