Research Opportunities

It is becoming clear that the human microbiome extends beyond the gut with bacteria and fungi found in our cells and tissues. In a range of chronic diseases, evidence is emerging that combinations of pathogens are involved in disease.  Myalgic Encephalomyelitis/Chronic fatigue (ME/CFS), Chronic Lyme disease (CLD) and PANS/PANDAS have been linked to the presence of currently unknown pathogens. In CLD and PANS/PANDAS patients antibiotic treatments have been shown to improve symptoms. In ME/CFS raised levels of anti-microbial peptides, increased gut permeability and elevated levels of antibodies raised against specific bacteria have been found in blood. Data from our collaborator SoftCell biologicals indicates that high levels of wall less bacteria (L-Forms) can be cultured from blood, with high numbers of pathogens also detected by deep sequencing.

In this project we will examine blood samples of PANS/PANDAS, ME/CFS, CLD and healthy controls using metagenomic sequencing approaches. L-Form cultures will be established and subjected to anti-pathogen agents. Cell lines will be infected with L-Form organisms and thoroughly characterised using Raman microscopy and assays of mitochondrial function/dynamics. Oxford studies have shown that peripheral blood mononuclear cells from individuals with ME/CFS, multiple sclerosis and healthy controls are very different. Mitochondria also directly interact with parasites. Anti-pathogen agents and drugs which modulate mitophagy will be tested to determine if they can enhance the clearance of pathogens. The impact of Oxidative phosphorylation, glycolysis and different fuels on mitochondrial pathogen clearance will be investigated.

In contrast to patients after myocardial infarction, fish can fully regenerate their hearts. However, not all fish are able to regenerate to the same extent, allowing comparative inter- and intra-species analysis to identify novel mechanisms controlling successful heart regeneration. We have compared the response of seven different wild type zebrafish strains as well as Astyanax mexicanus surface and cavefish to cryo-injury. Preliminary data shows that there are large differences in regeneration within each species. Using RNAseq, we have identifed OXPHOS as a crucial regulator of this difference with increased OXPHOS being beneficial to long term regeneration. This finding indicates that the current stance in the field, that OXPHOS is damaging the ability for heart regeneration, needs to be re-evaluated.

In this project, we will investigate the mechanisms underlying the beneficial role of OXPHOS during regeneration and the techniques you will perform are targeted metabolomics, QTL analysis, RNAseq and Electron Microscopy. As the human heart relies on OXPHOS for energy, the findings from this project could help identify therapies that can direct OXPHOS to enhance cardiomyocyte proliferation and harness the potential of the human heart to regenerate.

The past decade has seen the emergence of population-level magnetic resonance imaging (MRI) studies like the UK Biobank, which is scanning an unprecedented 100,000 individuals. This imaging has enormous potential to inform about early pathology or susceptibility to disease. However, to translate insights from population-level health data resources into the clinic, we require approaches to translating, or ‘harmonising’, between datasets acquired under very different conditions.

A newly funded collaboration between Oxford and the NIH aims to deliver a novel harmonisation approach by linking relevant tissue biology to the physics of the imaging measurement. Core to this ‘biophysical’ approach is a framework for predicting imaging phenotypes from multi-dimensional spectral measurements of MRI-relevant tissue properties.

This DPhil project will deliver the multi-spectral measurements at the heart of this prediction framework. The student will work within our collaborative team to:

• Year 1: implement multi-spectral acquisition protocols and associated analysis pipelines for use in a large cohort;
• Years 2-3: develop novel biophysical modelling that enables us to characterise and restrict the number of modelled tissue compartments, enabling fewer measurements for clinical scanners;
• Year 4: demonstrate the ability to predict imaging phenotypes based on these measurements in order to harmonise measurements from multiple protocols.

This project would be jointly supervised by the neuroimaging experts in Oxford who are leading brain MRI in UK Biobank (Miller) and physics experts at NIH who have pioneered these multi-spectral measurements (Benjamini).

Most of the current vaccines require two or three doses for optimal efficacy. Missed booster doses contribute to incomplete immunisation coverage globally, resulting in an increased disease burden and delaying pathogen eradication. Achieving full immunisation with a single injection containing both the priming and a booster dose has been a long-standing goal in vaccinology; here the booster dose is encapsulated in polymer microparticles for a delayed release within the body after a pre-defined time period post-injection.    

We have developed a novel microfluidics-based technology for vaccine encapsulation that allows burst-release of the booster vaccine after a range of time intervals and can provide the booster immunisation in vivo. However, recent publications suggest that a superior immune response might be achievable with a repeatedly (continuously) administered vaccine, instead of a standard prime-boost, involving immunological mechanisms such as antibody affinity maturation.

This project will utilise our existing delayed release technology and develop new continuous release formulations, in order to explore the immunological outcome of different modes and kinetics of vaccine delivery, i.e. burst vs. continuous. Immunogenicity and efficacy of vaccines delivered by the two approaches will be evaluated in murine models.

The prospective student will be trained and mentored by Dr Anita Milicic (Jenner Institute) and Prof. Eleanor Stride (Institute for Biomedical Engineering), a cross-disciplinary supervisory team with skills in vaccine formulation, immunology, microfluidics systems, particle engineering and polymer chemistry. In addition, the student will be trained by postdoctoral researchers working on related research programmes focusing on methodologies for particle formulation and characterisation as well as in vivo mouse model systems. 

The brain is continuously bombarded with visual input but has limited processing capacity. Learning to selectively process visual features relevant for behaviour is therefore crucial for optimal decision-making and thought to rely on activity of GABAergic inhibitory interneurons. Altered inhibition is linked to perceptual and learning impairments and associated with neurodevelopmental disorders including schizophrenia and autism.

The aim of this project is to understand the precise role of different types of GABAergic inhibitory interneurons during visually-guided learning and decision-making. Mice have a similarly organized visual cortex and show complex decision-making behaviours. Mouse brain circuits can be measured and manipulated during behaviour in ways not possible in humans.

Our approach is to train mice, including pharmacological and genetic mouse models of neurodevelopmental disorders and healthy controls, in visual decision-making tasks. We measure activity in visual cortex in specific cell types using 2-photon imaging and electrophysiology and use optogenetics to activate or inactivate activity of specific interneuron cell types. We will also apply two new innovative methods to optically measure the inhibitory neurotransmitter GABA (developed in the Looger lab, UCSD) and to locally pharmacologically manipulate GABA levels in the brain (collaboration with Malliaras and Proctor labs, Dept of Engineering, Cambridge) during visual learning and decision-making.

The PhD project is associated with a Wellcome Trust funded Collaborative programme with a cross-disciplinary international research team to investigate the role of GABAergic inhibition in both mice and humans at different scales, from local circuits to global brain networks.

Lab website: https://www.pdn.cam.ac.uk/svl
Contact: Jasper Poort jp816@cam.ac.uk

One of the major obstacles to effectively treating central nervous system (CNS) tumors is the integrity of the blood-brain barrier (BBB). The BBB prevents systemic drug delivery from reaching the brain and brain tumor tissue. While previous studies have mainly focused on circumventing the BBB, very few agents or mechanisms have been explored that modulate the tumor microenvironment to enhance effective therapies for malignant brain tumors. Our studies focus on understanding the heterogeneity of BBB permeability amongst malignant tumor cells and the role of the supportive BBB in tumor growth. Our collaborative laboratory and clinical investigations center around BBB biology, cancer biology, pharmacokinetics and pharmacodynamics related to optimal CNS drug delivery.

Using a clinical/translational approach, we aim to:

1) Evaluate the efficacy of targeted tumor and BBB directed therapy

2) Define the mechanisms that drive differences in neuropharmacokinetics of agents to the CNS

3) Identify exquisite parameters via neuro-imaging of CNS permeability amongst malignant brain tumors.

Our overall goal is to enhance our understanding of the heterogeneity of blood-brain barrier permeability among tumor cells and develop mechanism-based therapeutic interventions to treat affected brain tumor patients at the NIH Clinical Center. We use a combination of cell biology, molecular biology, imaging, pharmacokinetics and animal tumor models.

During development, brains grow rapidly as behaviors develop. Impairment in early brain development often leads to neurodevelopmental conditions, including a number of neuropsychiatric disorders. From early postnatal period throughout adulthood, learning leads to important and dynamic changes in brain circuitry, and in an animals’ behaviors to adapt and sense the environment. The hierarchical yet reciprocal interaction between thalamus and cortex is one of the key brain circuits that are involved in learning-related changes from early development to adulthood.

To investigate the development of thalamocortical connection in the context of sensory learning, this project aims to understand 1) the specificity and plasticity in the interaction between thalamus and cortex during both early development and later life, and 2) how the impairment in this functional connection during early development results in long lasting effects on the capacity for learning in the adult brain. Specifically, we will study how different neuronal types and neuromodulators play a role in the developmental and adult plasticity of thalamocortical connectivity.

To address these questions, we will use the rodent whisker-related sensory-motor system because it is ecologically relevant and critical to the animal’s abilities to navigate and engage in goal-directed behavior. We will apply a multidisciplinary approach that combines molecular and genetic techniques with in vivo intracellular and extracellular electrophysiology, in vivo longitudinal calcium imaging, viral tracing, optogenetic and pharmacogenetic methods, and quantitative behavior and anatomical analyses.

Lee’s lab at NIH will focus on early developmental studies and Bruno’s lab at Oxford will focus on adult plasticity. The two labs will use complementary approaches. A student working with Drs. Lee and Bruno will have a unique opportunity to learn conceptual perspectives from both labs, as well as a wide range of experimental and analytical methodologies in the field of system neuroscience. 

There has been increasing interest in applying computational methods in medicine, to make sense of cancer’s ‘big data’ problem by exploiting recent advances in data-processing and machine learning to capture and integrate clinical, genomic, and image data collated from hundreds of cancer patients in real-time. Such methods can be applied to digital clinical images to extract image information about patterns of pixels that are not perceivable to the human eye, allowing characterisation of tumour.  Prostate cancer is the 2nd commonest male cancer worldwide, and MRI is the diagnostic tool of choice, however, MRI can miss 10% of significant tumours and leads to unnecessary (invasive) biopsy in around 1/3rd patients who do not have cancer.  

We will use a prototype AI system (Pi) developed with Lucida Medical on retrospective data, in a prospective clinical study. We plan to link histological data to imaging features derived from MRI (including texture analysis) to identify predictors of lesion aggressiveness and need for sampling, using biopsy cores and surgical specimens from the prospective cohort. Further work will link biopsy tissue to MRI data to identify radiogenomic markers of disease aggressiveness. The project presents an opportunity for AI to answer key clinical questions at the intersection of interpretation, imaging and biopsy.  

The project will involve working with an established interdisciplinary programme of researchers and help in the assessment of cross-cutting “multi-omic” approaches to cancer assessment, involving integration of advanced image analysis, transcriptomic, genomic, tissue, and patient outcomes to inform the design of diagnostic strategies.

We are developing artificial multi-valent proteins capable of liquid-liquid phase separation (LLPS) with the aim of building multi-functional biomolecular condensates and thereby harnessing specific cellular enzymes to target disease-associated proteins for destruction. We propose to design condensates that contain a class of proteins known as tandem-repeat proteins (RPs). We have shown that RPs are strikingly amenable to rational design and can be engineered to simultaneously bind multiple proteins, bringing them into specific spatial proximity in such a way as to enable a chemical modification of the target protein. The rational design of LLPS systems capable of selectively recruiting client proteins into them to drive specific biological reactions would enable both a deeper understanding of the role of biomolecular condensates in nature as well as the exploitation of their remarkable physico-chemical properties for therapeutic effect. 

Key areas of interest include: 
 

1. Understanding the molecular grammar of protein phase separation to define rules for creating designer LLPS systems. 

2. Developing novel hetero-bifunctional phase-separating proteins to recruit disease-associated targets to the protein degradation machinery. 

3. Translating the designed LLPS proteins into biomolecular condensates in the cell capable of enhancing targeted protein degradation. 

“Life will find a way….” In a now famous quote from the 1993 movie Jurassic Park, the “chaotician” Ian Malcolm nicely captures the essence of adaptation through evolution. But series evolutionary change often requires multiple mutations to arise – the changes arising from SNPs and indels in single genes usually amount to little more than phenotypic “tinkering”. So what would happen if we could “step on the evolutionary gas pedal” and accelerate the pace of change? Or alternatively, what would be the consequences of “slamming on the evolutionary brakes” to prevent adaptation? Well, these are just the kind of approaches that we have developed in the Welch lab, and we are applying these to look at how the opportunistic bacterial pathogen, Pseudomonas aeruginosa, adapts to the presence of infection-relevant selection pressures. Essentially, we’ve engineered the mismatch-repair system to come under the control of an inert chemical inducer, and so can “rheostatically” modulate the rate of mutation from very high (1000 x the wild-type level) to very low indeed (eliciting a state of “hypomutation” in which evolutionary change essentially grinds to a halt).

Using this system, we aim to investigate the evolutionary trajectories of P. aeruginosa when challenged with intense selection pressures e.g., in a polymicrobial environment, or upon exposure to antimicrobial agents or nutrient limitation. Project will involve elements of synthetic biology, microbiology, evolutionary biology, modelling and genomics. A stable polymicrobial culture system has recently been developed by the lab and is available for use.  

The brain is a site of relative immune privilege, long considered isolated from the peripheral immune system. We recently identified a population of resident T cells in the healthy mouse and human brain, important for the maturation of microglia (Pasciuto et al, Cell 2020). By analysing the kinetics of migration between the blood and brain, we found that the key bottleneck controlling the number of anti-inflammatory regulatory T cells in the brain was the high rate of cell death the cells exhibit when housed within the brain. Through developing a unique tool, with potential therapeutic application, we were able to deliver a biologic directly to the brain and enhance the size of the regulatory T cell population. The approach protects mice from brain damage following traumatic brain injury, stroke and multiple sclerosis. In this project we wish to explore the immunological processes that drive damage during neuroinflammation, and to harness immune-modulating biologics to prevent damage to the brain. 

Despite recent improvements in population health and prevention, heart failure prevalence and mortality are stagnant overall, with a disproportionate burden in Black, Hispanic and South Asian populations.

Single centre studies provide highly phenotyped populations covering genomics, metabolomics, advanced imaging and longitudinal health trends. In contrast large centralized healthcare data covers decades of hospital admissions and mortality for millions of people, with this data growing in depth, richness and complexity. Collaborations that leverage both approaches have the unique potential of providing needed new insights in the poorly understood heart failure syndrome.

Using advanced cardiac magnetic resonance imaging capabilities and novel biomarkers (NIH), we will conduct deep phenotyping in a diverse cohort of patients with heart failure to elucidate disease phenotypes and differences between races. At a national level (University of Cambridge) we will look at equitability of access to advanced imaging (such as MRI) and interventions (implantable defibrillators) and the impact of these on health outcomes.

Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark of cardiovascular diseases such as atherosclerosis, which cause heart attack and stroke. In healthy vessels, VSMC contraction regulate blood flow and blood pressure but loose their contractile function and undergo extensive transformation upon vasuclar insult. This process results in the generation of a wide spectrum of phenotypically changed cells within atherosclerotic lesions, which are predicted to impact differently on disease progression. Using clonal lineage tracing in mouse models of atherosclerosis, we demonstrated that disease-associated cell accumulation result from extensive proliferation of a small subset of VSMC that can generate the full range of distinct cells. By combining lineage tracing with single cell RNA sequencing (sc-RNAseq) in mouse models, we have identified signatures of VSMC-derived cells subpopulations. Interestingly, cells displaying mesenchymal stem cell character are rare in healthy vessels and their numbers increase in disease models. The aim of this project is to understand how specific VSMC-derived cell populations in human disease arise, using a combination of genomics and functional assays, in order to allow efficient cell targeting in atherosclerotic lesions.

The human placenta is the first organ of the embryo and it is functional immediately after implantation. Before fetal organogenesis, the placenta holds a multi-functional and unique role as a physical, chemical, and cellular barrier. It alone orchestrates the chemical communication between mother and fetus. Most of this communication is mediated by the secretion of specific placental peptide hormones (hCG, hPL, etc.) into the maternal bloodstream. Despite these hormones having developmental and irreplaceable functions, little is known about their intracellular life: synthesis, intracellular traffic, secretion, and degradation. More importantly, many pregnancy disorders are associated with lower expression and levels of these hormones in circulation, such as fetal growth restriction and preterm birth. The cell biology of these diseases is not well understood.

With the recent advance in human placenta organoid development and novel culture techniques of trophoblasts derived from stem cells, we can now finally interrogate the fundamental questions about placental hormones' intra and extra-cellular fate. In combination with the diverse set of advanced imagining methods available between the co-mentors of this project (advanced fluorescence and cryo-electron microscopy), innovative multi-omics techniques, and advanced biochemistry and cell biology approaches, we propose to 1) discover the diversity of secretory granules (SGs) expressed in and secreted from the human placenta; 2) implement a novel in vitro secretomics approach to determine the molecular machinery that regulates the secretion of the SGs and their content; 3) validate the mechanisms using human placenta and isolated trophoblasts from donated tissue and new placenta organoids culture.

The successful candidate will have the opportunity to train on several modern imaging techniques and learn about the fundamentals of placenta development and physiology while using a multi-disciplinary approach in a team of expert cell biologists from both institutions and generating impactful basic and applied research.

Adolescence and early adulthood are important developmental periods when young people develop health-related habits that are likely to persist through their adult life. This is also a period when health inequalities emerge, as young people finish their education and enter the labour market, developing their individual socioeconomic position. Improving our understanding of the factors that contribute to the development of diet, related health behaviours, and health inequalities over this life stage will help to identify targets for public health policy and intervention.

We currently know little about the factors which influence changes in health behaviours over the transition from secondary education into further education and employment. This PhD project will focus on this question through analysis of data from the US-based NEXT Generation Health Study and from the UK-based DEBEAT study, applying epidemiological methods to assess changes in health behaviours (diet, physical activity and sleep) through adolescence and early adulthood, analyse dynamic relationships between different behaviours, and investigate how differences in these patterns of development between different groups of the population contribute to health inequalities.