Human Practices
Paclitaxel Manufacturing
Forming the Scope of Our Project
The UNSW HP Framework
Our approach to Human Practices
Investigating HP Issues
Applying the UNSW HP Framework
Paclitaxel Manufacturing
Forming the Scope of Our Project
Paclitaxel is one of the most important chemotherapeutic agents we have to date. It is used in the treatment of a wide variety of cancers and new research is showing it can be used outside the context of cancer, treating disorders such as skin diseases, renal and heptic fibrosis, and much more1. On top of this, Paclitaxel is used to derive newer and more effective drugs such as Abraxane, Taxoprexin and Opaxio2,3,4. These factors point towards an increasing demand for Paclitaxel, a drug that is already used in the treatment of 60-70% of all cancer patients. However, due to inefficiencies in the current reaction pathway, the production of Paclitaxel may struggle to meet this rising demand in a way that is both efficient and sustainable.
This has formed the scope of our project - addressing these inefficiencies to pave the way for a better manufacturing process. The solutions we have devised this year were guided by our Human Practices work, and range from improving the rate-limiting step in Paclitaxel semi-synthesis, to developing a more sustainable production pathway, and to even working with Himalayan communities and environmentalists to create a sustainable farming guideline. Through investigating these issues closely with relevant communities from: the Government, Environment, and Professionals, our team has been able to make a positive impact on Paclitaxel manufacturing. We have carefully considered the issues present in Paclitaxel production, and have thought about how we can apply synthetic biology to pave for a better world.
The UNSW HP Framework
Our approach to Human Practices
This year, we took a different approach to Human Practices, developed from the Design, Build, Test and Learn (DBTL) cycle of engineering. Whilst the DBTL cycle is great for developing a strong project/system, we noticed one fundamental flaw. The learn stage of the DBTL cycle is inherently narrow, and incorporates purely the quantitative/qualitative data obtained from the test stage.
In other words, the DBTL cycle is not conducive to the ethical and forward thinking frameworks that iGEM and society values in the development of engineering projects.
We felt an amendment was necessary, one that would incorporate Human Practices work, and encourage continual consideration of the values of the many relevant communities affected by our project. In this method, we developed 3 new stages based off of the Human Practices guideline provided by iGEM. These stages are Consider, Engage, and Integrate. The consider stage is a separate branch from the Learn stage, and encourages engineers to think beyond the physical data, and how their project at its current stage may impact upon different communities. It asks these engineers to engage with these relevant communities, and integrate their concerns and values into the design stage of their project. As a result, engineers are able to integrate more than just data into the design of their project, and holistically improve upon their project.
We call this framework the impactful engineering cycle.
The UNSW HP Framework
Integrated Human Practices
What role did IHP play in our project?
The Human Practices framework presented above helped guide our interactions and integration of new understandings in our project. We were able to make changes to our project on a macro and micro scale which will be reviewed below.
On a macro scale, we integrated new understandings to refine our projects purpose through iterative steps that helped ensure we could address inefficiencies in Paclitaxel production. We used this information to inform the next iteration of our project, and what work needed to be done in it. The main iterations of our project were:
- Improving the efficiency of Paclitaxel production
- Making Paclitaxel production more sustainable
- Incorporating concepts of Green Chemistry
- Improving the commercial readiness of our pathway
On a macro scale, we integrated new understandings to refine our projects purpose through iterative steps that helped ensure we could address inefficiencies in Paclitaxel production. We used this information to inform the next iteration of our project, and what work needed to be done in it. The main iterations of our project were:
- Improvements in how we scaffold the enzymes in Paclitaxel semi-synthesis, to improve the efficiency of the rate limiting step. We were also able to better accommodate for the tetrameric nature of our enzyme PAM, improving how we model and attach the enzyme to our scaffold. Finally, we were able to gain a better understanding of the need for more efficiency in Paclitaxel semi-synthesis.
- Expansion on the work we did in the lab towards addressing sustainability issues in Paclitaxel production. We worked closely with Professor Ping Zhu to scaffold the enzymes Xylosidase and DBAT to Assemblase, helping develop the production of Paclitaxel from the abundant analogue XDT. We also took a proactive approach to reduce the negative impacts of our project, through developing a sustainable Yew Tree farming program. We integrated the perspectives of communities in the Himalaya, Environmentalists, Botanists, and Nepali Academics, to create a program that would combat our pathways potential to increase exploitation of the endangered Himalayan Yew, and help regenerate the tree.
- The integration of green chemistry principles into our pathway. Introducing atom economics to our pathway through recycling byproducts back into the current semi-synthetic pathway. This provides stakeholders the ability to produce Paclitaxel from both pathways viably. We also integrated methods of moving our pathway towards zero waste, through extracting our waste produce Xylose via Boric Acid. We considered a potential future direction of turning waste biomass produced by by Paclitaxel production into Acetyl CoA to refunnel back into our pathway.
- Finally, the integration of advice from stakeholders and experienced commercial scientists helped position our pathway for commercial success. We adjusted the focus of our business model and plan from our production pathway, towards Assemblase, and its wide range of potential uses. We also found a cheaper reagent for our pathway, and worked with the UNSW Recombinant Products Facility to prepare our pathway for scaling up. Here, we designed filters and large scale production methods for easy separation of products and retrieval of Assemblase for reuse.
References
- Zhang D, Yang R, Wang S, Dong Z. Paclitaxel: new uses for an old drug. Drug Des Devel Ther. 2014 Feb 20;8:279–84.
- Markovsky E, Baabur-Cohen H, Satchi-Fainaro R. Anticancer polymeric nanomedicine bearing synergistic drug combination is superior to a mixture of individually-conjugated drugs. Journal of Controlled Release. 2014 Aug 10;187:145–57.
- Liu J, Li H, Jiang X, Zhang C, Ping Q. Novel pH-sensitive chitosan-derived micelles loaded with paclitaxel. Carbohydrate Polymers. 2010 Sep 5;82(2):432–9.
- Miele E, Spinelli GP, Miele E, Tomao F, Tomao S. Albumin-bound formulation of paclitaxel (Abraxane® ABI-007) in the treatment of breast cancer. Int J Nanomedicine. 2009;4:99–105.