Discretionary Award - Open research

Outbreak Science Rapid PREreview – COVID-19 response The coronavirus pandemic has led to an unprecedented uptake of preprints, with researchers from all over the globe collaborating and sharing information at record speeds. The Wellcome Trust-funded open source platform Outbreak Science Rapid PREreview (https://outbreaksci.prereview.org) launched by our team on January 1, 2020, is well-positioned to help provide rapid feedback and a help filter the high number of COVID-19 preprints for quality and potential impact.

In just a few months, the platform has reached about 500 users, 80 rapid reviews, and more than 230 requests for reviews, the majority of which are for COVID-19-related preprints. These numbers grow every day, and so do opportunities for collaborations with third-party sites and efforts that can increase the discoverability of the content and accessibility to the tool.

To leverage our platform and aid in tackling this pandemic, our team asks for financial support for the following activities and positions:

 Feature implementation and customization of our open API to make COVID-19-related content more discoverable via integration with third-party sites, such as preprint servers and research platforms;

 A full-time project manager to lead and coordinate the work.


Clinical Research Career Development Fellowship

Designer biology to live image purine metabolism at single-cell resolution I recently discovered the function of a previously uncharacterised gene, FAMIN, that is linked to Crohn’s disease, leprosy and arthritis. A multifunctional purine enzyme, FAMIN is the pacesetter for purine recycling and hence determines cellular redox status, pH balance and energy production. Altogether, these control macrophage functions, such as bacterial killing and cytokine production. Importantly, my work has established this therapeutically targetable purine pathway as a direct driver of human inflammatory disease. However, further investigation of this pathway is currently limited by the inability to directly visualise and study purine metabolites in-situ, in real-time, and at single-cell resolution. Thus, the spatiotemporal dynamics of purine metabolism are mostly unknown. Assessing these dynamics will be crucial in understanding how purine dysfunction emerges in individual cells and can influence disease pathogenesis, for example through affecting redox state. Samie Jaffrey has pioneered technology that could overcome this hurdle. His group has generated programmable RNA-biosensors capable of live-imaging metabolites in single cells. I intend to learn these techniques and will engineer bespoke sensors for purine metabolites. I shall use these biosensors to dynamically track purine metabolism, and interrogate how environmental triggers can cause the purine dysfunction seen in numerous pathological contexts including chronic inflammatory diseases.

Grants awarded from 1 October 2005 to 30 June 2021

Creative Commons Attribution 4.0 International (CC BY 4.0)


Discretionary Award - Public Engagement

Tackling Taboos: Co-creating startup solutions for under-served health issues The early stages of health startups are science-rich environments that provide opportunities for the public to engage in health research and co-design new solutions. However, many user groups - especially those who are underserved by existing digital health solutions - are not empowered to engage with the research activities of startups. This is particularly evident for health issues considered ‘taboo’, such as incontinence, menopause, fertility, IBS, and mental ill-health. The result is a startup landscape that is overly focused on a narrow set of health issues and populations.

This project will launch a new programme of public engagement at Zinc, providing formal support and a structured programme to ~6 startups that are science-rich, dealing with taboo health issues, and committed to empowering underrepresented ‘expert users’. Working closely with specialist consultants, we will create opportunities for the public to contribute to, and learn about, health research and innovation. This work will advance the evidence-base for public engagement - in particular, our understanding of how founders and researchers can more effectively engage with publics underserved by digital health solutions. Longer-term, our aim is that this will lead to better integration of academic health research, public engagement, and commercial tech innovation.


Healthy Food, Healthy Planet (Europe)

Discretionary Award - OPOH

Healthy Food, Healthy Planet (Europe) Healthy Food, Healthy Planet (Europe) (hereafter HFHP) is a collaboration of philanthropic and civil society organizations. Our goal is to support the formation of a movement across Europe advocating for a global food system compatible with climate, health, biodiversity, animal welfare, and just transition goals.

To execute a scoping strategy and facilitate scoping phase grantmaking of HFHP, ClimateWorks Foundation will establish a pooled fund with an option for aligned funding. The HFHP Fund has a target size of approximately USD $1 million, and will be managed by ClimateWorks.

The project will have two phases. The first phase will run from June to October 2020. It will culminate in an investment prospectus indicating opportunities for donors to support a European food movement. The second phase will run from October 2020 to July 2021 and will culminate in a strategic framework describing tactics for the movement.

The activities of both phases of HFHP will be overseen by a Project Lead who will design and execute consultative processes, work to ensure that research deployed and the materials produced reflect priorities of civil society, and incorporate learning from the research and consultative processes in the investment prospectus and the strategic framework.


X-gene functions in spermatogonia, and their role in idiopathic and sex chromosome aneuploidy associated infertility. The sex chromosomes underscore basic differences between males and females, and the X and Y chromosomes have specialized functions in the gonad and germ cells. Sex chromosome aneuploidies, i.e.  Klinefelter (XXY), Turner (XO) and double-Y (XYY) syndromes), form the largest group of chromosomal abnormalities and are associated with infertility. While recent studies have defined the mechanisms for germ cell loss in XO and XYY mice, Klinefelter syndrome (KS) infertility remains poorly understood. KS males experience an early spermatogonial block and germ cell loss initiates in utero. The early loss of gonadal function has significant long-term consequences.

Gametogenesis in males occurs throughout their lifespan and relies on germline (spermatogonial) stem cells (SSCs), differing with females. Recent work from our group has identified the concerted activity of gene networks in driving spermatogenesis, and unique regulation of X-linked genes during this process. We observe that a number of X-genes express specifically in SSCs. However, regulation of SSCs self-renewal vs. differentiation dynamics, and the functional importance of X-linked genes in this process, remain poorly understood. We aim to understand physiological gene regulatory networks functional in SSCs using a combination of single-cell methods, to explain how perturbation in X-gene dosage in SSCs may cause infertility.


Disorders of human pubertal timing

Disorders of human pubertal timing My proposal is focused on understanding the genetic basis, and consequently the pathophysiology, underpinning disordered human puberty.

Pubertal disorders are common, but associated with severe comorbidities. Delayed puberty presents a diagnostic challenge in adolescence, as conditions of gonadotropin deficiency and isolated delayed puberty display the same clinical and biochemical phenotype. However, correct management is vital because the former is associated with infertility and requires intensive reproductive therapy, whereas the latter is self-limiting but associated with a shortened reproductive lifespan. The biological mechanisms of precocious puberty, a condition associated with increased long-term cardiovascular and cancer risk and thus with significant impact on public health, remain similarly opaque.

The identification of causal genetic defects in disordered puberty allows interrogation of the key regulators of human puberty.

I will use whole genome sequencing, comparative transcriptomics and methylomics studies in my large human cohort with disordered puberty, to define shared exonic and regulatory mutations resulting in delayed and precocious puberty. I aim to characterise the biological mechanisms underlying pubertal disorders through functional characterisation of novel genomic defects using cellular assays and animal models. These findings will ultimately translate to improved diagnostics, tailored therapeutic management and improved long-term outcomes for patients with disorders of puberty.


Coronavirus

Dr Janice Caoili, Dr Muge Cevik, Dr Fernando Bozza, Dr John Amuasi, Dr Janet Scott, Prof Madiha Hashmi

Enabling ISARIC Clinical Characterisation Protocol (CCP) roll out in LMICs By bringing GOARN Research and ISARIC partners together in the LMIC setting during COVID-19 we hope to strengthen the clinical, social science  and operational research response.

Aim: to support the roll out of the ISARIC WHO natural history protocol (known as the Clinical Characterisation Protocol - CCP) across LMICs:

Overarching goals:

 Support the roll out/uptake of the CCP across 5 countries per region, where feasible* (across four ISARIC regions of S America, Africa, S Asia  &  SE Asia).

 Support the set up and running of local dynamic clinical data dashboards in at least 10 sites per ISARIC region

 Share the aggregate data with WHO to assist with providing a global picture on the incidence and presentation of moderate to severe cases across a representation of the LMICs to inform clinical management and public health planning and control.

 Support the establishment of follow up modules and programmes for discharged hospitalised cases in 5 sites per region to evaluate longer term health impacts of COVID-19 on individual, health services and society to inform prevention and care planning.

*Brazil are in an intense first wave and reaching out to another 4 S. American countries would be challenging at the time of writing.


UNITE Global Summit: Virtual 2020

Discretionary Award - Policy

UNITE - Association of Parliamentarians to End Infectious Diseases

UNITE Global Summit: Virtual 2020 The Wellcome Trust Fund and UNITE collaborate to build the capacity of parliamentarians to advocate for the elimination of infectious diseases in their countries and around the world. Collaborations include activities designed to strengthen the exchange of evidence-based knowledge through dialogue and information sharing on infectious diseases, legislative processes and policymaking.

The UNITE Global Summit: Virtual 2020 will convene online on 7-8 September 2020. This event will bring together members of parliament from around the world in order to commit, inspire and empower policy makers towards the achievement of the UN Sustainable Development Goals over the next decade. Participants will work to develop a roadmap of clear policy actions to eliminate the threats posed by communicable diseases. This alignment of a common vision will culminate in the signing of UNITE’s 2020 Declaration.

Wellcome Trust will play a key role in Panel Session 1: Epidemics – What are we learning from the global response to COVID-19, by co-sponsoring the UNITE Global Summit: Virtual 2020 with the Coalition for Epidemic Preparedness and Innovations (CEPI).


Innovations AIGH Enterics Flagship

Full Value of Vaccines Assessment for invasive Non-Typhoidal Salmonella Vaccines The need for vaccines against invasive non-typhoidal salmonella (iNTS) is now increasingly being recognized, but there is no iNTS vaccine available for use in humans. Several potential candidate vaccines against iNTS are being developed. Vaccine development considerations include a bivalent iNTS vaccine (Typhimurium and Enteritidis) or possibly a trivalent vaccine (Typhi/iNTS). Such financial investments not only need public-private partnerships, but also demand economic and public health justification. The World Health Organization (WHO) and other global partners have recently highlighted the need to justify investments in vaccines from a multi-stakeholder perspective.
The overall objective of this project is to develop a Full Value of Vaccine Assessment (FVVA) to understand the value of investment in an iNTS vaccine from a multi-stakeholder perspective. The long-term goal of this proposal is to pave the way for the development of a safe and efficacious iNTS vaccine, in-country licensure (marketing authorization in the country of manufacture), any necessary policy recommendations from the WHO Strategic Advisory Group of Experts (SAGE) on Immunization, WHO prequalification (PQ), Gavi financing, UNICEF purchasing and national technical advisory groups recommendations for vaccine use. This will be achieved as a joint IVI/WHO leadership and collaboration through a consensus process in partnership with multiple stakeholders."


Not available

Research on Research Institute Grant

Research on Research Institute – CWTS-Leiden Costs Not available


Discretionary Award - Open research

afrimapr R building-blocks for the operational COVID-19 health response We will develop software building-blocks to facilitate the use of operational health data in Africa to aid the COVID-19 response. The main gap the new work addresses is the use and re-use of health data in the immediate operational response to COVID-19. The project will run under the umbrella of afrimapr, an existing Wellcome Open Research Fund project improving the use of health research data. The project philosophy is the same: firstly to develop open-source R components to assist African data scientists in creating tools to address local issues, secondly to develop training resources and thirdly to promote them within African data communities. We have already started assessing, and improving access to, open-data on African health facility locations. This extension will allow us to continue working with new collaborators; healthsites.io and OpenStreetMap communities that collate and crowdsource health facility data. We will reach out to African data communities through DFID advisers to African ministries, national statistics institutes through the Global Statistical Service, and our networks and social media. Components for working with African health zones will also be developed. Increasing the use of open-access health data has the co-benefit of incentivizing improvements to the availability of the data themselves.


Discretionary Award - Snakebite

A Rapid and Substantial Increase in Supplies of an Effective, Safe and Affordable Antivenom to sub-Saharan Africa The project will be directed by MicroPharm and will include contributions by scientists at the Liverpool School of Tropical Medicine.  It is in direct response to the WHO's stated aim of reducing the mortality and morbidity of snake envenoming.

The aim of the project is to re-establish supplies of Fav-Afrique in its current format as an equine F(ab’)2 based antivenom suitable for the treatment of Category 1 venomous African snakes. Sanofi-Pasteur will continue to supply large pools of plasma from horses immunised with venoms from Echis, Bitis, Naja or Dendroaspis species respectively.  The manufacturing procedures will be modernised and simplified to increase yield and decrease cost.  Initial supplies will be available for clinical use in Africa by 2023.


International Intermediate Fellowship

Longitudinal maternal and early life (neuro)immune mechanisms underlying neurodevelopmental and behavioural impairments in HIV-exposed uninfected children in a South African birth cohort While prevention of mother-to-child transmission (PMTCT) success has resulted in the decline in paediatric HIV infection, the number of HIV-exposed uninfected (HEU) infants has rapidly risen. In 2018, the population of HEU children in sub-Saharan Africa was estimated to be 13.2 million. In utero exposure to HIV may exert detrimental influences on the intricate neurodevelopmental processes during the first five years of life, with long-lasting effects on cognitive performance and behaviour. Our understanding of the pathophysiological mechanisms that are involved in conferring risk for neurodevelopmental deficits due to HIV exposure remains limited.

Altered neuroimmune regulation during pregnancy and early life may negatively affect neurodevelopment in children and in the context of maternal HIV infection may, in part, explain the delayed neurodevelopment observed in HEU children. However, the temporal regulation of neuroimmune markers during the critical period of the developing brain in HEU children remains unexplored. Importantly, it is also unknown at which stage (from in utero through to five years of age) the developing brain in children with HEU is affected. This study proposes to investigate longitudinally the association between maternal and infant neuroimmune function and brain development and neurodevelopmental outcomes in South African HEU children.

Infectious Disease Transmission, Vertical


International Training Fellowship

Centre National de Recherche et de Formation sur le Paludisme

Assessing the impact of a new class of insecticide treated net (Interceptor G2) on malaria vectors population dynamics, ecology and behaviours in the Cascades Region of Burkina Faso. Long-Lasting Insecticide-Treated Nets (ITNs) are the most successful method for malaria vector control in Africa. Growing evidence indicates changes in mosquito vector biting and resting behaviours in several African settings where high ITN coverage has been achieved. These combined with growing resistance to pyrethroids, the insecticide class used in all nets, can reduce intervention success. This is the case in Burkina Faso where high outdoor biting and pyrethroid resistance is reducing the efficacy of standard ITNs. In response to this Burkina Faso, adopted the newly developed ‘Next Generation Nets’ in its 2019 mass distribution campaign, becoming the first country to deploy Interceptor G2 (IG2), a net combining a pyrethroid with chlorfenapyr, an insecticide that should be effective against pyrethroid-resistant vectors. However, my initial results from laboratory and semi-field studies on mosquitoes from the Cascades Region of Burkina Faso indicate much lower moralities with IG2 nets than expected from earlier trials raising concerns that local vectors may have already developed resistance to this insecticide class.
Combining field and laboratory works in the Cascades Region I will assess for chlorfenapyr-resistance, its potential mechanisms and the impact of IG2 on Anopheles gambiae s.l. demography, behaviours (resting and biting) and malaria transmission potential.


International Training Fellowship

Optimising dosing of dihydroartemisinin-piperaquine for malaria preventive treatment in Malawian infants  The World Health Organisation recommends use of sulphadoxine-pyrimethamine (SP), administered with routine immunisation, for intermittent preventive treatment of malaria in infancy (IPTi) in areas of moderate to high transmission in sub-Saharan Africa. However, there is limited uptake of this recommendation and increasing resistance of malaria parasites to SP. Fortunately, another antimalarial drug, dihydroartemisinin-piperaquine (DP), has shown higher protective efficacy than SP. However, there is paucity of evidence to guide its optimal dosing in infants. Additionally, IPTi is usually given to infants born to women who received SP or DP for intermittent preventive treatment of malaria in pregnancy (IPTp). The impact of using DP for IPTp on subsequent metabolism and efficacy of DP in infancy is not well understood.

In this Fellowship, I will develop optimised dosing regimens of DP for IPTi by applying population pharmacokinetic-pharmacodynamic modelling techniques on data obtained from:

 Evaluating the pharmacokinetics, efficacy and safety of DP for IPTi, in a randomised-controlled trial, in infants born to Malawian women who received DP compared to SP for malaria prevention in pregnancy.
 Understanding age-related changes in piperaquine pharmacokinetics during infancy.

This work will provide the much-needed evidence to inform DP dosing for IPTi, when administered with routine immunisation.


International Training Fellowship

Interactive play:  a strategy to improve nurturing care and movement behaviours for infants The persistence of under- and over-nutrition, in conjunction with poor adherence to movement guidelines and lack of stimulation evident among South African children, is indicative of a generation being raised in an environment that is not conducive to optimum early childhood development. This perpetuates an intergenerational cycle of health inequality.

Nurturing care is essential for early childhood development, and relies on responsive and sensitive interactions between caregivers and infants. Considering the importance of caregiver-infant interaction, as well as of infant movement behaviours, I hypothesise that encouraging interactive play could improve childhood growth and developmental through both the biological pathways linked to infant movement, and nurturing care pathways that promote attachment and emotional development.

This study proposes to test this hypothesis by designing, implementing and testing the efficacy of an intervention that encourages interactive play during infancy. This study uses a novel objective assessments of interactive play, as well as rapid participant feedback tools and an adaptive intervention design to enhance behaviour change and therefore intervention adherence.


International Intermediate Fellowship

Investigating the prevalence, clinical consequences and associations of red blood cell alloimmunization among children with sickle cell disease in Kilifi Kenya  Sickle cell disease (SCD) is the most important genetic disorder in sub-Saharan Africa, where over 280,000 affected children are born every year. Although children with SCD represent only 1-2% of all births within the region, they receive between 10 and 25% of all the blood transfusions administered to children

My fellowship has two main aims. First, I will describe the prevalence and consequences of alloimmunization among children attending the SCD clinic at Kilifi County Hospital in Kenya. Second, I will explore potential risk factors for the development of alloimmunization, including levels of inflammation within transfusion recipients and red blood cell genetic diversity in both donors and recipients.  By identifying risk factors that contribute to alloimmunization, I will contribute to the development of better strategies that reduce the chance of development of alloimmunization for the transfusion management of patients with SCD in Africa.


International Intermediate Fellowship

Enhancing growth and development among malnourished infants recovering from serious illness Globally, acute malnutrition affects 8.5 million infants under 6 months of age (u6m). Malnourished infants u6m are at elevated risk of death during admission and after discharge from hospital and of subsequent neurodevelopmental impairment. WHO nutritional rehabilitation guidelines for u6m focus on re-establishing exclusive breastfeeding (EBF) with discharge when consistent weight gain ( > 5g/kg/day) is achieved on breastmilk alone.  My pilot study examined breastfeeding peer supporters to facilitate guideline implementation among hospitalised malnourished infants.  We achieved 81% exclusive breastfeeding by discharge with 67% attaining the WHO recommended growth velocity on breastmilk alone. However, criteria for full nutritional recovery were generally not met 6 weeks after discharge. I now hypothesise that providing support during transition to home will improve nutritional recovery. In Phase 1 I will develop and pilot a breastfeeding support intervention among 30 recovering infants u6m. In Phase 2 I will apply a randomised controlled trial to evaluate effectiveness of the finalised intervention compared with standard care among 250 malnourished infants (4-12 weeks old) recovering from an illness. The primary outcome is growth (weight gain) assessed at age 6 months, with follow up to 12 months. Results will inform efforts to improve post-discharge management of recovering vulnerable infants u6m.


International Training Fellowship

Effects of intra-uterine HIV exposure on antibody functionality and B cell development Approximately 30% of pregnant women in South Africa are HIV-infected resulting in over 300 000 infants exposed to HIV in utero every year. Rates of infectious mortality are reportedly higher among HIV-exposed uninfected infants (iHEU) compared to HIV-unexposed uninfected infants (iHUU). Studies evaluating the effects of maternal HIV infection on vaccine responses in their respective infants show that iHEU have similar antibody titres as those elicited in iHUU. These results imply efficacious vaccination in iHEU which contradicts the observed higher morbidity and mortality rates in iHEU. Therefore, I hypothesise that exposure to HIV in utero may impact the maturation of B cells leading to production of antibodies with poor Fc functions. Our preliminary analysis revealed altered B cell phenotypes across age in iHEU compared to iHUU. Therefore, in this study I aim to characterise B cell properties such as reduced somatic hypermutation for affinity maturation among iHEU using RNA-sequencing. Furthermore, I will analyse IgG Fc glycosylation that is associated with Fc-FcR affinity and Fc effector functions. Subsequently, I will develop in vitro models to measure antibody dependent cellular phagocytosis (ADCP) and cytotoxicity (ADCC) specific to early childhood vaccines.


International Intermediate Fellowship

London School of Hygiene & Tropical Medicine

Integrated primary eye care interventions in Ethiopia Context:
There are 2.2 billion visually impaired people globally. About 90% of these live in low-and-middle- income countries, 80% have avoidable conditions, which are amenable to well-established cost- effective interventions. WHO is promoting Universal Eye Health through integration of Primary Eye Care (PEC) into Primary Health Care (PHC). However, there is little evidence how and what interventions work to effectively and sustainably integrate PEC services into PHC in low-income settings.

Proposed Research:
The following studies will be conducted in Ethiopia in four phases:

Phase 1: Population-based cross-sectional studies to assess eye care need, inequalities, eye health-seeking behaviour and capabilities.

Phase 2: Health System Preparedness Evaluation Study to assess the health system's capacity and gaps to deliver integrated PEC interventions.

Phase 3: Intervention Development, informed by Phase 1  &  2, through Participatory Action Research (PAR) to develop contextually appropriate, feasible, community owned-and-led integrated  &  sustainable PEC services.

Phase 4: Iterated testing and piloting of the identified PEC interventions both individually and as integrated package at community, health facility, and healthcare organisation level to identify a working PEC intervention that will inform scaled-up delivery of equitably accessible, quality, and sustainable PEC services integrated with PHC.


Strategic Support: Science

Dr Alison Price, Dr Antonia Ho, Dr Charles Mwansambo, Dr Chris Jewell, Dr Abena Amoah, Dr Jonathan Read, Dr Tonney Nyirenda, Dr Annie Chauma Mwale, Dr Peter MacPherson, Prof Nyovani Madise, Prof Victor Mwapasa

SARS-CoV-2 immunoepidemiology in Wellcome-funded urban and rural cohorts in Malawi : generating evidence to inform regional medium and long term decision making General population serosurveillance in low-income Africa is fundamental to understanding the population exposure to SARS-CoV-2, to explain the observed epidemiology and to ensure that ongoing control measures in the region are proportionate and are not guided by observations from very different settings. Detailed longitudinal immunological studies of infected individuals will be key to determining the long-term strategy in managing COVID-19 in highly vulnerable African populations.

Utilising the longitudinal urban and rural cohorts established by the Malawi Epidemiology and Intervention Research Unit, and supported by international and national expertise, we will undertake population immunoepidemiological surveillance to understand the trends in exposure and transmission of SARS-CoV-2, risk factors for SARS-CoV-2 infection and severe disease, as well as the proportion of asymptomatic or pauci-symptomatic infection in the population to enable an accurate estimate of infection fatality rate. Furthermore, we will recruit individuals with evidence of past SARS-CoV-2 infection to a nested cohort with 3-monthly sampling, to explore the magnitude and duration of antibody response and protective immunity in the Malawian population, and at the same time creating a biorepository for further in-depth virological and immunological studies.

Grants awarded from 1 October 2005 to 30 June 2021


Shigella Vaccine Value Proposition

Discretionary Award – Innovations

Shigella Vaccine Value Proposition Public Health Value Propositions, also called Full value Vaccine Assessments, are critical, evidence-based analyses conducted to ensure that efforts to develop new vaccines align with the needs, interests and capacity  of intended beneficiaries. We are developing a Shigella vaccine Value Proposition (svvp) to assess and possible enhance the probability that appropriate vaccines targeted at the diarrhoea-causing bacterium Shigella will be developed, produced, financed, widely recommended and adapted in low-middle income countries (LMICs)where it is endemic. The SVVP will inform late stage development investments in Shigella vaccine candidates. We are assessing and synthesizing relevant epidemiological, economic, policy regulatory and manufacturing aspects to address five broad questions and inform the SVVP.

1. How strong is the evidence linking Shigella to stunting, and what would be the economic consequences of vaccine-induced reductions in stunting?

2. What would be the projected impact on and cost effectiveness of the prevention of Shigellosis by effective vaccines?

3. What is the potential demand for Shigella vaccines across different markets?

4. What would be the optimal pathogen composition of a Shigella-containing combination vaccine potentially available in the near- or medium-term?

5. From the perspectives of LMIC-level policy makers and other key stakeholder, what would be the perceived value of a shigella-containing vaccine?


Discretionary Award - Vaccines

Sabin-Aspen September Convening on sustainable vaccine ecosystem The COVID-19 pandemic underscores the urgency and importance of vaccines and immunization to global health. There are significant and pressing scientific, technical and policy solutions needed to tackle the enormous challenges we face in a world with COVID-19. Bold thinking across disciplines, actionable recommendations and strong advocacy are all urgently needed to advance innovative ideas, overcome these hurdles and inform future programmatic work, in particular in light of the COVID pandemic. The goal of this project is to virtually convene The Sabin-Aspen Vaccine Science  &  Policy Group (Vaccine Group) in September 2020 to explore how the effort to accelerate the development of COVID-19 vaccines through ACT Accelerator and other initiatives can be harnessed to bring about a "new normal" for vaccine/vaccination ecosystem and ensure that vaccines for diseases with epidemic potential or those affecting low income populations are developed. The Sabin Vaccine Institute and the Aspen Institute, co-conveners of the Vaccine Group, will draft and disseminate a meeting report on the convening with principal findings and recommendations to inform program and policy planning.


Sir Henry Dale Fellowship

Royal Society/Wellcome Trust Sir Henry Dale Fellowship

Sir Henry Dale Fellowship Interview Committee

TRANSCRIPTIONAL REGULATION OF SELF-RENEWAL IN HUMAN HAEMATOPOIETIC STEM CELLS Generation of functional HSC from pluripotent cells and robust HSC expansion in culture are limited by our incomplete understanding of the self-renewal process. My goal is to unveil the regulatory pathways that sustain HSC self-renewal, based on modulation of gene expression at pre- (chromatin modification) and co-transcriptional  (transcriptional elongation and RNA polymerase II pausing) levels and as directed by the metabolic state of the cell. I will carry out my scientific goals with the following aims:

 Determine the regulation of HSC self-renewal though modulation of transcriptional rate and RNA polymerase II activity.
 Understand the role of HSC metabolism and nutrient availability in the regulation of the HSC self-renewal gene regulation machinery.
 Modulate HSC transcriptional regulation to achieve successful HSC generation in culture.

These research avenues will lead to a better understanding of the molecular basis of self-renewal and will provide a foundation to improve the generation and expansion of engraftable human HSCs in culture, in order to fully exploit their potential for clinical applications. This work will expand our current knowledge of the HSC self-renewal process and provide new insights into the molecular features of stemness, with implications for other tissue stem cells and the cancer field.


Sir Henry Dale Fellowship

Socio-ecological dynamics of zoonotic and vector-borne diseases in changing landscapes: implications for surveillance and control Landscape changes disrupt infectious disease dynamics, requiring new approaches to characterise risks and prevent outbreaks. Focusing on emerging (Chikungunya, Zika) and epidemic (malaria, dengue) zoonotic and vector-borne diseases in Malaysia and the Philippines, I aim to design and evaluate enhanced surveillance systems linking health and environmental data to detect and prevent pathogen spillover and transmission. By developing novel models relating social and ecological processes across spatial and temporal scales, I will bridge critical gaps linking environmental change with human behaviour and health systems. Fine-scale studies of human mobility, behaviour and infection risks will be integrated within a large-scale experiment on tropical forest modification to understand how landscape change both interacts with and alters environmental factors (e.g. seasonality, biodiversity) and socioeconomic and biological factors (e.g. demography, mobility, immunity) to determine disease dynamics. Statistical and mathematical models will be used to explore factors across ecological settings, integrating routine surveillance data, population-based serological surveys and multitemporal Earth Observation data to reconstruct historical disease transmission over major environmental shifts. Predictive models will be designed to identify how future land use can reduce disease risks and how control programmes can use environmental data from new sources of real-time Earth Observation data to improve disease surveillance.


Investigator Award in Science

Understanding non-coding genomic variation in neurological disorders The vast majority of DNA is non-coding, repetitive, encompasses a significant proportion of disease risk and is divergent across populations. Major bottlenecks in the past restricted our understanding of this genomic region, including limited analysis techniques, inability to sequence large repetitive, homologous regions and the paucity of population control datasets. These restrictions have largely been overcome, and through early translation we have highlighted the importance of non-coding genomic factors with the identification of pathogenic recessive repeat expansions, homologous replicated regions and gene amplification events as major causes of neurological disease.

The overarching theme of this proposal is to investigate four large diverse neurology cohorts, where genome sequencing has explained less than one-third of cases. Initially, we will examine non-coding, short-read genome sequencing data using optimised and newly developed algorithms. Next, to overcome the limitations of short-read sequencing, we will apply and integrate long-read Oxford Nanopore genome sequencing and optical genome mapping to a range of neurological disease trios and paired brain and blood samples. Finally, we will comprehensively interpret and validate data, reannotate against diverse control genomes, compare disease-relevant transcriptome builds, interrogate collaborator cohorts and use transcriptome sequencing to inform on pathogenicity, identify mechanisms and pathways impacted by genetic vulnerability.


Collaborative Award in Science

Defining the molecular determinants required for Leishmania life cycle progression and virulence Leishmania parasites cause a neglected disease on the WHO priority list. During their life cycle, these single-celled parasites must migrate through the sandfly (promastigotes), pre-adapt for mammalian infectivity (metacyclic promastigotes) and proliferate inside macrophages (amastigotes) while withstanding host immune defences. Adaptation to these radically different environments involves many changes, including metabolic and cell structure specialisations, ensuring survival and transmission. However, current understanding of these processes is disjointed and biased towards predicted/expected pathways. Half of Leishmania’s protein-coding genes, including most unique to Leishmania, have no known or predicted function, (the "dark genome"), leaving potentially exploitable parasite biochemistry untapped in the search for new therapeutics. We aim to identify all major parasite pathogenicity factors.  We will determine a) the subcellular localisation of all proteins with poorly predicted function (~50% of the genome) and b) the fitness cost of gene deletion in each life cycle stage (100% of the genome). Integrative analysis of this deep dataset will identify key pathways in 1) organelle adaptation for an intracellular parasitic lifestyle and 2) host interaction, which we will then functionally dissect. This will identify virulence factors on a genome scale, determine the most important pathways required for parasitism and illuminate the ‘dark genome’.


Collaborative Award in Science

Dr Brandon Kohrt, Dr Mark Jordans, Prof Lydia Krabbendam, Dr Tarun Dua, Mr Nagendra Luitel, Prof Mauricio Avendano

ALIVE: Improving Adolescent mentaL health by reducing the Impact of poVErty Depression and anxiety are leading contributors to the burden of disease among adolescents in low- and middle-income countries (LMIC), and they disproportionally affect adolescents living in poverty. Yet, the evidence base for interventions that effectively prevent depression and anxiety among adolescents living in poverty is weak. One major shortcoming is that interventions often fail to address poverty-related social determinants of mental health and neuropsychological consequences of poverty (such as impaired self-regulation). The aim of this study is to develop and pilot-test an intervention that equips adolescents with skills to escape poverty and strengthens self-regulation, thus preventing adolescent depression and anxiety in urban LMIC settings.The study objectives are to: (1) develop a theoretical model of the causal mechanisms linking poverty, self-regulation, and depression and anxiety among adolescents (age 10-19 years); (2) collaboratively develop a multi-component selective prevention intervention targeting self-regulation and skills for academic and employment success  among adolescents at high risk of developing depression or anxiety living in urban poverty in Colombia, Nepal and South Africa; (3) adapt and validate key instruments to measure eligibility, implementation, mediators, and outcomes of the intervention; and (4) undertake a 4-arm pilot randomized controlled trial of the selective prevention intervention in each site.


Plasticity of visual circuits

Investigator Award in Science

Plasticity of visual circuits How does a circuit of neurons process sensory information?  And how is processing adjusted in relation to changes in the sensory environment or internal state of the animal? These questions will be investigated in larval zebrafish, where visual circuits and the behaviours they drive are altered in the context of

i) changes in the visual environment, such as luminance or contrast,
ii) information arriving through chemical and mechanical senses,
iii) the internal state, such as arousal or satiety, and
iv) circadian mechanisms.

To investigate how visual processing is adjusted under these different conditions we will use larval zebrafish to image neural activity through the retina and brain of the behaving animal. Zebrafish generate distinct motor responses to stimuli of different contrasts, size and speed, allowing us to investigate the plasticity of computations directly linked to behaviour.

Our guiding hypothesis is that the plasticity of visual circuits reflects use-dependent changes in synaptic strength and the actions of neuromodulators that reconfigure signal flow.  A comparison of computations carried out in different circuits will be key to identifying general mechanisms by which the brain adjusts sensory processing to the sensory environment and/or internal state of the animal.


Investigator Award in Science

Epilepsy and neurodegeneration : disease mechanisms and early detection Cognitive decline represents a significant and debilitating co-morbidity for patients with epilepsy which is poorly understood with an urgent clinical need for diagnostic, preventative and treatment strategies. Large epilepsy MRI datasets confirm progressive cortical atrophy and white matter abnormalities ; age-accelerated Tau protein accumulation has been reported in surgical resections, correlating with cognitive decline. We propose a comprehensive evaluation of mixed neurodegenerative processes integrating cross-sectional and longitudinal MRI, DWI, DCE-MRI and Tau-PETimaging with quantitative neuropathology  measurements of cortical, white mater atrophy and vascular pathology and pTau in resected surgical specimens in the context of cognitive impairment and genetic risk. We aim to characterise tau forms in surgical and post-mortem cohorts compared to Alzheimer's disease and other tauopathies. In prospective surgical cohorts, Tau-PET will be correlated with CSF markers, tissue levels using autoradiography and extent of cortical atrophy with high resolution in-vivo 7T and ex-vivo 9.4T MRI. In addition, cellular drivers for tau accumulation, as MTOR and seizure activity,  will be explored through human slice culture experiments with gene-expression analysis and the kinetics of tau incorporation through SILK studies and mass spectroscopy of tissues. These studies will elucidate pathomechanims of cognitive impairment, identify early disease-stage biomarkers enabling prediction and preventative strategies.


Senior Research Fellowship

A cross-species, cross-modal approach to computational neuroanatomy In vivo methods for mapping brain connections are increasingly used in systems neuroscience but are yet to have significant clinical impact. We propose to develop new computational approaches that bridge information from precise but invasive methods in animals to enhance in vivo methods in humans. We translate this framework into clinical care in surgical patients:

In Aim 1, we will leverage a unique resource of macaque tracers currently being digitised. We will use state-of-the-art machine learning to automate quantification, and image processing for mapping histology to MRI, to produce a unique resource of macaque ground truth connectivity.
In Aim 2, we will develop computational approaches to enable macaque anatomical tracers, alongside multimodal MRI in macaques and humans, to be used to improve the accuracy of methods developed in humans.
In Aim 3, we will build end-to-end approaches for connectivity-based functional localisation, and deploy this as a tool to aid pre-surgical planning for localisation of subcortical targets in deep brain stimulation and for localisation of eloquent cortex in tumour surgery.


Investigator Award in Science

Plasmid biology in human adapted pathogens Plasmids are responsible for virulence and antimicrobial resistance in many bacteria. We will dissect fundamental mechanisms of plasmid maintenance in the obligate human pathogens, Shigella spp. and Neisseria gonorrhoeae, declared as high priority organisms by WHO/CDC. Toxin:antitoxin (TA) systems (addiction systems) are important for plasmid maintenance by eliminating bacteria failing to inherit a plasmid after cell division. For example, the VapBC TA system is essential for maintaining the 210kb Shigella virulence plasmid. Additionally, TA systems (including VapBC) are increasingly recognised for their role in antibiotic tolerance, often a precursor to resistance. Despite this, little is known of how plasmid maintenance is integrated with the bacterial host, and how TA systems are activated after plasmid loss/during tolerance. Combining our understanding of variation in VapBC and the VapC toxin target tRNAfMet with multidisciplinary approaches (mutagenesis/structural:function studies/single cell analysis), we will define mechanisms of TA system activation and the temporal dynamics of events following plasmid loss that culminate in cell death. We will examine the acquisition and maintenance of resistance plasmids in Shigella and N. gonorrhoeae, and the interactions between plasmids and their contribtion to tolerance and horizontal transfer.


Investigator Award in Science

Computational Modelling and Inference of Neurodegenerative Disease Propagation This project uses computational modelling, machine learning, and big-data analysis to address key unknowns on the biology of neurodegenerative disease: when and where it starts; how it spreads over the brain ("propagates"); how it varies among diseases, subtypes, and individuals; how risk factors influence mechanisms. Current models linking imaging and other clinical data to propagation mechanisms are crude, and evaluation remains largely qualitative. The project introduces a powerful Bayesian inference framework, accounting for uncertainties throughout the data-processing pipeline, to enable robust evidence quantification of new and detailed computational models of disease propagation. The approach demands a rethink of contributing technologies. First, we unravel patient heterogeneity, which confounds propagation-model evaluation, through a new generation of data-driven disease progression models that identify fine-grained disease subtypes characterised by temporal trajectory of multi-modal biomarkers. Second, propagation models use brain connectome estimates and are confounded by high connection-error rates. We establish a new probabilistic connectomics paradigm that quantifies likelihoods of false positive and negative connections enabling models to mitigate their inevitable presence. We use the framework to provide the first truly quantitative evaluation of propagation models against state-of-the-art data sets leading to fundamental new insights on the mechanisms of pathology propagation in neurodegenerative diseases.


Investigator Award in Science

Molecular regulators of the alarmin IL-33 in health and disease IL-33 is a critical cytokine in allergy, obesity, helminth infection, sepsis, and respiratory viral infection. Blockade of IL-33 (or its receptor, ST2) is currently being trialled in a range of allergic and inflammatory conditions, including Covid-19. The cytokine has a short half-life on release, but conversely has effects at distal sites and over long periods. Furthermore, innate immune cells in the intestine are poorly responsive to IL-33, but susceptibility to intestinal helminths is strongly controlled by IL-33.

This project will investigate:

1) How, at a protein structural level, parasite proteins effectively block IL-33 responses. Determination of the effects on the parasite and host of blocking parasite modulation of the IL-33 pathway.

2) What are the roles and targets of IL-33 released from the intestinal epithelium, both locally (in parasite infection) and systemically (in diet-induced obesity).

3) The role of soluble IL-33 receptor in stabilisation of IL-33, and its effects at distal sites.

To achieve these aims will we will use structural biology, in vivo models of IL-33-dependent responses, creation of cell-specific ST2-deficient mouse strains, and generation of a soluble ST2-deficient mouse. Finally we will use human blood samples and three-dimensional culture methods to ensure translation of these findings to humans.


Investigator Award in Science

The role of epithelial cell extrusion in asthma Asthma is an airway inflammatory disease, defined by bronchoconstrictive attacks that can be life-threatening. The two essential tissue components of the bronchioles are the airway epithelium and the underlying smooth muscle. In asthma, the smooth muscle is remodelled and becomes hyper-responsive, leading to excessive contractility. We have shown that epithelia are exquisitely sensitive to mechanical forces. Cell crowding triggers cell extrusion, while stretching triggers cell division. We recently discovered that the asthmatic bronchoconstrictive attack, causes excess airway epithelial extrusion and damage, compromising the barrier function, leading to inflammation. We propose that in healthy lungs, epithelia and smooth muscle communicate with each other to ensure sufficient epithelial cells numbers, essential to a tight barrier. However, in asthma, excess epithelial extrusion signals smooth muscle remodeling, actuating further rounds of more intense bronchoconstriction. This feed-forward cycle could perpetuate asthma attacks. We believe that our mechanochemical and cell biological insight into asthma will reveal novel ways to prevent it. We will investigate this hypothesis by addressing the following questions:

1) How are airways remodelled to cause an attack?
2) Do epithelia regulate constriction?
3) Does extrusion shed rhinovirus, yet trigger asthma attack


Investigator Award in Science

Molecular mechanisms of DNA synthesis by the human replisome Before mitosis, cells must make two accurate and complete copies of their genome, to ensure genetic stability across cellular generations. This challenging biochemical task requires complex molecular systems that duplicate chromosomal DNA and repair lesions that stall DNA synthesis. Sporadic or inherited defects in the cellular apparatus of genomic duplication cause genetic instability, which is responsible for developmental and degenerative pathologies and for cancer predisposition.

Our knowledge of the molecular basis of eukaryotic DNA replication and related repair processes is incomplete, and this is especially true of genomic duplication in human cells, the most relevant to our health. Our proposal aims to provide a high-resolution view of the molecular mechanisms of DNA replication, using state-of-the-art biochemical and biophysical approaches. We will focus on components of the human replisome, the multi-protein assembly responsible for DNA synthesis in our cells.

There is intense medical interest in the molecular mechanisms responsible for genomic integrity and the rationale for the consequences of their occasional failure. In this respect, the work of our proposal is highly significant as it aims to deliver a comprehensive description in atomic detail of the complex and dynamic processes of DNA replication, when our genome is at its most vulnerable.


Sir Henry Dale Fellowship

Factors of biological ageing: does it all go together when it goes? Ageing-related cognitive decline carries a huge personal, societal, and financial cost. Understanding its underlying mechanisms with a view to ameliorating age-related cognitive decline is a huge challenge. It is essential to identify biomarkers of cognitive ageing and their potential determinants. Brain structural imaging markers in older age, their correspondence with proteomic and other biomarkers, and their potential determinants, are poorly characterised. Our understanding is informed by cross-sectional studies (which cannot fully reflect the dynamic within-person processes of ageing) and mainly univariate longitudinal data (i.e. describing how brain regions individually decline over time): most aspects of brain structure decline, on average.

However, these approaches do not tell us whether there are important patterns of coordinated change, nor are they well-aligned with other levels of biological explanation. Such information could potentially aid stratification of risk and identification of important clusters of determinants of brain and cognitive ageing.

I will apply cutting-edge factor-analytic methods to large longitudinal datasets to detect and validate patterns of correlated biological changes (brain structure, serum proteomic and DNA transcriptomic). I will test how these dimensions of ageing are associated with each other and with cognitive ageing, and use several techniques to ascertain their lifestyle, genetic and epigenetic predictors.


Investigator Award in Science

Structural mechanism of genome acetylation and 3D folding Recent chromosome capture experiments have revealed a hierarchical 3D organisation of the genome ranging from Topologically Associating Domains (TADs) to larger-scale active, euchromatic and inactive, heterochromatic compartments. TADs arise through chromatin loop extrusion by cohesin/CTCF while compartments arise through epigenetic modification of the chromatin polymer. It has long been known that dynamic histone acetylation switches between repressive and permissive chromatin, a key event in transcriptional activation. We aim to capture cohesin in different structural states to understand how it is regulated and catalyses large-scale chromatin transactions. We also aim to understand the molecular mechanism behind acetylation-dependent activation of chromatin a reaction that is critical for the establishment of active euchromatin and may contribute to genome compartmentalisation and enhancer-promoter interaction. This proposal has the potential to transform our understanding the molecular mechanism behind two key reactions that contribute short- and long-range 3D genome architecture. It is possible that both mechanisms are interconnected and provide unifying principles to explain gene regulation with broad implications for health and disease.


Sir Henry Dale Fellowship

Ringing the changes: how bacterial enzymes convert ribosomally-synthesised peptides into antibiotics The project aims to investigate the mechanism of peptide transformations carried out by YcaO enzymes and to use this knowledge to create novel antimicrobials.

Bacterial YcaO proteins are essential for the biosynthesis of multiple classes of peptide natural products through their ability to introduce important structural modifications including heterocycles, macrocycles, and thioamides. YcaO repurposing and swapping between different pathways offers exciting possibilities to create novel artificial peptides bearing such modifications. Despite much recent progress, we still do not really understand how these proteins work, and how their activities are coordinated within multisubunit enzyme complexes. I will use cryo-EM in combination with X-ray crystallography to solve the structures of YcaOs within their native complex assemblies trapped at different catalytic stages. In parallel, I will discover and characterise new YcaO proteins to further expand their known catalytic repertoire.

Finally, the promiscuity of YcaOs allows for the production of large genetically encoded peptide antibiotic libraries. I will generate these by co-expressing randomised precursor genes along with modification systems. A high-throughput fluorescence-based version of a Waksman platform will be used for screening, where nano-sized "Petri dishes" (hydrogel beads) will be inoculated with both producer and reporter strains and sorted by FACS.

Grants awarded from 1 October 2005 to 30 June 2021


Senior Research Fellowship

Targeting remodelling of lung stem and niche cells: lessons from regeneration to disease Lungs possess a remarkable regenerative capacity by dynamic multicellular responses following injury. However, chronic damage makes these responses persistent, leading to fibrosis. We will define the mechanisms by which productive regeneration programmes are diverted to disease remodelling, with the ultimate goal of uncovering therapeutic strategies that can treat or prevent lung fibrosis.

We recently identified Damage-Associated Transient Progenitors (DATPs), a functional mediator of alveolar stem cell differentiation, emerging during lung regeneration. Notably, chronic inflammation leads to accumulation of DATPs displaying defective differentiation, resulting in impaired alveolar regeneration. We aim to identify strategies to target DATPs in chronic injury by dissecting changes in them and their niche environments. Specifically, we will define (1) key DATP-niche interactions during different phases of regeneration, and how to these evolve during disease progression utilising a novel niche-labelling system; (2) transcriptional and epigenetic changes mediating damage-associated reprogramming following injury at single-cell resolutions, and key signalling modules conferring lineage flexibility of stem/niche cells; (3) conserved regenerative programmes and potential therapeutic targets in preclinical 3D human lung disease models we have developed. Our work will provide fundamental insights into defining the cellular and molecular basis of lung regeneration as well as identifying selective therapeutic targets in lung diseases.


Investigator Award in Science

Genetic approaches to studying early lineage specification in human embryos The goal of this proposal is to transform our understanding of the molecular mechanisms that control early human development. The mechanisms that regulate early cell fate decisions in human development remain poorly understood, despite their fundamental biological importance and wide-reaching clinical implications for understanding infertility, miscarriages, developmental disorders and therapeutic applications of stem cells. We seek to uncover when and how human embryonic epiblast cells are established and maintained, and to understand the molecular mechanisms that distinguish these pluripotent cells from extra-embryonic cells during embryogenesis. We will further develop pioneering methods to investigate gene function during human embryogenesis using CRISPR-Cas9-mediated genome editing, TRIM-Away protein depletion, constitutively active and kinase dead variants of proteins and small molecule inhibitors and activators. These approaches will enable us to directly test the function of genes involved in Hippo and TGFb signalling, and key transcription factors downstream of these pathways, which we hypothesize are involved in the first and second cell fate decisions, respectively. Altogether, we expect this program to make significant advances in our understanding of the molecular programs that shape early human embryogenesis, which has the potential to provide fundamental insights and to drive clinical translation.

Gene Expression Regulation, Developmental


Collaborative Award in Science

Dr Sudha Seshadri, Dr Rebecca Gottesman, Prof Aroon Hingorani, Prof Gill Livingston, Prof Eric Brunner, Prof Archana Singh-Manoux

Taking the long view: Identification of plasma protein biomarkers for dementia risk The overarching goal of this collaborative project is to make a step change in knowledge of dementia biomarkers by focusing on plasma proteome. We hypothesize that plasma is biologically informative due to the presence of protein signals: imprints of subclinical dementia progression that can be identified via repeated proteomic profiling decades before clinical symptoms, providing novel candidate targets for preventative treatments.

We will use the largest plasma proteome platform currently available, with three aims, to (1) prospectively examine 4,993 plasma proteins in relation to subsequent accelerated cognitive decline and clinical dementia across multiple cohort studies; (2) determine whether the protein hits identified in aim 1 have a causal association with dementia, whether modifiable and druggable, using analysis stratified by time between protein measurement and dementia onset and Mendelian Randomization framework in relation to novel genome-wide, and druggable-genome arrays; and (3) examine whether proteins predicting dementia risk are imprints of risk factors for dementia.

The expected new outcomes include protein targets for drug development; improved identification of potentially modifiable lifestyle risks; dementia trials surrogate outcomes; improved diagnostic markers, plus data resource for future in-depth research on the multisystem aetiology of dementias and proteomics of a range of major diseases beyond dementia


Dis-Ease

Discretionary Award – C&S

Dis-Ease Declaring "war on disease" affects how we treat sick people, how we define the "public" in public health, and how we respond to real-world pandemics.. This was demonstrated vividly during the COVID-19 crisis, when these declarations of war initiated militarized states of emergency, prompted border lockdowns, and refreshed old fears about "foreign" pathogens. But why was this public health crisis being treated as a national security issue? What else does this metaphor do in the world? And what if it weren't a war?

To answer those questions, the feature-length documentary "Dis-Ease" retraces the origin and evolution of our "war on disease" through the history, philosophy, culture, and pop-cultural imaginaries of medicine. It is constructed around particular episodes in the history of human encounters with epidemic, endemic, and pandemic diseases, including plague, malaria, cholera, tuberculosis, influenza, HIV/AIDS, and COVID-19. By examining the cultural history that runs alongside the growing scientific understanding of these diseases over time, DIS-EASE looks to understand how pandemic preparedness became framed as biodefense, and how that has contributed to the present crisis. And it proposes alternatives for the future.


Investigator Award in Science

Maladaptive thinking patterns in depression Depression is amongst the most burdensome disorders world-wide because it is a common disorder with frequent relapses. Relapse risk is increased by maladaptive thinking patterns such as rumination and helplessness, and by antidepressant discontinuation, which in turn increases maladaptive thinking patterns.

Maladaptive thinking patterns shape emotions and are influenced by emotions. However, we do not know the neurobiological mechanisms underlying these interactions. First, I propose to study this by measuring maladaptive thinking patterns directly using a decoding approach to magnetoencephalography (MEG). MEG decoding reveals fast sequences of stimulus representations during tasks. These sequences can then be compared to computational models to understand the algorithms the brain uses to prioritize information processing.

Maladaptive thinking patterns are targeted by psychotherapeutic interventions and are sensitive to serotonergic manipulations.  I will examine how psychotherapeutic interventions influence the interaction between thoughts and emotions, and how an acute reduction in serotonin through tryptophan depletion affects them. The latter study will be performed in remitted depression and allow us to test whether the mechanisms are involved in subsequent relapses.

Overall, I aim to provide a comprehensive account of how objectively-measured thought processes relate to emotions and to the prevention of depression relapses.


Senior Research Fellowship

TDP-43 Misregulation in neurodegeneration TDP-43 is a conserved RNA binding protein central to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 normally autoregulates its expression by binding to the 3’UTR of its cognate transcript. We have linked disrupted TDP-43 autoregulation to disease, showing that disease-linked TDP-43 missense mutations disturb TDP-43 autoregulation causing a gain of function, finding that ALS patients harbour non-coding variants in the 5’ and 3’UTRs of TDP-43 that could disturb TDP-43 expression and observing that TDP-43 misregulation in mice causes selective brain atrophy reminiscent of human ALS-FTD. We will follow these leads to understand the causes and consequences of TDP-43 misregulation and elucidate therapeutic targets and biomarkers for ALS-FTD. Specifically, we will dissect the TDP-43 autoregulation protein interactome in wild-type and TDP-43 missense mutant cells by performing in-cell protein-RNA interaction studies and native mass spectrometry. To determine the significance of ALS-linked UTR variants in regulating TDP-43 expression we will perform an in-vitro CRISPR/Cas9 mutagenesis screen with parallel genomic and transcriptomic sequencing. To understand how TDP-43 misregulation causes regional and cell type-specific neurodegeneration we will use in situ sequencing of mouse brain sections to obtain transcriptomic information with single cell resolution.


Sanger Resource Collaboration


Sir Henry Dale Fellowship

Structure, mechanism and dynamics of recoding in viral infection Many RNA viruses (e.g. SARS-CoV-2, HIV-1) have evolved ways of reprogramming translation to expand the coding capacity of their small genomes. ‘Recoding’ events such as -1 frameshifting, stop codon read-through and StopGo peptide release are necessary for viral replication, producing viral proteins in optimal ratios for efficient assembly. Recoding is regulated by a complex interplay between the elongating ribosome, cis-acting elements in the mRNA or nascent peptide, and trans-acting protein factors. Elucidating the structural basis of recoding is essential to understand viral pathogenesis. However, classical biochemical approaches cannot accurately capture kinetics or per-ribosome heterogeneity, making it difficult to define a window of opportunity for structure determination. Recent technological advances allow single-molecule fluorescent imaging of translation in real-time. I will apply these methods to study recoding in vitro and in live cells, starting with -1 frameshifting in SARS-CoV-2, HIV-1 and EMCV, which utilise topologically-distinct stimulatory elements. I will determine the structure of key ribosomal states by time-resolved cryo-EM, and investigate the structure and stability of stimulatory elements using crystallography, single molecule FRET and optical tweezers. Longer-term, this approach will be applied to investigate other recoding events, thus revealing universal and case-specific mechanistic principles, and highlighting new avenues for therapeutic intervention.


Sir Henry Dale Fellowship

Exploring the role of glypicans in modulating morphogen signalling and stem cell dynamics Wnt and Hedgehog signalling regulate intestinal stem cell dynamics to ensure intestinal renewal, function and integrity is maintained. The activation of these two pathways involves crosstalk and communication between the mesenchymal and epithelial layers of the intestine. However, a puzzling conundrum is that both Wnt and Hedgehog carry hydrophobic lipid moieties that are required for receptor binding and signalling but that also hinder their solubility and diffusion and hence ability to move between intestinal cells. In Drosophila, the glypican Dally-like protein (Dlp), which possess a lipid binding pocket, binds and shields the lipid moiety of Wnts to aid transport. Dlp is also essential for initiating Hedgehog signalling but its precise mechanism of action is unknown. I will determine if Dlp also binds the lipid moieties of Hedgehog and what such binding means for Hedgehog solubility, transport and receptor engagement. I will determine if mammalian homologues of Dlp also bind the lipid moieties of Wnt and Hedgehog to regulate their activity and whether they are required in the mouse intestine for Wnt and Hedgehog signalling to orchestrate stem cell dynamics. A deep understanding of how glypicans modulate Wnt and Hedgehog signalling will answer major questions in developmental and stem cell biology.


Investigator Award in Science

Probing cellular heterogeneity in the pancreatic microenvironment The overarching goal of this proposal is to elucidate the functional diversity of the pancreatic mesenchymal lineage. In embryonic tissues, epithelial progenitors receive paracrine signals from the surrounding mesenchymal niche, which can modulate their ability to proliferate and differentiate. The pancreas consists of a variety of specialized epithelial cells, including endocrine and acinar cells, surrounded by a poorly defined heterogeneous mesenchyme. We hypothesise that different mesenchymal lineages define local instructive microenvironments, including cell–cell crosstalk, ECM and signalling molecules, which eventually trigger distinct differentiation programmes from pancreatic progenitors. Sc-RNA-sequencing has generated a transcriptional map of the pancreatic mesenchyme in the mouse embryo. Here, we will unravel the spatial architecture of the identified mesenchymal cell states, linking their position to emerging pancreatic cell identities. Next, we will assess if mesenchymal lineages with a distinct spatial address underlie unique niche regulatory functions, promoting acinar or beta-cell differentiation. Finally, we will study the organisation and function of the identified niche microenvironment(s) in human tissue and pluripotent stem cells. The proposed programme will yield novel insight into pancreas biology and will set the stage for manipulating combinatorial pancreatic niches - an important step towards engineering functional beta-cells for regenerative medicine applications.


Sir Henry Dale Fellowship

Novel multi-nuclear magnetic resonance spectroscopy approaches for the sensitive and robust assessment of human cardiac energetics Altered cardiac metabolism is now recognized as an important component of many cardiovascular diseases, including heart failure. Accurate assessment of cellular energetics promises significantly better disease staging and treatment monitoring in such conditions. Current non-invasive techniques based on magnetic resonance spectroscopy (MRS) are not precise enough to reliably define cardiac energetics in individual patients.

In this fellowship, I will develop new highly-sensitive MRS techniques for complete cardiac energetics assessment at 7T. The main goals of this research are:

 To establish a robust, patient-specific platform for cardiac energetics quantification, by developing novel approaches to overcome a range of technical challenges associated with 31P-MRS;
 To develop advanced methods that will allow for complete assessment of cardiac energetics, including quantification of Gibbs free energy of adenosine-triphosphate (ATP) hydrolysis (deltaG), and of complete myocardial ATP fluxes;
 To demonstrate the sensitivity of these novel methods to measure impairments in total cardiac ATP dynamics in patients with type II diabetes and to detect changes in cellular energetics that accompany the transition to heart failure.

These new measures will help provide unique insight into the pathophysiology of the failing heart and will be applicable in future studies monitoring novel metabolic therapies in cardiovascular disorders.


Investigator Award in Science

Unravelling the molecular mechanisms of invasive pneumococcal disease Invasive pneumococcal disease causes over a million deaths per year worldwide, particularly in sub-Saharan Africa. Streptococcus pneumoniae strains vary considerably in virulence, but the reasons for this are unclear. Capsular serotype 1 strains are particularly invasive and cause a major proportion of severe infections, including meningitis, but are poorly studied, partly because they have been genetically intractable. We want to understand why serotype 1 strains are highly invasive, and to identify mechanisms that distinguish aggressive S. pneumoniae strains from less aggressive variants. Furthermore, a low-cost serotype 1 vaccine is urgently needed, especially in sub-Saharan Africa. In this project, we will combine and exploit (i) recently-developed in vitro and in vivo infection models, (ii) bacterial RNAseq data (including our data obtained from cerebral spinal fluid from Malawian meningitis patients) and (iii) our methodologies for mutating serotype 1 strains, to identify and characterise the roles of multiple novel genetic determinants important for the pathogenesis of invasive S. pneumoniae infections. We will also characterise in detail the zwitterionic capsular polysaccharide that defines serotype 1 strains and assess its role in pathogenesis. Finally, we will exploit Protein Glycan Coupling Technology (pioneered by the applicants) to produce a much-needed and affordable glycoconjugate serotype 1 vaccine.


Investigator Award in Science

Targeting membrane proteins in their native environments - Mass spectrometry meets cell biology  The overarching goal of my research is to understand the relationship between membrane proteins and their lipid surroundings. This is important since many membrane proteins are unable to retain their structure and function when extracted from their native environment and reconstituted into a membrane mimetic. Dynamic proteins, for example G-protein coupled receptors, solute carriers and sigma receptors, are intimately connected to their membrane environments and prone to loss of function and activity in detergent micelles.  To overcome this disconnect we will develop and apply our mass spectrometry approaches to examine dynamic drug targets within their membrane context. Our key goals will be to challenge these receptors and transporters with agonists, antagonists, inhibitors and lipids effectively in situ. Examples include solute carriers which during tumour progression respond to the need for an altered metabolism by increasing expression. Analogous methods will be used to uncover the targets of mitochondrial and lysosomal therapies.  Many of our research themes converge on consequences of the COVID-19 pandemic.  While this remains an area of intense scientific scrutiny we will focus on the less-studied receptors and ‘infection enhancers’, and contribute to understanding the roles of lipids in the endocytosis and viral recognition pathways.


Investigator Award in Science

Distributed brain systems for motivation and action The overarching aim is to understand the neural mechanisms of learning, decision-making, and motivation in humans. We will examine how they emerge from distributed patterns of activity across networks of subcortical nuclei such as the basal forebrain and dorsal raphe nucleus. While we know about such subcortical areas from animal studies, they have been under-investigated in humans. New imaging and uni- and multivariate analysis methods now make it possible to examine the distributed patterns of activity that arise in these areas. We have recently shown that we can record from these areas of the human brain using ultra high field magnetic resonance imaging. In addition, we know that these nuclei interact with cortical areas, especially in orbitofrontal, anterior cingulate, and insula cortex (regions that are especially prominent in humans and other primates).  We aim to record from both cortical and subcortical areas and to understand how they interact during learning, decision making, and motivation. The final aim is to assess whether new ultrasound stimulation tools that make it possible to alter neural activity in a minimally invasive manner even in brain areas far from the surface can be used to manipulate brain activity in these circuits in humans.


Discretionary Award - Public Engagement

Children and Young People's Participatory Research and Communication for Change Aligned with Wellcome’s commitment to leveraging public partnership – throughout the cycles of response, recovery and resilience/sustainable preparedness – to inform research, create trusted research, and increase the access and use of research more equitably across communities, this project will (1) Fill a current gap in children and young people (CYP) insights around Covid-19 and other issues of health and science related research, (2) Equip young people with participatory research and multi-media production skills, and (3) Develop a scaleable participatory model of research and communication for change.

To achieve this, UNICEF C4D, a leader in using communication strategies to empower CYP as critical actors in research and development, will partner with innovative multi-media platforms -- inclusive of video, community radio, and mobile-based platforms -- to facilitate CYP-led cross-country surveying, personal stories (via video), in-depth interviews (with/by CYP), and deliberative dialogues (via community radio, video and mobile-based platforms), that will uncover CYP needs, behaviours and experiences with COVID-19 and other priority health and science challenges. UNICEF and its partners will develop a replicable model and partnership base for CYP-led research and engagement to influence social and behaviour change to support future joint research engagement to inform policy and programmatic decision making.


Investigator Award in Science

Understanding Chemotaxis Towards Self-Generated Gradients Using Computational Models, Model Organisms and T cells Cell migration is essential to processes throughout biology, especially embryonic development and immune function. Migration must be steered to be physiologically effective. Steering cues are not well understood; we know a lot about how cells interpret them, but relatively little about how they are generated.
The basic premise of this work is that the cells often generate their own cues, by breaking down attractants that are widely present (and thus initially give no steering information) into local gradients. Attractant breakdown and migration happen simultaneously. This mechanism - chemotaxis up self-generated gradients (SGGs) - is hard to dissect because it is complex, and based on positive feedback loops. We therefore propose a four-pronged, iterative approach, in which we combine less challenging components to create an understanding of the underlying biology.
Key goals are:
(1) explore possible mechanisms and new extensions using computational models;
(2) test outcomes using chemotactic Dictyostelium in custom microfluidic devices;
(3) verify these data by establishing cultured T cells chemotaxing to CCL19 as a model SGG;
(4) combine findings from parts 1-3 to make a 3D, SGG-based model of a lymph node.
Together they will illuminate chemotactic steering in general, by focussing on one physiologically important system.


Sir Henry Dale Fellowship

Conformational Surveillance of signalling proteins in the plasma membrane The distinct activities of polytopic channels, transporters and receptors are essential for cell signalling in response to external stimuli, and their dysfunction is frequently associated with disease. My research has revealed that these plasma membrane proteins undergo Conformational Surveillance by intramembrane proteases: their distinct conformations are recognised and subsequently downregulated by transmembrane domain cleavage. Substrates have never been identified for many intramembrane proteases; I propose this is largely due to a previous lack of systematic screening approaches, and that proteins with more than one transmembrane domain have not been fully explored as substrates.

The overarching aim in this fellowship is to discover the mechanisms that underpin Conformational Surveillance, and to reveal its full repertoire of functions.

My four main goals are:

1) to explore newly identified examples of Conformational Surveillance;
2) to examine whether intramembrane proteases of different families share this molecular activity;
3) to understand the mechanistic coupling of intramembrane proteolysis and lysosomal degradation;
4) to investigate Conformational Surveillance in neurons, where many intramembrane proteases are highly expressed.

Overall, this research programme will shed light on a potentially widespread yet overlooked branch of cell surface proteostasis.


Investigator Award in Science

The molecular aetiology of central obesity: moving from variant to function using large-scale data-driven approaches. Central obesity is a leading contributing cause of illness and death across the world. Currently available strategies for prevention and treatment of this condition are manifestly inadequate. The research proposed here aims to identify fundamental processes involved in the development of central obesity. I plan to harness the power of human genetics, fused with deep molecular characterisation of the adipocytes to generate novel insights into the biology of central obesity. This ‘multi-omics’ approach will provide the basis for more effective preventative and therapeutic approaches that reduce the burden of central obesity and associated disease.

Grants awarded from 1 October 2005 to 30 June 2021


Investigator Award in Science

CTP switches in bacterial chromosome segregation and physiology: structures, functions, and mechanisms ATP and GTP switches are extensively used to control conformations and functions of proteins in a wide range of biological processes. However, CTP switches have rarely been found in biology. Recent work from our laboratory and others has shown that ParB is a founding member of a CTPase protein family that uses a CTP switch to regulate bacterial chromosome segregation. We hypothesize that CTP switches are currently unappreciated and may be widespread. In the proposed work we will exploit the tripartite ParABS system from Caulobacter crescentus to elucidate the structure, function, and mechanism of the CTP switch that ensures faithful chromosome segregation. Next, we will investigate how other CTP switches regulate membrane association and gene expression by employing Noc and KorB (proteins crucial for chromosome integrity and plasmid transmission, respectively) as models. Lastly, we will  identify and characterize other CTP switch proteins in C.crescentus and systematically discover putative CTP-binding/CTPase proteins across all sequenced bacterial genomes. Altogether, this work will provide fundamental knowledge on the mechanism and evolution of CTP switches and open new and unexpected horizons in numerous fields beyond bacterial chromosome segregation. Moreover, our immediate research on plasmid/chromosome segregation and transmission may inform strategies to combat plasmid-borne antibiotic resistance.


Collaborative Award in Science

Prof Abigail Fraser, Prof Christian Delles, Dr Carmel McEniery, Prof Kate Tilling, Prof Lucilla Poston, Prof Alun Hughes, Prof Christoph Lees, Prof Asma Khalil

Preconception to pOst-partum study of cardiometabolic health in Primigravid PregnancY:  POPPY  The clinical manifestations of placental dysfunction include pre-eclampsia, gestational hypertension and fetal growth restriction. Women who experience placental dysfunction have a two-fold risk of cardiovascular disease (CVD) and diabetes in later life compared to women with uncomplicated pregnancies. However, it is unclear whether placental syndromes have a direct adverse effect on cardiometabolic health, whether a healthy pregnancy is protective, or whether women who experience a placental syndrome simply had poorer cardiometabolic health prior to pregnancy. If placental syndromes do lead to CVD and diabetes independently of established cardiometabolic risk factors (e.g. by causing end organ damage), a focus on CVD/diabetes prevention in this high-risk group of women is likely to reduce the burden of these diseases. Conversely, if pre-pregnancy factors are more important, improving cardiometabolic health in young women prior to conception is key and could reduce the incidence of placental syndromes. We plan to assess cardiometabolic risk factors and validated intermediate phenotypes of CVD/diabetes before conception, during pregnancy, and post-partum to determine whether placental syndromes affect post-partum maternal cardiometabolic health independently of pre-conception cardiometabolic health. This will help to determine the optimal timing and nature of prevention strategies to reduce the burden of diabetes/CVD in women, in future trials.


Investigator Award in Science

Determining the limits for reversing hearing loss Progressive hearing loss is very common but there are no medical treatments to slow down or reverse it. Histopathological reports suggest three main sites of lesion in the cochlea can be involved: sensory hair cells; synapses of hair cells with cochlear neurons; and the stria vascularis which produces a potassium-rich fluid with an endocochlear potential of +100mV that is essential for hair cell sensitivity. This research has three goals that will provide the scientific underpinning for development of new treatments for hearing loss. Firstly, we will investigate whether hearing loss in each of the three pathological categories can be reversed and hearing improved. Secondly, the research will determine what the limiting factors to reversal of hearing loss are and how these define the critical period for intervention. Thirdly, we will develop new diagnostic tools to distinguish the three sites of lesion using objective measures of auditory responses, to establish the underlying pathological contributions to hearing loss in an individual, and hence determine the optimum treatment. To achieve these goals, we will use mouse mutants with well-characterised cochlear pathology as examples of each site of lesion, and a new approach to reactivating a mutant gene after the onset of hearing loss.


Sir Henry Dale Fellowship

The mechanism of recombination and its impacts on human mutation and disease

Meiotic recombination is essential for creation of haploid gametes. Errors in this process cause miscarriage, infertility, and developmental disorders. Recombination proceeds via repair of programmed DNA breaks; however, the molecular mechanisms ensuring their repair are not well understood. My work reveals that these breaks are a significant mutagenic force, leading to de novo mutations (DNMs) in 1 in 3 sperm and 1 in 13 eggs. My proposed research will harness cutting-edge experiments in genetically-engineered mouse models to generate novel data and will further leverage existing population-scale human genetic and phenotypic data. I will integrate these data through sophisticated statistical analyses to answer the following questions:

 What are the properties, causes and impacts of recombination-associated mutations on human health? I will characterize these mutations comprehensively in humans and infer their molecular causes. I will investigate their impact on common and rare diseases.
 What is the mechanism of break repair in recombination? I will build on my recent work and interrogate meiotic break repair through specialised experimental assays on key proteins in genetically-engineered mice.
 What is the mechanism of mutagenesis? I will characterize the impact of pathways that are identified above as causal by disrupting them in genetically-engineered mice.


PlanetDivoc91

Discretionary Award – C&S

PlanetDivoc91 A 9-part digital comic for young adults (YA) aged 16-25 providing an alternative, character-based narrative about a pandemic. Co-created with young adults from across the globe, multidisciplinary researchers and experts, renowned comic writers and artists, PlanetDivoc91 offers audiences diverse perspectives on how to make sense of a pandemic. It connects and empowers YA - whose voices have been marginal in the COVID crisis - to be heard in current and future pandemic research and policy. This proposal builds on work already started in the UK and internationally, to extend in greater depth globally, particularly in India and South Africa (SA).


Investigator Award in Science

The dynamics of cell entry and genome replication in a model complex virus Bluetongue virus (BTV), a complex non-enveloped virus with a genome of ten double-stranded RNA segments, is an important pathogen and model for many similar large non-enveloped viruses (including the medically important rotaviruses). Previous studies have provided a well-understood replication cycle, a large range of research reagents and many novel assay systems, all complemented by high resolution atomic structures of many viral proteins. Notably, the recent structure of the viral polymerase in situ, a critical point of replication, has provided a unique opportunity to investigate many details involved in the virus life cycle. To achieve this we will will use state-of-the-art techniques such as cryoEM, cryo-ET, FCS and FRET in addition to our established in vitro and in vivo assays to determine how BTV entry to the cell causes the polymerase to initiate genome transcription from the 10 genomic dsRNAs and how this process differs from the later process of genome replication which follows the packaging of RNA during assembly. We will define how these processes link to the maturation of newly assembled virus particles and their exit from the cell. Our findings will have the potential to develop laboratory data to translational applications in future design of antiviral and vaccines.


Sir Henry Dale Fellowship

Understanding the interaction between human milk oligosaccharides and the gut microbiome in preterm infant health and disease Necrotising enterocolitis (NEC) is a leading cause of death in babies born extremely preterm. NEC infants generally have increased gram-negative bacteria compared to matched controls, potentially resulting in an LPS-stimulated increase in TLR4 and inflammatory cytokines in the intestinal epithelium, ultimately leading to the breakdown of epithelial integrity and necrosis. My recent work has shown that human milk oligosaccharides (HMOs) promote the establishment of a protective microbiome in the infant gut, which is associated with reduced risk of NEC.

This project will identify specific HMOs and bacteria that promote gut health and reduce NEC in preterm infants. The project will take advantage of a host-microbe model system I have recently developed. This will provide new insights into NEC pathogenesis, potentially leading to the development or refinement of therapeutics. I will achieve this by answering four critical questions:

1.    What specific HMOs and microbial species are associated with NEC or gut health?
2.    Do HMOs directly influence the epithelial integrity and inflammation observed in NEC?
3.    How do specific bacterial species interact with the preterm intestinal epithelium?
4.    Can a combination of HMO (prebiotic) and bacteria (probiotic) promote gut health and protect against NEC?


Senior Research Fellowship

Contribution of the miRNA-interferon interaction to human disease The type I interferon (IFN) response is the major antiviral pathway in mammals but needs to be tightly regulated to ensure effective defence against viruses whilst avoiding the negative consequences of their overproduction, resulting in autoimmune and autoinflammatory diseases.
I have recently demonstrated a central role for microRNAs (miRNAs) in maintaining optimal IFN levels, and conversely, that IFNs are important regulators of miRNA expression. These results led me to hypothesise that there is a tight interaction between the IFN and miRNA pathways, which contributes to specific traits of human diseases where one component of this interaction is altered.
Supporting this hypothesis, our unpublished results show that diseases characterised by altered miRNA expression, such as 22q11.2DS, exhibit a dysregulated IFN response. Vice versa, diseases characterised by an abnormal IFN response, such as systemic lupus erythematosus, display altered miRNA levels. I aim to identify the mechanisms by which the miRNA biogenesis and IFN pathways interact and study the role of this interaction in diseases where the IFN or miRNA biogenesis pathways are altered. These results will provide a mechanistic perspective to some of the common but unexplained traits presented in these diseases and provide novel targets for intervention strategies.


Investigator Award in Science

Exploring innate-like and adaptive gamma delta T cell paradigms in health and disease gammadelta T-cells have been retained in vertebrates for ~500million years, and are of increasing therapeutic interest, but their mode of ligand recognition and immunological niche has remained largely mysterious. Here we build on the emergence of parallel innate-like and adaptive human gammadelta T-cell paradigms to address unresolved ‘keystone’ questions in gammadelta T-cell biology. Firstly, we will exploit multidisciplinary approaches to explore the diversity of innate-like and adaptive gammadelta biology in different tissues, their coordination with other immune responses, and how these change in disease states such as inflammation and cancer. Secondly, we will identify molecular targets of gammadelta-TCRs from innate-like subsets and structurally characterise their TCR/ligand interactions and cellular/molecular recognition mechanisms, focussing significantly on the strong emergence of Butyrophilin family molecules as critical TCR-ligands for such populations. Thirdly we will exploit cytomegalovirus infection as a unique human model to identify novel ligands for antigen-experienced adaptive-like gammadelta T-cell subsets. Finally, we will develop and apply new methodology to image and phenotype distinct human gammadelta T-cell subsets in solid tissues, using multispectral immunofluorescence and digital spatial profiling. This programme should help revolutionise our understanding of gammadelta T-cells, and provide a solid foundation for ongoing efforts to therapeutically harness the gammadelta T-cell compartment.


Discretionary Award – C&S

A collaborative platform and network for responsive infectious diseases bioethics research We seek to establish a research network and collaborative platform for rapidly identifying and analysing ethical and policy issues arising in infectious disease treatment, research, response, and preparedness, and engaging in research on the profound ethical challenges presented by infectious diseases across the globe.  The platform and network will provide real-time ethics and policy support, create a mechanism for collaborative responsive research as well as forward-looking projects with longer timeframes and engaging with crucial stakeholders from across high-resource and LMICs, all focusing on the critically important area of infectious disease and global health bioethics.  In addition to being responsive to the needs as identified by the network, we expect the platform and network to be available to respond to needs identified by the WHO Public Health Emergency Ethics Preparedness and Response (PHEEPR) Network and other global bioethics efforts. The Platform and Network will be structured into two related and overlapping sets of activities, which will complement and build on each other. These will comprise: an Infectious Disease Ethics Forum for discussion of emerging ethical issues, a Collaborative Network to identify important issues for policy response and research; and, a programme of global health ethics research focusing on infectious disease.


Quorum sensing in African trypanosomes

Investigator Award in Science

Quorum sensing in African trypanosomes Trypanosomes undergo development in both their mammalian host and in the tsetse fly to optimise their disease spread. In mammals, the parasites use quorum sensing (QS) to control their virulence and prepare for tsetse uptake through the generation of arrested stumpy forms, which are found in Trypanosoma brucei but not other African trypanosome species (namely, Trypanosoma congolense or Trypanosoma vivax). We recently discovered that oligopeptide signals can drive QS in Trypanosoma brucei, this activating a signal transduction cascade, some components of which we have already identified. We will now explore how the external signal connects to the identified signalling cascade to drive the differentiation response and how this is disrupted in laboratory-selected and naturally occurring trypanosomes that show reduced QS (so-called 'monomorphs'). We will also compare the distinct mechanisms used by different trypanosome species to prepare for transmission to tsetse flies. This will include characterisation of a cryptic 'stumpy like' stage in T. congolense and its developmental loss of the adherence phenotype characteristic of that species. Our research questions are:

 How do trypanosomes generate, detect and transduce external QS signals?
 How is QS lost in laboratory and natural parasite populations?
 How do different trypanosome species prepare for transmission?


Snakebite Grant – Next Generation Treatments

Snakebite Advisory Panel (one-off committee)

Dr Delavar Shahbazzadeh, Dr Pierre Lafaye, Dr Salma Djilani, Prof Mohamed HAMMADI

Developing the next generation of anti-venoms to improve management of cobra poisonings in low and middle incoming countries We propose a different approach to antivenoms, based on recombinant nanobodies (Nbs), targeting the lethal cobra toxins, to reduce morbidity and mortality. Nbs have a high affinity for selected epitopes, allowing rapid recognition of antigens even if bound to cholinergic receptors, combined with a capacity to dislocate neurotoxin from the receptor.
This COBRA-NGaV project brings together research teams with extensive experience in venomics and antivenomics to provide the proof-of-concept (PoC) for cobra toxin-specific Nb candidates as a novel generation of antivenoms and to address the dual obstacle to neutralise cobra toxins: weak immunogenicity and fast diffusion.
Preliminary results have been obtained so far: i) strong and specific responses were elicited in dromedaries immunised against the toxic fractions of N. legionis, N. haje and N. oxiana; ii) phage display screenings were adopted to rescue strong Nb binders specific towards relevant N. l., N. h. and N. o. toxins; iii) several clusters of Nb sequences specifically binding cobra toxins have been identified.
Herein, Nb selections and combinations for optimal synergic effects and best cross-species performances will be generated. Best-in-class candidates will be tested in a pre-clinical study in mice and sheep according to GMP rules. Cost effectiveness will be established.