Download Bringing an Ag Biotech Seed Product to Market

Bringing an Ag Biotech Seed
Product to Market
Laura Privalle, Ph.D.
April 14, 2015
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Agenda/
Content
Bringing an agbiotech product to market
Possibilities vs. realities
What have we learned?
Summary
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Biotechnology is an Extension of Traditional Plant Breeding
TRADITIONAL PLANT BREEDING
Many genes are transferred
Desired Gene
X
Commercial Plant Variety
Donor Plant
New Plant Variety
PLANT BIOTECHNOLOGY
A single gene is transferred
Desired Gene
Desired Gene
Donor
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+
Commercial Plant Variety
Improved Commercial Plant Variety
PRODUCT DEVELOPMENHT
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Phase 0
DISCOVERY PHASE – Product concept and gene discovery
Phase I
PROOF OF CONCEPT – Transformation and optimization
Phase II
EARLY DEVELOPMENT – Elite event identification
Phase III
ADVANCED DEVELOPMENT – Regulatory approval
Phase IV
LAUNCH – Product introduction and life cycle management
Product Concept
Scientifically what is possible
Single Gene
•
Phenotype
Herbicide tolerance:
• Modified mode of action (i.e., CP4 EPSPS)
• Herbicide detoxifier (i.e., PAT)
• Insect Resistance:
• Cry proteins
• Vip proteins
• Disease resistance
More Complex Traits
• Metabolic pathways
• Yield enhancement
• Nutrient enhancement
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Critical Steps in Transformation
•
Getting the gene into the plant genome
•
Getting the plant cell to turn into a plant…
• …That expresses the gene
•
Getting a transformed plant to be fertile
•
Getting the progeny to express the phenotype…
• …Without yield drag
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DOES IT WORK EVERYTIME?
NO!!!!
Why Not?
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WHAT CAN GO WRONG?
Idea is bad
Trait is complex
Gene is not expressed
Gene is inserted in a poor location
• Harms plant (does not survive through tissue culture)
•
Impacts plant metabolism
•
Impacts plant phenotype
•
Impacts plant fertility
Not inherited in a Mendelian fashion
Yield Drag
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It’s a numbers game – start BIG
Many ideas to get the RIGHT one
Many cells transformed to get multiple events
Many events evaluated to get THE RIGHT One
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$
http:www.croplife.org/PhillipsMcDougall Study
DISCOVERY
Gene/Trait
Identification
AVERAGE
DURATION1
Mean units
Tested
Regulatory
Activities
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PHASE I
Proof Of
Concept
PHASE II
Early
Development
PHASE III
Advanced
Development
PHASE IV
Pre-launch
53.9 MONTHS
27 MONTHS
30 MONTHS
37.2 MONTHS
48.8 MONTHS
10209
511
1302
2
1
In silico
screening
Preliminary
Digestive Fate
Molecular
Characterization
Full Regulatory
Study Package
Data Defense
Many Ideas Don’t Make it Past the
Discovery Stage – Regulators never see
X 10 – 15% don’t pass allergen/toxin homology bioinformatics screen
X May not be expressed in planta
X No efficacy
X Scientifically feasible, market cannot support
•
Only the best performers with the correct attributes get promoted
•
Economics also plays a role
•
Some products providing good solutions can’t support the cost
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Is this any different from Conventional
Breeding?
•
80 -100 crosses are typical (although some breeders make 600).
•
Similar for all crops.
•
Utilizing contra-season nurseries, it takes about 6 - 7 years to develop a new
cotton, soybean or wheat variety.
•
Marker assisted breeding can assist in the development of multiple traits at
one time.
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Conventional Breeding continued.
•
Chemical mutagenesis is useful for simple and single gene traits. Variety
development can not start until correctly identified and will take longer than
the 6 – 7 years.
•
Biotech traits (ELITE events) can be incorporated using forward breeding
methods or they can be presented as populations in a trait introgression
project.
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Selection of the ELITE Biotech Event
 Efficacy
 Agronomic Performance
 Yield
 Other agronomic parameters
 Inheritance pattern
 Molecular characteristics
 Single locus
 Single gene inserted
 Lack of vector backbone
 Integrity of insert
 Stability across generations
 Insertion site
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How Important is Insertion Site?
May play a role in efficacy of trait
Determines design of event specific test
Impacted by crop genome information available (rice, soy, potato, maize, cotton, tomato,
wheat, barley, papaya, sorghum, grape)
Important to regulatory agencies in EU, Japan and elsewhere
• Interrupted gene
• Locus organization – deletion, rearrangement, insertion
• Ignores performance – agronomic or composition
• Ignores plasticity of plant
Over-interpretation, varietal differences?
Modern events produced using Agro transformation
have fewer insertion issues.
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Plasticity and Ploidy in Plants
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Biolistics vs. Agro transformation
•
Earliest events used biolistics (or similar brute force transformation)
•
Transformation using Agrobacterium tumefaciens is more precise
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Once EVENT identified –
Safety assessment conducted.
• Safety assessment for plant biotech products is mandatory worldwide
• Considers human + animal health as well as environmental safety
• Approval only if authorities conclude: Genetically optimized plant is as safe as a conventionally bred plant
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Safety Assessment is a multi-pronged undertaking
Crop Safety
Gene / Protein
Food / Feed
and
Environmental Safety
 Gene(s)
 Protein(s)
 Crop Characteristics
 Food/Feed Composition
 Environmental Safety
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Most Studied Food – Safety Reviewed
by Agencies all Around the World
Production Countries
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Importing countries
Comparison of Approvals
Country
Approvals1
Pending
Crops
Australia*3
64
Brazil
23
3
Canada*^
106
17
China
27
5
EU2
50
Japan*
84
8
Korea
64
7
US*4
115
2
51
6
9
9
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*breeding stacks not regulated
^includes nonGM novel plants
1Most
data from http://cera-gmc.org/index.php?action=gm_crop_database&mode=newquery
2Devos
et al. Transgenic Res. 2013
3 http://www.foodstandards.gov.au/consumer/gmfood/applications/Pages/default.aspx
4http://www.aphis.usda.gov/biotechnology/petitions_table_pending.shtml
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What we have learned
TERMINATED BEFORE Approvals sought
x Brazilnut protein to increase methionine content in soybean
x Bean amylase inhibitor in pea
$ Many vegetable examples
x Amylose potato
x Nutritionally enhanced tomato
WITHDRAWN after approval
x High lysine maize
$ Triffid Flax
x Amflora potato
$ NewLeaf Plus®
x Maximizer Bt176
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Once Approved – Consumers may never see
product – or not for long
•
Demand for the FLAVR SAVR tomato was high and remained high, but the product
was never profitable (because it wasn’t in
the right varieties)
the right varieties..
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Summary
•
It takes a lot of effort to produce the single ELITE event (not unlike plant
breeding)
•
Evaluation of plant performance eliminates events in which the insertion site
was detrimental (not unlike plant breeding) THUS REGULATORS NEVER
SEE THEM
•
The structure of the insert is an important factor in elite event selection
•
Characterization of the insert is an element of a dossier
•
Reviewers around the world evaluate the safety packages – most highly
studied food/feed consumed
•
Many products fail due to issues NOT associated with safety
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No product has been withdrawn
or not approved due to an
unintended effect related to
insertion into the genome.
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Thank you!