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The Epigenetic Landscape


Peter D'Adamo, ND



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Introduction

Epigenetics is the study of changes to our gene function that occur without a change in the actual sequence of our DNA. To better understand this, imagine that 70% of your genes come with a little 'volume control' attached to them. Like a volume control on an amplifier, turning the control increases the gene activity, whilst turning it down decreases the gene activity. Although this sounds far-fetched, it happens all the time: In fact anytime, we must adapt to a change in our environment. For example, our first drink or cigarette is virtually always an unpleasant experience. This is because we do not have the detoxifying enzymes that can help us break down the alcohol and nicotine. These enzymes must be produced, and before that the genes that control their production must be induced.

Epigenetics is also the study of the processes involved in the unfolding development of an organism. Yet in both cases, the object of study is how gene regulation (our volume control analogy) and and its information that is not expressed in DNA sequences is transmitted from one generation to the next - that is 'in addition to' the genetic information encoded in the DNA. In essence you not only inherit your genetic sequences from your parents, but to a large degree the 'volume settings' on those genes as well. Add to that the fact that a host of environmental influences, from stress, to diet, to pharmaceuticals, to toxins constatly force us to adjust and readjust our genetic volume controls.


The Central Dogma

Historically, the notion that biological information flows in a downward direction, from DNA, to RNA, and eventually to proteins and the cell, has almost become dogmatic. Indeed the concept has been referred to, only somewhat humorously, as 'The Central Dogma' or the Primacy of DNA by Francis Crick, one of the co-discoverers of the structure of DNA (along with James Watson and Rosalind Franklin). Anyone who studied genetics during the 1980’s and 90’s learned to think of the flow of genetic information in these terms. When viewed under these circumstances, it is no wonder that Lamarck was despised by most geneticists; all the molecular biology facts and data clearly indicated that information was stored and coded for by the DNA of the genes; and, in a step by step fashion, scientists could follow this very logical flow of data. From DNA to RNA, to determine the amino acid sequence, then to the ribosomes for the assembly of amino acids into proteins, and finally climaxing with these proteins assuming their 3-D origami shape and thus morphing into a myriad of different enzymes, which go on to catalyze life itself.

To assume anything different would be the equivalent of driving in the oncoming lane of a superhighway and expecting to get somewhere. The Central Dogma was elegant, it was logical, and it worked.

However, as they say, sometimes your karma can run over your dogma.

One of the problems with The Central Dogma (and Natural Selection itself) was that it appears awfully slow and inflexible given what we know about the changeable ability of the environment. If the only way that organisms can react and adapt to a changeable environment is through random mutations and survival of the fittest, you are asking a lot to assume that these environmental conditions are just going to sit on their hands while we wait until a random mutation occurs. There had to be some other mechanism that allowed for adaptation to the environment in a much timelier manner.

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



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.

'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.' (3)

'Epigenetic alterations have been known to be of importance in cancer for over 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.' (4)

Not all genes are epigenetically regulated. About 30% of our genes, the so-called ‘household' genes, are not open to epigenetic influences. However, upwards of 70% of our genes, the 'luxury' genes are amenable to epigenetic change. In these genes, it is almost as if there is a great, big volume control on the gene, which the environmental conditions adjust upwards or downwards depending on whether more or less of what that particular gene codes for (enzymes, proteins, hormones, etc.) is required.

Amazingly, the epigenetic influence on a luxury gene is as heritable as the gene itself; not only do we start out in life with a blend of our parent’s genome, but we also inherit the initial settings of those epigenetic volume controls as well.

Environmental influences can be inherited even without any mutations in the genes themselves. Mother rats exposed to hormone-mimicking chemicals during pregnancy gave birth to four successive generations of male offspring with significantly reduced fertility. Only the first generation of mothers was exposed to a toxin, yet four generations later the toxic effect could still be detected.

If genetic mutations are 'typos' and relatively easy to test for, epigenetic changes are analogous to the formatting of the text (e.g. font, size, and color) and are much less well understood.

Epigenetics adds a whole new take on inheritance extending way beyond DNA: A control system of switches that silence or activate genes in response to things that we experience. Now all of a sudden, we are discovering that environmental and lifestyle factors, such as nutrition and stress, can exert tremendous control on these switches and their action can be passed on as part of a non-DNA form of inheritance: A whole new game of chutes and ladders. Lamarck himself visualized evolution as a 'Ladder of Life'; a linear order of progress stretching from its early origins in pond life and ending with man, the highest of all animals.

  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)
  3. Catherine Gallou-Kabani, and Claudine Junien Nutritional Epigenomics of Metabolic Syndrome. Diabetes 54:1899-1906, 2005
  4. Ashok R Amin, Seth D Thompson & Shailey A Amin. Future of genomics in diagnosis of human arthritis: the hype, hope and metamorphosis for tomorrow. Future Rheumatology August 2007, Vol. 2, No. 4, Pages 385-389