Global Institute for Food Security and National Research Council-Saskatoon

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
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.