Development of an improved biomanufacturing platform for a key pharmaceutical

Paclitaxel is a blockbuster anticancer drug with an annual world market value of ~$3.5 billion.
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. Thus, demand continues to increase. The route of paclitaxel biosynthesis is highly complex and not fully known, precluding production of this key drug by synthetic biology approaches. Further, its regulatory control remains largely undetermined, hindering yield increasing biochemical engineering strategies. Paclitaxel is present in extremely low concentrations, for example 0.001-0.05% (dry weight) in Taxus brevifolia. Thus, eight sixty-year old trees are required to treat one cancer patient. While the total chemical synthesis of paclitaxel was a major scientific breakthrough, this approach to paclitaxel production is not economically viable. Paclitaxel is therefore predominantly sourced from the bark and needles of Taxus species. Due to the slow growth of yew trees and expanding demand, this strategy is not sustainable. In collaboration with industry we have isolated, characterised and cultured, on an industrial scale, plant cambial meristematic cells (CMCs). These stem cells circumvent many of the problems associated with the growth of plant cells on an industrial scale. Significantly, CMCs from yew produce strikingly more paclitaxel than typical cell cultures compromised of dedifferentiated cells (DDCs). To further increase production of this key pharmaceutical from CMCs insights into the regulation of paclitaxel synthesis is required. This project will characterise two key regulatory switches that control the synthesis of this drug. Furthermore, these regulatory switches will be integrated into a novel biomanufacturing production platform for producing enhanced and sustainable production of paclitaxel, securing the supply of this important pharmaceutical.

Paclitaxel is a blockbuster anticancer drug with an annual world market value of ~$3.5 billion. 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. Thus, demand continues to increase. In collaboration with industry we have isolated, characterised and cultured, on an industrial scale, plant cambial meristematic cells (CMCs). These stem cells circumvent many of the problems associated with the growth of plant cells on an industrial scale. Significantly, CMCs from yew produce strikingly more paclitaxel than typical cell cultures compromised of dedifferentiated cells (DDCs). To further increase production of this key pharmaceutical from CMCs insights into the regulation of paclitaxel synthesis is required. This project will characterise the function of two key transcriptional regulators that control the synthesis of this drug by utilising RNA-Seq, chIP-Seq, directed metabolics and 13C-Metabolic Flux Analysis, to identify metabolic targets for biotechnological exploitation. Furthermore, these regulatory switches will be integrated into a novel biomanufacturing production platform for producing enhanced and sustainable production of paclitaxel, securing the supply of this important pharmaceutical.

Who will benefit from this research?

This work will benefit a broad range of academic researchers, the industrial biotechnology and health care industry and patients at a national and international level (as also described above) including:

1. Paclitaxel is a WHO designated essential medicine and demand can not meet supply. The development of a more efficient and sustainable bio manufacturing production platform for this essential
medicine will therefore have a significant positive impact on health care internationally.
2. The Industrial Biotechnology sector in the UK - high value chemicals from plants are recognised as being an important
component of the bioeconomy.
3. The global pharmaceutical industry and more significantly, through the industrial partner, the UK pharmaceutical business, as detailed in the industrial partner supporting statement.
4. The local Scottish bioeconomy, this project will aid the development of a SME embedded in an centre of excellence for UK industrial biotechnology.
5. Policy makers, by providing an exemplar of how the UK academic knowledge base can be translated into new activities related to the UK industrial biotechnology sector.
6. The UK general public, as project outputs will support continued delivery of existing drugs and the production of new drugs that are currently under development.

How will they benefit from this research?

Academic beneficiaries will benefit through new knowledge and understanding of how paclitaxel biosynthesis is regulated
and where the key bottlenecks for future biotechnological innovation may reside. Also, it is envisaged key information related to
the biochemical flux flowing into the end products of taxane biosynthesis will be of significance. This knowledge and tools
forthcoming from this research may therefore be of value to academic and industrial scientists enabling the engineering of diterpenoid metabolism for the production of paclitaxel and potentially a range
of other higher value taxanes.

The bio manufacturing platform developed during this project will benefit the pharmaceutical and health care sectors including in the UK due to the increased efficiency, sustainability and enhanced cost
effectiveness of this bio manufacturing process. As detailed in the industrial partner's letter of support present demand for paclitaxel is rising steeply and numerous novel applications for this
pharmaceutical are also being discovered on a regular basis.