Tag Archives: GM crops

Who’s Afraid of the Big, Bad ORF?

A recent paper in the journal GM Crops and Food has generated an outsized splash in the press, particularly in biotechnology-averse Europe. I won’t reward a muckraking tabloid with a link, but here’s a screenshot that shows the basic theme:

Daily Mail hype.

Oh No, Toxic Genes!

Apparently the genetically modified food crops that hundreds of millions of people around the world have been eating without incident for more than a decade are in fact horribly toxic. But it turns out that the research that triggered this alarm proves no such thing. How did an arcane scientific finding get turned into a completely incorrect, apocalyptic headline? Let’s dig into it like scientifically educated journalists.

If we start by going to the source, we immediately hit an obstacle: there’s the abstract, but if we want to read the paper itself we’re expected to pony up $29. It would probably help a lot if journals made papers about important public policy issues freely accessible by default, but we don’t live in that world yet. Fortunately, journalists have an easy way to get around this: contact the authors directly. The Daily Mail appears to have failed at this, as all of the quotes in their article are from other sources. Other articles on the new work similarly lack any representation by the folks who actually did it.

It’s rare for scientists to blow off reporters completely, but sometimes they can be hard to reach, out of the office until after the deadline, or just uninterested in helping. Perhaps that was the case here. Let’s see. The first author is Nancy Podevin of the European Food Safety Authority in Parma, Italy. When I sent a note to her identifying myself as a journalist and asking for a reprint, she replied minutes later: “Please find the article attached. Please be aware that the content of the article has been incorrectly reflected in recent press articles.”

Not exactly hard to reach. Or reticent.

Alright, let’s dig into the work. Here’s the basic plan from the introduction:

Bioinformatic tools are increasingly being used in the evaluation of transgenic crops. Guidelines, proposed by WHO/FAO19 and EFSA, include the use of bioinformatics screening to assess the risk of potential allergenicity and toxicity. With this aim, the EFSA GMO Panel has updated its guidance for the risk assessment of GM plants and proposed to identify all new ORFs due to the transformation event. New ORFs are defined as strings of codons uninterrupted by the presence of a stop codon at the insert genomic DNA junction and within the insert. The putative translation products of these ORFs are then screened for similarities with known toxins and allergens.

This is a study done entirely on computer databases, in which the scientists looked for novel open reading frames (ORFs) in the transgenes of modified crops, then checked to see if any of those ORFs match any known allergens or toxins. The existence of an ORF doesn’t prove that it gets transcribed and translated into a stable protein, so we’re still several steps short of reality here, but it’s a useful exercise to define what might be possible. In this case, the investigators are looking specifically at a sequence called P35S, a gene promoter borrowed from cauliflower mosaic virus (CaMV). P35S promotes constitutive (constant) expression of the gene in front of it, so it’s been a popular choice for driving introduced transgenes in genetically modified crops. 54 of the transgenic crop strains currently approved in the US use this promoter.

In its original context, the P35S sequence overlaps with a CaMV sequence called gene VI. That means that the P35S sequence could potentially encode a piece of gene VI. Podevin and her colleague Patrick du Jardin searched the various P35S sequences used in transgenic crops, and identified a couple of ORFs. Remember, this is all on a computer. The paper contains no wet lab experiments showing that these ORFs are actually producing stable proteins in any cell. But let’s assume they do for now.

Translating those ORFs on the computer and searching against databases of known allergens and toxins, the researchers found … wait for it …

Nothing.

That’s right, these hypothetical proteins that might not even exist don’t match any known allergens or toxins anyway. They did an additional test that sets the bar lower, and found that by this standard, one of the putative proteins might be allergenic. But it’s a stretch:

The vector support machines (SVM) in AlgPred indicated on the basis of the dipeptide composition that the ORF that encoded part of P6 might have some allergenic properties. The sensitivity and specificity of this method is 88.87% and 81.86% respectively and should therefore always be used in combination with other tools.

All the other tools, though, found no allergenicity. Having established that there’s essentially no human risk, the authors speculated that there could still be effects on the plants themselves, such as plant stunting and late flowering. Considering that the entire point of most crop biotechnology is to increase yields, it seems unlikely that this applies to any of the current commercial strains, but product developers should probably keep an eye out for it in future strains. Either that, or they could simply follow the authors’ final advice:

The -343 variant [of P35S], identified by Odell and colleagues, contains all of the necessary elements for full promoter activity and does not appear to result in the presence of an ORF with functional domains, rendering it and its related variants the most appropriate promoter variants for avoiding unintended effects.

To put this all in context, plant viruses commonly infect all sorts of crops. One survey (PDF here) found CaMV and its colleagues widespread in numerous types of produce. We’re already eating huge quantities of plant viral proteins – not hypothetical ones, real ones – all the time. If there is an ORF from CaMV gene VI being expressed as a protein in transgenic crops, it’s likely one you’ve digested before, even if you eat exclusively organic food.

So there you have it. This was a research paper that used bioinformatic methods to ask yet again if GM crops are any more dangerous than non-GM crops. It ended up adding to the large pile of established data showing that they are not. Through what can only be described as laziness and ideologically blinded reporting, it served as a handy news hook for stories claiming exactly the opposite.

Update 2013.1.22 12:49: After writing this post, I saw this discussion thread, in which several smart folks make essentially the same points.

Update 2013.1.23 7:07: After Dr. Podevin graciously sent the paper, I pinged her with a few additional questions about the work because, well, that’s what I do. I received her reply this morning:

I have been overloaded with requests for the paper and as I am no longer working at EFSA it is difficult for me to react.

To answer you[r] questions I am not planning to work on this topic further. It is difficult how headlines on toxic genes in GMOs can be seen to be linked to our paper as we concluded that there are no indications for toxicity of the encoded protein. This virus has been infecting Cauliflower and related plants with no recorded health effect.

It should also be noted that this promoter [has] an ORF overlaps with Gene VI but that no functional gene is present. So in most cases this gene fragment will not lead to the production of a protein.

Update 2013.1.24 15:06: I’ve now received a note from the journal publisher as well:

I am the publishing director at Landes Bioscience – and for GM Crops & Food. Thanks for your excellent piece which was just brought to my attention. Would also quickly like to note that we have now made this paper OA, ie, freely available to anyone who wants to download and read. [link]