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Recipients:
University of Cambridge

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

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. 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.

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

Menstruation and the moon in early modern England 08 May 2018

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 the moon’s ability to disturb a woman’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’s knowledge, the relationship between natural and occult philosophy, and the link between theory and practice in medicine. 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.

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

Schwann cell-axonal communication during axonal degeneration and regrowth 25 May 2017

Myelinating and non-myelinating Schwann cells are reprogrammed after nerve injury into repair Schwann cells, specialized for maintaining survival of injured neurons and supporting axonal regeneration. This process is regulated by Schwann cell-intrinsic signals, such as the transcription factor c-Jun, however few other candidates have been identified. It is, currently, unknown how Schwann cell reprogramming is initiated, but unidentified extrinsic signals from injured axons are likely candidates. I aim to delineate the spatial and temporal regulation of Schwann cell-intrinsic downstream signals in real-time and define their role in repair Schwann cell function and axonal regeneration. Secondly, I aim to test the hypothesis that axon-derived signals initiate Schwann cell reprogramming during nerve injury. I will use cell culture, in vivo mouse models and a live and dynamic zebrafish larval model of nerve injury. This study will be the first to investigate how axon-intrinsic mechanisms of nervous system injury interplay with glial cell molecular responses to nerve damage, in real-time. Using cutting edge techniques in two species, this project will significantly advance our understanding of Schwann cell-axonal biology and tissue repair. Excitingly, this research may identify new potential therapeutic targets to improve poorly regenerating human nerves and treat patients with neuropathies.

Amount: £426,876
Funder: The Wellcome Trust
Recipient: University of Cambridge

Putting genomic surveillance at the heart of viral epidemic response. 05 Apr 2017

This proposal is to develop an end-to-end system for processing samples from viral outbreaks to generate real-time epidemiological information that is interpretable and actionable by public health bodies. Fast evolving RNA viruses (such as Ebola, MERS, SARS, influenza etc) continually accumulate changes in their genomes that can be used to reconstruct the epidemiological processes that drive the epidemic. Based around a recently developed, single-molecule portable sequencing instrument, the MinION, we will create a 'lab-in-a-suitcase' that will be deployed to remote and resource-limited locations. These will be used to sequence viral genomes from infected patients which will then be uploaded to a central database for rapid analysis. We will develop methods for a wide-range of emerging viral diseases. Novel molecular biology methods will allow us to sequence individual viruses within a patient. Bioinformatics tools will be developed simple enough for non-bioinformaticians to use, without reliance on Internet connectivity. We will develop software to integrate these data and associated epidemiological knowledge to reveal the processes of transmission, virus evolution and epidemiological linkage. Finally we will develop a web-based visualization platform where the outputs of the statistical analyses can be interrogated for epidemiological insights within days of samples being taken from patients.

Amount: £482,639
Funder: The Wellcome Trust
Recipient: University of Cambridge

Understanding mammalian interphase genome structure in mouse ES cells 05 Apr 2017

The folding of genomic DNA from the beads-on-a-string like structure of nucleosomes into higher order assemblies is critically linked to nuclear processes, but it is unclear to what degree it is a cause or consequence of function. We aim to understand whether the Nucleosome Remodeling and Deacetylation (NuRD) complex regulates chromatin structure to control transcription, or whether it is NuRD’s regulation of transcription that results in global changes in chromosome structure. We have calculated the first 3D structures of entire mammalian genomes using a new chromosome conformation capture procedure, which combines imaging with Hi-C processing of the same single cell. Our objectives are now: To study: 1) how interphase mammalian genome structure is established in G1; 2) the factors that drive this formation and; 3) how this organisation is regulated by chromatin remodellers (such as the NuRD complex) as mESC’s differentiate. To build a dedicated bespoke microscope for 3D double helix point spread function detection with light sheet activation, optimised for 3D single-molecule/super-resolution imaging of proteins such as the NuRD complex. To combine 3D super-resolution imaging and the biochemical processing steps of single cell Hi-C to directly correlate binding of protein complexes to regions of the structures.

Amount: £2,031,409
Funder: The Wellcome Trust
Recipient: University of Cambridge

An advanced cryoEM instrument for the University of Cambridge 07 Dec 2016

We seek support to consolidate an advanced electron cryo-microscopy (cryo-EM) facility dedicated to structural studies of biological macromolecular assemblies. The facility would provide a revolutionary new tool to the large structural biology community in the University that would enable acquisition of critical data in support of a wide and diverse range of projects tackling fundamental problems in molecular biology relevant to human health. Currently, the named applicants primarily use X-ray crystallography to study large assemblies, but many of these samples cannot be readily crystallised. The recent development of a new generation of direct electron detectors, together with sophisticated data-processing software, has dramatically improved cryo-EM analysis, which now achieves routinely sub-nanometer resolution. Until recently, researchers in the university did not have access to cryoEM, but this has changed with the recent Wellcome Trust award to purchase a cryo-EM instrument for sample screening and intermediate resolution structure determination. We are building on this support, to develop the second phase of our strategy and seek funding for an advanced microscope capable of high resolution structure determination to complement and extend our existing instrumentations.

Amount: £3,000,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Transgenerational Epigenetic Inheritance - Cichlid as the New Model 05 Dec 2016

I aim to take advantage of the cichlid fish of Malawi to study the interaction between transposable elements, non-coding RNAs, epigenetics and heritability. This is in line with the overall goal of my Investigator Award. I believe this system to be superior to equivalent experiments we might conduct in mice. This is due largely to the high phenotypic diversity and low genomic diversity of these fishes. At the time of writing of my Wellcome Trust Investigator Award the cichlid model was too immature to proceed with an experimental plan. Now we have the required genomics, RNomics and epigenetics (DNA methylation) are all in place

Amount: £218,440
Funder: The Wellcome Trust
Recipient: University of Cambridge

The metabolic regulation of hypoxia inducible transcription factors. 05 Dec 2016

We have recently identified a novel pathway for metabolic regulation of HIF1 alpha by the OGDHC1. To continue this new area of research, it is essential that we have the necessary funds to maintian our competitive edge within the field, without diverting resources from our successful ubiquitin studies. The initial research on HIFs has been conducted by a talented graduate student, Stephen Burr. The timing of this funding request is particularly important, as it will allow Stephen to transfer his skills with a sufficient overlap for a new postdoctoral researcher to pursue this project.

Amount: £127,447
Funder: The Wellcome Trust
Recipient: University of Cambridge

Computational tools for analysing developmental morphogenesis at the tissue-scale 05 Dec 2016

Computational tools for analysing developmental morphogenesis at the tissue-scale

Amount: £47,159
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role of aberrant RNA processing in the pathogenesis of Multiple Myeloma. 30 Sep 2017

A role for RNA binding and processing proteins in the control of eukaryotic cellular processes and in disease, including cancer, is emerging . I led the initial sequencing of the myeloma genome at the Broad Institute of MIT and Harvard. A key finding was mutations in RNA processing genes, DIS3 or FAM46C in 25% of cases. These findings have been independently corroborated, establishing these mutations as genuine drivers of the disease. DIS3 is the catalytic component of the exosome, an essenti al RNA processing complex. FAM46C is poorly characterized, but available evidence suggests it has roles in RNA processing in a lineage-dependent manner. This proposal seeks to better characterize these genes and mutations. Characterization of FAM46C mutations will be performed by knock-out of the gene from the DT40 cell line, determination of phenotype and rescue experiments. Lineage-dependent transcriptional pathways affected by altered transcript stability will be identified by RNA sequenci ng and confirmed in primary myeloma samples. Known aberrant RNA processing phenotypes associated with DIS3 loss/mutation will be sought by RNA sequencing in primary myeloma samples. The pathways affected by mutant DIS3 in myeloma will be identified using yeast genetic screens and classical yeast complementation experiments.

Amount: £250,346
Funder: The Wellcome Trust
Recipient: University of Cambridge

In vivo mechanisms of epithelial tissue morphogenesis 11 Jul 2017

Understanding how a tri-dimensional tissue is built from the genetic blueprint is a key frontier in biology. In addition to genes known to be important in specific aspects of morphogenesis, physical constraints and properties play a major role in building tissues. In this proposal, I aim to understand how the genetic inputs integrate with the mechanical properties of the cells and tissues to produce form. To investigate this, we study the early development of the Drosophila embryo. We have found previously that actomyosin-rich boundaries play an important role in two fundamental and conserved morphogenetic phenomena, axis extension and compartmental boundary formation. We have also found that an extrinsic force contributes to axis extension. We will build on these findings by first investigating how the actomyosin-rich boundaries form and how they might repair genetic patterns during axis extension. Second, we will ask how, during compartmentalisation, they control the planar orientation of cell division and also epithelial folding. Finally, we will examine the impact of actomyosin-rich boundaries and extrinsic forces on epithelial tissue mechanics. Our approaches will be interdisciplinary, combining genetic, quantitative and in silico analyses to find novel and universal morphogenetic rules.

Amount: £1,440,082
Funder: The Wellcome Trust
Recipient: University of Cambridge

The complete synaptic-level connectome of a nervous system and experimental connectomics 30 Nov 2016

Animals sense the local environment, learn and remember past events, predict future ones, and combine current and past information to choose appropriate motor responses. Underlying these capabilities is the nervous system, which continuously integrates multiple sources of information and chooses one response in exclusion to all others. Our vision is to study neural circuit function on the basis of known synaptic-level wiring diagrams. In Aim #1, we propose to map the complete wiring diagram of an insect, the Drosophila larval central nervous system, using serial electron microscopy. With the knowledge of the circuits formed by the identified and genetically accessible larval neurons we can study how circuits change either by experience or in disease. In Aim #2 we propose to read out the engrams, the persistent yet reversible structural circuit patterns that form in response to learning and that underlie long-term memories, using associative memory in the larval mushroom bodies as the model system. For circuits to assemble correctly while remaining plastic, hundreds of genes need to work in concert. In Aim #3, we will study the effects of mutations in select genes associated with neural diseases on the synaptic-level circuit structure, causing the disease phenotype.

Amount: £1,763,361
Funder: The Wellcome Trust
Recipient: University of Cambridge

Metabolic and Cardiovascular Disease. 30 Sep 2017

Not available

Amount: £2,352,000
Funder: The Wellcome Trust
Recipient: University of Cambridge

Developmental mechanisms 30 Sep 2017

Not available

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

Mechanisms of transport of the leaderless protein galectin-3 to the cell surface 31 Jan 2017

Unconventional protein secretion is a poorly understood physiological process in which proteins without an N-terminal signal sequence exit the cell. There are currently four proposed pathways by which unconventionally secreted proteins are thought to exit the cell: by direct translocation across the membrane, via secretory lysosomes, by release from exosomes or multivesicular bodies, or through membrane blebbing. No complete mechanism has been described for any of these pathways, representing a significant gap in our knowledge of protein trafficking. Unconventionally secreted proteins play important extracellular roles physiologically, but abnormal levels are associated with several human diseases, including metabolic disease. As such, this mechanism is interesting to gain an insight into disease as well as to broaden our understanding of cell biology. I will investigate the unconventional transport of galectin-3 to the cell surface. Galectin-3 will here be used as a model to understand the mechanism of unconventional secretion. Data-driven and hypothesis-driven approaches will feed into each other to form a picture of how galectin-3 is secreted. A CRISPR-Cas9 screen has identified potential proteins that decrease cell surface galectin-3, providing the starting point for further investigation. Hypothesis-driven experiments will be used to investigate aspects of the models previously proposed.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

The role and regulation of UHRF1 during epigenetic reprogramming 31 Jan 2017

During both mouse and human embryonic development there are two waves of global DNA demethylation associated with an increase in developmental potential: firstly during the development of the inner cell mass from the gametes, and secondly during the development of primordial germ cells. Although some of these changes in DNA methylation are correlated with gene expression, it is not understood why this epigenetic reprogramming is consistently so extensive. Until recently it was believed that most of this erasure of DNA methylation occurred actively. However, recent research has revealed that regulation of maintenance methylation accounts for the differing rates of demethylation in different reprogramming contexts. Across the majority of these different contexts, the activity of maintenance methylation is controlled by regulation of UHRF1 protein. This project aims to elucidate the mechanism by which UHRF1 protein is regulated during epigenetic reprogramming, then to use this knowledge to assess the importance of this regulation to the acquisition of pluripotency during mammalian embryonic development. This will improve our understanding of developmental and reproductive health and may even shed light on new or improved methods of reprogramming cells for therapeutic applications.

Amount: £26,820
Funder: The Wellcome Trust
Recipient: University of Cambridge

Machine Learning methods for microscopy image data in high-content screening 31 Jan 2017

An important area in drug development is understanding low-level molecular processes and pathways that cause diseases. These cellular phenotypes are high-dimensional and are increasingly being captured using single-cell assays and high-content imaging. In understanding natural cell trait variation and engineered variants, we can elucidate the cellular consequences of disease mutations. In my project, I will exploit cellular images in a range of contexts to investigate the link between genetic variation and cell trait variability using both natural genetic variation and engineered variants. To do so, I will develop machine learning methods to extract features from high throughput microscopy data, and to accurately account for genetic, environmental, and experimental sources of variability in them. Furthermore, I will work on integrative approaches using public genomic data to bring in other omics modalities, thereby tackling key challenges in the larger aim of deciphering disease and fostering drug development. I will use existing data from the HipSci project, high throughput drug screens from AstraZeneca, and, in addition, will design and oversee the generation of datasets through high-throughput CRISPR knockouts as part of Leopold Parts’ group at the Wellcome Trust Sanger Institute and Oliver Stegle’s group at the European Bioinformatics Institute.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Systematic Identification of Lineage Specification in Murine Gastrulation 31 Jan 2017

Single-cell genomics is a fantastic tool for studying developmental biology: it allows unbiased and large-scale study of gene expression at the correct resolution for cell fate decision making. New fluidics systems provide the capability to study tens of thousands of cells simultaneously - as many as there are in the young embryo. For my PhD, I will analyse scRNA-seq data generated on this platform, studying mouse gastrulation between E6.5 and E8. I will be able to study this process at both an exceptional cell-level resolution (thanks to the fluidics) and at an unprecedented time resolution, at 0.1 day intervals. My focus will be on identification of lineage specification, and how cells make their fate choices. I will need to develop new methods to account for the large numbers of cells assayed, the numerous lineage decisions made, and heterogeneity of speeds of development across and between embryos. I hope to produce a map of lineage specification from epiblast (E6.5) cells through to every cell type present at E8. This work will provide a developmental atlas through gastrulation, and general inferences on cell fate decisions may provide insight for cellular reprogramming and regenerative medicine.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge

Functional proteomic analysis of novel antiviral restriction factors in primary leukocytes 31 Jan 2017

This project aims to identify and characterise novel antiviral restriction factors (ARFs) that play key roles in preventing infection of primary leukocytes. ARFs may function by preventing viral entry or exit at the cell surface, or replication at various intracellular stages. I will focus on the subset of plasma membrane (PM) ARFs, which will be identified by two properties: interferon (IFN) induction and virally-induced downregulation. For this I will employ tandem mass tag-based MS3 mass spectrometry, enabling quantitation of PM proteins in primary leukocytes. Key Goals: 1. Use IFNs and infection with two important human pathogens, human cytomegalovirus and HIV as a functional screen to identify novel cell surface ARFs 2. Investigate how these ARFs inhibit viral infection, and how are they targeted for destruction by viruses. The use of IFN as part of the functional screen will additionally enable exploration of the difference in effects between IFNalpha, beta and lambda at the PM, a subject which is currently surprisingly poorly understood. This will provide important insights into human immunity in its own right. Understanding how viruses interacts with and targets ARFs for destruction will have important implications for therapy.

Amount: £0
Funder: The Wellcome Trust
Recipient: University of Cambridge