Link between GMOs and gluten allergies

http://www.flickr.com/photos/bike/3752517045/

So, my former work spouse asked me to write an article on gluten allergies, and I had read a few times that GMOs might cause gluten allergies, so I thought I'd give it a shot. I knew nothing about gluten, other than the fact that I hear more and more about gluten allergies and gluten-free diets (apparently, a third of the US population want to cut back or cut-out gluten from their diets). I relied on Wikipedia more than usual to learn about this (I know... Not always the best source of information...), but looked into a lot of papers as well. Here's a summary of what I've gathered:

According to Wikipedia, gluten is a protein composite (a mixture of glutenin and gliadin) found in wheat and other grains. It helps dough rise and gives it that delicious chewy texture. Are you imagining a freshly baked loaf of bread right now? Is there any scent in the world more apetizing than that of fresh bread?? I'm drooling a-la Homer Simpson right now. Anyway, gluten has been in our diet for over 10,000 years, so I have to assume that we've been digesting it successfully for that period of time.

Individuals who have autoimmune reactions to gluten have Celiac Disease, which is characterized by irritation in the small intestine, which over time, leads to the loss of the lining of the gut. Over time, you may lose the ability to absorb nutrients.  There are both environmental and genetic factors that play a role in susceptibility to the disease.

There are two additional categories to gluten allergies: allergies to wheat, and the newly labelled "gluten sensitivity". The former is a "standard allergy": skin reaction, wheezing, etc. The latter category are cases where there is neither an allergic nor autoimmune reaction. Individuals who experience "distress" when eating wheat and other grains, feel better when switching to a gluten free diet. Basically, these  individuals might have some of the symptoms of celiac disease (such as bloatedness or diarrhea) and feel better when they switch to gluten free. Their small intestine is usually normal. The issue is that it's difficult to diagnose, because there's no real immune response, and it's subject to a placebo effect. In addition, there's a whole slew of symptoms for "gluten sensitivity" (also known as "non-celiac gluten sensitivity"), including eczema, headaches, fatigue, depression, anemia, joint pain, etc. Additionally, there's evidence that patients with irritable bowel syndrome may also have gluten sensitivity.

Now we get to a huge point of contention: are gluten allergies on the rise?

The stats for celiac disease are all over the place. Two decades ago, it was considered to be extremely rare in the United States (1:10000). But more recent studies, with more accurate methods of detection, place the incidence rate as high as 1:33 or 1:57. So, it seems like the increase in incidence may have to do with our methods for diagnosis and definition of the disease (for example, in the first paper, the definition of celiac disease was a patient with diarrhea plus diabetes or short stature. In the latter paper, the definition included a category where the only symptom was abdominal pain). Additionally, and as mentioned above, "gluten sensitivity" is a category that has only recently been added to the medical lingo.

This review points out that our change in diet may also be cause of the increase in gluten-related disorders. The authors point out that the spread of the Mediterranean diet, increase in the amount of gluten used in the production of bread, mechanization of farming and overall increase use of wheat, may all be contributing to "gluten-related pathology". A paper published in 2010 identified that the variety of wheat we use today has more gluten than varieties that were cultivated over 100 years ago. So it sounds like traditional plant breeding may be to blame!

So, the conclusion I'm coming to is that our definition of gluten-allergy/sensitivity has broadened AND we've gotten better at diagnosis PLUS there seem to be changes in how much and the types of wheat we eat. However, there are a LOT of people jumping on gluten-free because it's the latest fad. Gluten sensitivity is very difficult to diagnose, and apparently, the best way to do it is through a "double-blind, placebo-controlled gluten challenge test", which is not easy to do, so it's possibly being over-diagnosed (and in many cases self-diagnosed). In a double-blind test, 68% of patients receiving gluten had clinical symptons, versus 40% of those receiving the placebo (the numbers for placebo effects in wikipedia suggest that 40% is on par with other studies).

So now we get to the key question for this blog: do GMOs have anything to do with the "increase in gluten allergies"?



Midichlorians from http://starwars.wikia.com/wiki/Midi-chlorian

The tubes are exploding with "evidence" on how GMOs are the cause for gluten allergies (there were too many links to provide here). However, a search in pubmed found 0 studies linking the two. Reading through a few of webpages, it's evident that it's another case of association, not causation (similar to how TV sales irradicated polio or my kid's growth has contributed to my shoe purchases). The theory that's currently proposed, is that Bt from corn and other GMOs (Bacillus thuringiensis, please see previous blogs for explanation on Bt) is leading to a "leaky gut". As outlined previously, we lack any receptors for Bt. There is greater evidence for midichlorians than there are for the "leaky gut". After all, George Lucas showed us the midichlorians in their full glory, and even produced a blood test for them.

But in my mind, the greatest evidence that GMOs are not tied to gluten allergies, is that GMO wheat is not yet on the market. It's in development and is being tested, but isn't available. You really can't argue with that. Wikipedia, Monsanto, and several other sites all say the same thing: GMO wheat is not commercialized.

An interesting side tidbit is that if the gluten-free trend continues, there may be financial reasons to produce low-gluten GMO wheat. According to gmoanswers.com (which is set up by a bunch of agro companies to answer questions on GMOs), there are two papers that have been published where they've managed to decrease the amount of gluten produced in wheat (one in 2010 and the second in 2011). Wouldn't it be funny if we had to turn to GMO to address an issue that may have arisen through traditional plant breeding? Hilarious!! OK, maybe only to the geeky people...

Next week's blog may be delayed. I'm switching jobs (no... I won't be working for agribusinesses... Actually, the FAQs about Biochica don't even need to change), so I have to wait to find out if I'll have journal access. Fingers crossed for a smooth job transition and awesome journal subscription services!!

GMOs and Reproductive Problems

This week, I resume the task of reviewing the health impact of GMOs, as outlined on the Institute for Responsible Technology's webpage. As a reminder, I have yet to find a single item that is a true health concern from their page, yet it remains one of the most highly cited anti-GMO pages. So, I must march-on!!

This week, I'm going to tackle the section entitled "GMOs, reproductive problems, and infant mortality". We'll go through these statement by statement.

• More than half the babies of mother rats fed GM soy died within three weeks. This statement is attached to three references. The first is from a talk or abstract at a conference, the second is from a news article in a Russian paper, and the third is a reference to preliminary (i.e unpublished) studies. As outlined in my explanation on types of references, none of these are vetted, peer reviewed sources of information. All three are from the same author, I.V Ermakova, so I decided to check pubmed to see her publications. There are 33 publications by the author and only one was about GMOs. The publication in question was a letter published in Nature Biotechnology (note that it was not a scientific paper). And then I started reading it... Holy GM controversies, Batman!! So here's the TMZ scoop: in 2007, Nature Biotechnology interviewed Dr Ermakova. She had reported that feeding Round-up Ready GM soy beans to rats leads to pups with low survival rates or stunted growth. The report had been widely circulated in the press, leading to calls for independent studies of GM crops. However, two years later (in 2007), Dr Ermakova's study had not been published (and based on my pubmed search, it still isn't published). So Nature Biotechnology (a very high impact journal) decided to do an interview with Dr Ermakova to ask for a detailed account of her work. And then they brought in experts to review the information that she provided, who proceeded to point out all the flaws including:
• The feed that she used didn't exist. Literally. The author claims that she purchased the soybeans from a company in the Netherlands, but that company had never sold the type of materials she used in her study.
• The study didn't meet the standard norms for number of animals
• The author claimed that over one-third of surviving pups born to mothers who were eating GM soy had stunted size and low birth weight. Additionally, she claimed that males have high levels of anxiety and aggression. As if that weren't bad enough, mice who were fed GM soy failed to breed to a second generation. No evidence or data was presented, and Dr Ermakova's description of issues/results do not match with previous reports in the literature which have looked at GM soy beans (last week's blog looked at multi-generational effects of GMOs, if you're interested).
• The author claimed that 50% of pups died by the end of the 3rd week when fed GM soy, versus 8% in the controls (they actually shared the numbers for mortality). The panel of experts point out that 99.5% of the control rats should survive for the strain being used; since only 92% are surviving, probably something wonky was going on and quite possibly, they just weren't taking good care of their mice. Additionally, no post-mortem examination was performed and no cause of death is given. They state that a 50% pup mortality rate defies credibility and such a strong lethal effect would have never escaped researchers or agricultural agencies (I completely agree!! 50% mortality rate???)
• The author claimed that 33% of the pups from rats fed GM soy had smaller sizes and lower weights than the controls. The critics point out that more than 90% of the control rats were more than 20% below normal weight, suggesting that they were malnourished or subject to poor environmental conditions.
• The author concludes that Round-up Ready Soy has a negative influence on the strain of rat used, as well as their offspring, causing high mortality, infertility, decreased weight gain, change in behaviour, and changes in internal organs. The critics conclude that no meaningful conclusions can be drawn because there were so many flaws in the study.
• One of the more intriguing sections of the interview was when Dr Ermakova was asked why she hadn't yet published her findings. She explained that she had presented her data at several conferences, where she had appealed to scientists to repeat her experiment, which drew the attention of a journalist, and things took off from there.  However, she explained that she was in the process of submitting her finding for publication. The critics rightly point out that if "she had questions about her own results, as she says she did, she should not have devoted so much time to publicizing what are demonstrably flawed studies". Ouch.
• You'd think that the saga would have ended there. But... no! Dr Ermakova wrote back to Nature Biotechnology to try to polish the turd. That letter is the one article by Dr Ermakova that I was able to find in pubmed on the topic of GMOs. Dr Ermakova basically blamed Nature Biotechnology for misrepresenting her work, for not giving her the chance to defend her responses prior to publishing, and questions why the journal would not publish her paper yet would publish such a long interview and she suggests that perhaps this is due to the "reluctance of the predominantly industry-funded agbiotech community to condone the publication of studies that detail negative effects of GMOs". The letter also includes corrections by Dr Ermakova (such as details on how the rats were raised, etc).
• The fact remains that 6 years later the study has not been published and has not been reproduced. That says more than a dozen interviews or letters ever could regarding the quality of the study.

There's no doubt that Dr Ermakova felt insulted by what she considered to be mistreatment by the journal. And I can't help but sympethize for her, because some of the comments made by the critics were personal. At one point, the critics actually point out that maybe all the mistakes made were because of the fact that Dr Ermakova didn't have proper training in performing a reproductive toxicological animal study. That's a pretty personal diss. But I don't think that the journal did anything wrong here: the study was making so much ruckus in the news that the editors probably felt compelled to step in to figure out what was going on; yet, at the same time, the study wasn't good enough to publish. So what other options could there have been?

Well, I was going to go through the rest of the reproductive risks, but I think I'll resume next week.

In summary, Dr Ermakova's findings which are plastered all over the interwebs have never been published, most likely due to the quality of the study. Since my legilimency skills are not strong enough to sneak into her mind and see what the study entailed, I must discard references to her "findings".

Long-term health impact of GMOs

From Occupy-Monsanto.com

One of the more common arguments against GMOs is the lack of data or studies performed. As was eloquently stated in this viral interview from the CBC, "we're the guinea pigs" in the GMO experiment, particularly when it comes to the long-term health impact of GMOs.

I've actually been really surprised at the number of papers there are in pubmed when I've look up references and sources. The GENERA project looks at peer-reviewed studies to assess the risk of GMOs and  their database has 600 papers, 1/3 of which are independently funded. A quick pubmed search revealed that there are over 130 papers on MON810 (that's Monsanto's Bt corn); of course, not all of them were about health: a large number of papers were environmental studies, looking at the impact to soil, bugs, etc, and a fair number were methods papers describing ways to identify the GMO based on DNA or protein.

In trying to learn about the long-term health impact of GMOs, I didn't know where to start, so I decided to read a 2012 literature review that examined long-term and multigenerational impact of GMOs to health. If you have access to the paper, I suggest you take a look. The review has a helpful table, where each study is listed together with the source of funding, # of animals in the study, parameters that were examined, conclusions, and criticisms, among many other things. The long term studies, defined as any study greater than 96 days, ranged from 26 weeks to 104 weeks, used various model organisms (including cows) and the authors examined 12 of them. Some studies did not meet international standards (ironically, two of these were reviewed last week where I stated that they were indeed horrible papers). The most common criticism for several of these studies is that they didn't use isogenic lines as controls. An isogenic plant is the genetic equivalent to the GM variety, but without the GM trait. Why is this important? Well, take the corn that popcorn kernels are derived from vs the sweet delicious corn that you eat with butter in the middle of summer. As learned in my "Plants as Human Resources" course in my sophomore year, the two have different amounts of starch and sugar. So if you were to make a GM-variety out of the sweet corn, but use popcorn as your control, then the study will not be accurate. You won't know if your results are a consequence of the GM trait or if it's because of nutritional differences.

Anyway, getting back to the review: papers that met International Standards generally concluded that feeding GMOs to animals was safe and there were no long term effects. After looking at all the long-term studies, the authors conclude "the available long-term studies do not yield new safety concerns and confirm that the studied GM varieties ... are nutritionally equivalent to their non-GM conventional counterparts)."

Moving on to the multigenerational studies, these also used a variety of different model organisms, and the authors again looked at 12 papers. These ranged from 2 to 10 generations, and goal of all the papers was to determine if feeding GM plants to one generation would have an effect on the next. Several papers suffered from the same issues regarding controls. Two papers observed unexplained differences (one saw a difference in lactic dehydrogenase enzyme activity, which may affect metabolism; a second found changes in the immune system). The review concludes "overall, the multigenerational studies on animals fed GM plants do not reveal signs of toxicity or other macroscopic effects on health ... The relevance of the observed differences in some of the parameters is not known and may reflect some natural variations. The authors suggest that additional multigenerational studies should be done in order to study the reproducibility of these results and to try to find the true causes of the detected changes." The authors go on to repeat that several studies had serious flaws so "the data cannot be interpreted in terms of toxicological effects".

The authors' discussion had a few interesting points:

• They point out that there are norms and standards for feeding studies, and that all these studies (which were publicly funded for the most part) just have to stick to the rules in order to be successful.
• They point out that long term studies didn't discover anything new. They suggest that long term studies should be carried out only if there's something odd or alarming in standard 90 days feeding studies (I'm not sure I agree with this, but it's an interesting argument. I think that studies longer than 90 days add value to the debate regarding GMOs and should be conducted at this point in time).
• The authors point out that their critical examination found that studies where changes in some parameter were identified did not follow the required standard protocols.
• That due to "recurrent lack of compliance with international standards of many studies", the private sector is now unwilling to provide plant material for studies (it's no wonder after scenarios like the whole Seralini publication disaster). They highlight that without some level of cooperation, scientists may never be able to get the appropriate controls for their studies.
• The authors suggest that protocols and methods should be harmonized and standardized. They highlight that no two studies in their review were conducted the same way. Each study used a different organism, different duration for the study, different parameters, etc. Having a standard experimental design would help control for variability. I couldn't agree more.

As a side note, I think we can all agree that scientists need to quit making either a) making stupid mistakes or b) being misleading. There's no other explanation as to why you would perform a study that doesn't meet International Standards. And on top of that, journals should stop publishing crummy papers.

But let's get back to the crux of the matter. The review highlights the fact that, other than the poorly designed studies, no paper has found significant differences between GM and non-GM. So... when is the evidence sufficient enough to be conclusive? How long does a study have to be or how many generations need to be examined? That's a great question. There seem to be quite a few papers published where no difference was found between GM and non-GM food. In fact, if I were running my own lab, I'd be pretty unwilling to perform another study because a) animal studies are expensive, particularly large mammals and b) odds are, I wouldn't find anything and the absence of interesting data generally does not lead to high impact/sexy publications. So given the fact that getting grant money is pretty difficult and using private sector funding would label my study as being biased, what options are there? I think collaboration between public and private sectors may be needed, and perhaps oversight is required to ensure that studies remain impartial.

In investigating this topic, I think that the statement "long-term studies have not been performed" or "we're the guinea-pigs for the GMO industry" are false and misleading. However, I do think that norms and standards need to be universally adopted for these studies, and once a well-designed experiment is performed, it's findings need to be accepted. For example, there is a study that examined the impact on milk when feeding Bt corn to cows for 100 weeks. According to this review (note: I haven't read the paper myself), there are no criticisms of the study and it concludes that there are no differences in milk yield and composition when feeding Bt corn to cows. So, do we need another study? Or is it time to start to break out the celebratory chocolate milkshakes made with milk derived from Bt-corn-fed cows? Given the number of 90 day studies that exist examining Bt-corn and the testing standards adopted by the biotech industry, I vote for the latter.