PhD Projects

Join the Alcolea Group for a project on 'Mutant clone competition in squamous epithelial tissues; relevance for early tumour formation' (wet lab project).

Keywords: Mutant clonal competition, Early tumorigenesis, Squamous epithelia, Epithelial stem cells, Cell fate

Project Overview

Mounting evidence show that healthy human epithelial tissues accumulate cancer-associated mutations with age, revealing that mutations do not represent the sole cause of cancer. Instead, tumour formation is now believed to depend on a combination of genetic and environmental factors; with competition between adjacent mutant clones acting as critical modulators during early tumorigenesis. However, despite significant efforts in the cancer field, we still know virtually nothing as to how mutant competition is affected by ageing, and whether this contributes to differences in tumour incidence with age.

This PhD project will address the question of how ageing impacts mutant clone dynamics to promote early tumour formation. In particular, we will focus on understanding how mutant clonal competition changes with age, from birth through to late stages in life, using a squamous oesophageal model.

Importantly, work in this area will provide a benchmark to identify new actionable targets of potential use in cancer therapeutics and diagnostics, and to develop strategies to prevent the onset of this aggressive disease.

Main Techniques

To dissect the cellular and molecular mechanisms underlying mutant competition and early tumorigenesis, we will implement a multidisciplinary approach combining our expertise in mutant clonal dynamics in vivo and ex vivo using 3D organ cultures, single-cell multiomics, and mathematical network analysis. Specific techniques will include:

• New long-term 3D Epitheliod cultures (Herms et al. BiorRxiv 2023).
• 3D organoid cultures.
• Clonal lineage tracing.
• Immunostaining of tissue wholemounts.
• 3D whole-organ confocal microscopy.
• Single-cell RNA sequencing and multiomics data mining.
• Gene Regulatory Networks will be assessed using the relevant models, including genetic manipulation via CRISPR/Cas9.

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Composite created with images produced by members of the Alcolea Lab and collaborators.

Join the Boroviak Group for a project on 'Engineering primate embryo implantation platforms'.

Keywords: human embryo implantation, primate embryogenesis, implantation platforms, endometrium

Project Overview

Embryo implantation is one of the most critical and complex events in early pregnancy. Central to this process is the establishment of a functional vascular network, which delivers oxygen and nutrients to support embryonic growth.

In this project, we will develop a vascularised endometrial implantation platform that mimics the spatial and functional organisation of the maternal–fetal interface to study primate embryogenesis ex vivo.

Embryo implantation requires the endometrium to undergo cyclical transformation. In humans and great apes, the endometrium undergoes cyclical transformations, including the decidualization of stromal cells and secretory changes of the glandular epithelium in response to progesterone. A key and often overlooked aspect of embryo implantation is vascularisation. Endometrial blood vessels, particularly spiral arteries, undergo extensive remodelling during early pregnancy, ensuring nutrient and oxygen delivery to the developing embryo. Yet current in vitro models insufficiently capture the spatial and functional complexity of this vascular network.

Our goal is to build a vascularised implantation platform. This bioengineered system integrates human stromal, endothelial and epithelial cells into a patterned hydrogel scaffold. The platform will feature two distinct compartments: (i) a vascularised stromal layer, in which microvessels spontaneously arise from embedded endothelial cells; and (ii) macrovascular channels created by 3D printing and perfused with endothelial cells to generate lumenised vessels. Upon assembly, the platform will be transferred into a microfluidic culture device that allows long-term perfusion. This setup supports the integration of micro- and macrovascular components and mimics physiological perfusion of the endometrium. Endothelial integration, hormonal responsiveness and tissue viability will be assessed using confocal imaging and spatial transcriptome profiling.

The student will learn endometrial organoid culture and differentiation, vascularised tissue bioprinting and microfluidic assembly, immunostaining, 3D imaging and image analysis, qPCR and gene expression analysis, as well as comparative primate developmental biology.

Ultimately, this project aims to recapitulate the critical features of the maternal-fetal interface and establish a foundation for modelling primate embryogenesis outside the womb.

References:

1. Bergmann S, Schindler M, Munger C, Penfold CA, Boroviak TE. Building a stem cell-based primate uterus. Commun Biol. 2021.
2. Siriwardena D, Boroviak TE. Evolutionary divergence of embryo implantation in primates. Phil Trans R Soc B. 2022.
3. Rawlings TM et al. Modelling embryo implantation in human endometrial assembloids. Elife. 2021.
4. Turco MY et al. Long-term, hormone-responsive organoid cultures of human endometrium. Nat Cell Biol. 2017.
5. Zhang J et al. Modeling embryo-endometrial interface recapitulating human embryo implantation. Sci Adv. 2024. doi:10.1126/sciadv.adi4819

Main Techniques

• Organoid culture
• Generation of implantation platforms
• Confocal microscopy
• Single-cell transcriptome profiling
• Spatial transcriptome profiling.

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Microvasculature embedded in human stromal and endometrial cells, generated in the Boroviak lab.

Join the Göttgens Group for a project on 'Decoding Stem Cell Fitness: Interpretable Gene Programs in Haematopoiesis and Ageing'.

Supervisors: Bertie Göttgens & Nicola Wilson

Project Overview

Single-cell transcriptomics has revolutionised our understanding of cellular diversity, but translating this complexity into mechanistic insights remains challenging. Traditional methods often reduce rich cellular states to single vectors, limiting interpretability and masking key regulatory processes.

This project builds on Tripso, a deep learning framework developed by the Lotfollahi group in collaboration with the Gottgens lab. Tripso uses gene program (GP)-specific transformers to learn multiple interpretable representations of gene activity at the single-cell level. Applied to over 500,000 haematopoietic cells, Tripso revealed age-specific GP usage and uncovered novel programs driving cell fate decisions and stem cell fitness.

A core aim is experimental validation of GP-based hypotheses. The student will collaborate with computational researchers to identify candidate programs and targets, testing predictions via CRISPR perturbations, pharmacological treatments, and flow cytometry. Functional outcomes will be assessed using molecular characterisation techniques, building on prior success such as Tripso’s prediction that SEC61 inhibition enhances stem cell maintenance.

This interdisciplinary project bridges computational modelling and experimental haematology. The student will gain training in single-cell transcriptomics, machine learning (including transformers and optimal transport), and hands-on lab techniques. They will learn to generate hypotheses from large-scale data and design experiments to test gene program function across developmental stages and ageing contexts.

Ultimately, the project aims to uncover mechanisms regulating stem cell fitness, ageing, and lineage commitment, with implications for regenerative medicine and stem cell therapies.

Join the Káradóttir Group for a project on 'Determining mechanism of progression in MS'.

Keywords: CNS, myelin, Oligodendrocyte, neuroscience, stem cells, brain, Multiple Sclerosis

Project Overview

Myelin is essential for normal brain function. Throughout life ligodendrocyte precursor cells (OPCs) which are stem cells in the brain and the main proliferative cells in the adult central nervous system, differentiate into myelinating oligodendrocytes to maintain normal brain function. While OPCs in young animals effectively differentiate and respond to demyelinating lesions as occurs in multiple sclerosis (MS). However,  with ageing their differentiation capacity declines, which thought to be the main contributor to progressive disability in diseases like MS. Recent genome-wide association studies have identified a genetic variant that accelerates MS progression, with carriers reaching severe disability years earlier and showing greater brain atrophy and lesion burden.

We are establishing a humanised mouse model for this gene variant to investigate how it affects OPC biology and myelin regeneration. Preliminary single-cell analyses suggest this variant causes vulnerability in oligodendrocytes with emerging senescence signatures in glial cells. This studentship will characterise the stem cell regenerative programme in these mice, examining OPC proliferation, differentiation, and remyelination capacity to identify the cellular and molecular mechanisms underlying accelerated disease progression in genetic variant carriers.

Main Techniques

• confocal imaging
• in vivo photometry
• stereotaxic surgery
• histology

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Image shows: Microglia (red) hugging demyelinating neuron (in blue). Image credit: Omar de Faria

Join the Khaled Group for a project on 'Understanding and intercepting precancerous cellular changes in the breast'.

Keywords: Tumour initiation, Cancer Prevention, lineage tracing

Project Overview

Understanding the molecular and cellular mechanisms of how epithelial tissues maintain a homeostatic state throughout the lifespan of mammals is a major challenge for developmental and stem cell biology. From a developmental perspective, the epithelium of the mammary gland is unique as it undergoes most of its development during adulthood. Despite recent efforts of characterising the tissue homeostasis at a cellular level little is known about how this is affected by various developmental processes such as pregnancy or ageing and how this might ultimately disrupt epithelial homeostasis resulting in malignant outgrowth. In this study we wish to further our understanding of the changing nature of the differentiation dynamics of the mammary gland. To fully understand how tissue homeostasis is affected by parity and other events it is mandatory to characterise the differentiation dynamics in an age-dependent manner. This becomes evident when looking at epidemiological data. Age is the greatest risk factor for breast carcinomas, and it has been suggested that this is not only due to accumulation of mutations but also due to decreased clonality and selection of clones with proliferative advantage. To tackle these questions our lab has been using single cell genomics, mouse models and human samples to study the effects of parity, ageing and germline mutation (BRCA1/2) on the homeostasis of the mammary gland in mouse and human. For this project the student will be using a new lentiviral system we developed in the lab that is designed to induce and facilitate comprehensive characterisation of dynamic changes in the mammary epithelium of Cre-inducible mouse models, such as confetti and tumour suppressor flox mouse models. In addition, the student will have the opportunity to validate some of the findings using orthogonal spatial technologies as well as perform pre-clinical in vivo cancer interception studies.

Main Techniques

• Spatial transcriptomics
• Single cell genomics
• Tissue scale imaging
• Mouse models

Join the Teichmann Group for a project on 'Multiomics to decipher T cell development in the thymus'.

Keywords: T cell development

Project Overview

Ongoing projects in the Teichmann team are generating scRNA-seq and chromatin accessibility profiles of thymic cells using the 10X multiome kit, combined with multiplex protein staining. The project will examine how altered chromatin states might direct specific T cell fates, examining both T cells and thymic epithelial cells in fetal and paediatric thymi. We have established artificial thymic organoids (ATO) culture systems and will test our insights from single cell data to modulate T cell development in vitro via overexpression of specific transcription factors (TFs) to direct T cell fates. Computational models will be harnessed to predict which TFs may be essential to drive different effector T cell fates.

Main Techniques

• Computational analysis of existing data, plus new data generation using cutting edge TCR repertoire analysis.
• Thymic organoid culture and transfections.

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Image credit: Ioannis Sarropoulos

Join the Teichmann Group for a project on 'Deciphering gut microbe-immune interactions in health and disease'.

Keywords: Gut, immunology, microbiome, T cells

Project Overview

A fundamental role of our immune system is to defend against harmful threats, whilst minimising immune-mediated pathologies. The maintenance of immune tolerance across barrier surfaces such as the gut where the self interfaces with the microbial non-self represents unique challenges to the mucosal immune system. The gut is colonised by a large community of commensal bacteria that contributes to health through a complex dialogue with the host to promote tolerance and defence. 

The study of microbe-immune crosstalk is therefore highly relevant to understand how tolerance is broken in pathologies such as inflammatory bowel disease and gut graft versus host disease. This project incorporates 3 broad aims: 

1.    Develop spatial tools to analyse high-resolution spatial transcriptomic gut tissue data 

2.    Generate spatial data to investigate host-microbe interactions using human gut biopsies across the spectrum of health and disease 

3.    Use iPSC and patient-derived intestinal organoid lines established in our group to test new mechanisms by which the host co-exists with microbes.

Main Techniques

• Computational analysis of existing data
• Generation of new data generation using cutting edge spatial transcriptomics technology (e.g., VisiumHD)
• Intestinal organoid culture

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Generation of human intestinal organoids from induced pluripotent stem cells (iPSC). Image credit: 

Join the Tzelepis Group for a project on 'Identification of pathways regulating the presentation of csRBP-glycoRNA clusters on the surface of mammalian cells'.

Keywords: RNA biology, Epitranscriptomics, stem cells

Project Overview

Immunotherapies for acute myeloid leukemia (AML) and other cancers are limited by a lack of tumor-specific targets. We recently discovered that RNA-binding proteins and glycosylated RNAs (glycoRNAs) form precisely organized nanodomains on cancer cell surfaces. We characterized csNPM1 (George et al, Nature Biotechnology 2025) and csDDX21 (Perr et al, Cell 2025) as abundant cell surface proteins on a variety of tumor types. We develop a monoclonal antibody to target csNPM1 and csDDX21, which exhibit robust anti-tumor activity in multiple syngeneic and xenograft models of AML, including patient-derived xenografts, without observable toxicity. Our data suggest that csNPM1 and its neighboring glycoRNA–cell surface RNA-binding protein (csRBP) clusters may serve as an alternative antigen class for therapeutic targeting or cell identification.

For this project, we have performed genome-wide CRISPR screens and have catalogued gene targets that changed the levels of the above glycoRNA–cell surface RNA-binding protein (csRBP) clusters. Using sophisticated functional genetic and molecular biology techniques, we are aiming to validate and characterise the most promising targets we have recently identified, that either increased or decreased the presence of glycoRNA–cell surface RNA-binding protein (csRBP) clusters on the surface of normal and malignant models.

Main Techniques

• Cell culture
• CRISPR editing
• flow cytometry
• western blotting
• cell imaging
• There is also potential to perform translational studies using mouse models of disease that are established in the lab.