Research Opportunities

Mitochondria are present in every nucleated cell and perform many essential functions. Their primary role is the efficient generation of adenosine triphosphate (ATP) which is required for all active cellular processes including protein synthesis, cell growth and repair. Mitochondrial dysfunction is seen in many common and rare diseases, but given their central role in cell homeostasis, it remains puzzling why this targets some cell-types and not others. We have developed new single-cell methods allowing us to address this question by studying tens of thousands of cells in the brain over the life course. This will cast light on the role of mitochondria in human ageing and neurodegenerative diseases.

There is a need for new drugs to combat viruses that threaten our health. Most existing antivirals inhibit virus attachment/entry or target critical enzymes, and new antiviral targets are needed to develop novel treatments and counter antiviral resistance. One key process in the life cycle of many viruses is the formation of dynamic organelles called viral factories. There is increasing evidence that some viral factories form via liquid-liquid phase separation (LLPS), including SARS-CoV-2, influenza, and measles virus. These compartments concentrate viral replication enzymes and sequester replication intermediates from the immune sensors. Targeting the physicochemical process of phase separation is an emerging paradigm that may underlie the discovery of novel, broad-spectrum antivirals, but this can only be realised by first understanding how viral factories form. This research project will focus on dissecting the physicochemical properties of these viral condensates to understand how their dynamic conformations and posttranslational modifications that affect charge mediate assembly of viral factories, and in doing so, identify targets for future therapeutic intervention. To quantitatively describe the formation of these condensates, we will examine the observed phase transitions of binary and tertiary mixtures of recombinantly produced viral proteins, as well as viral RNAs in vitro using the recently developed high-throughput microfluidics platform PhaseScan. These findings will lead us to define a new model of viral replicative condensate formation that addresses protein-specific attributes (posttranslational modifications, conformation), and their highly selective RNA composition (partitioning of cognate viral transcripts and exclusion of non-viral RNAs). The insights gained from these approaches will underlie the search for compounds that could serve as drug templates for prospective therapies for RNA viruses and improve our fundamental understanding of the synergistic interactions of viral proteins that spontaneously form complex condensates that are involved in viral replication.

This project will provide an excellent research environment that will foster the future development of the PhD candidate through extensive multi-disciplinary training in
i) microfluidics;
ii) protein biochemistry;
iii) biophysics of condensates;
iv) machine learning approaches required for bespoke data analyses.

This project will provide a unique training environment required for training next-generation biochemists interested in exploring biomolecular condensates and their roles in viral replication and assembly, with an ultimate goal of identifying new druggable antiviral targets.

This team is interested in the development and repair of musculoskeletal tissues. Diseases of the musculoskeletal system include those that arise during development, including inherited connective tissue diseases such as Marfan Syndrome and chondrodysplasias, as well as the highly prevalent age-related disease of joints, osteoarthritis. The team uses model systems as well as large human datasets to explore molecular drivers of disease and mechanisms that underly chondrogenesis and cartilage repair, including stem cell biology and deciphering intrinsic cartilage repair mechanisms.

Burkitt lymphoma (BL) is an aggressive cancer of germinal centre B cells that largely affects children globally. In sub-Saharan Africa, Burkitt lymphoma is an endemic disease associated with Epstein-Barr Vius (EBV) and Plasmodium falciparum infection. Unfortunately, children in sub-Saharan Africa have a far worse outcome with about 40% of children surviving compared to greater than 90% elsewhere, particularly in high income countries in Europe and North America. This is due to low access to reliable pathology diagnosis, limited access to specialized oncology centres, where the effective cytotoxic treatments and necessary life support can be given to patients during care. However, there might be biological factors that contribute as well to differences in outcome> For example, Burkitt lymphoma in sub-Saharan Africa is associated with EBV and Plasmodium falciparum infection, which may mediate a different tumour landscape (predominated by action of mutator enzyme adenosine-induced cytosine deaminase), whereas elsewhere these factors are lacking and the tumour landscape is influenced by accumulation of mutations in genes influencing apoptosis. In Cambridge, Prof. Turner has developed in vivo models of both sporadic and endemic Burkitt lymphoma that facilitate comparative research into disease mechanisms. In this project, these will be employed to understand the clonal heterogeneity of these malignancies using a combination of in vivo CRISPR screens and lineage tracing. Data will be validated using a large resource of primary patient specimens available within the EMBLEM study coordinated by the National Cancer Institute. Ultimately, data will be analysed with a view to developing biomarkers of disease prognosis as well as novel therapeutic approaches. In both cases the resource settings of sub-Saharan Africa will be considered towards sustainable and achievable approaches. The student will have the opportunity to travel to Uganda during the course of their studies.

Globally, HIV and schistosomiasis are leading causes of death due to infectious diseases. Despite available interventions, the infections remain uncontrolled in low-income settings causing acute and chronic morbidities. Intestinal schistosomiasis is caused by a parasitic blood fluke, most commonly of the species Schistosoma mansoni, and is predominantly found in sub-Saharan Africa. Chronic infections lead to advanced disease including liver fibrosis, portal hypertension, upper gastrointestinal tract bleeding, and severe anaemia. In the context of coinfections, severe clinical outcomes including death may be likely due to immune failure, interactions related to general fibrosis, and responses to starting antiretroviral therapy. In this project, you will have the opportunity to work with cutting-edge statistical and big data approaches alongside state-of-the art immunology to examine disease progression in the context of schistosome and HIV coinfections in arguably some of the poorest settings worldwide.

The group of Associate Prof. Chami studies schistosomiasis evaluating transmission, clinical outcomes, and treatment strategies, especially for liver fibrosis, in the SchistoTrack Cohort with the Uganda Ministry of Health. This Cohort is the largest individual-based cohort tracking individuals prospectively in the context of schistosomiasis. At Oxford, students can get exposure to computational, big data approaches to clinical epidemiology and field experience in global health research.

The group of Dr. Sereti studies HIV immune pathogenesis with a focus on inflammatory complications related to HIV and coinfections. Studies on biomarkers and how they may assist in identifying early people with HIV who may develop inflammatory and other adverse complications is currently an active area of investigation in the lab as they can also inform disease pathogenesis and new targeted interventions.

At the NIH, students can get experience in immunology research (wet lab) with optional exposure to complicated cases within a clinical setting.

Globally, HIV and schistosomiasis are leading causes of death due to infectious diseases. Despite available interventions, the infections remain uncontrolled in low-income settings causing acute and chronic morbidities. Intestinal schistosomiasis is caused by a parasitic blood fluke, most commonly of the species Schistosoma mansoni, and is predominantly found in sub-Saharan Africa. Chronic infections lead to advanced disease including liver fibrosis, portal hypertension, upper gastrointestinal tract bleeding, and severe anaemia. In the context of coinfections, severe clinical outcomes including death may be likely due to immune failure, interactions related to general fibrosis, and responses to starting antiretroviral therapy. In this project, you will have the opportunity to work with cutting-edge statistical and big data approaches alongside state-of-the art immunology to examine disease progression in the context of schistosome and HIV coinfections in arguably some of the poorest settings worldwide.

The group of Associate Prof. Chami studies schistosomiasis evaluating transmission, clinical outcomes, and treatment strategies, especially for liver fibrosis, in the SchistoTrack Cohort with the Uganda Ministry of Health. This Cohort is the largest individual-based cohort tracking individuals prospectively in the context of schistosomiasis. At Oxford, students can get exposure to computational, big data approaches to clinical epidemiology and field experience in global health research.

The group of Dr. Sereti studies HIV immune pathogenesis with a focus on inflammatory complications related to HIV and coinfections. Studies on biomarkers and how they may assist in identifying early people with HIV who may develop inflammatory and other adverse complications is currently an active area of investigation in the lab as they can also inform disease pathogenesis and new targeted interventions.

At the NIH, students can get experience in immunology research (wet lab) with optional exposure to complicated cases within a clinical setting.

There is a pressing need to improve the understanding of morbidity for schistosomiasis. These parasitic blood flukes afflict over 250 million people worldwide with over 700 million people at risk. For Schistosoma mansoni (a species that causes the intestinal form of schistosomiasis), untreated individuals can develop severe or functional morbidities such as enlarged livers/spleens, periportal fibrosis, oesophageal varices, anaemia, and chronic gut inflammation. The onset and progression of these morbidities is a complex interplay of host genetics and immune response, environmental factors, coinfections, and social determinants. This project is an exciting opportunity to combine work in immunology with epidemiology, providing opportunities to apply computational approaches, experimentally test mechanistic hypotheses found in humans in mice, and gain fieldwork experience in global health research. The candidate will gain skills in both wet lab work and fieldwork in Uganda. You will join multidisciplinary labs at the NIH-NIAID and Oxford.

Many pathogens can infect a wide range of potential hosts. Understanding the factors that control pathogen host range is critical for understanding host-pathogen biology and for identifying potential reservoirs of disease. A major determinant of a pathogen’s host range is the compatibility between the pathogen’s effectors and key host proteins, such as host receptors required for infection or host immune proteins whose function the pathogen specifically neutralizes. We are developing and utilizing a new approach to systematically explore which animals carry host proteins that are susceptible to particular pathogen effectors. For a known targeted host protein, we identify thousands of homologs from across the space of sequenced genomes, and then synthesize the surface of the homologs bound by the effector and test whether the effector can bind them.

This project will involve selecting an important human pathogen, such as malaria, HIV, plague, or any other pathogen of interest to the student, and applying our systematic approach to determining its potential host range. We are also interested in exploring other applications of this novel approach, such as testing a single host protein against a range of pathogen effectors to determine the space of potential future pathogens. Please get in touch if you have ideas anywhere in this space!

Creatine is an important energy storage and transfer molecule in muscle and brain but is synthesized primarily in the kidneys and liver. Hence, creatine uptake in skeletal muscle, brain, and heart is dependent on the creatine transporter (CrT or SLC6A8). Loss-of-function mutations in CrT are the second most common cause of X-linked intellectual disability and low tissue creatine levels result in skeletal muscle atrophy and are closely associated with heart failure. Cells down-regulate expression of CrT when creatine levels are high, but the mechanisms underlying this autoregulation and the importance to normal physiology and disease are unknown.

Recently, we found that creatine feedback inhibits translation of the CrT mRNA to control transporter production, and we identified elements in the CrT mRNA that are important for this control. This PhD project will involve molecular genetic analyses to more fully characterize the translational control mechanism(s) by which creatine feedback inhibits its own cellular uptake. In addition, CRISPR-Cas technology will be used to eliminate the translational control mechanisms in mice, and then physiological studies of the mice will be used to characterize the role of CrT autoregulation.

In the last decade alone, degenerative diseases have featured heavily in the ten leading causes of death. Degenerative diseases and injuries have not only seen a marked increase in mortalities but are also the major contributor to the rising disability in our aging populations. As a result, there has been significant interest in developing improved implantable medical devices, which aim to replace, support, and restore the function and mobility lost by diseased tissues.

The extra cellular matrix (ECM) of tissues is an excellent base material for therapeutic and regenerative biomedical devices, since they can mimic the biological, chemical and physical environment experienced by cells in healthy tissue. However, the biomedical devices currently fabricated from the ECM have limited tunability or dynamic control once implanted within the body. The aim of this project is to develop soft robotic biomedical devices from biological polymers. Soft robots are flexible, have a high specific strength and high response rates which make them ideal for applications requiring sensitive motions. Biopolymers are an attractive material choice for biomedical soft robots: they are abundant, biodegradable, and can offer excellent biomimicry if derived from the ECM. However, these polymers typically display limited stimulus-driven shape change on their own.

As part of the project, the student will optimise the electroactivity of tissue-derived biopolymers and eventually develop a proof-of-concept therapeutic device for an application of their interest. Possible applications include (but are not limited to) drug delivery, neural and cardiac stimulators, sensors for cell attachment and proliferation. The project will involve the fabrication and structural characterisation at the nano- and micro-scale, assessment of electrical activity and opportunities for in-vitro/in-vivo testing.

The laboratory of Prof. Bridge in Oxford uses multi-modal MRI to understand the pathways in the human visual system, and how they are affected by vision loss early or late in life.

The laboratory of Dr. Nienborg at the NIH combines behavior, neurophysiology, and videography in mammalian animal models to better understand how the visual system processes information depending on the animal’s behavioral and cognitive state. 

Visual processing during natural behavior requires subjects to distinguish between changes in visual information caused by a subject’s own body movements (e.g. by walking along a street), and those caused by changes in the external world (e.g. a car driving by). How the brain achieves this is fundamental to understanding visual perception. Moreover, the degree to which their own body movements affect processing in visual cortex in normally sighted and blind subjects has direct implications for the development of neural prostheses targeting the visual cortex.

The project will have two objectives:

1. Identify how spontaneous body movements affect processing in the visual cortex in a mammalian animal model during head-free, naturalistic behavior.
2. Compare the modulations in the visual cortex by a subject’s own body movements in sighted and blind human participants.

This project will allow students to learn wireless electrophysiological recordings in mammalian animal models (e.g. non-human primates or a highly visual rodent species) combined with videography during naturalistic behavior. Students will also be able to learn how to leverage recent machine learning approaches for the analysis of the video and neural data. Additionally, students will have the opportunity to learn how to acquire and analyze functional MRI data in sighted and blind human subjects, using a variety of tools.  

Evolution has produced an arms race between viruses and the cells they infect. Studying this battle provides key insights into cell biology and immunology, as well as the viruses themselves. It may even lead to the development of novel therapeutics. The Matheson lab therefore focuses on two pandemic viruses with a major impact on human health: HIV and SARS-CoV-2.  

We have previously used unbiased proteomics to quantify dysregulation of hundreds of proteins and processes in infected cells, and now aim to understand the importance of these targets for both viral pathogenesis and normal cellular physiology. Because HIV regulates numerous cell surface amino acid transporters, we are particularly interested in amino acid metabolism and protein biosynthesis.  

Depending on the interests of the student, this project will therefore focus on either (1) an orphan cell surface amino transporter downregulated by SARS-CoV-2 infection of respiratory epithelial cells or (2) an ancient metabolic enzyme regulating ribosomal frame shifting depleted by HIV infection of primary human CD4+ T cells.  

In either case, the aims will be to: validate the target in different systems; define the mechanism of viral regulation; determine the functional effects of target depletion in biochemical and cell biological assays; and characterise the impact of target depletion on viral infection. Opportunities will be available to conduct further proteomic screens, perform ribosomal profiling and/or stable isotope-based metabolomics.   

The project will provide training in a wide range of molecular and biochemical techniques, whilst allowing the student to explore an important aspect of the host-virus interaction. The Matheson lab is based in the brand new Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), including the largest academic Containment Level 3 (CL3) facility in the UK. The student will be supervised by an experienced postdoc in a friendly, supportive group. 
 

Our research group aims to understand hypertensive disease progression of women and their children following pregnancy complications, such as hypertensive pregnancy and preterm birth, to identify optimal approaches to reduce long term risk. This includes development of new clinical tools to identify, track, and slow the disease progression as well as novel interventions.

This project will apply computational modelling and machine learning to large scale imaging datasets to study disease progression related to a hypertensive pregnancy across multiple modalities and organs. The insights into key structural and functional changes at the organ-level that describe stages of disease will be used to identify potential intervention targets.

Furthermore, we will use imaging data collected within our ongoing clinical trials to help us understand how interventions modify the underlying disease development and how this could be incorporated in clinical practice to transform long-term patient outcomes after a hypertensive pregnancy.

Our group works to enable health research in diseases, communities and settings where evidence to enable prevention, treatment and management of devasting burdens to health are woefully lacking. Our research sets out to understand how research methods, processes, skills and implementation could happen better, and be locally-led, in the most underserved regions across the globe. Our approaches are typically participatory, mixed-methods action research. This could be exploring health research study design, or how to work with the community to tackle perceptions about research and how to overcome these.

We work with health research teams and health workers across Africa, Asia and Latin America and work together to look closely at the challenges they are experiencing in the design, set-up, operational delivery and reporting of their research. We seek to work with them to identify better methods and approaches. We work in delivering skills training and capacity development and we also use digital technology and want to use advances in machine learning to drive equity in access to knowledge so that researchers, wherever they are, have access to the same quality and volume of training and resources.

Undertaking a DPhil with us could involve clinical trial design, or the application of AI in healthcare. It could have a social science or health economic component. Our DPhil projects always involve working in partnership with our collaborators in the Global South, and therefore travel and capturing data in those settings would be very likely. All our research is about tackling the inequity about where health research happens, who leads and who benefits from the data.

What sets the brain apart from other organs is its complex connectivity. In order to study brain function, we need techniques for measuring brain connections with high precision in living humans. The goal of this project is to develop new methods for measuring brain connections using magnetic resonance imaging (MRI).

The project focuses on the cortex, a thin sheet of grey matter surrounding the brain. The cortex is well developed in primates, particularly humans, and plays a key role in cognition. It has a characteristic layered structure; each layer containing different varieties of neurons and connections. The input and output of a cortical region is determined by the connections of the layers. Thus, measuring layer connectivity can give us key insight into information flow in the brain. But these detailed anatomical patterns have only been studied in animal brains, where it is possible to precisely delineate connections.

This project aims to develop new methodology to study layered connectivity in the human brain using MRI. The incredible flexibility of MRI allows us to sensitise the measured signals to multiple aspects of tissue microstructure. We will use this flexibility to create MRI measurements that are sensitive to cortical lamination and integrate these measurements with computational models of laminar connectivity.

This project will open the door to addressing new questions about human brain organisation, such as whether brain areas are organized hierarchically, how information flows across the brain during cognition, learning, and memory; and what happens in diseases that disrupt brain connections