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Interview with Dr. Mehmet Oz, Oprah and Friends on XM Radio, February 13, 2008

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)

Although I’m probably only one of five people on the planet who have not read it, the blockbuster success The DaVinci Code is just another indication that we humans have an innate curiosity about codes and their relationships and meanings. This blog will take us into the ultimate code of them all: The Code of Life.

By general agreement, a code is a rule for converting a piece of information into another form or representation, not necessarily of the same type. For example, I often write computer programs, most often to do some particular job or another on my website. Most programmers refer to this a “writing code.” Computer programming code appears to the non-programmer as a series of arcane jottings and numbers, but to both the programmer and computer, this code is in reality a series of highly specific instructions, executed step by step, that result in the computer performing some real world action; perhaps posting a message to an internet bulletin board or sending along an email.

Since computer programs are often rather large affairs with many loops and computations, writing good computer code is a daunting -if at other times stimulating- pursuit. It can be reassuring to remember that at any moment in time only very simple, rather dumb things are happening. What makes the computer program so powerful is that all these simple dumb things are happening extremely fast with a tremendous degree of accuracy.

Very few computer programmers can ever claim to have written a perfect program straight off. There are too many places that things can go wrong, computers being the terribly literal creatures that they are. For example, a command that tells a computer to print Hello World! to the screen might look like this:

23. PRINT “Hello World!”;

Simple enough, eh? Like the way we humans typically read books (from front to back and top to bottom) computers execute code from the top down. Thus, our line of computer code is numbered 23, so we can assume that there are twenty odd lines of computer code in front that will be executed before our screen lights up with the words “Hello World!” Perhaps line 22 tells the computer to make the screen font red, in which case our “Hello World!” would be rendered in red colored type. If we remove that line and run the program again, our font color goes back to black.

Look at our line 23 again and you will notice that the phrase you see -- Hello World! -- is in quotes, because in our simple computer language putting a phrase in quotes tells the computer where is the beginning and end of what you want sent to the screen is located. Without this type of instruction, computers are actually quite dumb, and have to rely on us to tell them where the beginning and end of various human things lie. Also notice that at the end of the line is a semi-colon, which in our little computer language tells the computer that this is the end of that particular line of code, so move down one line and execute that command next.

Computers are so literal that a mistake of even one character can cause a program to malfunction. For example, if you saw this line:

23. PRIINT “Hello World!”;

You’d probably guess that something is supposed to be printed. However the computer does not see PRIINT as the equivalent of PRINT. On the other hand if your code looked like this:

23. PRINT “Hello Wurld!”;

The program would probably still execute, since as far as the computer is concerned the command is correct and it’s in quotes, so it assumes that this is probably what you wanted. Once the command is correct, the computer doesn’t care if you tell it to write “Hello Wurld” or “Kick Me”. As long as its own language is correct, the computer will chug happily along, performing its assigned tasks.

Like computers, first impressions, and that light switch on the bathroom wall, genetics is remarkably digit business: On-Off; Yes-No; Love-Hate. So even if it looks complicated at times, don’t be fooled: It’s not. Just remember, like computers, genetics is simply a lot of small things happening in a clear-cut manner and if you get perplexed or lost, just take a step or two backwards and start again.

The mechanism of the genome is surprisingly similar to our simple line of computer code; so simple in fact that I will provide you with an “executive summary” of the whole affair in just two paragraphs.

A molecule called DNA periodically assembles copies of various parts of itself that are called RNA. RNA then travels to other parts of the cell where it is read as an instruction template, assembling chains of amino acids into something very useful: protein molecules of delightfully complex three dimensional shapes that are most often a class of proteins called enzymes.

Enzymes are special speed-up molecules that greatly foster the production and metabolism of the body’s tissues and secretions. Without them many biochemical reactions would occur so slowly as effectively negate their value. Just think about the difference between soaking a dirt stain in plain water for four days, versus soaking it for four minutes in a solution of water and laundry detergent and you’ll get an appreciation for the action of enzymes.

Enzymes catalyze many of the reactions involving proteins, fats, carbohydrates and minerals. Hormones, mucus, neurotransmitters, you name it; they are all made from enzymes.

Bingo. Life.

It sobering and a bit humbling, to ponder the fact that when we eat any kind of protein, we’re actually consuming the results of something’s DNA and some of their DNA as well. However we usually break down dietary proteins to their amino acid building blocks and start all over again.

Occasionally, wild molecular gyrations occur as the incredibly DNA long molecule prepares to replicate by winding itself up tighter and tighter on a tubular scaffold of its own creation. Splitting from the ends much like an old Manila hemp rope would, each of the two unraveling single strands then begins to assemble a copy of its missing partner, producing two unique strands of DNA and creating two daughter replicas from one original.

What happens is surprisingly simple. Good things are like that; a strong underpinning of fact and analysis, and a veneer of simplicity and common sense. Now why, on the other hand, is quite a different story.

Been very busy with the redesign of the NAP website. Part of the problem is that I am Perl/PP/Unix centered and the NAP software and server are ASP Microsoft .NET. No matter, I enjoy learning this kind of stuff.

Generated quite a bit of new content. NAP needed simple FDA compliant explanations for the GenoType Diet formulas, and I wanted to release some additional information on the GenoType profiles that had been prepared for the book but not used. So I combined both jobs these into six monographs:

• The Hunter
• The Gatherer
• The Teacher
• The Explorer
• The Warrior
• The Nomad

Enjoy.

One of the features that can be of most use when GenoTyping someone is actually one of the hardest to come by: Getting the ABO blood groups of your parents.

Its importance should come as no surprise, since epigenetic changes are largely influenced by the patterns of gene activation and silencing that occur as part of

• The heritable epigenetic component (you start off with the patterns of gene expression that your parents give you)
• The prenatal environment (there are two major bursts of methylation activity in the fetus: at about 8-12 weeks, then again in the last trimester)
• The immediate postnatal environment (these are mostly related to gene expression due to hormones such as growth factors)

In fact one of the studies that got me interested in the largely unrecognized effects of blood groups as a modulator of the epigenetic environment was a study that looked at childhood ear infections and blood groups. However, unlike most epidemiologic correlation type studies, this one looked at the blood group of the child’s mother.

Maternal blood group A gave a relative risk (RR) for intervention of 2.82. The noted occurrence of an attack of acute otitis media (AOM) before the first birthday gave a RR of 6.13. When these two factors were used together, the RR climbed steeply to 26.77.

Now to understand just how strong this association is we should look at exactly what a RR (relative risk) is. Basically it is just the odds (over 1) that something will occur over it being random. An RR of 2 (about the RR of elevated cholesterol causing a heart attack) means that people with elevated cholesterol are twice as likely to get a heart attack as people whose cholesterol levels are more desirable. Thus the study is saying that if you are a kid with an ear infection in the first year of life, and you mother is blood group A, you are 26 times more likely to have a recurrence.

Here is a chart I made which compares relative risks for several common problems and factors associated with that risk. Obviously, this is a very strong association.

Are the effects of having a blood group A mother and getting ear infections the result of some sort of fetal programming? We know that some studies have linked the ABO antigens to cellular differentiation (the process where developing cells move from general embryonic 'germ' types to cells with more specific functions, like a pancreatic or epidermis cell.)

ABH antigen expression was considered as suggestive evidence for the assumption that blood group antigens could serve as early immunomorphologic markers of endothelial differentiation of mesenchymal cells, thus specifying the location of future blood vessels. Extending the conceptual framework of blood group antigens' significance we consider them as being possibly involved in the process of fetal morphogenesis.

In epigenetic terms, we may wind up being more interested in your parent's blood types are that perhaps we need be with yours.

Every once in a while, amid the junk mail, bills and catalogs, I receive a letter which surpasses all prior. In a wonderfully sycophantic endeavor this gentleman writes to ask me for a complete set of my works so he can continue on his mission to educate the Indian public about healthy living. Apparently the gentleman does it free of charge.

Sir, your books are on their way.