Soon, maybe within a year, Americans could be eating two new varieties of apple that won’t turn brown after slicing. To make these new transgenic apples, Okanagan Specialty Fruits, Inc., a Canadian company, turned to an advanced biotechnology called RNA interference (RNAi). Okanagan insists its modified Granny Smith and Golden Delicious varieties— called Arctic Golden and Arctic Granny — are safe to eat. “By the time Arctic apples reach your market, they will be one of the most researched and tested foods on the planet,” the company says on its website. Despite this assurance, a number of disturbing questions remain about how RNAi technology might affect human health.
Photo by Liz West
US Department of Agriculture and the Food and Drug Administration have already cleared the fruits for sale in the US, much to the disappointment of many food and environmental activists as well as scientists who are concerned about the unintended consequences of the technology used to create these apples. The Environmental Protection Agency is currently reviewing concerns about RNAi technology raised by several research papers. But the agency’s authority to regulate transgenic crops is limited (See inset). Meanwhile, several other RNAi-altered fruits and vegetables, including non-bruising potatoes, called Innate Potato, and a new kind of pest-resistant corn, are on their way to supermarket shelves.
These new transgenic crops will be much different from most genetically modified foods currently in the market. Traditional GMOs have been altered through gene splicing — a technique that usually adds a new genetic sequence to the plant’s DNA. But these RNAi-altered crops will not be sporting any new genes. Instead, they have been created by shutting down or “suppressing” certain preexisting genes in the vegetables and fruits.
Let’s back up and look at the basic science a bit. RNA and DNA are part of the genetic coding in the cells of every plant and animal. The DNA contains the genes, while the RNA transcribes the genes into messages that dictate proteins, which in turn determine specific traits in a plant or animal. RNAi technology, which is part of a suite of “gene silencing” techniques, allows scientists to manipulate or interfere with those messages. The Arctic Apples, for instance, are created by inserting new DNA capable of producing double-stranded RNA molecules (dsRNA) into regular Granny Smith and Golden Delicious apples. The dsRNA suppresses the expression of four related genes, one of which produces polyphenol oxidase, a chemical that causes apples to oxidize or turn brown after slicing.
It turns out that RNAi isn’t really a new technique. It had been used by the food and biotech industry to alter certain fruits and vegetables as far back as the 1990s. For instance, It had been used to delay ripening in a genetically modified tomato variety (called Flavr Savr Tomato, the world’s first GMO fruit), to increase a soybean’s production of healthy monounsaturated fatty acid, and to provide pinto beans, the European plum, and the Hawaiian papaya immunity from plant viruses. It’s just that back then plant biotechnologists did not fully understand that the techniques they were using to modify DNA involved RNA interference.
The term “RNAi” was coined in 1998 by two molecular biologists, Craig Mello and Andrew Fire, in a paper in the journal Nature where they explained how the technology worked. The duo won the 2006 Nobel Prize in Physiology or Medicine for their discovery. Back then it was assumed that the technology would be used mostly in biomedical research to develop treatments for viral infections, cardiovascular diseases, cancer and several other medical conditions (by say, turning off key genes in pathogens or silencing a gene causing high blood cholesterol levels etc). While the technology has indeed been used in many pharmaceutical products, in the past several years several food crops utilizing RNAi too, have been developed. The most troubling among these are the ones developed for pest control.
Soon on the Menu: Insecticidal Tacos
Agribusiness giant Monsanto has come up with a transgenic corn, dubbed SmartStax Pro, which uses RNAi technology to give the corn plant a potent new weapon in its battle with its chief nemesis — the western corn rootworm. One of the costliest of agricultural pests, the rootworm destroys nearly $1 billion worth of corn every year in the nation’s cornbelt, which stretches from Colorado to Pennsylvania.
SmartStax Pro, or “MON 87411,”represents a major scientific breakthrough — it has been engineered to produce a dsRNA in the corn that would inactivate a gene —not in the corn, but in the pest that ingests the corn. When the rootworm munches on MON 87411, it ingests the dsRNA produced in the corn tissue, which then turns off a gene in the insect called Snf7 that is essential for rootworm survival. This could be an effective way to deal with the insect that has become resistant regular pesticides and as well as to Monsanto’s insecticidal Bt corn (which was created by splicing insecticidal protein genes from the soil bacterium Bacillus thuringiensis or Bt into the corn).
SmartStax Pro awaits final clearance from the USDA, but because it is a pesticide, the Environmental Protection Agency must weigh in as well. Under the Federal Insecticide, Fungicide and Rodenticide Act, the nation’s primary pesticide law, the EPA evaluates the safety of pesticidal products, including ones derived from RNAi, which it calls “plant-incorporated protectants (PIPs).” (In January Monsanto announced that it was also developing an RNAi-based pesticide that would kill the Colorado potato beetle, a dreaded pest that attacks potatoes and other nightshade plants.)
The EPA says it expects to complete its review of SmartStax Pro by July 2016. EPA spokeswoman Cathy Milbourn says the public will have a chance to comment before a final decision is made.
Although USDA is performing its own review of the health implications of SmartStax Pro, it is likely that it will rely heavily on EPA for its analysis. Hence, all eyes are on the EPA review, which is expected to be the most comprehensive among the three agencies.
If the EPA review finds that RNAi-derived pesticides threaten human health or the environment, consumers would have their strongest reason yet to doubt the safety of GMO foods. Efforts seeking to require labeling of GMO products — such as those now in effect in Vermont, Maine and Connecticut — would surely benefit.
However, states may not get another chance to pass another labeling law. Recently, the US House passed the Safe and Accurate Food Labeling Act of 2015 (dubbed by anti-GMO activists as the DARK Act — the Deny Americans the Right to Know Act), which would negate all GMO labeling laws and ban new ones, should it pass the Senate and be signed by President Obama.
SmartStax Pro may be effective at killing rootworms, but what happens when other beneficial insects eat this corn? Would it interfere with their genes too? What kind of impact would the corn have on the environment and human health? These are some of the questions that the EPA review will attempt to resolve
In October 2013, EPA scientists outlined their concerns about RNAi-derived pesticides in a white paper and in January 2014, the agency convened a Scientific Advisory Panel to respond to the white paper and explore the issue further. While the EPA has yet to finish its assessment of SmartStax Pro, the FDA has already completed its voluntary assessment and found that it presents no concerns.
Dr. Margaret Mellon, a consultant to the Center for Food Safety who considers herself “a thoughtful critic of the technology,” described the FDA’s review as “superficial.”
“FDA didn’t consider any risks specific to the RNAi process, including the possibility off-target effects,” she said. “dsRNA can turn off many more genes than intended, and in many cases the changes will be subtle.”
In a letter to the EPA, Brett Adee of the National Honey Bee Advisory Board said: “To attempt to use this technology at this current state of understanding would be more naive than our use of DDT in the 1950’s, and far more irresponsible given our recent history of failures in sustaining our environment alongside increased food productivity.”
Concerns about the use of RNAi extend beyond crops genetically engineered to carry their own pesticides, to the more benign-seeming ones like Arctic Apples and Innate Potato. (Read the Journal’s earlier report on Arctic Apples here.) These concerns tie in with the larger long-running debate over the safety of transgenic crops. While it’s possible that RNAi technology might help stave off various pests and diseases in crops or make some fruits and veggies look appealing for a longer period of time, critics of the technology say that federal regulators haven’t been adequately assessing the possible negative impact of these crops on our health and the environment.
In terms of human health, the major issue is whether plant RNA molecules can pass through the intestine wall in humans, enter the bloodstream and reach body tissues, where — as one Chinese study found — they can shut off genes, potentially causing serious health problems. Monsanto contends that the RNAi molecules never reach the bloodstream, but instead are almost completely destroyed in the highly acidic environment of the human gut. The EPA’s white paper points to two studies that support Monsanto’s point of view, including papers written by researchers at Johns Hopkins University and New York’s Barnard College.
But the EPA white paper fails to mention several other studies that contradict those findings. That’s possibly because most of these papers (a review of the scientific literature published by Dr. Kendal Hirschi of Baylor University College of Medicine described eight such studies) were published after the EPA published its white paper, including two this year and another due next April.
The most well-known of these papers was published in 2011 by a team of researchers from China’s Nanking University led by Chen-Yu Zhang. It found that tiny microscopic RNA molecules from ingested rice and other plants entered the bloodstream of both mice and humans. The RNAs then made their way into a variety of tissues, where the study said they could regulate some genes. Specifically, Zhang found that they suppressed genes that cleared cholesterol levels from the liver, an effect that could potentially lead to higher cholesterol levels in the blood and contribute to heart disease.
Another study by Dr. Vicki Vance, a biology professor at the University of South Carolina, found that dietary RNAs from plants could cross the gastrointestinal barrier and act as a potential cancer treatment. “This study is groundbreaking in that it alters our concept of the relationship between health and nutrition and potentially opens up new vistas for gene therapy,” Hirschi’s review of the paper said.
But Vance urges those who use RNAi for agricultural purposes to proceed with caution.
“Many of these GM crops will harbor populations of small RNAs that don’t exist in nature and may have potential to suppress mammalian gene expression in unexpected ways,” she says. “This is perhaps more of a concern for RNAi-based pesticides because that approach produces small RNAs designed to kill the targeted organism when it feeds on the plant.”
Monsanto’s researchers suggested that contamination of lab equipment may have skewed some of these results. But Vance says that, “In view of the novel potential risks of RNAi-based GM crops, it seems that a careful re-evaluation of current risk assessment strategies is warranted.”
Vance has seen first-hand happens what can happen to scientists who criticize GMOs. She was a strong supporter of genetic engineering until she was approached by Monsanto officials who tried to quash her research that showed dietary RNA had crossed the gastrointestinal barrier in ways that were consistent with the Zhang study. In 2013, after she refused to ignore her findings, Monsanto cancelled her scheduled address to an international symposium on the biosafety of GMO food products.
RNAi technology, Vance says, may be a mechanism for creating “an effective, nontoxic, noninvasive and inexpensive preventative (or treatment) for cancer and perhaps other diseases. It’s very exciting from that angle. From the viewpoint of Big Ag companies, however, it raises unfortunate questions about the safety of RNAi food crops that, I think, they would rather deny than address.”
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