ASSEMBLASE
Manufacturing Paclitaxel
About Paclitaxel
Paclitaxel is an extremely important chemotherapy agent. In fact, 60-70% of all cancer patients will encounter the use of the Paclitaxel within their treatment plans. With an ageing population, and new uses for the drug being found, its demand will only increase as time goes on. The problem, is this demand is being met with production methods that are complex, and use unsustainable precursors. Chemical synthesis steps also produce racemic mixtures and use damaging reagents and solvents. These inefficiencies result in demand being supplemented through extracting Paclitaxel directly from the bark of the Yew tree, driving species such as Taxus Contorta and Taxus Wallichiana towards endangerment. Our solution is applying a Synthetic Biology tool, Assemblase, to optimise biosynthetic manufacturing of Paclitaxel in a way that helps meet increasing demands efficiently and sustainably.
About Assemblase
Assemblase is a hexameric protein scaffold developed by the 2018 UNSW iGEM team. This year we've built upon their work, producing the scaffold and using it to improve upon Paclitaxel manufacturing. Through attaching key enzymes onto the scaffold, production can benefit from co-localisation effects, reducing intermediate diffusion times, and increasing product turnover rates. We applied Assemblase to 2 Paclitaxel manufacturing pathways - the first improved the current semi-synthesis methods by attaching rate limiting enzymes in Paclitaxel side chain biosynthesis (PAM and TycA) onto the scaffold. By, scaffolding the second enzymatic pathway we aim to produce Paclitaxel from a more sustainable precursor and in turn, develop it for long term and commercial use.
Our Journey
Human Practices
We incorporated our UNSW HP framework; consideration, engagement and integration to selectively understand the problem faced by our community surrounding Paclitaxel manufacturing. Through exploring a myriad of diverse perspectives, we could create the necessary changes to our Assemblase Scaffold that would maximise the outcome for the community.
Experiments
Our laboratory component encompasses the production of all the necessary components to make this project from idea to reality. It consists of three main objectives: 1. the production of our Assemblase scaffold, 2. the synthesis of our enzymatic compounds and finally, 3. the measurements to demonstrate everything works.
Modelling
Our modelling efforts are centred around Molecular Dynamic (MD) analysis of our Assemblase system. From our MD simulations, measuring size and flexibility of Assemblase as well as, the distance between the active sites in our system. Additionally, we created a guide on building protein models for future iGEM teams that was based on the construction of our physical model of Assemblase.
Entrepreneurship
In an attempt to maximise the effect Assemblase would have on the community we created a business plan. This business plan had foundations in Lab, Modelling and Human practices exploring how Assemblase could be incorporate into all biochemical manufacturing pathways. This effort culminated in a $100,000 commitment to invest.
The UNSW iGEM Team
The key to our project this year has been the interdisciplinary nature of our team. On top of biotechnologists and microbiologists, we have many members with combined degrees in either Business, Chemistry, Engineering or Bioinformatics. Having diverse skillsets has allowed our team to explore areas that we would not have been able to otherwise. For instance, using chemistry techniques such as H-NMR for assays, creating extensive molecular dynamics models, or commercialising our tool with venture capitalists and startup incubators. Our team is a prime example of the many relationships that Synthetic Biology has with other disciplines.