PhD Studentship in H&SS

Mapping critical psychiatry: a transnational study of critical psychiatry’s reception in Western Europe and the US, 1965-today The 1960s and 1970s marked a decisive change in the history of psychiatry critique, when in the UK, in Germany, and the US therapeutic communities and patients’ collectives formed outside of psychiatric institutions. Some of them were guided by psychiatry reformists, for instance R. D. Laing, others were self-managed by psychiatric patients as a counter-reaction to existing psychiatric institutions.

My research pursues two main goals: first, to offer an understanding of critical psychiatry as an international counter-cultural network which circulated knowledge and subversive practices across national borders; second, to analyse how psychiatry critique became a powerful tool for patients to confront social marginalisation, lack of rights and isolation.

Based on original oral history, archival sources, and literary sources, I will map out a transnational historiography of critical psychiatry that revises existing narratives within the limits of national borders. My project constitutes the first attempt to examine in depth the Philadelphia Association, the governing body of various housing projects for psychiatric patients in London, as well as it does justice to the under-researched critical psychiatry scenes in Germany and the US.

In sum, I will produce new perspectives on key historical developments that have lead up to critical psychiatry’s contemporary significance.


PhD Studentship in H&SS

ERG11 Social Science and Bioethics, Early Career Awards

Changing minds: mapping out the bioethical dimensions of psychedelic-assisted psychotherapy Psilocybin-assisted psychotherapy is likely to become a licensed treatment in the US within two years. However, clinically-relevant doses have a number of surprising ‘side-effects’: they can cause long-term changes to political values and personality, increase prosociality and aesthetic appreciation, and induce mystical experiences of long-lasting spiritual significance connected to changes in religious belief. These changes remain under-researched but challenge several ethical concepts, including authenticity and autonomy, beneficence, and informed consent. The project will begin by systematically reviewing the non-clinical changes reported in the empirical literature to develop a conceptual analysis of these changes within a medical ethics framework. In addition, the perspectives of patients and practitioners of psilocybin-assisted psychotherapy concerning these changes remain unknown, and they are not addressed either in the informed consent process or in therapist training manuals. As such, the project’s second stage will use qualitative empirical methods to provide an account of their experiences and understanding of these changes. Together, the two elements of the project will demonstrate how psilocybin-assisted psychotherapy challenges orthodox conceptualisations of psychiatry, which marginalise spirituality and experiences of awe, as well as requiring policymakers such as NICE and their National Collaborating Centres to revise their approach to foreseen-but-unintended consequences of treatment.

Grants awarded from 1 October 2005 to 30 June 2021

Creative Commons Attribution 4.0 International (CC BY 4.0)


PhD Studentship in H&SS

ERG10 Medical Humanities, Early Career Awards

The Transparent Womb: Gestational Labour, Reproductive Technologies, and the Politics of Visual Culture Particular reproductive technologies can make visible elements of the process of biological procreation, but this is not a neutral process. How these technologies see, and are themselves seen, influences the way reproduction itself is understood. Even within current feminist theorising, there is insufficient research into the role of visual cultures of reproductive technologies in the construction of cultural imaginaries surrounding biological reproduction.

Using social reproduction theory as a framework, this PhD will explore the gender politics of the visual representation of historical and emerging reproductive technologies, and investigate the cultural impact of this representation. It will use archival research (extending to advertising, product design, media coverage, and activist ephemera) to explore three case studies: 1. Conception – egg-freezing and IVF; 2. Gestation in process – from ultrasound to the artificial womb; 3. Political contexts – alternative feminist reproductive technologies.

The thesis will explore the gender (and racialised) politics of how historical and emerging reproductive technologies represent gestation, and how they themselves are visually represented. It will analyse the effect of this representation of reproductive technologies on the cultural imaginary, particularly in terms of its role in facilitating or prohibiting social recognition of gestation as a form of reproductive labour.


PhD Studentship in H&SS

Exploring Everyday Ethics in Palliative Care in China: A Qualitative Empirical Bioethics Study Existing research and training in palliative care ethics appear not to focus on, or be tailored to, practice in China. This research aims to fill these gaps by: first, identifying and exploring the ethical challenges Chinese healthcare professionals have confronted during their provision of palliative care; second, identifying the ethical training they have received and the extent to which they feel prepared to address relevant challenges; and, third, proposing changes, for example, to existing training in order to better equip these professionals. The significance of this research includes offering up-to-date knowledge of palliative care provision and relevant ethical training in China, assessing the utility of these training schemes and eventually making insightful suggestions.

This is an empirical bioethics project, which has three phases (mapping-framing-shaping). The mapping phase involves literature reviews. The framing phase involves qualitative research. The researcher plans to retrieve and thematically analyse empirical data via one-to-one semi-structured interviews. Considering the unique cultural and social background, the data collection will be undertaken in Mandarin in selected hospitals in China. The shaping phase then combines the previous theoretical and empirical findings, using an empirical bioethics methodology - reflexive balancing - with a view to making recommendations for future practice.


Innovations AIGH Enterics Flagship

Dr Tonney Nyirenda, Dr Marc Henrion, Prof Neil French

Seroepidemiology in Africa for iNTS vaccine (SAiNTS) Invasive non-typhoidal
Salmonella (iNTS) is estimated to cause 535,000 illnesses, 77,500 deaths, and the loss of
4,263,500 disability-adjusted life years (DALY’s) every year, with 86.7% of the global burden
falling in sub-Saharan Africa (sSA). The proposed SAiNTS study will work with the EU-funded
Vacc-iNTS consortium, and will complete a comprehensive rural community-based seroepidemiological
study in a malarial area, measuring age-stratified exposure, susceptibility and
natural immunity to NTS, and leveraging multiple additional cohort datasets, with the
overarching goals of:
- Accelerating the clinical development of 3 new iNTS vaccines in early clinical
development through phase 1 and phase 2a immunogenicity studies
- Providing a model contributing to realistic assessments of the impact of iNTS
vaccination in varying epidemiological settings across Africa.
The SAiNTS study, accordingly, has the following specific aims:
Aim 1: Develop a regression model for age-dependant, naturally acquired immunity against
iNTS disease (alphaLPS-IgG antibody and SBA) and compare to the age-stratified incidence of
Salmonella enteric infections (eNTS).
Aim 2: Estimate a Correlate of Protection for invasive NTS, based on naturally acquired
antibody levels and known age-stratified disease incidence.
Aim 3: Assess the effect of different iNTS risk factors on the age-dependent acquisition of
natural immunity, and how they might impact on estimated correlates of protection and iNTS
vaccine impact in different scenarios.


PhD Studentship in H&SS

Living in a World of Voices: An Interdisciplinary Investigation of Non-Clinical Voice-Hearers in Context A growing body of psychological research has identified a population of individuals who hear voices outside of the context of pathology. These "non-clinical" voice-hearers have been the subject of a variety of studies aimed at understanding their relationship with clinical voice-hearers. This research, which often relies on standardized psychological measures, fails to explore the broader context in which these experiences occur. Non-clinical participants are often recruited from spiritual communities who accept anomalous experiences and offer meaningful frameworks in which to understand them. The proposed research will address this gap in the literature.  Drawing on theory and methodology from anthropology, psychology, and philosophy this research will explore the ways in which the voice-hearing experiences of these individuals are shaped by the larger contexts of their lives. In particular it will seek to understand the ways in which community attitudes towards anomalous experience such as voice-hearing may impact appraisals of these experiences.


PhD Studentship in H&SS

The Doctrine of Signatures in Early Modern Medical Practice Early modern Paracelsian physicians, natural historians, chemists and lay practitioners were united in their belief that a plant’s morphological resemblance to a human body part indicated its curative effect. My doctoral research will result in the first monograph to examine how the doctrine of signatures was applied, developed and transformed through medicinal and chymical practice in Germany and England. Through the exploration of personal archives, prescriptions and recipes, I will trace the formation and transmission of this doctrine among chymical physicians, apothecaries and domestic practitioners. I hope to connect histories of mystical philosophy and intellectual developments with recent works on the practices of healing and knowledge transmission. I hold that the doctrine of signatures was not a unified mystical theory once proposed and discredited by "modern science", as argued by philosophers and historians since Michel Foucault, William Ashworth, James Bono or Peter Harrison. Instead, it was a fluid, malleable set of ideas developing in conversation with humanistic learning, experiential knowledge and everyday practice, which survived well into the late seventeenth century. In this way, I hope to challenge the still-dominating narrative on the rise of modernity and scientific revolution.


PhD Studentship in H&SS

Informality and the Right to Health: How informal networks shape access to water in the Makoko settlement This interdisciplinary PhD explores how different stakeholders involved in water delivery affect access to water in the Makoko settlement in Lagos, and which implications this holds for socio-spatial health inequalities. In Lagos, vested interests behind public health agendas manifest through urban water insecurity while informal water networks emerged as a counter-narrative to public service absenteeism partly rooted in a colonial urban planning legacy. The main hypothesis is that the reproduction of power relations along socio-spatial gradients is facilitated by reinforced idioms of informality, aiming to justify the lack of water infrastructure and underservicing of specific low-income groups and thereby intrinsically re-producing the very informal networks that disrupt municipal water services and leading to a widening of the urban health gap. Methodologically, I will intersect statistical and geographical data with cognitive mapping, semi-narrative qualitative interviews and dwellers’ self-report on health conditions. Further linking historical explanations for the water crisis to empirical data, my research strives to challenge orthodox development and planning discourses based on notions of an "African exceptionalism" vis-à-vis the "European master narrative" while contributing to the theoretical and empirical development of the "right to health" as a prerequisite for the "right to the city" and the universal human rights.


PhD Studentship in H&SS

Writing mental illness: narrative insurgency and experimental form in British and American women’s writing from 1965 This thesis will consider experimental form in female-authored representations of mental illness in British and American writing, 1965-present. The narrative and formal experimentation of modern women’s literature challenges both literary conventions and the valorisation of testimonial mimetic narratives about mental illness within the Medical Humanities. Previous study on the topic of women and madness focuses on the content of women’s writing about mental illness more than their formal strategies, thus assessing their writing for its testimonial value rather than its literary sophistication. This thesis will locate illness, not as a metaphor or a device, but as an embodied state, which produces rich aesthetic possibilities and textual forms. It will investigate the opportunities that intermediality - images and non-standard typography - offers for challenging narrative homogeneity and how women writers have critiqued the narrative expectation of empathy in the context of mental health. Considering women’s experimental literature as a genre, I will look at prose fiction, graphic novels, and zines. By comparing the relationships between activism and art, personal experience and experimental fiction, image and text in women's writing, this thesis will offer a fresh framework for approaching the representational politics of mental health across disciplines and within mental healthcare provision.


Strategic Support: Science

Dr Sam Behjati, Prof Neil Lawrence, Dr Kerstin Meyer, Prof Elizabeth Robertson, Dr Omer Bayraktar, Prof Berthold Gottgens, Dr John Marioni, Dr Sarah Teichmann

Human Cell Atlas - development atlas extension We propose to generate an in-depth single cell and spatial atlas of embryos during late organogenesis, at 6/7 post conception weeks (PCW). This project will form a blueprint for a complete HCA development cell atlas, which will ultimately cover all accessible developmental stages week by week.  We will leverage genomics technologies to profile single cells from dissociated tissues and within intact tissue sections, and deploy cutting-edge computational methods to reconstruct, in silico, a three-dimensional atlas of the whole human embryo.  This work will significantly extend our existing WSSS-funded Development Cell Atlas research programme, which is focused on organ-based profiling.  Our reconstruction of a complete human embryo atlas will provide a blueprint for establishing high resolution molecular-based anatomical landmarks during human development, harmonizing developmental knowledge across species, and establishing a foundational resource with significant implications for developmental and childhood disorders, regenerative medicine and tissue engineering.


Sanger Resource Collaboration

Dr Omer Bayraktar, Dr Sam Behjati, Prof Neil Lawrence, Dr Kerstin Meyer, Prof Berthold Gottgens, Dr John Marioni, Dr Sarah Teichmann, Prof Elizabeth Robertson


Strategic Support: Science

Dr John Marioni, Dr Sam Behjati, Prof Neil Lawrence, Dr Kerstin Meyer, Prof Berthold Gottgens, Prof Elizabeth Robertson, Dr Sarah Teichmann, Dr Omer Bayraktar


Strategic Support: Science

Dr Sam Behjati, Dr Omer Bayraktar, Dr Sarah Teichmann, Prof Neil Lawrence, Dr John Marioni, Dr Kerstin Meyer, Prof Berthold Gottgens, Prof Elizabeth Robertson


Strategic Support: Science

Dr Kerstin Meyer, Dr Sarah Teichmann, Prof Berthold Gottgens, Dr John Marioni, Dr Omer Bayraktar, Dr Sam Behjati, Prof Neil Lawrence, Prof Elizabeth Robertson


Principal Research Fellowship Renewal

The role of non-histone proteins in chromosome structure and function during mitosis I propose to study how a set of key proteins (condensins I/II, cohesin, Kif4A, topo IIalpha) mold the chromatin fibre into its characteristic rod-shaped helix of loops in mitosis. Using a transformative system allowing us to obtain cultures entering mitosis with near-perfect synchrony we will adopt an interdisciplinary approach involving genomics (Hi-C, Capture-C, cut & run), proteomics, crosslinking, microscopy and molecular modelling to resolve changes in chromatin fibre and chromosomal protein organisation on a minute-by-minute basis during mitotic entry. Using non-toxic synchrony methods plus acute (and reversible) protein depletion with auxin degrons, we will determine when, where, how and with whom these proteins act to shape mitotic chromosomes. Access to the single copy chicken Z chromosome with its unique-sequence centromere allows us unprecedented mapping of the chromatin folding and protein distribution at a vertebrate centromere during this process. Following our discovery that RNAs mediate assembly of the mitotic chromosome periphery compartment (MCPC) downstream of Ki-67, we will initiate a new research direction identifying the proteins and RNAs involved, and determining their functional significance for chromosome segregation. Lastly, we will optimise methods for isolating human artificial chromosomes (HACs), avoiding unwanted DNA rearrangements that endanger future synthetic genome efforts.


Research Fellowship in H&SS

Social Science and Bioethics Interview Committee

The ethics of tracking infectious disease transmission New ‘pathogen sequencing technologies’, which have the power to identify and describe infectious disease transmission networks, are transforming public health practice. They also raise practically important ethical questions (for example regarding privacy protection), as-well-as conceptual and normative questions concerning responsibility for disease transmission, blame and the obligations of various actors.

This empirical bioethics study will combine qualitative research with normative ethical analysis to develop an account of ethical practice in the use of technologies that can identify and describe infectious disease transmission networks.

This will be achieved by answering the following research question:

 What are expert and lay views on the potential social consequences and ethical risks of identifying transmission networks through the use of pathogen sequencing technologies?
 What ethical norms concerning transmission of infectious disease underpin these views?
 How do the concepts of personal responsibility, blame and obligation bear on the ethics of using pathogen technologies to identify and describe infectious disease transmission networks?
 What contextual factors influence ethical norms and ethical practice in this area?


PhD Studentship in H&SS

London School of Hygiene & Tropical Medicine

A health policy analysis of vaccine policy decisions in the Association of Southeast Asian Nations region to develop a framework to guide vaccine policy decisions: emergence of mandatory vaccine agendas, decision making process and influences.  Vaccine policy agendas, decision making process and influences to the decisions highly vary across countries. In recent years, mandatory vaccination policies have been introduced globally, to enforce specific vaccinations on target populations in a country. The policies pose various ethical and legal dilemmas that have been highly debated by academics, policy makers, and country citizens. Some studies have evaluated the policy impact on vaccine coverage and discussed ethics and perspectives of stakeholders. However, research has been geographically biased to Europe and United States; though the policies have been adopted globally, including among the member states of the Association of Southeast Asian Nations. Given the disparities in results and controversy of the policy, the policy decision-making on mandatory vaccinations have not been well understood. To fill this gap in research, this qualitative study will select two countries in ASEAN as cases, and apply policy theories to data collected through literature reviews and key-informant interviews. The study aims to understand the emergence of mandatory vaccinations in policy makers agenda and the actors involved, context of policy adoption and the process and influences of the policy decision. This study aims to develop a vaccine policy decision framework to guide future vaccine policies.


Research Fellowship in H&SS

Understanding ethnic variations in the prevalence and experience of food insecurity, and its interaction with mental health: A mixed-methods longitudinal research programme This Fellowship will explore the intersection of contemporary marginality, ethnicity and mental health through an integrative mixed methods study of the prevalence, causes, and lived experience of food insecurity in the UK.

The goals are to:

 understand variations in the prevalence and socio-demographic correlates of food insecurity, and its interaction with mental health, among UK ethnic groups
 understand how different ethnic groups conceptualise ‘food insecurity’ and how this shapes its interaction with their mental health
 understand ethnic variations in the lived experience of food insecurity, including food bank use, and its interaction with mental health
 theorise the nexus of marginality, ethnicity and health in post-industrial Britain
 provide a platform for mixed-methods, longitudinal analyses of food insecurity.

The Fellowship is composed of two interlinked studies, integrated within a new theoretical framework on contemporary marginality. Study 1 employs Qualitative Longitudinal Research methods (N=30) over two years to explore the experience of food insecurity, the contingent nature of ethnicity, and the interaction of food insecurity, ethnicity and mental health.

Study 2 will estimate the prevalence, socio-demographic correlates and mental health causes and consequences of food insecurity and food bank use among UK ethnic groups, using existing and commissioned national and local survey data.


Coronavirus

Prof Benjamin Cowling, Dr Stefan Fernandez, Dr Chee Fu Yung, Dr Kathryn Anderson, Prof Lin-Fa Wang

Serological studies to quantify SARS-CoV-2 population infection risk in Singapore, Hong Kong and Thailand We propose a prospective serological study to investigate the incidence of SARS-CoV-2 infection in the general population in three Asian settings: Singapore, Hong Kong and Thailand. The study will aim to measure the age-specific seroprevalence and incidence of SARS-CoV-2 infection at 3 time points, each 6 months apart. Age-specific incidence estimates will be applied to the census population to obtain numbers of infections in the population at each time point. These estimates will be compared with external data on COVID-19 hospitalisations and deaths in each setting, to calculate age-specific infection-hospitalisation and infection-fatality ratios. SARS-CoV-2 antibody kinetics will be defined by studying changes in antibody titres over time. Risk factors for infection will be studied by comparing SARS-CoV-2 seroconverters and non-seroconverters with respect to epidemiological exposures. This study will provide crucial information regarding population exposure and SARS-CoV-2 transmission dynamics, and will provide a complete picture of the relationship between clinically apparent and asymptomatic infections.


Coronavirus

Dr Oumou Maiga-Ascofare, Dr Amadou Sall, Dr Tajudeen Raji, Dr Anani Badje, Dr Mathias Altmann, Dr Fabien Taieb, Dr Kenneth Baillie, Prof Peter Horby, Prof Souleymane Mboup

Kwame Nkrumah University of Science and Technology

The African coaLition for Epidemic Research, Response and Training, Clinical Characterization Protocol (ALERRT CCP) As part of the response to the emergence of COVID-19, the World Health Organization Africa Regional Office is organizing various Infection Prevention and Control (IPC) and critical care training activities targeted at Low and Middle-Income countries (LMICs) in Africa. While the initiatives taken by WHO/AFRO are critical, training for research into the disease also needs to be targeted at the same LMICs, because being an Emerging Infectious Disease, we need to "learn-as-we-go". Clinical research on COVID-19 will have to be closely integrated with the IPC, clinical care, and epidemiological training activities, including use of the WHO First Few X (FFX) Cases and contact investigation protocol for COVID-19. ALERRT proposes to work closely with the WHO/AFRO and Africa CDC and existing networks and structures across Africa and globally to provide the fore-mentioned clinical research training and support. ALERRT is a member of the Global Federation - ISARIC, which has developed a Clinical Characterization protocol for COVID-19. This protocol been endorsed by the WHO and is currently being used in China and across the UK and Europe.Being already established and conducting activities in sub-Sahara Africa, the ALERRT network has the capacity to effectively implement the proposed project.


Coronavirus

Prof Juliet Pulliam, Dr Jinal Bhiman, Prof Neil Martinson, Dr Cecile Viboud

Characterization of SARS-CoV-2 transmission dynamics, clinical features and disease impact in South Africa, a setting with high HIV prevalence Factors prevalent in Africa such as malnutrition, HIV, tuberculosis and limited access to healthcare, among others, may impact both transmission dynamics and disease progression associated with SARS-CoV-2 infection as well as the burden on the healthcare system and society.We aim to characterize key transmissibility and clinical features of and the antibody response to SARS-CoV-2 as well as to enhance surveillance for COVID-19, identify groups at increased risk of severe illness, estimate the disease burden of medically- and non-medically attended mild, severe-non-fatal and fatal illness and forecast the impact of the outbreak on the healthcare system and the society in South Africa. Particular emphasis will be given to HIV-infected individuals. The aims will be achieved through the implementation of shedding and household transmission studies, collection of sequential serum samples, enhanced facility-based (hospitals and clinics) surveillance among patients with mild and severerespiratory illness in well-established population-based surveillance sites where incidence can be calculated, and healthcare utilization and serological surveys in selected communities. In addition, digital surveillance (based on Google searches) will be used to complement virological surveillance and nowcasting and short-term forecasting (up to 4 weeks) will be implemented over the duration of the epidemic.


Coronavirus

Dr Jennifer Hill, Prof Adrian Hill, Prof Tandakha Dieye, Prof Katie Ewer, Dr Charles Agoti, Prof Andrew Pollard, Prof George Warimwe

Investigation of pre-existing immunity to coronaviruses; implications for immunopathology and pathophysiology of COVID-19 disease Background; It is unknown how prior exposure to commonly circulating human coronaviruses (HCoV) impacts immunity against highly-pathogenic species (SARS, SARS-CoV-2  &  MERS). There are limited data, across Europe, Asia and Africa, on the prevalence of infection and seroconversion against widely circulating and mildly symptomatic HCoVs (229E, NL63, OC43, and HKU1). There is a current supposition that antibody-dependent-enhancement (ADE) may play a role in the pathophysiology of COVID-19. ADE occurs when non-neutralizing antiviral proteins facilitate virus entry into host cells, leading to increased infectivity in the cells. In such cases, higher viremia has been measured and the clinical course of disease can be more severe. In preclinical animal models, immunopathology was observed after challenge following vaccination with some SARS vaccines. Therefore, concerns have been raised regarding the impact of immunopathology and ADE on prophylactic vaccination against SARS and possibly SARS-CoV-2.

Goals: to perform detailed systems serology of pre-existing immunity, in children and adults, from the UK and Africa, towards novel and commonly circulating coronaviruses.

Impact: These studies highlight the limited knowledge in the field and a need for a systematic approach to investigate cross-reactive humoral immunity against HCoV to  inform the immunopathology and pathophysiology of COVID-19.

Grants awarded from 1 October 2005 to 30 June 2021


Coronavirus

Prof Matthew Keeling, Prof Xavier Didelot, Dr George Githinji, Prof Matthew Cotten

COVID-19 Intervention Modelling for East Africa  (CIMEA) COVID-19 is a global threat to health, with many countries reporting extended outbreaks. To date 9 countries in Africa have recorded infection and it seems imminent that East Africa will have introductions and onward transmission. The SARS-CoV-2 virus (the aetiological agent of COVID-19) spreads rapidly (R0~2, serial interval about 1 week), and hence control will be difficult.  National plans for dealing with this public health emergency will benefit from predictions of the expected rate, distribution and extent of spread in countries throughout the region, and on the likely impact and feasibility of isolation and contact tracing interventions. We will support the emergency preparations through bespoke modelling, incorporating known demographic population structure, age-related contact patterns and existing mobile phone population movement data. In Uganda and Kenya we will collect epidemiological, genomic and behavioural data through health facility surveillance, household follow-up and contact studies to quantify uncertainties of SARS-CoV-2  virus epidemiology and contact patterns in well and unwell individuals. Results from the study will be rapidly communicated to the relevant authorities, and modelling code and analysis, and data including sequences, placed in the public domain in near real-time. This project could have lasting impact on the role of research in policy decisions.


Coronavirus

Dr Nigel Temperton, Prof Kwok Yung Yuen, Prof Honglin Chen, Prof Zhiwei Chen, Dr Peter Kelleher, Prof Gavin Screaton

A comprehensive study of immunopathogenesis of SARS-CoV-2 infection Since December 2019 the emergence of severe acute respiratory infections (COVID-19) in China, caused by the new coronavirus SARS-CoV-2, has posed a huge threat to global health with fatality rates up to 10% in elderly patients. Almost 100% of patients showed bilateral patchy shadows or ground glass opacity in their lungs by chest CT scans indicating acute lung injury (ALI). Therefore, understanding the underlying mechanism(s) of ALI induced by SARS-CoV-2 is very important to inform vaccine safety and immunotherapeutic strategies. In this proposal, we will investigate the host immune responses and their association with severity of ALI in patient samples and animal models. We will bring together a team of experts with complementary expertise including immunopathology in coronavirus infections, up-to-date lab technologies, and know-how to ensure the feasibility of this study with the following goals:
1)    defining SARS-CoV-2 specific serum profiles (epitopes) using yeast display antigen library
2)    determining antibody functions including antibody-dependent enhancement (ADE) vs neutralizing activities in vitro assays
3)    studying T cell (CD4 and CD8) responses to whole SARS-CoV-2 genome
4)    evaluating ALI in response to live SARS-CoV-2 infection with or without passive immunity (antibody or T cells) generated from vaccine candidates in a humanized mice model.


Coronavirus

Prof David Robertson, Prof Martin Antonio, Prof James Nokes, Dr Ke Yuan

African COVID-19 Preparedness (AFRICO19) Our project, AFRICO19, will enhance capacity to understand SARS-CoV-2/hCoV-19 infection in three regions of Africa and globally. Building on existing infrastructures and collaborations we will create a network to share knowledge on next generation sequencing (NGS), including Oxford Nanopore Technology (MinION), coronavirus biology and COVID-19 disease control. Our consortium links three African sites combined with genomics and informatics support from the University of Glasgow to achieve the following key goals:
1. Support East and West African capacities for rapid diagnosis and sequencing of SARS-CoV-2 to help with contact tracing and quarantine measures. Novel diagnostic tools optimized for this virus will be deployed. An African COVID-19 case definition will be refined using machine learning for identification of SARS-CoV-2 infections.
2. Surveillance of SARS-CoV-2 will be performed in one cohort at each African site. This will use established cohorts to ensure that sampling begins quickly. A sampling plan optimized to detect initial moderate and severe cases followed by household contact tracing will be employed to obtain both mild to severe COVID-19 cases.
3. Provide improved understanding of SARS-CoV-2 biology/evolution using machine learning and novel bioinformatics analyses. Our results will be shared via a real-time analysis platform using the newly developed CoV-GLUE resource.


Wellcome Leap Inc. – Interim award

Wellcome Leap Inc.

Wellcome Leap Inc. – Interim award In early February 2020 Wellcome’s BoG approved the appointment of Regina Dugan as CEO of the Wellcome Leap Fund (WLF), the relocation of the WLF’s primary place of business to the U.S. and the creation of a U.S. not-for-profit entity within the Wellcome group (Leap US). This grant is a mobilisation fund to support the initial activities required for Leap US’ set up and strategy development, prior to the awarding of full grant which will be administered upon BoG approving the CEO’s strategy and business plan for the WLF.


Strategic Support: Science

Global Genomic Medicine Collaborative (G2MC)

IHCC Development of 2020 Scientific Strategy and Long-term Plan

   This proposal is for partial funding of the IHCC as it transitions from a nascent organization to a mature and sustainable one.  The IHCC’s inaugural summit was funded by the Wellcome Trust, the NIH, and the Medical Research Council of the UK. Since, the NIH has provided support for both administration of the IHCC, its second and third summit and pilot work on the Atlas and scientific projects.  The funding period from June 2020-2021 will be one of organizational maturing, strategic planning, demonstration of feasibility of prioritized cross cohort projects and the development of a business plan. Funding from new industry members and from HIROs is anticipated for growth and sustainability.  The Wellcome Trusts’ investment will be highly levered with NIH’s investment and is key to allowing the IHCC to launch itself with a robust charter and organizational structure, a scientific plan an Atlas and data structure that will make the IHCC’s assets accessible. Deliverables from this funding will be a) a strategic plan, b) a 4th ICS, c) completion of 3-5 pilot cross- cohort demonstration projects, and d) a compendium of opportunities for research across the globe, and e) formal engagement of funders toward a sustainable funding model.


Core costs grant

Not available

Discretionary Award – Directorate


Research Resources Award

Healthy Minds and Active Bodies: the promotion of health and wellbeing by UK youth movements This 24-month project focuses on cataloguing and preserving the archives of two influential youth movements:

 The Young Men’s Christian Association (YMCA)
 The Youth Hostels Association (YHA)

Both archives are held at the Cadbury Research Library, University of Birmingham.

Health and welfare of young people are guiding principles of these charities. Since their creation, both organisations have focused their activities on improving the mental and physical health of young people, with emphasis on working with those from disadvantaged backgrounds.

The YMCA archive comprises 978 boxes and the YHA archive comprises 405 boxes; all of which require detailed cataloguing in order to realise their full research potential. Both collections include minutes, reports, publications, photographs and ephemera. Material documents the work of both charities in improving young people’s physical health, mental wellbeing, and general fitness.

The outcome of this project will be two fully searchable electronic catalogues which will enable access and reveal the full research potential of these internationally significant collections.

Engagement activities with academics, researchers, students and members of the public will ensure that the collections are visible across a broad range of audiences.


Collaborative Award in Science

Prof Mary Reilly, Prof David Bennett, Prof Ahmet Hoke

Preventable axon degeneration in human disease Programmed axon degeneration (or Wallerian degeneration; WD) is a preventable and druggable mechanism of axon loss. WD is well-characterised in animals and highly conserved. Blocking WD alleviates axon loss and symptoms in multiple disease models, suggesting a common, downstream mechanism. Human data are essential to confirm the role of WD in specific human diseases, ensuring drugs under development are tested in highly-relevant disorders and patients. We reported mutations in rare human axonopathies that aberrantly activate WD, and lifelong rescue of a related mouse model. Our programme determines the wider involvement of WD in rare and common human disorders, specifically peripheral neuropathies and ALS, where axon degeneration is important. We use online resources (100,000 Genomes, Project MinE, UK Biobank, etc.) and targeted sequencing of well-phenotyped cohorts and test roles of gene variants in causation, risk and severity. We determine their functional impact using complementary human iPSC and mouse modelling and develop specific biomarkers of WD for clinical samples. This project will provide insight into pathogenic mechanisms and a firm platform for developing and testing therapeutics. Our team, a world leader in Wallerian degeneration and leading neurogeneticists in rare and common neuropathies and human iPSC modelling, is uniquely placed to deliver this.


Investigator Award in Science

Informing strategies for malaria eradication: a combined epidemiological and economics approach The last decade has witnessed substantial declines in the global burden of malaria; however, in recent years progress has stalled. We aim to combine a mathematical modelling framework with economic analyses to gain insight into the optimal global, regional and country strategies to achieve the ultimate aim of malaria eradication. Specifically:

 What is the optimal strategy to achieve malaria eradication? Should resources initially focus on high burden countries, elimination countries or a balance between these? How does this change as burden and transmission decline? How do competing aims in the short-term (e.g. the need to reduce morbidity and mortality) hamper achieving longer-term eradication aims?
 What is the trade-off between country priorities and regional and global strategies? How do competing national priorities determine regional and global success? What degree of international cooperation is needed and at what scale? What are the economic benefits and costs of co-operation to countries?
 How are strategies influenced by the wider political economy? How do competing priorities influencing national decision makers impact wider eradication efforts? How does weak governance and political constraints in national and international decision-making reduce the effectiveness of strategies?


Investigator Award in Science

Lymphatic biology in kidney development, health and disease The lymphatic vasculature is essential for health in vertebrates. Alongside roles in tissue fluid balance, cholesterol transport and immunomodulation, lymphatic vessels possess remarkable organotypicity, which underpins organ-specific lymphatic functions during embryonic development, health and disease.

Using the mammalian kidney as a model system, I will study two concepts responsible for the organotypicity of lymphatics: the cellular sources of lymphatic endothelial cells and molecular crosstalk between lymphatics and epithelia, a paradigm that may be applicable to other organs like lung and gut. I will focus on these processes in embryonic development, health and polycystic kidney disease (PKD); the most common genetic renal disorder, which features dysfunctional lymphatics. I will use several emerging technologies including high-resolution three-dimensional imaging, single-cell RNA sequencing, novel in vivo imaging modalities, targeted kidney delivery of therapeutics and computational modelling.

The insights arising from these experiments in this Investigator Award will enhance our understanding of lymphatic biology in kidney development, physiology and disease; areas in which the contribution of lymphatics is poorly understood. The findings will provide new directions and tools for understanding and manipulating lymphatic function in organogenesis, health and multiple disease processes.


Investigator Award in Science

Rhomboid-like proteins: from molecular principles to pathophysiological significance The goal of this proposal is to transform our understanding of both the molecular mechanisms and the pathophysiological roles of members of the rhomboid-like superfamily. At the mechanistic level, our long-term research into this group of polytopic membrane proteins has led us to the hypothesis that the core function of the rhomboid-like domain is specific TMD recognition of substrates (of the rhomboid intramembrane serine proteases) and clients (of the non-protease members of the clan). Using a structural and biochemical approach, we seek to understand the molecular details of how this specific recognition is achieved.

Biologically, rhomboid-like proteins have many functions, but we still have little understanding of their role in mammals, particularly of the rhomboid proteases. Building on our mechanistic aims, we plan to break this log-jam by pioneering systematic methods of substrate identification. We already know that iRhoms, catalytically inactive homologues of rhomboids, regulate inflammation, growth factor signalling and, as we have recently discovered, tumour growth. We plan to further elucidate these roles, both at the level of fundamental cell biology but also with a goal to reveal their potential medical significance. By the end of this work we expect to know which rhomboid-like proteins are useful therapeutic targets.


Senior Research Fellowship

The development of neural circuits for episodic and general memories This proposal aims to understand how neural networks for memory emerge during post-natal development, both during normal development and following early-life brain damage.

Episodic memories (memories of events and their spatio-temporal context), and generalised learning such as semantic memories (factual world-knowledge) are supported by different brain networks. Episodic memories are thought to be encoded initially by the hippocampus, whilst general knowledge would be extracted by integrating across experiences via hippocampus-neocortical interactions.

However, the ontogenetic unfolding of memory runs counter to this framework. Early development is characterised by the rapid acquisition of general knowledge, despite amnesia for specific events. Furthermore, sustaining early-life hippocampal damage results in dense amnesia for specific episodes, but general learning is relatively preserved.

We aim to resolve this apparent paradox by studying neural circuit activity in vivo, in conjunction with behaviour, in developing rodents.

Our goals are to:

1) Understand the development of hippocampal mechanisms supporting the generation of memory traces of specific events;

2) Understand the neural mechanisms that enable the association of items with their spatio-temporal context (episodic memory processing);

3) Discover how neural coding for generalised knowledge emerges across cortical-hippocampal networks during normal development, and identify networks supporting preserved learning after early-life hippocampal damage.


Investigator Award in Science

Population genomic analysis of HIV transmission fitness This proposal concerns the identification of genetic polymorphisms which alter the fitness of Human Immunodeficiency Virus (HIV-1), the robust estimation of virus fitness, and the characterization of how polymorphisms influence replicative fitness within hosts versus transmission to new hosts.

HIV evolves to evade the immune system, resist antiviral medications, and maximize its rate of replication within infected hosts. But at the epidemic level, natural selection promotes evolution of variants which are more transmissible. Natural selection within and between hosts can act in opposing directions, and evolutionary trends have been discerned from population based sampling of HIV such as a hypothetical transmission/virulence tradeoff.  Because HIV evolves at multiple scales, the fitness of a particular polymorphism should be characterized along multiple dimensions including its impact on replication within hosts and transmission to new hosts. We will develop a framework for characterizing genetic fitness along multiple dimensions by building on theory developed for estimating state-dependent speciation rates. These methods will be applied to several large population-based samples of whole-genome deep sequencing (WGDS) of HIV. The outcome of this analysis will be an unprecedentedly detailed characterization of how particular genetic substitutions influence HIV pathogenesis and transmission at the epidemic level.


Investigator Award in Science

Deciphering Bifidobacterium-diet-immune interactions in global infant populations  ‘First contact’ between Bifidobacterium and their infant host represents a critical developmental window.

Our studies show that supplementation with Bifidobacterium isolates that metabolize breastmilk positively influences the preterm infant microbiota. We have also shown that: full-term infants have mini-bifidobacterial ecosystems that form dietary (breastmilk) cross-feeding networks; that geographically-separated infants harbour Bifidobacterium isolates with key differences in genomic content, and that particular Bifidobacterium genetic variants drive beneficial immune programming.

Building on our established findings and preliminary data, bringing together global maternal-infant cohort samples and using integrated multi-disciplinary approaches, we will:

 Genetically characterise geographically distinct intra- and inter-infant Bifidobacterium populations
 Profile geographically divergent maternal breastmilk samples, link them to genetic and phenotypic variation in Bifidobacterium, and define novel breastmilk metabolism pathways.
 Determine how different Bifidobacterium communities influence immune responses, and how this relates to vaccine-related immunity.

We will significantly expand our fundamental knowledge by elucidating how Bifidobacterium species and genetic variants co-operate within an early-life diet (breastmilk) environment and define ‘signatures’ across different geographical regions. In a direct link to infant health, we will probe how these communities alter immune system development and vaccination responses. A fundamental understanding of these features will allow selection of Bifidobacterium-communities for next-stage translational projects.


Senior Research Fellowship Renewal

Defining ‘clinically actionable’ genetic mechanisms in atopic eczema risk and resolution Atopic eczema is an itchy condition characterised by skin barrier dysfunction and inflammation. It frequently causes chronic morbidity, but a subset of cases enter long-term remission, demonstrating that resolution may be a tractable therapeutic aim.
Eczema is highly heritable. Null mutations in FLG are the strongest genetic risk and a locus on chr11q13.5, for which the nearest gene is EMSY, has a multiplicative effect. We have shown that EMSY is a transcriptional regulator in skin, controlling multiple aspect of barrier formation.
We will investigate molecular mechanisms at these two major risk loci: chr1q21.3 (FLG, FLG-AS1 and related genes) and chr11q13.5 (EMSY and LRRC32), aiming to define pathways contributing to eczema resolution. Findings will be tested in a well-characterised birth cohort (ALSPAC), to confirm clinical relevance.
Analyses of European cohorts (n > 25,000) show evidence of gene-environment interactions in eczema, but these findings require validation. We will use an optimised skin organoid model to investigate three environmental factors (tobacco smoke, wash-products and pet allergens) for which there is evidence of interaction with FLG genotype. Detailed functional and biochemical phenotyping will increase understanding of gene-environment interactions.
This work will inform eczema prevention strategies and characterise mechanisms contributing to eczema resolution, as future therapeutic targets.


Investigator Award in Science

B cell activation in human GALT: drivers and consequences We have identified bifurcation in human B cell development from shortly after bone marrow exit. B cells following one trajectory express high levels of IgM and have a gut-homing phenotype when in blood. They selectively migrate through gut and ultimately give rise to marginal zone B cells (MZB). The other branch expresses low levels of IgM and is systemic. All stages of the gut-homing branch are vastly depleted in the autoimmune disease lupus nephritis.

We will ask:
1. What drives the lineage split that commits a subset of developing B cells to migrate into GALT, and how does this fail in lupus nephritis?
2. What happens to MZB and their precursors in GALT?
3. Do MZB emergent from GALT enter spleen and respond to further tissue specific cues?

We will apply cutting-edge technologies to identify the epigenetic marks and transcriptomes that reflect the key events in vivo and use these to compare pseudotime developmental sequences. We will merge deep single cell phenotype in tissues with paired transcriptomes of single cells in suspension to create a multidimensional map of events in GALT, and track subsequent clone evolution across tissues.

This understudied area of basic immunology is fundamental to good human health.


Collaborative Award in Science

Dr Luigi Sedda, Prof Koen Peeters, Dr Hmooda Kafy, Associate Professor Elfatih Malik, Dr Anne Wilson, Dr David Weetman, Prof Delenasaw Yewhalaw, Dr Endalamaw Belachew, Dr Thomas Churcher

Controlling emergent Anopheles stephensi in Ethiopia and Sudan (CEASE) Malaria is predominantly a rural disease in Africa and whilst urbanisation is occurring rapidly it was thought unlikely to lead to substantial increases in malaria transmission because Africa lacks an urban-adapted malaria vector. However, Anopheles stephensi, a common and efficient urban malaria vector in South Asia and the Persian Gulf, has recently been found in the Horn of Africa, including Ethiopia and Sudan and is associated with a rise in malaria in Djibouti. This prompted the WHO to call for urgent action to control the spread of the vector. This proposal brings together biologists, epidemiologists, mathematical and geostatistical modellers and medical anthropologists with the aim of preventing the spread of An. stephensi in Ethiopia and Sudan. The research will: (i) investigate the distribution, routes of introduction/reintroduction and spread of An. stephensi; (ii) quantify the importance of An. stephensi for malaria transmission and iii) evaluate multi-sectoral vector control strategies. This incredibly timely research will quantify the threat posed by An. stephensi in Ethiopia and Sudan and identify control measures to reduce populations and combat further spread in Africa. Historic examples (e.g. An. gambiae in Brazil) demonstrate that without prompt action, invasive species can become established with massive impacts on morbidity/mortality.


Collaborative Award in Science

Prof Saeed Hamid, Prof Eleanor Barnes, Prof Peter Vickerman, Prof Dr Saad Niaz

Treating hepatitis C in Pakistan. Strategies to avoid resistance to antiviral drugs Hepatitis C infection can be cured by affordable drugs, leading to calls to expand treatment among the 70 million infected people worldwide. Many countries have initiated ‘test and treat’ programmes. e.g. India have reported treatment for ~40,000 patients in Punjab. However, 5-10% of infected people don’t respond and may develop viral resistance and go on to develop liver cancer. Salvage regimens are often unaffordable/unavailable.

We will address the remaining questions in hepatitis C therapy. We will work in Pakistan where hepatitis C is highly endemic (4.8% sero-prevalence) with regions reaching sero-prevalences of 10-20% (hot-spots). We will link with the government HCV programme to determine the most effective treatment for people who don’t respond to initial therapy. We will examine viral resistance in treatment failures to determine whether resistance dissemination is problematic and develop strategies to address it. We will determine whether some viruses are more oncogenic, allowing targeted surveillance. We will measure incident infection in the uninfected population (in hot-spot areas) and treated people, using modelling to determine what proportion of people must be cured to prevent disease recurrence. These data will inform the global elimination agenda and provide crucial data to develop optimised elimination programmes.

Grants awarded from 1 October 2005 to 30 June 2021


Investigator Award in Science

Studying lentiviruses to understand mechanisms, regulation and consequences of nucleic acid sensing I propose a new overarching hypothesis that innate immune sensing of nucleic acids, cell cycle regulation, and a hitherto unappreciated function of endogenous viral elements, contribute to an integrated system of regulating inflammatory responses to infection. Encouraged by preliminary data we will investigate the relationship between cell cycle and innate immune sensing by manipulating cell cycle and measuring responses to infection and relating expression of endogenous viral elements to cell cycle and their activation of nucleic acid sensing. We will also study the mechanisms of lentiviral Vpx/Vpr proteins taking molecular genetic and structural approaches to examine their enhancement of viral expression, manipulation of endogenous element expression and inhibition of innate immune signaling. We will also investigate the role of G3BP1 stress granules and their role in coordinating nucleic acid sensing with regulation of translation by PKR, mediated through cyclophilins. Overall our approach is to manipulate cellular pathways, for example cell division, and test sensing responses or manipulate virus and measure activation of sensing or viral inhibition of sensing. We expect to reveal mechanisms of nucleic acid sensing that can be tractably inhibited therapeutically and provide new mechanistic knowledge of inflammatory pathways broadly relevant to infectious and inflammatory diseases.


Investigator Award in Science

Roles of intron retention and splicing factors in axons In recent years, RNA dynamics in axons and dendrites have arisen as central to neuronal maturation and maintenance of healthy neuronal connectivity. However, the functional roles of transported mRNAs and their binding proteins are scarcely understood. Some of the proteins associated to local mRNAs are splicing factors and spliceosome proteins.
We recently demonstrated that their axonal role is complex, as, in developing neurons in vivo, the splicing factor SFPQ and the U1 spliceosome protein snRNP70 locally control axonal shape and connectivity, through modulation of the local transcriptome. These findings open two essential questions: how are these splicing proteins shaping the transcriptome landscape locally and what is the molecular nature of the axonal interactions between specific mRNAs and these two proteins?
Moreover, the recent findings of axonal and dendritic partially spliced mRNAs, retaining a single intron, open the additional question of the role(s) of intron-retaining transcripts in neurites and the possibility of direct functional interaction between retained introns and splicing proteins.
We propose to answer these essential questions, at cellular and molecular levels, using zebrafish developing neurons (in embryos and in culture) as experimental models.


Investigator Award in Science

Exploiting genomic approaches to identify the environmental basis of depression Despite major advances in our understanding of depression’s genetic architecture, there remain major gaps in our understanding of its environmental risk factors that impede prevention. Using studies of both related and unrelated individuals, I will identify the genetic changes and behaviours in those individuals that lead to depression in those individuals, as well as in their relatives. I will compare these changes with the genetic signatures of lifestyle factors (e.g. obesity) and behaviours, such as smoking and alcohol consumption, to identify if they are environmental risk factors for depression. In a complimentary approach, I will measure epigenetic changes in DNA methylation associated with depression and its risk factors. I will use optimise these epigenetic measures to improve the prediction of depression and the measurement of its risk factors. Finally, I will optimise the prediction of depression and its risk factors by applying these findings to prospective longitudinal dataset where depression and environmental risk factors have been measured on multiple occasions. These studies will be used to refine the accuracy of each predictor and estimate how it would behave in unseen samples of individuals, in whom it may be applied for prevention in future studies.


Investigator Award in Science

Hybridisation in urogenital schistosomiasis (HUGS): A multidisciplinary longitudinal population study revealing the transmission biology, epidemiological impact and clinical importance of Schistosoma haematobium-hybrids in Malawi Our discovery of Schistosoma haematobium hybrids co-infecting Malawian children exposes critical knowledge gaps in WHO’s preventive chemotherapy (PC) strategy for schistosomiasis. Our HUGS (hybridisation in urogenital schistosomiasis) study will generate robust evidence that best informs medical, veterinary and environmental sectors in schistosomiasis control and interruption of schistosome transmission. This 4-year multidisciplinary investigation will develop new molecular assays that quantify multihost transmission dynamics and zoonotic spill-overs. We will reveal which pre- or post-zygotic drivers facilitate saltatory hybrid evolution. HUGS is set out in four objectives [% allocation] that:

Obj-1 [25%]: Test if the proportion of hybrid co-infection is (non)uniform across two representative communities where S. haematobium-mattheei or S. haematobium-bovis occur, inclusive of household GPS mapping and identification of associated risk factors by questionnaire;

Obj-2 [45%]: Verify, in a 2-year longitudinal population follow-up study with annual PC, if the above proportions and spatial patterns of hybrid co-infection hold or alter in the two communities;

Obj-3 [15%]: Ascertain if there is any increased host morbidity (e.g. anaemia or urogenital disease) in hybrid co-infection(s) as measured by point-of-contact assays and portable ultrasonography;

Obj-4 [15%]: Reveal hybrid environmental transmission by malacological inspections, livestock tracking and abattoir surveillance, with advanced molecular typing of collected schistosome material.


Senior Research Fellowship Renewal

Systematic discovery and analysis of novel molecular mechanisms in protein synthesis Protein synthesis is one of the most fundamental processes in all organisms. Due to the unique constraints under which RNA viruses evolve, non-canonical mechanisms are particularly prevalent in RNA virus gene expression. Thus, we are using viruses as a source for the discovery of novel gene expression strategies. We will leverage our expertise in computational biology to mine public transcriptomic datasets for 10000s of novel virus species, and use our expertise in virus comparative genomics and molecular biology to identify and characterize novel translational mechanisms. An important feature of the research strategy is close synergistic interaction between the bioinformaticians and experimentalists in my team, which allows us to efficiently investigate new discoveries.

Key goals are to:

 Search ~120,000 RNA-Seq datasets for RNA virus-derived sequences from diverse host organisms from protists to mammals.

 Use comparative genomics to predict novel cases of non-canonical gene expression.

 Experimentally characterize the most interesting novel mechanisms.

Characterizing these exceptions to the rules of canonical translation will provide new insights into the mechanisms underlying protein synthesis, reveal new modes of cellular gene expression, and provide new tools for molecular biology research, biotechnology and synthetic biology. Thus the results will have broad applications in fundamental molecular biology.


Investigator Award in Science

Alternative lengthening of telomeres: induction, maintenance and vulnerabilities To maintain unlimited proliferative capacity, cancer cells must maintain their telomeres. ~85% of cancers achieve this by up-regulating telomerase, while the remaining ~15% of cancers employ the Alternative Lengthening of telomeres (ALT) pathway. Currently, there are no targeted treatments for ALT cancers, which have a poor prognosis and are universally aggressive. Insights into the mechanisms that promote/are essential for the ALT process may reveal vulnerabilities that could be exploited therapeutically. However, the lack of a cellular model that permits the induction of ALT has severely limited our ability to interrogate the underlying mechanisms. We have recently made a key discovery that Kaposi’s Sarcoma Herpes Virus (KSHV) infection triggers the stable acquisition of ALT. In this application, we will exploit KSHV to identify the host and virally encoded factors that are critical for ALT induction. Using PICh to interrogate the proteomic composition of telomeres, we have identified 703 proteins that are specifically enriched at ALT telomeres. We will perform a "703 ALT" CRISPR dropout screens to identify genes that modulate/are essential in ALT cancer cells but are dispensable in normal cells. Our proposal will expand our understanding of the ALT process and may identify critical vulnerabilities, which could be targeted therapeutically.


Genetic Code Compression and Expansion

Investigator Award in Science

Genetic Code Compression and Expansion Genetic code expansion enables the site-specific, incorporation of non-canonical amino acids (ncAAs) into proteins, and has enabled diverse biological discoveries. Most experiments incorporate ncAAs in response to amber stop codons.  This strategy is limited to incorporating one type of ncAAs into a protein at a time, and there are no other natural blank codons that can be used for ncAA incorporation.

We synthesized a 4 Mb E. coli genome with a compressed genetic code, through the genome-wide substitution of three target codons by defined synonyms.  The resulting cell, Syn61, uses 61 codons to encode the 20 canonical amino acids.

In Aim 1 we address the limitations of genetic code expansion by encoding multiple distinct ncAAs in response to blank codons in Syn61. This dramatically expands the applications of ncAA incorporation.

The recoding of Syn61 was based on the prior identification of a synonymous codon compression scheme (a rule that defines which codons to remove and which codons to replace them with).  In Aim 2 and Aim 3 we systematically discover allowed synonymous codon compression schemes that we use to create deeply compressed synthetic genomes using accelerated genome synthesis methods. This creates more blank codons that may be reassigned to ncAAs.


Investigator Award in Science

Molecular mechanisms determining the polarised synaptic distribution and molecular function of the retrograde endocannabinoid signalling system The endocannabinoid system (ECS) acts as a negative feedback mechanism to suppress excitatory and inhibitory synaptic transmission. This is critically important for a wide range of brain functions including appetite, pain, and cognition. Moreover, ECS dysfunction is implicated in multiple neuropathologies, and there is increasing scientific and public interest in drugs that target the ECS, including medical marijuana.

The molecular organisation of the ECS is highly unusual because, in reverse to other neurotransmitter systems, endocannabinoids are released from the postsynaptic membrane to activate receptors at the presynaptic membrane. Despite its importance, remarkably little is known about how the enzymes and receptors essential for ECS ‘backwards’ transmission are targeted to, and retained at, opposing sides of the synapse.

Focusing on the primary cannabinoid receptor CB1R and the major endocannabinoid synthesising  enzyme diacylglycerol lipase alpha (DAGLalpha) as prototypic examples, we will investigate the protein interactions and pathways that determine the architecture and organisation of the ECS.

Our goal is to define how the differentially polarised trafficking of ECS components to synapses is orchestrated.

This mechanistic knowledge of the ECS will advance understanding of neuronal protein polarisation and inform the design of future strategies to modulate ECS signalling for therapeutic benefit.


Investigator Award in Science

Erythrocyte invasion in malaria: molecular mechanism to precision therapeutics Invasion of erythrocytes is one of the most critical steps in the life cycle of the malaria parasite. Prevent erythrocyte invasion, and we can prevent parasite growth, disease symptoms and transmission.

Essential for erythrocyte invasion is the PfRCR complex of Plasmodium falciparum, consisting of PfRH5, PfCyRPA and PfRIPR. This proposal will use structural insights to guide experiments to understand the function of PfRCR in erythrocyte invasion, and to guide development of future vaccines and therapeutic antibodies. Over the next five years, I will:

(i)        Determine structures of PfRCR and PfRIPR and understand whether complex formation is necessary for invasion.
(ii)       Understand molecular mechanisms of the most invasion-neutralising human antibodies targeting PfRH5, PfCyRPA and PfRIPR.
(iii)      Determine how PfRH5 induces calcium flux in erythrocytes.
(iv)      Use structural insights to design improved therapeutic monoclonal antibodies and vaccine immunogens targeting PfRCR.

These studies will deepen our understanding of this critical event in erythrocyte invasion. They will reveal the human antibody response to PfRCR vaccination and use this insight to guide design of the malaria therapeutics of the future.


Collaborative Award in Science

Prof Derek Macallan, Prof Benjamin Willcox

Unconventional dynamics: turnover, structure and maintenance of the γδ T cell population in humans   For 500 million years, vertebrates have retained three distinct lymphocyte lineages bearing rearranged receptors– alphabeta T-cells, B-cells, and gammadelta T-cells - suggesting that each compartment is critical to host immunity. We have a good understanding of classical alphabeta T-cells and B-cells but our knowledge of "unconventional" gammadelta T-cells lags far behind. There has been a recent explosion of interest in the gammadelta population and considerable excitement around their therapeutic potential. This is motivated by their unique recognition capabilities, their enrichment at sites of pathogen entry, and potent antimicrobial/antiviral/antitumour activities. Previously assumed to sit at the interface of innate and adaptive immunity, recent work has shown that gammadelta T-cells can be divided into functionally-distinct innate-like and adaptive-like subsets. A knowledge of the dynamics that critically underpin such diverse populations is lacking, hindering fundamental understanding and therapeutic exploitation. We will investigate gammadelta T-cell dynamics in humans including quantification of in vivo lifespans, maintenance mechanisms (de novo production versus self-renewal), and repertoire dynamics relative to canonical adaptive (CD8) and innate-like (MAIT) populations. We will establish benchmark in vivo dynamic measurements for  "innate" and "adaptive" human gammadelta T-cell subsets, and generate the first quantitative models of the human gammadelta T-cell compartment.


Investigator Award in Science

Exploiting divergent biology of two fission yeasts to understand membrane function Membrane function is fundamental to life. Deregulation of the membrane lipid repertoire has severe consequences for cellular and organismal fitness. Defining how lipid composition controls membrane organization and cellular physiology remains a major challenge in biology. Membrane lipid composition is subject to complex feedbacks and reflects the metabolic and regulatory capabilities of the specific experimental system. I propose to attack this problem by exploiting the natural divergence in membrane lipid composition between S. pombe and S. japonicus, two related genetically tractable fission yeasts with different lifestyles. I believe that our research program integrating comparative analyses and reverse engineering of cellular mechanisms with biophysics and systems approaches, provides an unmatched discovery platform capable of revealing the core principles that govern membrane organization and function. Our research will explain how changes in the architecture of glycerophospholipid fatty acyl tails affect membrane properties. It will provide insights into the organization and evolution of genetic networks regulating membrane homeostasis. Finally, it will test if acquisition of new lipid metabolic functionalities engenders diversification of cellular pathways and organismal physiology.


Senior Research Fellowship Renewal

Engineering genomic features to better understand the molecular basis of immune mediated diseases and their treatment Genetic and transcriptional studies have demonstrated that shared aetiology between immune-mediated diseases (IMD) is reflected in shared patterns in both data types, and suggested new targets for treatment. However, the huge number of variants and genes measured mean that only a minority of potential information in these data has been harnessed, and disease prognosis and treatment success remains variable and unpredictable. My goal is to overcome this dimensional challenge by developing genomic feature engineering which exploits these shared patterns, to extract new insight from jointly analysing over a hundred existing datasets.

I will generate summary features by tailoring dimension-reduction strategies and applying them to genetic and transcriptomic data from patients and cohorts with related traits measured. I will investigate how each feature contributes to rare and common IMD risk, and prognostic variability within diseases. I will correlate features with molecular measurements and clinical data to understand the gene products they represent, and the situations (cell type, disease state/subtype) in which they are relevant. Finally, through predictive modeling, I will explore the expected impact of targeting these gene products in different diseases and subtypes, to generate, and test, hypotheses about which targets might modify specific IMD activity or progression.


Investigator Award in Science

Proteostasis and Autophagy in Immune Senescence Lymphocyte function underpins effective immunity to infection and cancer, and is adversely affected by age in a process called immune senescence, a major obstacle to having a healthy lifespan. The cellular basis of T cell senescence is largely unknown. Maintaining proteostasis, regulated by protein synthesis and degradation, in the face of intrinsic and environmental insults is a key determinant of cellular and organismal lifespan. We will address the hypothesis that modulating the conserved degradation and recycling process known as autophagy, can restore immune responses in lymphocytes in the elderly. We have shown that autophagy prevents immune aging, and demonstrated a decline in autophagic flux in lymphocytes with age, and a global age-related decline of protein translation. But it is uncertain which of the synthesized and degraded proteins are most important. It is clear, however, that the induction of specific repair pathways, including autophagy, extends life and health span. We have uncovered a novel pathway that rejuvenates lymphocyte function by regulating autophagy translationally, which we intend now to fully characterize. Our goal is to identify potential therapeutic strategies for restoring health span in the elderly. This work will also address fundamental gaps in our understanding of the aging process.


Investigator Award in Science

Specialization of chromosome segregation mechanisms in meiosis Meiosis generates gametes with half the parental genome through two consecutive chromosome segregation events, meiosis I and meiosis II. Meiotic errors are prevalent in humans, accounting for frequent miscarriages, birth defects and infertility, yet the mechanistic origins of these errors are undefined. Our vision is to discover the molecular basis of the adaptations that sort chromosomes into gametes during meiosis. We will exploit the tractability of yeast meiosis to overcome the limitations of protracted meiosis and scarcity of material in other systems, to address three complementary aims. First, we will determine the mechanism by which kinetochores suppress crossover recombination near centromeres during meiotic prophase, and the significance of this suppression for chromosome segregation. Second, we will reveal how sister kinetochores are specifically fused, and the surveillance machinery re-wired, to permit sister chromatid co-segregation only during meiosis I. Third, we will identify the modified cell cycle controls that drive two consecutive chromosome segregation events during meiosis and determine how these controls couple chromosome morphogenesis to gametogenesis. The molecular pathways we discover will provide a framework for identifying potential sources of meiotic errors in humans.


Investigator Award in Science

Mechanism of cell-to-cell transmission of flaviviruses This proposal will investigate the mechanism of cell-to-cell transmission and spread of flaviviruses using Dengue and Zika as model systems. We will therefore address a longstanding debate on how they exit from infected cells, and preferentially spread into specific cell types. Dengue and Zika are the two most prevalent flaviviruses worldwide, sharing significant overlap in their genome architecture and biology. Dengue infects  > 50 million people annually, causing severe pathologies. Zika too has emerged as a global threat with recent outbreaks linked to serious neuro-developmental complications in children and Guillain Barré syndrome in adults. No vaccines or therapeutics exist for these viruses, and our current understanding on mechanisms of their transmission and spread is severely limited.
            Viral infections spread by overcoming multiple barriers to move from cell to cell. Viral progenies can move across extracellular space either as free particles via fluid phase diffusion, within vesicles, or by cell-cell contacts. To understand transmission, we will therefore address: (i) characteristics of the extracellular virus populations, (ii) whether multiple transmission routes exist (iii) whether the viral envelope is the primary determinant of transmissibility. This proposal builds on our previously published and ongoing studies on viral manipulation of autophagy for assembly and spread.


Investigator Award in Science

Checkpoint control of T cell-B cell collaboration in the regulation of autoimmunity Productive communication between T cells and B cells is vital for protective immunity, however dysregulation of this process can trigger autoimmunity.  Costimulatory checkpoints limit T cell help for B cells by controlling the differentiation of follicular helper T cells (Tfh), a cellular subset overrepresented in multiple autoimmune diseases. We have found that anti-CTLA-4 antibodies can trigger spontaneous Tfh differentiation in mice. Targeting CTLA-4 with checkpoint inhibitors in cancer patients may therefore induce Tfh, potentially relevant to the autoimmune side-effects seen with these treatments. Despite their escalating clinical burden, the cellular mechanisms underpinning checkpoint-inhibitor induced autoimmunity remain poorly understood.

In this proposal I will investigate the hypothesis that induction of Tfh responses is a general feature of autoimmunity, reflecting a loss of costimulatory (checkpoint) control. I will explore how CTLA-4 and PD-1 co-operate to regulate Tfh differentiation, and establish the consequence of a Tfh response for tissue autoimmunity. Insights will be drawn from autoimmune patients treated with CTLA-4-Ig, and cancer patients treated with CTLA-4 antibodies. Building on exciting preliminary data, I will determine whether Tfh populations have value in predicting outcomes in classical autoimmunity as well as in checkpoint-inhibitor induced disease.


Sanger Resource Collaboration


Interdisciplinary Hub

Mrs Kaisa Kerätär, Dr Ayesha Ahmad, Ms Sheila Ghelani, Mr Romit Raj, Ms Babitha George

Solastalgia - The impacts of Environmental Change on mental health  A two year exploration of Solastalgia - mental distress specifically caused by environmental change, defined as a land disease of "place-based lived experience".

Our team is a global collective of artists, researchers, designers, conservationists, technologists and activists from fields including psychology, arts, sustainability, sociology, design and medicine. Through the Hub we will place lived experiences at the forefront of understanding Solastalgia. We will use human centred design, storytelling and creative media arts to deeply explore human experiences and relationships with the natural world as an alternative to the current dominant, data-driven discourses.

Through a network of global field stations, sited in critical landscapes, we will work closely with local and indegnous communities to understand and communicate their connection to land and their lived experiences of climate change.  Looking at Solastalgia through the lens of these communities we will together explore the complex, fragile relationship of psyche and land.

Through the Hub we will open up this urgent and timely discussion to multiple audiences. Incorporating diverse knowledge and perspectives, lived experiences that are complex and layered through storytelling and artistic approaches we will identify context-specific pathways towards a sustainable future.

Grants awarded from 1 October 2005 to 30 June 2021


Coronavirus

Dr Amadou Sall, Dr Emily Adams, Prof Luis Cuevas, Prof Sanjeev Krishna

Detecting and Excluding Coronavirus disease 2019 (COVID-19) at the Point of Need Rapid diagnostics have been identified by the WHO R & D Blueprint as a critical unmet need for the control of COVID-19 - particularly in the absence of a vaccine and proven antiviral agents. Our primary objective is to develop a low cost, high performance rapid test for the detection and exclusion of SARS-CoV-2, the causative virus of coronavirus disease 2019 (COVID-19).

The technology will be made available in line with the Global Access Policy for Gavi-eligible countries that are most vulnerable to onward transmission of COVID-19 and of limited detection due to insufficient laboratory capacity. The RDT will be appropriate for assembly and manufacture with multiple quality-assured partners to meet demand.


Investigator Award in Science

Sleep circuitry: linking homeostasis, sedation and stress This proposal aims to understand:
1) What circuitries sense the inexorable drive to sleep when we are sleep-deprived?  We will investigate if sleep need is sensed locally in the brain by a distributed circuit network that feeds into a central hub, the lateral hypothalamus, providing global restorative sleep. We have identified neurons in the mouse prefrontal cortex, preoptic hypothalamus, and ventral tegmental area (VTA) that sense sleep need and contribute to inducing sleep after sleep deprivation. Learning how responses to sleep deprivation are embedded in distributed sleep circuitry would explain how sleep homeostasis works at the circuit level.
2) Do sedative drugs promote these restorative sleep pathways? How do two important drugs, propofol and dexmedetomidine, intervene in the sleep-homeostasis circuitry? We will search for cells that respond to sedatives to induce restorative  sleep without deleterious effects (hypothermia). Understanding this circuitry may identify new drug targets.
3) What is the significance of sleep-promoting circuitry we have discovered in the basal ganglia and midbrain (globus pallidus to lateral habenula to VTA to lateral hypothalamus), which overlaps with circuitry that responds to aversive outcomes and stress? We will investigate if this basal ganglia-triggered sleep helps offline processing of negative experience.


MQ Strategy Implementation 2020/2021

Discretionary Award - Mental Health

MQ Strategy Implementation 2020/2021 This grant will enable MQ to deliver two key activities in 2020/21: the implementation of our income generation strategy, and the development and delivery of the MQ Annual Mental Health Science Meeting 2021.

MQ exists to ‘create a world where mental illness is understood, effectively treated and one-day prevented’. In 2019, MQ worked with the agency Open Creates to develop a new income generation strategy to deliver these ambitions - bringing the public and scientists together to fund ground-breaking mental health research, more quickly.

With the support of this grant, MQ will work with Open Creates to define and test priority research themes that align with the views of target audiences. Following identification of priority theme(s), MQ will then roll out activity to build public awareness, engage and grow a base of supporters, and raise funds for mental health research against a compelling research and organisational strategy.

This grant will also support MQ to work with the mental health science community and key supporters to develop and deliver a successful Mental Health Science Meeting in 2021, championing collaboration and knowledge sharing amongst researchers, and showcasing the potential of mental health science to excite and motivate our supporters and stakeholders.


Coronavirus

Prof Henry Mwandumba, Dr Jennifer Cornick, Dr Peter MacPherson, Prof Stephen Gordon

Malawi-Liverpool-Wellcome Trust COVID-19 Epidemic Preparedness Malawi is at high risk of COVID-19 epidemic spread, the healthcare system is fragile and the population vulnerable to severe disease. This application proposes Malawi Liverpool Wellcome Trust Clinical Research Programme preparedness activities for epidemic COVID-19 disease. These are split into three work packages: 1) Diagnostic capacity and genomics surveillance; 2) Secondary care; 3) Epidemiology and control. Strategically, we have designed our activities to develop a platform for MLW to rapidly pivot into response mode to both support the healthcare system and deliver excellent research for current and future epidemic disease threats.

Key goals for this proposal are:

 Provide diagnostic capability in Malawi for the COVID-19 epidemic
 Develop clinical and epidemiological tools to manage epidemic disease in Malawi


Sir Henry Dale Fellowship

Royal Society/Wellcome Trust Sir Henry Dale Fellowship

Sir Henry Dale Fellowship Interview Committee

Does stroke impair immunological memory and increase infectious disease risk during the chronic phase of recovery Stroke patients are increasingly surviving long-term after the primary neurological insult. Post-stroke complications have thus rapidly become an area of unmet clinical need. Infection is a common and dangerous complication of stroke associated with increased death and disability. Stroke-induced immune suppression is associated with infection susceptibility, but the majority of studies have focused on short-term (hours to days) changes to immune function. My recent data show early reduced numbers of lymphocytes and dendritic cells in experimental and clinical settings. It is unknown whether this impacts adaptive immune function and immunological memory. Using experimental animal models and parallel analysis of population health data sets, key goals of this proposal are:

1. To understand the extent and persistence of changes to adaptive immune cells after stroke and how this relates to infection susceptibility.
2. To determine if previously generated adaptive immunological memory is lost after stroke.
3. To determine if generation of new adaptive immunological memory is impaired after stroke.

This will generate understanding of the extent of adaptive immune memory deficits after stroke and the window of susceptibility in which stroke patients are vulnerable to infection and could result in new therapeutic approaches to reduce infection and improve long-term patient outcome.


Global Forum on Bioethics in Research

Global Forum on Bioethics in Research Fellowships Committee

Decoding Genetic Studies from Pakistan - A Review of International, Regional and Local Guidelines and Compliance. I conducted research for my Masters thesis to explore, identify and examine ethical guidelines available for genetic studies and to then analyse and describe the extent to which researchers in Pakistan, comply with existing ethical standards specified for genetic research. I report in my thesis that there are no guidelines for genetic research, gene therapy or gene editing in Pakistan. I also found some other patterns in the studies reviewed that I would like to present in the form of a publication in a peer reviewed journal as I feel they will provide a foundation of behavioural practises of researchers in Pakistan.

I would also like to use the findings as a starting point to develop and propose guidelines for researchers for genetic research, gene therapy and gene editing in Pakistan. I want to propose guidelines that can be incorporated effectively into practise for which I will need to identify effective training, implementation and monitoring of the guidelines.

Key goals:

1. Develop a better understanding of the ethical review process of international collaborations in the UK

2. Produce a draft of a paper for submission to a peer reviewed journal

3. Propose an outline of guidelines for researchers in Pakistan


Asian Clinical Trial Network

Discretionary award – DRI

Asian Clinical Trial Network Drug-resistant infections (DRIs) have recently been recognised as a major challenge by the G20 and the UN General Assembly, with a disproportionate impact on the people of Asia. Potential solutions will require multidisciplinary and multi-country collaboration in order to successfully address in terms of innovative discoveries, implementation of policies and roll-out and evaluation of the best evidence based clinical practices.

The current model of clinical research in low and middle-income countries (LMICs) is to fund individual clinical trials on an ad-hoc basis, with each trial requiring significant investment in research infrastructure and skills development in addition to the trial-specific costs. This model is inefficient scientifically, developmentally, and financially.

In response to the challenge of AMR, Wellcome plans to set up a pilot clinical trial network (CTN) in SEA. The CTN will significantly increase the quality and efficiency of clinical trials in the region, resulting in an improved understanding of DRI, improved treatment of those infections and an increase in the supply of new drugs to fight AMR. The support hub for this clinical trial network will be based in Singapore.


Discretionary Award - Policy

Young European Takes on “Healthy Lives and Well-Being for all” The European Youth Parliament (EYP) is based on the idea that the great challenges of our time cannot be tackled on a national level alone, but need to be addressed multilaterally. Moreover, the EYP leverages a new generation of young changemakers to be part of the solution.

As the umbrella organisation of the EYP, the Schwarzkopf Foundation Young Europe is proposing a project that will bring various interconnections between "Health" and "Politics" to the forefront of debate among young people across Europe. The project will bring together young people from across Europe with decision-makers and experts, to debate today’s pressing topics in the field of health, and to develop positions that will be shared with decision-makers and the public. Discussions will take place in a variety of formats and settings, constituting a broad consultation process that will aggregate "young opinions" from across Europe, which are then to be shared in close-up debates with decision-makers (especially in the context of Germany’s EU Council presidency) - as well as with young peers, and the broader public.


PhD Training Fellowship for Clinicians

Defining optimal interventions for Perinatal Anxiety (PNA) in a general practice population: a mixed methods study. Background to the research problem

Perinatal anxiety (PNA) is anxiety that occurs during pregnancy or up to twelve months postpartum. The global prevalence of PNA is estimated to be over 15% and at least as common as perinatal depression (PND).  PNA can adversely impact both mother and child. Whereas a significant amount of research has been conducted into PND; i in comparison there is very little work published that reviews PNA. The National Institute for Health and Clinical Excellence has recommended that further research is needed in order to develop psychological interventions to identify and treat moderate to severe anxiety disorders in pregnancy which is where my research intends to fill a vital gap.

My approach

My PhD aims to define optimal interventions for PNA. The PhD comprises of several parts including a systematic review of published literature, interviews with PNA stakeholders such as patients and professionals who deliver perinatal care with the final aim to co-develop an intervention for PNA with stakeholders.

Expected impact of my work

After development of an intervention I hope to secure funding after my PhD to test it. I hope that it may be recognised and recommended in clinical practice.


Discretionary Award – C&S

Greater Manchester Coalition of Disabled People

GMCDP Archive Assessment and Collections Appraisal GMCDP’s archive collection reveals the changing perspectives, language and attitudes towards disabled people that have occurred over recent decades. It highlights changes in medical practices, discussions and debates around bio-ethics and end of life issues, campaigns for independent living, the self-organisation of disabled people, development of disability culture, and the significant impact of wider health determinants.

Following on from feedback on a previous application to Wellcome Trust, GMCDP recognises the need to have a more detailed, specialist assessment of our collection in order to be able to move forwarded to the next stage. GMCDP are therefore seeking to carry out an archivist assessment and collections appraisal of our archives, and will commission Janice Tullock Associates (archivist) and Sharon Oldale (conservator) to provide the following outcomes:

 Survey the collection to assess its needs.
 Assess the level of cataloguing the collection requires.
 Develop a statement of the significance of the collection.
 Provide a detailed report on findings, with recommendations.
 Develop a project plan for the cataloguing of the archive.
 Assess the level of archivist and specialist input required throughout the duration of the project.
 Conservation assessment and recommendations.


Prof Moffat Nyirenda, Prof Andrew Morris

International Intermediate Fellowship

Assessing the impact of genetic variation on chronic kidney disease in Africa In sub-Saharan Africa, over 50 million people have chronic kidney disease (CKD) making Africa the continent with the highest burden of CKD in the world. With rapidly increasing urbanisation, trends towards unhealthy diets, obesity and increases in metabolic risk factors, the projected increase in the prevalence of CKD may be even greater in Africa than in other parts of the world.

Over the past decade, genome-wide association studies have uncovered numerous genetic determinants of CKD in European and Asian ancestry populations. These studies have led to numerous novel findings, which are helping improve our understanding of factors and pathways affecting both normal and pathologic kidney function. However, to date, there is no known published GWAS of CKD in any continental African population.

Key goals include

 Conduct large-scale genomic studies of CKD in Africa which will potentially provide new opportunities to identify the biological determinants of CKD in individuals of African ancestry.
 Leverage the low linkage disequilibrium between genetic markers in African populations to conduct fine-mapping of novel and previously identified signals in the trans-ethnic meta-analysis.
 Develop a Polygenic Risk Score for CKD risk in Africa and assess whether cardiometabolic traits/diseases are causally related to the risk of CKD in Africans.


Not available

Discretionary Award – C&S

Teacher Research Grant - Project Evaluation Not available


Dr Lisa Ranford-Cartwright, Dr Samuel Dadzie

International Intermediate Fellowship

Noguchi Memorial Institute for Medical Research

Elucidating the mechanisms and functions of bacterial-derived mediators on Plasmodium falciparum.  Some bacteria species in the mosquito midgut demonstrate anti-Plasmodial effect independent of the mosquito immune system. Understanding this mechanism could help propose bacteria-mediated strategies for targeting and blocking transmission without producing transgenic bacteria. This project proposes to identify mosquito midgut bacteria that secrete anti-parasitic factors and investigate their variations in natural Anopheles mosquito populations. Mosquito stages of P. falciparum will be exposed to spent culture media of midgut bacteria species through in vitro and in vivo (using axenic mosquitoes) assays and developmental and functional parasite effects assessed by immunofluorescence microscopy. The biological significance of the bacteria secreted products will be confirmed by comparing with parasite exposure to bacteria cells. The natural prevalence of effective bacteria will be investigated in blood-fed field-caught Anopheles malaria vector species from areas of high and low malaria transmission using 16S sequencing. In addition, bacterial metabolites will be identified by LC MS/MS for further investigations into their mechanisms of cell activity. It is expected that results from this study will increase our knowledge in the biological role of specific bacteria in natural variations of vector competence and reveal bacterial products from mosquito microbiome that can be further explored for parasite transmission-blocking in the mosquitoes.


Clinical Research Career Development Fellowship

The role of IDH mutation in liver cell plasticity and cancer The application of next generation sequencing to bile duct cancers (cholangiocarcinoma) has revealed a subgroup with mutations in the Isocitrate Dehydrogenase (IDH1, IDH2) genes, which appear non-overlapping with other drivers including TP53 and KRAS and which are associated with relatively favourable, but still poor, clinical prognosis. IDH1/2 mutations result in neomorphic production of the oncometabolite 2-hydroxyglutarate (2HG), which causes cell toxicity, DNA hypermethylation, and repression of cellular differentiation. This project tests two hypotheses. First, it seeks to determine whether 2HG production can metabolically reprogramme liver cell identity, triggering a cell fate change from a hepatocyte to a biliary phenotype, thereby promoting the formation of cholangiocarcinoma. I will seek to define the cell populations in the liver in which IDH1 mutations occur in disease and use lineage tracing techniques to establish whether IDH1 mutation results in an increase in hepatic progenitor or ductal cells in vivo, as well as which cell types give rise to these ductular reactions. Second, I shall examine whether 2HG causes non-cell-autonomous local toxicity or inflammation, and determine whether this contributes to tumorigenesis. My results will elucidate fundamental mechanisms of biliary carcinogenesis and suggest the likely efficacy of targeted 2HG inhibition or, indeed, 2HG overexpression.


Decoding macrophage functional heterogeneity in the pathogenesis of Crohn's disease The accumulation of intestinal macrophages (iMphis) and presence of a distinct mononuclear phagocyte gene-expression profile, predict treatment failure and adverse clinical outcomes in Crohn's disease (CD). Preliminary scRNA-seq data demonstrates that a transcriptionally distinct iMphi subtype (CD-MPhi) accumulates in human and murine colitis, which I have prospectively validated. Unbiased CD-MPhi-epithelium, ligand-receptor interaction analyses reveals CD-MPhi derived activin signals to cognate receptors on colonic epithelium. CD-MPhis are the exclusive iMphi source of activin in mouse and humans, a TGF-beta superfamily member with cell-specific cytokine, growth and hormone effects. Activin administration to human colonic epithelium inhibits proliferation with a dose-dependent effect on cytokine, chemokine and pattern recognition gene expression.

Aims

 Define iMphi heterogeneity and dynamics in CD
 Interrogate the functional role of a novel pathogenic subset (CD-MPhi) in regulating intestinal inflammation
 Investigate CD-MPhi driven activin signalling as a therapeutic target for intestinal inflammation

Methods
Using a novel, human, biopsy-based sampling approach, I will perform scRNA-seq of iMphis in newly diagnosed, treatment naive CD patients, with longitudinal, flow cytometry-based intestinal characterisation to reveal iMphi dynamics over time. Lastly, I will manipulate cell-specific activin-signalling in transgenic animals and primary human epithelium co-culture models to probe the mechanisms of activin-mediated epithelium dysfunction in CD.