The <scp>EU</scp> Court of Justice extends the <scp>GMO</scp> Directive to gene‐edited organisms

Abstract

On the 25th of July, the EU Court of Justice (ECJ) ruled that all plants obtained through gene editing techniques are subject to the obligations laid down by the GMO Directive 2001/18/EC. To understand the significance of this ruling, we need to look at the history behind it. The directive defines a GMO (Genetically Modified Organism) being ‘an organism […], in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination’. Such alterations may include the addition of foreign genetic material (transgenesis), or the mutation or deletion of an autochthonous gene. About 60 years ago, artificial means of modifying genetic traits were adopted, including radiation-driven mutagenesis and chemical-driven mutagenesis, both of which induce mutations in a completely random manner in terms of kind, site and number of mutations. These methods are currently referred to as ‘classical mutagenesis’. The breeders would then select for the desired phenotypic traits even without knowing what mutation actually generated them. In the 1990s, the application of genetic engineering (transgenesis) in plants became broadly established. In parallel, early investigations of the oligonucleotide-driven mutagenesis techniques were also performed, albeit with a certain degree of imprecision. In 2001, the new EU directive on the deliberate release of GMOs into the environment was put into place. Specifically, it categorizes GMOs that have a history of safe use (e.g. GMOs derived by mutagenesis) as exempted from further obligations, and other GMOs (among which were transgenic organisms) that have to undergo a comprehensive and restrictive risk assessment. The latter category must be labeled as GMO when marketed in the EU. Precisely targeted mutagenesis or genome editing was boosted by the CRISPR/Cas system only after 2012, and therefore the ECJ considered that it does not have a long ‘history of safe use’. As a result, with its latest ruling, the ECJ clarified that genome-edited organisms are not exempt from GMO obligations. In 2016, the European Commission had requested from its Scientific Advice Mechanism (SAM) to review the new breeding techniques in agricultural biotechnology. In April 2017, the SAM published its explanatory note, which compared classical breeding, classical mutagenesis, genetic engineering (transgenesis) and genome editing. It states: ‘[…] An assessment of safety can only realistically be made on a case-by-case basis and depends on features of the end product […].’ [1] We contacted the European Commission and were informed that at this stage it is carefully analyzing the ruling. The ruling was also discussed on September 11th with Member State representatives in the Standing Committee on Plant Animal Food and Feed and on October 18th 2018 in the Regulatory Committee 2001/18, where the Commission underlined the need for Member States to implement the court ruling at all levels. The European Commission also invited Member States to specifically state what they expect from the Commission and to submit specific information detailing their state's position. In the past few months, many scientists from across Europe have raised their voices against the court ruling. The implications of this very strict interpretation of the current legislation are far-reaching, and are likely to affect both the economy, in terms of trade and competitiveness, and research. Many demand an open and constructive discourse between scientists and politicians throughout Europe, in order to clear up old prejudices and initiate a paradigm shift. We interviewed Dr. Stefan Jansson, Head of the department of Plant Physiology at the University of Umeå, Sweden, and Dr. Ralf Wilhelm, Head of the Institute for Biosafety in Plant Biotechnology at the Julius Kühn-Institut Federal Research Centre for Cultivated Plants, Germany, to shed light on this intricate situation. Dr. Stefan Jansson, photo by Per Melander, Umeå University Dr. Ralf Wilhelm, photo by Wolfgang Borgmann ‘The major complication lies in the way the EU directive was formulated in 2001. It first stated which techniques give rise to GMOs (including all kinds of common mutagenesis techniques), and in step two it stated which GMOs are exempt from regulation (i.e. those created by classical mutagenesis). So, according to the EU law, basically all plants that we eat are GMOs, but GMOs that are not regulated; this makes it really complicated. The exemption had to be made when the law was written, as we would simply not have anything to eat if all plants were under strict regulation. Now, the ruling states that gene-edited plants are GMOs (that was expected) but not GMOs exempt from regulation. The irony is that the results from gene editing could be identical to those of classical mutagenesis techniques, but with fewer side effects. So the less-safe technologies are unregulated while the safer ones are regulated’, says Dr. Jansson. ‘The European Court of Justice dealt with an action brought before the French Council of State by a French agricultural union contesting the fact that herbicide-resistant seeds have been obtained by in vitro mutagenesis, resulting in the same effect obtained by introducing a foreign resistance gene by transgenesis. It appears that the ECJ bears in mind the trait “herbicide tolerance”. Interestingly the argumentation actually sketched a product-related “risk” – linked to herbicide tolerance – rather than a process-based one. Indeed, herbicide tolerance is a major trait in commercialized transgenic plants; it can also be achieved by classic mutagenesis or genome editing – and it can also occur through natural mutation. Just think about how herbicide-tolerant weeds evolved in Europe without the cultivation of GMOs’, explains Dr. Wilhelm. ‘The problem is that the definition was based on the knowledge available in the 1990s and is now outdated or even obsolete, so the court had to decide which part of the definition to pay attention to and which not. For example, the consensus among scientists is that ‘altered in a way that does not occur naturally by mating and/or natural recombination’ would mean that many genome editing events (like deletions or point mutations) could not be covered, since they do occur naturally. But that aspect was ignored by the court’ says Dr. Jansson. ‘It is actually somewhat tricky’, adds Dr. Wilhelm. ‘There can be natural transgenic plants, like sweet potato. Nevertheless, this transgenesis was not derived through a technical, but a natural process. Therefore, a sweet potato is not considered a GMO.’ According to Dr. Jansson, ‘The only logical legislation would be to either regulate all plant varieties that have been bred, or none of them. However, politicians cannot choose the first option, as most of us would starve to death, nor the second, since the anti-GMO sentiment is so strong. So it simply becomes an impossible task.’ ‘A product-based risk assessment regime can acknowledge where we have already gained familiarity with the use of genetic variability and the related traits in breeding independently from the techniques used to generate or select the trait. The key question should therefore be what is actually a novel product to which an (eco-)system is exposed,’ explains Dr. Wilhelm. Many of our cultivated plants bear non-nutrients, allergens or even toxins. The issue with transgenic plants is the introduction and hence the combination of genes that have not been evolving in the common gene pool of the species. Nevertheless, none of the transgenic plants released to the market in the last 20 years have shown to be hazardous to human or animal health or the environment. Yet, mistakes in the management of let's say GM crops may lead to environmental risks or even damage, but that is the case with conventional crops just as well. The modifications induced by genome editing (i.e. targeted mutagenesis) are derived from the autochthonous gene sequences of the organism, and might also occur through natural mutation. So the generated varieties are based on the gene pool of the species or variety. Recently, problems related to climate change have pushed forward the importance of drought tolerance, disease resistance, and several other traits. Such kinds of traits are hardly visible in the products that we consume (like our bread), but secure that they are (sufficiently) available today and in the future. ‘Gene derivation and biodiversity are fundamental for plant breeding. They have been used through selection over thousands of years of breeding. Our cultivated plants often look very different from their wild ancestors. They would hardly have evolved into what they are now without active selection and propagation by man (Fig. 1). I do not see risks specifically associated with genome editing or targeted mutagenesis techniques, compared with classical breeding based on natural variation and selection. A risk is linked to the product, whatever the technology used to generate the plant. Genome editing and targeted mutagenesis are based on detailed knowledge about the genomic sequences. This enables a thorough planning and control of the genomic effect. Beyond that, the good practice of variety breeding will apply as for conventionally bred plants. And a good agricultural practice should ensure to minimize further unintended impacts by crop management.’ What is the role of the European Food Safety Agency (EFSA) regarding GMOs? EFSA carries out the risk assessment of GMOs in the European Union. EFSA's GMO Panel is responsible for preparing and adopting the GMO risk assessments. EFSA stands ready to provide scientific and technical assistance to the European Commission. When drafting its opinions EFSA consults with the competent authorities of the Member States and the public and responds to their interventions. Based on EFSA's scientific opinions on the safety of GMO applications, EU Member States and the European Commission decide on GMO authorizations. It is to be noted that while EFSA provides a risk assessment, the Commission and Member States as risk managers also take into account other considerations in deciding whether or not to authorize a GMO. What does the risk assessment of a GMO entail? Each application received by EFSA is subject to a thorough review by EFSA's GMO Panel, which has 18 independent scientific experts, supported by EFSA staff members. The risk assessment follows the framework laid down in the EC Directives and Regulations, which are transferred to practice in EFSA's guidance documents. EFSA approaches each GMO risk assessment on a case-by-case basis. There is no presumption of safety for any GMO, as each GMO is unique and must be assessed individually to ensure that it poses no risk to human or animal health and the environment. ‘Small and medium sized breeders in Europe have now hardly a chance to use genome editing techniques for the development of new varieties. The Agricultural technology Working group of the European Plant Science Organization tries to track possible impacts on ongoing research projects and future calls. Researchers throughout Europe fear that public funders may alter their strategies, and that field releases become even more challenging. Many research projects need to “map” the value chain and cooperate with SMEs. With regard to the applications of genome editing in plant science the ruling is undermining this strategy as the scope for a market application and the use by SME is lost or at least questioned.’ ‘Genome editing is expected to shorten the breeding process. Nevertheless, breeding a new variety up to market release will still be a process of years. For fruit trees like apples, the advantage may be considerably high, as breeding is otherwise an effort for generations of breeders. Of course, the speed and applicability depends on the species, available genomic data and the complexity of traits to modify. All in all, genome editing may complement rather than substitute other classical breeding techniques, for example by a targeted improvement of disease resistance of an otherwise already high value variety. There might be a misperception about “speed” in breeding caused by the rapid development of CRISPR/Cas applications in plants. On the other hand, the agricultural ecosystem is not static and changes may occur within their intrinsic time scale, such as the breakdown of a disease resistance. Such changes pose a time challenge to plant breeding and crop management.’ ‘There is no general answer to that question. If the modification is identical they are not different. However, one can also do modifications using CRISPR that could hardly be done with other techniques, and they are, of course, different.’ ‘They cannot. Or more precisely, a scientist or breeder who knows exactly what edit has been made can, of course, design two specific PCR primers, amplify and sequence that particular region of the genome. But if she/he does not know, or is unwilling to disclose what has been done, there is simply no way to find out. The consequences for international trade are hard to overlook. A growing fraction of the plants in the world will not be GMOs where they are grown, but should become GMOs when entering the EU (and labeled), and there is no way to test for it. Retailers that want to label their food “non-GMO” will face the same problem. Those that want to cheat will have an easy time.’ ‘The debate after the ruling has been dominated by us scientists, who think this is a bad decision. I am sure that very many decision-makers are uncomfortable with it as they realize that European competitiveness is threatened. So I am convinced it will have to change, the question is just when’, says Dr. Jansson. ‘It will depend on the policy of the Member States and the EU whether and how they will promote plant research and the application of genome editing techniques, as well as whether a change in the regulation is envisaged. I can also see some organic farmers changing their mind, as the need to adapt plants quickly to the impacts of climate change becomes more and more evident’, comments Dr. Wilhelm.