The Lewis Spitz Surgeon Scientist PhD programme - projects portfolio

This page contains projects available as part of the Lewis Spitz Surgeon Scientist PhD call.

The Lewis Spitz Surgeon Scientist PhD programme is supported by the Great Ormond Street Hospital (GOSH) Charity and National Institute for Health and Care Research (NIHR) GOSH Biomedical Research Centre (BRC) to develop future surgeon scientist leaders with excellence in translational research. Successful candidates will pursue a doctoral research degree based at the UCL GOS ICH undertaking one of the projects from our portfolio listed below. Projects are listed by the surgical speciality of clinical supervisor at GOSH.

Applications for the PhD programme have closed on 26 November 2023. You can refer to the full guidance to learn more about the programme.

Cardiothoracic surgery

Variations in interventional treatment pathways and their relationship to important clinical outcomes in complex biventricular congenital heart conditions

Academic supervisor: Deborah Ridout
Clinical supervisors: Victor Tsang Consultant Cardiac Surgeon

Additional supervisors and collaborators: Katherine Brown, Nigel Drury, Sonya Crowe, Anusha Jegatheeswaran
The post-operative survival rate of paediatric cardiac surgery is now >98%. This is a fantastic achievement however, there is now a focus on improving longer-term survival and quality of life, especially amongst children with complex defects, who generally need to have more than one operation in early life. Our research group, based between Great Ormond Street Hospital and UCL, has undertaken research with population-based data related to paediatric cardiac surgery since 2010, including the development of national methods for risk adjustment and outcome monitoring. Recently we used national linked datasets that contain information about ~65,000 children with heart disease born between 2000 and 2022, to estimate the survival rates of children with nine heart defects selected by patients, parents, and clinicians as the most important ones. During the course of this population-based research, (Congenital Heart Audit: Measuring Progress In Outcomes Nationally, funded by the Department of Health and Social Care's Policy Research Programme), we noted that surgical treatment strategies vary. Variation occurs in the degree to which interventional cardiology versus surgical approaches are used, and the degree to which serial palliative versus single stage reparative procedures are used. The data also indicate that surgical reinterventions are common with complex congenital heart defects and vary in frequency.

In this PHD, the student will work within our experienced research group, to explore the variation in surgical approaches for selected complex two-ventricle heart defects, (pulmonary atresia, aortic stenosis, atrioventricular septal defect). The student will explore links between surgical pathways and longer-term patient outcomes, by cardiac condition. The student will assess quality of life in a sample of older children with these complex congenital heart conditions. The project ultimately aims to use advanced health informatics and phenotyping in congenital heart disease surgical treatments, translating any findings into future recommendations for personalised care of complex congenital cardiac malformations.

Ear, nose and throat

Gene-corrected mucosal epithelium for the children with airway epidermolysis bullosa

Academic supervisor: Christopher O’Callaghan
Clinical supervisor: Colin Butler, Consultant Paediatric ENT Surgeon

Additional supervisors and collaborators: Rob Hynds, Elizabeth Maughan, Richard Hewitt

Epidermolysis bullosa (EB) in children is a rare genetic disease mainly affecting the skin. Treatment strategies for EB include replacing the affected epidermis with gene-corrected epithelium. Clinical studies using this approach has been shown to be effective for external skin. Airway involvement in EB is very rare but affected patients experience extensive inflammation, scarring and narrowing of the airway. Currently there are no treatments for airway involvement in EB other than symptom control. These patients often succumb to airway problems, as such, there is an ongoing need for treatments that address this unmet clinical need. 

At Great Ormond Street Hospital, a cohort of children with EB have mutations in LAMA3 gene. Our team have successfully cultured epithelial basal cells from their upper airways and gene-corrected them using a lentiviral approach. Expression of wildtype LAMA3 cells restores cell adhesion to levels seen in healthy donors. This project aims to deliver gene-corrected autologous cells to children with airway disease, as tissue engineered sheets. This PhD project addresses current hurdles to clinical application, focusing in identifying optimal methods to improve transduction efficacies and tissue engineering methods for long-term engraftment. 

The PhD candidate will work primary airway epithelial cells from patients, creating a lentiviral construct that will be specifically optimised for airway basal cells which will be progressed for potential clinical delivery. The proposal will further test preconditioning methods in an airway surgical model, to determine the optimal methods for engraftment of autologous epithelial cells. The results will be relevant to early phase human clinical studies involving gene-corrected epithelial cell transplantation in the airways. It has also significant applicability to engineering airway constructs for other disease processes of the airway, as such has significant applicability to surgeon scientists in this field.  

Neurosurgery

Aetiopathogenesis and restoration of neural function in Terminal Myelocystocele

Academic supervisor: Gabriel Galea
Clinical supervisor: Dominic Thompson, Consultant Paediatric Neurosurgeon

Terminal Myelocystocele (TM) is a closed spinal dysraphism with largely unknown aetiology and heterogenous presentation. It is a highly complex condition associated with both spinal neurological deficits and malformations of other organs, including cloacal exstrophy and musculoskeletal abnormalities. Unlike open spina bifida, the effectiveness of its prevention by folic acid is unknown and fetal surgery is not beneficial for individuals who have it. Great Ormond Street Hospital is a National referral centre for the management of this condition, the project’s clinical supervisor has reported advances in its post-natal neurosurgical management (Quong et al, Int Soc Ped Neurosurg 2015) and spinal neurosurgery is performed in approximately two cases per year. The primary supervisor’s group has recently characterised a transgenic mouse model which recapitulates many of the spinal and extra-spinal features commonly seen clinically in patients who have TM. This mouse model provides the first experimental evidence of a cellular signalling pathway underlying development of this condition: abnormal spinal cord dorsoventral patterning secondary to deficient Fibroblast Growth Factor (FGF) signalling. 

The proposed project will i) use a comparative pathology approach to determine the fetal therapeutic window during which spinal neural function may be rescuable, ii) test potential treatments in our pre-clinical model, iii) develop human models of the condition using stem cells or fetal tissue slice cultures, iv) identify patient cohorts with clinical features broadly attributable to FGF disruption, and v) advance our ability to provide genetic diagnoses for individuals affected by TM.

Cerebrospinal fluid: role in the Chiari II brain malformation

Academic supervisor: Andrew Copp
Clinical supervisor: Dominic Thompson, Consultant Paediatric Neurosurgeon

Additional supervisors: Simon Eaton

In spina bifida (myelomeningocele), leakage of cerebrospinal fluid (CSF) has been implicated in the hindbrain herniation that characterises the Chiari II malformation. Other brain defects in Chiari (e.g. neuronal migration disorders) are common and underlie learning difficulties in many children with spina bifida. However, the cause of these brain defects is unknown. 
In this project, the PhD student will test the hypothesis that CSF composition may differ in spina bifida (e.g. because of rapid fluid loss and replenishment), and this may adversely affect neuronal migration during embryonic and fetal brain development. 

The student will collect CSF from children with Chiari II undergoing surgery, using CSF from children receiving surgery for other brain conditions as matched controls. CSF will also be obtained during fetal surgery for spina bifida. Compositional analysis of the CSF (e.g. by proteomics, metabolomics) will reveal any differences between spina bifida and controls. CSF will be studied in parallel in a recently developed mouse genetic model of Chiari II. To determine whether neuronal migration is affected by CSF composition, the student will prepare and culture brain slices from mouse embryos, with addition of different CSF samples, and analysis of neuronal migration by immunolabelling with cell type-specific antibodies. Human embryonic brain slices may be studied using material from the Human Developmental Biology Resource. This project aims to significantly advance our understanding of how brain defects arise in children with spina bifida, and to suggest new approaches to prevent these disorders.

Uncovering network connectivity of the thalamus to guide deep brain stimulation for children with drug-resistant epilepsy 

Academic supervisor: Torsten Baldeweg
Clinical supervisor: Martin Tisdall, Consultant Paediatric Neurosurgeon

Additional supervisors: David Carmichael; Tim Denison; Chris Clark 

Deep brain stimulation (‘DBS’) devices are long-term implants used to deliver stimulation directly to deep targets in the brain to alleviate the symptoms of neurosurgical disease. DBS is emerging as a therapy for children and adults with drug-resistant epilepsy, yet further evidence is required to reveal the mechanisms by which DBS effects epilepsy and to predict patient candidacy and treatment response at pre-operative patient selection.

This PhD will investigate brain network connectivity profiles associated with treatment success in children with Lennox-Gastaut Syndrome undergoing DBS of the centromedian nuclei of the thalamus. It will be intricately linked with the CADET Project: ‘The Children’s Adaptive Deep brain stimulation for Epilepsy Trial’, an upcoming clinical trial led by GOSICH. The CADET Project will implant 26 children with Lennox-Gastaut Syndrome with a next-generation DBS device called the ‘Picostim DyNeuMo’ – which has both brain stimulation and brain sensing capabilities (a ‘brain-machine interface’). Funding for this study is already secured.

The primary project of the PhD will be a prospective, observational neuroimaging study in collaboration with the Department of Bioengineering at Oxford University and the London Collaborative Ultrahigh Field Scanner (LoCUS) at Kings College London. High-field (7-Tesla) magnetic resonance imaging (MRI) will be performed on children recruited to the CADET Project and diffusion and functional MRI will be used to investigate alterations in thalamic connectivity. Using outcome data from the CADET Project, the PhD Fellow will investigate pre-operative imaging correlates of treatment response to refine DBS targeting strategies.   

The PhD Fellow will have the opportunity to undertake secondary projects that utilise neurophysiological recordings acquired from scalp electroencephalography and thalamic recordings (local field potentials) acquired during the CADET trial. These data will allow us to study dynamic network-alterations associated with thalamic neuromodulation and uncover the therapeutic mechanisms of the treatment. 

Advanced MR imaging in craniopharyngioma – surgical planning and hypothalamic protection

Academic supervisor: Chris Clark
Clinical supervisor: Kristian Aquilina, Consultant Paediatric Neurosurgeon

Additional supervisors: David Carmichael

Adamantinomatous craniopharyngiomas are rare tumours that arise in the sellar and suprasellar regions in children and adults. Although biologically benign, their involvement of the pituitary gland and stalk, as well as the optic apparatus and the hypothalamus often leads to severe disability. In particular, hypothalamic injury causes a metabolic syndrome characterised by obesity, as well as fluid and electrolyte disturbances, eating disorders, reduced energy levels and severe impairment of memory and education. It is also associated with a shorter life expectancy. The ideal treatment for craniopharyngiomas is complete surgical resection, but involvement of the hypothalamus often precludes this, with preference to hypothalamus-sparing partial resection plus radiotherapy or radiotherapy alone. Radiotherapy is associated with a long-term risk of new malignant brain tumours as well as vascular disease. In addition, the tumour recurrence rate after radiotherapy may be up to 30%.

The decision regarding role and extent of surgical resection is therefore crucial and is currently made on the basis of standard MR imaging. We propose to use advanced MR imaging in a 7T MRI scanner to define the hypothalamus and its efferent tracts. We plan to recruit 30 patients with new or recurrent craniopharyngioma over the course of the PhD and undertake pre- and post-operative advanced MR imaging to determine the extent of hypothalamic nuclear injury and involvement of its principal outflow tracts, particularly the fornices, the mammillothalamic tracts and the mammillotegmental tracts. This will be correlated with clinical status pre-operatively and at follow up. We will also carry out a retrospective review of the imaging of children with craniopharyngioma who have already undergone treatment and where possible will evaluate the available imaging using advanced multi-shell tractography and fractional anisotropy. We aim to identify novel imaging biomarkers that will be useful in surgical decision-making and preventing hypothalamic injury in these children. 
 

Advanced drug delivery for paediatric brain tumours

Academic Supervisor: Darren Hargrave
Clinical supervisor: Kristian Aquilina, Consultant Paediatric Neurosurgeon

Additional supervisors: Karin Straathof; Elwira Szychot 

The project focuses on both the neurosurgical and the translational aspects of two planned inter-related clinical trials in high-risk paediatric brain tumours utilising novel drug delivery techniques. The first of these is the funded CARMIGO study which has recently opened at GOSH and will evaluate a specific anti-GD2 CAR T cell developed at UCL in diffuse midline gliomas (DMGs), which have a dismal prognosis. This first in human brain tumour study will administer CAR T cells intravenously and directly into ventricular CSF via a surgically implanted Ommaya reservoir. The latter will give direct access to CSF for the study of related biomarkers. 

The second trial being developed is a convection enhanced delivery (CED) trial using four implanted microcatheters in a chronic delivery system of a novel agent directly into paediatric brain tumours. This will allow the drug to be delivered into the tumour, bypassing the blood brain barrier. With this implantable system multiple and regular injections of drug are possible without the need for multiple surgical procedures. Novel software will be used to position the catheters stereotactically in a way that optimises drug distribution within the tumour. This will be evaluated and quantified on sequential MR imaging. We also plan to implant an Ommaya reservoir through which drug will be injected into the CSF. It is hoped that this will reduce the incidence of tumour dissemination through the CSF.  In this study we will also explore the use and value of tumour biomarkers in the CSF. 

This project will allow a neurosurgical trainee to participate in novel research into unresectable brain tumours in children, including translational biomarker studies, and learn new techniques which are expected to become essential to surgical neuro-oncology in the near future. 

Mapping and Modulating Disrupted Brain Networks in Paediatric Focal Epilepsy

Academic supervisor: Konrad Wagstyl
Clinical supervisor: Martin Tisdall, Consultant Paediatric Neurosurgeon

Epilepsy is a complex neurological disorder affecting millions of children worldwide. Seizures are often accompanied by a range of comorbid conditions, including Autism Spectrum Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD), depression, and intellectual disability. These symptoms significantly impact the physical, cognitive, emotional, and social health of affected children. However, the underlying neurobiological mechanisms connecting focal epilepsy, comorbidities, and potential treatment interventions remain inadequately understood.

Epilepsy is a disorder of disrupted brain networks. Paediatric focal epilepsy is often caused by structural malformations which disrupt brain networks leading to both seizures and comorbidities. However, precise networks underpinning these symptoms are poorly characterised. This PhD project aims to address this knowledge gap through a multidisciplinary approach that combines invasive and non-invasive techniques to comprehensively map and modulate disrupted brain networks.

Project 1: Mapping and Modulating Thalamic Involvement in Paediatric Focal Epilepsy
This project's objective is to systematically investigate the role of thalamic nuclei in epileptogenic networks and assess the impact of thalamic deep brain stimulation (DBS) on cortical neurophysiology in paediatric focal epilepsy. The key outcome measures include identifying thalamic nuclei involvement in seizure networks and evaluating the effects of thalamic DBS on cortical brain network connectivity.

Project 2: Lesion-Symptom Network Mapping of Comorbidities in Focal Epilepsy
The goal of this project is to analyse the associations between lesion location, disrupted functional networks, and comorbidities in paediatric focal epilepsy. This will involve identifying lesion-related functional networks associated with common comorbidities and developing models to quantify the likelihood of developing comorbidities based on lesion locations.

The projects will utilise advanced neurosurgical, neuroimaging and analytical techniques and to advance our understanding of seizures and associated comorbidities in paediatric focal epilepsy. This research has the potential to inform personalised treatment strategies, potentially transforming the care of children with focal epilepsy, and providing unique contributions to the broader field of neuroscience.

Ophthalmology

Transplantation of a tissue engineered retinal patch using stem cell-derived photoreceptors to treat retinal dystrophy

Academic supervisor: Jane Sowden
Clinical supervisor: Robert Henderson, Consultant Ophthalmic Surgeon

Additional supervisors and collaborators: James Wawrzynski, Nicola Elvassore, Damien Yeo

This project will focus on the development of a cell therapy for retinal dystrophy using tissue engineering approaches. Diseases of the retina, resulting in the death of the photoreceptor cells are a leading cause of irreversible blindness. Children with inherited retinal dystrophies face progressive loss of vision.  
 
In this project retinal imaging will be used to assess cell degeneration and to determine the optimal time period for intervention. Novel micro-engineering approaches will be used to create a human retinal tissue patch that could be used to repair the retina. As the inner retinal neurons and optic nerve that transmit visual information to the brain remain largely intact, connecting a new patch of photoreceptors could restore light perception to people with retinal dystrophy. Human pluripotent stem cells will be differentiated in vitro into retinal organoids that resemble developing retinal tissue and produce new cone and rod photoreceptor cells. Different approaches will be investigated to grow layers of photoreceptor cells on novel microengineered biocompatible scaffolds and to evaluate the biocompatibility of the stem cell-derived photoreceptor cell patch in animal models. 
 
The project will suit a candidate with an interest in stem cells, retinal development and disease as well as therapeutic development for retinal dystrophy. The research fellow will be trained in retinal organoids from human pluripotent stem cells, tissue engineering using microengineering technologies and animal model characterization. The position will best suit a candidate with some experience in Ophthalmology and retinal examination (commencing ST3-5 at the start of the project) who will also attend the paediatric inherited retinal disease clinics at Great Ormond Street to gain an understanding of the progress of inherited retinal disease. 

Minimising adverse long term outcomes following childhood cataract surgery through data science

Academic supervisor: Ameenat Lola Solebo
Secondary supervisor: Jugnoo Rahi
Clinical supervisor: Chris Lloyd, Consultant Ophthalmic Surgeon and Paediatric Ophthalmologist

Additional supervisors and collaborators: Joe Abbott; Damien Yeo; Jessy Choi

Childhood cataract is the most important cause of global avoidable childhood blindness. Early and appropriate intervention, achieved in many setting through universal screening of newborns, is key to avoiding visual disability for affected children.1 Despite significant advances in our scientific understanding of supporting post-operative visual rehabilitation, alongside significant improvements in surgical techniques and correction of surgically created focusing power deficits (refractive errors), a notable proportion of children still fail to achieve good vision – half of all children with bilateral cataract have moderate visual impairment or worse, half of all children with unilateral cataract have severely impaired vision or worse in the affected eye, and one in five children develop a secondary, sight threatening glaucoma.
There are key evidence gaps on the child and intervention specific determinants of long term outcomes for children who have undergone cataract surgery.2 As childhood cataract is uncommon, a key challenge to research in this area is the need to undertake research across large, usually national level, populations, usually comprising children managed in specialist tertiary centres. Within the UK many of these centres are aligned to an NIHR Biomedical Research Centre.  We propose to harness the power of data science to develop robust and validated algorithms based on these determinants would support decisions on frequency and duration of follow up following surgery (by identifying those groups who are high risk for adverse outcomes). 
The project offers an unique opportunity for an ophthalmic surgeon in training to acquire academic skills and training in epidemiology and data science through a project that has high translational impact.

Evaluation of cell free circulating DNA as a prognostic and predictive biomarker of retinoblastoma

Academic supervisor: John Anderson
Clinical supervisor: Richard Bowman 

Retinoblastoma (Rb) is the commonest form of childhood eye cancer and the commonest cause of death from eye cancer worldwide, but almost no-one dies in richer countries.
Liquid biopsy is a new technology looking at fragments of cancer DNA in blood or other body fluids which could replace having to a surgical biopsy to determine what type of cancer is present, how far it has spread and what treatment should be given. This has been applied to Rb but mainly to fluid from the eye. This still requires surgery and potential spread of tumour outside the eye. A blood test would be simpler and safer.
Exploratory work on using blood would best be carried out in children whose disease has spread beyond the eye which only occurs in poorer countries. These countries badly need research into how to improve management of advanced disease. Hence this is a perfect scenario for north south collaboration. The project will compare existing with new technologies to compare them for feasibility and sensitivity of detection of tumour DNA. This will facilitate the development of scaled down affordable tests to translate into clinical practice

Plastic and reconstructive surgery and Craniofacial surgery

Development and testing of stem cell engineered cartilage constructs for ear and facial reconstruction

Academic supervisor: Patrizia Ferretti
Clinical supervisor: Neil Bulstrode, Consultant Plastic and Reconstructive Surgeon

We are seeking an enthusiastic and able PhD student to join our established research team made up of highly experienced and renowned academics and clinical supervisors.
 
Our clinical aim is to develop a viable stem cell and tissue engineered cartilage that can be used successfully to reconstruct children’s ears and faces. 

The reconstruction of ear and facial deformities require harvesting tissues from other areas of the body such as cartilage from the rib and ear. These donor sites are painful and can affect form and function. We intend that one day this will not be necessary.

We will compare stem cells from different sources including umbilical cord, paediatric abdominal fat and those derived from reprogrammed healthy somatic cells. We will optimise the environment where the stem cells can multiply, grow and differentiate into cartilage. These cells will be seeded into different scaffolds and culture conditions and will be examined for their ability to survive and acquire cellular, molecular and mechanical properties similar to native cartilage. 

Specific shapes will be generated either by using moulds or by using a “bioprinter”. The properties of the bioengineered cartilage will be assessed using a range of tests available in our laboratories. The preparation and handling of selected cartilage constructs will be further developed under conditions suitable for clinical use. The ability of these constructs to survive the effects of being implanted will be tested as the next step on the journey to develop an ear shaped cartilage substitute so that we do not need to take rib cartilage from the child.

The successful candidate will be mentored, closely supervised and supported to ensure they will acquire new interdisciplinary skills, broad experience, scientific and surgical rigour.

Objective Assessment and Treatment Optimisation for Craniosynostosis: A Multicentric Approach to Improve Paediatric Cranial Care

Academic supervisor: Silvia Schievano
Clinical supervisors: Juling Ong Consultant Craniofacial and Plastic Surgeon and Owase Jeelani Consultant Paediatric Neurosurgeon

Learn about Craniofacial Research Group

This project, a collaborative effort with the highly specialised Craniofacial Units of GOSH (London), Birmingham Childrens’ Hospital and Alder Hey (Liverpool) focuses on improving the understanding, diagnosis and treatment of craniosynostosis. This condition, impacting 1 in 2,000-2,500 newborns, is characterised by premature fusion of one or more sutures in the skull, and results in abnormal head shapes and several potential developmental problems.

In this study, we first aim to establish normative data for paediatric head volume and shape, including growth curves using statistical shape models based on machine learning algorithms. These will help with accurate quantification of deformities in craniosynostosis patients. Second, we will develop models to objectively measure the severity of deformities across various craniosynostosis types and analyse the changes that occur with growth and because of surgical interventions. The developed models will be incorporated into the creation of a secure, online platform, designed to analyse cranial deformities from CT scans, but also 3D photographs, offering a radiation-free, accurate method for evaluation of these conditions. The tool will enable early diagnosis, and consistent and objective pre and postoperatively assessments, facilitating personalised treatment strategies.
Patient and Public Involvement and Engagement activities will be crucial to our project. The involvement of patients and parents will ensure that the developed tools are user-friendly and meet the needs of both clinicians and families. This will empower patients/families with knowledge about the severity of the condition, and the potential outcomes of surgical (and non-surgical) interventions, allowing for more informed decisions.

By integrating advanced computational tools and methodologies into craniosynostosis clinical care, this research will support surgeons with standardised, quantitative information on the severity of deformities and optimised interventions strategies, reducing reliance on subjective assessments. This, in turn, will promote evidence-based decisions, ultimately improving the quality of care and long-term outcomes for children with craniosynostosis.

Specialist Neonatal and Paediatric Surgery (SNAPS)

Advancing translational cell therapy for Hirschsprung disease

Academic supervisor: Conor McCann
Clinical supervisor: Paolo De Coppi, Consultant Paediatric Surgeon, Nuffield and NIHR Research Professor

Hirschsprung disease (HSCR), a life-threatening intestinal disorder affecting 1 in 5000 live births, is caused by the absence of enteric neurons in the distal bowel, which loses propulsive gut motility and ultimately results in intestinal obstruction. The current treatment is surgical resection of the affected bowel. Whilst lifesaving, this surgical treatment often results in patients experiencing life-long gastrointestinal problems including constipation, faecal incontinence, and enterocolitis, which significantly contribute to poor quality of life. 
Recent pre-clinical evidence in animal models suggests that human pluripotent stem cell (hPSC)-derived enteric nervous system (ENS) progenitor transplantation, aimed at replacing lost neurons, is a potentially viable therapy. These data provide a strong basis for further translational investigation of this novel cell therapy. However, a major limitation, which precludes clinical application, remains a lack of knowledge surrounding the integration of hPSC-derived ENS progenitors in human tissue and the effects of immunosuppression on the efficacy of any ENS progenitor therapeutics. 

The aims of this project are to: (i) Evaluate the ability of hPSC-derived ENS progenitors to integrate within human HSCR patient-derived gut samples in a novel ex vivo culture system (ii) Examine the effects of current clinical immunosuppression protocols on hPSC-derived ENS progenitors and (iii) Generate “universal” hPSC-derived ENS progenitors to overcome potential immune response barriers.
This project sits at the translational interface between basic and clinical science by making use of surgically resected human HSCR discard tissue as the foundation of its basic research investigation. As such, the results of this project will be directly translatable, informing future efforts to bring hPSC-derived ENS progenitors to the clinic. The novel data and tools developed through the course of this project could potentially transform approaches to cell therapy treatments in the intestine and beyond.

Development of a Multimodal Artificial Intelligence Algorithm for the Diagnosis of Necrotising Enterocolitis

Academic supervisor: Simon Eaton
Clinical supervisor: Stavros Loukogeorgakis, Consultant Neonatal and Paediatric Surgeon, Associate Professor

Additional supervisors: Evangelos Mazomenos, Danail Stoyanov, Susan Shelmeridine, Simon Hannam, Maria Chalia

Necrotising Enterocolitis (NEC) is a severe neonatal condition with significant morbidity and mortality. Timely surgical intervention for NEC is challenging due to ambiguity in presentation, limited access to surgical/radiologic expertise in many neonatal units and difficulty in arranging in transfer to a surgical centre when surgical expertise is not available on site. Consequently, many infants with NEC die without having surgery. 
 
We intend to devise a multimodal AI algorithm utilising clinical and imaging data that facilitates the diagnosis of NEC in non-specialist centres.  We aspire to address the problems created by limited human expertise in the field and facilitate earlier diagnosis and transfer to a surgical centre. Furthermore, we currently struggle to risk stratify NEC and determine which patients would benefit from earlier surgical intervention and an AI based algorithm may help predict the need for early surgery. The outcomes from this study will should confirm transferability of the technology and facilitate approval for integration of the algorithm in the NEC detection workflow locally and nationally

Autologous tissue engineered oesophagus: understanding the regenerative processes following in vivo transplantation

Academic supervisor: Simon Eaton
Clinical supervisor: Paolo De Coppi, Consultant Paediatric Surgeon, Nuffield and NIHR Research Professor

This project aims to upscale our existing model to provide a functional, tubular, tissue-engineered conduit for replacement of an oesophageal deficit in a porcine long-gap OA model. This will act as an in-vivo feasibility study prior to proceeding with phase I clinical trials in humans for the treatment of long-gap OA. 

Mini-pigs share anatomical and physiological similarities with humans and therefore make size-matching by weight appropriate for future translational use. Additionally, they are known to have better tolerance to surgical interventions than rabbits and do not practise coprophagy, making them the ideal choice of animal model.  The overall aim of this PhD is to determine the potential of our tissue engineered oesophageal solution to be used for longer oesophageal grafts. In order to achieve this, the PhD student will develop methods to track cells and extracellular matrix from a tissue engineered graft which is then implanted in vivo.

Urology

A human slice model to understand and treat fibrosis in children with bladder exstrophy

Academic supervisor: David Long
Clinical supervisor: Navroop Johal, Consultant Paediatric Urologist

Additional supervisors: Charlotte Dean

Bladder exstrophy is a rare disease characterised by widely separated abdominal muscles and pelvis, an open exposed bladder and abnormally developed genitals in boys and girls. There are various strategies for treating bladder exstrophy, but all involve major reconstructive surgery. However, outcomes for the surgery are poor with even high-quality centres only capable of helping these children attain urinary continence in 25% of patients. On top of this, a proportion of these children will also develop kidney damage, which is a lifelong medical burden in these patients as well as the psychological impacts arising from concern about the function and appearance of their genitalia.

The root cause of the poor outcomes in bladder exstrophy is that surgical interventions do not reverse the underlying damage to the bladder that impairs its normal function. Therefore, new strategies are required. Work from our laboratory and clinical teams has focussed on normal and abnormal function of the muscles in the bladder. We have shown that most of the bladder muscles are replaced by scar tissue in exstrophy. This occurs via a process called fibrosis, which is also implicated in many other conditions; hence there are a number of new drugs being developed to treat fibrosis which have not yet been tested in exstrophy. Indeed, in pre-clinical studies of other bladder disorders we have found exciting new anti-fibrotic medicines which can reduce bladder scarring and improve its ability to recover and function normally. In this project, we aim to examine if anti-fibrotic drugs can be used as a treatment for bladder exstrophy. We will do this by taking part of the abnormal bladder that is removed during routine exstrophy surgery and cutting it into slices which will be cultured in a dish. We will then use this as a model to test drugs to stop (or reverse) fibrosis in bladder exstrophy. Collectively, this translational project will identify new therapies that could be used clinically in the future to treat bladder exstrophy.

Profiling patterns of vascular invasion in paediatric renal cancers

Academic supervisor: David Long
Clinical supervisor: Naima Smeulders, Consultant Paediatric Urologist

Additional suprvisors: Tanzina Choudhury; Kathy Pritchard-Jones, Daniyal Jafree, Reem Al-Saadi

This PhD project aims to study the invasion patterns of blood vessels into kidney cancers in children, and the clinical and pathological implications of this invasion. To achieve this, the project includes the following objectives:

1. Using 3D imaging to profile invasion patterns in paediatric renal cancers: by harnessing a novel technique to perform 3D imaging of vasculature in human tissues excised after surgery, the student will identify blood vessels in different types of renal cancer (Wilms tumour, malignant rhabdoid tumour of the kidney, renal cell carcinoma) and correlate these with clinically important outcomes for patients including metastasis, tumour recurrence and survival.
2. Studying invasiveness of blood vessels into paediatric renal cancers ‘in a dish’: The student will isolate tumour cells from the different kinds of kidney cancer described above. Having achieved this, the student will utilise engineered blood vessels developed in our laboratory and develop an assay to study how blood vessels invade kidney tumours in vitro, and if this varies between different kinds of tumour
3. Does chemotherapy impact the invasion or patterning of blood vessels into paediatric renal cancers?: The student will compare patterns of blood vessel invasion in children who have received chemotherapy before surgery as compared to after surgery. By developing and utilising trans-Atlantic collaborations the student will acquire chemotherapy-naive tumour samples, and pre- and post-chemotherapy samples will be compared for the presence and patterning of blood vessels to see how these drugs impact tumour vascular patterning.

This PhD project provides a unique opportunity for a trainee interested in paediatric oncology surgery to develop laboratory skills at the cutting-edge of science whilst answering fundamental clinical questions about how the tumour microenvironment impacts outcome of children with cancer.

Projects selected by successful PhD candidates in Round 1

Selected by a successful candidate: Investigating spatial and temporal tumour heterogeneity in neuroblastoma to improve surgical clearance and develop novel techniques for loco-regional control

Academic supervisor: John Anderson
Clinical supervisor: Stefano Giuliani, Consultant Neonatal and Paediatric Surgeon

Additional supervisors: Sally George, Louis Chesler

Neuroblastoma is a paediatric cancer arising during development in the neural crest. It has a wide range of clinical outcomes, from spontaneous remission to aggressive metastatic disease.  Neuroblastoma is responsible for 15% of all childhood cancer deaths, and five-year survival rates are 40 – 50% in high-risk disease. Prognosis has not dramatically improved in the last 20 years. 
 
Studies have identified that certain molecular alterations and tumour immune microenvironment (TIME) changes are associated with poorer outcomes. However, there is a high degree of spatial and temporal heterogeneity. Chromosomal aberrations and druggable-target gene mutations are variable at diagnosis and relapse, suggesting ongoing clonal evolution. This evolution may cause heterogeneity in the TIME and cell surface marker expression. 
 
Surgery remains a critical component in the multimodal management of neuroblastoma. Surgical resection is associated with complications and it can be challenging intra-operatively to discriminate neuroblastoma from non-cancerous tissue. Residual tumour associates with local recurrence and poorer outcomes. Fluorescence-guided surgery (FGS) is an evolving technology that enables surgeons to identify and remove tumour material using neuroblastoma-specific probes incorporating fluorophores. GD2-specific tracers have shown promise in pre-clinical studies. But they are limited by heterogeneity and GD2 is down-regulated in response to immunotherapy. 
 
There is a paucity of evidence describing the heterogeneity of the molecular, TIME and cell surface marker profiles in neuroblastoma. In this study we will perform imaging-guided, multi-regional biopsies of diagnostic and post-treatment tumour material. Samples will undergo genomic, transcriptional and multiplex spatial analysis. These profiles will be integrated to generate phenotypes predictive of clinical outcome. Multiplex imaging will be used to evaluate the TIME and identify new targets for FGS. We envision that the comprehensive mapping of neuroblastoma heterogeneity will enable the development of multiple FGS probes which can identify specific subclones. This would improve intra-operative decision making, allowing surgeons to identify areas of aggressive tumour and discriminate viable from non-viable tissue.

Selected by a successful candidate: Cochlear gene therapy to treat progressive hearing loss in Norrie Disease

Academic supervisor: Jane Sowden
Clinical supervisor: Robert Nash, Consultant Paediatric Otolaryngologist

Additional supervisors: Aara Patel; Deepak Chandrasekharan; Waheeda Pagarkar

This project will focus on the development of a gene therapy for Norrie disease to prevent progressive hearing loss.  

Norrie disease is an X-linked condition, caused by mutation of the gene NDP. Boys with Norrie disease are born blind with severely disrupted retinal vasculature. Almost all develop progressive hearing loss that becomes profound. No curative treatment currently exists. Children with Norrie disease are regularly seen at Great Ormond Street Hospital (GOSH) after referral for congenital blindness and genetic testing. Our multidisciplinary research team comprising clinicians and scientists aims to address the challenge of finding treatments for Norrie disease and works together with the patient family led UK-based registered charity, the Norrie Disease Foundation UK. 
 
NDP encodes a small secreted protein, Norrin that activates the canonical Wnt/b-catenin signalling pathway in endothelial cells to control retinal vascular growth. Norrin is also essential for normal function of the microvasculature in the cochlea with the later loss of sensory hair cells causing profound hearing loss.  

This project will use a mouse genetic model of Norrie disease to evaluate molecular therapies for Norrie disease. We have studied the early stages of disease and established several assays to measure abnormalities of the cochlear vasculature and sensory hair cell that will be used to assess whether NDP gene replacement therapy ameliorates the cochlear phenotype. 

The aim is to perform a pre-clinical gene therapy trial in the Ndp-KO mouse model using an NDP adeno-associated viral (AAV) vector designed for clinical use and direct cochlea injection based on the efficacy of a GFP tagged prototype vector already tested in our laboratory. We will deliver the human NDP gene sequence to the cochlea via intracochlear injection and measure the outcomes of prevention of hair cell death and hearing loss.