Regulations For Intentionally Modified Genomic DNA In Animals: An Overview

Potential Benefits of Gene Editing in Livestock Breeding

As per the rule proposed, a revised draft was issued by FDA to regulate intentionally modified Genomic DNA in animals and clarifying the overall approach. The key focus is on animals involved in deliberate modification of genomes by the utilization of molecular technology. As per the rule proposed, every organism under this procedure should be undergoing a long and stringent process of approval similar to process a new drug for checking the usefulness and safety.

The groups who are against this rule lay specific emphasis upon agriculture. Gene editing is among the most promising and newest tools of biotechnology. This biotechnology is helpful for animal breeding in making beneficial modification of genes without the introduction of unwanted genetic modifications. Considering the process of traditional breeding, there is a tremendous potential of genetic editing for boosting sustainable production of livestock. This allows the enhancement of food animal welfare and health. The potential advantages of gene editing were examined by scientist Alison Van Eennaam in the meeting conducted by American Association for Advancement of Science (Bailey, 2017). Several methods of breeding such as cross-breeding, embryo transfer, artificial insemination, and genomic selection is being used for improving the dairy industry. In the current scenario, genome editing is crucial for complementing traditional programs of breeding by the precise introduction of desired genetic different in the programs of livestock breeding. It has been noted that there is significant use of genome editing for the prevention of livestock disease such as the increased resistance of pigs to respiratory virus, and porcine reproduction (Bailey, 2017). This has also enhanced animal welfare by the development of dairy cows without the necessity to remove their horns. In addition, research is being conducted for extending the applications related to gene editing in the years to come. In the near future, gene editing enables the production of offspring with the involvement of only one gender. The potential for application of gene-editing techniques for improving production of food animal which highly hinders the future processes of regulation (Bailey, 2017). There is still less clarity regarding the production of regulator status for food animals involved in gene editing. It is to be noted that gene editing does not result in transferring novel DNA to the animals. This can be utilized for changing the individual genes of these animals. The supporters of gene editing state that the resulting sequence of DNA is identical to the naturally occurring current sequences of DNA. The prospect is that application of animal drugs is a major concern for breeders showing eagerness in the employment of gene editing for the complementary programs of traditional genetic improvement (Bailey, 2017).

Debate Around the Proposed FDA Rule

The groups who are supporting this rule lay specific emphasis upon consumers and their safety. In supporting this guidance, it can be stated that altered genomic DNA is the intentional modification of animal’ genes (Wells, 2016). Unless under exclusion criteria, the modification of genomic DNA is similar to inducing a drug in the animal. This is as per the Federal Food, Drug, and Cosmetic Act (FD & C Act) under section 201(g). The reason is that altering the DNA of a subject with the intention of offsetting the function or structure of the animal body. In majority of the cases, the key intention is to prevent, treat, mitigate, cure, and diagnose the diseased animal (Food and Drug Administration, 2017). Modified genomic DNA takes place from targeted or random changes in DNA sequence such as nucleotide deletions, substitutions, or insertions, or additional technologies for introducing certain changes in the animal genome. Modified, non- inheritable genomic DNA hold the intention of affecting the function or structure of the resulting animal or for curing, mitigating, or treating the diseased animal. This tends to be meeting the definition of drug. It must be noted that the FDA guidance allows addressing heritable alterations of genes. A specific alteration of DNA is a subject meeting the defined criteria of a new drug for animals at all sites where there is occurrence of alteration within the genome (Food and Drug Administration, 2017). The specific sequence of alteration and the site locating alteration can impact the health of animals while levelling and controlling the expressed modified sequence impacting the effectiveness in the future lineage. In general, every genomic modification is a separate subject of approval requirements for new animal drug. If any sponsor holds the willingness of introducing multiple gene modification in single animal lineage, it is recommended by the FDA that the sponsor should communicate with the agency for discussing upon the options of regulations along with scientific queries for addressing the application (Food and Drug Administration, 2017). In the phase of investigation, there can be establishment of a single INAD file for several genomic modifications. The file can consist of data on the animals investigated that consist different categories or numbers of intentional genomic modifications. These include the ones taking place across different areas of the genome, before selecting the animal lineage to intentionally modify the genomes with the intention to commercialize.  

The Consumers Union prefers that every animal under genomic alteration should deal with rigorous assessments of safety for both environmental effects, and human health as per the specified legislation for animals facing genetic engineering. The group is strongly supporting the treatment of FDA involving the process of safety assessment related to the new animal drugs. In simple terms, there should be treatment of gene-edited animals similar to other animals facing genetic engineering (Hansen, 2017). Consumers Union perceives the potential to stem unanticipated impacts from the utilization of techniques related to gene editing like the system of CRISPR-Cas9 in animals. There should be a mandatory analysis of all animal through the whole sequencing of genome along with epigenetic profiling for the detection of off-target effects. This is based on the recommendations of National Academy of Sciences and Codex Alimentarius on animal testing for the determination of potential health effects of the unintended and intended changes made in the animal due to the process of genetic engineering (Hansen, 2017). Further ahead, every food product obtained from animals under genetic engineering should have a label for ensuring maximum transparency in front of the consumer along with the identification of every unexpected post-market health effect.

Gene Editing and Animal Drug Approval

Exemplar Genetics is a company of biomedical research that focuses on the application of biotechnology for the development of superior pre-clinical efficiency model in utilizing therapeutic establishment (Fiksel & Covello, 2013). It willingly supports the attempt of FDA for clarifying the oversight of animals under genetic engineering with the full agreement for regulating products in the way of commensurating the potential risks. Oversight of regulations should be based on science with key emphasis upon the attribution of potential risk for the novel product (Division of Dockets Management, 2008). The company believes that the FDA should be categorizing novel products on the basis of phenotypic application and expression along with reducing or eliminating the oversight of regulations over such products in which there is not warranty of exposure and hazards. It is agreed by the company that FDA holds the full authority of regulating these products based on the definition of animal drug providing the exemption or modification of regulatory authority in concern with the soundness of policy (Bruce, 2017). According to Exemplar Genetics, no scientific base is legitimate for the treatment of animals under genetic engineering with sole dependence on molecular techniques utilized for the intentional modification of the DNA. The company demands adequate assurance with respect to the containment and disposition of these animals only for non-food purposes. The company believes that animals under genetic modification are beneficial for human nutrition and health, and animal health, along with the environment, key concern is that continuous innovation can result in unpredicted risks in the shorter or longer run (Division of Dockets Management, 2008).

BIO has supported the decision of FDA for applying the approval process of new animal drug for animals under genetic engineering. Specifically, FFDCA (Federal Food, Drug, and Cosmetic Act) also regulated genetic construct in animal as a new drug for animals (BIO, 2008). BIO believes that proper regulatory processes are crucial for the maintenance of viability across the international and domestic industry platform (Meghani, 2017). Therefore, it is recommended by BIO that there should be finalization of this Draft Guidance to the earliest. BIO applauds FDA for the clarification of recommendations and requirement for the developers and producers of animals and the related products. According to BIO, the proposed regulation will allow facilitating commercialization and approval of products, improving transparency for the public, and enhancing industrial credibility and consumer acceptance (BIO, 2008). BIO urges the continuous active review for Applications of New Animal Drug that will commercialize the GE animal along with their products. Therefore, BIO strongly supports the implementation of proposed regulation. 

Support and Opposition to the Proposed Rule

The AABP is the biggest organizations of cattle veterinarian services in the United States of America with more than 5,000 members to ensure the productivity and health of the national dairy and beef cattle. AABP perceives that the technology of genomic editing like Cas9/CRISPR has valuable applications to the production of animal agriculture, resistance of disease, and welfare of livestock (AABP, 2008). Examples for these types of applications substitute the cattle’ polled allele for the creation of polled animals and the development of animals that resist certain diseases and their impact such as respiratory syndrome virus, porcine reproductive virus, and bovine tuberculosis (Lin, 2017). The AABP is known for supporting the scientific validity for general safe status for animals with genome modification. However, the regulation is not supported without the consideration of specifically altered genome in the subject of new animal drug. This should be based on the new requirements of animal drug approval. The proposed regulation has specific flaws over a number of levels. There is no equation regarding the risk or harm caused to humans due to intentionally altering DNA. There is safe verification of the DNA. The DNA of such animals mostly consist of no novel set of genetic material (AABP, 2008). Therefore, humans consuming such animal products or animals can be considered safe for consumption. It has been suggested by AABP that the FDA should be wary to apply the precautionary principle for the purpose of regulating the animals with genome editing for a number of reasons (Kornfeld & Titus, 2017). There have been no unique risks related to the utilization of recombinant technology in the DNA.

The comments placed by the Department of Zoology shows specific concern for the proposed guidance of off-target SNP-Types genetic modifications considered for knocking out the genes and introducing the indel mutations. There is no consideration of transgenic techniques concerning the insertion of exogenous DNA within the cell. As provided in the research, there is application of a gene knock-out nuclease to the animal cell for making a double stranded break of DNA at the predetermined space or the target location. The repair is further done by the scope of cellular machinery (Department of Zoology, 2017). However, due to the imperfect fidelity of the nuclease, it tends to bind with other off-target areas as well. As a consequence, there can be rise in sequence modifications at areas over the genome apart from the target location because of imperfect repairs (Custers, 2017). These normally include small insertions, base changes, and small deletions. While there are specific approaches for minimizing the case of off-target genetic modifications so they only take place at lower frequency, there are less chances for completing the prevention (National Research Council, 2000). As a consequence, there can be rise in sequence changes at areas over the genome apart from the target site because of imperfect repairs. The proposed regulation is implying that there will be a need for regulating off-target mutations. This mandates the application of new animal drug (Department of Zoology, 2017). Therefore, there is mitigation of obvious issues that categorize off-target impacts as drugs while leaving out the significant problems. Therefore, the Department of Zoology at the University of Oxford rejects the proposed regulation. 

NCFC is well-known for supporting policies that allow the enhancement of producers’ ability to utilize new technologies and practices for the production of agricultural products (Strauss et al., 2010). Therefore, if practices are set as per scientific evidence, NCFC ensures environmental and economic soundness and assurance of food safety. According to the agricultural community, genome editing is a combination of tools with vast potential for the improvement of agricultural scope (NCFC, 2017). With the application to fish, poultry, and livestock, the tools allow controlling diseases, improving safety of food, enhancing animal welfare, facilitating the responsible utilization of antibiotic and decreasing the ecological effects of animal agriculture (Maxmen, 2015). NCFC is specifically concerned that the revised proposal will result in impeding the accessibility of these tools for the producers of USA. It has been repeatedly stated by the FDA that the risk related to biotechnology product is set as per the product’ nature, instead of the process utilized for its production. In addition, FDA provides that the level of regulation should maintain consistency with the level of risk (NCFC, 2017). However, in the revisions proposed, FDA has specific focus on processing genome editing followed by the exclusion of products under other processes of genetic modification like chemical mutagenesis from the requirement of oversight pre-market. According to NCFC, the revisions are based on the assumption that every animal established under the respective technique involves various risks and holds a requirement of pre-market oversight  due to each and every genome edited animal (Cohen & Adashi, 2016).

In conclusion, the proposed rule should not be passed as the argument against the rule are supported by logic and evidence. FDA is not providing any justification based on risk to expanding the scope of this entire guidance for including animals under genomic modification (Carroll et al., 2016). The base is that it expands the simple scope of oversight as it holds the authority of the same. There no clarity how it has been determined by the FDA regarding the utilization of genome editing that allows the presentation of unreasonable risks (Meghani & Kuzma, 2018). There is most preciseness and predictability of these techniques established till date while utilizing the development of product in similarity with products present in the market. FDA should be acknowledging the long historical establishment of safe utilization. The position of new traits involves animals utilizing the tools of genome editing that is a precise essential way of inducing mutagenesis or cross-breeding without any different treatment from the perspective of regulations in comparison with the modification of organisms by traditional methods of breeding.  

References

AABP (2008). Guidance for Industry #187 Regulation of intentionally Altered Genomic DNA in Animals; Draft Guidance. American Association of Bovine Practitioners

Bailey, P. (2017). Gene Editing can Complement Traditional Food-Animal Improvement. Food and Agriculture. Accessed from: https://www.ucdavis.edu/news/gene-editing-can-complement-traditional-food-animal-improvements/ 

BIO (2008). Department of Health and Human Services, Food and Drug Administration, Guidance for Industry, Regulation of Genetically Engineered Animals Containing Heritable rDNA Constructs. BioTechnology Industry Organization.

Bruce, A. (2017). Genome edited animals: Learning from GM crops?. Transgenic research, 26(3), 385-398.

Carroll, D., Van Eenennaam, A. L., Taylor, J. F., Seger, J., & Voytas, D. F. (2016). Regulate genome-edited products, not genome editing itself. Nature biotechnology, 34(5), 477-479.

Cohen, I. G., & Adashi, E. Y. (2016). The FDA is prohibited from going germline. Science, 353(6299), 545-546.

Custers, R. (2017). The regulatory status of gene-edited agricultural products in the EU and beyond. Emerging Topics in Life Sciences, ETLS20170019.

Department of Zoology (2017). Comment on the Food and Drug Administration’s Draft Guidance for Industry, Regulation of Intentionally Altered Genomic DNA in Animals, 82 Fed. Reg. 6561. University of Oxford.

Division of Dockets Management (2008). Draft Revised Guidance for Industry #187: Regulation of Intentionally Altered Genomic DNA in Animals [Docket No. FDA-2008-D-0394]. Exemplar Genetics.

Fiksel, J., & Covello, V. T. (Eds.). (2013). Biotechnology risk assessment: issues and methods for environmental introductions. Elsevier.

Food and Drug Administration. (2017). Guidance for Industry-Regulation of Intentionally Altered Genomic DNA in Animals. U.S. Department of Health and Human Services. Accessed from: https://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/ucm113903.pdf 

Hansen, M., (2017). Comments of Consumers Union to the Food and Drug Administration on the Notice of Availability: Regulation of Intentionally Altered Genomic DNA in Animals; Draft Guidance for Industry Docket No. FDA 2008-D-0394. Consumers Union: Policy and Action for Consumers Report.  

Kornfeld, D. S., & Titus, S. L. (2017). Ethics: More research won’t crack misconduct. Nature, 548(7665), 31.

Lin, A. C. (2017). Mismatched Regulation: Genetically Modified Mosquitoes and the Coordinated Framework for Biotechnology. UCDL Rev., 51, 205.

Maxmen, A. (2015). Gene-edited animals face US regulatory crackdown. Seeds.

Meghani, Z., & Kuzma, J. (2018). Regulating animals with gene drive systems: lessons from the regulatory assessment of a genetically engineered mosquito. Journal of Responsible Innovation, 5(sup1), S203-S222.

Meghani, Z. (2017). Genetically Engineered Animals, Drugs, and Neoliberalism: The Need for a New Biotechnology Regulatory Policy Framework. Journal of Agricultural and Environmental Ethics, 30(6), 715-743.

National Research Council. (2000). Genetically modified pest-protected plants: Science and regulation. National Academies Press.

NCFC (2017). FDA-2008-D-0394: Regulation of Intentionally Altered Genomic DNA in Animals; Draft Guidance for Industry; Notice of Availability. National Council of Farmer Cooperatives. Submitted Electronically via Federal eRulemaking Portal (https://www.regulations.gov)

Strauss, S. H., Kershen, D. L., Bouton, J. H., Redick, T. P., Tan, H., & Sedjo, R. A. (2010). Far-reaching deleterious impacts of regulations on research and environmental studies of recombinant DNA-modified perennial biofuel crops in the United States. Bioscience, 60(9), 729-741.

Wells, K. D. (2016). History and future of genetically engineered food animal regulation: an open request. Transgenic research, 25(3), 385-394.