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Unintended Outcomes and Off-Target Effects in New GMOs

In a 2018 Washington Post article, new GMO techniques were described in blushing terms: "the future of food" and "precise, […]

Unintended Outcomes and Off-Target Effects in New GMOs

In a 2018 Washington Post article, new GMO techniques were described in blushing terms: "the future of food" and "precise, […]

In a 2018 Washington Post article, new GMO techniques were described in blushing terms: "the future of food" and "precise, fast and inexpensive." While new techniques including gene-editing, gene-silencing and synthetic biology proliferate across industries, there are serious concerns about their precision and efficiency. 

Read our recent blog post New GMOs and Where to Find Them

Before we look at what can go wrong, let us see what happens when gene-editing goes right. The most commonly used technique of the up-and-coming gene-editing lineup is undoubtedly CRISPR, which is relatively inexpensive and accessible (CRISPR kits are even available by mail order for the home geneticist).

In a theoretical nutshell, here's how CRISPR works: Scientists gather up their ingredients — an enzyme that will cut a strand of DNA as well as RNA that acts as a guide to exactly where the enzyme should cut. These ingredients are then injected into a living cell of the plant or animal that is being modified. The guide RNA finds the location in the DNA where the scientists want the cut to be made, and the enzyme does the cutting. The modification of the organism — the part of the process that brings about those new traits that the scientists are hoping for —  happens while the DNA is repairing itself from the cut. 

That is the theory. However, the devil is in the details, and a pattern of unexpected outcomes have led to questions about the precision of gene-editing techniques.

Gene-editing misses the mark

First up: Location, location, location. 

How effective is that guide RNA? Can it reliably locate the right spot, or will it go to another spot? Or, will it go to the right spot and another spot? When the guide RNA selects locations other than the intended target — which is quite common — the resulting cuts and repairs produce "off-target effects" that interfere with the normal functioning of genes. That can cause serious problems, such as mutations, disease, allergens or toxins. 

Off-target effects are a big deal, scuttling some of the most ambitious plans to "rewrite the code of life." Molecular geneticist Dr. Michael Antoniou took part in the Non-GMO Project's panel New Techniques, Same GMOs last October. Dr. Antoniou spoke about the conundrum of off-target effects:

"You hear people in an agricultural context say, 'If we can simply avoid these off-target cuts in the genome of the plant, then we'll only get what we want and therefore there's nothing to worry about.' But actually, what has been discovered in more recent years is that there are numerous types of unintended mutations, even at the intended gene-editing [site]. When you take these outcomes — both off-target and unintended on-target mutations — the claims of precision and predictability go out the window."

By modifying the pattern of gene function, Dr. Antoniou says, the plant biochemistry is inherently changed.

The unexpected results of new GMO techniques are of particular concern because the regulatory framework for traditional GMOs is ill-equipped for these new technologies. The products of new GMO techniques don't necessarily leave behind foreign DNA in the organism being modified, and many of them will not require disclosure under the new Bioengineered Foods labeling law.

And off-target effects aren't the only issue when it comes to gene-editing.

The confounding complexity of genes: Unknown ≠ Unimportant

Even when the cut is made at the correct spot, the outcome can still be unpredictable because of the complexity of gene functions. A single gene can be involved in several different and seemingly unrelated functions. Our understanding of how genes work is growing, but it's still limited. We see that play out in the narratives of some gene-editing experiments.

In early efforts to create the bull that is now called Cosmo  — the manliest of all manly bulls — scientists were looking for a section of DNA in the bovine genome where they could make a cut and insert genetic material without disrupting the necessary functions. They found what they thought was a promising section of "blank" DNA, but once edits were made to that spot, the embryos died. It's function was unknown, not unimportant. According to an article in Grist, "It was only blank because it was unexplored." In some as-yet-undiscovered way, that blank section of DNA was critical to the life of the growing organism. 

Another gene-edited bull, this one called Buri, was modified to produce offspring without horns. TALEN was the tool of choice in this work, and the company responsible for the work claimed success after ensuring no off-target effects had occurred during the editing process. Later, a researcher at the FDA was reviewing Buri's DNA records, and found that a section of non-bovine DNA — potentially antibiotic resistant — had attached itself to the bull's genome. In describing what had happened, one FDA official remarked, "Ideally, [the cell] will repair itself correctly. But it can also integrate any DNA that’s around. There’s that potential.”

Integrating any DNA that's around sounds less like an effective and precise method of genetic modification and more like a Spiderman villain's origin story.

Holistic solutions for systemic problems

At its core, there's a profound disconnect between the logic that underpins new GMO techniques like gene-editing and the types of problems they are aimed at. The problems of modern agriculture are systemic. They affect entire ecosystems, billions of organisms and millions of people. 

Soil loss across the corn belt, for example, is as bad as it is because of the cumulative effects of a century of extractive industrial agriculture. There is no GMO silver bullet that can produce meaningful change if synthetic fertilizers and pesticides continue to decimate biodiversity above and below the ground and genetically modified corn dominates the landscape. A commitment to regenerative farming practices can help rebuild soil, but these methods are neither genetically engineered nor patentable.

Or, consider genetically modified plants engineered to adapt to a changing climate. There are a variety of these crops in development and some already commercially available. But the most desirable traits for adaptability and stress tolerance are complex traits, involving multiple genes interacting in elaborate ways. True crop resilience depends on much more than a strategic snip of DNA.

The greatest problems are not with the plants or crops or livestock, but the systems that currently govern them. System-wide problems need system-wide solutions, and geneting engineering — even "targeted" gene-editing — isn't up to the task. 

Good science

There is amazing work being done by researchers, agroecologists, activists, environmental groups and concerned citizens all over the world to rebuild how food is produced in North America. There are committed regenerative farmers restoring land and indigenous peoples whose stewardship of the earth's biodiversity has never waivered. 

And there are farmers working on small plots the world over. These small-holder farms produce 70% of the world's food without GMOs — and do so with about a third of the resources used by industrial agriculture.

There is a world full of problems, yes, but there are also solutions. Another esteemed panel participant and friend of the Non-GMO Project, Dr. Vandana Shiva, sums up our concerns and our hopes beautifully:

"For 50 years, we were told repeatedly that only chemical agriculture is 'scientific agriculture.' They said they'd feed us with chemical fertilizers and pesticides. We put that aside. Then they came with GMOs. That's dead. Now, they're coming with the new GMOs. This will die, too, as long as people retain their thinking, as long as people make their choices with informed knowledge."

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