Global Institute for Food Security and National Research Council-Saskatoon are pleased to invite you to a special seminar: Dr. Ian Graham Centre for Novel Agricultural Products (CNAP) Department of Biology University of York, UK Molecular breeding of medicinal crops and discoveries along the way (abstract attached) Friday, May 6, 2016 9:30 to 11:00 a.m. University of Saskatchewan campus NRC Building, 110 Gymnasium Place Atrium Light refreshments will be served. Molecular breeding of medicinal crops and discoveries along the way Ian A. Graham, Centre for Novel Agricultural Products (CNAP) Department of Biology University of York, UK From Sweet Wormwood to Opium Poppies The Chinese medicinal plant Artemisia annua (Sweet Wormwood or Qing Hao) is the primary source of the leading anti-malarial drug artemisinin. This sesquiterpene lactone is produced in glandular secretory trichomes on the surface of leaves. With the aid of funding from the Bill & Melinda Gates Foundation we published the first genetic map of A. annua in 2010, along with quantitative trait loci accounting for much of the variation in key traits controlling artemisinin yield (Graham et al., 2010, Science, 327:328-31). This work laid the foundation for the selection of elite parents for F1 hybrid production. In 2011 the University of York signed an agreement with East West Seeds, an international seed production company, to produce and market improved hybrid seeds, the performance of which has been proven in extensive field trials carried out in East Africa, Madagascar, India and China. Enough CNAP hybrid seed has been sold in Africa in the last three years for annual production of over 100 million artemisinin combination therapy treatments. Opium poppy (Papaver somniferum) remains one of the most important medicinal plants in the world due to the presence of a diverse set of benzylisoquinoline alkaloids with potent pharmaceutical activities. We have been working with the pharmaceutical industry to develop new poppy varieties with improved levels of target alkaloids including noscapine, which has been used as a human cough suppressant for decades and more recently has been shown to have anticancer properties. Very little was known about the biosynthesis of noscapine in opium poppy prior to our discovery of a cluster of ten genes encoding five different enzyme classes responsible for the production of this alkaloid (Winzer et al., 2012, Science, 336:1704-8). Functional characterisation of a number of these genes by virus induced gene silencing allowed a novel biosynthetic pathway to be proposed and molecular markers are now allowing the gene cluster to be selected as a single locus in a breeding programme that is delivering new poppy varieties. Most recently our lab discovered the long sought-after gene encoding the last uncharacterised but critical gateway step of morphinan biosynthesis (Winzer et al., 2015, Science, 349: 309-312). This discovery represents the first identification of a non-redox partner P450–oxidoreductase fusion protein in any species and was the first report of a bifunctional P450 fusion protein in a higher eukaryote. The Euphorbiaceae or spurge family of plants produce a diverse range of diterpenoids, many of which have pharmacological activity. These include ingenol mebutate, which is licensed for the treatment of a precancerous skin condition (actinic keratosis), and phorbol derivatives such as resiniferatoxin and prostratin, which are undergoing investigation for the treatment of severe pain and HIV respectively. Despite the interest in these diterpenoids, their biosynthesis has been poorly understood; the only characterized step being the conversion of geranylgeranyl pyrophosphate into casbene. Using a combination of genome mapping, mining and biochemical characterization we have recently discovered a cluster of diterpenoid biosynthetic genes from castor, including casbene synthases and cytochrome P450s involved in the biosynthesis of this family of medicinally important diterpenoids (King et al., 2014, Plant Cell, 26:3286-98). Evidence of similar gene clustering was found in two other Euphorbiaceae, including Euphorbia peplus, the source plant for ingenol mebutate. This breakthrough opens the way to elucidating diterpenoid biosynthetic pathways and developing new production platforms for their synthesis.