In an analysis of genome-edited cattle and an accompanying letter to the editor, the FDA defended its proposal to regulate gene-edited animals as veterinary drugs, arguing the regulation would help prevent “unintended consequences” that could arise from the use of new breeding techniques such as CRISPR-Cas9. Nature responded in a sharply worded editorial claiming the agency’s proposal is at odds with the evidence, and saying it appears primarily designed to avoid legal battles with litigious anti-GMO groups.
In January 2020, Genetic Literacy Project released its Global gene-editing regulation tracker and index, evaluating nations based on how their laws encourage or hinder innovation. These tools illustrate that the US is a pioneer in agricultural gene-editing research, ranking seventh in the world by maintaining sensible rules that protect public health while developing novel food crops that are addressing important nutritional and environmental challenges.
The one exception in US policy is animal biotechnology. Brazil, Argentina, Japan, Canada and Australia have thus far taken a much more progressive stance on this issue. There are currently no gene-edited animals approved for human consumption in the US.
Under the FDA’s oversight, only one genetically engineered animal, the transgenic (GMO) fast-growing AquAdvantage salmon developed by AquaBounty has received regulatory approval, which took roughly 20 years. Because of political wrangling, the salmon is not yet sold in the US, but salmon eggs imported from Canada are being raised at an AquAdvantage fish farm in Indiana. In May 2016, the Canadian Food Inspection Agency approved the sale of the GM fish, and AquaAdvantage salmon fillets became available to customers in Canada.
The FDA is now poised to classify gene-edited animals as veterinary drugs, which would put them in the same regulatory bucket as GMO animals, such as AquaBounty’s salmon, which is engineered in part using genes from another fish species.
Critics contend this proposed policy would trigger extensive, costly premarket regulatory review that would severely limit the ability of scientists to breed gene-edited animals, though the FDA says it will balance its guidelines to protect public health without hampering innovation. The agency’s proposal has been panned by animal biotech scientists, some of whom have moved their breeding programs to countries with less restrictive regulations.
FDA stands its ground
Writing in Nature Biotechnology on February 7, FDA Center for Veterinary Medicine (CVM) Director Steven Solomon explained the rationale guiding the agency’s proposal. Citing the examples of a gene-edited bull whose genome was unintentionally altered to contain bacterial DNA and a conventionally bred animal from the 1950s, Solomon argued that:
The intended genome edit sought to introduce the Celtic POLLED allele into Holstein cattle. This allele exists in some other cattle breeds and results in the animals lacking horns (or being ‘polled’) …. [H]owever, the editing also produced unintended modifications …. Unintended alterations can have unexpected and deleterious consequences no matter the size of the alteration or how it was produced …. There is a particularly compelling example of the risks of occult genomic alterations in cattle produced by traditional breeding techniques: a high incidence of bovine leukocyte adhesion deficiency (BLAD) syndrome, a lethal autosomal recessive disease, in Holstein calves.
The selection of a particular Holstein bull for superior milk production genetics resulted in wide dissemination of carrier bulls’ semen for breeding beginning in the 1950s and 1960s. It turned out that the selected bull was a carrier of a naturally occurring single point mutation that causes BLAD when two copies are present. The extensive use of carrier bulls’ semen led to an eventual 23% BLAD carrier frequency in Holstein calves in the United States. It took a decade to effectively breed the genetic mutation that causes BLAD out of dairy cattle genetics.
…. We recognize that there is tremendous excitement over quickly embracing and bringing to market the fruits of genome editing technology, as well as the critical importance of adequately identifying potential risks, efficiently evaluating whether the risks do in fact exist, and determining whether the risks pose an actual safety hazard in a timely manner.
It is the FDA’s role to balance these competing imperatives. We want to support the timely development of beneficial products, but not at the expense of abdicating our critical role in protecting consumer and animal health. We have a public health obligation to protect consumer and animal health that we must balance with the potential of this innovative technology to enhance human and animal health and food production.
Nature Biotechnology’s editorial board found Solomon’s case unpersuasive. If anything, they wrote, his examples undermine the justification for strict FDA oversight of gene-edited animals:
BLAD is not a justification for mandatory regulation of all gene-edited animals …. [I]t illustrates that conventional breeding might warrant tighter FDA oversight, especially when rapid breeding expansion programs thrust particular genetic profiles to the fore …. [I]f the BLAD case history tells us anything, it is that the origin of a DNA arrangement (conventional breeding, recombinant DNA or gene editing) makes little difference to an animal.
While the editorial authors conceded that “the presence of extraneous donor plasmid in the gene-edited POLLED Holstein DNA was unexpected and initially missed,” they said the unintended edit should be properly contextualized. The genomes of domesticated cattle contain north of 86 million mutations–”insertions, deletions and single nucleotide variants”–and none of these changes is linked to negative health outcomes in humans who consume milk or meat from cows. “Amidst this background of innocuous variation, how can the presence of one identifiable variant justify the costs and delays of mandatory FDA oversight?” the authors asked.
The answer, they continued, has more to do with politics than science. Anti-GMO groups have utilized every tool at their disposal to restrict the progress of agricultural biotechnology. One of their most potent weapons has been a constant stream of litigation aimed at the USDA, FDA and EPA, the three federal agencies tasked with oversight of biotechnology. Activist litigation was a primary factor in the delayed approval of AquaBounty’s salmon, for example. The groups behind the mass of lawsuits have also successfully stoked consumer concern about the alleged risks of genetically engineered crops and animals. Meanwhile, the relatively small animal biotechnology industry doesn’t have anywhere near the same the public relations and legal resources. As the editorial explained:
[T]here are very few companies in this sector to argue the case for genetically engineered (including gene-edited) animals …. On the other hand, there is a powerful and litigious anti-GMO/pro-organic lobby that repeatedly challenges the legitimacy of regulatory rulings and attempts to block market access following approval.
Life-saving biotech drugs gain wide support in Washington. But there is little political capital invested in backing gene-edited animals. Food remains plentiful and, if anything, the public mood is shifting to vegetarianism and animal-substitute products. Scientists and breeders want to use new technology in agriculture, but public sentiment nostalgically harks back to Victorian farming practices in a way that it doesn’t for Victorian medical practices.
A cautious, process-based regulatory route keeps the FDA out of trouble and lowers litigation risks for CVM’s lawyers.
The authors ended with a proposal of their own, urging the FDA to regulate gene-edited animals based on the risks they may pose to human health, not the process that was used to breed them:
Mandatory oversight could be phased out to a system whereby the agency exercises discretion over which gene-edited animals are regulated according to the hazard represented by the introduced trait. This would be consistent with USDA policy and longstanding US regulatory policy. It would give the animal biotech sector a chance to bloom. And it would counter the narrative of fearmongers who would taint all gene-edited animals as hazardous to public health and injurious to animal welfare.