Gene-edited animals must be regulated to protect public health – US FDA

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Edited cattle containing antibiotic resistance genes are FDA's "Exhibit No. 1" in arguing for strict rules. Report: Claire Robinson

The US Food and Drug Administration (FDA) has issued a strong statement endorsing the need for strict oversight of gene editing (aka genome editing) in animals in order to protect public health. The FDA’s stance is of note because the biotech industry and its supporters have been strongly lobbying governments to forego regulatory oversight of gene-edited animals and plants, claiming that gene-editing makes such precise changes to the genome that oversight is unnecessary. In support of this argument, it has also been claimed that the edits are indistinguishable from alterations occurring in nature. But the FDA's own research, newly published in a peer-reviewed journal, shows that both arguments are false. The FDA's statement offers a mix of hype over the supposed potential of gene editing and strong caution about the risks. It says: “Genome editing is a groundbreaking technology used to introduce intentional genomic alterations in animals and has the potential to improve human and animal health, animal well-being and to enhance food production and quality. It is paramount, however, that as we move forward, we maintain standards of safety and effectiveness. “This is a tremendously exciting field. Because we’re committed to fostering advances in this space, we take a risk-based approach to oversight. We want to ensure that the intentional genomic alterations in animals are safe for the animal, safe for people eating food products from the animal and that the alteration does what it’s intended to do... The FDA is leveraging our scientific and technical expertise and regulatory experience to oversee intentional genomic alterations in animals developed using novel techniques, such as genome editing, through a timely and efficient process. The agency is a trusted global regulator and we are committed to overseeing this space in a manner that fosters innovation, promotes consumer confidence and protects the public health.”

The FDA's statement announces the publication in Nature Biotechnology of the FDA's groundbreaking research study in which FDA scientists discovered previously unreported alterations in gene-edited hornless cattle (the study was originally published on the pre-peer-review site BioRxiv). In this study, the FDA scientists unexpectedly found that the gene-edited cattle contained antibiotic resistance genes. This was in spite of the fact that the developer company Recombinetics, had claimed that the animals were free of any unexpected alterations and that they were exemplars of "precision breeding". These gene-edited hornless cattle that went badly wrong have rightly become the FDA's Exhibit No. 1 in arguing for strong regulation. In the agency's statement, it said that its discovery "emphasizes the FDA’s expertise and critical role in risk-based evaluation of intentional genomic alterations". The FDA added, “Our analysis demonstrated that genome editing in animals can have unintended consequences, and in this case, it caused foreign DNA to be integrated into the animals’ genomes. While the existence of an unintended alteration does not necessarily mean that the genome edit is unsafe to animals or consumers, it does show that both scientists and regulators need to be alert to the potential for such unintended alterations to take place."

As a companion piece to the new study publication, FDA scientist Steven M. Solomon published a commentary in the same journal, titled, "Genome editing in animals: why FDA regulation matters". The paper contains an incendiary quote explaining the hype versus the reality of the gene-edited hornless cattle, which should be etched into the minds of all policymakers. Solomon writes, "This edit was designed... to produce an alteration mimicking a sequence 'found in nature.' This characterization of the alteration is significant because some policymakers and scientists have argued that using genome-editing techniques to replicate a ‘natural’ mutation should not be of regulatory concern because it is equivalent to existing, naturally occurring alleles. 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... The analysis shows that genome editing in animals can have unintended consequences and that regulators must be alert to the possibility of such consequences."

Interestingly, Solomon is quick to state that "our statement... relates to intentional genomic alterations in animals; we are not commenting on alterations in plants or other organisms". It would be interesting to know whether he came under any political pressure to make this statement, because in reality, unintended effects from the gene editing of plants is at least as likely to place the public at risk. That's because plants can easily become toxic or allergenic as a result of unintended effects of genetic engineering techniques – see GMO Myths and Truths for a selection of animal feeding studies showing such outcomes with first-generation transgenic GM plants. No one knows if the same types of effects will arise from gene-edited plants, as no one has done the studies. It's possible that Solomon doesn't want to sacrifice his laudable intent to push for regulation of gene-edited animals by making himself a target of the abuse that's often directed at anyone who urges caution around gene-edited plants. That's understandable from the political point of view, though it would be gratifying to see the FDA standing up for public health with regard to gene-edited plants in the same way as they're doing with gene-edited animals.

A flavour of what Solomon might expect as "punishment" for wading into this quagmire of pro-GMO lobbying is provided by Nature Biotechnology's somewhat sinister editorial attacking the FDA's plan to carry out mandatory pre-market reviews of all gene-edited livestock. The editorial patronisingly states that the US FDA "should rethink" its stance and change course from its "maverick journey to process-based, rather than product-based, oversight" of GM animals. Process-based regulation begins by considering the process by which the GMO was made, whereas product- or trait-based regulation ignores the process and only focuses on the intended trait. The EU's GMO regulation is process-based (while also taking account of the final product) – much to the fury of the GMO lobby, which wants to dismantle it in favour of product-based regulation. This would remove any special oversight of GMOs based on the inherent risks and uncertainties of the GM process and would effectively abolish stringent safety assessments and labelling for these products. The Nature Biotechnology editorial claims that "the origin of a DNA arrangement (conventional breeding, recombinant DNA or gene editing) makes little difference to an animal" since naturally bred cattle have millions of natural gene variants which haven't caused ill effects on consumers of milk or meat. In this statement, the editorial manages to miss the point quite spectacularly, raising the question of whether the person who wrote it understands the research that the journal has just published. The FDA scientists' findings were revolutionary precisely because they demonstrated problems with the process, thus showing that process-based regulation was necessary. If regulation had been in place that only focused on the intended product, the gene-edited hornless cattle would have been seen as no different from naturally hornless cattle and the antibiotic resistance genes would have been missed. After all, the cattle looked just like cattle in every other respect. The invisible yet crucial difference was the antibiotic resistance genes, which got into the animals via the genetic engineering process used to generate them. As noted above, they were not spotted by the developer. The Nature Biotechnology editorial assumes that there would have been no effects from these rogue genes on consumers' health. But this is an assumption not borne out by evidence. The risk is that the antibiotic resistance genes could transfer to pathogenic bacteria, thus exacerbating the already serious problem of antibiotic resistant diseases. The editorial doesn't even address this possibility, let alone refute it. But in reality, it doesn’t matter how seriously we regard the risk that the antibiotic resistance genes could transfer to pathogenic bacteria. The critical point is that the genetic engineering process caused changes that the developer missed, and if that can happen, then those changes could be of significance and so are worth checking out. That alone calls for process-based regulation, whether or not you accept that the changes in any particular case represent a significant threat. The editorial, expressing incomprehension at the FDA's caution, goes on to lament the fact that the lobby for GM animals is weak: "There 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." Astonishingly, the editorial writer blames the "anti-GMO" lobby for the fact that the AquaBounty GM salmon is still not on the market – apparently he is oblivious to the owner company Intrexon's financial upheavals and the fact that the "final major regulatory barrier" to the US market was removed in March 2019. As is often the case, anti-GMO sentiment is blamed for the inherent failures of the agbiotech industry model.

All the gene editing of animals that has happened so far starts with isolating cells from an adult animal. As an example, these could be fibroblasts. These are grown in the laboratory in a process called tissue culture. Genetic engineers then carry out a gene-editing procedure (e.g. CRISPR editing) on the cells. Following the gene-editing procedure, individual cells are expanded (cloned) to generate sufficient numbers for molecular and biochemical characterisation. Once a candidate cell clone is identified that contains the desired gene-editing event and which is healthy in all other respects (i.e. doesn’t appear to have acquired adverse genetic mutations and properties), this is used in the animal cloning procedure. To do this, the genetic engineers isolate eggs from the (natural) animal from which the cells were originally derived, i.e. the same type of animal from where the gene-edited cells were derived. They remove the nucleus from the immature eggs, and then introduce the nucleus from the gene-edited adult cells into the eggs in place of the original nucleus. In the environment of the egg, or oocyte, the genetic material of the adult cell nucleus gets re-programmed so that it takes on the characteristics of embryonic cells rather than adult cells. This whole procedure is known as somatic cell nuclear transfer because the nucleus from a somatic cell has been transferred into an immature egg whose own nucleus has been removed. The re-programming of the somatic cell nucleus to an embryonic state by being in the egg environment causes the cell to start dividing, just like a fertilised egg will start dividing. Once it has reached a certain stage (early stage embryo), this is then implanted into the uterus of a pseudo-pregnant animal (e.g. a ewe, sow, or cow, which is induced by hormone treatment to mimic pregnancy), where it can implant and mature, it is hoped, into a foetus that is carried to term. We can see that gene editing of animals at the moment is inseparable from the cloning procedure, with all of its complications of inefficiency and high frequency of birth defects. The whole procedure is laboratory-based until the egg is implanted into the animal. But even at that point it is not really farm-based. The animal that has received the gene-edited cloned egg is kept in a research establishment in a contained environment, not out on a farm somewhere.

Within the European Union, up to this point in the gene-editing procedure, animal gene editing is classed as research and development and is regulated under the contained use (GMO) regulation. Then if the EU institutions approve the gene-edited animal for food and feed, it can be commercialised. There is currently nothing in the EU regulations that prevents this commercialisation, but so far no gene-edited or transgenic GM animals have been submitted for approval.

Given the intrinsic risks and inevitable animal suffering involved in gene editing and the associated cloning processes, what's needed is a moratorium on animal gene editing and cloning. But if there isn't enough political will to get that, then strict regulation of the type being asked for by the FDA scientists could at least protect the consuming public from some of the risks.