Supervisors and Projects

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Associate Professor Rachael Bashford-Rogers

Project Code M1

Project A: Optimising B Regulatory Cell Development for Clinical Translation

Project B: Deciphering Spatial Immune Networks in Disease Heterogeneity

Project C: Integrating Hormonal Control of Immune Programming

Engineering Immunology by Design

The Bashford-Rogers lab aims to combining high-throughput experimental assays with novel computational approaches to learn the cellular fate rules to autonomously design optimal protocols for programming any desired immune states. Starting with genetic, imaging or cell stimulation experiments on primary cells or tissues, we will train models that predict responses and reverse-engineer therapeutic protocols. This shifts biology from observation to engineering-led design for rational cellular therapies. Three projects: (A) optimising Breg development for clinical translation through signal decoding and protocol standardisation; (B) understanding spatial immune networks driving disease variation using multicellular AI models; (C) integrating hormonal influences on immune programming for sex-specific therapies. This represents a paradigm shift from observational biology to engineering-led cellular design, with the ultimate goal of rational design cellular therapies for cancer, autoimmunity, and beyond based on understanding the dynamic signalling driving fate choices.

These projects are open to either experimentalists, computational biologists or both!

Project A: Optimising B Regulatory Cell Development for Clinical Translation

This programme leverages our technologies to systematically decode the molecular signals governing B regulatory cell (Breg) differentiation, addressing critical gaps in our understanding of how to efficiently generate therapeutic Bregs from primary human B cells. Through high-throughput screening and computational model-guided exploration, the research will identify optimal signal combinations, timing parameters, and novel stimulation protocols that exceed current manual approaches. The programme's experimental strategy combines systematic mapping of stimulation landscapes with functional validation in disease models, ultimately developing standardised protocols suitable for clinical translation.

Project B: Deciphering Spatial Immune Networks in Disease Heterogeneity

Building on our novel imaging analysis (SpatioEv) and experimental capabilities, this programme expands into multicellular systems to understand how spatial organisation of immune cells drives patient-to-patient variation in cancer and autoimmune diseases. By integrating spatial transcriptomics and multiplexed imaging with AI predictions, the research will model tissue-specific microenvironments and identify cell-cell interaction networks that determine therapeutic outcomes. This approach promises to deliver patient stratification algorithms for precision medicine, novel combination therapies targeting specific interaction nodes, and diagnostic tools that predict treatment resistance based on spatial immune profiles.

Project C: Integrating Hormonal Control of Immune Programming

This programme addresses a critical but understudied aspect of immune regulation by incorporating sex hormone influences into a predictive framework. Through systematic hormone gradient testing and longitudinal modelling, the research will determine how fluctuating levels of oestrogen, testosterone, progesterone and other hormones modulate immune cell programming and identify optimal therapeutic windows during hormonal cycles. The outcomes will include sex-specific therapeutic protocols, adaptive cellular therapies that respond to changing hormonal environments, and novel insights into hormone-dependent differences in disease susceptibility and treatment responses across conditions like pregnancy, menopause, and andropause.

Key publications:

SpatioEv: Spatial evolution of protein and morphological features reveals development dynamics of cells and spatial neighbourhoods (Under review, Nature Methods, 2025)

(https://www.biorxiv.org/content/10.1101/2025.06.30.662328v1.full.pdf)

Shihong Wu, Sakina Amin, Carl Lee, Jean-Baptiste Richard, Nabeel Merali, Caroline Morrell, Lauren Overend, Weijia Gao, Felicia Tucci, Alex Gordon-Weeks, Adam Frampton4, Nicola Annels, Emma Culver, Michael Dustin, Kim S. Midwood, Rachael Bashford-Rogers

Defective peripheral B cell tolerance leads to dysregulated B cell responses in Fibromyalgia Syndrome (Under review, Nature Immunology, 2025)

(https://www.researchsquare.com/article/rs-6836742/v1)

Alexander Long, Antonio Choi Chiu, Orthi Onupom, Richard Berwick, Dimitra Psyllou, Jane Pernes, Katy Plant, Harvey Neiland, Andy Cross , Felicia Tucci, Andreas Goebel, Rachael Bashford-Rogers

Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms (Nature Communications, 2025)

(https://www.nature.com/articles/s41467-024-55424-2)

Shivan Sivakumar, Ashwin Jainarayanan, Edward Arbe-Barnes, Piyush Kumar Sharma, Maire Ni Leathlobhair, Sakina Amin, Lara Heij, Samarth Hegde, Assaf Magen, Felicia Tucci, Bo Sun, Shihong Wu, Nithishwer Mouroug Anand, Hubert Slawinski, Santiago Revale, Isar Nassiri, Jonathon Webber, Adam Frampton, Georg Wiltberger, Ulf Neumann, Philip Charlton, Laura Spiers, Tim Elliott, Pallavur V. Sivakumar, Alexander V. Ratushny, Mark Middleton, Dimitra Peppa, Benjamin Fairfax, Miriam Merad, Michael L. Dustin, Enas Abu-Shah, Rachael Bashford-Rogers

Predictability of B cell immunosurveillance in metastatic breast cancer (Nature Immunology, 2024)

(https://www.nature.com/articles/s41590-024-01821-0)

Stephen-John Sammut, Jacob D. Galson, Ralph Minter, Bo Sun, Suet-Feung Chin, Leticia De Mattos-Arruda, Donna K. Finch, Sebastian Schaetzle, Jorge Dias, Oscar M. Rueda, Joan Seoane, Jane Osbourn, Carlos Caldas, Rachael J.M. Bashford-Rogers

Unravelling B cell heterogeneity: Insights into flow cytometry-gated B cells from single-cell multi-omics data (Frontiers In Immunology, 2024)

(https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1380386/full)

Jane I. Pernes*, Atheer Alsayah*, Felicia Tucci, Rachael J. M. Bashford-Rogers

Associate Prof Rachael Bashford-Rogers | Biochemistry

For informal enquiries: Rachael.bashford-rogers@bioch.ox.ac.uk

Dr Rebecca Berrens

Project Code M2

Transposable element-derived isoforms during mammalian preimplantation development

The mammalian embryo undergoes extensive transcriptional reprogramming during the first few days of development as control shifts from maternally deposited RNAs to activation of the embryonic genome. This process is accompanied by widespread changes in promoter usage, alternative splicing and transcript architecture, generating thousands of transcript isoforms that contribute to developmental progression and lineage specification. At the same time, transposable elements (TEs) are among the most highly expressed sequences during preimplantation development and have emerged as important regulators of gene expression. While TEs are well recognised as developmental promoters and enhancers, much less is known about their contribution to transcript diversity during early embryogenesis.

Recent advances in long-read sequencing now make it possible to resolve full-length transcripts originating from repetitive regions of the genome, providing an unprecedented opportunity to investigate how transposable elements shape the embryonic transcriptome. This project will use long-read transcriptomic datasets generated from mouse preimplantation embryos to identify TE-derived transcript isoforms, including alternative promoters, novel first exons, exonisation events, alternative splice junctions and transcript termination events. These analyses will establish how TE-derived transcript structures change throughout preimplantation development and identify the transposable element families that contribute most strongly to transcript diversity.

The project will then investigate how these TE-derived isoforms are regulated during development and whether they represent reproducible developmental programmes or stochastic transcriptional events. By integrating long-read transcriptomics with publicly available datasets describing chromatin accessibility, transcription factor occupancy and gene expression, the student will explore the regulatory mechanisms underlying TE-derived transcript formation and identify candidate transcripts that may contribute to early developmental transitions.

Finally, selected candidate isoforms will be validated experimentally using two-cell-like cells (2CLCs), which provide a tractable in vitro model of zygotic genome activation. Candidate transcript structures will be confirmed using targeted molecular approaches, and the regulation of selected TE-derived isoforms will be investigated during transitions into and out of the 2CLC state.

The project combines computational biology with molecular and developmental biology and will provide training in long-read transcriptomics, bioinformatic analysis of repetitive sequences, transcript annotation, mouse embryonic stem cell culture, 2CLC biology and molecular validation techniques. By focusing on transcript architecture rather than transposable element expression alone, the project aims to understand how TEs contribute to transcriptome complexity during the earliest stages of mammalian development. The work will provide new insight into how transposable elements diversify the embryonic transcriptome and establish a framework for investigating the role of TE-derived transcript isoforms in early development.

Dr Rebecca Berrens | Biochemistry (ox.ac.uk)

For informal enquiries: rebecca.berrens@bioch.ox.ac.uk

Associate Professor Jani Bolla

Project Code M3

Structural and functional basis of LPS transport

Antibiotic-resistant bacteria pose a major public health concern, particularly for Gram-negative bacterial infections. One such example is multidrug-resistant Pseudomonas aeruginosa. This pathogen commonly causes infections in immunocompromised individuals, such as those with AIDS, cancer, burn wounds, and cystic fibrosis. These infections are difficult to treat due to their asymmetric outer membrane (OM), composed of phospholipids on the inner leaflet and lipopolysaccharides (LPSs) on the outer leaflet. LPSs are extracted from the inner membrane (IM) and shuttled to the OM by seven LPS transport proteins: LptA, LptB, LptC, LptD, LptE, LptF and LptG [1-4]. As the transport of LPS is essential for the survival of Gram-negative bacteria, inhibiting this vital function can prevent the formation of the OM and effectively eradicate the pathogen. However, the molecular mechanisms governing this process have not been fully elucidated, with several key steps unresolved, especially how the bridge protein, LptA, connects both the membrane components and mediates LPS transport. Our goal is to determine the structures of several subcomplexes and the fully assembled complex, and to elucidate the molecular mechanisms of LPS transport mediated by the Lpt system. The knowledge generated will then be utilised to design potent compounds that inhibit its ability to transport.

[1] PMID: 38816673, [2] PMID: 36473551, [3] PMID: 33036869, [4] PMID: 32955879

Associate Prof Jani Bolla | Biochemistry

For informal enquiries: jani.bolla@bioch.ox.ac.uk

Professor Nynke Dekker

Project Code M4

Single-molecule studies of DNA and chromatin replication

During DNA replication in eukaryotes, the replisome must faithfully copy the parental DNA, which is tightly packaged into chromatin, and coordinate this with proper nucleosome assembly onto the daughter DNAs. Doing so relies on a complex interplay between replisome proteins and histones, as well as accessory factors such as histone chaperones. To probe the dynamics of this chromatin replication, we employ an in vitro reconstitution approach based on the Saccharomyces cerevisiae (Sc.) replicative helicase CMG to study the replisome-nucleosome interactions using at the single-molecule level using fluorescence microscopy. Doing so requires labelling replisome components, histone chaperones, and the histones themselves. To probe the direct interactions between individual replisome components or histone chaperones and individual histones in real time, however, we aim to use specialized form of single-molecule fluorescence microscopy, called single-molecule FRET, because it can report on whether labelled components are in molecular contact with one another. We would like to use this approach to map out the pathway of an individual nucleosome through the replisome, aided where histone chaperones where necessary. This project would be an excellent match for a student interested in combining biochemistry (protein purification and protein labelling by making good use of available structural tools) and biophysics (microscopy, quantitative analysis) to understand the mechanistic molecular aspects of chromatin replication – interest and aptitude in both biochemistry and quantitative analysis is a must.

Prof Nynke Dekker | Biochemistry (ox.ac.uk)

For informal enquiries: nynke.dekker@physics.ox.ac.uk

Associate Professor Dmitry Ghilarov

Project Code M5

From bacterial molecular machines to antibiotics of the future

Research in Ghilarov lab aims to reveal fundamental principles of organisation and mechanism of bacterial molecular machines. Understanding these principles allows to control the activities of molecular machines and ultimately to design better antibiotics targeting these machines.

In our research, we are using a combination of single-particle time-resolved cryoEM, biochemistry, genetics and chemical biology approaches and collaborate with experts in modelling, protein design and single-molecule methods. Specific DPhil & MSc projects will be tuned to candidates’ interests, but must be related to one of the two main lab themes:

Theme I: Ribosomally synthesized post-translationally modified peptides (RiPPs)

Post-translational modifications control fate and function of proteins in all living organisms. However, as part of the ongoing warfare between them, bacteria evolved sophisticated systems that change peptide scaffolds beyond recognition: converting amino acids into aromatic heterocycles, cyclising and knotting peptides, or introducing D-aminoacids are but a few examples. Biosynthesis of these ribosomally-synthesized post-translationally modified peptides (RiPPs) is controlled by a specific region of the peptide that guides its association with a particular enzyme to start the chemical transformation cascade. This property provides a golden opportunity for biotechnology and medicine: by understanding where and how modifications are introduced, we can engineer systems to incorporate them into any peptides and proteins of our interest resulting in designer natural products.

We are interested in reconstituting complete RiPP biosynthetic systems including linear azole-containing peptides, lasso-peptides and thiopeptides to understand their architecture, dynamics, ecological role and the potential to engineer them to design bespoke RiPPs[1,2].. We directly follow modification process in time using time-resolved cryoEM, bespoke peptide substrates that arrest the modification reaction, and native mass-spectrometry in collaboration with Justin Benesch (University of Oxford).

Theme II: Bacterial DNA topoisomerases

Bacterial type II topoisomerases gyrase and topoisomerase IV are essential for removing positively supercoiled DNA in front of the progressing polymerases, introducing negative supercoiling required for chromosomal homeostasis, and segregating daughter chromosomes after replication. They work in close connection with the replisome and SMC proteins, directly and indirectly affecting all genomic transactions in the cell. The research in the lab aims to address fundamental questions of how topoisomerases use energy of ATP to introduce defined topology in DNA and how gyrase and topoisomerase IV recognise different topologies of DNA[3]. As most interesting stages of gyrase catalytic cycle, many of which are targeted by the drugs, are short-lived, we are developing time-resolved cryoEM approaches, and collaborate with physicists at the department to develop innovative single-molecule approaches using DNA nanotechnology. In addition, we maintain an international network of collaborations in DNA topology field. We are also interested in protein and small molecule inhibitors of topoisomerases as inspiration for a new generation of antibacterial drugs[4,5], and in understanding mechanisms of resistance to antibiotics related to topoisomerases such as Qnr proteins[6].

[1] Ghilarov et al. Mol Cell (2019) https://doi.org/10.1016/j.molcel.2018.11.032

[2] Travin et al. JACS (2018) https://doi.org/10.1021/jacs.8b02277

[3] Michalczyk et al. PNAS (2024) https://doi.org/10.1073/pnas.2407398121

[4] Bakker et al. Nat Chem (2024) https://doi.org/10.1038/s41557-024-01516-x

[5] Michalczyk et al. Nat Catal (2023) https://doi.org/10.1038/s41929-022-00904-1

[6] Mazurek et al. Nucl Acids Res (2021) https://doi.org/10.1093/nar/gkaa1266

Ghilarov lab website: ghilarovlab.com

Associate Prof Dmitry Ghilarov | Biochemistry

For informal enquiries: Dmitry.ghilarov@bioch.ox.ac.uk

Associate Professor Nate Goehring

Project Code M6

Cell polarity, asymmetric cell division, and cell fate control during embryonic development

Arguably, the central challenge in developmental biology is to understand how the enormous diversity of cell form, fate, and function that is typical of multicellular organisms arises from a single fertilized egg. To address this challenge, we use the early embryo of the nematode C. elegans as a model as it provides a rich and highly tractable experimental playground for defining core principles in cell and developmental biology.

One common feature of embryonic development that is linked to specification of cell fate is asymmetric cell division - the process by which a single mother cell gives rise to daughter cells with distinct identities. Asymmetric divisions are common in stem cell-like lineages and turn out to be a defining feature of the early develoment of C. elegans.

Beginning with the division of the fertilized egg (zygote), a series of asymmetric divisions specify the major developmental lineages that make up the adult tissues. During each of these cell divisions, the cell must first convert specific spatiotemporal cues into stable molecular asymmetries, a process referred to as cell polarization. The polarized cell must then ensure fate specifying molecules are differentially inherited by the two daughter cells where they can induce distinct developmental programmes.

Much of the work in the lab focusses on this process of cell polarization as specified by a set of proteins known as the PAR-titioning defective or PAR proteins. During asymmetric division, PAR proteins self-organise into opposing membrane-associated domains, which then serve as the key spatial regulators that direct division asymmetry.

Projects in the lab generally centre around (but are not limited to) two core themes:

Elucidating design principles underlying self-organization of PAR proteins into patterns – What are the relevant network feedback circuits, how do they emerge from underlying molecular behaviours (diffusivity, oligomerization, kinase-substrate interactions, membrane association), and how do they drive the emergence of stable patterns?
Integrating polarity into developmental programmes – How does the polarity network integrate information from developmental cues? How do considerations of time (cell cycle, developmental stage) and space (cell size/shape) impact polarity? How is polarity “read out” robustly by downstream processes to allow cells to make robust decisions?

To address these questions, we take an interdisciplinary approach that spans disciplines and scales of analysis, often moving between in vivo, in vitro, and computational studies. This approach is aided by the reproducibility of early C. elegans development and as well as its amenability to quantitative perturbation and imaging techniques. This approach lets us link processes occurring at various scales from molecule to system and thereby identify core design principles of how these networks operate. Candidates will be exposed to a range of techniques and approaches which may include CRISPR, chemical and opto-genetics, advanced confocal and widefield imaging, quantitative image analysis, and mathematical modelling.

Note that this project description illustrates the types of questions that occupy us in the lab. Projects will be developed together with the supervisor, taking into account the student’s background and scientific interests.

Dr Nate Goehring | Biochemistry

For informal enquiries: nate.goehring@bioch.ox.ac.uk

Dr Morgan Jones

Project Code M7

How do cells copy and read their DNA at the same time?

Faithful genome duplication is essential for all dividing cells. This process is driven by the replisome, a macromolecular machine that unwinds and copies DNA. Rather than operating on an isolated template, the replisome functions within the crowded environment of the chromosome, where the same DNA molecule can be replicated, transcribed, repaired and packaged into chromatin simultaneously. As a result, the replisome encounters numerous proteins and nucleic acid structures that can impede its progression. Among the most significant of these are collisions with the transcription machinery, known as transcription-replication conflicts (TRCs). TRCs are a major source of genome instability, and increasing evidence implicates them in cancer development. Despite their importance, the molecular mechanisms that govern these encounters remain poorly understood.

This project aims to understand how DNA replication is coordinated with transcription to preserve genome integrity. To achieve this, the student will reconstitute mammalian transcription–replication conflicts from purified proteins and investigate the mechanisms governing their formation and resolution using complementary structural, biochemical and biophysical approaches.

Key questions the student will explore include:

How does the replisome respond when it encounters the transcription machinery?
How do helicases and other genome maintenance factors promote replisome progression through transcription-associated obstacles?
How do these mechanisms coordinate DNA replication with transcription and prevent genome instability?

To address these questions, the student will combine biochemical reconstitution with cryo-electron microscopy, cross-linking mass spectrometry and time-resolved structural approaches to capture the molecular architecture of transcription-replication conflicts. These studies will be complemented by functional DNA replication and transcription assays, with opportunities to collaborate on single-molecule experiments to directly visualise these dynamic processes in real time.

Dr Morgan Jones | Biochemistry

For informal enquiries: morgan.jones@bioch.ox.ac.uk

Professor Syma Khalid

Project Code M8

Combining molecular simulations and machine learning to find the vulnerabilities in the cell envelopes of Gram -negative bacteria

Harmful, disease-causing Gram-negative bacteria protect themselves against antibiotics in many different ways, which make them formidable foes. Despite bacteria being simple organisms compared to us, we still do not understand many of the molecular processes that bacteria exploit to protect themselves. We will use a combination of molecular simulations and machine learning, combined with experimental data from our collaborators to characterise the interactions of a chemically diverse range of antibiotics within the membranes and the periplasm of Gram-negative bacteria. The programme of research provides training in state-of-the-art molecular dynamics simulations, machine learning techniques, coding and statistical analyses and involves interaction with world-leading experimental scientists for collaborative work.

Prof Syma Khalid | Biochemistry

For informal enquiries: syma.khalid@bioch.ox.ac.uk

Professor Petros Ligoxygakis

Project Code M9

Project 1: Exploring the metabolic requirements shaping the dynamics of phagocytosis.

Project 2: Studying the integration of Toll/TLR/NF-κB signalling in intestinal stem cell proliferation.

Project 1: We have developed a live-imaging approach to quantify multiple aspects of the phagocytic capacity of Drosophila larval macrophages (Vaz et al., Cell Reports, 2019; Wang and Ligoxygakis, bioRxiv, 2026). We now aim to apply this technique to investigate the metabolic requirements of phagocytosis during host–pathogen interactions in real time. By combining advanced live microscopy with the powerful genetic toolkit available in Drosophila melanogaster, we will dissect how insulin, Akt, mTOR, and nutrient-sensing pathways regulate actin cytoskeletal remodelling in macrophages during bacterial infection.

Project 2: The intestinal epithelium maintains tissue homeostasis through a finely balanced interplay between epithelial renewal, barrier function, and immune regulation. How these processes are integrated by intracellular signalling pathways remains incompletely understood. In a recent study, we investigated the role of the evolutionarily conserved Toll/NF-κB innate immune pathway in Drosophila intestinal regeneration (Udayakumar et al., Development, 2026). We found that the core components of the canonical Toll pathway are required for intestinal stem cell (ISC) proliferation during both homeostasis and infection. Ectopic Toll activation was sufficient to drive ISC mitosis and commitment to the enteroblast (EB) lineage but blocked EB differentiation, resulting in the accumulation of both ISCs and EBs. Mechanistically, these effects were mediated through JNK and Akt/TOR signalling, as reducing the activity of JNKK, JNK, Akt, or TOR in intestinal progenitors suppressed ISC proliferation. Together, these findings support a model in which Toll signalling integrates JNK and Akt/TOR pathways to coordinate epithelial renewal while maintaining control of the commensal microbiota. Building on this work, we will isolate Toll-expressing ISCs by fluorescence-activated cell sorting (FACS), establish ex vivo cultures, and characterise their tumour-like properties, including single-cell signalling dynamics and metastatic potential following transplantation into healthy wild-type flies. Leveraging the powerful genetic toolkit of Drosophila, we will define the molecular mechanisms that drive the metastatic behaviour of Toll-expressing ISCs and identify the genetic determinants that enable the recipient host to suppress tumour dissemination.

Prof Petros Ligoxygakis | Biochemistry

For informal enquiries: petros.ligoxygakis@bioch.ox.ac.uk

Associate Professor Faraz Mardakheh

Project Code M10

Defining the interplay between p53 and ribosome biogenesis in colorectal cancer

Ribosome biogenesis is amongst the most energy-intensive processes in human cells. In normal cells, this process is tightly regulated to ensure balanced cell growth and proliferation. In cancer cells, however, this regulation is frequently disrupted, leading to increased ribosome production that supports uncontrolled tumour growth. Although dysregulated ribosome biogenesis is recognised as a hallmark of cancer, the molecular mechanisms underlying this process remain poorly understood.

It is now known that defects in ribosome biogenesis can activate the tumour suppressor p53 through the Impaired Ribosome Biogenesis Checkpoint (IRBC), a highly conserved stress response that protects cells from malignant transformation. The evolution of this pathway highlights the intimate relationship between ribosome biogenesis and tumour suppression. However, while the mechanisms by which defective ribosome biogenesis activates p53 are well established, it remains unclear whether p53 itself directly regulates ribosome biogenesis, and how this contributes to its tumour-suppressive function.

Our laboratory has recently discovered that activation of p53 following the induction of IRBC feeds back to inhibit ribosomal RNA (rRNA) synthesis, establishing a positive feedback loop that reinforces the shutdown of ribosome biogenesis during cellular stress. The molecular mechanism underlying this feedback regulation, however, remains unknown. This project aims to address this question by defining how p53 suppresses rRNA synthesis and ribosome biogenesis at the molecular level, and determining whether this pathway is required for p53-mediated tumour suppression in colorectal cancer. The student will use isogenic colorectal cancer cell models with either intact or disrupted p53 signalling, combined with state-of-the-art transcriptomic and proteomic approaches to identify the molecular mechanisms linking p53 to rRNA synthesis and ribosome biogenesis. The project will provide training in cutting-edge molecular biology, functional genomics and proteomics, and systems-level data analysis, while addressing a fundamental question in cancer biology with potential implications for the development of novel therapeutic strategies.

Associate Prof Faraz Mardakheh | Biochemistry

For informal enquiries: faraz.mardakheh@bioch.ox.ac.uk

Dr João Monteiro

Project Code: M11

Bacterial coordination of the cell cycle during intracellular infection

Antibiotic failure has been typically attributed to antimicrobial resistance (AMR); however resistance is not always detected in these cases. Rather, contextual, non-genomically encoded, antibiotic tolerance plays a significant role in the persistence of chronic and relapsing infections. Innate immune cells, especially phagocytes, serve as the first line of defence against invading microorganisms. However, if bacteria survive phagocytosis, they can paradoxically become carriers of highly virulent pathogens. Intracellular bacteria are often shielded from antibiotics due to reduced penetration and/or outright inactivation of some antibiotic classes, while some have the ability to reversibly switch to metabolically slow persister phenotypes that confer tolerance to drugs.

We will study coordination of cell wall synthesis in S. aureus internalised in macrophages. We will start by measuring the cell morphology and the timings of the phases of the cell cycle of internalised S. aureus and compare to extracellular culture and determine whether different phases of the bacterial cell cycle are more or less susceptible to killing by the host and tease out the mechanisms of killing by measuring the integrity of cell wall, membrane and DNA over time.

A conserved mechanism that bacteria use to adapt to changing environmental conditions is via two component systems (TCS). TCS are canonically composed of a membrane bound histidine kinase that directly or indirectly senses a perturbation and a cognate response regulator that activates the transcription of target genes. S. aureus contains 16 TCS that respond to a wide variety of environmental cues including temperature, metabolic challenge, population density, and cell wall damage and mount an appropriate response to increase survival and/or modulate virulence. In order to determine whether TCS are important for survival in macrophage phagosomes, we will delete select TCS individually and assess rates of bacterial survival in a model of phagocytosis.

We will then test if TCS contribute to persister formation. Persisters are bacterial subpopulations that adopt a transient metabolically slow (or inactive) state, conferring tolerance to lethal dosage of antibiotics. We will challenge intracellular TCS mutants with antibiotics targeting cell wall, membrane, DNA or protein synthesis to assess the impact on persister formation and survivability in the host. Finally, we will infect adult flies with TCS mutants to correlate bacterial survival in phagocytes with the outcomes of systemic infection. This set of experiments will reveal which TCS are important for survival in the host and determine their contribution to antibiotic tolerant phenotypes.

Monteiro lab website: Dr João Monteiro | Biochemistry

For informal enquiries: joao.monteiro@bioch.ox.ac.uk

Professor Nicole Robb

Project Code M12

Unravelling Influenza Virus Replication using Real-time Single-Molecule Microscopy

General background: Influenza viruses are a persistent global health threat - seasonal influenza causes hundreds of thousands of deaths annually, whilst pandemics result in millions of deaths. Given the significant health, social and economic impact of these viruses the need for fundamental research into their lifecycle is vital.

Influenza viruses use a viral enzyme called the RNA polymerase (RNAP) to replicate their genomes. The RNAP poses an excellent antiviral drug target due to its crucial role in the viral life cycle. It also plays a pivotal role in allowing influenza viruses to overcome host-specific defences, potentially leading to sustained transmission in the new host species, for example, in viruses that cross over from birds to humans and may cause pandemics.

Objectives: Advances in cryo-electron microscopy have provided us with insightful structures of the influenza RNAP, which show that multiple copies of the RNAP come together to form functional replication complexes during the life cycle. These complexes interact with different orientations and stoichiometry during different stages of the life cycle. We don’t fully understand the order in which replication complexes form, whether intermediate complexes exist, and how stable the complexes are.

Using pioneering single-molecule imaging methods that we have developed, we aim to directly observe, for the first time, how influenza RNAPs come together to form replication complexes. We will use this information to study how best to interrupt formation of these complexes, providing a framework for novel antiviral inhibitor design.

Methodology: This project is inherently multidisciplinary, combining molecular biology, biochemistry, structural virology, single-molecule biophysics and analysis using custom computational tools to extract precise, time-resolved measurements of molecular interactions.

Impact: Our proposed work will apply cutting-edge techniques to a long-standing challenge in influenza biology, with direct implications for pandemic readiness and efforts to develop new, targeted antiviral treatments against the influenza RNAP.

Why us? Our lab offers a highly supportive and well-resourced environment for MSc and DPhil students and will provide an excellent training environment across multiple disciplines. We collaborate with multiple laboratories and public health agencies who you will have the opportunity to work with, as well as being able to attend national and international conferences

For informal enquiries: nicole.robb@bioch.ox.ac.uk

Professor Lothar Schermelleh

Project Code M13

Interrogating nuclear structure-function relationships in mammalian cells by advanced super-resolution imaging

Three-dimensional (3D) chromatin organisation plays a crucial role in regulating mammalian genome functions such as RNA transcription, replication and DNA repair. Population-based sequencing approaches (e.g. Hi-C) have highlighted the compartmentalisation of chromatin into 0.5-1 MB sized topologically associating domains (TADs). However, many of the physical features at the single-cell level are still underexplored. Our primary research objective is to identify principles and underlying mechanisms of functional chromatin organisation in mammalian cells. Specifically, we aim to understand the interplay between biophysical forces, epigenetic memory, and cohesin complex activity to modulate cell-type-specific transcriptional programs by directly visualising dynamic nuclear organisation and gene activity in living or 3D-preserved cells. To this end, we employ a combination of genetic editing with innovative in vivo/in situ fluorescence labelling and super-resolution imaging approaches. Our activities are closely linked to the Micron Oxford Advanced Bioimaging Unit and supported by our well-established ties to leading chromatin and epigenetic research groups within the Department and across the University of Oxford.

For a MSc/PhD project, we seek (an) enthusiastic, proactive, and adventurous student(s) eager to immerse themselves in the latest imaging technologies to study topographical and biophysical aspects of gene regulation in an interdisciplinary environment. The topic of the project can be along the lines of either (1) studying transcription factor dynamics within the context of mesoscale chromatin domains using correlative single-molecule tracking and super-resolution SIM imaging, (2) analysing loop-extruding and sister chromatid cohesive and loop-extruding cohesin complexes by super-resolution expansion microscopy (ExM) and/or super-resolution 3D correlative light and electron microscopy (CLEM), (3) studying the effect of directed phase separation on mesoscale domain organisation and transcriptional modulation, (4) examining mechanisms of gene reactivation during de-differentiation and/or epigenetic memory (e.g. after IFγ response), or (5) examining enhancer-promoter interactions e.g. in the alpha-globin locus, using multiplexed RNA-DNA-Immuno-FISH and correlative 3D super-resolution light end electron microscopy. The details of any project will be subject to personal preferences and will be worked out closer to the start date.

Main techniques: Mammalian tissue culture, molecular cloning, transfection, immunofluorescence labelling, fluorescence in situ hybridisation (DNA/RNA FISH), super-resolution structured illumination microscopy, single-molecule imaging, focussed ion beam scanning electron microscopy (FIB-SEM), computational image analysis.

Relevant papers:

Miron E, ..., Schermelleh L. 2020. Chromatin arranges in chains of mesoscale domains with nanoscale functional topography independent of cohesin. Science Advances 6, eaba8811.

Brown JM, … Schermelleh L, Buckle VJ. 2022. RASER-FISH, a non-denaturing fluorescence in situ hybridization for preservation of three-dimensional interphase chromatin structure. Nat Protoc 17, 1306-1331.

Ochs F, ..., Schermelleh L, Nasmyth KA. 2024. Sister chromatid cohesion is mediated by individual cohesin complexes. Science, 383: 1122-1130.

Schermelleh L et al. 2019. Super-resolution microscopy demystified. Nat Cell Biol 21: 72-84.

Associate Prof Lothar Schermelleh | Biochemistry (ox.ac.uk)

For informal enquiries: lothar.schermelleh@bioch.ox.ac.uk

Associate Professor Madhusudhan Srinivasan

Project Code M14

Project A: How do chromosomes sense and respond to mechanical force?

Project B: Mechanisms of Topoisomerase II regulation by chromosome organizing SMC complexes

The Srinivasan laboratory combines chromosome biology, protein biochemistry, cell engineering and single-molecule biophysics to uncover the molecular mechanisms that organise and faithfully segregate chromosomes. We develop and apply cutting-edge approaches spanning CRISPR genome engineering, mammalian cell culture, budding yeast genetics, purification of large chromosome organising protein complexes, and single-molecule optical tweezers with fluorescence microscopy to study chromosomes across scales: from individual protein-DNA interactions to intact mitotic chromosomes. Our research seeks to understand how molecular machines such as cohesin, condensin and DNA topoisomerase II generate chromosomes that are simultaneously dynamic, mechanically robust and capable of faithfully transmitting genetic information.

Project A: How do chromosomes sense and respond to mechanical force?

Chromosomes are remarkable biological materials. During mitosis they must be sufficiently stiff to withstand spindle-generated pulling forces, yet sufficiently elastic to avoid catastrophic breakage. Although recent work has begun to define the mechanical properties of isolated chromosomes, chromosomes are unlikely to behave as passive elastic objects. Instead, they are dynamic structures built from ATP-dependent molecular machines, including cohesin, condensin and DNA topoisomerase II, which continuously reorganise chromosome architecture. Whether chromosomes actively remodel their structure in response to mechanical force, and the molecular mechanisms underlying this response, remain completely unknown.

This project will investigate how mitotic chromosomes respond to mechanical stress using a unique combination of chromosome engineering, cell biology and single-molecule biophysics. Human mitotic chromosomes will be isolated from cultured cells and manipulated using the Lumicks C-Trap optical tweezers platform, enabling precise measurements of chromosome extension, relaxation and viscoelastic behaviour under controlled forces. Rather than treating chromosomes as static materials, the student will determine whether chromosome mechanics evolve over time when force is applied, revealing active force-dependent remodelling. Using our established CRISPR-based chromosome engineering platform, cohesin, condensin and Topoisomerase II will be acutely inactivated on pre-assembled chromosomes, allowing their individual contributions to force adaptation to be determined without disrupting chromosome assembly. These experiments will establish whether chromosome-organising enzymes act as dynamic regulators of chromosome mechanics or simply provide passive structural support.

To complement the mechanical measurements, fluorescence imaging will be integrated with force spectroscopy to visualise structural changes within individual chromosomes during force application. The student will develop quantitative computational approaches to relate chromosome architecture to mechanical behaviour and test how ATP, chromatin modifications and chromosome-associated proteins influence force-dependent remodelling.

This interdisciplinary project combines chromosome biology, CRISPR genome engineering, optical tweezers, fluorescence microscopy and quantitative biophysics. The student will receive comprehensive training in advanced single-molecule methods and chromosome engineering while addressing a fundamental question in cell biology: are chromosomes passive mechanical materials, or active structures that continually adapt to mechanical forces during cell division? Answering this question will establish a new framework for understanding chromosome mechanics and provide fundamental insight into how cells protect their genomes during mitosis

Project B: Mechanisms of Topoisomerase II regulation by chromosome organizing SMC complexes

The faithful segregation of chromosomes requires the timely resolution of DNA entanglements by DNA topoisomerase II (Topo II). While Topo II is essential for genome stability, how its activity is regulated within the complex environment of chromosomes remains one of the major unanswered questions in chromosome biology. Recent work from our laboratory suggests that cohesin and condensin differentially influence the persistence of DNA entanglements in vivo, raising the possibility that chromosome-organising SMC complexes regulate Topo II activity. The molecular basis of this regulation, however, remains unknown.

This project will combine protein biochemistry, genetics and single-molecule biophysics to determine how cohesin and condensin control Topo II activity. The student will first establish in vitro reconstitution assays using purified proteins and defined DNA substrates before developing novel single-molecule assays on the Lumicks C-Trap optical tweezers platform. These experiments will directly visualise Topo II-mediated DNA strand passage and decatenation under precisely controlled mechanical tension, allowing the effects of cohesin and condensin on individual Topo II reaction cycles to be measured in real time.

By integrating biochemical reconstitution with state-of-the-art single-molecule analysis, the project will provide the first mechanistic understanding of how chromosome-organising SMC complexes regulate Topo II. The student will receive interdisciplinary training in chromosome biology, protein biochemistry, optical tweezers, fluorescence microscopy and quantitative single-molecule analysis through collaborations with leading experts in chromosome organisation and biophysics.

Research environment

The Srinivasan laboratory provides a friendly, collaborative and highly interdisciplinary research environment in which researchers from diverse scientific and cultural backgrounds work together to tackle fundamental problems in chromosome biology. We are committed to fostering an open, inclusive and supportive laboratory culture, where curiosity, creativity and collaboration are valued as highly as technical excellence. Students are encouraged to develop their own ideas, learn across disciplines and benefit from close mentoring while gaining increasing scientific independence.

Relevant Recent publications:

George Cameron et al., Sister chromatid cohesion establishment during DNA replication termination. Science 384,119-124(2024).DOI:10.1126/science.adf0224

Aditi Kaushik et al., DNA catenation is essential for Sister Chromatid Cohesion. Under review in Nature bioRxiv 2026.07.16.738924; doi: https://doi.org/10.64898/2026.07.16.738924

Dr Madhusudhan Srinivasan | Biochemistry

For informal enquiries: madhusudhan.srinivasan@bioch.ox.ac.uk

Professor Stephan Uphoff

Project Code M17

How do bacteria survive stress, and evolve resistance?

Bacteria are remarkably adaptable. This enables them to colonise new hosts, evade immune defences, and survive antibiotic treatment. When exposed to harmful conditions, bacterial cells activate protective stress responses, while some acquire mutations that increase their ability to survive future challenges.

Research in the Uphoff Lab seeks to understand how short-term, phenotypic stress responses shape long-term genetic adaptation. We study different bacterial species including human pathogens like Salmonella enterica and Acinetobacter baumannii, and Escherichia coli as a non-pathogenic model organism. We have pioneered single-molecule and single-cell microscopy approaches that allow us to observe bacterial adaptation across extraordinary spatial and temporal scales, down to molecular events inside individual cells.

By combining advanced fluorescence microscopy, microfluidics, quantitative image analysis, and molecular genetics, we investigate three closely connected research themes. Specific MSc projects will be developed jointly with candidates according to their interests and experience.

Theme 1: Revealing the hidden complexity of bacterial stress responses

Single-cell studies have challenged conventional models of how bacterial stress responses are regulated and what they achieve. We have found that stresses including reactive oxygen species, DNA-damaging agents, and antibiotics can generate striking phenotypic diversity within bacterial populations.

Why do individual cells respond so differently to the same environment? Does this diversity help populations survive unpredictable conditions? Projects in this area will investigate the molecular origins and functional consequences of cell-to-cell variation, and determine how heterogeneous stress responses influence survival, persistence, and adaptability.

Theme 2: Tracing the transition from phenotypic tolerance to genetic resistance

DNA sequencing can identify mutations associated with antibiotic resistance, but it cannot reveal the molecular events that produced them. We are developing methods to observe mutation and adaptation as they happen in living cells.

Our laboratory pioneered microscopy-based detection of mutation events in real time, enabling us to connect a cell’s physiological state with its subsequent genetic fate. Using microfluidic devices, we can follow thousands of individual bacteria for several days under precisely controlled treatments.

These approaches have revealed that mutation rates can increase during stress and vary substantially between individual cells. We are now asking whether rare subpopulations with elevated mutation rates disproportionately drive evolutionary adaptation. Understanding these processes could ultimately improve our ability to predict and limit pathogen evolution.

Theme 3: Understanding bacterial survival inside immune cells

During infection, bacteria encounter severe stresses imposed by the host immune system. Phagocytes attack invading microbes using reactive oxygen species and other antimicrobial mechanisms, yet intracellular pathogens can survive and even replicate within these cells.

We have adapted single-molecule imaging to visualise bacterial DNA repair proteins inside living phagocytes. This provides a unique opportunity to investigate, in real time, how pathogens detect damage, activate protective responses, repair their DNA, and survive immune attack.

Prof Stephan Uphoff | Biochemistry

For informal enquiries: Stephan.uphoff@bioch.ox.ac.uk

Associate Professor Tobias Warnecke

Project Code: M18

Chromatin evolution in prokaryotes

We are interested in how (and why!) chromatin evolved across the tree of life. What are the fundamental differences between chromatin in bacteria, archaea, and eukaryotes? Are there any? Why do eukaryotes only use histones as their principal chromatin protein? What’s so great about histones? Can we use proteins other than histones to build chromatin with similar properties? And can we imagine (and build!) a cell without chromatin whatsoever?

Our group combines computational (phylogenomics, structural modelling, functional genomics, machine learning) and experimental techniques (biochemistry, microbiology, genetics) to pursue these questions from multiple angles [1-5].

During this studentship, we want to tackle one of the following projects:

Ultimate compaction. Histones are the principal building blocks of chromatin in eukaryotes but were generally thought to be absent from bacteria. We have recently discovered that this is not 100% true – there are some bacteria that encode and use histones to make chromatin [4]. One of these is the predatory bacterium Bdellovibrio bacteriovorus, which hunts and invades other bacteria. B. bacteriovorus is remarkable because their swimming “attack phase” cells are very small and somehow manage to condense an E. coli-size genome into a fraction of the volume [6]. We want to find out how they do this. Are histones involved? If not, what do the histones in these bacteria actually do?

DNA glues. There are some proteins, like protamines in human sperm, that strongly compact DNA. They do so by virtue of being packed full of charged amino acids, notably arginine. Some bacteria also strongly compact their DNA (e.g. B. bacteriovorus, see above). Do they use similar proteins? For some species, like Chlamydia trachomatis, the answer appears to be yes [7]. For most others, we do not know. Do they encode their own unique toolkits? How do they manage the (often rapid) transition from a condensed to a decondensed state? This project will combine computational and high-throughput experimental approaches to characterize the repertoire and logic of these bacterial DNA glues.

Unusual histones in archaea (MSc project). Many archaea encode non-model histone proteins the functions of which are poorly understood. For your Masters project, you will investigate one of these histone homologs from the hyperthermophilic archaeon Pyrococcus furiosus, including through phenotyping of deletion mutants, in vitro characterization or DNA binding behaviour, and reconstruction of its evolutionary history.

What will you learn during your DPhil.MSc?

I am keen for students to master a broad range of tools, including both computational and experimental approaches. You can expect to learn how to culture and genetically manipulate a variety of microbes, to describe prokaryotic genome function using systems-level functional genomics approaches, and to analyze microbial evolution on a genome-wide scale.

Rojec et al. Chromatinization of E. coli with archaeal histones. (2019) eLife 8:e49038
Hocher et al. Growth temperature and chromatinization in archaea. (2022) Nature Microbiology 7:1932
Stevens et al. Histone variants in archaea and the evolution of combinatorial chromatin complexity. (2020) PNAS 117:33384
Hocher et al. Histone-organized chromatin in bacteria. (2023) Histones with an unconventional DNA-binding mode in vitro are major chromatin constituents in the bacterium Bdellovibrio bacteriovorus. Nature Microbiology 8(11):2006-2019.
Hocher & Warnecke (2024) Nucleosomes at the Dawn of Eukaryotes. Genom Biol Evol 16(3):evae029
Sockett. Predatory lifestyle of Bdellovibrio bacteriovorus. (2009). Annu Rev Microbiol 63:523
Barry et al. Nucleoid condensation in E. coli that express a chlamydial histone homolog. (1992) Science 256:377

Associate Prof Tobias Warnecke | Biochemistry

For informal enquiries: tobias.warnecke@bioch.ox.ac.uk

Dr Antoni Wrobel

Project Code M15

Molecular mechanisms underlying viral evolution and host changes

We seek to understand how enveloped viruses evolve and use this knowledge to come up with ways to deal with future pandemics.

Many deadly human pathogens, such as influenza and SARS viruses, are made up of just a few components but can infect a number of different hosts. How is it possible that these components suffice to fulfil all the functions necessary for a virus to infect the cell and then to assemble into a new viral particle? How do viral proteins perform multiple functions and how does the virus manage to retain all these functions as it evolves? How does a virus infect different hosts using the same set of its own proteins to engage a range of machineries of different hosts? And, finally, how does a virus evolve and ‘learn’ to optimise its interactions with a new host?

The recent COVID-19 pandemic has demonstrated that these questions are key to understand where new viruses come from and how they evolve upon transmitting to a new host. We have used biochemical, biophysical, and structural methodologies, mainly cryoEM, to reveal the mechanisms by which SARS-CoV-2 became able to infect humans and then further evolved to optimise viral infectivity in the variants of concern. [1-7]

The lab continues to work on coronaviruses and studies influenza viruses to understand how their proteins achieve the versatility needed to infect diverse hosts and fulfil multiple functions during infection. In particular, we want to explain how related viral strains use similar glycoproteins to engage receptors as different as glycans and proteins. We are also interested in understanding how viral proteins come together during virus assembly: how do they find other viral components, how do they ‘coerce’ the host to transport them, and how do they exclude hosts proteins from growing viral particles.

Tackling these questions can directly impact public health. The more we understand the rules governing the evolution of viral proteins, the better we can predict the impact of emerging viruses and thus increase our pandemic preparedness. Our long-term aim is to use structural and mechanistic insights to guide design of much-needed new antivirals and vaccines against zoonotic viruses.

Several projects encompassing areas above are available in the lab. If you are interested, please apply and do not hesitate to get in touch earlier to discuss more details. I am committed to working with you to scope projects that combine your interests in specific research questions as well as methodologies, your long-term career aspirations, and available expertise and pilot data in the lab. In this way we will devise the MSc or DPhil project that bests suit you.

REFERENCES (#co-first, •corresponding):

Antoni G. Wrobel# (2023) “Mechanism and evolution of human ACE2 binding by SARS-CoV-2 spike” Current Opinions in Structural Biology 102619.

Valeria Calvaresi#, Antoni G. Wrobel#, Joanna Toporowska, Dietmar Hammerschmid, Katie J. Doores, Richard T. Bradshaw, Ricardo B. Parsons, Donald J. Benton, Chloë Roustan, Eamonn Reading, Michael H. Malim, Steven J. Gamblin, Argyris Politis#. (2023) “Structural dynamics in the evolution of SARS-CoV-2 spike glycoprotein” Nature Communications, 14 (1), 427

Antoni G. Wrobel*#, Donald J. Benton*#, Chloë Roustan, Annabel Borg, Saira Hussain, Stephen R. Martin, Peter B. Rosenthal, John J. Skehel, Steven J. Gamblin# (2022). “Evolution of the SARS-CoV-2 spike in the human host” Nature Communications 13, 1178.

Antoni G. Wrobel*#, Donald J. Benton*#, Pengqi Xu, Annabel Borg, Chloë Roustan, Stephen R. Martin, Peter B. Rosenthal, John J. Skehel, Steven J. Gamblin# (2021). “Structure and binding properties of Pangolin-CoV Spike glycoprotein inform the evolution of SARS-CoV-2.” Nature Communications, 12 (1), 837.

Donald J. Benton*#, Antoni G. Wrobel*#, Chloë Roustan, Annabel Borg, Pengqi Xu, Stephen R. Martin, Peter B. Rosenthal, John J. Skehel, Steven J. Gamblin#. (2021) “The effect of the D614G substitution on the structure of the spike glycoprotein of SARS-CoV-2” Proceedings of the National Academy of Sciences, 118(9), e2022586118.

Donald J. Benton*#, Antoni G. Wrobel*#, Pengqi Xu, Chloë Roustan, Stephen R. Martin, Peter B. Rosenthal, John J. Skehel, Steven J. Gamblin# (2020) “Receptor binding and priming of the spike protein of SARS-CoV-2 for membrane fusion” Nature 588(7837), 327–330.

Antoni G. Wrobel*#, Donald J. Benton*#, Pengqi Xu, Chloë Roustan, Stephen R. Martin, Peter B. Rosenthal, John J. Skehel, Steven J. Gamblin# (2020) “SARS-CoV-2 and bat RaTG13 spike glycoprotein structures inform on virus evolution and furin-cleavage effects.” Nature Structural and Molecular Biology 27, 763–767 (2020).

Dr Antoni Wrobel | Biochemistry

For informal enquiries: antoni.wrobel@bioch.ox.ac.uk

Dr Haoxi Wu

Project Code: M16

How cells make T-cell receptors

Accurate biogenesis of multi-subunit membrane protein complexes is vital for human health, with improper assembly of specific complexes associated with diverse diseases. Despite their critical roles in human physiology, our understanding of how these complexes assemble is still limited. Our group aims to address this knowledge gap, contributing fundamental insights into basic biology with important implications for translational science and human diseases.

To address this challenge, we will study the assembly of the human T-cell receptor as a foundational paradigm. T-cell receptors play essential roles in fighting pathogens, preventing autoimmunity, and developing personalised medicines, each of which relies on precisely controlled receptor assembly. Although downstream signalling pathways have been thoroughly characterised, how the T-cell receptor assembles from eight independently produced cognate subunits with accurate timing and stoichiometry remains elusive. Using a cell-free reconstitution approach, we have identified the first factor that is required for early steps of T-cell receptor assembly, which we will now thoroughly characterise using multi-disciplinary approaches such as in vitro reconstitution, flow cytometry, live-cell imaging, and structural studies. We will continue to systematically identify and characterise key factors required for each step of T-cell receptor assembly, providing comprehensive insights into the assembly pathway.

This project not only lays the foundation for understanding general principles of membrane protein complex assembly but also offers perspectives on exploring the therapeutic potential of targeting assembly pathways.

Some of my group's previous work, expertise, and techniques are highlighted here: https://tinyurl.com/haoxiwugooglescholar

Rollins MG*, Tang J*, Wan Y*, Sundaram A*, Wu H*, Li Q*, et al., Keenan RJ. Cotranslational membrane protein biogenesis by an EMC-bound translocon. Nat Struct Mol Biol. 2026

Smalinskaitė L*, Wu H*, Hegde RS. Pairwise transmembrane domain insertion during multipass protein biogenesis. Mol Cell. 2026

Wu H^#, Hegde RS^#. Design principles of human membrane protein topology. J Cell Biol. 2026

Wu H, Smalinskaitė L, Hegde RS. EMC rectifies the topology of multipass membrane proteins. Nat Struct Mol Biol. 2024

Wu H, Hegde RS. Mechanism of signal-anchor triage during early steps of membrane protein insertion. Mol Cell. 2023

Wu H, Voeltz GK. Reticulon-3 Promotes Endosome Maturation at ER Membrane Contact Sites. Dev Cell. 2021

Ho N*, Yap WS*, Xu J*, Wu H*, et al. Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress. J Cell Biol. 2020.

Wu H, Carvalho P, Voeltz GK. Here, there, and everywhere: The importance of ER membrane contact sites. Science. 2018

^*These authors contributed equally ^#Co-corresponding authors

Dr Haoxi Wu | Biochemistry

For informal enquiries: haoxi.wu@bioch.ox.ac.uk

Expand All

Dr Lindsay Baker

Project code D1

Bacterial responses to stress

The Baker lab routinely uses cryogenic electron tomography (cryoET) to observe cell structure and how it changes in response to its environment.

Recently, we have observed profound structural changes in bacterial cells in response to stress, including membrane remodeling, crystal formation, and cytoplasmic alterations. This project will zoom in on these features and ask what proteins underlie the morphologies, and what advantage they provide to stressed cells. By targeting features that provide a significant adaptation, we hope to find new ways to manage bacterial populations.

CryoET can visualise cell environments at molecular resolution, revealing the structures and interactions that underpin cellular function (1). However, identifying the responsible proteins can be challenging. We use a variety of methods to move from structure to mechanism, including correlative light and electron microscopy (CLEM), focused-ion beam milling and volumetric EM, and mass spectrometry (both proteomics and native MS). We also use DNA-based nanostructure tags known as SPOTs, which serve as markers for protein identification in cryoET (2). SPOTs are readily visualised within tomograms and can be engineered to selectively bind target proteins.

References: (1) Turk, Martin, and Wolfgang Baumeister. "The promise and the challenges of cryo‐electron tomography." FEBS letters 594.20 (2020): 3243-3261.

(2) Silvester, Emma, et al. "DNA origami signposts for identifying proteins on cell membranes by electron cryotomography." Cell 184.4 (2021): 1110-1121.

Dr Lindsay Baker | Biochemistry (ox.ac.uk)

For informal enquiries: lindsay.baker@bioch.ox.ac.uk

Professor Frances Barr

Project Code D2

Understanding p53-dependent cellular responses to mitotic stress in normal and cancer cells

Cell cycle checkpoints preventing the replication and inheritance of damaged DNA are crucial for maintaining genome stability and stopping the growth of damaged cells. Canonical checkpoints do this by preventing passage between cell cycle phases until damage has been repaired, or by promoting cell cycle exit. Our recent work shows checkpoint integration between cell cycle phases linked to the MDM2-p53 pathway. We have found that extended spindle assembly checkpoint surveillance in mitosis is a danger signal triggering a prolonged p53-dependant G1 cell cycle arrest. In this project we will study the mechanistic details of this pathway and its dysregulation in human cancers.

Prof Francis Barr | Biochemistry

For informal enquiries: francis.barr@bioch.ox.ac.uk

Associate Professor Rachael Bashford-Rogers

Project Code D3