dsRNA in the field is bad news

August 2013

Test tubes in a biotechnology lab.
CC photo by wistechcolleges on Flickr

The latest thing in GM technology uses a new tactic: it doesn't involve inserting genes, but creates 'RNA-interference' to alter the expression of existing genes. Crops using one form of this technology, insecticidal double-stranded RNA (dsRNA), are already in the pipeline.

Just when the official damage-limitation response to New Zealand scientist Jack Heinemann's warnings about the risks of dsRNA was fully underway in Australia and New Zealand [1, 2, 3], an even more detailed critic emerged unexpectedly from the 'father' of GM, America.

Regulatory body FSANZ (Food Standards Australia and New Zealand) insists that:

• The weight of scientific evidence published to date does not support the view that small double-stranded RNAs (dsRNAs) in foods are likely to have adverse consequences for humans.
• There is no scientific basis for suggesting that small dsRNAs present in some GM foods have different properties or pose a greater risk than those already naturally abundant in conventional foods.
• The current case-by-case approach to GM food safety assessment is sufficiently broad and flexible to address the safety of GM foods developed using gene silencing techniques (dsRNA can prevent gene expression)

The first two points are true: so little science has been done on artificial dsRNA safety that there is certainly very little evidence of harm: there's very little evidence, and no real scientific basis for risk assessment whatsoever.

In Heinemann's words, the FSANZ proposes not to test for even the smallest risk until the “weight of evidence” suggests dsRNA is actually doing harm.

On the third point about the adequacy of existing assessments, Heinemann points out simply “FSANZ is silent on what specific tests and techniques it uses to guard against unintended effects from the new dsRNA molecules that it is approving as safe for use in GM food crops”.

Heinemann has called for regulators to require extensive experimental evaluations, including bioinformatic sequencing, in vitro tests, animal feeding trials and potentially even clinical trials, before any approval of GM foods using dsRNA technology.

Biotech scientists in Australia and New Zealand reacted with 'shock-horror' to these suggestions. Little did they know that the American warning, which is much wider in the scope of its analysis than Heinemann's, proposes a testing regime which is even more extensive.

USDA scientists, Lundgren and Duan, are entomologists with expertise in the environmental risks of pest management. They point out that dsRNA will never present the familiar toxic dose-response in key model organisms which have previously been standard in the risk assessment of pesticides.

The major difference is that RNA-interference only alters gene expression and therefore its effects are only seen when the genes express themselves. This means that harmful effects could depend on a huge number of factors such as individual physiology, age, life-activities, health or disease status, nutrition, and environmental factors. It also means that harmful effects of RNA-interference are unlikely to be directly lethal but may compromise long-term life-supporting aspects such as health, behaviour and reproductive success. Risk assessment of dsRNA must therefore cover the whole life-span, subsequent generations, and exposure to all major stresses and conditions.

Double stranded RNA is not one simple active substance. In the cell, it is cleaved to release numerous smaller interfering RNA molecules, each of which can interfere in its own specific way: each active unit will have to be risk assessed individually and in combination.

Natural small interfering RNAs in the diet are known to circulate in the body and are not damaging. However, the artificial forms are intended to kill insects: they are specifically selected or designed to overcome animal cellular defences and be lethal to the consumer.

Artificial interfering RNA may be present at unusually high levels in such GM food. It's possible

this unnatural excess could saturate the cells' machinery for its own natural interfering-RNA turnover. This would compromise cell and tissue health.

Besides these avenues of potential harm from such novel RNA in food, its persistence in the environment could pose unique risks which must be assessed. Artificial interfering-RNA will be found not only in plants, but in wildlife, water, air, soil, microbes, fungi etc. Where it ends up will be affected by the extent of binding to materials in the environment and by incorporation into genomes.

Even in a monoculture 'desert', the ecology of an area involves a dynamic and interdependent system of hundreds of animals, plants, and fungi and unquantifiable numbers of microbes which change with the weather, season and land-management.

Lundgren and Duan suggest many gaps in the science which must be filled before interfering RNA technology can be realistically assessed for risk, including: actual exposure of non-target organisms to the novel RNA, and identification of genomic sites which are vulnerable to RNA-interference in all non-target organisms

Background reading:

[1] RNA-MODIFIED FOOD -  July 2013

[2] dsRNA: SILENCING REGULATION - July 2013

[3] dsRNA MEDIA CENTRE - August 2013

OUR COMMENT

Bear in mind that humans are one of GM interfering-RNA's non-target organisms, and the ecosystem which must be included in the risk assessment is ours too.

It will be interesting to see what happens next. Lundgren and Duan seem to have blown all notions that RNA-interference is 'intrinsically safe' out of the water. Either the pro-GM American regulators silence their own USDA scientists, or everyone starts testing the products of RNA-interference technology for safety. Testing will only happen if the public insist.

SOURCES:

• Lundgran and Duan, 2013, RNAi-Based Insecticidal Crops: Potential Effects on Nontarget Species, BioScience 63:8
• FSANZ defends stance on gene 'silencing' - experts respond, www.sciencemediacentre.co.nz
• RNA-interference pesticides will need special safety testing, American Institute of Biological Sciences Press Release, 16.07.13