Given that no single GE food animal product is currently commercially available in the United States, animal breeders are perhaps the group most aware of the chilling impact that regulatory gridlock can have on the deployment of potentially valuable breeding techniques. This would suggest that the FDA’s regulatory approach is unfit for purpose as there does not appear to be a viable path for safe products to come to market.30,32 In addition, the historical focus on the potential effects of an intergeneric rDNA as a new animal drug is not applicable to gene editing strategies that result in no transgenic DNA. Examples of GE animals include disease-resistant animals,33,34,35,36,37,38 products with improved quality attributes39 and/or lacking common allergens,40 and production animals with reduced environmental footprints.41 The prohibitive cost of achieving regulatory approval has limited the development of improved GE animal lines by public sector scientists and small companies.42 Delaying or preventing the use of this technology in animal breeding programs is associated with very real opportunity costs in terms of foregone genetic improvement.32,43

The advent of gene editing offered an opportunity to rethink the regulatory approach to the products of modern biotechnology, and a number of authors have argued that the trigger for regulatory review should be novel product hazards/risks, if any, weighed against the resulting benefits.30,32,42,44,45,46,47,48,49 Researchers are already working on a range of beneficial gene edited food animal applications14,45,50 addressing important zoonotic disease and animal welfare traits such as dehorning and castration. Great potential exists to use gene editing to translate the understandings that have been derived from the significant public investment in food animal genome sequencing projects51,52,53,54,55,56 into useful practice.2 Some of the most well-known of these food animal applications include disease resistant animals such as pigs carrying a deletion that provides resistance to the devastating porcine reproductive and respiratory syndrome (PRRS) virus,57,58,59 and dairy cows that carry a naturally-occurring bovine allele for the POLLED gene,60 which means that they do not grow horns and are therefore spared the painful process of their physical removal. Both of these examples benefit animal health and welfare which are improvements that tend to be favorably viewed by the public.61

In neither of these examples is there a transgenic rDNA combination of genetic material, and yet under the draft 2017 FDA guidance, both of these examples will be subject to a mandatory regulatory review prior to commercial release under the auspices of the new animal drug provisions of the FD&C Act. In one case the absence of DNA (a gene deletion) is the “drug”, a drug that will be transmitted to all descendants of that animal via reproduction. In the other case the drug is a naturally-occurring 212 bp DNA sequence62 that is not otherwise regulated and that we routinely consume in products from beef cattle. This sequence will be regulated as a drug when edited into a dairy cattle genomic background solely based on the process used to produce the variant (Fig. 1). Regulatory oversight should be commensurate with risk meaning that products that pose no/low risk should have minimal regulatory oversight, while those that pose high risks should face extensive regulatory scrutiny. Additionally, regulation should be even-handed, meaning products with the same level of risk should receive equal scrutiny irrespective of the process used to produce them.

A large breeding company, Genus PLC, has announced it will take the PRRS-resistant gene deletion pigs through the FDA’s regulatory review process. Given the importance of this disease to the global pig industry, and the resources available to a large company like Genus, this is perhaps a reasonable decision. However, academic researchers and small companies face a dramatically different situation. The draft guidance suggests the need for genotypic and phenotypic durability studies over multiple generations, including, where feasible, data on inheritance from at least two generations, preferably more, and recommends that at least two of the sampling points be from non-contiguous generations (e.g., F1 and F3). Further, the draft guidance recommends that all surplus investigational animals and their biological products be disposed of by incineration, burial, or composting. Multigenerational studies with large food animals like cattle take years and are beyond the resources of most academic laboratories, especially if the investigational animals have to be incinerated rather than sold for food purposes. And while these requirements might make some sense in the context of animals expressing a pharmaceutical protein (i.e., an actual drug), they make little sense in the context of a DNA deletion or a naturally-occurring allele in food. How can the absence of small piece of DNA rationally be considered a drug?

Another requirement outlined in the draft guidance is “full characterization of the site of intentional alteration, any unintended alterations (e.g., off-target alterations, unanticipated insertions, substitutions, or deletions)”. It is further recommended that researchers evaluate whether there are any unintended interruptions of coding or regulatory regions. Given the millions of natural genetic variations that exist between any two individuals, and the observation that unanticipated insertions, substitutions, or deletions occur every meiosis,12 it is unclear how this requirement can be fulfilled in a way that differentiates between unintended alterations and spontaneously-occurring insertions, substitutions, deletions, and other unanticipated naturally-occurring alterations as shown in Fig. 2. The analyses and interpretation of whole-genome sequencing data can also be inconsistent among research groups, making it difficult to standardize from a regulatory perspective.13 Animals produced by conventional breeding methods are not routinely evaluated for unintended effects at the molecular level.3

Such heavy regulatory burdens would be anticipated to be associated with very high-risk products. And yet it is actually difficult to come up with a unique hazard (harm), let alone risk (probability of harm), associated with animals that could otherwise have been developed through traditional breeding techniques based solely on the fact that they carry intentional genomic alterations introduced by gene editing. The draft guidance divides food safety risk into two overall categories. The first is examining whether there is any direct toxicity, including allergenicity, via food consumption “of the expression product of the article”. And while this risk might be associated with the expression product of a transgene, it again makes little sense for animals that could otherwise have been developed through traditional breeding techniques. The fact that such studies are not required or performed on animals developed through traditional breeding techniques makes this requirement disproportionate from a regulatory perspective, especially given the low historical food safety risks that have been associated with conventional animal breeding.

The second category of purported food safety risk requires performing studies to identify indirect toxicity associated with any biologically relevant changes to the physiology of the animal, and to determine if the composition of edible tissues from the animals whose genomes have been intentionally altered differs from conventional products. This high level of regulatory scrutiny is perhaps intended to assuage public fears or placate opponents. However, the disproportionate regulatory burden for products that could have been achieved using conventional breeding will likely disincentivize the use of gene editing in U.S. food animal breeding programs, and result in the choice of less-efficient processes (e.g., introgression) to introduce useful genetic variation purely for their immunity to premarket regulatory hurdles.

It should be emphasized that existing breeding programs already thoroughly phenotype selection candidates, looking for undesired phenotypes or negative correlations that might exist between important selection objectives. For example, one large breeding company phenotypically evaluates broiler selection candidates for 56 traits, and more than 50% of these traits are measures of fitness and health. These traits include skeletal and leg abnormalities, various physiological measures of heart and lung functions, and specific causes of mortality.63 As with plant breeding, “off-types” do not advance to become parents of the next generation. Selection pressure for viable and healthy individuals is intense at the pedigree level of the breeding pyramid, where each successful candidate can potentially give rise to millions of descendants.64

Finally, there is the incompatibility of the proposed FDA regulatory approach with the structure of animal breeding programs. A number of lines and/or breeds, and therefore multiple “founder” animals, will likely need to be edited for the exact same trait. For example, in the broiler chicken industry, most primary breeders cross multiple different breeding lines to service different industry needs. And in the case of the dairy industry, the POLLED allele would need to be introduced into horned breeds (e.g., Holstein and Jersey). And to prevent genetic inbreeding and loss of diversity, the same modification will often need to be introduced into numerous elite artificial insemination bulls.65

The FDA draft guidance suggests that each new animal drug application would generally only cover animals derived from a single alteration event. If each individual edited animal is required to go through a multigenerational mandatory premarket regulatory evaluation prior to commercialization, then there will be a fundamental disconnect between the proposed U.S. regulation of gene edited animals, and the realities of genetic improvement programs where future parents are selected from every subsequent generation because those animals are genetically superior to their parents.

It is no accident that gene edited food animal applications are moving to countries with novel product-based regulatory triggers for gene edited animals. Argentina was the first country to publish their proposed approach to the regulation of gene edited organisms.66 They plan to regulate plants and animals in the same way, and the trigger for regulation will be whether plants or animals carry a “novel combination of genetic material” (i.e., intergeneric). Those that do will be considered a “GMO” under Argentine law, and those that do not will not trigger additional regulatory oversight irrespective of the use of modern biotechnologies or rDNA techniques in the breeding process (Fig. 3). Canada, the only country that has ever allowed the commercial sale of a GE animal, the AquAdvantage GE salmon approved in 2016,28 has a product-based regulatory system triggered by product novelty, regardless of the breeding technique that was used to obtain the plant or animal end product.47

Fig. 3 Flow map contrasting proposed regulation of genome-edited food animal species applications in (a) Argentina (modified from Whelan and Lema68), and (b) proposed United States regulation. Modified from Van Eenennaam (2018)49 Full size image

The gene-editing company Recombinetics, has announced an alliance with bovine genetics provider Semex in Canada to introgress the naturally-occurring POLLED allele into their elite dairy genetics using gene editing.67 In October 2018, the National Technical Biosafety Commission (CTNBio) in Brazil concluded that semen from an edited bull carrying the P C POLLED intraspecies allele substitution60 would not be considered a “genetically modified organism” under their regulatory schema.68 Likewise, Argentina's National Advisory Commission on Agricultural Biotechnology (CONABIA) has evaluated proposed gene edited animals that do not contain any foreign DNA or a new combination of genetic material and judged them to be exempt from GM regulation. These include gene edited applications in fish (tilapia), cattle, and horses. In the absence of regulatory harmony, breeders in some countries will have the ability use gene editing in agricultural breeding programs, while those in other countries will not, resulting in disparate breeder access to these tools, and ultimately the potential for trade disruptions.

The FDA’s draft “Guidance for Industry #187” entitled “Regulation of Intentionally Altered Genomic DNA in Animals” is not fit for purpose as it relates to food animals that could otherwise have been developed through traditional breeding techniques. We reject the idea that intentional genomic DNA alterations should be regulated as a veterinary drug in food animals, and consider that the proposed approach will thwart the development of genetic approaches by public sector researchers and small companies to use gene editing to solve zoonotic disease and animal welfare problems in the United States. We further support the call made by scientists at the 2019 Plant and Animal Genome meeting (https://www.gopetition.com/petitions/harmonize-us-gene-edited-food-regulations.html) that the U.S. regulatory system should be harmonized so that both plants and food animals that could otherwise have been developed through traditional breeding techniques are not subject to additional premarket regulatory requirements based solely on the fact that intentional genomic alterations were introduced using modern biotechnologies or rDNA techniques in the breeding process.