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Methods of Epigenetic Inheritance
Peter D'Adamo, ND

DNA Methylation is ability to attach and detach methyl (M) groups to the cytosine © nucleotides in 'CpG Sites' (a location when a guanine [G] follows cytosine [C] is a prime method by which the environment acts to silence or activate genes. Clusters of CpG sites, called 'CpG Islands' often mark the beginning of a gene; their methylation is a way of turning the entire gene off. Image courtesy of U.S. Department of Energy Human Genome Program (http://genomics.energy.gov); modified by the author.)

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There are two main mechanisms of epigenetically programming our DNA to silence or activate our genes.

Methylation

The first is the best known and understood. It is called DNA Methylation because it involves putting a molecule called a methyl group onto the cytosine (the 'C" of the ATCG DNA code) nucleotide of the DNA double helix. This is done by a class of enzymes called methyltransferases, and once it occurs, any further the reading of the DNA is effectively blocked, sort of like when the villains place a tree trunk across the railroad track to stop the train. In humans, approximately 1% of DNA bases undergo DNA methylation. DNA methylation was first noticed in the late 1960's when it was suggested it might be responsible for the mechanism of long-term memory.

In adult tissues, DNA methylation typically occurs in regions of DNA where a cytosine nucleotide occurs next to a guanine nucleotide, what geneticists call CpG Site. Unlike adult cells, embryonic cells appear to have methylated cytosine bases all over the place. Some regions of DNA have higher numbers of CpG sites strung together; these are known as CpG Islands. CpG Islands appear to act as a marker for the start of a new gene; about half of all of our genes have CpG islands associated with the start of a gene. DNA methylation is the mechanism that is used to determine which allele (maternal or paternal chromosome) for a particular gene will receive precedence. Once made, that switch is non-reversible, like being born with brown eyes and blood group A becomes part of your inheritance.

Cancer cells tend to have highly methylated CpG Islands, but the rest of the cancer genome tends to be very much unmethylated. This is because cancer cells are experts at turning off genes that would work to nag them to death until they finally did the only decent thing and committed suicide. These nagging genes are called tumor suppressor genes and are probably one of the prime reasons that we do not go on to get cancer within the first five minutes of life. Let's face it, with a few trillion cells reproducing every day, it does not matter how good your system is, you are going to have slip-ups. Nature recognized that, and built in several systems that allow a cell with genetic problems to behave 'altruistically' and do something bad for itself personally but for the greater good of the organism. Green tea is a food product that seems custom-designed for reeking havoc for cancer cells; some anti-cancer foods remove the methyl groups from the CpG islands while others remethylate the rest of the genome. Green tea does both.

Global decreases in methylation levels is commonly observed in aging cells, as well as in early event neoplasia. Unlike defective genes, which are damaged for life, methylated genes can be demethylated. And, methyl tags that are knocked off can be regained via 'nutrients, drugs, and enriching experiences.'

DNA methylation experiences two major 'pulses' during development: Methylation patterns are reset early in embryogenesis and reset again in the second half of gestation. After that, they are thought to be relatively stable.

Histone Acetylation Histone (de)acetylation

The second method in which the environment acts to control genes is through the addition or removal of acetyl groups from the proteins that the DNA strands wrap around, the histones. The histones control whether the DNA is in a free, unwound form, ready to be read, or tightly wrapped up into chromatin, the packed mass of DNA and proteins in the nucleus.

Histone Deacetylation causes the histones to wrap DNA up into highly condensed chromatin, causing the DNA to become tightly wrapped up and its genes therefore silenced. Source: http://www.genome.gov/

To imagine a chromosome, think of wool yarn and how it is usually sold wrapped in skeins. These skeins might be formed by wrapping the yarn around a simple piece of cardboard. Keep playing with this idea; since it is a perfect description of just how the cell, an entity so small that you need a microscope to see it, manages to neatly and efficiently wrap up a molecule which, when unwound, is over six feet long. So, in our little analogy, the wool yarn is the DNA, the cardboard that wraps the yarn into the skein, the histones. Normally, when a histone is full of acetyl groups, it relaxes, and the DNA unwinds in such a way that it can be read. On the other hand, when DNA is acted upon by an enzyme called histone deacetylase, it starts pulling acetyl groups off the histone. The histones start coiling up into chromatin, effectively silencing any further DNA reading.

Other Methods

Other mechanisms of epigenetic inheritance are though to include:

  • Translation Blockage: DNA is the template for the construction of proteins. This process, known as translation, innvolves DNA first being copied to RNA and then the RNA being 'read' to string together amino acids into a viable protein. So it is difficult to imagine that, like taking the microphone away from a bad kariouki singer, block the translation process is a simple way of silencing genes. Examples are: Maternal RNA, RNAi (interference RNA) and small interfering RNA strands (siRNA)
  • Histone Methylation: Like DNA methylation, methylation of histone polypeptides can mark a gene to be or not be transcribed.
  • Protein Ubiquitination: Ubiquitin is a small regulatory protein that has been found in almost all tissues ('ubiquitously') of higher organisms. It directs proteins to compartments in the cell, including the proteasome which destroys and recycles proteins. Proteosomal destruction is a means of regulating small molecules that help regulate gene activation known as transcription factors.
Maternal Effect

The maternal effect occurs when and where the genotype of a mother is expressed in the phenotype of its offspring, unaltered by paternal (fatherly) genetic influence. This is usually attributed to maternally produced molecules, such as RNA that sort of kick start protein machinery and perhaps possess some crucial key knowledge about the maternal environment that the embryo must have in order to sort things out for itself. We've learned that RNA is the messenger molecule for DNA, which heads out into the cell and tells the cell machinery which amino acids to assemble into which proteins. A lot of this pre-made maternal RNA seems to be involved in the embryo getting some sort of idea about where it is in three dimensional spaces and to orient it along the axis of symmetry in the body. Apparently many of these RNA molecules can transmit information by moving about the early embryo from cell to cell.

Stem cells are still in the bootstrap stage, and we've got to get our germ layers going so we can get started on transitioning from a blob into a little baby. This is done by the migration of certain cells in the center of the blob and their embarking on a complex sequence of layering and folding, a process called embryogenesis, which lasts approximately 14 weeks. This infolding produces the tube-within-a-tube that will go on to become the digestive tract and internal organs. Since we are not jellyfish, and are capable of bilateral symmetry, we have three types of germ layers:

  • The Ectoderm is the start of a tissue that covers the body surfaces. It emerges first and forms from the outermost of the germ layers. It goes on to form the skin, nerves, brain, the spinal cord and parts of the lens of the eye.
  • As cells begin to migrate inward to produce the tube-within-a-tube, the inner layer, or Endoderm, begins to form. The endoderm goes on to form the glands of the body, the liver and pancreas, the respiratory tract and all the digestive organs.
  • The Mesoderm forms when some of the cells migrating inward to form the endoderm form an additional layer between the endoderm and the ectoderm. The mesoderm goes on to form the bones, muscles, reproductive tract and most of the circulatory system including the heart, red blood cells and arteries. It is the possession of a mesoderm layer that separates us from jellyfish.

What is amazing is just how much variety it is possible to achieve through just these three portals. It also makes Waddington's concept of an Epigenetic Landscape come to life, as it should be easy to see how we start from multipotential blob, then morph into a series of vanilla, chocolate and strawberry choices, and finally refine these choices until we have a veritable bee-hive of specialized cells all working together.

The Placenta

In higher animals, most maternal-fetal exchange takes place across the placenta, a temporary organ that is implanted in the wall of the uterus, where it receives nutrients and oxygen from the mother's blood and passes out waste. The placenta is composed of two parts, one of which is genetically and biologically part of the fetus, the other part of the mother. This interface forms a barrier, the placental barrier, which filters out some substances that could harm the fetus. By week 12 the placenta is usually fully functional, and evidence suggests that the size of the placenta is a major determinant of fetal health and one's subsequent fitness as an adult. In addition to nutrients, the placenta is important for the exchange of hormones between the mother and fetus.

It is interesting to note that the placenta itself is a major consumer of oxygen and nutrients, such as glucose, and can account for half of all the consumption of these key life-sustaining factors. Because of the design of the blood flow to the uterus and across the placenta, on average the fetus must live with a bloods oxygen tension of only 25% that of its mother, or as Peter Gluckman and Mark Hanson point out in their insightful book The Fetal Matrix, it's as if the fetus is living at the top of Mount Everest without any oxygen cylinders. When oxygen gets scarce, the fetus usually shifts its blood flow to critical areas and shuts down non-essential functions. Brain, heart and placenta itself are supported, but even non-essential aspects of these key organs are sacrificed. Finally, if oxygen or nutrients are severely restricted, the fetus will stop growing altogether.

As in life, there can be conflicts between parents and offspring. Common maternal-fetal conflicts result because the genome of the fetus is not purely that of the mother; the genome of the father is also a fact that must be considered. Conflicts can include potentially hostile immunological reactions, such as a blood type incompatibility between mother and fetus. The mother and fetus can also be in competition for nutrients, especially if these are in short supply. From a survival standpoint, the deck is stacked against the fetus, if push comes to shove, it will be the success of the mother that will be paramount, from a survival standpoint, she is much harder to replace.

Maternal Constraint

Another potential type of conflict is maternal constraint, which is just the sum total of all process that are employed by the mother to limit the growth of the fetus to the point which pelvic delivery is still possible. Like the man who builds a sailboat in his garage only to find out that it does not fit past the door, the size of the fetus must be carefully calculated to allow it to pass through the pelvic canal, which is probably the reason that as a species humans are born in such a helpless state; if we were delivered at full neurological capacity, we'd probably never get out!

We've always know that maternal lifestyle and nutrition does much to insure a healthy baby, and up until recently advice based on these observations was pretty much limited to minimizing alcohol consumption and quitting smoking. But recently, evidence began to accumulate that the fetus responds to subtle messages from its mother about the current state of her nutritional status, and even more surprisingly, seems to remember those responses for a long, long, time.

You may be familiar with what the Dutch call 'Hongerwinter'. During World War II, the Dutch met vast destruction and famine at the hands of the Nazis during one of the coldest winters on record. By early 1945, official rations were 400-800 calories per day and approximately 30,000 Dutch people had starved to death. The winter of 1944-45 saw the birth of almost 40,000 babies, each of whose vital statistics, such as name, birth date and weight, were duly recorded by the Dutch authorities. In the 1960's researchers began to study these now fully-grown famine survivors, and the results were shocking. All had the usual complications, but in particular those fetuses who were in their last trimester during the height of the famine, had very low birth weights. They did grow up normal, but later suffered from very high rates of diabetes. On the other hand, babies who were in the first six months of gestation during the height of the famine, were normal weight at birth but when they reached adulthood went on to give birth to unusually small babies.

Those fetuses exposed to famine during gestation also went on to develop more obstructive pulmonary and kidney disease. Those whose mother's starved at the beginning of the pregnancy gestation have more atherosclerosis, altered blood clotting, more obesity, and a three-fold increase in cardiovascular disease. Daughters of mothers pregnant during the famine were significantly more diabetic and obese at midlife than average and men have higher rates of schizophrenia and an exaggerated response to stress.

What had happened to produce these dramatic health effects, and even more significantly how did it somehow go on to become inheritable, as in the case of those women who were babies in their first trimester of the Hunger Winter, and imparted small size to their offspring, decades after the famine? In any case, the evidence seems to be building that you are not what you eat, but rather more likely what your grandmother did not.

What links the observed effects of starvation in those post war survivors of the Dutch hunger winter and the changes that you can produce in a golden furred mouse by altering the diet of its mother is a concept increasingly recognized as being of a profound significance to the health of our generation and the generations to come after us. Termed the Predictive Adaptive Response (PAR), it posits that the quality of the nutritional environment of the mother is interpreted as a judgment on environmental conditions which the fetus can be expected to experience in its future life. It's as if the fetus could, for a moment, stick out its head, have a look around, then go back in and configure itself to respond best to what it saw out there. Thus, the womb acts as a delicate programming device controlling development of the fetus as a way of insuring its survivability.

Thrifty Genes

In 1986, David Barker and his colleagues from University of Southampton reported an observation that the geographical distribution of heart disease in the UK was more closely related to where a person was born than it was to where they currently lived. His research group was at the time trying to reconcile the rather curious fact that coronary heart disease was the most common cause of death among men who were at low risk for it, being slim, non-smokers, and having a low blood cholesterol. This led them to suppose that some early life event had programmed these individuals in a way that eclipsed some of the risk factors seen in later life. So they began to search around for ways of comparing the living conditions of people born at least 60 years ago with their present day health status.

Using midwife Ethel Margaret Burnside's data and information from the National Health Service, Barker was able to determine that of the 15,000 born before 1930, three thousand were dead, almost half from heart disease, and a disproportionate number of these deaths were in people who weighed less than 5 pounds. At one year the rate of heart disease in men who weighed 18 pounds or less was three times that of those who weighed 27 pounds or more.

This lead Barker to hypothesize that in bad conditions a pregnant female can modify the development of her unborn child such that it will be prepared for survival in an environment in which resources are likely to be short, resulting in a what he called 'The Thrifty Phenotype'. Those with a thrifty phenotype who actually develop in an affluent environment may be more prone to disorders such as diabetes, whereas those who have received a positive maternal forecast will be adapted to good conditions and therefore better able to cope with rich diets. This has been termed 'The Fetal Origins Hypothesis' or 'The Barker Hypothesis' and dozens of later studies have convincingly demonstrated a powerful link between low birth weight and an increased risk of developing chronic medical disorders decades later --a significant body of literature that most physicians are completely unaware of.

Poor prenatal and early postnatal nutrition can invoke the following later life changes:

  • Changes in the profile of the variety of enzymes made by the liver, the composition and ratios of the blood lipoproteins, clotting factors in the blood
  • The uptake of glucose by the organs of the body, the filtering capacity of the kidneys
  • The hormone responses to stress, the ability of insulin to signal the cells properly
  • The levels of leptin, a hormone that plays a key role in regulating energy intake and energy expenditure, including the regulation of appetite and metabolism

Put these all together and you wind up with virtually all the diseases of Western Society: coronary heart disease, stroke, Type 2 Diabetes, and Metabolic Syndrome (Syndrome X) all of which have been shown to be increased in low birth weight babies. These fetal adaptations may well have had survival value 20,000 or 50,000 years ago, when starvation was a constant threat.

Barker's Thrifty Phenotype Hypothesis owes much to an earlier theory by geneticist James Neel called (perhaps unsurprisingly) The Thrifty Genotype Hypothesis. Neel did a lot of fine detective work in the 1950's principally with hemoglobin and sickle cell anemia. He also worked with blood groups as genetic markers and studied the effects of radiation on the survivors of the Hiroshima and Nagasaki bomb blast. In 1962, Neel proposed the 'thrifty gene' hypothesis to explain the tendency of certain ethnic groups to develop obesity and diabetes (diabesity). It postulated that certain genes in humans have evolved to maximize metabolic efficiency and food handling behavior, and that in times of abundance these genes predispose their carriers to diseases caused by excess nutritional intake, such as obesity.

The thrifty genotype and the thrifty phenotype hypotheses both assume some individuals can be programmed for scarcity and metabolically biased in a way that favors their survival during famine and which leads to their suffering disease when instead placed in an affluent environment. But what Neel saw as a classic interplay of a classic case of Natural Selection (genotype), Barker saw as a more immediate and dynamic physical response to the immediate environment (phenotype).

The consequences of the thrifty phenotype hypothesis may well prove catastrophic for the emerging nations, especially those with large populations, such as India and China. These societies have had long histories of marginal subsistence nutrition, malnutrition and famine. As food consumption begins to achieve Western style standards, we may be faced with an epidemic of diabetes; heart disease and obesity that will make our current concerns in the West appear completely insignificant. What the final burden will be on the health care systems of these emerging countries and who will pay the bill is a very scary thought.

Hereditability of Epigenetic Changes

Evidence is accumulating that more than fetal malnutrition may be at work in producing life-long health problems. After the attack on the World Trade Center in 2001 researchers studied the effects of post traumatic stress on a group of women who were pregnant at the time and either inside or close by the Twin Towers. Using the stress hormone cortisol as a barometer, their results suggest that the chemical effects of stress in the mother were passed down to the unborn child. Other studies in animals indicate that exposure to toxins such as fungicides and pesticides cause biological changes that persist for at least four generations.

The most fascinating medical studies of the new millennium were not even performed on humans, but rather a chubby golden yellow strain of mice that are called 'agouti,' named after a variant of gene that they possess that in normal circumstances gives them yellow fur. However, if the agouti gene is silenced by having methyl groups attached to it, then agouti instead gives a brownish color to the fur. In addition to a golden yellow coat, the strain of agouti mice used for the study was bred to develop both diabetes and obesity early in life.

In the first study published in 2002, pregnant agouti mice were fed lab chow mixed with methyl-rich supplements such as vitamin B12, betaine hydrochloride and folic acid. In the control group then pregnant mice were simply fed lab-chow. When the offspring were born and grew, visible changes in the baby mice born to mothers who had received the supplement were quite obvious. They had mostly brown fur, and were leaner than the control mice unsupplemented. The control mice on the other hand had higher susceptibilities to obesity, diabetes and cancer. What was most fascinating of all was the fact that the methylated, lean, brown mice went on to maintain that state throughout their lifespan. Supplementing with methyl groups had modified the agouti gene, not just in the mother but in her offspring as well. A more recent 2006 study used a phytoestrogen from soy called genistein, with the same results.

What makes these studies so important is that they clearly demonstrate that environmental factors, in this case diet, can dramatically influence the function of genes epigenetically without ever modifying what is written in the gene.

It's not too difficult to imagine how lifestyle choices other than those imposed by war or famine could be interpreted through this par to seem to require a need for thriftiness. A poor diet, even beginning months or years prior to conception, smoking, lack of exercise, use of devitalized foods such as simple carbohydrates and sugars, and trans fats can all be interpreted by the fetal matrix as indications of a potentially possible future of compromised nutrition and the epigenome of the fetus readjusted accordingly.

'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.'

Conclusions

First we must accept the fact that young girls, pregnant moms, fetuses and very young children are situations that are characterized by a high degree of plasticity, which in this case can be defined as the property of a body to undergo a permanent change when subjected to some sort of influence. Growing things and the bodies that support them are highly plastic; because they are already in a state of flux, are able to be influenced by stresses and actions that take place during their developmental processes. Once we pass a certain point on the timeline, probably by our mid-twenties, we rapidly lose plasticity (since we are moving out of the growth flux stage of life and into the static stage) and so the plan should become less one of trying to engineer epigenetic changes and more one of trying to determine the range of the patient's predictive adaptive response so we can best design a lifestyle that allows them to function within their limits.

A New Role For Morphology in Diagnosis

'Anatomy is destiny,' wrote Sigmund Freud. Since epigenetics charts the trajectory of one's journey through the 'Epigenetic Landscape' from genotype to phenotype, not surprisingly many of its most distinguishable marks can be determined via physical inventory of the patient. These include:

Fluctuating Asymmetries

  • D2/D4 Index (prenatal androgen exposure)
  • Dermatoglyphics (developmental instability)

Biometrics

  • Dermatoglyphic ridge patterns (fetal oxygen tension, placental acidity, glucose levels)
  • Somatotype (uterine contraint, maternal nutrition)

Biomarkers

  • ABO Blood Groups (Cell-to-cell adhesion)
  • ABH Secretor Status (Growth and development of the embryo,especially mesodermal tissues )
  • PROP/PTC taste (thriftiness )

Anthropometrics

  • Torso- Leg Ratio (maternal constraint)
  • Upper-Lower Leg Ratio (growth factor levels)
A New Definition of Treatment

We've all seen families in which it seems the occurrence of dementia or diabetes or cancer is much higher than average. Perhaps we've also observed other families where the opposite is true, where no one seems to develop cancer or heart disease, and secretly wished we could somehow be adopted into them! Should we assume that these families possess some putative single gene that dooms them to their fate? Not likely.

More probable is that these familial tendencies are not the result of single genes in the family line, but rather the pattern of epigenetic programming conveyed down the generations.

Because of this, epigenetics offers an unparalleled 'indirect effect' on the treatment of illness. Like all health care systems, naturopathic medicine tends to park the ambulance at the bottom of the cliff. We 'treat' illness. However, what if the best cure for a certain disease was for all of us to simply agree to deny it further existence?

Given 100 years, where will we be with regard to our war on cancer? Perhaps we will have a complete cure; perhaps it will turn out to be a much more vast and imponderable problem than we thought. What if we instead worked to eliminate cancer-proneness one family epigenome at a time?

The therapeutic potential of epigenetics within the framework of naturopathic healthcare is enormous. Think of the possibilities inherent in improving the epigenomics of a patient's lineage in such a way that in four generations (about 100 years) you could engineer sufficient epigenetic optimization in a client's familial epigenome to minimize:

  • Obesity and its consequences
  • Type II diabetes
  • Hypertension
  • Autism, Depression and Schizophrenia

While also curtailing or completely eliminating certain variations of:

  • Malignancy
  • Cardiovascular disease
  • Type I diabetes
  • Auto-immunity

Surprisingly we need not await the arrival of new agents. The vitamins, flavones, amino acids and minerals that prompt epigenetic change are here already. They simply await our repurposing the usage.

This approach to holistic health and healing leads a basic Naturopathic Principle, Heal the whole person: Tolle Totum.This requires a comprehensive approach to diagnosis and treatment. Perhaps we should amend this classic naturopathic aphorism so as to also include 'treat the family, Tollo Sustuli Prosapia.

The current epigenetic literate is enormous and growing exponentially. These suggestions can be considered but a start:

  • Evolution in Four Dimensions: Genetic, Epigenetic, Behavioral, and Symbolic Variation in the History of Life by Eva Jablonka, Marion J. Lamb (The MIT Press) is very good.
  • The Fetal Matrix: Evolution, Development and Disease by Peter Gluckman, Mark Hanson (Cambridge University Press) is an excellent overview of fetal environment's effects on health, disease and mortality.
  • The Genotype Diet by Peter D'Adamo synthesizes much of what has been discussed in the article into a series of six individualized epigenetic protocols. Broadway Books, 2008 New York, NY

REFERENCES

  1. Asim K. Duttaroy Evolution, Epigenetics, and Maternal Nutrition 2006 Darwin Day Celebration.
  2. Anway M, Cupp A, Uzumcu M, and Skinner M, Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility, Science Vol. 308, June 3, 2005, pp. 1466-1469.
  3. Barker DJ. The origins of the developmental origins theory. J Intern Med. 2007 May;261(5):412-7
  4. Cooney CA, Dave AA, Wolff GL.Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring.J Nutr. 2002 Aug;132(8 Suppl):2393S-2400S.
  5. Damiani G. The yin and yang of anti-Darwinian epigenetics and Darwinian genetics. Riv Biol. 2007 Sep-Dec;100(3):361-402.
  6. Dolinoy DC, Weidman JR, Jirtle RL. Epigenetic gene regulation: linking early developmental environment to adult disease. Reprod Toxicol. 2007 Apr-May;23(3):297-307.
  7. Duttaroy A. Evolution, Epigenetics, and Maternal Nutrition 2006 Darwin Day Celebration. http://www.muktomona.com/Special_Event_/
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  8. Feinberg AP. Epigenetics at the epicenter of modern medicine. JAMA. 2008 Mar 19;299(11):1345-50.
  9. Holliday R. DNA methylation and epigenotypes. Biochemistry 2005; 70:612-7.
  10. Montague T. A New Way to Inherit Environmental Harm. Synthesis/ Regeneration 39 (Winter 2006)
  11. Peedicayil J. Beyond Genomics: Epigenetics and Epigenomics. Clin Pharmacol Ther. 2008 Feb 27;
  12. Ross SA, Milner JA. Epigenetic modulation and cancer: effect of metabolic syndrome? Am J Clin Nutr. 2007 Sep;86(3):s872-7.
  13. Waterland RA, Jirtle RL. Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition. 2004 Jan;20(1):63-8.


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