I tend to think that when they start throwing ad hominems at you, it is a sure sign of victory.’

–Christopher Hitchens

One of the things I’ve never quite understood about the proponents of the various assorted theories of nutrition is why, for many, the only way to prove your method is by denigrating of the methods of others. Most of the time we’re talking about money, and occasionally, lots of it. Perhaps such is the case for the so-called ‘DNA Diet,’ whose marketing strategy seems to rely on the fact that it is ‘better than the Blood Type Diet (BTD)’.

Perhaps it is. However the poorly-chosen means by which they make their argument seems to imply that they are stupendously ignorant about the basic effects of blood group genetics on physiology. Thus, yet again, your humble blogger is forced to participate in another episode of cheerless infanticide.

These DNA Diet tests are typically direct-to-consumer (DTC) panels of single nucleotide polymorphisms (SNPS) that look for variations in genes that control a diverse number of body functions, such as inflammation, clotting, and detoxification. Lifegenetics is one of the many purveyors of this technology. Others include 23 And Me and multi-level marketers such as Amway and Market America. In a recent New England Journal of Medicine article the ultimate value and benefit of these DTC SNP panels has been called into question. Several authorities have made the point, quite clearly, that molecular diagnostics still have a long way to go before they can properly deliver on all their promises.

Who to believe: Me or your lying eyes?

‘The Blood Type Diet is OUT, the DNA diet is in!

Lifegenetics, marketers of the DNA Diet, breathlessly announce in bold headlines across a gotcha page that compares the Blood Type Diet with the DNA Diet and concluding, not surprisingly, that the DNA Diet is far superior.

Unfortunately, a closer examination of their claims yields no such certainty. Indeed the presentation of the evidence is at times so skewed, and the selected points so cherry-picked, that one wonders how supposed experts in nutritional genomics could be so willing to ignore basic and widely known facts about a very well-studied gene. Let’s take a look:

This diet was started by American Peter D’Adamo. It was founded on observations of his father, a physician James D’Adam [sic], who has alleged that certain blood types are associated with the response to different types of food, and even the type of personality.

True but. The use of the word alleged is a bit snarky, but I suppose acceptable. Like my father, I am a physician. I am indeed American, though I consider myself more a ‘citizen of the world’. Neither myself or my father alleged anything about personality, other than report that it was the object of intense interest in Japanese pop culture. However, there are, had Lifegenetics actually consulted the standard medical reference databases, numerous studies showing links between ABO blood genetics and other genes that do influence nervous function, such dopamine beta hydroxylase, which has been linked to differences in ABO blood group. I’ve made a strong case that ABO does indeed influence many elements and parameters of the digestive tract, including tissue glycosylation, intestinal alkaline phosphatase secretion levels (which controls much of how we process dietary fat), our stomach acid secretions, blood viscosity and even the makeup of our intestinal flora (microbiome).

The whole idea is based on one of the 30 up-to today known systems of blood groups, AB0 system. AB0 group is usually determined from the drop of blood using different reagents. It is therefore a serological and not a genetic test, as some think. It is true that our blood group is written in the genes, but it has no scientifically proven link with the metabolism of our body’s response to food.

This is utter bullocks. Although ABO is one of the many blood grouping systems, the effect of ABO blood type on phenotype (the process by which genetics influences our eventual physical characteristics) is greater than all the other blood systems combined. ABO controls much of the immune reactivity of our tissues –which is why organs must be matched to ABO blood type when transplanted. Your ABO blood type is sprinkled all over your digestive tract, especially in the secretions and protective mucus. It’s ironic to me that they choose to differentiate a serologic test versus a genetic test, as if the methodology in some way led to a different conclusion –other than the fact that former is about 5% of the price of the latter. You could easily determine ABO type via genetic SNP analysis; but the ABO antigens are so biologically prevalent that there is simply no economically viable, common-sense reason to do it.

Basically, every person needs a balanced diet that allows him or her to get all the micro-and macronutrients, essential for the normal functioning of the body, so the exclusion of any food without professional good reason can be dangerous. In the case of eating by blood type diet makes it difficult to understand why many people should not consume certain types of food (such as those containing gluten – which is known to cause problems only to individuals with Coeliac disease).

Not much of a point here. Pray tell, what is a ‘balanced diet’? To my line of reasoning ‘balanced diets’ are what got the largely obese and deconditioned Western world into problems in the first place. A rudimentary analysis of any of the suggested diets for the blood types easily shows that they are nutritionally complete, and indeed even at their extreme represent healthy versions of other current one-size-fits-all diets: The basic type O diet is a healthy low-carb diet, the type A diet is a very healthy Mediterranean type diet. Many individuals, particularly blood group A, seem quite healthy despite the exclusion of certain foods ‘without professional good reason’. Here on planet Earth we call these people “vegans”.

If we look into the databases of journals and scientific papers, we do not find a single research or clinical study by Peter D’Adamo that could scientifically support his theory. Digestion and metabolism are very complex processes, dependent on hundreds of parameters. Therefore any generalization of their properties and furthermore prescribing certain food groups on the basis of a single variable, such as blood type, is pointless. A simple proof for that is a quick look at the blood types of the population of adults with lactose intolerance (who in fact should avoid eating dairy products) – we can find people with all blood types that are lactose intolerant.

There is no shortage of publications written by yours truly on the importance of blood groups available. I’ve even written a textbook on the subject. It is true that lactose intolerance is not predictable by blood group. It is also true that most people who are lactose intolerant do not need a very expensive genetic test to figure this out for themselves. Incidentally, a scan of Medline (PubMed) for any studies associated with the term ‘LifeGenetics’ did not yield a single result.

Follow the money.

A quick tour of the website offered some other interesting points of comparison. Concerned about that mid-life sprawl? Why not order the ‘DNA Slim Test'(249 Euros, 327 USD). Ever-anxious new parents can order the ‘DNA Test Baby Panel’ (299 Euros, 393 USD) to make sure their kid is all there. Why stop? LifeGenetics can supply you with a ‘Complete Healthy Makeover’ for the small sum of 399 Euros (525 USD). In terms of profitability, the BTD does indeed makes a rather poor showing. One can usually find out their blood type for free at any blood bank or blood drive; lacking that availability, FDA-approved home blood typing tests are available for under 10 USD.

It’s disgraceful when a supposedly science-based corporation feels a need to market their products in this manner. Yet, in a way, I can understand why Lifegenetics would feel such a need to disparage the me and the BTD. The BTD books are worldwide multi-million copy bestsellers and the concept has huge name-brand recognition. In other words, in some scientific circles, my work would be more likable if it were just not so wildly popular. I suppose they just resent having to answer questions about the BTD all the time. Many corporate dinosaurs have yet to realize that this type of marketing does not work in the age of social media, and when the chosen target so chooses to confront assertions with facts, can risk becoming converted into a form of self-immolation.

Personally, I lost interest in SNPs long ago when I became aware of the more direct effects that diet had on gene expression via the various epigenetic mechanisms.

Tags: blood type diet | DNA Diet

Wikipedia is an amazing online resource for reliable information. Most of the time.

In general, Wikipedia is most reliable when the entries are devoted to technical topics for which there is little controversy or a minimum of divergent opinion. Entries that are devoted to topics which may have minority opinions that diverge from the currently accepted norms are often less reliable or do not always provide coverage from a neutral point of view.

Neither I (nor apparently anyone else) cannot add supportive research evidence on the page devoted to the blood type diets. My personal page was such as source of upset to my kids that I petitioned WP to take me off. Apparently there is no way to do this, other than to make the case that you are not notable. So I asked someone over there to declare me to be ‘not notable.’ After I was removed I read on several websites a gloating note that I was removed from WP because they had decided that I was not notable. Now if you type in my name it goes to the entry for the BTD which, of course, takes me back to square one. That’s why I decided to write Alternapedia.

Keeping the 99%. Fixing the 1%.

Alternapedia was written to offset the institutional bias against many forms of integrative and alternative medicines often displayed in Wikipedia entries. Ninety-nine percent of the time Alternapedia provides content via a direct link to a reliable Wikipedia entry, albeit in an aesthetically nicer package. In instances where the Alternapedia editors feel that the Wikipedia entry on a subject is faulty, Alternapedia editors instead create an ‘alternative article’ that is stored on our server that provides content to a more balanced, neutral appraisal. Alternapedia is not designed to restrict your access to information: When it supplies one of its alternative entries, you are also given a direct link to the original Wikipedia entry as well, so you can best judge for yourself the relative merits of each.

Despite these problems, Wikipedia remains a huge force on the internet, and supporters of natural health and integrative medicine cannot simply accept the current situation. If every one of our readers with internet and especially Wikipedia skills, took a hand in writing and creating alternative articles with Alternapedia, using verified scientific information with suitable citations, the situation could be improved radically. Now more than ever this is especially important, as health consumers deserve the best information possible.

Alternapedia Link.

Tags: Perl

“At one time, the earth was supposed to be flat. Well, so it is, even today, from Paris to Asnieres. But that fact doesn’t prevent science from proving that the earth as a whole is spherical. No one nowadays denies it. Well…we are still at the stage of believing that life itself is flat, the distance from birth to death. Yet the probability is that life, too, is spherical and much more extensive and capacious than the hemisphere we know.”

-Vincent van Gogh

Towards a Theory of Generativity

Allegorical indications of generative-type thinking exist as far back as the written record. Early cave paintings of animal herds represent a primordial attempt at modeling a complex phenomenon. Most early societies placed the priest-healer-shaman right at the center of the local belief system, responsible for the weather, crop yields and success on the battlefield as much as the health of the populace. Their observation that sick people often seemed to miraculously self-heal lent a strong argument to the notion that the cure was often in large part spiritual and mystical, although these early physicians were practical enough to investigate the use of herbs and other natural products as well. However these agents were more or less tried against the ‘system as a whole,’ as this was best where the salutary effects of the agent could be noticed.

In time as the practice of medicine became more refined as an elemental splanchnology (the anatomy of viscera) became more integrated into medical thinking, undoubtedly, at least initially, from its use in haruspicy (divination through entrails) and eventually surgery. From this developed the initial awareness most of the organs were critical to life, and that somehow their proper integration was critical to optimum health. Thus evolved the paradigms of balance, which came to dominate the medical doctrines of virtually all the great cultures of the ancient world. Excesses and deficiencies of energies in the great organs of the abdomen, chest and pelvis would be treated by intervention until some degree of harmony was achieved.

Because each individual had their own degree and topology of imbalance, prescriptions were highly personalized and many of the agents employed were quite sophisticated in their actions and clinically effective: a testimony to this is the fact that their indications and usage persists in large parts of the world to this day.

The inductive methods that have gone on to typify Western scientific thought were first advanced by Francis Bacon (1561 – 1626), whose Novum Organum (1620) was the first attempt at a replacement for the analytics of Aristotle’s Organon and the subsequent culture of Aristotelianism with its excessive emphasis on teleology (the belief that final causes exist in nature) that had hampered scientific investigation during the medieval age. The Posterior Analytics section of the Organon deals with the demonstration of scientific knowledge, maintaining that ‘to know a thing’s nature is to know the reason why it is.’ [1]

Swarm behavior

Bacon’s method consisted of procedures for isolating and further investigating the form nature, or cause, of a phenomenon, including the method of agreement, method of difference, and method of concomitant variation. [2] Thus, if a plant yields more fruit when watered daily, and less fruit when watered weekly and when it is more or less successful according to the frequency of watering, then it is scientifically reasonable to say that being frequent watering is causally related to the plant’s fruit yield. Throughout the subsequent centuries, Bacon’s method of induction was amplified and further developed by René Descartes (1596 – 1650) who advanced the idea of mechanistic reductionism.

Reductionism can best be seen as an approach to understanding the nature of complex things by reducing them to the interactions of their parts, or to simpler or more fundamental things. Reductionist philosophy holds that a complex system is nothing but the sum of its parts, and that an account of it can be reduced to accounts of individual constituents. The basic question of reduction is whether the properties, concepts, explanations, or methods from one scientific domain, typically at higher levels of organization, can be deduced from or explained by the properties, concepts, explanations, or methods from another domain of science, typically one about lower levels of organization. [3]

Clocks and Blenders

Unlike the generativity, reductionism cannot readily impute the behaviors of a complex system, given that its basic methodology depends upon the interpretation of discrete linear cause and effect relationships that often fail to typify the world at large. One can dismantle a spring-driven clock rather easily, and with a minimum of mental effort, soon clarify the relationship between the power train, gearing, escape mechanism, verge, crutch and pendulum. However it would take an enormous leap of imagination to discern that the major function of the device was to simply convert energy stored in the spring into the a reflection of the passage of time. The account of the device cannot understood from the role of the elements of the device, because the account is simply the length of time the clock has run, which is really reflective of information gain and not work performed.

Dismantling a clock does not give an indication as to its ultimate purpose.

An example of this is the time-honored tendency in medical education to split the life sciences into two very distinct and teachable subjects: the study of normative processes; physiology, and the study of diseased processes; pathology. Attempts to employ a more nuanced approach to the subject, i.e. textbooks in pathophysiology typically describe one aspect or the other, with perhaps the added convenience of the entire exercise finding itself within the confines of a single cover.

The goal of this monograph is not to criticize reductionist thinking, nor proffer the suggestion that generative strategies somehow substitute for reductionist thinking. Reductionism has few faults as a logical device when employed under the conditions for which it was designed. Most of the problems with reductionism lie with the thinker, not the paradigm, since a difficulty usually arises when the scientist misapplies it as a modeling device, or expects its predictive capabilities to be uniform under any and all scenarios and circumstances. Reductionism has traditionally stood opposed to the precepts of vitalism; the premise that living organisms are fundamentally different from non-living entities because they contain some non-physical element or are governed by different principles than are inanimate things. [4] The generative paradigm can be seen as a tool with the capacity to extend the utility of both systems.

The mathematical biologist Jack Cowan devised a simple thought experiment to help determine if the reductionism is suitable for a proposed experiment: Simply drop the object of interest into an imaginary kitchen blender and throw the switch. If after a minute or so, the experimenter is still interested in the material in question, the investigation can proceed via purely reductionist modeling. [5]

From its earliest beginnings naturopathic philosophy has simultaneously struggled and embraced the dualities of reductionism and holism, linear and non-linear determinism and the reality of complex adaptive systems, because it held to the tenets of vis medicatrix naturae (Vis) long after most other medical disciplines had rejected its precepts as simple vitalism. The generative paradigm attempts to fit the doctrines of holism, complexity and the Vis into a framework that is buttressed by the recent advances in bioinformatics, molecular genomics and network combinatorics. The result provides a new, exciting and helpful way of predictive modeling that combines traditional naturopathic healing wisdom with a strong and robust conceptual framework.

1. Aristotle, Posterior Analytics. Mure, GRG (translator) (2007); The University of Adelaide: http://ebooks.adelaide.edu.au/a/aristotle/a8poa/contents.html
2. Hesse MB. ‘Francis Bacon’s Philosophy of Science’, in A Critical History of Western Philosophy. (1964); O’Connor, DJ (editor) New York, pp. 141—52.
3. Brigandt I and Love A. ‘Reductionism in Biology.’ in: The Stanford Encyclopedia of Philosophy (Summer 2012 Edition), Edward N. Zalta (ed.), http://plato.stanford.edu/archives/sum2012/entries/reduction-biology
4. Bechtel W and Richardson. ‘Vitalism’. in: Routledge Encyclopedia of Philosophy. (1998) London: Routledge. Craig E. (Ed.)
5. Wimsatt W. Re-Engineering Philosophy for Limited Beings: Piecewise Approximations to Reality. Cambridge: Harvard University Press. (2007)

I wrote this note as a comment on my colleague Rick Kirschner’s blog:

I thought long and hard on this, especially since I’ve spent a lot of time dealing with misrepresentations of my own work. On one hand there is the ever-present desire to turn the other cheek and convert my response into a teaching opportunity. This works in certain circumstances –often if the skeptic is actually curious about that which they are skeptical of.

Most are not.

In most other circumstances, turning the other cheek will often get that side of your head smacked as well. As Ho Chi Minh once said in reference to Mahatma Gandhi, “Had he grown up in Vietnam, he’d have ascended into heaven long before he did.”

Because these people are often prisoners of their own zealotry their tactics are not very often of the velvet-glove variety. Since they don’t respect that which they are skeptical of, and anything goes and every tactic is permissible

Of course this automatically brands them as pseudo-skeptics not skeptics, since true skeptics are more than happy to amend an existing opinion with the presentation of new evidence. Most of these guys just feel that modern allopathic medicine (and hence the public) is under attack from vicious, dangerous woo-merchants and it is their anointed job to exterminate this vermin.

Thus it is unlikely that appeals to reason will ever work effectively, since dialogue is not what they are interested in — anymore than someone would ever be interested in dialoging with a cockroach before they stepped on it. People who dialogue with cockroaches usually don’t step on them.

Like Ho, Adolf Hitler also had an opinion of Gandhi, remarking once to Lloyd George: ‘Why doesn’t someone just shoot him and be done with it?’

Let’s call a spade a spade: The more extreme of these ‘anti-SCAM’ pseudo-skeptics will not rest until we’re completely discredited and eliminated.

Thus their tactics and criticisms are almost always of the ‘gotcha’ variety. This is usually performed by trying very hard to cover their opponents in manure so that they can stand back, point to them and say ‘look, they are covered in manure.’

Gerhard Uhlenbruck, the worlds leading lectin researcher, and one of the few scientists who has openly acknowledged the value of my work has a nice way of reflecting on the silliness of what these people do with their time:

“Never chase a lie. Let it alone, and it will run itself to death.”

Stephen Jay Gould also had a nice way of turning the tables on pseudo-skeptics. This from ‘The Structure of Evolutionary Thinking’ (2002):

“If none of the foregoing charges can bear scrutiny, strategists of personal denigration still hold an old and conventional tactic in reserve: they can proclaim a despised theory both trivial and devoid of content. This charge is so distasteful to any intellectual that one might wonder why detractors don’t try such a tactic more often, and right up front at the outset. But I think we can identify a solution: the “triviality caper” tends to backfire and to hoist a critic with his own petard — for if the idea you hate is so trivial, then why bother to refute it with such intensity? Leave the idea strictly alone and it will surely go away all by itself. Why fulminate against tongue piercing, goldfish swallowing, skateboarding, or any other transient fad with no possible staying power?

So, if Uhlenbruck and Gould are correct, why do so many people spend some much time making life miserable for people with new ideas?

Probably because, although we talk of ideas, it all distills back down to power and money. New ideas often threaten the exact type of person who (personality-wise) would go on to make the perfect pseudo-skeptic. The type of person who buys into the existing power structure, hook, line and sinker. Anything that takes away from the reflected light (‘My son the doctor.’) they have spent so much time and money on gaining. For which they so sacrificed and assiduously played the game in order to secure. This is not just a threat — it is also a nightmare.

So what is the answer?

Like any test of will (and for a myriad of reasons) victory goes to those with the ultimate staying power.

In military terminology there is a tactic called ‘the refuse.’

Back in the old days, these guys would just line up opposite each other on some level field and go at it. Typically, since most people are right-handed, the right side of an army’s line would often be stronger than the left. Thus the idea of any good commander would be to ‘refuse’ to fight (usually by slowly pulling back) on his left side while trying to press the advantage on his right.

This is a fundamental tactic in Aikido martial art. It is called ‘entering,’ the idea being to enter inside the physical space of the attacker and then by turning as you enter, you align your force with his and for a brief transcendental moment, see the world as he sees it. Very hard to have a fight with someone who is trying their hardest to see your point of view. It is very hard to hit something which has as its ultimate goal to be where you are not.

I stopped writing for pseudo-critics years ago: You can’t please them, they won’t buy your books anyway and the people I really want to help educate don’t want to read that type of stuff.

I just refused to do it.

Now, while most magazine articles critical of my theories have long-ago been relegated to the landfill, you can still buy my first book only in hardcover despite being twelve years in print.

Why? Because the theory works in many people and they go on to tell other people.

Now, if I need to buy a new hammer I’d be somewhat interested in reviews that tell me which hammers ‘not to buy,’ but ultimately if my best friend tells my which brand of hammer he’s happy with, I’m probably going to go with that advice. I would also find questionable reviewers who had nothing good to say about all hammers in general.

Let’s commit to always doing the hard work. Let’s accept the fact that we practice a revolutionary form of medicine and let’s stop looking for approbation from the very people whose preeminence we threaten and who cannot appreciate the strides we’ve made and the struggles we’ve endured in order to put this profession back on its feet.

Let every patient see the value of what we can do. These pseudo-skeptics will always have their coffee claches; their little goldfish bowls, where naturopaths do nothing right and allopaths nothing wrong. But let’s refuse to make it into something bigger than it really is, because that is not the main battlefield.

Instead, let’s wake up every day determined to redouble our efforts to improve the lives of our patients.

I’ll end this diatribe with two more Vietnam Era quotes, which to me seem oddly relevant since US health care is currently in a Vietnam-like quagmire.

The first is from Lyndon Johnson, a fundamentally un-quotable president. Johnson did once say something I thought was of note. In dealing with criticisms of his Great Society program, he was heard to say:

‘It takes a master carpenter to build a good barn. Funny thing though, is that any fool with a match can then burn it down.’

Let’s remember that we are master carpenters. The public can be trusted to see the benefit of good barns. Let’s also refuse to put the matches in the hands of our opponents.

The second quote is from a meeting between a Vietnamese general and an American general in Hanoi several years after the war ended.

‘You know’ said the American general, ‘you never beat us in a single battle.’

‘Yes, that is true.’ replied the Vietnamese general, ‘however it is also irrelevant.’

Remember water always beats rock. That’s because water can go around rock. Let’s refuse to butt heads with rocks.

And as the quote goes “Medicine progresses funeral by funeral.”

They were referring to the doctor’s funeral, not the patient’s.

A few months after his death in 1528, Vier Bücher von menschlicher Proportion (“The Aesthetic Anatomy of Human Proportion”) by German artist Albrecht Dürer was published in Nuremberg. This work, written, illustrated and designed by Dürer, with woodcuts on virtually every page, was the first book to discuss the problems of comparative and differential anthropometry. The classic aesthetic treatises of Villard de Honnecourt, Vitruvius, Alberti and da Vinci influenced Dürer, however, Dürer’s study of the different human physiques—fat, thin, tall, short, baby, child and adult —was entirely original.

Dürer held that the essence of true form was the primary mathematical figure (e.g., straight line, circle, curve, conic section) constructed arithmetically or geometrically, and made beautiful by the application of a canon of proportion. However, he was also convinced that beauty of form was a relative and not an absolute quality; thus, the purpose of his system of anthropometry was to provide the artist with the means to delineate, on the basis of sheer measurement, all possible types of human figures.

Albrecht Dürer, German Northern Renaissance Painter and Engraver, 1471-1528

Generally, morphometrics (from the Greek: “morph,” meaning shape or form, and “metron,” meaning measurement) comprises methods of extracting measurements from shapes. In most cases applied to biological topics in the widest sense. Schools of morphometrics are characterized by what aspects of biological “form” they are concerned with, what they choose to measure, and what kinds of questions they ask of the measurements once they are made. In many cases involves calculating angles, areas, volumes and other quantitative data from landmark and segmentation data.

Auxology is a meta-term covering the study of all aspects of human physical growth; though, it is also a fundamental of biology, generally. Auxology is a highly multi-disciplinary science involving health sciences and medicine (pediatrics, general practice, endocrinology, neuroendocrinology, physiology, epidemiology), and to a lesser extent nutrition, genetics, anthropology, anthropometry, ergonomics, history, economic history, economics, socioeconomics, sociology, public health, and psychology, among others.

Directly observable characters —such as the shape, size, and color of the body and its parts —were formerly the only means of classifying individuals and populations. They have several disadvantages for this purpose, particularly their complex inheritance, and the fact that almost every character is influenced both by heredity and by environment.

Although they have, for these reasons, largely been superseded for purposes of classification by the blood groups and other hereditary genomic markers; it must be kept in mind that they are still the means by which, in everyday life, we recognize people. We should also recall that quantitative observations of them are the only means we have of comparing skeletal material and observations made on the living before the discovery and application of the blood groups, with people living today. They also present very clear indications of probable natural selection in relation to the environment.

They must therefore continue to be observed with as much precision as possible. It would be a great advantage if their heredity could be more fully understood. It is now clear that almost any one single character, such as stature, is the effect of genes at a considerable number of different loci, so that they are known as polygenic characters.

Developmental noise is defined as perturbations in the developmental environment that arise from random fluctuations at the molecular and cellular level and canalization is the buffering of development against many, if not all of those perturbations. There is currently a bit of a debate as to whether canalization and developmental stability are the same thing. Arguing against this is the fact that canalization reduces the effects of environmental and genetic insults and thereby reduces variation. (1,2) It is sometimes the practice to speak of homeorhesis (“stabilized flow”) a phrase coined by Waddington, (3) and encouraged by others (4) to describe a sort of a developmental trajectory, distinct from canalization, that refers to the capacity for a structure to develop along an ideal developmental trajectory under a particular set of environmental conditions. The sensitivity to random perturbations —or developmental noise— can be viewed as the tendency of a developmental system to produce a morphological change in response to these perturbations and is often called developmental instability.

1. Wilmore KE and Hallgrimsson B. Within Individual Variation. In: Variation, A central concept in Biology. Elsevier Academic Press. London (2005)
2. Van Valen L. A study of fluctuating asymmetry. Evolution, 16. (1962).
3. Waddington, C. H. (1957). The Strategy of the Genes. London: George Allen & Unwin.
4. Zakharov, V. M. 1992. Population phenogenetics: Analysis of developmental stability in natural populations. Acta Zool. Fenn. 191: 7-30.

A design for a book jacket that kills other diet books.

One of the features of any network is the appearance of motifs, patterns (sub-graphs) that recur within a network much more often than expected at random. These small circuits can be considered as simple building blocks from which the network is composed. This analogy is quite useful, since many of these motifs would appear to have their corollaries in electronic circuitry. Motifs appear to play an important role in transcription factor regulation, which is pretty significant, because transcription factors regulate the expression of most genes.

Electronic circuits spend a lot of their time filtering out noise, and many motifs in molecular biology do this same function. Most of this noise is stochastic: a charmingly ancient Greek word that more-or-less equates to random, but not exactly, being derived from the Greek stochastikos, ‘skillful in aiming.’ To me, stochastic embodies the old saw that ‘if something can happen, it will.’

Stochastic occurrences mess up our pretty, deterministic, view of how things happen. For example, the response of our bodies to radiation therapy is stochastic since not every cell receiving the radiation energy is at a point in its life cycle when the radiation therapy can effect it: Some cells are (those currently reproducing) whilst other cells are not (those currently at rest). This is a problem when one uses methods of measurement that are Gaussian (i.e they ‘average things out’) because these types of measurement will yield indications of a more gradated response than really occurred.

Stochastic music was pioneered by the composer Iannis Xenakis. Unfortunately, while undoubtedly making for interesting math, I agree with this author that the music sounds more or less like an hour-long extended visit to a junk yard. I do like some of Xenakis’ other music though, such as Metastaseis..

Stochastic versus graded response.

Most network motifs try to soften up the responsiveness of transcription factors to stimulus with a high signal to noise ratio, sort of like how an experienced parent can tell the difference between a crying child who just needs to nap versus a child in true distress.

Since developing the Quodlibet module in Datapunk I’ve been increasingly aware of the need to incorporate these types of motifs in my network calculations, when and where they show up. Quodlibet currently does quite a bit of graph/network/combinatorial calculation already (click on the Analytics link in any molecular map to see it at work) so looking for network motifs seemed the logical next step.

I mostly work in Perl, so I often take advantage of CPAN (The Comprehensive Perl Archive Network) which hosts a wealth of Perl modules, including a terrific collection of bioscience libraries, such as Bioperl. These modules are what makes Perl so great: you do not have to reinvent the wheel and in many instances you don’t even have to know exactly how the wheel works. Just plug it in, feed it good stuff and get the output. CPAN has been a great asset with Quodlibet, but contained no modules for network motif detection. Fortunately an online homework assignment provided me with the means to get started.

However, before I launch into any of that stuff, in my next blog I’ll take a look at the most common network motifs. These have been identified largely through the work of Uri Alon and his lab at the Weizmann Institute of Science in Israel, and if your interest runs in the direction of computational biology, I recommend that you take a look at his book Introduction to Systems Biology: Design Principles of Biologic Circuits (Chapman and Hall/CRC). The loop is a basic network motif, so next blog we’ll take take a look a a few variations to get an idea about how these things work things.

Like the digital circuitry in your computer, clusters of network motifs are capable of computational processes. Think about this: Humans share about 98% of their genome (at least the sequences) with apes. This of course begs the question ‘why are we not more similar?’ The answer is that while we share much of the base sequences, there are tremendous differences in the ‘computational knowledge’ that acts upon these sequences, in particular the networks involved in transcription factor regulation: operons, regulons and modulons. It is the ‘combinatoric wisdom’ that seems to differentiate between the classes of life forms.

It is not enough to be in the right place at the right time. You should also have an open mind at the right time. –Paul Erdos

One thing I’ve noticed about my work with blood groups, which has done much to convince me that it is truly valuable, is the fact that it seems to make a considerable number of conventional and alternative practitioners equally apoplectic.

Recently, on a Facebook group that I belong to, a participant asked the other members what they ‘thought about the Blood Type Diet’. I was surprised by the intellectual horizon of many the responders. It seemed that the practitioners who were skeptical of the theory had tried it once for a while, or had known or heard of someone who had tried it unsuccessfully, and did not support its use for these or similar other reasons.

I had left this group a while back, after a particularly snarky attack from a Ayurvedic practitioner, who went to great lengths to prove that Ayurvedic classifications were superior; using, of course, himself as an example. As a blood type A, he tried to make the point that while a vegan, he was always sick, as if to prove that the type A diet is a vegan diet, which it is not.

It brought back to mind this quote from Sinclair Lewis:

It is difficult to get a man to understand something, when his salary depends upon his not understanding it.

This current discussion thread included a response from an acupuncturist and was quite typical of the more negative responses:

I don’t think its ready for prime time. Lectins in blood are not the whole story. When I eat as recommended for my blood type I get bloated and gain weight.

To me this brought up the question of what happens when we evaluate information simply and exclusively by whether we like or agree with it. Read any diet blog, pro or con something, and you’ll quickly see just how pervasive this is.

I wrote this response and thought I’d share it.

In any discussion one can expect a combination of facts, experiences and opinions. All are valid in their own way. Partial stories can be helpful as well.

Some basic facts: the digestive tract normally glycosylates in a manner influenced by age, diet, pathology, species, microbial load, ABO group and ABH secretor status. That is just basic glycobiology and this list of contributing factors is well-known.

The same is true in any scenario characterized by aberrant glycosylation, which in its own right, characterizes an extraordinary range of pathology: malignancy, inflammation, dysbiosis, and aging all show derangement in glycosylation. Indeed in most cases it is their preeminent phenotypic manifestation. So at its very minimum, as a member of this list, ABO/secretor is a partial predictor of all this. Aside from that a variety of phosphatases, brush border hydroxylases, and who knows how much of the microbiome is conditioned by ABO expression in the gut. Any PubMed search should suffice to prove the point.

Out of the box, the basic ABO-only diets developed for each blood group work in about 80% of the people who employ them. That percentage is from over 8000 case reports generated off of our main website from 1999-2003. Certainly not perfect, but then again what is?

Confirmation biases aside (and they are obviously there), the data showed one particularly interesting trend: the 80/20 percentage was consistent across the groups. In other words, 80% of the type Os claimed the diet was beneficial, as did 80% of the Bs, 80% of the As, etc. Now as anyone who has read even the basic book can tell you, the A diet looks nothing like the O diet. However 20% is obviously a large number of unhappy people, and it is entirely feasible that any given person can reside there. There can be a plethora of reasons why the the recommended diet for a blood type could fail, perhaps in the great majority of cases even for reasons that have nothing to do with blood type.

Although cheap as hell, a simple ABO is a still a pretty rudimentary approach and a second gene (FUT2) which controls one’s ability to ‘secrete’ their blood group substance in a free unbound form can be an important additional discriminant. Adding this to the mix does clean up the results a bit, especially by identifying the the so-called ‘nonsecretors’ who are genetically unable to secrete their blood group antigens in an unbound form. Interestingly enough, nonsecretors make up 20% of the population and the literature is rich in references to a variety of pathology issues linked to this outcome. But that is another story.

Now, what to do about experiences and opinions? They can be honored in their singular nature, but they don’t move the discussion very far. To a person who has gotten no results from acupuncture, homeopathy or Ayurveda, these are all useless things. But we all know that in larger data sets they can and do appear to help a great majority of people. Something doesn’t have to work in everyone, or every practitioner, to be useful.

Thanks for reading.

Take your everyday Super Bowl stadium.

Now multiple that by 48.

Although the post spends a lot time discussing the 20% who don’t respond to the basic ABO diet, let’s spend a few moments describing the societal effects of the 80% who apparently do. As of December 2011, my books have sold a total of approximately six million copies. Assuming that each book is used by one individual (a moderate estimate, since most purchasers seem to implement the program for other family members as well) and then subtracting 20% (1,200,000) from this number (assumed non-responders) yields about 4,800,000 individuals who may have theoretically benefited from changing their diet in this manner.

Let’s put a visual on this. Assume that the average Super Bowl audience is 100,000 fans. An aerial shot of the number of people who have benefited from this theory would have to include 48 fully-packed Super Bowl stadiums.

As Vladimir Lenin quipped, ‘Quantity has a quality all of its own.’

Although participating in these types of discussions is much like shoveling the stables of King Augeas, it made me think about how flippant we can be with our words and deeds and how much truth gets locked away in a vault of our own mind, simply because, as F. Scott Fitzgerald famously alluded, we failed the test of having the ability to hold two opposed ideas in mind at the same time and still retain the ability to function.

* BTW: Most common discovery about people who visit the forums on my main website and report that the diet did not work for them: They had their blood typed wrong or had remembered or been told incorrectly.

Peter D’Adamo, ‘Practical Glycomics’ (10/23/11)

Initial hour of six-hour, day-long seminar done for the UB Nutrition Institute, October, 2011.

Peter D’Adamo, Flying Spines (1981)

Imagine that you are the owner of a small factory that makes replacement windows.

Normally, your ordering department does a pretty good job of things and the supply of the constituent parts necessary to make a decent replacement window (one assumes these to be things like glass, vinyl, aluminum, hardware, etc.) arrive punctually and in sufficient amounts to allow you to make the maximum number of windows with the minimum amount of wastage.

However, over time changes in personnel lead to problems of supply and demand. Tired, jaded people in the ordering department forget a decimal point and you wind up with an excess of window locks; poorly-trained workers on the assembly line make a variety of newbie-type errors that result in windows that are unsellable. Over time this pile of unsellable windows begins to accumulate to the point where it begins to clog up the aisles, creating an unhealthy workplace. Soon the corporate bank account is drained due to excessive purchasing and the assembly area is choked with unusable, unsellable, windows. Workers begin to grumble about the unsafe working conditions and a few threaten to strike unless conditions improve. An investigation seems to indicate that your factory supervisor, Mr. Mtor, has a grudge against you due to his being passed up for a promotion at his last salary review and has been going around sabotaging things by telling the workers to not bother about quality control and cleaning up after themselves.

Concerned about the future of the family enterprise, you fire Mr. Mtor and hire a sharp graduate of Wharton School of Business and soon things begin to right themselves. A special work team is put together to go through the piles of unsellable windows, cannibalizing parts that can be reused to create properly constructed, sell-able windows. All new orders are now reviewed to insure that no duplication or excess inventory is allowed to siphon off precious capital and storage space. Soon conditions begin to improve, your workers seem much more happier, and productivity and profitability skyrocket.

Welcome to the wonderful world of cellular autophagy.

Autophagy (‘self-eating’) is a catabolic (breakdown) process used by cells to degrade and remove some of their internal components deemed to be unnecessary or undesirable. Like our window company, cells are little factories of a sort, and as such they function under many of the same dynamic considerations: Things accumulate; byproducts are produced that can’t do anything, etc.

In cells these byproducts are usually some sort of misshapen protein that folded in some manner incomprehensible to the cell and hence not usable. This is not all that uncommon and many common chronic diseases are characterized by the production of proteins that did not fold properly. Much like having a rock in your shoe, having misfolded proteins in the synthetic/secretory parts of the cell factory (an organelle called the endoplasmic reticulum) results in what is known as the unfolded protein response, a stress reaction to these weird proteins.

Eat them up yum yum.

This phenomenon is called ‘ER Stress’ and can result in either of two outcomes.

Try to fix things or at least spit it out: The response to the misfolded proteins can trigger molecules called chaperones that can attempt to fix/refold the proteins into something usable. Lacking this response, the cell can attempt to encapsulate the offending stuff, digest it, and then spit the capsule out. This is autophagy.

Failing that, call it quits: If things are so bad, sometimes the cell just calls it a day and commits at type of cellular hari-kari suicide called apoptosis.

In addition to acting as a type of cell cleansing mechanism, autophagy is a very old survival tool. Like a factory deprived of raw materials because of a transit site, cells deprived of nutrients will scrounge around the workplace looking under tables and behind cabinets for surplus parts. In the cell’s case, when deprived of nutrients like the amino acids tyrosine and methionine, the cell will begin to breakdown parts of itself to keep going. Much of the time, this breakdown is a good thing, and perhaps explains why things like calorie restriction seem to increase lifespan: under those conditions the cell is munching away at itself, and since it is no fool, a lot of what it munches away at is junk best gotten rid of anyway.

Autophagy is normally kept under control by a protein called MTOR that acts as a sensor for conditions that might require autophagy. Normally MTOR blocks autophagy, so when it is inhibited, autophagy strikes up the band. MTOR can get screwed up in cancer, which is not a great thing since autophagy tends to block the apoptosis suicide mechanism (why kill yourself when things are working this great?) This has led some to posit that enhancing autophagy might not be a great thing. However it is probably not this simple as other genes that act as tumor suppressors appear to enhance autophagy by blocking MTOR, so we still don’t know the complete answer on that one.

Two things for sure: autophagy looks like a winning strategy when it comes to neurodegenerative disease and aging. Slower aging associated with decreased MTOR activity, while disease like Parkinsons and Alzheimers are linked to blockages in autophagy.

Some natural products, including epigallocatechin gallate (EGCG), caffeine, curcumin, and resveratrol, have also been reported to inhibit MTOR when applied to isolated cells in culture. More work is needed to see if these work at the level of dietary supplementation.

There are sugars,and then there are sugars.

One interesting agent with well-recognized effects on autophagy is the natural disaccharide sugar trehalose, a sugar produced by bonding two glucose molecules together in a way that differs significantly from the sugar on top of a jelly donut. Trehalose is found in many organisms, including bacteria, yeast, fungi, insects, invertebrates, and plants. It functions to protect the integrity of the cell against various environmental stresses like heat, cold, desiccation, dehydration, and oxidation by preventing the screwing-up of the cell’s protein insides.

Extracting trehalose used to be a difficult and costly process, but recently an inexpensive extraction technology has allowed for its use in a broad spectrum of applications. Trehalose prevents cells from dehydrating, a phenomena that disrupts much of the cell’s insides in way that are not reparable. Trehalose-treated cells seem to resist this because the trehalose ‘splints’ their guts in place, so that when the cells get a chance to rehydrate they come back good-as-new. Dehydrated cells are common with aging, as the aging process tends to thin out the cell membrane, making it harder and harder for the cell to maintain its internal water balance.

Trehalose has been accepted as a novel food ingredient under the GRAS terms in the U.S. and the EU. Trehalose has also found commercial application as a food ingredient. It is available in dietary supplement form.

Maybe the most interesting property of trehalose is its ability to enhance autophagy. Neurofibrillary tangle (NFT) is a characteristic hallmark of Alzheimer’s disease. The accumulation of a protein called tau in the NFTs is one of the characteristic features of several diseases known as tauopathies. In cell culture studies trehalose treatment exhibited significantly decreased level of tau in all tau species.

What is especially interesting about trehalose is that it works in ways that are independent of the MTOR protein, leaving it free to do its work as a sensor of changing environmental conditions.

Turns out we didn’t have to fire Mr. Mtor after all.

The more technically inclined, with an up-to-date modern browser, may want to check out the autophagy network map in Quodlibet.

1. Kim SI, Lee WK, Kang SS, Lee SY, Jeong MJ, Lee HJ, Kim SS, Johnson GV, Chun W. Suppression of autophagy and activation of glycogen synthase kinase 3beta facilitate the aggregate formation of tau. Korean J Physiol Pharmacol. 2011 Apr;15(2):107-14. Epub 2011 Apr 30. PUBMED
2. Rodríguez-Navarro JA, Rodríguez L, Casarejos MJ, Solano RM, Gómez A, Perucho J, Cuervo AM, García de Yébenes J, Mena MA.Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiol Dis. 2010 Sep;39(3):423-38. Epub 2010 May 28. PUBMED
3. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein.J Biol Chem. 2007 Feb 23;282(8):5641-52. Epub 2006 Dec 20. PUBMED
4. Krüger U, Wang Y, Kumar S, Mandelkow EM. Autophagic degradation of tau in primary neurons and its enhancement by trehalose. Neurobiol Aging. 2011 Dec 12. [Epub ahead of print] PUBMED

Tags: autophagy | mtor | Trehalose