MSc by Research – Harnessing viruses to control skin-associated bacterial pathogens: synthetic, selective and scalable

Primary Supervisor: Dr Sean Meaden (Univeristy of York)

Co-Supervisors: Dr Paul Fogg and Prof Gavin Thomas (University of York)

Bacterial pathogens contribute to a range of skin diseases, with Staphylococcus aureus (SA) being a major opportunistic coloniser of damaged skin, leading to wound infection. These diseases can range from moderate skin infection to sepsis, with treatment complicated by increasing levels of antibiotic resistance. Alternative treatments are required with the natural healthy skin microbiome holding great potential for novel control strategies. Recent advances in our understanding of the skin microbiome have revealed the diversity of the microbes that SA must overcome in order to cause disease. A major, but often overlooked, component of this microbiome are viruses, including a class of viruses known as bacteriophages, or phages for short, that infect and destroy bacteria. These viruses provide a potential solution for eliminating pathogenic SA, while leaving the remaining healthy microbiome intact, providing they can be harnessed and deployed effectively. Individual phage proteins have also successfully been applied to deplete SA in an in vivo skin model, demonstrating the required selectivity. Such viruses have been applied to treat diverse diseases for over 100 hundred years, however modern synthetic biology approaches provide an opportunity to drastically up-scale and improve the precision of this phage therapy technique. This project aims to leverage the natural resource of phages, using global and local collections of skin microbiomes, in combination with synthetic biology, to develop a prototype therapeutic phage application.

Research objectives:

1. Mining microbiome data for a database of skin-associated viruses.

Global repositories of microbiome data provide a rich resource for mining of viral sequences. Metagenomic sequencing collects DNA sequences from all microbes

present, including bacterial and viral. State of the art bioinformatic tools allow us to search for viral (phage) genomes within these data using known marker genes and machine-learning approaches. By combining metagenomic data with an in-house collection of clinically relevant SA genomes, we will mine for phage genomes. The resulting database will be used in objective 2 to modify and synthetically ‘reboot’ a functional phage with high virulence.

2. Synthetic ‘rebooting’ of SA infecting phage

Isolating and characterising therapeutic phages is labour intensive and scales poorly. A platform to synthetically construct phages with the desired infection properties would overcome these issues. The potential to reboot functional phages from synthetic DNA sequences was previously demonstrated in Staphylococcus and we will build on these techniques. We will first synthetically reboot a phage known to infect our target SA strain. We will then apply the same method to reboot a prophage genome identified using our phage database (objective 1) and predicted to target our SA. Successful completion of this aim will serve as a proof-of-principle pipeline that is highly scalable.

Full training will be delivered in the bioinformatic analysis (Meaden lab), synthetic phage rebooting (Fogg lab) and skin microbiology (Thomas and Rudden labs). The student will also benefit from the wider Skin Research Centre network across the University of York and Hull York Medical School.

Entry Requirements: Students with, or expecting to gain, at least an upper second class honours degree, or equivalent, are invited to apply. The interdisciplinary nature of this programme means that we welcome applications from students with any biological, chemical, and/or physical science backgrounds, or students with mathematical background who are interested in using their skills in addressing biological questions. 

The Department of Biology is ranked in the top 10 overall in the UK for research excellence according to the Times Higher Education ranking of the latest REF results. We are committed to recruiting extraordinary future scientists regardless of age, ethnicity, gender, gender identity, disability, sexual orientation or career pathway to date. We understand that commitment and excellence can be shown in many ways and have built our recruitment process to reflect this. We welcome applicants from all backgrounds, particularly those underrepresented in science, who have curiosity, creativity and a drive to learn new skills. We’re exceptionally proud to have held an Athena SWAN Gold award since 2014 in recognition of our commitment.

Programme: MSc by Research in Biology (1 year full time)

Start date: 16th September 2024