Sunday, January 27, 2008

Wheat and lactose and Cordain

In the comments thread of another post "g" pointed me to this ref. It's very interesting about WGA (Wheat Germ Agglutinin) hitting the nuclear pore, so stopping all sorts of cell signaling traffic. But this business about lactase is very dubious.

From here on down the inverted coma bits are direct quotes from Cordain, the other bits are me. EGF-R is epidermal growth factor receptor, a cell signaling and growth regulating receptor.

"Once in gut cells (enterocytes) WGA gains access to the circulation via the lymph and is not removed from circulation by the liver or by gamma globulins. Hence, within an hour of consumption WGA is found in plasma in physiological meaningful concentrations (as high as 5ug/ml). Because EGF-R are found on virtually all cells in the body, WGA now can enter the cellular compartment of all cells in the body. Once within cells, WGA wreaks more havoc by binding a structure called the nuclear pore and thereby impedes or prevents the cytosolic transport of the vitamin D receptor and its ligand (1,25 hydroxyvitamin D3) to the nucleus which results in impaired vitamin D utilization and systemically will result in rickets if high dietary levels of whole wheat are chronically consumed."

This is very interesting, it looks like Cordain follows Pusztai's line of thinking on systemic absorption of WGA and is citing a new toxicity. This time via the vitamin D receptor and rickets. Nice.

However Cordain always seems to blot his copybook. Let's try and make head or tail of the next paragraph. It goes like this:

"Lactase is an enzyme technically known as lactase phorizin hydrolase or LPH. LPH [lactase] is a carbohydrate enzyme (glycosidase) belonging to the beta galactosidase family and it catalyzes the sugar beta-galactosidase in addition to catalyzing lactose, the sugar in milk."

What does this mean? Beta-galactosidase is not a sugar, it's the enzyme family to which lactase belongs, as Cordain has just told us. So this has to be a typo, which leaves us in the dark as to exactly what Cordain intended to say. Was it beta galactosamine he was talking about, as in the next sentence? Is he suggesting that lactase either breaks down or synthesises beta galactosamine?

"Beta galactosamine is a key structural sugar in the EGF-R."

I'll take that on trust.

"Hence the adult retention of LPH [lactase] was strongly selected in Neolithic N. European populations because it could compete with WGA for the EGF-R and thereby, in effect, displace WGA from the EGF-R."

Now what does this mean? Is he saying lactase binds directly to the EGF-R on the gut to stop the ingress of WGA in to enterocytes and thus in to the lymphatics and systemic circulation?

"WGA preferentially binds the sugar n-acetylglucosamine which is also present in the EGF-R."

This is true (taking on trust that n-acetylglucosamine is present on EGF-R).

"Consequently, the evolutionary selection for LPH [lactase] occurred as direct competition for the EGF-R rather than LPH binding WGA directly."

The implication from this is that lactase is binding to beta galactosamine on EGF-R of enterocytes and this binding is stopping WGA from binding to the n-acetylglucosamine of same EGF-R molecule. Cordain doesn't mention the gut cell surface as the site of interaction but never suggests that lactase ever reaches significant concentrations in the systemic circulation, so let's stick with gut. He finishes:

"In summary then, the simulataneous selection for LPH [lactase] and dermal de-pigmentation were two changes in the genome of Northern Europeans that were a direct evolutionary response to increased consumption of whole wheat"

I can buy the need for pale skin on a Vitamin D deficient diet in Northern climates. Grains are the pits for deficiency diseases. The nuclear pore blockade should actually predict that WGA consuming people need a higher absolute level of vitamin D for health. I wonder if this is true?

But I don't buy the lactase part.

Lactase is part of a family of enzymes for cleaving terminal sugar moieties. Why should it just sit on the EGF-R to keep WGA off? I can believe it might visit EGF-R briefly to chop up the beta galactosamine (but why?) whenever it's not actively chopping up lactose, but would it sit there attached to beta galactosamine (without cleaving it?) when it should really be getting on with its next lactose cleavage job? Also, would a mammal put in to its infant food a sugar which induces lactase production if that lactase was then going to slip away and sit on the glycation moiety of one of its growth factor receptors? EGF-R is there for cell signaling and the beta galactosamine is a "key structural sugar", not decoration. Maybe it actually needs its beta galactosamine component to work.

On the other hand wheat is looking for a free ride for its seeds. WGA is its lectin, which uses n-acetylglucosamine moieties on cell surfaces specifically to become endocytosed. Once inside the cell all WGA needs to do is produce as much damage as possible, so disrupting digestion, which will maximise the chances of any still undamaged wheat seeds being passed through the gut in tact. Then these can seed the next piece of clear ground which the herbivore poops on.

I notice the email comment is dated Feb 2006. It's now late Jan 2008 and the publication has not hit Pubmed yet. Maybe that one final experiment didn't work?

What's wrong with WGA damaging everyone, full stop? And that lactase persistence is rapidly selected for in people who keep cows for milk, otherwise they get gut rot? Do the Maasai loose lactase when weaned from their mothers because they don't eat wheat? They would no more eat wheat than Cordain would live on sour cow's milk, bulked up when necessary with fresh cow's blood!



PS I'm surprised Cordain didn't suggest a statin to raise vitamin D levels!


melaniejovet said...

"Once within cells, WGA wreaks more havoc by binding a structure called the nuclear pore"

A nuclear pore is simply a hole, isn't it? How does a molecule manage to bind to a hole???

Peter said...

Hi melanijovet,

Nuclear pore is my next reading subject, but I'm assuming it's a route in and out of the nucleus for signaling molecules. If it has n-acetylglucosamine residues on or around its structure I can see that WGA could attach and act as a plug. Probably much more complex that that but it's my working theory until I get to read more...


melaniejovet said...

I was being facetious! A nuclear pore is a hole, an absence of anything. Nothing can bind to a hole!
ps about time you learnt how to spell your wife's name...

Peter said...

Ooooooops HKC xxx


You don't think too much of Cordain then?

Stephan Guyenet said...

The nuclear pore is a huge protein complex consisting of many subunits that regulates the traffic of medium-to-large proteins and RNA in and out of the nucleus. It sits in the nuclear membrane and it's so large you can see it on an electron micrograph.

I know you were just joking about binding a hole, but the nuclear "pore" really isn't a hole at all, it's more like a transportation dock that is very selective about what it lets across.

Peter, since you're interested, traffic across the pore is regulated by "importins" and "exportins" that bind the pore structure. They also bind specific motifs on proteins called "nuclear localization signals" and "nuclear export signals".

Peter said...

Hi sasquatch,

Thank you for that. I take it there are potentially a multitude of sites where a lectin could find a sugar moiety to attach to, so placing a 36 kDa spanner in the works. Apparently sialic acid would do as well as n-acetylglucosamine...


Stephan Guyenet said...

Oh, I also wanted to point out that I think the vitamin D receptor is a nuclear protein. It seems to be retained in the nucleus, so it only needs to be transported across the nuclear membrane once. So the interference with nuclear transport at the pore would have to be truly severe to prevent it from entering the nucleus, at which point the cell would probably die for other reasons.

Unless the interference were really specific for the VDR.

Vitamin D is a steroid, and steroids (like testosterone) pass freely across membranes. I think the VDR is similar to the androgen receptor, which hangs out in the nucleus until it's bound by androgen, at which point it binds DNA and causes transcriptional changes. So I don't think the VDR has to actively transport vitamin D into the nucleus.

Peter said...

Doesn't leave much to Cordain's publication. No wonder it's not out yet!


JohnN said...

Sciam has a piece about copycat scientific articles that reminds me of Cordain's publication.
He expressed puzzlement when milk (full fat low fat or otherwise) didn't behave as predicted per the glycemic index.
Most laughable are those papers discussing the saturated fat content in paleolithic diet.

Peter said...

From Cordain's Dec 2006 newsletter:

Perhaps a better strategy would be to stop drinking betacellulin containing cow’s milk which may over stimulate EGF receptor signaling in the first place. Although observational epidemiological studies cannot show cause and effect between diet and disease, they suggest that milk drinking and dairy consumption is linked to a variety of cancers including:

ovarian (16-19), breast (20-26), colon (20, 27-29), lung (20, 30-32), stomach (20, 33), pancreatic (34-36), and prostate (37-40).

Obviously these cancers are rife in the Maasai. Oh, they're not? Back to the drawing board.


Anonymous said...

I'm so tired of Cordain's allusions to epidemiological studies to prove his bias against dairy. There are a million factors in the modern diets that could explain these cancers as for instance the consumption of low fat meat, reduced-fat dairy, sugars and non-sprouted grains, high-PUFA, non-fermented dairy, egg whites and other artificial foods, etc. I will give him this much - I think cheese and butter (or ghee) would probably be better than fresh milk or cream. Pure sour cream and yogurt are also better than fresh dairy, IMO.

Peter said...

Yes, fresh milk is unusual. Refrigeration is about 100 years old. Before that all milk was either straight from the cow or soured in some way. As to low fat and UHT and homogenised and....... bleuh!


Anonymous said...

Also, Walter Voegtlin points out in his book "The Stone Age Diet" that only people living on farms had the option of consuming fresh milk all the time. For city-dwellers, all or most of the milk they had would've been fermented or processed to make butter, cheese, yogurt, etc.

MiguelC said...

Hi peter.

I'm an Exercise Physiologist from Spain, obtaining a PhD in Nutritional Biochemistry.

I do not agree with some of your ideas. Nevertheless, I love your blog and your ideas and comments, because it is normal and healthy to disagree. What I don't like is the fact that sometimes (and please don't take me wrong) you and some people on this blog attack others, simply because they have different and questionable ideas and that is something I'm really not used to in Spain, where I have numerous friends and colleagues who have different views and ideas, but we don't attack each other because of it. Instead we discuss it in order to progress.

I know Cordain for some time and have to tell you that he's the nicest guy I've met and always gives polite answers to people and provides references and full papers so they can look up themselves and always says: let the data speak for itself!
Yet he is attacked by vegetarians and traditional RDs on one hand (BTW, the department of Nutrition at CSU where he works doesn't really like him, because of his take on grains, milk and animal foods) and by low carb fans on the other, because he believes that 12:0, 14:0 & 16:0 downregulate LDL receptor and, especially because he was a co-author of a cardiologist who believes in Statins (although he only wrote the evolutionary part and he doesn't take statins himself or recommends it)

Some people ridicule his work, but forget that he has published some great papers, linking Diet to Acne (he was the first one to show this to the dermatology community), Myopia, Auto-Immune Diseases (even Pustzai admires his work, as he told me at a lectin conference I attended), etc. Just check Medline to see what I mean.

Regarding ALP, he has abandoned the lactose connection for some time and he believes that the selective pressures for ALP were malaria in Africa & Rickets in Northern Europe (milk contains Calcium & also BTC, which is something to be taken seriously and as far as I know, he was the first one to suggest this, after Australian researchers discovered BTC in Bovine milk in 2001).

Actually there is an in vitro study showing WGA blocks the nuclear pore, but I'm not versed in this mechanism, so I won't make any comments.

Regarding Cancer, It is my opinion that, as it happens with most diseases, there isn't one cause, but multiple factors involved and Milk may just be another one of them, which may turn out to be irrelevant if other more important causes do not exist (For instance, the Masai live in Africa and spend their day outdoors, which would lead to high plasma 25OHD3 [which seems to have a bigger influence on Cancer than many dietary factors], they don't eat vegetable omega 6 rich oils, trans fat, cereal grains [at least I think they don't] and isolated sugars, etc, etc. )

Nevertheless, this doesn't mean that we shouldn't try to study each and every one of these possible causes in order to try to eliminate them and this BTC connection may just be another one of those causes.

As for Milk and insulin (as someone on the blog talked about, while ridiculing Cordain’s paper on it), I have discussed this with a food scientist who is researching milk, and he showed me the references that cow's Milk elevates insulin as much as white bread and he told me that his lab is performing some experiments with various milks and so far, they all show a high insulinotropic effect (even raw goat's yogurt, which is heavily used in Spain).

Again Peter, I really enjoy your blog and hope that you don't take this the wrong way.

All the best


latorquemada said...

While I can't pretend to understand the biochemistry of this all, I found the ideas in the post fascinating because my mother and I, Scandinavians who were both fully lactose tolerant our entire lives have recently both become lactose intolerant (my mother more so -- she is about 70 now -- I tolerate it better, but nothing like when I was eating gluten) about two years after eliminating gluten entirely. Obviously just an anecdote, but interesting to me.

Peter said...

Hi Latorquemada,

That definitely goes under file and think about it. Now what's going on there...


Peter said...

Hi Miguel,

A long and very interesting comment which needs and deserves an appropriate response (can't get to do it just yet). Thanks for the feedback and yes, Cordain's diet is streets ahead of Ornish, McDougal, AHA and similar people. That's partly why his strange take on cholesterol drives me up the wall...