Yellow Gold: Innovative systems for sustainable daffodil-derived galanthamine production in the uplands.

Lead Research Organisation: Aberystwyth University
Department Name: IBERS

Abstract

The number of people suffering from dementia is large and growing at a considerable rate. In 2010, there were over 35.6 million dementia sufferers worldwide and 4.6 million cases are diagnosed each year. Alzheimer's Disease (AD) accounts for between 50 and 75% of these cases. Galantamine has been approved by the US Food and Drug Administration, the UK Medicines and Healthcare Products Regulatory Authority and the European Medicines Agency as an AD treatment since 1998. Galantamine is mainly produced from plants, and although chemical synthesis is possible, it is difficult and expensive. Galan/th/amine is the natural plant alkaloid used to produce the pharmaceutical product galan/t/amine. It is currently being extracted from daffodils/Narcissus (in central and western Europe), Leucojum (in eastern Europe) and Lycoris (in China). However, with the exception of daffodils the source plants are wild flowers not suitable for agricultural exploitation due to limitations in either resources or research. Thus daffodils are the only economically-viable world-wide source for galantamine. The annual global consumption of galantamine is currently constrained to 3-4 t/yr by existing production levels, but published figures predict the potential global market could be nearer 40 t/yr. Independent reports project the competitive Active Pharmaceutical Ingredient price for galantamine drugs to remain between £15,000 - £18,000/kg in the medium term.

The UK uplands are characterised by poor growing conditions brought about by a combination of factors including: low temperatures; exposure to wind; high rainfall; winter frosts; thin, stony soils; and a shortage of major nutrients. Consequently agricultural production is generally limited to grassland-based beef and sheep systems that are currently heavily reliant upon Government support payments to be economic. However, previous research ('Sustainable production of the natural product galanthamine'; Defra project NF0612) esblished that the environmental challenges associated with upland areas trigger a 50% higher yield of galanthamine in daffodils that are grown there when compared to those grown in lowland conditions. Daffodils grown for galanthamine production therefore offer a novel, potentially high value crop for UK upland farmers that could provide an important new income stream, increasing their economic resilience. However, for this to happen, underpinning research is required to evaluate and overcome any problems associated with integrating daffodil production into existing pastoral based farming systems. This project will design, test and evaluate machinery for planting bulbs under long-term grass leys and selectively harvesting the subsequent green daffodil material. Field-scale agronomy trials over a 4 year period will assess establishment rates and the extent to which these are influenced by seasonal variation. Full-scale production trials will quantify the impact of incorporating daffodil production into grazed pastures on animal performance and the stock carrying capacity of the land. The extent to which fertiliser inputs influence the competitive ability of the daffodils and the yield of galanthamine obtained will also be determined in order to develop protocols which optimise simultaneous production of galanthamine and livestock from hill and upland farms. Growing daffodils in this way will ensure that the ecosystem services associated with grazed grasslands in the uplands are maintained.

Technical Summary

In 2010, there were over 35.6 million dementia sufferers worldwide and 4.6 million cases are diagnosed each year. Alzheimer's Disease (AD) accounts for between 50 and 75% of these cases, and galantamine has been approved as an AD treatment since 1998. Galantamine is mainly produced from plants, as although chemical synthesis is possible, it is difficult and expensive. Galan/th/amine is the natural plant alkaloid used to produce the pharmaceutical product galan/t/amine. It is currently being extracted from daffodils/Narcissus (in central and western Europe), Leucojum (in eastern Europe) and Lycoris (in China). However, with the exception of daffodils the source plants are wild flowers not suitable for agricultural exploitation due to limitations in either resources or research. Previous research has shown that the environmental challenges associated with upland areas trigger a 50% higher yield of galanthamine in daffodils that are grown there when compared to those grown in lowland conditions. Daffodils grown for galanthamine production therefore offer a novel, potentially high value crop for UK upland farmers that could provide an important new income stream, increasing their economic resilience. This project will deliver a new approach for producing daffodil-derived galanthamine based on integrating daffodil growing into existing upland pasture while avoiding the need to plough the field. This will increase the economic sustainability of hill farming by providing farmers with a high value crop while maintaining traditional farming systems in the upland areas. The project will develop the required machinery, quantify the yield of galanthamine achievable, and assess the impact on sheep performance of incorporating daffodil production into grazed pastures. Growing daffodils in this way will ensure that the ecosystem services associated with grazed grasslands in the uplands are maintained.

Planned Impact

The project is designed to deliver impact at the industry level and industry leadership. The worldwide AD drug market is currently estimated to exceed $4.2 billion and is growing rapidly due to the aging demographic. Sales of galantamine are currently in excess of $500 million per year, with the clinical need growing at 14% per year in the UK alone. The UK is already the world's largest producer of daffodil and narcissus cut flowers and also produces about half the world's daffodil bulbs, and there is now a clear opportunity to add galanthamine production to the UK's world-leading daffodil-based industries. The knowledge gained from these studies will be disseminated to the academic community by publications in high quality journals and presentation at conferences and meetings; to the agricultural industry through demonstration days and articles in the farming press; and to the general public via agricultural shows and events in target upland regions (e.g. the Royal Welsh show, Builth Wells) and popular media including newspapers and television programmes.

The main beneficiaries of his project will be:

Economic
From the project AP will gain proven protocols for environmentally sustainable galanthamine production that it can provide to upland farmers to grow daffodils under contract, allowing it to consolidate its position as the lowest cost galanthamine supplier in the market. It will also achieve a consistent chain of supply of galanthamine through more farmers being motivated to grow daffodils, allowing the company to increase galanthamine production, and thus be better able to service the demand in this supply constrained market place.

Upland farmers will have an important new income stream, increasing their economic resilience, whilst maintaining the cultural landscape (and associated tourism-related income) associated with upland areas.

Social
Additional income for upland farmers will in turn support the wider rural community in areas which are at risk of de-population, while reduced reliance on agricultural support payments will benefit taxpayers. The concept of sustainable intensification has particular resonance for upland areas. Focusing livestock production in such areas turns forages and poor-quality feeds into human edible products while freeing up better quality land for arable food and biomass crop production. Integrating daffodil growing within pasture rather than replacing livestock systems should enable galanthamine production to be achieved without significantly reducing or affecting the land area available for food production.

From the project AD sufferers will get access to a new, economically viable source of one of the few drugs of proven efficacy. Dementia is one of the most significant social and health crises of the 21st century, with a new case of dementia diagnosed every 4 seconds. In total, dementia is estimated to cost the UK £23 billion a year, with projected costs for 2038 expected to be in the region of £50 billion. Making galantamine accessible to more AD sufferers, particularly early-stage sufferers, has the potential to generate huge social, as well as cost-saving benefits.

Environmental
Currently daffodil-derived galanthamine production requires annual ploughing up of pasture. This results in release of greenhouse gases, which would be particular undesirable from carbon-rich upland soils. The topography and climate of most uplands areas means that they would also be at risk of erosion if ploughed. Integrating daffodils into permanent pasture rather than ploughing it up will ensure that the ecosystem services associated with grazed grasslands in the uplands, such as carbon capture, water management and biodiversity, are maintained.

Publications

10 25 50
 
Description We have established that daffodils can be successfully established under permanent pasture in upland areas using purpose-built machinery. The green material (leaves and flowerstems) of the plants have been harvested in spring, and while biomass yields to date have been lower than anticipated, results to date suggest the concentrations of galanthamine (the chemical produced by the plant which can be used to treat Alzheimer disease) have been higher. Following harvest ewes and their lambs were turned out onto the plots. Regular assessments of sheep health and performance have shown that neither are compromised by the presence of daffodil plants. These findings indicate dual-cropping systems which integrate galanthamine production from daffodils with traditional pasture-based sheep production in upland areas are possible. Agronomy measurement over multiple seasons have shown that a similar overall yield is achieved if biennial rather than annual harvesting is undertaken. Likewise, harvesting can be delayed until the second year after establishment without a reduction in overall yield.
Exploitation Route Little is understood of the biochemical pathways within the daffodils which produce galanthamine (which is one of 300 alkaloids produced by the plant). We are interested in characterising these and investigating the extent to which they can be manipulated to increase galanthamine yields. Data from the range of experiments undertaken during this project reveal considerable plant-to-plant variation in galanthamine concentrations under the same growing conditions. The sources of this variation should be explored and defined in order identify strategies for increasing galanthamine concentrations and their consistency.
Sectors Agriculture, Food and Drink,Chemicals,Pharmaceuticals and Medical Biotechnology

 
Description The findings from our research have formed part of the justification for funding put forward by the Commercial Partner in the InnovateUK project when applying for a Welsh Government RDP-funded Supply Chain Efficiency grant. The grant has been awarded, and is being used to create a growers network in Wales.
First Year Of Impact 2018
Sector Agriculture, Food and Drink
Impact Types Economic

 
Description Knowledge Transfer Partnership
Amount £54,413 (GBP)
Funding ID No KTP009998 
Organisation Government of Wales 
Sector Public
Country United Kingdom
Start 11/2015 
End 10/2016
 
Description Poster presentation at European Grassland Federation Conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation and related conference proceedings on the impact on sheep performance and welfare of incorporating daffodils into permanent pasture. The conference was attended by more than 300 scientists, advisors and policy makers from across Europe.
Year(s) Of Engagement Activity 2018
 
Description Presentation at 19th EGF Symposium 2017: Grassland resources for extensive farming systems in marginal lands: major drivers and future scenarios; 07/5/2017 - 10/05/2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Offered talk on "Incorporating daffodil-derived galanthamine production into upland grassland systems" given to a audience consisting predominately of grassland scientists from across the EU. The presentation generated a lot of questions, and further information was sought by delegates.
Year(s) Of Engagement Activity 2017
 
Description Presentation at the Hay Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact An hour-long event at the Hay Festival on "Engineering Landscapes: past, present and future innovation for upland farming" consisted of a 45 min presentation mixing history, science and poetry, followed by Q&A. There was considerable interest from the audience in the research covered, including this project.
Year(s) Of Engagement Activity 2019
 
Description Presentation on project and field visit for visitors attending research centre Open Day. 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Approximately 70 - 80 people attend the Open Day each year. There was lots of interest, particularly form the farming community, with many pertinent questions asked. Fact sheets were prepared and available to all.
Year(s) Of Engagement Activity 2016,2017
 
Description Presentation to delegation from Welsh Government 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact A talk on the project was included in the itinerary for an 'away day' for staff from the Land, Nature and Forestry Division within Welsh Government.
Year(s) Of Engagement Activity 2016
 
Description Pwllpeiran Facebook page 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Pwllpeiran has it's own Facebook page that covers on-going activities at the centre, and which has a total of over 600 regional, national and international followers. On average two posts per week are added to the page and these include updates on this project. Given the number of shares which posts generally receive the reach for an individual post is often 1000-1500 and on occasion can be over 2000.
Year(s) Of Engagement Activity 2017,2018
URL https://www.facebook.com/pwllpeiran/
 
Description Pwllpeiran Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact As part of Open Day activities at the research centre delegates were given in introductory talk followed by a tour of related experimental plots. There was a lot of interest in the project given current uncertainties about the future of farming in marginal areas and the need to improve grassland productivity and persistency, with many follow-up questions asked. Fact sheets were prepared and available to all.
Year(s) Of Engagement Activity 2018
 
Description Visit by MP 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Visit by Ben Lake MP to find out more about current research underway at the Centre. Yellow Gold was one of the projects focused on given the potential to improve farming incomes in the constituency. The project was covered in a related press release from the MP's office.
Year(s) Of Engagement Activity 2018
URL https://www.westwaleschronicle.co.uk/blog/2018/08/22/ceredigion-mp-commends-pioneering-work-at-pwllp...
 
Description Visit by Options Explorer secondary school pupils 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Twenty pupils visited as part of a week long course run by the University's Centre for Widening Participation. The goal was to encourage pupils who might not be expected to go on to higher education to consider opportunities within STEM. A talk and tour led to lots of discussion and questions.
Year(s) Of Engagement Activity 2018
 
Description Visit by students from Royal Agricultural University 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact Visit from a group of MSc students studying Sustainable Agriculture and Food Security. Lots of interest in alternative management options for marginal area.
Year(s) Of Engagement Activity 2018