Monsanto’s Driverless Car: Is CRISPR Gene Editing Driving Seed Consolidation?

Last week the European Union cleared the way for the ChemChina–Syngenta takeover, suggesting the other two mergers may be imminent. If that happens, the resulting three companies would control nearly 60 percent of global seedstocks (including as much as 80 percent of U.S. corn seeds) and 70 percent of the global pesticide market. And these companies are also making a bid to control much more than seeds and pesticides. Monsanto, for example, is already making a play to control many other facets of modern agriculture—including tools for precision planting and high-tech weather prediction.

So while much of the media coverage of gene editing has pointed to its potential to break molds and change the genetic playing field, when it comes to agriculture, it will likely follow a more familiar path: CRISPR and other similar technology will most likely be used by scientists mainly to continue developing seeds that withstand consistent doses of pesticides on large, industrialized farms.

“Monsanto has been conducting research with genome-editing techniques for years, and we are excited to be integrating additional technology from licensing partners in to this body of work,” Tom Adams, biotechnology lead for Monsanto, said in an email. Over the past year, the company has announced several licensing agreements that will allow it to access gene-editing technologies, such as CRISPR/Cas9 and CRISPR-Cpf1 (which is said to be more precise), as well as a tool from Dow AgroScience called EXZACT™ Precision Technology^® Platform, among others.

Although Adams said this work is still in its early days, he added, “we believe that genome-editing techniques have great potential to improve and unlock capabilities across our leading germplasm and genome libraries to enable a wide variety of improvements across crop systems.” However, he added, “We do not view it as a replacement for plant biotechnology.”

SEED: The Untold Story will premiere on the PBS series Independent Lens on April 17, 2017 at 10PM. Learn more.

Gene Editing vs. Genetic Engineering

Since 1996, Monsanto has released a series of genetically engineered herbicide-resistant seeds, beginning with Roundup Ready soybeans in 1996, and moving on to corn, cotton, sugar beets, canola, and more. Today, Roundup Ready crops account for over 94 percent of the soybeans and 89 percent of the corn grown in the United States.

As these products have come to dominate the farm landscape, weeds have also become resistant to Roundup. According to the Weed Science Society of America, “overreliance on herbicides with a single mechanism of action to control certain weeds has led to the selection of weeds resistant to that mechanism of action.” Similarly, incidents of pesticide resistance have also been on the rise.

As a result, farmers often find themselves on what critics call a pesticide treadmill, where each new form of resistance requires a more powerful solution. Companies have spent the last several years working on seeds with “stacked traits,” which combine two or more genes of interest into a single plant. In the case of Monsanto, that has meant, for instance, breeding seeds that tolerate both glyphosate and a second herbicide called dicamba.

The main difference between gene editing and classical genetic engineering is that the former allows scientists to manipulate the genetic makeup of an organism—by changing or “knocking out” the function of a gene—without introducing genes from other organisms. This last part is key, because it’s often the combination of parts of various organisms—such as genes from bacteria added to corn to create herbicide resistance or genes from an arctic flounder added to strawberries to make them able to withstand cold weather—that has made the public wary of GMOs in their food.

But the image of CRISPR/Cas9 and other gene editing tools as an “entirely pristine” technology that rules out all foreign DNA isn’t entirely accurate, says Maywa Montenegro, a Ph.D. candidate in Environmental Science, Policy, and Management at University of California, Berkeley.

“They aren’t wrong in saying CRISPR doesn’t need to introduce foreign DNA, but it absolutely can. That’s what it’s very good at,” she said. “But it’s also important for people to understand that you can create huge, impactful changes in a plant’s functioning without introducing anything foreign.” De-activating, or knocking out, a gene function, can significantly change the plants and animals involved.

In the case of the mildew-resistant wheat developed in China, for instance, scientists were able to introduce “targeted mutations” using CRISPR/Cas9 without inserting new genes. In another example, Cibus, a San Diego-based startup, has produced (and commercialized) an herbicide-resistant canola using another early gene-editing technique called Rapid Trait Development System (RTDS).

The company also says it has other crops, such as herbicide-resistant rice and flax seeds, in the pipeline. DuPont is also working with the Berkeley-based start-up Caribou Biosciences (founded by Jennifer Doudna, one of the founders and patent-holders of CRISPR/Cas9 technology) to develop gene-edited, drought-resistant corn and wheat varieties.

The most widely discussed food produced using gene editing today is a non-browning mushroom developed using CRISPR/Cas9 at Pennsylvania State University. The mushroom received a great deal of media attention last spring, when the Penn State scientists received a letter from the U.S. Department of Agriculture (USDA) informing them that the agency would not be regulating its field testing.

At the time, a number of media outlets reported that the mushroom had “escaped regulation,” suggesting that gene editing was not only remarkably different than tradition genetic engineering in crucial ways, but that it also might be the key to avoiding government oversight. But on both accounts, the reality may be less cut and dried.

Will Gene-Edited Seeds be Regulated?

Doug Gurian-Sherman, director of sustainable agriculture and senior scientist for the Center for Food Safety (CFS), says the letter USDA sent to Penn State about the non-browning mushroom was just one of over 30 that went out at that time in response to requests by a variety of entities working with gene-editing technology.

While the USDA did clearly mention the fact that the mushroom didn’t contain any foreign DNA in its response, that wasn’t the only reason it abdicated its regulatory authority. Just as important, it seems, is the fact that the mushroom was not in any way considered a “plant pest.”

You see, when it comes to regulating GMO crops, plant pests have been at the heart of the USDA’s regulation approach; all other genetically engineered products fall under the auspices of either the U.S. Food and Drug Administration (FDA) or the Environmental Protection Agency (EPA). (A document from the Pew Charitable Trusts includes a handy chart detailing which agency is supposed to regulate what types of organisms.)

In fact, the letter sent to Penn State concluded with this sentence: “Please be advised that the white button mushroom variety described in your letter may still be subject to other regulatory authorities such as the FDA or EPA.”

So gene editing was by no means the only factor at hand. “As soon as they put genes in from any plant pest they would immediately become regulated by USDA,” said Gurian-Sherman.

Of course, exactly how the FDA plans to regulate gene editing is yet to be seen. Since January, the agency has been seeking public input on the topic in both medical research and agriculture. One core question at hand is whether gene editing will be considered “genetic engineering.” And at a time when a growing number of consumers want to know exactly what’s in their food—and around 90 percent of Americans say they want to see genetically engineered ingredients in food labeled—this is as much a question of consumer demand as it is a question of regulation.

“We already see lots of people who are supportive of genetic engineering, calling [gene editing] ‘advanced breeding,’” said Gurian-Sherman. But, he added, “In terms of most of the legal definitions of genetic engineering that are out there right now, it applies. I think it is a legitimate area for argument whether this is generally safer or not or more acceptable, but they clearly don’t want to label it genetic engineering.”

According to Michael Hansen, senior staff scientist at Consumers Union, “the FDA’s documents now clearly say their definition of bioengineering is the same as the definition of modern biotechnology held by Codex Alimentarius.” That’s the “Food Code” established by the U.N. Food and Agriculture Organization and the World Health Organization. The Codex definition refers to any organism made using “the application of in vitro nucleic acid techniques.” And since gene editing does precisely that, Hansen believes the answer is clear: Gene editing should be seen as genetic engineering.

But not everyone agrees. In an editorial last January, for instance, the editors of Nature endorsed “the principle of transparency in the production of genome-edited crops and livestock…with no further need for regulation or distinction of these goods from the products of traditional breeding.”

U.C. Berkeley’s Montenegro describes CRISPR/Cas9 as a kind of Swiss army knife with the potential to be paradigm-shifting. But, she adds that, for that reason, it calls for a lot more scrutiny and regulatory oversight

Hansen agrees. Using gene editing, he said, “You can identify a key sequence you want to cut. But wherever that sequence occurs in the genome, you would get a cut. And you will also get a cut at sequences that look similar.”

Hansen also points to the fact that scientists have experienced at least some off-target effects with most gene editing technology to date. He points to the case of an effort to destroy the HIV virus with CRISPR/Cas9. Although scientists engineered T-cells with CRISPR to recognize and destroy HIV, he said, “it took the HIV just a couple of weeks to evolve resistance to CRISPR.”

And in a recent effort to artificially synthesize a new genome for E. coli, a group of scientists decided not to use gene editing because, they wrote, “these strategies…likely would introduce off-target mutations.”

Despite these concerns, CFS’s Gurian-Sherman says there are big questions about how regulatory bodies under the Trump administration will choose to respond to the technology. For one, he says, gene editing could be much harder to test for.

“Detecting [transgenic] engineered changes, for a molecular biologist is really, really easy,” he said. But some of these [gene edits] are not going to leave much of a fingerprint, if at all, and they’re going to be very hard to trace,” he said. “So something like the kind of testing the Non-GMO Project does probably wouldn’t be possible in foods edited with CRISPR.”

Ultimately, Monsanto appears to be preparing for the possibility of regulation. When Lux Research, an independent technology research and advisory firm, looked into the Monsanto-Bayer merger in December, they surmised that gene editing was an important part of Monsanto’s appeal to Bayer, but that it was by no means the only technology they’re banking on.

“Monsanto’s advantage in the space is that they’re super diverse and they have their hands in all the cookie jars,” said Laura Lee, the author of Lux’s report. “So they’d be able to advance traits using CRISPR, or if the regulatory bodies step in and decide to classify CRISPR as genetic modification or put a harmful label on it, they’ll have of other options.”

“More Accessible” Technology

While CRISPR and other gene editing tools are seen as more affordable and more efficient, they’re also being touted as more accessible than traditional genetic engineering—and they are already being used in small private laboratories.

“We think the fact that this science is accessible to and being explored by many researchers across the public and private sectors is exciting—and will only improve the types of products that will ultimately be accessible to farmers,” said Monsanto’s Tom Adams.

Indeed, most traditional genetically engineered traits take years and cost millions to produce (an average of $136 million to be exact). So bringing that number down could bring more constituents into the fold, despite the consolidation at the top.

But seeds produced this way will still be subject to strict intellectual property fines, says Gurian-Sherman. “[CRISPR] won’t be as controllable by the big companies, but the patenting (or lack thereof) could really be a limiting factor for smaller companies,” he said. Case in point, a non-exclusive license to use CRISPR/Cas9 is valued at $265 million.

Of course, if that license is used to create a handful of seed traits, it could be more than worth the investment for a company like Monsanto—particularly if it can deliver on sought-after traits such as drought tolerance. And it might lead one to deduce that a newly merged company such as Monsanto-Bayer would use gene editing to bring down its overall R&D budget.

But that’s not necessarily the case, says Montenegro. In addition to facing pressure from the Trump Administration to spend mightily in the U.S., she points to an economic phenomenon called Jevons paradox, wherein technology makes a process more efficient, but that efficiency ends up leading to increasing demand. (Jevon first observed the phenomenon while observing the coal industry of the 19th Century.)

Another important question is whether this more accessible technology will be put to use to create seeds designed for alternative or more sustainable farming systems.

Montenegro says she has heard from one plant breeder at the University of Minnesota who was interested in using CRISPR/Cas9 for participatory plant breeding—a tactic involving farmers that is often used in the developing world—and to breed plants that could be amenable to diversified organic farming systems. But she says it’s not likely that a wider playing field will change the basic premise of the bulk of the work done using gene-editing technology—which is to engineer seeds used on large-scale industrial farms.

“While I don’t want to foreclose the possibility of using CRISPR for agroecology, [companies and institutions] are underinvesting and undercutting basic agroecology research to such a large degree that even the lower-hanging fruit hasn’t yet been picked,” Montenegro said. This “massive asymmetry” makes her doubtful that the technology will help researchers tread new paths when it comes to sustainable practices.

Gurian-Sherman is no more optimistic. “There are ways you can breed or adapt crops for sustainable agricultural systems that don’t rely on inputs like fertilizers and pesticides as much,” he said. “You can breed crops that attract natural enemies, or take advantage of the slower release of organic nutrients from cover crops and manure. I can go on and on about traits that are valuable to sustainable farming. But that’s not going to be of interest to these companies because they’re actually antithetical to their business models.”

Consumers Union’s Hansen says the current excitement about gene editing reminds him of the very early days or genetic engineering. “In the late 80s and early 90s, they were saying they’d be able to do everything with GE. Thirty years later, all you have is herbicide-tolerant plants and Bt plants. Or that’s the vast majority.”

This story was created in partnership with ITVS.