Une première base solide et prometteuse sur laquelle s’appuyer.

Le 18 janvier 2018, l’avocat général de la Cour de Justice de l’Union européenne (CJUE) a rendu des conclusions préliminaires sur la question de savoir si certaines des nouvelles techniques de génie génétique entrent dans le champ d’application de la législation européenne sur les OGM (affaire C-528/16).
Pour un aperçu de ce que sont les NBT (New Breeding Techniques), leur classification juridique dans l’UE et en particulier la pertinence de cette application des nouvelles techniques dans l’agriculture de l’UE, vous trouverez ici notre rapport (LINK).
Tout d’abord, ce que l’avocat général M. Michal Bobek a fait était de fournir une interprétation juridique en réponse à l’enquête de la France de 2016, qui demandait à la CJUE de préciser si un type de colza résistant aux herbicides devaient subir le processus d’approbation pour les OGM, et donc si les plantes résultant des nouvelles techniques seront couvertes par la législation de l’UE sur les OGM – Article 2 (2) de la Directive OGM 2001/18 / CE. Puis, l’opinion de l’Avocat général tente de préciser si et dans quelle mesure les organismes développés par des techniques conventionnelles et innovantes de sélection végétale (spécifiquement la mutagenèse) doivent être régulés soit par le même cadre que la sélection végétale conventionnelle soit comme organismes génétiquement modifiés (OGM).

Brussels, January 18th

“Ever since humans have grown plants and raised animals for food, they have selected plants and animals with beneficial traits for further breeding. Such traits reflected naturally occurring genetic variations and resulted, for example, in an increased yield or resistance to diseases or environmental pressures”.

EFSA (European Food Safety Authority)

“Targeted genome modification techniques could have revolutionary applications in agriculture. They consist in introducing very precise genetic modifications which make it possible to accelerate the selection speed. They represent a fundamental departure from the « old » GMOs, insofar they could occur naturally and are virtually undetectable”.

French Parliamentary Office for evaluation of scientific and technological options (OPECST)

Today, January 18th 2018, the European Court of Justice (ECJ) Advocate General issued preliminary conclusions on whether some of the new genetic engineering techniques fall within the scope of the European legislation on GMOs (Case C- 528/16).

It is true that this is only a first opinion on the long-standing issue, whose final conclusions, and the related framework, are expected to be presented by the ECJ by summer 2018, however it has to be underlined what this outcome may entail for the future of plant improvements at European level.

For an overview of what NBTs are, their legal classification in the EU and in particular the relevance of these New Techniques application in EU agriculture, here you find our report (LINK).

On this issue, it is absolutely necessary to focus first and foremost on facts, namely scientific arguments.

First of all, what the Advocate General Mr. Michal Bobek did today, was to provide a legal interpretation as a response to France enquiry in 2016, which asked the ECJ to specify whether a type of herbicide-resistant rapeseed obtained through gene- editing should undergo the approval process for GMOs, and so if plants resulting from the new techniques will be covered by the EU GMO legislation – Article 2(2) of GMO Directive 2001/18/EC. To be even more precise, French Council of the State posed to the ECJ four interlocutory questions (available here) on the scope of the EU’s GMO legislation and specifically, (i) if classical and/or newer site-directed mutagenesis plant breeding techniques produce GMOs and (ii) if EU Member States retain any discretion in transposing these EU Directives to their national laws.

“Directive 2001/18/EC regulates the deliberate release into the environment of genetically modified organisms (‘GMOs’) and their placing on the market within the Union. In particular, the organisms covered by that directive must be authorized after an environmental risk assessment. They are also subject to traceability, labelling and monitoring obligations”.

“Article 3(1), read in conjunction with Annex I B, states that the GMO Directive shall not apply to organisms obtained through certain techniques of genetic modification, such as mutagenesis (‘the mutagenesis exemption’)1”.

The Advocate General’s opinion attempts to make clear if and to what extent organisms developed through conventional and innovative plant breeding techniques (specifically mutagenesis), are to be regulated either through the same framework as conventional plant breeding or as genetically modified organisms (GMOs). It is necessary to specify that under the current EU legislative framework, organisms developed through traditional mutagenesis breeding techniques are regulated as conventional and are therefore exempt from the EU’s main GMO regulation, Directive 2001/18/EC.

“In my view, provided that they meet the substantive conditions of Article 2(2) of the GMO Directive, organisms obtained by mutagenesis are GMOs within the meaning of the GMO Directive (a). However, as long as the process of mutagenesis does not involve the use of recombinant nucleic acid molecules or GMOs other than those produced by one or more of the techniques listed in Annex I B, those organisms are exempt from the obligations laid down by the GMO Directive by virtue of Article 3(1) of the GMO Directive, read in conjunction with its Annex I B (b)”. – Advocate General on the scope of the GMO Directive and of the mutagenesis exemption.

Furthermore, he also specified that: “Like the Commission, I am of the opinion, that there is only one relevant distinction that should be made in order to clarify the scope of the mutagenesis exemption: the caveat set out in Annex I B, namely whether the mutagenesis technique involves ‘the use of recombinant nucleic acid molecules or [GMOs] other than those produced by … mutagenesis [or] cell fusion … of plant cells of organisms which can exchange genetic material through traditional breeding methods’ (‘the Annex I B caveat’)(1). No further distinctions should — or even could — be made judicially”.

Having in mind that this legal advice is not binding but that it is usually followed by European Court of Justice (ECJ) panel of judges, what it states in short is that crops obtained by the plant breeding technique of mutagenesis do not fall under laws restricting the use of genetically modified organisms ( G M O s ) however, and this is a point which has to be thoroughly analyzed, the Advocate General pointed out that the Directive 2001/18 does not preclude

1 “Mutagenesis involves an alteration of the genome of a living species. Unlike Transgenesis, which is a genetic engineering technique that consists in inserting one or more genes from other species into the genome of another species, it does not, in principle, entail the insertion of foreign DNA into a living organism. Techniques of mutagenesis have evolved over time as the result of scientific progress in biotechnology” Source: Case C-528/16 – OPINION OF ADVOCATE GENERAL BOBEK, 18 January 2018(1)

Member States from adopting measures governing mutagenesis provided that, in so doing, they respect the overarching obligations arising from EU law.

“Against this background, I am of the opinion that Member States have the competence to regulate organisms obtained through mutagenesis provided that they comply with their overall EU law obligations, whether of secondary law origins or the rules of primary law, such as Articles 34 and 36 TFEU”.

For a more precise explanation here below an extract from the Advocate General’s conclusion:

(1) Provided that they meet the substantive criteria of Article 2(2) of Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC, organisms obtained by mutagenesis are genetically modified organisms within the meaning of that directive;

The exemption laid down in Article 3(1) of Directive 2001/18, read in conjunction with its Annex I B covers all organisms obtained by any technique of mutagenesis, irrespective of their use at the date of the adoption of that directive, on the condition that they do not involve the use of recombinant nucleic acid molecules or genetically modified organisms other than those produced by one or more of the methods listed in Annex I B.

(2) Council Directive 2002/53/EC of 13 June 2002 on the common catalogue of varieties of agricultural plant species is to be interpreted as exempting varieties obtained by mutagenesis from the specific obligations laid down therein for the inclusion of genetically modified varieties in the common catalogue of agricultural plant species.

(3) Directive 2001/18 does not preclude Member States from adopting measures governing mutagenesis provided that, in so doing, they respect the overarching obligations arising from EU law.

As clarified by a USDA-FAS Report on January 16th on the expected legal opinion for New Breeding Techniques in the EU, “Advocates General are assigned to most cases before the ECJ to serve as an advisor to the court on how the case should be resolved. Their opinions are given considerable weight, and often are followed by the court, but are non-binding in all cases”. Furthermore, USDA Rapporteur found that by reviewing ECJ case law, what appears is that the majority of ECJ judgements complement the opinions of the advocate general.

In order to provide a brief background on the issue but without going back to the far past, last year, on April 28, 2017 the SAM-HLG (Scientific Advice Mechanism -High Level Group) released its explanatory Note in response to the request, formulated in the Scoping Paper (adopted by the HLG on 25 November 2016), by the European Commission, to provide an up-to-date overview and a comprehensive scientific comparison on new techniques in agricultural biotechnology, including their potential agri applications in both fields of synthetic biology and gene drives, considering the key characteristics of each of these new techniques.

Among the others, the Note highlighted that “all breeding techniques applicable in agriculture (conventional breeding techniques, CBT; established techniques of genetic modification, ETGM; and new breeding techniques, NBT) make use of genetic diversity and change whether naturally occurring or resulting from human intervention, in order to select or generate plants, animals or microorganisms that exhibit preferred characteristics” and that “the NBT of genome editing offer not only the ability to target insertions (resulting in comparatively fewer unintended effects on the expression of other genes or their disruption) but also the ability to make small, precise and specific changes, such as point mutations, which can also be observed in nature”.

This independent explanatory note, as also specified in the Scoping Paper, does not take a position; it does not cover legal issues and it does not make policy recommendations to policymakers. It is another piece to the puzzle.

Background notes :

New Plant Breeding Techniques (notably the CRISPR-Cas9, which is basically a technology that uses a DNA-cutting enzyme called nuclease to edit in a very targeted way parts of the genome, by removing, adding or altering sections of the DNA sequence) can play a key role in allowing plant breeders to introduce in an efficient way, very precise, targeted genetic modifications, which have the capacity to fasten the selection speed, when compared with conventional plant-breeding techniques. NBTs allow to develop plant varieties that can adapt to climatic changing conditions and ensure high level of biodiversity.

As also outlined in the Explanatory Note, “the speed with which mutations can be introduced using NBT is often higher (in particular when using the CRISPR-Cas genome editing system) than that which can be achieved with ETGM and CBT, mainly due to the reduced need for time-consuming screening procedures and/or back-crossing, with correspondingly lower costs”.

CRISPR-Cas9, for instance, is already a technique, which is having a great impact on our society. It is the most tangible example of how biotechnology has been able to make considerable progress with the targeted modification technologies of genome.

By focusing on the potential application in agriculture and food systems, some induced mutations that this technique could target are, among the others:

– “Bad” traits such as allergens or toxins can be selectively inactivated
– Specific mutations (herbicide resistance to more environmentally friendly substances or insect resistance) can be knocked-in
– Flowering time
– Metabolic engineering (starch, fatty acid profile)

On the other side of the Atlantic, the US Department of Agriculture (USDA) has changed the attitude toward genetic engineering, specifically with the new gene- editing techniques of plant breeding. In a recent article published on Nature Biotechnology, it is explained that the agency is giving “free-pass” to some plant varieties developed with CRISPR technique. In other words, CRISPR-Cas 9-edited plants can be cultivated and sold free from regulation burden and costs, so they fall outside USDA’s authority. For instance, in April 2016, the USDA clarified that it would not have regulated a non-browning mushroom genetically modified using CRISPR–Cas9 – the first US CRISPR-edited product to obtain “green light”2.

Aiming to provide a full picture, there are indeed other agricultural products (i.e. commodity crops such as corn, soybeans, canola, rice, wheat) which are undergoing targeted genetic engineering for drought resistance, pest resistance or higher yields. There is currently a quite wide consensus among scientists, who believe in the capacity of innovative NBTs to help farmers deal with climate change and a growing population.

In the overall discussion, taking into account the legal, scientific and of course societal aspects, we should keep in mind that greater priority has to be given to research in this area, since, as also the US concrete and illustrative example shows, the development of NBTs is happening in any case outside Europe.

In this context, there is a clear challenge : not to lose ground at global level and above all, not to neglect the revolutionary contribution and benefits of these new techniques to the sustainability and competitiveness of EU agriculture.

Today’s decision marks another relevant step towards the need for the EU to develop a clear legal framework for the new plant breeding techniques (NBTs), and so enabling these tools of agricultural innovation to be separated to the EU’s current laws on genetically modified organisms (GMOs) and thus ensuring regulatory clarity in view of the commercial application of these products, which could bring tangible benefits and potential improvements to crop productivity, quality, sustainable farming methods and, in general, addressing current and future agricultural and food challenges.

2 Available here: http://www.nature.com/news/gene-edited-crispr-mushroom-escapes-us-regulation- 1.19754

Today, the agri-food sectors are more than ever confronted with 3 major demands from our society:

• –  To provide safe and quality food not only to European citizens but as well to world markets, having in mind the segmentation of these markets, considering both commodities, mid-range and premium markets. Each of them deserves to be considered.
• –  To keep rural areas lively and viable. This means, first and foremost to maintain and develop a profitable farming activity in all rural areas across the EU. Agriculture is indeed the basis of any possible economic development. Can you build a house without solid foundations? No, indeed. Same story when it comes to economic development of rural areas.
• –  To optimize the good management of the environment and to fight more effectively against climate change and risks linked to wider and wider spread diseases.Being able to answer jointly to these three challenges is for sure a challenge itself, but a feasible one, if you accept to make effective use of science and concentrate your efforts on double performance: economic performance and environmental performance.

  This is the very basic condition of any success of the EU and the EU agriculture to ensure both growth and job and more environment.

To reach this objective, we need to change our attitude, to live in our time and consider what science tells us, and not what some say that science could tell.

This is true when it comes to precision and smart farming and how policies can incentivize the move of the EU agriculture to a modern, a more eco-environmentally efficient agriculture.

This is true as well when it comes to genetics.

For more than a decade, the global productivity of the EU farming sector has halved. During this decade, the capital productivity of this sector has become negative. According to the EU Commission, this trend would result in a new decrease by 14% of the EU agri incomes in the next 10 years.

Should you accept this simply as a fate? For sure not.

Productivity of EU agriculture has been stagnating for years. It is time now to reinvest in innovation and research, to reinvest in genetics and develop a concrete science- based approach in that respect.

In this framework, objectivity and transparency will be key.

New breeding techniques are said to be promising as modern and faster extension of usual traditional breeding techniques.
But if the aim is to develop sensible policies and orientations based on solid ground, the first question to be answered when it comes to NBTs is: what are we talking about?

– Scientifically, what are NBTs, what does it mean in simple words?
– Economically, what are the expectations and what is already known for sure? – On Environment, is there any added value?

New Plant-Breeding Techniques in a nutshell

New Plant-Breeding Techniques (NBTs) are methods allowing the development of new plant varieties with desired traits, by modifying the DNA of the seeds and plant cells. They are called ‘new’ because these techniques have only been developed in the last decade and have evolved rapidly in recent years.

Moreover, as these practices are still continuously evolving, there is no limited set of techniques that can be put under the ‘umbrella term’ of NBTs.1 Based on assessments of the European Commission, the following plant-breeding techniques can currently be considered as the main NBTs:

1) Site-Directed Nucleases (SDN) (including ZFN-1/2/3 and CRISPR systems); 2) Oligonucleotide Directed Mutagenesis (ODM);
3) Cisgenesis;
4) RNA-dependent DNA methylation (RdDM);

5) Grafting (non-GM scion on GM rootstock); 6) Reverse breeding;
7) Agro-infiltration. 2

These New Plant-Breeding Techniques, which have emerged as the result of advances in scientific research, enable more precise and faster changes in the plant’s genome than conventional plant breeding techniques, which use chemical and radiation processes to alter the genetic characteristics of plants.3

As such, they have a significant potential for the plant breeding and agri-food industry, as they entail technical advances, economic savings and the improvement of crop characteristics.

First of all, NBTs have technical advantages compared to traditional plant breeding techniques. Some techniques (such as ODM and ZFN) allow site-specific and targeted changes in the genetic material of the plants, and for many of the techniques, the genetically modified code for the desired trait is only present in the first plant, but not in their offspring.

Secondly, NBTs have economic advantages, as the use of these techniques reduce the necessary time for plant breeding compared to conventional approaches (for which breeding can take up to 10 years), thus leading to lower production costs.

Crop improvements as a result of NBTs include the resistance of plants to diseases and drought tolerance, which can lead to higher yields, as well as higher nutritional qualities and storage or processing qualities.4

New Plant Breeding Techniques are currently in an uncertain situation regarding their legal classification, as there is considerable debate on how these practices should be

1 European Parliamentary Research Service, New plant-breeding techniques: Applicability of GM rules, 2016, p. 2.
2 European Commission, New plant breeding techniques, https://ec.europa.eu/food/plant/gmo/legislation/plant_breeding_en.

3 EPRS, op.cit., pp. 1-2.
4 Joint Research Centre of the European Commission, er the genetic characteristics of plants-the-art and prospects for commercial development’evJRC Scientific and Technical Reports, 2011.

regulated and whether they (or some of them) should fall within the scope of the EU GMO legislation. 5

Registration and certification of non-GM and GM seeds in the EU

Seeds, the main focus of New Plant-Breeding Techniques which aim at improving their genetic characteristics, are regulated in the EU by 12 Directives: Directive 2002/53/EC on the common catalogue for varieties of agricultural plant species and 11 sectoral Directives that govern the seeds of specific crop species (for beets, cereals, fodder plants, forest material, fruit plants, oil and fiber plants, ornamental plants, potatoes, vegetables, and wine).

The legislative framework for seeds is based on two elements:

1)  Registration of the seed varieties;

2)  Certification of the seed varieties before they can be sold on the EU market.

The general principle is that companies can register their new seed varieties in the national catalogue of one of the EU Member states, which needs to notify the Commission, after which the seed variety will be registered in the Common Catalogue of the EU.

Before registering the variety, the seed needs to be tested for 4 elements:

– Distinctiveness: it needs to differ clearly on, at least, one important characteristic from another registered seed variety;

– Uniformity: all resulting plants should be identical;
– Stability: the plant characteristics should remain in place over generations;
– For agricultural crops, the ‘Value for Cultivation and Use’ needs to be proven. 6

The first three elements are assessed through so-called DUS-tests (Distinctiveness, Uniformity, Stability), while agricultural plant varieties are subjects to additional VCU trials (Value for Cultivation and Use). The DUS-tests allow for the identification and description of varieties, while VCU trials test the agronomic performance of the plants resulting from the seeds, for instance on their yields. In order to be registered in the catalogue, the VCU tests need to show that the seed offers better results in terms of

5 EPRS, loc.cit.
6 Library of the European Parliament, Seeds and other plant reproductive material: towards new EU rules, 2013, pp. 2-3.

cultivation or use than other varieties that are available on the market. In general, DUS tests are conducted over a period of 2 years, while the VCU trials usually last between 2 and 3 years.

Before the seeds can be legally sold on the EU market, they also need to undergo a certification procedure, through inspections that verify and guarantee their identity, health and quality (for instance in terms of disease resistance). This is applicable to both seeds from inside the EU and seeds coming from outside the EU.

For most varieties, seeds are required to have multiplied over at least two generations (corresponding to around 2 years of control) and need to be sealed, labelled, sampled and tested to ensure that they meet the prescribed minimum standards. Seed certification costs usually account for 1 to 2% of the total production costs, which are mostly shared between the public authorities and the industry

For GM seeds, the legislation also requires the varieties to be authorised in line with the procedures outlined in GMO Directive 2001/18/EC before they can be included in the Common Catalogue and be sold on the European market. If the GM seed will also be used in food and feed, it has to follow the rules of Regulation (EC) 1829/2003 on genetically modified food and feed as well. As a result, the registration of GM seeds requires significant additional costs compared to non-GM seeds.

The authorisation process of “novel foods”

Novel foods are food or food ingredients that have not been consumed significantly within the European Union before 1997, when the first Regulation 258/97 on novel foods entered into force. It involves food from new sources; food obtained through new technologies (such as nanotechnology) or the use of new substances (for instance plant sterols), as well as food traditionally eaten outside of the EU (for example chia seeds). 7

A novel food requires a scientific safety assessment and an authorisation before it can be sold on the EU market, and must fulfil the following criteria in order to be authorised:

7 EFSA, Novel and traditional food: guidelines finalised, https://www.efsa.europa.eu/en/press/news/161110.

• –  it must not pose a risk to human health
• –  it must not be less nutritious if it replaces a similar food, and
• –  it must be labelled to avoid misleading the consumers. 8Companies need to submit their applications for the marketing of their novel food to the relevant Member State authority, and are required to present several types of scientific data on the compositional, nutritional, allergenic and toxicological characteristics of the products, as well as information on the production process and the intended use. The authority can allow the marketing of the product if the Commission and other EU Member States do not object, and are also able to ask EFSA for an additional assessment. If a decision of the Commission is needed, it will ask the opinion of the Standing Committee on Plants, Animals, Food and Feed. 9

  The rules applicable to novel foods will be updated in 2018, with the entry into force of Regulation (EU) 2015/2283. Within this new regulatory framework, an authorisation procedure can be started by an interested party, a country of by the Commission itself. The Commission will have to possibility to ask EFSA for an opinion on the safety of the novel food and will also need the endorsement of the Standing Committee on Plants, Animals, Food and Feed.

  The legislation on novel foods does not cover additives, flavourings, extraction solvents, and most importantly, does not apply to GMOs – which are subject to Regulation EC 1829/2003 on GMOs for food and feed.

  So far, there have been around 180 applications for novel foods (7 to 10 applications per year), of which 80 have been authorised for use in the European Union. 10

  The average cost of submitting an application for novel foods is estimated at between €20 000 and €45 000, although based on the fees charged by the national authorities and the data requirements, the expenditures can vary between a few hundred to one million euro. The Novel Food Regulation also foresees the possibility of a simplified procedure for foods similar to existing products, for which the requested fee ranges from €900 to €2000. The average period between the application and the final authorisation is 2 to 4 years. 11

  8 European Parliamentary Research Service, Updating rules on novel foods to keep up with scientific advances, 2015, p. 2.
  9 EFSA, loc.cit.
  10 European Commission, Authorisations, http://ec.europa.eu/food/safety/novel_food/authorisations_en.

  11 European Parliamentary Research Service, Updating rules on novel foods to keep up with scientific advances, 2015, p. 3.

Main legislation

GMOs

• –  Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms
• –  Regulation (EC) 1829/2003 on genetically modified food and feed
• –  For cultivation: assessments of the environmental risks, monitoring of the GMOs after their release, labelling and registration requirements, and public consultations.
• –  For food and feed: authorisation; supervision; and labelling (if they contain more than 0.9% of GMO components).- Registration fee: up to € 90 000
  – Total costs of €6.8 million on average for the required data collection (has varied from €3.8 million to €10.3 million)

• –  For cultivation: 3 years
• –  For food and feed: 3 to 4 years

Seeds

– Directive 2002/53/EC on the common catalogue for varieties of agricultural plant species

– 11 sectoral Directives

– GM seeds also need to follow the GMO legislation: Directive 2001/18/EC and Regulation (EC) 1829/2003

– For registration:
* DUS tests: identification and description of the seed variety.

* VCU trials (for agricultural crops): to test the agronomic performance of the plants resulting from the seeds.

– For certification: inspections verifying and guaranteeing the identity, health and quality of the seeds; labelling; and tests of samples.

Registration:
– DUS tests: €90 – €2000

per year *
– VCU tests: €1000 –

€2550 per year *

Certification: 1% – 2% of total seed production costs *

* mostly shared or even fully paid by the public authorities

Registration:

– DUS tests: 2 years

– VCUtests:2to3 years

Certification: at least 2 years

Novel foods

– Regulation 258/97, which will be replaced by Regulation (EU) 2015/2283 from 2018 onwards

– Does NOT apply to GMOs, which are subject to Regulation (EC) 1829/2003 on genetically modified food and feed

Safety assessment and authorisation, requiring data on the compositional, nutritional, allergenic and toxicological characteristics of the products, as well as information on the production process and the intended use.

€20 000 – €40 000 (but can vary from a few hundreds to one million euro)

For the simplified procedure of novel foods similar to existing products: between €900 and €2000

2 to 4 years

Requirement s

Average costs for approval

Average duration for approval

Relevance of “New Techniques” application in EU agriculture

Given the enormous pressure that EU agriculture has to face, such as high population growth, climatic events and shrinking natural resources, the biggest challenge is how to meet increasing food demand (over 9 billion people by 2050), ensuring a high rate of productivity, without impacting the environment.

In this overall alarming context, the use of some of these NBTs can play a key role in allowing plant breeders to introduce in an efficient way, very precise, targeted genetic modifications, which have the capacity to fasten the selection speed. In other words, this translates into: low cost, ease of use and speed up of innovation processes, when compared with conventional plant-breeding techniques. Furthermore, NBTs are not only a valuable option for breeders, but these modern biotechnologies also allow to develop plant varieties that can adapt to climatic changing conditions.

To summarize, NBTs’ potential application in agriculture and food systems12 can be identified in:

• Precise and rapid alteration of crops to boost yields (genetic engineering is more predictable than conventional approach, given the targeted way through which direct modifications of an organism’s own genetic sequence are inserted)
• Improved crop & vegetable resource efficiency
• Reduced inputs needs
• Plants with herbicide tolerance
• Plants with pest or insect resistance
• Plants with drought or flood resistance (climate change resilience)
• Enhanced nutritional quality of food crops
• Changes in composition of nutrients in plants (i.e. vitamins or fatty acids)
• Food crops with reduced allergenicity (for example wheat without gluten)
• Increased fruit and vegetable shelf-lifeFocusing on the health-safety dimension, as highlighted by the SAM-HLG explanatory note “an assessment of safety can only realistically be made on a case- by-case basis and depends on features of the end product including:
  unintended and intended effects, the species, the environment in which the product is used, the agricultural practice in question, the intended use and the exposure”.

  12 European Parliamentary Research Service, New plant-breeding techniques: Applicability of GM rules, 2016 p. 2

Accordingly, NBTs should go hand in hand with good agricultural practices. This means that the potential benefits of these new techniques should be further evaluated by considering their complementarity to the conventional farming methods.

Positions of experts, EU institutions and Member States on NBTs High Level Group of the Commission’s Scientific Advice Mechanism (SAM)

In October 2007, upon the request of the EU Member States, the European Commission set up an expert working group composed of nationally appointed scientists, in order to assess whether or which NBTs should be regulated by the GMO legislation. The working group examined the following techniques: ODM, ZFN, cisgenesis and intragenesis, grafting, agro-infiltration, RdDM, reverse breeding and synthetic genomics. 13

The working group completed its work in 2012, but the final report was never released due to a lack of consensus among the members. While the experts unanimously agreed that plants developed through cisgenesis and intragenesis should fall under Directive 2001/18/EC, opinions were still pending on the regulatory status of the remaining NBTs. 14

On April 28, 2017 the SAM-HLG released its explanatory Note in response to the request, formulated in the Scoping Paper (adopted by the HLG on 25 November 2016), by the European Commissioners for Health and Food Safety, Vytenis Andriukaitis and for Science, Research and Innovation, Carlos Moedas to provide an up-to-date overview and a comprehensive scientific comparison on new techniques in agricultural biotechnology, including their potential agri applications in both fields of synthetic biology and gene drives, considering the key characteristics of each of these new techniques.

The Note underlines, among the other, that:

• “All living organisms are subject to alterations to their genetic information due to molecular processes which can occur spontaneously and due to exposure to environmental stressors”.

• “All breeding techniques applicable in agriculture (conventional breeding techniques, CBT; established techniques of genetic modification, ETGM; and new

13 European Commission, loc.cit. 14 EPRS, op.cit., p. 4.

breeding techniques, NBT) make use of genetic diversity and change whether naturally occurring or resulting from human intervention, in order to select or generate plants, animals or microorganisms that exhibit preferred characteristics”.

• “There is heterogeneity within the NBT, and some similarities between some NBT and some CBT and some ETGM, and this is reflected in the variety of end products which can result from the employment of NBT. These similarities and differences relate to 1) molecular mechanisms; 2) the size, location and frequency of the resulting genetic changes (precise and intended vs. imprecise and unintended); 3) the extent to which ETGM are employed in NBT; and 4) the presence or otherwise of exogenous nucleic acids (DNA or RNA) in intermediate and end-products. These factors affect among others the extent to which the genetic changes are detectable”.

• “The genome editing subset of NBT can produce precisely located alterations to DNA sequences, ranging from ‘point mutations’ (changes of one or a few nucleotides, which may be either random or specified) to the insertion of (endogenous or exogenous) genes. Other NBT, such as RNA-dependent DNA methylation (RdDM) make no changes to DNA sequences at all”.

• “The end products of NBT may or may not contain exogenous DNA depending largely on the technique(s) employed. The development of an end product that involves the use of NBT may additionally use ETGM in one or more intermediate steps (e.g. in genome editing, RdDM), agro- infiltration, etc.), and as a consequence, exogenous nucleic acids may be present in intermediate products but not necessarily in the end product”.

• “This variety and versatility of NBT explains why comparisons between NBT and CBT, and NBT and ETGM, in the Note are only made where relevant, and suggests that grouping techniques together as NBT may not be optimal for scientific or other reasons”.

• “Differences between the groups of techniques (CBT, ETGM, and NBT), of relevance to unintended effects and efficiency, depend on the extent to which changes can be targeted, and how precisely they can be made. Changes made with CBT, in particular by mutation breeding in plants, require the screening of a large population in which changes have been randomly induced and the selection of desirable progeny. ETGM and NBT by contrast do not require such extensive screening as pre-defined changes are made to defined genetic sequences or to gene expression”.

• “ETGM and NBT differ in the extent to which they produce ‘unintended effects’. Unintended mutations do not however always have phenotypic effects, and not all phenotypic effects are detrimental”.

• “Random insertion of nucleic acids is characteristic of the employment of ETGM in plants and animals, and multiple insertion events can also occur at untargeted and therefore uncontrolled genetic locations. By contrast, the NBT of genome editing offer not only the ability to target insertions (resulting in comparatively fewer unintended effects on the expression of other genes or their disruption) but also the ability to make small, precise and specific changes, such as point mutations, which can also be observed in nature. The employment of the NBT of gene editing does not exclude ‘off-target’ effects, where a precise change is made to a genetic sequence identical or similar to that in which the change is desired, but in another location. By contrast with unintended effects resulting from ETGM and CBT, NBT off-target effects are rare, and in general, the frequency of unintended effects in NBT products is much lower than in products of CBT and ETGM”.

• “The precision available from the employment of NBT and efficiency of their use means that some products can only be realistically obtained with the use of these techniques and not through the use of CBT or ETGM. The issues of unintended effects due to NBT (and in particular, genome editing related off-target effects) are the subject of much research at present as evidenced by the rapidly growing number of publications in the field”.

• “The Note makes qualitative statements about the relative costs and speed of product development. The speed with which mutations can be introduced using NBT is often higher (in particular when using the CRISPR-Cas genome editing system) than that which can be achieved with ETGM and CBT, mainly due to the reduced need for time-consuming screening procedures and/or back-crossing, with correspondingly lower costs. The time and costs related to subsequent regulatory approval are not within the scope of the Note”.

This independent explanatory note, as also specified in the Scoping Paper, does not take a position; it does not cover legal issues and it does not make policy recommendations to policymakers.

The European Food Safety Authority (EFSA)

The European Food Safety Authority (EFSA) has published opinions on two specific types of NBTs and their safety assessment, namely on plants developed by cisgenesis and intragenesis, and on the Zinc Finger Nuclease 3 technique. EFSA concluded that the existing rules on risk assessments for GMOs are appropriate for cisgenic and intragenic plants, as well as for the ZFN-3 technique.

In its opinion on cisgenesis and intragenesis, EFSA argued that cisgenic plants have similar risks than plants bred with conventional breeding techniques, but that intragenic (and transgenic) plants can involve additional risks. It notices that all of these breeding techniques can produce ‘variable frequencies and severities of unintended effects’, which cannot be predicted beforehand and need to be assessed on a case-by-case basis. In general, however, such unwanted genetic traits can be removed by breeders during the selection and testing phases. EFSA concludes that the risks of these NBTs for human and animal health will depend on factors such as the extent to which the plant is cultivated and consumed. 15

In its opinion on Zinc Finger Nuclease 3, EFSA found that this technique can minimise the risks of genetic disruption compared to the currently used transgenesis methods, as it allows a more precise insertion of DNA into a defined area of the plant genome. These techniques would also involve less olve less invchanges in the plant genes than most mutagenesis techniques, and when these changes do occur, they would be similar to those produced by conventional breeding techniques. 16

The Joint Research Centre (JRC)

In 2011, the Joint Research Centre (JRC) of the European Commission published a report on ‘New plant breeding techniques: State-of-the-art and prospects for commercial development’, which includes an assessment of the intended and unintended changes and effects of NBTs.

The JRC concludes that it is currently impossible to identify the genetic modification for plants bred with the following NBTs: ZFN-1 and 2, ODM, RdDM, grafting, reverse breeding and agro-infiltration. On the condition that information on the introduced DNA is provided, it is however possible to identify the genetic modifications created through ZFN-3 technology, cisgensis/intragenesis and floral dip. Without any prior knowledge on the DNA introduced by the NBT, it is not possible to identify genetic modification in the modified plants.

The European Parliament

On 25 February 2014, the European Parliament issued a resolution on ‘Plant breeding: What options to increase quality and yields?’, in which it stressed the importance of developing and using NBTs that respond to societal and agricultural demands and being open to the new technologies available. The Parliament also

15 EFSA, 退 Scientific opinion addressing the safety assessment of plants developed through cisgenesis and intragenesisn, EFSA Journal, Vol. 10, No. 2, 2012.
16 EFSA, 退 Scientific opinion addressing the safety assessment of plants developed using Zinc Finger Nuclease 3 and other Site-Directed Nucleases with similar function’, EFSA Journal, Vol. 10, No. 10, 2012.

expressed concerns over the delayed regulatory assessment of NBTs and called on the Commission to clarify their legal status as a matter of urgency. 17

France

In France, the Environmental Code excludes organisms obtained through mutagenesis from the GMO regulation through Article D.531.2. Nine organisations and trade unions have challenged the legality of this article and requested its repeal to the Prime Minister, who in turn has requested the Council of State (Conseil d’Etat) to repeal the article and pronounce a moratorium on herbicide-tolerant plant varieties obtained through mutagenesis.

On 3 October 2016, the Council of State referred 4 questions to the European Court of Justice (CJEU), related to whether a variety of herbicide-resistant rapeseed obtained through New Plant Breeding Techniques should follow the GMO approval process. These questions especially address the NBTs of ODM (oligonucleotide directed mutagenesis) and SDN (site directed nuclease), and revolve around the following issues:

1) Do organisms obtained through mutagenesis constitute GMOs, and are they therefore subject to the rules of Directive 2001/18/EC on the deliberate release into the environment of genetically modified organisms? Or are these organisms, or some of them, exempted from the precautionary measures, impact assessment and traceability requirements included in this Directive?

2) Do varieties obtained through mutagenesis constitute ‘genetically modified varieties’ subject to the rules laid down by Directive 2002/53/EC on the common catalogue of varieties of agricultural plant species, or are they exempted from the obligations laid down in this Directive?

3) If organisms obtained through mutagenesis are excluded from Directive 2001/18/EC, does this mean that EU Member States are not allowed to subject these organisms to the obligations laid down by the Directive, or do they have a margin of appreciation to define the regime applied to these organisms?

4) Does the precautionary principle, guaranteed by Article 191.2 of the TFEU, call into question the validity of Directive 2001/18/EC? Should we take into account the evolution of genetic engineering processes, the emergence of plant varieties obtained through these techniques and the current scientific uncertainties about their impacts and the resulting potential risks for the environment and human and animal health?

17 European Parliament, Resolution on iament, ressing the safety assessment of plants developed usin, 2014, p. 6.

The Council of State will rule on this matter after receiving the opinion of the Court of Justice, which is now foreseen on the 20th of December 2017. 18

On 29 March 2017, the French Parliamentary Office for evaluation of scientific and technological options (OPECST)19 – assisted in its work by a Scientific Committee – issued a report on “the economic, environmental, health and ethical challenges of biotechnology in the light of new research tracks”, which adopts an holistic perspective on the topic, by examining research in biotechnology, applications of new biotech to human medicine, to the environment, agricultural applications (NBTs), legal and security issues as well as risk assessment and public discussion.

The Report was published after more than a year of study. The overall process gathered a wide variety of actors: from scientists, doctor and academics, to politicians, industries and representatives of civil society.

Having developed this holistic approach, “the rapporteurs support the development of new breeding techniques, which will happen in any case outside Europe”.

The rapporteurs call for greater priority to be given to research in this area and decisions to be taken to avoid EU researchers and companies to relocate and so the EU and its Member States to lose ground at global level on this key economic sector.

Regarding the potential role of new breeding techniques applied to agriculture, the rapporteurs, after consultations with scientific experts, concluded that :

• –  “New Plant-Breeding techniques should be considered on a case-by-case basis to fully understand the impact of a new genetic trait on the environment”;
• –  “Targeted genome modifications techniques could have revolutionaryapplications in agriculture, as consisting in the very precise introduction of genetic traits, which enable to accelerate the selection speed. Furthermore, they could occur naturally and are virtually undetectable”;
• –  “NBTs are complementary to the other agroecology methods. They can be appropriate for both big and small producers”18 Feed Navigator, France asks ECJ to decide if plants from new breeding techniques are GMOS, http://www.feednavigator.com/Regulation/France-asks-ECJ-to-decide-if-plants-from-new-breeding- techniques-are-GMOs.
  19 OPECST, which was set up by Act n° 83-609 of July 8, 1983, following a unanimous vote of the French Parliament, aims  » to inform Parliament of scientific and technological options in order, specifically, to make its decisions clear « . OPECST  » collects information, launches study programmes

and carries out assessments ». More details available here: http://www.assemblee- nationale.fr/11/documents/index-oecst-gb.asp

Overall, the rapporteurs specify that “new breeding techniques are not GMOs within the meaning of the EU Directive 2001/18” and that “assessments must be adapted to the risks involved”.
With regard to the public opinion dimension, and by recognizing the difficulties that the process would involve, they consider necessary to engage the public in a renewed debate on these new biotechnologies, “even if they are still at an experimental stage”, by adopting a multidisciplinary approach.

Germany

On Thursday 24 November 2016, Minister of Agriculture Schmidt (CDU/CSU) announced that the Federal Government adopted a draft amendment to the Genetic Engineering Act (18/10459). Under the proposal, organisms obtained through new breeding techniques are not necessarily regarded as GMOs; whether the techniques would fall under the Genetic Engineering Act or not would be assessed on an individual case-by-case basis, and will be both process- and product-related.

The views on NBTs also remain highly divided within the German government. For instance, a legal analysis commissioned by the German Federal Agency for Nature Conservation concludes that the organisms produced by NBTs fall under the scope of Directive 2001/18/EC. The analysis based this judgement on the fact that genetic modifications are carried out purposefully by NBTs and lead to changes in the organisms which do not occur naturally. 20 Meanwhile, the German Federal Office of Consumer Protection and Food Safety argues that certain techniques – ODM and CRISPR-Cas9 – do not constitute GMOs in the sense of the Directive, because the modifications can also be generated through conventional mutagenesis techniques and cannot be distinguished from them. 21

Other EU Member States

Opinions on the legal status of the various NBTs also differs widely between other Member States and their national government agencies.

In 2015, the Board of Agriculture of Sweden announced, after questions from Swedish researchers, that some Arabidopsis plants that were developed using the CRISPR-Cas9 technology do not fall under the EU definition of a GMO and thus fall outside the scope of the Directive.

20 German Federal Agency for Nature Conservation, Legal Analysis of the applicability of
Directive 2001/18/EC on genome editing technologies, 2015.
21 German Federal Office of Consumer Protection and Food Safety, Opinion on the legal classification of New Plant Breeding Techniques, in particular ODM and CRISPR-Cas9, 2016.

In the United Kingdom, the Advisory Committee on Releases to the Environment indicated that only plants obtained through cisgenesis and intragenesis should be recognised as GMOs. On the contrary, the Commission on Genetic Modification (COGEM) of the Netherlands has argued that cisgenic plants should be exempt from the GMO Directive, as this technique only inserts genetic elements from the same or cross-compatible plant species.

Furthermore, the crop development company Cibus has also asked six countries for their opinion on the ODM technique, namely Finland, Germany, Ireland, Spain, Sweden and the United Kingdom. All of these Member States told Cibus that they do not consider the ODM-technique to lead to a GMO as defined by EU legislation.

ANNEX: Short explanations of technical NBT terms

1) Site-Directed Nucleases (SDN)

SDN refers to the general technology of using a DNA-cutting enzyme (nuclease) to generate a targeted break in the DNA. The aim is to take advantage of the DNA break and the plant’s natural repair mechanisms to introduce targeted changes in the plant characteristics.

The various applications of SDN are usually called SDN-1, SDN-2 and SDN-3, depending on the specific DNA break and repair process. Examples of SDN techniques include Meganuclease (MN), Zinc Finger Nuclease (ZFN), Transcription Activator-Like Effector Nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR).

2) Oligonucleotide Directed Mutagenesis (ODM)

The ODM technology uses a site-specific oligonucleotide (an organic molecule that forms the basic building block of DNA) to cause a specific single-base change to one or only a few bases of the DNA. The oligonucleotide is identical to the DNA sequence in the plant, except for the single base-pair change. The plant cell will repair this ‘mismatch’ by incorporating it into its own DNA sequence, resulting in a desired specific change in the plant’s genome (the oligonucleotide is degraded by the cell after a short period of time).

3) Cisgenesis/Intragenesis

Cisgenesis and intragenesis refer to the introduction of a DNA fragment into a plant that is derived from the same or closely related species, in order to transfer useful genes.

While cisgenesis refers to the introduction of whole unchanged genes, intragenesis uses a new combination of DNA fragments taken from the species itself or from compatible plant species. As such, only cisgenesis can achieve results that are also possible through traditional breeding methods (although in a much shorter time period), while it also entails less risks for unintended effects than intragenesis.

4) RNA-dependent DNA methylation (RdDM)

RdDM uses epigenetic processes to change the activity of targeted genes without changing the DNA itself. As such, it regulates the gene expressions induced by developmental or environmental changes, for instance drought resistance when plants are exposed to drought conditions. These changes in plants are mediated by small interfering RNA (hence the name RNA-dependent methylation), and may persist for a number of generations, after which the effect will gradually fade away.

5) Grafting (non-GM scion on GM rootstock)

Grafting involves attaching a non-genetically modified scion (the upper part of the plant) onto a genetically modified rootstock. Examples include fruit trees, grapes, tomatoes, cucumbers, and roses.

6) Reverse breeding

Reverse breeding is a method in which the order of events leading to the production of a hybrid plant variety is reversed. The resulting hybrid plant is genetically similar to the original plant and does not contain foreign DNA.

7) Agro-infiltration

Plant parts, mostly leafs, are inserted in the plant through liquid Agrobacterium tumefaciens in order to transfer desired genetics or genetic expressions to the genome of the plant. The response of the plant is monitored to select plants for further breeding. This technique is mainly used to create resistance for crops against diseases.