PhD Studentship (Basic)

Investigation into the effects of elevated oxidative stress on wound healing in vivo Body tissues, such as the skin, must be able to rapidly repair themselves in response to injury. However, some individuals (particularly those with underlying health conditions) suffer from debilitating ‘chronic’ wounds that fail to heal, which are often persistently infected. These non-healing wounds are poorly understood and represent a significant burden to healthcare systems and economies.

Damaged tissues recruit immune cells to ‘clean’ the wound, removing dead cells and producing toxic oxygen molecules to kill invading germs. This inflammatory response is essential for normal wound healing. However, overproduction of toxic molecules could cause ‘collateral damage’ to our own cells (termed ‘oxidative stress’) and hinder repair. To combat this, we have evolved a powerful network of ‘biological shields’ to protect injured tissues, including antioxidant production.

My work will explore whether defects in this protective machinery are responsible for the failure of infected/diabetic wounds to heal and whether we can rescue healing by boosting protection. For this, I will use the fruit fly (Drosophila), exploiting their translucency (and genetic tractability) to study wound repair live ‘in vivo’. In parallel, I will use ‘genetic epidemiology’ to investigate their clinical relevance, by seeing if variations in equivalent human genes have links to disease.


PhD Studentship (Basic)

Molecular, genetic and life course approaches to investigate the role of reproductive factors on risk of breast cancer in women  Breast cancer (BrCa) is one of the most common forms of cancer, affecting 1 in 7 women and accounting for 7% of all deaths in the UK between 2015-2017. Numerous risk factors have been associated with BrCa including age, family history and body mass index, as well as factors involved in women’s reproductive health. Reproductive events such as early puberty and later menopause have been associated with increased BrCa risk. Much of the current literature has assessed reproductive events independently without consideration of other reproductive events, and these event’s causal role in BrCa development has not been fully investigated.

My aim is to use multiple approaches to explore the role of reproductive events for improving understanding of BrCa. Firstly, I will assess how these reproductive events have an effect, either independently or in combination, on BrCa risk, across the life course. Secondly, I will use newly developed methods to further assess if reproductive events play a role in causing BrCa. Finally, I will assess to what extent epigenetic modifications, changes to the DNA which influence gene regulation, play a role in the relationship between reproductive events and BrCa. This work will improve our understanding of the causes of BrCa.

Grants awarded from 1 October 2005 to 30 June 2021

Creative Commons Attribution 4.0 International (CC BY 4.0)


PhD Studentship (Basic)

Functional Studies of Mutations in Osteoporosis Drug Targets in the Zebrafish Osteoporosis is a disease which weakens bones, making individuals more prone to fractures even after a minor fall. It is a prevalent disease, affecting around 1 in 3 women and 1 in 5 men which accounts for 28 million people over the age of 50 across Europe. Individuals suffering with osteoporosis put a significant burden on health care services as they can require long term hospitalisation after surgery, as well as social care packages and physiotherapy. Current treatments aim to stop bone degradation, whereas there are few treatments available to re-build bone and thus help prevent further fractures. New bone-building drug targets can be discovered by investigating the genetic changes which cause people to have naturally high bone mass. In my project, I will use human genetic datasets for genetic changes relevant to bone metabolism to select two novel candidate genes. I will use zebrafish as a model, since their rapid life cycle and transparent bodies allow for imaging of fluorescent proteins that help us understand how the candidate genes affect bone homeostasis. Cultured zebrafish scales will be used to screen for compounds targeted to these candidate genes to test their bone-building capacity informing potential novel osteoporosis treatments.


PhD Studentship (Basic)

An Investigation into the Fundamentals of Mitochondrial ‘Stop-Transfer’ Import and Processing  Background

Mitochondria are membrane-bound organelles implicated in cellular energy generation and an increasing number of cellular processes. Critically, these processes rely on proteins being imported into the mitochondria via the mitochondrial protein import apparatus. ‘Stop-transfer’ import (Figure 1) is a means to achieve delivery of proteins to a mitochondrial sub-compartment termed the inter-membrane space (IMS). PTEN-induced kinase 1 (PINK1), a mammalian mitochondrial protein kinase and Mgm1, a mitochondrial protein in yeast, are both implicated in mitochondrial ‘health’ and are critical substrates of this pathway.

Approach

Thorough mechanistic characterization of stop-transfer protein import and the role of processing of these proteins is required to better understand delivery to the IMS in native and damage contexts. I will apply biochemical and biophysical (spectroscopic) approaches to report on import into the IMS using purified PINK1 and Mgm1 in mammalian and yeast cell-based import assays respectively, while also focusing on the role of interacting proteins during the import process, markedly TOM/TIM proteins and PGAM5.

Impact

Design of a probe to report on mitochondrial import into the IMS will reveal new details of the molecular control of stop-transfer import and its regulation, markedly for critical substrates such as PINK1 implicated in human disease.


PhD Studentship (Basic)

Investigating the regulation of NETs by cell cycle proteins. Neutrophils are the most abundant immune cell in circulation. They are the first to respond to infection and tissue damage. Once activated, they migrate into affected tissues to kill microbes using effector mechanisms. These are: pathogen engulfment, secretion of toxic granules, or, releasing neutrophil extracellular traps (NETs). NETs are large, web-like structures comprised of DNA and neutrophil proteins. NETs trap microbes to prevent them spreading and therefore limit tissue damage. However, NET production is tightly controlled because they can also damage our own tissues. Moreover, uncontrolled neutrophil activity and NET release can exacerbate some diseases such as cancer and malaria.

Despite their disease relevance, how neutrophils ‘decide’ to react to microbes and inflammation is not well known. Therefore, the aim of this project is to understand which genes control neutrophil behaviour. We will test the hypothesis that the same set of genes that regulate cell division, also regulate NET release. Furthermore, we will also examine if neutrophil changes during cancer make them more prone to making NETs and contribute to disease progression.

This project will lead to deeper understanding of the role of cell cycle genes in NET formation and elucidate their role in neutrophil populations associated with inflammatory disease.


PhD Studentship (Basic)

How does wound inflammation impact on other cell lineages at the repair site – in vitro and live imaging studies in zebrafish Wound healing is the process by which skin integrity is restored following injury. At any site of tissue damage, the body activates a complex series of events to heal the wound. Each stage is necessary for effective tissue repair. Inflammation has evolved to prevent infection by pathogens. Besides killing bacteria, signals from inflammatory cells also coordinate other aspects of wound healing. However, these signals may also have negative consequences such a scarring, and if inflammation is not resolved, this can lead to chronic wounds such as diabetic foot ulcers can result. During my PhD I will investigate how inflammation impacts on three lesser studied cell types in wound healing, melanocytes (pigment cells), adipocytes (fat cells) and the cutaneous nerves in skin. It is thought these three cells could play interesting, but as yet unknown roles in wound repair, which may aid repair or be pathological. I will use live imaging in the translucent zebrafish to look at how these cells interact with inflammation, and what signals may cause this. This work could reveal the impacts of inflammation at the wound repair site, which could have impact on wound treatment in the clinic.


PhD Studentship (Basic)

The Human Gut Microbiome as a Modifier of Human Health My project will aim to investigate the role of the human gut microbiome in health and disease outcomes, in particular to assess its role in the link between dietary composition and obesity. The human gut microbiome is a huge community of microorganisms that exist within our digestive systems that interact to aid digestion, protect against pathogens and create metabolites. Although previous evidence suggests the gut microbiome plays a role in health and diseases, much of the literature (arising from animal or observational human studies) attempting to assess this relationship has so far been inconsistent and unable to prove cause-and-effect relationships. I aim to combine epidemiological, genetic and causal inference methods to establish relationships between dietary composition and the microbiome and between the microbiome and health outcomes (focusing on obesity). Dietary composition is one of the key exposures dominating the literature as a likely regulator of the gut microbiome, with a diet high in dietary fibre for example being correlated with high microbial diversity. Lower microbial diversity has been observed in the gut of people with obesity, amongst other diseases. By filling the gaps in the evidence, this research has the potential to be translated into clinical practice and industry.


PhD Studentship (Basic)

Dissecting causal relationships and molecular mechanisms in disease using genetic risk profiles Many common diseases such as obesity, diabetes and hypertension are caused by a combination of genetic, environmental and lifestyle factors. Better understandings of the causal factors of complex diseases may aid disease prevention and health research. Conventionally, studies on disease causal factors rely on health intervention experiments which cost enormous time and labour. The recent availability of large-scale databases, which contains genetic, lifestyle and disease information on tens of thousands of individuals, allows researchers to construct polygenic risk scores (PRS) to represent individuals’ genetic liability to develop a trait or disease. This score could be used to investigate disease causal factors in Mendelian randomisation (MR) analyses, a genetics-based approach analogous to a randomized controlled trial. My PhD will involve constructing and analysing the PRS for complex diseases and generating a large resource of PRS and MR results which we plan to share with the scientific community. I will improve the method of PRS constructions and develop analytical pipelines to identify causal modifiable risk factors for diseases, key genes and pathways underlying disease mechanisms. Furthermore, I will also assess the capability of PRS to predict causal risk factors during childhood which may therefore have important implications for preventing later life disease.


Innovator Award

Prof Guillaume Lessene, Dr Melissa Call, Prof Marc Pellegrini

Walter and Eliza Hall Institute of Medical Research

Development of small molecule inhibitors of the SARS-CoV-2 protease PLpro for the treatment and prevention of Covid-19 The SARS-CoV-2 pandemic is a global health emergency that highlighted the need for new antiviral medicines and better pandemic preparedness. Our drug-discovery program focusses on a critical protein present in all coronaviruses, the papain-like protease PLpro. PLpro is essential for viral replication, but also stops our alarm systems to respond to viral infection, To achieve the latter, it removes ‘ubiquitin’ and ubiquitin-like signals required for inflammation and anti-viral signalling. Our world-leading experts in ubiquitin research, drug-discovery and infectious disease biology have leveraged our state-of-the-art facilities to identify new drug candidates to block PLpro. We have screened  > 400,000 small molecule compounds and identified new chemical scaffolds that inhibit PLpro from SARS-CoV-2 without affecting human enzymes. Our program will deliver new antivirals to prevent or treat COVID-19 and also develop a library of efficacious drug candidates to combat future coronavirus outbreaks


Innovator Award

Prof David Porter, Dr Alex McConnachie, Dr Natasha Fullerton, Dr Shajan Gunamony, Prof Keith Muir

Development of in-vivo 19F Clinical MR imaging Using a Novel 19F/1H Coil in Combination with an Intravenous Perfluorocarbon (ABL-101) Inflammation is part of the body's defence system against a wide range of harmful stimuli.
Inflammation also plays an important role in human diseases, including stroke, Alzheimer's,
hardening of arteries, arthritis, and cancer. The ability to image inflammation inside the
human body would provide an improved understanding of this process and provide new
opportunities for diagnosing disease and guiding treatment. ABL-101 is a fluorinated oxygen
carrier which is being investigated for treatment of stroke. It is made up of a large number of
fluorine atoms that can be visualised in MRI using a detector that is tuned to fluorine (19F
MRI). Once injected, cells that are also part of the inflammatory response (macrophages)
take up ABL-101. ABL-101 could therefore be an imaging agent for inflammation. 19F MRI
uses a specially developed radiofrequency coil and some specialised programming that Dr
Santosh and the team at the University of Glasgow wish to assess as a vital step to
developing clinical uses.


PhD Studentship (Basic)

Investigating Intracellular Processes in Macrophages During Candida albicans Infection While most fungal infections are cleared by the immune system in healthy individuals, in immunocompromised people or in patients after invasive medical procedures these pathogens can cause life threatening systemic infections. With mortality rates around 50%  our current treatments are insufficient. Thus, research to better understand these infections is required.

Candida albicans is the most common human fungal pathogen and a frequent cause of hospital acquired infections. Macrophages are one of the first cells in our immune system to identify Candida and initiate an antifungal response; but how infection affects intracellular processes in macrophages is not completely understood.

I intend to further investigate which intracellular processes are altered during Candida infection. In previous work, we studied the total proteins in macrophages during infection, and we found Candida infection appeared to dysregulate an oxidative stress mechanism, Nrf2/Keap1, in a novel way. We plan to further study this mechanism, as well as more broadly look for novel mechanisms of regulation. This project will contribute to understanding our immune system’s functional response to fungal infection and will bring us closer to creating new therapeutics to prevent systemic fungal infections.


PhD Studentship (Basic)

Structural and molecular investigation of neuronal adenylyl cyclases underlying synaptic plasticity Long-lasting changes in strength between synapses are a key element of learning and memory. The intracellular second messenger cyclic AMP (cAMP) plays a key role alongside Ca2+ in coordinating such synaptic plasticity. cAMP signalling operates in localised ‘nanodomains’ that are centred on the enzymes that synthesize cAMP – adenylyl cyclases. In neurons, two Ca2+-sensitive cyclases (AC1 and AC8) are particularly important in signalling underlying synaptic plasticity. These enzymes are relatively understudied, partly due to technical hurdles.

I will take advantage of novel crosslinking approaches, and state-of-the-art mammalian cell expression systems to overcome these hurdles and study the enzymes in three ways. First, I will use crosslinking of extracts from rat cerebellum (where the cyclases are abundant) to identify and characterise their molecular interactions. Second, I will employ inducible expression in suspension cultures of mammalian cells to express large amounts of the cyclases. This will enable me to study their three-dimensional structure – a key step in fully understanding their function. Third, I will use a high-throughput assay to screen for novel ligands of neuronal cyclases. This multidisciplinary approach will address a basic element of neuronal signalling that is critical in brain regions including the cerebellum, hippocampus, and the striatum.


Clinical Trial Community Engagement Lab

Discretionary Award - Public Engagement

Clinical Trial Community Engagement Lab Community engagement is an essential component in clinical trials, and it is regarded as an ethical requirement of most ethics review committees before the trial protocols can be approved.  However, there is a scarcity of studies that have objectively assessed the impact of best engagement practices on recruitment and retention rates.

Using an in-depth review of the literature, in-depth interviews, and focus group discussions with relevant stakeholders, we will develop clinical trial community engagement best practices. We will then establish and pilot an implementation assessment tool that would be used to assess the extent of implementation of these practices.  Finally, we will conduct a randomized controlled study to assess the efficacy of best practices on the recruitment and retention rates of clinical trials in a randomized controlled trial, where trials in the intervention arm will be assigned to implement the new best practices, and control trials will implement their originally planned engagement approaches. The implementation assessment tool will be used to measure the extent of adherence to the newly established best practices in both arms. We will then assess the enhancers and barriers to the successful implementation of clinical trial best community engagement practices.


Discretionary Award - Vaccines

Ready2Respond, a public-private collaborating platform to address pandemic preparedness gaps in lower income countries Early 2019, a group of global health leaders with expertise in influenza, vaccinology and pandemic preparedness convened  in London, for a Wellcome Trust-supported "Shaping Meeting to explore the value of a coordinated work plan for epidemic and pandemic influenza vaccine preparedness." Ready2Respond was formed as a global collaboration of partners committed to enhancing lower income countries’ readiness to respond against influenza and respiratory viral pandemics. With a Secretariat established at The Task Force for Global Health, Ready2Respond identified challenges and actionable solutions to promote pandemic preparedness. Though initially based on influenza preparedness, these priorities now include COVID-19.

Three Expert Working Groups will design and execute cross-collaborative projects within three strategic priorities.

 Burden of Disease
 Risk Communication and Community Engagement
 Vaccine Access

Ready2Respond seeks an initial grant from the Wellcome Trust of US$ $196,650. This initial grant will allow to:

 retain a Director, tasked with developing a comprehensive action plan with potential projects to start in 2021.
 execute a mapping study of organizations and agencies working on global seasonal and/or pandemic vaccine preparedness to ensure the relevance of Ready2Respond’s mission and activities in the preparedness ecosystem.
 support communication activities to secure funds for identified projects from potential partner organizations.


Sir Henry Dale Fellowship

Royal Society/Wellcome Trust Sir Henry Dale Fellowship

Sir Henry Dale Fellowship Interview Committee

Controlling thymus function to improve T-cell immunity in the aged. Effective adaptive immunity is dependent on T-cell development in the thymus. The thymus undergoes age-related involution, leading to reduced T-cell output. This is suggested to compromise T-cell immunity and increase risk of disease severity in the elderly. However, it was unknown whether enhancing thymic function would ameliorate the immune defects observed in the elderly.

Transcriptional assessment of thymic epithelial cells (TECs) through development facilitated the generation of genetically altered mouse models in which thymic involution was prevented or reversed. Both models restored normal peripheral T cell populations, and, critically, enhanced the survival of aging hosts when challenged with Toxoplasma gondii. Therefore, TEC-mediated restoration of thymic function improves immunity with age.

Based on these findings, I propose to identify progenitor-successor relationships within adult TECs that maintain the adult thymus and identify age-associated alterations in these populations that could contribute to thymic atrophy. Moreover, I will investigate the mechanisms by which restored thymus function improves immunity in aged mice. Collectively, my proposal will provide an important understanding of how TECs shape immune responses in the elderly, and inform TEC-mediated approaches of thymic regeneration to aid prevention of the degeneration of T-cell immunity that accompanies aging.


Sir Henry Dale Fellowship

The origins of individuality in the Drosophila visual system Why are all brains different from each other and where does this variability come from? A plethora of animal experiments demonstrate the importance of environmental and genetic influence in creating behavioural variation. A third factor named stochastic developmental processes is less established. Despite recent advancements, a systematic review of variation in brain wiring, its origins, and behavioural consequences is still lacking.

My main research goal is to understand the contributions of genetic, stochastic, and environmental factors to variation in brain wiring and behavioural individuality. Recently, I have shown that stochastic, non-heritable developmental processes can result in individually variable wiring diagrams that are associated with individual behavioural characteristics. This system provides a tractable genetic and neuronal model for individuality.

Based on this work, I hypothesize that (1) stochastic developmental processes are a general neuronal property affecting synaptic distributions, wiring and behaviour, and (2) that stochastic wiring differences affect several behaviours ranging from visual guided responses to circadian activity patterns. Within this framework, I aim to answer two key questions on the origins of individuality:1. Is circuit variability a general nervous system property and what are its origins? 2. Does circuit variability contribute to other visual and non-visual behavioural paradigms?


Sir Henry Dale Fellowship

Dissecting robustness mechanisms via signalling adaptation and trafficking plasticity during developmental and pathological cell migration Robustness mechanisms are ubiquitous in biological systems where they act to ensure a stable outcome despite intrinsic (genetic) and extrinsic (environmental) variabilities. However, the underlying mechanisms are often unclear. In my proposed research, I will investigate the mechanistic basis of how systems deal with change in the context of cell migration during development, immune responses, and cancer invasion. Cell migration models I will use for my study include: the posterior lateral line primordium (pLLP) migration in development and macrophage recruitment during wound immune response in zebrafish, and invasion of cultured cancer cells.

The main goals of the proposed original project are: (1) Characterizing the molecular mechanisms and network architectural designs that enable robust adaptation during cell migration in a multicellular organism, (2) Analysing the requirement of regulated membrane trafficking switching during chemotactic adaptation, and (3) Quantitatively defining the role of dynamic buffering in breast cancer spreading.

To achieve these goals, an interdisciplinary approach will be taken, combining live imaging, genetics, biochemistry and phosphoproteomics. I will generate datasets bridging molecular, cellular, and tissue scales to obtain a systems level understanding of adaptive responses. This work will have broad implications for understanding chemotactic adaptation in development, physiology and disease.


Sir Henry Dale Fellowship

The roles of modern and ancestral visual pathways in the mammalian brain, for defensive behaviours and spatial navigation In order to survive, animals need to avoid predators and skillfully navigate the environment. These behaviors critically depend on the sense of vision. In mammals, two distinct systems process visual information: the evolutionarily ancient superior colliculus and the modern visual cortex. We will define their relative functions in two natural behaviors essential for survival: (1)innate defensive responses and (2)spatial navigation.

1)We will study the visual cortex's role in controlling innate defensive behaviors triggered by the superior colliculus. We will focus on the mouse postrhinal-cortex (POR), capitalizing on my discovery that the superior colliculus has, through POR, a dedicated cortical space from which it receives direct excitatory feedback.(Beltramo,Science,2020). We will test the hypothesis that POR, relaying contextual information about the estimated threatening nature of visual stimuli, controls collicular function's plasticity. By silencing distinct cortico-collicular projections, we will determine how the visual cortex shapes the flexibility of colliculus-mediated innate behaviors.

2)We will investigate the contributions of the two visual pathways in spatial navigation, studying how visual input is transformed into the spatial maps found in the entorhinal/hippocampal formation. Perturbing the activity of distinct visual streams, we will establish how the superior colliculus and visual cortex influence the internal maps that guide navigation.


Sir Henry Dale Fellowship

Placental epigenetic programming: elucidating a role in cellular identity and transcriptional plasticity Pregnancy complications affect as many as one in four pregnancies, yet there remains a critical gap in our knowledge of their underlying aetiologies. As the maternal-foetal interface, the placenta is essential for healthy pregnancy, with poor function being strongly associated with pregnancy complications. However, there is little mechanistic understanding of the molecular events regulating placental development. My research programme will investigate mechanisms of epigenetic programming and gene regulation in early placental trophoblast and reveal how these underpin the development of a functional placenta. Specifically, I will test the hypothesis that epigenetic programming in placental trophoblast is critical for (1) setting up the gene regulatory landscapes in placental cell types and (2) directing appropriate differentiation during placentation. I will apply cutting-edge ultra-low input sequencing methodologies to characterise gene expression, epigenetic marks, transcription factor binding and 3D chromatin folding in multipotent trophoblast cells in mouse embryos. Using single-cell sequencing and histopathology, placental genomic regulation and function will be evaluated in knockout mouse models for epigenetic modifiers, including several histone and DNA methyltransferases. This research will be fundamental to our understanding of placental development and provide novel insights into how errors in epigenetic programming can lead to compromised placental function in pregnancy.

Grants awarded from 1 October 2005 to 30 June 2021

Gene Expression Regulation, Developmental


The mechano-biology of cell division

Sir Henry Dale Fellowship

The mechano-biology of cell division Cell division in epithelial sheets is crucial for tissue renewal, yet unchecked division leads to tissue dysplasia and ultimately cancer. The aim of this project is to discover how cell division is regulated in normal epithelial tissue and how it is perturbed by oncogenic mutations to disrupt tissue integrity. In previous work, I showed how activation of an oncogene, Ras, directly impacts cell division by controlling the shape, contractility and mechanics of single mitotic cells. I now ask how this finding plays out in a complex tissue environment. To do this, I will employ a multi-disciplinary approach, combining imaging and quantitative cell biology with biophysical techniques to study cell division mechanics in normal epithelial monolayers and Ras-mutant pancreatic cancer tumoroids. I will ask how the actin cytoskeleton is regulated during epithelial cell division to permit dynamic cell shape changes while maintaining cell-cell adhesion and preserving barrier function. I will determine how k-Ras activation perturbs this, identifying key mechanistic links between Ras/ERK-dependent transcription and morphological phenotypes. Finally, I will address how these Ras-induced changes to cell division alter the growth and organization of 3D tissue structures in pancreatic cancer.


Coronavirus

Prof Willem Hanekom, Dr Lynette Oyier, Honorary Professor Robert Wilkinson, Prof Stephen Gordon

National COVID Testing Africa AAPs/Centre Aims and key deliverables;

 To provide consistent technical support to national testing programmes for SARS-CoV-2 in Kenya, Malawi and South Africa.
 To support epidemiological research, clinical trials, immunological studies and genomics work
 To consolidate and maintain positive relationships with national policy makers.

Our respective Wellcome AAPs/Centre (i.e. MLW, KEMRI-Wellcome, AHRI and CIDRI-Africa) have responded to the COVID-19 pandemic by making resources and staff available for SARS-CoV-2 testing, accounting currently for significant proportions of the local and/or national testing capacities, especially during surges.  It is ethically imperative to provide national support alongside research-driven testing, and we have found this testing provided an opportunity to develop stronger relationships with national Government, with the potential for research that is better aligned to informing policy and with a better position to communicate.  The immediate need has been covered by re-allocating resources for paused activities.  The proposal here will bridge the gap between our immediate response and more sustainable long-term funding. This will allow us to sustain the enhanced relationships developed through our response to the pandemic, and will avoid the reputational risks that might be associated with failing to support the obvious ongoing need while establishing more sustainable long-term projects and core provisions.


Sir Henry Dale Fellowship

Dissecting the molecular basis of single gene choice in African trypanosomes      Several pathogens, such as African trypanosomes or malaria parasites, undergo antigenic variation in order to evade the host immune response. A key feature for successful antigenic variation is the ability to express a single antigen at a time, in other words monogenic-expression. Trypanosomes express a single variant-surface-glycoprotein (VSG) from thousands of possible genes, a fine example of extreme biology.

     Single gene choice remains one of the biggest mysteries of eukaryotic gene expression and the machinery responsible remained elusive in every organism. I recently identified a protein complex that sustains VSG-monogenic expression and is responsible for the spatial integration of the single active-VSG with an RNA-processing centre. I will study the function of this novel protein complex, identify other relevant factors and use VSGs as a model-system to study how nuclear compartments can be organised to enhance gene expression. To pursue these questions, I will apply a wide range of genetic and biochemical approaches that include proximity labelling coupled with mass-spectrometry, next-generation-sequencing, CryoEM, super-resolution and live microscopy.

     The mechanistic understanding of how monogenic-expression is initiated and maintained is of great value as it is critical for sustaining infections by trypanosomes, as well as several other pathogens that undergo antigenic variation.


Sir Henry Dale Fellowship

Understanding the role of myosin super relaxation in cardiac health and disease A novel energy conserving mechanism, myosin super relaxation (SRX) has recently been discovered in cardiac muscle. SRX is a structural state of myosin, where myosin heads are folded away from actin, preventing force producing actomyosin interactions and contraction.

Little is known about the key regulatory systems that govern the formation of myosin SRX in cardiac biology. It is evident that phosphorylation of key sarcomeric proteins play an important role, but the cellular signalling that underlies these changes is poorly defined.

I aim to define these cellular signalling pathways and how they control sarcomeric protein phosphorylation. I will define how far reaching myosin SRX destabilisation is as a disease causing mechanism. To do this I will employ CRISPR/Cas-9 technologies to develop stem cell models of hypertrophic cardiomyopathy, HCM, a debilitating genetic condition that affects 1 in 500 people. I will augment these human stem cell models with human and murine tissue samples to define SRX abundance and regulation in acquired cardiovascular conditions including atrial fibrillation, heart failure, hypertension, myocardial infarction, and ageing.

In doing so I will define sub-sets of disease pathomechanisms in inherited and acquired cardiomyopathies to allow precision targeting of therapeutics, which will bring significant benefit to patients.


Sir Henry Dale Fellowship

Healthy, sustainable and equitable: Integrating knowledge on food choice to optimise interventions Changing diets could lead to substantial benefits both in terms of health and environmental impact, with the urgent need to change food consumption being increasingly recognised. Drawing on evidence from interventions targeting unhealthy diets could accelerate progress towards more sustainable diets by quickly narrowing down the choice of interventions to improve food selections. However, we need to ascertain whether key differences between healthier vs. more sustainable foods (including social norms, preferences and knowledge) impact on intervention effectiveness, and/or contribute to inequalities in responsiveness to these interventions.

This programme of work will examine differences in the impact of interventions targeting (a) healthier vs. less healthy foods and (b) more vs. less sustainable foods, and whether impact differs by socioeconomic position (SEP). It will identify key moderators and mediators of the impact of interventions, and the extent to which these contribute to any differential impact by intervention target or SEP.

The programme comprises (1) a conceptual review; (2) experimental studies; (3) field studies in worksite cafeterias and in stores; (4) secondary analyses of purchasing data (e.g. from supermarkets). Identifying the moderators and mediators of dietary interventions will help prioritise the most promising interventions for sustainable and equitable diets.


Investigator Award in Science

Transmissible cancer evolution and host interaction Transmissible cancers are malignant somatic cell lineages that spread between individuals by the allogeneic transfer of living cancer cells. These cancers, whose three known instances in mammals affect dogs and Tasmanian devils, provide a unique perspective on cancer evolution and host interaction. I will investigate this by deeply sequencing whole genomes from 1100 tumours selected from across each cancer’s range, together with matched bulk RNA sequencing and targeted single-cell RNA sequencing. Time-resolved phylogenetic trees for each clone will be annotated with mutation and gene expression data, and the source and consequence of mutation explored. Host cell contribution to the tumour microenvironment, and its variation across hundreds of tumours, will be assessed using allelic and cell-type deconvolution. Combining genetic, microenvironment composition and clinical data, I will explain how the immunological interface between allogeneic cancer and host varies between individuals, and how this interaction controls the outcome of disease. The inherent heterogeneity and short lifespans of most cancers may obscure their underlying biological patterns. By capturing variation in hundreds of clonally derived tumours inhabiting different hosts, I seek to deeply probe the mutational, evolutionary and immunological principles of cancer.


Sanger Resource Collaboration


PhD Studentship (Basic)

Differential immune transcription in health and disease In immune conditions such as sepsis, treatment options can be limited by a lack of understanding of the causes of the condition, as well as the vast differences in how the immune system of the patient can respond. While expression differences between genes explain some of the variance between patient outcomes, there is still a lot of variability unaccounted for, and how this relates to the genome remains to be studied. RNA sequencing performed on samples from large existing cohorts of patients will give transcript level information, revealing not only the expression levels but also information such as how the genes are differentially spliced between individuals. With paired medical records I will relate these observed transcript differences with patient outcomes, as well as infer how innate genotypes can modulate these effects. Provided microbiological information on the cause of the condition or infection will allow me to also understand the differences in human responses to infection type. This knowledge will lead to a more personalised treatment regime for patients based on the course of their illness and innate characteristics, as well as giving the option to better predict and address the cause of their illness.


PhD Studentship (Basic)

Beyond GWAS: Exploring complex disease with WGS and scRNA-seq Inflammatory bowel disease (IBD) is a disease of the gut affecting over 2.5 million people in Europe alone. Through genome-wide association studies, over 240 genomic regions have been identified as significantly associated with the disease or its two subtypes: Crohn’s disease and ulcerative colitis (1,2). However the mutations, genes and cell-types that drive disease progression, are still unknown and for many patients, IBD remains incredibly difficult to treat. The Anderson group has undertaken two distinct, large-scale projects in an effort to fill in many of the gaps in existing knowledge. Firstly, whole genome and exome sequencing of large cohorts of healthy and diseased individuals is being undertaken to better understand the disease-associated regions. During my PhD I will use this data to examine the effect that deletions, insertions and inversions of large chunks of DNA can have on IBD. The second major ongoing project is single-cell sequencing of terminal ileum, rectal and blood samples taken from healthy individuals and patients with Crohn's disease. In the second half of my PhD project, I will use the single-cell data to determine the genes, pathways and cells involved in Crohn’s disease.


PhD Studentship (Basic)

Four-Year PhD Studentship in Basic Science  UNS118254 Metabolic health depends on a myriad of genes and the environment. Variation in these genes across individuals can predispose them to obesity, Type II Diabetes (T2D) and other metabolic syndromes. Early works focused on how a few mutated genes could cause rare and severe metabolic diseases. A lot has been learnt about appetite and weight regulation by studying those genes whose mutations have large impact on metabolic health. However, common forms of obesity and T2D are attributed to multiple genetic variations, whose individual effects are hard to observe. We aim to understand how these mutations with little observable impacts affect our metabolic health. We hope to gain more insights into the fundamental genetics of metabolism from these rare mutations by combining data-driven epidemiological methods and molecular biology techniques. Epidemiological methods will statistically identify how the presence of some mutated genes correlate with alterations in metabolic health. Then, using molecular biology techniques, we will investigate the causations and mechanisms of these statistical correlations. To this end, we will clone the mutated genes in cellular models and measure the changes in their activities.


PhD Studentship (Basic)

Mechanisms and regulation of PEPITEM secretion The migration of immune cells such as T-lymphocytes to areas of inflammation plays an important role in the inflammatory response. T-lymphocyte migration follows a circadian (daily) rhythm, with more T-lymphocytes migrating into tissues in the morning than the evening. If this process is not carefully regulated, this can lead to an exaggerated inflammatory response which contributes to diseases. PEPITEM is a small peptide hormone which inhibits T-lymphocyte migration and is made by another type of immune cells, B-lymphocytes. Patients with inflammatory diseases cannot make PEPITEM in sufficient quantities to control T-lymphocyte migration. Our preliminary studies indicate that a protein able to cleave other proteins (protease) is responsible for PEPITEM release from B-lymphocytes and that this might be under circadian control. In my project, I aim to identify the protease that leads to PEPITEM release, and investigate how the PEPITEM pathway follows circadian oscillations. I will look at the expression of genes and proteins involved in the PEPITEM pathway at different time of the day to see how this pathway is regulated by circadian rhythms. This project will help to understand the dysregulation of inflammation that occurs in many chronic inflammatory diseases.


Not available

Discretionary Award – C&S

Climate, Health and Behaviour – A One Year Research and Development Grant. Not available


PhD Studentship (Basic)

A Multifunctional Genetic Probe for Networking Lysosomal Calcium Biology The lysosome, once thought to be a cellular ‘trash-can’, is now found to be the key to understanding the signalling controlling human ageing, neurodegeneration, and a range of diseases from diabetes to cancer. Developing tools to understand how the lysosome works will be key to future biological studies.

In this project, we will develop and analyse a new imaging probe which will allow us to examine calcium signalling in functional lysosomes in live-imaging, proteomic and lipidomic modalities to develop a fine-grained understanding of how lysosomes function in health and disease.

The genetic probe we are developing makes it easy to isolate, image, and manipulate lysosomes in living cells and in cellular extracts using one transfectable tool, offering many avenues of application to basic and industry-focused research. One key regulator of lysosomal calcium storage is the messenger NAADP, which we will examine in detail. We will produce coordinated maps of the behaviour of calcium levels inside the lysosome under conditions known to alter NAADP signalling, coupled with the metabolic and proteomic profiles of lysosomes in the same conditions and in mutants of the muscular dystrophy gene INPP5K: giving a comprehensive map of the regulation of this key signalling axis.


PhD Studentship (Basic)

Characterisation and modulation of CTLA-4 trafficking: Focus on reversible ubiquitylation  Cancer immunotherapy harnesses the potency of the immune system to reinvigorate anti-tumour effects. CTLA-4 is a protein that acts as a brake on the immune system; blocking CTLA-4 can disengage the brake on immune cells, thereby freeing our immune system to attack tumours.  Although therapies entailing a CTLA-4 blockade has led to promising results, they have yet to achieve their full clinical potential. To improve CTLA-4-targeting treatment, a thorough understanding of CTLA-4 function at the cell biology level is essential. Modulating the number of CTLA-4 present on the surface of immune cells is an emerging therapeutic strategy in cancer immunotherapy. Generally, protein levels at the cell surface are controlled by two major events: protein internalisation and transport to the cell surface. Very often, internalised proteins that will be degraded by the cell’s "garbage disposal system" are temporarily tagged by ubiquitin, which will later be removed by an enzyme. Here, we aim to explore how CTLA-4 traffics in the immune cells by 1) identifying the key proteins that regulate CTLA-4 levels on the cell surface and 2) characterising the enzymes that control CTLA-4 degradation using state-of-the-art screening approaches.


PhD Studentship (Basic)

Decoding the enigma of PhosphoUbiquitin and PINK1 Mitochondria are organelles within cells which are responsible for energy production. High energy demands or cellular stress can result to dysfunctional mitochondria. When mitochondria become damaged, they should be removed, in order to keep cells healthy. Cells have complicated mechanisms for recognizing and successfully destroying damaged mitochondria, as well as other dysfunctional organelles and proteins. The aggregation of dysfunctional organelles or proteins is the hallmark of many neurodegenerative diseases. A main degradation system in cells is autophagy, which essentially means self-eating, during which the damaged cellular components are isolated in a vesicle to be broken down. The autophagy of mitochondria is called mitophagy. The first step for mitophagy is the ‘decoration’ of mitochondria with a protein called ubiquitin. Ubiquitin in several cases acts a signal for degradation not only for damaged mitochondria, but for other dysfunctional organelles and proteins. In mitochondria, specifically, the addition of phosphate in ubiquitin is critical for initiating their degradation. Here, we want to define if these phosphoubiquitin tags are also found in proteins outside of mitochondria, and which proteins are capable of recognize these unique tags. These experiments will help us to understand deeper the fundamental process of mitophagy, which is disordered in Parkinson’s disease.


PhD Studentship (Basic)

Functional characterisation of CYP2C9 variants of uncertain significance The liver is the main site for the elimination of medicines taken by people (a process termed drug metabolism).  There are many enzymes involved in drug metabolism – one of these is cytochrome P450 2C9 (CYP2C9). CYP2C9 metabolises approximately 13% of all clinically used medications.  One example is warfarin [1].

The activity of CYP2C9 varies between individuals which can affect drug efficacy and increase the likelihood for adverse drug reactions [2–4].  This is due to several factors including concurrent disease and the intake of other medications.  Genetic factors also affect the activity of CYP2C9 – these are termed genetic polymorphisms.  The function (i.e. whether they increase or decrease activity of CYP2C9) of almost half of these polymorphisms is not well-defined [5]. Preliminary work performed in the Pirmohamed lab has identified 16 high impact (e.g. frameshifts), 159 moderate impact (e.g. missense variants) and more than 8000 non-coding variants.

The key goals of the project are:

 Correlate genetic variation in CYP2C9 to clinical outcomes using the UK BioBank, 100K Genomes Project and a well-characterised warfarin cohort
 Assess the effect of genetic variants on metabolomic parameters
 Prioritise variants for in vitro functional studies using CRISPR-Cas9, with effects on metabolism evaluated using LC-MS


PhD Studentship (Basic)

Investigating the cytoprotective role of NRF proteins against drug-induced cardiovascular toxicity Many drugs used to treat cancers and HIV cause life-threatening heart problems which limits their use. Research into how to reduce this risk has previously been difficult due to a lack of experimental methods which accurately mimic the human cardiac system. However, new 3D human-cell models have been developed which reproduce the adverse drug reactions seen in patients. These new models have been used to show that increased expression of an important protective protein NFE2L (NRF2), provides protection from the toxic effects caused by a commonly used breast cancer drug. We believe that by increasing the activity of human NFE2L proteins (NFE2L1-3), we may protect cardiac cells from other adverse drug effects. Here, we will combine 3D human cardiac models with gene editing methods and advanced cell imaging techniques to manipulate expression of all NRF family proteins and monitor the protective effects under normal and high-glucose conditions, which are known to reduce the protective effects of NRF2. The results from this study will aid the development of new therapeutic strategies to prevent or reverse heart toxicity from commonly used cancer and HIV drugs.


Investigator Award in Science

Evolutionary epigenetics of X-chromosome inactivation How epigenetic pathways regulate development and disease remains a major question in human biology. A remarkable paradigm for understanding epigenetic mechanisms is X-chromosome inactivation, the silencing of one X chromosome in females (XX) that equalises X-dosage with males (XY). X-inactivation in eutherian (placental) mammals is mediated by the non-coding RNA (ncRNA) Xist. How Xist silences the X chromosome, and how expression of Xist is regulated, remain poorly understood. Marsupials diverged from eutherian (placental) mammals 160 million years ago, and exhibit distinctive developmental features that make them ideal for studying development and disease. Using our colony of opossums, we identified RSX and XSR, the marsupial equivalents of Xist and Tsix, providing a comparative system for understanding RNA-mediated chromatin remodelling. In this proposal, we will deploy the opossum model system to identify deeply conserved epigenetic mechanisms regulating mammalian X-inactivation and X-chromosome reactivation, and to elucidate how they interface with global epigenomic changes in the early embryo and germline. Our datasets will shed light on the evolution of mammalian lineage specification, pluripotency, imprinting and germline development. We will apply genome editing to marsupials for the first time, accelerating discovery in other research fields, including cancer biology, neurobiology and infectious disease.

Grants awarded from 1 October 2005 to 30 June 2021


Senior Research Fellowship

Regulation of immune signalling via ubiquitin-mediated receptor degradation Immune receptor turnover and subcellular localisation are regulated by attachment of ubiquitin, which controls receptor internalisation and endosomal-lysosomal degradation. Receptor ubiquitylation is fine-tuned by ubiquitin-processing enzymes, ligands and adaptor proteins, which regulate immune signalling output in a spatio-temporal manner. We identified a new signalling complex called BRISC, which is a deubiquitylase (DUB) and required for recycling of interferon and Toll-like receptors (TLRs). BRISC partners with adaptor proteins SHMT2 and EPS15 to regulate interferon and TLR signalling, although the role for each adaptor is unclear.

My laboratory uncovered a fascinating molecular mechanism by which vitamin B6 regulates BRISC activity, thus revealing a new example of metabolic control of immune signalling. Here, we aim to uncover how BRISC activity is controlled and directed to immune receptors. Using an integrated structural biology approach we aim to understand how BRISC partners with new adaptor proteins to perform its functions. Using BRISC-selective chemical probes in cell-based assays we aim to ascertain BRISC’s role in elevated inflammation in normal and disease conditions. These new tool compounds represent an exciting opportunity to better understand BRISC activity, receptor degradation and immune signalling functions, and how DUBs can be exploited as therapeutic targets for autoimmune diseases.


Investigator Award in Science

Predicting Acute and Post-Recovery Outcomes in Cerebral Malaria by Optical Coherence Tomography  Severe brain swelling leads to death in cerebral malaria (CM) but detection requires MRI. Almost no children with CM have access to MRI, therefore an alternative is required to identify patients for intervention. Optical coherence tomography (OCT) can detect raised intracranial pressure and ischaemic injury by imaging the optic nerve head, and retina respectively. We aim to study OCT as a method to identify patients at risk of death from brain swelling and disability from ischaemia; and to develop a low-cost OCT device with integrated AI image analysis.

We will conduct a controlled cohort study of 120 children with CM in Malawi to compare OCT to MRI in detecting severe brain swelling. We will follow them for a year with neuro-developmental assessments to investigate retinal OCT in predicting neurological deficits; and correlate retinal and cerebral atrophy. We will also assess OCT in quantifying raised intracranial pressure in non-malarial coma, and retinal haemorrhages for predicting worsening of brain swelling in CM.

We will use fibreoptic and micro-electromechanical advances to develop handheld OCT design and make a low-cost, robust device suitable for malaria-endemic settings. We will develop AI techniques to automatically segment and quantify optic nerve head swelling and intraretinal hyper-reflectivity (ischaemia).


Investigator Award in Science

Defining the functional basis of the enhanced survival and replication of African Salmonella in human phagocytic cells Invasive non-typhoidal Salmonella disease (iNTS) has emerged as a major killer in sub-Saharan Africa, responsible for ~500,000 deaths since 20091. The disease primarily affects people who are immunocompromised by HIV, malaria, anaemia or malnourishment2, and has a high case-fatality-rate (14.5%1).

In Africa, iNTS is caused by one clade of S.Typhimurium and two clades of S.Enteritidis3–5. Despite many decades of research on gene function and infection biology of Salmonella, the pathoadaptive mutations that have driven the emergence of African clades are unknown. Such knowledge is vital to decipher iNTS pathogenesis and develop control strategies in the future.

To address this knowledge gap, I will decipher the mechanisms that African and gastroenteritis-associated Salmonella employ to survive and replicate within a core niche, human phagocytic cells. I will achieve this using our powerful combination of comparative genomics and transcriptomics, plus new innovations in experimental evolution and genome-wide, high-throughput fitness assays.

By understanding the molecular basis of the intra-macrophage lifestyle, I will determine whether these neglected African-Salmonella pathovariants have used common or divergent approaches to combat the antibacterial properties of human cells.

My Research Question is:

How do African Salmonella pathovariants survive and replicate so effectively in human macrophages?


Discretionary Award – C&S

Putting bioethics at the heart of WHO and beyond The WHO Global Ethics Unit is part of the newly formed Science Division and would like to capitalize on the potential of the division and the global leadership shown by the team during the current COVID-19 pandemic, to truly embed ethics at the heart of decision-making at WHO.

This proposal focuses on adding value to our current work programme. Additional technical and coordinating capacity will allow us to better leverage our vast bioethics networks and collaborative partnership with bioethics groups around the world to: support regional and in-country bioethics capacity needs; further develop a community of ethics experts; develop the global ethics agenda and focus on key areas of unmet or continuing need, including health emergency preparedness and response. Additional resource will also allow us to be more responsive to demand set by the WHO and global research and health communities.


Investigator Award in Science

Mitochondrial dynamics in CNS health and disease The tight regulation of mitochondrial transport and anchoring in brain cells is essential for providing ATP at the correct spatial location to power neural function and computation, and for providing calcium buffering at sites of calcium entry or release. Using a multidisciplinary approach, combining imaging, biochemistry, electrophysiology and mouse transgenics we will determine the molecular and cellular mechanisms by which the cytoskeleton coordinates mitochondrial transport, localisation and remodelling in neurons and glial cells. The influence of this regulation on the development and maintenance of neuronal connectivity, function, plasticity and pathology will then be determined in vitro and in vivo. The main objectives are to define (i) the role of Miro proteins as central coordinators of the activity-dependent transport, positioning and remodelling of mitochondria through the microtubule, actin and septin cytoskeletons; (ii) how mitochondrial position and calcium buffering in neurons and glia impacts the formation, maintenance and plasticity of synapses; and (iii) the mechanisms by which disrupted mitochondrial dynamics lead to neuronal pathology and neurodegeneration. Our proposal will provide unique insight into how mitochondrial networks in neurons and astrocytes contribute to regulating the operation and plasticity of synapses and how their disruption leads to neuronal pathology in brain diseases.


RNA processing and degradation

Principal Research Fellowship Renewal

RNA processing and degradation All living systems – cells or organisms – operate in and must adapt to constantly changing environments. RNA transcription, processing and assembly with protein complexes form the core of the gene expression system, but many key features remain unclear. At times, very substantial changes take place; for example, in response to sudden environmental changes, following infection or during developmental progression. To address unresolved questions in RNA biology, we developed biochemical techniques to identify key, relevant RNA-protein, RNA-RNA and protein-protein interactions. These will be improved and applied in the proposed work, supported by bioinformatics. RNA systems are highly conserved in evolution, so techniques developed in yeast can be adapted for human cells and applied to understand disease. RNA biology in a cellular context is subject to dynamic changes. Kinetic analyses will therefore be applied, particularly during changes in cell state.
Specific topics:
1: How is the nascent RNA linked to transcription termination and RNA processing
2: How does RNA metabolism respond to environmental stress?
3: How is host RNA metabolism remodelled during Coronavirus infection?
4: What are the roles of ncRNAs in neuronal development?
The insights generated, and the experimental and bioinformatics techniques developed, will underpin future work by many groups.


Investigator Award in Science

Understanding proteins that interpret genome context to stabilise cell states The character of a cell is determined during differentiation by selective gene activation and silencing. In addition to high level decisions about which genes are on or off, it is now clear that levels of transcription in each differentiated cell must be precisely calibrated. This proposal seeks a comprehensive understanding of two proteins, SALL4 and MeCP2, that optimise transcription programmes in order to stabilise cellular states. Despite very different biological outputs, SALL4 and MeCP2 share striking similarities. Both are DNA binding proteins that recognise short, frequent DNA sequence motifs; both interact with histone deacetylase-containing corepressor complexes to modulate expression of many genes; and both are of proven biological and biomedical importance. Our intention is to study these proteins in parallel using a molecular genetic approach in order to elucidate fundamental mechanisms that consolidate cell identity before and after differentiation. To explore the generality of this form of transcriptional control, we will screen for novel transcription modulators that also interpret regionally variable genomic features by sensing short DNA sequence motifs. Our findings will have implications for regenerative medicine and reveal the molecular basis of diseases caused by deficiency of these and similar proteins, including Rett syndrome, Okihiro syndrome and cancer.


Collaborative Award in Science

Dr Clark Freifeld, Dr Luana Bontempo, Prof Federico Varese, Prof Ben Cooper, Prof Rob Ogden, Prof Heather Hamill

Forensic epidemiology and impact of substandard and falsified antimicrobials on public health Substandard and falsified (SF) antimicrobials are a massive but underappreciated global health challenge in great need of innovative research to inform interventions. We will build on our collective pioneering research, to construct an innovative, multidisciplinary research hub that will improve understanding and inform global policy and action. Leading specialists investigating illegal wildlife trade, forensic genomics and chemistry, social network analysis and modelling, will work together to answer two main aims:

1.  How can innovative forensic tools be used to identify sources and trade routes?

How can novel genomic (‘pharmabiome’), chemical and isotopic analysis with social network techniques be used to characterise the epidemiology of SF antimicrobials to inform policy and action to improve our global pharmaceutical supply quality? We will conduct high-throughput sequencing and novel chemical analysis of falsified and genuine antimicrobials to determine their comparative pharmabiome/chemical spectra, followed by social network analysis of  origins and trade routes.

2.  What are the public health impacts of SF antimicrobials?

What are the modelled impacts of SF antimicrobials on patient outcome, global public health, especially engendering antimicrobial resistance and how can these be minimised? Using a One Health approach, which pathogen-antimicrobial pairs are at greatest risk of SF antimicrobials?


Investigator Award in Science

How cells convert cytosol-invading bacteria into anti-bacterial signalling platforms Our cytosol could provide ample resources for invasive bacteria, yet is maintained in a remarkably sterile state. We recently discovered that cells deposit polyvalent protein arrays at bacterial surfaces to convert cytosol-invading bacteria into anti-bacterial signalling platforms. The deposition of M1-linked ubiquitin chains by the E3 ubiquitin ligase LUBAC recruits and activates IKK complexes, resulting in NF-kB signalling, while the deposition of guanylate-binding proteins (GBPs) recruits and is required for the LPS-dependent activation of Caspase-4, resulting in pyroptotic cell death and the release of IL-18. Here, we will explore this novel principle of cell-autonomous immunity to better understand cytosolic anti-bacterial defence.

We will therefore investigate

 The origin and function of ubiquitin-dependent signalling platforms, with special emphasis on the ubiquitylation of bacterial lipopolysaccharide (LPS) by the E3 ubiquitin ligase RNF213, which represents the unprecedented ubiquitylation of a non-proteinaceous substrate
 The origin and function of the GBP-dependent signalling platform, specifically its assembly mechanism and how it promotes activation of caspase-4 and other downstream effectors.


Investigator Award in Science

How does the purine metabolic checkpoint FAMIN prevent immunopathology? Children with Still's disease, the paradigm of autoinflammation-cum-autoimmunity, are predisposed to developing a cytokine storm with excessive activation of T lymphocytes upon viral infection. Loss-of-function of FAMIN is the sole known cause for monogenic Still's disease. We de-orphaned FAMIN as an unprecedented purine nucleoside enzyme that combines ADA-, PNP- and MTAP-like activities with adenosine phosphorolysis – challenging fundamental principles of purine metabolism. Dendritic cells with absent FAMIN activity prime for excess antigen-specific cytotoxicity, IFNgamma secretion, and T cell expansion, resulting in exaggerated virus-specific T cell responses and immunopathology. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ~6.3% of mankind is homozygous, and which predisposes for Crohn's disease and leprosy. Here we will address FAMIN biology from virtually atomic to organismal resolution: We will explore how FAMIN operates in a cell, and how it controls energy metabolism, ascertaining redox and pH homeostasis. We will investigate how FAMIN in dendritic cells potently restrains T cell priming, and whether the FAMIN-coordinated biochemical mechanisms are involved in often fatal virus-induced cytokine release syndromes. This work will reveal an ancient biochemical mechanism that potently controls adaptive immune activation at a very fundamental level, providing insight into immunity to pathogens, autoinflammation and autoimmunity.


Investigator Award in Science

Protein phosphorylation dynamics: investigating a new dimension of regulatory control during mitosis  Protein phosphorylation regulates protein function in a switch-like manner. Although each phosphorylation site only exists in two states (on/off), the frequency of switching between these states can vary dramatically. Individual molecules that flash on and off rapidly can possess unique signalling properties, but these are difficult to study because dynamic information remains hidden from current analytical methods. We will use heavy-[18O2]-ATP and mass spectrometry to quantify, for the first time, the rate that individual substrates are phosphorylated and dephosphorylated over time. We will measure this globally and characterise different complexes during mitosis that rely on phosphorylation-dephosphorylation cycles to function correctly (BUBc/RepoMan/Centralspindlin/COMA). We will study how these cycles control signal-switching and protein binding-release events, which we predict are needed to order mitotic progression, generate gradients of activity and/or assemble protein complexes. These concepts will be tested with purified components, mathematical modelling and quantitative microscopy. Although we use mitosis as a model system, this work has far-reaching implications. If binary phosphorylation events generate more complex outputs by varying their on/off rates, then any pathway could use this property to transmit information differently. It is therefore crucial to investigate this phenomenon because these rates could be modulated to drive both signalling and disease.


Investigator Award in Science

Understanding the diverse molecular mechanisms of chromatin-targeted histone deacetylase complexes Eukaryotic gene regulation depends upon a plethora of multi-protein complexes that both control the organisation of chromatin and establish specific patterns of post-translational modifications of histone tails. These histone marks are key to the processes of gene regulation. Deciphering the roles and mechanisms of the complexes that regulate chromatin is one of greatest challenges in understanding how genome activity is controlled.

We aim to understand the roles and mechanism of action of a family of essential, non-redundant histone deacetylase complexes that control chromatin accessibility across the genome. These HDAC complexes share a common catalytic engine, but contain very different accessory proteins and have diverse oligomeric states. Although these are essential complexes, conserved from nematodes to man, we have only a very limited understanding of their mechanism of action.

We will take two approaches to determine the mechanisms through which these complexes engage with their chromatin substrates and to understand how this determines their biological function.

We will use structural techniques to determine the architectures of three exemplar complexes in complex with chromatin. We will use genomic and proteomic techniques to explore how these structures mediate their distinct biological activities.


Therapeutics Accelerator

Design and implementation of a translational drug development platform for COVID-19 to generate preclinical evidence in support of treatment arms of the ANTICOV clinical trial  Through the rapid establishment of a translational pathway, DNDi and its partners aim at providing the next generation of candidate medicines for SARS-CoV-2 clinical trials as well as integrating back-translations to validate the most appropriate preclinical models. The project is planned to run from September 2020-December 2021, with a total budget of 1.97M GBP, split into three pillars of activities composed of short and medium- term deliverables:

 Pillar 1 : Selection of the best combination of repurposed antiviral drugs to include into the 3rd arm of the ANTICOV clinical trial and the next back-ups

 Pillar 2 : Support candidate progression through an integrated pharmacometrics package involving both Physiologically-Based Pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) modelling approaches

 Pillar 3 : Development of a translational platform and performance of a comparative analysis of selected drugs/combinations (including those from Pillar 1) to better understand and refine the screening cascade with best translational value; definition of a Target Candidate Profile (TCP) for SARS-CoV-2 mild infection

This project will cement a collaborative partnership in the SARS-CoV-2 translational space that will pave the way to future longer-term discovery projects and preparedness for additional future threats.

Key words: COVID-19 / Drug re-purposing / Translational drug development pathway


Investigator Award in Science

Regulation of innate immune responses by the TPL-2/ABIN-2/NF-κB1 p105 complex The TPL-2/ABIN-2/NF-kappaB1 p105 complex is essential for transmitting Toll-like receptor (TLR) signals, turning on inflammatory responses via TPL-2 kinase activation of ERK1/2 and p38alpha MAP kinases. This proposal will investigate the roles in innate immunity of the newly discovered functions of the TPL-2 complex in stimulating phagosome maturation in macrophages independently of MAP kinase activation.

1) TPL-2 and ABIN-2 regulation of phagosome function in professional phagocytes.

Mechanisms of TPL-2 and ABIN-2 regulation of phagosome maturation in mouse and human macrophages will be established.

Roles of TPL-2 and ABIN-2 regulation of phagosome function in mouse neutrophils and dendritic cells will be investigated.

2) TPL-2 and ABIN-2 regulation of innate immune responses to pathogenic bacteria.

Roles of TPL-2 and ABIN-2 regulation of phagosome function in mouse immune responses to Staphylococcus aureus will be determined.

3) TPL-2 induction of phagosome maturation in inflammatory bowel disease (IBD).

The human MAP3K8 gene encoding TPL-2 is linked genetically to the development of IBD, an auto-inflammatory disease that involves an abnormal mucosal immune response to intestinal bacteria. The role of TPL-2 regulation of phagosome function in gut inflammation will be investigated, using human monocyte-derived macrophages from IBD patients/control individuals, and the Citrobacter rodentium mouse model of colitis.


Cell cycle control in archaea

Investigator Award in Science

Cell cycle control in archaea To sustain life, cells must first duplicate their genome and then segregate both copies into two daughter cells at division. This requires regulation. In eukaryotes, the timing of DNA replication, segregation and cytokinesis are coordinated by a cell cycle clock, which marks time through the rise and sudden fall in the activity of a conserved set of CDK-Cyclins. Interestingly, the archaeon Sulfolobus acidocaldarius possesses a cell division cycle like ours, with distinct phases of DNA replication and cell division separated by gap phases, while lacking obvious homologues of CDK-Cyclins. Since Sulfolobus and eukaryotes are thought to share a common ancestor ( > 1,000,000,000 years ago), and use similar machinery to fire origins and to complete cell abscission, this suggests that cell cycle regulation predates eukaryotes and the evolution of CDK-Cyclins. Building on our recent discoveries, in this proposal we aim to test this hypothesis by studying the role and regulation of proteasome-mediated protein degradation in resetting the Sulfolobus cell cycle. Through this work we expect to identify core common regulatory principles of cell cycle control and to identify cell cycle control machinery that has been conserved from archaea to eukaryotes - shedding new light on the origins of the eukaryotic cell cycle.


Principal Research Fellowship Renewal

Neural mechanisms of memory & prediction, finding structure in experience Higher cognitive functions by which we learn to understand our environment and behave flexibly within it rely on the construction, from sequential experience, of a coherent representation of our situation (aka an internal ‘model’ or ‘cognitive map’). I aim to understand the neural basis of his process via precise mathematical models that directly link low-level neuronal mechanisms to behaviour in prediction, planning, generalisation and memory. This project involves convergent computational and experimental work in mice and humans at the neuronal, systems and behavioural levels, using methods ranging from multi-photon imaging in mice, through virtual reality and neural-level electrophysiology in mice and epilepsy patients, to functional brain imaging in healthy volunteers. Three streams of work address the integration of sensory information and actions into a common representation, how representations of states structured by transitions allow path integration and prediction for planning, and how such representations interface with encoding and retrieval during memory. Success will provide a quantitative understanding of how neural activity in medial temporal, retrosplenial and medial prefrontal brain areas support these complex cognitive functions, and a starting point for relating cognitive symptoms to dysfunction of this neural system in conditions such as posttraumatic stress disorder, schizophrenia and Alzheimers disease.


Principal Research Fellowship Renewal

Boosting memory consolidation for rehabilitation  Rehabilitation after brain damage such as stroke depends in part on the brain’s ability to reorganise. It is therefore critical that we understand how brain plasticity after injury happens, and how it can be influenced.
Clinical gains with rehabilitative training should depend not only on gains made during practice but also on offline consolidation, particularly during sleep. Therefore, if we can identify modifiable processes of consolidation, and amplify those to boost consolidation, that would be predicted to improve outcomes.
Using rodent models to understand the mechanisms of offline consolidation, we will identify (1) modifiable electrophysiological signals (reactivation, slow waves, or sleep spindles) that occur with consolidation and (2) imaging read-outs of plasticity, including myelin plasticity, associated with successful consolidation. These will be taken forward into human studies to develop non-invasive closed-loop devices to manipulate functional processes of consolidation during sleep after stroke. This will pave the way for future trials to test whether low-cost interventions that boost consolidation and plasticity can deliver lasting clinical improvements.


Investigator Award in Science

Brain CD4 T cells and their influence over microglial homeostasis Microglia are the main immunological cell of the brain. These residential cells possess both immunological and neurodevelopmental functions, and have pathological roles during age- and injury-associated dementia. We recently characterised a new addition to the neuroimmunological landscape: transiently-resident brain CD4 T cells. Brain T cells are required to trigger the post-natal differentiation of foetal microglia, licensing their neurodevelopmental functions. Much remains unknown about potential further interactions between brain CD4 T cells and microglia. We have adapted cutting-edge technology to enable the parallel study of brain CD4 T cells and microglia. First, will use an adapted flow-based ProCode approach to unravel the molecular control over CD4 T cell entry to the brain and acquisition of the residential phenotype. Second, we have developed a novel genetic tool for competitive chimeric analysis, allowing us to study microglia niche-sensing and the role of interaction with CD4 T cells on microgliosis. Third, we will single cell lineage tracing to dissect the clonal evolution of microglia, and the influence of CD4 T cell interaction on microglial clonal dominance during ageing and following traumatic brain injury. The results will generate new insight into neuroimmune inter-cellular dynamics, and will validate new tools with broad applicability to biomedical sciences.

Grants awarded from 1 October 2005 to 30 June 2021


The Research Software Alliance (ReSA)

Discretionary Award - Open research

The Research Software Alliance (ReSA) Research software is a critical component of open research, and an increased focus on research software challenges will further the objectives of Wellcome Trust’s Open Research programme to maximise research impact. The Research Software Alliance (ReSA) advances the vision that software is valued as a fundamental  component of research. This proposal will support ReSA to bring research software communities together to collaborate on the advancement of research software, utilising application of the FAIR principles as a catalyst for this global endeavour.

This project seeks USD$157,250 to engage the research software community to apply the FAIR principles to research software. to achieve three aims:

 FAIR4RS WG project direction to develop agreed FAIR for research software principles
 FAIR4RS Roadmap leadership to map FAIR for research software projects into a longer-term strategic framework

 People Roadmap to support the development of career paths and reward structures to complement the FAIR4RS Roadmap

This proposal will accelerate the development of an open research system that recognises and supports research software. This will provide researchers with the skills and resources to fully utilise research software, in a system where policy makers and funders value research software, and where organisations adequately reward staff with software expertise.


Interferon and Human Pandemic Viruses

Investigator Award in Science

Interferon and Human Pandemic Viruses  We wish to define the key interferon (IFN)-stimulated gene (ISG) effectors for three pathogenic human viruses – HIV-1, SARS-CoV-2 and influenza virus – and understand the molecular basis for antiviral function.  Specific ISGs will be identified in unbiased gene silencing (siRNA/ CRISPRi) screens, some of which we have developed.  For HIV-1, we will initially focus on the antiviral mechanisms and post-transcriptional regulation of post-entry inhibitors we have identified, human-TRIM5alpha and MX2, including the central roles played by ubiquitination and phosphorylation.  Our discovery that NCOA7 suppresses endocytic virus infection (e.g., SARS-CoV-2) provides the opportunity to study how the endolysosomal system can be dysregulated, potentially through altering vacuolar-ATPase activity.  New screens for ISGs targeting SARS-CoV-2 or influenza virus will be undertaken using wild-type viruses as well as engineered strains carrying disruptions in candidate IFN- or ISG-antagonists.  We will explore the molecular mechanisms and regulatory pathways used by the most potent ISGs using multiple complementary experimental approaches, including proteomic and approved drug screens, and determine how these viruses escape or survive ISG action.  By understanding the ISG effectors that can control these viruses, we will gain fresh insights into viral replication strategies, disease processes and host immunity, and inform future antiviral therapeutic development.


Not available

Discretionary Award – C&S

Development of community-led approaches to support sexual and reproductive health among survivors of trafficking in Uganda and Sierra Leone. Not available


Mobile health for mobile people.

Not available

Discretionary Award – C&S

Mobile health for mobile people. Not available


Not available

Discretionary Award – C&S

Consortium on improving access to integrated Sexual and Reproductive Health and Mental Health services among mobile populations. Not available


Not available

Discretionary Award – C&S

There isn't an app for this! Regulating the Migration of Health Data in Africa. Not available


TYPIST ARTIST PIRATE KING

Discretionary Award - Public Engagement

TYPIST ARTIST PIRATE KING Typist Artist Pirate King is an innovative and accessible dramatic feature film drawn from the extensive archives of art, diaries and letters held at Wellcome of artist and mental health survivor, Audrey Amiss. The film is a first person account and offers a rich insight into how Amiss saw and experienced the world.
            Amiss described herself as someone who people crossed the road to avoid. The film does not ‘other’ her, and, for those who did cross the road to avoid her, creates the opportunity to identify with her. The film is a powerful contribution to conversations about mental health stigma and plays an important role in creating representation that can help erase stigma.
            For the many people who define themselves as mental health patients/ clients/ users/ former users/ survivors, the film is actively speaking to them. It does not merely address a so called "neuro-normal" audience but represents how ways of thinking, experiencing and seeing the world are diverse and urgently deserve to be represented in their complexity for all to see and engage with.
            We anticipate a significant international release of the film, followed later by it being used as valuable study material within academia.


Not available

Discretionary Award - Snakebite

Risk-benefit assessment of snakebite antivenoms Not available


Discretionary award – DRI

Designing Sustainable Market Systems for New Antibiotics In partnership with the Wellcome Trust, the Milken Institute's FasterCures and the Financial Innovations Lab program will examine ways to engage, accelerate or modify existing models or design new models that can support the development and commercialization of new antibiotics. The project will look to thoroughly vet the barriers and incentives for implementing a more sustainable system, focusing on identifying fund models and financing mechanisms that are applicable across disease areas and markets. The Lab will utilize the Milken Institute’s network and expertise to thoroughly vet funding models to ensure they are operational and provide a platform towards implementation.

Using the Lab’s signature model, the project will: 1) complete independent research and stakeholder interviews on the nuances of the issue area to complete a landscape analyses; 2) host a moderated, in-person roundtable with interdisciplinary leaders, including non-governmental organizations, researchers, policymakers, investors, financial institutions, academics, and industry experts to generate market-based solutions, and 3) produce a summary report on the findings of the roundtable, including policy recommendations and models for financial incentives. By leveraging a diverse pool of knowledge, the Lab will develop solutions to help fund and expedite new, innovative ways of funding new antibiotic development and commercialization.


Discretionary Award – DSH

IDDO: FAIR, equitable and sustainable data platform for infectious diseases The COVID-19 pandemic has once again exposed the lack of coordination and cooperation across the research and development efforts of the infectious disease community. A key indicator of this failing is the lack of international, interoperable data platforms to provide rapid insight into disease pathogenesis and treatment. Access to data is an important tool for accelerating evidence, product development, and scientific innovation.

Enhanced technology, infrastructure and systems for data platforms will increase Findability, Accessibility, Interoperability, and Reuse (FAIR), so that science can advance in a rapid, robust and innovative way, saving lives in the affected communities.

Recognising the importance and complexity of the task at hand, this project brings together the vast experience of IDDO, Vivli, and other key stakeholders to deliver a broad, effective, and sustainable data platform(s) for infectious diseases.

In this project, IDDO will:

 Enhance its platform for improved findability, discovery, and persistence which ensures that data are available in the long-term;
 Optimise and accelerate its data curation capacity;
 Streamline and accelerate its data access workflow;
 Develop a business plan to secure the sustainability and success of the platform


Human Infection Studies (Full)

Prof Peter Openshaw, Prof Wendy Barclay, Prof Helen McShane

Manufacture of a GMP SARS-CoV-2 challenge agent In the current COVID-19 emergency, a controlled SARS-COV-2 human infection model (CHIM) has the potential to accelerate the understanding of pathogenesis, induction of immunity and immune mechanisms of resistance to disease, as well as a means to test novel diagnostics and treatments, especially between waves of the pandemic, when occurrence of natural disease is relatively uncommon. A large number of SARS-COV-2 vaccine candidates are at various stages of development internationally including those which have recently entered mid-late stage clinical testing in field studies. In order to make the greatest public health impact, there is an urgent need to select the most promising vaccines in the shortest possible timeframe. In addition, human infection challenge can contribute to the identification of correlates and mechanisms of protection against infection and shedding of virus in vaccinated volunteers. Finally, the model may be useful in the determination of the durability of protection in seropositive individuals with documented prior wild type infection. This proposal is a dose titration study to generate two GMP challenge agents and establish the safety of a wild-type SARS-COV-2 controlled infection in the upper respiratory tract of young healthy volunteers that will allow swift and robust assessment of vaccine efficacy.


RECOVERY International

Therapeutics Accelerator

Prof Guy Thwaites, Dr Raph Hamers, Dr Buddha Basnyat

RECOVERY International The Phase 3 RECOVERY platform has been a success, recruiting over 13,500 patients and producing 3 clear, world practice-changing results in the first 100 days of recruitment. The RECOVERY team has been approached by clinical investigators from various LMICs who wish to participate in RECOVERY. As it becomes clear that this pandemic will continue at various locations and paces over the next 24 months, there is an opportunity to increase the impact of the RECOVERY trial by expanding internationally. Expansion has the potential to speed up the assessment of novel treatments, increase the global relevance of the trial results, build capacity, and reduce wasted efforts on small uninformative studies. The key goal is to establish RECOVERY internationally, initially in Indonesia, Nepal and Vietnam, with a view to opening sites also in Africa.


PhD Studentship (Basic)

What are the determinants of vulnerability to County Lines exploitation? What are the health and economic costs of County Lines? County lines (CL) trafficking is a model of illegal drug (heroin and crack cocaine) distribution that has emerged recently in the UK, whereby city-based dealing groups exploit the labour of children and adults, often in vulnerable circumstances in order to deal directly to smaller coastal and market towns. Involvement in CL is associated with experiencing a wide range of health harms including violence and sexual exploitation.

CL is causally complex. The many individual-level risk factors currently thought to lead to vulnerability CL exploitation (mental health issues, prior histories of abuse and neglect, being excluded from mainstream education, being in care, prior offending, drug addition, disability) are themselves determined by complex, interacting upstream socio-economic factors. In order to capture this complexity, I aim to take a systems modelling approach to CL trafficking – viewing the CL phenomenon as an emergent property of a dynamic and open, adaptive system. This model could then be used for ‘what-if’ policy scenario testing, estimating the possibility for cooperation or conflict between the goals and activities of a wide range of statutory bodies, and could guide the design of coordinated cross-sectoral interventions.


PhD Studentship (Basic)

Neural circuits regulating appetite in an uncertain environment Dietary sodium – typically, common salt – is essential to all animals for health and survival, but when consumed in excess it is profoundly damaging, being a leading risk factor for cardiovascular morbidity and mortality worldwide. Eating salty foods is often a pleasurable experience, leaving many individuals struggling to keep their diet healthy.

Whether the taste of salt is rewarding or not depends on the brain’s reward pathways, which make salt less rewarding when the body needs it less. However, periods of sodium deprivation can subvert this, often leading to consumption beyond physiological requirements. This response to a period of deprivation may explain why some individuals are unable to regulate their sodium intake in daily life.

To better understand the brain circuitry regulating sodium appetite, I will use a combination of animal behavioural and neuroscientific techniques. My focus will be on dopamine, a key neurotransmitter involved in the brain's reward pathways, in addition to electrical activity in the wider brain. I will observe these aspects of brain function during periods of sodium deprivation to shed light on their role in overextending the sodium appetite beyond healthy consumption, delivering new insights about the brain’s role in nutritional disorders and appetite regulation.


PhD Studentship (Basic)

Determining the role of ubiquitin in transmission stage Plasmodium Approximately half of the global population is currently at risk of malaria infection, with an estimated 0.5 million deaths annually. Malaria is caused by Plasmodium parasites, which have a complex life cycle involving a vertebrate host and mosquito vector. Blood stage parasites cause the symptoms of malaria in humans, and are therefore the target of most current therapies. In order to reduce the incidence of malaria, and therefore global disease burden, a drug to block transmission between the host and vector is needed. The complex regulation required in transmission stage parasites remains poorly understood. Ubiquitylation is a well-researched post-translational modification which is commonly associated with protein degradation, but also has a range of effects from protein re-localisation to induction or arrest of cell signalling events. The role of ubiquitin in transmission stage parasite development is unknown. We aim firstly to identify the ‘ubiquitome’ of Plasmodium bergheiparasites during transmission stage development using ubiquitin capture systems and mass spectrometry. We subsequently aim to investigate the role of these ubiquitylated proteins during transmission using genetic engineering. These results will improve our understanding of the role ubiquitin may play in the regulation of transmission stage parasite development, and inform future drug discovery efforts.


PhD Studentship (Basic)

Role of mixed lineage leukaemia (MLL) proteins 1 and 2 during mesoderm differentiation In the early mammalian embryo, there is a clump of identical "naïve pluripotent" cells. After implantation in the mother’s uterus, these cells diverge into a multitude of different cell types during a process called gastrulation. During this process, the three main lineages of the mammalian body, ectoderm, mesoderm and endoderm, are formed and shortly after, the basic body plan and body axes are established. Here, we focus on formation of mesoderm that gives rise to cell types such as blood cells.

While every cell in our body is in principle equipped with an exact copy of the same genetic information, in the form of DNA wrapped around proteins called histones, it is poorly understood how protein complexes that modify these histones, such as the MLL/COMPASS complex, control the process of mesoderm differentiation.

To address this, I will use advanced imaging techniques that can watch individual MLL/COMPASS or the DNA sites to which they bind. I will use embryonic stem cells that mimic in a dish the changes that occur as pluripotent cells differentiate towards mesoderm.

We hope to understand the driving forces behind the transition from pluripotent cells towards mesoderm lineages, providing overarching mechanistic principles of lineage diversification.


Discretionary Award – DSH

Building Trustworthy Clinical AI: from algorithms to clinical deployment The goal of this proposal is to develop, implement, and evaluate machine learning algorithms for trustworthy clinical AI. The proposed technology aims to support a wide range of healthcare
applications, including diagnostics, treatment personalization, and prediction of treatment outcomes. These applications utilize diverse sources of data, including clinical notes, images, and test results. Rather than designing a disease/application-specific AI algorithm, we are interested in developing a capacity that can be readily embedded into existing AI models to improve their transparency and ability to incorporate human feedback as well as strengthen their data privacy guarantees. The Jameel Clinic team has deployed AI tools in many clinical areas. These tools would be our testing ground for measuring the effectiveness and flexibility of the proposed platform.


PhD Studentship (Basic)

Economic modelling of cervical cancer control interventions in sub Saharan African countries: A scenario analysis of the 2030 elimination targets for Nigeria

Sub-Saharan African countries continue to bear the burden of cervical cancer. High cancer incidence and high mortality rates can be decreased by  available evidence-based interventions, such as vaccination, screening, and early referral for treatment, if they are implemented on a large scale. The large-scale programs though are expensive and not always affordable in low-income countries.

In this study, I aim to examine the economic costs and effect of the World Health Organization cervical cancer elimination strategy in Nigerian health system by 2030. The strategy involves attaining immunisation coverage of 90% for Human papilloma virus (HPV) vaccination, cervical cancer screening coverage of 70% and 90% treatment targets for identified cases .

I will review existing literature, conduct key informant interviews and simulation exercises to provide evidence on the appropriate resources and infrastructural investments required to attain the targets for HPV vaccination, cervical cancer screening and treatments of pre-invasive and invasive cervical cancer in Nigeria by 2030.

The study will provide evidence to guide decision makers in Nigeria and other sub-Saharan countries in allocating resources to address cervical cancer control in a  robust, evidence-based and equitable manner.


PhD Studentship (Basic)

Sources of relaxation differences in quantitative MRI Magnetic resonance imaging (MRI) it is a powerful technique which allows  brain tissue to be explored indirectly. Despite more than 40 years of innovation, the standard clinical MRI protocol remains largely unchanged: a set of 3 images influenced by ‘relaxation’ phenomena, namely how quickly tissue returns to equilibrium when perturbed by a radiofrequency pulse. Radiologists detect pathology through differences in relative intensity. While recent advances can estimate relaxation times directly, facilitating quantitative MRI, the biophysical origins of differences in relaxation times are poorly understood. In brain tissue, differences in cell size, orientation and make-up have all been posited, but their contributions have not yet been fully characterised. I will use computer simulations and real MRI experiments to tease-apart these mechanisms. This will include validating the specificity of different imaging parameters in animal-models using histology and further evaluating their sensitivity in the human brain at different stage of development. My aim is to make quantitative MRI more interpretable, boosting its clinical utility both in neuroscience and medicine.


PhD Studentship (Basic)

Examining the role of endothelial derived galectins in vascular inflammation The inflammatory response is a sophisticated mechanism used by the body to protect against injury and invading microorganisms and requires the trafficking of disease-fighting immune cells from the bloodstream to the site of injury. Resolution of the inflammatory response involves removal of immune-related infiltrate which if left unresolved can lead to chronic inflammatory pathologies. Carbohydrate-binding proteins called galectins, are expressed by cells that line the blood vessels and play fundamental roles in both the initiation and resolution of the inflammatory response. Changes in the frictional force generated by blood flow through the blood vessels can be detected by these cells which leads to subsequent changes in gene expression and release of these immune-modulating proteins. We aim to investigate and characterise the factors that regulate the endogenous expression of galectins from endothelial cells lining the blood vessels and the functional role they play in vascular inflammation. We aim to use a combination of inventive in vitro, ex vivo and in vivo experiments that combine physiological flow conditions and inflammatory mediators, to study the role of endothelial galectins in vascular inflammation and the mechanisms that underlie this.