Handling Rules

Fig.2: Policies on the classification and handling of genome-edited organisms under the Cartagena Act.

Living organisms regulated by the Cartagena Act are defined in Article 2. In this act, a “living modified organism” is defined as “an organism that possesses nucleic acid, or a replicated product thereof, obtained through use of the technologies for the processing of nucleic acid extracellularly.” The key factor in examining the handling of genome-edited organisms under the Cartagena Act is whether the organism falls into a “living modified organism,” i.e., whether it contains a foreign gene or a foreign DNA/RNA fragment (“foreign gene” hereafter). Therefore, it is first assessed whether a foreign gene is introduced into the organism in the process of genome-editing (Fig. 2).

(1) If a foreign gene is not introduced, the organism is classified as an organism that is not subject to the regulations. e.g., genome-edited organisms produced by delivering artificial nuclease proteins (TALEN, etc.).

(2) If a foreign gene is introduced, the organism is not subject to the regulations upon confirming the removal of the gene. e.g., Genome-edited organisms produced by delivering protein/RNA complexes (CRISPR/cas9 etc.) directly to the cells or by transferring and expressing the tool genes transiently in the cells. The tool genes must not remain in the cells eventually. Null segregants from which integrated foreign genes are ultimately removed also fall under this category.

Organisms that continue to contain a foreign gene or for which the removal of the gene cannot be guaranteed are regulated as living modified organisms.

If the organism is edited using the SDN-1 technique and falls into either case (1) or (2), it may not be regulated by the Cartagena Act (Fig. 3). However, organisms that are edited using the SDN-2 or SDN-3 technique are regarded as living modified organisms, as they obtain foreign sequences independently of the editing processes.

The policies pertaining to the handling of genome-edited organisms that are not considered “living modified organisms” under the Cartagena Act are not legally binding. However, those who use such organisms are strongly requested to submit information on the characteristics of the organisms and their potential adverse impact on biological diversity, etc. (Table 1) to the government agency to which the competent minister belongs. Once the information is accepted, a submission is not necessary for every use unless the information changes in some way (e.g., through further genetic modification). A submission is not necessary if the organisms are used in accordance with “Type 2 Use in Cartagena Act” in closed environments.

Fig.3: Comparison of the handling procedures under the Cartagena Act (living organisms) and the Food Sanitation Act (food products).

Under the Food Sanitation Act, genome-editing technologies are classified into either Type 1, Type 2, or Type 3, which employ SDN-1, SDN-2 and SDN-3 organisms, respectively. Independent of their class, genome-edited foods in which the tool genes remain (or their removal is not guaranteed) are subject to the Act for safety inspection. As for the tool gene-free organism, the judgment on whether the organism is subject to the regulations as a living modified organism is slightly different from that specified under the Cartagena Act (Fig. 3).

Foods classified as Type 1 may be exempted from the regulations of the Food Sanitation Act. Those classified as Type 3, which contain a foreign gene, are subject to the regulations. The judgements made by the Cartagena Act and the Food Sanitation Act may differ with respect to Type 2. The Type 2 technique involves the introduction of a foreign DNA fragment to mutate several bases in the target sequence. Although a foreign DNA segment is not introduced in Type 1 (SDN-1), it can sometimes induce mutations at higher magnitude than Type 2 (SDN-2). The report by the Research Committee for Newly Developed Food stated: “… Deletion and substitution of bases due to repair of cleavage sites of artificial restriction enzymes, deletion of genes that may occur in nature, and insertion of mutations of one to several bases as a result do not fall under the recombinant DNA technology under the Food Sanitation Act …,”. Therefore, it was decided that the assessment is carried out on the basis of the final product (product-based). However, the kind of Type 2 products that are exempted from the regulations have not been decided. It is likely to be examined when actual information is submitted.

It was decided that the handling of additives manufactured using genome-edited organisms should be treated at the same level (or a more relaxed level) than that for foods. On the other hand, the submission of necessary information, including the characteristics specific to each additive, is requested. This conclusion is based on the premise that the compositional standards of additives are officially established in general. If the technology used does not correspond to recombinant DNA technology, the submission of information is requested as in the case for the handling of foods. Submission is not requested for highly purified additives.

Information regarding genome-edited foods that are not subject to the regulations of recombinant DNA technology must be submitted to the MHLW before it is launched in the market (on a voluntary basis and no penalty is involved for violation). The ministry states that the accumulation of data related to genome-edited foods is socially important, and that the government needs to address the concerns of consumers on new breeding technologies. Table 2 presents the information that must be submitted. For item C, genomic sequences presumed to have high probability of off-target editing need to be predicted using multiple search tools. If a mutation is introduced unexpectedly, a confirmation must be issued that the mutation does not result in the production of allergens or enhancement of known toxic substances.