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)

Alison Van Eenennaam: key outside spokesperson and lobbyist for the agrichemical and GMO industries

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Alison Van Eenennaam, PhD, a cooperative extension specialist in animal genomics and biotechnology at the University of California, Davis, is a leading promoter of genetically engineered animals, crops and the pesticides that accompany them, and an advocate for deregulation.

Dr. Van Eenennaam argues GE animals should not be subject to pre-market safety reviews or labels.

Dr. Van Eenennaam is a former Monsanto employee who opposes requiring safety studies for genetically engineered animals and holds several patents involving genetic engineering. Her lab experiments include using CRISPR, a genetic engineering technique, to eliminate the horns of dairy cows and breed “all-male terminator cattle” to father only male offspring — a project she calls “Boys Only.” A proposal by the U.S. Food and Drug Administration to require safety and efficacy studies for genetically engineered animals is “insane,” according to Dr. Van Eenennaam.

See also: Wall Street Journal (12.14.2018),            Big Tongues and Extra Vertebrae: The Unintended Consequences of Animal Gene Editing 

Although often presented in the media as an independent scientist, Dr. Van Eenennaam coordinates with agrichemical companies and their PR firms on messaging, lobbying and PR activities, according to emails obtained by U.S. Right to Know and now posted in the UCSF Chemical Industry Documents Library. Examples of collaborations include:

Monsanto edited her remarks for the Intelligence Squared debate 

Emails show that Lee Quarles, Monsanto’s global communication lead, and Tony Zagora, senior vice president and partner of the FleishmanHillard PR firm, edited Dr. Van Eenennaam’s remarks for a December 2014 Intelligence Squared (IQ2) debate where she argued for public acceptance of genetically engineered foods alongside Robb Fraley of Monsanto.

Quarles also connected Dr. Van Eenennaam with higher ups at Monsanto and FleishmanHillard to discuss the core positions she and Fraley should align on, and he arranged for Zagora and the PR agency to provide her with guidance on “approach, tone, delivery and personal presentation. This will help you better understand what are the key things our team should consider as we work to win over the people in the room, as well as all of those consumers in the NPR rebroadcast of the event.”

Some of Monsanto’s edits to Professor Van Eenennaam’s remarks are shown in track changes:

 

Source documents linked here

Former Monsanto Communications Director Jay Byrne and industry PR firm Ketchum provided coaching for media interviews 

In 2012, Dr. Van Eenennaam assisted the industry-funded No on Proposition 37 campaign in California to oppose GMO labeling. Emails show that the “No on 37” campaign staff arranged for Dr. Van Eenennaam to appear on the Dr. Oz Show to speak against labeling, and also arranged for her to receive media and messaging training from Jay Byrne, Monsanto’s former head of corporate communications. (Emails also revealed that Jay Byrne worked with Monsanto to set up a front group to attack GMO critics and the organic industry while “keeping Monsanto in the background“.)

In 2014, the agrichemical industry’s lead public relations firm, Ketchum, pitched Dr. Van Eenennaam as a source and helped her prepare for a radio interview to debunk a study that linked genetically engineered animal feed to stomach inflammation. Ketchum provided Dr. Van Eenennaam with talking points from industry allies describing the stomach study as “junk science.”

Appeared at Hill briefing organized by climate science skeptic group 

In September 2012, Dr. Van Eenennaam appeared at a Competitive Enterprise Institute congressional briefing to argue for the deregulation of genetically engineered animals. The Competitive Enterprise Institute is an industry-funded group that promotes climate science skepticism and opposes regulations for the chemical industry. In 2013, donors to the Competitive Enterprises Institute annual fundraiser included Monsanto, Syngenta, FMC Corporation, the Biotechnology Industry Organization and Google, as well as oil and tobacco companies and foundations related to Koch Industries. In 2016, CEI’s Director of Energy and Environment Myron Ebell, a prominent climate science skeptic who has said the case for global warming is “silly,” was chosen by the Trump Administration’s to lead the transition team for the Environmental Protection Agency.

Coordinated lobbying efforts; defends pesticides 

Dr. Van Eenennaam has coordinated lobbying to deregulate genetically engineered crops and animals, and keep them unlabeled. In 2012, she wrote a letter to the Obama Administration on behalf of the American Society of Animal Science public policy committee arguing for approval of the Aqua Bounty genetically engineered salmon without rigorous safety testing or labeling. In 2015, she recruited professors to support deregulating the Simplot Innate 2.0 genetically engineered potato. “Simplot is looking for some comments on their deregulation … the antis are trying to get the comment period extended as usual,” she wrote to the professors.

Dr. Van Eenennaam also defends glyphosate, the world’s most widely used herbicide and a probable human carcinogen according to the World Health Organization’s cancer research agency. For a post on her website, she used pesticide industry sources and infographics to speculate about the market consequences of banning glyphosate, and characterized people raising concerns as the “worried wealthy.” The Monsanto (now Bayer) website promotes Dr. Van Eenennaam as a source to discredit a study that linked glyphosate to liver disease at low doses.

Some of Alison Van Eenennaam’s other industry collaborations 

  • Is a member of “AgBioChatter,” a private email listserve that pro-industry academics, senior staff of agrichemical companies and public relations consultants have used to coordinate messaging and lobbying activities.

Are You Ready for the New Wave of Genetically Engineered Foods?

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A version of this article was first published in Common Ground Magazine March 2018 (PDF version).

By Stacy Malkan

Everyone loves a feel-good story about the future. You’ve probably heard this one: high-tech foods enhanced by science will feed the 9 billion people expected on the planet by 2050. Food made in labs and crops and animals genetically engineered to grow faster and better will make it possible to feed the crowded world, according to stories that spin through our institutions of media and education.

“6th grade students brainstorming big biotech ideas to #Feedthe9″ touted a recent tweet tagged to the chemical industry’s promotional website GMOAnswers. Student ideas included “breed carrots to have more vitamins” and “corn that will grow in harsh winter conditions.”

It all sounds so promising until you look at the realities behind the rhetoric.

For starters, in a country that leads the world in growing genetically modified organisms (GMOs), millions go hungry. Reducing food waste, addressing inequality and shifting to agroecological farming methods, not GMOs, are the keys to world food security, according to experts at the United Nations. Most genetically engineered foods on the market today have no consumer benefits whatsoever; they are engineered to survive pesticides, and have greatly accelerated the use of pesticides such as glyphosate, dicamba and soon 2,4D, creating what environmental groups call a dangerous pesticide treadmill.

Despite decades of hype about higher nutrients or heartier GMO crops, those benefits have failed to materialize. Vitamin-A enhanced Golden Rice, for example – “the rice that could save a million kids a year,” reported Time magazine 17 years ago – is not on the market despite millions spent on development. “If golden rice is such a panacea, why does it flourish only in headlines, far from the farm fields where it’s intended to grow?” asked Tom Philpott in Mother Jones article titled, WTF Happened to Golden Rice?

“The short answer is that the plant breeders have yet to concoct varieties of it that work as well in the field as existing rice strains…When you tweak one thing in a genome, such as giving rice the ability to generate beta-carotene, you risk changing other things, like its speed of growth.”

Nature is complex, in other words, and genetic engineering can produce unexpected results.

Consider the case of the Impossible Burger.

The plant-based burger that “bleeds” is made possible by genetically engineering yeast to resemble leghemoglobin, a substance found in soybean plant roots. The GMO soy leghemoglobin (SLH) breaks down into a protein called “heme,” which gives the burger meat-like qualities — its blood-red color and sizzle on the grill — without the environmental and ethical impacts of meat production. But the GMO SLH also breaks down into 46 other proteins that have never been in the human diet and could pose safety risks.

As The New York Times reported, the burger’s secret sauce “highlights the challenges of food tech.” The story was based on documents obtained by ETC Group and Friends of the Earth under a Freedom of Information Act request – documents the company probably hoped would never see the light of day. When Impossible Foods asked the Food and Drug Administration to confirm its GMO ingredient was “generally recognized as safe” (GRAS), the Times reported, the agency instead “expressed concern that it has never been consumed by humans and may be an allergen.”

FDA officials wrote in notes describing a 2015 call with the company, “FDA stated that the current arguments at hand, individually and collectively, were not enough to establish the safety of SLH for consumption.” But, as the Times story explained, the FDA did not say the GMO leghemoglobin was unsafe, and the company did not need the approval of FDA to sell its burger anyway.

The arguments presented did not establish safety – FDA

So Impossible Burger is on the market with the company’s assurances of safety and most consumers are in the dark about what’s in it. While the GMO process is explained on the website it is not marketed that way at the point of sale. On a recent visit to a Bay Area restaurant that sells the Impossible Burger, a customer asked if the burger was genetically modified. He was inaccurately told, “no.”

Lack of government oversight, unknown health risks and consumers left in the dark – these are recurring themes in the unfolding narrative about the Wild West of genetic engineering experimentation that is galloping toward a store near you.

A GMO By Any Other Name …

Synthetic biology, CRISPR, gene editing, gene silencing: these terms describe the new forms of genetically engineered crops, animals and ingredients that companies are rushing to get onto the market.

The old method of genetic engineering, called transgenics, involves transferring genes from one species to another. With the new genetic engineering methods – what some environmental groups call GMOs 2.0 – companies are tampering with nature in new and possibly riskier ways. They can delete genes, turn genes on or off, or create whole new DNA sequences on a computer. All these new techniques are GMOs in the way consumers and the U.S. Patent Office consider them – DNA is altered in labs in ways that can’t occur in nature, and used to make products that can be patented. There are a few basic types of GMOs 2.0.

Synthetic biology GMOs involve changing or creating DNA to artificially synthesize compounds rather than extract them from natural sources. Examples include genetically engineering yeast or algae to create flavors such as vanillin, stevia and citrus; or fragrances like patchouli, rose oil and clearwood – all of which may already be in products.

Some companies are touting lab-grown ingredients as a solution for sustainability. But the devil is in the details that companies are reticent to disclose. What are the feedstocks? Some synthetic biology products depend on sugar from chemical-intensive monocultures or other polluting feedstocks such as fracked gas. There are also concerns that engineered algae could escape into the environment and become living pollution.

And what is the impact on farmers who depend on sustainably grown crops? Farmers around the world are worried that lab-grown substitutes, falsely marketed as “natural,” could put them out of business. For generations, farmers in Mexico, Madagascar, Africa and Paraguay have cultivated natural and organic vanilla, shea butter or stevia. In Haiti, the farming of vetiver grass for use in high-end perfumes supports up to 60,000 small growers, helping to bolster an economy ravaged by earthquake and storms.

Does it make sense to move these economic engines to South San Francisco and feed factory-farmed sugar to yeast in order to make cheaper fragrances and flavors? Who will benefit, and who will lose out, in the high-tech crop revolution?

Genetically engineered fish and animals: dehorned cattle, naturally castrated pigs, and chicken eggs engineered to contain a pharmaceutical agent are all in the genetic experimentation pipeline. An all-male “terminator cattle” project – with the code name “Boys Only” – aims to create a bull that will father only male offspring, thereby “skewing the odds toward maleness and making the (meat) industry more efficient,” reported MIT Technology Review.

What could go wrong?

The geneticist working on the terminator cattle, Alison Van Eenennaam of the  University of California, Davis, is lobbying FDA to reconsider its 2017 decision to treat CRISPR-edited animals as if they were new drugs, thereby requiring safety studies; she told the MIT Review that would “put a huge regulatory block on using this gene-editing technique on animals.” But shouldn’t there be requirements for studying the health, safety and environmental impacts of genetically engineered foods, and a framework for considering the moral, ethical and social justice implications? Companies are pushing hard for no requirements; in January, President Trump talked about biotechnology for the first time during his presidency and made a vague declaration about “streamlining regulations.”

The only GMO animal on the market so far is the AquaAdvantage salmon engineered with the genes of an eel to grow faster. The fish is already being sold in Canada, but the company won’t say where, and US sales are held up due to “labeling complications.” The urge for secrecy makes sense from a sales perspective: 75% of respondents in a 2013 New York Times poll said they would not eat GMO fish, and about two-thirds said they would not eat meat that had been genetically modified.

Gene silencing techniques such as RNA interference (RNAi) can turn genes off to create particular traits. The non-browning Arctic Apple was engineered with RNAi to turn down the expression of genes that cause apples to become brown and mushy. As the company explains on its website, “when the apple is bitten, sliced, or otherwise bruised … no yucky brown apple left behind.”

Are consumers actually asking for this trait? Ready or not here it comes. The first GMO Arctic Apple, a Golden Delicious, began heading for test markets in the Midwest last month. Nobody is saying exactly where the apples are landing, but they won’t be labeled GMO. Look out for the “Arctic Apples” brand if you want to know if you’re eating a genetically engineered apple.

“I am confident we’ll see more gene-edited crops falling outside of regulatory authority.” 

Gene editing techniques such as CRISPR, TALEN or zinc finger nucleases are used to cut DNA in order to make genetic changes or insert genetic material. These methods are faster and touted as more precise than the old transgenic methods. But the lack of government oversight raises concerns. “There can still be off-target and unintended effects,” explains Michael Hansen, PhD, senior scientist of Consumers Union. “When you alter the genetics of living things they don’t always behave as you expect. This is why it’s crucial to thoroughly study health and environmental impacts, but these studies aren’t required.”

A non-browning CRISPR mushroom escaped US regulation, as Nature reported in 2016. A new CRISPR canola oil, engineered to tolerate herbicides, is in stores now and may even be called “non-GMO,” according to Bloomberg, since the US Department of Agriculture has “taken a pass” on regulating CRISPR crops. The story noted that Monsanto, DuPont and Dow Chemical have “stepped through the regulatory void” and struck licensing deals to use the gene-editing technology.

And that raises another red flag with the narrative that new GMOs will provide consumer benefits that the old transgenic methods didn’t. “Just because the techniques are different doesn’t mean the traits will be,” Dr. Hansen pointed out. “The old method of genetic engineering was used mostly to make plants resist herbicides and increase sales of herbicides. The new gene editing techniques will probably be used in much the same way, but there are some new twists.”

Corporate Greed Versus Consumer Needs

The Atlantic’s “transforming food” summit was sponsored by DowDuPont. See our reporting on that story.

The world’s largest agrichemical companies own the majority of seeds and pesticides, and they are consolidating power in the hands of just three multinational corporations. Bayer and Monsanto are closing in on a merger, and the mergers of ChemChina/Syngenta and DowDuPont are complete. DowDuPont just announced its agribusiness unit will operate under the new name Corteva Agriscience, a combination of words meaning “heart” and “nature.”

No matter what re-branding tricks they try, these corporations have a nature we already know: all of them have long histories of ignoring the warnings of science, covering up the health risks of dangerous products and leaving behind toxic messes – Bhopal, dioxin, PCBs, napalm, Agent Orange, teflon, chlorpyrifos, atrazine, dicamba, to name just a few scandals.

The future-focus narrative obscures that sordid past and the present reality of how these companies are actually using genetic engineering technologies today, mostly as a tool for crops to survive chemical sprays. To understand how this scheme is playing out on the ground in leading GMO-growing pesticide-using areas, read the reports about birth defects in Hawaii, cancer clusters in Argentina, contaminated waterways in Iowa and damaged cropland across the Midwest.

The future of food under the control of big agribusiness and chemical corporations is not hard to guess – more of what they are already trying to sell us: GMO crops that drive up chemical sales and food animals engineered to grow faster and fit better in factory farm conditions, with pharmaceuticals to help. It’s a great vision for the future of corporate profits and concentration of wealth and power, but not so great for farmers, public health, the environment or consumers who are demanding a different food future.

Growing numbers of consumers want real, natural food and products. They want to know what’s in their food, how it was produced and where it came from. For those who want to be in the know about what they are eating, there is still a surefire way to avoid old and new GMOs: buy organic. The Non-GMO Project verified certification also ensures products are not genetically engineered or made with synthetic biology.

It will be important for the natural foods industry to hold the line on the integrity of these certifications against the wild stampede of new GMOs.

Stacy Malkan is the co-director of US Right to Know and author of the book, “Not Just a Pretty Face: The Ugly Side of the Beauty Industry.”