1 Introduction

The commercial use of genome editing technologies is closely linked to national legislation in the field of genetic engineering and biotechnology, as well as to consumer acceptance. The first genome editing techniques in plant breeding were developed before the beginning of this century, but it was not until the use of CRISPR-Cas systems that they became widely established in the range of applications. Since the technique represents an active intervention in the genome to insert a modification at a specific genomic site, the question also arose as to how the techniques should be classified under genetic engineering law. The rapid development of genome editing techniques poses a challenge to national regulations and international treaties worldwide, as most existing laws and regulations do not provide explicit reference to the techniques and their applications as such. To date few genome-edited products have entered the market in the North America (USA, Canada) and Japan (Table 25.1).

Current legislations or guidelines may distinguish between the genome editing techniques, SDN-1, SDN-2, SDN-3, respectively [1] and whether foreign DNA and/or sequence templates have been used during generation of the genome-edited organism.

Table 25.1 Genome-edited products/organisms released to national markets (until May 2023)
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2 Countries/Regions with Strict Regulations

Few countries/regions i.e. European Union (EU), New Zealand, South Africa, Venezuela, Peru and Costa Rica (Fig. 25.1) consider genome edited organisms (plant, animals, respectively; microorganisms maybe unclear) as GMO sensu stricto [7,8,9,10,11,12,13,14]. For these countries genome edited organisms bear broader challenges for law enforcement and compliance especially in relation to international trade. Though mutations can be detected with established molecular biotic methods the identification of the technique or the natural event that caused the mutation is bound to a priori information about the uniqueness of the event and the modified genome sequence(s) [15, 16]. Such data are rarely readily available and hence the detection of unintended residues from (prohibited) genome-edited plants in internationally traded commodities becomes erratic. This problem of law enforcement cannot be solved by labelling regulations and it is also challenging liability and redress. Nevertheless, labelling of “GMO” and the provision of a specific detection method prior to market release is mandatory e.g. in the EU regulatory framework. The EU as well as New Zealand are currently reviewing their respective GMO-regulations. The European Commission has published a legislative proposal in July 2023 that suggests regulatory relaxations for genome-edited and cisgenetic plants and starts the legislation process in the EU [17]. De facto or purposely interrelated, the EU initiated two further policy actions. There is the “Sustainable food system framework initiative” [18] as a framing regulation and the “Revision of the plant and forest reproductive material legislation” [19]. The latter is less acknowledged in the public discussions, but of considerable relevance for the breeding sector as well.

Fig. 25.1
An outline of the world map. The majority of the regions in North America and South America have G Ed crops regulated as conventional crops. India is marked as a special risk assessment for G Ed crops planned under specialized G Ed regulations.

Regulations on genome edited food around the world (updated [7]). The regulatory status of genome-edited (GEd) crops on a global schema

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Several countries are developing a liberal handling of organisms derived with new genomic techniques (NGTs) based on the Cartagena Protocol [20] that defines a living modified organism as “any living organism that possesses a novel combination of genetic material obtained through the use of modern biotechnology”, emphasizing the novelty of a (re)combined sequence. Nevertheless, different countries tend to deal with the novelty aspect considerably differently. This raises challenges for law enforcement, compliance and liability that result when the specific genome editing method would need to be identified from a DNA-sequence of a sample from unknown products or commodities.

3 Countries/Regions with Liberal Regulations for Specific SDN Applications

In Japan three genome-edited organisms have already been introduced into the market (Table 25.1) and crosses using these already registered organisms do not need to be evaluated again and are free from obligations. Japan [21] refers to the Cartagena protocol and exempt SDN-1, SDN-2 and Oligonucleotide-Directed Mutagenesis (ODM) as long as the absence of foreign DNA integration is proven in the latter cases. A guidance on how to proof the absence of foreign DNA with legal sufficiency is pending.

Australia [22] published legal guidelines that essentially exempt organisms derived by SDN-1 mechanisms from restrict regulations of GMO (i.e. if an external sequence template was not used and if the organisms are free from foreign sequences).

4 Countries with Liberal Regulations (for Organisms Free of Foreign DNA)

Several countries followed Argentina deregulating organisms derived by genome editing if they do not contain introduced foreign DNA-sequences. Argentina has updated the regulation several times and it now includes animals and microorganisms [23]. Nevertheless, a pre-assessment or notification may be necessary to assess compliance. This does not mean that sequence information is published as such. Since 2015 more than 35 Prior Consultation Instances has been raised, 66% of those from local developers. Similar regulations are established in Chile in 2017 [24], Brazil and Colombia in 2018 [24], Paraguay, Honduras, Guatemala and El Salvador in 2019 [24].

Likewise, Nigeria [25], Kenia [26] and Malawi [27] published guidelines based on notification and a case-by-case assessment which comes to a decision within few weeks. Essentially, the regulations refer to the absence of “novel combination of DNA” in the genomes whereas small InDels and substitutions are not seen as such.

There are no specific legislations for bioengineering in Canada and USA and at least one product is currently on the market (see Table 25.1). With regards to seeds, Canada follows a product based approach to regulation as recently confirmed by the Canadian Food Inspection Agency (CFIA): “It is the scientific opinion of the CFIA that genome editing technologies do not present any unique or specifically identifiable environmental or human health safety concerns as compared to other technologies of plant development. For this reason, genome-edited plants are regulated using a product-based approach, like any other product of plant breeding. Namely, it is the traits that a plant exhibits and whether these traits would have a significant negative impact on environmental safety that are used to determine whether a plant would be subject to Part V of the Seeds Regulations.” [28] Nevertheless, following the Division 28 of Part B of the Food and Drug Regulations about novel foods Health Canada states “Foods derived from plants that have been genetically modified such that they contain foreign DNA in the final plant product require pre-market notification and assessment as novel foods.” [29] “Novelty” essentially relates to terms like “history of safe use” and “familiarity” with the composition of the final food product. Residues of the CRISPR/Cas-System in the genome would trigger additional safety assessments like any other transgenic organism.

The legislation and regulation of genome-edited crops in the USA is more complex while a specific regulation for bioengineering does not exist but a “Coordinated Framework for regulation of Biotechnology” [30]. Based on the Plant Protection Act (PPA) the Animal and Plant Health Inspection Service of the U.S. Department of Agriculture (USDA/APHIS), based on the Food, Drug and Cosmetics Act (FDCA), the Food and Drug Agency (FDA) and based on the FDCA and the Federal Insecticide, Fungicide, and Rodenticide Act [FIFRA of the Environmental Protection Agency (EPA)] regulate products of biotechnology applications. For several years there are governmental activities to streamline the application. Since 2021 USDA APHIS implemented the Revised Biotechnology Regulations (previously SECURE rule) to provide clear and efficient regulatory pathways for applicants, when the plant products are unlikely to pose a plant pest risk. Products derived by means of genome editing under in most conditions are free from restrictions based on the PPA when changes in the plant product’s genome are either deletion(s), targeted substitutions of a single base pair or solely introductions from sequences derived from the plant’s natural gene pool or edits from sequences which are known to correspond in the plants natural gene pool.

The Philippines established a procedure to regulate genome-edited plants based on the key criteria are whether they possess novel combinations of genetic material not achievable by conventional breeding [31].

5 Other Regulatory Frameworks

China has released guidelines for the safety evaluation of genome-edited plants for agricultural use that do not harbour exogenous DNA-sequences (SDN-1, SDN 2). It provides a tiered assessment based on the risk profile of the target trait. The first category (low risk) refers to plants/traits that do not increase the risk to environmental and food safety, the second to increased environmental risks, the third to increased food safety risks, and the fourth to increases in both environmental and food risks. Different requirements apply for cultivation and or import aside from some general items describing the plant and trait: (1) molecular characterization, editing method applied, data on the edited sequence, presence of residual vector sequences, and off-target analysis; (2) stability of the edit and the trait over at least three generations. At present the guidelines do not specify how to classify a product according to the four categories, what may indicate a case-by-case decision procedure. These requirements are in line with the ones requested in the guidelines for safety evaluation of GMOs. However, genome-edited crops are still managed under GMO regulation, but may require much less complicated food and environmental safety evaluations compared to classical GMOs and may reduce time for regulation from six down to one to two years. However, these guidelines also differentiate between local and foreign developers as foreign firms are not allowed to invest in Chinas biotech sector [32].

A risk based concept was also implemented by India and an appropriate tiered based risk assessment is foreseen to categorizing genome editing in three categories. In a first category, products should be addressed with single or few base pair edits or In/Dels. The assessment confirms targeted edits as well as absence of any biological relevant off target genomic changes, and, if necessary, a phenotypic equivalence to a comparator will be checked on a case by case basis. The second category addressed targeted base pair edits in which the assessment is compiled by phenotypic equivalence and trait efficacy through appropriate contained and/or confined field trials. The third category addresses products harbouring targeted edit(s) with synthetic/foreign DNA. The assessment is the same as for traditional GMOs [33].

Thailand also drafted a risk assessment of genome editing products in which a liberal assessment of SDN1 has been foreseen. However, this draft has not passed official release, yet [34].

6 Other Countries – Ongoing Consultations

In Europe the policy of the EU is considerably important for non-EU countries – which are trading partners. Nevertheless, England, Norway and Switzerland have discussed somewhat differing regulations for genome-edited plants.

The Norwegian Biotechnology Advisory Board initiated a reconsideration of the regulatory framework for GMOs. It sketched a tiered scheme for risk assessment of GMOs including genome-edited organisms combining biological, environmental as well as social criteria [35].

The Swiss Genetic Technology Act (Art. 37a) [36] mandates the Federal Council to develop a draft decree for a risk-based approval procedure for transgene-free GMOs by mid-2024. The current genetic engineering act considers genome-edited organisms as GMO and the year-long moratorium for cultivation of GMO in Switzerland will apply. Nevertheless, field trials are supported.

In 2020 UK left the EU and England – independent of Scotland, Wales and Northern Ireland – moved towards specific regulations for genome-edited organisms. On 23rd March 2023 the “Genetic Technology (Precision Breeding) Act 2023” [37] came into force. It allows for genetic changes that could also have been produced naturally or through “traditional” breeding. It rules that genome-edited (precision bred) plants and animals can be released or marketed in England based on notification and risk assessment provisions.

It is expected that South Korea as well as Taiwan intend to publish clarifications on the status of genome-edited organisms in 2023. Several African countries are reconsidering the regulatory status of GE plants, but it remains open when decisions will be taken.

7 Compliance, Law Enforcement, Detection and Identification

As mentioned above, the legal framework is closely linked to the issue of enforcement and compliance as well as labelling demands, which in turn is linked to the issue of detection, i.e., identification of the genome editing process associated with the DNA sequence of an organism. Unlike organisms obtained by classical transgenesis, organisms edited by ODM, SDN-1, or SDN-2 do not contain sequence elements belonging to elements associated with tranformations (e.g. S35-promotor, Nos-terminator) that simplify broader screening. Moreover, a targeted mutation often does not differ from a random mutation. Hence, a precondition for identification is the information about the uniqueness of a sequence caused by genome editing. The unique sequence length cannot be freely set as recombination events (crossover at meiosis during seed propagation) as well as random mutations may alter the sequence “naturally” [38]. Even large modifications e.g. introgressions, occur in conventional breeding programs [39]. Therefore, there are calls for an international sequence database [40] for unique sequences that identify a genome-edited organism to support screening and detection. The crucial dependence on this information and detection challenges are nicely depicted by the debate about the detection of Cibus herbicide tolerant canola. There is no doubt that any SNP can be sensitively detected in a sample with mixed background. Since at various time Cibus provided contradictory information about the origin of the SNP in its modified canola variety, the sequence itself does not reveal the actual process of modification [41,42,43,44]. For genome-edited organisms that are not considered GMOs in various legislations there is neither a legal obligation to pass detailed sequence information to public international repositories nor an obligation to provide a detection method, as is requested for market release of GMOs in the EU. Within a territory with a uniform legal basis (e.g. in the EU), the establishment of a register may be considered possible, but considering international trade with mixed commodities, law enforcement is challenging. In jurisdictions with differing regulations for SDN-1 and SDN-2 the handling of genome-edited organisms will become even more problematic. In addition, laws that refer to equivalence of genome-edited sequences with sequences that may be generated through conventional breeding will need to specify borderlines. As large introgressions (>>1000 bp) occur naturally and deliberately in conventional breeding, the legally fixed sequence length may affect trade with conventional breeding products as well.

A positive or negative certification regime may be considered that is based on documentation. Such certification systems have been established e.g. in the organic food sector or for certified regional products. To scrutinize detailed compliance, audits based on extended documentation at each step of the supply or value chain would be necessary. Employing blockchain-based tracking systems is recently discussed for agro-food value chains [e.g. 45]. Nevertheless, monitoring the actual physical compliance would need appropriate identification methods (see above).

8 Conclusions

The majority of countries currently do not explicitly regulate genome edited organisms – for various reasons. The legal practice may stay unclear for some countries for the next years. Several major players in international trade (of agricultural goods) already clarified their legal classification of genome-edited organisms in specific legislations, guidance documents, decrees or else related to the handling of biotechnology and bioengineering (GMO). The countries are applying separate regulatory requirements for organisms that do not harbour foreign gene sequences while strict GMO regulations apply in a few countries and the EU. This challenges international trade and national law enforcement and compliance (detection and identification of genome-edited organisms) due to the international heterogeneity of regulations. Hence, there are frequent calls for international harmonisation of legislation on genome-edited organisms to end divergent national regulations.

This situation is likely continuing for at least a few more years, affecting international trade between some countries and preventing or delaying the application and use of genome editing and its products in regions with restrictive regulations. Therefore, the prospects and progress of genome editing in breeding will vary from region to region and also for international and regional players.