GMO Wheat and shouting “fire” in a crowded theater

Stoking fears to sway your emotions

ResearchBlogging.org
A report from an activist group called Safe Food Foundation (SFF) came out last fall that caused a minor stir upon it’s first release. They claimed that they had unearthed an issue with GMO wheat being studied by the Australian CSIRO researchers. The wheat under investigation has shown to provide improvements in digestive health in animal studies and could potentially lower the glycemic index of foods. SFF threw a press conference, did a YouTube video, and managed to get some press about it. Here’s a New Zealand newspaper that picked up the claims. But as the story unfolded, it quickly became apparent that their claims were wrong and irresponsible.

There’s an astonishing amount of misinformation propagated around the internet about GMOs. Most of it is so clearly science fiction and conspiracy theory that it’s just laughable. Sometimes, though, the information comes from what seems like a trustworthy source, such as a scientific journal. Even if it is published in a respectable journal, sometimes the statistics and results do not withstand scrutiny. Science is a process and claims made in publications need to be evaluated over time.

Another source of confusion can be the “gray literature“. Gray literature consists of publications such as reports that have generally not gone through the peer-review process that scientific studies generally do. Some gray literature is useful and valuable, and quite neutral, based on a balanced panel of participants with appropriate skills. Sometimes, though, there are reports that come out that are definitely not neutral, and represent merely the cherry-picked and distorted views of an industry or activist viewpoint, sometimes both. The Safe Food Foundation report on CSIRO’s wheat was one such example of gray literature.

As reported by the press: The scientists claim

* SiRNA, a form of ribonucleic acid, like DNA, could transfer to humans through food when produced in GM wheat.

* When eaten, the siRNA engineered to suppress the wheat-starch branching enzyme (SBE) would also silence the human-branching enzyme which produces energy-storing glycogen (GBE).

* This “unbranched” glycogen would have low solubility in human cells and could create build-up in the tissues of the body, especially in the heart and liver.

* This could lead to the disease Glycogen Storage Disease IV, resulting in an enlarged liver, cirrhosis of the liver, and failure to thrive.

The claim was that the sequence used in the CSIRO wheat would destroy the activity of the human GBE gene, leading to the same outcome as this disease that kills children by the age of five. Sadly, though, it was one of those cases of a biased report that would not have passed any legitimate peer-review. And although the press did bite because of the shocking claims, mostly the claims only made the rounds of the usual suspects who will reprint any shocking claim, without any ability to assess the validity.

Here at Biofortified we immediately saw what was wrong with this report. It was based on copious amounts of incorrect sequence data, and on sleight-of-hand with bioinformatics tools. I prepared a long technical post about the flaws in the claims of the Safe Food Foundation’s team of hired guns Jack Heinemann and Judy Carman, but as an obscure report that was so obviously wrong, we decided it wasn’t worth drawing any more attention to it.

It recently resurrected, though, at an unusual spot. Orac at Respectful Insolence actually took it on: Oh, no! GMOs are going to kill your babies and permanently change your gene expression! He does a good job of framing the issue and explaining the technology. He astutely writes about this report:

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.

Within the large record, only a small portion represents the SBE1 gene.

Bio-Dis-Informatics

I know my way around bioinformatics – in fact I teach it to others. So let’s take a brief trip through the DNA sequences in question to see what was really wrong about the Safe Food Foundation report. The concern they express, resurrected here, is that double-stranded RNA (dsRNA) produced by RNAi silencing in GE crops could silence our own genes if we eat them. The mechanism is complicated, but in short, before there can be any silencing there needs to be a sequence match between the dsRNA produced by these plants and the DNA of our own genes. Heinemann claimed that he found these sequence matches – but as I will demonstrate he didn’t find anything of the sort.

The claims Heinemann made were based on a sequence that was 25,187 bases long. In no way that was the appropriate sequence to use for the analysis. It was like throwing 25,000 strands of spaghetti at the wall to see what sticks. There were going to be false positives. And one of the pasta pieces that stuck was to the GBE human gene. This was the basis for the claims made by Judy Carman in her SFF report that provided the dire warning about how this wheat would kill your babies.

Within the large record, only a small portion represents the SBE1 gene. See the long image on the right. And even within the actual gene part of that record, only a fraction of that sequence would be in the constructs used. The key point to be made about this was that their analysis was pointless and wrong.

I learned from Orac’s piece that there had been an update to the analysis, though. Heinemann had apparently realized that the sequence he used was probably incorrect. (Yes, we here at Biofortified had spotted that immediately.) There’s a re-analysis with a different sequence that you can now examine.

The new sequence? Oh, it’s different, yeah. It’s found within this GenBank record. But it’s not even the whole record. It’s only bases 96-635. That’s right–540 bases, not 25 thousand. Mm hmm. In case you are curious, 25,187 / 540 = more than 45x too much sequence. That’s a lot of pasta.

So there’s less spaghetti now. But again, Jack is able to deliver some sticking to the wall. However, all of the matches he highlights are either to introns – which would not matter for the mechanism of action that is the issue here. Or they are in the genome desert areas, thousands of bases away from anything that appears to be a gene.

Result: Take a deep breath. The GMO wheat that forms the basis of this claim will not kill your children or permanently alter your genome.

More interestingly, I decided to check back and see if the human GBE gene is still sticking with this sequence switcheroo. The main fear-based claim was that the GBE gene would be suppressed and children with a disorder of this can die by the age of 5. So let’s see–let’s do an analysis of this new sequence and compare it to GBE. If you perform a BLASTn at NCBI with these two sequences and default settings as Jack says he does, what do we get?

The result? No significant similarity found.

That’s right. The entire foundation of the fear–the match to GBE–is gone. Evaporated. Vanished. Nada. Zip.

And yet people who don’t understand the data will continue to make this claim. They will continue to be wrong.

This is really a case of shouting “fire” in a crowded theater. Fires are something to watch out for. And it’s important to have professionals who assess building codes evaluate the theater, as we do for GMO foods. But causing a stampede for the exits also has consequences and can be harmful in its own way. Sadly there’s a lot of this on this topic.

What can you do?

  • Don’t base your decisions on scary graphics. They may not be right.
  • Be aware of the source of the information. And understand the difference between the peer-reviewed process and the gray literature.
  • When you do see claims, check them out. Or find a person qualified in the field to help you to understand the claims. Conspiracy theorists may not be a good place to find validation.

If this was a journal publication, I could write to the editor and ask for corrections or even a retraction. But that’s another problem with the gray literature. There’s no mechanism to do that. I checked with Retraction Watch to see if there was anything they knew of, but there isn’t any kind of a registry or anything. We can only hope that people will Google for facts. Unfortunately they will be swamped with the misinformation instead. At least you have the knowledge you need now. Do share it.

Reference:

Regina, A. (2006). High-amylose wheat generated by RNA interference improves indices of large-bowel health in rats Proceedings of the National Academy of Sciences, 103 (10), 3546-3551 DOI: 10.1073/pnas.0510737103

Mary is a genomics scientist, with credentials in microbiology, immunology, plant cell biology, and mammalian cell, developmental, and molecular biology (PhD). All comments here are my own, and do not represent my company or any other company.


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33 comments to GMO Wheat and shouting “fire” in a crowded theater

  • Chris Preston

    You could write to Safe Foods Australia and ask them to retract the claims of Judy Carman, now that one claims have been shown to be untrue. It would be the right thing to do in my opinion.

  • Hypothetically speaking, even if there was a 100 % match to the human gene, wouldn’t the siRNA molecule by chopped to bits in the gut? (Granted, knock-down by siRNA feeding seems to work in nematodes but I’ve heard they’re slightly different from us…) If we could knock-down our own genes by eating siRNA, it would be a multi-billion industry by know.

    • Yeah, there are a numbers of *miracle happens here* steps that would have to be invoked for this to actually have measurable impact on the human liver. After the first alarmist post by Ari Levaux about the Zhang paper Emily Willingham did some great backstory on the RNA aspect: Plant RNA Paper Questioned:

      The deeper question, Zamore said, lies in the assertion that single-stranded RNA molecules like these microRNAs, or miRNAs, which silence expression of their RNA targets, can survive the digestive tract. They are “very fragile,” he said. The idea that these RNAs would not be immediately destroyed by the digestive enzymes of the gut “is controversial, to say the least,” he added. “Hundreds of millions of dollars have been spent trying to stabilize single-stranded nucleic acids in the bloodstream, let alone the digestive tract, and unmodified RNA has never been found to survive.”

      So there’s that. But the whole SFF claim rests on this bioinformatics analysis, which was bogus.

      • The issue relates to how double-stranded RNA survives digestion, not single-stranded RNA.
        And it now appears that dsRNA survives digestion in C. elegans, some insects (patents have been filed on using RNAi in plants to kills insects that eat those plants) and now humans. Since RNAi works via ingestion in C. elegans and, apparently, in some insects it seems more logical to assume that it could also work in humans than to assume that it could not.

        • No, it does not seem logical to assume that nematode and insect digestion is the same as humans. Perhaps you would be familiar with Bt?

          Are you familiar with the concept of evidence?

          • It’s not a question of whether “nematode and insect digestion is the same as humans” but that we cannot assume that nucleic acids are destroyed during human digestion; evidence presented in Spisak et al. (2013, PLoS ONE 8:e69805), for example, indicates that lots of nucleic acids ingested by humans can survive digestion.

            And perhaps, as evidenced by the fact that different Bt proteins survive human digestion conditions better than others (like the one in StarLink corn), some nucleic acids may survive human digestion better than other nucleic acids as well.

            • Considering that we share at least 50% of our genes are shared with all of what we eat, we must be eating tons of exact matches to our nucleic sequences. Am i wrong?

              • Yes, exactly. Isn’t it funny that there’s no evidence if this with much more highly expressed genes, and more conserved sequences, that actually fall in exactly the right place to invoke this? In fact–you should be scared out of your mind that the mammals you eat are shutting off all your genes, I guess. Maybe PETA should join up with Jack and Belinda for their next wacky campaign.

                I can provide lists of thousands of genes from plants and animals that have much better sequences matches, and have much higher amounts of the mRNAs. I invite you to demonstrate that they survive, affect the genes, and influence human health.

    • Pdiff

      Wouldn’t similar iRNA forms be naturally occurring in the food we eat anyway?

  • JS Hoyer

    Are Karlin-Altschul statistics really relevant here? All that should matter is how complementary the siRNAs (particularly their seed region) are to human mRNA.

    • Feel free to look at this in other ways. My goal was to look closely at what Jack did to make his claims with his methods. In the first report he didn’t even describe what he did, and what he did show was completely misleading. You couldn’t reproduce what he did with what he showed in the appendix. It pasted two entirely different things together in the first section. And then he went around saying he had 700 pages of hits (or 400 pages, depends on the interview) and that had no actual meaning either. But I’m sure it impressed some of the folks who wanted to think it had value. And yet Judy Carman used that analysis as the basis for her scary claims.

      But the first real problem was that it wasn’t the right sequence to start with. That sort of sets you back.

      In this updated report I used what he said he did to look at the new claims.

  • Derek Rusell

    That is a very useful contribution. It is a pity that such time and effort has to go into debunking material which should never have been in the literature in the first place. We stopped looking at it when we saw that Heinemann did not even have the sequence CSIRO was using (and had assumed that CSIRO would not have had the sense to test for human matches). As you point out, the trouble with this kind of non-journal literature is that this will now hang around for years like the Serelini rats and the scottish potato story and there is no definitive way of debunking it other than by responding to each report.

  • There has been a response from the FSANZ food safety folks about the risks of the RNA that were seeded by this issue. Here are some links:

    A science blogger discusses it: Regulator rejects scientists’ GM concerns

    Science Media Center collects comments: FSANZ defends stance on gene ‘silencing’ – experts respond

    Response to Heinemann et al on the regulation of GM crops and foods developed using gene silencing

  • greg meyerson

    Hypothetically speaking, even if there was a 100 % match to the human gene, wouldn’t the siRNA molecule be chopped to bits in the gut? (Granted, knock-down by siRNA feeding seems to work in nematodes but I’ve heard they’re slightly different from us…) If we could knock-down our own genes by eating siRNA, it would be a multi-billion industry by now.

    Just to be gross for a second, if 100% match to the human gene were all that were required to change the expression of our genes, would this be bad news for the children of cannibals? [it’s a serious question actually–from an english professor!]

    Less gross, even if there were a match, what would the status of the claim be due to digestive work on the material? You sort of answer this question above, but not directly. does the original article raise the digestion issue at all?

    • Heh. You know, I had a brief thought about that species issue too–well, I didn’t come up with cannibals, but there are some pretty conserved segments among mammals. So you are actually quite right–you should be far far more afraid of burgers and sausages really.

      But you are also quite right on the digestion issue. It’s been very tricky to create RNA molecules that survive for significant time at all. That was addressed specifically by Emily Willingham in this piece when the first claims were being made about the rice:
      Plant RNA Paper Questioned

      The deeper question, Zamore said, lies in the assertion that single-stranded RNA molecules like these microRNAs, or miRNAs, which silence expression of their RNA targets, can survive the digestive tract. They are “very fragile,” he said. The idea that these RNAs would not be immediately destroyed by the digestive enzymes of the gut “is controversial, to say the least,” he added. “Hundreds of millions of dollars have been spent trying to stabilize single-stranded nucleic acids in the bloodstream, let alone the digestive tract, and unmodified RNA has never been found to survive.”

      The original paper made some comments about modifications to RNA that could stabilize it. But that’s still not certain to be sufficient for the effects that they claim that would reach all the way to liver cells.

      Good work Greg–you and the English professor nailed two items that definitely issues with this!

  • greg meyerson

    Thanks for the answer. I am the English Prof, by the way.

    I have another question that is not exactly on this narrow topic. Anti GMO people have made the argument that all transgenic work is trapped in the one gene/one protein paradigm we now know to be false.

    Okay: we do now know this to be false. I would bet (lots) that every biotechnologist knows this also. what do the anti gmo people think they are saying when they make this comment?

    One person working this angle suggested that because biotechs are working in the “old paradigm,” they will be unable to anticipate for the “rogue proteins” that will be produced by their experiments since they presumably don’t know that a gene can be involved in the synthesis of numerous proteins. I would be interested in an answer that showed how biotechs routinely take this knowledge they are presumed to be ignorant of for granted in a variety of useful ways. hope the question makes sense.

    • Quite right again Greg! They do make that claim a lot, I’ve seen it too. And then I ask if they’ve been asleep for 40 years.

      The “Central Dogma” issue. This is a model, and we all know what people say about models. But even funnier, it was never really “dogma”. Crick used the wrong word. He meant “hypothesis” or something much milder.

      To appreciate the significance of the concept, note that Crick had misapplied the term “dogma” in ignorance. In evolutionary or molecular biological theory, either then or subsequently, Crick’s proposal had nothing to do with the correct meaning of “dogma”. He subsequently documented this error in his autobiography.

      So I tell them that they are hanging on to this idea like the creationists are hanging on to the term “junk DNA”. They don’t really like to be told that, but it’s true.

      But on “rogue” proteins, we’re pretty keen on stuff like this actually–stuff going rogue is what fascinates most of us. And there’s plenty of “natural” rogue DNA and RNA too–I love the work coming out on chromothripsis. But even before we had the tools to look at this more closely we knew about jumping genes in corn, and the Philadelphia chromosome, and plenty of other rogue events.

      Do we know everything? Of course not. As Dara O’Brian says: “Science knows it doesn’t know everything. Otherwise it’d stop.”

      But we have really good tools to look for anomalies at the DNA, RNA and protein level. And we do look. I can’t even begin to describe all the tools we have in all these fields now–but we have lots of ways to look for DNA integration sites, sequence, RNA expression, protein differences, metabolite changes, and more. The techniques might vary a bit by species (plants have those nasty cell walls–sorry Frank…) and tissues are different.

      Here’s a fun example that might make people laugh: the marijuana genome. They compared hemp and pot (2 hemp and 2 pot strains). They looked at the DNA, RNA, different tissues in the plants , and more. And they can see differences between hemp and pot. You can look too. If we can do this for non-GMOs, we can do it for GMOs too.

      I feel like they are pretending that we don’t look at this stuff, when we definitely do. And the tools get better every day.

  • greg meyerson

    okay. thanks for that.

    I think what I’m trying to get at is the underlying view of life and the organism that the anti gmo people have. You respond to their “rogue protein” worry with a kind of gleeful, even joyous, “we’re interested in that!!!”

    Rogue proteins are a part of nature. But they see rogue proteins as created in the laboratory, as something monstrous and unnatural. It much reminds me of the discussions some greens have around nuclear power. Radiation is something produced in labs, by nuclear engineers, not in nature. or if it is in nature, that’s good radiation; but the gamma rays coming from npps are evil, etc. “Rogue” is a proxy in anti gmo talk for frankenfoods. I think this all ties in to green ideological understandings of the relation between nature and complexity. For them, nature is complex and very fragile. Humans are constantly threatening this complexity with their scientific reductionism. In this view, experiments are viewed with great distrust, as something endangering their fragile complexity. real scientists also view nature as incredibly even sublimely complex. but the understanding of the complexity is a lot different, one which often contributes to stability (genomic) instead of (genomic) fragility, breakability, destroyability. I don’t want to take this stability/fragility opposition too far; then it becomes itself a metaphysic. anyway, I’ll stop.

  • Interesting paper has come out that looked at miRNA in blood. See the news here, and the paper it describes.

    Hold Off On Buying That Chinese Miracle Lettuce

  • Here’s a good summary of recent follow-up work on the initial miRNA findings and subsequent fearmongering:

    http://phenomena.nationalgeographic.com/2013/07/04/so-science-might-have-gotten-it-wrong-now-what/#.UdWb5oWsXcw.twitter

  • In relation to your statement that “introns – which would not matter for the mechanism of action that is the issue here” please see Hoffer et al. (2011) PNAS 108:409-414 who found they could silence a gene in Arabidopsis using RNAi with both intron and 3′-UTR sequences.

    • So in case anyone was curious about how to look at a claim and assess its value, here’s what you do.

      First, find the paper Belinda thinks is relevant. Oh, look, here it is: http://www.pnas.org/content/108/1/409.abstract

      Then ask yourself a number of questions about her claim:
      1. Is this in humans? No.
      2. Is this about a different species exogenous RNA first accessing the cell’s cytoplasm? No.
      3. Does this paper explore exogenous RNA that enters a cells and then requires transporting to the nucleus? No.
      4. Does this paper tell us what levels of this transported RNA would be needed to impact human gene expression? Not even close.

      So thanks for playing, but this has zero to do with the claims being made on this topic.

      • Mendelian genetics was first discovered in a plant species, that didn’t mean it didn’t apply to humans. Model systems are important for exploring new phenomena like RNAi and the information discovered using them, as has so often been the case in the past, will likely inform us as to how those phenomena work in humans as well. The alternative would be to conduct gene-silencing experiments in humans…is that what you are advocating?

        And I had no intention of “playing” anything. I mistakenly thought I was participating in a scientific discussion, not playing some game. My bad.

        • Certainly DNA is a nice framework. One of the really great things is that 4 nucleotide “letters” can be used in innumerable ways to accomplish different things. Just because those 4 letters are used in everything from virus to humans doesn’t mean that the outcome is the same.

          Maybe you can think of it like the alphabet. Just because English, French, Spanish, and Italian use a lot of letters in common, it doesn’t suggest that the meaning and the strategies–and the outcomes–are the same in all cases and are simply interchangeable.

          Here’s another example that might help you to understand species differences: chocolate can kill your dog because they have different metabolism for theobromine, right? But mice and rats don’t process it that way. And neither do you. So if you wanted to study the effect of theobromine, you could certainly use worms to study that. But you wouldn’t know how it would affect other species from that, would you?

          Or are you suggesting that mechanisms and outcomes are always the same across species? Why bother having different species then?

          • greg meyerson

            hey mary: does the fear around foreign genes digested then invading our dna and shutting down gene expression have (apart from the question of its validity) anything at all specifically to do with GE? seems not. so why is it that people think this (bogus) fear is one applying to GE but not other foods? Is it merely that GE is “unnatural” and nature could never do such a thing as invade our genome and shut down gene expression?

            • No, that’s the odd thing about this conversation. It’s about any food that humans eat–any species could presumably be a threat if this is a common mechanism that shuts down human genes (which I don’t buy, but that’s the premise of these claims). The specific case that ignited all the drama (the first Zhang paper) was a naturally occurring rice gene.

              But if close sequence matches were a bigger threat–you’d have to think cow genes could shut that thing down even better.

              If you wanted to avoid ingesting foreign nucleic acids–well, cannibalism is your best bet. Something else I don’t really recommend, but I guess some people could think that was “natural”. But the matches to human DNA then…oh dear.

              I honestly don’t understand what the basis for this fear is.

              • Ewan R

                The basis is the gallop formerly known as Gish.

                It doesn’t matter how bad the arguements are, throw out enough and some people will accept some of them, and nobody has the time nor energy to counter every last one (nor indeed, one assumes, to actually research them in the depth you might like to be properly persuaded one way or the other).

                You only have to get a person to accept one out of the myriad bad arguements to have another convert. There is an abject lack of beauty in this view of life.

  • So this was funny:

    https://twitter.com/SusanStopsongs/status/392832708620984320/photo/1

    The false claims continue. But sadly, he’s not on the list with Joe Mercola anymore so we can’t hear this talk:

    http://screencast.com/t/Rxv7vAYz

    • gregory meyerson

      did anyone see this? pretty lame as their specifics are likely the usual debunked suspects. Note guilt by association trigger (GMO equals Monsanto).

      An international group of more than 90 scientists, academics and physicians released a statement today saying there is no scientific consensus on the safety of genetically modified (GM) foods and crops.

      The statement was issued in response to recent claims from the GM industry and some scientists, journalists and commentators that there is a “scientific consensus” that genetically modified organisms (GMO) were generally found safe for human and animal consumption. The statement calls these claims misleading and says, “This claimed consensus on GMO safety does not exist.”

      Moreover, the claim encourages a climate of complacency that could lead to a lack of regulatory and scientific rigor and appropriate caution, the group said, potentially endangering the health of humans, animals and the environment.

      “The statement draws attention to the diversity of opinion over GMOs in the scientific community and the often contradictory or inconclusive findings of studies on GMO safety,” said Dr. Angelika Hilbeck, chairwoman of the European Network of Scientists for Social and Environmental Responsibility (ENSSER) and one of the signers. “These include toxic effects on laboratory animals fed GM foods, increased pesticide use from GM crop cultivation and the unexpected impacts of Bt insecticidal crops on beneficial and non-target organisms.”

      Sigers of the statement include prominent and respected scientists, including Dr. Hans Herren, a former winner of the World Food Prize and this year’s Alternative Nobel Prize laureate, and Dr. Pushpa Bhargava, known as the father of modern biotechnology in India.

      Signers of the statement are calling for the compliance to the precautionary approach to GM crops and foods internationally agreed upon in the Cartagena Protocol on Biosafety and UN’s Codex Alimentarius.

      ENSSER released the statement the week after the World Food Prize was awarded to two executives of the GM seed giants Monsanto and Syngenta, provoking outrage worldwide.

      This article was published at NationofChange at: http://www.nationofchange.org/scientists-say-no-consensus-gmo-food-safet…. All rights are reserved.

      – See more at: http://portside.org/2013-10-22/scientists-say-‘no-consensus-gmo-food-safety’#sthash.OVFKzyTM.dpuf

  • […] 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 the likes of Jack Heinemann and Judy Carman and parroted by useful idiots like Heidi Stevenson generate heat, but no light. Nor does the latest round of attempts to generate hysterical fear mongering based on Carman’s latest study. Both Heinemann’s speculations and Carman’s most recent bit of data mining are of a piece. They are not designed to provide a dispassionate analysis of the true potential risks and benefits of GMOs. They are designed to be propaganda to produce fear, uncertainty, and doubt about GMOs, just like Andrew Wakefield’s studies about the MMR vaccine, just like Mark and David Geier’s studies of thimerosal in vaccines, just like the studies of any variety of antivaccine cranks. It is the equivalent of shouting “fire!” in a crowded theater. […]

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