Prof Charles Wondji, Prof Flobert Njiokou

International Intermediate Fellowship

Centre for Research in Infectious Diseases (CRID)

Impact of metabolic resistance to pyrethroids on the vectorial competence of the major African malaria vector Anopheles funestus Insecticide resistance is threatening effectiveness of insecticide-based interventions to control malaria across Africa. However, the impact of this resistance on malaria transmission remains a matter of debate. It is not yet well established whether insecticide resistance, particularly metabolic resistance, in addition to allow survival to insecticide exposure, positively or negatively affect capacity of vectors to develop and transmit malaria parasites. Taking advantage of the recent designs of the first simple DNA-based assays allowing to track cytochrome P450- and glutathione-S-transferase mediated metabolic resistance in the major malaria vector Anopheles funestus, this project aims at establishing the impact of metabolic resistance on malaria transmission in Africa, to improve resistance management. More specifically, I will: Aim1) Investigate the influence of metabolic resistance on the development of P. falciparum in An. funestus using GST and P450 markers; Aim2) Characterize the transcriptomic changes accompanying P. falciparum infection in metabolic insecticide resistant An. funestus using RNAseq; Aim3) Investigate interactions between metabolic resistance and Plasmodium immune response genes in An. funestus using functional genomics (RNAi).

This project will benefit from the expertise gained during my Wellcome Trust Training Fellowship including the successful rearing and establishment of experimental infections of field An. funestus using natural P. falciparum isolates.


International Training Fellowship

Intimate partner violence against women in low- and middle-income countries: associations with parenting practices and early childhood development. The 2030 Agenda for Sustainable Development highlights the need to prevent and respond to violence against women and girls. It also affirms the need to invest in early childhood care for the promotion of sustainable development in low and middle-income (LMICs). Intimate partner violence (IPV) is one of the most common and extreme manifestations of gender inequality worldwide, and has a higher prevalence and more severe consequences for women and children living in LMICs. I aim to examine the association of IPV with parenting practices and early childhood development in LMICs. This will be done using data from nationally representative household surveys (DHS) carried out since 2010 in at least 10 LMICs, and a large population-based prospective cohort study in Brazil, following over 4,000 children born in 2015. A key objective of the project is to explore whether women´s mental health mediates the proposed associations, and the role of women’s empowerment levels in the associations under study. The empirical evidence generated from this project will contribute to increasing visibility of the intergenerational consequences of IPV on children and provide guidance for the direction of global resources to prevent gender-based violence.

Grants awarded from 1 October 2005 to 30 June 2021

Creative Commons Attribution 4.0 International (CC BY 4.0)


Clinical Research Career Development Fellowship

Exploring the Role of MITOchondrial ImmunoMETAbolism in Neuroinflammation:  Mechanisms and New Targets for Progressive MS Treatment (MITO_META) People with progressive multiple sclerosis (P-MS) have substantial unmet clinical needs. While current therapies for MS are focused on manipulating the activity of the adaptive immune system, they have limited applicability for P-MS where a switch towards the chronic activation of innate immune cells, such as mononuclear phagocytes (MPs), occurs.

MITO_META aims to test the hypothesis that the detrimental activation of MPs in P-MS is dependent on their mitochondrial metabolism and that targeting mitochondrial complex I (CI) activity in MPs will lead to novel therapeutic approaches for P-MS.

To achieve this aim, I will adopt a combination of animal models and post-mortem biological samples obtained from MS patients. I will initially use the experimental autoimmune encephalomyelitis (EAE) mouse model of MS to study the effect of removing Complex I from MPs during neuroinflammation (Aim 1). I will then analyse how the metabolism of MPs changes during neuroinflammation, and compare these findings to those obtained from post-mortem analysis of people with progressive MS (Aim 2).

Elucidating the role of mitochondrial function in MPs during chronic neuroinflammation will advance our understanding of P-MS and lead to new therapies to interfere with the progression of disability.


Modulation of astrocytic gap junction coupling in focal epilepsy Understanding the mechanisms that underlie epileptogenesis is crucial for the development of new treatments. Recent evidence has implicated astrocytes as a key cell population in the aetiology of focal epilepsy. Astrocytic gap-junction networks perform vital functions in supporting neural activity, including the shuttling of essential metabolic fuels and the regulation of the extracellular ionic environment for neurons. The objective of this project is to understand the relationship between neuronal activity and astrocytic gap-junction coupling, and how this relationship may break down in epilepsy. This will build upon preliminary evidence that astrocytic gap-junctions can show rapid, activity-dependent changes, in a manner related to levels of neuronal activity. The work will use surgically-resected human brain tissue and mouse models in which it is possible to selectively manipulate defined cell types. There are three parallel research aims. First, glioma-associated brain tissue will be used as a test case to relate functional astrocytic gap-junction coupling and neuronal hyperexcitability in a human context. Second, in vivo optical studies in mouse will examine how epileptiform network activity influences dynamic astrocytic gap-junction coupling. And third, optogenetic and pharmacological strategies will be used to dissect the cellular mechanisms that mediate activity-dependent changes in astrocytic coupling.


Global Forum on Bioethics in Research

Global Forum on Bioethics in Research Fellowships Committee

GENOME EDITING IN AFRICA: ISSUES ARISING FROM ETHICS, GOVERNANCE, AND ENGAGEMENT The purpose of this proposal is to develop an African, Regional interdisciplinary forum on the ethics, governance, engagement and social acceptability of Genome Editing in Africa. In spite of the discussions on Genomics, most African countries are yet to adequately engage in the critical debate on the regulation and ethics of genome editing. It is pertinent to have collaborative partnerships to focus on prudent research-based advocacy, to ensure truly informed policy decision making on gene editing in Africa. The key goals of this proposal is to disseminate the key outcomes of the 2019 GFBR meeting on" Genome Editing for Human Benefit: Ethics, Engagement and Governance", and to develop a proposal to take the outcome of this meeting further so as to begin an African oriented discussion on genome editing from the perspective of Africans. There will also be a research paper to be published in a peer-reviewed journal. Also, the focus of this proposal is to have a two-day workshop  in Nigeria with key stakeholders from Africa discussing the ethical, governance and engagement issues relevant to Africa in Genome Editing that arose from the Singapore meeting.The meeting will promote collaborations between African Countries on the best practices in Genome Editing


International Training Fellowship

Characterization of the phenotypic and transcriptional profiles of B cells that encode broadly neutralizing antibodies against HIV HIV induces B-cell defects that could impair the development of effective antibody responses, such as broadly neutralizing antibodies (bNAbs). However, some rare patients still develop anti-HIV bNAbs. Such responses can be mimicked with vaccines for protection against HIV. The B cells that develop breadth despite the ongoing HIV-induced immune defects could have unique profiles that enable their survival and functionality. The aim of this work is to characterize the transcriptional and phenotypic profiles of B cells that encode for anti-HIV bNAbs and their precursors/intermediates. I will use longitudinal clinical samples from well characterized HIV-infected individuals who have broadly neutralizing sera. I have already isolated a bNAb from this cohort by FACS-sorting of epitope specific memory B cells and cloning the immunoglobulin genes. I am currently isolating bNAbs from the other individuals. This will create a platform for subsequent characterization of the B cells that encode for the bNAbs. I will then characterize the phenotypic and transcriptional profiles of epitope specific memory B cells that encode for the bNAbs lineages using paired flow cytometry, cloning and single cell RNA-seq. This will reveal the profiles that, if induced with appropriate adjuvants, could promote elicitation of protective anti-HIV bNAbs after vaccination.


Novel Non-invasive Haemodynamic Methods in Heart Failure with Preserved Ejection Fraction Heart failure with preserved ejection fraction (HFpEF) is prevalent, increasing and has a poor prognosis. Left ventricular (LV) haemodynamic assessment is needed to diagnose and manage patients with HFpEF. The reference method for it is an invasive study and is rarely done due to costs and risks. Doppler-derived velocity is used as a surrogate for LV pressure. However, because it is based on a number of assumptions, Doppler remains unreliable for detecting increased LV end-diastolic pressure (LVEDP). I have validated a four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) acquisition which addresses issues with Doppler. I have further developed an accurate quantification method, which uniquely, measures intra-ventricular blood flow in 4D. Other advantages are that it does not require any additional hardware and has demonstrated superior associated with LVEDP. In this Fellowship, I will develop 4D flow techniques for an accurate assessment of LVEDP and pressure-volume loop in HFpEF. In addition, I will learn from and collaborate with the world-renowned clinicians, software/hardware engineers and modelling experts in academia and industry, to improve the method’s accuracy and applicability. I will validate the method’s accuracy and generate clinical data to support future clinical trials, clinical translation and patient benefit.


International Training Fellowship

Investigating antimicrobial susceptibility of Rickettsia typhi Rickettsia typhi is an obligate intracellular Gram-negative bacterium causing murine typhus. The disease is globally distributed but neglected. It is an important cause of acute febrile illness in Laos. Although murine typhus is treatable, a clinical trial by Newton P et al. (2019) suggested that azithromycin is inferior to doxycycline. However conventional antibiotic susceptibility testing was not performed to corroborate this finding since no methods exist. Therefore, there is a need to develop a highly sensitive qPCR method comparable with the gold standard method of the plaque assay to assess antimicrobial susceptibility of R. typhi isolates as well as investigation of the genetics and/or metabolism of this bacteria, and to correlate the findings with clinical response to treatment. To estimate the rickettsia clearance, we will characterise the R. typhi DNA load using qPCR in patients from a pilot study of  murine typhus patients receiving doxycycline or azithromycin. Moreover, optimised conditions for R. typhi growth including nutrient requirement for development of a host cell-free culture medium using R. montana as a model to simplify antibiotic susceptibility testing of this bacteria will be investigated. The proposed work will improve our understanding of appropriate murine typhus treatment in Laos.


Prof Oye Gureje, Dr Stephanie Daley, Prof Jose Luis Ayuso Mateos

International Intermediate Fellowship

College of Medicine, University of Ibadan

Intervention for Depression In underserved Geriatric Populations (INDIGO)  Depression is a common and disabling condition among the rapidly growing population of older people in low- and middle-income countries (LMICs). The burden is particularly high among older Nigerians. Yet, there is a large unmet need for treatment, possibly in part because available care is inaccessible and not age-appropriate for the older person. In line with global priorities, as envisioned in the Sustainable Development Goals to leave no one behind in the provision of quality health care, there is a pressing need for an integrated model of community-based mental health care that encompasses health, social, and informal care for older people in LMICs. Building on prior considerable work by our group to scale-up mental health care with the aid of the W.H.O Mental Health Gap Action Programme Intervention Guide, we now wish to leverage on the e-version of the tool, by 1) adapting it for the care of older persons with late-life depression through a user driven iterative loop process in which contextual, socio-cultural and health factors in the lived experience of late-life depression are incorporated; and 2) testing, in a pilot hybrid (effectiveness-implementation) design, effectiveness, cost-effectiveness, and factors that may affect the delivery of the intervention in routine care.


Discretionary Award - Public Engagement

Guys and St Thomas's Charity Partnership We are applying to Wellcome for a £1.5M investment as match towards an overall £3M+ programme that will test new ways of working to embed health research in our practice.

This will be split between two priority portfolio areas; Adolescent Mental Health (AMH) and Multiple Long-term Conditions (MLTCs)
We will explore 3 opportunity areas, these are:

1. New models for generating and using public insight in research
2. New models for creating impact through investment partnerships
3. Accelerating our evidence

The work will be supported by research partnerships, a network of public engagement expertise and a partnership advisory group. We already have an existing relationship with KCL, with whom we currently run a £1m+ MLTC research challenge fund in the MLTC programme, as well as our cornerstone investment into the Science Gallery London https://london.sciencegallery.com/.  We would also like to deepen our relationships with other academic institutions as part of this work.

Please see Partnership Plan for details.

Please see Partnership Slide Deck


London School of Hygiene & Tropical Medicine

Cardiovascular disease in very low income sub-Saharan Africa: informing the response to an emerging epidemic I will improve understanding of key determinants and the incidence of cardiovascular disease in low-income sub-Saharan-Africa, capitalising on my expertise in stroke epidemiology in rural and urban Malawi and the research infrastructure across seven sub-Saharan-Africa population cohorts.

Information on the age- and sex-specific incidences of priority cardiovascular diseases is essential for health service planning in sub-Saharan-Africa. "Traditional" risk-factors (hypertension, type-2 diabetes and obesity) are highly prevalent and increasing in incidence and some, particular to low-income settings, such as chronic-infections, are not declining. The performance of diagnostic tools and risk prediction scores for cardiovascular disease developed in high-income settings need to be tested and adapted for use in low-income sub-Saharan-Africa.

I will build on the urban/rural cohort in Malawi, extending community and clinic surveillance with population-level questionnaire-screening (followed by a diagnostic pathway in those with "possible cardiovascular disease") to estimate the true incidence of various cardiovascular diseases. I will also extend the follow-up for our seven African cohorts and use this harmonised dataset to estimate the relative contributions of key drivers of cardiovascular disease and assess the performance of existing cardiovascular disease risk prediction scores.

This work will inform the planning of evidence-based, health-systems responses and context-relevant, individual, and population-level interventions.


Understanding and inducing immunity against rabies and Epstein Barr virus Class III fusion proteins Viral fusion proteins are important targets for vaccine-induced neutralising antibody. Structure-guided design of such antigens in pre-fusion conformation has created leading vaccine candidates against viruses with Class I and II fusion proteins, such as respiratory syncytial virus and dengue virus. Use of pre-fusion stabilised Class III proteins for vaccination has not yet been reported, but these too are major vaccine targets for rabies virus and the herpesviruses (the gB proteins).

I propose to build upon preliminary data demonstrating pre-fusion stabilisation of rabies glycoprotein. I will evaluate pre-fusion-stabilised immunogens for vaccines against rabies and a chosen herpesvirus, Epstein Barr virus (EBV). By isolating monoclonal antibodies against EBV gB, I will ascertain whether herpesvirus gB proteins contain pre-fusion-specific neutralising epitopes. In healthy EBV carriers, I will explore whether salivary EBV shedding can be used as a marker of immune control of virus reactivation, to dissect mechanisms of natural immunity, and to rapidly detect efficacy in future early-phase vaccine trials.

A low-cost single-dose vaccine based on stabilised rabies glycoprotein could help reduce the 60,000 deaths due to rabies each year. An effective EBV vaccine could reduce the  > 100,000 deaths per year due to EBV-driven cancers and, many believe, could also prevent multiple sclerosis.


PhD Training Fellowship for Clinicians

Effect of early-life nutrition and WASH interventions on the long-term health of Zimbabwean children Over 150 million children worldwide are particularly short for their age, and we say that these children are stunted. Stunted children have increased mortality and reduced intelligence, so stunting affects whole societies. Improving nutrition is currently the best intervention to reduce stunting, but typically only improves growth by a small amount. The first thousand days of life (up to the age of two years) are seen as a crucial period for child growth. The scientific community lacks complete understanding of how poor growth affects children at older ages, and what the impact of targeted nutrition or water/sanitation and hygiene (WASH) interventions is on the physical fitness and brain function of children.

This project will measure the long-term effects of stunting of children aged 6 years in Zimbabwe, some of whom received a targeted nutrition or WASH  intervention between 6-18 months. It will measure how they have grown together with their brain function, physical fitness and how much fat and lean mass they have. This data will give a complete picture of how well these children are functioning, and enable us to compare what the true impacts of the extra nutrition and/or WASH are.

Child Nutritional Physiological Phenomena


Defining Causal Variants and Associated Genes in Polygenic Nephrolithiasis Kidney stones, which are a major clinical and economic health burden, are commonly recurrent, and current stone prevention strategies are relatively ineffective. The renal tubular mechanisms underlying this disease are poorly understood, thereby limiting opportunities to develop novel therapies. Via a genome-wide association study (GWAS) we identified twenty genetic loci linked to kidney stone formation. However, the genes influenced by these loci remain to be elucidated. My goals are to: identify additional stone-associated loci by X chromosome and sex-specific GWAS studies; define biologically relevant renal cell types by identifying areas of accessible chromatin at relevant loci through single cell assays for transposase accessible chromatin (ATAC)-sequencing in renal tissue; determine causal GWAS-associated SNPs by examining local epigenetic modifications in relevant cell types via chromatin immunoprecipitation (ChIP)-sequencing; link causal SNPs to effector genes by determining the 3-dimensional chromatin landscape in relevant cell types through Next Generation Chromatin Conformation Capture; validate predicted genotype-phenotype associations in relevant cohorts; and elucidate the roles of effector genes in cellular function via in vitro studies. This research will provide new insights into tubular function and the molecular pathophysiology of renal stone disease and reveal new therapeutic targets for the prevention of kidney stone recurrence.


PhD Training Fellowship for Clinicians

Understanding the DNA Damage Driven Immune Response in Oesophageal Adenocarcinoma (OAC): Opportunities for Improved Stratification and Treatment Oesophageal cancer is the sixth most common cause of cancer death worldwide.  Even when treated with chemotherapy and surgery aiming to cure the disease, eight out of ten patients do not respond to chemotherapy and most patients relapse.

We have shown previously that genetic changes within the tumour can influence whether chemotherapy is effective.  We showed that a group of patients have tumours which respond better to chemotherapy than others.  This group is called ‘DNA damage immune response (DDIR) positive’. DDIR negative patients have worse outcomes.

In this project, we aim to use genetic information about DDIR positive patients who benefit from chemotherapy to improve outcomes for those who do not.

We will initially analyse genetic information from 548 oesophageal tumours.   We will identify the most common genetic changes in patients who benefit from chemotherapy. We then plan to model these changes in the laboratory in oesophageal cancer cells which are relatively resistant to chemotherapy to find out if they respond. We will confirm our findings in a range of laboratory models.

We expect that the knowledge gained will play a role in identifying new combinations of treatment to improve response to chemotherapy in patients who currently have poor outcomes.


PhD Training Fellowship for Clinicians

Radiotherapy-Related Adverse Cardiac Events In Lung Cancer The most important risk factor for lung cancer is smoking, which also causes cardiovascular disease. Due to other medical problems preventing surgery, or patient preference, many patients with lung cancer receive radiotherapy. Radiotherapy is high-dose X-rays and there are risks associated with this treatment, in particular to the heart. Little is known about why some patients’ hearts appear more sensitive than others.

The purpose of the RACING research project is to discover how radiotherapy affects the heart and if radiotherapy heart damage can be predicted before treatment. Laboratory experiments will test how radiotherapy can affect the pump action of the heart, and which parts of the heart are most likely to malfunction, and the mechanism of damage. Patients who’ve had radiotherapy previously will have their CT scans examined by advanced computer software to find clues that could help doctors avoid/reduce radiotherapy heart damage in future patients.


Not Available

Discretionary Award – Innovations

Foundation for the National Institutes of Health

Accelerating Medicines Partnership in Schizophrenia Not Available

Grants awarded from 1 October 2005 to 30 June 2021


Not Available

Discretionary Award – Innovations


PhD Training Fellowship for Clinicians

The effect of ageing on inflammation resolution and its causation in age-related immune dysfunction.  The immune system protects us from infection, however as we age it can weaken and even contribute to age-related diseases such as heart disease, cancer and arthritis. The exact reasons for this are not known, and new treatments could help us fight infection, treat age-related disease, and improve lifespan. This laboratory has discovered that one explanation may be that white blood cells cannot neutralise their targets at sites of infection properly, worsening the inflammatory response and causing excessive tissue damage. Another explanation may be that the management or oversight of the immune response seems to change with time. To examine these two ideas we plan to use a safe and effective model of skin infection in adults to look for subtle differences between the immune systems of young and elderly people, before and after local skin infections. If we find a cause for these differences, we will perform experiments in mice to see if they are a cause of age-related immune dysfunction. These results could then be used to design medications and further experiments to help improve the lives of patients with and without age-related disease.


PhD Training Fellowship for Clinicians

Catatonia: Neuroimaging, Immunology and Psychopathology (CAT:NIP) Background:

Catatonia is a severe psychiatric illness in which individuals have difficulties in moving and speaking. I aim to understand what brain changes occur during catatonia.

Approach:

Patients with catatonia are usually effectively treated using medications from the benzodiazepine class, which increase the activity of pathways relying on the neurotransmitter GABA. In addition, 88% of patients with a form of brain inflammation known as NMDA receptor encephalitis have catatonia, which suggests that the neurotransmitter glutamate might also be relevant.

To investigate the roles of these neurotransmitters, we have two main experiments:

 We will take blood samples from patients with catatonia to examine whether they have antibodies to cell surface components associated with GABA and glutamate transmission. We will use these blood samples to investigate whether any new antibodies or other proteins that bind to the brain or affect brain function can be found.
 We will conduct a form of brain scan called magnetic resonance spectroscopy on patients with catatonic features. This will allow us to examine the levels of GABA and glutamate in their brains and to compare these to other patients without catatonic features.

Impact:

We hope to identify what causes catatonia in order to appropriately target future treatments


Sir Henry Dale Fellowship

Royal Society/Wellcome Trust Sir Henry Dale Fellowship

Sir Henry Dale Fellowship Interview Committee

Optimising seasonal malaria chemoprevention and seasonal vaccination in childhood to address the resurgent malaria burden in Africa Almost half of the 435,000 malaria deaths each year occur in countries of the Sahel region of Africa, and the majority of these deaths occur during the three-four month rainy season. Monthly seasonal malaria chemoprevention (SMC) is highly effective in these areas, reducing malaria cases by 75-80% in trials, and malaria-specific mortality by 40-50% under programmatic conditions. However, malaria remains a leading cause of disease and death in several countries deploying SMC.

The key goals are therefore to understand how to 1) maximise the impact of SMC as currently designed (e.g. by timing it more accurately in different areas), 2) modify the SMC strategy to make it more effective (e.g. by identifying the causes of severe malaria in the context of SMC), 3) use other control tools, including seasonally-targeted vaccination, alongside SMC and 4) understand how improving malaria prevention in childhood would affect naturally-acquired immunity.

Analysis of data from a comprehensive evaluation of SMC in 7 countries, an SMC trial in 20,000 children, and the first-ever trial of seasonally-targeted vaccination alongside SMC provides a unique opportunity to answer these questions. Mathematical models incorporating these results will enable malaria prevention packages to be optimised according to the local epidemiology.


Sir Henry Dale Fellowship

Defining the impact of androgens on macrophage function during endometrial tissue repair Macrophages are essential mediators of tissue repair but we lack fundamental knowledge about how they are regulated in the endometrium. Androgens regulate macrophage function in other tissue repair contexts but their role in endometrial repair has not been defined. This project will determine how macrophages are regulated in endometrial repair by assessing their turnover and phenotype and how this is affected by androgens by using a highly reproducible mouse model of endometrial repair that we have developed.

The key goals of this project are;

 to determine whether monocytes contribute to the endometrial macrophage function in repair,
 to define how androgens mediate intrinsic and extrinsic effects on endometrial macrophage function and
 to investigate how androgen excess alter macrophage function in aberrant repair.

This will be achieved by using fate-mapping techniques, transcriptomics analysis, multiparameter flow cytometry and immunohistochemistry combined with pharmacological and genetic approaches to modulate androgen action.

These studies will establish that macrophages are critical mediators of endometrial repair and modulation of their phenotype by androgens determines the balance between healthy and disordered tissue repair. These important insights will provide a platform for assessing macrophage AR as a potential therapeutic target in reproductive health.


Research Career Development Fellowship

crAssphages - the most abundant viruses of the human gut The recently discovered crAssphages are the most abundant group of viruses in the human body, reaching up to 20% of gut microbial DNA. They infect bacteria of the order Bacteroidales and demonstrate incredibly stable, sometimes years-long colonisation of the human gut. Our preliminary results, based on the first isolation of a crAss-like phage in culture, indicate that they use an unusual mechanism of infection that allows them to continuously co-exist with the bacterial host population at high levels. I hypothesize that bacterial interactions with their phage ‘partners’ is an essential aspect of microbiome functionality. The long term persistence of crAssphages in the human gut microbiome is an epitome of such phage-host interaction. My key research question is to provide a mechanistic and structural explanation of this interaction and gain insights into its significance for host physiology and overall microbiome structure. My research program consists of three specific aims: 1) developing methods for genetic manipulation with crAss-like phages; 2) using structural biology to get insights into mechanisms of phage-host interaction; 3) investigate persistence mechanism and its effect on community structure. Taken together these efforts should significantly advance our understanding of this new and elusive group of viruses in the human microbiome.


PhD Training Fellowship for Clinicians

Investigation of the role of the VWF-ADAMTS13 axis in the pathogenesis of sickle cell vasculopathy in children  Sickle cell disease (SCD) is responsible for major global morbidity and mortality and more than 1,000 SCD children are born every day. Globally over half will die before five years of age and

A critical step in blood vessel blockage in SCD involves sickle red cells sticking to the blood vessel wall. Interestingly, evidence suggests a new role for the plasma clotting protein von Willebrand factor (VWF) in this process with increased VWF and reduced levels of ADAMTS13, the main protein responsible for breaking down VWF.

This study aims to define the molecular mechanisms underlying blood vessel blockage in SCD, including how VWF and abnormally large forms of VWF, influence paediatric SCD biology. We will specifically investigate the hypothesis that sickle red cell occlusion is promoted by a dysfunctional VWF-ADAMTS13 axis, leading to characteristic clinical complications. Novel findings from this research may inform future treatments to improve clinical outcomes.


Sir Henry Dale Fellowship

Molecular basis of phase separation in viral replication and neurodegenerative disease Membrane-less organelles (MLOs) are multicomponent structures that form by liquid-liquid phase separation (LLPS) of proteins/RNA. They play key roles in organising cells, signalling, stress and viral factory formation, whilst aberrant LLPS is associated with several neurodegenerative diseases (e.g. MND). MLOs are heterogeneous and dynamic, making it challenging to elucidate their composition, structure and biogenesis. New tools are urgently needed to study LLPS in vitro and in vivo to address fundamental questions of the molecular mechanism of LLPS, and to unravel how it contributes to homeostasis and disease. Here, I will develop a toolkit of MS-based methods to study LLPS, focussing on two systems: TDP-43, implicated in MND, and NSP2/NSP5, involved in Rotavirus viral factory formation. This will reveal new insights into the structure/dynamics of these proteins (which promote/suppress LLPS) and the protein-protein/RNA interactions which nucleate LLPS. I will study LLPS in vivo using, and developing, structural MS methods to reveal the proteins recruited into MLOs and the interactions mediating recruitment. This toolkit of MS methods, reinforced with biochemical/cellular/functional assays, will afford new mechanistic insights into two important systems, uncover new targets to combat neurodegeneration and viral infection, and open the door to revealing how LLPS controls many other cellular processes.


Sir Henry Dale Fellowship

Spatiotemporal single-cell multi-omics to unlock hair cell regeneration In humans, as with all mammals,, the loss of auditory sensory hair cells (HCs) is irreversible. However, different degrees of HC regeneration occur in vestibular sensory epithelia, at early developmental stages, or in non-mammalian species. HC regeneration results from division and/or trans-differentiation of neighbouring supporting cells (SCs). It is generally accepted that poor/absent HC regeneration relates to the differentiation state reached by SCs and HCs, but the mechanisms behind this are unknown.
What dictates HC regeneration potential? Taking on a multi-layered approach, combining single-cell multi-omics, in-situ sequencing and transcriptional manipulations, I will study the vestibular utricle to evaluate the connection between maturation and HC regeneration potential. First, I will identify the cell/tissue level factors that interact during maturation to distinguish the mouse (marginally-regenerating) and chick (fully-regenerating) utricle. Second, I will study the regeneration trajectories of postnatal and adult mouse utricle to zoom-in on the factors driving the age-related decrease in regeneration potential. Finally, I will perform simultaneous transcriptional manipulation of identified targets aiming to overturn the poor HC regeneration of the adult mammalian utricle.
My research will generate unprecedented cell/tissue-level insight on the maturation and regeneration of sensory epithelia, identifying potential novel therapeutic avenues for recovery from pathological HC loss.

Gene Expression Regulation, Developmental


Sir Henry Dale Fellowship

What makes a virus an intestinal pathogen? Enteric viruses are a major cause of mortality and morbidity in the young, the elderly, and the immunocompromised. Even after decades of research, it is still poorly understood why these viruses replicate particularly in the gastrointestinal tract and what triggers virus dissemination beyond the gut. Despite their worldwide prevalence, and recently emerged neuropathogenic strains, astroviruses represent one of the least studied groups of human RNA viruses, mainly due to difficulties with culturing and molecular manipulations.

My research will focus on understanding the molecular determinants of astrovirus infection – starting with basic replication mechanisms and moving towards physiologically relevant translational outputs. Key goals include:

 Characterisation of the viral RNA structure and replication strategy to understand their role during virus infection.
 Functional dissection of the astrovirus polyprotein processing strategy and its role in virus infection.
 Identification and assessing the importance of gut-specific determinants in virus infection.
 Identification of the molecular mechanisms responsible for neurovirulence.

Elucidation of the fundamental molecular biology of astroviruses underpins an understanding of their pathogenesis, both in the gut and in the central nervous system. It will also facilitate the development of vaccines and antiviral therapies, addressing an unmet need for young children in developing countries.


PhD Training Fellowship for Clinicians

Understanding how Salmonella interferes with the adaptive immune system Salmonella enterica is one of the four key causative agents of foodbourne diseases and each year it affects around 1 in 10 of the global population, according the World Health Organisation (World Health Organisation, n.d.). Salmonella enterica can cause a range of illness from a mild diarrhoeal illness to a widespread systemic infection known as typhoid fever. Successful clearance of the Salmonella bacteria from our bodies during an infection relies on part of immune system called the adaptive immune system. This part of our immune system not only produces a highly specific response but also provides long-lasting immunity. Salmonella has evolved to live within the hostile environment of our cells and is able to manipulate the host cell to aid its survival.  Recent work by the Holden Laboratory, Imperial College London, has shown that Salmonella produces a small protein, called SteD, that specifically interferes with a specific component of the adaptive immune system. Further work has identified two new genes required for SteD to function. In this project, I will establish how SteD hijacks these two proteins to disrupt the immune system.


PhD Training Fellowship for Clinicians

Defining the decline in endogenous insulin secretion in type 1 diabetes diagnosed after 30 years of age. Type 1 diabetes is associated with loss of insulin release, which results in high blood sugars. In children and young adults this loss of insulin is known to happen quickly. After just a couple of years of having type 1 diabetes, most of this age group will make almost no insulin. Research is trying to find new treatments to slow down and even stop this insulin loss. Those developing type 1 diabetes after 30 years of age are rarely included in these trials- despite making up nearly half of all cases of type 1 diabetes. This is because, in this age group, the rate of insulin loss is unknown. Finding out this rate and factors that effect it is an important step towards including older individuals in trials.

I also aim to test a new, simpler way of monitoring insulin loss by using a finger prick blood test.  This will hopefully make it possible to conduct research from home rather than in hospital. Together, the answers to these questions aim to make it easier to develop new treatments for type 1 diabetes, as these studies could recruit many more people, using a much simpler and cheaper measure of insulin loss.


PhD Training Fellowship for Clinicians

Clinical and molecular delineation of neurodevelopmental disease within genetically isolated communities. Inherited neurodevelopmental disorders affect brain development and function and occur as result of changes to the genetic code, which may be passed down through families. The causes of these disorders remain poorly understood, and they present an immense healthcare burden worldwide. This means that affected families may often undergo multiple investigations in search of a diagnosis.
Some neurodevelopmental disorders, which are otherwise rare in the general population, may occur more commonly in certain communities such as the Amish and Palestinian populations. The unique genetic make-up of these communities makes it easier for scientists to identify the genetic causes of inherited neurodevelopmental disease, which in turn greatly aids scientific understanding of brain growth, development and function. This project aims to identify new genetic causes of human inherited neurodevelopmental disease within these community settings. Studying the biological function of these genes will help us understand more about human health and the medical problems which arise when the genes involved do not function properly. This knowledge is ultimately important to develop better treatments for these disorders. Crucially, this work will also provide diagnoses for patients and their families, not just in these communities, but also worldwide.


Sir Henry Dale Fellowship

Integration of kinases with membrane trafficking machinery Endocytosis is a highly dynamic process that determines the composition of the plasma membrane (PM). The dysfunction of endocytic pathways is a causal factor behind a number of human genetic diseases, and its dys-regulation can contribute to neurodegeneration.

Despite the critical role that endocytosis plays in health and disease, surprisingly little is known about how it is regulated. A major potential regulation point is the dynamic phosphorylation of endocytic components by kinases. However, it is poorly understood which kinases (and phosphatases) control endocytosis and the PM proteome, even though they represent potential targets for disease-modifying therapies.

My long-term vision is to understand the integration of protein kinases  within membrane-trafficking machinery. My starting focus is on the Numb-associated kinase family (NAK). NAKs were identified as a susceptibility factor in Parkinson’s disease and neuropathic pain but the molecular mechanisms behind this are not clear.

I will elucidate the key cellular functions of NAKs: (1) which cellular processes and substrates are associated with NAKs (2) the consequences of their activity for cellular physiology and (3) the regulatory processes and interaction partners which govern NAK activity states.


PhD Training Fellowship for Clinicians

Discovering New Pathways of Preleukaemic Dysregulation from Single Cell Transcriptional and Chromatin Landscapes Blood stem cells ensure the constant supply of new blood cells throughout a person’s lifetime.  The normal function of blood stem cells critically depends on the fine tuning of which genes should be active at any given time.  Moreover, a large number of leukaemias arise when this fine balance of gene activities is disturbed.  Through my research I want to answer the following questions:

 What are the mechanisms which regulate gene activities to ensure normal blood stem cell function?
 Can we identify new strategies to treat leukaemia by reversing the disturbed balance of gene activities?

To answer these questions, I plan to use a combination of experimental and computational approaches, in order to discover how individual regulator genes are connected to form complex networks that control normal blood cell differentiation, and also reveal how perturbation of these complex networks can cause leukaemia.


PhD Training Fellowship for Clinicians

Improving engraftment for cell therapy in cholangiopathies The cholangiopathies are a group of diseases, which cause injury to the biliary system. The most prevalent of these are primary sclerosing cholangitis (PSC), and primary biliary cholangitis (PBC), both of which frequently progress to cause hepatic failure.

Liver transplant offers the only curative therapy for PSC and PBC however, there are a limited number of livers available and transplantation is associated with a significant risk of complications. Stem cell therapy has shown promise as an alternative treatment strategy, but delivery of cells to the biliary system is challenging.

Recently it has become possible to create particles which target specific markers in tissues and cells. Particles designed to target the biliary system can be attached to the surface of stem cells, creating a method for stem cells to home to the biliary system, in the hope of improving cell delivery and treatment efficacy.


PhD Training Fellowship for Clinicians

Measuring unmet need in sexual and reproductive health among women under the age of 25 When designing and evaluating health policies, there is a particular challenge that often arises - how do we work out the number of people who need healthcare but haven’t received it?  This is often referred to as ‘unmet need’.  Although a lot of data are collected regarding the use of healthcare services, by definition, the people who aren’t receiving the services that they require do not contribute to these datasets.  My thesis will look at the concept of unmet need through the lens of sexual and reproductive health, attempting to ascertain whether we can calculate levels of unmet need across England using the data that we already have available.

Through this project I will attempt to calculate the number of women in England under the age of 25 who did not receive the sexual and reproductive healthcare that they needed between 2010 and 2020. I will then use financial data to work out whether this unmet need was greater in areas that had smaller budgets for sexual and reproductive health during this period.

Grants awarded from 1 October 2005 to 30 June 2021


PhD Training Fellowship for Clinicians

Novel labelling and tracking strategies to understand mesenchymal stem/stromal cell populations relevant to musculoskeletal regenerative therapy Bone marrow-derived MSCs can exert strong therapeutic effects in the musculoskeletal system and cell therapies have developed to regenerate and repair cartilage defects. However, our understanding of the biology of this heterogeneous group of cells is incomplete and there are still many hurdles to their wide application in the clinic.

We will use a combination of labelling techniques and novel cell markers developed in Cambridge to track labelled cells in vivo to determine their survival, engraftment and distribution. The biology of unlabelled and labelled MSCs will be studied in vitro to confirm that the labelling does not affect the cells’ function. Labelled cells will be injected into a mouse knee (after creation of a cartilage defect) and repeated imaging will be used to track the distribution of these cells to study their biology in greater detail.

With the current focus on moving cell therapies to the clinic, in vivo tracking of these cells is critical in assessing their homing and proliferative potential over time. The novel genetic labelling strategies used will provide important information regarding graft behaviour in small animal models, offering both fast readouts of longitudinal cell survival and low costs per imaging study.


Discretionary Award - Mental Health

Continuing the Mental Health Agenda in 2020 This proposal aims to sustain lasting activity on mental health advocacy.  The United GMH team will leverage support from Wellcome to mobilise partners, and the wider global mental health community, to maintain the momentum built since 2018 to raise mental health further up the global political agenda in 2020. We are requesting £250,000 from Wellcome to further this work.

This proposal plans activities covering four streams:

 Sustaining the work of the BluePrint Group including delivery of the Kenya face to face meeting and a second meeting later in the year (TBC Sept/Oct)

 Leading the BluePrint Group and the wider mental health community to design and undertake a comprehensive multi-stakeholder consultation and create and finalise an action plan to ensure the Global Mental Health Roadmap is delivered; starting with the engagement with key stakeholders at Davos and at the Speak Your Mind and BPG meetings in February

 Working with WHO to develop the advocacy strategy, consultation process and finalisation of their WHO Mental Health Action Plan

 Working to incorporate messaging around the need for more mental health research as part of UnitedGMH’s research on broader advocacy


Clinical Research Career Development Fellowship

Investigating the contribution of gamma-delta T-cells to immunosurveillance of cancer and response to immunotherapy Gamma-delta T-cells are critical for protecting against carcinogenesis in mice but clinical associations have been equivocal and human trials of gamma-delta T-cell therapy have been disappointing.  Previous studies have been limited by unavailable technologies to describe these cells with sufficient granularity whilst clinical trials have largely focussed on the more numerous V-delta-2 subtype.  Using contemporary methods such as TCR-sequencing and ex vivo culture systems to extract gamma-delta T-cells from human tissues, we recently demonstrated that only certain subtypes of these cells, namely the V-delta-1 subtype, are associated with survival in triple-negative breast cancers.

This proposal aims to extend our previous findings to a pan-cancer setting by mapping, with greater and necessary detail, these cells in melanoma, breast, lung and other cancers with a particular focus on V-delta subtyping, differential effector functions and cell regulatory axes.  Importantly, we will also map gamma-delta T-cell interactions with alpha-beta T-cells as these cells have been established as being critical to cancer immunosurveillance.  We will stratify our findings to clinical outcomes to build a novel reference human tumour gamma-delta T-cell atlas to guide ongoing translational efforts in adoptive gamma-delta T-cell therapy.  Hence, this proposal may lead to rapid translation into clinical benefit.


Sir Henry Dale Fellowship

Understanding TB treatment response: a cross-disciplinary approach Tuberculosis is the leading cause of death from infectious diseases and requires a long treatment. Various initiatives aim to develop shorter and more effective treatment. However, this is complicated by the (1) absence of a biomarker that can predict treatment response during early phases of treatment and; (2) interactions between drugs when given together which makes dose selection/optimisation difficult.

My aim is to address these shortcomings by, for the first time, studying relationships between pharmacology, microbiology and immunology markers, using data from patients with drug sensitive and multidrug resistant tuberculosis and statistical modelling. This will help developing a test that predicts cure during the first 2 months of treatment which can contribute to improved efficiency of clinical trials evaluating tuberculosis treatment. Secondly, I aim to characterise overall antimicrobial activity and emergence of persistence and resistance, whilst accounting for drug-drug interactions using an innovative combination of in-vitro kill-curve and hollow-fibre experiments, in-vivo pharmacokinetic data and statistical modelling. This will inform optimisation of tuberculosis treatment.

I will undertake this work at University College London in collaboration with the University of Cape Town, South Africa, giving me access to a large and diverse tuberculosis patient population and state of the art laboratory facilities.


PhD Training Fellowship for Clinicians

 Cellular and genetic landscape of transformed myeloproliferative neoplasms This research project aims to understand how a group of slow cancers of the bone marrow - myeloproliferative neoplasms (MPN) - accelerate into a rapid and incurable leukaemia - advanced-phase MPN. This happens in up to one fifth of all MPN cases. Current treatments can allay symptoms but do not cure advanced-phase MPN. Patients' responses are short-lived, followed by relapse and very poor survival lasting weeks or a few months. We urgently need to understand how MPN cells progress to aggressive leukaemia, why they are so resistant to current treatment, and whether there are surface markers on the diseased cells that we could target with new drug therapies.

Our research draws on patient samples from a clinical trial called the Phazar study. This study examined patients with advanced-phase MPN, who received treatment with two drugs, ruxolitinib and azacytidine. About 40% responded to these drugs, but almost all subsequently relapsed. Using state-of-the-art technologies to examine these patient samples, we are seeking to understand the disease biology of this type of leukaemia, how it evolves from the more benign chronic phase, and why some patients respond to the current standard of care while others do not.


PhD Training Fellowship for Clinicians

Respiratory immune responses and their interaction in control of nasal colonization with Bordetella pertussis and Staphylococcus aureus in humans   This research study is designed to examine how the human immune system responds to different types of vaccines and to bacteria that commonly live in the nose, in particular Bordetella pertussis and Staphylococcus aureus. Infection with the bacteria Bordetella pertussis (‘B.pertussis’) causes whooping cough. Vaccines are routinely given in childhood to prevent whooping cough. If you received routine childhood vaccinations you will have received one of two B.pertussis vaccines depending on your year of birth. This study aims to look at how the human immune system responds to different types of B.pertussis vaccines that are or were in routine use.  Another important bacteria which  may cause disease in humans is Staphylococcus aureus (‘S.aureus’). Approximately 20-30% of healthy people carry these bacteria in their nose without it causing infection. This is called colonisation. However, in some people, infection with S.aureus can be potentially serious and require prompt  treatment. This study aims to look at the differences in how human immune system responds in people who are colonised with S.aureus and those who are not. It is hoped that this research will contribute to future work on vaccines that may benefit vulnerable patients susceptible to serious infections with both S.aureus and B.Pertussis.


PhD Training Fellowship for Clinicians

Novel genetic and neuroimaging biomarkers in the primary tauopathies Frontotemporal dementia (FTD) is a progressive and ultimately fatal disorder characterised by changes in behaviour, personality, language and occasonally movement, for which there is currently no cure. In the 45-65 year age range FTD has a similar prevalence to Alzheimer’s Disease. Pathological studies suggest that abnormal proteins accumulate in vulnerable brain regions, and then spread along anatomical connections . Tau protein, which is also important in Alzheimer’s disease pathogenesis, accounts for 40% of all cases of FTD. With potential therapeutic treatments targeting Tau on the horizon, there is an urgent need to develop biomarkers to correctly identify the underlying pathological protein in life, as well as well to monitor the effects of these treatments on disease progression.

My PhD aims to identify genetic risk factors that make particular regions of the brain vulnerable to tau pathology, and study how the disease progresses over time in the different subtypes (Picks Disease, MAPT mutations, Progressive Supranuclear Palsy and Cortico-Basal Degeneration).

Understanding the influence of genetics on the neuro-anatomical vulnerability of the brain to tau pathology may provide not only biological insight into the onset and progression of these disorders, but also biomarkers to better stratify patients in future disease modifying clinical trials.


PhD Training Fellowship for Clinicians

Mitochondrial Mechanisms And Therapeutics In Heart Transplantation Heart transplantation is the best available and life-saving treatment for end-stage heart failure. Unfortunately, there are far more patients in need of a heart transplant than there are suitable donor hearts and many patients die every year due to this shortage.

When a heart is donated for transplantation, it can spend several hours outside the body without any oxygen supply, before it is transplanted into the recipient patient. During this period, a molecule called succinate builds up in cells. When the oxygen supply is restored to the heart, succinate is rapidly broken down, leading to injury and ultimately death of heart cells.

We will use mouse, pig and human hearts to explore the events that damage donor hearts. This will help confirm that what we have learned from animal experiments are relevant to humans. We have also developed drugs that prevent succinate from building up in heart cells, and may be able to reduce damage during transplantation. We will test whether these drugs are safe and effective in reducing succinate build up, reducing damage to heart cells and improving donor heart function after transplantation. This treatment could result in more donor hearts being available and ultimately save lives.


PhD Training Fellowship for Clinicians

Understanding the gene expression dynamics that regulate glioma stem cell transitions  It is believed that glioblastoma multiforme (GBM), the most aggressive form of adult primary brain cancer, arises from abnormal cells of origin (stem cells) in the brain known as glioma stem cells (GSCs). There is no cure for GBM.

Importantly, GSCs can assume either an active or dormant state. Research suggests that GSCs in the dormant state are especially resistant to treatment and when made active again, result in deadly regrowth of cancer.

Findings from my host laboratory suggest that such cell-state transitions are controlled by unique patterns of gene expression ('expression' being the process by which a gene is converted to its relevant protein) as opposed to genes simply being turned on or off.

My research will use cutting edge tools to label genes of interest with markers that give off a fluorescent glow. This will allow us to identify patterns of gene expression that causes changes in GSC states.

If this research is successful, future treatments could be developed to give doctors control over these cell states. For example, we might be able to prevent dormant cells from becoming re-activated. By doing so, we can hopefully change what is currently a deadly disease into a chronic manageable condition.


PhD Training Fellowship for Clinicians

The Impact of Intensive Medical and Surgical Control of Diabetes on Experimental Rodent Diabetic Kidney Disease. Background:

Kidney disease affects 12 in every 100 people, most commonly due to diabetes. Kidney damage due to diabetes often persists despite treatment with the best available drugs. Most people with kidney damage from diabetes are overweight. Drug and surgical weight loss treatments help overweight people to lose more weight for longer periods of time, improve quality of life, and reduce the chance of dying. Helping people with diabetes to lose weight also slows kidney damage. How this happens remains poorly understood.

Approach:

We will study kidney damage caused by diabetes in rats as they age. We will also treat rats with diabetic kidney damage with drug and surgical obesity treatments to better understand how weight loss protects kidney tissue.

Expected Impact:

We will present our results at international scientific meetings and publish our results in scientific papers. We will present our results to patients attending our dedicated weight loss clinic for people with kidney disease, and involve patient stakeholders in planning future studies. Our studies may result in more people with diabetic kidney damage receiving weight loss treatments and may highlight important targets for new therapies for diabetic kidney damage.


PhD Training Fellowship for Clinicians

The Development and Optimization of Anti-CLEC12A Targeted Umbilical Cord Blood Derived CAR-NK Cells in Acute Myeloid Leukaemia. Acute myeloid leukaemia (AML) is an aggressive form of blood cancer. Current chemotherapy-based treatments cure less than half of all patients with AML. In many cases a relapse occurs which is very difficult to treat effectively. ‘Leukaemia stem cells’ which resist the effects of chemotherapy are an important cause of AML relapse. New treatments which can target and destroy these cells may reduce the risk of relapse and increase cure rates.

In certain other forms of blood cancer new treatments called CAR-T cell therapies have been very effective. These treatments retrain a patient’s immune cells (T-cells) to recognise cancer cells. These treatments are harder to develop for AML as it is difficult to identify a suitable target on the cells for immune attack. In this project we are developing a therapy using ‘retrained’ natural killer cells (CAR-NK cells) which recognise AML cells and leukaemia stem cells. The target for the CAR-NK cells is a protein called CLEC12A. We are also investigating ways of improving the ability of these CAR-NK cells to recognise and destroy leukaemia cells. One example of this is combining CAR-NK cells with medications or changing their genetic code to further boost their activity.


Sir Henry Dale Fellowship

Mapping the energetic pathways of the brain: Ultra-high-field MRI of cerebral oxygen and glucose utilisation Aerobic glycolysis (AG) plays a vital role in brain disease, development, and ageing. Elevated AG has been linked to axonal elongation and synaptogenesis in childhood, synaptic plasticity in adulthood, and is a hallmark of cancer. There is also evidence of a significant reduction in AG in older age and in neurodegeneration. The development of a non-invasive method for imaging AG has the potential for significant impact in basic neuroscience and clinical practice. For example, in cancer therapy, post-treatment mapping of AG is anticipated to be a sensitive measure for assessing recurrence and for the planning of salvage therapy.

I propose to develop ultra-high field (7T) MRI methods to safely and non-invasively map aerobic glycolysis and tissue oxygen availability in the human brain, providing a new window into brain metabolism and metabolic dysfunction. The methods development involves two main paths. 1) Glucose labeled deuterium imaging to directly map cerebral AG. 2) Development of vascular imaging methods, including deuterium perfusion and blood volume imaging. The combination of these two methods will enable calculation of cerebral glucose metabolism, oxygen metabolism, and tissue oxygen availability. These methods will be validated experimentally using a controlled pharmacological modulation of aerobic glycolysis with sub-anaesthetic ketamine administration.


PhD Training Fellowship for Clinicians

Trends in complications, morbidity and cause of death in diabetes patients in England Diabetes is a leading cause of mortality and morbidity in England, with significant impact upon individual patients,  and the NHS. Its significance is expected to increase in coming decades due to population ageing and obesity prevalence. Diabetes is associated with several sequelae including heart disease, stroke, and limb amputations, and more recently several cancers and dementia. Work in the US has identified an aggregate reduction in diabetes complications, particularly in vascular complications, with patients experiencing a more diverse range of complications with a growing proportional impact of non-CVD causes. How incidence of complications and mortality  has changed over the past two decades in England is unclear.

This research fellowships primary aim is to estimate trends in complications and outcomes in patients with type 2 diabetes in England 1998-2018. I will integrate large national datasets including the CPRD, a UK primary care database, linked to Hospital Episode Statistics, the National Cancer Registration and Analysis Service and death records and. Specifically, this fellowship will: 1. estimate trends in age-specific cause of death in patients with diabetes; 2. estimate trends in age-specific incidence of diabetes-related complications and health service-usage; 3. estimate trends in age-specific cancer incidence, survival and mortality in patients with diabetes.


PhD Training Fellowship for Clinicians

Investigating the interplay between interleukin-11 (IL-11) and senescence in cardio-renal aging. As chronological age increases, even in the absence of disease, vital organs accumulate changes which cause them to function less efficiently. Impaired efficiency of organs such as the heart or kidney are particularly common in older people causing the development of symptoms and require medical attention or hospital admissions.

Cells accumulate damage to their DNA with age which causes these cells to enter a protective dormant state known as senescence. This prevents these cells from dividing and passing on the damaged DNA, however, senescent cells release molecules which cause neighbouring cells to produce scar tissue called fibrosis which impairs the efficiency of these organs. Interleukin-11 is one of these molecules which is known to cause fibrosis in multiple different diseases and blocking its effects reduces the amount of fibrosis. We plan to use treatments to block Interleukin-11 in ageing mice to identify the effect this has on the health of these mice and the amount of fibrotic tissue that they develop. We will also analyse the effects of senescent cells on the surrounding tissues to identify the benefit of treatments which specifically remove these cells or stop their contribution to scar formation.


PhD Training Fellowship for Clinicians

Targeting oxidised low-density lipoprotein in atherosclerotic plaque with antibody-based constructs for imaging and therapeutics Background

Oxidised LDL (oxLDL) forms a significant component of fatty plaques, or atherosclerotic lesions, that accumulate in coronary artery disease and can cause heart attacks or strokes. We have recently developed an antibody to oxLDL, LO1,that can target atherosclerotic plaques.

Approach

I aim to harness LO1 and other antibody fragments for targeting of nanoparticles to atherosclerotic plaque. I will develop nanoparticles that are capable of carrying a drug, that will be released when it reaches its destination (i.e. the atherosclerotic plaque). I will produce varying designs with different drugs and targeting agents and aim to demonstrate effective delivery of the nanoparticles. I will test these nanoparticles in mouse models of atherosclerosis, as well as a newly developed original experimental model using an amputated human limb. I will then fill the nanoparticles with the drug and aim to demonstrate a beneficial effect.

Expected Impact

The novel nanoparticles targeted to atherosclerotic plaque will provide a means of local delivery of drugs directly to diseased areas. This will permit much smaller drug doses to be used, with therefore fewer unwanted side effects. In addition, the drugs can be tailored to an individual, utilising the most suitable drug to treat each patient’s atherosclerotic plaques.

Grants awarded from 1 October 2005 to 30 June 2021


PhD Training Fellowship for Clinicians

The role of enteropathy and systemic inflammation in severe acute malnutrition Being extremely underweight from lack of nutrition can lead to a condition called severe acute malnutrition (SAM). This can cause a number of problems including leaving children with thin and leaky guts. Children with SAM have a high chance of dying during hospital admission, and during the following year. The cause of this ongoing risk of death is unknown, but may be related to the changes in the child’s intestines which can result in the immune system not working properly, including not being able to fight off new infections.

From stored samples of a completed study of 200 children with SAM, I will look at different markers in the blood and stool to see how well the gut and the immune system are working, and see if these markers relate to the chances of the child dying or being
readmitted to hospital in the following year. After this I will look at some of these markers in a new trial that is looking at new medicines to improve the health of the gut in children with SAM. I will see if it also improves the markers of the immune system.


PhD Training Fellowship for Clinicians

Vaccine-induced systemic and mucosal immunity to Bordetella pertussis in infancy: bringing B- and T-cell responses together Whooping cough, known as pertussis, is a serious infection, especially in infants. Two types of pertussis vaccine exist: whole-cell (wP) and acellular (aP). We now think that aP vaccines may not be as long-lasting or effective in preventing infection as wP vaccines, but the cause remains unknown. It may be due to differences in specific groups of cells in the immune system called T-helper cells. The type of T-helper cells found in animals and humans who have received wP- compared to aP-vaccines is better at preventing bacteria from being passed on. We still do not know enough about all the important T-helper cells involved and there is no data in very young children. My project is set within a larger study in The Gambia that is vaccinating babies with aP or wP vaccine. I will investigate T-helper cells activated by these vaccines and see how they may help other components of the infant’s immune system. As well as taking blood samples, I will collect and analyse fluid from the infant’s nose (where pertussis bacteria initially infect), to provide further insight into how these vaccines differ in their action. My findings will help to design better pertussis vaccines in the future.


PhD Training Fellowship for Clinicians

Computer Aided Screening for Tuberculosis in Low Resource Environments (CASTLE) TB is very common among people living with HIV (PLHIV) in who are unwell and require admission to hospital. However TB can be difficult to diagnose.  Digital chest X ray with computer-aided diagnosis (DCXR-CAD) and a urine test may help promptly diagnose TB.

At a single hospital in Malawi, days of the week will be randomly assigned so that on some days patients with HIV coming into hospital will be offered a DCXR-CAD and urine test as well as usual care and on other days patients will be offered usual care only.  We will measure how many patients in each group die in hospital, how many start TB treatment, and how many patients have their TB diagnosis missed and therefore untreated by the time they leave hospital or die.

As part of this study a small number of patients will have enhanced laboratory tests for TB, monitoring of HIV severity, tests for other infectious diseases and tests of inflammatory markers.

The goal is to see if DCXR-CAD and urine testing reduces deaths among people with HIV who are in hospital, and to provide insight into what diseases are causing people with HIV to become unwell and need hospital admission.


PhD Training Fellowship for Clinicians

Working memory impairment in temporal lobe epilepsy This project examines how temporal lobe epilepsy (TLE) disrupts specific memory processes, through the integrated study of behaviour, neurophysiology, and multi-modal imaging . This is important because, within the peak age group 60–90 years of developing TLE, up to 60% of individuals demonstrate objective memory dysfunction, before starting anti-seizure medication. At present, there are no specific treatment targets for this significant problem.

Two factors which are associated with memory problems in TLE are higher number of seizures and co-existing cerebrovascular disease. However, it remains unknown how these two factors impact memory, whether they interact, and whether they both act by disrupting function of the hippocampus- our memory organ. I plan to:

 use a novel cognitive task to assess how TLE perturbs two specific facets of memory that are known to be less efficient with ageing and Alzheimer’s disease.
 establish the mechanistic contributions of electrical disruption and structural white matter abnormalities to memory impairment.

These cognitive processes, if affected, could explain memory deficits caused by acute and long-term effects of seizures. Ultimately, this project may help inform clinical assessment and guide specific management of sub-clinical seizure activity and vascular risk factors, to improve memory co-morbidity and quality of life in TLE.


Global Forum on Bioethics in Research

Towards an Appropriate African Framework for Public Engagement with Human Genome Editing The novel biotechnology of the CRISPR-Cas9 method has certainly precipitated unprecedented interest as well as concern with regard to the scientific reality of human genome editing. This excitement and anxiety become even more acute in resource-limited settings where there is limited awareness and engagement between the experts in human genomics and gene editing and the public. Hence, there is an urgent need for effective public engagement. The purpose of my fellowship is to get vital mentorship in public engagement with human genome editing. My aim is to benchmark with best practice at NHGRI and work towards developing an appropriate African framework for public engagement with human genome editing. My visit will also be a unique opportunity for me to network and cultivate opportunities for north-south collaborative partnerships. Besides, the acquired knowledge and skills will greatly contribute towards Africa’s capacity-building. I plan to effectively disseminate my work, including at least one publication in a reputable peer-reviewed journal. Thus my trip is in line with GFBR’s goal of bringing together key stakeholders from developing and developed countries in addressing frontier bioethical concerns in research. It is also relevant to GFBR’s goals of capacity-building and of fostering effective collaborative partnerships.

Clustered Regularly Interspaced Short Palindromic Repeats


PhD Training Fellowship for Clinicians

Genetics and Epidemiology of Diabetic Retinopathy Background
Diabetic eye disease, or diabetic retinopathy (DR), is a common complication of diabetes. 1.5 million people in the UK have DR of whom 140,000 have sight-threatening diabetic retinopathy (STDR). STDR is a leading cause of blindness in working age people, associated with lifetime costs of up to ~£237,000 per patient. It remains unclear why some patients with DR progress to STDR while others do not. Individuals with a family member who has STDR are more likely to develop STDR themselves, implying that genetics play an important role.

My approach
My study aims to determine what factors influence the development of STDR. Genetic, dietary and other lifestyle information gathered from  > 26,000 participants with diabetes in the UK Biobank and EPIC Norfolk projects will be linked with their eye records from the National Diabetic Eye Screening Programme. My analysis will then compare patients who have STDR with those who do not.

Expected impact of my work
Understanding the underlying genetics of STDR may reveal biological targets for new treatments. My findings could also help improve healthcare resource allocation by better predicting which patients with diabetes are at highest risk of developing STDR, based on their individual genetic and non-genetic risk factors.


Discretionary award – DRI

Dr Lou Atkins, Dr Raph Hamers, Prof H Rogier van Doorn

Barriers and enablers to the adoption of blood culture sampling recommendations Blood culture (BC), the core sample for antimicrobial resistance surveillance, is recommended to be sampled from all sepsis patients prior to administration of antibiotics. However, BC sampling rates are lower than recommended in both high-income countries (HICs) and low and middle-income countries (LMICs). Various barriers and enablers have been identified that impeded the adoption of BC sampling recommendations using different theories; however, a systematic review on this topic is not currently available.

We propose to conduct a systematic review to identify known barriers and enablers to the adoption of local and international BC sampling recommendations. We will use the theoretical domain framework (TDF), which has been developed by refining a wide range of theories, as a framework for synthesizing evidence on barriers and enablers. Findings will be stratified by HICs and LMICs. We will then conduct a survey study among medical doctors using face-to-face interviews and electronic questionnaires to explore generalizability of systematic review findings among medical doctors in Thailand, Viet Nam and Indonesia. All questionnaires (in Thai, Vietnamese, Indonesian and English) will also be made available online, and open for public participation.

A systematic summary of the existing evidence can inform the development of interventions.


Global Forum on Bioethics in Research

Engaging with Local Communities in Botswana: Understanding Cultural Values, Norms and Beliefs that may impact Genome-Editing Research in Botswana  The continuous growth and recent technical advances that have improved the precision, cost and simplicity of new gene editing technologies such as Somatic and germline therapy have since given birth to new hope in the fight against the burden of disease such as HIV in developing countries (sources). Despite facing dis-proportionally higher prevalence HIV rates, communities in Botswana to our knowledge the technologies have not been tried hence Batswana remain understudied in gene editing research.  Therefore, I am proposing a study to engage with local communities to educate them about gene-editing technology research and collect their perspectives on how their cultural values norms and beliefs can have positive or negative implications on their benefiting from this technology.

1. The overall goal of the project is to explore the perceptions of communities in Botswana regarding perceived and real social ethical issues (cultural values, norms and beliefs) surrounding gene-editing technologies regarding its use for health benefits?

2. The project also aims to empower communities with knowledge through education and engagement about gene-editing technology for better informed decisions in preparation for participation in gene-editing technologies as well as learning about its potential benefits, risks and use of genomics, gene-editing technologies.


PhD Training Fellowship for Clinicians

The potential role of IL-2 in preventing autoimmunity after alemtuzumab in multiple sclerosis Multiple sclerosis (MS) is a common autoimmune disease of young adults, in which the patient’s own immune system attacks their brain and spinal cord, causing disability. Alemtuzumab is a highly effective treatment that depletes lymphocytes (cells that normally fight infection but some of which cause damage in MS).

After treatment, the immune system returns without the MS-causing cells. However, in 40% of patients, as a consequence of treatment, the recovering immune system attacks another organ instead (e.g. the thyroid gland), limiting our use of alemtuzumab.

This complication partly results from an imbalance between self-reactive lymphocytes, and regulatory cells, which specialise in controlling the self-reactive lymphocytes. Boosting regulatory cell numbers after alemtuzumab could therefore prevent autoimmunity. Interleukin-2 (IL-2) is a naturally occurring substance shown to increase regulatory cell numbers and suppress autoimmune disease.

Using laboratory-based experiments, mouse studies and short dosing studies in patients, I will determine whether IL-2 can also increase regulatory cells after alemtuzumab treatment, hopefully providing evidence for a future clinical trial.

Preventing post-treatment autoimmunity would represent an important advance in the management of MS, saving the NHS and patients considerable costs. The wider implication of my work is a general strategy for manipulating human immune reconstitution.


PhD Training Fellowship for Clinicians

Discovering the Genetic Basis of Epilepsies through Computational Analysis of Clinical Phenotype Background
Epilepsy affects 1% of people and empirical treatment benefits only a third. Seizures and their treatments have serious health and socioeconomic consequences. Over a third of epilepsy is thought to arise from variation in the person’s genetic code. However, currently we can only rarely identify what this is, a necessary step towards using it to improve treatment. Studying people grouped by the symptoms of their epilepsy has successfully defined, and discovered the genetic causes of distinctive but rare epilepsies such as Dravet Syndrome, facilitating research that has improved their treatment.

Approach
The yield of large genetic studies of epilepsy is currently limited by the challenges of combining and interpreting vast quantities of complex information about participants' epilepsy symptoms. We will develop computational methods to make information about the symptoms of participants in Epi25 (the largest ever epilepsy study) more tractable. We will use these to identify new patterns of symptoms and their associated genetic causes.

Expected Impact
Identifying new genetic causes of epilepsy could help to us to personalise the selection of existing treatments more successfully within a few years, and to design new, precise treatments based upon newly discovered mechanisms. Our methods may be applicable to other diseases.


Global Forum on Bioethics in Research

Ethics of human genome editing from Islamic and Confucian perspectives This project aims to explore Islamic and Confucian perspectives on ethical issues pertaining to human genome editing namely safety and efficacy of the technology, human dignity and rights, modifying God’s creation, and human genetic enhancement.  It will identify the similarities and differences between both perspectives and highlight the common ethical principles that could be applied in assessing the permissibility of human genome editing technology. This project is a qualitative study that involve normative literature analysis and comparative analysis between Islamic and Confucian perspectives. Given that Islam and Confucianism are among the main ethical traditions in the world, findings from this project would help stakeholders in understanding both perspectives and formulating policies and guidelines regarding responsible research and use of human genome editing. It is hoped that it would encourage more cross-cultural studies that contribute to the global discussion on ethics of human genome editing.


PhD Training Fellowship for Clinicians

Dietary management of type 2 diabetes in primary care It is possible to reverse type 2 diabetes - where people return to normal blood glucose control without medications - through significant weight loss, using total diet replacement programmes ("soups and shakes" diets). However, diets using real food may be more acceptable to some people, and potentially more sustainable. My recent study demonstrated that it was possible for nurses to support patients with obesity and type 2 diabetes to adopt a real-food low-carbohydrate diet, helping them lose weight and improve their blood glucose in the short term. However, it is not clear what effects these diets have on appetite (which influences whether they might work longer-term), and whether other patient groups may benefit.

I will run an experimental study to investigate the effects of low-carbohydrate weight-loss diets on appetite in people with type 2 diabetes.  I will also run a pilot study to test if people with type 2 diabetes without obesity can adopt this low-carbohydrate diet, and whether this improves their blood glucose control.

These studies will inform the design of a full-scale trial testing whether low-carbohydrate weight-loss diets are effective for people with type 2 diabetes longer-term, and whether they should be recommended as part of routine care.


PhD Training Fellowship for Clinicians

Exploring the clonal determinants of T-cell anti-cancer and autoimmune responses after immune checkpoint blockade This research aims to improve our understanding of how an important immune cell, called a T cell, functions and changes when treated with a class drug called immune checkpoint blockers (ICBs). These drugs have been very successful in treating some forms of cancer - particularly skin cancers - but they don't work for everybody and some people suffer from severe side effects.

We will compare the T cells from patients with skin cancer with those from healthy volunteers. We will then analyse what happens to T cells when they are exposed to ICBs. First, we will look at which bits of DNA instructions they turn on and off . Second, we will look at which T cells are implicated in the autoimmune side effects with the objective of identifying which T cells drive these toxic responses.

Ultimately, this research will enable us to predict which patients are more likely to benefit from ICBs, and which are at higher risk of side effects, allowing patients and doctors to make better decisions about treatment . Also, by better understanding the autoimmune side-effects, we might gain insight into what goes wrong in many diseases caused by an over-active immune system.


PhD Training Fellowship for Clinicians

Investigating the diversity and evolution of Hepatitis B virus using Nanopore whole genome sequencing BACKGROUND

Chronic Hepatitis B virus (HBV) infection is a global health threat affecting 290 million people, causing 800,000 deaths a year from liver cirrhosis and liver cancer. The United Nations has set elimination targets to be achieved by 2030, however, existing strategies will not enable this goal to be met. Viral genetic sequence is linked to treatment response and clinical outcome. Studying the genetic sequence of HBV therefore provides an avenue to improve elimination strategies.

Recently, we have provided proof of principle that full-genome HBV sequences can be generated using the Nanopore platform. This method is ideal for studying viral diversity due to the long reads generated. I will use this method to study the diversity of HBV within and between hosts, capitalizing on well-established cohorts in South Africa and Uganda.

APPROACH

1. To optimize Nanopore methods for HBV full genome deep sequencing

2. To identify and characterise HBV strains circulating in sub-Saharan Africa

3. To characterise the kinetics of HBV evolution

4. To investigate the relationship between viral diversity and liver disease

EXPECTED IMPACT

This information can potentially be used to improve prognostication, understand immune control,

optimise drugs and vaccines, with the potential for high impact on global health.


PhD Training Fellowship for Clinicians

Optogenetics to model activity-dependent neurodegeneration in amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) causes motor neurons, nerve cells which control voluntary movement, to die. The cause is not fully understood but likely involves an interplay between errors in our genetic code (mutations) and the environment.

With stem cell technology, patient skin cells can be transformed into motor neurons in the laboratory. Our group has used this technique to identify important disease-related changes. However, in the body, motor neurons are highly electrically active and undergo repetitive 'firing' to activate muscles. Therefore, a complete understanding of motor neuron vulnerability in ALS requires a model in which the activity of these cells can be controlled.

In this project I will generate motor neurons from patients with disease-causing mutations, and insert a genetically-engineered light-sensitive 'switch' to control activity using light. I will light-stimulate them, both in isolation and with muscle cells. We hypothesise that stimulation will mature the cells, making them more representative of motor neurons in ALS, which start dying in later life. We also hypothesize that stimulation will drive disease-relevant changes. This impact of this work will be a contribution to our understanding of the causes of ALS, and a novel model of disease for further study and testing possible treatments.


Global Forum on Bioethics in Research

A Critical Investigation of Gene Drive Technology  There is established bio-ethical literature related to genomic research and technology, with this literature increasingly also focussing on gene drive technologies. While such questions are important, these questions often do not critically engage with how gene drive technologies interact with social, political and economic spheres. Furthermore, there is very limited critical discussion about these technologies from scholars situated in the global South, where some first field trials are set take place.

During this fellowship, I will work on a journal article for publication critically interrogating the social, political and economic dimensions of gene drive technology. This paper will focus on questions such as, why are the first field trials of  this controversial technologies organised in one of the poorest countries in the world, who actually benefits from such research, especially given the convergence of funding from Western governments, philanthropic funders, and the commercial agricultural sector, and what is the impact of these arrangements of local communities and governance structures where gene drive technologies have been proposed to be used. The publication will begin to articulate these kinds critical questions that must be engaged with, if we are to ensure gene drive technologies does not reproduce historic patterns of inequality.

Grants awarded from 1 October 2005 to 30 June 2021


Global Forum on Bioethics in Research

THE GOVERNANCE FRAMEWORK OF GENOME RESEARCH IN MALAWI The main intention of this fellowship is to document the distinct ethical issues related to the use of genome research in eradicating Malaria. This will then result in identifying an ethical acceptable framework for genome editing that necessitates the progress of scientific research.  The following key goals are expected to be  met in the 6 week period.

 Review and document the National commission for science and technology NSCT regulations and guidelines in regards to genome  editing.
 Review the regulations, guidelines and policies used by ethics committees and regulators at McMaster and some sub-Saharan countries that incorporates genome editing for malaria eradication.
     Establish and document evidence  that aid advocacy to implicating policies that are favorable for researchers to conduct genome research and at the same time beneficial for human health IN Malawi
     Recommend ethical acceptable approaches   and frameworks that can address the ethical issues surrounding genome research


Strategic Support: Science

The Global Alliance for Genomics and Health: Setting the Standards for Genomics and Health-Related Data Sharing The decreasing cost of genomic sequencing will yield millions of samples in the coming years from both research and healthcare. To make the most use of these data, the community must agree on common methods for collecting, storing, transferring, accessing, and analyzing data.

This proposal will support the Global Alliance for Genomics and Health (GA4GH; www.ga4gh.org) as it develops the standards and policies necessary for effective and responsible data sharing. With more than 1,000 active contributors working across more than 30 countries in the areas of healthcare, research, patient advocacy, life science, and information technology, this diverse organization enables broad sharing that transcends the boundaries of any single institution or country.

We envision a future in which the full suite of GA4GH standards enables all clinicians, geneticists, and researchers to search across the world’s collective genomic data to reveal unanticipated gene-disease associations, make otherwise impossible drug-response predictions, and generally participate in genomics at a competitive pace—regardless of their means or location.

The promise of genomic medicine lies at a crossroads that depends on community harmonization and will significantly enhance human health and medicine if we succeed. We believe GA4GH is necessary to that success.


PhD Training Fellowship for Clinicians

A Single-cell approach to probing proximal TCR signalling and early transcription of cytotoxic T cells Cytotoxic T cells (‘killer cells’) are a vital component of our immune system.  The human body is capable of mounting different responses to ensure defence against foreign invaders such as faulty cancerous cells, whilst protecting useful bodily cells from destruction.  Their ‘killing’ ability is the reason cytotoxic T cells are of great interest in the development of cancer treatments. However, more work is required if they can be harnessed as effective and yet safe therapies.

Studying cytotoxic T cells is difficult with conventional scientific methods, since our bodies are inherently designed to produce vast populations of T cells, each able to kill different infected or faulty cells.  The diversity and rapidity of these responses confer immunological advantages but make deciphering events on a per-cell basis perplexing.  This project proposes to use ‘single-cell resolution’ methods to study cytotoxic T cells. Mass cytometry and single-cell RNA sequencing are innovative techniques that are capable of simultaneously measuring multiple changes within each single-cell.  Together, these techniques will allow us to gain an in-depth understanding of the regulation of cytotoxic T cells, to improve and expand cancer immunotherapy.


PhD Training Fellowship for Clinicians

Leveraging electronic health records for the design of improved care for older surgical patients With an ageing population, increasing numbers of older patients are presenting for surgery.  Those with other health problems who undergo major operations are more likely to develop complications and fail to make a full recovery.  The complexity of modern healthcare means that approaches used to design other complex systems (such as energy or aviation) are increasingly advocated to understand, design, and improve health systems. In our project we aim to explore how healthcare data can be used to supplement such an approach; to identify events and factors associated with older patients losing independence after surgery or suffering another complication (such as a heart attack) whilst in hospital.

We will firstly gain consensus on what defines a 'high-risk' patient by searching the literature and canvassing the opinion of healthcare professionals.  This information will inform the generation of a large, anonymised dataset, extracted from our hospital's electronic health record and use this to identify events, conditions, and factors that are associated with poor outcome after surgery.  In the final phase we will use these findings to explore, simulate, and design potential solutions to these identified problems with the hope of exploring the beneficial effects of such a solution in future work.


Global Forum on Bioethics in Research

Centro De Estudios De Estado Y Sociedad Cedes

Community and stakeholders perceptions towards human gene editing. An explorative study in Argentina The project aims to develop a better understanding of the general public and various stakeholders views on human gene editing in Argentina. Focus group sessions will be conducted for an in-depth exploration and description of the general public, patients and members of REC attitudes and perceptions towards human gene editing.

Key goals are:

 The findings of the project will contribute to strengthening the evidence on an unexplored topic in Latin America.
 The results will also serve as a basis for future research in Argentina and other Latin American countries.
 The information obtained will provide information to Ministry of Health policymakers for future policy.
 An academic paper for publication in a peer-review journal will be produced.
 Key actors in Latin American countries will be identified to facilitate the dissemination of the findings.
 A human gene editing workshop with experts for research participants to disseminate the findings of the project and to promote dialogue among stakeholders will be conducted.


Discretionary Award – C&S

The Wellcome Screenwriting Fellowship 2019 This is a prize for a Screenwriting Fellowship, awarded in collaboration with the BFI and Film4 in 2019


Global Forum on Bioethics in Research

Building communication and trust in gene editing in human health To organize two meetings for the general public to raise awareness about gene editing in Argentina so they can be enriched with reliable information. The idea is to repeat the event held in Buenos Aires in 2018 that I presented in the Forum in Singapore 2019, in two different cities in Argentina: Santa Fe and Entre Ríos, in order to reach more people about the importance of this technology. A registration form will be available for the general public to sign up for the meetings.

On the other hand, Ana Palmero will apply to another Meeting Fellowship to organize a workshop to ask patients of gene therapies, which in the future could require treatment with gene editing, their opinion about the technique. This way, she will gather data.

Even my project can be carried out independently, the idea is to work together to empower the workshop of Ana Palmero. The patients of the interest for the workshop will be invited to participate in the meetings in where they will receive information that will be able to use later in the workshop. An informed person, can elaborate better answers.

This way, two ministries of Argentina will work together: Science and Health


PhD Training Fellowship for Clinicians

An investigation of white matter fibre tract topology, connectivity and microstructure to uncover the ictogenic network in focal epilepsy Epilepsy is the most common serious neurological disorder and one-third of those affected continue to experience disabling seizures despite taking regular medications. It is thought that there are abnormal cortical areas in the brain that, together with the white matter connections that join them, form pathological circuits responsible for seizures. These circuits vary between subjects in their properties, location and spread. Modern medical imaging and other investigations do not fully detect the abnormal circuits, leaving the majority of patients unsuitable for surgery or vastly reducing their chances of seizure freedom post-operatively.

Using state-of-the-art imaging hardware and methodology I will obtain high quality brain scans of 20 patients with epilepsy. I will look at the multiple qualities that can tell us about the state of the brain connections, producing very detailed maps of abnormalities. I will then test contribution of these abnormalities by mathematically simulating seizures and comparing my simulations with the real seizure activity we record from the same patients. This will help us describe the circuits or give us information about how these circuits work.

My approach will allow us better understand the exact mechanisms that drive epilepsy and may help develop better treatments for these patients.