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Peter K. Dearden

Today saw some discussion in the press about a statement by Canterbury University’s Prof Jack Heinemann,  Prof Judy Carmen (Flinders University) and Prof Michael Antoniou (King’s College, London), around the risks of a new transgenic wheat variety being assessed for release by CSIRO in Australia. These statements released by the Safe Food Foundation, provide an opinion on the safety of this new wheat variety, and are interesting reading.

The new wheat variety aims to increase the amount of resistant starch, making this starch less easy to digest with apparent health benefits for the consumer. To make this variety, CSIRO has used a transgene that suppresses two plant genes, genes that make easy-to-digest starch. They have utilized a technique called RNA interference to do this. RNA interference is a modern technique whereby a small piece of double stranded RNA is made that is the same sequence as a gene you want to turn off. Now, RNA, the molecule that takes the sequence of DNA and is translated into protein, is normally single stranded. Double stranded RNA appears to be a warning signal for many organisms because they generate a response to it that causes all RNA of the same sequence to be degraded, and DNA with the same sequence to be silenced. Thus because genes are first transcribed into  RNA before making protein, double stranded RNA causes any gene with the same sequence to be turned off.  In this case, a small bit of DNA that, when transcribed, makes double stranded RNA of the same sequence of the two enzymes involved in making easy-to-digest starch, has been inserted in the plant genome. When active, these make double stranded RNA and thus turn off these genes, presumably making the starch produced by the plant more resistant to digestion.

Clever huh!

Now plants, and animals, also use small bits of double stranded RNA to regulate our own genes. The machinery that recognizes double stranded RNA is present in our cells, and used by them to do important things. A recent paper also shows that some of these small double stranded RNAs from plants can be found in Humans who have eaten those plants, and that they might cause some silencing of human genes. So it is possible that the bits of RNA that CSIRO has put into the plants to silence the making of digestable starch, might end up in people eating that plant. Now this normally would be no problem, because the process is sequence-specific, only genes with the same sequence as the plant gene being silenced in our own genome might be affected. Unlikely you might think? Think again. Organisms share a great deal of genetic information, and we do have a gene, called GBE, in our genome with similarity to the plant genes (SEI and SEII) being targeted. GBE encodes a protein that makes branched glycogen molecules. Glycogen is our way of storing carbohydrates, and GBE makes branched versions. Humans unable to make branched glycogen have a disease called Glycogen Storage Disease IV, that leads to damage in the liver, as pointed out by Prof. Judy Carmen.

So is it possible that this new variety of wheat, by making bits of RNA to silence the plant genes, might silence the human GBE gene in our livers leading to Glycogen Storage Disease IV? Possible, but, in my opinion, easy to avoid and unlikely

Let’s take this in bits….

The key is sequence similarity. The human gene GBE has similarity to the plant genes SEI and SEII, but this is limited and not across the whole sequence. The similarity is probably in the active site of the enzyme, which is presumably doing a similar job. The important thing is not protein similarity though, but DNA sequence similarity, which is low. To avoid the problem, however, all you need to do is make the bits of RNA you are expressing in the plant, from regions of the plant genes that ARE NOT similar to the Human gene. Simple. Has this been done? Who knows? CSIRO have not released to the public the sequences that have been used to silence the plant genes (I assume the regulators have seen them).

Certainly if I were doing this, I would target a region of RNA at the end of the gene, which doesn’t encode protein, and evolves fast. This region, named the 3′ untranslated region, is not similar between plants and mammals, and is the natural target of the double stranded RNA system, so likely to be a safe and effective method of silencing.

Prof. Heinemann also suggests that the manner in which the double stranded RNA is made in the plant could produce molecules with unexpected targets, again causing problems in humans. This seems less likely. It is relatively easy, with modern sequencing techniques, and good control of transgenesis, to make sure that these unexpected molecules do not occur, or occur in such low amounts that they are unlikely to have an effect.

So while Prof Heinemann and friends do raise important points I think it unlikely that this crop will cause the disease.  It is important to say, however, that CSIRO needs to be sure that they aren’t using sequences found in humans, and need to disclose that. Part of the problem here is the secrecy around intellectual property. I cannot judge if they have or have not used the sequences similar to humans because they haven’t told me. They would be bloody stupid if they had used those sequences!  As an aside, it is also odd that, even though Prof. Heinemann is correct in his statement that the plant and human genes are similar, he uses a sequence from another plant, not wheat, in his analysis.

But the way this issue has been raised seems unhelpful. By producing a press release as the decisions on this crop are made, rather than engaging with the decision-making process, two things have been lost. One is credibility. By not engaging with the decision-making process, but then releasing a scientifically backed query about the plants, you make it look like your aim is to disrupt, rather than inform. The second thing lost is the opportunity to improve the plants being produced. No company wants to sell a new strain of plants that would cause a human disease, or even target a human gene unexpectedly. If CSIRO haven’t thought about, and mitigated against, the issues raised, then they may have done if they had been informed earlier. Now there is mistrust and anger, neither of which helps the general public get the high quality, safe products they deserve.

So two problems here; secrecy because of intellectual property, and lobbying, not engagement. We need light not heat!

Actually it’s freezing here in Otago, so heat would be good too….

Isn’t the really interesting thing here the idea that plants might make double stranded RNA to specifically target genes in herbivores. When you eat a carrot, is it directly suppressing some of your genes? And if so what, and why? Isn’t Science cool?