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

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. Galanthamine 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. Galanthamine is mainly produced from plants, as although chemical synthesis is possible, it is difficult and expensive. Galanthamine is the natural plant alkaloid used to produce the pharmaceutical product galanthamine. 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 galanthamine. The annual global consumption of galanthamine 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 galanthamine 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) established 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 acquire, re-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.

Galanthamine is a pharmaceutical compound that has been an approved Alzheimer's Disease (AD) treatment since 1998. Galanthamine can be synthesised chemically but it is a difficult and expensive process. Producing galanthamine from galanthamine extracted from plants is more cost effective, but supplies are limited. Daffodils are the only economically feasible plant source for cultivation in the UK. Research (Sustainable production of the natural product galanthamine: Defra project: NF0612, 2006) established that growing daffodils in upland areas triggers a 50% higher yield of galanthamine (the 'Black Mountain effect'). This proposal 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.

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.