About the Project
Dr Karen Scott (University of Aberdeen)
Dr Sophie Shaw (University of Aberdeen)
Live Biotherapeutic Products (LBPs) whereby bacteria are engineered to perform specific beneficial functions in-situ, within the gut is a scientific growth area with huge potential to improve human health and wellbeing. For instance a Lactococcus lactis strain has been genetically modified to produce human Proinsulin with the aim of preventing, delaying or reversing type-1 diabetes. Clostridium butyricum has been manipulated by the industrial partner, creating a bacterium with potential as a biotherapeutic to provide prolonged and controlled in situ delivery of other drugs/metabolites into the human intestine. It is essential to understand how these manipulated bacteria survive and interact with the host microbiota. This project aims to investigate specific bacterial interactions and ensure that overproduction of defined metabolites does not have unintended consequences on the existing microbiota (Objectives 1 and 2). It is also possible that alternative activities within key gut anaerobes, thus far unexamined, could have potential in development as new biotherapeutics, or that they may be more useful hosts to deliver activities within the complex gut ecosystem. These options will be assessed in Objectives 3 and 4.
Objective 1: Strain Identification. Investigate the interactions of the wild-type C. butyricum strains with a range of gut anaerobes sourced from the internal Rowett Culture Collection. Specific strains capable of utilising metabolites produced by C. butyricum, or of producing essential metabolites for growth of C. butyricum, will be identified by mining existing genomic datasets and the interactions confirmed in co-culture experiments. Strains that may compete for the same resources will also be investigated to determine relative survival in co-culture.
Objective 2: Strain Characterisation. Determine survival of specific introduced strains against a background of human gut microbiota and assess the impact on metabolite production. Specific strains identified in Objective 1 as interacting in positive ways will be evaluated in a background of other bacteria, and metabolite production and further bacterial cross-feeding interactions checked. Experiments will build up from small specified consortia to in vitro models of the complete gut ecosystem.
Objective 3: Engineering Tools. Existing genome sequence data from the extensive, unique collection of human gut bacteria held at the Rowett has revealed the existence of small potentially broad host range plasmids and antibiotic resistance genes, as well as novel biosynthetic pathways. These plasmids and genes will be fully characterised using additional bioinformatics techniques and expression and replication tested following introduction into new bacterial hosts.
Objective 4: Strain Engineering Assess potential for gene transfer methodology to introduce desired traits into additional bacterial isolates that could subsequently be developed as live biotherapeutics. The host range of novel broad host range plasmids will be tested in bacterial mating experiments. Those plasmids deemed most suitable will be manipulated to express a selectable phenotype (initially antimicrobial resistance and substrate utilisation) and the transfer potential to other host bacteria confirmed.
The appointed student would receive training in anaerobic culturing, bacterial strain engineering, advanced DNA transfer techniques, bioinformatics, and controlled continuous fermentation techniques, and would have a placement period with the sponsoring company CHAIN Biotechnology Ltd.
Please send your completed EASTBIO application form, along with academic transcripts to Alison McLeod at [Email Address Removed]. Two references should be provided by the deadline using the EASTBIO reference form. Please advise your referees to return the reference form to [Email Address Removed].
Candidates should have (or expect to achieve) a minimum of a 2:1 UK Honours degree, or the equivalent qualifications gained outside the UK, in a relevant subject.
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