Will new regulations stifle innovation in plant and animal breeding?

Author: Philip Brasher and Steve Davies

Gene editing is touted as a promising new way of altering the DNA of plants or animals to speed their growth, enhance flavor, extend shelf life or combat viruses. But those who see it as a key component of agriculture’s future want to make sure that the regulations written for it do not stifle its promise.

“What we need to have is an environment where the regulation fits with the risk, and regulation fits with the application” of the technology, says Kevin Folta, professor and chairman of the Horticultural Sciences Department at the University of Florida. “Let’s not bottleneck innovation.”

New methods such as CRISPR may allow plant breeders to avoid the regulatory bottlenecks. Harry Klee, a colleague of Folta’s at the University of Florida who is working to improve the taste of tomatoes, says he’s using CRISPR instead of “traditional genetic engineering” that uses foreign DNA.

“We are hopeful that a clean gene-edited mutation with no foreign DNA that is equivalent to a natural mutation will be free and clear of regulations,” he said in an email. “Being able to take such a mutation and introduce it widely into many elite breeding lines without the need for extensive backcrossing is a potential game changer in breeding programs.”

So far, the odds are good that Klee will get his wish. All of the gene-edited products APHIS has reviewed thus far under its “Am I Regulated” process have received “no” answers – including a non-browning mushroom developed at Penn State using CRISPR/Cas9.

But that's not the case for gene-edited animal products.

For now, the Food and Drug Administration (FDA) defines all intentionally altered genomic DNA as a new animal drug, irrespective of how or why they were changed. For example, firms that use gene editing to develop pigs with PRRS resistance, would have to go through FDA’s process for evaluating a drug.

“It’s a nonsensical position,” says Alison Van Eenennaam, a cooperative extension specialist in animal genomics and biotechnology at the University of California-Davis who has conducted extensive research on gene editing with cattle.

“Regulatory processes should be proportional to risk and consistent across products that have equivalent levels of risk,” she explained. For now, “GE animal regulatory burdens are disproportional high and associated with unaccountable delays and considerable uncertainty. These regulatory burdens are not justified by scientific evidence or experience," she adds. And they require elaborate and costly studies, not to mention time delays.

So for many industry stakeholders, there is still a great deal of regulatory uncertainty. And it's not clear how the regulations might change in the future.

Mike Firko, deputy administrator for APHIS' Biotechnology Regulatory Services, said at BRS’s recent annual stakeholders meeting that the track record so far isn’t necessarily predictive of the future.

“We decided that those particular products that were put before us would not be regulated,” he said. “CRISPR is a very powerful tool. It may very well be possible that we will soon see a product produced with CRISPR technology where we would say, “Oh, yes, that falls within our regulatory authority, under our current regulation.’ So, I want to make it clear that our decisions haven't been about all products produced with CRISPR technology – only those that we've seen so far.”

It may be some time, before there are clear answers on where the federal agencies responsible for regulating genetically engineered products draw the line. Given the fractured nature of the current regulatory framework, that will take a lot of meetings, talk and compromise.

There are also major trade concerns to address: Exporters of grains, oilseeds and other commodities have raised concerns about an overhaul of U.S. regulations, saying that any changes need to be coordinated with importing countries to make sure that shipments of gene-edited products will be accepted. Many countries, from the nations of Europe to Japan and New Zealand, are in various stages of assessing how they will regulate products of various gene-editing techniques.

Nicholas Jordan, University of Minnesota

As for the effort to modernize U.S. regulations, “My feeling is it’s pretty stalemated,” said Nicholas Jordan, a professor at the University of Minnesota who has studied and written about biotech regulation. “There are such divergent ideas about what the future regulatory system should look like.”

That’s not just because of rapidly advancing technology, which makes it difficult – if not impossible – for regulators to keep up. It’s also because of the three-legged approach used to regulate biotech in the U.S.

Currently, the USDA’s Animal and Plant Health Inspection Service regulates genetically engineered plants if they are deemed to pose a plant pest risk. APHIS also reviews petitions to determine whether new genetically engineered products pose enough of a safety risk to even warrant regulation.

Also in the regulatory mix: The Food and Drug Administration, which regulates plant and animal food products derived from conventional breeding techniques or genetic engineering. Finally, the Environmental Protection Agency regulates plant-incorporated protectants – “plants that have been genetically altered to produce proteins that are harmful to certain insect pests,” EPA explains, citing as examples Bt corn and Bt cotton, engineered to resist pests such as corn rootworm and cotton bollworm.

Despite their best efforts to coordinate oversight of GE products, the arrangement has occasionally led to confusion, as with Oxitec’s attempt to release male mosquitos with a “self-limiting” gene that causes offspring to die before reaching adulthood. Initially, FDA performed an environmental assessment on the mosquitos based on its conclusion that they were “animal drugs,” but later it kicked the regulatory responsibility to EPA after both agencies concluded that “articles or categories of articles that control the population of mosquitoes are most appropriately regulated as pesticides.”

“When you’re mostly trying to eliminate a pest population, why not just let one agency do it?” says Jaydee Hanson, senior policy analyst at the Center for Food Safety, who pushed for the change.

Everyone in the biotech realm – including government officials, private industry, non-governmental organizations and plant breeders – agrees that clear lines of responsibility are essential. The recent report from the Trump administration’s Rural Prosperity Task Force calls on the administration to “develop a streamlined, science-based regulatory policy” that ensures products are assessed “in a risk-based manner, providing predictable pathways for commercialization.”

President Trump signed the executive order creating the Rural Prosperity Task Force on Ag Secretary Sonny Perdue's first day on the job.

“We’re hopeful that perhaps that’s kind of the hook that USDA will start taking some leadership in getting other agencies to move in a similar direction… and with some leadership from the White House as well,” says Clint Nesbitt, director of regulatory affairs for food and agriculture at the Biotechnology Innovation Organization (BIO).

“It is important that you have a regulatory system that does give consumers the reassurance that these products have had the appropriate amount of regulatory oversight,” Nesbitt says. “That doesn’t mean that every single thing necessarily needs one-by-one review.”

But every sensible recommendation comes with a caveat. In order to fashion a coordinated approach, there must be people in place to do the coordinating. And the Trump administration has been slow to get its political appointees in place.

The Rural Prosperity report, for example, recommends that the White House Office of Science and Technology Policy coordinate interagency biotechnology efforts. In addition, the report recommends the administration “create a forum led by (OSTP) that connects regulators with the funding and R&D agencies to increase awareness and speed the safe commercialization of novel biotechnology products.”

Building on the task force report, USDA and FDA announced a joint agreement Jan. 30 that pledges to carry out a 2015 strategy, spearheaded by OSTP under the Obama administration, for modernizing the government’s regulatory process for biotechnology.

Just one problem: OSTP still doesn’t have a director, more than a year after President Trump took office. It’s the longest stretch the position has been vacant since OSTP was established in 1976.

Nesbitt says that BIO hasn’t yet had detailed discussions with agency regulators about biotech, citing in part the dearth of officials in positions of responsibility.

One area that is of particular interest encompasses what are known as the Part 340 regulations, which govern how APHIS deals with plant pests. APHIS released a proposal to rewrite those regulations the day before President Obama left office.

The proposal, which would have required upfront analysis of the risks of GE organisms, was roundly criticized by stakeholders on all sides of the issue and was eventually withdrawn in November.

Firko called the comments on the Part 340 changes “a head-scratcher” at BRS’s annual stakeholder meeting in November. One group of commenters said, “Oh my gosh, this is so much more regulation,” Firko said. “And then there's a whole 'nother bunch of people (who called it) dramatic underregulation.”

“Somewhere in our communications, different groups of people are interpreting our proposed rule very differently,” Firko said. “So, that's why we need to engage with stakeholders more... try to figure out what was going on there, why different groups of people viewed our proposed rule so dramatically differently. And that's what the new stakeholder engagement is intended to address.”

So far, however, there have been no announcements about stakeholder engagement.

“As of this moment, we don’t have any specific dates for public meetings and things like that,” said APHIS spokesman Rick Coker.

Nesbitt said early stakeholder input is crucial so APHIS understands the concerns with the proposal. “Fairly widely within the industry, we all felt that the proposal was confusing, complicated, created a lot of unanticipated problems that they didn’t intend,” he said.

The American Soybean Association, for example, said the “upfront risk analysis” sought in the proposal “all but guarantees that only the largest companies would have the time and resources to undergo this lengthy and costly process. Furthermore, it would deter much needed research at our universities and elsewhere.”

“If the U.S. is to be at the forefront of innovation and advancements in technology, we cannot create a regulatory system that stifles this goal and leaves U.S. businesses at a competitive disadvantage,” ASA said.

Grain and oilseed exporters, however, repeatedly raised concerns with the Obama administration about streamlining the Part 340 regulations without first making sure that the changes would be accepted by the importing nations. The exporters repeated the concerns to the Trump administration, urging APHIS to withdraw the proposed rule.

The exporters are still smarting from the 2014 disruption in shipments to China when Syngenta commercialized its Agrisure Viptera corn seed in the United States prior to getting import approval from China. The industry estimates the disruption cost it $1.5 billion to $4 billion during the 2013-14 marketing year.

In joint comments filed with APHIS, the Corn Refiners Association, National Grain and Feed Association, National Oilseed Processors Association, North American Export Grain Association and North American Millers’ Association called for the administration to pursue a “comprehensive engagement strategy” with other countries in order to “build international regulatory compatibility and acceptance around a new, more science- and risk-based approach” to regulating genetically modified plants.

“To be clear, this does not mean that other countries need to adopt a regulatory approach to new plant-breeding techniques that is identical to a future approach employed by APHIS. But, emphatically, it does mean that APHIS’s regulatory approach must be recognized by, and acceptable to, government regulatory authorities in U.S. export markets so as not to trigger regulatory action against U.S. commodities produced using genetic engineering or plant-breeding innovation, including gene-editing, in international commerce,” the groups said.

Bobby Frederick, director of legislative affairs and public policy for the National Grain and Feed Association, applauded USDA’s decision to withdraw the Part 340 rule, saying it gave APHIS time to pursue the internationally coordinated approach that the exporters have been seeking. “You can’t guarantee seamlessness, but you can line things up where they are more clear,” he said.

The exporters are simultaneously urging the FDA to require companies to notify the agency before they go to market with new gene-edited products. Not only is that premarket notification necessary to protect consumer confidence, it also would be “invaluable in facilitating the domestic and international marketability of crops utilizing these new techniques, thereby benefiting agricultural producers, the value chain, consumers and ultimately plant breeders,” the groups wrote in their joint comments.

Gene editing also has raised trade issues in the meat and dairy sectors. Industry groups are worried that FDA will move ahead with regulating all intentionally altered genomic DNA as a new animal drugs, the approach the agency now uses for all genetically engineered animals.

“Treating these animals as drugs also will likely have a negative impact on domestic and international trade,” the North American Meat Institute said in comments to FDA. NAMI noted that some foreign countries may not regulate gene-edited animals.

National Pork Producers Council President Ken Maschhoff says it would be “indefensible” for FDA to regulate all gene-edited animals as animal drugs.

"We ask the FDA to acknowledge that not all gene editing applications to animals require approval as new animal drugs under the Food, Drug and Cosmetic Act (FD&C Act)," Maschoff wrote in public comments to FDA in June 2017. "Such an interpretation of the FD&C Act—especially as applied to many potential uses of gene editing techniques in livestock— mischaracterizes resultant edited genomes as an 'article,' creates potentially insurmountable practical barriers to enforcement by the FDA and utilization by industry, and is not in keeping with federal policy and precedence - and indeed, global regulatory trends—concerning the use of biotechnology in agriculture."

Ken Maschhoff, NPPC

Chinese scientists have published dozens of papers on their use of CRISPR techniques, while the agriculture ministry is finishing work on its regulations for gene editing, according to FAS.

In Japan, the government has been handling gene-edited products “on a case- by-case basis,” according to the FAS report. “Consequently, researchers have been taking a relatively conservative and cautious position towards R&D.” South Korea, which hasn’t decided how to regulate gene editing yet, “is closely watching developments in other countries to determine how they can regulate innovative technologies,” FAS said.

But in South America, Argentina and Chile have decided that some plant products of certain gene-editing techniques as well as conventional breeding may not be regulated as GMOs when the traits could be obtained through conventional breeding or mutagenesis, according to the FAS survey. Products will have to be considered on a case-by-case basis, however.

Brazil’s agriculture ministry has not finalized that country’s policy. However, based on what has been proposed so far “it seems that all these three countries are going in the same direction,” said Diego Risso, executive director of the Seed Association.

The industry may have to live with the idea that products will be assessed on a case by case basis, however. “We need to accept that it’s the way the regulators feel more comfortable,” Risso said, speaking at the American Seed Trade Association’s annual meeting in December.

The South American countries’ policies are also expected to apply to gene editing of animals, according to the FAS survey.

Even in Europe, where there has been strong resistance to biotechnology, some governments want to take a different approach to regulating gene editing, at least when it comes to plants.

Several members of the European Union are awaiting a European Court of Justice opinion clarifying whether products of gene-editing techniques that are considered mutagenesis would be regulated as GMOs. A non-binding advisory opinion provided by the court’s advocate general in January was mixed. A final decision by the court is expected this summer.

The Netherlands, meanwhile, has proposed to the European Commission that many gene-edited products be exempt from regulations as GMOs if the same modifications could be achieved through conventional breeding. FAS cautions that a decision by the Commission could take years.

Back in the United States, the proposed Part 340 revisions also came under fire from groups traditionally critical of biotechnology. The Center for Food Safety (CFS) criticized APHIS’s proposal to exclude three classes of organisms from regulation, saying that “would allow GE organisms that could cause (Plant Protection Act) risks to entirely escape review and regulation by APHIS.”

“Any type of change in a gene sequence can potentially cause phenotypic changes that have significant consequences, whether the change could occur naturally or not,” CFS said in its comments. “Moreover, genome editing methods are still in early development, and risks of their use are not known well enough to predict impacts” without actually observing how they work in nature.

BIO, meanwhile, "believes APHIS could go a long way in improving the current regulatory system in the near term without revising the regs while still moving forward with rulemaking on a parallel track in the longer term.”

“They could push the boundaries a little further in terms of deregulating categories of things similar to things they’ve already seen,” BIO's Nesbitt said. In its comments to the agency on the proposed 340 changes, BIO said, “We believe that there will be many instances in which it is more scientifically justifiable to assess the regulatory status of whole categories of organisms, such as those of the same combination of species and trait.”

Greg Jaffe, CSPI

Paul Schickler, former president of biotech seed giant DuPont Pioneer, has cautioned the biotech industry against using gene editing to avoid regulation. Speaking at The World Food Prize’s Borlaug Dialogue in 2017, he said, “If we do position gene editing as an end-around of regulatory systems, it will be the failure of gene editing as a technology.”

But clearly, something has to give on the regulatory front if researchers and investors are going to advance both plant and animal agriculture.

FDA has approved one genetically engineered animal for food use: AquAdvantage salmon, genetically engineered by AquaBounty to grow much faster than non-GE farm-raised Atlantic salmon. But it took 20 years for that process to play out, “so that’s not a working regulatory system,” Nesbitt said. And the salmon have yet to be sold in the U.S.

“All kinds of animal companies are working in the space, but there’s just not a clear path forward, and clearly the process at FDA is not working,” he said.

FDA says the regulatory process it went through with AquAdvantage salmon does not necessarily provide lessons for future animal applications.

In response to questions posed by Agri-Pulse, FDA said, “Application of the regulations to individual products is highly case-specific so the experience with one application, such as the one for the GE salmon, may not be relevant to other applications.”

But Karen Batra, a BIO spokesperson, says that “A lot of our member companies are looking to that as kind of the model. They’re saying, "Well, I’m going to go to Brazil, I’m going to go away from this regulatory system. I’m not going through what (AquaBounty) went through.'”

Nesbitt adds, “For those things where there’s not a clear path to market, they just won’t even invest in the research in the first place, so until we have these clear paths, a lot of these companies won’t even be investing in this space.”

J.R. Simplot Co. also commented on the chilling effect that the draft FDA guidance could have on new opportunities for agriculture.

If FDA “were to regulate animals with intentionally altered genomic DNA as a new drug, the regulation would be disproportionate to the risk and not based in science. In fact, it would regulate the identical animal differently depending on whether the altered genomic DNA occurred naturally or by genomic editing," Simplot wrote.

"The consequence that follows is that it will become nearly impossible to effectively use promising and emerging technologies in animal genetics.”

At this point, it’s not clear where FDA will end up. It did not say when it will release its final guidance.