Research Opportunities

We are interested in a variety of topics related to “Deciphering cellular heterogeneity in tumor microenvironment using single cell data”, “Functional characterization of tumor infiltrating T cells”, “Links between embryonic development and cancer”, “Functional characterization of non-coding somatic mutations”, and “Methods for single cell omics”. These projects involve non-trivial  methods development as well as sophisticated data analysis but the focus is always on the biological question. Our lab is involved in several collaborations with immunologists and cancer biologists.

Our group focuses on how human health is affected by the normal microorganisms that live on our skin (collectively termed the microbiome). Our emphasis is on eczema (also called atopic dermatitis or AD), which is an inflammatory disease of the skin associated with reduced quality of life and high risk of developing asthma, allergic rhinitis, and food allergies. Recent work has uncovered that the skin microbiome is significantly different between healthy controls and patients with AD and that early commensal diversity may protect against development of AD. These realizations suggest that the skin microbiome contributes to AD presentation through both harmful and protective pathways. Our group identified a species of bacteria from normal healthy skin, called Roseomonas mucosa, which showed promising features in cell culture and mouse models that suggested the bacteria might be able to treat patients with eczema. We have since transitioned into a clinical trial using Roseomonas mucosa as a topical treatment for eczema. 

The posterior Lateral Line primordium is a group of about a hundred cells that migrates under the skin, from the ear to the tip of the tail, periodically forming and depositing sensory organs called neuromasts, to spearhead formation of the zebrafish Lateral Line sensory system. In recent years, this relatively simple and accessible system has emerged as an attractive model for understanding various aspects of morphogenesis in the developing embryo, including the guidance of cell migration, tissue patterning and organ formation. The goal is to use a combination of cellular, molecular, genetic and biomechanical manipulations coupled with live imaging, image processing and the development of multi-scale computational models to understand the self-organization of cell-fate, morphogenesis and migration of the lateral line primordium. Specific focus will be on developing tools and methods for investigating, imaging, quantifying and modelling the mechanics of collective migration, morphogenesis of epithelial rosettes and the intercellular and intracellular signaling networks that coordinate lateral line primordium development.

I founded a new ultra-high field (7T) MRI physics group in Cambridge in autumn 2017. We develop cutting-edge methods for studying the human brain and body using Cambridge’s state-of-the-art Siemens Terra 7T MRI scanner. My group have active collaborations with clinicians in clinical neurosciences, psychiatry, oncology, and cardiology (Papworth), and with experts in cognitive neuroscience. I welcome PhD students to join the group. The following are areas of strong interest from our community, which would be suitable to develop a PhD project in discussion with me.

(i) Developing new spectroscopic imaging pulse sequences to map neurochemical profiles across the whole brain in a single scan. We have hardware available to apply these methods to study metabolites containing 1H (e.g. NAA, creatine, GABA, GSH) or 31P (e.g. PCr, ATP, in vivo pH mapping) or 13C (e.g. labelled glucose or succinate).
(ii) Developing new methods for neuroimaging, particularly for imaging blood flow in small vessel disease, or for rapid, motion-corrected fMRI in deep brain nuclei.
(iii) Developing new metabolic imaging methods for use in the human body. These would use a new multinuclear (1H and 31P) whole-body coil being built for me by Tesla Dynamic Coils (Netherlands). This could be developed in collaboration with colleagues at Papworth and Radiology for studies in the heart.
(iv) Imaging of metabolism by 2H deuterium metabolic imaging (DMI). 

Repetition priming (RP) is a basic form of memory, whereby prior exposure to a stimulus facilitates or biases subsequent responses to that stimulus. From a neuropsychological perspective, RP is interesting because it can occur without awareness, and despite the damage to the medial temporal lobe (MTL) system that produces amnesia. Many functional neuroimaging studies using fMRI and MEG/EEG have investigated the brain regions and neuronal dynamics associated with RP. However, the results are complex, depending on several important variables, and suggesting multiple underlying neural mechanisms. Recent computational models provide some insight, and the proposed project will extend these models to a broader range of neuroimaging data, including existing data from intracranial recording in human and non-human primates.

Population genomic approaches across diverse species have traditionally used short read sequence data to investigate population structure and signatures of selection. In the recent past, long reads are more traditionally used to build reference genomes to which the short read data can be aligned and evaluated. However, the cost of long read sequencing as well as the DNA input required to generate high quality long read data is dropping rapidly. We foresee a future where population genomics transitions to long read data.

Using these emerging technologies, this project will begin to evaluate what new insights are gained for the Anopheles gambiae species complex, a set of mosquito species famous as the vector of malaria and known to exhibit porous species boundaries and abundant structural variation.  We anticipate that long-read approaches for haplotype phasing and structural variant discovery will enable much clearer resolution of gene flow within species, introgression between species, and alleles under directional or balancing selection.  Insights gained from this project are likely to influence approaches taken for other species that are known to have similar complexities (e.g., Heliconius butterflies, African cichlid fishes).

This project will involve developing and applying new computational methods for analysing long-read sequencing data in an Anopheles population genomics context. The collaborating laboratories at the Sanger Institute and NHGRI are experts in these respective areas and well-suited to provide the appropriate mentorship.

The opportunistic human pathogen, Pseudomonas aeruginosa, is a commonly-found inhabitant in the airways of patients with chronic respiratory ailments such as COPD and cystic fibrosis (CF). Short chain fatty acids (SCFAs) such as acetate and propionate accumulate to high levels in the airways of these patients. In mutants of P. aeruginosa that are unable to catabolise SCFAs, these compounds are toxic and lead to cessation of growth. In this project, we aim to use fragment-based drug discovery to identify inhibitors of the key enzymes involved in propionate catabolism (PrpB and PrpC) and acetate assimilation (AceA). We have recently solved the x-ray crystal structure of each enzyme, and are supported by the Diamond Light Source to initiate a FBDD programme. Challenges will be to identify high affinity binders with specificity for the intended targets. Cell permeability and efflux of the “hits” will need to be investigated, as will “off target” effects, cytotoxicity to mammalian cells, and likely resistance mechanisms. Species specificity of inhibition will be examined in an in vitro polymicrobial system recently developed in the lab.   

We have an interdisciplinary program with biomaterials, clinicians, surgeons, electrical engineers and chemical engineers to 3D fabricate cochleas with microanatomy similar to living cochleas, embedded with sensors that can sense current spread from cochlear implants, or ion gradients from various inner ear cell types that can generate them. Our goal is to develop these types of constructs, seed them with 3D cultures of various  inner ear cell types and examine how cochlear implants can activate auditory neurones, or how regeneration or pharmacologic support for hearing loss can be developed.  his is in order to develop the next generation of inner ear hearing loss therapies.

We are interested in the transmission of bacterial pathogens and AMR determinants at multiple scales from the within-hospital level to global networks. Projects are possible on many large-scale datasets, primarily using population genomic and phylogenetic approaches to investigate these processes.

We have several lines of research that accommodate excellent PhD candidates. These revolve around the theme of RNA viral pathogens, antibodies/B-cell responses and immunodeficiencies.

The first involves understanding Immune Correlates of protective immunity, specifically which types of B-cell response and their fine specificities are important for protection against specific RNA viral pathogens (RNA viruses from HIV, HCV to Ebola) how B-cell responses to correlate with protection by vaccines to specific pathogens. The 2nd project involves using broadly neutralizing monoclonal antibodies to develop improved and novel vaccines against notoriously variable viruses. The 3rd project involves understanding how the resident virome in primary, acquired or induced immunodeficiencies leads to chronic immune activation and poor prognosis, with an emphasis on mucosal immunity.

We have the largest world-wide collection of patients suffering from rare-inherited immunodeficiency that have been whole-genome sequenced (1500+ cases). Using established analytical expertise the candidate will use novel methods to interrogate and filter potential genetic mutations, we will identify novel candidate genetic loci in patients grouped by disease phenotype or familial relationship. Candidate genetic loci will be investigated using CRISPR-editing of patient derived material (lymphoblastoid, fibroblast and iPS cell lines). Confirmatory studies at mRNA, protein and functional level will be carried out to validate the link between variant and disease.

1. Models of ion channel regulation in single cells and small circuits
2. Modelling robust neuromodulation
3. Regulation and control of neural activity and circuit dynamics

The project aims to develop and exploit high transconductance organic electrochemical transistor-based bio-sensors and ultra-low power thin-film electronics as emerging ICT tools with perfect fit to the targeted application domain. The proposed sensors and interfaces will provide unprecedented ability to detect and monitor small metabolites both in vitro and in vivo, to map immunometabolism of organs and tissues, and to test new drugs in situ.

In this project, we will investigate how different stimuli including IgG-immune complexes and TLR ligands affect the ability of DCs to influence T cell autocrine complement regulation. This is of relevance to our understanding of how inflammation is propagated in autoimmunity and for vaccination boost strategies.