Are there unintended health effects of genetic engineering?

61 comments

1. First, I’d like to say thanks to Dr. Thicke for proposing these questions. This is an important topic with a lot of myths going around.
   I think I’ll dive in with a quick discussion of the Ewen (1999) study and go from there because I think the points I’d like to bring up apply to the way other studies should be (and many are) preformed (and how they shouldn’t). One unique factor of the study is that it attempted to isolate the effect of genetic engineering from the effect of the protein being expressed by testing both GM potatoes expressing lectin and extracted lectin. This is important because there is a difference between testing for the safety of the process of genetic engineering and the safety of a particular transgene.
   I say they attempted to isolate the effect of genetic engineering because they didn’t control for genetic background (what variety of potatoes the GM and non GM were) or the environment (where the potatoes were grown – soil and weather can make a difference). Both of these could cause many differences in the compounds present in the potatoes. There have been many studies showing an effect of genotype and environment on metabolites. For example Röhlig (2009, Europe, independent funding) and Skogerson (2010, Monsanto funded) came to the same conclusions – that both genotype and environment have a significant effect on metabolites. For potatoes, ignoring these differences could mean that one sample could have higher concentrations of poisonous glycoalkaloids. Ideally, the GM and non-GM samples would be of the same genetic background and grown in the same place at the same time under identical conditions.
   They also didn’t control for event or generations. Each time a transgene is integrated into the genome of a single cell, that’s an “event”. Because the transgene is integrated into a random place in the genome, there could be events where the integration site causes a native gene to be interrupted which could cause an unintended effect. It could be inserted in a non-coding region where the transgene might not be translated into protein. Or, it could be inserted in a place where it is translated yet doesn’t interfere with any native genes. Many studies on the safety of GE crops test the specific event that is on the market, which makes sense if you just want to know what is the safety of that event. But if you want to ask a broader question then you need to look at different events. I wasn’t able to find any good studies with a quick search, but this is something a researcher in my lab is looking at, I helped with the pollinations this summer.
   Finally, they also didn’t control for problems caused by tissue culture. We know that tissue culture itself (needed in most species to get a plant to grow from a transformed embryo) can cause mutations. Best practice is to backcross the resulting plant multiple times to get rid of unwanted mutations. The GM potatoes used in this experiment were too few generations away from tissue culture so that could have been another source of error.
   I’ll let someone with more experience with rodents and feeding studies discuss those aspects of the paper.

2. The main question: “Do you think there are unanswered questions about the health effects of GE foods?”
   The answer is: Of course. That’s because most of the questions about GE foods are intentionally posed in such a way as to make them impossible to answer.
   Or, and this is my favorite: questions posed which impose constraints on testing that lead to uninterpretable results — generally known as the “long-term multi-generation” question. The longer the term, and the more generations involved, the more uncontrollable/extraneous variables intrude, making the results dependent on factors we can only guess at.
   There is no better testing regime than short, tightly-controlled procedures aimed squarely at a meaningful hypothesis. I trust this is widely enough known that a citation is unnecessary.

3. I tried to read this paper again with fresh eyes, and specifically didn’t go to re-read any of the critiques I have seen in the past. I tried to treat it like it just came out today.
   My first thought was this didn’t seem nutritionally sound. And it concerned me that it would make any other physical assessments a bit cloudy.
   My next thought was–this is pretty short. It’s less than 2 page, it’s not very detailed on many of the crucial aspects. But one of the lightest parts to me was the lack of any example images. This is pathology–it should be all images. I wanted to see a the controls (and there should have been several) with representative images, and then the supposedly affected samples. Now, it’s easy to choose images to make your case from large numbers of samples. But I still would like to have seen a sample of the affected tissue with a demonstration of what the measurements entailed.
   And if there was this “unexpected proliferative effect” was it visible in the cell structures? Can we see evidence of increased cell divisions? Cell counts? Could this have been checked with cell cycle markers? This would have been more convincing with another type of supporting evidence.
   And the claim that this was caused by the vector is not supported–as that just wasn’t tested. A vector-only potato (without the lectin sequence) needed to be included to make that claim.
   Without the images I can’t tell how good their measurements were, so it’s difficult to assess the numbers. I would also have been concerned if the samples were blinded or not. (I subsequently read in a critique that they were not).
   In short, it was thin and light on support. The conclusions were not justified by the design, in my opinion.
   I’m going to read the accompanying commentaries now.

4. I haven’t studied the paper in detail, and I am not a geneticist, so much of the terminology is unfamiliar to me, so I would like to ask a more general question.
   When Pusztai came to ISU to give a seminar several years ago, I asked him if his research had been replicated to see if the effects would be reproduced. He replied: Are you kidding? After what they did to me, who in his right mind would try to replicate my experiment.
   Anastasia, Eric and Mary have pointed out what they thought were flaws in the research design. My question is, has anyone tried to repeat the experiment with a design that would eliminate those confounding factors?

5. I don’t know if there has been a replication of this paper. I agree that it probably would have been asking for trouble, and completely thankless–no matter what the data said.
   1. I don’t know if the potatoes are available anymore.
   2. It’s very hard to get negative data published. If it came out that there was no change in the tissues, reviewers would say that it’s very difficult to prove a negative.
   I do know this, though: I worked at one of the premier mouse facilities in the world, starting in 1998. At that time–and since then–all production mouse chow probably has GMOs. To see some sample lab animal diets, you can go to Harlan: http://www.harlan.com/online_literature/teklad_lab_animal_diets
   You’ll see corn, soy, beets, and yeast among the ingredients. (I actually don’t know if the yeast is GMO–I’m actually curious about that now). Not organic, anyway.
   Lab animal techs are very sensitive to diet changes. These are production facilities with good stats. If there had been issues with the health of these animals, it would be known. And it would not have been suppressed by some giant conspiracy team–many of these are academic facilities.
   I can remember a case in the earlier 90s of a particular batch of rodent chow that was missing vitamin E. Techs around the country were noticing the problems–and it was traced back to the chow. And fixed.
   Millions of lab animals around the world have been on these diets. If corn/soy/beet modification were killing them, and reducing fertility, causing bizarre phenotypes, we’d know.

6. Let me ask you this: are you qualified to assess the animal diets? Please list for me the components of the food in the Pusztai paper. And compare them to the Harlan diets.
   Also, if you could, as the Harlan ingredients fact sheet mentions–evaluate the phyotestrogen components that may have been involved. As the Harlan data shows (which granted, is not peer reviewed) the soy is pretty variable batch-to-batch.
   In a diet study, how important would you say the understanding of the components should be? How would you replicate it with what we have been provided?
   If you question the safety of the commercial feeds today–what do you think that says about all the biomedical research that’s been done in the past 10 years? Is it all up for dispute?

7. “Millions of lab animals around the world have been on these diets. If corn/soy/beet modification were killing them, and reducing fertility, causing bizarre phenotypes, we’d know.”
   Yep, but what happens if a future version has an unexpected bug?

8. Mary,
   I am not sure I follow your reasoning. Are you saying that Pusztai’s experiment has not been replicated because it would be thankless regardless of the results, and that it doesn’t need to be replicated because lab rats eating gmo diets are not dying en mass? I am having trouble following the scientific reasoning for that. Could there not maybe be more subtle health effects of gmos that would require controlled studies to ascertain?
   I readily acknowledge that I am not an expert on the health effects of gmos, and not very familiar with the scientific literature on it. Can you tell me, have there been many feeding trials on gmos that have confirmed the null hypothesis, i.e., no health effects of feeding gmos?

9. I am not a geneticist or nutritionist. I am not familar with the Harlan diet. I am probing to learn how much research has been done on the health effects of gmos through feeding trials. I trust that researchers in this area would be able to sort out confounding factors in designing the appropriate feeding trials.

10. No, I did not say that. I agreed with you that people would be reluctant to do that same experiment because it would be a flashpoint.
    But can you tell me: are the same potatoes still available to do this?
    Is your field really that different–is it easy to get negative data published? “We didn’t find anything” is something I always thought was a pretty tough paper to publish in all fields based on conversations with other scientists.
    So–to reiterate point 1–yes, it would be unappealing to do it, and point 2–if there were no effects, it’s not easy to publish. This is still the case since the first time I wrote it.
    I added additional information I have from biomedical research animal situations.
    The Biofortified team has provided a database of papers on GMOs. Please see their Genera tab: https://biofortified.org/genera/ Select any one of those and ask the Biofortified folks to open another thread on it so we can dissect them.

11. In your coursework you never covered animal feeds? Can you tell me more about the kind of research you’ve done?
    But ok–anyway: I’d be delighted to have Marion Nestle speak to the quality of the data and the conclusions. Is there any way we could get her over to help out with the evaluation of the diet and the components of the feed?
    Can we maybe ask her for a design that would be appropriate?

12. My Ph.D. is in soil fertility. I am now a dairy farmer and devise my dairy rations, but have never had coursework in feeding laboratory animals.
    Can you send me to links of research feeding trials testing the health effects of gmo crops? In particular, do you know of feeding trials testing the health effects of crops engineered to produce the Bt pesticide?

13. Whoops, this comment was supposed to go down below Mary’s last comment.

14. Anastasia,
    Are you casting doubt on FDA’s postion that gmos are “substatially equivalent” when you say
    “Because the transgene is integrated into a random place in the genome, there could be events where the integration site causes a native gene to be interrupted which could cause an unintended effect.”

15. Francis Thicke

    Are you casting doubt on FDA’s postion that gmos are “substatially equivalent” when you say
    “Because the transgene is integrated into a random place in the genome, there could be events where the integration site causes a native gene to be interrupted which could cause an unintended effect.”

    I’d say no – because to be recognized as substantially equivalent an event has to go through the regulatory process – part of the process is a check on where the event is integrated – if you’re integrating into a gene then you aren’t going to get regulated (to the extent that events will be dropped during molecular characterization if they’re sitting in a gene, or even particularly close to a gene – thankfully the genome is a huge place with lots of non-gene space for transgenes to land in) – another reason you’re unlikey to see this occuring is that you’d generally want yield parity with a transgenic – if you do interrupt native gene function it’s generally more likely you’ll decrease yield than see anything good.

    I am having trouble following the scientific reasoning for that. Could there not maybe be more subtle health effects of gmos that would require controlled studies to ascertain?

    Lab rats and other animals are bred in their tens of thousands and fed precise diets, and checked meticulously for any changes from their normal phenotype (phenotypes which are largely predictable due to the nature of inbred lines of lab animals) – while not precisely a scientific test it would be remarkable if there were effects of GMOs that had gone unseen (Now would be a good time for Mary’s tale about an instance where feed abnormalities were turned up by animal handlers)
    Have Putzai’s exact experiments been replicated? No (afaik)- they’re pretty worthless anyway, they look at the integration of a gene that isn’t useful commercially into a crop that until recently hasn’t been commercialized (in a GM form) – far more pertinent are the many feeding studies on actual commercialized GMOs – if Putzai’s findings were broadly applicable (as he claimed they were) then they would have been uncovered in other feeding trials – they haven’t been ergo they aren’t broadly applicable – even if true all we’d be able to say is that the events Putzai generated (or tested) should not be allowed into the food chain.

    Can you tell me, have there been many feeding trials on gmos that have confirmed the null hypothesis, i.e., no health effects of feeding gmos?

    Google scholar is thy friend. example of a search which turns up many results, the majority of which will be null hypothesis confirmations
    Hushed Puppy

    Yep, but what happens if a future version has an unexpected bug?

    This is why the regulatory process is in place to test every new GMO – to catch any issues before they make it to consumption.

16. Consider this hypothetical: a company using conventional breeding develops a line of maize with some outstanding, valuable trait. The company patents it. (Yes, you can get a patent for a conventionally-bred plant.)
    To protect its interests, the company inserts a snippet of DNA which is unique, but is not patented and codes for nothing. It’s simply there so that theft of the conventional germplasm can easily be detected.
    What is the justification for requiring this product to go through the registration process?
    Would Pusztai’s test regimen discover that justification?

17. How do you assess what to feed the animals? Really–I’m wondering what components you include and how you balance them. Would you be able to read materials for feed products?
    It would really surprise me if you don’t have enough appropriate science to pull the materials out of this paper. It’s not genetics and it’s not nutrition per se. It’s just the ingredients. I really wish you’d give it a try.
    Consider it a challenge. Imagine if you had to, I don’t know, make regulations about animal feeds and had to be able to evaluate something of this nature.
    But if you still aren’t comfortable giving that a try–who would you trust? Do you know anyone who works with animal feeds who could do this for us? I’m willing to hear what they might say about that.

18. I have a comment stuck in moderation for Francis, that points to the Genera paper list and offer to examine any of the ones in there like we are doing with this paper–it’s like a journal club! I don’t want to link again because that seems to be what got me stuck in moderation.
    Or bring any other paper that Francis is aware of that we should evaluate.

19. Nope 🙂
    Here’s how we do it in my lab, other labs might be different (maybe Ewan can enlighten us on what Monsanto does). Each event is evaluated and the ones that have obvious problems (such as might be caused if the transgene landed in an important gene) are discarded. The events that don’t have obvious problems then are backcrossed for many generations. Any gene fragments, etc that might have been integrated at sites other than the primary insertion site will be bred out during the backcross process. This also needs to be done since the variety that is transformed has poor agronomic traits (but is highly transformable) so we want to get the gene into a variety that has good agronomic traits. Additionally, this needs to be done because tissue culture itself (used both for biotech and non-biotech purposes) can introduce mutations and epigenetic weirdness that needs to be bred out. This backcrossing process is also used for traits generated through mutagenesis because the mutagen could cause changes in other parts of the genome and other problems.
    During the backcrossing, we evaluate the expression of the transgene and choose the events that have high expression and that are consistent expressers (sometimes the gene gets silenced). During the process, we’re also evaluating for any weird phenotypes and roughing those out. After about 3 generations of backcross (at this point only about 6.25% of the genetic material from the transformed plant remains) we’ll start to do more detailed transgene evaluation, but the goal would be at least 6 backcrosses where only 1.62% remains). If we had more money then we could use marker assisted selection in the backcross process to make sure the gene was the only thing left from the transformed line.
    If I recall correctly, the potatoes used in the Ewen (1999) experiment were not backcrossed or anything, they weren’t phenotyped, they weren’t ready for these sorts of tests. Anything found in the feeding experiments could be attributed to tissue culture, integration of gene fragments, etc.

20. These sorts of papers can be found on PubMed, a database maintained by NIH. Use search terms like Bt feeding study and you’ll find many. Unfortunately, lots of these papers are pay-per-view if you don’t have university access. If there are any papers you want to look at, let me know and I can send them to you.
    Karl and I are working on a database called GENERA that will make these papers more accessible to people. It’s time consuming, though, so it’s taking a lot longer than I wanted, I’m really sorry about that.
    I have had time to enter one of my favorite papers on Bt into the database, though. It’s called Effects of long-term feeding of genetically modified corn (event MON810) on the performance of lactating dairy cows by Steinke (2010). I hope you’ll check it out!

21. If anyone wants to discuss specific papers (or news articles, etc) feel free to start up a forum post.

22. Interesting hypothetical. I think that one could argue that the insertion process itself could cause unintended effects and that at least some testing of metabolites or something to determine substantial equivalence between the line with the insertion and an isoline without the insertion. Of course the new trait developed with breeding requires no testing, even if it is truly novel.
    Ewen (1999) tried to separate the effect of the transgene insertion process from the effect of the gene product. An interesting idea that you bring up is that one could test for the effect of transgene insertion separate from the effect of the gene product by inserting a non-coding sequence. One could also test this using a gene that expresses a protein that is well known to be benign – something that is being and has been done.
    I am doing some work on unintended consequences of transgenes using GFP (green fluorescent protein) which has been determined to be non-toxic. For example: Safety assessment of recombinant green fluorescent protein orally administered to weaned rats, Richards (2003) tested the effect of canola expressing GFP compared to non-transgenic canola (they tested 2 GFP events and the non-transgenic progenitor line). Canola expressing GFP from both events was digested with no apparent ill effect to the rats. The researchers also fed GFP spiked food to the rats in far higher amounts than was in the GFP-canola and the only result was that the rodents’ fecal pellets contained GFP (too much protein to digest). They also found that GFP has no similar amino acid sequences to known food allergens. In addition, animals expressing GFP themselves are not harmed.
    If there was some unintended consequence of the gene insertion process, it would have been picked up by Richards (2003). Of course this is only one study, but there are others. Specifically, one could argue that the gene used in glyphosate resistant crops EPSPS (5-enolpyruvoyl-shikimate-3-phosphate synthetase) is an benign protein. It’s an enzyme that has no target in a mammalian system. Many studies have been done on the effect of the altered EPSPS gene. For example, Effect of feeding glyphosate-tolerant (roundup-ready events GA21 or nk603) corn compared with reference hybrids on feedlot steer performance and carcass characteristics, Erickson (2003). Again, if there was some effect of the transgene insertion process itself, it would have been found in these studies.

23. Hmm. I was thinking about the GFP feeding study Richards (2003) that I mentioned below some more and it just occurred to me that this is a replication of Pusztai’s research that eliminates many of the confounding factors. It might not be about potatoes expressing lectins, but it is about isolating the effect of transformation from the effect of the protein itself which I believe is what Pusztai was trying to do. I bet there are more similar studies out there that I just don’t know about yet because I haven’t looked for them in this context.
    As far as I know it is fairly rare in science that an exact experiment is duplicated. Instead, similar experiments are conducted. I talked about this idea a bit at the end of a past post Does the source matter? The relevant part is below.

    Imagine that the entire body of peer-reviewed research for a subject area is a deck of cards that we’ve placed on the table, 52 card pickup style. Each card is a paper that is related to some of the other papers. Some papers cover very similar areas, totally overlapping. Others are only slightly related, with just a tip overlapping. Any one of those cards won’t tell us that much about what’s really happening, but when we look at the whole pile, particularly the overlapping areas, we can start to understand what’s really happening.

    Papers like Richards (2003) don’t completely overlap with Ewen (1999) but the subjects definitely overlap. Let’s see if we can find some more.

24. Nestle isn’t even interested in discussion on her own blog. I asked some specific questions a while back and checked up to a month later and there wasn’t any response from her, although some other commenters did discuss a bit. Anyway – I don’t know if that’s going to happen.
    But I bet we could find a toxicologist of some sort that does have experience in this area that could help. Maybe on Twitter? Are there any toxicology blogs?

25. (maybe Ewan can enlighten us on what Monsanto does).

    I’ll actually have to look into how much of our exact process I can disclose – again the pains of corporate science – afaik it’s pretty similar to what Anastasia lays out – marker assisted breeding will be used to integrate traits into commercial germplasm (odds are transformation germ won’t be commercial particularly due to the 10 year lag between proof of concept work and commercial release so even if you transformed directly into the best germ available now it’d be in an obsolete line in 10 years time – you categorically do not, in commercial lines, want to mess with the line any more than you have to – precision molecular breeding is used to make sure you get very little other than the GOI in the final product (having seen the difference between academic genetic maps and in house ones let’s just say that when big-ag does marker assisted breeding they have a superior toolbox to use (because they can throw silly amounts of money at it))

26. Oh yes, I forgot that Monsanto has the ability to transform right into elite lines but doesn’t want to tell anyone else how. :p I understand why and all that but it sucks to have to transform HiII which is a really crappy hybrid. If we could at least transform into an inbred that would help but as far as I know no one besides the big companies has figured it out yet, mainly because no one has the money to spend on testing the transformability of different lines.

27. Oh yes, I forgot that Monsanto has the ability to transform right into elite lines but doesn’t want to tell anyone else how.

    Elitish… I don’t know much about the details of plant transformation that we do, but I do know that you’d have a job for life and a life of leisure if you could perfect a technique which worked for all lines all of the time.

28. That’s a very good analysis of the paper. I don’t have much experience with rodent studies so I found your comments on the “unexpected proliferative effect” particularly useful.

29. Eric:
    Are you aware of any instance where this hypothetical has been implemented? I’m well aware that conventionally bred crops can be patented, but am not sure why anyone would go to the trouble to add DNA. Genetic id of germplasm is easily sophisticated enough to assure a developer that his or her proprietary interests are protected.
    Indiscriminately adding DNA just because you can seems worse than reckless.

30. Mary:
    I’m not an animal nutritionist either. But I would like to weigh in a little on the isoflavone issue you raised:

    Also, if you could, as the Harlan ingredients fact sheet mentions–evaluate the phyotestrogen components that may have been involved. As the Harlan data shows (which granted, is not peer reviewed) the soy is pretty variable batch-to-batch.

    I got a copy of the Teklad Global Rodent Diets from the website you linked to (and thanks for that link BTW). While this may not be peer reviewed, it passes the sniff test for me. They do cite a peer reviewed paper by Ju et al. 2001 J Nutr. which examines the effects of one particular isoflavone (genistein) on tumors in mice. However the take home from this particular product sheet is that isoflavones have powerful effects in rodent physiology and therefore they (Harlan) go to great length to formulate diets with reduced or well controlled amounts of soybean meal (a major source of isoflavone).
    For full disclosure (Ewan you’ve inspired me on this issue) I am a soybean breeder – primarily for non-GM soy that is used for human foods such as tofu and soymilk. The non-GM aspect is not significant for most of the debate here (it is very significant in some markets however). Anyway, isoflavones have garnered a lot of attention in the soyfood universe. They are not only significant in rat and mice physiology – their chemistry is such that they mimic estrogen which is a very potent hormone. To the soybean plant the isoflavones (there are about twelve – two are most important, genistein and daidzein) are secondary metabolites. There is genotypic regulation of isoflavone concentration, but there is very significant environmental influence on expression (thus batch to batch levels will vary even for seed from an IP program).

    If you question the safety of the commercial feeds today–what do you think that says about all the biomedical research that’s been done in the past 10 years? Is it all up for dispute?

    Maybe not all of it…
    For Anastasia – Professor Patricia Murphy of the ISU Food Science faculty is one of the best authorities on the issue of soy isoflavones.

31. I have actually taken a class from Dr. Murphy before. Any particular questions you’d like me to ask her?

32. No one wants to challenge my claim that Richards (2003) and many other studies are replications of Ewen (1999)? I was expecting at least some dissent – come on, people!

33. I’ll apologise in advance for the length of this post but below you will find a list of feeding studies from peer-reviewed journals that have been performed by researchers completely independently of the GM industry both in terms of scientific input and funding. Please feel free to point out if this is not the case.
    Francis has asked several times now for examples of feeding studies that look at the effect of GM. They aren’t often obvious to the casual observer because, to be frank, no-one mentions most of them on the web because they don’t show any harmful effect of GM and that’s not what the NGOs and protest groups want to hear. Most I’ve read show no effect of the GMO although some show differences. You’d have to critically assess the findings individually to say whether these are differences relevant. You often get small differences between two experimental groups even when treated the same, so that has to be borne in mind.
    Jonathan
    Ash J, Novak C, Scheideler SE (2003) The fate of genetically modified protein from Roundup Ready Soybeans in laying hens. Journal of Applied Poultry Research 12:242-245
    Aulrich K, Bohme H, Daenicke R, Halle I, Flachowsky G (2001) Genetically modified feeds in animal nutrition 1st communication: Bacillus thuringiensis (Bt) corn in poultry, pig and ruminant nutrition. Archives of Animal Nutrition-Archiv fur Tierernahrung 54:183-195
    Barriere Y, Verite R, Brunschwig P, Surault F, Emile JC (2001) Feeding value of corn silage estimated with sheep and dairy cows is not altered by genetic incorporation of Bt176 resistance to Ostrinia nubilalis. Journal of Dairy Science 84:1863-1871
    Batista R, Martins I, Jeno P, Ricardo CP, Oliveira MM. (2007) A proteomic study to identify soya allergens–the human response to transgenic versus non-transgenic soya samples. Int Arch Allergy Immunol. 2007;144(1):29-38.
    Batista, R., Nunes, B., Carmo, M., Cardoso, C. et al., Lack of detectable allergenicity of transgenic maize and soya samples.(2005) J. Allergy Clin. Immunol. 2005, 116, 403–410.
    Bohme H, Aulrich K, Daenicke R, Flachowsky G (2001) Genetically modified feeds in animal nutrition 2nd communication: Glufosinate tolerant sugar beets (roots and silage) and maize grains for ruminants and pigs. Archives of Animal Nutrition-Archiv fur Tierernahrung 54:197-207
    Bondzio, A., Stumpff, F., Schoen, J., Martens, H., Einspanier, R., (2008) Impact of Bacillus thuringiensis Toxin Cry1Ab on rumen epithelial cells (REC) – a new in vitro model for safety assessment of recombinant food compounds, Food and Chemical Toxicology 46: 1976-1984
    Brake DG, Thaler R, Evenson DP (2004) Evaluation of Bt (Bacillus thuringiensis) corn on mouse testicular development by dual parameter flow cytometry. Journal of Agricultural and Food Chemistry 52:2097-2102.
    Brake, D.G., Evenson, D.P., 2004. A generational study of glyphosate tolerant soybeans on mouse fetal, postnatal, pubertal and adult testicular development. Food Chem. Toxicol. 42, 29–36.
    Chambers, P.A., Duggan, P.S., Heritage, J., Forbes, J.M. (2000). The fate of antibiotic resistance marker genes in transgenic plant feed material fed to chickens. J. Antimicrob. Chemother. 49, 161–164.
    Chen ZL, Gu H, Li Y, Su Y, Wu P, Jiang Z, Ming X, Tian J, Pan N, Qu LJ. (2003) Safety assessment for genetically modified sweet pepper and tomato. Toxicology. 2003 Jun 30;188(2-3):297-307.
    Chowdhury EH, Mikami O, Murata H, Sultana P, Shimada N, Yoshioka M, Guruge KS, Yamamoto S, Miyazaki S, Yamanaka N, Nakajima Y (2004) Fate of maize intrinsic and recombinant genes in calves fed genetically modified maize Bt11. Journal of Food Protection 67:365-370
    Chowdhury EH, Shimada N, Murata H, Mikami O, Sultana P, Miyazaki S, Yoshioka M, Yamanaka N, Hirai N, Nakajima Y.(2003). Detection of Cry1Ab protein in gastrointestinal contents but not visceral organs of genetically modified Bt11-fed calves. Vet Hum Toxicol. 2003 Mar;45(2):72-5.
    Chowdhury, E.H., Kuribara, H., Hino, A., Sultana, P., Mikami, O., Shimada, N., Guruge, K.S., Saito, M.,Nakayima, Y. (2003). Detection of corn intrinsic and DNA fragments and Cry1Ab protein in the gastrointestinal contents of pigs fed genetically modified corn Bt11. J. Anim. Sci. 81, 2546–2551.
    Chrenkova M, Sommer A, Ceresnakova Z, Nitrayova S, Prostredna M (2002) Nutritional evaluation of genetically modified maize corn performed on rats. Archives of Animal Nutrition-Archiv fur Tierernahrung 56:229-235
    Domon, Eiji, Hidenori Takagi, Sakiko Hirose, Koichi Sugita, Saori Kasahara, Hiroyasu Ebinuma, Fumio Takaiwa (2009) 26-Week Oral Safety Study in Macaques for Transgenic Rice Containing Major Human T-Cell Epitope Peptides from Japanese Cedar Pollen Allergens, Journal of Agricultural and Food Chemistry 2009 57 (12), 5633-5638
    Einspanier R, Lutz B, Rief S, Berezina O, Zverlov V, Schwarz W, Mayer J (2004) Tracing residual recombinant feed molecules during digestion and rumen bacterial diversity in cattle fed transgene maize. European Food Research and Technology 218:269-273
    El Sanhoty R, El-Rahman AA, Bogl KW (2004). Quality and safety evaluation of genetically modified potatoes spunta with Cry V gene: compositional analysis, determination of some toxins, antinutrients compounds and feeding study in rats. Nahrung. 48:13-8.
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34. Jonathan – thank you for being awesome.
    That is all.

35. I have been out of the loop, caught up in other things, and am just now catching up on all the dialogue here. I appreciate your discussion.
    I was surprised to see the long list of papers Jonathon presented that he said were feeding trials. I certainly haven’t had time to read them. Jonathon, do you know if they all showed no detrimental health effects?
    Ewan provided a Google link to papers that he thought “the majority of which will be null hypothesis confirmations.” I clicked on the link and found the sixth article (not a scientific paper) in the list to be by Jeffrey Smith. Smith summarizes a study by Irina Ermakova that purportedly showed low birth weights and high death rates of rats fed GM soy. I expect you have seen that before, and I would be interested in your analysis of Smith’s summary (I haven’t yet looked for the original paper). The link to the list is http://scholar.google.com/scholar?hl=en&q=GMO+feeding+trial&as_sdt=0%2C26&as_ylo=&as_vis=0

36. Hi Francis. I haven’t by any means critically read all those papers in full but have read quite a few. I have however read the abstracts of them all to get the general conclusions.
    I think there are 65 papers listed mainly from the list published on GMOPundits blog. All were carried out independently of the GM industry as far as I can tell from the authors affiliations and the stated funding sources. Of the 65, 56 show no effect of GM and the other 9 describe differences. A difference doesn’t necessarily mean a negative effect of the GM fed animals, just that a difference that was noted. You’d have to critically assess those differences individually and decide whether they were relevant, significant or point to a negative/positive impact.
    Interesting to me are that most of the multigeneration studies such as Flachowsky’s 10 gen quail study, Brakes Bt mouse study, Jaszczak’s 5 gen mouse study and Rhee’s 5 gen rat study showed no effects of GM whatsoever. You don’t find Jeffrey Smith and his ilk ever mentioning these publicly available and funded studies and have to ask why when considering their motives.
    You have to also remember the vast majority feeding studies are done by the GM industry as they have to for regulatory reasons. They all show no effect, but I avoided them in my original post for two reasons.
    1) the people we are trying to convince here won’t even consider an industry study despite them generally being conducted to a higher standard on bigger sample sizes and are monitored for quality under strict GLP (Good Laboratory Practice) legislation.
    2)It is often said that no independent testing of GMOs has ever been done and as my (far from complete) list shows that is clearly untrue.
    Jonathan

37. Francis – you really don’t have to go any further than the name Jeffrey Smith on that article to conclude it is rubbish (again even using google scholar requires a little know how – it filters out most, but not all, of the nonsense)
    Afaik Ermakova’s work is known and has been discussed previously – time permitting I’ll take a bit of a better look around for that – I seem to recall that her death rate was high (may be confusing studies here – so forgive me if that’s the case) and really all one need do is look at the purported differences to have alarm bells go off – again getting back to the lack of any difference being seen in lab test animals – 55.6% of GM fed animals died within 3 weeks – can anyone seriously contend that feed with a 50% kill rate would not have been uncovered through just regular use? Given that clearly something was going on with this group outside of the effects of GM (on the premise that a 50% kill rate is simply ludicrous and suggests someone was poisoning the animals with something else to get a result) absolutely no conclusions can be made

38. This is why I recommend PubMed, not Google Scholar. Google Scholar does find a lot of good things, but too much non-peer reviewed non-reliable sources get included.
    The main problem with Ermakova’s work, as Ewan pointed out, is that she had huge numbers of rodent deaths in the control group. I can’t imagine what sort of horrible conditions she had the rodents in to have such a high death rate, but one thing I do know is that this problem invalidates the rest of the experiment. Need more? She had very small sample sizes, much smaller than other feeding studies that have found no result, and she didn’t follow anything even similar to established international rodent feeding study guidelines. In addition, she went to the press instead of using the peer review system, probably because she knew such shoddy work would never be published.
    Don’t take my word for it. Here’s a summary of the problems with the study: http://academicsreview.org/reviewed-content/genetic-roulette/section-1/1-14-roundup-ready-soy-is-safe-5/
    And a Nature interview where Ermakova herself describes the study in detail with a point by point critique by 3 experts. http://www.nature.com/nbt/journal/v25/n9/full/nbt0907-981.html Strangely, in this article she repeatedly calls the negative control of rat chow alone the positive control but maybe that’s a language thing.
    It pains me to think that Ermakova is out there mistreating more rodents and producing more useless data with poor experimental design and poor procedures.

39. I’ve never been overly good at doing pubmed searches – my mind works in googlese – I always get a better list out of google, although it does require a post filter that probably isn’t required by pubmed – GMO food safety in pubmed pulls up a whole bunch of results which aren’t quite what I’m after whereas scholar tends to hit pretty much what I want (and is prettier to behold, which imo is of more importance than relevance!)

40. Mary discussed industrial rat raising that, by necessity, requires vast amounts of grain, gmo or otherwise; and, which has gone on for many generations. Could such intense selective pressure on these strains already have selected for rats ‘immune’ to effects from gmo traits?
    Has that been looked at? Were I to raise rats or other animals industrially, I would, at outset, feed to select for robust animals.
    Perhaps an illustration might be in order, ture, though anecdotal. A friend of mine began a cheese factory, but had trouble getting his ‘bugs’ to ferment the purchased milk due to its high antibiotic load. He eventually had to contract with a milk scientist to select for ‘bugs’ that could live in the commercial milk he purchased to make into cheese.
    Caveat, I have been out of academia, and my former graduate neurophysiology since 1987: please excuse my loose language.

41. They’d have noticed during the transition – also I’m not sure what exactly is meant by raising rats “industrially” I assume you refer to

    I do know this, though: I worked at one of the premier mouse facilities in the world, starting in 1998. At that time–and since then–all production mouse chow probably has GMOs. To see some sample lab animal diets, you can go to Harlan: http://www.harlan.com/online_literature/teklad_lab_animal_diets
    You’ll see corn, soy, beets, and yeast among the ingredients. (I actually don’t know if the yeast is GMO–I’m actually curious about that now). Not organic, anyway.
    Lab animal techs are very sensitive to diet changes. These are production facilities with good stats. If there had been issues with the health of these animals, it would be known. And it would not have been suppressed by some giant conspiracy team–many of these are academic facilities.

    Which I dunno if you’d refer to as industrial (maybe, but industrial has connotations of mass production sans oversight, whereas premier mouse breeding facilities are going to be keeping exceptional records) but regardless – for such a selection to have been taking place there would have to have been noticable – you’d suddenly, inexplicably, see differences in survival of your rats or different brood sizes, or something – this would be investigated – perhaps Mary can tell us a little more about what is done to check genotypes etc – I’d guess (but am purely speculating) that there are checks on inbred lines to make sure variation is minimal – possibly various genetic markers etc – which one might expect to see change should a strong selective force be applied

    Has that been looked at? Were I to raise rats or other animals industrially, I would, at outset, feed to select for robust animals.

    If you’re raising rodents to be used in scientific testing you want to produce rats that are just like those already used – and robustness is probably the exact opposite of what is demanded – uniformity is key I guess and depending on the type of study the rats are to be used in various levels of robustness may be wanted (toxicological testing for instance would, I’d imagine, demand sensitive little beasties – although there could be scope here for industry to demand robustness – however given that your type of rat has to be disclosed in any paper you publish (has to meaning nobody is going to take it remotely seriously if you omit this) this would be immediately caught – so is doubtful.

    friend of mine began a cheese factory, but had trouble getting his ‘bugs’ to ferment the purchased milk due to its high antibiotic load. He eventually had to contract with a milk scientist to select for ‘bugs’ that could live in the commercial milk he purchased to make into cheese.

    Sounds kinda made up to be perfectly fair – I seriously doubt that milk contains enough antibiotics to matter – what testing did your friend do to prove this, and who did he take to court for selling him unsafe milk?

42. I don’t know much about rat breeds used in feeding experiments, but I do know there have been feeding studies with a variety of other species that haven’t been specially bred for lab work – quails, for example. Other experiments have looked at other traits besides weight and survival – for example, earlier in this thread I provided a link to a study that examined milk composition from cows fed Bt or nonBt corn stalks, leaves, and grain.
    Where was your friend making cheese? In the US, milk is tested and if it has any antibiotics it is destroyed. Sick cows on antibiotics are isolated from the herd and their milk is destroyed. Perhaps the bacteria he had just weren’t the right type?

43. Actually, it is more correct to say that if milk has any detectable antibiotics in it it is destroyed. It has happened more than once that milk samples from a milk truck tested positive, but the milk was not intercepted before it was dumped into a large milk silo, which then tested negative for antibiotics. In other words, the milk was diluted to below the detection limit of the test used. However, I would be surprised if antibiotics below a standard detection limit would interfer with a bacteria culture — but perhaps it could.

44. I thought, too, that the treatment effects were unbelievably large.
    Earlier, I asked for examples of research studies in which the null hypothesis was affirmed. I was surprised at how many you provided, although I haven’t had time to read them.
    Now I would like to ask the reverse question: Are you familiar with studies on the health effects of gmos that have rejected the null hypothesis, i.e., have found a statistically significant effect of a gmo treatment compared to a non-gmo treatment. In other words, do you know of studies that have found a health impairment from feeding gmo feeds?

45. Actually, no, quite the opposite really. These animals are probably significantly more fragile than wild-type animals because they have been selected for a bunch of things including reduced aggression (to not bite handlers) and to tolerate humans. Many of these strains have been in use for decades. Even if they were somehow tolerant to the chows, if something suddenly very damaging and toxic showed up, it would have been noticed.
    In fact, it’s nearly a joke in the cancer field that the rats get cancer from everything. Check out the story in Anastasia’ recent “Chemicals in Plants” post and watch the video in there. Bruce Ames actually has a cartoon of that.
    However, there are hordes of sub-types of these animals with different characteristics. The chance that none of them would be affected is quite a stretch if these foods have all these dire effects over time. Some of them mimic human genetic conditions really well.
    But here’s a good question: can anyone tell me which rats were used in this Pusztai study? What do we know about them? I can’t find anything. How did this paper get past reviewers?
    Research animal facilities are very high-tech operations with very active management. Check out this source: http://jaxmice.jax.org/index.html And look over their “Animal Health and Genetic Quality” link. Ongoing assessments are always underway. You can even get Health Status Reports by room.
    Every handler is trained and encouraged to watch for changes–any changes. In fact, when I was there, they had this hilarious day once a week called the “deviant search”. Any animal that was not quite what was expected was brought over to the researchers who would examine them specifically looking for novel effects and mutations. These are actively monitored in so many ways it’s remarkable, really.

46. Ah, here’s the diagram I wanted: many of the founding strains of these mice were from the 1920s, 30s, 40s, and so on. Some even earlier.
    Go to this page: http://www.informatics.jax.org/mgihome/genealogy/ And click the PDF chart. Look how long some of these strains have been in use.
    To assume they were selected in 1930 to tolerate GMOs is, well, you can decide.

47. Mary
    Regarding Pusztai’s paper you say “How did this paper get past reviewers?”.
    In my former life as a plant molecular biologist I used to work in the same building as John Pickett, one of the original reviewers of the Pusztai paper. He has no idea either!! He certainly rejected it hands down.
    Francis said…
    “Are you familiar with studies on the health effects of gmos that have rejected the null hypothesis…..do you know of studies that have found a health impairment from feeding gmo feeds?”
    As I said 9 of the papers in the list above certainly show differences, but whether that constitutes a health impairment from feeding gmo feeds is certainly not a straightforwards conclusion. If you want to find out which ones I suggest you get the abstracts from them all (free on the internet), read them to find which and then get the full papers of those you are interested in to see whether you think the findings represent a “health impairment” or just a difference thrown up by the experimental conditions. I’m certainly not going to do the cherry-picking for you to go away and become the next Jeffrey Smith 😉
    Jonathan
    PS no bacteria would be killed off by sub-quantification concentrations of antibiotics. These things have ultra short replication rates. Unlike humans they wouldn’t have time to set up protest groups to defend their rights against chronic poisoning by undetectable concentrations of chemicals produced by “Evil Big Pharma”.

48. Jonathon,
    I wouldn’t expect you to go through all those studies with significant effects to see if any indicate a health impairment. Actually, I was impressed that you even found the time to make such a long list. I don’t have the time either — and probably not the expertise.
    What surprises me is that there doesn’t seem to be a clearinghouse at FDA or somewhere that would have already done that in a public setting so that information would be readily available. Perhaps the doctrine of substantial equivalence deems that unnecessary.
    If this were merely an issue of the agronomic efficacy of the crops, it would not be so important. But here we are talking about health effects of foods that are being eaten ubiquitously.

49. I have one more question, if you are willing to indulge me.
    It has often been said that FDA does not have specific research requirements that must be met and submitted by companies that want to get a new trangenic crop approved, that the companies voluntarily submit their data. Do you know if that is correct, or does FDA have specific research data requirements that must be met for new transgenic crops to be considered for approval?

50. Francis, my understanding is that the FDA has no statutory authority to require these tests, but that all the GMO developers have voluntarily agreed to submit test results that FDA has asked for. Frankly, when anti-GMO propagandists present this as if it represents some sort of cover-up, I find it offensive.

51. “What surprises me is that there doesn’t seem to be a clearinghouse at FDA or somewhere that would have already done that in a public setting so that information would be readily available. Perhaps the doctrine of substantial equivalence deems that unnecessary.”
    I would expect that funding would be a more likely reason why the FDA hasn’t put together a big resource like that. It’s why we started the GENERA project, to try to make accurate summaries of the often paywall-restricted 300+ peer reviewed studies available. I can’t tell you how many times I’ve heard someone say there are little to no studies related to relative risks of GE foods, and when I plop a link to the big list on their blog they either ignore it, go away, or in one case, stopped blogging entirely. (Probably a coincidence but that did happen)
    Plopping a big list doesn’t solve the communication issue, however, as in this discussion above it will take quite some time to go through all of these papers, even just the abstracts, to gauge the content of the whole of the literature. And each time it is brought up, someone has to go through the list again. It would be much easier to have a careful read-summarize-review process that would be displayed online for everyone to see.
    Substantial equivalence is a regulatory term, and it not assumed for GE crops, as is often claimed. In order to be deemed ‘substantially equivalent’ the companies have to provide data about nutritional content, composition, etc. The reasoning is that if the GE crop does not differ significantly from the range of phenotypic changes that normal breeding can cause, that it would not pose much of a risk of unintended consequences and would not be need to be labeled as being different. The FDA guidelines on GE labeling actually say very specifically that GE crops must be labeled if they significantly differ nutritionally.

52. Yes, the FDA does not require these test results, but all of the GE companies have complied so far. We can debate whether or not such tests should be required, and maybe for traits that cause large changes in plant structure and/or composition they should be required as a rule.
    It has been suggested on this blog several times that the USDA and/or FDA could set up a public testing program that takes the actual testing out of the hands of the companies, which would make it more independent and transparent. It might also get rid of little differences there may be in the extent of the tests done by each company, although there is probably some general consistency between the tests conducted on each crop because in the consultation process the FDA makes specific suggestions. But I’d be willing to wager that even if a public system or facility was set up like that, that many anti-GE people and groups would just call it a sham controlled by the biotech companies. 🙁

53. My understanding of the publishing of Pusztai’s study is that there was significant debate about their unpublished findings. So the Lancet decided to publish it with a disclaimer saying that they published it so that people can see what the claims were, and decide for themselves.
    (Just confirmed it with this summary of the issue, but the links to the original source don’t work anymore: http://www.sirc.org/news/pusztai_published.html ) They also apparently wanted to avoid the implication that science was being suppressed.
    So while it is published in the Lancet, its status is not the same as if it went through the normal peer review process and was approved.

54. Another aspect of this is that a narrow focus on the FDA, or on the USDA, makes little sense – regulatory approval is not just required by the FDA or USDA for a crop to be marketable to farmers – you need to hit most, if not all, of the major export markets or your commercial release will be a flop – so the bigger picture needs to look at what the Japanese regulatory body requires (Japan is one of the biggest importers of grain globally – hardly surprising given their topography), what do the Australians demand? What does Europe ask for? It would be utterly possible for the US regulatory agencies to be utterly corrupt and to still be unable to release an even vaguely dangerous GMO commercially. (Not that I’m suggesting they are, just that the conspiracy would have to run deeper than US regulators)
    At present the regulators most feared (last time I talked to someone from regulatory) are the Japanese – they have apparently crazy requirements, but given the size of the market Japan represents the hoops will be jumped through with great vim and vigour.
    It’d be nice, imo, if there were a mandatory list that had to be checked, if only to ameliorate fears that there isn’t a mandatory list to be checked – perhaps even a mandate that if data requested isn’t fulfilled then a transgenic doesn’t make it through the process (I sort of get the feel this is how things are anyway – how exactly do we think the FDA would react if they asked for some data and were told point blank that no actually, we don’t want to do those tests, or share that data, so suck it? My money is on either rejection or prolonging of the process until the test is completed.

55. Substantial equivalence doesn’t mean quite what people think it means. I have a post on the subject here: https://biofortified.org/2010/10/substantial-equivalence/

56. You all seem to have a lot of confidence in biotech companies doing adequate research on the health effects of transgenic crops and volutarily submitting all their data to FDA, whether the data would be favorable for them or not.
    What is your reaction to the letter that was sent to EPA by 26 research scientists complaining that biotech companies were thwarting their research. Granted, the scientists were referring to research on the efficacy and environmental effects of transgenic crops, but one might suspect those same companies could have reason to want to limit exposure of research data on health effects too, especially since they generate those data inhouse and they have the option of voluntary submission of data.
    http://www.nytimes.com/2009/02/20/business/20crop.html?_r=1

57. Francis, are you aware that the companies have already made changes to those policies which have satisfied those 26 researchers?

58. No, please tell me about it — or point me to a reference.

59. http://www2.dupont.com/Biotechnology/en_US/intro/plant_biotech/CommercialResearch_StatementofPrinciples.pdf

60. So, we’ve talked about a lot of things in this thread and I just wanted to wrap things up a little to see if we’ve all made some conclusions.
    Here’s what I’ve concluded, anyone got anything different?
    There’s been a lot of testing on various genetically modified plants, by companies, by governments, and by academic scientists without connection to industry (and things in between). We can divide the studies into two categories: those that have proper controls and experimental design, and those that lack proper controls and experimental design and/or have really scary flaws like 10% of their control animals dying. Of the former category, some have shown differences between the genetically engineered plants and their genetically similar non-genetically engineered counterparts, but those differences seem to be rather minor. Overall the studies show that the process of genetic engineering does not cause harm, but it is important to evaluate each new event because we understand the biological mechanisms by which unwanted things can occur, such as mutations due to where the new gene integrates into the genome. Substantial equivalence is something that needs to be determined, it is not assumed.

61. I’m curious: why has Stanley Ewen not achieved the same notoriety that Arpad Pusztai has?

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