Global development of GMOs,

and new breeding techniques

challenging biosafety regulations

ENCIBio/EBBio 2018

Vitória, ES, BRAZIL, 1-4 October 2018

by Bertrand Dagallier, OECD

I. Global development and use of GMOs, where are we?

– Plants

– Animals

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II. New breeding techniques– Promising developments

– Challenge for biosafety

– In search for clarifying regulation; examples of country steps

III. International cooperation in biosafety– At OECD, with Brazil participation

Global Area of GM Plants, 1996 to 2017

= 3 to 4% of global

agriculture areas.

17 million farmers + families

= 65 million people (=0.8%

of global population)

4 crops

= 99.1% of total GM area

Other GM crops? 0.9% area for seven species only:

Alfalfa, Sugar beet, Papaya, Squash, Potato, Eggplant and Apple

No other major staple crops (rice, wheat, cassava…), and ~ no GM trees3

99.9% for 2 types of traits:

insect/disease resistance,

herbicide tolerance, or both

Global Adoption Rates (%) for main GM Crops, 2017

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Areas of GM Crops by countries, 2017

24 countries have grow GM crops in 2017.28 countries few years ago, 26 in 2016 (Slovakia and Czech Rep. stopped planting last year)

ISAAA, 2017

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Approved Events for GM Crops used in Food,

Feed, Processing, and Cultivation

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Recent trends in biotech crops

• Stacked-traits varieties: 71% of the newly approved

events (ISAAA, 2017)

• New hosts: approved products of apple , safflower,

pineapple…

• Consumer-targeted traits: nutritional content (e.g.

golden rice…), non-browning, storage capacity…

• Abiotic stress traits: tolerance to drought, high salinity, flood…

• Products in R&D pipeline: greening-tolerant citrus, blight-resistant chestnut, biofortified banana,

high-oil-content micro-algae, etc. 7

1) Atlantic salmon• A domesticated fish reared for food production

• Fast-growing GM strain approved in several countries

• Reported to have hit the market in Canada

Current applications in GM Animals:

early stage

2) Mosquitoes Aedes aegypti /Anopheles gambiae

• Vectors of viruses for tropical diseases, incl.

dengue, yellow fever, Chikungunia, Zika, malaria

• Self-limiting GM strain approved in several countries and

(experimental-local) releases taking place = Brazil

• Possible application of gene drive

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For agriculture

• Contribute to farmers’ income

• Increase crop productivity: participate in food security, &

sustainable balance in agriculture-pasture-forest

• New varieties might help adaptation to climate change

For environment

• Provide a better/healthier envir.: less pesticide applications

• Contribute to biodiversity preservation: no-tillage

For consumers

• Some less costly commodities/food/feed; will others to come?

• Reduce food waste

• Contribute to disease fighting: health improvement (mosquito)

GMOs benefits

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• Fear of innovation/safety concerns by (urban) consumers

for which GM benefits seem far/not perceived: Are GMOs safe for my food? the environment?...

= science-based AND emotional AND ethical considerations

• Wish for increased protection. What could be the unintended

effects of GMOs in longer term?

• GMOs ‘in the hands of multinationals’, for ‘intensive’ agriculture

only = socio/economics considerations

• Green trends in (wealthy) societies, ‘traditional’ products,

eat&consume locally, ‘healthier’ diets

Recent example in media: glyphosate safety in question

GMOs perceived risks

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• National biosafety/novel food-feed safety systems

in place to protect the citizens and living environment. Scientists and public opinion impacts legislation

• YES/NO/partial approvals of GMOs for production;

for use/consumption; or for both. On product-by-product basis.

• Diversity of national regulations,

incl. costly/complex/highly-demanding risk assessment and

approval process, control, labelling

• But harmonised approaches/some common

understanding/ regarding RA – incl. Basic RA principles developed by OECD/WHO/FAO, and

elements to consider for biosafety and food safety RA (e.g. OECD

‘Blue book’ (1986), Codex principles for food safety, OECD Consensus Documents)

Non-harmonised GMO biosafety regulations,

but common views on risk assessment (RA)

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• Slow adoption of some GM species, limited expansion. Approval asynchronicity = trade disruption (incl. LLP issues)

• GM production of the ‘big 4 GM crops’ will continue as

providing key commodities at low cost; will others progress?

• Evolution in opinions with better-perceived benefits? health, climate change, industrial applications e.g. energy,

bioremediation…?

Non-harmonised GMO biosafety regulations

- Consequences

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Researchers have long sought better ways to edit the genetic code in

cultured cells and organisms to:

• insert new genes (= ‘GMOs’)

• correct targeted genes

• activate or inactivate genes (knock-out)

in order to provide beneficial applications, from agricultural to biomedical.

GM and ‘newer’ Breeding Techniques

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OECD Workshop on new plant breeding techniques (2014) Site Directed Nucleases (SDN)

Oligonucleotide Directed Mutagenesis (ODM)

Cisgenesis/Intragenesis

Reverse Breeding

RNA-directed DNA methylation (RdDM)

Grafting on GM-rootstock of wild-type scion

Agro-infiltration

Some use GMOs during the process, but not kept in the final product

OECD Workshop on high-throughput DNA sequencing in GM plant safety

assessment (2016)

OECD Conference on genome editing applications in

agriculture (2018); SDN and ODM mainly.

‘Precision-breeding’ techniques (Brazil Norm.Resol.16 -Jan. 2018)

New Breeding Techniques at OECD

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Zinc-finger nucleases, ZFNsMeganucleases, homing endonucleases

TALENsCRISPR-cas

The four families of gene editors

TALEN: Transcription Activator-Like Effector Nucleases

CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats 15

Properties of genome editing tools: faster,

cheaper

The four families of gene editors

Meganuclease(1985)

ZFNs(2003)

TALENs(2010)

CRISPR-cas(2012)

Number of proteins 1 2 2 1+1 RNA

Production difficult not very easy easy very easy

Cost of production 50 000 euros 5 000 1 000 10

Time needed for an experiment

months months weeks days

Oligonucleotide Directed Mutagenesis (ODM): an approach by which specific mutations can be introduced in a defined place in a plant genome. Works on

one DNA strain (not the pair). Then traditional breeding (filtering) processes to keep the desired mutation only.

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Genome-edited products in R&D Pipeline -

Plants

1) Next generation waxy corn• Under development by Dow DuPont

• Deletion of the entire allele by SDN-1 via CRISPR/Cas9

• Reported to have improved the maize varieties faster with no linkage

drag compared to conventional breeding

2) Tomato with high-storage capacity• Under development by Tsukuba University (Japan)

• Substitution of one base pair in the relevant allele via CRISPR/Cas9

• Reported to have remained unrotten for 60 days, thereby possibly

enabling long-distance transport and reducing food loss

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Genome-edited products in R&D Pipeline -

Animals

1) Hornless cattle• Under development by University of California - Davis

• Substitution in horn-growing allele via TALEN

• Eliminating the need to manually remove horns to protect human

handlers and other animals

2) Fast-growing porgy fish• Under development by Kyoto University (Japan)

• Knock-out of the allele restricting muscle growth via CRISPR/Cas9

• Reported to have grown 50% larger in body size

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NBT Regulatory Challenges/Considerations

• Mixed situation across countries as to ‘if’ and ‘how’ various

genome-edited products should be regulated (SDN-1, SDN-2, SDN3…)

• Applicability of GMO regulation to these products often unclear

from legal definitions, and thus has to rely on interpretation

• Difficulty in implementation: e.g. detection and identification of

some genome-edited products

• Inadequacy in knowledge/evidence regarding risk and safety of

these ‘new’ products in particular

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United States.USDA

- 2011: "Am I regulated?" process. Cases of non-regulated genome-edited plants and animals.

- 2017: Proposed change to current regulation; withdrawn in Jan. 2018 (public opinion).

- March 2018, Agr. Secretary statement: no regulation for gen. deletion of any size, single pair substitution and

null segregants (= not containing transgene in final product)

FDA - 2017 public comment process on reg. approaches for plants and animals. Underway for better clarification

EPA - Underway for better clarification

European Union.

- Discussions by scientists expert group since 2008 upon request by NLD; conclusion in 2012 that SDN-1, SDN-2 and

ODM are exempted from GMO directive, but no action taken by European Commission.

- 2015: Case brought to French court on GM law applicability to genome editing products; sent to Court of Justice of

the European Union. Jan 2018, CJEU Advocate General advised for non applicability for techniques non involving

rDNA or GMOs

- July 2018, CJEU stated that only organisms obtained by conventional mutagenesis are excluded from GMO

directive, thus no exemption for gene-edited products.

- How to apply it?

Seeking for clarifying NBTs regulations: examples (1)

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Canada.

Novelty trigger continues to apply to the products of NBTs. Therefore no specific consideration, conventional breeding

products, GMOs and genome-edited products are considered in the same way.

Japan.

- Aug. 2018: following discussions among Ministries, expert meeting conclusion that SDN-1 genome-edited products

might be exempted from biosafety law, but future reporting requirement to be developed

- Public consultation underway. Decision by Ministry of Environment expected early 2019.

- Similar process to start for the food products derived from genome-edited organisms.

Seeking for clarifying NBTs regulations: examples (2)

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Australia/New Zealand.

Australia OGTR

- 2016/2017: Public consultation process on 4 options of approach to genome-edited products

- Public consultation underway on proposed changes to regulation: SDN-1, null segregants and RNAi products

might be exempted from gene technology act; decision to be taken by OGTR

New Zealand- EPA

- 2012: a genome-edited pine tree exempted from requirement of Hazardous Substances and New Organisms Act

- 2013: decision challenged by env. NGOs, and Court declared nullity of the decision. Regulation amended for

all biotech products developed after HSNO Act are treated as GMOs.

Australia/New Zealand- FSANZ (incl. novel food & feed safety)

- 2017: public consultation process on regulatory approaches; report under preparation. Decisions on future actions to

be taken by FSANZ

Seeking for clarifying NBTs regulations: examples (3)

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Seeking for clarifying NBTs regulations: examples (4)

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Seeking for clarifying NBTs regulations: examples (4bis - Australia)

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Argentina.

- 2015 Resolution on NPBTs: For final genome-edited products not containing any transgene, then non

regulated as GMOS. But early consultation with the biosafety Authority CONABIA is required.

- Many contacts taken by Argentina (exporter) with other (importing) countries for seeking clarification and mutual

exchange of information. Active follow-up of the moving/quickly evolving situation in the different regions of the world.

Seeking for clarifying NBTs regulations: examples (5)

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Extract from Dr. M. Lema/Argentina presentation

at OECD Conference on genome editing, June 2018

Brazil…

Seeking for clarifying NBTs regulations:

examples (4)

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1) ENVIRONMENTAL safety of GEOs (biosafety)

Working Group for the Harmonisation of Regulatory

Oversight in Biotechnology

2) FOODS/FEEDS derived from GEOs

Working Group for the Safety of Novel Foods and

Feeds

OECD Bio&Food safety work: 2 programmes

Aim: Help to address human health and environmental safety issues, through

science-based risk assessment, for products of modern biotechnology

(G.E.O.s): plants, animals, micro-organisms

These groups are composed of bio/food safety

National Authorities: regulators, risk assessors &

experts (and observers from Organisations)

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Purpose:

Assist countries to evaluate potential risks of biotech. products

for human-animal health and environment safety

Limit duplicative efforts: mutual understanding, acceptable data

Reduce the potential for non-tariff barriers to trade

OECD Biosafety Work Basic Principles

Means:

Harmonisation of approaches and regulatory frameworks

Share/disseminate common base of scientific information

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“Consensus” and Guidance Documents

- to help national assessment and decision-making process

- practical tools for comparing conventional and “GE” products

- Scientific information, internationally-recognised, a common basis;

however NOT prescriptive

- available online

OECD Biosafety Work Main Outputs

Exchange/cooperation

between biosafety Authorities (incl. Brazil as OECD ‘Key partner’)

on current and new issues – meetings, workshops, other events

Database

on G.E. products approved for release in the environment and/or food

and feed use (incl. Brazil) – 285 entries, 17 plant species – available online

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Consensus document: outputs

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Environmental Safety

Environmental Considerations (incl. Brazil)

Molecular characterisation

Low level presence (incl. Brazil)

New Plant Breeding Techniques

General documents on ES work

8 Microorganisms

5 Traits introduced

Information on

19 Crop plants (cassava, cowpea, common bean…)

13 Trees

3 Fruits

1 Mushroom

2 Animals (Atlantic salmon, mosquito Ae. aegypti;

coming A.gambiae)

Biology of

Food/Feed Safety

Animal feedstuffs

Emerging feed ingredients?

General documents on F/F S work

17 Crop plants (cassava, common bean…;

coming soon: cowpea)

2 Mushrooms

1 Fruit

Composition on

OECD Biosafety and Food/Feed Safety team:

Peter Kearns, Bertrand Dagallier, Ryudai Oshima, Yoko Takasu, Emily Seftel

Consensus Documents & Product database available at:

www.oecd.org/biotrack

Thank you!