Genome Editing - Impact of European Court of Justice (ECJ) Judgment on Plant Breeding

Mutations have enabled plant breeders for millennia to produce plants or varieties with new traits. As part of this process, random mutations have been used all along. Since about the middle of the last century mutants that appeared after mutagenic treatment with radiation or chemicals (conventional mutagenesis) have also been successfully used in breeding. About 20 years ago, new methods were developed, which made it possible to specifically generate mutations in desired genes with only minimal change of the genome (‘genome editing’). The resulting mutations are molecularly indistinguishable from mutations introduced by random or conventional mutagenesis. These new procedures represent extraordinary advances in scientific research and are a promising tool for plant breeding applications.

In its judgment dated 25/07/2018 [PDF, 236KB], the European Court of Justice has ruled that both mutations produced with conventional and with the new mutagenesis methods are genetically modified organisms (GMOs) (see also the press release of the ECJ [PDF, 117KB]). Thus they fall under the regulations of EU Directive 2001/18/EC on the deliberate release of GMOs into the environment (GMO Directive). However, GMOs produced by conventional mutagenesis are excluded from the applicability of the Directive. The judgment constitutes a legal interpretation of the GMO Directive and applies immediately throughout the EU.

From the point of view of the Central Committee on Biological Safety (ZKBS), the ruling is not based on the scientific state. It does not take into account the previous evaluations by renowned institutions, such as the European Academies Science Advisory Council (EASAC), the High Level Group of Scientific Advisors (part of Scientific Advice Mechanism - SAM) [PDF, 2.37MB] or the German Academy of Sciences Leopoldina, the German Research Foundation (DFG) and the German Academy of Sciences acatech.

Since forever, humans have been cultivating and selecting certain plants in order to obtain agricultural crops with beneficial traits. This includes, for example, increasing the yield or resistance to pests or drought. Since the discovery of the laws of inheritance by Mendel, great progress has been made in modern agriculture, since it has since been possible to specifically develop varieties with desirable traits through targeted combination of suitable crossing partners. Each new variety is tested by both the breeder and the licensing authority in a costly procedure over several years before it enters the market.

Since about the year 2000, new mutagenesis procedures have been available, which are summarized under the term genome editing (see Fig. timeline). These new methods allow targeted modification in the genome of crops as well as faster and more efficient breeding progress. The breeding progress is accelerated because the change of certain traits is achieved by the targeted modification of the corresponding genes. Lengthy backcrosses are becoming superfluous.

An overview of already more than 50 different agricultural crops and ornamental plants with over 100 new traits, which have been successfully modified with the genome editing methods, can be found here.

The new procedures can be divided into two (main) categories:

1. The Oligonucleotide-directed mutagenesis (ODM) and

2. Methods using sequence-specific endonucleases, so-called gene scissors (which include: zinc finger nucleases [ZFN], Transcription Activator-like Effector Nucleases [TALENs], Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated [Cas]).

The methods of both categories can be used to produce minimal change (e.g. a point mutation) at a defined position in the genome of the target organism.

In addition to minimal changes, the second method can also be used to induce larger deletions and even insertions (e.g. of foreign genes). These types of changes, which generally fall under genetic engineering act anyway, are not considered here. This article focusses only on minimal genome changes, analogous to the treatise in the ECJ judgment. Such minimal genome modifications can also occur naturally or be induced by conventional mutagenesis. The cause of a mutation cannot be determined at a later point.

According to the ZKBS, the judgment of the ECJ does not represent the current scientific state of knowledge. The following points and justifications of the judgment do not reflect the view point of the ZKBS.

1. The ECJ notes ‘... that organisms obtained by mutagenesis are GMOs within the meaning of the GMO Directive, in so far as the techniques and methods of mutagenesis alter the genetic material of an organism in a way that does not occur naturally.’ (press release of the ECJ, highlights by the ZKBS; see paragraph 29 of the judgment)
   
   This conclusion is scientifically incoherent. Mutations caused by the use of traditional mutagens such as radiation or chemicals cause genetic modifications, as they occur under natural conditions due to natural radiation and other environmental influences. They are based on the same mechanisms. Specifically, natural mutations can arise through the following processes:
   1. Spontaneous, random DNA damage (e.g. deamination of bases, loss of base)
   2. Replication errors and missed repair operations (e.g. mismatch repair)

   3. Influences of the natural environment on the integrity of the genetic material, e.g. radiation (UV radiation from the sun, radiation from natural radioactive decay or the universe), natural inorganic chemical compounds and ions (e.g. nitrous acid, Mn++) and natural organic compounds (e.g. aflatoxins).

      Human-induced conventional mutagenesis is thus based on the same mechanisms as the generation of natural, environmentally induced mutations.

      The extent to which mutations occur naturally is illustrated by the calculation of Prof. Dr. D. Weigel (personal communication), Director of the Max Planck Institute for Developmental Biology, who has identified the occurrence of natural mutations in plants (in the thale cress Arabidopsis thaliana; Ossowski et al., 2010). According to him, around 40 billion natural mutations per generation would occur on a one hectare wheat field. Thus, statistically speaking, there are different mutations in every wheat gene on a small field.
       

2. The ECJ further concludes: ‘… that it is apparent from the GMO Directive that it does not apply to organisms obtained by means of certain mutagenesis techniques, namely those which have conventionally been used in a number of applications and have a long safety record.’ (press release of the ECJ, highlights by the ZKBS; see paragraphs 54 and 68 of the judgment)

   The plants obtained through conventional mutagenesis methods are thus excluded from the applicability of the directive, but not the plants produced by new methods.

   A frequent argument is that additional undesired mutations could also occur beyond the desired location in the genome through the genome editing method. However, they can be identified and the corresponding mutant can be discarded.

   However, many undesirable mutations occur in conventional mutagenesis. And since it is not targeted, the number of unknown background mutations there is even much larger than in genome editing. Years of backcrossing eliminate unwanted mutations in conventional plant breeding. Nonetheless, many background mutations remain undetected in the plant. With that in mind, the question arises as to why conventional mutagenesis is considered safe, but the new methods are not. Furthermore, the ZKBS considers that conventional mutagenesis methods are safe because the plant varieties produced have proven to be safe and stable.

   The new methods can finally generate the same mutations as conventional mutagenesis. The decision of the ECJ judgment may in the future lead to two genetically identical plants being regulated differently in this regard. This fact demonstrates that an assessment of the risk based on the method used, i.e. a process-based risk assessment, is not adequate.

3. Citing the conclusions of the French Conseil d'Etat, the ECJ states ‘... that the risks linked to the use of these new mutagenesis techniques might prove to be similar to those that result from the production and release of a GMO through transgenesis, since the direct modification of the genetic material of an organism through mutagenesis makes it possible to obtain the same effects as the introduction of a foreign gene into the organism ...’ (press release of the ECJ, highlights by the ZKBS; see paragraph 48 of the judgment)

   The mutation changes in the genetic material of a plant should therefore be just as risky as the insertion of foreign genes. This statement is scientifically incorrect.

   In transgenesis, genes and thus traits of crops are transmitted across species. Since these new traits can lead to new or altered risks in crops, they are assessed in accordance with genetic engineering laws. With the new methods of directed mutagenesis, however, modifications can be achieved that may also occur naturally or through conventional mutagenesis (point mutations, deletions). It is therefore scientifically unreasonable that such changes produced by new mutagenesis procedures should be subjected to a separate risk assessment.

4. The ECJ also states: ‘... those new techniques make it possible to produce genetically modified varieties at a rate out of all proportion to those resulting from the application of conventional methods of mutagenesis. In view of these […] risks …’ (press release of the ECJ, highlights by the ZKBS, see paragraph 48 of the judgment)

   This statement is not further explained by the ECJ and is scientifically untenable. It is technically and factually unjustifiable that a hazard arises from the fact that new varieties can be produced faster and to a greater extent using the new mutagenesis methods.
   Regardless of the procedure, each new variety is tested by both the breeder and the licensing authority in a complex procedure over several years before it enters the market.

The genome editing techniques discussed here and in the ECJ judgment are designed to produce only minimal change in the genome of the target organism. The resulting modification can usually be detected analytically, but not the underlying process that led to the genome change (see above). Thus, such a plant is indistinguishable from a plant produced naturally or by conventional mutagenesis.

Many large agricultural countries, such as the US, Brazil, Canada and Argentina, assess the risk of the crops produced, i.e. the product (so-called product-based risk assessment). Plants generated by genome editing and their products are not defined as genetically modified in these countries and may be marketed without the regulatory requirements for GMOs. In terms of global trade, this raises the issue for the European authorities regarding the consequences of the ECJ judgment on how to detect changes in imported food and feed produced by genome editing in order to be able to apply the GMO Directive.

The ZKBS sees no scientific basis for the interpretation of the GMO Directive by the ECJ with regard to genome editing in plants.

As a result of the judgment, the extensive requirements of the GMO Directive must be met in the future in the EU for the development and testing (release) of new plants modified by genome editing. Moreover, the plants developed this way must undergo the elaborate GMO approval process before being cultivated in the EU or used as feed or food.

Furthermore, the fact that outside the EU plants modified by genome editing are not regarded as GMOs in many large agricultural countries and therefore do not require labelling there, creates major problems with international trade and monitoring by the competent European law enforcement authorities.

It is the opinion of the ZKBS that the European genetic engineering act, which is essentially based on the 1990 state of knowledge, urgently needs to be adapted to the current state of knowledge.

Position paper of european research institutions

European Plant Science Organisation (EPSO)

Group of Chief Scientific Advisors (part of Scientific Advice Mechanism -SAM)

Bioeconomy Council of the Federal Republic of Germany

Max Planck Institute for Plant Breeding Research

published: December 2018