Although just about everyone knows something about DNA, I’d like to take a few moments to introduce you to RNA, the real power behind the throne.

Protein represents what biologists call phenotype – the living, breathing, metabolizing part of life. DNA is information. Other than acting as a blueprint and occasionally remembering to replicate itself, it doesn’t have a single real world obligation. It is RNA that acts as the bridge between DNA and protein, translating the message of DNA into the reality of proteins. All the basic functions of the cell require RNA. Copies of the desired DNA gene message are first copied onto one type of RNA, which is then read by a machine composed in part by some more RNA to create proteins by linking amino acids which are delivered by another type of RNA.

Let’s start the second part of our story with the sweet, if short life of Messenger RNA, or mRNA.

At a certain point in its life, the cell may get an urge to make some sort of protein or enzyme. Let’s say that you have developed an untidy habit, like smoking cigars. As anyone who has ever tried one can tell you, the first experience with nicotine is usually far from pleasant, with dizziness and nausea the usual end result. This reaction occurs because the new smoker has yet to habituate himself to the poisons in the cigar and has not yet developed a way to detoxify and break them down. Over time the continued smoking of cigars sends an environmental message to cells of the liver telling them that they need to make higher levels of the enzymes used to detoxify tobacco toxins. This message (“hey, he’s trying to kill us out there!”) travels to the cell nucleus, where special machinery locates the section along the DNA that contains the gene to produce these detoxifying enzymes, snips it open and unravels that part of the DNA to expose the blueprint.

At that point an enzyme called RNA polymerase comes along, reads the DNA code and makes an RNA copy by linking together similar building blocks (a stretch of RNA is similar to DNA except that RNA is almost always single-stranded and uses the nucleotide Uracil instead of Thymine). This is called “transcription” and just like a court stenographer transcribes the court proceedings, so RNA transcripts the proceeding necessary to make a protein. The RNA strand, called Messenger RNA, (mRNA) is then extensively primped and tweaked to clean it up and get it just right. From here it is about to embark on the ride of its life.

Once everything is set to go, the mRNA is shot through the one of the many pores which act as gates between the cell body and the nucleus. Once out into the cell proper it is carried to the real workhorses of protein synthesis, the ribosomes. Using a railroad analogy, you can think of a ribosome as a dispatcher in the rail yard, whose job it is to assemble an entire freight train. Each time the phone rings the dispatcher gets his next order:

“Fetch the Baltimore and Ohio flatbed with the Honda Hybrids on it. Attach it to the Union Pacific 3985 locomotive.”

“Next, locate and attach the milk tanker from Happy Cow Farms.”

And on and on, until you have one of those interminably long freight trains that take twenty minutes to pass by the railroad crossing as you desperately try to get to the airport.

Just like our rail dispatcher, ribosomes get the information from messenger RNA, by zipping along the code like an old fashioned ticker-tape, reading the code called 'codon triplets' to determine which amino acid to fetch, then linking that amino acid to the prior one, and fetching the next instruction, etc. until it gets a stop message.

In this job the ribosome is assisted by a different type of RNA called Transfer RNA which acts like a crusty old rail yard worker, bringing the appropriate amino acid to the ribosome. At some point the protein is finished up and released, and the messenger RNA decomposes back to the basic building blocks of DNA and RNA, called nucleotides, and ready to do it all over again.

From there the sky is the limit. Proteins are interesting in a lot of ways but perhaps most interesting in their folding tendencies, a molecular origami if you will. Depending on the amino acid sequence and length proteins will fold into a myriad number of complex three dimensional shapes, and it is these shapes that give them their unique powers over the environment.

For example a protein of a certain shape may function as an enzyme, taking sugar molecules and attaching them together, turning single sugars onto cellulose, an important dietary fiber. The protein that results from our string of amino acids might be an insulin molecule, helping to control the owner’s blood sugar, or even a protein that helps DNA do its job, perhaps even part of another ribosome!

As I said, the sky is the limit.

The RNA Queen is so basic to life that many scientists think that perhaps life originated with it, and not with DNA: That DNA came along later as a way to 'memorialize' the work of RNA.

Because I attended a Catholic grammar school which was private and did not receive any state or government funding, we were often dispatched on extenuated and cheerless forays out into the public in a quest for its nickels and dimes. This usually included the sale of various candies or 'chance books,” a cluster of five or ten tickets which entered the owner into a drawing of some sort, for a variety of possible prizes.

Never mind that this same public (due to the limitations of spatial geography and the ambulatory capacities of a ten-year old) was already paying through a myriad of other schemes to keep their kids in this very same school. Typically after suitable introductions had been made and accompanied by sufficient eye-rolling and entreaties heavenward, the wallet would be procured and another book of chances sold. Usually, I’d take the opportunity to remind them of what a wise investment they had made, only to be greeted by the sobriquet “Sonny,” and the dismissal of a future possibilities with an off-hand “I’ve never won anything, and I’m not very lucky.”

From that point to this, I’ve always marveled when people tell me that they aren’t very lucky, since of course it is not true. Just wondering about your unluckiness, marks you as being among the luckiest of all. As a matter of fact, you have won one of the greatest raffle prizes of all time; at odds so astronomical so as to be incalculable. You’ve won the raffle of life.

Just think. Your parents first needed to have come from genealogical lines that survived through all the plagues, wars and accidents of time. Second, they needed to be in physical proximity, so as to come into contact with each other. Third, they had to be attracted in such a manner as to stimulate (hopefully) the urge for procreation in each other. Fourth, they had to be in that particular mood at just the time when the team “up at bat” sperm and egg-wise was you. Fifth, the sperm that carried the genetic information from your father had to compete with millions of other sperm in a race that would make the New York City Marathon look like a trip to the store for a newspaper. Sixth, even upon winning, that sperm had to find an egg at just the exact time when it was ripe for fertilization. Finally, after fertilization, the embryo had to travel through the Fallopian tubes and implant in the uterus where it developed form the cluster of cells into something that would eventually grow to the point where it could take care of itself.

So who among us is unlucky?

9/11/09

Last night Dr. Andrew Weil was on the CNN's The Larry King Show. Dr. Weil, reacted to a question about blood types and diet with the response that he thought of the BTD had "no scientific basis". He verified this by saying that if people tested the blood of dogs they would say they should be vegetarian rather than carnivores. I have already addressed this mistaken assertion of Dr. Weil's (humans and other species glycosylate their tissues differently, and linkages of certain physiologic functions to the blood group genes also vary by species), but it seems that he needs to keep re-asserting this incredibly naive argument.

In a series of rotating criticisms Dr. Weil other venues asserted that the problem with the BTD was that he "sees no convincing link between lectins and the molecules which determine blood type." (AARP Magazine) After being subsequently challenged by numerous editorial letters, he eventually responded that "he did not agree with restrictive diets." I've previously responded to Dr. Weil's assertions in this blog, but wanted to resurrect my most recent response and make it a bit more current.

Finally I'd like to challenge Dr. Weil to an open forum discussion of the scientific merits of the theories and associations developed, observed or reported by myself and my father. This can occur at any time or place of his choosing. If he is as committed to investigating the truth of his assertions as one would suspect, I have no doubt that he will be as anxious as I for this to occur. I can be contacted through this blog, or at my clinic.

[Now on to the previous blog entry]

8/18/08

The more I read of Andrew Weil's efforts to debunk the work of my father and myself, the more I'm convinced I can't simply turn the other cheek and let these so-called skeptics just get away with disingenuous portrayals of the science behind this diet. His recent slag-job in AARP Magazine is just more proof that I will need to react in a timely and concise manner going forward.

"D'Adamo theorizes that the basis for such differences is our reactions to certain food proteins called lectins. Lectins are common in plant foods, especially grains and beans, and may be involved in food allergies and some immune disorders. But there is no convincing evidence for any interactions between lectins and the molecules that determine blood type."

"Yet some people swear the blood type diet has worked for them. There's a reason for that. Making changes in how we eat is not easy. To follow any prescribed dietary program with rules and restrictions represents a significant commitment of mental energy toward self-improvement. That alone can lead to a greater sense of well-being and better health. But if you want to eat a better diet, I recommend you rely on information grounded in nutritional science."

I think I got on Dr. Weil's bad side a few years ago when I replied to a question posed to me about my recommendation that blood type As eat peanuts, while Dr. Weil was saying that peanuts were dangerous because of the aflatoxin. My response was that this was a silly piece of advice since the only place you can get aflatoxin is in health food stores when you grind your own peanut butter; all the commercial forms must be assayed for it before they can be sold.

Over the next few years Dr. Weil kept up a consistent attack on me and the theory, usually basing his case on the rather odd observation that animals have blood types and yet don't follow the Blood Type Diet.

However with the AARP column Dr. Weil instead shifted to what he considers the lack of proven association between dietary lectins and blood groups.

It's a bad place to pick an argument, since at that point the argument moves up the academic ladder to areas he would be wise to not tread. There are numerous and well-documented links between lectins and blood groups. Searching MEDLINE for the terms ABO Blood Groups and Lectins yields 687 published studies[0] In fact the term ‘lectin’ was derived in 1954 from the Latin for legere, to pick or choose, it having been coined thus to call attention to their blood type specificity.

Dr. Weil's claim appears to have not been researched to any great degree since it appears to me to have been taken from an incorrect assertion that often finds its way onto the Wikipedia entry on the Blood Type Diet.

In fact, blood group specificity is listed as one of the nine major factors influencing glycosylation in the gut (glycosylation is the process of manufacturing the sugar molecules that lectins bind with). Other factors include diet, age, animal species, disease and bacterial population.

Independent of the lectin hypothesis, in my opinion the secretory differences (digestive enzymes, etc.) between the blood groups are an even more significant reason behind the need for the tailoring nutritional needs to these genetic markers.[1] But Dr. Weil doesn't know about these links or chooses to ignore them altogether. Then again, every critic seems to have their own favorite aspect of the theory.

Given his harsh take on my work, it was surprising to read some of his statements about the need for keeping an open mind about alternative medicine. Kinda wish he would practice what he preaches. In a reply to one of his own critics (Arnold S. Relman, editor-in-chief emeritus of the New England Journal of Medicine)[2], he writes:

"As a researcher, you have the luxury of insisting on rigorous scientific testing, and you have the leisure to wait for results to come in. As a practitioner, you are in the trenches, working with patients who have medical needs. And you often have to guess, and you have to make use of your best medical judgment in the absence of definitive evidence."

No argument there.

"In my experience-- I consider experience to be one valuable source of data--many patients use alternative methods because they find that they work. And if a patient has tried a method and found that it works, that patient needs no further proof, does not need to read the reports of a randomized, double-blind, controlled trial in a medical journal to be convinced of the efficacy of treatment."

Even better.

"I don't think you can have it both ways; you can't demand evidence, and then when evidence comes in that contradicts your preconceptions, say you aren't going to look at it."

Words to live by.

Now if Dr. Weil were to keep an open mind, I'd recommend that he read up on the work of William Boyd, who first wrote of the blood type specificity of lectins more than a half centry ago [3] or review the research of Martin Nachbar[4] from the 1980's. Lots of interesting stuff there. A trip to MEDLINE would also be helpful.[5],[6],[7]

In an article critical of Dr. Weil written for the New Republic Relman touched on many of Weil's factual inconsistencies and concluded that:

Weil considers himself an authority on almost every field of medicine. [8]

Finally, it could be argued that the possible reason Dr. Weil supplies for why some people swear that the blood type diet has worked for them ("a significant commitment of mental energy toward self-improvement") may well be the exact same reason some people derive benefits from his own books, tapes and recommendations!

But let's at least end on a somewhat positive note, with a quote from someone who does have experience with lectins. Gerhard Uhlenbruck is one of about three or four top lectinologists of the last century and renowned for discovering the structure of the Thomsen-Friedenreich antigens and the structure and specificity of (aflatoxin-free, I'm sure) peanut lectin. This is what he recently said:

When I first heard of Peter D'Adamo's blood group diet, of course I was very skeptical: Should we have missed in our book (Prokop/ Uhlenbruck: Human Blood and Serum Groups) such an important aspect? But years later, my interest switched to the nutritional field while working on the so-called Metabolic Syndrome, my interest increased in studying the role of genes in metabolic processes. I found out, that Peter D'Adamo's blood group orientated diet could probably be a first step in the right direction..

Back soon with a more positive, happy and helpful blog.

More 'damned data' (Charles Fort's words, not mine): studies from the scientific literature which could pass for some of the more outlandish statements in The GenoType Diet:

The phenotype of an individual is the result of complex interactions between genotype, epigenome and current, past and ancestral environment, leading to lifelong remodelling of our epigenomes. Various replication-dependent and -independent epigenetic mechanisms are involved in developmental programming, lifelong stochastic and environmental deteriorations, circadian deteriorations, and transgenerational effects. Several types of sequences can be targets of a host of environmental factors and can be associated with specific epigenetic signatures and patterns of gene expression. Depending on the nature and intensity of the insult, the critical spatiotemporal windows and developmental or lifelong processes involved, these epigenetic alterations can lead to permanent changes in tissue and organ structure and function, or to reversible changes using appropriate epigenetic tools. Given several encouraging trials, prevention and therapy of age- and lifestyle-related diseases by individualised tailoring of optimal epigenetic diets or drugs are conceivable. However, these interventions will require intense efforts to unravel the complexity of these epigenetic, genetic and environment interactions and to evaluate their potential reversibility with minimal side effects.

Nutri-epigenomics: lifelong remodelling of our epigenomes by nutritional and metabolic factors and beyond. Clin Chem Lab Med. 2007;45(3):321-7

Epigenomics or epigenetics refers to the modification of DNA that can influence the phenotype through changing gene expression without altering the nucleotide sequence of the DNA. Two examples are methylation of DNA and acetylation of the histone DNA-binding proteins. Dietary components - both nutrients and nonnutrients - can influence these epigenetic events, altering genetic expression and potentially modifying disease risk. Some of these epigenetic changes appear to be heritable. Understanding the role that diet and nutrition play in modifying genetic expression is complex given the range of food choices, the diversity of nutrient intakes, the individual differences in genetic backgrounds and intestinal physiological environments where food is metabolized, as well as the impact on and acceptance of new technologies by consumers.

Epigenomics and nutrition. Forum Nutr. 2007;60:31-41.

Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables, such as broccoli and broccoli sprouts. This anticarcinogen was first identified as a potent inducer of Phase 2 detoxification enzymes, but evidence is mounting that SFN also acts through epigenetic mechanisms. SFN has been shown to inhibit histone deacetylase (HDAC) activity in human colon and prostate cancer lines, with an increase in global and local histone acetylation status, such as on the promoter regions of P21 and bax genes. SFN also inhibited the growth of prostate cancer xenografts and spontaneous intestinal polyps in mouse models, with evidence for altered histone acetylation and HDAC activities in vivo. In human subjects, a single ingestion of 68 g broccoli sprouts inhibited HDAC activity in circulating peripheral blood mononuclear cells 3-6 h after consumption, with concomitant induction of histone H3 and H4 acetylation. These findings provide evidence that one mechanism of cancer chemoprevention by SFN is via epigenetic changes associated with inhibition of HDAC activity. Other dietary agents such as butyrate, biotin, lipoic acid, garlic organosulfur compounds, and metabolites of vitamin E have structural features compatible with HDAC inhibition. The ability of dietary compounds to de-repress epigenetically silenced genes in cancer cells, and to activate these genes in normal cells, has important implications for cancer prevention and therapy. In a broader context, there is growing interest in dietary HDAC inhibitors and their impact on epigenetic mechanisms affecting other chronic conditions, such as cardiovascular disease, neurodegeneration and aging.

Dietary histone deacetylase inhibitors: from cells to mice to man. Semin Cancer Biol. 2007 Oct;17(5):363-9. Epub 2007 May 5

The purpose of this paper was to selectively review the literature on the role of epigenetics in mental illnesses. Aberrant epigenetic regulation has been clearly implicated in the aetiology of some human illnesses. In recent years a growing body of evidence has highlighted the possibility that epigenetics may also play a key role in the origins and expression of mental disorders. Epigenetic phenomena may help explain some of the complexity of mental illnesses and provide a basis for discovering novel pharmacological targets to treat these disorders.

Role of epigenetics in mental disorders. Aust N Z J Psychiatry. 2008 Feb;42(2):97-107.

A complex combination of adult health-related disorders can originate from developmental events that occur in utero. The periconceptional period may also be programmable. We report on the effects of restricting the supply of specific B vitamins (i.e., B(12) and folate) and methionine, within normal physiological ranges, from the periconceptional diet of mature female sheep. We hypothesized this would lead to epigenetic modifications to DNA methylation in the preovulatory oocyte and/or preimplantation embryo, with long-term health implications for offspring. DNA methylation is a key epigenetic contributor to maintenance of gene silencing that relies on a dietary supply of methyl groups. We observed no effects on pregnancy establishment or birth weight, but this modest early dietary intervention led to adult offspring that were both heavier and fatter, elicited altered immune responses to antigenic challenge, were insulin-resistant, and had elevated blood pressure-effects that were most obvious in males. The altered methylation status of 4% of 1,400 CpG islands examined by restriction landmark genome scanning in the fetal liver revealed compelling evidence of a widespread epigenetic mechanism associated with this nutritionally programmed effect. Intriguingly, more than half of the affected loci were specific to males. The data provide the first evidence that clinically relevant reductions in specific dietary inputs to the methionine/folate cycles during the periconceptional period can lead to widespread epigenetic alterations to DNA methylation in offspring, and modify adult health-related phenotypes.

DNA methylation, insulin resistance, and blood pressure in offspring determined by maternal periconceptional B vitamin and methionine status. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19351-6. Epub 2007 Nov

Major efforts have been directed towards the identification of genetic mutations, their use as biomarkers, and the understanding of their consequences on human health and well-being. There is an emerging interest, however, in the possibility that environmentally-induced changes at levels other than the genetic information could have long-lasting consequences as well. This review summarises our current knowledge of how the environment, nutrition, and ageing affect the way mammalian genes are organised and transcribed, without changes in the underlying DNA sequence. Admittedly, the link between environment and epigenetics remains largely to be explored. However, recent studies indicate that environmental factors and diet can perturb the way genes are controlled by DNA methylation and covalent histone modifications. Unexpectedly, and not unlike genetic mutations, aberrant epigenetic alterations and their phenotypic effects can sometimes be passed on to the next generation.

Environmental and nutritional effects on the epigenetic regulation of genes. Mutat Res. 2006 Aug 30;600(1-2):46-57. Epub 2006 Jul 18

The British biologist Conrad Hal Waddington conceived of genotype (your genetic plan) passing through environment into phenotype (the physical you) as a walk through an 'Epigenetic Landscape'. He conceived a mode of visualizing this process, in which phenotype development is seen as marbles rolling downhill. In the beginning development is plastic, and a cell can become many fates. However, as development proceeds, certain decisions cannot be reversed. This Landscape has hills, valleys, and basins and marbles compete for the grooves on the slope, and eventually coming to rest at the lowest points, which represent the eventual types of tissues they become.

The Epigenetic Landscape. (After Waddington, C. H., 1956, Principles of Embryology)

Waddington was a big thinker. Not only did he visualize development as passing through the peaks, slopes and valleys of the Epigenetic Landscape, he considered this process one of increasing constraint, or as being "canalized� as he referred to it: That the early choices influence the later options. If we think of the canals of Venice, the analogy works even better; our little gondola floats from one canal into another and then another. Each choice leaves it fewer options than before, and since gondolas need water, so we can't just pick it up and put plunk it into another canal.

Now just for a moment visualize a newly fertilized egg. It already contains all the wisdom and information needed to eventually go on to produce a completely formed human being in its DNA, but over time it must develop various cell lines (called germ layers) that can then go off and further distinguish themselves as arteries, nerves and organs. Its unfolding is stochastic (a process that is non-deterministic in the sense that the current state state does not fully determine its next state.).

"Stochastic" is one of those great words that is more often misunderstood than understood. It is often quoted as being synonymous with random, but the actual Greek seems to imply something closer to "unknowable." It's often used in the arts (very often in music composition.)

In short: We know it's going to happen; we just don't know what is going to happen.

Your journey from genetic imprinting (the genes that were determined at conception) to full phenotype (the physical you) is to a great degree a stochastic process. which is why Waddington's metaphor is so great. Any architect will tell you that a house almost never winds up like that original plans. Environmental variables (cost of materials, availability) alter reality as the construction project moves from one stage to the other. We cannot always predict the eventual outcome, but we can describe and learn about the landscape in which it takes place and that, to a degree allows us to understand things.

Hindsight is always 20/20, because the outcome almost always describes the process.

That journey started long before your conception, since epigenetic gene control is hereditable.

You are in essence, not what you eat, but rather what your parents, grand parents and even great grandparents ate. Unlike defective genes, which are damaged for life, epigenetically controlled genes can be repaired. And, activation and silencing tags that are knocked off can be regained via nutrients, drugs, and enriching experiences. (1)

Conceivably the cancer you may get today may have been caused by your grandmother's exposure to an industrial poison 50 years ago, even though your grandmother's genes were not changed by the exposure… or the mercury you're eating today in fish may not harm you directly, but may harm your grandchildren (2)

These inherited traits can continue to influence the onset of diseases like diabetes, obesity, mental illness and heart disease, from generation to generation.

All in all, the next few years should prove most interesting...

The post-genomic era, which is fueled by automation and other technologies, provokes a change in our grossly naive view of genetic determinism (that single genes govern complex traits) to the obvious reality that most human diseases are complex entities. Gene(s), although necessary, contribute only partially to disease, while environmental factors, lifestyles, epigenetics and epistasis significantly influence pathophysiology and, eventually, the expression of transient biomarkers that can be utilized for diagnosis and prognosis. Human osteoarthritis and rheumatoid arthritis are multifactorial, complex diseases. The genetic inheritance of these diseases remains elusive, although they tend to run in families wherein some siblings have a two- to tenfold increased risk of developing the diseases.

From: Future of genomics in diagnosis of human arthritis: the hype, hope and metamorphosis for tomorrow
Ashok R Amin?, Seth D Thompson? & Shailey A Amin
Future Rheumatology
August 2007, Vol. 2, No. 4, Pages 385-389

Epigenetic alterations have been known to be of importance in cancer for ~2 decades. This has made it possible to decipher epigenetic codes and machinery and has led to the development of a new generation of drugs now in clinical trials. Although less conspicuous, epigenetic alterations have also been progressively shown to be relevant to common diseases such as atherosclerosis and type 2 diabetes. Imprinted genes, with their key roles in controlling feto-placental nutrient supply and demand and their epigenetic lability in response to nutrients, may play an important role in adaptation/evolution. The combination of these various lines of research on epigenetic programming processes has highlighted new possibilities for the prevention and treatment of metabolic syndrome.

From: Nutritional Epigenomics of Metabolic Syndrome
Catherine Gallou-Kabani, and Claudine Junien
Diabetes 54:1899-1906, 2005

Full Article

1. Asim K. Duttaroy Evolution, Epigenetics, and Maternal Nutrition 2006 Darwin Day Celebration.

2. Montague T. A New Way to Inherit Environmental Harm. Synthesis/Regeneration 39 (Winter 2006)