The concept of a new bacteria-eating virus designed to fight the modern-day superbug Clostridium difficile, has been developed by a team of University of Nottingham students in a global competition.
The ‘bacteriophage’ was devised by the team as part of their synthetic biology project that recently won a prestigious Gold Medal at the International Genetically Engineered Machine (iGEM) competition in Boston, USA.
C. difficile infection is the most common cause of antibiotic-associated diarrhoea in the western world and is a big problem in hospitals and healthcare facilities. The disease symptoms are caused by the release of two major toxins by the bacterium.
Under normal circumstances, a healthy gut microbiome prevents the proliferation of C. difficile. However, when these good bacteria are obliterated by the use of broad-spectrum antibiotics, the bug proliferatesand causes disease. One way to counter the expansion in numbers of toxin-producing C. difficile is to use competing strains that are not producing toxin as a probiotic.
The aim of the Nottingham iGEM team’s project, called ClostridiumdTox; it’s not sodifficilewas to engineer a C. difficile bacteriophage (phage), to produce factors that would suppress toxin production. They demonstrated that the latest gene-editing techniques could be used to repress expression of both toxin genes (tcdAand tcdB) by targeting their mRNA. The ultimate goal is a C. difficile-specific bacteriophage therapeutic which stops toxin production in those cells that are infected with the phage, converting them into health-promoting probiotics. Unlike antibiotics, phage cause no collateral damage to the native gut microbiome.
The team was also nominated at iGEM for ‘Best New Composite Part’. A composite part is a functional unit of DNA consisting of two or more basic parts assembled together. These must include all characterisation information and be added to the Registry.
Around 400 teams of more than 5,000 undergraduate and postgraduate students from 45 countries competed at iGEM. They were tasked with using the principles of synthetic biology, the ‘Engineering of Biology’, to design biological parts, devices or systems to address a real-world problem or to perform a novel, previously unseen function. The best ‘parts’ of every project are then submitted in the form of a ‘BioBrick’ to the iGEM BioBrick registryfor use by others.
Director of the University of Nottingham’s Synthetic Biology Research Centre, Professor Nigel Minton, said: “This was a tremendous achievement considering the short time that the team had to design, build and test the parts needed for the innovative project they devised. We broke new ground for iGEM by engineering a strict anaerobic bacterium, rather than the more traditional chassis other teams focus on. This was made possible by the extensive skills and expertise available through the involvement of SBRC researchers who gave so much of their free time to supervise the team.”
The University’s Gold-winning team members were; Lucy Allen, Hassan Al-ubeidi, Ruth Bentley, Sofya Berestova, Eun Cho, Lukas Hoen, Daniel Partridge, Varun Lobo, Fatima Taha and Nemira Zilinskaite. For the duration of their project they were embedded within BBSRC/EPSRC Synthetic Biology Research Centre (SBRC) at Nottingham, under the overall guidance of Nigel P Minton and Philippe Soucaille and under the close supervision of a dedicated multidisciplinary team comprising Louise Dynes, Daphne Groothuis, Dr Christopher Humphreys, Dr Carmen McLeod, Dr Michaella Whittle and Dr Craig Woods.
Computer Science undergraduate, Hassan Al-ubeidi, said: “Taking part in iGEM has given me a holistic understanding of the synthetic biology process. Coming from a Computer Science background, I had no knowledge of the science prior to iGEM, but working alongside talented team-mates meant that I left with a much better understanding of our project. I feel that my communication skills have improved since starting iGEM, as it has allowed me to interact with students and experts from many disciplines”.
Ruth Bentley, who is studying for a Maths degree, said: “iGEM was an exciting challenge. As the sole modeller for our team, I improved my ability to work independently to research and solve problems. I learnt how to communicate my work in a way such that those with less technical knowledge can understand. Attending the Jamboree and seeing other projects made me appreciate the power of synthetic biology to build a better world”.
Human Practices and Public Engagement
The team devised a number of activities that explored how their creation, ClostridiumdTox, could impact society. This included mining and carrying out a sentiment analysis of data from hundreds of social media comments on an online phage therapy video and exploring the current legislation surrounding phage therapy. They also researched what makes C. difficilesuch an important issue to society and how their project can help make a positive impact on communities by working towards the development of a novel therapy for its treatment. Finally, they held a discussion group with non-scientists, and interviewed five leading scientific experts in the field, including the UK Public Health England lead on C. difficileinfection, to understand how the team could make their project as effective as possible.
Public engagement was an important focus for the team, which developed hands-on workshops to communicate the project in local schools, libraries, the media and to staff and students at the University.
What the Judges said
“Great project, great wiki!! You just light up so many questions in my mind and actually this is the key of synthetic biology! Thank you so much for your effort and all hard work!”
“Super interesting idea to use temperate phages for this! …. You are clear on your achievements and reasoning throughout, which is super refreshing. Great effort!”
“Really terrific modelling efforts! I really liked how thoroughly your work was documented on your wiki; everything was very clear.”
“Overall the project idea was very innovative, and you have great characterization on your parts. Good job!”
“Very impressive! It is very inspiring that your project used phage therapy, RNA interference and the extended application of CRISPR/Cas technology.”
“Amazing job, I hope that you continue this project.”
Sponsors
Nottingham’s iGEM team was generously supported by the University of Nottingham’s Research Priority Area in Industrial Biotechnology, through grant funding from the Wellcome Trust, the Biotechnology and Biological Sciences Research Council (BBSRC) and the National Institute for Health Research (NIHR) via the Nottingham Digestive Diseases Centre, by generous cash donations from Don Whitley Scientific Ltd, LanzaTech and Seres Therapeutics and through in-kind support from Qiagen, Millipore Sigma, Promega, Eppendorf, New England Biolabs, LabFolder and Snapgene.
Collaborators
The team is also grateful for the support given by the following collaborators: Team Biomarvel Korea and the teams from Imperial College London and the University of Warwick.
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