Heidi Stevenson amuses me. I know, I know, I've started a previous post with exactly this sentence a mere month ago, but it's so damned appropriate that I can't help but try it again.

A homeopath (which means that she's reality-challenged to begin with), she's produced some of the most hilariously off-base, pseudoscientific, and downright antiscientific articles I've ever seen. Examples include the times when she launched a truly nonsensical attack on Stephen Barrett of Quackwatch, lectured scientists about anecdotal evidence, or, most hilariously of all, utterly misunderstood the concept of prior plausibility in evaluating why homeopathy is so ridiculous from a scientific standpoint. So when I saw that she wrote an article in which she claimed that genetically modified wheat may damage human genetics permanently, I couldn't resist. Never mind that somehow I missed it the first time around, when it was first published last October. Better late than never, I say, particularly when there is a "teachable" moment! I mean, Stevenson even includes a picture of a ghostly skull floating above a wheat field. It's comedy gold, I tell you! It doesn't get much better than this, as far as blogging goes. It also allows me to teach a bit about something I'm very interested in scientifically. Win-win!

Stevenson prefaces her article with this scary paragraph:

The Australian government, in the form of its science research arm, is joining Agribusiness profiteering by designing a GM wheat that could kill people who eat it & be inherited by their children.

Scared yet? Does Stevenson have your attention? Who are these nefarious scientists, and why would they want to make genetically modified wheat that would do these things? They wouldn't, of course, but, like the Frankenstein that anti-GMO activists think scientists are, it's a matter of messing with nature resulting in unintended consequences. In fact, the hilarity is such that I think it's worth quoting a decent sized chunk of the first part of Stevenson's article:

We have not yet seen the worst damage that genetic engineering may do. Australia's governmental agency, Commonwealth Scientific and Industrial Research Organisation (CSIRO), is developing a wheat species that is engineered to turn off genes permanently. Professor Jack Heinemann at the University of Canterbury's Centre for Integrated Research in Biosafety has studied the wheat's potential. Digital Journal reports that he says1: What we found is that the molecules created in this wheat, intended to silence wheat genes, can match human genes, and through ingestion, these molecules can enter human beings and potentially silence our genes. The findings are absolutely assured. There is no doubt that these matches exist. The implications are clarified by Professor Judy Carman of Flinders University: If this silences the same gene in us that it silences in the wheat—well, children who are born with this enzyme not working tend to die by the age of about five. Silencing the equivalent gene in humans that is silenced in this genetically modified wheat holds the potential of killing people. But it gets worse. Silenced genes are permanently silenced and can be passed down the generations.

So basically, the claim being quoted by Stevenson is that a variety of genetically modified wheat under development by the CSIRO will kill your children. I kid you not. Of course, Stevenson apparently doesn't see the contradiction between saying that this GM wheat will kill your children but that its gene-silencing effects will also be passed down the generations. In any case, I could recognize some amazing speculation and fear mongering right off the bat; so it's time to explain.

Gene "silencing" means what the name implies: Shutting down the activity of a gene so that it stops making its gene product. Of course, gene silencing is not an all-or-nothing phenomenon. Like other forms of gene regulation, silencing happens on a continuum from zero to complete silencing, depending on the level and activity of the silencing agent. In this case, the silencing agent that is being turned into the bogeyman du jour is RNA. Specifically, it's a type of RNA-mediated gene silencing called RNA interference (or RNAi), also known as post transcriptional gene silencing (PTGS). The idea is that the CSIRO is apparently engineering a strain of wheat that produces a short RNA molecule designed to silence specific genes in the wheat. Most of the time, when we talk about RNA, we talk about messenger RNA (mRNA), the RNA that is the intermediary between DNA and protein. However, back in the late 1990s, it was discovered that there are other RNA molecules that actually regulate gene expression by binding to complementary sequences on mRNAs. These molecules include classes of RNAs called microRNAs, as well as double-stranded RNA molecules known as short inhibitory RNA (siRNA), that can participate in cellular pathways that contribute to gene silencing, most commonly through binding to complementary sequences and inducing the degradation of different mRNAs in a sequence-specific manner. In fact, siRNAs were first discovered in plant genetics and only later was it discovered that short RNAs serve as a gene regulatory mechanism in mammalian cells as well.

An excellent video explanation of RNAi can be found, courtesy of Nature:

So what's the problem? University of Canterbury Professor Jack Heinemann is apparently worried that the siRNA that will be used to silence two genes in wheat called SEI and SEII. Heinemann apparently did an analysis based on the sequence of the SEI and SEII genes, comparing them against the human genome and looking for matches. He found them in the gene for the enzyme mentioned by Judy Carman. In humans, the equivalent gene is known as glucan (1,4‐alpha‐), branching enzyme 1, abbreviated GBE. Based on some similarities he found between SEI and GBE, Heinemann sounded an alarm through an anti-GMO activist group known as the Safe Found Foundation & Institute. Humans store carbohydrates as glycogen is our way of storing carbohydrates, and GBE makes branches in glycogen. There is a consequence to not being able to branch one's glycogen, although not branching it in wheat could be useful for decreasing its glycemic index. There is a disease known as Glycogen Storage Disease IV, which leads to damage to the liver over time. That's the disease that Judy Carmen was referring to.

Of course, the problem with Dr. Heinemann's highly speculative analysis is that he didn't know the actual siRNA sequences that were going to be used. Without that information his analysis was pretty pointless. At the very best, it was highly speculative. At the worst, it was ideologically and politically motivated.

So how could this possibly matter? After all, it's RNA. It's really unstable, isn't it? Well, not exactly. Single stranded RNA is very unstable. It can't survive long outside of the cell. However, dsRNA can be quite stable, even outside of a cell. But that still leaves the question of whether dsRNA from a plant that is eaten can have any effect. To do that, the siRNA would have to survive digestion, be absorbed into the bloodstream, enter other cells, and act on gene expression. Heinemann notes that such a phenomenon can be observed in insects and worms.

But can it happen in humans? Well, there is one paper that Heinemann latched on to because he thinks it demonstrates that the same phenomenon can happen in humans. It's a paper by Zhang et al published in Cell Research that showed that showed that a plant-derived microRNA (miR-168a) from rice can be found in human serum after ingesting rice and that it can actually bind to the mRNA for low-density lipoprotein receptor adapter protein 1, thus inhibiting the expression of this protein. It's an interesting observation, but there are a number of questions. For one thing, although the microRNAs are detectable in serum they circulate at a really low concentration, namely the femtomolar range (10-15 mole/Liter). News stories describing the study at the time were quite credulous, but a better discussion can be found at Sandwalk. In any case, the exceedingly low concentration of microRNA observed in the bloodstream leaves a huge question in that there is no known mechanism by which such a low concentration could have such an effect. When I first read the study, I thought it plausible, but the more I think about it the more I agree with the Sandwalk commenter who says it screams "artifact" to him. Or this commenter:

There is probably 10 fM of everything in the blood. Sheesh, that's less than 4x10^9 molecules per whole body consisting of about 7x10^12 cells and containing no more than 7x10^10 hepatocytes. That's less than 0.1 miRNA per liver cell in the best possible scenario. What are these RNAs, totally magic?

Stoichiometry is your friend when figuring these things out. Personally, I'll wait for some confirmation that this happens from other groups before I buy it. True, another group has reported finding miR-168a, but it also reported a huge variety of microRNAs in the serum from a variety of sources, including including bacteria and fungi as well as from other species, such as various insects. Basically, we're awash in microRNAs from other species that we come into contact with. So far, the only evidence that they have any effect whatsoever is that one study suggesting that miR-168a might regulate one gene, even though it's hard to figure out by what mechanism it could possibly accomplish this. Add to that the utter lack of evidence that any circulating microRNA can not only silence a gene in human cells but actually induce epigenetic changes, and Professor Heinemann's speculation becomes ever more...speculative. This is true particularly in light of the fact that we regularly plants that make many siRNAs and microRNAs. Why would GM wheat siRNAs be any different or more dangerous, particularly given the very low concentrations involved.

Let's put it this way. For Heinemann's fear mongering to be a real concern, any siRNA or microRNA from genetically modified wheat would not only have to be made in sufficient quantity at least to equal the normal concentration of miR-168a in rice, be stable enough to pass through stomach acid and the gut lining undigested, and get into the bloodstream at a high enough level to affect gene expression. That's leaving aside the question of whether there is even enough sequence match that the siRNA could even target the human GBE mRNA in the first place, which is impossible to say because we don't know the actual sequence of the siRNA being used. It's true that Heinemann has updated his "report." However, that update doesn't really show anything new or contribute to the plausibility of Heinemann's concerns. In fact, it trashes the plausibility even more because the homology (in laymen's terms, match) to the glycogen enzyme that Heinemann was promoting pretty much disappears. Add to that the enormous lack of likelihood that, even if the siRNAs and microRNAs in GM wheat could actually make it into the bloodstream in concentrations sufficient to alter gene expression, it's incredibly unlikely that such RNAs could actually induce "permanent" epigenetic changes to justify the fear mongering.

Even if there were a legitimate scientific concern raised by Professor Heinemann, as has been pointed out, the way he raised it was about as far from helpful as there is. It was fear mongering based on pure speculation, and Heidi Stevens—surprise! surprise!—eats it up to come to this mind-numbingly predictable conclusion:

The Australian government appears to have become nothing more than another Agribusiness corporate entity. They're using the people's money to fund a massive profit-making venture in genetic engineering without any consideration for the potential harm that may be done to either the environment or the welfare of the people. Not only are they willing to risk mass deaths from products they're hoping to put on the market, they also seem to have no concern for whether they might be doing permanent damage to generations that follow.

There might be questions about GMOs, but by and large they are not issues of safety. Rather, they are issues of intellectual property; i.e., how large companies developing GMOs behave. Hysteria of the like generated by Professor Heinemann and parroted by useful idiots like Heidi Stevenson generate heat, but no light.