Research Opportunities

My group studies the human malaria parasite Plasmodium falciparum.  Collaborative PhD projects can be offered in research areas centered around Plasmodium DNA biology: we are particularly interested in the molecular mechanisms underlying DNA replication and cell cycle control in Plasmodium, which replicates by an unusual method called schizogony.  We are also interested in mechanisms for silencing and promoting the recombination of a family of key virulence genes called var genes - particularly the role that G-quadruplex DNA structures may play in var gene control.  In fact, we have recently discovered that G-quadruplexes and their helicases have more general roles in genome stability and evolution in the malaria parasite as well.

This collaborative project between Dr. Steven Holland’s laboratory at the NIH and Dr. Lalita Ramakrishnan’s lab at the University of Cambridge will seek to understand the mechanistic basis of human susceptibility to environmental mycobacteria that are nonpathogenic to most people but can cause serious disease in individuals with specific immune deficiencies. Dr. Holland runs an international referral service that takes care of a unique cohort of patients with genetic susceptibility to nontuberculous mycobacterial infections. In the lab, they are mapping these susceptibilities and have found then to map to distinct immune genes, e.g., IRF8 and GATA-2, myeloid growth factors, IL-12R, the GTPase Rac2, to name only a few. 

Dr. Ramakrishnan’s group has pioneered the optically transparent and genetically tractable zebrafish as a model for mycobacterial pathogenesis. The use of the zebrafish has enabled discoveries about TB immunopathogenesis and the genetic basis of susceptibility to TB which has led to the discovery of a variety of inexpensive, approved drugs that can be used to treat TB, often in a patient genotype-directed manner. They have also used the zebrafish to understand the mechanism of leprosy neuropathy.

Through this joint project, the two labs will work together to harness the power of the zebrafish to understand the molecular and cellular basis of the human susceptibilities identified by Holland. The student will move between humans and fish (and Bethesda and Cambridge) to uncover fundamental mechanisms of mycobacterial disease pathogenesis while acquiring mastery over the disciplines immunology, infectious diseases, genetics, molecular biology and cell biology.

There are more than 200 million clinical cases of malaria each year, leading to nearly half a million deaths, primarily among children in Africa. The two major tools for malaria control, antimalarial drugs and insecticides, are both seriously threatened by resistance, making the search for a highly effective malaria vaccine more urgent than ever. My lab focuses on the malaria parasite blood stages, during which parasites invade, multiply inside and consume human erythrocytes. The process of erythrocyte invasion represents a brief extracellular window in the parasite life cycle when parasites are exposed to the antibody-mediated immune system, making it a potential vaccine target. A number of vaccine-related projects are available that intersect with the interests of NIH collaborators in the NIAID Malaria Research Program, from systematic screening of new potential vaccine candidates, to deep structural understanding of current high-profile candidates, to understanding natural immunity to malaria by working with partners in endemic countries in order to inform better vaccine design. All could involve a mix of new technologies, including CRISPR/Cas9 engineering of parasite genomes, and represent an opportunity to contribute to the long-term battle against one of humanities oldest and most persistent infectious disease foes.

A signalling pathway linking nutrient availability to changes in gene expression that hinges on the phosphorylation of translation initiation 2 (eIF2) has long been known to exist. Recognized initially as the yeast General Control Response, recent convergent lines of research have implicated its metazoan counterpart, the Integrated Stress Response, in diverse physiological processes ranging from immunity to memory formation.

This PhD programme will exploit our emerging detailed understanding of translation initiation and termination to shed light on unanticipated mechanistic aspects of the ISR. An understanding of these details may inform efforts to target the ISR to therapeutic ends.

Apicomplexan pathogens are highly-adapted intracellular parasites of humans causing disease including malaria, toxoplasmosis and cryptosporidiosis. These parasites actively confront, subvert and defend themselves against host immune attack using a complex suite of parasite surface and secreted proteins that hijack immune signalling pathways. Moreover, transmission and generation of genetic novelty occurs in definitive hosts where differentiation into sexual parasite forms occurs. Relatively little is known, however, of the molecules and processes that drive these events, particularly during the sexual stages of parasite development. This project will use new methods in in vitro culture of sexual development in Toxoplasma, advanced methods for global spatial characterisation of parasite cell proteomes in order to identify specific proteins thought to be implicated in these interactions, and then utilise CRISPR/cas9 mutagenesis tools to engineer pools of strains deficient in these specific proteins. By assaying mutant pools both in vitro, and through the definitive host we will identify proteins and processes required for sexual stage conversion.

Primary progressive multiple sclerosis (PPMS) is a chronic demyelinating disease of the central nervous system, which currently lacks restorative therapies. Transplantation of neural stem cells (NSCs) has been shown to promote healing of the injured CNS, but previous work has demonstrated that NSCs from patients with PPMS are prematurely senescent. Cellular senescence causes a pro-inflammatory cellular phenotype that impairs tissue regeneration. Senescence in PPMS NSCs was found to be associated with increased secretion of HMGB1, a pro-inflammatory alarmin found to inhibit oligodendrocyte differentiation, and also found increased within white matter lesions of PPMS autopsy tissue. This project aims to understand the role of HMGB1 in PPMS NSC senescence using techniques such as CRISPR-Cas9, RNA sequencing, and functional NSC assays. The longterm goal of this project will be to determine the cause of senescence in NSCs from patients with PPMS and if these cells are suitable for therapeutic use.

Andrew Holmes’ Lab (NIH/NIAAA) and Armin Lak’s Lab, Oxford University

Several decades of research has shown that medial frontal cortical neurons, as well as the neuromodulatory system that innervate the medial frontal cortex, notably the dopamine system, are important in reward valuation and decision making. However, it is not known whether different regions of medial frontal cortex play distinct roles in guiding decisions. Moreover, the role of frontal dopamine signals in shaping and regulating decisions has yet to be established. To address these questions, this project will use a combination of large-scale Neuropixels recording across the medial frontal cortex, as well as optical measurement of dopamine release in the medial frontal cortex during decision making in mice. At Oxford, the project will use Neuropixels probes to record the activity of many neurons across different regions of medial frontal cortex while mice perform a task that systematically manipulates the value of choice options. This data will allow us to investigate the relation between frontal neuronal activity and decision-making variables, and characterize distinct roles of different medial frontal regions in choice behavior. At NIH, the project will take advantage of optical and genetic methods to measure the dynamics of dopamine release in frontal cortical regions identified in the electrophysiological recordings. These experiments will reveal the roles that frontal dopamine play during decision making. In analyzing the electrophysiological and optical data, we will use computational models of learning and decision making to relate neuronal signals with trial-by-trial model-driven estimates of decision variables. The project is primarily experimental in nature but will provide an opportunity to develop computational skills. Together, the project will provide fundamental insights into behaviorally-relevant computations that neurons across the medial frontal cortex perform during decision making, and will reveal the roles of frontal dopamine signals in shaping choice behavior. For more information please visit: https://www.niaaa.nih.gov/laboratory-behavioral-and-genomic-neuroscience and https://www.laklab.org.

*This project is available for the 2021 Oxford-NIH Pilot Programme*

This project will explore ex vivo the characteristics of those cells which may contribute to persistent HIV infection. Undertaken in state-of-the-art facilities at the Peter Medawar Building in the University of Oxford, the project will combine flow cytometry, cell sorting and gene expression approaches (including RNAseq and single cell technologies) to characterise in detail those cells that contain latent HIV infection. Applying these techniques to individuals who stop antiretroviral therapy and are monitored longitudinally for viral rebound will allow further definition of the environment in which viral transcription is initiated.

The candidate will map the immune responses of individuals started on early antiretroviral therapy to determine how these are impacted by starting ART and which components of the immune response correlate with the reservoir and persisting viraemia. Additionally, samples from individuals under-going treatment interruption will allow further detailed  characterisation of immune correlation of rebound and remission.

The candidate will combine flow cytometry and molecular techniques to help clarify the phenotype of cells latently infected with HIV. Further objectives will explore changes in cell phenotype and gene expression profile that associate with rebound viraemia. Additionally, exploration of the antigen-specificity of latently infected cells through other approaches such as TCR sequencing and the ability to which these cells can be targeted by the immune system will be a parallel component of this project.

Asthma is the world’s commonest chronic lung disease, affecting 350 million people worldwide. The advent of novel ‘biologic’ therapies targeting specific phenotypes of asthma is currently revolutionizing the treatment of patients with type 2 inflammation. However, there are no specific treatments available for the 50% of patients with type 2 low disease. The Levine group has identified a novel pathobiologic mechanism involving dysregulation of apoplipoproteins, which may play an important role in this phenotype by regulating the recruitment and function of innate and adaptive immune cells, which may have relevance for resistance to corticosteroids. Peptide mimetics of these molecules have potential as novel therapies for asthma, especially for patients with type 2 low neutrophilic inflammation. Dr Hinks group uses in vitro, murine and ex vivo human studies on highly phenotyped asthmatics to explore the biology of the inflamed airway mucosa, particularly innate and adaptive immune cells. Through this collaboration the student would use a range of techniques and a mix of wet lab science and human experimental medicine to understand the translational potential of apolipoprotein biology in human asthma.

The Domingos laboratory researches neuroimmune mechanisms underlying obesity. We discovered the sympathetic neuro-adipose junction, a functional synapse-like connection between the sympathetic nervous system and white adipocytes (Cell 2015). We found that this neuro-adipose junction is necessary and sufficient for fat mass reduction via norepinephrine (NE) signaling (Cell 2015, Nature Comm 2017). We then discovered Sympathetic neuron-Associated Macrophages (SAMs) that directly import and metabolize NE. Abrogation of SAM function promotes long-term amelioration of obesity independently of food intake (Nature Medicine, 2017). Given the recent discovery of SAMs, virtually nothing is insofar known about the cell biology of these cells or what other immune cells populate the SNS to cross talk with SAMs.

This PhD project aims to uncover  biological mechanisms of SAM biology. Using single cell sequencing methods, the student will unravel the heterogeneity of the sympathetic neuro-immune cross talk involving SAMs. By identifying novel immune cell mediators, we will have a better understanding of how SAMs are regulated, and pave the way to the identification of cellular and molecular targets that would then be amenable to drug delivery. We will be guided by singe cell sequencing dataset for formulating hypothesis that model fundamental aspects regarding the biology of these cells. The interactions between SNS axons and SAMs, or other resident cells identified by single cell sequencing, will be resolved by super resolution microscopy and 3D reconstruction, for a better understanding of the intricate topology of SAMs’ morphology in relation to SNS axons (Nature Medicine 2017). The PhD candidate can also use optogenetics to probe neuro-immune interactions (as in Nature Medicine 2017), as well as 3DISCO imaging for mapping the distribution of the aforementioned cells in adipose tissues. This project will give a candidate a tremendous opportunity to apply cutting-edge methods in the growing field of neuroimmune biology.

Alzheimer disease (AD), dementia with Lewy bodies (DLB) and Parkinson disease (PD) are the most common neurodegenerative diseases that create an enormous public health burden with a rapidly aging population. There is currently no definitive test that allows doctors to determine if someone has or will get one of these disorders. At present, the diagnosis is purely based on the symptoms, but by the time this is made the disease process is already too advanced for any therapies to have full impact. There is a clear and urgent need for reliable diagnostic tests that can identify early signs of dementia and movement disorders, and methods that can distinguish between the different types of neurodegeneration e.g. AD / DLB / PD so that drug treatment can be prescribed in a patient specific manner. Early, sensitive and reliable diagnostics will inevitably open an invaluable window for not only to early treatment but also towards finding a cure.

The intention of this DPhil project is to develop such a diagnostic method where samples taken from patients can be  interrogated using a highly sensitive and specific clinic-ready technique/ “kit” called Real-Time Quaking-Induced Conversion (RT-QuIC). An RT-QuIC method, which detects multiple sticky proteins in cerebrospinal fluid (CSF) as a surrogate marker of brain pathology has already been established by the Parkkinen lab to identify signs of early onset Parkinson’s disease (http://www.bbc.co.uk/news/health-37196619). Our aim here is to develop complementary RT-QuIC methods for AD and DLB patients. We anticipate that this will serve as a powerful predictive tool for patients at high risk of developing dementia i.e. patients with mild cognitive impairment, and enable a personalised test that can identify specific variants of the disease. In addition, we are using the RT-QuIC method to understand the disease pathogenesis, particularly the role of different conformational variants, or “strains” of proteins that may contribute to the tremendous heterogeneity of neurodegenerative diseases by showing different morphology, seeding and/or cross-seeding propensities, strain-specific neuropathology and different levels of neurotoxicity.

The proposed project will require vast biochemical, biophysical, molecular neuroscience and pathological skills and knowledge provided by the unique translational training environment formed by Dr. Parkkinen and her local and international collaborators who are all experts on the field. Dr. Parkkinen’s Molecular Neuropathology research group is based at state-of-the-art facilities at the Academic Unit of Neuropathology (AUN) and Oxford Brain Bank which are part of the Nuffield Department of Clinical Neurosciences (NDCN) in the University of Oxford. Research into neurodegenerative diseases has a high priority and profile within the University of Oxford and especially NDCN. Dr. Parkkinen is also an integral part of the Oxford Parkinson’s Disease Centre (https://www.dpag.ox.ac.uk/opdc) which is a multidisciplinary group of internationally recognised scientists with strengths in genomics, imaging, neuropathology, biomarkers and cell and animal models. Regular meetings are arranged for all post-graduate students within AUN/NDCN, and feedback and guidance is provided to ensure completion of the degree within the allocated time. All the necessary funding is provided by Dr. Parkkinen’s successful Weston Brain Institute and Parkinson’ UK grants.

At the National Cancer Institute, we have demonstrated that higher levels of moderate to vigorous intensity physical activity are associated with a lower risk of cancer, including cancer in the breast, colon, endometrium, bladder, kidney, and stomach1. However, due to a reliance on self-reported measures of physical activity, a number of key questions remain unanswered on what overall volume of physical activity, and what types of physical activity, are associated with lower cancer risk. In addition, previous studies are observational by nature and are therefore unable to determine causality due to unmeasured or residual confounding.

At Oxford, our group has shown that wearable sensors such as wrist-worn accelerometers can be used to noninvasively measure physical activity status in large-scale biomedical studies. For example, we have measured physical activity status in 103,712 UK Biobank participants who agreed to wear a wrist-worn accelerometer for seven days2. These measurements are now actively used by health researchers worldwide to demonstrate that simple measures of overall activity are cross-sectionally associated with cancer outcomes3. However, no large study of device measured physical activity has yet taken place to assess associations with incident cancer outcomes with sufficient longitudinal follow-up. Furthermore, activity trackers often capture ~180 million data points/participant/week and therefore have the potential to identify other powerful behavioural signals to detect future cancer risk.

Machine learning methods can help maximise the utility of data from wearable sensors. These methods attempt to automatically detect patterns in data and then use those uncovered patterns to predict future data. Our group has demonstrated the utility of supervised machine learning to identify sleep and functional physical activity behaviours from raw accelerometer data4. However, there is a broad concern around the lack of reproducibility of machine learning models in health data science5. It is therefore important to carefully consider how to promote robust machine learning findings and reject irreproducible ones, to ensure credibility and trustworthiness.

This DPhil project therefore proposes to use the world’s largest available datasets to investigate what types of physical activity are associated with a lower incidence of cancer. Working with colleagues at the University of Oxford and the National Cancer Institute, you will have the opportunity to address the following important questions:

1. What behavioural measurements of physical activity status can be reliably ascertained from accelerometer datasets?
You will have the opportunity to develop reproducible machine learning skills to develop methods to identify physical activity behaviours from raw accelerometer datasets. Specifically, you will develop semi-supervised machine learning methods which seek to combine supervised methods (good quality labels, small datasets) with unsupervised methods (no labels but large datasets which are less prone to sampling bias). This will involve use of the largest available accelerometer datasets with reference measurements for physical activity behaviours in free-living environments (using wearable cameras)6.

2. What physical activity behaviours are associated with incident cancer events?
Here, you will have the opportunity to develop new skills in epidemiological data analysis. You will have the opportunity to use the UK Biobank dataset which has collected wrist worn accelerometer data from 103,712 participants2. This dataset includes information on participants’ first hospital admission or death from cancer, identified from linkages to the national death index, Hospital Episode Statistics, and cancer registries.

3. Are physical activity behaviours potentially causally associated with cancer?
You will have the opportunity to develop genetic epidemiology skills by implementing two-sample Mendelian Randomization7 to assess potential causal effects of accelerometer measured physical activity and cancer. For cancer outcomes, summary genetic association data will be obtained from existing collaborators from International cancer consortia.

Candidates should have a BSc, or ideally MSc, in a discipline with a substantive epidemiological, computational, or quantitative component. We very much welcome prospective candidates to directly contact us to further develop this proposal.

The mortality rate for COVID-19 pandemic has been two-fold higher in men than women. Similar observation extends to susceptibility and outcome of most other infectious diseases. For instance, after initial Hepatitis C Virus infection women are 2-3 times more likely to spontaneously clear the virus without any interventions and in HIV infection females are 5 times more likely to achieve elite control (complete suppression virus without therapy) than men. However, a consequence of the more vigorous immune response observed in females is more immunopathology and auto-immune diseases (such as lupus) in women than men. For the same reasons, females make stronger immune responses to vaccines but suffer more adverse events. Despite large evidence for sex differences in autoimmune diseases and susceptibility and outcome of infectious diseases, data addressing the biological mechanism are remarkably scarce.

In this project you will use computational and experimental methods to probe differences in immune system that lead to sex differences in infectious diseases. We will investigate this question across many infections including HCV, HBV, HIV and COVID-19. You will start with analysing the available RNA-seq and genomic data from our cohorts and other public databases to understand the role of heterogeneity in X chromosome inactivation in female immune cells and the transcriptional consequence and its contribution to better outcome in infectious diseases. In the next stage you will stimulate male and female immune cells with different immunogens and perform single cell RNA-sequencing to evaluate differential responses across distinct cell types and their association with sex. The project will also use samples and data from vaccine clinical trials. The baseline samples will be compared to the post-vaccination samples and differences in immune systems between sexes will be investigated.

Genome-wide association studies (GWAS) aim to identify the genetic basis of phenotypic traits using the variation that exists within natural populations. Uniquely for infectious diseases, the inter-individual heterogeneity in disease phenotype is linked to both host and pathogen genetic variation. Traditionally, genetic studies of infectious diseases have sought to explain between-individual variation in disease phenotypes by assessing genetic factors separately in humans or pathogens, under the assumption that these factors are independent. Although reasonable for some variants, there is strong theoretical and empirical evidence that genetic interactions between host and viruses play a major role in viral disease aetiology.

In this project you will integrate host and viral genomic data from the same patients to better understand viral pathogenesis and between-individual heterogeneity in disease outcomes. By analysis of paired host-virus genomic data from well-characterised cohorts you will gain novel insights on (a) host polymorphisms linked with viral sequence variation, (b) virus sites under strong host genetic selective pressures, (c) host and virus genetic factors independently contributing to disease phenotypes and (d) host-virus genetic interactions contributing to disease phenotypes. The findings have the potential to: (I) revolutionize our understanding of host-virus interactions and human biology; (II) aid in development of more effective vaccines, drug targets and immunotherapies; and (III) permit better use of therapies through patient stratification. In the age of “Big Data” and “Personalised Medicine”, analysis of paired host-pathogen genomic data will become increasingly important to uncover the mechanisms driving pathogen adaptations and heterogeneity of infection outcomes.

The Higgins laboratory are expert in the structural studies of host-parasite interactions in parasitic diseases such as malaria. They study how interactions at the heart of processes such as erythrocyte invasion are mediated. They explore how parasite surface proteins manipulate the human immune system. They examine antibodies produced in response to human vaccination and determine how these function, and they use this information to design improved vaccine components.

To discuss possible projects, contact: matthew.higgins@bioch.ox.ac.uk