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Recipients:
6th East Paddington Brownie Guide Unit
University of Cambridge
Amounts:
£0 - £500
£500 - £1,000
Award Year:
2018

Results

Common Variant Genetics of Autism and Autistic Traits (GWAS) Consortium 27 Nov 2018

<p style="margin-left: 0cm; margin-right: 0cm">Autism is a life-long developmental condition with a prevalence of approximately 1%, and heritability estimates of between 64-92%. It is polygenic, with variants across the frequency spectrum (from rare to common) contributing to risk. Considerable progress has been made in identifying rare variants in autism, but the largest genome-wide association study (GWAS) of autism (18,000 cases, 28,000 controls)&nbsp;identified only five loci associated with autism, compared to 179 in schizophrenia (40,000 cases, 65,000 controls). Polygenic scores account for 2.45% of the variance in autism, despite 30-50% of the variance in risk for autism being attributable to common variants, suggesting many more common variants remain to be found. Additionally, autistic traits are normally distributed in the general population, but there is no well-powered GWAS of autistic traits. The proposed research aims to accelerate the discovery of common, low frequency, and copy number variants in autism and autistic traits. Specifically, we will: (1) Establish a UK-wide Autism Biobank (N = 10,000 cases), with links to electronic health records and who can be recalled by genotype; (2) Conduct a GWAS of autism in 100K cases from around the world; and (3) Conduct a GWAS of autistic traits in the population in 250K individuals</p>

Amount: £3,182,054
Funder: The Wellcome Trust
Recipient: University of Cambridge

Evolutionary basis of human diseases in western Eurasia: Insights from ancient genomics 27 Nov 2018

<p>Although large differences in disease susceptibility among present-day human populations have been widely reported, their evolutionary underpinnings remain poorly understood. This project aims to examine how, and to what extent, pathogens shaped disease susceptibility among present-day western Eurasians. We will use whole-genome sequence data from ancient humans and their pathogens to identify novel human genetic variants targeted by past selection, and catalogue novel pathogen variability, including that of now-extinct lineages. Next we will reconstruct the evolutionary history of these newly identified variants and lineages, along with those already known to be associated with disease susceptibility in present-day populations. Finally, we will uncover new associations between human genetic variants and infectious diseases. The focus will be on the last 10,000 years of human history, which encompass some of the greatest changes in our lifestyle, including the agricultural revolution, first known epidemics, and early urbanisation. The proposed study will provide fundamental insights into the evolutionary basis of disease susceptibility in present-day human populations, as well as the evolution of human pathogens. These findings will inform future experimental and clinical research, impact upon current and future healthcare strategies, including the design of diagnostic tests and drug development, and improve global pathogen outbreak monitoring.</p>

Amount: £4,153,544
Funder: The Wellcome Trust
Recipient: University of Cambridge

The proteomic architectures of apicomplexan cells: the molecular complexity of pathogens revealed 27 Nov 2018

<table border="1" cellspacing="0"> <tbody> <tr> <td> <p>Apicomplexan parasites represent highly adapted eukaryotic pathogens that have evolved to exploit multiple human and animal niches causing widespread disease and food deprivation. Key to their success as parasites are novel organelles and structures adapted for invasion and mediation of interactions with their hosts. They have also reprogrammed canonical cell compartments with modified metabolic capacities and regulatory control. An overwhelming obstacle to understanding the biology of these parasites and their mechanisms of pathogenesis is that much of the parasite proteome is unique in Apicomplexa, with most proteins of unknown location or function.</p> <p>My group uses a novel method for whole-cell spatial proteomics in apicomplexan parasite-host systems that simultaneously captures the locations and associations of thousands of parasites proteins. This provides intimate and thorough illumination of the architecture and adaptations of these devastating pathogens at an organelle-, sub-compartment- and protein complex-level. We will define the commonalities and differences between major pathogen groups <em>Plasmodium</em> and <em>Toxoplasma</em>, the destinations of proteins they export into their hosts, and the spatial dynamics of their proteomes during infection developmental cycles. This comprehensive knowledge will enable molecular mechanistic understanding of these pathogens that is essential for effective design and implementation of disease management and prevention strategies.</p> </td> </tr> </tbody> </table>

Amount: £1,687,461
Funder: The Wellcome Trust
Recipient: University of Cambridge

Oxygen and immune response 27 Nov 2018

<p>Our goals are centered on understanding how hypoxic response&nbsp;affects immunity.</p> <p>The experiments described are in&nbsp;three key areas:&nbsp;</p> <p>The first of these is myeloid immunosuppression by hypoxia, and the mechanisms of immunosuppression that are regulated by the&nbsp;hypoxia inducible transcription factor (HIF). Here, we will characterize and determine the range of&nbsp;factors produced by M1- and M2-polarized macrophages in HIF1a- and HIF2a-dependent manners by macrophages; we will ask how HIF-driven nitric oxide (NO) homeostasis regulates immunosuppression in hypoxia;&nbsp;and we will determine how HIF-driven myelosuppression acts in a model of acute and chronic viral infection.</p> <p>In the second aim, we will focus on cytotoxic T cell activation by hypoxia and HIF. Here, we will address the role of directed HIF expression on T cell function; and the differential metabolism of T cells as regulated by the VHL- and FIH-mediated control of HIF; including immunometabolic analysis of&nbsp;how those two factors&nbsp;affect T cell function.</p> <p>Our third aim concerns the role of the immunometabolite 2-hydroxyglutarate, and here we will carry out work on enantiomer-specific biology of the metabolites; map chromatin and RNA modifications induced by 2-HG; and investigate the potential use of 2-HG to enhance CAR-T therapies.</p>

Amount: £2,499,897
Funder: The Wellcome Trust
Recipient: University of Cambridge

Insights into metabolic health and disease from human genetic variants with major functional impact 27 Nov 2018

<p>The metabolism of macronutrients is controlled by the interplay of key organs, including liver, muscle and adipose tissue,&nbsp;orchestrated by hormonal and other signals. Disturbances in this network are associated with metabolic disease. We will build on our experience of using human genetics to illuminate mechanisms of insulin resistance to enhance understanding of the molecular control of human&nbsp;metabolism and its dysfunction in a range of diseases. We will use three independent but related approaches, each of which will <strong>exploit the power of rare non-synonymous human genetic variants with major functional impact. &nbsp;</strong></p> <ol> <li>We will study rare mutations significantly associated with metabolic phenotypes in large epidemiological studies.</li> <li>We will identify and study&nbsp;rare, functionally significant mutations in genes that are known from studies in cells and animals to be important for metabolic control but where little information is currently available in humans.&nbsp;&nbsp;</li> <li>We will study humans with rare extreme metabolic phenotypes; continuing to&nbsp;discover&nbsp;new genetic disorders&nbsp;and adding to knowledge of genotype/phenotype correlation.</li> </ol> <p>Each approach will involve the deep phenotyping of cells and humans. Any required extension of work into transgenic murine models will be the subject of a bid&nbsp;for additional, independent funding.</p> <p>&nbsp;</p>

Amount: £1,894,039
Funder: The Wellcome Trust
Recipient: University of Cambridge

Coated vesicle adaptors 27 Nov 2018

<p>Coated vesicles transport molecules from one membrane compartment of the cell (a &quot;donor&quot; compartment) to another (&quot;acceptor&quot;) compartment.&nbsp; Adaptors are the components of the coat that select the vesicle cargo. The adaptor protein complexes AP-1 and AP-2 are associated with clathrin-coated vesicles (CCVs), while APs 3, 4, and 5 appear to be clathrin-independent. I have been working on adaptors for over 35 years, but there are still many unanswered questions. We plan to focus on the following areas:</p> <p>1. The AP-1 pathway. How are the AP-1 donor organelles related to each other, and how are the vesicles recognised so they fuse with the right acceptor compartment?</p> <p>2. AP-4, AP-5, and hereditary spastic paraplegia. How do AP-4 and AP-5 select cargo and make vesicles, and why do mutations in either of them cause hereditary spastic paraplegia?</p>

Amount: £1,469,608
Funder: The Wellcome Trust
Recipient: University of Cambridge

Contribution of transposable elements in cell fate decision 31 Oct 2018

<p>Transposable elements (TEs) are long known to be expressed in different cells during early mammalian development. However, the role of TEs in cellular differentiation has remained elusive. This proposal aims to develop new experimental and computational methods to understand the role of TEs in cellular differentiation. Single cell (sc) RNA sequencing (RNA-seq) has been developed extensively in recent years to study cell-to-cell variability of gene expression. These methods, however, have exclusively used short read sequencing technologies, which do not allow for TE mapping. I will develop a novel plate-based long read scRNA-seq protocol, which will overcome this limitation. Transcripts will be tagged with unique molecular identifiers (UMIs) prior to amplification, permitting accurate transcript counting. I will devise a computational method to error correct reads using UMIs, by calculating a consensus from multiple sequence alignments of all reads flagged as PCR duplicates. This protocol thus allows for accurate sequencing of complete transcripts in single cells, which I will apply to cells during mouse embryonic development to investigate the role of TEs in cellular differentiation. In particular, I will investigate whether TEs exhibit heterogeneous expression across cells. Together, these methods and experiments will improve our understandings of TEs in mammalian development.</p>

Amount: £300,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Uncovering the roles of dynamic RNA interactions during assembly and assortment of multi-segmented viral genomes 17 Oct 2018

<p>Rotaviruses (RV) comprise a diverse and rapidly evolving group of segmented double-stranded (ds)RNA viruses of the <em>Reoviridae</em> family that cause deadly gastroenteritis in children worldwide. A hallmark of rotavirus morphogenesis is the stoichiometric assembly of eleven distinct genome ssRNA segment precursors prior to packaging. Elucidating the mechanism of accurate &lsquo;molecular counting&rsquo; of RNAs is essential to understanding RV replication and their evolution. Our recent studies suggest that segmented genome assembly in RVs, and potentially other <em>Reoviridae</em>, requires the formation of an RNA assortment complex, whose assembly is facilitated by the non-structural proteins that accumulate in viroplasms. The key goals of this proposal are: a) to investigate how the dynamic RNA structures control accurate assembly of a multi-segmented genome; b) to directly visualize the assembly of distinct ssRNAs and to identify pathways for disrupting this process. To achieve these goals, I will combine structural probing of ssRNAs, tools for detecting inter-molecular RNA-RNA contacts and structural modeling. To visualize multiple interacting ssRNAs <em>in situ</em>, I will employ recently developed quantitative super-resolution multiplexed RNA imaging approaches. These fundamental studies will pave the way for identification of routes for controlling RV assembly, having potential uses in the development of antivirals and rationally designed vaccines.</p>

Amount: £1,177,077
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mechanisms of epithelial polarity in flies and mammals 26 Nov 2018

<p style="margin-left: 0cm; margin-right: 0cm">AS/A/GCSE-level biology specifications have recently shifted toward an increased focus on practical skills<sup>1</sup>that teachers and schools don&rsquo;t necessarily have the equipment or knowledge to confidently foster across the biology curriculum<sup>2</sup>.&nbsp;The Scientists' Collaborative Project with Educators (SCoPE) is a pilot public engagement project aiming to create three practical toolkits for use in biology classrooms. The toolkits will be connected to the national curriculum and also strongly linked to research developed at the Gurdon Institute. They will be co-created through a series of interactions between state school AS/A/GCSE-level teachers and scientists, together with professional designers. Toolkits could include laboratory materials, videos, and more.&nbsp;&nbsp;They will be re-usable and shareable and made available to teachers across the country. According to our research, the UK doesn&rsquo;t have any other programmes with a similarly intense focus on teacher-scientist co-creation<sup>3-8</sup>.</p> <p style="margin-left: 0cm; margin-right: 0cm">SCoPE will foster a culture of mutual learning between scientists and teachers while bringing new practical activities and contemporary research into the classroom. Scientists will develop greater understanding of how their research fits in with the education system and is perceived students. Teachers will deepen their knowledge of fundamental biology and current techniques and expose their students to materials and information that they may not otherwise have access to. Students will perceive the importance of the topics they are studying when connected to current research, encouraging them to see research as a relevant and attractive career choice.&nbsp;SCoPE will be assessed and evaluated in partnership with the University of Cambridge Faculty of Education.</p>

Amount: £42,756
Funder: The Wellcome Trust
Recipient: University of Cambridge

Salary support 2018 - 2023 30 Sep 2018

<p>N/A</p>

Amount: £1,494,699
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding Medical Black Boxes: A Philosophical Analysis of AI Explainability 26 Jul 2018

<p>I plan during the next two years to develop a major, multi-year project into AI explainability in medical contexts. This project will connect existing literatures in philosophy of science, philosophy of medicine and medical ethics, where problems of understanding and explanation have been extensively studied, to the emerging literature on explainability in machine learning and the ethics of AI. The aim will be (i) to enhance our understanding of the problems AI systems raise for explainability in medical contexts and (ii) to collaborate with machine learning researchers to develop technical research apt to address these problems.</p> <p><br> The existing literatures on explainability and understanding in medicine are vast and have not previously been systematically connected to the ethics of AI. To lay the groundworks for a later grant proposal, this application proposes to conduct three pilot-studies, focusing on potential challenges from AI to: (1) mechanistic understanding, (2) clinical judgement and diagnostic reasoning and (3) informed consent. A part-time research assistant will assist in scoping the relevant literatures. Travel to groups at other universities and a workshop in Cambridge will furthermore help establish contacts with a network of researchers interested in the ethics of AI and AI explainability in medical contexts.</p>

Amount: £86,561
Funder: The Wellcome Trust
Recipient: University of Cambridge

Liability for Harms Caused by Artificial Intelligence in Healthcare 26 Jul 2018

<p>How will legal liability be assigned when an AI system causes harm? &nbsp;Does the law need reform?&nbsp; In a report&nbsp;published earlier this year, the House of Lords Select Committee on Artificial Intelligence identified these as crucial questions for on-going innovation in the AI sector.&nbsp; &nbsp;We will&nbsp;explore these questions in the healthcare context, providing an analysis of the liability landscape for harms caused by the use of machine learning algorithms in clinical care. &nbsp;Our analysis will focus on three different types of liability frameworks that might apply&mdash;negligence, product liability, and <em>sui generis</em> legislation&mdash;each of which raises legal and normative questions that have received insufficient attention. &nbsp;&nbsp;This research project will have three core outputs: (1)&nbsp;a summary report explaining the legal landscape and policy-relevant findings for a multidisciplinary audience; (2) a substantial piece of legal scholarship analyzing the contours of the landscape and the potential ways in which the law might be reformed to serve different&nbsp;policy goals; (3) a grant proposal for a multi-year research programme to examine in more detail some of the under-theorized legal and normative questions identified by this project.</p>

Amount: £55,719
Funder: The Wellcome Trust
Recipient: University of Cambridge

Health, Medicine and Society 11 Jul 2018

<p>The MPhil in Health, Medicine and Society (HMS) provides students with interdisciplinary training in the history, philosophy, anthropology and sociology of health and medicine. The programme is structured around taught modules across the four disciplines. These are keyed to three research essays (one pass/fail of 3,000 words; two of 5,000 words), supported by one-to-one supervisions. Students are guided by an overall course manager and individual subject managers to choose their modules and to identify a dissertation topic. The 15,000-word dissertation, also supported by one-to-one supervision, allows students to master a particular topic and the appropriate methods for addressing it. The programme is distinctive in training students in these four disciplines. No other programme in the UK does this. Moreover, because it is situated within a vibrant international hub of humanities and social sciences research in health and medicine, students are supervised by leading scholars in the field. Students arrive with a first-class degree (or equivalent) and learn to think critically and independently, employing a range of methods, about the meanings of health and medicine. HMS was launched in 2017, and from the outset has attracted outstanding students with tremendous promise for the future.</p>

Amount: £94,994
Funder: The Wellcome Trust
Recipient: University of Cambridge

Advanced photomanipulation microscopy at the Cambridge Advanced Imaging Centre 05 Jul 2018

<p>The Cambridge Advanced Imaging Centre (CAIC) is a research facility in the School of Biological Sciences at the University of Cambridge. Since opening in 2013, physical scientists at CAIC have worked with biologists to bring online several new and unique microscopes which are now utlised by over 100 research labs from 16 Departments.</p> <p>While pushing the frontiers of imaging technology, we have identified a critical lack in the ability to perform photomanipulation experiments combined with fast imaging. These experiments include optogenetics, photoactivation, ablation or bleaching specific regions of&nbsp;cells or&nbsp;parts of cells, sometimes deep in tissues, whilst imaging in real time from millimetre to nanometre&nbsp;scales. Research that will benefit from this technology spans multiple departments and a diverse range of groups, including many Wellcome Trust funded researchers.</p> <p>We are requesting resource to develop an advanced microscope capable of a wide range of manipulation and imaging modalities. This technology will require three major components:&nbsp; adaptive optics for fast shaping of light; extensive range of lasers to enable exploitation of existing and emerging fluorophores and the newest generation of spinning disk confocal&nbsp;unit with cameras for fast and and low photon number imaging.</p>

Amount: £586,743
Funder: The Wellcome Trust
Recipient: University of Cambridge

Ultrastructural imaging 05 Jul 2018

<p>This application is for funds to purchase a Transmission Electron Microscope (TEM) and necessary accessories to enable post-embedding immuno-electron microcopy to be performed. We also request funds for salary support for a full-time specialist technician to oversee tissue preparation, sectioning and microscope operation.&nbsp; The microscope will be located within the imaging facility within Capella (due to open in November 2018), a new research-dedicated building on the Cambridge Biomedical Campus (CBC), which will house the Wellcome Trust-MRC Cambridge Stem Cell Institute (CSCI) and the Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), and will be available for use by other research groups across the CBC.&nbsp; Access to ultrastructural imaging is <em>essential</em> for many research groups working with Capella and across the CBS.&nbsp; This investment will establish a core EM facility on the CBC, the importance of which is reflected by both the large number of PIs who have expressed their support for this application and the wide range of research questions for which ultrastructural imaging data will play a key role. The establishment of a core EM research facility for the CBC will provide the basis for subsequent expansion, enabling, for example, addition of equipment for 3D ultrastructural reconstruction.&nbsp;</p>

Amount: £251,744
Funder: The Wellcome Trust
Recipient: University of Cambridge

Rapid spatial imaging of subcellular dynamics 05 Jul 2018

<p>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.</p> <p>&nbsp;</p> <p>&nbsp;</p> <p>&nbsp;</p>

Amount: £300,420
Funder: The Wellcome Trust
Recipient: University of Cambridge

Menstruation and the moon in early modern England 08 May 2018

<p>The association of menstrual synchrony with the moon relates back to ancient mythologies. Historians largely dismiss the relevance of a lunar theory of menstruation by the Middle Ages, but&nbsp;the moon&rsquo;s ability to disturb a woman&rsquo;s womb through her menstrual blood was continuously discussed by early modern medical and natural philosophical writers. This project asks how the sympathetic connection between menstruation and the moon was manifest in learned discourses, vernacular knowledge, and everyday practices. Answering this requires studying women&rsquo;s knowledge, the relationship between natural and occult philosophy, and the link between theory and practice in medicine.</p> <p>This research draws together rich, diverse manuscript and printed sources to demonstrate how the influence of the moon over the female body was ubiquitous in early modern medicine and natural philosophy. In vernacular medical handbooks, the moon was a popular socio-cultural symbol of femininity and sexual difference. Its power over the female body was demonstrated through practice in recipe books, casebooks, female-authored almanacs and medical treatises on phlebotomy. The cause and consequences of its influence were debated through learned discourse, highlighting the temporal dynamics of menstruation, and the continuous significance of fluids to changing intellectual frameworks of the body.</p>

Amount: £100,057
Funder: The Wellcome Trust
Recipient: University of Cambridge

Uncertainty in the hippocampus 17 Jul 2018

<p>Hippocampal neurons are tuned to abstract, behaviourally highly relevant variables, such as the location of the animal (&quot;place cells&quot;), or particular memories being recalled (&quot;memory cells&quot;). However, it is unknown how these neurons represent a behaviourally equally important kind of information: the <em>uncertainty about location or memory</em>. Building on recent advances in the neural coding of perceptual uncertainty in neocortical sensory areas, we will develop computational models to study hippocampal population codes for uncertainty in location and memory. These models will unify a diverse set of empirical data, including place field stability and neural oscillations, under a coherent functional account. Moreover, as neocortical findings suggest that response variability may provide crucial clues about the neural coding of uncertainty, we will also make explicit predictions about this almost entirely neglected aspect of hippocampal representations: <em>response variability</em>, and its modulation under conditions associated with different levels of uncertainty. We will test these predictions by conducting novel analyses of hippocampal recordings in rats and humans. Our work will thus reveal how the &quot;GPS system&quot; of the brain achieves what any truly well-functioning GPS must: to not only represent a single point estimate of location but also the uncertainty about it.</p>

Amount: £1,140,205
Funder: The Wellcome Trust
Recipient: University of Cambridge

Mechanisms of lineage restriction in development and reprogramming. 17 Jul 2018

<p>Mechanisms that lead to the establishment and maintenance of cell identity are paramount for organismal health.&nbsp; They also underpin successful cellular reprogramming for disease modelling and cell replacement therapies. We will investigate the roles played by the epigenome and co-factors in regulating lineage transcription factor-mediated establishment and stabilisation of cell fate <em>in vivo</em> and <em>in vitro</em>.</p> <p>&nbsp;</p> <p>Firstly, controlled activation and degradation of engineered transcription factors (TFs) will be used to challenge cell identity in developing frog embryos.&nbsp; We will compare transcriptional profiles and chromatin landscape in &ldquo;permissive&rdquo; tissues that respond to TF over-expression by undergoing full lineage reprogramming, and &ldquo;non-permissive&rdquo; tissues that resist reprogramming, as well as probing heterogeneity of transcriptional response in individual cells. Secondly, mechanisms responsible for differential response to TF will be identified through interference with the epigenome as well as via alteration of the co-factors repertoire present in embryonic tissue. Finally, we will explore mechanisms underlying lineage fidelity in mammalian ES cells that have been engineered to co-express TFs specifying conflicting lineages.</p> <p>&nbsp;</p> <p>Overall, this work will reveal how the response to lineage determining TFs is controlled by integration of epigenetic features and co-factor availability in both the developing embryo and in reprogrammed mammalian cells.</p>

Amount: £1,998,310
Funder: The Wellcome Trust
Recipient: University of Cambridge