Month: December 2020

This is part 3 of a 1, 2, 3, 4 part series on Regulation of Genetically Modified Animals

So what is the USDA’s proposal for the regulation of genetically engineered animals? In a nutshell, it proposes moving regulation of food animals that are genetically engineered for agricultural purposes such as human or animal food, fiber, and labor from FDA to USDA. This means that intentional genomic alterations in food animals would no longer be automatically and mandatorily regulated by the FDA as “drugs”. That is good news, because genetic variation between individuals cannot reasonably be considered a drug. All life on Earth is made up of genetic alterations. It is the very foundation of all selection programs, and indeed evolution itself. In some ways it is going back to the future, as APHIS oversight of  agriculture and forestry products developed by modern biotechnology was envisioned in early discussions of the regulation of biotechnology.

APHIS would conduct a safety assessment of animals that have been modified or developed using genetic engineering subject to the Federal Meat Inspection Act (FMIA), and the Poultry Products Inspection Act (PPIA) with a specific eye to alterations that may increase the animal’s susceptibility to pests or diseases of livestock, including zoonotic diseases, or ability to transmit the same. The Food Safety and Inspection Service (FSIS) would also conduct a pre-slaughter food safety assessment to ensure that the slaughter and processing of certain animals modified or developed using genetic engineering would not result in a product that is adulterated or misbranded, as they do with animals produced using conventional breeding.

This is a definite improvement over the FDA approach. Period. Clearly the approach being proposed has been used in plants, and has allowed at least some genetically engineered crops to come to market, albeit mostly those developed by large biotechnology companies. However, there are still some logical inconsistencies in the proposal as it stands. And I realize that perfect is the enemy of good enough, but I can’t help but look at this from my perspective as an academic working in livestock improvement, who has seen the promise of genetic engineering wither on the vine. Regulatory evaluations have included “Alice-in-Wonderland” evaluations that include questions that have no right or wrong answer. If there is no hypothesis to test it is not possible to do a power analysis or design a sensible experiment. Studies that product developers have conducted to try to address these questions have been used by groups opposed to the technology to suggest the whatever data is provided indicates unacceptable risks as discussed here. At least the USDA proposal is seeking to identifying “plausible” risks, suggesting the need to test at least some hypothesis, rather than a fishing expedition.

First, lets look at what genomic alterations are covered. Specifically, those that are introduced into animals of the “amenable species” (cattle, sheep, goats, swine, horses, mules, other equines, fish of the order Siluriformes (catfish), chickens, turkeys, ducks, geese, guineas, ratites, and squabs) modified or developed using genetic engineering that are “intended for agricultural purposes” such as human or animal food, fiber, and labor. FDA would continue its review of amenable species modified or developed using genetic engineering intended for non-agricultural purposes, including medical and pharmaceutical purposes (other than veterinary biologics), and gene therapies; and in non-amenable species. So genomic alterations in non-food animals remain with the FDA, and so does non-agricultural genetic engineering. Sorry dog and cat people – you remain with the FDA, irrespective of the nature of your edit.

And what is “genetic engineering” in this case? It is defined to mean “techniques that use recombinant, synthesized, or amplified nucleic acids to modify or create a genome”.  Note how this is a technique-based definition. Already, we have run afoul of the 1986 Coordinated Framework for Regulation of Biotechnology which states, exercise of regulatory oversight should be product-risk based…”and should not turn on the fact that an organism has been modified by a particular process or technique.”

The proposed rule goes on to clarify it would “not include conventional breeding methods such as directed breeding, artificial insemination, embryo transfer, selective breeding, cross breeding, genetic backgrounding for purposes of studding, or other practices commonly available to and employed by producers.” I have worked in animal genetics my entire career, and have not the slightest idea what “genetic backgrounding for purposes of studding” means. Seriously. NO IDEA. I am also not sure the difference between directed breeding and selective breeding, but maybe I do not get out enough.

Onwards to some other concerns, there does not seem to be any clear distinction between genome edited animals without intergeneric DNA combinations that could have been achieved using conventional breeding, albeit likely less efficiently that can be achieved using traditional approaches, and genetically engineered animals harboring an rDNA transgene. This distinction was clearly made in the SECURE revision of APHIS’ biotechnology regulations for plants; but not in this contemplated regulatory framework for animals. This seems strange.

The proposal reads “The regulatory framework that USDA is considering would be conceptually similar to the recently updated USDA regulations for the movement of organisms, notably plants, modified or developed using genetic engineering, (i.e. SECURE).  However, due to the differences in experience, biology, and breeding practices of animals as compared to plants, there would be some differences between these regulatory frameworks.  For example, although SECURE includes up-front exemptions from the regulations for certain types of modifications [i.e. plants without intergeneric DNA combinations that could have been achieved using conventional breeding], we envision that all amenable species modified or developed using genetic engineering and intended for agricultural purposes would be subject to permitting requirements for their import, interstate movement, or environmental release until they have undergone an expedited safety review or an animal health risk assessment and been determined not to pose an increased risk to animal health.  We do seek comment on this issue.“

Well I certainly have some comment on this issue!  What are the “differences in experience, biology, and breeding practices of animals as compared to plants” that make a SNP in a plant eligible for an up-front exemption from the regulations, but a SNP in an animal not? Crops naturally produce allergens, toxins, or other anti-nutritional substances, and some rare safety issues that have been associated with conventional plant breeding, such as allergens in Kiwi fruit, or high levels of solanine in potatoes. I have a hard time coming up with analogous examples from animal breeding despite intensive selection for traits of interest. So what is uniquely hazardous, or even risky, about genomic alterations that could have been achieved using conventional breeding in animals, but not plants, that makes cisgenics, SNPs and deletions ineligible for an up-front exemption from the regulations? At the end of the day – both kingdoms provide food, and different regulations for the different kingdoms makes little scientific sense.

I have many more specific comments on this proposal, but they all will come back to this basic point. Regulation should be proportionate to risk, and agnostic to method. If regulations are being proposed that mandate a more onerous pathway for identical products produced one way as compared to another, or differ between kingdoms, or require additional testing only of products produced using one method, then they will tilt the scale to the less onerous pathway. This may not always be in the best interests of society. For over 30 years now animal geneticists have had little ability to employ genetic engineering in animal breeding programs. This comes with an opportunity cost as detailed here.

In contemplating  an improved regulatory approach for genetically modified animals, perhaps it is time to ditch the process-based trigger which requires additional regulatory scrutiny of plants and animals that could have been achieved using conventional breeding, and rather take the advice of the 1996 Coordinated Framework, and that is that regulatory review should be confined to organisms deliberately formed to contain an intergeneric combination of genetic material from sources in different genera (aka foreign or transgenic DNA that could plausibly produce a toxin or an allergen), and that oversight should be exercised only where the risk posed by the introduction is unreasonable, that is, when the value of the reduction in risk obtained by additional regulatory oversight is greater than the cost thereby imposed.

This is part 2 of a 1, 2, 3, 4 part series on Regulation of Genetically Modified Animals

The “Guidance for Industry #187” entitled, “Regulation of Intentionally Altered Genomic DNA in Animals” was published in the Federal Register in 2017, and a public comment period followed. I wrote about my concerns regarding this approach in a previous BLOG. The FDA took comments on this draft revised guidance during the 90-day public comment period which closed June 19, 2017. As I wrote in a BLOG in January 2019, and what remains true today, is that there has been ZERO formal response to the many comments by public sector scientists working in this field who submitted detailed comments, and who see that this regulatory approach will make food animal research using genome editing cost prohibitive, and effectively preclude the use of gene editing in food animal breeding programs.

To date, there have been two food use approvals for genetically engineered animals in the US, ever. One, the AquAdvantage salmon, the founder event of which occurred in 1989, and which has still yet to be sold in the US despite approval in 2015 as discussed here. AquaBounty estimated it has spent $8.8 million on regulatory activities to date including $6.0 million in regulatory approval costs through approval in 2015, $1.6 million (and continuing) in legal fees in defense of the regulatory approval, $0.5 million in legal fees in defense of congressional actions, $0.7 million in regulatory compliance costs (~$200,000/year for on-going monitoring and reporting including the testing of every batch of eggs), not to mention the $20 million spent for maintaining the fish while the regulatory process was on-going from 1995 through 2015.

And on December 14, 2020 the FDA announced it second food animal approval for an Alpha-gal (galactose-α-1,3-galactose) knockout “GalSafe” pig. The press release announced the “First-of-its-Kind Intentional Genomic Alteration in Line of Domestic Pigs for Both Human Food, Potential Therapeutic Uses.” This wording “intentional genomic alteration”, at first made me think this was approval for a genome edited knockout. But then I read an article quoting a spokesperson for the developer saying they have been working on the GalSafe pigs since 2007. That is pre-genome editing in food animals. I searched PubMed and realized that this approval was for a traditional gene knockout approach to achieve a homozygous founder event that was followed by cloning, aka old school genetic engineering, and that was first published in the peer-reviewed literature in 2003.

A petition calling for a harmonization of the U.S. regulatory approach to gene editing in food species so that both plant and animal breeders have access to gene editing innovations to introduce useful sustainability traits like disease resistance, climate adaptability, and food quality attributes into U.S. agricultural breeding programs was launched at the Plant and Animal Genome Conference in 2018, and signed by over 300 scientists, and was shared with the federal regulatory agencies in June 2018.

Comments from scientists included:

“It is long-standing U.S. policy to regulate an item derived from biotechnology as a product, not by the process through which it was produced. We must base oversight based on assessed risk, not on the basis of political considerations.”

“Regulatory uncertainty and inconsistency are barriers to innovation. Importantly, it prevents small to medium businesses from having a pathway to market for products that could be of immense benefit, including the welfare of animals. Draft Guidance for Industry #187 is out of step with crop plants and is not consistent with a science-based risk based regulatory framework. It is disappointing that this Draft undermines a regulatory system that has, until now, been regarded as robust and well respected. The Draft is not fit for purpose.”

In the meantime, USDA announced the SECURE (Sustainable, Ecological, Consistent, Uniform, Responsible, Efficient) revision of APHIS’ biotechnology regulations that was published in the Federal Register on May 18, 2020 following a detailed response to the public comments. It includes up-front exemptions from the regulations for certain types of modifications, specifically a modification (1) resulting from natural cellular repair of a targeted DNA break without any introduced DNA to direct the repair;  (2) that is a targeted single base pair substitution; or (3) that introduces a gene known to occur in the plant’s gene pool, or causes a change in a gene that corresponds to a version of that gene present in the organism’s gene pool.  These exemptions were primarily designed to exclude from oversight plants without intergeneric DNA combinations that could have been achieved using conventional breeding, albeit likely less efficiently. Food (e.g high oleic oil from company Calyx) from genome edited plants has already entered the US market.

The FDA doubled down on their new animal drug regulatory approach in a 2020 Nature Biotechnology correspondence entitled “Genome editing in animals: why FDA regulations matters” There, FDA Center for Veterinary Medicine (CVM) Director Steven M. Solomon made the case for

“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.” He then specifically distances his argument from intentional genomic alterations performed in organisms from other kingdoms that we eat, i.e. plants and microbes, with the statement “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.”                      FDA CVM

As I wrote in my BLOG earlier this year, Nature Biotechnology published its own editorial response the FDA’s correspondence countering that, “the origin of a DNA arrangement (conventional breeding, recombinant DNA or gene editing) makes little difference to an animal. The genomes of domestic cattle contain millions of natural variants: the 1000 Bull Genomes Project found >86.5 million differences (insertions, deletions and single nucleotide variants) among cattle breeds. According to prominent researchers in the field, none of these variants has been shown to produce ill effects on consumers of milk or meat. Amidst this background of innocuous variation, how can the presence of one identifiable variant justify the costs and delays of mandatory FDA oversight?

Nature Biotechnology finishes with the argument that,

“A cautious, process-based regulatory route keeps the FDA out of trouble and lowers litigation risks for CVM’s lawyers. But the agency could still alter course without reversing direction completely.

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.”                                          Nature Biotechnology

And so we come to December 2020, and the UDSA advance notice of proposed rulemaking “Regulation of the Movement of Animals Modified or Developed by Genetic Engineering “ which was published in the Federal Register on 12/28/2020. What is the USDA proposing? And how does it differ from the FDA’s approach? Does the contemplated regulatory framework improve things? More on that in the next BLOG.

This is part 1 of a 1, 2, 3, 4 part series on Regulation of Genetically Modified Animals

Ever since the US Food and Drug Administration (FDA) announced its plans to regulate genomic alterations in genome edited animals as veterinary drugs in January 2017, I have been a vocal critic of this regulatory approach. I am a livestock geneticist, and have seen the negative impact that this expensive and unpredictable regulatory approach has had on the development of genetically engineered animals. Even today, there has not yet been the sale of a single food product from a genetically engineered animal in the United States, although AquaBounty is getting close with their approved, fast-growing AquAdvantage Atlantic salmon. And just this month a second product, a gene knock-out pig was approved by the FDA, although the company has also not yet sold any pork product to consumers.

Compare that to the progression of genetically engineered crops which have been commercialized for more than 22 years, and in 2019 alone they were grown on 190.4 million hectares by 17 million farmers in 29 countries. Clearly there is something different about the trajectory of genetically engineered food products developed in the animal kingdom as compared to the plant kingdom. Yet at the end of the day, products from both kingdoms end up on the plate of omnivorous consumers. Is there something inherently risky about genetically engineered food animals that explains this discrepancy?

Recently, the United States Department of Agriculture (USDA) came out with an advance notice of proposed rulemaking which was published in the Federal Register on 12/28/2020. This proposal contemplates a different regulatory approach for genetically engineered animals of certain “amenable” food animal species that are “intended for agricultural purposes”. There is a lot to unpack in this document, and so first some background information might be helpful. This is going get a little wonky.

Thirty five years ago, the first paper documenting the production of genetically engineered food animals was published in 1985. A year earlier, a December 1984 Notice “Biotechnology regulation; coordinated framework” came out in the Federal Register, with the introduction reading, “Only forty years ago, DNA was discovered to be the repository of genetic information…”.

In that document, USDA outlines it plan to use its existing  regulatory framework to regulate agriculture and forestry products developed by modern biotechnology. In 1986, the White House, Office of Science and Technology Policy (OSTP) published the Coordinated Framework for Regulation of Biotechnology. This document states, “This framework has sought to distinguish between those organisms that require a certain level of federal review and those that do not. This follows a traditional approach to regulation. Within agriculture, for example, introductions of new plants, animals and microorganisms have long occurred routinely with only some of those that are not native or are pathogenic requiring regulatory approval.” The document goes on to clarify that for genetically engineered plants, the “regulated article” would be defined as any organism or product altered or produced through genetic engineering, if the donor organism, recipient organism, or vector or vector agent belongs to a group of organisms designated by the proposed regulations as having plant pests or any organism or product which USDA determines is a plant pest. A similar approach was envisioned for the regulation of genetically engineered animals.

The Coordinated Framework was subsequently updated in 1992 to include “Exercise of oversight in the scope of discretion afforded by statute should be based on the risk posed by the introduction and should not turn on the fact that an organism has been modified by a particular process or technique”. Additionally, it was clarified that “(O)versight will be exercised only where the risk posed by the introduction is unreasonable, that is, when the value of the reduction in risk obtained by additional oversight is greater than the cost thereby imposed.”

Back in 1992, genetic engineering typically involved random genomic insertion of intergeneric DNA combinations (i.e. transgenic construct) that expressed a protein which resulted in a desired outcome in the target species. For example, fast growth in the case of the AquAdvantage salmon, disease-resistance in the case of a mastitis-resistant cow, or decreased phosphorus in the manure of the “EnviroPig”.

For a number of years, regulatory oversight of the movement of both genetically engineered plants and animals rested with the USDA. Early work with transgenic goats undertaken by my colleagues at UC Davis in the early late 1990s and early 2000s was done in consultation with the USDA’s Animal and Plant Health Inspection Service (APHIS). Under the Animal Health Protection Act (AHPA), APHIS is authorized, among other things, to prohibit or restrict the importation and interstate movement of live animals to prevent the introduction and dissemination of diseases and pests of livestock within the United States.  The AHPA broadly defines the terms “livestock” as “all farm-raised animals”, and “animal” as “any member of the animal kingdom (except a human)”. APHIS currently uses its plant pest authorities under the Plant Protection Act to assess and regulate the movement of genetically engineered plants into the environment.

A chapter in a 2004 PEW report which came out almost 20 years after the first genetically engineered livestock were reported in 1985 entitled “Regulating Genetically Engineered Animals”, read

“because GE animals are so new and are still largely being used only in research, the agencies likely to oversee them have not yet established clear overall or product-specific policies for regulating them under existing laws. Regulators, researchers, developers, and potential consumers are thus currently navigating in uncertain waters, and the discussion of regulatory policies in this chapter is necessarily somewhat speculative.”

In that PEW report the terms “genetically engineered” and “transgenic” were used synonymously, as genetic engineering at the time involved the random insertion of recombinant DNA (rDNA) constructs.

Then in 2009, the FDA Guidance for Industry #187 entitled, “Regulation of Genetically Engineered Animals Containing Heritable rDNA Constructs”, announced FDA’s intent to regulate all genetically engineered animals modified by rDNA techniques, including the entire lineage of animals that contain the modification, under the new animal drug provisions of the Federal Food, Drug, and Cosmetic Act (FD&C Act). In that act, a new animal drug is defined as “an article (other than food) intended to affect the structure or any function of the body of … animals.”

The FDA clarified that they considered the rDNA construct and its expression product in a genetically engineered animal to be the drug, not the genetically engineered animal itself. Although the FDA’s regulatory evaluation was based on attributes of the product, the method used to produce the genetic change, that is rDNA techniques  versus other breeding methods, was the trigger for regulatory oversight. In other words, the trigger for regulatory oversight was based on the process designed to produce the genetically engineered animal, not on the risks associated with the specific characteristics of the animal or its food products (milk, meat or eggs).

And so it continued until January 2017, when the FDA came out with its updated draft “Guidance for Industry #187” entitled, “Regulation of Intentionally Altered Genomic DNA in Animals”. This guidance proposed to regulate all food animals whose genomes have been intentionally altered using modern molecular technologies including gene editing technologies which may include random or targeted DNA sequence changes including nucleotide insertions, substitutions, or deletions, or other technologies that introduce specific changes to the genome of the animal as veterinary drugs.

So there has been a gradual metamorphosis over the past 30 or so years from a proposal for USDA to oversee the regulation of  genetically engineered food animals that pose “unreasonable” risks regarding introduction and dissemination of diseases and pests of livestock under APHIS, to a 2009 draft guidance requiring mandatory FDA premarket new animal drug approval for all animals modified by recombinant DNA techniques; to an updated 2017 draft guidance requiring mandatory FDA premarket new animal drug approval of any “intentionally-introduced genomic DNA alteration in animals produced using modern molecular technologies”, irrespective of risk or even the presence of a heritable rDNA construct. I think that is called regulatory creep. A set of administrative rules giving rise to unintended consequences, because of their broad industry reach.