As a clinician scientist, I engage in both clinical and laboratory research, which is internationally recognised, with publications in Lancet, Journal of Clinical Oncology, Journal of the National Cancer Institute, Nature Clinical Oncology, Clinical Cancer Research, Annals of Oncology Breast Cancer Research and Treatment and other journals. I lead the Clinical Bone Oncology and Biomarkers Group in University of Sheffield (LINK), which has a particular focus on the impact of cancer on the skeleton in patients with breast, prostate and renal cancer. Our recent research includes the use of biomarkers in established bone metastasis to aid patient management and studies of the negative impact of cancer treatments on bone health. One of the main objectives of our current clinical and laboratory work is to develop novel prognostic and predictive biomarkers for clinical use in patients with early cancer to help in prevention or delay of cancer metastasis to bone, after which disease is incurable.

I also run clinical studies to develop innovative therapeutic approaches in breast, renal and prostate cancer. As Chief Investigator, I currently lead a large UK-wide, 40 centre, clinical trial (STAR) funded by NIHR, to determine whether treatment breaks in patients with renal cancer receiving targeted therapies, can reduce toxicity and have health economic benefits, without loss in efficacy. I am also PI on a clinical study funded by Cancer Research UK aimed at evaluating a potentially exciting new form of virotherapy in patients with prostate cancer.

Research Interests

Tumour microenvironment and the unfolded protein response, breast cancer in the elderly, psych-oncology, familial breast cancer, breast screening.

I am a GP with an interest in diagnosis, particularly cancer diagnosis, in general practice. My work has predominantly focused on lung cancer.

My major areas of interest are management of urological cancers, clinical trials, early drug development and translational medicine. I have set up a large number of clinical trials from early phase to late phase studies during my career. My work on organ preservation in bladder cancer moved all the way from an early phase I study (Hussain et al Annals of Oncology 2001), to phase II efficacy study (Hussain et al BJC 2004) that led to a Cancer Research UK funded study BC2001 trial that was reported in New England Journal of Medicine (James, Hussain, Hall et al April 2012). This study has now changed the standard of care for patients with muscle invasive bladder cancer opting for organ preservation treatment.

Research interests

I am a Professor and Honorary Consultant in Oral and Maxillofacial Pathology. Prior to that, I worked as a Senior Clinical Lecturer (2016-2022) and as a NIHR Academic Clinical Lecturer/ Honorary Specialist Registrar (2011-2016) at the University of Sheffield.

I have a strong interest and am actively involved in research and teaching (undergraduate, postgraduate, clinical) as well as diagnostic oral, maxillofacial and head and neck pathology. I am the founder and Lead of the NEOPATH Research Group working with a team of researchers and clinicians on various aspects of head and neck cancer diagnosis and prognosis prediction. In addition to local research projects, my group is working with a wide range of collaborators and funders across the world.

I am passionate about raising the profile of Pathology as a specialty and raising awareness of head and neck cancers. I work closely with a number of patient groups and charities and am a Trustee and Patron for The Swallows Head and Neck Cancer Charity.

Research Interests

My research is focused on advanced breast and prostate cancer with particular emphasis on bone metastases. Primarily, this involves using a complement of in vitro and in vivo model systems to investigate the molecular alterations responsible for metastases to bone and response to treatment. Metastases are a result of a stepwise accumulation of genetic/epi-genetic mutations promoting distinct molecular alterations that drive different stages in the metastatic process; mutations involved in intravasation are not the same as those involved in tissue homing and colonisation. Importantly, molecular alterations acquired by tumour cells have profound effects on cytokine production and immune cell regulation. My research team hypothesise that cytokine driven changes to the tumour immune environment promotes metastatic spread and that pharmacological regulation of immunity may provide effective treatment methods for, currently incurable, bone metastasis. The aims of my research are to: (A) Identify specific molecular and immune cell regulatory determinants involved in tumour cell intravasation, homing to bone and colonisation of the metastatic site. (B) Decipher how these determinants impact on treatment efficacy in different cancer subtypes. (C) Establish more effective treatments for metastatic breast and prostate cancers.

Research interests

My research group is interested in how our bones function in health and disease with an emphasis on cancer. We are interested in knowing why primary bone cancers occur and how to best treat them. We are also interested in trying to understand why and how primary cancers such as breast and prostate spread preferentially to bone. Other interests include investigating mechanisms leading to osteoarthritis and failure of orthopedic implants. We use cutting edge scientific techniques and technologies, both in vitro and in vivo,  to answer clinically relevant questions.   

Research interests

The interests of our research group fall in three broad interlinking areas, all of which seek to identify novel opportunities to improve quality of life.

Molecular mechanisms of cell:cell communication in ageing and cancer 

The behaviour of all cells is dictated by the signals derived from the surrounding microenvironment. In ageing and cancer, these signals may become corrupted by changes in surrounding cells, or by biomechanical or chemical changes to the extracellular matrix (ECM). A major focus of our work is to identify the mechanisms by which these signals, become corrupted. We are particularly interested in the role of signals derived from senescent cells, particularly the major cell type of connective tissue, fibroblasts, which accumulate with age and in several diseases, including cancer.  These signals include proteins, RNA (particularly non-coding RNA), DNA and extracellular vesicles.

Spatial analysis of the tissue microenviroment

In order to understand the mechanisms outlined above, we need to better understand the changes that happen within tissue in ageing and cancer. We are applying cutting edge spatial 'omics' techniques to understand, at an unprecedented level of resolution, the changes occuring in the phenotype of cells in aged and diseased tissue.  This will allow us to much more accurately model changes in the tissue microenvironment and identify potential new, individualised, therapeutic opportunities. We are also working closely with biomaterials scientists to use this information to use materials to mimic the tissue microenvironment, allowing us to accurately model the processes occuring in the body and also develop new ways to reverse disease-associated changes and regenerate damaged tissue.

Biomarker discovery 

The diagnosis and monitoring of many diseases, including cancer, requires painful collection of tissue. We are working closely with world-leading physical scientists to develop new ways to detect 'biomarkers' of cancer in blood and saliva, allowing non-invasive or entirely painless disease diagnosis and monitoring. These approaches include nanoplasmonics and other methods not routinely used for biological applications, but with the promise to revolutionalise disease sensing. We are also applying these technologies to the analysis of senescence, to allow accurate determination of biological age and support the development of drugs designed to reduce the health impacts of ageing.

My main research interests are myeloma-induced bone disease and dormant tumour cells. Over the last 12 years I have developed and established several preclinical murine models of myeloma to study therapeutic agents in the early, mid and late stages of the disease. This has led to an increased understanding of the role of the bone microenvironment and how it influences tumour growth. I am currently investigating the use of bisphosphonates in combination with other bone modulating agents to repair myeloma-induced bone disease and using novel agents to target dormant myeloma cells in the bone marrow, with the aim of translating these findings into patients.

My broad research is focused on mathematical modelling within health economics. I have gained significant expertise and experience in two related areas:

• Bayesian calibration of cancer natural history models: This is my main methodological research theme, please see MDM publication http://mdm.sagepub.com/content/31/4/625 and Example Excel model using the Metropolis Hastings algorithm to calibrate a state transition model available to down load from the Downloads box)
• Early diagnosis of cancer: I have substantial experience having worked on more than 15 projects in this area of applied research.
• In addition to these main research themes I have undertaken research to inform policy making: Health Technology Assessment (HTA) for NICE (https://www.shef.ac.uk/scharr/sections/heds/collaborations/tag) , and research as part of the Policy Research Unit in Economic Evaluation of Health and Care Interventions (EEPRU) for DH (http://www.eepru.org.uk/)

Vanessa’s research focuses on tissue engineering as a tool to both understand the fundamentals of disease processes and to develop novel diagnostic and treatment strategies.

Tissue engineering of soft tissues for the treatment of disease

Vanessa is interested in developing tissue engineered products and biomaterials for the treatment of disease or injury, in particular those affecting the oral mucosa. She has a strong interest in clinical translation and has a network of clinical collaborators.

Three dimensional in vitro models of oral cancer

Vanessa, along with colleagues in the School of Clinical Dentistry, developed a series of tissue engineered models ranging from healthy oral epithelium to precancerous dysplastic lesions and invasive squamous cell carcinoma. These three dimensional in vitro models provide a valuable tool for studying many aspects of tumour biology  as well as novel diagnostic and therapeutic technologies.

Fat derived cells for soft tissue wound healing

It is well known adipose tissue contains large quantities of mesenchymal stems cells but how best do we isolate, process and utilise these cells from fat to heal soft tissue wounds?

Research interests

I have a major research interest in the mechanisms of altered neuronal excitability that occur under the pathological conditions of nerve injury and inflammation, and which contribute to the development of chronic pain, including that in the oro–facial region. Much of this research has been done at the academic–industrial interface. Collaborations with GSK, Pfizer and Eli Lilly have funded a wide range of pre-clinical translational studies, using pre-clinical models and human tissues to identify and validate a range of regulators of neuronal excitability as potential targets for the development of novel analgesics and anti-inflammatory mediators.

Other research projects are directed towards improvement of nerve regeneration. This work investigates methods of improving nerve repair through the use of a range of anti-inflammatory and anti-scarring agents, and includes collaboration with the Department of Engineering Materials at the University of Sheffield to develop bioengineered conduits to enhance nerve regeneration. In other projects I collaborate with the Sheffield Institute for Translational Neuroscience (SITraN) investigating the role of chemokines in CNS disease.
I also have a significant research interest in neural–immune interactions and their role in the development of disease. I have a number of pilot projects underway in this field investigating neural interactions in the generation of cancer pain and tumour progression.

Research interests

Main interests are centred on oral epithelial biology, the mechanisms of oral disease pathogenesis and development of new treatment strategies. I am particularly interested in how immune cells are recruited to and act at diseased oral sites and how they interact with other cells/microbes within the local microenvironment. My group has developed novel tissue engineered in vitro models of both healthy and diseased oral mucosa (and skin) to investigate disease processes. I have a long-standing track record of utilising these in vitro 3D engineered tissues as well as zebrafish larvae as direct replacements for animal models and have used these to study the role of oral microorganisms in mucosal and systemic disease. I’m also involved in projects aimed at fabricating oral patches and microneedles made from mucoadhesive polymers for oral mucosal drug delivery. Here we have produced electrospun patches to deliver small molecule drugs such as glucocorticoids, analgesics, antifungals and larger molecules such as antibodies and mRNA for vaccine delivery. I also work within a consortium of researchers developing electrical impedance as a form of non-invasive early diagnostics for the detection and management of oral premalignant disorders.

Current projects include:

• Novel forms of oral mucoadhesive drug and vaccine delivery and the role of xenobiotic metabolising enzymes in the oral mucosa.
• Development of tissue engineered oral mucosal and skin model - atopic dermatitis, oral lichen planus
• Host-pathogen interactions at the mucosal surface.
• Role of innate immune cells in head and neck cancer.
• Use of zebrafish to examine the role of oral microbes in systemic disease.

Research Interests

Replication and gene regulation in papillomavirus.
Structure and function of helicases and replication/transcription control proteins.
DNA helicases involved in the DNA damage response and their potential as therapeutic targets in cancer.

Research Interests

* Modelling in public health

* Modelling in cancer and cancer screening

* Methodological modelling interests including:

• the modelling process and errors in HTA models
• cognitive mapping for systematic reviews in complex settings
• structural uncertainty in models
• Bayesian analysis of joint disease natural history and test characteristics in screening
• value of information methods
• probabilistic sensitivity analysis methods
• meta modelling
• information gathering processes for models

Research Interests:

Mammalian genome stability in health and disease. I head the human DNA repair group aiming to understand how defects in repairing DNA damage cause degenerative disorders and cancer. Our lab is primarily funded by fellowships from the Wellcome Trust and the Lister Institute of Preventive Medicine.

Research interests

Membrane trafficking and signalling in polarised cells. Role of multi-PDZ domain proteins in cancer formation, metastasis and tumor invasion.
Our group is interested in the regulation of membrane trafficking and its relation to human diseases. In particular we are interested in the molecular mechanism leading to Lowe syndrome, a X-linked disease characterized by congenital cataracts, mental retardation and kidney failure. Moreover, we analyze the molecular function of multi-PDZ domain proteins (PTPN13 and FRMPD2) in vesicular trafficking and signal transduction as well as their role in cancer development and progression.

My research interests include prognostication and clinical decision-making, particularly with respect to end of life care.  In addition to developing my own ambitions, I have worked with St Luke’s on their existing research portfolio, including EnComPaSS and project ECHO. 

I have collaborated with researchers nationally to support St Luke’s involvement with the £1.3m Yorkshire Cancer Research funded RESOLVE study, and the NIHR portfolio StOIC study, exploring management of opioid-induced constipation in cancer patients.

In collaboration with colleagues at ScHARR, I am undertaking research into Avoiding Emergency Admissions in Palliative Patients, funded by the Sheffield Health Care Challenges Collaboration.

Research Interests

A key stage in cell division is the copying of DNA (DNA replication). The proteins involved in replication (the replication complex) move along DNA copying it, however, if they come across a section of DNA that is damaged, replication stops. At this point multiple proteins are activated, they serve to stabilise the replication complex and help by-pass or correct the problem. If the damage is too great to repair, normal cells have a self-destruct mechanism called apoptosis. Through repair and apoptosis normal cells ensure that damage in DNA is not passed to their daughter cells, this is important as damage can lead to dysfunction of the proteins encoded in that section of DNA and thus to cellular dysfunction and disease.

In cancer cells there can be defects in the repair and apoptosis pathways which cause inaccurate copying of DNA and further contribute to the cancer. Chemotherapy causes massive damage to DNA at the point of cell division, in this way in dividing cells it triggers cell death (hence the tumour dies and we see side effects in normal tissue). Some cancers can also become resistant to chemotherapy as they no longer have a functional self-destruct mechanism. In these cases the tumour continues to grow with increasing amounts of damage being passed onto the new tumour cells.

The aim of my research is to understand what happens in a cell when DNA replication is slowed or stopped by damage in DNA. I want to understand which proteins bind to the arrested DNA, whether they are modified in any way and what significance this has on the reestablishment of replication.
By understanding the normal control mechanisms in cells I aim to understand why defects in the proteins involved are associated with cancer. I want to pinpoint differences between dividing tumour cells and dividing normal cells and determine which are important in cancer development. This will enable us to develop drugs which can specifically kill the tumour cells rather than just all dividing cells.

We have particular interests in the mechanisms of genetic instability in bladder, breast and uveal cancer and enjoy close ties with our clinical colleagues in the Royal Hallamshire Hospital (including several joint projects). This enables us to translate our research quickly into potential therapies.

Research Interests

James currently runs a lab in the Academic Unit of Molecular Oncology, encompassing 2 post-docs, 2 technicians, 3 Phd students and 1 ACF.  They research the translational application of molecular biology to urological malignancies, and in particular Bladder and Prostate Cancer.  James's particular interest is in the epigenetic alterations seen within these tumours.

I conduct qualitative research to understand the experience of living with long term conditions such as MND, dementia and cancer. I am particularly interested in the design and evaluation of complex interventions within social care.

Offering PhD opportunities in the following areas:

• Improving social care for people with long term health conditions
• Designing and evaluating complex interventions for social care
• Assessment and diagnosis experiences for people with MND
• Emotional labour of conducting research with people with long term health conditions

Research interests

My research falls into 2 areas. First, I have a long standing interest in bone biology, particularly the way that the skeleton responds to exercise and specifically the cellular and molecular mechanisms behind that response. My second area of interest is in the development of a new therapeutic target for cancer and other diseases targeting a receptor mechanism with novel chemical and biological agents.

My current research is focused around the Social Accountability of Medical Schools, the impact on medical students and community organisations working in partnership with the university. This involves supporting students to become more aware of health inequity and social determinants of health and the broader implications for society.

My background is in academic psychology and counselling and I have a longstanding interest in the psychosocial impact of illness, in particular in relation to cancer survivorship and the management of children with long term conditions

Research interests

My laboratory researches Human diseases, using 2D and 3D models. We have a particular passion for making Human organoids derived from induced pluripotent stem cells, as they are a more robust model than non-Human counterparts. Colorectal cancer is one of the major killers in the world and we are taking a number of novel approaches to learn how this disease progresses and to see if we can understand more about it using our organoids. As part of this work we use functional genomics, siRNA genome screens, drug screening and our cell and organoid models of Human disease.

Read more at the Sheffield RNAi Screening Facility

Research interests

My research interests focus on economic evaluation methodology, with a particular emphasis on the incorporation of survival analysis within economic models. My doctoral and post-doctoral research has focused primarily on methods for adjusting survival estimates in the presence of treatment switching - that is, when patients in the control group of a clinical trial switch onto the experimental treatment, thus confounding estimates of the treatment effect (where the relevant question for an economic analysis is what would have happened if control group patients did not receive this experimental treatment). Adjustment methods are primarily from the causal inference literature, and I have a related interest in the use of causal inference methods to estimate comparative effectiveness from registry datasets, particularly in the area of cancer.

Research Interests

My research focus around designing and applying Artificial Intelligence (AI) and Machine Learning (ML) models in two major areas:

1. Computer Vision: Industry and Academics research projects in areas of Object Detection (YOLO, SSD, RetinaNet), Image Segmentation (Segment anything Model SAM, U-Net), Image Classification (MobileNet, ResNet, VGG, DarkNet), Few Shot Learning, 3D Point Cloud (PointNet, SPVCNN), and these approaches with Supervised, Semi-Supervised, and Unsupervised
Learning.

2. Health Sciences: Electronic Health Records, Multiple Long-Term Conditions (MLTC), Multimorbidity, Temporal Graph Neural Networks, Codelists (SNOMED, MedCodes), Designing Deep Neural Networks for diagnosing medical conditions like Arthritis, Hospital Admissions, Face Injuries, Skin Cancer, Brain Tumour, and other use cases.

3. Other research areas: Internet of Multimedia Things (IoMT), Publish Subscribe Paradigm Multimedia Event Processing (MEP), Complex Event Processing (text data queries).
Please find details in research publications at:

(https://scholar.google.com/citations?user=bfXlzuMAAAAJ&hl=en)

Codings, Tools, and Implementation (Help for PhD Students in): Python, Tensorflow, CUDA, Pytorch, Pytorch Lightening, TensorFlow, Keras, Pandas, NumPy, SciPy, Jupyter Notebooks, GPU servers, Visual Studio, entwine, CloudCompare, MLflow, Jira, confluence.

Major Research Areas can be summarised as: Computer Vision, Deep Neural Networks, Smart Cities, and Health Sciences.

Research Supervision

I am looking for PhD students interested in Interdisciplinary projects involving Artificial Intelligence (AI) and Machine Learning (ML) applications in multiple domains. Some of the potential examples are included below:

- AI based models for processing Heterogenous data for Early Diagnosis of Life-threatening Conditions.
- Asset Inspection with 3D Image Segmentation.
- Generative AI Models for Skin Cancer Detection on Phone Images.
- Automatic generation of Object Detection Dataset (ObjectNet).
- Pattern Detection in Patient Trajectories using Temporal Graph Neural Networks.

The research in Wong group focuses on applying advanced protein engineering technique, specifically directed evolution, to tailor the properties of enzymes for industrial and pharmaceutical applications as well as to elucidate the design principles used by Nature. There are three key areas that we are currently working on:

1) Development of novel molecular biology tools to advance the field of directed evolution (e.g., method to create high quality mutant library).
2) Application of directed evolution to improve existing properties of industrially relevant enzymes (e.g., cytochrome P450s, carbonyl reductases, aromatic peroxygenases and hydrolases) or to create novel functions.
3) Development of computational tools to facilitate and expedite experimental design (e.g., method to analyse genetic diversity).

One of our current research projects is to develop biological carbon dioxide capture and utilization (CCU) strategies for bulk, fine and specialty chemical syntheses, capitalizing on our interest in directed evolution and synthetic biology.

Complementing protein engineering, we also apply a wide array of biophysical techniques to study various properties of biomolecules (e.g., structure, stability, oligomeric state, protein-protein interaction, and protein-DNA interaction etc.). We characterize proteins and complexes involved in cancer, ageing and mutational diseases.

Research Topics:

• Protein Engineering (Directed Evolution)
• Biocatalysis and Industrial Biotechnology
• Synthetic Biology
• Biological Carbon Dioxide Capture and Utilization
• Biophysics
• Cancer and Ageing

• Pawel Jajesniak (Poland)
• Hossam Eldin Omar Ali (United Kingdom)
• Amir Zaki Abdullah Zubir (Malaysia)
• Abdulrahman H. Alessa (Saudi Arabia)

Bacterial infections such as sepsis and meningitis are huge problems worldwide. Bacterial adhesion to host cells is essential for both colonisation and infection. New therapies to prevent adhesion could significantly decrease disease and reduce the burden of antibiotic usage.

We have identified a superfamily of proteins which appear to control bacterial adherence to epithelial cells. These proteins, the tetraspanins, do not act as receptors but organise and cluster hijacked host proteins in to 'adhesion platforms' to allow efficient adherence and entry of bacteria to cells. Blockade of these proteins leads to a significant reduction in bacterial adherence of many Gram negative and Gram positive bacteria. Using a variety of techniques we identify members of these adhesion platforms and new ways to inhibit their function during infection. Furthermore, we investigate changes to the composition of both bacterial membrane proteins and host adhesion platforms during tetraspanin-mediated infection utilising a number of bacteria as models.

We are also interested in the importance of the bacterial microbiome in humans and how dysbiosis of this flora can affect various diseases ranging from skin afflictions to cancer. We currently run a number of studies which utilise Oxford Nanopore Technology sequencers to delineate the microbiome.

Research Interests

The focus of both my clinical and basic research is on optimising pituitary hormone replacement. My group have identified and characterised uncommon mutations in the growth hormone receptor which have led to fundamental observations on the mechanism by which the growth hormone receptor signals through a pre-formed dimer. This work has led to a greater understanding of the regulation of growth hormone secretion and recently the group have developed a long acting form of growth hormone which has exceptional pharmacokinetic properties that means administration may only be required once a fortnight or once a month. This work was published in Nature Medicine in 2007.

The Clinical Research Programme has been investigating different regimens for replacing cortisol, testosterone and oestrogen in hypopituitary, hypogonadal and adrenal insufficient patients. The group have designed a new modified release form of hydrocortisone, Chronocort, which in phase 1 studies has proven to replicate the normal circadian rhythm of cortisol. This work is currently being taken through to phase 2 studies in congenital adrenal hyperplasia patients. Other work has examined the incidence of hypogonadism in cancer survivors and optimising oestrogen replacement in young women of fertile years.

I co-chair the Endocrine Unit Management Team which consists of 6 Consultant Endocrinologists and runs a number of unique and innovative specialist clinics in the Health Care Trust including: Pituitary Clinic, Transition Clinic for Paediatric Endocrinology, Late Effects Clinic for Cancer survivors, Joint Surgical Endocrine Clinics, Obesity Clinic, Genetic Endocrine Clinic and a Pituitary Multidisciplinary Team.

Publications and Patents: 234 publications during career, 34 publications in the last 5 years, Scopus h-index of 34, 7 papers cited over 100 times, 2 over 200 times and 1 over 300 times.  35 patents granted from 7 independent patent families.

1. Patent granted 2010: C Strasburger, M Bidlingmaier, Z Wu, G Matarese, R Ross. Leptin antagonist and method for quantitative measurement of leptin. US 7,807,154 B2
2. Patent granted 2012: R Ross, P Artymiuk, J Sayers.  Fusion protein compromising growth hormone and growth hormone receptor. US 8,173,782 B2

Tissue Repair and Immunity in Ageing (TRIA)

Why we age and whether we can therapeutically prevent associated diseases has been my continued research motivation. And this is because age is the greatest risk factor for chronic diseases such as cancer, frailty, muscle atrophy, arthritis and many others. This means we are living longer than ever before, but with a heavy burden of disease which impacts on our quality of life and poses serious socio-economical challenges we must meet.
Ageing is underlined by a progressive decline in tissues ability to repair and maintain themselves. This is what is called tissue homeostasis impairment and sets the ground for age-associated diseases. A key mechanism contributing to this is telomere shortening and dysfunction. In organisms with restricted telomerase activity, which is the case of humans and zebrafish, telomeres shorten and get damaged with ageing, causing cells to die or become senescent. Senescent cells no longer divide and secrete factors that somehow impair the repair capacity of our tissues and organs, thereby contributing to disease.

Tissue homeostasis requires a tight balance between the clearance of senescent and damaged cells by the immune system and the replenishing of new cells from the stem cell niche.

My research programme focuses on understanding the interplay between immune regulation and tissue homeostasis in health and with ageing, using zebrafish as a model. My ultimate aim is to identify therapeutic targets that can be used to incentivate tissue rejuvenation and ameliorate multiple co-morbidities of ageing

How do cells integrate information to make decisions about what genes should be expressed at a given time and in a given place? How do these processes malfunction to produce disease states? The correct regulation of gene expression is essential for the proper functioning of the cell, and incorrect regulation of genes is central to the mechanisms of many diseases. My interests rest in understanding how the many levels of eukaryotic gene regulation work together to perform these functions, using computational and functional genomics tools.

The role of microRNAs in regulatory networks

microRNAs (miRNAs) are short, single stranded RNAs that act to down regulate the expression of their targets by transcript destabilisation and translational inhibition. What roles to these molecules play in the information processing systems of the cell? How might these roles differ from that provided by transcriptional inhibitors? We know that miRNAs are found enriched in different topologies of network motifs than transcription factors. What might explain this?

Mathematical modelling suggests that miRNAs might threshold the expression of their target genes, only allowing protein production once transcription exceeds a particular rate. However, thus far experimental tests of this model are lacking in realistic in vivo settings. We are studying evidence that might speak to the applicability of this model in real biology, and studying the consequences of this behaviour on regulatory networks and the identification of miRNA targets.

Misregulation of chromatin structure in disease

A cell’s DNA does not exist as a single extended string of nucleic acids in the way often imagined, but rather is packed and folded in a myriad of ways to form a complex three dimensional structure. At least some of this structure is thought to be important for the regulation of gene expression. Transcription of metazoan genes is regulated by sequences known as enhancers which integrate diverse signals to make decisions about expression, and then communicate these decisions through their interactions with promoters. This communication is thought to take place via physical interactions between promoters and enhancers.

Together with collaborators from the Imperial University we are investigating how this three dimensional structure might contribute to the miss-regulation of gene expression in both monogenic disease and cancer using high-throughput, next-generation sequencing based assays of chromatin conformation.

When the immune system does not function properly, for example, in HIV infection (the virus that causes AIDS), cancer and old age, we are vulnerable to microbes that normally do not cause disease. One such microbe is the fungus Cryptococcus that causes an estimated 600,000 deaths each year. I want to understand why we become vulnerable to infections such as Cryptococcus.

We already know that Cryptococcus can avoid parts of our immune system, for example it escapes immune cells whose job it is to eat and digest microbes, but we do not know how single aspects like this come together to cause life-threatening disease. The zebrafish represents a unique opportunity to study these interactions as they are transparent in their early life and have an immune system that is similar to our own. I have developed ways to look at zebrafish in three-dimensions over time that mean I can study the individual behaviour of many immune cells and microbes at the same time during infection. I believe that this will dramatically further our understanding of how microbes cause disease, how the immune system is able to respond and how to develop new treatments and therapies.

Technical Summary

Understanding of the macrophage interaction with pathogens is crucial for the study of infectious disease, with many important pathogens known to manipulate phagocyte function (e.g. HIV, Tuberculosis, Salmonella). However, there are very few examples of where this interaction can be studied at a cellular level, in vivo during infection, especially with high-resolution light microscopy, a technique that has proved fundamental for insights in vitro.

Cryptococcus is a fatal fungal infection of humans causing death through meningitis. C. neoformans is a significant pathogen of the immunocompromised, especially AIDS patients, and causes an estimated 600,000 deaths per year. In contrast, C. gattii is predominantly a pathogen of immunocompetent individuals and although predominantly localised to the tropics and sub-tropics, there are increasing numbers of cases outside of this region, in particular the Vancouver Island Outbreak (VIO), which highlights how particular groups of C. gattii are becoming hypervirulent.

By evading or manipulating phagocytes, particularly macrophages, Cryptococcus is able to cross the immune barriers that normally prevent fatal disseminated disease. Current studies focus on in vitro analysis in isolated (mammalian) cells, such as macrophages or in vivo studies in rodent hosts. However, such approaches are unable to capture the complex cellular events that define how this fatal disease progresses or is stopped. Therefore, I have developed a new integrated model of cryptococcosis in zebrafish to simultaneously study host and pathogen factors that determine disease progression and outcome in vivo. Zebrafish (Danio rerio) are proven models of human disease as well as immune cell and infection biology and are unparalleled for this work due to the ability to perform in vivo sub-cellular resolution imaging in the entire body of a living vertebrate.