Gene Editing Mishaps Highlight Need for FDA Oversight

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A Midwestern company’s quest to genetically engineer the world’s first hornless dairy cows hit a snag this summer when the U.S. Food and Drug Administration found extra genes in the cows that weren’t supposed to be there. The mistakes that FDA caught – but the company missed – highlight the importance of government oversight of gene-edited foods at a time when industry groups are pushing for deregulation.

Cows without horns: a job for gene editing?

Pork producers, for example, “say the federal government should ease regulations on the use of gene editing in livestock,” which they claim is slowing down research and development, the Wall Street Journal reported last week. The producers want oversight moved from the FDA to the U.S. Department of Agriculture, which already allows gene-edited crops to be planted and sold with no regulatory oversight.

But the FDA plans to require pre-market safety assessments for gene-edited food animals, as they do for new animal drugs. The regulations will ensure that genetic changes are safe for animals and consumers, and help consumers get comfortable with the technology, an FDA spokeswoman told the Journal.

The FDA’s discovery of extra genes in the hornless cattle, and other recently reported mishaps involving new genetic engineering techniques, bolster the case for government scrutiny, and have industry groups scrambling to control the public relations fiasco.

The extra genes Recombinetics missed

Researchers at the Minnesota-based company Recombinetics, Inc., reported in a 2016 paper that they created the first polled (hornless) cows using a gene editing technique called TALENS to alter the gene sequence in the cows. The researchers reported finding no unintended impacts. They wrote, “our animals are free of off-target effects.”

But when FDA researchers reexamined the DNA this summer, using genome sequences that had been posted online by Recombinetics, they did find off-target effects. Two edited cows carried copies of the entire bacterial plasmid used in the editing process, including two antibiotic resistance genes in virtually every cell of their bodies. The genes don’t normally occur in cattle.

This “raises issues of biosafety given that there is a strong global push to limit the spread of genes conferring antibiotic resistance,” writes Jonathan Latham, PhD, in Independent Science News. It also raises questions about the lack of precision of gene editing techniques and gives weight to arguments for government oversight. Plans to breed the hornless cows in Brazil were scrapped after the off-target effects came to light, Wired reported, because regulators there could no longer consider the cows non-GMO.

The FDA researchers said their discovery “highlights a potential blind spot in standard genome editing screening methods,” and said they suspect integration errors are “underreported or overlooked” in genome editing experiments. They noted other examples of unexpected alterations – a 2017 mouse study that found complex deletions and insertions in an edited mouse genome, and a 2018 study that reported DNA damage in human cell lines.

So how did the Recombinetics researchers miss the unintended DNA integrations?

“we didn’t look”

“It was not something expected, and we didn’t look for it,” said Tad Sonstegard, CEO of Recombinetics’ agriculture subsidiary Acceligen, according to MIT Technology Review. A more complete check “should have been done,” he said. Wired magazine quoted Sonstegard explaining, “We weren’t looking for plasmid integrations. We should have.”

That should have been an obvious place to look, says Michael Hansen, PhD, Senior Scientist, Advocacy, of Consumers Reports. “Whether any DNA from the bacterial plasmid used in the gene editing process got picked up and transferred would be one of the first things you would look for if you were interested in finding off-target effects,” Hansen said.

In his view, the fact that Recombinetics missed the problem suggests that, “they didn’t do the necessary oversight. That’s why we need government oversight,” including requirements for pre-market safety assessments, he said.

Latham, a biologist and former genetic engineer, also points to recent findings from Japan that he believes may be more consequential than the FDA’s findings, and have greater implications for the regulatory landscape. In a 2019 study, Japanese researchers reported that edited mouse genomes had acquired DNA from the E. coli genome, as well as goat and bovine DNA. This stray DNA came from the gene editing reagents, the delivery method used to make the edits.

These findings “are very simple: cutting DNA inside cells, regardless of the precise type of gene editing, predisposes genomes to acquire unwanted DNA,” , Latham wrote in Independent Science News. He said the findings “imply, at the very least, the need for strong measures to prevent contamination by stray DNA, along with thorough scrutiny of gene-edited cells and gene-edited organisms. And, as the Recombinetics case suggests, these are needs that developers themselves may not meet.”

Next logical step

Recombinetics has “noisily objected” to FDA oversight all along and lobbied the Trump Administration to wrest oversight powers away from the food safety agency, according to MIT Technology Review. And when Recombinetics claimed in 2016 that its gene-edited hornless cows were “free of off-target effects,” that finding was immediately deployed as a lobby tool in the campaign against FDA scrutiny.

In a commentary that ran alongside the company’s study, five university researchers argued that pre-market safety assessments for gene-edited food animals are onerous and unnecessary. One of the authors, Alison Van Eenennaam PhD, an animal extension specialist at UC Davis and a leading advocate for deregulation, has described FDA’s plan to require pre-market safety assessments as “insane.”

“The effects of gene editing are largely identical to natural processes,” the researchers wrote in their commentary. Any “off-target effects can be minimized by careful design and extensive testing,” they said, noting that the researchers from Recombinetics “found none” in their gene-edited cattle.

They also claimed, inaccurately as it turned out, that the gene-edited cattle carried the same DNA “that has been consumed by humans for over 1,000 years.” The “next logical step,” they wrote, would be to spread the edited genome sequence “into global dairy populations.”

The disconnect between the rush to market genetically engineered foods, and the need for due diligence to understand off-target effects of gene manipulations and their possible impacts on health and the environment, has long been a sticky point in the GMO debate. For most GMO foods, the companies have been in charge of safety assessments all along, with little or no government oversight. But what incentive do companies have to look for problems?

Back in 1998, in an interview with Michael Pollan for the New York Times, Monsanto’s then director of communications was blunt in his assessment of where the industry’s interests lie: ”Monsanto should not have to vouchsafe the safety of biotech food. Our interest is in selling as much of it as possible. Assuring its safety is the FDA’s job.”

Further reading

Gene editing needs to become more precise to live up to its promise — by David Edgell, The Conversation (10.7.19)

Gene-editing unintentionally adds bovine DNA, goat DNA, and bacterial DNA, mouse researchers find — by Jonathan Latham, PhD, Independent ScienceNews (9.23.19)

Gene-edited cattle have a major screwup in their DNA — by Antonio Regalado, MIT Technology Review (8.28.19)

FDA finds unexpected antibiotic resistance genes in ‘gene-edited’ dehorned cattle — by Jonathan Latham, PhD, and Allison Wilson, PhD, Independent Science News (8.12.19)

Off-target mutations not the only concern in gene-edited plants — GM Watch (7.10.19)

Why the “molecular scissors” metaphor for CRISPR is misleading — by Elinor Hortle, The Conversation (7.4.19)

CRISPR causes unexpected outcomes even at the intended site of genetic modification — GM Watch (4.16.19)

CRISPR spin-off causes unintended mutations in DNA — GM Watch (3.13.19)

CRISPR base editing, known for precision, hits a snag with off-target mutations — by Sharon Begley, STAT (2.28.19)

Big tongues and extra vertebrae: The unintended consequences of animal gene editing — By Preetika Rana and Lucy Craymer, Wall Street Journal (12.14.18)

Potential DNA damage from CRISPR has been ‘seriously underestimated,’ study finds — by Sharon Begley, STAT (7.16.18)

Turns out CRISPR editing can also vandalize genomes — MIT Technology Review (7.16.2018)

A serious new hurdle for CRISPR: Edited cells might cause cancer, two studies find — by Sharon Begley, STAT (6.11.18)

Farmland gene editors want cows without horns, pigs without tails, and business without regulations — by Antonio Regalado, MIT Technology Review (3.12.18)

Report: Gene-edited animals will intensify factory farming and the climate crisis, could harm human health — Friends of the Earth (9.17.19)

Are you ready for the new wave of genetically engineered foods? — by Stacy Malkan, USRTK (3.16.18)