Understanding the regulation of alkaloid biosynthesis in opium poppy and breeding new varieties

Lead Research Organisation: University of York
Department Name: Biology

Abstract

Plants have evolved to produce a vast array of complex chemical structures to fight off attacks from herbivores and pathogens and to protect themselves from often hostile environments. These chemical structures also provide plants with medicinal properties that human civilisation has relied on for millennia. Opium poppy is one of the most important medicinal plants in the world and represents the largest single source of natural products used by the pharmaceutical industry. Opium poppies produce opiate alkaloids such as morphine and codeine, which are one of the main classes of painkiller drugs. The chemical structures of these opiate alkaloids are very complex and plants remain the best factory for their production. Opium poppy also produces hundreds of other alkaloids and these have been a source of several other drugs. Opium poppy is commercially grown using broad acre farming methods and the crop is harvested mechanically and shipped to factories for extraction of the high value chemicals. Pharmaceutical companies such as GlaxoSmithKline and Johnson & Johnson have their own production systems for production of opiate alkaloids from opium poppy. Our group in the Centre for Novel Agricultural Products at the University of York have been working with GlaxoSmithKline to develop new varieties of poppy that produce more of the morphinan alkaloids such as morphine and codeine.
We have also been investigating how opium poppy produces noscapine, an anti-tumour alkaloid that stops human cells dividing. Noscapine has been used as a human cough suppressant for decades. Its effectiveness in tackling various forms of cancer has been demonstrated more recently, and early stage clinical trials are in progress in the USA. We particularly wanted to discover how noscapine is made in opium poppy as this would help us to breed new varieties that make more of it and also to gain insight into related molecules that may also have useful pharmaceutical activity. Our work led to a major breakthrough that was published recently in the leading journal Science (Winzer et al, Science 2012, 336:1704-8). By comparing opium poppy varieties which make noscapine with those that do not we discovered that the pathway for synthesis of noscapine is controlled by a complex cluster of ten genes encoding five different enzyme classes. This is the most complex gene cluster ever found in plants and provides invaluable insights into the process of gene duplication and re-organisation driving cluster evolution.
This proposal builds on our exciting breakthrough and aims to establish if the gene cluster is also present in other related species that also make noscapine. This will provide new insight into the mechanisms and processes involved in gene cluster evolution. Elucidating details of the biochemical pathway we discovered for noscapine biosynthesis will make us better able to design strategies for improved production of noscapine and related molecules. Noscapine is produced by a separate branch of the alkaloid biosynthesis pathway to the one used to produce morphine and codeine. What regulates the flow of molecules into these different branches is not understood and we now have the tools and knowledge to address this important question for the first time.
Answering these questions not only adds to our knowledge of the most important medicinal plant in terms of natural product feedstock for the pharmaceutical industry, it also provides us with the knowledge platform and tools to develop new varieties of opium poppy that are optimised for production of alkaloids such as noscapine, morphine and codeine. The final objective of this proposal is to use molecular breeding methods to develop new varieties of opium poppy with optimised levels of key opiate alkaloids for the benefit of the pharmaceutical industry and the UK industrial biotechnology sector.

Technical Summary

Papaver somniferum (opium poppy) remains one of the richest sources of natural products for the pharmaceutical industry. We recently reported that opium poppy contains a cluster of ten genes encoding five different enzyme classes responsible for the biosynthesis of noscapine (Winzer et al, Science 2012, 336:1704-8), an antitumour alkaloid that is currently in clinical trials in the USA. Our discovery of the ten gene cluster in opium poppy allowed us to rapidly elucidate the main steps in the previously unknown noscapine biosynthetic pathway. In the current proposal we will use a combination of metabolite profiling and next generation sequencing to establish if related species that also produce noscapine have an equivalent gene cluster, allowing us to gain new understanding about the evolution of gene clusters in higher plants. We will also characterise those remaining steps in the biochemical pathway which are not fully understood using a combination of in-planta based Virus Induced Gene Silencing (VIGS) and in-vitro characterisation of enzymes obtained by heterologous expression. Major questions remain about the regulation of flux into the noscapine branch versus the morphinan branch of alkaloid biosynthesis and to address these we will use a combination of RNA sequencing, quantitative proteomics and isotope labelling followed by deep metabolite profiling to pinpoint the regulatory steps. In order to learn more about the control of flux and to develop new poppy varieties we will cross noscapine producing poppies into a number of mutant backgrounds that produce altered levels of morphinan alkaloids including morphine, codeine, thebaine and oripavine. This will result in new varieties producing novel combinations of opiate alkaloids that are required by the pharmaceutical industry. The research programme will therefore contribute both fundamental knowledge and improved sustainable feedstocks for the pharmaceutical industry.

Planned Impact

Who will benefit from this research?
In addition to benefiting a broad group of academic researchers as detailed above, this research will also benefit a wider group including:
1. The pharmaceutical industry and in particular the industrial partner on this proposal, GlaxoSmithKline.
2. The Industrial Biotechnology sector in the UK - high value chemicals from plants are recognised as being an important component of this sector - and therefore the UK economy.
3. Policy makers who require examples of how the UK knowledge base can be used to attract new activities into the high value chemicals from plants /industrial biotechnology sector in the UK
4. The general public - the outputs of this work will lead to the sustainable production of feedstocks to support continued delivery of existing drugs and the production of new drugs that are currently under development.

How will they benefit from this research?
Global demand for the opiate alkaloid, noscapine, presently exceeds supply. Currently the global manufacture of noscapine is focused on its recovery as by-product from opium produced mainly in India. Opium supply has reduced over time due to inefficient production methods (lancing poppy capsules), diversion concerns and complex downstream processing requirements. The majority of major opiate alkaloids (morphine, codeine, thebaine and oripavine) are produced through broad acre farming of poppies followed by chemical processing occurring on the deseeded harvested dry poppy capsule (poppy straw). The production of a high yielding noscapine poppy that can be processed as poppy straw is the key to unlocking a new and more secure supply chain for noscapine. With noscapine and noscapine derivatives presently undergoing Phase 1 and Phase 2 clinical trials as a low toxicity anti-cancer agent there is a global need for the development of a new noscapine supply chain.
In addition to a focus on noscapine, the GlaxoSmithKline (GSK) Opiates Business is presently pursuing a number of activities centred on a northern hemisphere base. Several of these projects have arisen from the strategic focus on new business opportunities for the Opiates Business. These are seen as priority business outcomes for GSK supported from the proposed R&D programme with the Centre for Novel Agricultural Products (CNAP) at the University of York:
i) Development of a secure global poppy straw based supply chain for the economic production of the opiate alkaloid, noscapine
ii) Northern hemisphere (UK & Europe) poppy crop trials and poppy crop sourcing options
iii) Development of a supply chain for the production of the opiate alkaloid, noscapine
iv) Chemical extraction of poppy actives and development of a European based opiate raw material supply
v) Advancing the fundamental understanding of poppy plant biochemistry and plant breeding to increase commercial poppy productivity and identify new pharmaceutical product opportunities
vi) Underpinning the GSK global opiate R&D footprint, providing indirect support for a planned technical transfer to the UK & Ireland of some opiate manufacture and the development of value added opiate products.
The Department of Business Innovation and Skills has identified Industrial Biotechnology as having significant growth potential for the benefit of the UK economy over the next 15 years. Developing centres of excellence that facilitate specific aims such as high value chemicals from plant biomass for use in the pharmaceutical sector has been identified in the roadmap as necessary to fulfil the potential of Industrial Biotechnology in the UK. The outputs of this research programme will contribute significantly to such aims by facilitating the development of industrial biotechnology to the benefit of the UK economy and the economic competitiveness of the UK in this important growth area.
 
Description We made a major genetic discovery that uncovers key tool for morphine production in poppies that may pave the way for more effective painkillers. The discovery, published in the leading journal Science in 2015, revealed the long sought after gene that is seen as a critical gateway step in the synthesis of the morphinan class of alkaloids, which include the painkiller drugs morphine and codeine. The gene, called STORR, is only found in poppy species that produce morphinans. The STORR gene evolved when two other genes encoding oxidase and reductase enzymes came together millions of years ago. The resulting gene fusion plays a key role in production of morphine. The breakthrough came when we identified poppy plants that were not able to produce morphine or codeine but instead accumulated another compound called (S)-reticuline. These plants were found to carry mutations in the STORR gene. These mutations cause a roadblock in the pathway to morphine production in poppy plants. We were able to show that the non-mutated wild type gene can overcome the roadblock, by expressing it in yeast cells.

The naturally occurring opiates of the morphinan class of alkaloids include morphine, codeine and thebaine. Morphine and codeine can be directly used as analgesic painkillers. Thebaine is widely used as the starting point for synthesis of a number of semi-synthetic opiates including hydrocodone, hydromorphone, oxycodone, and oxymorphone. Thebaine is also used to synthesise the opioid antagonist naloxone, which is used to counter the effects of opiate overdose. The discovery of the STORR gene completes the suite of genes thought to be required for production of morphinans in microbial systems. Plants remain a proven and efficient production system delivering Kg amounts per hectare of active pharmaceutical ingredients (API) at relatively low cost. Discovery of the STORR gene has enabled an alternative microbial based supply route to be evaluated.

We also sought to establish if the ten-gene cluster for noscapine biosynthesis we had discovered previously evolved before or after Papaver somniferum speciation. Following the discovery of STORR (see above) we included the STORR gene fusion and evolution of morphinan biosynthesis in our analysis. Morphinan biosynthesis also appears to have first arisen in the genus Papaver, and only those species found to express full length STORR accumulate morphinan alkaloids. These findings support our hypothesis that the formation of the gene fusion was a crucial event in the evolution of morphinan alkaloid biosynthesis. To provide a solid foundation for further evolutionary studies and address the lack of draft genome sequences in the genus Papaver, we, together with colleagues from the Wellcome Trust Sanger Institute, UK and Xian Jiaotung University, China, produced a high quality draft assembly of the opium poppy genome, which was published in Science (Guo et al., 2018). The publication provided new insight into the evolution of alkaloid metabolism, including the likely origin of the STORR gene fusion event and a clustered arrangement of 15 coordinately regulated genes associated with both noscapine and the morphinan class of alkaloids.
Evolutionary origins of BIA metabolism have been investigated as described in a recent publication from the Graham lab entitled 'Over 100 million years of enzyme evolution underpinning the production of morphine in the Papaveraceae family of flowering plants'. This work shines a light on how evolution can give rise to complex chemicals that human civilisation use as medicines.
Exploitation Route Discovery of the STORR gene completes the set of genes needed for genetic engineering of morphine production in microbes such as yeast. Whether or not this can compete commercially with plant based production remains to be seen.

Together with colleagues from the Wellcome Trust Sanger Institute, UK and Xian Jiaotung University, China, we produced the first high quality draft assembly of the opium poppy genome, which was published recently in Science (Guo et al., 2018). This provides a solid foundation for further evolutionary studies by the wider science community.
Sectors Pharmaceuticals and Medical Biotechnology

URL http://www.york.ac.uk/news-and-events/news/2015/research/poppies-morphine/
 
Description Our findings with respect to discovery of the STORR locus are being used to inform our molecular breeding programme that is being carried out in collaboration with our industrial partner, Sun Pharmaceutical Industries Australia Pty Ltd. In addition, our discovery of the STORR gene provides the missing link for reconstruction of the entire morphinan pathway in microbes and a number of groups around the world are now using this new knowledge for microbial engineering purposes. A new variety of poppy containing a larger amount of the cough suppressant and potential anti-cancer agent noscapine has been bred, thanks to our research collaboration, and provided an estimated 80% of global noscapine supply for cough suppressants in 2017-18. Noscapine is beneficial as a cough suppressant, because it is effective and has low toxicity.
First Year Of Impact 2015
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description Report produced by BBSRC on our poppy work used as contributing section to 2017 BBSRC Impact Report
Geographic Reach National 
Policy Influence Type Citation in other policy documents
 
Title NOVEL CYTOCHROME P450 FUSION PROTEIN 
Description This disclosure relates to the isolation of a nucleic acid molecule[s] that encode a novel cytochrome P450 and an oxidoreductase from a Papaver somniferum [P. somniferum] cultivar, transgenic cells transformed with said nucleic acid molecule and sequence variants thereof; and including methods for the production of intermediates in the production of morphinans. 
IP Reference WO2015173590 
Protection Patent application published
Year Protection Granted 2015
Licensed Yes
Impact Follow on research. The intellectual property protected in this patent continues to be developed by the Industrial Partner, Sun Pharmaceuticals with national filings of the patent in Australia, Canada, Europe, New Zealand and the USA.
 
Title PRODUCTION OF NOSCAPINE 
Description This disclosure relates to high noscapine producing plants comprising functional or a non-functional or partially functional copy of a cytochrome P450-oxidoreductase catalysing the conversion of (S)-reticuline to (R)-reticuline in plants of the genus Papaver. 
IP Reference WO2016207643 
Protection Patent application published
Year Protection Granted 2016
Licensed Yes
Impact Follow on research. The intellectual property protected in this patent continues to be developed by the Industrial Partner, Sun Pharmaceuticals with national filings of the patent in Australia, Europe and New Zealand.
 
Description BBSRC News report our STORR gene discovery 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Press release by BBSRC, reporting on our STORR gene discovery that had recently been publishes in the journal Science.
Year(s) Of Engagement Activity 2015
URL http://www.bbsrc.ac.uk/news/health/2015/150626-pr-genetic-discovery-tool-morphine-production-poppies...
 
Description Contribution to the BBSRC 2017 Impact Report 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact After discussions with a BBSRC Policy and Strategy Officer, a short report on our work was produced, which has been used as a contributing section to the 2017 BBSRC Impact Report 'Harnessing the power of biology'. The section of the report on our work is titled 'New poppy variety benefits pharmaceutical industry', and is on page 19.
Year(s) Of Engagement Activity 2017
URL https://www.bbsrc.ac.uk/news/policy/2018/harnessing-the-power-of-biology-impact-report-2017/
 
Description Ian Graham was a keynote speaker at the 2018 Driving Engagement, Innovation and Impact in Plant Sciences event at the University of Sheffield. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact This event was hosted by the Knowledge Transfer Network and P3 at the University of Sheffield. In his keynote presentation Ian Graham spoke about his BBSRC funded poppy research, in addition to some of his other research.
Year(s) Of Engagement Activity 2018
 
Description Ian Graham was an invited Major Symposium Speaker at the ASPB President's Symposium on Translational Science in 2018. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Ian Graham was an invited Major Symposium Speaker at the ASPB President's Symposium on Translational Science, which was held at the start of the ASPB Plant Biology 2018 meeting in Montreal, Canada. He spoke on the subject of 'Unlocking the secrets of medicinal crops'.
Year(s) Of Engagement Activity 2018
URL https://community.plantae.org/article/4938184912814475104/aspb-president-s-symposium-translational-s...
 
Description Invited Special Seminar given by Professor Ian Graham at the University of Melbourne, Australia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor Ian Graham gave an invited Special Seminar at the Molecular Science & Biotechnology Institute at the University of Melbourne, Australia. His talk was titled 'Molecular breeding of medicinal crops and discoveries along the way'.
Year(s) Of Engagement Activity 2015
URL http://www.bio21.unimelb.edu.au/professor-ian-graham-presents-molecular-breeding-medicinal-crops-and...
 
Description Invited speaker (IAG) at 1st Cologne Conference on Food for Future. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Ian Graham gave an invited talk on 'Mutation breeding in the genomics era - developing bespoke medicinal crops'.

It was stated by the organisers of the conference that "achieving global food security is one of the most pressing issues of our times. Scientists took the opportunity to discuss possibilities to tackle this challenge at the '1st Cologne Conference on Food for Future', which the Competence Area 'Food Security' at the University of Cologne hosted from 5 to 7 September in Cologne. The focus of the programme was on 'Orphan Crops', 'Functional Food' and 'Innovative Food Sources and Production Systems'. In addition to promoting interdisciplinary discussion, the organisers sought international exchange, especially with scientists from emerging countries."

For further details see: https://www.portal.uni-koeln.de/13380.html?&L=1
Year(s) Of Engagement Activity 2018
 
Description Invited speaker at Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Shanghai, China 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor Ian Graham gave an invited talk at the Institute of Plant Physiology & Ecology, Shanghai Institutes for Biological Sciences, Shanghai, China, in July 2017. Earlier in the same week he was an invited plenary speaker at the ICPM2017 conference in Dalian, China, and he was invited to extend his trip to also give a talk at the Institute in Shanghai.
Year(s) Of Engagement Activity 2017
 
Description Invited speaker at International Conference on Natural Product Biotechnology (ICNPB), held in Aberdeen 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Professor Ian Graham gave an invited talk at ICNPB conference held in Aberdeen in September 2017. The audience was 50:50 from research and industry, and very much an interdisciplinary meeting, with participants aiming to get an overview of developments across different parts of the bio-economy. The ICNPB conference was described by the organisers as a research, knowledge transfer and business development conference for the Life Science and Biotechnology community internationally, building on the understanding of Natural Product resources, sustainable technologies, the circular economy, and established research and business links.
Year(s) Of Engagement Activity 2017
URL http://www.icman-iuphar-np-2017.org/about/icnpb-2017/
 
Description Invited speaker at School of Biosciences, University of Kent, Canterbury 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact In December 2017 Ian Graham gave an invited seminar on his research at the School of Biosciences, University of Kent.
Year(s) Of Engagement Activity 2017
URL https://www.kent.ac.uk/bio/news.html?view=1757
 
Description Invited speaker at first CEPLAS 2017 summer school on Frontiers in Plant Science, at Hennef, near Cologne, Germany 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Professor Ian Graham was an invited speaker at the first summer school of the Cluster of Excellence on Plant Science, (CEPLAS), which is a research initiative of the Max Planck Institute for Plant Breeding Research, the University of Cologne, the Heinrich Heine University Düsseldorf and the Jülich Science Centre. They focus on the analysis and implementation of complex traits in plants in four different research areas covering annual and perennial life histories, C4 photosynthesis, plant-microbe interactions and metabolic interactions. Their main goal is to understand these complex traits to the point, where we can create artificial modules and use them to obtain more reliable food sources and higher yields in the future. The summer school was part of the CEPLAS training activities and was directed towards Ph.D. students and young postdocs. Their aim was to accommodate 80 early career researchers, with half of them having an international background. Thematically the summer school was focused on the understanding and presentation of emerging fields within plant sciences and their possible future directions. Ian was given the honour of presenting the first talk of the event, which was on his high impact work in molecular breeding in two of the worlds major major medicinal crops - Artemisia and poppy - with various discoveries that relate to the metabolism of high value chemicals and implementing these into a breeding programme.
Year(s) Of Engagement Activity 2017
URL https://www.ceplas.eu/en/training-careers/ceplas-courses-and-excursions/ceplas-summer-school-2017/
 
Description Our poppy research was used as a BBSRC impact case study 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A BBSRC impact case study was prepared together with a BBSRC Policy and Strategy Officer, and in consultation with our commercial partner, and was published on the BBSRC website on 27 September 2018. See:
https://bbsrc.ukri.org/research/impact/poppy-research-creates-new-cough-suppressant-supply/
Year(s) Of Engagement Activity 2017,2018
 
Description Poster presented by Dr Thilo Winzer at 2015 Gordon Research Seminar on Plant Metabolic Engineering, Waterville Valley, USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dr Thilo Winzer presented a poster at the seminar titled 'The gateway reactions to morphinan biosynthesis in opium poppy are performed by a novel cytochrome P450 - oxidoreductase fusion protein'. The 5th Gordon Research Seminar (GRS) on Plant Metabolic Engineering provided a unique forum for graduate students, post-doctoral researchers, and other scientists with comparable levels of experience and education to present and exchange new data and cutting edge ideas. The seminar brought together leaders from the international plant science community for an enthusiastic and constructive discussion about propelling the field to meet the challenges of the 21st century. Through poster and oral presentations, the 2015 GRS featured new, unpublished progress in the following fields of plant primary and specialized metabolism:
- Harnessing Plant Chemical Diversity;
- Advances in Bioinformatics and Mining Big Data;
- Pathway Engineering and Deciphering Plant Metabolic Networks;
- Omics Approaches for Plant Improvement.
Year(s) Of Engagement Activity 2015
URL https://www.grc.org/programs.aspx?id=14145
 
Description Press release issued by University of York re our Guo et al 2018 Science paper 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact The paper below was published in one of the top international journals for scientific research:
Guo, L., Winzer, T., Yang, X., Li, Y., Ning, Z., He, Z., Teodor, R., Lu, Y., Bowser, T.A., Graham, I.A., Ye, K. (2018). The opium poppy genome and morphinan production. Science, 362: 343-347.
A press release was issued by the University of York (https://cmsmigrate.york.ac.uk/biology/news-events/news/scientists-decode-opium-poppy-genome/ ) to highlight the publication of the poppy genome in the journal Science. This news was reported by the BBSRC and others, as listed below:
https://bbsrc.ukri.org/news/fundamental-bioscience/2018/180830-n-scientists-decode-opium-poppy-genome/
https://www.sciencedaily.com/releases/2018/08/180830143149.htm
https://eurekalert.org/pub_releases/2018-08/uoy-sdo082818.php
https://cosmosmagazine.com/biology/poppy-genome-reveals-opiate-evolution
https://www.insidescience.org/news/unraveling-genetic-mysteries-opium-poppy
Year(s) Of Engagement Activity 2014,2018
 
Description Prof Ian Graham interviewed by Bloomberg 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Project PI, Prof Ian Graham, gave an interview to a Bloomberg Opinion columnist regarding the Guo et al poppy genome paper that had recently been published in the Science journal. The resulting entertaining article was published online in Bloomberg Opinion, with the title ' How Did Poppies Get Into the Opium Business Anyway?'.
Year(s) Of Engagement Activity 2018
URL https://www.bloomberg.com/opinion/articles/2018-08-31/how-the-poppy-genome-mutated-to-create-opiates
 
Description Radio 5 live Science Podcast, The Naked Scientist 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Project PI, Professor Ian Graham, was interviewed by Chris Smith for BBC Radio 5 for their 'Naked Scientist' programme about the new STORR gene discovery recently published in the journal Science.
Year(s) Of Engagement Activity 2015
URL http://www.bbc.co.uk/programmes/p02vql2m
 
Description STORR paper press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A press release was issued by the University of York to highlight the new STORR gene discovery that was published in the journal Science. This news was picked up by many media organisations across the world, who also reported the discovery, including the following:

http://news.sciencemag.org/biology/2015/06/final-step-sugar-morphine-conversion-deciphered
http://www.york.ac.uk/news-and-events/news/2015/research/poppies-morphine/
http://cen.acs.org/articles/93/i26/Key-Enzyme-Poppies-Use-Synthesize.html
http://uk.reuters.com/article/2015/06/25/us-science-poppies-morphine-idUKKBN0P52GZ20150625
http://www.washingtonpost.com/news/speaking-of-science/wp/2015/06/25/scientists-find-the-gene-that-lets-poppies-make-morphine-the-final-step-to-making-home-brewed-heroin/
http://www.sciencedaily.com/releases/2015/06/150625143714.htm
http://www.latimes.com/science/sciencenow/la-sci-sn-poppy-home-brew-heroin-20150624-story.html#page=1
http://www.voanews.com/content/scientists-find-gene-secret-lets-poppies-make-morphine/2837877.html
http://www.wired.com/2015/06/last-step-fermenting-opiates-yeast/
http://www.in-pharmatechnologist.com/Ingredients/UK-scientists-discover-key-poppy-alkaloid-production-enzyme
http://www.healthcanal.com/medical-breakthroughs/64848-genetic-discovery-uncovers-key-tool-for-morphine-production-in-poppies.html
Year(s) Of Engagement Activity 2015
URL http://www.york.ac.uk/news-and-events/news/2015/research/poppies-morphine/
 
Description THYME Entrepreneurship Workshop - Mentoring the aspiring biobased business leaders of tomorrow 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Ian Graham mentored the aspiring biobased business leaders of tomorrow using experience gained in conducting world class research with impact. This presentation was part of the BioVale THYME project: https://www.biovale.org/about-us/biovale-projects/thyme/
Year(s) Of Engagement Activity 2019
 
Description University visit (Xi'an Jiaotong University PR China) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact IG gave a talk titled 'Unlocking the Secrets of Medicinal Crops: From Artemisinin to Morphine, Why are Plants Still Better than Bugs at Making these Drugs?' at Xi'an Jiaotong University PR China.
Year(s) Of Engagement Activity 2019