Dr. Peter D'Adamo: Personalized Healing

You are a collection of cells, literally trillions of them, each with a specific design and function. With a few exceptions, cells have a basic architectural design, most of the time being depicted as looking like a fried egg cooked sunny side up. However, in reality they are three dimensional beings, so it might be better to think of the average cell as a golf ball that you’ve cut across its midline. The “white” of our cell model is the body of the cell, and here are found many specialized areas called organelles that do particular jobs, much like our own internal organs have specific jobs as well. The “yolk” of our cell model is called the nucleus, and in this compartment there lies the object of our affections, the chromosomes.

Chromosomes were first discovered at the end of the 19th century by a German biologist named Walther Flemming. Flemming was looking at cells under a microscope and got the idea to use colors to dye the cell to make it easier to see things. The idea must have worked better than anticipated since he at once began to see spaghetti looking things in the nucleus that dyed a very deep color. As is the fashion, he named these entities chromosomes which is Greek for “colored bodies”.

Chromosomes are one of the more dynamic faces of Nature; they have to be, since they are responsible for the passing on of the Baton of Life that we call reproduction. The number of chromosome in the cell nucleus differs somewhat from species to species. We human have 46 chromosomes; dogs have 78; alligators 32; cabbage plants 18.

Your chromosomes are both the governess and chauffeur of the most important molecules in your body; DNA. Like any blueprint, DNA needs to read in order for the work order to be constructed. Now, DNA is a long, long molecule. If it were completely unraveled it would be about six feet long, yet so thin that it would be invisible. If the entire DNA, in every cell of your body, was stretched out and laid end-to-end in a straight line, it would reach to the sun and back over one thousand times.

I think an effective way of describing the dynamic qualities of the chromosome is to use a few metaphors. My older daughter likes to knit, so we often visit the knitting supply shop in town for fresh yarn. Yarn usually comes wrapped in skeins, a length of yarn wound around a reel. Most yarn comes in lengths of 80-150 yards. One of the nice things about buying yarn this way, rather than just as one long unwound string, is that you can put it under your arm and walk to the car. This is certainly better than tying a knot to the rear bumper and pulled the unwound string all the way home. Thus, the first important lesion of chromosome dynamics; if you’re going to reproduce you’ve got to stuff that entire DNA into a very small, tight package. Chromosomes are just that: tight packages of DNA.

On the other hand, it is very difficult, if not downright impossible to knit anything if the skein of yarn still has the paper label wrapped around it. In order to use the yarn, you have to unwind it. That’s the formula: when the cell needs to use DNA to get information about how to make a protein, it has to unwind it. When it needs to reproduce, or turn off the DNA information flow, it needs to concentrate and condense it.

DNA is packaged and concentrated by special proteins termed histones. This concentrated DNA is called chromatin, which is the DNA plus the histones that package DNA within the cell nucleus. Chromatin structure is also relevant to DNA replication and DNA repair.

Histones are very cool bead-like proteins that spool the DNA in a way that makes it either tighter or looser, sort of like the cardboard around which our skein of yarn is wrapped. Histones respond to changes in their structure by tightening the DNA wrap or loosening it. Whenever a cell needs to access the genetic information encoded in its DNA, the histones on the section of the DNA that is needed undergo a chemical reaction called acetylation by which a molecule called an acetyl group is stuck on the histones, causing them to relax and unravel. When business is concluded for the day, special enzymes come along and chomp off the acetyl group cause the histones to become de-acetylated, which makes them tighten up again, sending the DNA in the region back to its resting state. Think of it like this; when your DNA needs to work its histones chow down on acetyl groups for breakfast and they do yoga; when it needs to reproduce or shut down, the histones lift weights --the strain of which causes the acetyl group to pop out of their mouths.

Only until recent times have we understood this mechanism, and of its supremely paramount importance: That it is used by the environment to influence gene function and that influence, for either good or bad, can be passed on as inheritance. Amazingly, we not only inherit the genes from our parents, but state of histone acetylation of the genes as well. Thus, the histone acetylation patterns of the genome are a prime mechanism of epigenetic inheritance, along with DNA methylation.

Scientists have given each human chromosome a number, according to its size; thus chromosome number 1 is the largest, then number 2, etc. Chromosomes come in pairs, one from each parent. So there are 23 pairs, for a total of 46 in us humans. Numbers 1-22 are non-sex chromosomes called autosomes, and pair 23 contains the X and Y sex chromosomes.

In the few minutes it has taken to read up to here, this, around 400 million of your red blood cells were depleted and replaced, consistent with the set of genetic instructions contained in your DNA. This is where the genetic code comes in.

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.

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)

From Percept Mot Skills. 2008 Dec;107(3):737-46.

Twin and family study findings indicate a substantial heritability of digit ratio (2D:4D), a putative marker for the masculinizing effects of prenatal androgen exposure. Functional polymorphisms of the X-linked androgen receptor gene, i.e., androgen sensitivity, contribute somewhat to the expression of 2D:4D in men, but otherwise the genetics of 2D:4D is unknown. This study investigated differences in 2D:4D by self-reported ABO blood type and Rhesus factor, two easily collectible genetic traits, in two samples (combined N=1273). Effects of blood groups on 2D:4D were small and not significant in all tests in both samples; however, two consistent patterns emerged across samples. Of the ABO types, AB had the lowest right-hand 2D:4D, the highest left-hand 2D:4D, and the lowest right-minus-left difference in 2D:4D, and Rhesus factor Rh- had higher left-hand 2D:4D and lower right-minus-left difference in 2D:4D than Rh+. If replicable, this may suggest genes contributing to the expression of 2D:4D reside in the vicinity of the gene loci (chromosomal locations: 9q34.2 and 1p36.11) of these blood groups or pleiotropic effects of the blood-group genes.

PubMed Link