2024 summer projects
Examining the roles and status of non-physician health providers
Supervisors: Yingxi Zhao and Mike English
Location: Peter Medawar Building, Oxford
Healthcare systems globally are experiencing physician shortages, and many countries have non-physician provider roles that are not trained as physicians but take on many of the clinical functions to support service delivery. In Africa, non-physician clinicians and nurses fill the gaps and deliver over 80% of primary care and sometimes the most common cadres in first-referral hospitals. They have been important for delivering and scaling up programmes such as HIV/AIDS, immunisation, acute infectious diseases, and nutrition. Similar roles are also emerging in high-income countries – for example the UK has a short history of training physician associates but now over 20 universities are offering such training. Nonetheless, there has been debate about their scope-of-practice and regulation, and recently doctors have created an increasingly hostile narrative towards their roles especially on social media.
Building on work led by the Health Systems Collaborative team focusing on the workforce in the UK and Africa, this intern will conduct a series of literature and policy reviews to investigate the background, role and regulatory status of non-physician providers globally but with a specific focus on European and African countries. The intern will gain skills in literature/policy review and the use of analytical theories and framework.
Mapping the RNA epitranscriptomic modifications
Supervisor: Chunxiao Song
Location: Oxford Ludwig Institute, NDM Research Building, Old Road Campus, Headington, Oxford
Our genome is not a static state; it contains dynamic epigenetic modifications that play crucial roles from development to pathogenesis. Our group aims to unravel the intricate world of DNA and RNA modifications, collectively known as epigenetic and epitranscriptomic modifications. We are focused to advancing the field of epigenetics and epitranscriptomics through technology development, functional studies, and clinical applications. We employ a combination of chemical biology and genome technologies to develop novel tools to analyse the epigenome and epitranscriptome. In this project, you will contribute to the development of cutting-edge technologies designed to identify important RNA epitranscriptomic modifications, with the goal of advancing our understanding of these crucial processes.
References:
Liu, Y.et al. Bisulfite-free direct detection of 5-methylcytosine and 5-hydroxymethylcytosine at base resolution. Nat. Biotechnol. 37, 424-429 (2019).
Siejka-Zielińska, P. et al. Cell-free DNA TAPS provides multimodal information for early cancer detection. Sci. Adv. 7, eabh0534 (2021).
Xu, H et al. Modular oxidation of cytosine modifications and their application in direct and quantitative sequencing of 5-hydroxymethylcytosine. J. Am. Chem. Soc. 145, 7095–7100 (2023).
Xu, H et al. Absolute quantitative and base-resolution sequencing reveals comprehensive landscape of pseudouridine across the human transcriptome. bioRxiv 2024.2001.2008.574649 (2024).
The role of lysosome: mitochondria contact sites in regulating cellular metabolism
Supervisor: Ira Milosevic
Location: Milosevic Lab, Centre for Human Genetics, Nuffield Department of Medicine
Cellular organelles are in constant communication with each other through specialized regions called membrane-contact-sites (MCS). This inter-organellar communication is essential do drive numerous cellular functions. Moreover, there is increasing evidence of MCS dysfunction playing a role in several human diseases. The emerging biological importance attributed to MCS has led to the development of new tools and assays that have helped the identification and characterization of different types of contact sites.
This project aims to employ these novel techniques for studying lysosome:mitochondria contact sites. Specifically, we will use split-GFP-based contact site sensors (SPLICS) and proximity ligand assays (PLA) to be able to visualize and quantify lysosome:mitochondria MCS. These techniques are already used in the lab, and we aim to expand the cellular models where they are currently being applied, including both immortalized cell lines as well as primary cell cultures. The candidate will optimize and validate SPLICS and PLA in these new models, for which different transfection techniques coupled with immunofluorescence and confocal microscopy will be used. The goal here is to better understand the role of lysosome:mitochondria contact sites in regulating cellular metabolism, and uncovering new facets of different lysosomal/mitochondrial pathologies.
Contact: ira.milosevic@well.ox.ac.uk
Association between suicide and air pollution in Thailand
Supervisors: Richard James Maude and Chawarat Rotejanaprasert
Location: Epidemiology Department, Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand
Air pollution is a major health issue in developing countries with Thailand experiencing some of the worst levels due to burning of agricultural land compounded by traffic and industrial emissions. Some of the health impacts of air pollution have been well characterized, for example, increases in asthma, heart attacks, strokes and high blood pressure and increased transmission and mortality from infectious diseases such as influenza and COVID-19. The association between air pollution and mental illness has been less well studied. Air pollution impacts on quality of life, with people staying indoors, wearing masks and limiting their physical activity on days with high pollutant levels. This can lead to anxiety, reduced ability to socialise and loss of income due to inability to work. The extent to which this may contribute to mental illness is not clear. In Thailand, air quality data are collected in real-time by a network of air monitoring stations throughout the country. Details of PM2.5, PM10 and various toxic chemicals are collected. In addition, there is a robust system for collecting detailed data on suicides across the country. This project will aim to assess and quantify the relationship between air pollution and suicide using longitudinal data.
Developing a TMLE (Targeted Maximum Likelihood Estimation) Analytic Pipeline for Evaluating Hospital Interventions on Patient Outcomes
Supervisors: Esteban Garcia and Laura Merson
Location: New Richards Building, Old Road Campus, Headington, Oxford
Objective: To create a scalable and reusable analytic pipeline based on Targeted Maximum Likelihood Estimation (TMLE) for assessing the causal impact of a hospital interventions on patient outcomes, with a focus on COVID-19 as an initial application area.
Background: Hospital care for acute conditions utilizes a variety of interventions with uncertain effectiveness. This project seeks to develop a flexible analytic pipeline capable of estimating the causal effects of diverse interventions—ranging from respiratory support to pharmaceutical treatments—on key patient outcomes.
Data: ISARIC COVID-19 Dataset.
Methodology: Design a modular TMLE analytic pipeline that includes data preprocessing, machine learning for modelling, and a targeting step for adjusting confounders. The pipeline will be adaptable to various interventions, outcomes, and datasets.
Expected Outcomes: An adaptable TMLE-based analytic pipeline capable of providing causal estimates for multiple interventions from observational data. Initial application to COVID-19 will allow its development and illustrate its utility, with broader implications for future healthcare research.
Impact: This project will improve evidence-based decision-making in healthcare by providing a tool for detailed analysis of intervention effectiveness, contributing to better patient care and outcomes.
Supporting 1000 nurses, community and other allied health workers in leading pragmatic health research studies to outcomes in their patients whilst developing skills and leadership experience
Supervisor: Trudie Lang
Location: Ewert House, Summertown, Oxford
There is vast inequity in where research happens, who leads and who benefits from the evidence. Too few studies address health issues where pragmatic solution could change outcomes in patients. Also, many healthcare professionals are not supported, encouraged or mandated to undertake research that could practically and effectively reduce the burden of a devasting health challenge – and tackle gaps they see every day.
This project is a bold new initiative being rolled out across the world by The Global Health Network and Nursing Now to enable 1000 nurses, midwives, community health workers and other allied health professionals in low-resource settings to lead research studies that gather evidence to address priority issues in their communities. This is a powerful opportunity for leadership and career development delivered through workplace learning whilst generating vital evidence to improve health outcomes in their communities, and by doing so achieve leadership experience.
The student will undertake activities including: mapping of relevant resources for research capacity building, digital content development and management, implementing communication strategies, drafting of manuscripts, developing frameworks for measuring impact of the activities implemented, document preparation (reports, collaboration agreements) and driving of uptake through correspondence with partners and collaborators in the regions.
Strengthening antimicrobial resistance research capacity in low-resource healthcare settings by fostering global AMR knowledge exchange and collaboration
Supervisor: Trudie Lang
Location: Ewert House, Summertown, Oxford
The Global Health Network (TGHN) is a facility that works across all aspects of health research with the objective of embedding health research where evidence is lacking by bringing support, training and resources for faster and higher-quality research processes. This is achieved through an online platform for knowledge sharing, strategic partnerships, and training and career development for research teams and individuals.
As part of a highly-interconnected network of communities of practice (CoPs), TGHN coordinates the Antimicrobial Resistance (AMR) Knowledge Hub and CoP, dedicated to facilitating AMR research in places and communities where evidence is lacking, seeking to ensure equity in where AMR research happens, and who benefits. The AMR Knowledge Hub aims to build capacity via the development and dissemination of free, open-access resources designed to support AMR researchers, in addition to providing a forum for AMR researchers to connect, collaborate and strengthen their knowledge and research skills. As of December 2023, this community had over 10,500 members worldwide.
The student will undertake activities to support TGHN’s AMR initiatives including: digital content development, drafting of manuscripts, supporting online event coordination, resource mapping, participation in collaborator discussions, maintenance of excellent partner relationships and the support of in-house and collaborative AMR research projects.
Strengthening research capacity in low-resource healthcare settings through building the regional networks, coordination of training and knowledge sharing activities and measuring impact of the initiatives implemented
Supervisor: Trudie Lang
Location: Ewert House, Summertown, Oxford
The Global Health Network (TGHN) is a facility that works across all aspects of health research with the objective of embedding health research where evidence is lacking by bringing support, training and resources for faster and higher-quality research processes. This is achieved through an online platform for knowledge sharing, strategic partnerships, and training and career development for research teams and individuals. TGHN has adopted a model of federated and regional leadership in which partner research institutes in Africa, Asia, Latin America & Caribbean and Middle East & North Africa lead the organisation and delivery of context-relevant research training and capacity strengthening initiatives.
The student will undertake activities within the regional programmes including: digital content management, implementing communication strategies, drafting of manuscripts, developing frameworks for and measuring impact of the activities implemented, document preparation (reports, collaboration agreements), mapping resources relevant to the knowledge communities across all four regions, with a particular focus on projects related to Environmental Surveillance and Artificial Intelligence in Global Health.
Optimising crystallography for viral NS2B/3 Protease for the development of broad-spectrum small molecule inhibitors
Supervisors: Lizbé Koekemoer and Annette von Delft
Location: Centre for Medicines Discovery (CMD), Old Road Campus, Headington, Oxford
The current antiviral pipeline does not match the scale of the public health emergency caused by flavivirus infections (Dengue and Zika). This global health problem claims over >30,000 lives a year. Currently we don’t have small molecule inhibitors for the treatment of Dengue haemorrhagic fever, the main clinical complication of the virus. Therefore, the discovery of novel compounds remains a priority.
NS2B/3 proteases are essential for viral replication and are well validated targets in flaviviruses such as Hepatitis C virus (HCV). However, the current HCV inhibitors lack cross-reactivity to other flaviviruses such as Dengue, Zika, Japanese Encephalitis and West Nile Fever. Since the protease has a conserved active site across the various flaviviruses, it is amenable for the development of cross-reactive inhibitors.
Here, we propose structural evaluation of the flavivirus NS2B/3 proteases, with the aim of exploiting broad-spectrum cross-reactivity. This project is based at the CMD’s protein crystallography small research facility (PX-SRF) which specializes in structure-based drug discovery providing gene-to-structure expertise and efficient crystallographic fragment screening. Tapping into their knowledge, you will establish a flavivirus protease crystallography panel suitable for fragment screening to identify the chemical matter that can be developed into novel broad-spectrum small molecule inhibitors.
Modelling gastric reflux using stomach stem-cell driven cultures
Supervisor: Francesco Boccellato
Location: Ludwig Institute for Cancer Research, Old Road Campus, Headington, Oxford
Background
Epidemiology suggests that Helicobacter pylori infection and reflux correlate with an increased incidence of gastric cancer development. While the role of Helicobacter pylori in stomach pathogenesis has been studied extensively, the role of reflux is less clear.
Aim of the project
To develop a in-vitro model to study the effect of gastric reflux on the stomach epithelium.
Methods
We developed “mucosoid cultures”: a stem cell-driven model for the stomach epithelium. Healthy human stomach cells in the mucosoid form a monolayer of polarised cells with tight junctions with regenerative capacity. The mucosoids accumulate mucins on the apical side and their cells can differentiate to produce digestive enzymes and gastric acid. As such, the mucosoids are a unique, advanced cell culture model that mimics most of the features of a real healthy gastric mucosa. Mucosoids were successfully used to model Helicobacter pylori infection. We propose to model the effect reflux on the stomach epithelium by treating the gastric mucosoids with human gastric juices from patients with reflux.
Expectations and future plans
We expect reflux to impact on cell viability and epithelial barrier integrity. We will investigate how regeneration and differentiation is altered in the presence of gastric reflux.
Re-examining diplomacy for health equity and international cooperation from a low- and middle-income country perspective
Supervisors: Roger Nascimento and Proochista Ariana
Location: International Health & Tropical Medicine, NDM-CGHR, Peter Medawar Building, Oxford
In the current post-pandemic or inter-pandemic period, we are interested in investigating the interplay of global public health and international politics. The structures and processes of the international health system presuppose stakeholders' participation in global health governance. Diplomatic relations can play a pivotal role in realising the functions, fulfilling the mandates, and achieving the goals of global health. International and interdisciplinary efforts of science diplomacy can contribute towards enhancing scholarship and professional practice in health diplomacy.
Drawing on the agreement between the Oswaldo Cruz Foundation (Fiocruz) and the University of Oxford, the research groups concerned with international health at each institution are co-sponsoring a student exchange initiative. Fiocruz has been hosting Oxford IHTM students on 8-week placements at its designated PAHO/WHO Collaborating Centre for Global Health and South-South Cooperation. The NDM Summer Studentship will enable a Fiocruz student (from any AU, LAC or LC country*) to be hosted at Oxford and design a DPhil proposal on health diplomacy with a focus on a low- and middle-income country (LMIC).
The summer project will analyse the Fiocruz Global Health Observatory methodologies and insights informing diplomacy efforts for health equity and international cooperation. Using qualitative approaches to documentary review, the report and presentation will showcase a topic, area or population that demonstrates an LMIC perspective. There will be an opportunity to test AI applications that optimise data processing of publicly available digital textual and audio-visual sources. Overall, we are investing in a broader scope, novel methods, and innovative leaders for health diplomacy.
*AU = Africa Union, LAC = Latin America and the Caribbean, LC = Lusophone Commonwealth (CPLP)
Nature-based Solutions for mitigation of climate change and antimicrobial resistance
Supervisors: Sonia Lewycka and Ngo Hoang Tuan Hai
Location: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, UK/Oxford University Clinical Research Unit, Vietnam
Project Duration: 8 weeks
Project Summary:
Climate change and drug resistant infections are both major global health threats. An estimated 1.27 million deaths were attributed to antibacterial resistance, with low- and middle-income countries (LMICs) being disproportionally affected. Two-thirds of antibiotics are used in agriculture, resulting in contamination of the environment with antibiotic residues and resistant bacteria. Intensification of agriculture is also responsible for a significant proportion of greenhouse gas emissions that contribute to climate change, as well as changing patterns of land use, pollution, and biodiversity loss. Nature-based Solutions have been proposed as an approach to mitigate climate change through sustainable environmental management, benefitting people and nature. Nature-based Solutions could also be beneficial for combatting antimicrobial resistance.
Oxford University Clinical Research Unit is leading a British Academy funded Global Convening Programme to explore a Just Transition for sustainable and equitable mitigation of antimicrobial resistance. The summer student project aims to synthesize worldwide evidence from studies, evaluating Nature-based solutions for mitigation of climate change and antimicrobial resistance. The project will involve performing a systematic review of the available literature, extracting key points, and summarising evidence. This work will contribute to a peer-reviewed publication and inform future research proposals to implement and evaluate Nature-based Solutions that could be successful in mitigating climate change and antimicrobial resistance.
Understanding impact pathways for complex public health interventions
Supervisor: Sonia Lewycka
Location: Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, UK/Oxford University Clinical Research Unit, Vietnam
Project Duration: 8 weeks
Project Summary:
The Oxford University Clinical Research Unit in Hanoi is leading trials of a range of public health interventions, particularly aiming to tackle inappropriate antibiotic use and antibiotic resistance. Achieving population-level impact through public heath interventions may require changing multiple intermediary behaviours along the pathway. To better understand how complex public health interventions can achieve impact, we will learn from previous cluster randomized trials of participatory community interventions to reduce maternal and neonatal mortality in low- and middle-income countries (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(13)60685-6/fulltext ). These interventions demonstrated impacts on maternal and child mortality, but smaller effects on intermediary behaviours such as antenatal care attendance, use of insecticide treated bednets, and skilled birth attendance. The student may also explore the role of participation in health interventions on empowerment and self-esteem, and the mediating effect of this on health behaviours. This project will explore the impact of intervention participation on the coverage of key maternal, newborn and child health behaviours, and the role of these intermediary behaviours on reducing maternal and child mortality.
There is growing literature on the measurement of “co-coverage” for complex maternal and child health interventions. This approach acknowledges that improvements in health and reductions in mortality due to complex public health interventions may arise from the adoption of multiple health behaviours. Indeed, public health interventions that target multiple behaviours simultaneously may have the most powerful effects. However, the analysis of trials typically focuses on the impact of interventions on separate individual behaviours. This project will involve a secondary analysis of data from trials conducted in Nepal, India, Bangladesh, and Malawi. The student will create a “co-coverage” index relevant to this study, and use this to measure the impact of the intervention on health behaviour. Further analyses will explore other ways of grouping health behaviour variables, such as calculation of a composite index.
The role of CMV in accelerated immune ageing in adolescents living with HIV in Zambia and Zimbabwe
Supervisor: Sarah Rowland-Jones
Location: Department of Immuno-Oncology, Old Road Campus Research Building, Roosevelt Dr, Headington, Oxford
Cytomegalovirus (CMV) causes lifelong latent infection for which research primarily occurs in resource-rich settings among the elderly and immunocompromised. However, CMV disproportionately impacts children in low- and middle-income countries who acquire it perinatally, before their immune system fully develops. Among children with perinatally-acquired HIV, CMV coinfection is ubiquitous. These HIV/CMV co-infected children are susceptible to stunted growth, chronic lung disease, and neurological diseases. Poor immune control of CMV is implicated in the development of these comorbidities.
We propose a study embedded within the recently completed VITALITY trial, which collected musculoskeletal and immunity data in adolescents with perinatal HIV. With specimens stored in Oxford from 842 participants in Zambia and Zimbabwe, we will determine whether CMV infection severity is related to immune function and ageing. The Student will measure CMV antibody and DNA levels in VITALITY plasma samples using ELISA and qPCR, respectively. The Student will then analyse the CMV data to investigate associations with T cell distribution and telomere length (already measured).
Although immune damage by CMV is evident in the elderly, the relationship between CMV severity and HIV/CMV-related morbidities is largely unknown in children. These data may shed light on the utility of controlling CMV in this vulnerable population.
Fate mapping cell-cell interactions in cancer
Supervisor: Richard White
Location: Oxford Ludwig Institute, Old Road Campus Research Building, Roosevelt Dr, Headington, Oxford
Project Summary:
Cancer cells exist in a dynamic ecosystem composed of many other cell types within the tumour microenvironment (TME). The interactions between the cancer cells and TME cells has a major influence on tumour initiation and progression. The major challenge in understanding these interactions is mapping the mechanism by which these cells communicate with one another. To address this, our lab has previously developed an inter-cellular fate mapping system for tracking and perturbing these interactions. Using zebrafish as a model system, we engineer melanoma cells to express a secreted form of Cre recombinase. This Cre will then be taken up by TME cells with a floxed GFP to tdTomato reporter. Thus, any TME cells which is in direct communication with a melanoma cell will be permanently marked by tdTomato expression. Using this system, we have previously demonstrated interaction between melanoma cells and keratinocytes, which is mediated by molecules such as GABA. In this summer project, we will now expand upon this preliminary work to map cells other than keratinocytes in the TME. The student will be closely mentored by graduate and postgraduates in the lab. They will learn imaging, CRISPR, and techniques such as qPCR or Western blot.
References:
Hunter MV, Montal E, Ma Y, Moncada R, Yanai I, Koche RP, White RM. Mechanical confinement governs phenotypic plasticity in melanoma. Nature, in review. Available at: https://biorxiv.org/cgi/content/short/2024.01.30.577120v1
Tagore M, Hergenreder E, Perlee SC, Cruz NM, Menocal L, Suresh S, Chan E, Baron M, Melendez S, Dave A, Chatila WK, Nsengimana J, Koche RP, Hollmann TJ, Ideker T, Studer L, Schietinger A, White RM. Electrical activity between skin cells regulates melanoma initiation. Cancer Discovery 2023 Aug 9:CD-23-0389
Weiss JM, Hunter MV, Tagore M, Ma Y, Misale S, Simon-Vermot T, Campbell NR, Newell F, Wilmott JS, Johansson PA, Thompson JF, Long GV, Pearson JV, Mann GJ, Scolyer RA, Waddell N, Montal ED, Huang T, Jonsson P, Donoghue MTA, Harris CC, Taylor BS, Ariyan CE, Solit DB, Wolchok JD, Merghoub T, Rosen N, Lezcano-Lopez C, Hayward NK, White RM (2021). Anatomic position determines oncogenic specificity in melanoma. Nature. 2022 Apr;604(7905):354-361
Baggiolini A+, Callahan SJ+, Montal E, Weiss JM, Trieu T, Tagore MM, Tischfield SE, Walsh RM, Suresh S, Fan Y, Campbell NR, Perlee SC, Saurat N, Hunter MV, Simon-Vermot T, Huang TH, Ma Y, Hollmann T, Tickoo SK, Taylor BS, Khurana E, Koche RP, Studer L*, White RM*. +co-authors, *co-corresponding authors. Developmental chromatin programs determine oncogenic competence in melanoma. Science 2021 Sep 3;373(6559):eabc1048.
Developing vaccines against Epstein-Barr virus-associated malignancies
Supervisor: Carol Leung
Location: Centre for Immuno-Oncology, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford
World-wide, over 25% of cancers are caused by infections. One of them is Burkitt’s lymphoma (BL), the most common form of cancer found in children living in equatorial Africa. BL is closely linked to malaria and Epstein-Barr virus (EBV) that plays a key role in BL development and progression. Despite initial success with chemotherapy, relapse rates in sub-Saharan Africa remain high. Dose intensification led to improved outcomes in high-income regions but is associated with high toxicity and requires supportive care unavailable in Africa. Cancer vaccines have the potential to induce anti-tumour responses that can eradicate tumour cells. Our project aims to develop a novel vaccination strategy targeting EBV for preventing relapse of BL. We have designed and generated EBV vaccines that target a range of viral proteins, the next step is to investigate the anti-tumour effect of the EBV vaccines in vitro and in vivo. Given EBV's association with other malignancies such as nasopharyngeal carcinoma and gastric cancer, our research will also inform vaccine development for these diseases. The student will learn techniques in molecular biology and immunology.
References:
J Rühl, C Citterio, C Engelmann, TA Haigh, A Dzionek, JH Dreyer, R Khanna, GS Taylor, JB Wilson, CS Leung*, C Münz*. *Corresponding authors. (2019) Heterologous prime-boost vaccination protects from EBV antigen expressing lymphomas. J Clin Invest. 129(5):2071-2087.
J McAuliffe, HF Chan, L Noblecourt, R Ramirez-Valdez, V Pereira-Almeida, Y Zhou, E Pollock, F Cappuccini, I Redchenko, AV Hill, CS Leung* and B Van den Eynde. *Corresponding author. (2021) Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy. J Immunother Cancer. 9(9): e003218.