Rare Disease PhD: Using Gene Editing and Zebrafish Models to Study NF1 Variants

Rare Disease PhD: Using Gene Editing and Zebrafish Models to Study NF1 Variants

Quick Decision

This four-year Exeter MRC FGx-DLA project follows human NF1 variants from population-level prioritization to cell signalling assays and zebrafish phenotypes. The student would use genetic data and prediction models to select variants, test their effects in human cells, then build a humanized zebrafish model for tissue-level imaging and drug-response experiments. The proposed replacement of zebrafish nf1 with human NF1 is ambitious because zebrafish have two paralogs, nf1a and nf1b; the target, timeline and fallback strategy should be discussed with the team.

The project suits applicants who want to bridge variant interpretation and experimental disease models. Exeter lists 5 January 2027; an earlier public record gives 8 December 2026. International applicants should also reconcile the national no-top-up guidance with the award page’s UK-fee wording. Confirm the operative deadline, fish-line plan, model validation and written funding terms before committing.

Research Problem and Doctoral Work

What Is Unsolved and Why It Matters

Neurofibromatosis type 1 (NF1) is a variable multisystem disorder caused by pathogenic variants in NF1, which encodes neurofibromin. The central problem here is not simply whether a variant is present, but how variants in different parts of the gene alter protein-dependent signaling and produce distinct cellular or organism-level phenotypes. Current clinical and biological knowledge underscores substantial variability in NF1 presentation; a predicted or experimentally measured effect in one model should not be treated as a clinical diagnosis by itself. The project describes seven functional domains of neurofibromin, while one recent domain-based association analysis uses eight annotated domains. These counts may reflect different annotation schemes rather than a simple factual error, but they make the chosen transcript and domain definition important for variant selection and interpretation. The association study also has a published correction, so its corrected details should be checked before using specific numerical estimates. GeneReviews, international NF1 diagnostic consensus, recent NF1 domain-association study, published correction

Neurofibromin’s Ras-GAP activity provides a clear signaling rationale, but literature describes additional functions beyond this pathway. A readout limited to one Ras/MAPK measurement may therefore miss some effects of variants in other domains. The project’s goal is a functional map linking variant identity, signaling activity and organismal phenotype; this is an intended research outcome, not a guaranteed deliverable. Review of neurofibromin functions beyond the GAP domain

Work, Methods, and Potential Outputs

The official project description sets out a linked experimental/computational sequence:

1. Identify and prioritize human NF1 variants. Use population data, with a focus on genotype–phenotype association, to select pathogenic variants for follow-up.
2. Predict functional effects and select representatives. Use AI approaches such as biological foundation models to estimate variant effects and select variants from different NF1 domains. The project does not name a particular model, variant database, transcript or calibration benchmark. A recent genome-scale prediction resource illustrates the field’s direction, but remains a preprint and prediction scores require experimental calibration. AlphaGenome Atlas preprint
3. Measure effects in human cell culture. Test how the selected variants affect neurofibromin-dependent downstream signaling, quantitatively measure cell phenotypes and assess whether existing compounds, including MEK inhibitors targeting the Ras pathway, can rescue selected readouts. Rescue in an experimental system would not establish patient benefit or predict clinical response.
4. Build and use a humanized zebrafish platform. The project proposes using CRISPR/Cas9 to excise the zebrafish nf1 protein-coding sequence and replace it with human NF1. It then proposes introducing selected variants into the replacement sequence using precise editing such as prime editing or donor-DNA-based knock-in. Imaging of transgenic reporters for oligodendrocytes, Schwann cells or vascular endothelial cells would be used to assess tissue patterning and pharmacological responses. These stages connect molecular results to developmental and tissue-level outcomes.

The model-building stage is the largest technical uncertainty. Zebrafish have two human NF1 orthologues, nf1a and nf1b, with partly overlapping developmental functions; the project description refers to “nf1” in the singular but does not specify whether one paralog or both will be replaced. Existing work supports the use of zebrafish for NF1 developmental phenotypes and precise short edits, but does not establish that full coding-sequence humanization is already routine. Ask which paralog(s) will be targeted, whether the plan is to establish a stable line or initially use mosaic editing, how replacement will be validated, how many variants can realistically be introduced, and what fallback project remains if the full replacement is delayed. Zebrafish NF1 mutant study, zebrafish NF1 cardiac and vascular study

School, Programme and Field Context

The project PDF identifies the University of Exeter and its Living Systems Institute (LSI) as the project setting. Exeter offers postgraduate research routes in Biological Sciences and an MPhil/PhD in Complex Living Systems, an interdisciplinary programme covering areas such as genome editing, advanced imaging and cross-disciplinary supervision. The project PDF does not state the formal degree registration title, so the exact route and registration conditions should be confirmed. The MRC award links six core universities through shared training and research activities; this network does not establish a joint or double degree. Exeter Biological Sciences PGR, Complex Living Systems MPhil/PhD, Living Systems Institute, MRC FGx-DLA programme

For subject context, Exeter’s REF 2021 results show the Biological Sciences Unit of Assessment with 41% of outputs rated world-leading (4*) and 49% internationally excellent (3*). Exeter’s programme page also reports a Top 20 UK position for world-leading Biological Sciences research based on REF 2021 4-star work. These describe submitted subject research, not the quality of this specific project, its supervision or an individual student’s experience. The award page names Exeter as the relevant host for this project; confirm the degree registration route with the PGR admissions team. REF 2021 results

Supervisor and Lab Assessment

Supervisor Research Directions

The named project lead is Yosuke Ono. His profile lists CRISPR/Cas9 genome editing and molecular signaling research, and identifies his Exeter LSI affiliation. The project’s combination of genome editing, cell signaling and in vivo phenotype analysis is therefore close to his stated methods background. The full supervisory team and task allocation are not specified in the project PDF. Steffen Scholpp’s Exeter profile and group research focus on developmental signaling and zebrafish, but he is not named in the project document; do not assume his formal role. Ask who will supervise the population-data/modeling, cell-culture and fish work, and who owns the day-to-day animal and imaging support. Yosuke Ono profile, Steffen Scholpp profile

Recent Important Publications

• Ono et al., eLife (2026): optimized prime-editing approaches for precise insertions and substitutions in zebrafish. This is the closest technical precedent for the advertised variant insertion work. It supports method development at tested loci but does not demonstrate replacement of the entire NF1 coding region. Publication record
• Zhang et al., Nature (2024): showed cytoneme-mediated transport of active Wnt5b–Ror2 complexes in zebrafish, combining live imaging with developmental signaling analysis. The paper supports nearby LSI expertise in zebrafish imaging and mechanism, but it is not an NF1 study and does not validate the humanized model. Paper
• Ou et al., Scientific Reports (published 2025; version of record 2026): analyzed genotype–phenotype associations by NF1 protein-domain annotation. It is relevant to the project’s variant-domain prioritization, but reported clinical cohorts and annotation choices limit causal interpretation. A correction appeared in 2026, so numerical claims should be checked against that corrected record. Study, correction

Lab, Resources, and Collaboration Environment

Exeter’s Aquatic Resource Centre describes 14 aquaria and a zebrafish unit with more than 2,500 tanks, while the Bioimaging Centre supports LSI and Biosciences. The project PDF names support from the Aquatic Resource Centre and Bio-imaging Centre, so this is a relevant local infrastructure match. However, Bioimaging access requires a supervisor-authorized request, induction and full economic costing; the public facility page does not guarantee microscope time, a fish line, project priority or a charge code. Confirm which reporter lines already exist, whether the proposed work can access the relevant imaging systems, and whether time and usage costs are included in the research budget. Exeter zebrafish hub and ARC, Bioimaging Centre access and costing

Funding, Application, and Living Cost

The official Exeter award is the MRC Functional Genomics Doctoral Landscape Award, reference 6025, for September 2027 entry. Current Exeter award and programme pages set the deadline at 5 January 2027. Another public project record says 8 December 2026, a material date discrepancy. Plan to the earlier date until the Admissions team confirms the deadline, exact cutoff time and time zone in writing. The official project, award and programme pages identify MRC FGx-DLA; another public record incorrectly labels the award as EPSRC. Award 6025, MRC programme page

The studentship lasts four years full time; part-time study is available. It covers UK tuition fees, a UKRI minimum stipend of £21,805 per year for 2026/27 (updated annually), and up to £5,000 per year for research/training support. The latter is a project/training allocation, not extra personal stipend. UKRI guidance says its tuition contribution is capped at the home-fee level; the Exeter award specifies UK fees. International applicants are eligible under the programme and subject to the applicable UKRI international-student limit. The current FGx-DLA international-fees page says Exeter students do not need to supplement UKRI funding, while award 6025 itself specifies UK tuition fees; use the programme guidance and confirm that the individual offer follows it. The reviewed Exeter materials do not explain how the 30% limit is counted across the six-institution programme. UKRI stipend and fee guidance, UKRI international eligibility guidance, UKRI studentship framework

The programme requires a relevant 2:1 honours degree or international equivalent. Accepted subject examples include genetics, molecular biology, biomedical science, human biology, biochemistry, medicine/health professions, bioinformatics, computer science and statistics. The typical English threshold is IELTS 7.0 overall with no component below 6.5, or an accepted equivalent. These are award-level formal criteria; the project methods do not make prior fish work, prime editing, a named AI model or a particular coding language a separate published prerequisite. Application materials include the online form, transcripts, a CV of no more than two pages, two references and the FGx-DLA applicant questionnaire; English evidence is required where applicable, and qualifications need certified English translations. The questionnaire covers programme motivation/longer-term goals, a significant experience, reflection on research experience, and use or non-use of generative AI. Applicants may list up to three preferences but may submit only one application. References must not be from the prospective supervisor team; if shortlisted, applicants must arrange for academic referees to email letters seven days before interview. All documents must be in English. Exeter award application and reference requirements

Exeter estimates living costs at £1,300–£2,000 per month, based on average local spending in April 2026. Dividing the annual stipend by 12 gives an indicative £1,817 per month—within that range, but around £183 below its upper end. This comparison excludes one-off arrival expenses and any visa, travel, fee-gap or personal costs; the monthly average is not a guarantee of how stipend payments are scheduled. Exeter student budget

Applicant Fit and Preparation

Required Background and Skills

The formal threshold is the programme’s relevant 2:1/equivalent degree and English requirement. The programme lists genetics, molecular biology, biomedical science, human biology, biochemistry, medicine/health professions, bioinformatics, computer science and statistics among eligible areas. No source states that applicants must already be proficient in a particular programming language, have independently generated transgenic fish, or have mastered prime editing.

Preferred Experience and Suggested Preparation

Before applying, prepare examples showing how you reason through uncertain biological data, evaluate model assumptions and connect a computational or genetic observation to an experimental test. Quantitative applicants can show curiosity about cells and developmental models; life-science applicants can demonstrate readiness to work with population-level data, reproducible analysis and model predictions. These are preparation suggestions, not additional eligibility conditions. Understanding the distinction between model prioritization, functional evidence and clinical interpretation is especially relevant to NF1. NF1 GeneReviews, NF1 diagnostic consensus

The field offers adjacent paths in academic genetics/developmental biology, research bioinformatics, functional genomics and biotech discovery research. Skills England’s 2026 life-sciences assessment projects about 66,000 additional and 52,000 replacement workers in priority occupations to 2035 and highlights demand for science/data combinations. These are broad, uncertain sector projections rather than estimates of PhD vacancies. A clinical scientist career is a separate route: the NHS Scientist Training Programme includes three years of work-based training and a funded master’s, leading to eligibility for HCPC registration; this PhD alone does not confer clinical registration. Skills England life-sciences assessment, NHS Scientist Training Programme

Next Actions and Questions to Verify

Before Applying

• Ask Exeter PGR Admissions to confirm in writing whether the operative deadline is 8 December 2026 or 5 January 2027, including the time and time zone. The online award page currently states 5 January; preparing to the earlier date avoids relying on a later interpretation.
• Confirm how the programme applies the international-student limit across its six institutions; the current FGx-DLA guidance says Exeter students do not need to supplement UKRI funding, and the written offer should confirm the award terms for this project.
• Confirm the formal degree-registration route, the accepted qualification equivalencies and the correct English-language evidence deadline.

At Interview

• Which zebrafish paralog(s), nf1a, nf1b or both, will be humanized? What editing strategy will replace the coding sequence, how will a stable line be distinguished from mosaic editing, and what are the validation milestones and fallback plan?
• Which transcript and domain annotation will define the project’s variant groups, given the project PDF’s seven-domain description and the eight-domain scheme in recent association work? Which variant database, population dataset and biological foundation model will be used?
• Which human cell line, downstream signaling readouts, quantitative phenotypes, MEK inhibitors/other compounds, controls and rescue criteria are part of the planned work?
• Which reporter fish lines are available for oligodendrocytes, Schwann cells and vascular endothelium, and what portion of the project is expected to produce these lines or assays?
• Who are the complete supervisory team and methods contacts, and how are the computational, cell-culture and zebrafish components divided?

Before Accepting an Offer

• Obtain a written funding breakdown covering tuition, stipend, research/training support and part-time pro-rating if relevant; confirm the offer follows the FGx-DLA guidance that Exeter students do not need to supplement UKRI funding.
• Confirm costed access to the Aquatic Resource Centre and Bioimaging Centre, the reserved or expected facility time, any queue/induction, and what happens if model generation or imaging is delayed.
• Confirm the precise PGR registration title, supervisor allocation, annual progress milestones and how the research scope will be adjusted if full humanization proves infeasible within the funded period.

Evidence and Sources

Project, award and eligibility

• Official NF1 project description
• Exeter MRC FGx-DLA award 6025
• MRC Functional Genomics Doctoral Landscape Award
• UKRI stipend and fee guidance
• UKRI international eligibility guidance
• UKRI studentship framework
• UK Human Functional Genomics Initiative international-fees guidance

University, programme and facilities

• Exeter Biological Sciences PGR
• Complex Living Systems MPhil/PhD
• Exeter REF 2021 results
• Living Systems Institute
• Exeter zebrafish hub and Aquatic Resource Centre
• Bioimaging Centre access and costing

Supervisors and relevant research

• Yosuke Ono profile
• Steffen Scholpp profile
• Ono et al., zebrafish prime editing (2026)
• Zhang et al., Wnt5b–Ror2 signaling in zebrafish (2024)
• NF1 domain genotype–phenotype study
• Correction to the NF1 domain study
• Neurofibromatosis 1 - GeneReviews
• International NF1 diagnostic consensus
• Neurofibromin functions beyond Ras-GAP activity
• Zebrafish nf1a/nf1b mutant study
• Zebrafish NF1 cardiac and vascular study
• AlphaGenome Atlas preprint

Costs and career context

• Exeter living-cost budget
• Skills England life-sciences assessment
• NHS Scientist Training Programme