Interdisciplinary strategies to uncover the missing enzymes and regulatory machinery in the biosynthesis of paclitaxel, a plant derived, WHO essential medicine

Pharmaceuticals from plants. Plants produce a vast array of secondary metabolites that can be exploited for biomedicine. Since the 1940s 73% of anticancer drugs have been natural products and most of these trace their origins to plant sources (1). However, there in vitro chemical synthesis is routinely not commercially viable and the relevant biochemical pathways remain opaque. Further, the plant source may not be domesticated, is typically slow growing, with a limited population and the concentration of target molecules is routinely extremely low (2).

Plant cell culture as a biomanufacturing platform for higher value chemicals. Plant cell culture provides an attractive alternative biological manufacturing route to plants, because it is sustainable, efficient, independent of environmental conditions, standardised and provides a robust supply of product that is free of zoonotic viruses (3).

Paclitaxel a blockbuster anti-cancer drug. Paclitaxel is a diterpenoid natural product sourced from trees or cultured cells of the genus Taxus. Demand for this World Health Organisation (WHO) essential medicine typically outstrips supply due largely to its low abundance in Taxus species. Additionally, paclitaxel-based treatments are being developed for other forms of cancer, Alzheimer’s disease, post-heart surgery patients, skin disorders, renal and hepatic fibrosis, limb salvage and inflammation (4).

Plant suspension cultures as a source of paclitaxel. Plant cell suspension culture is largely dependent on the application of dedifferentiated cells (DDCs), derived from a selected plant organ, producing a heterologous culture of many cell types. There are significant issues associated with DDCs. Green Bioactives have developed novel procedures to isolate, culture and subsequently scale-up innately non-dedifferentiated cells, i.e. plant stem cells (PSCs), circumventing issues associated with the application of DDCs (5). Thus, PSCs are an attractive source for paclitaxel production. 

Paclitaxel biosynthesis. Paclitaxel is a complex tetracyclic diterpene, produced in response to attempted microbial infection. The biosynthetic pathway is believed to contain nineteen steps; however, the enzymes required for a number of transformations remain to be identified and the regulatory machinery remains to be discovered (6). The identification of these key biochemical transformations and regulatory mechanisms are critical to facilitate improved cell culture approaches for paclitaxel production, to meet increasing patient demand. 

 PhD student training. This project will provide cutting-edge training in gene-editing technologies, bioinformatics, protein expression, enzymology, biochemistry and plant cell culture technology, orchestrated between national and international collaborations and the biotechnology industry. The student will have access to a myriad of soft skills courses and also a large tranche of academic courses to support their academic and career development. In addition, the student will work closely with industry and spend 6-12 months at the industrial partner, Green Bioactive, embedded within the world-leading Roslin Innovation Centre, providing deep insights into industrial biotechnology. 

This PhD Studentship is part of the IBioIC CTP programme, please visit their webpages to familiarize yourself with training opportunities and requirements this will entail. www.ibioicctp.com

https://www.green-bioactives.com/ 

https://loake.bio.ed.ac.uk/

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