Triple-negative breast cancer (TNBC) is highly aggressive but lacks established biomarkers. Increasing evidence links tumour stiffness to TNBC behaviour, while recent studies suggest that mechanical cues can regulate alternative splicing in cancer. However, an in vitro framework connecting ECM stiffness, splicing-factor regulation, alternative splicing and TNBC progression is still lacking. Using RNA-seq from TNBC cells cultured on matrices of defined stiffness, I identified stiffness-dependent splicing events with two bioinformatic pipelines. Candidate cassette exons were prioritised using TCGA stiffness surrogate signatures, followed by motif analysis, IF and RT-PCR. I identified five stiffness-driven splicing events linked to three RNA-binding protein families.
Human pluripotent stem cells (hPSCs) are widely used in regenerative medicine to replace damaged tissues. However, the large-scale cell growth needed for these applications can introduce genetic changes, some of which resemble those seen in cancer, raising safety concerns. The persistence of these changes depends on three steps: mutation, tolerance, and selection, suggesting that some mutations confer a growth advantage. We have shown that hPSCs experience elevated DNA damage, particularly double-strand breaks, linked to replication stress. Such damage may be repaired incorrectly, producing mutations, or remain unrepaired, leading to cell loss. This project investigates how hPSCs respond to DNA damage at the molecular level. We induce damage and quantify key repair markers using imaging. Ongoing work examines how damage influences cell fate decisions during differentiation, with the aim of improving culture conditions and reducing the expansion of genetically altered cells.
Urban trees provide key resources for biodiversity but face high levels of stress, including elevated temperatures from climate change and the urban heat island effect. Planting non-native species may increase the resilience of urban forests, but the effect of elevated temperatures on their relative suitability for biodiversity is poorly understood. We tested the effects of a +4°C increase in temperature on leaf quality, metabolite content, and subsequent indirect effects on a generalist herbivore (Spodoptera littoralis) across five native and non-native pairs of UK urban tree species. Elevated temperature reduced larval growth, altered leaf biochemistry, and accelerated leaf emergence. Reductions in performance were twice as severe for insects fed heat-exposed native compared to non-native trees. Our study indicates non-native tree species may be more resilient to elevated temperatures than native and provide a means to mitigate expected quality loss.
My PhD research, “Understanding signalling pathway diversity in cancer-associated fibroblasts through agonist stimulation,” investigates how fibroblasts in the breast cancer tumour microenvironment exhibit heterogeneous signalling responses. The project focuses on comparing normal fibroblasts and cancer-associated fibroblasts (CAFs) by analysing activation of key pathways including the ERK signalling pathway, NF-κB signalling pathway, and STAT signalling pathway. Using live-cell fluorescent imaging and automated microscopy, signalling dynamics are monitored through nuclear translocation following stimulation with specific agonists. This work aims to identify signalling patterns that distinguish CAFs from normal fibroblasts and to develop protocols that induce CAF-like behaviour in vitro, improving understanding of stromal signalling heterogeneity in breast cancer.
Streptococcus pyogenes is a major human pathogen responsible for around 500,000 deaths annually and is commonly linked to skin infections and Rheumatic Heart Disease in The Gambia. To better understand how this bacterium interacts with the human body, we studied 105 isolates from The Gambia and examined their ability to attach to human extracellular matrix proteins (collagen I, collagen IV, fibronectin and fibrinogen) and to primary skin and tonsil cells. The isolates showed varied binding to these proteins, with the greatest variation seen for collagen, suggesting that genetic differences influence collagen binding. Overall, 28% of isolates bound collagen IV, 25% bound collagen I, and 23% bound both. Adhesion to human cells also differed between strains: emm119 isolates preferred tonsil cells, whereas emm229 isolates adhered better to skin cells. These differences suggest that strains may use distinct infection mechanisms, which require further investigation.
The endoplasmic reticulum (ER) is an essential cellular structure that helps proteins fold correctly, stores calcium, and communicates with other organelles such as mitochondria. These interactions occur at specialised regions known as membrane contact sites, which allow cells to coordinate metabolism, stress responses, and energy production. However, the molecular mechanisms that control communication at these contact sites remain poorly understood.
This project investigates a small protein modification called SUMOylation, which can rapidly alter how proteins function and interact with other molecules. In particular, the study focuses on BiP, a key ER chaperone that helps cells manage stress caused by misfolded proteins.
Using biochemical assays, live-cell imaging, and proteomics, this work aims to identify SUMO-modified proteins at ER contact sites and determine how they regulate calcium signalling and inter-organelle communication.
Skeletal muscle regeneration is driven by muscle stem cells (MuSCs), or satellite cells (SCs), which remain quiescent until activated by injury. They then proliferate, self-renew, or differentiate to form new muscle fibres. The primary cilium acts as a signalling hub regulating these processes.
Obesity is linked to disrupted cilia function and impaired SC activity, suggesting metabolic alterations may hinder muscle regeneration. This project investigates how an obesogenic diet affects SC regenerative capacity and self-renewal, and how metabolic changes influence primary cilia function during muscle repair.
Streptococcus pneumoniae is a leading cause of pneumonia, and rising antimicrobial resistance requires deeper understanding of its peptidoglycan (PG) cell wall. Unlike other Gram-positives, S. pneumoniae undergoes cell division with simultaneous synthesis and hydrolysis. While fluorescence identifies the timing and location of nascent PG synthesis, and Atomic Force Microscopy (AFM) reveals nanometer-scale surface topography, but alone each does not provide a complete structural-functional map. We present "STORMForce," a correlative approach to overcome technical incompatibility between fluorophore blinking buffers and AFM cantilever interactions. Using click chemistry and automated analyses, we achieve 20nm resolution to map PG architecture throughout the division cycle. These findings reveal how PG evolves, offering new insights into ovococcal shape maintenance, and provide a powerful tool for characterizing bacterial phenotypes.
Despite being widely accepted as key drivers of variation in plant demography, density dependence and persistent seedbanks are often absent in empirical population studies. Whilst direct observation of these phenomena can be challenging, with sufficient data they can be estimated using probabilistic computational methods. We combine a Bayesian modelling approach with a multi-year international dataset to explore the recruitment dynamics of Plantago lanceolata L., a herbaceous perennial with economic and ecological importance as a forage crop and an invasive weed. We find evidence of a persistent seedbank, and examine how both seed availability and establishment opportunity can act to mediate recruitment in P. lanceolata across its native and invasive ranges.
Enhancer regions are regions within genomic DNA that are integral for the regulation of gene transcription. Non-coding RNA molecules are produced at these regions, and they have been shown to activate histone acetyl transferases such as CBP, leading to the 'switching on' of targeted genes. I aim to investigate the interaction between these RNAs and CBP with Cryogenic electron microscopy.
Ageing “biomarkers” can be used to make predictions of an individual’s age, health, and potential lifespan. In recent years, the most exciting biomarker is DNA methylation. Addition and removal of methylation happen across the genome and can be used to create age predictive models called epigenetic clocks. To create an epigenetic clock for the Soay Sheep, we used 1067 blood samples from 764 individuals. Using a specialised DNA sequencing technique, we measured the methylome for the whole age range (0-15) of Soay Sheep, from both sexes. We used a statistical method called elastic net regression to select the most informative methylome positions, called CpG sites, for predicting age, and then validated the model using a technique called leave one animal out cross validation. The resulting epigenetic clock was able to predict age to within 0.77 years for males and 1.05 years for females. There was a correlation of 0.820 between an individual’s true chronological age and the predicted age.
The inner ear contains three fluid-filled loops that control our sense of balance. Building these loops requires cells to project and fuse together — if this fails, balance is permanently disrupted.
We study this process using zebrafish, whose transparent embryos let us watch organ development in real time. We investigated a mutant zebrafish line, tp219e, in which these projections fail to fuse correctly, leading to balance problems.
To find the faulty gene, we sequenced RNA from mutant and normal fish to identify genes behaving differently, and used DNA mapping to narrow down the location of the mutation. This pointed us to a gene called tmprss5, which is normally active at the tips of the growing projections. We confirmed this using CRISPR gene-editing to independently disable tmprss5, which produced identical defects.
tmprss5 had no previously known role in ear development. Understanding how it works could shed light on the genetic causes of balance disorders in humans.
The absence of Myosin VI causes non-syndromic deafness in mammals, which leads to stereocilia abnormalities, MET dysfunction and abnormal signal transduction at ribbon synapses. However, these conclusions were obtained using constitutive mutant mouse models, which lose Myosin VI from embryonic stages, leading to secondary effects derived from the abnormal development of the stereocilia, which bias our understanding on its true role in hair cells. Therefore, the proposed study aims to investigate the direct role of Myosin VI in the function of hair cells without the bias of secondary effects. This project will reveal the mechanism regulated by Myosin VI in hair cells and also identify potential therapeutic targets for future hearing restoration.
Urban vegetation plays a critical role in carbon storage and sequestration, yet the contribution and species-specific variation of non-forest plant groups remains poorly quantified. This PhD aims to demonstrate the carbon storage and sequestration potential both under current and future climate, of nursery-grown trees, shrubs and herbaceous plants, for real-world application in cultivated green spaces. This research aims to quantify growth, photosynthetic rates and the above/below ground biomass of a range of native /non-native species and cultivars within those plant groups. These results will culminate to create an understanding of urban plant carbon storage and sequestration potential which will aid in identifying species suited for sustainable planting in urban green spaces.
The growing global population and recent increases in world hunger highlight the urgent need to improve food production sustainably. Nitrogen is essential for crop growth, but more than half of applied nitrogen fertilizer is lost through processes such as leaching, volatilization, and nitrous oxide emissions, causing environmental damage and contributing to climate change and soil degradation. This project investigates nitrogen cycling and nitrogen losses after fertilization using contrasting barley lines. By combining advanced techniques to measure microbial nitrogen cycling activity, community dynamics, and plant traits, the study aims to understand how plants can help regulate nitrogen cycling and reduce its negative environmental impacts. Experiments will assess nitrification and denitrification under controlled conditions using stable isotope methods and real-time PCR to link nitrogen transformation rates with microbial community function.
Salmonella enterica includes ~2400 non-typhoidal serovars that cause gastroenteritis and four typhoidal serovars that cause typhoid fever and chronic infection. Typhoidal strains produce typhoid toxin, which triggers host DNA damage responses (DDRs) and may help bacteria persist in the host. A small subset of non-typhoidal strains, including Salmonella Javiana, also produce this toxin. In vitro studies show that typhoid toxin can induce persistent DDRs that drive cellular senescence, a permanent cell-cycle arrest linked to inflammation and tumour suppression, but whether this occurs in vivo remains unclear. My PhD investigates whether typhoid toxin induces senescence during infection, using mouse cancer models, and better understanding the mechanism of the Typhoid toxin in vitro.
Sensorineural hearing loss (SNHL) is the leading cause of hearing loss worldwide. It arises due to damage to specialised sensory cells in the inner ear – primarily the inner ear hair cells or the spiral ganglion neurons. Unfortunately, treatment options to reverse hearing loss are limited.
Human embryonic stem cells (hESCs) are a promising resource for the development of cell therapies that could go some way to restoring biological hearing. hESCs can be driven to produce a variety of cell types in vitro through manipulation of well-established biological pathways. Using this technology, it is possible to generate populations of hair cell precursor cell types, known as otic epithelial progenitors (OEPs). Whilst OEPs have been produced successfully under research conditions, existing protocols are unsuitable for clinical use. The primary goal of this project is to optimise a clinical grade protocol for the generation of functional OEPs from hESCs, as a potential cell therapy for SNHL.
Special locations where mitochondria and ER touch called MAMs. They move lipids, stabilise Ca2+, and communicate between cells. FKBP8, also known as FKBP38, regulates apoptosis, autophagy, protein folding, and transport. Evidence suggests that FKBP8 is necessary for MAM production, which may impact cell communication. Mitophagy requires FKBP8's LIR motif-like sequence (LIRL). A new study shows that FKBP8 shapes mitochondria. Mammalian cells generate MAM by binding to PDZD8, an ER protein. SUMOylation, a post-translational modification that can be undone, links small Ubiquitin-like Modifier (SUMO) proteins. Some tests reveal that FKBP8 can be SUMOylated, which may affect MAM synthesis.
Zebrafish have a high capacity to regenerate damaged tissues and are widely used as a model organism to study regeneration. Our previous work showed that several keratin genes change their expression during regeneration, with some becoming upregulated and others downregulated. Based on this pattern, we classified these genes into two groups, krtup and krtdown.
During regeneration, epidermal cells in the fin fold migrate, whereas epidermal cells in the trunk show no movement. This observation suggests that krtup genes may promote cell migration, while krtdown genes may help stabilise cells. To investigate this idea, we study the zebrafish lateral line, which migrates cells rapidly during development. Krt18b (krtup) and krt15 (krtdown), are expressed in this system and provide a useful model to study the potential role of keratins in cell migration. Understanding how keratin proteins influence cell movement may provide insight into mechanisms underlying tissue regeneration.
In 1996 the population of house sparrows (Passer domesticus) on the island of Lundy declined sharply. In a measure to aid this population, 50 sparrows were introduced to the island from Sheffield. Translocations of individuals, such as the one described above are a common conservation measure. However, the results of these translocations are often difficult to evaluate, primarily due to the requirement of long-term population monitoring. Data from the Lundy Sparrow Project has been used to evaluate the initial and long-term results of the translocation. For initial results, a genetic pedigree was used to compare the breeding success of the native and introduced birds. The breeding success of their offspring was also evaluated to establish if parentage affected their reproductive fitness. For long term result, whole genome sequencing data was used to compare the overall genetic similarities between the introduced and native birds, as well as the descendent population on the island.
Trogocytosis is a conserved process, whereby cells can “nibble” off and engulf fragments of other cells. In immune cells such as T cells and macrophages, trogocytosis contributes to immune regulation, cell–cell communication, and responses to pathogens. However, the molecular mechanisms that drive trogocytosis remain poorly understood.
Recently, we discovered that the model organism Dictyostelium discoideum can also readily perform trogocytosis, opening up a new powerful way to investigate the underlying mechanisms. Dictyostelium is a genetically tractable and highly phagocytic amoeba, which shares key cytoskeletal and signaling pathways with mammalian immune cells, making it an excellent system to uncover conserved mechanisms of trogocytosis.
In this project, by combining cell biology techniques, we investigate the molecular mechanisms of trogocytosis and its significance in physiology.
Congenital hearing loss is the most common congenital disorder, affecting around 1 in 1000 newborns, and age-related hearing loss is one of the most prevalent disorders in the ageing population. Around half of congenital deafness is caused by mutations to connexin 26 and connexin 30, and they have been shown to exacerbate age-related hearing loss in mouse models. Connexin 26 and connexin 30 are proteins that connect adjacent supporting cells within the cochlear sensory epithelium. Recent success with gene therapy has been seen in treating congenital deafness due to mutations affecting sensory hair cells, however there is limited research on gene therapy targeting supporting cells or age-related hearing loss. Therefore, this project aims to investigate the suitability of gene therapy using adeno-associated virus (AAV) to treat congenital and age-related deafness caused by supporting cell dysfunction.
Human chromosome ends are protected by structures called telomeres; repetitive DNA bound by proteins known as Shelterin. Where Shelterin is absent or dysfunctional, cellular processes recognise telomeres as damaged DNA, leading to chromosome instability; a hallmark of cancer. However, we lack a detailed understanding of how Shelterin interacts with DNA, and the full six-subunit structure of Shelterin still remains unknown.
Here, we produced the full human Shelterin complex in insect cells and characterised it with biophysical methods. Shelterin molecules were weighed by mass photometry to give insights into their structural composition and heterogeneity. Using optical tweezers, we directly observed fluorescently labelled Shelterin bind DNA at the single-molecule level, measured biophysical properties, and evidenced a DNA packaging property of Shelterin.
This work contributes towards a broader understanding of telomere biology and how its dysfunction may result in genome instability.
From parrots to penguins, birds everywhere are under threat. Nearly half of all species are declining due to threats such as habitat loss and overuse by people. Yet birds are vital: they pollinate plants, disperse seeds, control pests and inspire cultures worldwide. Conservation is effective, but there’s still a major “conservation action gap” between what we know needs to be done and what is happening.
This research assesses how conservation needs and implementation vary across IUCN Red List of Threatened Species categories, ecological traits, taxonomic groups and geographic regions. This approach identifies where efforts are falling short, highlights priority species and regions, and provides a framework to guide more effective global bird conservation.
Streptococcus pneumoniae is considered one of the most problematic pathogens by the WHO and CDC due to increasing levels of antibiotic resistance. Invasive infections are commonly treated with penicillin-like antibiotics and if we are to continue to treat them in the long-term, we need to identify points of weakness in bacterial cell metabolism that support resistance.
We carried out a genetic screen to identify new cellular targets that could enhance penicillin treatment. We validated these hits and characterised their effects. Subsequent work has focused on the clinical effect these genes might have if they were targeted by new treatments in combination with penicillin.
From the genes identified in our screen, nine were shown to significantly enhance the effectiveness of penicillin. To assess their potential as drug targets, we tested gene inactivation mutants across twelve S.pneumoniae strains, including lab wild-type strains, international standards, and clinical isolates.
Cancer-associated fibroblasts (CAFs) are key components of the tumour microenvironment and exist in multiple functional states, including contractile myofibroblastic CAFs and inflammatory CAF-like populations that influence tumour–stroma interactions. Here, we established a reproducible in vitro model to induce an inflammatory fibroblast activation state in human dermal fibroblasts using tumour-derived secreted factors. Marker-based analyses were used to characterise fibroblast activation and distinguish inflammatory features from contractile signatures. Transcriptome profiling further revealed consistent gene expression changes associated with inflammatory signalling and microenvironmental interactions.
Streptococcus pneumoniae is a global pathogen causing a wide range of diseases such as meningitis and septicaemia. While β-lactam antibiotics are the standard treatment, the rise of antimicrobial resistance (AMR) increasingly renders them ineffective. Therefore, it is important that we understand the mechanisms driving resistance. The secondary messenger c-di-AMP is a suspected contributor, as high levels have been linked to resistant strains in S. pneumoniae. As a signalling molecule, c-di-AMP regulates cellular processes by interacting with specific proteins. Identifying these binders is key to understanding its role in AMR. To isolate these proteins, a c-di-AMP capture compound will be synthesised for use in a pulldown assay. Captured proteins will be analysed via mass spectrometry, followed by testing to establish their specific links to resistance. This approach aims to uncover novel pathways that could be targeted to bypass or reverse antibiotic resistance in S. pneumoniae.
Homeostatic plasticity is a compensatory mechanism that is important for neuronal function to maintain a stable state in the face of intrinsic and extrinsic changes. We aim to address the current lack of understanding of the molecular mechanisms underlying homeostatic regulation. This project investigates homeostasis using the mushroom body of Drosophila melanogaster as a model. We use a non-specific heat sensitive cation channel, dTrpA1 as a tool to perturb the excitatory-inhibitory balance within the circuit. RNA sequencing and conditional labelling techniques are used to identify genes that are up and downregulated during homeostatic compensation. I also plan to perform conditioning experiments on flies with overactivated Kenyon cells to understand how perturbations to the excitatory-inhibitory balance affect flies on a behavioural level. Overall, this project studies homeostatic compensation from molecular and behavioural perspectives.
Enterococcus faecalis is an opportunistic pathogen and a major cause of hospital-acquired infections. Therefore, it is important to understand how E. faecalis causes disease. A major driver of virulence is the Enterococcal Polysaccharide Antigen (EPA), a cell wall component composed of a rhamnose backbone, and a strain-specific decoration region, which is involved in critical function such as host immune system evasion and infection by bacteriophages.
Using an NMR approach, the structure of EPA_B (EPA from the strain E. faecalis OG1RF ΔepaB), has been solved, revealing that in EPA_B, decorations directly anchor to the peptidoglycan. However, this strain is avirulent and is not infected by bacteriophages, functions driven by the decoration region, hence epaB deletion may also cause changes to the enterococcal cell surface. Solving the structure EPA_B provides further insight into EPA biosynthesis, and elucidates how structure and ultrastructure influence enterococcal cell wall function.
Morphological variation (disparity) is a metric for analysing macroevolutionary dynamics. However, our understanding of these patterns is hampered by an incomplete fossil record. Ancestral state estimation (ASE) can be used to fill these gaps, but estimations carry significant uncertainty. Using simulations, we evaluated methods for integrating uncertainty into traitspace analyses. We compared point-estimate and probabilistic approaches across various models and fossil sampling. We find that ancestral states generally improve the recovery of true disparity signals, though the optimal method depends on the data. For continuous traits, distribution-based methods are favoured but sensitive to model misspecification when data is sparse. For discrete traits, probabilistic methods are best when fossils are sparse, whereas point estimates become more reliable as sampling increases. The results provide a framework for using ASE to estimate disparity under different models and fossil levels.
Chemoresistance is one of the reasons behind the low survival rates of pancreas cancer patients. The pancreatic cancer tumour microenvironment is characterised by a dense and desmoplastic stroma, featuring excessive amounts of extracellular cellular matrix (ECM) components. These are primarily secreted by fibroblasts, mesenchymal stem cells (MSCs) and cancer-associated fibroblasts (CAFs). The desmoplastic stroma prevents chemotherapy, increases nutrient scavenging, and activates pro-survival signalling pathways. This project hypothesises that cell-ECM interactions induce chemotherapy resistance in PDAC. The objectives are to determine how ECM composition and nutrient availability effect the chemotherapy sensitivity, to define the molecular mechanisms behind this, to understand the contribution of MSCs and CAF to ECM remodelling and chemotherapy sensitivity and to elucidate the metabolic changes associated with ECM-dependent drug resistance.
Cocoa production sits at a critical intersection of land-use change, atmospheric chemistry, and climate vulnerability. This research investigates the ""net climate impact"" of expanding cocoa plantations in the tropics, focusing on greenhouse gas emissions and the release of biogenic volatile organic compounds (BVOCs), which influence cloud formation and air quality.
A key focus is evaluating Enhanced Rock Weathering (ERW)—a technology involving spreading crushed silicate rocks on soil to capture CO₂ and reduce nitrogen emissions. Using the Community Earth System Model (CESM), the study addresses a major gap: existing climate models fail to accurately represent cocoa. By developing a specific ""cocoa plant functional type,"" this project provides a high-fidelity simulation of how different management strategies alter regional warming. This work offers a scientific foundation for climate-smart agriculture and the sustainability of the global chocolate industry.