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The Wellcome Trust


CRISPR–Cas mediated cleavage of invading nucleic acids 08 Sep 2017

<p>My lab focuses on structural and functional studies of the CRISPR-Cas system and prokaryotic Ago, anti-virus defense systems mediated by small RNA or DNA. We are interested in spacer acquisition in the CRISPR-Cas system and have shown how Cas1-Cas2 captures foreign DNA. We plan to solve the structure of the complete integrase complex to understand how it binds target DNA and inserts protospacers into the CRISPR locus. Cas4 is also involved in spacer acquisition in some CRISPR types. We will identify the structural basis of acquisition in Cas4-containing systems and elucidate the roles of Cas4. In addition, we plan to identify the unknown RNase that trims crRNA from its 3&rsquo;-end, and address the molecular mechanism of RNA-induced silencing in type III systems.</p> <p>Our previous study suggested that bacteria have a DNA interference system. We demonstrated the molecular mechanism of DNA-guided DNA interference using structural and functional studies. We will now focus on the guide DNA biogenesis pathway. Ago also has potential to be a genome editing tool due to its sequence-specific DNA cleavage activity. We will optimize the TtAgo sequence to screen for mutants which have high cleavage activity at 37&deg;C.</p> <p>&nbsp;</p>

The Sick of the Fringe – Discretionary award 30 Sep 2017

<p>Funds are provided to In Company Collective to support a proportion of the core staff time, increasing capacity to enable the team to:</p> <p>- formalise the operating structure of The Sick of the Fringe and its relationship with In Company Collective;</p> <p>- define the vision and objectives for The Sick of the Fringe;</p> <p>- work with an external consultant to develop the business plan and business model for In Company Collective and The Sick of the Fringe working together.</p> <p>&nbsp;</p> <p>The role and objectives for the external consultant will be agreed between In Company and Wellcome.</p> <p>&nbsp;</p>

Amount: £50,000
Funder: The Wellcome Trust
Recipient: In Company Collective Ltd

Cuttin' It Secondary Schools Tour 30 Jul 2017

<p><em>Cuttin&rsquo; It </em>is a multi-award winning new play about Female Genital Mutilation (FGM) by Charlene James first staged at the Royal Court in 2016. In January 2018, the Royal Court aims to revive the play for a younger audience, in collaboration with experts on the impact of FGM. We will tour the show and an accompanying workshop programme to 15 secondary schools in London and five schools in Birmingham. Through targeting schools in economically deprived areas, <em>Cuttin&rsquo; It </em>will reach a new, under-served audience who have little opportunity to engage with professional theatre.</p> <p>&nbsp;</p> <p>Key advisors will be Louise Williams- a specialist nurse in paediatric FGM at UCLH and Lorraine Anderson of Solace Women&rsquo;s Aid.&nbsp; They will ensure medical accuracy within the play and inform about mandatory reporting and the referral process should young participants wish to disclose that they have been affected by FGM. Their expertise will help us to engage young people in the issue of FGM from a robust but culturally sensitive standpoint in a supported environment.&nbsp;</p> <p>&nbsp;</p> <p>Up to 1,800 young people aged 14-18 from across Greater London and the West Midlands will benefit and&nbsp;engage in the debate around the ethical, medical, and cultural issues of FGM.</p>

Amount: £69,539
Funder: The Wellcome Trust
Recipient: Royal Court Theatre

Extending the 14-day rule: what do citizens believe is right? 30 Jul 2017

<p>Research on human embryos can only happen under a license in the UK and it is currently illegal to keep them alive in laboratories for more than 14 days after fertilisation &ndash; the &ldquo;14-day rule&rdquo;. Research normally takes place on surplus embryos taken during IVF which would otherwise be discarded. Some scientists recently called for an extension of up to 28 days to enable better research into why early miscarriage occurs, and to improve our understanding of diseases. However, religious and ethical objections have also been raised based upon the idea that at least by the end of the 14th day the embryo is a distinct individual that deserves the respect that we show all human beings.</p> <p>&nbsp;</p> <p>In a recent survey of 1740 people, 48% supported extending the 14-day rule. However, 25% were unsure. This is a complex question and unlike (for example) citizens&rsquo; juries, surveys do not provide sufficient evidence to enable people to make informed judgements. This Wellcome application seeks funding to scope and develop a subsequent Wellcome application for a project to engage the public in this important question using a variety of methods including citizens&rsquo; juries. Participants will be &ldquo;ordinary&rdquo; citizens who rarely attend consultation events.</p>

Amount: £5,897
Funder: The Wellcome Trust
Recipient: University of Manchester

Drug Regimes in Southern Africa: Pharmaceutical Regulation and Consumption in Twentieth Century Contexts 30 Jun 2017

<p>Applicants request support for three activities with five objectives:</p> <ul> <li>To build a collaborative network of scholars working on twentieth century histories of pharmacy and pharmaceuticals, medicinal substances, narcotics, and veterinary medicines in southern Africa;</li> <li>To draft and review research papers within a focus area identified by the network which, in combination, will constitute a special edition of a peer-reviewed journal;</li> <li>To advance the research capacity of scholars working within universities in South Africa;</li> <li>To draw the attention of historians to lesser known sources of data for writing pharmaceutical histories in this region;</li> <li>To produce and disseminate new research on pharmaceutical histories in South Africa, and to expand the critical, contextual basis for studies of the pharmaceutical humanities within the burdgeoning field of the medical humanities.</li> </ul> <p>To facilitate these aims, this project has four proposed outputs:</p> <ol> <li>Establishment of a working group for the pharmaceutical humanities, made up of interdisciplinary scholars based at universities in South Africa.</li> <li>A workshop held at University of Johannesburg in mid-November.</li> <li>A tour and introduction for workshop participants of two local archives relevant to writing pharmaceutical histories in this region..</li> <li>Drafting, review and submission of a series of journal articles for publication in a special edition.</li> </ol>

Amount: £4,516
Funder: The Wellcome Trust
Recipient: University of Johannesburg

HHMI / Welcome International Research Scholar Award 08 Sep 2017

<p>The sympathetic nervous system (SNS) innervates all known organs, but its molecular and cellular organization is essentially unknown. The era of molecular genetics has made great strides in the mechanistic dissection of brain circuits as well as the immune system, but such endeavor has not yet reached the SNS.</p> <p>We have recently discovered a direct connection between the SNS and the adipose organ. Moreover, we found that this neuro-adipose junction mediates lipolysis and fat mass reduction. Therefore, direct and targeted activation of sympathetic inputs to adipose tissues could represent a new strategy for the induction of fat loss and, ultimately, a new anti-obesity therapy that would circumvent current therapeutic challenges such as central leptin resistance and drug delivery to the brain.&nbsp;We aim at discovering fundamental biological mechanisms that could render this idea possible. A key part of this is to explore the emerging link between the SNS and immunity. My lab has identified a novel population of sympathetic associated macrophages (SAMs) that appear to suppress the output of SNS neurons in fat.&nbsp;</p> <p>Moreover, we are developing molecular genetic tools to systematically establish a functional and molecular neuronanatomical map of the SNS.</p> <p>&nbsp;</p>

Amount: £500,404
Funder: The Wellcome Trust
Recipient: Instituto Gulbenkian de Ciencia

Chloroquine/Hydroxychloroquine prevention of coronavirus disease (COVID-19) in the healthcare setting; a randomised, placebo-controlled prophylaxis study (COPCOV) 30 Sep 2020

There is no proven treatment, chemoprophylaxis or vaccine for COVID-19. This is the most serious pandemic emergency for 100 years. Healthcare workers are being affected disproportionately in the continuing epidemic threatening an imminent breakdown of health services. Chloroquine and hydroxychloroquine are safe and well-tolerated medications which can be taken for years without adverse effects.Both have significant antiviral activity against SARS-CoV-2 and there is emerging evidence from China and Europe of efficacy in treatment. Unfortunately there is also premature recommendation from countries such as India which now recommends low dose hydroxychloroquine for prophylaxis in health care workers. We propose conducting a multi-centre, multi-country randomised, double blind, placebo controlled assessment of the prophylactic efficacy of chloroquine (Asia) or hydroxychloroquine (Europe) in preventing COVID-19 illness in at-risk healthcare workers and other frontline staff. At least 40,000 participants in Asia and Europe will be randomised 1:1 to receive chloroquine or hydroxychloroquine or a matched film coated placebo as daily prophylaxis for three months. The study’s objectives are the prevention of symptomatic coronavirus disease (COVID-19) and the attenuation of the clinical severity.

Amount: £6,920,135
Funder: The Wellcome Trust
Recipient: University of Oxford
Amount: £224,392
Funder: The Wellcome Trust
Recipient: University of Sheffield

Serological studies to quantify SARS-CoV-2 population infection risk in Singapore, Hong Kong and Thailand 30 Sep 2020

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.

Amount: £823,390
Funder: The Wellcome Trust
Recipient: National University of Singapore

The African coaLition for Epidemic Research, Response and Training, Clinical Characterization Protocol (ALERRT CCP) 30 Sep 2020

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.

Amount: £1,416,424
Funder: The Wellcome Trust
Recipient: Kwame Nkrumah University of Science a...

Characterization of SARS-CoV-2 transmission dynamics, clinical features and disease impact in South Africa, a setting with high HIV prevalence 30 Sep 2020

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.

Amount: £2,003,681
Funder: The Wellcome Trust
Recipient: Wits Health Consortium (Pty) Ltd

Investigation of pre-existing immunity to coronaviruses; implications for immunopathology and pathophysiology of COVID-19 disease 30 Sep 2020

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.

Amount: £1,217,834
Funder: The Wellcome Trust
Recipient: University of Oxford

COVID-19 Intervention Modelling for East Africa (CIMEA) 30 Sep 2020

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.

Amount: £1,030,349
Funder: The Wellcome Trust
Recipient: University of Warwick

A comprehensive study of immunopathogenesis of SARS-CoV-2 infection 30 Sep 2020

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.

Amount: £864,564
Funder: The Wellcome Trust
Recipient: Imperial College London

African COVID-19 Preparedness (AFRICO19) 30 Sep 2020

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 30 Sep 2020

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.

Amount: £782,901
Funder: The Wellcome Trust
Recipient: Wellcome Leap Inc.

Core costs grant 30 Sep 2020

Not available

Amount: £50,000
Funder: The Wellcome Trust
Recipient: Genetic Alliance UK

Detecting and Excluding Coronavirus disease 2019 (COVID-19) at the Point of Need 30 Sep 2020

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.

Amount: £888,104
Funder: The Wellcome Trust
Recipient: Mologic Ltd

Malawi-Liverpool-Wellcome Trust COVID-19 Epidemic Preparedness 30 Sep 2020

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

Amount: £249,926
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Decoding Genetic Studies from Pakistan - A Review of International, Regional and Local Guidelines and Compliance. 02 Mar 2020

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

Amount: £4,707
Funder: The Wellcome Trust
Recipient: The Aga Khan University, Pakistan