Degenerative and man-made diseases in the developing world

I came across a relatively recent article by Kuper and Kuper in the Financial Times on the rise of degenerative and man-made diseases in the developing world that I suggest reading. The advent of smoking and low-quality industrial food is making many of the world's poor less healthy even as medicine manages to fight back infectious diseases around the globe.

This paragraph, however, made me laugh:

We now know that Omran failed to foresee a fourth stage of the transition: the decline of chronic diseases. The west – and particularly its richest inhabitants – has now reached this stage. Thanks to the “cardiovascular revolution” – the medical advances in treatment – the past 30 years have seen death rates from heart disease fall by 70 per cent in the US, the UK, Australia, Canada and Japan. That translates as 14 million American and eight million British lives saved between 1970 and 2000.

Part of the problem with modern medicine is that mortality trumps morbidity, every time in funding, in research effort, and in much every aspect of the system. Eventually I think the system will figure things out, but there's a lot of inertia to overcome as well as moneyed interests who benefit from people in poor health. The whole article is really a great example of the common wisdom facilities that need to be overturned so we can get anywhere.

I have been a little snowed under lately with work so no substantive posts. I am going surfing in Tofino for reading week, maybe I will work up a post while I am away, or maybe not...

Foxa2 Transcription Factor Implicates Direct Role for Insulin in Hunger

Insulin has a number of down-stream targets (receptors), one of which has the highly descriptive name foxa2 (aka hepatocyte nuclear factor 3-beta). This receptor is closely tied to the liver and how it reacts to insulin (Wolfrum, 2004). Essentially foxa2 is one of the regulators responsible for the production of enzymes that are involved in beta-oxidation of fatty acids and the production of ketones. Insulin binds to foxa2, making it unable to perform its function in activating the production of these important fatty-acid metabolism enzymes. In this manner, insulin shuts down fatty acid metabolism.

First a little background on gene expression if you didn't implicitly understand what I wrote above. About 1 % or so of your DNA encodes for proteins. To make a protein, the DNA has to be pulled apart and a complementary single-stranded RNA polymer built to match. This is called messenger RNA and it is sent off to an organelle known as a ribosome which actually assembles the protein that the DNA encodes for.

The rest of your DNA is functional with 'dead space' being a common function. DNA, when being unzipped typically folds in on itself, so sections of the DNA well ahead of the protein encoding region often have functions related whether or not that protein encoding region is actively being transcribed or not. Other proteins literally sit on these spaces and their interaction with the enzymes that unzip and transcribe DNA determine whether messenger RNA is produced or not. Foxa2 is one of these gene transcription activators, so it operates at a very basic level of cellular mechanics. However, it can only do this when insulin is bound to foxa2. Presumably the binding of insulin to foxa2 reconfigures the shape of the foxa2 protein; with proteins, function follows structure/shape.

Silva et al. (2009) published in the journal Nature that this same receptor, foxa2, is found in the hypothalamus (of mice) and it directly effects the hunger reflex. What they did was to take normal and genetically obese mice, fast them, and inject some of them with insulin to put them into the 'fed' state. They then sacrificed the mice and dissected their brains, using an antibody-based stain to identify neurons that were positive for foxa2 and orexin and melanin-concentrating hormone (MCH). Orexin and MCH are known to be associated with feeding and, incidentally, sleep behaviour (Willie, 2001). From their results the authors concluded that the production of the neuropeptides orexin and melanin-concentrating hormone (MCH) were promoted by the foxa2 receptor (but only with insulin attached to it). One of the stronger pieces of evidence was that foxa2 was found in the cytoplasm of the mouse neurons when in the fasted state but in the nucleus when in the fed state. Transcription of messenger RNA occurs in the nucleus.

Supplementary Figure 1 (from Silva, 2009): Author's impression on how the foxa2 receptor cycles in and out of the nucleus in response to insulin.

I put mice in parenthesis in the preceding paragraph because there have been significant differences found between how various pieces of molecular machinery are distributed in rodents versus humans. A good example of this is selano-deiondinase type 2 (D2), which converts the inactive form of thyroid hormone, T4, into the active form T3. It's found in the skeletal muscle of humans but not rats ( Heemstra, 2009 and Larsen, 2009). Incidentally, both papers have fascinating implications for fasting in humans as well as sick euthyroid syndrome.

Interestingly the way they found the distribution of the Foxa2 receptor amongst neurons of the hypothalamus was through the use of specific antibodies as a microscopy fluorescence stain. I'm not clear on how these antibodies are fabricated from the supplemental literature, and a search for, "foxa antibod*" on PubMed didn't return any pertinent hits. I'm sure this is a common method as I've seen it before in fluorescence microscopy, but I am curious about the potential for an associated autoimmune disease.

If you read my previous post on leptin and anorexia (01/12/2010), there is additional support in Silva for the notion of hyperactivity in a fasted state:

Interestingly, the Nes-Cre/+;Foxa2T156A^flox/flox allele was associated with dramatic increases in spontaneous locomotor activity relative to control mice (Fig. 3i). The difference between the locomotor activity of Nes-Cre/+;Foxa2T156A^flox/flox mice and that of Foxa2T156A^flox/flox or Nes-Cre/+ mice was similar to the increase in movement of fasted wild-type mice relative to fed wild-type mice (Fig. 3j). The types of physical activity induced in Nes-Cre/+;Foxa2T156A^flox/flox mice included searching as well as intense grooming, rearing and face-washing behaviour.

If you can get past the ridiculous names of the mice variants, the English here is pretty clear.

Now it's very easy to get lost in minutiae such as this and lose clarity in the process. Of course, minutiae does have value for the task of bamboozlement. If we pull back and look at the big picture, the key point here is that insulin has been directly implicated in the hunger reflex for the first time, to my knowledge. Previously I assumed that only leptin and ghrelin can effect hunger. Now, when I read this article I did ask the question, has insulin been implicated to interact with this receptor at a biochemical level, or perhaps it is stimulating some other intermediate hormone which in turn interacts with foxa2? The answer is, yes, insulin is the actor and it directly binds to foxa2 (Wolfrum, 2003).

Leptin and Anorexia

I have, off and on, entered into discussions with other bloggers on the role of leptin in long-term energy storage. Leptin, we know, is strongly related to long-term storage of fat and is probably one of the primary hormones associated with obesity (Kelesidis, 2006). It is thought, along with ghrelin, to be one of the hormones responsible for appetite.

One question I've posed is does leptin have an antagonist hormone? Most hormones have complements that act to oppose their action. For example, insulin versus glucagon/growth hormone. As an aside, please recall that growth hormone is primarily a catabolic hormone that turns on the body's fat metabolism, a state we call fasted. Generally an antagonist allows the endocrine system to respond more rapidly than simply waiting for the pertinent hormone's concentration in the blood to clear. Does leptin need an antagonist? Or does it operate over such a long time-span that it normally wouldn't need one? Is the lack of an (apparent) antagonist perhaps one of the reasons leptin metabolism can go screwy?

As an alternative to looking into why leptin makes people fat, I thought it might be interesting to examine how a lack of leptin makes people skinny, or anorexic. Anorexia just means 'skinny' refers to a lack of appetite in medical parlance, while anorexia nervosa (AN) refers specifically to the eating disorder that we've all heard about in the news. People can have abnormally low-body fat without having an eating disorder. For example, individuals with cortisol insufficiency (such as Addison's disease, an autoimmune condition involving destruction of the adrenal cortex) tend to have very low body fat levels, but not necessarily a lack of lean body mass. The lack of cortisol just mutes the body's stress response to store an emergency reserve of fat.

One of the markers that characterizes anorexia nervosa is low circulating leptin levels.

Now, leptin likes to interface with the hypothalamus, which is the part of your brain that essentially acts as an interface between the digital-fast (neural) and analogue-slow (endocrine) control systems of the human body. Lot's of things like to interface with the hypothalamus though, so please do not take this role of leptin as dogma. Together, the hypothalamus and pituitary are the master endocrine organ system, regulating the serum concentration of most of the hormones in your body. Essentially it integrates many different signals, and based on those signals decides what quantity of eight primary hormones to release (i.e. oxytocin, argigine vassopressin, adrenocorticotropic hormone, growth-hormone, thyrotropin (TSH), prolactin, luteinizing hormone, and follicle-stimulating hormone). The hypothalamus plays a crucial role in regulating immune function, metabolism, sex function, and mood/anxiety amongst many others.

The hypothalamus (and the pituitary by extension) tends to release hormones in pulses. When I say the hypothalamus exists on the border between digital and analogue that is nearly literally true. The hypothalamus samples the blood-stream for various feedback mechanisms (i.e. hormones) and when it adds together enough signals that indicate the system needs more growth hormone, it generates a pulse. This is done by the combination of neural and endocrine tissues. Leptin is one of the signals that contributes to whether or not pulses are released from the hypothalamus. If everyone's leptin receptor cells are identical, which is not likely, then low leptin levels will probably down-regulate some of the hypothalamic-pituitary hormones and up-regulate some others, while high leptin levels will do the opposite.

One very common side-effect of AN is the loss of the menstrual cycle (which has the scientific name amenorrhea) The menstrual cycle is initiated by a luteinizing hormone pulse, which implies that very low leptin levels have effects beyond simply regulating fat levels. This is not a surprising result; we would expect the body to shut down non-essential functions when it is starving. This result is correlated to circulating leptin levels (Blüher, 2007). Blüher has some interesting comments on the matter of leptin release:

Leptin secretion can be stimulated by insulin, glucocorticoids (RM: cortisol), and cytokines (RM: immune system catnip) (i.e. tumor necrosis factor [alpha]), whereas catecholamines (RM: "adrenaline"), free fatty acids, cold exposure and thyroid hormones inhibit leptin release [18,19]. Estrogens induce leptin production whereas androgens (RM: male sex hormones) suppress it, providing an explanation for the sexual dimorphism in serum leptin levels [19]. Although anthropometric and clinical features (gender, fat mass/fat distribution, hormones and cytokines) may influence the secretion pattern of leptin, the crucial factor in regulating serum leptin levels seems to be caloric intake and the amount of energy stored in adipocytes [5].

Another side-effect of AN is increased activity (aka hyperactivity), which is a homeostatic method to increase caloric expenditure. This is called activity-based anorexia (ABA) and is one of the primary animal models of anorexia. A review by Hillebrand et al. (2008) shows that leptin itself appears to be signaling the hypothalamus to encourage the brain to engage in this sort of behaviour, and that leptin-replacement therapy suppressed this activity. It's been hypothesized that hyperactivity would promote foraging behaviour in the paleolithic-era and in wild animals. Leptin also has a role in the homeostatic mechanisms behind thermogenesis via the basal metabolism of the thyroid hormones and brown adipose tissue (Rogers, 2009).

This result begs the question, are obese individuals sedentary because they have high circulating leptin levels? Was Gary Taubes, of Good Calories, Bad Calories fame, right in the lack of a relationship between exercise and obesity, even if he didn't know why? If so, hyper/hypoactivity as it relates to leptin would appear to be a case of positive feedback, where the signal tends to reinforce itself over time. It's only because gathering food requires so little energy investment today (get off couch, walk to pantry, grab chips) that this positive feedback cycle blows up so spectacularly. Historically putting on some fat might discourage activity via leptin, giving the organism a rest period.

Now on another front, anorexia nervosa patients who recover from the condition and regain body weight often regain too much and become overweight. This occurred even when caloric-intake and leptin levels were monitored during the body weight gain period to prevent excessive weight gain (Lob, 2003). So once again we see the dominance of the endocrine system and homeostasis over counting calories.

What might cause this higher than normal set-point of body mass index (BMI)? This question does not seem to have a firm answer quite yet so I'm going to speculate. The hypothalamus is a union of neural and endocrine tissue. Neurons, in particular, are quite plastic in that the amount of stimulus you have to apply to get them to fire changes depending on their exposure history. This is how memory is thought to work, for example. My hypothesis is that the neural component of the hypothalamus habituates to long-term leptin exposure.

There are clearly some threshold levels where leptin indicates an organism is in semi-starvation mode and generates compensatory behaviour (Müller, 2009). I can postulate that there may also be hibernation morphology at the top-end of the leptin spectrum. If the organism stays in semi-starvation mode for long enough, perhaps the sensitivity to leptin in the hypothalamus is reduced by the plasticity of the neural component. In this case, a crash weight-gain diet would not give the hypothalamus's neurons sufficient time to change their sensitivity to leptin, and adapt a new set point.

Maybe this is the reason why fast weight-loss programs typically fail miserably. The leptin set points for semi-starvation modes are at at abnormal levels, and pushing leptin through them induces behaviour that likely results in a rebound. The solution then is to be patient and go slow with weight loss or gain. If my hypothesis is correct, losing weight too fast may actually permanently distort leptin regulation.

Composition of Gut Biofilms

There was a very interesting article published in the 05 November 2009 issue of Science magazine on the composition of bacterial colonies in humans. A human has more bacterial cells living in and on it than it does have human cells. Costello et al. (2009) (also see Supplemental Online Material which I think is free access and comprises 90 % of the article) took bacterial samples from 7-9 humans (likely the authors' themselves) over several months to assess both the composition of bacterial colonies from various sites such as the gut, forehead, and nostril, and to assess whether the composition changed with time. They found significant variation from person to person but not a lot of change over time. Hence the notion that we all have our own individual bacterial flora.

Table 1: Average composition of bacteria in human gut

Gut Bacteria Phylum	Proportion of Nucleotide Sequences (approximate %)
Firmicutes	35
Proteobacteria	5
Bacteroidetes	60
Verrucomicrobia	0.24
Lentisphaerae	0.05

Bacteria on the surface of the various membranes that separate our innards from our environment are essentially the first line of defense against intruders. They form more or less continuous biofilms consisting of bacteria held together by a matrix of congealing substance, such as mucous. Bacteria colonies on our bodies are mostly symbiotic, although they can be parasitic at which point they become pathogens. So there are 'good' and 'bad' bacteria. What determines whether we have mostly 'good' symbiotic bacteria or not? How do we encourage the development of 'good' bacterial flora and discourage harmful flora? Good bacteria can out-compete pathogens, predigest anti-nutrients before they can penetrate the gut lining, thereby providing useful symbiotic services to us.

These are questions I do not have answers to, but I do have hypotheses.

Bacteria are prokaryotes, which means they are much much smaller and simpler than any one of our cells in our body. In fact they are about the same size as the mitochondria organelles in our cells. Mitochondria are the ATP-producing energy factories of our cells, and all they do is break apart fatty acids (called beta-oxidation) and oxidize Acetyl-CoA, the produce of beta-oxidation and glycolysis of glucose. A bacterium has to to all that and more all in a small package. As a result, bacteria often can only exist on certain nutrients: lactose, glucose, fatty-acids with a certain number of carbons, etc. These are called metabolic pathways, and they represent a specific set of chemical reactions that eventually result in the production of ATP, the energy currency of living things.

The obvious conclusion to draw here is that macronutrient ratios will likely be fairly important for determining the composition of gut flora, but it will not be a question of carbohydrate versus fat. It will be a question of 4-chain saturated fatty acids versus 18-chain monounsaturates, glucose versus fructose versus galactose, because that's the level of detail required for metabolic pathways. In addition, there is almost certain to be some synergy between various forms of bacteria when they form little symbiotic colonies, with one living off the metabolic produces of the other.

Micronutrients may also matter to gut biofilm composition. Most biochemical processes in the body require enzymes to catalyze the reaction. Enzymes are usually protein chains in which one amino acid group has had a elemental substitution that acts as an active site with chemical activity. An example is the iron site on hemoglobin that binds oxygen in your red blood cells. I would guess that bacteria can do the substitution themselves, which is to say they should be able to build their own enzymes from the elemental forms of the required minerals rather than necessarily requiring the amino group preformed. The point I am trying to make is mineral deficiencies might kill off various strains of gut bacteria.

Overall I think this line of research is very interesting and likely to provide many interesting results. This might, for example, end up being a very strong argument against the prophylactic employment of antibiotics. At a minimum, patients should be prescribed probiotic cultures after their antibiotic treatments, and, oh yeah, those probiotics should actually be, you know, alive when ingested.

A useful research project would be a large-scale longitudinal study (tens of thousands of patients over 10 - 15 years), where patients' gut bacterial colonies are sampled at regular intervals and the patients are monitored for the development of various diseases. The initial states of gut flora, if they remain consistent, may produce correlations for the relative risks of various diseases. If the composition changes, the natural question is if any new diseases presented at the same time. The US National Institute for Health has instituted a survey program to determine the genomes of gut flora, the Human Microbiome Program, which is an important first step.

I started taking a Lactobacillus and Bifidobacterium probiotic a couple of weeks ago as a trial. I did notice changes in my stool almost immediately; for the sake of brevity I will spare you the details. Bacterial cultures, like fish oil, should be stored in the refrigerator but unlike fish oil bacteria don't withstand freezing too well.

Clarifying Butter (i.e. Ghee) Guide

Mmm... butter, one of the tastiest of all fats. It also happens to be one of the most nutritious forms of dietary fat, containing the fat soluble vitamins A and D in their animal usable forms. It is also a good source of vitamin K₂, which regulates calcium metabolism; K₂ has become quite rare in our modern diet with its lack of fermented foods. Unfortunately, butter does contain some milk solids, so if you are gluten intolerant you may also be intolerant of the α-casein that makes up some 80 % of cow milk proteins. It also contains a little bit of lactose, which might make someone with lactose intolerance hurl. What to do? Why remove the milk solids of course. This process is called clarification and can easily be done on the stove top. The finished produce is often called Ghee, as it was once a staple of Indian cooking.

An additional advantage to clarifying butter is that it does not brown or burn nearly as easily so cooking with it at high temperatures is safer. Traditionally ghee is often flavoured with cinnamon or cloves. Incidentally cinnamon is a folk-method for treating diabetes; it has an insulin-like effect in addition to being high in chromium.

I typically clarify two pounds of butter at a time. Since the volume of the butter will be reduced by about 1/4 (primarily water and the filtered milk solids) this yields about 750 mL of high quality cooking fat. You'll want the following ingredients and apparatus:

• 2 lbs. butter (cultured butter will taste better)
• optional: wholes cloves and cinnamon stick
  
• sauce pan
• ladle
  
• thermometer, digital w/ alarm
• strainer
• elastic band (like the type broccoli stalks come with)
• terrycloth or cheesecloth

First start by melting the butter in the pan on low. As it melts to cover the bottom of the pan you can turn it up to medium and stick your thermometer into the oil. Set the alarm to 110 °C (230 °F). You don't want to use high heat here, as there's only a limited amount of water in the butter so it's mostly just a matter of time for the oil to heat up.

When water evaporates it takes away an enormous amount of heat, so the temperature of the ghee will stall a bit at or just above 100 °C (212 °F). At this point, the butter will separate into its three constituents: the milk solids, which will settle on the bottom, the golden-coloured oil itself, and a layer of foam on the top.

The foam does not contain casein, but it is unsightly and we want to get rid of it with our strainer. Just skim around the top, and then wash the strainer off with hot water. After 2-3 skims, you should have a cleaner looking product.

After cleaning off the foam you are essentially just boiling away the water content of the butter. Honestly if you know what you're doing and watch the butter carefully you don't need the thermometer. As the oil heats up, the bubbles will get smaller and smaller. When the oil stops bubbling, that means all the water has evaporated and the temperature of the oil will start to rise very quickly. When or if the milk solids at the bottom of the pan start to turn brown, remove the pan from the heat immediately. I generally wait until 125 °C (257 °F) to finish heating.

At this point it's time to transfer the clarified butter into your jar. I use terrycloth instead of cheese cloth for a few reasons. One, it is far cheaper and easier to find. It's even reusable, and it seems to do a better job of filtering the milk solids than cheesecloth. I do wash it beforehand. The elastic is wrapped around the base of the strainer to hold the filter in place.

That's it! Now just cap your jar and clean up. The hot ghee will be transparent and look a fair bit like thick urine. If any milk solids did make it through the filter process, they will settle on the bottom. As it cools to room temperature, it will become more solid and turn a pale yellow colour.

Ghee is shelf-stable although I would store it in a cupboard away from light. It can be refrigerated but it becomes very hard at colder temperatures and impossible to get out of the jar with a spoon.

If you can't afford high-quality grass-fed organic butter (I certainly can't), you may want to consider adding vitamins D₃ and/or K₂ if you can buy them in drop form. Add them to the finished ghee in the jar and stir.

The Paleolithic Principle

I would like to share an overview of how and what I eat, and why. Rather than list individual food items, I will discuss the approach in general terms. I won't really be rigorously supporting many of my statements since that would require an entire book or more worth of writing. I will try to keep this brief and information dense.

I structure my nutritional philosophy around the notion of the Paleolithic Principle. The principle is that the human animal has been around and eating a relatively consistent diet for a couple of million years with Homo Sapiens being around for almost 100k years. It was only really with the introduction of the neolithic age that technology brought new foodstuffs to consume such as dairy, grains, and the other modern cultivars of plants that we eat. The paleolithic principle states that we have not fully adapted to these new types of foods and hence they may be harmful to our health, on a case by case basis.

These new sources of food were introduced roughly 5000 - 7000 years ago, which is perhaps some 300 generations worth of time. Humans, being long-lived, evolve quite slowly. Humans, being highly social sentient apex predators, also don't necessarily experience the same degree of natural selection as other species. The question is then, just how well adapted are we to these neolithic food groups?

We know for a fact that food tolerances have an ethnic bias. We know that the closer one's ancestors hailed from Mesopotamia the less likely they are to be intolerant to wheat gluten. Similarly, Asians are far more likely to be lactose intolerant than Europeans. Thus, clearly, only certain segments of the human population have adjusted to each particular Neolithic foodstuff. These are established facts, and they provide a basis for the paleo principle as a reasonable hypothesis.

If one has an ethnic background that strongly identifies with a particular ethnic diet then you might be best off following it since you're probably selected for it. This doesn't always work well however, especially in the immigrant nations such as the USA and Canada, where there has been a great deal of mixing in ethnic groups. Personally, I'm a mix of Polish-Romanian jew, Italian, French, Norwegian, Scottish, Austrian, and English, with a few other nationalities thrown in for fun. If I were to follow an ethnic diet, which of the ten or so should I pick? Almost all of the neolithic food groups give me some trouble. Perhaps I'm simply lacking in intestinal fortitude.

The largest quantity of pharmaceuticals that one ingests by far is in the form of foodstuffs. Plants especially contain an enormous number chemical compounds, not all of which are broken down before they cross the gut-blood barrier. For whatever reason, the gut-blood barrier and the associated bacterial biofilm has broken down more commonly in modern man.

Of course, even foodstuffs that we have been (slowly) adapting to over 5000 - 7000 years have changed a great deal. For example, the heavy fertilization of dwarf wheat strains has resulted in higher protein yields but that protein predominantly comes in the form of increased gluten content. So when people scratch their heads about the increased incidence of celiac and other gluten related autoimmune disorders, it may just be that the wheat is changing rather than the people, n'est-ce pas? Similarly ever compared a wild strawberry to a super-fertilized all-season Californian monstrosity? We have started supplementing our diet with artificial food additives, such as mono-sodium glutamate (MSG), which only further complicates our understanding of nutrition.

Modern farming practices, cultivars of plants, and breeds of animals sacrifice micro-nutrient content for economy in the form of macro-nutrient content. In some cases, you don't even get more macronutrient, but just more water content for the check-out scale. Thus you have the paradox of a person who is obese yet simultaneously starving thanks to a diet of soda pop and it comes about due to the imbalance in the ratio of micro-nutrients to macro-nutrients in the foods we eat. This is the tyranny of the middles aisles in the supermarket.

Now, the paleolithic principle is sort of like using a sledgehammer to pound in a finishing nail (HT: Chris). It works, it works quite well actually, but it is an excessive means to the task. I don't ascribe to the fairy tale view that everyone was engaged in happy-fun-time back before the introduction of agriculture but there's little doubt that hunter-gatherers were physically far more impressive animals than the more numerous agriculturalists and pastoralists that out-competed them.

It's clear to me that industrialization and technology has had a number of negative consequences to human health which we call the "diseases of civilization." The most obvious of these are heart disease, diabetes and obesity (including metabolic syndrome), but they also include autoimmune disorders (which are far more common than is generally recognized) as well as many neurological disorders. I don't think it has to be this way, but there have been some very wrong-headed paths taken in the field of nutrition over the past fifty-odd years.

From an evolutionary perspective, the more recently a particular foodstuff was introduced, the more likely it is to cause distress. This implies that refined oils and large quantities of fructose, both of which were entirely absent in the 1800s, are two of the more obvious places to eliminate and cut-back in order to restore the good health nature intended us to have.

If I were to sum up a reasonably brief list on what to do and what not to do, this would be it:

1. Control appetite hormones like gherlin by eating regular, satiating meals. By satiating I mean protein, fat, and fibre. Try to avoid snacking.
   
2. Restrict fructose and alcohol consumption to reasonable levels, day-to-day. 20 g/day of both combined would be a very healthful level, 50 g/day is I think an upper bound for people with healthy livers.
3. Eliminate industrial, refined oils, particularly refined polyunsaturates such as soy and canola oil. Go for fresh and high quality fats, in particular clarified butter, extra-virgin coconut oil, extra-virgin olive oil, and the fats from animals fed their native diet. Unstable oils should be stored in the refrigerator or freezer to prevent them from going rancid, e.g. Omega-3 fish oil capsules. Most industrial oils are deodorized to prevent you from smelling when they go bad.
   
4. Eat more than just muscle meat from an animal. Have you eaten liver pate or roasted heart lately? Bone broth?
5. Fast occasionally for approximately 24-hours to give your liver a break and restore insulin sensitivity. Many religious groups noted for their good health (i.e. Seventh-day Adventists, Mormons, and the Greek-Orthodox of Crete and Corfu) regularly fast — is the the shared common trait. Fasting and starving are not the same thing, don't conflate the two.
6. Go on elimination dietary trials of the common food allergies: wheat (including barley and rye), cow dairy, legumes, especially soy and peanuts, tree nuts, eggs, fish, and shellfish. Test assays may be insufficient to recognize many of the idiopathic problems (i.e. autoimmunity, neurological disorders) that these types of food may induce. It took me six months wheat-free to get better.
   
7. Supplement with Vitamin D, on the order of 1000 IU/12 kg of body mass per day. Consider that the recommended doses for infants are 400 IU/day, so if you mass ten-times that of an infant, you need ten-times as much vitamin D; recommended adult doses are a joke. Also consider that you produce about 10,000 IU/ 30 minutes in full-sun. Vitamin D is not a vitamin, it is the precursor material to most of the steroid hormones in your body. When the endocrine (hormone) system has adequate signaling compounds, the whole body works better.

I do not eat much in the way of carbohydrates primarily since wheat and dairy are off-limits to me but even more so was the realization that foodstuffs that are good sources of glucose are also bereft of micro-nutrients. I.e. they are empty calories. You know how some people drink socially? I eat grains socially (with the notable exception of wheat, which I find incredibly destructive to my body). This said I don't believe glucose is inherently a problem and I do carb-load from time to time.

You may have noticed that I haven't talked about exercise at all, and that's because I think it is relatively unimportant. If you apply the 80/20 rule to how well you feel, I think perhaps 80 % of your wellness comes from diet, 15 % from adequate restful sleep, and perhaps 5 % from physical activity. Trying to lose body fat from exercise is a fool's errand and more than likely will result in over-training and the associated chronic injuries. While I personally do get a lot of physical activity, it's all for fun. My current hobby is whitewater kayaking, so any physical training I do is oriented towards improving my performance in that regime rather than building bulging biceps. I don't bother lifting weights in the gym since I find it quite dull. The fact of the matter is I got healthy through diet first and only then started exercising more.

Now, you may have noticed me talk about autoimmunity a lot and that is because I think it plays a key role in the diseases of civilization. Autoimmunity is simply the case in which the immune system, which is responsible for both healing and repealing foreign invaders, starts attacking the tissues of its host body. Autoimmunity has a genetic component, but something needs to trigger it. Examples are viral or bacterial infections, or dietary allergies. Celiac is one type of autoimmune disorder, type 1 diabetes is another.

If the diet is introducing strange, novel foreign bodies into the gut and the gut is compromised, they will penetrate into the circulatory system. The immune system sees these foreign bodies and goes berserk trying to hunt them all down and destroy them. Then, four to six hours later, you eat another meal and the cycle repeats. The solution is to remove the stimulus, i.e. fix the diet.

Any sort of food allergy or intolerance is likely to result in the immune system being depressed. The immune system only has a finite capacity for fighting infection, and if you're making it waste its time chasing gluten peptides or whatever, it is not going to be so strong at fighting off the latest pathogen. Similarly if you are not providing the immune system with enough micro-nutrients to operate at full capacity you will not only get sick more often, but you will also heal more slowly.

If I could sum up my nutritional philosophy in one sentence it would be:

Don't eat things that cause your immune system to run around like it has a hole in its head.

A touch different from Michael Pollan, but I digress.

Breakthough in Flow Batteries?

So there's been a little Google explosion on the subject of flow batteries recently, with a German group claiming a breakthrough. From the press release,

Until now, however, redox flow batteries have had the disadvantage of storing significantly less energy than lithium-ion batteries. The vehicles would only be able to cover about a quarter of the normal distance – around 25 kilometers – which means the driver would have to recharge the batteries four times as often. “We can now increase the mileage four or fivefold, to approximately that of lithium-ion batteries,” Noack enthuses.

Mmm... vague, yes? As anyone who has been following the alternative energy scene for any length of time knows, the bigger the claim and the fewer facts behind it, the more likely it is to be BS. As always, it pays to be skeptical rather than credulous.

If you aren't familiar with the technology of flow batteries, I suggest you buck up to Wikipedia and take a read. The strong point of flow batteries has always been that the power and energy storage characteristics are decoupled: the power is a function of the size of exchange membrane, while the energy storage is determined by the volume of the storage tanks. In this fashion, they are a lot like fuel cells except that they are reversible. However, the energy density (as a function of weight or volume) has never been terribly impressive, lying around that of lead acid batteries.

The engineer who is quoted in the story, Noack, appears to be involved with the design of the exchange membrane and I can't see the mechanical bits resulting in a 4 - 5 fold improvement in energy density. I found a paper he wrote here comparing the various known chemistries applied to a new membrane stack design. There must have been some new chemistry developed, either that or there's smoke and no fire here. The article does mention collaboration with the University of Applied Sciences, Ostphalia [sic], but I can't find anything pertinent on the university's web site.

The previous king of the various redox flow battery chemistries is the Vanadium redox battery. It can, in general, obtain a 75 % round-trip efficiency which is fairly decent, being roughly in-between Li-ion batteries and Nickel-metal hydride batteries. The Achilles heel has always been the chicken and egg problem of the cost of Vanadium. Vanadium is not a particularly rare element, but it isn't mined in large quantities due to lack of demand and hence it is quite expensive. A single utility scale redox battery would consume a significant portion of the world's annual Vanadium production. Thus the conundrum, if no one can afford to buy a Vanadium redox battery, you'll never generate enough demand for Vanadium to open up new mines and drive the price down. The best hope, I always thought, was for one of the Vanadium-contaminated oil deposits of the world to be developed and glut the world Vanadium market.

As far as I know the intellectual property behind the Vanadium redox battery was held by VRB Power Systems but they went bankrupt earlier this year. They seem to have been acquired by a Chinese firm, Prudent Energy. It's probably worthwhile that the dollar numbers for Vanadium redox batteries didn't work out, even way back in 2005 when I last looked at it.

The Chronic Infection Theory of Heart Disease

Introduction

Heart disease, or more specifically atherosclerosis, is a chronic disease whereby cardiac arteries become partially occluded by the growth of plaques. Narrowed arteries are more likely to trap dislodged blood clots, resulting in blood supply being cut off to a portion of the heart, resulting in oxygen depletion of the cardiac muscle tissue and eventually myocardial infarction or heart attack.

Contrary to common wisdom, dietary fat does not deposit on the arterial wall and "clog your arteries;" plaques grow inside the arterial cell wall and consist of a mix of the smooth muscle cells that naturally line the interior lining of the artery and immune-system cells such as macrophages and lymphocytes. Macrophages, or white blood cells, are the large, amoeba-like cells that form the last line of defense for the immune system. This mix of cells are called foam cells. Foam cells tend become bloated by absorbing large amounts of cholesterol from the blood stream and they form a cyst or lesion which compresses the arterial wall, reducing the effective diameter.

By way of background, there are three times of muscle in the body: cardiac, skeletal (meat muscle, like your bicep), and smooth muscle (such as your scalp or vital organs). Smooth muscle is quite a bit different from the other types in that its cytoskeleton has no deterministic, regular structure. Rather, it just consists of a chaotic jumble of actin filaments. Unlike the other two types, smooth muscle is not normally controlled by the electronic action potentials of the nervous system; rather, it is controlled by the much slower chemical hormonal system.

With time, atherosclerotic lesions may harden by absorbing calcium from the blood which makes the artery stiffer and tends to result in high blood pressure. This is not unlike how bone tissue is formed by the mineralization of connective tissue, which in turn suggests some sort of hormone dysfunction is in play. Hardened arteries are considered more hazardous than pliable yet still narrow arteries. The likely reason for this is that a narrowed yet pliable artery can distend under pressure to allow a blood clot through, while a calcified artery cannot.

Thus we have three criteria for heart attacks (with some simplification):

1. The wall of the cardiac artery has to be sufficiently narrowed so that,
2. A dislodged blood clot gets stuck in it, and/or an atherosclerotic lesion ruptures (in the majority of heart attacks anyway), and
3. The arterial wall is too stiff to allow the build-up of pressure caused by the obstruction to allow the clot through, resulting in down-stream oxygen deficiency and eventually cell death.
   

To reduce heart attacks, you can attack any of these three processes. Take the Masai tribesmen of Tanzania: they have a great deal of atherosclerosis thanks to their milk-based diet, but they don't necessarily suffer heart attacks, likely due to their adequate intake of vitamin K₂.

I want to talk about the first requisite, atherosclerosis. The question is of course, what causes immune system bodies to form colonies inside the lining of one's arteries? There are two basic possibilities: auto-immune disorder, where the immune system recognizes legitimate tissue as foreign, or actual foreign bodies, such as chronic bacterial or viral infection of the blood vessel. Or both.

Enter Chlamydia pneumoniae, bacterium

The idea that atherosclerosis might be caused by chronic infection of the lining of blood vessels is not a new one. In 1999, the American Heart Journal devoted a supplementary issue to the topic. It is, essentially, an alternative theory for heart disease as compared to the diet-heart hypothesis, whereby diet modifies serum cholesterol levels which in turn causes heart disease by some unknown mechanism. As it contraindicates the standard lipid model, it is considered controversial. The first potential pathogen candidate was cytomegalovirus (aka herpes) but it turned out to be a bust.

Further research suggested a better candidate. Chlamydia pneumoniae (aka Chlamyophila pneunomiae) is the bacterium most commonly associated with heart disease in the literature. As the name suggests, it is one of the sources of pneumonia and other respiratory infections. It has also been associated with Alzheimer's and asthma. It is a relatively recently discovered pathogen (in that the diet-heart hypothesis was formulated before anyone knew it existed), and its responsibility for respiratory infection was only discovered in 1986 (Grayson etl al., 1986). The association with heart disease was made very quickly (Saikku et al., 1988), since the hunt for a potential atherosclerotic pathogen had been underway since the early 1980s.

Bellard et al. (2003) lay down the case for C. pneumonaie succinctly,

Exposure to Chlamydia pneumoniae is extremely common, and respiratory infections occur repeatedly among most people. Strong associations exist between C. pneumoniae infection and atherosclerosis as demonstrated by: (i) sero-epidemiological studies showing that patients with cardiovascular disease have higher titres of anti-C. pneumoniae antibodies compared with control patients; (ii) detection of the organism within atherosclerotic lesions, but not in adjacent normal tissue by immunohistochemistry, polymerase chain reaction and electron microscopy and by culturing the organism from lesions; and (iii) showing that C. pneumoniae can either initiate lesion development or cause exacerbation of lesions in rabbit and mouse animal models respectively.

This list is not exhaustive, and it does not note probably the most important point: C. pneumoniae can create foam cells in vitro (i.e. in a Petri dish). C. pneunomiae has been shown to infect the constituent cells in foam colonies (i.e. macrophages and smooth muscle) (Fryer et al., 1997), inhibit the mechanism whereby cholesterol (LDL) is relinquished (Kalayoglu, 1999), and oxidize low-density lipoprotein (LDL) via releasing heat shock proteins (Kol et al., 1998). More on this later.

The physical presence of C. pneunomiae in atherosclerotic lesions has, as previously mentioned, been detected by a wide variety of methods. It's also highly prevalent. Of many studies that have found C. pneumoniae in foam colonies, (Muhlestein et al., 1996) is probably the most solid. From a population of 90 patients, they found evidence of C. Pneumoniae in 79 % of atherosclerotic plaques, but only 1 of 24 control biopsies.

A basic question then is how does one particular type of bacteria manage to not only evade the immune system, but distort its response in order to cause great harm to the host? (Belland et al., 2003) explore the mechanism,

Chlamydial growth is biphasic, consisting of two alternating functional and morphological forms (Fig. 1). The elementary body (EB) is the metabolically inert, infectious form of the organism that is capable of transient extracellular survival. EBs bind to as yet undefined host cell receptors, are internalized via a pathogen-specified process and are detectable within a membrane-bound vesicle immediately after entry. This vesicle is capable of interacting with post-Golgi secretory vesicles in ways that allow for the incorporation of host phospholipids [RM: phospholipids are cell membranes, i.e. camouflage] (Hackstadt et al., 1996; 1997). Chlamydiae also block intracellular host cell responses, such as fusion of the pathogen-containing endosome with lysosomes, and thus avoid host cell factors that would be detrimental to intracellular survival. Soon after entry, chlamydiae differentiate from infectious EB to the intracellular replicative form of the organism, referred to as the reticulate body or RB. This differentiation, which is dramatic in terms of altered chlamydial morphology, must reflect an orchestrated sequence of differential gene expression. Transformation of EB to RB results in loss of the disulphide cross-linking of the outer membrane complex, decondensation of the genome and initiation of DNA, RNA and protein synthesis. RB multiplication results in the formation of an intracellular microcolony (termed the inclusion) of chlamydiae.

Ok so that's a wordy quote, but to sum it up in one word it is mimicry. A big area of research in bio-nanotechnology is the development of phospholipid coatings on implanted medical devices to prevent the immune system from recognizing them as foreign and attacking them. This technique is known as, "stealth technology." Here we have an example of an organism that has evolved this technique. <acerbic>But don't you dare eat any eggs, they have cholesterol in them</acerbic>.

It's not clear if C. pneumoniae causes all atherosclerosis but I do believe it causes a majority of such. Another potential source of plaque-forming bacteria is Helicobacter pylori, which among other things, is thought to be responsible for ulcers. Unlike C. pneumoniae, which enters through the lungs, H. pylori typically lives in the gut. A study by Mayr et al. (2000) found an association between H. pylori antibodies and cardiovascular disease, but only in the low status (i.e. poor) individuals in their population. This study was conducted in Austria, so one wonders what might poor Austrians be eating that would cause them to suffer H. pylori infections?

The same paper also found odds ratios for: IgA type antibodies to the C. pneumoniae bacteria, elevated C-reactive protein levels in the blood, and (clinical) chronic respiratory infection. Now, odds ratio is a funny, non-intuitive statistic, but we can directly compare it to odds ratios found in other studies.

Table 1: Odds ratios for various diseases of affluence.

Description	Odds Ratio
Top quartile LDL cholesterol developing coronary artery disease within six years. (El Harchaoui et al., 2007)	1.73
Any one of: IgA antibodies to C. Pneumoniae. Elevated C-reactive protein levels. Clinical chronic respiratory infection.	1.5
Two of above.	4.33
Three of above.	10.28
Smokers developing Lung Cancer, versus non-smokers (Doll & Hill, 1956)	12.8

As you can see, three out of three is quite a strong association, far stronger than the cholesterol testing that is the most common method of screening for heart disease risk in medicine today. It is actually getting close to that of smoking and lung cancer, which is the gold-standard for causation. If you break it down individually, the strongest of the three criteria is chronic respiratory infection (OR of 3.8), followed by C-reactive protein (OR of 2.4). Since C. Pneumoniae antibodies has the poorest odds-ratio, while the chronic conditions are much higher, we can probably surmise that being infected once isn't going to cause atherosclerosis, in the same sense that over-drinking once is not going to cause fatty liver disease. Heart disease is a chronic condition, caused by chronically applied vectors (i.e. diet and environment). For the same reason, antibiotics were found to be ineffective in treating atherosclerosis: they are effective for acute infection, but in the long run they cause as many problems as they solve, since many of the bacteria in our bodies are beneficial and help out-compete teh nasties [sic].

Heat Shock Proteins

Another issue, that I eluded to above, is what exactly is causing inflammation in this case? Medicine has identified oxidized-LDL as a major danger factor, but is this a cause or just a symptom?

One potential candidate is a class of proteins that are produced by cells under stress, collectively known as heat shock proteins. The name is not well chosen, heat shock proteins should be termed temperature stress proteins. They are produced by cells that are under elevated temperatures (or many other forms of environmental stress) and they protect the other functional machinery of the cell from future elevated temperatures. They are considered to be a part of the general inflammation response of the body, although they tend to operate on a small, single-cell (i.e. autocrine) scale.

Foam cell colonies produce one particular type of heat shock protein, HSP60, in large amounts.
This particular heat shock protein is usually associated with mitochondria, the energy factories of cells, but it's also known to interfere with apoptosis, or programmed cell death. Apoptosis is the way in which the body normally disposes of broken or old cells. Elevated levels of HSP60 prevent apoptosis from occurring (Gupta and Knowlton, 2005).

One study on 1003 Chinese men found an odds ratio of 2.3 for atherosclerosis by simply being in the top half of the population for HSP60 levels in the blood (Zhang et al., 2008, full-text link on Pubmed is broken and is available here). Those in the top quartile for HSP60 levels had an odds ratio of 4.87, which higher yet than the range usually seen for c-reactive protein, which is the standard marker for inflammation.

The high odds ratio with c-reactive protein has been seen as one of the supporting features for the slowly evolving, mainstream view that inflammation and not blood lipids are responsible for heart disease. But is inflammation the cause or symptom again, and what causes localized inflammation of the blood cell wall anyway? The fact that arterial foam cells produce heat shock proteins and a bevy of other inflammatory markers in quantity suggests that atherosclerosis causes inflammation, rather than the other way around. Indeed, studies have claimed that the chlamydial heat shock protein 60 (cHsp60) oxidizes LDL particles in a test tube (Kalayoglu et al., 1999). This is big deal, since the actual mechanism whereby LDL oxidizes isn't known. For example, see Steinberg, 1997:

First, patients and animals totally lacking the LDL receptor nevertheless accumulate cholesterol in foam cells much the same way as do patients and animals with normal LDL receptors; second, the two cell types in lesions that give rise to cholesterol-laden foam cells (the monocyte/ macrophage and the smooth muscle cell) do not accumulate cholesterol in vitro even in the presence of very high concentrations of native LDL (3,4). This paradox could be resolved if circulating LDL underwent some form of modification and if the modified form, rather than native LDL itself, then served as the ligand for delivery of cholesterol to developing foam cells.

There are no paradoxes in medicine, just an inadequate understanding of nature. That, and a heaping load of bias. If it is the heat-shock proteins that are causing much of the trouble, then we have some idea as to why foam cells are sustained by the body. The heat shock proteins produced by these bacteria closely mimic the same heat shock protein produced by the arterial wall (Hsp60). Heat shock proteins are one of the basic lego blocks of living cells, and there's not a great deal of variation between those HSPs produced by highly evolved human cells compared to say, yeast. The fact that HSP60 inhibits programmed cell death is another fascinating thread to pull on. Another possibility that occurs to me is that real bacterial infection may be transformed over a long time into an auto-immune disorder, even if the original bacteria have died off. More research is needed to assess just what the half-life of C. pneumoniae is in foam cell colonies.

Known correlations with heart disease

So how are these bacteria getting through the mucous tissues and into the blood stream? The correlation between smoking and heart disease is explained nicely by this hypothesis. Smoking compromises the lungs, leading to C. pneumonia or some other form of infection, which in turn results in atherosclerosis.

One might expect then that other chronic conditions that break down the walls of the mucous membrane/exterior environment barrier could also lead to atherosclerosis: dietary components that cause leaky gut, periodontal disease, and possibly fungal infections. Alternatively, substances that suppress immune system function could be associated with cardiovascular disease.

Other chronic diseases that results in a breakdown of the bloodstream-mucus-environment barrier should also show increased rates of heart disease. The two most obvious choices to me are celiac disease (where wheat gluten destroys the lining of the intestines) and periodontal disease (of the gums in the mouth). For celiac disease, there doesn't seem to have been any research on the topic. Of course, it would be ethically impossible in a clinical setting to find undiagnosed celiac patients and follow them to assess heart disease. Once celiacs are diagnosed, their treatment is straight-forward (i.e. don't eat wheat or casein). However, perio is more difficult to resolve and the results on periodontal disease seem to be consistent, with perio causing a small (relative risk 1.24-1.34) yet consistent and significant increase in heart disease average over many studies (Cronin, 2009).

Similarly, substances or deficiency of certain materials in the diet that suppress or deform the immune system response could have an impact on heart disease. The most obvious would be insufficient vitamin D intake.

Conclusion

When it comes to the diseases of Western civilization/diet, we always must ask the question, what is the mechanism? A top-down approach is simply insufficient because separating correlation and causation in living organisms is so difficult and one is consistently tempted to simplify the details rather than break them down into first principles. Hence the enormous failure of pursuing cholesterol as a cause of heart disease, instead of recognizing it as a symptom. The false path of the cholesterol hypothesis has to rank of one of the greatest scientific blunders of all time and is indirectly responsible for the premature deaths of millions.

On the other hand, the chronic infection theory of heart disease is internally consistent with the data that are available to us. We know that C. pneumoniae is a common form of respiratory infection, and that once in the bloodstream it can infect smooth muscle and macrophage cells both in vivo and in vitro. We know that C. pneumoniae can disrupt the cholesterol metabolism of foam cell colonies in vitro. The chameleon nature of C. pneumoniae illustrates how foam colonies can be be persistent in the face of the immune system and morph an acute infection into a chronic condition. I just don't see any gaping holes in the theory. We still need to explain why C. pneumoniae (and other bacteria like H. pylori) affects some individuals and not others, but the how is reasonably explained and justified.

Author's note: I started writing this post on May 13th, 2009.

Feynman Lectures on the Web

Bill Gates recently purchased the rights to a series of lectures by renowned physicist and teacher Richard Feynman. Feynman was a nobel winner for and essentially the father of the field of quantum electrodynamics, and also did a lot of work on superfluidity of liquid helium. The breadth of his contributions has to mark him as one of the top physicists of all time, possibly top-five, certainly top-ten.

Feynman proves the adage that it is not science that is staid and boring, but rather scientists are staid and boring. Anyone who has written journal publications will know what I'm talking about here.

Project Tuva: The Messanger Series

You will need to download and install (Firefox users: manual installation) a Microsoft plug-in to view them but they are really a great resource. In short, they are a perfect way for someone who has only a cursory understanding of science and wants to know more, yet doesn't know where to start. For experts, they are still useful to get your mind out of the minor details that dominate scientific discourse today and thinking about the big picture once again.

My favourite lecture by far is #6 on the dual wave-particle nature of fundamental particles like photons and electrons. This lecture is very close to one of my thesis topics, on the double slit experiment. Interestingly, around thirty minutes in Feynman becomes partially incorrect as he talks about the coherent and incoherent modes as in reality, there is only partial coherence.

Har har har... (you have to be a physicist).

For very small angle scattering, i.e. ΔE/E_o is very small, the interference is less but still present. To put numbers on these, we're talking about ΔE=1-20 eV energy loss compared to E_o=300,000 eV in the denominator, or angles less than 0.004 °.

Vacation

I'm going to Richmond, VA for a conference followed by vacation in Ottawa, ON until the 7th of August. I might crank out a post in the in-term, although I wouldn't bet on it.

Toodles.