A sustainable production platform for industrially relevant phytochemicals

A clinical trial run by an established UK company has identified two natural plant molecules that inhibit skin inflammation. Unfortunately, the amount of these molecules from the source plant is very low and therefore extraction from the source plant is not feasible on an industrial scale. A potential solution to this problem is to use cultured plant cells, which can been grown on a large scale in multi-tonne bioreactors and optimised for the production of these target plant natural products. Significantly, by employing non-GM genetic approaches, the yield of these target molecules will be significantly increased in these cultured plant cells. This approach will also enable new insights into the biochemical regulation of these molecules within the source plant, potentially leading to further improvements in yield. The target natural products isolated from the generated plant cell lines will also be tested and compared to the same molecules extracted from the source plant in a large number of biomedical-based assays. It is anticipated this work will show the molecules produced from the generated plant cell lines are functionally equivalent to those extracted from the source plant. Once confirmed, and beyond the scale of this particular research project, the company will scale-up the growth of the generated plant cells and isolate the target molecules for their introduction into commercial products.

The global "botanicals" business had sales of $54.6 billion in 2013 and it is expected to reach a value of $90.2 million by 2020, representing a significant market opportunity. The development of plant sourced chemicals with superior sustainability credentials (e.g. low cost of production and minimal environmental impact) is a key long term priority for industry. In this context, an important theme is to identify natural ingredients with anti-inflammatory and anti-oxidant activity for use in topically applied skin products. An internal Unilever screen of plant-based naturals revealed that two natural products that had strong anti-inflammatory and anti-oxidant activity. A subsequent human clinical trial, demonstrated their ability to reduce scalp inflammation and irritation by modifying blood flow. Collectively, these data suggest these chemicals maybe of significant benefit to human health. However, to fully exploit the health benefits and commercial potential of these molecules a sustainable, facile, high yielding and economically viable method for their industrial production is urgently required.

The Loake lab working in combination with Unhwa Corp. have isolated, characterized and cultured on an industrial scale, plant stem cells. These cells exhibit faster growth, reduced cell aggregation, enhanced stress resistance and strikingly increased yields of target chemicals. Thus, CMCs represent a cost-effective, environmentally friendly, sustainable source for the industrial scale production of the identified natural products. In addition, we will apply both classical genetics in combination with cutting-edge gene editing technology to improve the yield of these target molecules in our cultured plant cells. Thus, the Loake lab is a natural fit to work with Unilever to apply this technology platform for the industrial production of these plant natural products.

Academics and researchers: This project will develop new technology platforms in cultured plant cells for the industrial production of two high value plant chemicals. In addition, it will generate important insights into the control of a key plant secondary product pathway and the regulation of cognate enzymes. Data and outputs from this project will therefore be of significant interest to wide areas of the academic community including: industrial biology, synthetic biology, plant biology, plant biochemistry and plant tissue culture.
Implementation: We will publish our findings in high impact journals (open access, where possible). We will also present our findings at national and international meetings.

Product development: A novel technology platform embedded within cultured plant cells will be constructed for the industrial production of two high value plant chemicals that will subsequently be introduced into commercial products for the market.
Implementation: The generated pinocembrin and pinostrobin will feed into preexisting product development pipelines at Unilever and the best product format and formulation for the market determined. A supply chain will then be established. Pilot and commercial scale production of formulations will then occur at one of Unilever's manufacturing bases in the UK e.g. the state-of-the-art manufacturing centre in Liverpool. In order to allow quick market introduction preexisting supply chains will be used as far as possible. A "test-launch" in the UK would be foreseen within 4-5 years after project completion. Hereafter, expansion to other markets (EU, US, Asia) would occur.

Intellectual property: We anticipate significant intellectual property (IP) will be generated during this project relating to the generation of novel plant cell culture lines enabled for the production of two high value plant chemicals. Further, IP may be developed around technological advances associated with the construction of these novel plant cell culture lines.
Implementation: This IP will be protected as appropriate in consultation between Unilever and UoE.

Public awareness: We will engage with the public to communicate the human health, wellbeing and economic benefits of IB and Synthetic biology. This project will also be a good example of how a UK university can collaborate with a UK multinational to create excellent science with significant impact. A priority for BBSRC.
Implementation: UoE has an excellent public relations team and the PI is committed to communicate his research through visits to local, national, and international media.

Post-Doctoral Research Assistant (PDRA): The project offers unique training opportunities in multiple disciplines. The PDRA will be encouraged to further develop his/her writing and communication skills. Furthermore, the PDRA will be supported to develop her/his future applications to become a principal investigator.

Implementation: The PDRA will be trained in a number of cutting edge techniques described in this application. UoE offers a wide range of courses for PDRA career development, including scientific writing and communications courses which the PDRA will be encourage to attend.