Agronomic processes to optimise galanthamine content of daffodil biomass (AGROGAL)

Lead Research Organisation: National Institute of Agricultural Botany
Department Name: Centre for Research

Abstract

This project aims to build on a previous one-year study undertaken by Alzeim in collaboration with IGER, where the feasibility of Narcissus cultivation was considered under selected environmental regimes and at different harvest dates (Morris et al 05). At that time, the economic returns were forecast to be only moderate, since pharmaceuticals containing galanthamine were protected by patents and API levels were quite low allied to high extraction and transport costs. Formulations containing the API are now generic and the research detailed in this proposal will build on sequential harvesting of different Narcissus tissues, containing significantly higher galanthamine levels, already piloted at Alzeim. The findings and research that will be addressed within this project will seek to further drive down costs by applying the latest biorefinery principles, coupled to entirely novel harvest and extraction regimes, which are then allied to developments in agronomy, choice of plant genetic resources and savings through reduced transport of feedstocks. Sales of the biorefinery 'side-streams' should result in spin-off benefits to the local economy through supply of products to support the tourism industry (perfume, paper, wax). Although focused on the objective of maximising the alkaloid content of daffodils, the research will also provide information that can be directly utilised by flower growers and indirectly by other producers seeking to use plants as sources of secondary metabolites. Specifically, the research will demonstrate the response required from growers to climate change. The innovative qualitative models produced by the research should capture all pre-existing knowledge and provide coherent tests of the results of the various trials. In addition, they should provide the foundation for models for analogous systems. The qualitative models should enable prospective growers to determine the expected returns on their investments.

Technical Summary

This project will build on a previous one-year study undertaken by Alzeim in collaboration with IGER, where the feasibility of Narcissus cultivation was considered under selected environmental regimes and at different harvest dates (Morris et al 05). At that time, the economic returns were forecast to be only moderate, since pharmaceuticals containing galanthamine were protected by patents and API levels were quite low allied to high extraction and transport costs. Formulations containing the API are now generic and the research detailed in this proposal will build on sequential harvesting of different Narcissus tissues, containing significantly higher galanthamine levels, already piloted at Alzeim. The findings and research that will be addressed within this project will seek to further drive down costs by applying the latest biorefinery principles, coupled to entirely novel harvest and extraction regimes, which are then allied to developments in agronomy, choice of plant genetic resources and savings through reduced transport of feedstocks. Sales of the biorefinery 'side-streams' should result in spin-off benefits to the local economy through supply of products to support the tourism industry (perfume, paper, wax). Although focused on the objective of maximising the alkaloid content of daffodils, the research will also provide information that can be directly utilised by flower growers and indirectly by other producers seeking to use plants as sources of secondary metabolites. Specifically, the research will demonstrate the response required from growers to climate change. The innovative qualitative models produced by the research should capture all pre-existing knowledge and provide coherent tests of the results of the various trials. In addition, they should provide the foundation for models for analogous systems. The qualitative models should enable prospective growers to determine the expected returns on their investments.

Planned Impact

This partnership is very well placed to provide the necessary know-how to enable farmers to produce the crop to required industrial specifications. NIAB has members associated with high affiliation of arable and horticultural growers. Alzeim has a well co-ordinated network of growers and farm specialists within Wales with whom the Consortium will place contracts and ensure a scientifically- led development of the crop. Grower guides and demonstrations plots will be made available via specialist meetings and workshops, such as Members Days at NIAB and choice of cultivars and production methods will be published as part of the NIAB publication set when the crop is at a suitable stage of development. Meetings and workshops will be held to demonstrate the potential of this crop to meet the requirements of farmers, processors and the food companies. These will include the NNFCC at York and other bodies. It is probable that upland growers will be the first to participate and benefit, but when the `Black Mountains Effect' is understood it is hoped that growing can be extended to other altitudes and areas.

Publications

10 25 50
 
Description The project and subsequent work funded by innovateUK was able to show that galanthamine can be produced from daffodils cultivated in stressed upland sites and this can fprofide hich quality feedstocks that are able to significantly improve quality of life for people suffering from Alzeimers Disease.
Alhough Agroceutical has received interest from large pharmaceutical companies, as a small rural farm, they don't have the resources to straight away provide the significant amounts of galanthamine that would be required from a partnership like this. Agroceutical discovered that these organisations require 100s of kilos on the shelf to give Agroceutical a sales contract. But, in order to up-scale production at the farm, they first need the financial stability that a sales contract would provide.

The longer term aim is to provide a better future for Alzheimer's patients. Agroceutical has always, however, been keen to benefit welsh farmers as part of the production system. This was difficult because large pharmaceuticals are not keen to work with farmers and demand large production volumes. Secondly, for small welsh farmers with low numbers for cattle and sheep farming in Wales, the resultant subsidy is invariably being greater than the profit line.

This is what led Agroceutical MD K Stephens to look at how the farm might also produce natural pharmaceutical products, creating an additional income as opposed to an alternative one, so traditional farming could be maintained. Significant development of the idea has resulted in a sustainable, efficient and low-cost method to producing galanthamine. Kevin believes he now has a working production model. This is provided through a partnership with a small Canadian research company that works on a different scale to the major pharmaceutical companies. Engaging with smaller companies is potentially economic feasible, unlike large pharmaceuticals that request very large quantities, beyond the abilities of a co-operative of welsh farmers. This small company only want kilos to start with, not 100s of kilos. Some might see this as a disruption to the model of traditional pharmaceuticals, but for another industry - farming - Kevin's methods could also provide an element of stabilisation that so many rural farmers seek.
Exploitation Route The work has now led to production of galanthamine and to the benfit of upland welsh farmers also producing livestock in a dual cultivation system
Sectors Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://www.agroceutical.com/default.html
 
Description This project focussed on the need to understand how plant genetic resources used for the production of bio-pharmaceuticals is impacted by environmental perturbations. In particular; it aimed to quantify which environmental factors impact on the active ingredient and whether this knowledge could be used to improve predictable economically viable production of this vital pharmaceutical. The crop of interest is daffodil and the (active ingredient) AI is Galanthamine; used in the treatment of Alzheimer's. The impact of this work is significant in that it has enabled the industry partners to inform and expand their commercial outputs. The lead partner of this project (Agroceutical) area an SME that was set up to consider precisely how the crop responds to climatic and other abiotic conditions alongside development of novel extraction methods; using both bulb and leaf material to supply pharmaceutical companies with pure extracts. The project has led to findings relating to the importance of geographical site, temperature, light quality (UV:IR) pH and weather patterns (especially wind) on the levels of galanthamine that can be extracted from tissues. The work at NIAB, which was completed at field scale, complimented the work at Bangor University, which was undertaken using hydroponics under very controlled conditions. NIAB and Agroceutical are now developing a 'Growers Manual' for precise delivery of improved cultivation practices with close participation of farmers. Furthermore additional work has been initiated in which Agroceutical are analysing both Galanthamine (and other pharmaceutical alkaloids) and soil physico-chemistry. This is being built into the data set including latitude, altitude, etc, This useful body of data is was necessary to both target commercial growing locations, and will also provide some very interesting information to supplement the LINK programme's analysis of agronomic factors. Additional selection work undertaken at NIAB in collaboration with second industry partner (New Generation Daffodils) has enabled us to identify improved germplasm and we anticipate that this will lead to sales into this niche market. The results of this project have now been used to set up a new Galanthamine processing plant in south Wales by the Lead Partner. A small factory has been set up in the past six months in 2016- 2017 with pharmaceutical markets secured. The new factory is now producing pharmaceutical grade galanthamine and other useful extracts from the crop are being investigated. The website is up and running and the company newly named since the inception of the project as Agroceutical, is now producing galanthamine in collaboration with local farmers. The work has recently received government help in enabling sheep farmers to diversify to production of daffodil feedstocks to this pharmaceutical product
First Year Of Impact 2019
Sector Agriculture, Food and Drink,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology,Other
Impact Types Societal,Economic

 
Description Support for welsh farmers via the 'Business Wales' on line support.
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Working with Agroceutical Ltd, The local welsh government has been providing advice to farmers on how to improve income in upland regions. This work and training has emerged from the knowledge that daffodils - the feedstock for galanthamine production - cam be planted among sheep pastures. The bitter unpalatable nature of the plants prevents their predation leading to two economic outcomes for hill farmers.
URL https://businesswales.gov.wales/farmingconnect/skills-and-training/e-learning/agroceuticals-daffodil...
 
Description Talk and discussion with government funding organisations and independant charity funders
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
Impact Change of acceptability of Galanthamine based pharmaceuticals for treamemnt of Alzheimer's disease in the National Health Service as determined by NICE
 
Description ?HVCfP Network BIV Project
Amount £30,000 (GBP)
Funding ID HVCFP-BIV-JUL14-001 
Organisation Royal Agricultural University (RAU) 
Sector Academic/University
Country United Kingdom
Start 07/2014 
End 07/2015
 
Description Galanthamine from Smart BioProcessing of Daffodils TSB Project (131150) 2013-05-01 - 2014-04-30
Amount £35,000 (GBP)
Funding ID (131150) 2013-05-01 - 2014-04-30 
Organisation Innovate UK 
Sector Public
Country United Kingdom
Start 05/2013 
End 04/2014
 
Title Cultivation System for Daffodil 
Description This research resulted in an alternative method for cultivating daffodils, which ensured that the quantity of the key pharmaceutical component - galanthamine (GA) - was optimised. There were a number of components in the improved system, which can only be described in outline due to some confidentiality issues. 1) Cultivation under environmentally stressful conditions causing the crop plant to increase GA content; in particular in windy upland situations 2) harvest of foliar components just prior to full flowering 3) sequential harvesting of leaves followed by a 'fermentation' 4) final harvest of bulbs once exhausted The cultivation system was also altered to enable co-cultivation with grazing; since the daffodil material is highly unpalatable, sheep and other livestock avoid this material, enabling soil conservation and a more sustainable use of these upland pastures 
Type Of Material Biological samples 
Year Produced 2015 
Provided To Others? No  
Impact ability of more upland farmers, especially in Wales to consider cultivation of this crop, when it would not otherwise be economically viable 
URL http://www.agroceutical.com/growers.html
 
Description Brought Agroceutiicals ltd together with a new company Bioextractions 
Organisation BioExtractions (Wales) Ltd
Country United Kingdom 
Sector Private 
PI Contribution The original industrial partner Alzheim (now changed to Agroceuticals ltd with an additional firm looking at novel methods for identifying and extracting other compounds: BioExtractions (Wales) Ltd. have the expertise and systems that can help you do it. They provide a contract service to the pharmaceutical, agrochemical, chemical, food industries or any industry that needs to separate key compounds from their base complex mixtures. They are now connecting with NIAB and additional extractions from the feedstocks being considered
Collaborator Contribution The main CEO of Agroceuticals have joined the firm as a consultant and are working closely with them to improve extracted material they are working to market. The collaboration has further extended to consideration of rosemary extracts. BioExtractions (Wales) Ltd. is based on the Tafarnaubach Industrial Estate in Tredegar, Wales where they have a 10,000 sq/ft warehouse and laboratory facility; this was a vital next step for Agroceuticals in terms of up-scaling Galanthamine extraction
Impact still confidential
Start Year 2017
 
Description Collaboration with Royal Agricultural University Cirencester 
Organisation Royal Agricultural University (RAU)
Country United Kingdom 
Sector Academic/University 
PI Contribution Interaction with highly focused controlled growing systems at Bangor University Interactions with farmer focussed - practical outcomes for growers take up of the research results Potential new contributions to teaching and learning by staff at NIAB on RAU MSc courses being delivered in 2017
Collaborator Contribution RAU has provided assistance with sample analysis and expertise towards this end. The University has a good and increasing reputation in agricultural science and innovation and will be setting up an MSc course within the next year to specifically cover issues such as High value end products; Pharmaceuticals; Biochemical analyses of active ingredients; Patenting law; etc
Impact Optimisation of extraction and analysis procedures Consideration of tissue and micro-propagation Link with Chinese pharmaceutical industry
Start Year 2014
 
Description Mechanical production improvements in biomass preparation 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Interaction with agricultural engineers to ensure grower needs are accurately articulated to enable development of improved specialist equipment
Collaborator Contribution Dr Kevin Wall CEng FIChemE Research Fellow has been instrumental in defining the mechanical needs and development required in preparing a range of types of biomass material harvested from both bulls and leaves of daffodils collected in the field To help develop machinery for daffodil planting, green top harvesting and lifting and a 'mobile pre-processing unit'
Impact Development of machinery for daffodil planting, green top harvesting and lifting and a 'mobile pre-processing unit' Improved harvesting of foliage Networking and Knowledge exchange with University of Manchester
Start Year 2013
 
Title Production of pharmaceutical grade Galanthamine 
Description Small scale industrial production of purified Galanthamine has been completed by the lead industry partner and a contract for sales secured 
IP Reference  
Protection Protection not required
Year Protection Granted 2015
Licensed Commercial In Confidence
Impact Improved UK source of vital pharmaceutical for future treatment of disease
 
Title Refined Galanthamine 
Description The product has been refined to the requirement of industry and a buyer has been found 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2015
Development Status Under active development/distribution
Impact Further impacts will arise once harvesting and processing is further improved 
 
Company Name Agroceutical 
Description After a tough period when business angels pulled out Agroceutical was established using some of the materials from Alzeim Ltd. Using the results of the BBSRC funded project together with a subsequent project funded by Innovate UK the company has in the last 6 months re-established itself at a site in south Wales; a new factory has been set up and galanthamine is being extracted from daffodils grown in Wales and south west England 
Year Established 2012 
Impact Pharmaceuticals being used in the UK to treat Alzheimer's disease
 
Description Directors VIP Day 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Specialist day for major industry and other stakeholders in agricultural research and development; talks and discussions over the course of the day
Year(s) Of Engagement Activity 2014,2015
 
Description Farmer - NIAB open day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Talks to groups of Farmers, Policy Makers, Industry and researchers over the course of a day and a half; description of the research funded by BBSRC and the anticipated outcomes- with provision of feedback and views from the participants
Year(s) Of Engagement Activity 2013,2014,2015,2016
 
Description Improving biopharmaceutical content from crops 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Delegation from the University of New Jersey USA that were specifically concerned with biopharmaceutical crop research - the talk and following debate workshop centred on use of Artemisia annua for artemisinin production and daffodils for galanthamine production
Year(s) Of Engagement Activity 2016
 
Description Lecture and tour University of TA 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Two hour lecture and tour with hands on consideration of growing material
Year(s) Of Engagement Activity 2016
URL http://www.innovationfarm.co.uk
 
Description Lecture to University of Nottingham MSc students 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact This talk was part of a full day workshop visit for the students; discussion was useful and stimulating
Contact was made with a group working on comparable areas of interest

A follow-up visit next year was suggeted
Year(s) Of Engagement Activity 2013,2014
 
Description Lecture to University of the Third Age 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Talk sparked considerable discussion and questions
The participants although mainly retired are part of farming families and involved in chairing local boards so have some influence in the industry


Useful contacts were made within local farming community
Year(s) Of Engagement Activity 2014
 
Description Maximising Galanthamine production for treatment of Alzeimers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Half day talks and view of demonstration material; 45 MSc and PhD students visited from the University of Nottingham to see impact of research
Year(s) Of Engagement Activity 2016
 
Description NIAB Innovation Farm demonstration of research projects - open days throughout the year 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Many questions and discussion about the benefits of the project. The visitors arrive in groups of between 5 and 50 most composed of technically expert growers and practitioners with links directly to industry. In the two groups that involved children impact was more geared to understanding the need for research and the importance of outcomes

none
Year(s) Of Engagement Activity 2012,2013,2014,2015,2016
 
Description Open day event for farmers 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talking to farmers growers and agronomists visiting an annual open day; this led to questions relating to growing requirements, suitability of the different regions for cultivation etc

Engagement with new grower groups
Year(s) Of Engagement Activity 2013,2014
 
Description Student Lecture and Tour Nottingham University 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Lecture and Tour of growing material
Followed by mediated discussion forum
Year(s) Of Engagement Activity 2016
URL http://www.innovationfarm.co.uk