FDA’s (our, we) analysis illustrates, however, why it is necessary for there to be regulatory oversight of intentional genomic alterations in animals, even when the intended modification seeks to replicate a naturally occurring mutation. (Readers should note that our statement here relates to intentional genomic alterations in animals; we are not commenting on alterations in plants or other organisms.) The analysis shows that genome editing in animals can have unintended consequences and that regulators must be alert to the possibility of such consequences. The existence of an unintended alteration does not necessarily demonstrate that edits of an animal’s genome are unsafe, either to the animal or to anyone consuming food from the animal. The unintended alteration in this case resulted in the integration of a bacterial plasmid containing various sequences designed for use in molecular biology, including antibiotic resistance markers. These markers are controlled by a bacterial promoter and thus are unlikely to be expressed in a eukaryotic genome; similarly, the integration of the plasmid itself does not necessarily represent a safety concern in this instance and we want to emphasize that we are not suggesting that it does. However, these findings demonstrate that there is good reason for regulators to analyze data on intentional genomic alterations in animals to determine whether there are any unintended results, either on- or off-target and, if so, to determine whether they present any cause for regulatory concern.
Unintended alterations can have unexpected and deleterious consequences no matter the size of the alteration or how it was produced. For example, the diseases sickle cell anemia and cystic fibrosis both result from single nucleotide mutations. 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 1960s3,4. It turned out that the selected bull was a carrier of a naturally occurring single point mutation that causes BLAD when two copies are present4. The extensive use of carrier bulls’ semen led to an eventual 23% BLAD carrier frequency in Holstein calves in the United States5. It took a decade to effectively breed the genetic mutation that causes BLAD out of dairy cattle genetics3. There are also many examples from murine genetic engineering in which unexpected genomic events have led to the production of alleles with significant unintended consequences6,7. To avoid this type of damaging outcome occurring through an intentional genomic alteration, given the FDA’s authority and public and animal health responsibility to regulate, the FDA wants to know that an intentional genomic alteration in animals will not inadvertently produce such a result.
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