Gene editing in animals: Miracle or madness?

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Observing the novelty and intrigue of an operating government from the front row seat of a congressional office was a highlight of my veterinary career. The AVMA Congressional Fellowship provided that opportunity and much more. As one might anticipate, certain issues occasionally warrant our profession’s attention and potential action but, for many reasons, are glossed over because other pressing concerns take priority. Such is the case for genetic modification in animals.

Where we stand today

Advances in genetic modification have surged at warp speed in recent years. While geneticists have been mapping human and animal genomes and linking specific alleles and their loci to their function, new tools have been developed to restructure the genetic architecture with amazing efficiency. As with many emerging issues, our legal and regulatory agencies find themselves in a situation in which they must respond without the luxury of time to understand all the scientific implications.

Gene editing in animals has the potential to add new dimensions to our ability to relieve animal suffering while also creating an opportunity for unbridled changes to the physiology, anatomy, and functionality of animals in our care. Perhaps veterinary engagement will provide advocacy and transparency for species that can’t speak for themselves.

The contemporary topic of genetic modification has not yet been lauded as the scientific phenomenon that it is because, like an iceberg, many issues beyond the science are not readily visible and have yet to surface. Scientists and entrepreneurs began disclosing details of recent breakthroughs with implications that boggle the mind.

With a high degree of certainty, these technologic conquests will provide incredible new options for the treatment of inherited disease, prevention of infection, and improvement in the efficiency of meat and milk production. These scientific advancements have outpaced clear guidance from federal regulators and the counsel of bioethicists.

CRISPR: simpler and less expensive

The innovation responsible for the quantum leap is known as clustered regularly interspaced short palindromic repeats (CRISPRs) and CRISPR-associated (Cas)9 system.^1-5 CRISPR allows precise modification of the genetic architecture capable of knocking out a gene(s) or inserting small genetic segments.

Terms such as genetic engineering, genetic modification, and genetically modified organisms (GMOs) are somewhat familiar to many, as they are widely used in describing techniques associated with enhancing productivity and disease resistance of plants for crop production. To the nonexpert, a simple description of genetic engineering or modification conveys a rather complex process of splicing genetic segments from one species into another to achieve the desired trait. In contrast, the simpler CRISPR technology is less expensive and enables modification(s) to a targeted single gene or group of genes.⁶

Opportunity knocks

Application of the technology has significant upside potential. Gene-edited pigs resistant to infection from porcine reproductive and respiratory syndrome virus are at the forefront of candidates to enter the market.⁷ Not far behind is genetic dehorning in cattle.⁸ Holstein cattle are universally horned, and the common practice is to dehorn calves via cautery. Dehorning has raised animal welfare concerns because it is typically implemented without anesthesia. However, by transferring a gene from a polled breed with the use of transcription activator-like effector nucleases (TALENs) and CRISPR-stimulated homology-directed repair technology, the welfare issues could be resolved.⁹

An example of an innovative dimension is the creation of surrogate sires, whereby the male germinal tissue is destroyed chemically and new germinal tissue from another (potentially genetically edited) sire or germline is subsequently introduced into the testicular stroma.¹⁰ The resulting mature male would theoretically be capable of natural mating. The potential implications here include breeding endogenous parent stock adapted to the native environment while yielding progeny with enhanced capacity for meat or milk production, thereby introducing the desired traits (eg, polled cattle or even disease resistance).

Current regulatory environment

Regulation of animal genetic modifications in the United States has been determined by the Food and Drug Administration (FDA) to fall under that agency’s authority via the federal Food, Drug, and Cosmetic Act (FD&C Act); food animals have received the mainstay of their oversight.¹¹ The altered animal’s genome is to be the targeted regulatory domain and the process will follow the design afforded to new animal drug applications (NADAs).

But transference of this nomenclature has sparked some confusion. Use of the term “animal drug” to also apply to the altered genome creates a framework for regulatory oversight. For example, “a new animal drug is ‘deemed unsafe’ under section 512(a)(1) unless the FDA has approved a new animal drug application (NADA) for its intended use.”¹¹

The FDA will likely retain the option to grant exceptions to all or portions of the traditional NADA through enforcement discretion, which could be loosely interpreted to mean that marketing could proceed following a satisfactory risk assessment and establishment of reasonable assurance of a safe food product. If at any time the FDA’s assessment of the safety changes, the enforcement discretion can be withdrawn and marketing must cease.

The first FDA review of a genetically modified species intended for human consumption was a transgenic Atlantic salmon developed by AquaBounty Technologies of Maynard, Massachusetts.¹² The review process appears to have been quite rigorous.

The alteration results in increased production of endogenous growth hormone, allowing the fish to reach market size and be harvested in a much shorter period of time (perhaps 18 months vs. 36 months in wild varieties). The fish are all female and, even though they are raised in aquatic farms, escape or inadvertent introduction would likely not impact native species through cross-breeding.

The review process has consumed a decade and a significant financial investment. Because the modification involved transfer of genes from one species to another, the intensive regulatory view could be deemed as warranted and certainly sets a precedent for future reviews. Minor modifications made via CRISPR logically may warrant lower hurdles. In either case, postapproval monitoring and reporting requirements can be anticipated.¹³

Further clarification of the FDA’s intent to regulate gene editing via CRISPR techniques is provided in a 2018 draft guidance for industry titled “Regulation of Intentionally Altered Genomic DNA in Animals.” An excerpt from this draft indicates that offspring from cross-breeding will also prompt regulatory oversight and reads as follows¹¹:

“Each new animal drug approval covers all animals containing the same genomic alteration(s) (the regulated article or new animal drug) derived from the same alteration event(s). Animals containing the genomic alteration as a result of breeding between an intentionally altered animal and its nonintentionally altered counterpart animal are covered by the new animal drug approval.”

This poses questions as to how the agency will regulate subsequent generations. It also will require new models for commercial entrepreneurs regarding collection of royalties or other trailing revenue streams. The FDA has also suggested that non–food animals would be subject to far less regulatory oversight under enforcement discretion.

The industry and regulatory intersect

Scientists and industry groups have been seeking an abbreviated regulatory path for animal modifications that would be less expensive, perhaps seeking precedent from GMO crop regulations. Although the framework for regulating food was established through the FD&C Act, the FDA has regarded most genetically modified crops used for food as substantially equivalent to non–genetically modified plants and subsequently designated them as generally recognized as safe (GRAS).¹⁴

Meanwhile, under the Plant Protection Act, the US Department of Agriculture Animal and Plant Health Inspection Service has regulatory oversight of plant products from biotechnology with focus on risk from pests and diseases.¹⁵ Animal geneticists and their commercial partners contend that the trait(s) derived from CRISPR gene modifications are minor and could have occurred naturally or in a controlled breeding environment, thus warranting a hands-off approach.¹⁶ 

As mentioned, the FDA has signaled that some oversight will be provided, with enforcement discretion based on the results of a risk assessment that includes human food safety, animal safety, and environmental safety. Thus, genetically modified meat could enter the food chain without supplemental identification or labeling.

In contrast to the FDA plan, Brazil, Argentina, and potentially other countries have identified a gated regulatory process. If the food animal has had only minor genetic edits (vs significant genetic modification), it will be classified as non-GMO and allowed to be marketed without further review. The meat can enter the food chain without restriction.

Scientists and entrepreneurial organizations point out that if off-shore regulations are less stringent, the technology will relocate to countries with more lenient regulatory climates. Currently, imports of meat products from countries that have approved gene-edited animals will not be required to be identified or labeled accordingly. And, because the meat product(s) is indistinguishable from that of non–gene-edited animals, enforcement of potential label requirements would be virtually impossible.

Humans versus animals

Human gene editing has garnered attention from both Congress and regulators. Concern for manifestation of unintended consequences has slowed adoption of heritable gene editing in humans.^17,18 It appears to be of less concern in animals.

In contrast, ex vivo gene therapy in humans has been met with enthusiasm, as it provides nonheritable solutions. Ex vivo gene therapy involves modification of cells that are recovered from the patient, subsequently edited, and returned to the same patient or used as an allotransplant whereby the altered genes moderate or eliminate the disease condition. Examples include cures for sickle cell anemia and significant promise for certain types of cancer.¹⁹

Congress has conveyed its caution regarding the editing of human embryos by withholding federal funding for research. The concern centers on lack of complete confidence that a gene’s secondary or indirect influence (off target) will not impact other body functions or systems. Potential chimeras or embryos containing both edited and nonedited cells are also an enigma and further compromise confidence in the exactness of an anticipated outcome. Because changes made to an embryo’s genome will be passed to future generations, trepidation centers on the realization that genome editing has the potential to reduce diversity. And, while editing genes may mitigate a genetically mediated condition or even cancer, the patient may be more prone to unforeseen complications, such as premature aging.

Calls for stringent ethical and social review of potential applications include assessment of the impact on social justice, geopolitics, and potential social discrimination and division targeted at the individual or perhaps the nonedited population.²⁰ Despite the concern, however, a path to designer babies may not be too distant in the future.²¹

During a recent review of the genetic sequence of the newly created hornless cattle, it was revealed that inadvertent insertion of DNA from the bacterial plasmid had occurred in one animal.^22,23 Although it is impossible to anticipate any manifestations of the presence of the foreign DNA, the review has continued after exclusion of the impacted animal. More regulatory scrutiny can be anticipated for any human procedure in which the edits are heritable.

Non–food animals will apparently fall outside the planned regulatory structure. Without federal oversight, assurances of the animal’s welfare are ambiguous or nonexistent. Consideration for the impact of gene-edited characteristics on the athletic attributes of animals has yet to receive significant discussion. In theory, if oversight is imposed, it will likely be under the voluntary administrative oversight of the respective breed registries or organizers of competitive events. It could be speculated that inspection and enforcement of any genetically based enhancement would require genetic sequencing of each animal competing in the event and thus be cost-prohibitive.

Communicating to the public

Messaging from the scientific community has justified genetic editing as a response to the need to feed a growing population as efficiently as possible. In reality, most communications have focused on academic achievements. Fact-focused statements and scientific logic may not be adequate to drive a favorable reception for nonscientific audiences.

If issues such as animal welfare and a less-than-natural food source are not considered before developing commercial messaging, consumer acceptance may be negatively impacted. Justification for gene editing in animals has and will continue to involve narratives for increasing the efficiency of meat production, enhancing animal welfare via disease prevention, avoiding heritable conditions that negatively impact the animal’s or human’s quality of life, and preserving endangered species.

Although selective breeding has influenced domestic animals for centuries, deliberations on the impact of enhancing the athletic ability or cosmetics of an animal via genetic editing has yet to commence. Maintaining the recognizable, phenotypic characteristics of current heritage breeds may become blurred. Genetic diversity could be severely limited.

Ethics is a topic that may have been inadvertently ignored in the rush to be the first to market. An ethical discussion might entertain the question: We can, but should we? For example, the “should we” segment could be relevant when testing the ethics of unleashing muscle growth in puppies after the knockout of a gene that regulates myostatin production.²⁴ The puppies’ phenotypic appearance is referred to as “double-muscling,” a phrase that also applied to Belgian blue cattle.

It’s time to claim your voice

Many medical advances involving modification of the human and animal genomes will occur outside the purview of traditional veterinary medicine. Technologies that involve growing humanized organs for transplant or using animals as a means of manufacturing human therapies will not involve client-owned pets or food-producing animals.

But veterinarians will encounter genetically altered pets and production animals during obstetric procedures, while providing traditional primary health care to animals, or when consulting for competitive events. Veterinarians will also be called on to answer questions about potential unintended consequences and the safety of meat sourced from gene-edited animals. The latter question should be simple, because the gene-edited meat will not be distinguishable from traditional meat. Other questions will invoke the need to understand whether genetic modifications impact the patient’s ability to metabolize a pharmaceutical at the same rate or whether a vaccine might cause a gene-edited animal more harm than good.

We must appreciate that the FDA’s first responsibility is to protect the public by focusing on the safety of the food supply, but disclosures for regulatory oversight of gene editing in non–food animals is vague or nonexistent. Will there be regulatory considerations for the well-being of non–food animals?

Likewise, there appears to be no governmental agency or central body presently tasked to categorize and coordinate key physiologic information that may impact medical diagnostics and treatment plans. Because identification of animals that might have been modified to enhance athletic capabilities will not be feasible (or perhaps not within the realm of possibilities), will veterinarians be engaged to consult on an animal’s eligibility to compete? Will the FDA expand its future oversight?

As a congressional fellow, I advocated for a congressional hearing to identify key issues and explore options for oversight of genetic editing in non–food animals; hopefully this will find support in the near future as awareness and concern grow. Veterinary practitioner awareness is critical to prepare for engagement, but perhaps more important is for the profession, and specifically the AVMA, to commission a genetic-editing panel that provides guidance for ethical considerations, anticipates the physiologic impact, and serves as a sounding board for regulatory agencies.

Finally, as I reflect on the issues that whizzed by my eyes as an AVMA Fellow, I am aware that my personal concern centers on the perception that this ship seems rudderless. Without effecting collaborative action among scientists, commercial stakeholders, bioethicists, and veterinarians, the long-term impact of an amazing new tool on our domestic breeds will remain undetermined.

Dr. Lehman, an alumnus of Oklahoma State University, was a 2018-2019 AVMA Congressional Fellow. He built and operated a veterinary hospital and has had roles in academia and industry.

References

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