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Biomedical Sciences Masters by Research

Biomedical Sciences Masters by Research

Projects and Supervisors

Choose from the projects listed below.

Applicants will be expected to have experience and evident knowledge of molecular cell biology, biochemistry.

Dr Hrvoje Augustin
Biology of ageing: investigating the effect of novel compounds on longevity and functionality

One of the goals of ageing research is to identify compounds that can extend lifespan and/or improve physical and cognitive performance in old age. The research of the last 20 years revealed a high level of conservation of genetic pathways and biochemical processes that regulate lifespan in organisms as diverse as yeast, worms, flies and humans. The fruit fly Drosophila, in particular, emerged as a pre-eminent model system for studying changes that occur during both normal and pathological ageing (~75 per cent of the genes that cause disease in humans are also found in the fruit fly!). The advantages of Drosophila include their relatively low cost, ease of use and a range of powerful tools available for their genetic manipulation.

Our Department recently identified several compounds with possible pro-longevity effects. The aim of this project is to assess the effect of these compounds during healthy ageing and in various Drosophila models of human diseases. The initial lifespan studies will be followed by an array of molecular, biochemical, imaging and functional analyses.

Modelling dementia-related synaptic dysfunction in Drosophila

Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD) are the most common causes of neurodegenerative dementias. These diseases are characterised by presence of various types of aggregates of misfolded proteins in the neuronal tissue; however, evidence suggests that dysfunction and loss of the synapse might be a common pathological feature underlying the cognitive decline and memory loss in these neurodegenerative disorders.

An intronic GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of both FTD and Amyotrophic Lateral Sclerosis (ALS). We will first overexpress the mutated form of C9orf72 in Drosophila larval motor neurons innervating the neuromuscular junction, causing a drastically reduced transmission across the synapse. We will then screen the fruit-fly genome searching for the genes that can correct (‘cure’) this synaptic phenotype. The genes identify in the screen can be potential targets for therapeutic interventions in humans. Electrophysiology will be used as the primary screening tool. Other techniques: confocal microscopy, genetics and biochemistry/molecular biology.

Dr Philip Chen
Pharmacology of glycine-site agonists at NMDA receptors

This project will characterise a number of novel agonists at NMDA receptors using molecular biology and recording glutamate evoked inward currents from oocytes injected with mutant NMDARs under two-electrode voltage clamp configuration. The project will involve molecular techniques such as subcloning, site-directed mutagenesis, PCR and in vitro cRNA synthesis, injection of cRNA into Xenopus oocytes and two-electrode voltage clamp electrophysiology.

Examining the consequences of altered RNA editing on neuronal function

RNA editing is a process by which specific nucleotides are modified following gene transcription and disruptions in these processes have been linked to certain neurodegenerative conditions. We have developed a number of genetic tools to manipulate RNA editing and would like to explore their consequences on cell function. This project would involve mammalian tissue culture, RNA extraction, cell transfection and RT-PCR.

Research page - Dr Chen

Professor Simon Cutting
Mucosal vaccines

Work consists of innovative bacterial delivery systems for mucosal vaccination (i.e. against malaria or TB). Due to the dynamics of our projects, they are ongoing and subject to change on a regular basis and cannot be specified in advance.

Research pages - Professor Cutting

Dr James McEvoy
Antibiotic resistance in bacterial biofilms on orthopaedic pins

Bacterial biofilms are a common cause of infection in surgical implants, and pin tract infection is the major complication of external fixation of fractures. Furthermore, biofilm-focused infections are phenotypically resistant to antibiotic therapy. In this microbiological project, run in collaboration with Dr Shobana Dissanayeke (Royal Holloway) and Mr Arshad Khaleel (St Peter’s Hospital, Chertsey), you will use a bioreactor to grow bacterial biofilms on orthopaedic pins and study their response to antibiotic treatments. Guided by recent results from our laboratory1 you will investigate the social aspects of genotypic antibiotic resistance in multi-strain biofilms, extending this work by the addition of clinically relevant b-lactamase inhibitors. Our long-term objective is to inform surgical practice and reduce pin tract infection rates.

1. Amanatidou, E.; Raymond, B., Biofilms facilitate cheating and social exploitation of β-lactam resistance in Escherichia coli. npj Biofilms and Microbiomes 2019, 5, 36-36.

Research pages - Dr James McEvoy

Dr Linda Popplewell
Upregulation of Klotho expression using dSaCas9-TET1

Klotho, the anti-aging gene, is epigenetically silenced in dystrophic muscle, as a result of increased methylation of CpG sites around its promoter. Delivery of Klotho transgene has been reported previously to reduce muscular atrophy and fibrosis, alongside improving muscle function and increasing regenerative capacity in a mouse model of Duchenne muscular dystrophy (DMD). Catalytically inactive SpCas9 (dSpCas9) tethered to the hydroxylase catalytic domain of Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) has been used to demethylate the Klotho promoter and restore expression.

To address the bodywide pathology of DMD, systemic treatments are required. Efficient targeting of skeletal muscle could be made possible through packaging and delivery using AAV9 vectors; the large size of the dSpCas9-TET1 transgene currently hinders this. This project would therefore be focused on the design and construction of a dSaCas9-TET1 AAV plasmid and testing of its efficacy in vitro to switch on Klotho expression at the RNA and protein levels.

Development of a gene therapy for c.4610dup (p.Asn1537fs) mutation in exon 33 of the DMD gene

We have been in discussions with the father of a child recently diagnosed with Duchenne muscular dystrophy. His son carries a mutation of c.4610dup (pAsn1537fs in exon 33 of his DMD gene. This project would focus on an examination of potential strategies, including antisense oligonucleotide-induced exon skipping and genome editing, to restore dystrophin protein expression for this mutation and their subsequent optimisation. The work would involve in silico analyses, cell culture, transfection, RNA purification, RT-PCR analysis, and potentially molecular cloning, DNA purification, PCR and sequencing analyses.

Chemical enhancement of lentiviral delivery of transgenes to skeletal muscle

Gene addition therapies for monogenic loss-of-function diseases using adeno-associated viral (AAV) vectors for delivery are moving through clinical trials, including microdystrophins for Duchenne muscular dystrophy (DMD). The limited packaging capacity of AAVs and the high incidence of pre-existing immunity to certain serotypes may limit applicability. Delivering as much of the DMD cDNA as possible would be predicted to result in more functional protein being expressed and improved clinical outcomes. Lentiviral vectors can tolerate larger transgene sizes but show poor uptake into skeletal muscle.

The aim of this project would therefore be to examine whether certain small molecules are able to enhance the uptake of lentiviral vectors and transgene delivery to skeletal muscle. This would be examined using a GFP reporter gene as delivered transgene and assessment of GFP expression at the RNA and protein level. The project will involve molecular cloning, lentiviral production, qPCR for viral titration, protein and RNA harvest, western blot and RT-qPCR.

Research pages - Dr Popplewell

Professor Pankaj Sharma
Epidemiology of global stroke in South Asians

You will be based in a group headed by a clinical academic.

Stroke is the third commonest cause of death in the UK. WHO estimates that by 2050 around 80% of all stroke will be in India and China. Our group has amassed the largest database of South Asian stroke in the world. We have data from UK, India and the Middle East.

It is expected that these projects will lead to publications in major international peer review journals.

This project will allow students to analyse this extensive database to search for interactions between stroke and established risk factors

Risk factors in South Asian stroke

You will be based in a group headed by a clinical academic.

Stroke is the third commonest cause of death in the UK. WHO estimates that by 2050 around 80% of all stroke will be in India and China. Our group has amassed the largest database of South Asian stroke in the world. We have data from UK, India and the Middle East.

It is expected that these projects will lead to publications in major international peer review journals.

This project will allow students to analyse this extensive database to search for novel risk factors in South Asians and compare and contrast such factors with stroke in Caucasians.

Designing a new strategy for ‘five-a-day’ intake

You will be based in a group headed by a clinical academic and be supervised by two clinicians.

The 5-a-day campaign was launched by the UK Government to ensure that the population eats at least five fruit and vegetables per day. Research suggests that those that do this have a lower risk of cardiovascular disease.

However, the evidence is that most people do not remember how many of their 5-a-day they have eaten. We propose to develop a new colour based flag strategy for each meal to replace the 5-a-day slogan.

This work potentially has large and important clinical and public health implications.

Research pages - Professor Sharma

Dr Mikhail Soloviev
Cryptanalysis of recombinant DNAs

Naturally occurring DNA typically has coding and non-coding regions (genes and various regulatory sequences respectively), there is also mitochondrial DNA and chloroplast DNA in plants. The genome complexity and chemical nature varies considerably between Viral, Prokaryotic and Eukaryotic genomes. A large number of recombinant (artificially created) DNA and RNA sequences have been deposited into sequence databases in the last few decades. Most of these sequences encode expression vectors, native or modified recombinant proteins, and a number of structural nucleic acids. But Nucleic acid sequences contain much more information than just the encoded coding and non-coding regulatory sequences. This project aims to decipher the hidden complexity of recombinant nucleic acid sequences with the view to develop algorithms to assist identifying artificially created sequences form naturally occurring ones. The algorithms will be applied to analyse viral DNA or RNA genomes in sequence databases which became available recently.

Antigenic epitopes: prediction and validation. Antigenic epitopes of COVID protein antigens.

Generation of high affinity antibodies against given antigens for therapeutic or biotechnology applications is among the major challenges for the biopharmaceutical industry. Recombinant therapeutic proteins and antibodies occupy almost all of the top 20 places in the list of best-selling medicines over the last decade. One of the challenges in generating useful antibodies relates to the selection of antigenic epitopes. This project will build upon the previous of our recent research and will also include analysis of the Immune Epitope Database (IEDB) and Virus Pathogen Resource (ViPR) with the overall aim to develop algorithms for selecting antigenic epitopes for generation of high affinity antibodies. These will be tested and validated experimentally using polyclonal antipeptide antibodies developed against the receptor binding domain of the Spike protein (S) exposed on the SARS-CoV-2 viral envelope. Such antibodies will be used for the development of a point of care (POC) antibody based test for detecting COVID-19. The methods can be adapted to target other common viruses.

DNA based multiplex detection of viral infections

Clinical diagnosis of Coronavirus is often achieved using real time PCR (RT-qPCR) to detect minute quantities of viral RNA fragments in the samples tested. The use of suck kits has increased substantially during the 2020 COVID-19 pandemic.  Many different coronaviruses exist in the family of Coronaviridae. Some of these infect humans, causing mild (common cold) or severe acute respiratory syndrome (SARS viruses). Coronaviruses may infect a range of farm animals causing serious problems to the farming industry. A qPCR based test is relatively simple and is very sensitive. Ultimate sensitivity for the detection of a single RNA deletion is achievable in principle. But PCR/RT-PCR tests are often limited to the analysis of a single RNA or DNA target. PCR reaction may be multiplexed but only to a limited degree. This project aims to devise a simple single PCR reaction based test capable of detecting many common strains of the coronavirus in a single test reaction. This technology may be applied to human rhinoviruses (common cold) of which about 160 recognized types are known.

Engineering of Protein-A derivatives for biotechnology applications

Staphylococcal Protein A (Protein A or "SPA") is a 42 kDa virulence factor produced by Staphylococcus aureus (S. aureus) in its cell wall. SPA is well known for its ability to bind IgG molecules with very high affinity. It is widely used in biotechnology applications, such as antibody capture, immobilisation or purification to name just a few. SPA has been used widely in Life Sciences, but it has a few serious limitations. SPA recognises and binds IgGs of many different isotopes, but not all. For example native SPA does not recognise or binds human IgG3 and a few other IgGs. This severely limits its application range. This project aims to engineer SPA analogues capable of binding human IgG3. This research has huge commercial implications.

Protein based assays for POC molecular diagnostics

In the course of our current research we developed antibodies against a range of known and putative cancer markers and also against known acute-phase proteins. This project will explore multiplexing options for use with the available antibodies in order to create a point of care (POC) diagnostic assay for health monitoring and early cancer detection. A large selection of antibodies is available for the student to choose the preferred research focus (cancer, inflammation, health monitoring and forensic applications).

Serum Albumin as a drug-carrier protein for therapeutic applications

The efficacy of a therapeutic drug is affected by many factors, among which bioavailability, serum half-life, organ targeting, dosage and side effects play major roles. Serum albumin is the most abundant protein in blood serum in humans. One of the major roles of Albumin is to serve as a carrier protein for low molecular weight (LMW) molecules such as fatty acids, hormones, peptides and small serum proteins. Albumin binds many LMW therapeutic molecules, which affects their free and total serum concentrations, hepatic and renal clearance and therefore serum half-life, which will strongly influence the drug pharmacokinetics and the drug-dosing regimen (for a brief review see Merlot et al 2014). Albumin has multiple LMW binding sites and has been shown to interact with a multitude of LMW molecules and drugs (for a summary of drugs and methods used see Shahani 2014). Another widely investigated approach to utilize albumin for drug delivery requires generating albumin based nanoparticle-drug conjugates (for a recent review see Lamichhane and Lee 2020). This project aims to use a combination of chromatography, mass spectrometry, fluorescence analyses and other analytical tools and methods to study drug-albumin interactions. One other research option will focus on exploring stimuli-sensitivity of Albumin for remotely controlled drug delivery and release.

Stimuli-responsive biopolymers for life science, materials and therapeutic applications

The scientific motivation behind this project is to generate remotely controlled molecular systems capable of changing their physical or molecular properties in response to external stimuli. Such stimuli include but are not limited to ultrasound, electromagnetic radiation, exposure to infrared light, thermal, mechanical or chemical stimulation. We have developed a number of thermally activated protein-based systems. One such system comprises a range of sequence specific self-assembling polypeptides developed in collaboration with the University of Lincoln and the UK’s national synchrotron science facility Diamond Light Source Ltd. A common feature of these molecular systems is the ability to self-assemble and then disassemble in response to thermal stimuli. Another important feature is the ability to carry and release therapeutic load. Combining such systems with stimuli-specific sensitive elements such as light excitable groups, magnetic nanoparticles, elastic nanoparticles, chemically modifiable groups and their combinations yields highly tuneable stimuli-responsive biomaterials suitable for a variety of life science and therapeutic applications.

The key aim of this project is to engineer new biomaterials by combining multiple stimuli-specific sensors with functional biological molecules and to test physical, chemical and biological properties of the newly generated smart composite biomaterials. Due to the multidisciplinary nature of this research project, applications from students with the background in physics, chemistry, biophysics, biochemistry, nanomaterial and protein based therapeutics are especially welcome. 

Recent publications by the group MSc students:

Research pages - Dr Soloviev

Dr Jorge Tovar
In vitro study of the cell-cell interactions between Aspergillus fumigatus and Bdellovibrio relevant to cystic fibrosis patients.

Cystic fibrosis (CF) is a genetic disorder caused due to mutations in CFTR gene. The gene is important for the regulation of epithelial fluid transport in the exocrine glands, situated largely in respiratory and alimentary systems. The lung of CF patients is increasingly found co-infected with fungal and bacterial pathogens (deDios et al, 2017; Middleton et al, 2013). Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa are the most common bacteria found in the CF lung. Aspergillus spp., Candida spp., Scedosporium spp., and Exophiala spp. are the most frequently detected fungi (Williams et al, 2016), with a reported 10-57% prevalence for A. fumigatus (deVvrankijker et al, 2017).

Recently published research identified the presence of two predatory bacteria in CF lung microbiota, Bdellovibrio and Vampirovibrio. They limit CF pathogens by feeding on them (deDios et al, 2017). Interestingly, their predatory effect on fungi has not been investigated. This project will aim to understand the interaction between A. fumigatus and Bdellovibrio at the cellular level and will provide training in microbiology and advanced microscopy skills (brightfield and confocal). If Bdellovibrio can exert fungicidal or static effects it could potentially be used to treat CF patients and other manifestations of aspergillosis

Developing novel platforms for the molecular diagnosis of fungal infections

Human fungal infections represent one of the most pressing health problems in recent years. Endemic infections affect healthy immunocompetent individuals causing a range of diseases which generally resolve with chemotherapy but hospital-acquired nosocomial infections pose a serious threat to immunocompromised patients in hospital wards and intensive care units worldwide. Despite the availability of chemotherapy nosocomial infections frequently result in high mortality rates, often exceeding 50%. The development of timely and more efficient molecular diagnostic methods, along with the development of new drugs and anti-fungal vaccines, was recently identified as one of the most pressing needs in medical mycology research.

We are interested in developing and implementing simple nucleic acids diagnostic tests for a range of fungal infections, including both endemic and opportunistic. Using fungal genome data mining and isothermal DNA amplification this project will use Candida – the causative agent of endemic and nosocomial candidosis – to develop simple diagnostic tools that are both amenable to automation and applicable at the point of care.

Research pages: Dr Tovar

Dr Chris Wilkinson
Melanoma and centrosomes

Melanoma, in common with all solid tumours, displays excessive numbers of centrosomes, which help form the mitotic spindle. Such supernumerary centrosomes are thought to drive carcinogenesis by contributing to aneuploidy and chromosomal instability. However, much remains to be understood about the origin and the contribution of excessive centrosomes in tumorigenesis. This Masters project will continue published work (by our laboratory, doi: 10.1016/j.jid.2020.01.024) on how centrosomes and cilia are affected in melanoma. The mechanisms underlying these changes will be investigated with the aim of developing better diagnostics and treatments. A combination of cell biology, immunocytochemistry, epifluorescence microscopy and protein analysis such as Western blotting will be used in this project.

Polycystic kidney disease and cilia

Cilia are hair-like structures on the surface of many animal cells. Cilium malfunction is linked to autosomal dominant polycystic kidney disease (ADPKD), which affects 1 in 1,000 of the population, as the cilium houses polycystin-1 whose gene is frequently mutated in ADPKD. This project will investigate the role of a novel protein that interacts with polycystin-1, in collaboration with Dr Richard Sandford at University of Cambridge. A variety of cell biology and embryological techniques will be used to investigate its function using cultured fish cells and zebrafish embryos.

Novel antibiotics from fish

Polyketide synthases are a class of enzymes that produce many of the antibiotics and other drugs used clinically today. Most polyketides are sourced from soil bacteria and fungi. They are also found in plants but have not been found in animals until now. We recently published a paper (https://doi.org/10.1016/j.mod.2019.04.001) showing for the first time that one such enzyme is present in fish. Although we studied the zebrafish enzyme, homologues are present in other fish as well as reptiles, birds and some mammals. What chemical is produced by this enzyme is unknown. This project will discover the product of this enzyme and test if it has antibacterial effects or other pharmaceutical activities. A combination of protein expression in cultured fish or mammalian cells or yeast or E. coli, followed by bioassays will be used in this project.

Parkinson’s disease and cilia

A hallmark of Parkinson’s disease is the presence of large aggregates of protein called Lewy Bodies in affected neurons. In collaboration with colleagues at the University of Cambridge, we have recently published a paper (doi: 10.1242/bio.054338) that shows that related, possibly precursor, structures called aggresomes prevent the centrosome and cilia from functioning. The centrosome is the microtubule organising centre of the cell and contributes to the internal organisation of the cell and intracellular transport. Loss of these functions could lead to neuronal disease. Notably, cilia are involved in olfaction, the sense of smell, which is lost in Parkinson’s disease, and the presence of aggresomes prevents cilia from forming. This project will investigate the mechanisms by which the aggresome affects these other two organelles. A combination of cell biology, immunocytochemistry, epifluorescence microscopy and zebrafish genetics will be used in this project.

Ear development

Early ear development in fish involves the formation of otoliths, protein-calcium calcium carbonate complexes whose generation and anchoring both involve the action of cilia. They are related to the structures in the human ear used in the sense of balance. We recently published, in collaboration with Ken Kramer and colleagues at Creighton University in the USA, a paper (doi: 10.1016/j.mod.2019.04.001) showing that a novel type of enzyme is involved in formation of these structures. This project will investigate the mechanism by which this enzyme contributes to otolith formation. A combination of zebrafish genetics, embryology and tissue expression techniques will be used in this project.

Cilia to control cancer

In many cancers the primary cilium that is present on healthy cells is lost. This may contribute to cancer development by disturbing the reception of the signals a cell receives that regulate cell division. Furthermore, cilia are incompatible with cell division, which is inappropriately and excessively occurring in cancer, as the component centrioles are required to form the poles of the mitotic spindle. In 2017 we published a paper (doi: 10.1242/jcs.196642) showing that a centrosome satellite protein called BCAP was a novel inhibitor of ciliogenesis. This project will test if inhibiting or removing BCAP from cells can prevent cell division and therefore be a potential anti-cancer drug target. A combination of cell biology, immunocytochemistry, epifluorescence microscopy and protein analysis such as Western blotting will be used in this project.

Research pages - Dr Wilkinson

Professor Robin Williams
Molecular Cell Biology studies in Biomedical research using a tractable model system

Research into improving our understanding of disease treatments is often focused on the characterisation cell signalling regulation caused by current or new medicines or bioactive natural products. Rodents are traditionally used as models for these studies, in addition to human or mammalian cell lines. The models are often difficult to manipulate, and can be associated with ethical considerations. Our laboratory specialises in these studies using an innovative model system, the social amoeba Dictyostelium discoideum. This system allows the rapid manipulation of cells, including CRISPR knockout approaches and expression of fluorescently tagged proteins in isogenic cell line enabling biochemical assays, to discover the molecular and cellular effects and mechanisms of action of medicines or health/disease related natural products (e.g. Warren et al 2020 PNAS; Perry et al 2019 BJP; Sharma et al 2019 Autophagy). We used Dictyostelium to modelled the effects of compounds relating to a range of diseases include various cancer types, multiple epilepsies, Alzheimer’s disease, bipolar disorder, infection and polycystic kidney disease and others. We also often works with industry, focusing on wide-ranging compounds including various cannabinoids, medium chain fatty acid related to ketogenic diets, naturally occurring antibiotics, flavonoids, and traditional (herbal) remedies from around the world.

A Maters student joining our laboratory will learn a wide variety of key skills used widely in molecular cell biology and modelling, to equip them for ongoing academic studies or to move into an industry setting. We are fully equipped for research with bespoke facilities for tissue culture, microscopy and molecular biology studies. 

We would be delighted to hear from high-achieving students with some background and interest in molecular cell biology, who are keen to developing their careers in a scientific setting.

Research Pages - Professor Williams

Professor Rafael Yanez
Gene therapy, viral vector, Spinal muscular atrophy

Our laboratory (http://AGCTlab.org) works on the development of new gene and stem cell therapies for rare and common diseases. Recently we have been working on novel therapeutic strategies for spinal cord injury, spinal muscular atrophy and ataxia telangiectasia (A-T). The latter is a rare disease characterised by progressive degeneration in cerebellum, high risk of cancer and immunodeficiency. It is caused by defects in the gene known as ataxia telangiectasia mutated (ATM). The most advanced gene therapy technology, “genome editing”, can be used to introduce specific changes in the DNA, including the repair of a faulty gene: this could be applied as a therapy for A-T. Genome editing has undergone a revolution over the last few years with the introduction of a system called CRISPR, which has greatly facilitated the process. For this research project we will use the CRISPR system to test several ways to repair the faulty gene in A-T. We will initially work with easy-to-grow human cells in the lab, and eventually the most effective A-T gene repair strategies will be tested in human blood stem cells. If our proposed studies are successful, follow-up projects would explore these novel gene repair methods in blood stem cells from people affected by A-T. We will also study possible side effects of these gene repair methods. If successful, this work could eventually pave the way for the treatment of blood disease in A-T.

Research pages - Professor Yanez

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