The Case for Evolution - Octopuses, Grandmothers, Iceland, and Poor Dr. T. Colin Campbell

It has been a while since I reviewed my basic premise, that homo sapiens walk around in bodies and brains exceptionally well suited for hunting and gathering in small family groups in the wilderness, and that we are not evolved for agriculture as a whole, and industrial agriculture in particular. I subscribe to the concept of Evolutionary Medicine, that diseases of civilization (I'm focused on mental health in my blog) are caused by differences between our current lives and our evolutionary suitability, and that replicating a hunter-gatherer life in many ways (as makes scientific and practical sense) can lead to better health, both physical and mental.

Here's what T. Colin Campbell, PhD and full professor (of nutritional biochemistry) at Cornell has to say about that (1): "Those who follow evolutionary history and who support the inclusion of substantial amounts of animal protein as a recommended dietary practice, make this error. Our dietary evolutionary history, while interesting, absolutely does not yield critical clues for optimal nutritional practices. Human evolution required that our ancestors make dietary choices that maximized gene proliferation."

To which I say - maximized gene proliferation means living past 30 and well into old age. Humans have grandmothers. Women are designed to live 20-30 years past menopause in order to favor a higher overall birthrate as grandmothers helped gather for their offspring's offspring and taught valuable cultural information (Textbook of Evolutionary Psychiatry: The origins of psychopathology). How could tens of thousands of generations not have selected for relative longevity and freedom from disease (both mental and physical) based on our evolutionary diets? For me it honestly makes no sense to view health data from another perspective. Bizarrely, Campbell goes on to write of how chimpanzees eat a plant-based diet (we split off from chimpanzees 5 million years ago) so the preponderance of evolution data must lean towards a plant-based (low protein) diet. So evolution (of an entirely different species) is important when it explains his theories, but not so when it doesn't.

If you watched the television series "Life," you might have seen the segment about the octopus that reproduces once then dies, leaving a zillion offspring who feast on mom's dead body, and hopefully a few make it to go on. I am not an octopus! Humans are rather on the extreme "k" side of the r versus k selection species. We have few, quality offspring and spend a lot of energy nursing them to reproductive age and beyond. Our genes want us to live for a very long time, to teach our toddling young and their toddling young how to make it in this big, bad world. What plants to eat, how to chase down a large land mammal, how to set fishing traps, where the best water holes are, how to select the "Children and Family ages 2-4 movies" on netflix and how to get the kangaroo through the alphabet maze on starfall.com (seriously, I never get to use my own computer anymore) - all of this is knowledge we are not born with, and is most efficiently learned from our elders. Though my youngest figured out how to post on facebook all on her own at 12 months. Darned intuitive apple iPhone technology!

(An aside - I definitely recommend Evolution's Captain: The Story of the Kidnapping That Led to Charles Darwin's Voyage Aboard the Beagle if you are a student of evolution. Darwin was selected to go on the voyage as a gentleman companion to the young Captain Fitzroy, who had a family and personal history of depressive mental illness, in order to offer him company and hopefully to forestall any depression on the long voyage returning some kidnapped Tierra del Fuegans back to the southernmost part of South America (no, I am not making this up). Sadly, Fitzroy, who ended up being the second governor of New Zealand and was also a devout Christian, eventually killed himself a few years after watching a debate on evolution between the Archbishop of Canterbury, Thomas Huxley, and Samuel Wilberforce.)

But what about those genetic diseases that occur after reproducing? Diseases such as Huntington's Chorea? Clearly those genes survived and are genetic, not dietary, so that evolutionary (dietary) paradigm doesn't support links to those aspects of ultimate human health. Cardiovascular disease and those other diseases of civilization (let's leave out acne and many autoimmune diseases which strike young) get us when we are old and no longer contributing to the gene pool (tell that to my 9th grade band director who died in his late 40s of an MI). Okay, decent argument, but that brings me to Iceland.

Way back in the infancy of my blog, a commenter from Iceland left me two links to some very interesting information. Turns out there is an autosomal dominant genetic disease in Iceland called Hereditary Cystatin C Amyloid Angiopathy. It is caused by a mutant protein that is deposited in the walls of small arteries, leading to brain hemorrhage and death in young adults (average age of 30). Since this is Iceland, and everyone knows everybody, the family trees of everyone with the disease were deciphered and studied. Turns out the deadly hereditary cystatin C mutation occurred in Iceland sometime around 1550, and carriers of the gene lived normal lifespans until 1830, when over the next 70 years the lifespan of those afflicted decreased from 65 to 30. "This change in life-span is an indication of a strong environmental effect on the penetrance of the mutation. The effect must have been very common as it happened in [almost] all families simultaneously in all parts of the country." In the time from 1830 to 1900, Iceland changed from a traditional cow and milk based diets to a more "Western" diet similar to Europeans. In one remote region of Iceland, the lifespan shortening occurred 20 years later than in the other related family groups - that was one of the later regions to adopt the Western diet. So here we have an example of how an autosomal dominant genetic disease seems to be affected by diet.

Which brings me back to Huntington's Chorea. In my last post, I mentioned a study that showed that carriers of the mutant huntingtin gene (an autosomal dominant gene with complete penetrance, meaning everyone with the gene gets a progressive, deadly neurological illness with no cure but steady and inevitable degeneration leading to death over 20 years that begins between the ages of 20 and 44, thereabouts) had a much higher rate of positive test for anti-gliadin (wheat protein) antibodies than the general population. The huntingtin gene probably codes for a type of microtubule or vesicle protein, basically structural proteins that anchor the mitochondria in nerve cells. The mutant, deadly gene has extra trinucleotide repeats of CAG, coding for an unstable version of the huntingtin protein. A normal gene will have less than 20 CAGs in a row. A mutant gene 36 or more. The more trinucleotide repeats, the earlier the disease seems to strike. What does this have to do with wheat?

Here's the really weird part. That CAG DNA code repeat I was talking about? CAG is the genetic code for the amino acid glutamine. The mutant extra repeats is called a "polyglutamine repeat", and there are a number of genetic diseases that are also caused by this polyglutamine repeat. Turns out that polyglutamine tracts are also present in gliadin - the wheat protein. A possible explanation is that the body recognized the abnormal polyglutamine tracts made in the cells with the abnormal gene, and the wheat proteins looked a lot like the abnormal protein so that the people with Huntington's mounted an immune response to the wheat proteins. But wheat protein exposure has also been associated with non-Huntington's ataxias. Could wheat gliadin polyglutamine exposure itself and an abnormal autoimmune response lead to the protein aggregation in Huntington's disease? In other words, does our ubiquitous exposure to dietary wheat protein modify the natural history of Huntington's disease? Somewhat like Western dietary exposure seems to modify the natural history of Hereditary Cystatin C Amyloid Angiopathy?

No one knows.

But an evolutionary perspective would lead one to pursue those questions.

For decades, the U.S. government has been freewheeling with sugar and heart disease, repeating the fact that there was no data to suggest sugar had anything to do with it. Well, here's an abstract from a study in JAMA in April of 2010, showing a strong correlation between dietary sweetener consumption and a bad cholesterol profile (low HDL and high triglycerides). The money quote from the abstract? "No known studies have examined the association between the consumption of added sugars and lipid measures."

That's right. No one bothered to publish a study on sugar and blood lipid profiles until 2010.

The jury on wheat is still out. In the mean time, I'll fall back to the safe evolutionary medicine position, and avoid it.

Woe is Wheat

(Shirt available at Cafe Press)

I don't eat wheat as a general rule, and the reasons I don't are circumstantial, to be sure.  The most compelling reasons to me are all those healthy non-wheat eating cultures.  Read enough of Food and Western Disease: Health and nutrition from an evolutionary perspective, or The Primal Blueprint: Reprogram your genes for effortless weight loss, vibrant health, and boundless energy, or Dangerous Grains: Why Gluten Cereal Grains May Be Hazardous To Your Health, and wheat just doesn't seem tasty anymore.  If it ever did.  Well, maybe in a pizza.

However, the beautiful Ms. Minger has used the (admittedly fairly useless) China Study data to make the smokey fire around wheat flare up again.  The handsome Dr. Guyenet has a reasonable overview at his site.  (Hmmm... there seems to be a strong correlation between non-wheat eating blogging and good health and good looks.)

And, very recently, Dr. Rodney Ford published a paper where he makes an argument that there should be a medical condition labeled "The Gluten Syndrome,"  and that everyone with many common neurological and psychiatric conditions (such as ataxia, hypotonia, developmental delay, migraine, depression, anxiety, etc.) be tested for gluten sensitivity via the IgG anti-gliadin antibody.  His reasoning being that IgG antigliadin positive people can have negative intestinal biopsies (if they have latent disease or patchy involvement of the intestine), and they can also have negative IgA tTG testing (another pretty specific celiac antibody test) and still have improvement in symptoms on a gluten free diet.

While looking into the matter, I stumbled upon a very good paper called Neurological complications of coeliac disease: what is the evidence?  If you have institutional access, I highly recommend checking this one out.  It has some nice suggestions for teasing out biases and inaccuracies in research papers, and it has a good review of the pathophysiology of celiac disease.   Neurologists are one of my favorite species of doctor, as they tend to be brilliant and cranky*, and these authors point out very fairly that the evidence linking gluten exposure to ataxias, certain types of epilepsy, and peripheral neuropathy is often poor and contradictory.  Bless their clinical hearts, though, they end up recommending a trial of gluten-free diet for anyone who's game, educated about the type of data there is, and who has a positive celiac biopsy or positive celiac or gliadin antibody testing for those with certain neurologic conditions, recognizing that the harm of a gluten-free diet is minimal, and there are some case reports where going gluten-free improved ataxias, peripheral neuropathy, and seizures.


I have the same take with schizophrenia - the indirect evidence is damning, the direct not as much, but enough case studies and small studies to suggest that at least some (especially new onset) schizophrenics could really benefit from a gluten-free diet.  And seeing as how we are dealing with a progressive, devastating brain illness with no cure, it seems fair to give patients and families the option and explaining the data.  For most it won't make a difference, but for a few... I wouldn't hold off medication for a new onset psychosis to try a gluten-free diet, though. 

I'm not sure about testing everyone with depression and anxiety (or schizophrenia) for IgG or IgA ani-gliadin, or even IgA tTG.  I'd probably just recommend the gluten-free diet trial idea to anyone interested.  Mostly it's the schizophrenia data that puts me in this mindset.  All sorts of anti-wheat antibodies were found in the serum and urine of schizophrenics, after all, but most of them were entirely different than the celiac antibodies.  Until we know more about what to test for, I think you risk giving someone with a negative test a false sense of security about gluten.

No classical music link this week.  Nope.  It's a holiday weekend and there's a hurricane coming, and that calls for something a little more modern.

I'll still be blogging over the weekend, though.  Did you know that in a study of 52 patients with Huntington's disease (invariably fatal genetic autosomal dominant ataxia condition), 44% had a positive IgA or IgG (or both) anti-gliadin antibodies?  The general population is about 4.8% positive.  Wild, huh?  (No, don't jump on that and say OMG WHEAT causes HUNTINGTON's because that might not be what it means at all.  But still, pretty wild). This means a post on evolution, Iceland, genetics, anthropology, and even a mention of poor Dr. T. Colin Campbell. In the mean time, keep eating meat, fish, veggies, and a bit of fruit and nuts.

*Neurologists are almost always right handed.  The field of psychiatry has more left handers (I have no source for this and it may be an urban medical myth).  There was a Nova episode last year about Oliver Sachs (famous neurologist) and music.  In it he admitted to preferring Bach to Beethoven.  I think that is the very definition of a neurologist.

Wheat and Schizophrenia

I'm in the middle of an introduction to vegetable oils post, but in the midst of tweaking that one, my youngest woke up from her nap, and I moved to the family room to observe her toddling about while I glanced at this seriously interesting paper, Genetic Hypothesis of Idiopathic Schizophrenia: It's Exorphin Connection. Free full text! Click the gray box on the upper right.

Schizophrenia is an unfortunate brain disease. Inherited often, progressive, presents usually with social withdrawal, paranoia, hearing voices, that sort of thing. After a while you get a kind of "burnout" effect where the voices and whatnot lessen, but the afflicted is left with all the negative symptoms of social withdrawal, thought blocking, and an inexpressiveness known as "flat affect." MRI of the brain will show "large ventricles" at this point, meaning cell death (brain damage) has caused the active, lively part of the brain to shrink. Dementia, basically. You'll see schizophrenia in any large public park in any major city. Go ask the guy on the bench with holey shoes if he wants a sandwich, and see what he says. If it's paranoid meaningless word salad, that's schizophrenia, most likely. He had parents, brothers, sisters, maybe even a college degree. There aren't enough group homes, even if he were willing to stay.

Anyway, most of the research is focused on dopamine and genetic polymorphisms of the receptor (yawn), some on acetylcholine, histamine, serotonin. The usual questions about ineffective brain chemistry. The usual treatment is neuroleptic medication (hopefully decreases excess dopamine in the right place and leaves it well enough alone in other corners of the brain). Read a popular press book called "The Food-Mood Connection" which sounds like my sort of book, really, until the the author (who has a PhD of some sort!) explained that schizophrenia in a certain case was caused by childhood teasing. Poor man was treated with horrible prescription medicine and his genetics were examined, but I suppose some serious teasing psychoanalysis would have cured that schizophrenia eventually...it must have been his mother, come to think of it.

Anyway, there's a funny thing about schizophrenia, turns out that quite a few of the adult schizophrenics on Handford's inpatient unit in 1967 happened to have a major history of celiac disease (gluten/wheat intolerance) as children. As in 50-100 times the amount of celiac disease that one would expect by chance. Celiac doctors also noticed their patients were schizophrenic about 10X as often as the general population. That's a lot!

Allow me to paraphrase and expand on Table 1 of this paper, "Major Evidence that Peptides from Grain Glutens Evoke Idiopathic Schizophrenia in Those with Its Genotype"

1) In the 1960s, many observations suggested celiac disease and schizophrenia shared some genes. The role of gluten in schizophrenia was examined.
2) Epidemiologic studies showed a strong, dose-dependent relationship between grain intake and schizophrenia (Pacific islanders who ate no wheat had extremely rare occurence of schizophrenia - 2 in 65,000 rather than about 1 in 100 as we have in the grain-eating West. Then the same islanders changed their diet and began eating wheat - and schizophrenia became common).
3) Clinical trials and showed that gluten made new-onset acutely ill schizophrenics worse. Only occasional long-term patients responded to gluten restriction (remember, the affected brain cells of the long-term schizophrenics are already dead, so getting rid of the possible poison that killed the cells won't make much difference).
4) NIH investigators looked for poisonous protein fragments derived from gluten, gliadin, and casein. They found them - potent opiate (yes, opiate as in morphine. Or heroin) analogs they called "exorphins." They did these studies in rats, and I've read several of them. Very creepy. Turns out, you take wheat gluten, add stomach enzymes, and you end up with fragments of proteins that are potent opiates (1). The cute thing is these fragments aren't digested by the small intestine and definitely end up in the body and brain of rats that are fed gluten orally. Inject these same proteins directly into the brains of poor unfortunate rats, and you get rat seizures.
5) People with schizophrenia have a lot of these opioid-like small gluten-derived peptides in their urine. Way more than people without schizophrenia.


Let me review what is perhaps the most important part of the paper - a gluten-free diet definitely improved some of the new-onset schizophrenics on the inpatient unit. Not all of them. But 2 out of 17 or so. Putting back the wheat made the affected a lot worse. 115 patients on a locked ward were all given a gluten free milk free diet (remember the casein issue). They were released into the community (got better?) on average twice as fast as the similar patients on another, diet as usual ward (p=.009). It is of note that repeat studies didn't show the same thing, but instead of 17 or 115 patients, these studies had 4 or 8 patients, and they used chronic schizophrenics (end stage, when the brain cells are already gone).

Historically, prior to WWII, when grain consumption was super-high and neuroleptics (those medications, as you recall, which affect brain dopamine levels and are used to treat schizophrenia) did not yet exist, there are reports of schizophrenics having marked, unexplained fluctuations in weight and gut symptoms, poor iron absorption just like celiac sufferers, and "post-mortem abnormalities like those subsequently discovered in celiac patients." Why aren't these found now? Well, it turns out that a side effect of neuroleptics is that they decrease the permeability of the gut. Meaning gluten may not be able to weasel through quite so easily.

Which begs the question, is that the side effect? Or perhaps the principle effect?
Who knows?

Not psychiatrists in 2010. The paper (from 1988) finishes by suggesting a number of methods to investigate this connection further. One of the suggestions was morally bankrupt (feed the identical twins of schizophrenics a high gluten diet to see what happens!), but intriguing. That study wasn't done (fortunately). Nor, looking at pubmed (via eCommons), were any others (that I could find. I'm not the wiliest research paper discoverer so I might have missed one). The article is mentioned in a few review articles, and schizophrenics were left to eat wheat in peace.

Edit: I shouldn't be such a cynic, and I should search harder before I post - Here are more recent studies, including one from last month (Thanks to the commenter for the link - why I love blogging. Interactive! Editable! We can all stand on eachother's shoulders and the shoulders of past giants). All told, they throw out some more "biochemical smoke" about the link between schizophrenia and gluten:

Markers of Gluten Sensitivity and Celiac Disease in Recent-Onset Psychosis and Multi-Episode Schizophrenia: Conclusions - Individuals with recent-onset psychosis and with multi-episode schizophrenia who have increased antibodies to gliadin may share some immunologic features of celiac disease, but their immune response to gliadin differs from that of celiac disease.

Novel immune response to gluten in individuals with schizophrenia: The researchers here looked at all sorts of different anti-gliadin antibodies and celiac disease associated biomarkers (meaning some different antibodies and also specific celiac MHC genes - basically genetic predispositions to have autoimmune response to wheat). They also did some fancy chromatography to find if the schizophrenic's blood reacted to other wheat proteins, and then it sounds like they used "peptide mass mapping" to figure out what the wheat proteins were that the schizophrenics were reacting to - and the results were... schizophrenics of the wheat-reactive subtype had lots of anti-wheat protein immune response, and a lot of them were completely different than those found in celiac disease.

A Case Report of the Resolution of Schizophrenic Symptoms on a Ketogenic Diet That link is to the full text. It doesn't need much translating to make it more understandable - the title says it all.

This article from 2006 is also cited often, and I did look at it before I posted the first time, but it doesn't add that much: The gluten connection: the association between schizophrenia and celiac disease. Basically it says there are case reviews in the literature that show dramatic improvements in schizophrenia on a gluten-free diet (these studies were the same ones commented on in the original paper that I reviewed in detail at the top of the post) and that only a subset of schizophrenics are affected. (The researchers in residency would always refer to them as "the schizophrenias" rather than "schizophrenia." It is several different diseases, lumped into a similar symptom cluster because we don't fully understand the pathology, and in psychiatry, lumping is done by symptoms, as that made the most sense for research purposes.)

I would love to take a look at this one, but my institutional access won't get me there for the moment - A PILOT STUDY OF THE KETOGENIC DIET IN SCHIZOPHRENIA
PACHECO et al. Am J Psychiatry.1965; 121: 1110-1111. We'll track it down eventually.


The bottom line? Schizophrenia is a progressive and destructive psychotic mental illness that, at the moment, can sometimes be managed with medications and community therapeutic support, but does not have a cure. Some people with schizophrenia are bound to have the gluten-sensitive variety, and a few lucky souls apparently have been cured among the case reports. A gluten-free diet is safe and doesn't have side effects - I don't see a good argument against giving it a try for anyone with schizophrenia who is willing to give it a go, at least for a few months (how long? 3? 5? I'll look more into that one), while more data is being gathered. (You *might* get even better results with stabilizing your GABA receptors and whatnot via a ketogenic (very low carbohydrate) diet. More on this later! Very little research in psychiatry...) The worst thing that happens is you find you are not one of the gluten-sensitive schizophrenics, and you've gone without bread for a little while. The best thing that happens is that your symptoms get better, possibly quite a lot better.