Regulatory Policies of Genome Editing Products around the World

Genome editing is one of the powerful tools that has been applied to the improvement of plants, animals and microorganisms, and human therapy. The regulation of genome editing products vary among nations. Here we summarize the legislation of genome editing in different nations to let people know how genome editing products have been regulated in different nations. Additionally, the departments responsible for genome editing regulation in each nation are provided in this review.

Genome editing technology has been developing rapidly since Cas9 was first used to modify target genes in human cells [1]. Various Cas orthologues and variants have been identified and created to overcome the limitations of Cas9, such as protein size, PAM limitation and specificity. Nm2Cas9 was an alternative type II Cas9 protein for genetic engineering and gene therapy with potential for human therapy [2]. The VQR-Cas9 and VRER-Cas9 variants were generated with PAM from NGA and NGCG by random mutation of the PAM interaction domain in SpCas9 [3]. XCas9 was developed, which can recognize "NG, GAA and GAT" PAM, facilitating application to a wide range of target sequences. Although xCas9 potentially recognizes more non-target sequence variations, it showed less off-target activity than SpCas9 [4]. A high-fidelity CRISPR-Cas9 (SpCas9-HF1) with no detectable genome-wide off-target was developed by modifying DNA contacts in the Cas protein. SpCas9-HF1 reduced almost all genome-wide off-target effects to undetectable levels [5]. Many homologous proteins of Cas9 have been developed for different purposes and with unique advantages. Examples include Cas12a, CasX, Cas12i, Cas12g, Cas12f and so on [6,7]. In addition to modifying protein structure and developing homologues, precise editing tools, including base editing and prime editing, have been developed to increase target specificity. David Liu's lab created a base editing tool by fusing a cytidine deaminase enzyme and Cas9, which can directly convert C to T or G to A without DNA cleavage [8]. Subsequently, several base editing tools were developed to expand the scope of base editing, such as A/T to G/C [9]. A prime-editing tool was also developed that overcame almost all the limitations of CRISPR [10]. This technology incorporates reverse transcriptase and a short DNA donor into the Cas9 nickase system, which avoids double-strand breaks and donor delivery. Prime editing successfully eliminates concerns about double-strand breaks in the clinical setting. Recently, an upgraded version of Prime Editing has been developed, which is the smallest tool that can be packaged in a single adeno-associated virus [11].

Due to the ease of construction of the CRISPR-based target-gene editing vector and its powerful target-gene editing capability, genome editing has been widely applied to animals, plants, microorganisms and in the field of gene therapy. The more mature technology applied in gene therapy is T-cell design. T-cell design based on CRISPR shows great potential for the treatment of cancer, such as PD-1 knockout to treat lung cancer, Epstein-Barr virus-positive gastric cancer, glioblastoma, colorectal cancer, ovarian cancer, bladder cancer, melanoma and so on [12,13]. In plants, genome editing tools based on CRIPSR have been used to develop many new traits, including salt and drought tolerance, yield enhancement, quality improvement, heat or cold tolerance, etc. [14]. In animals, as a precise, fast and efficient genome editing tool, CRISPR technology is widely used in animal breeding and disease therapy, including disease resistance [15-17]. Performance improvement [18,19] milk quality [20,21]. Animal welfare [22] and disease therapy by knocking out disease-causing genes [23,24]. In microbes, the main applications of the CRIPSR tool have been in metabolic design and genome function. For example, the creation of the mass synthetic compound succinate in Synechococcus elongates [25] and the modification of fungal sensitivity to certain chemicals [26].

It is easy to see that CRISPR-based genome editing is a powerful technology for developing new products in almost all organisms. The widespread use of genome editing in all kinds of organisms has prompted governments to consider how to regulate these new products and improve the traits of crops and animals. Different countries are developing their own regulations. In general, regulations in various countries are based on the principle of determining whether the genome-edited product can be produced through conventional breeding.

Regulation policy in US

Regulations on biotechnology products are enforced by the US government through three main departments: The United States Department of Agriculture (USDA), the Food and Drug Administration (FDA), and the Environmental Protection Agency (EPA). The primary purpose of these entities is to guarantee the safety of genomic engineering in plants, animals, and microorganisms, not just for human health, but also for the environment and agriculture. A framework for regulating biotechnology was introduced in 1986, followed by several rounds of modifications in the following years. Three guidelines have been established over the past decades: 1. biotechnology products are not necessarily different from conventional products; 2. regulation should focus on products, not processes; 3. regulation must be based on use.

For plants, under this framework and in line with the rapid pace of application of genome editing technology in agriculture, the Office of Science and Technology Policy (OSPT) issued the National Strategy for Modernizing the Regulatory System for Biotechnology Products in 2016. Then, an update to the Coordinated Framework (CF) for the Regulation of Biotechnology was issued in 2017 [27], proposing to include genome edited crops in the regulatory framework for GM products. However, soon after, the USDA, having heard the objection from scientists, agreed that genome edited crops should be treated similarly to those developed through conventional breeding techniques. In 2018, the FDA announced the Plant and Animal Biotechnology Innovation Action Plan, which clarifies policy on gene editing and ensures that developers can efficiently bring products to market [28]. In 2019, a new Modernised Regulatory Framework for Agricultural Biotechnology Products was created to exempt low-risk products from regulation and create a unified platform for approving products developed through biotechnology. Finally, in 2020, the framework called the Movement of Certain Genetically Engineered Organisms (also known as the SECURE Biotechnology Regulation) was finalized by USDA. Under the new framework, plants that could otherwise have been developed through conventional breeding will not be subject to additional regulation [29]. The EPA announced that a class of plant protection products created by gene editing technology wouldn't be regulated as genome-edited organisms. This announcement encouraged more researchers to develop gene-edited products and improve gene-editing tools [30].

Animal biotechnology is regulated by the FDA. Both transgenic and gene-edited animals are regulated based on the process, not the product. The federal Food, Drug and Cosmetic Act of 1938 has been expanded to regulate both gene-edited and transgenic animals. Research animals must obtain food approval by submitting an FDA Investigational New Animal Drug (INAD) before entering the food supply. In 2018, the FDA declined to transfer oversight to the USDA. Then, in 2019, FDA proposed a risk-based regulatory framework instead of the current process-based structure. Although many scientists suggest that oversight of transgenic or edited animals should be transferred to USDA, the new administration is still based on the previous regulatory structure. To date, three genome-edited animals are commercially available in the US, namely a transgenic salmon with a faster growth rate [31], a transgenic pig with low allergy [32], and a gene-edited cattle with short hair and heat tolerance [33].

Regulation policy in Brazil

Brazil and 12 other countries, including the United States, Argentina, Australia, Colombia, Dominican Republic, Honduras, Guatemala, Paraguay, Uruguay, Vietnam, Jordan and Canada, issued a joint declaration to "avoid arbitrary and unjustifiable distinctions between end products derived from precision biotechnology and similar end products derived from other production methods". The National Technical Commission on Biosafety (CTNBio) is responsible for regulating Genetically Modified Organisms (GMOs). In 2018, CTNBio decided that New Breeding Technologies (NBTs) that don't contain foreign genes will not be regulated as GMOs [34]. This means that Brazil will regulate NBTs based on the products, but not the process of producing NBT products. In 2018, four genome-edited yeast varieties were approved for bioethanol production and other purposes. Several other genome-edited crops are being developed in Brazil, including nematode-resistant soybean [35], waxy maize [36] and antioxidant tomato [37]. Gene-edited animals are regulated in a similar way to gene-edited crops. Gene-edited animals that don't have DNA from other species are regulated as non-GM animals. Until now, there has been a concentration on breeding hornless cattle [38], despite recent developments in Brazil such as heat-tolerant [39] and marbled cattle [39] as well as high-yield tilapia [36].

Regulation policy in EU

The European Union is taking a very close look at the regulation of gene-edited crops and foods. In 2018, the European Court of Justice (ECJ) ruled that gene editing should be regulated under the 2001 GMO Directive. Although gene editing was classified as a type of induced mutation, like chemical induction or radiation-induced mutation, the oversight system emphasized that the EU's regulation was focused on the process, as it was for the production of GM seeds. But not the end products. The strict policy resulted in many companies moving their programs or focus to other countries. This 2018 regulatory work frame was also opposed by individual member states, independent institutions, agriculture ministers and scientists. The EU Commission was asked to carry out a study and make proposals. By 2021, the EU Commission concluded that the current legislation was outdated and not suitable for some New Genomic Technologies (NGTs) and their products. Since then, a new oversight structure was discussed and a draft named "Regulation of the European Parliament and of the Council on plants obtained by certain new genomic techniques and their food and feed, and amending Directives 68/193/EEC, 1999/105/EC, 2002/53/EC, 2002/55/EC, and Regulation (EU) 2017/625" was produced in early 2023. The Regulation is limited to NGT plants only. NGT plants only include plants produced by mutagenesis, cisgenesis and intragenesis. NGT plants, which have been identified through a notification procedure as having been obtained by traditional breeding methods and which do not contain traits that are harmful to humans or the environment, are not subject to the provisions of the GMO legislation. All other NGT plants (category 2 NGT plants) will be regulated under the GMO legislation with different authorization procedures. The draft proposal still has to be examined by the European Council and Parliament. Animals and micro-organisms are excluded from the scope and remain subject to GMO legislation.

Regulation policy in Russia

Three organizations are responsible for regulating genetically modified plants and animals in Russia. The Federal Service for Surveillance of Consumer Rights Protection and Human Welfare (Rospotrebnadzor) is responsible for developing legislation on genetically modified food products, as well as monitoring the effects of genetically modified crops and products on human health and the environment. Clear guidelines ensure the safe use of GM technology in food and farming. The Ministry of Agriculture is responsible for the development of policies on the use of genetically modified crops and animals in agriculture. The Federal Service for Veterinary and Phytosanitary Surveillance (VPSS) regulates genetically modified crops used for feed. As part of a federal program in 2019, it was announced that certain gene-edited crops would be exempt from a 2016 law that prohibited the cultivation of genetically modified organisms. The Russian government has allocated £1.7 billion to advance genetic technologies between 2019 and 2027 [40]. The implementation of gene editing technology has the potential to increase the adoption of genetically edited crops and animals in Russia. The Russian Academy of Sciences (RAS) is in the process of developing disease-resistant potatoes and sugar beets. The Vavilov Research Institute of Plant Industry and RAS [41]. Utilized gene editing technology to create easily processed and more nutritious wheat and barley. However, there is no gene edited animals developed in Russia.

Regulation policy in United Kingdom

Since the United Kingdom's departure from the EU, regulations concerning genome edit products have been relaxed. In January 2022, Parliament clarified that genetic edits are distinct from GMOs, negating the need for developers to submit a risk assessment or seed consent from the Secretary of State when applying for crop cultivation. Notification to the Department for Environment, Food, and Rural Affairs remains mandatory for field trials. In March 2023, a Genetic Technology Law was enacted in England [42], which permits the cultivation of gene-edited crops and raising of animals on UK farms, while maintaining restrictions on GMOs. Further, the new regulation does not mandate the labelling of gene-edited food that can also be obtained through conventional breeding. It should be noted that this legislation is not applicable in Scotland, Wales and Northern Ireland, which continue to follow EU regulations.

In the United Kingdom's relaxed regulatory environment, genome editing has been widely utilized to improve crops and animals. In 2022, Oleic oil-rich Camelina sativa was approved for use in food, as it contains higher levels of oleic oil [43]. Another approved gene-edited crop is wheat, which was developed by Rothamsted Research and has reduced cancer risk [44]. Field trials were conducted in 2021.

Regulation policy in Africa

Many African countries lack clear legislation for regulating gene editing products. Only Nigeria and Kenya currently regulate gene edited crops on a case-by-case basis. The Kenya National Biotechnology Authority is currently drafting guidelines for gene edited animals. The majority of African nations classify gene edited crops and animals as genetically modified and regulate them accordingly. South Africa was the first country to approve the planting of genetically modified crops. Genome-edited crops and animals are regulated as genetically modified organisms under old legislation. African scientists are using gene editing technology to enhance crops. In 2022, Kenyan scientists successfully developed weed-resistant sorghum, whereas Ugandan scientists have been working on developing a cassava resistant to brown streak disease since 2020. One of the targets pursued by Kenyan scientists is climate-smart banana [45].

Regulation policy in China

China's legislation surrounding gene-edited crops is more conservative than that of the United States, yet more relaxed than the European Union's. The Chinese government has strongly supported agricultural gene editing research since 2016, although the regulation of genome editing products was unclear at the time. The Ministry of Agriculture and Rural Affairs (MARA) announced regulation guidelines for gene-edited plants in 2022. The guidelines simplify the application process in order to expedite the release of gene-edited crops to the market. Adhering to these guidelines, applicants can apply safety certification by skipping the environmental release and productive trial phases, provided that no environmental or food safety risks are identified during intermediate testing. In early 2023, MARA (P020230428546705804523.pdf (moa.gov.cn)) approved the first genome edited crop in China - a soybean with high oleic acid developed by Shandong Shunfeng Biotechnology Co. Ltd.

China regulates gene edited animals just as strictly as genetically modified animals. Currently, no specific regulatory work frame has been published, although numerous researchers aim to improve traits through genome editing. Most genome editing research for animals in recent years has focused on improving traits such as muscle mass, growth rate, disease resistance, and decreased fat deposition in species such as pigs, monkeys, goats, cows, and others.

Regulation policy in Japan

Japan imports nearly 100% of its corn and 94% of soybean supply to meet domestic demand. The majority of the imported crops are biotech products, but the country's production of such crops is limited. These ministries include the Ministry of Agriculture, Forestry and Fisheries (MAFF), the Ministry of Health, Labor and Welfare (MHLW), the Ministry of Environment (MOE), and the Ministry of Education, Culture, Sports, Science and Technology (MEXT). Four government ministries in Japan are responsible for regulating genetically modified food products. In 2019, MHLW released its final guidelines regarding the safety assessment of genome-edited foods and food additives. One year later, MHLW published the final guidelines. Since then, developers are no longer required to conduct safety and environmental assessments, unless the product contains DNA from other species that belong to SDN2 or SDN3 [46]. However, developers still need to notify the government, even if the genome-edited crops or animals are created using SDN1. The gene-edited crops or animals developed using SDN2 must be regulated on a case-by-case basis. Crops edited by SDN3 are classified as GMOs. Local governments have the authority to establish additional regulations for the oversight of genome-edited crops and animals.

In Japan, a diverse range of genome-edited crops have been cultivated, such as GABA-enriched tomatoes [47], rain-resistant wheat [48], seedless tomatoes [49], and albino apples [50]. Among them, GABA-enriched tomatoes have been commercially viable. Moreover, genome-edited animals have also been created in Japan. For instance, Kyoto University developed red sea bream with increased flesh edibility using CRISPR [51]. National Agriculture and Food Research Organization developed disease-resistant cattle using CRISPR [52], and NH Foods created pigs with amplified muscle using TALEN [53]. However, there is currently a lack of commercially available genome-edited animals in Japan.

Regulation policy in Australia

In Australia, gene-edited plants and animals are subject to regulation by the Gene Technology Regulator (GTR). Food Standards Australia New Zealand (FSANZ), which is authorized by GTR, is responsible for regulating food in Australia and establishing pre-market regulation and labeling standards for gene-edited food. Australia is one of 12 nations that have issued a joint statement regarding the avoidance of arbitrary and unjustifiable distinctions in gene editing regulations. Since 2019, gene-edited plants and animals without the integration of foreign DNA are not classified as Genetically Modified Organisms (GMOs) in Australia. However, due to the limitations on gene-editing regulations in New Zealand, no gene-edited crops and animals have been approved. Researchers have used simple gene-editing technology to develop fungus-resistant wheat, virus-resistant barley, and sticky rice, among others. Nonetheless, these products are not yet available on the market.

Regulation policy in New Zealand

Gene-edited crops and animals are strictly regulated in New Zealand, where all gene-editing products are considered GMOs. Under the Hazardous Substances and New Organisms (HSNO) Act 1996, the Environmental Protection Authority (EPA) oversees gene-edited crops and GMOs alike. The Act mandates regulation of all gene-edited plants and animals, regardless of whether foreign genes are integrated. Food Standards Australia New Zealand (FSANZ) develops and establishes food standards, which include the regulation of gene-edited food. Any food produced by gene technology requires approval from FSANZ before it can be marketed, and must comply with the corresponding labeling standards. As New Zealand regulates NGTs based on process rather than solely on products, its regulation departments are currently investigating and monitoring how gene editing technologies are treated in different countries. This is to ensure that New Zealand's regulations continue to keep up with the demands of new technologies [54]. Currently, developments in hypoallergenic milk [55] daughterless mice [56] and drought-tolerant grass [57] are underway, although no gene-edited crops or animals have been approved as of yet.

Regulations on the use of gene editing in agriculture across various nations are summarized. Although different countries have varying legislation on gene editing of crops and animals, the primary objective of these regulations is to ensure product safety for both humans and the environment, whilst simultaneously promoting the development of gene editing in agriculture. Regulations should not hinder technological advancements, even though weighing the advantages and disadvantages may prove challenging. Countries worldwide are making significant strides in comprehending gene editing technology and the resulting products. This represents a promising start, as the application of gene editing technology to enhancing agricultural traits has the potential to considerably benefit society.

This article is supported by project Scientific Innovation - 2030 Major Project, Innovation of Excellent Germplasm with High Yield and Strong Marginal Advantages of Corn.

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