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It makes sense to exercise caution when we’re fiddling with genes in food. Food Ethics Council

Securing the safety of genetic modification

Most genetically modified (GM) crops are based on moving DNA from one organism to another to introduce a new protein. Now a growing number of genetically modified crops are based on intentionally changing RNA. However this new technology may prove to be risky business.

RNA world

RNA or ribonucleic acid is the neglected stepsister of DNA, but it is quickly becoming the Cinderella of biotechnology.

DNA (deoxyribonucleic acid) is the material basis of the genome of most organisms, it’s what encodes our genes. RNA is the second stage of a process that produces proteins in cells. It’s the messenger and is normally single-stranded. However, when it’s double-stranded, RNA is sometimes also a molecule that can turn genes on off.

The RNA molecules used in genetic modification are known as double-stranded RNAs. These RNA molecules are already being explored for a number of uses.

A number of companies are planning to engineer plants with double-stranded RNAs to kill pests. Some are also planning to make sprays that carry RNA into the cells of weeds.

Double-stranded RNA is being tested as a feed supplement to make bees resistant to viruses, or to kill bee mites.

And GM plants with nutritional characteristics altered through the introduction of novel double-stranded RNAs are already being grown for the human food supply.

RNA: the “new DNA” of genetic modification

Most traits in existing commercial genetically modified organisms are due to the introduction of one or more proteins by modifying DNA. But new modifications are based on the double-stranded RNA molecules that regulate production of proteins.

Double-stranded RNAs can “silence” genes. For example, a small double-stranded RNA molecule has been developed based on a fragment of the dvsnf7 gene. This can kill western corn rootworms when the molecule is added to their food, or when it is expressed (by GM) in the corn plants which the worms eat.

Although the mechanisms for this are still being described, there are already a number of GM crops based on this principle. It is also probable that all commercial GM crops produce unintended regulatory RNA molecules that have not been tested as part of the routine risk assessment.

Worse, one double-stranded RNA can produce unintended secondary RNA molecules that have different sequences and therefore potentially different targets. These can arise in the modified plant or in the cells of those who eat the modified plant.

Not just food: double-stranded RNA (dsRNA) is already used in other consumer products.

We are concerned that what happens to pest insects and nematodes that eat these RNA molecules can also happen to other insects, wildlife and people. An increase or decrease in cell proteins can have important effects on our health. These effects vary depending on the protein, and the cells, organs or tissues to which the double-stranded RNA is delivered.

Small changes in the DNA sequence can change the spectrum and number of potentially affected genes. That is why in our view a risk assessment needs to consider each novel RNA created specifically, whether deliberately or inadvertently.

Risk assessment

The risks of double-stranded RNA have not been systematically evaluated by any regulatory agency we know of, and there are no standard safety testing procedures.

In a recent issue of Environment International we published peer-reviewed research looking at risk assessments done by three different regulators affecting three countries. In all cases the regulators didn’t assess the risk of new double-stranded RNA molecules.

In Australia and New Zealand, a genetically modified plant is subject to an environmental risk assessment if it is to be used in a field trial or released for cultivation. A food safety assessment if it is to be used in food or animal feed.

Food Standards Australia New Zealand assesses GM plants that are safe for use as food. Seven plants approved by Food Standards have been deliberately modified to produce double-stranded RNAs.

Various GM wheat varieties have been assessed for field trial by the Australian Office of the Gene Technology Regulator. These use the same double-stranded RNA technology. Neither regulator, to our knowledge, has assessed a GM plant for unintentionally created double-stranded RNAs.

Exposure incorrectly assessed

Double-stranded RNA produced in plants can be taken up by people through food, as shown in studies last year. Insects also take up RNA through food, which is why manufacturers are patenting dietary-based insecticides.

In another study a naturally produced double-stranded RNA was found to alter gene expression in mouse livers. Double stranded RNA could also alter gene expression in human tissue culture cells.

Until now regulators have rejected the possibility that people can be exposed to double-stranded RNA through food. There has therefore been no research into the safety of these molecules. In short, regulators avoid assessing potential safety issues by saying there were no risks to start with.

Were the regulators right but for the wrong reasons?

Various commentators have argued since RNA is already in the food we eat, it must be safe. Without evidence this reasoning is far from reassuring.

Only a small number of plants have been bred with intended changes to double-stranded RNA. And most of these have been withdrawn from sale, are not grown on commercial scales, or are in boutique crops such as Hawaiian papaya.

The amount of these RNAs in food now is unknown but is probably very small. Thus the argument of safety from existing experience is, at best, speculative. And it fails to account for unintended double-stranded RNAs.

If there are no experiments, we won’t know if double-stranded RNAs have an adverse impact or no impact. While we test food to some extent, there are no studies of other important sources of exposure such as inhalation. And critically, these studies are not on humans: even small differences between our genomes and those of the animals used in tests might have large consequences.

If we are to safely produce products that might contain novel double-stranded RNA molecules, there needs to be routine bioinformatics and transcriptomic testing.

The power of RNA should be used for the betterment of all. On the way, it should not become the snake oil of the 21st Century or the cause of avoidable catastrophes.

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