Fixed-term

Mechanism-based design and screening for synthetic inhibitors targeting the small GTPase splice variant RAC1B

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Details RAC1 is a small GTPase protein that functions as a key signaling node downstream of various microenvironmental signaling pathways. RAC1B, a RAC1 variant with an extra19 amino acid insert, is overexpressed in various cancers, including breast, colorectal and lung cancers [1]. This project will seek to unravel the differences in signalling mechanism of RAC1 and RAC1B leveraging structural biology, high-throughput 19F NMR, advanced molecular simulation, combined with the design, synthesis and biophysical evaluation of small chemical tool compounds that bind tightly and selectively to RAC1B over RAC1. Thus, this interdisciplinary project combines computational, chemical and biophysical aspects to offer an exciting research opportunity at the experimental medicine and enzymology interface. [1] Chen F., et al. RAC1B function is essential for breast cancer stem cell maintenance and chemoresistance of breast tumor cells. Oncogene, (2023), doi:10.1038/s41388-022-02574-6 Entry Requirements Applicants should hold (or be about to obtain) a First or Upper Second class (2:1) UK honours degree, or international equivalent, in a relevant subject. Application Guidance Candidates must contact the primary supervisor before applying to discuss their interest in the project and assess their suitability. Apply directly via this link: https://tinyurl.com/m87wpezv or on the online application portal, select “PhD Structural Biology” Programme as the programme of study. Please ensure that your application includes all required supporting documents: · Curriculum Vitae (CV) · Supporting Statement · Academic Certificates and Transcripts Equality, diversity and inclusion are central to the University’s activities. The full statement can be found here: https://www.bmh.manchester.ac.uk/study/research/getting-started/equality-diversity-inclusion/ Funding Notes This 4 year PhD project is for self funded students. At Manchester we offer a range of scholarships, studentships and awards at university, faculty and department level, to support both UK and overseas postgraduate researchers applying for competition and self-funded projects. For more information, visit our funding page or search our funding database for specific scholarships, studentships and awards you may be eligible for. References 1. P. Baumann, Y. Jin*. Far-reaching effects of tyrosine64 phosphorylation on Ras revealed with BeF3- complexes. Comm. Chem. (2024) 7, 19. 2. E. Pellegrini, P. Juyoux, J. von Velsen, N. Baxter, Y. Jin, H. Dannatt, M. Cliff, J. Waltho, M. W. Bowler. Metal fluorides – multi-functional tools for the study of phosphoryl transfer enzymes. Structure (2024), 32, 1–13 3. Q. Zhou, P. Catalan, H. Bell, P. Baumann, R. Evans, J. Yang, Z. Zhang, D. Zappala, Y. Zhang, G. M. Blackburn, Y. He*, Y. Jin*. An ion-pair induced intermediate complex captured in Class D carbapenemase reveals chloride ion as a Janus effector modulating activity. ACS. Cent. Sci. (2023), 9, 2339–2349. 4. S. El-Sayed, S. Freeman and R. A. Bryce*. Probing the effect of NEK7 and cofactor interactions on dynamics of NLRP3 monomer using molecular simulation. Protein Sci. (2022) 31, e4420. 5. M. A. Elhemely, A. A. Belgath, S. El-Sayed, K. K. Burusco, M. Kadirvel, A. Tirella, K. Finegan, R. A. Bryce*, I. J. Stratford, and S. Freeman. SAR of novel 3-arylisoquinolinones: meta-substitution on the aryl ring dramatically enhances antiproliferative activity through binding to microtubules. J. Med. Chem. (2022) 65, 4783-4797.

Understanding the contribution of SHANK3 LLPS in autism and cancer

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Details In this exciting research project, you will investigate SHANK3, a key protein that facilitates communication and adaptation in brain cells. SHANK3 acts as a molecular ‘organiser’, bringing together receptors, signalling molecules and the cell’s internal skeleton to promote healthy brain development and learning. If SHANK3 does not function properly, the consequences can be severe. Genetic changes in SHANK3 are one of the most common single-gene causes of autism spectrum disorder (ASD). Emerging research also suggests that this same protein may influence pathways related to cancer, including K-Ras and Wnt signalling. This project will explore how these seemingly different diseases may share common molecular mechanisms. The student will: – Gain hands-on experience with cutting-edge tools such as cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) to visualise proteins in great detail. -Discover how SHANK3 organises receptors and shapes the cell’s internal framework (the actin cytoskeleton), thereby influencing learning, memory and cell growth in our neuronal models. -Investigate disease-causing mutations. Explore how genetic mutations alter protein structure, disrupt cellular organisation and contribute to neurodevelopmental disorders and cancer. -Work with human stem cell-derived neurons. Assess how structural changes translate into functional consequences in human neuronal models. This interdisciplinary project sits at the intersection of neuroscience, structural biology, cell biology and cancer research. The successful applicant will benefit from a structured teaching environment at the Manchester Cell Matrix Centre, in collaboration with the University of Liverpool, where we have our own in-house cryo-electron microscope, NMR spectrometer, and stem cell facilities. Enquiries are welcome. Eligibility  Candidates are expected to hold a minimum upper second class honours degree (or equivalent) in a related area / subject Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Cell Matrix Research Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/ References Xingchen Li, Rafaella Konstantinou, Saba Notash, Tom Whalley, Paul Atherton, Igor Barsukov, Thomas Zacharchenko, Christoph Ballestrem, * Talin-tensin3 interactions regulate fibrillar adhesion formation and tensin3 phase separation. J Cell Biol (2026) 225 (1): e202503155. Li X, Goult BT, Ballestrem C, Zacharchenko T*. The structural basis of the talin-KANK1 interaction that coordinates the actin and microtubule cytoskeletons at focal adhesions. Open Biol. 2023 Jun;13(6):230058. doi: 10.1098/rsob.230058. Epub 2023 Jun 21. Lilja J, Zacharchenko T*, Georgiadou M, Jacquemet G, De Franceschi N, Peuhu E, Hamidi H, Pouwels J, Martens V, Nia FH, Beifuss M, Boeckers T, Kreienkamp HJ, Barsukov IL*, Ivaska J. SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras. Nat Cell Biol. 2017 Apr;19(4):292-305. doi: 10.1038/ncb3487. Epub 2017 Mar 6.

Roles of negative transcriptional regulators in breast cancers

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Details Breast cancer is a widespread and life-threatening condition that affects millions of women globally. Understanding the complexity of gene expression associated with this disease is essential for developing targeted interventions that can revolutionize its diagnosis, treatment, and prevention. Deregulation of transcription factors is one the most common factors contributing to carcinogenesis as precise control of transcription and RNA processing is essential for the correct gene expression. While the activation of transcription is widely studied, knowledge about transcriptional repression is comparatively limited. The downregulation of transcription allows the reduction of gene expression by limiting RNA synthesis. This can be achieved by premature transcription termination, decreased transcription rates or increased promoter-proximal RNA Polymerase II (Pol II) pausing. The persistent presence of Pol II on the gene allows for a rapid shift from an “off” to “on” state when needed. Such transitions are essential for survival strategies including stress responses and cellular signalling. A successful candidate will study the functions of protein interacting with RPRD (Regulation of Nuclear mRNA Domain-Containing) proteins (RPRD1B, RPRD1A and RPRD2) which have been identified in our lab as negative transcription factors. RPRDs belong to the family of important transcriptional regulators interacting with RNA Polymerase II, are present on actively transcribed genes and their levels correlate with the cellular transcription rates. Most importantly these proteins are heavily overexpressed in breast cancer cells originating from primary and metastasis patients. Thus, the project will dissect the mechanistic details of how proteins interacting with RPRDs enforce transcription downregulation with a special focus on processes mediating the transition from transcription initiation to elongation in cancer cells. Our group is based at the University of Manchester, which has a reputation for pioneering research and innovation with 25 Nobel Prize winners. The University was ranked 32nd in the world in the 2024 QS University Rankings and 2nd in the world for social and environmental impact in the THE Impact Rankings. Manchester is a friendly city with award winning museums and world famous football clubs, and has regularly been voted the UK’s best city to live. Eligibility Candidates are expected to hold (or be about to obtain) a minimum 2:1 Bachelors Degree with Honours (or equivalent) in a related area/subject. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Molecular Biology Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/

(SATURN CDT) Genomic and metatranscriptomic approaches to understand and control microbial communities in nuclear facilities

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Details Saturn_Nuclear_CDT UoM_Nuclear The Sellafield site contains several Spent Nuclear Fuel Ponds (SNFPs) that store some of the UK’s legacy nuclear waste. These engineered facilities were originally assumed to be too radioactive to support microbial colonisation and growth. However, it is now well established that diverse microbial communities not only exist in these environments but can thrive. Microorganisms colonising these facilities have the potential to form microbial blooms, drive biofouling, induce microbial induced corrosion and influence the behaviour of radionuclides. Understanding how these microbial communities’ function is therefore important for the safe management and decommissioning of nuclear facilities. Our previous research has used amplicon metagenomic sequencing to fingerprint the microbial communities in the ponds (1-3), helping to inform strategies to control microbial blooms. However, metabolic activity and ecological behaviour of these microorganisms in radioactive environments remains poorly understood. This PhD project will develop and apply advanced genomic and metatranscriptomic approaches to characterise the microorganisms in SNFPs and reveal how they function in significantly radioactive environments, generating new insights into how microbial processes may influence these engineered systems. The outcomes of this project will help to address key challenges in nuclear decommissioning including improved waste management and the development of more effective strategies to manage and control microbial activity in nuclear facilities. This project aims to characterise microbial communities and their metabolic functions in engineered radioactive facilities. The specific focus of the project includes: – mapping microbial communities and their distribution across hydraulically linked SNFPs – developing and validating methods (e.g. metatranscriptomics) to assess microbial activity in radioactive samples – apply methods developed to identify active microbial communities present in SNFPs The project will combine lab-based experimental approaches alongside bioinformatic analysis to determine metabolically active microbial communities. The experimental work will focus on the development of methods that can be applied to radioactive samples to isolate RNA, which will then be analysed. The work will be carried out using specialised experimental facilities within the NNUF RADER (https://www.nnuf.ac.uk/rader) and the Williamson Research Laboratories (https://www.ees.manchester.ac.uk/wrc/). Bioinformatic pipelines will be used to analyse the (meta)transcriptomics data, providing new insights into metabolically active microorganisms in radioactive facilities. About SATURN This PhD is based with the SATURN Centre for Doctoral Training. SATURN is made up form a consortium of NW Universities that include Manchester, Bangor, Leeds, Liverpool, Lancaster, Sheffield and Strathclyde. The ethos of the programme is to recruit students from across STEM and give them the necessary skills and training to become a subject matter expert in the nuclear sector in either industry or academia. You will be recruited with a cohort of other researchers all looking at nuclear- focused research but from across the breadth of the sector. Your training will include an introduction to nuclear course, as well as opportunities to do a deep dive in the areas that really interest you. You will also have the opportunity to broaden your experience and skills by visiting internationally relevant facilities, having an industry secondment, undertaking leadership training, and involving yourself in outreach and public engagement activities. If this sounds like the sort of opportunity that you are looking for, we would love to hear from you. Eligibility Applicants should have, or expect to achieve, at least a 2.1 honours degree or a master’s (or international equivalent) in a relevant science or engineering related discipline. Before you apply We strongly recommend that you contact the supervisor(s) for this project before you apply. For informal enquiries, please contact Lynn Foster at lynn.foster@manchester.ac.uk. Projects are subject to funding confirmation How to apply Please complete the Enquiry Form to express your interest. We strongly recommend you contact the project supervisor after completing the form to speak to them about your suitability for the project. If your qualifications meet our standard entry requirements, the CDT Admissions Team will send your enquiry form and CV to the named project supervisor. Our application process can also be found on our website: here If you have any questions, please contact SATURN@manchester.ac.uk Equality, diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. We know that diversity strengthens our research community, leading to enhanced research creativity, productivity and quality, and societal and economic impact. We actively encourage applicants from diverse career paths and backgrounds and from all sections of the community, regardless of age, disability, ethnicity, gender, gender expression, sexual orientation and transgender status. We also support applications from those returning from a career break or other roles. We consider offering flexible study arrangements (including part-time: 50%, 60% or 80%, depending on the project/funder). Funding Notes The EPSRC funded Studentship will cover full tuition fees at the Home student rate and a maintenance grant for 4 years, starting at of £26,000 pa. for 2026-2027. References 1) Foster, L., Boothman, C., Ruiz-Lopez, S., Boshoff, G., Jenkinson, P., Sigee, D., et al. (2020). Microbial bloom formation in a high pH spent nuclear fuel pond. Sci. Total Environ. 720:137515. doi: 10.1016/j.scitotenv.2020.137515 2) Ruiz-Lopez, S., Foster, L., Boothman, C., Cole, N., Morris, K., and Lloyd, J. R. (2020). Identification of a stable hydrogen-driven microbiome in a highly radioactive storage facility on the Sellafield site. Front. Microbiol. 11:587556. doi: 10.3389/fmicb.2020. 587556 3) Foster L, Boothman C, Harrison S, Jenkinson P, Pittman JK and Lloyd JR (2023) Identification of algal rich microbial blooms in the Sellafield Pile Fuel Storage Pond and the application of ultrasonic treatment to control the formation of blooms. Front. Microbiol. 14:1261801. doi: 10.3389/fmicb.2023.1261801

[PhD by Enterprise FSE] Field-Deployable Genotyping for Animal Health and Biosurveillance

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Details The Covid19 pandemic demonstrated that testing in a home setting using lateral flow tests (LFTs), which are affordable and usable by non-specialists, was an effective tool for the management of patient isolation and pandemic monitoring. From a biochemical perspective, the current LFT formats utilise the capture of viral proteins by cognate antibodies. However, this is a fundamentally less sensitive approach since it is unable to detect prodromic infections where levels of the pathogen are low, and it is unable to differentiate different strains of the virus. Rather, what is required is a method of detecting the DNA/RNA of the pathogen, but with a sensitivity that is sufficiently high for early detection. CRISPR-based diagnostics, including DETECTR (DNA detection) and SHERLOCK (RNA detection), are emerging as powerful platforms for rapid and highly specific molecular detection. These systems combine a Cas enzyme (Cas12a or Cas13) with a programmable CRISPR RNA (crRNA) designed to recognise a target sequence. Upon binding the target, the enzyme becomes activated and exhibits collateral nuclease activity, cleaving fluorogenic reporter probes, resulting in very sensitive fluorescence signals. However, current CRISPR diagnostics rely on laboratory-based spectrofluorometers, limiting their use in field environments. This research aims to develop CRISPR-based diagnostics in LFT format. Such LFT formats are particularly applicable in this context, being cheap, rapid, sensitive and portable; and can be used without specialist training or equipment – and hence deployable outside a laboratory setting. This research will suit a chemist, molecular biologist or microbiologist with an interest in working on a varied and multidisciplinary project. The successful candidate will receive a broad scientific training across these areas, as appropriate to their background. They will join a growing team of researchers from a range of backgrounds. The research will be based across the Manchester Institute of Biotechnology and the Genome Editing Unit at the University of Manchester, both of which offer state-of-the-art laboratories, instrumentation and facilities. Informal enquiries can be directed at the supervisor Dr. Lu Shin Wong (l.s.wong@manchester.ac.uk). This is not a traditional PhD. As part of the PhD by Enterprise Programme, you will receive dedicated training in entrepreneurship, innovation, and venture development. You will be supported to explore market opportunities, develop a business plan, and potentially contribute to the creation of a spin-out company based on your research. Applicants are expected to hold (or about to obtain) a minimum upper second-class undergraduate honours degree (or equivalent) in chemistry, molecular biology, microbiology or related subject.  Research experience in diagnostics, virology or analytical (bio)chemistry are desirable. To apply for this project please select PhD Enterpise (FSE). FSE_Enterprise Funding Notes Fully funded studentships are available to start in 2026/27 and provide the following: ·      Funding at the UKRI stipend rate, £21,805 ·      Tuition fees ·      Up to £20,000 RTSG per studentship, depending on the research project ·      Additional support for entrepreneurship training and customer discovery activities ·      Visa and immigration costs reimbursed for successful international PGRs References 1. T. Hall, S. Gulati, R. Sang, Z. Jia, F. McKinnirey, G. Vesey, E. Goldys and F. Deng, Trends Anal. Chem., 2025, 189, 118275. https://doi.org/10.1016/j.trac.2025.118275 2. J. S. Gootenberg, O. O. Abudayyeh, J. W. Lee, P. Essletzbichler, A. J. Dy, J. Joung, V. Verdine, N. Donghia, N. M. Daringer, C. A. Freije, C. Myhrvold, R. P. Bhattacharyya, J. Livny, A. Regev, E. V. Koonin, D. T. Hung, P. C. Sabeti, J. J. Collins and F. Zhang, Science, 2017, 356, 438-442. https://doi.org/10.1126/science.aam9321 3. J. S. Chen, E. Ma, L. B. Harrington, M. Da Costa, X. Tian, J. M. Palefsky and J. A. Doudna, Science, 2018, 360, 436-439. https://doi.org/10.1126/science.aar6245 4. M. J. Osborn, A. Bhardwaj, S. P. Bingea, F. Knipping, C. J. Feser, C. J. Lees, D. P. Collins, C. J. Steer, B. R. Blazar and J. Tolar, Bioengineering, 2021, 8, 23. https://doi.org/10.3390/bioengineering8020023

(PhD by Enterprise) Autologous tumour-derived nanocarriers for precision drug delivery in Glioblastoma

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Details Glioblastoma is one of the most lethal cancers. Despite maximal therapeutic intervention, most patients survive less than 18 months. The fundamental reason treatment fails is the blood-brain barrier, a highly selective biological filter that prevents almost all drugs from reaching the brain tumour. This PhD trains a researcher to tackle this problem using a novel class of drug delivery vehicle built not from synthetic materials, but from the patient’s own cancer. You will produce exosome-like nanoparticles (ELNs) from cells taken from patient brain tumour organoids, which are miniature tumours grown in the laboratory from real patient tissue. An established patented method is used to convert these cells into nanoparticles carrying the precise molecular signature of the patient’s own cancer. Because these particles are made from the tumour itself, they are designed to home back to it with a specificity that no synthetic carrier can replicate. You will load these nanoparticles with anti-cancer drugs, including the current standard of care and agents under active clinical investigation, and test their performance in the most clinically realistic models available: patient-derived organoids and animal models of glioblastoma. You will be joining a well-resourced, active research environment. The supervisory laboratory already holds funded programmes in biological nanocarrier development and has generated preliminary data on this technology, which has attracted competitive funding. You will build directly on this foundation, inheriting validated protocols and working within an established collaboration between two world-leading groups. As part of the PhD by Enterprise programme, you will develop a full business plan and commercialisation strategy alongside your experimental research, working directly with the University’s Innovation Factory and engaging with prospective industry partners. You will be mentored on IP strategy by a supervisor who is himself navigating a live commercialisation process and will receive an industry perspective on clinical translation from a co-supervisor with prior experience as an Oncology R&D Director at a global pharmaceutical company. By the time you graduate, you will be a researcher with deep technical expertise in one of the most challenging areas of nanomedicine and the commercial acumen to take a laboratory discovery toward clinical and market impact. Entry Requirements Applicants must have obtained, or be about to obtain, a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in Pharmacy, Biomedical Sciences, Biochemistry, Cancer Biology, Chemical Biology or Pharmacology, with essential proven experience in cell culture and/or nanoparticle/exosome characterisation (NTA, DLS, TEM, WB). Preferred experience includes drug delivery, in vivo animal work, and organoid models. Candidates should demonstrate strong enthusiasm for translational/commercial research, intellectual curiosity, and interdisciplinary teamwork in an enterprise-focused PhD environment. Application Guidance Candidates must contact the primary supervisor before applying to discuss their interest in the project and assess their suitability. Apply directly via this link: https://shorturl.at/BRKKT or on the online application portal, select PhD by Enterprise Programme as the programme of study. Please ensure that your application includes all required supporting documents: Curriculum Vitae (CV) Supporting Statement Academic Certificates and Transcripts Incomplete or late applications will not be considered. Further details are available on our website: PhD by Enterprise | Biology, Medicine and Health | The University of Manchester Equality, diversity and inclusion are central to the University’s activities. The full statement can be found here: https://www.bmh.manchester.ac.uk/study/research/getting-started/equality-diversity-inclusion/ Funding Notes This PhD by Enterprise studentship provides full funding for tuition fees and a stipend at the UKRI rate for four years starting in September 2026. This funded scheme will also allow for Visa and Immigration Costs to be reimbursed for successful international PGRs.

Combining genetic and biophysical approaches to understand the structure function relationship of the Notch Abruptex domain

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Details Notch is a developmental signalling receptor with widespread roles in metazoan development and adult stem cell regulation. Precise control of Notch signalling levels is crucial for proper development and health. Inherited mutations of Notch are associated with genetic disease that involves misregulated development, and somatic mutations are linked to cancer. Understanding the link between genetics of Notch and its varied phenotypic outcomes is therefore important for developing novel therapeutic strategies. In our research we have identified a region of the Notch extracellular domain, outside of the ligand binding domain, where mutations cause altered endocytosis and upregulated signal activation. This project will combine genetic, biochemical and biophysical approaches to understand the mechanisms by which this region of Notch regulates its activity, using Drosophila Notch as an experimental model system. In particular, the student will examine how mutations affect structure and regulatory interactions of Notch, understand the mutant impact on Notch trafficking and signalling, and examine how disruption of function in this region leads to changes in gene expression networks. The work will combine biophysical techniques of NMR spectroscopy and crystallography to determine structure, biochemical methods of proximity biotin labelling to identify interacting partner proteins, and RNAseq experiments to understand the consequences of Notch mutations on the transcriptome. Eligibility  Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a biology-related subject. Candidates with experience in either Drosophila research, structural biology or biochemical approaches are encouraged to apply. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Developmental Biology Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website: https://www.bmh.manchester.ac.uk/study/research/fees/

(PhD by Enterprise) Genome safeguarding technologies for synthetic phage therapeutics against multidrug resistant bacterial infections

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Details Rising levels of antimicrobial resistance pose a serious threat to global health and modern medical treatments. The slow pace of antimicrobial discovery has driven the rediscovery of an old idea: using the natural viral predators of bacteria, phages, to treat infections. Conventional phage therapy, using naturally occurring phages, has been proven safe and effective across 1000s of individual patients for a wide range of bacterial diseases. Rollout of conventional phage therapy in the clinic has, however, been slowed by logistical, regulatory and commercialization barriers. Synthetic genomics allows phage genomes to edited, recombined or designed from scratch. Synthetic phages are a pathway to more standardized, scaleable and commercializable phage therapeutics, overcoming regulatory and commercialization barriers. Robust genome safeguarding will be essential for the broad adoption of synthetic phage therapeutics. In this project we will develop genome safeguarding technologies for synthetic phages that prevent their unwanted release into natural environments and ensure robust protection of intellectual property. These genome safeguarding technologies will be built-in to synthetic phage therapeutics for treatment of multidrug resistant bacterial infections and tested in relevant preclinical infection models. The project will offer broad training in synthetic genomics and synthetic biology, microbiology and phage biology, infection biology and evolutionary biology. The student will gain expertise in statistical analysis, bioinformatics, data visualisation and experimental design. The project will provide experience in developing a novel biotechnology including training in innovation, commercialisation and business development and opportunities to interact with regulators and policy-makers. Entry Requirements Applicants should hold (or be about to obtain) a First or Upper Second class (2:1) UK honours degree, or international equivalent, in a relevant subject. Application Guidance Candidates must contact the primary supervisor before applying to discuss their interest in the project and assess their suitability. Apply directly via this link: https://shorturl.at/BRKKT or on the online application portal, select PhD by Enterprise Programme as the programme of study. Please ensure that your application includes all required supporting documents: Curriculum Vitae (CV) Supporting Statement Academic Certificates and Transcripts Incomplete or late applications will not be considered. Further details are available on our website: PhD by Enterprise | Biology, Medicine and Health | The University of Manchester Equality, diversity and inclusion are central to the University’s activities. The full statement can be found here: https://www.bmh.manchester.ac.uk/study/research/getting-started/equality-diversity-inclusion/ Funding Notes This PhD by Enterprise studentships provide full funding for tuition fees and a stipend at the UKRI rate for four years starting in September 2026. This funded scheme will also allow for Visa and Immigration Costs to be reimbursed for successful international PGRs.

Utilizing machine learning to decipher the mechanism of protein-DNA binding

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Details Transcriptional gene regulation, or the ability to control the timing and levels of gene expression through binding of transcription factors (TFs) to DNA, is a defining feature of life. It allows organisms to coordinate function internally and to respond to external changes in the environment. The main mechanism through which gene regulation occurs, especially in bacteria, relies on binding between a protein (transcription factor, or TF) and DNA. TFs bind DNA in a sequence-specific manner, preferring some residues over others and in doing so enabling regulation to be specific and efficient. In spite of the importance and the central role that the specificity of transcription factor-DNA binding plays in gene regulation, we know little about how 3D protein structure determines this specificity. The aim of this interdisciplinary project is to utilize cutting-edge machine learning tools and techniques to decipher how the 3D structure of the TF determines its sequence-binding specificity. We will do this for TetR, a bacterial transcriptional regulator that is critical in the regulation of antibiotic resistance to an entire category of antibiotics, tetracyclines. To achieve this aim, the student will address the following objectives: 1. develop a model to predict sequence-binding specificity of wildtype TetR: utilize Alpha Fold and Rosetta to simulate how the wildtype TetR protein binds to a range of different DNA sequences and use those predictions to reconstruct the biophysical sequence-binding specificities of TetR. Binding specificities for TFs are currently determined experimentally and Lagator group did so for TetR, providing a unique experimental reference dataset to validate and fine-tune the model on. Achieving this objective will enable and demonstrate how to determine sequence specificity of TFs computationally. 2. characterize sequence-binding specificity of TetR variants: currently, almost nothing is known about how binding specificity changes as the protein sequence changes. Here, we will rely on the novel aspect of Alpha Fold, namely, its ability to predict structure of protein-DNA complexes, to simulate a large number of TetR variants with mutations in the DNA-binding domain. Then, the student will utilize the model from Objective 1 to determine sequence-binding specificities of all these variants. This will mark the first study to characterize how binding specificity changes as a consequence of changes to protein sequence. 3. decipher how structure shapes binding specificity: armed with a large number of TetR variants with characterized binding specificities (from Objective 2), the student will interrogate the relationship between the differences in their structure and in their binding specificities. Doing so will allow us to identify, for the first time, how changes to protein structure alter its binding. Achieving the aim and objectives of the study will: (i) provide key novel insights into the relationship between protein sequence, structure and function (i.e., its binding specificity). As such, the project will be the first to unravel this critical relationship, and to do so for a key regulator of antibiotic resistance. (ii) develop new techniques at the interface between machine learning, structural biology and biophysics, and demonstrate how they can be applied to tackle key outstanding questions of relevance to the study of gene regulation, evolution, molecular and synthetic biology. To achieve the aim and objectives will require an interdisciplinary team, with expertise in the biology and biophysics of gene regulation (Dr. Lagator), structural biology (Prof. Lovell) and machine learning/AI (Prof. Rattray). The student will therefore have all the critical support in place to tackle this project, which can be found with the supervisors and the members of their research groups. Each of the supervisors will provide bespoke support for the student, depending on their background and development needs. The student will have a weekly meeting with the supervisors, and will also be assigned an advisor to help identify, signpost and develop their skillset to tackle the project aim. They will also be invited to join respective group meetings, providing an opportunity to regularly present their work and benefit from the experience of other PhD students and postdocs. The student will have access to various workshops and courses offered within the Faculty, aimed at developing research and soft skills of PhD students. The student will also be integrated into the Microbial Evolution Research Manchester (MERMan) group, one of Europe’s biggest clusters of researchers working on various aspects of microbial ecology and evolution, where they will be invited to give seminars and expand their research network. Eligibility  Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in computer science, physics, mathematics, bioinformatics or other related disciplines. Alternatively, the candidates would exhibit strong experience in computational biology and coding. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Bioinformatics Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 2(med) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/

Turbocharging T cell therapeutics for solid cancer

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Details T cell–based immunotherapies have shown promise for certain malignancies, yet multiple factors limit their effectiveness in solid tumors. This project seeks to address those limitations through a multipronged strategy that combines interventions and genetic modifications known to yield incremental improvements when used individually. Specifically, the student will explore approaches such as (1) modulating T cell subsets (e.g., T stem cell memory or naïve T cells) through small molecules and cytokines during expansion, (2) employing next-generation T cell engineering (e.g., advanced CAR constructs, CRISPR/shRNA-mediated gene edits), and (3) introducing molecular enhancements (e.g., forced expression of tumor-infiltration–promoting factors). By systematically combining these tactics, we aim to discover synergistic effects that can overcome the immunosuppressive environment of solid tumors. The project will maintain flexibility, allowing the student to adapt interventions and modifications as new insights emerge, with the overarching goal of driving T cell therapies toward more profound and durable therapeutic responses. Eligibility  Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area/subject. Candidates with experience in cell culture, molecular biology and genetic modification and mouse cancer models are encouraged to apply. Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application. How to Apply To be considered for this project you MUST submit a formal online application form – on the application form select PhD Immunology Programme. Full details on how to apply can be found on the Website: How to apply for postgraduate research at The University of Manchester If you have any queries regarding making an application please contact our admissions team FBMH.doctoralacademy.admissions@manchester.ac.uk Equality, Diversity and Inclusion Equality, diversity and inclusion is fundamental to the success of The University of Manchester, and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website: Equality, diversity and inclusion (EDI | Postgraduate Research | Biology, Medicine and Health | University of Manchester Funding Notes Applications are invited from self-funded students. This project has a Band 3 (high) fee. Details of our different fee bands can be found on our website https://www.bmh.manchester.ac.uk/study/research/fees/

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