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Introduction

Let us take stock of the nutrient requirements for the methylation cycle:

All of the nutrients shown in the diagram are contained in food and many more besides in a whole food supplement which is of course the best option. However, as I mentioned before scientific evidence gained from the mapping of the human genome has uncovered some gene anomalies. These ‘ anomalies ‘ display slight variations in the DNA strands within the general population. Before the human genome project was undertaken it was always thought there was a single human genome, but as is generally the case, the medical arrogance of the ‘not invented here syndrome’ dismissed the life’s work of Dr Roger Williams’s life work on nutrition from his classical monographs ‘The wonderful world within us’ and ‘Biochemical Individuality’ written in 1953 and 1977.  Dr Williams who discovered Pantothenic acid ( Vitamin B5) and his involvement in Folate (Vitamin B9) discovery, wrote about the anatomical differences between humans with respect to the size of stomachs where some hold 6-8 times as much as others, and the various positioning of the stomach from the tip of the sternum ( breastbone) to the bottom of the stomach could be anyway between 1-9 inches below. In his study of 209 men concerning the respiratory tract he found the average tidal air ( the amount of air passing into and out of the lungs from one ordinary breath varied from 350-1299cc and the ventilation in litres/minute varied from 3.5-14.4 litres/minute. We don’t have the same fingerprints do we ?, and what is also significant is our DNA ‘footprint’ is also unique, so of course there will be genetic differences.


In the beginning….

In order for the human embryo to grow the epigenome must be erased or reprogrammed, meaning that the inherited gene expression profiles complete with a full epigenetic tag profile must be erased returning the cells into a ‘blank slate’ after the egg and sperm development stage. There is a small subset of genes that bypass this epigenetic reprogramming mechanism called imprinted genes

Global demethylation

Since we inherit a set of 2 of the same genes, one each, from our parents, that are epigenetically programmed as our parent’s genes were, some on ( Acetylated Histone), some off (Methylated). This is very simplied explanation but actually the actual gene expression is environmentally controlled/epigenetically controlled like a dimmer switch on a light fixture, also influencing the state of other genes.  Soon after conception, the total reprogramming occurs just after ‘global demethylation’ of the fertilised egg, of  both Maternal and Paternal Primordial precursor cells epigenetically. This reprogramming is completed so the eventual newborn will begin life with a brand new set of genes with normal methylated/acetylated footprints. However, it is this reprogramming period which can also put the embryo at risk of affecting the phenotype from environmental signals that cause steady changes in gene expression and nutrient deficiency. As the environmental signals are received Epigenetic tags record the empirical signals on the DNA, and this period of risk, with the continuous mapping of the fetal epigenome continues until the end of the first 3 months of fetal development.  The first 3 months is the formation and development, while the next 6 months is growth. This is why birth defects generally originate from negative environmental signals and/or lack of a crucial nutrient(s) and very rarely from heritable mutancy. This is why conventional medicine correctly advocate that the mother refrain from consuming anything toxic such as smoking or alcohol, or even undue stress which can transmit negative environmental signals to the embryo. Genetic imprinting concerns some 75 genes that have one copy permanently silenced and the other permanently expressed Our chromosomes contain 2 copies of the same gene and approximately < 1% of all our genes are imprinted which tend to be associated with growth and metabolism.

Imprinted genes

There is a small subset of genes that we inherit from both parents that are primarily  involved with growth, cell proliferation and cell regulation. The difference between the 2 copies of all other working genes, only one is expressed and the other silenced.  The intelligence of the body decides which copy is expressed and which copy is silenced based on where the copy came from, either from Mum or Dad. The silencing occurs via the addition of methyl groups during the egg or sperm formation stage. You can read more on this subject in the articles ‘Epigenetics’:

https://www.drjohnbergman.com/epigenetics-which-gene-copy-do-i-use/

Examples of Imprinted genes

For example, the growth gene IGF2 ( Insulin like growth factor 2) that plays a pivotal role in growth and development of the fetus before birth, controlling cell division and proliferation in many different tissues. Associated with Somatropin or growth hormone (GH) is a known imprinted gene and the Maternal copy (Moms copy) is always silenced while the Paternal copy (Dad’s copy) is expressed. This is the body’s intelligent decision making by using the paternal gene to produce maximum growth, and not squeezing the resources from the mother, whose responsibility, and the use of her own resources, is directed toward survival of herself and her baby. Conversely,  another known imprinted gene is H19, which is referred to as a long non-coding RNA ( transcripts longer than 200 nucleotides that are not translated into proteins), which is maternally transcribed only ( Dad’s copy is methylated and silenced, while Mum’s copy is hypomethylated and turned hard on). This gene is involved in skeletal muscle development, and is down regulated in all tissues after birth except for skeletal muscle. It also plays a role as a ‘break’, or limiting factor in terms of cell proliferation suggesting it acts as a regulator to the IGF2 gene which obviates its need to be expressed simultaneously ( both are neighbours on Chromosome 11)


Polymorphisms

It is stated by today’s science that any 2 genomes are 99.9% identical, which still leaves millions of differences among the 3.2 billion base pairs that make up the total human genome.  As I have stated before, just because there are nucleotide differences such as Single nucleotide polymorphisms ( SNPs). Tandem repeat(TRs), polymorphisms and insertion/deletion (INDELs) polymorphisms, it is the way the gene(s) are epigenetically expressed.  It is the environment that we experience and how we deal with these experiences internally that dictate how the epigenetic tags (Methyl groups) are applied during gene expression. Actually, a regulatory gene protein attaches to a specific sequence of DNA, enzymatically adding epigenetic tags to either or both the DNA and Histones, allowing to body to remember how its genes will function. If you have read my articles on epigenetics, you will recall that Histones are the ‘Scaffolding’ proteins that DNA is tightly wrapped around, which can be enzymatically manipulated to unravel parts of the DNA in order to be read and make a copy of.  The diagram below has been reproduced to depict this process.

Single Nucleotide Polymorphisms

SNPs appear at 0.3-1 kb (average) intervals which total between 5-10 million out of 3.3 billion base pairs. TRs number approx 100,000 base pairs, and INDELs probably a number between 100,000 and 5-10 million base pairs ( somewhere between the number of TRs and INDELs).  If a DNA sequence variation occurs at least >1% it is termed a polymorphism. If a DNA sequence variation is present <1% it is termed mutant.  In terms of epigenetics some SNPs exist within the regulatory DNA sequence, affecting the amount of protein produced while others have no effect at all, and SNPs that occur within the DNA coding sequence could change the amino acid sequence ( the protein).  You may recall that our genes are part of the DNA made from chemical substances Adenine, Cytosine, Guanine and Thymine A,C,G,T. Since DNA is a double helix, A can only pair with T, and C with G which are base pair nucleotides. Three DNA nucleotides together are called a codon So for example A nucleotide sequence or codon GCA expresses amino acid Alanine. In one individual it might be correct as GCA, but in another it could be GCG, but it will still express the amino acid Alanine. On the other hand codon AGA for Arginine may be expressed correctly but the wrong amino acid may be expressed if the codon was AAA. The question is. Is this significant ?.

Genetic significance of Methylation

If this area of biological science interests you, there is a mountain of information on the web and books have been written as well.  The story is that, some significant genes in some individuals that express the proteins that manufacture the crucial enzymes required for this very important process may be defective.  This of course is associated with my discussion in the previous article that modern medicine believe that the human today is basically defective; what else can explain why some societies especially in the west are so sick with millions/year suffering from various degenerative diseases, and millions/year are dying from degenerative diseases assisted by the poisonous drugs that are administered.  Geneticists and biologists are completly convinced that thousands of diagnosed ‘diseases’ can only be accounted for by genetic defects, which is why many people are walking around like cripples, completely discounting any other possiblities….it can’t possibly be the prescription medication…oh no…. that is administered to help you  Even some official websites state that this disease or that disease is caused by either a genetic flaw or environmental…so how do the biased scientists explain that one…maybe its the environment that actually makes the gene operate defectively.

MTHFR

The methylation genes in question include MTHFR (The king of all defective genes). The acronym MTHFR stands for Methylenetetrahydrofolate Reductase.  As is shown in the diagram below, it converts  5,10 Methylenetetrahydrofolate (5.10 MTHF) to the methyl group donated to the Methionine cycle  to 5-Methyltetrahydrofolate (5-MTHF). This conversion also requires nutrients Vitamin B3 (Niacin), and Riboflavin (Vitamin B2). This 5-MTHF methyl group is necessary for the Methionine cycle to function, that is for Methionine to produce the methyl group SAMe to be applied to many other methylation processes including DNA gene expression.  If MTHFR malfunctions this will have an effect on the Methionine cycle that normally shows up as high Homocysteine levels in the blood, well that is, according to the ‘science’. In fact, Ben Lynch in his book ‘Dirty genes’ states that if MTHFR is born dirty its strength is that is provides ( I assume heightened) Intensity, alertness, productivity, focus, improved DNA repair, and decreased risk of colon cancer.  Its weakness ( causes) depression, anxiety, autoimmunity and migraines, increased risk of stomach cancer, autism,pregnancy complications, down’s syndrome, birth defects and cardiovascular conditions. Even Dr lynch concludes that if you apply his clean genes protocol it can improve the effectiveness of this essential gene..and what is his clean gene protocol?…Diet ensuring you take leafy green vegetables, avoid synthetic folate acid and taking B vitamins, protein and magnesium, avoid toxic exposure to chemicals and heavy metals, and avoid stress.  However, Dr Lynch explains it, in the end he is advocating what the body needs and what it needs to avoid. I might add that if you receive a diagnosis that your homocysteine levels are inappropriate, it is extremely likely that you are nutrient deficient or toxic, and your stress levels may be too high depleting essential nutrients from your body. Although Dr Lynch is criticised by some that disbelieve MTHFR gene mutations or containing SNMPs causes the myriad of diseases as claimed by Dr Lynch, he is actually correct, but just explaining the ‘terrain’ from a slightly different direction, but still advocating that all these conditions are caused by a nutrient deficient/toxic lifestyle.  So does it matter, the treatment is the same, your lifestyle and dietary choices are everything to determine physiological/psychological health or ill-health.

Taking advantage of the ignorant

Unfortunately, the very professionals that advocate alternative medicine and holistic approaches to medical practice, are recommending genetic testing and the leader of the pack is MTHFR. Heather Millar, recalls in her 2017 article, a woman in her 30’s visited a genetic counsellor working in a reproductive clinic with a $800 bag of monthly supplements that she was advised to take to help her start a family. Having previously visited a homeopathic physician who advised her to test her MTHFR gene that, resulted positive for SNMPs, and recommended she take various supplements to compensate for the SNMPs.  Once she stopped taking the supplements, advised by the Genetic counsellor, her blood was sampled and her homocysteine levels were normal despite the transcription errors in this gene. My very first article was entitled ‘Ome research’ and I mentioned that in 2003, when the human genome project was completed, a new medical religion was born called Pharmacogenomics. I would like to recall some of the text from this article.


Pharmacogenomics

A new ‘religion’ was born from the Human Genome Project (HGP) called Pharmacogenomics. This involves more personalised medicine. Once prescription drugs are metabolised the recipient’s response is determined, partially by their specific gene states ( expressed (ON ) or silenced (OFF)), so with this understanding, physicians can determine specific drugs and dosages on an individual level.  The ultimate goal is to develop genetic tests to predict how patients are going to respond. Coupled with this testing tool it is envisaged that side effects can be minimised. I know a better way to minimise side effects, don’t take the drug at all. The HGP identified changes in the nucleotide bases ( A,C,G,T) referred to as SNP (Single Nucleotide Polymorphisms) between individuals, and structural changes in various DNA sections altering chromosomes (affecting some 12% of the genome), including translocation (genetic material is exchanged between chromosomes).  Scientists realize that it’s difficult to ascertain which part of the SNP cause disease and which do not, except through statistical analyses between a number of individuals. They’re looking not only for genes but gene variants that cause disease. This also can involve multiple genes and multiple variants; a bit like trying to hit a moving target.

Researcher’s quest to find mutant genes

According to research, SNMPs variances occur once in every 300 nucleotides ( a nucleotide which is the basic unit of DNA consists of a 4 molecule base A,T,C or G. A 5 carbon sugar (deoxyribose for DNA or ribose for RNA, and a phosphate group) on average. This means there are approx 10 million SNMPs in the human genome, and most are found within the non coding section of the genes, acting as biological markers. Forty six chromosomes containing 6.6 billion base pairs in total, and there are estimated to be 20 million base pair differences between individuals which amounts to 0.6% of the total 3.2 billion base pairs.  These figures were established by the 1000 genomes project which was launched in 2008, and by 2012, 1092 genomes of individuals from different countries were complete. According to Wikipedia, as a result of common diseases involving numerous genetic variants and environmental factors, investigators stated that the involvement of differentially distributed alleles (definition: one of two or more alternative forms of a gene that arise by mutation and are found at the same place on a chromosome) have small to moderate effects. They also state that:

However, in none of these cases has allelic variation in a susceptibility gene been shown to account for a significant fraction of the difference in disease prevalence among groups, and the role of genetic factors in generating these differences remains uncertain (Mountain and Risch 2004).”

What does all this mean ?

It means that despite the genetic variants that must exist in order for the human to possess biochemical individuality in terms of causing disease from a supposed mutant gene, the risk is almost non existent.  If you consider the MTHFR gene, some 5000 studies that have been produced, attempting to link MTHFR variants to some 400 serious health conditions, almost none could show this correlation. Despite the fact that researchers claim that approximately 60-70% have at least one copy of at least one MTHFR gene variant that differs from the reference genome, and 20-30% have 2 copies of an MTHFR variant.  If in a rare case, this gene causes problems it is going to be very early in life, not in a 30 year old mother wanting to start a family, but of course she should be taking all 90 essential nutrients anyway.  In fact according to Heather Millar’s article the US Preventive Services Task Force, the American Academy of Family practitioners, the American Heart Association, and the American college of Medical Geneticists all advise against MTHFR testing if symptoms do not exist.  i have even be informed that resulting from a genetic test, taking into consideration the ethnic origin and the population sample on the database, some individuals are told they have a predisposition of contracting celiac disease for example.  I have to say, that’s just as informative as reading tomorrows weather forecast, ‘during the day it will be light, and at night it will be dark’.  What I mean is that anybody can have a predisposition to celiac disease if their gut gets out of balance by eating poisonous food, be very stressed, not taking any supplements and taking prescription medicine.


Supplementation

Throughout my articles I always advocate physiological, psychological balance which includes microbiota balance and I agree with Chris Kresser that Methylation balance is also fundamentally important.  We have to respect the body’s intelligence to manage its own biological balance providing you as the host, consume the required 90 essential nutrients. Too many physicians want to second guess the body, believing they know better, and possess the knowhow to apply the answers to improve the way the body naturally works.  Nutrients required for methylation are included in the 90 essential nutrients as shown in the diagram above and as Chris Kresser points out in his 2017 article, the Health Diagnostics and Research Institute (HDRI) can run a comprehensive test called ‘the Methylation Pathways Panel’ to get a snapshot of a patient’s methylation process. A conventional physician can do a similar panel as part of a health diagnostic. What concerns me is that there are supplements available that you can take that drive ‘supplemental nails’ into the methylation cycle such as Levodopa, a dopamine supplement that boosts dopamine. If you recall the BH4 cycle L-DOPA, the bodies natural protein precursor made from amino acid L-Tyrosine is responsible for manufacturing the body’s Catecholamines ( dopamine, norepinephrine ), in conjunction with enzymes Aromatic L-Amino acid Decarboxylase (AADC), and Dopamine beta Hydroxylase (DBH).  Since other enzymes Monoamine oxidase (MAO) and Catechol-o-methyltransferase (COMT), metabolise these catecholamines, what will happen if a synthetic L-DOPA (Levodopa or L-Dihydroxyphenylalanine) is introduced to these enzymes.  Dr Lynch in his book ‘dirty genes’ states that it can put a big strain on the COMT gene, increasing a product called Dopamine quinone. This was confirmed by a study conducted in 2003 that found long term administration, of L-DOPA induced neurotoxicity,  due to the reactive oxygen or nitrogen species, produced by the enzymatic oxidation of DOPA, causing neuronal damage and fatal cellular damage. The metabolites formed from DOPA contain hydroxyl residues, that exert cytotoxicity in dopaminergic neuronal cells due to DOPA quinones. The study states that these DOPA quinones may irreversibly alter protein function, by the formation of 5-S-cysteinyl-conjugates of catecholamines that induce cell damage, extensive DNA base modification and increase caspase-3* activity in the neuron. A caveat to this is assuming that Glutathione levels are low which could occur in some cases.

*Caspase 3 is from a family of protease enzymes that play a central role in the sequential activation of cell death or Apoptosis.  Caspase is an acronym for Cysteine-Aspartic Protease.

Supplementary ‘Nails’

By all accounts, SAMe (S-adenosyl-l-methionine) works well for depression, if taken as a supplement, since methylation is associated with many other conditions, and it is the master methyl donor for many processes in the body, found in every cell in the body. Patricia Gerbarg, psychiatrist at the New York Medical college, has been recommending SAMe for depression for 20 years.   I personally do not like single supplements since they may upset the balance of the body, but taking SAMe, is a better choice than taking a prescription antidepressants, but I would always advocate fixing the underlying cause of the depression, which is probably an imbalance in the gut. I have discussed the gut as the second brain and its essential communication via the gut-brain barrier.  Pathogenic overgrowth that is a consequence of gut imbalance cause their toxic metabolites to cross the blood brain barrier and upset the psychological/physiological balance in the brain causing many cognitive dysfunction including depression, ADHD, Autism etc. If you do not suffer from depression than taking SAMe as a supplement to boost your methylation cycle may not be the best idea, going back to Chris Kresser’s comment about methylation balance.  5-MTHF ( 5-Methyltetrahydrofolate or L-Methylfolate as a supplement is the biologically active form of Folate (B9) but its still synthetic, and again if you are told that you are undermethylating, due to folate deficiency, ensure you add folate rich foods in your diet like leafy greens before considering a supplement substitute. You might also be told that your MTHFR gene is underperforming, so taking the supplement form of folate, you bypass the need for this MTHFR enzyme, but I would be hesitant in taking a supplementary nail unless it is scientifically proven that it would add value over taking natural food.  For this same reason, taking a SAMe supplement completely bypasses the folate cycle and the methionine cycle, so beware. Unless you are dietary nutrient deficient, and 99% of the planet have nothing wrong with their MTHFR gene, it is questionable that these supplements will provide any benefit, and in terms of methylation balance taking a bypass supplement may drive your methylation in the wrong direction. Despite the criticisms directed toward Dr Lynch, I believe his message is the same, and be on the side of caution…proper natural food is always best, and as he advocates, it is the best solution to scrub your dirty genes clean.

Another story of deception

In Heather Millar’s great 2017 article ‘MTHFR’ she relates a story from Amy Shealy a genetic counselor at the Cleveland clinic who met a woman suffering from fatigue, who had previously been seen by a functional medicine clinic. After they completed some blood work and of course they found 2 variants in her MTHFR gene…surprise..and she was told that this was the source of her depression, but she replied “I am not depressed, I’m just fatigued” and the functional medicine fizzician said “ Well you have been depressed for so long you don’t realize it”…this reminds me of a great clip from MPFC the holy grail: scene 2 ‘The black death’

Mortician “Bring out your dead”…..”Bring out your dead”

Customer “Here’s one…nine pence”

Dead man “I’m not dead”

Mortician “What was that”

Customer Nothing…here’s your nine pence”

Dead man “I’m not dead”

Mortician “Here..he says he’s not dead”

Customer “ yes he is”

Dead man “I’m not!”

Mortician “ He isn’t”

Customer “Well, he soon will be, he’s very ill”

Dead man “I’m getting better”

Customer “No you’re not…you’ll be stone dead in a moment”

Mortician “ Oh I can’t take him like that…it’s against regulations

Dead man “ I don’t want to go into the cart”

Customer “ Oh don’t be such a baby”

Mortician “I can’t take him…”

Dead man “I feel fine”

Customer “Oh do us a favor..”

Mortician “I can’t”

Customer “Well can you hang around for a couple of minutes?, he won’t be long”

Mortician “Naah I got to go to the Robinson’s…they’ve lost 9 today:

Customer “Well when is your next round?”

Mortician “Thursday”

Dead man “ I think I will go for a walk”

Customer “You’re not fooling anyone y’know. Look isn’t there something you can do?”

Dead man “I feel happy…I feel happy”

Finally the ‘dead man’ gets hit across the head from a club by the customer and the Mortician accepts the dead man

Mortician “Ah thanks very much”

Anyway, she managed to escape from the office of the functional medic, possibly believing that they had run out of supplements to treat fatigue, but plenty to treat depression…lol.   As Jay Flanagan. A genetic counselor in a reproductive clinic commented, that around 50% will test positive toward variants in their MTHFR gene, and then they will google this and find plenty of articles that will say that this will cause a myriad of health problems, diverting their anxiety about their actual health challenge, and worry more about their ‘mutant’ gene.


Check out the Previous Article in this series:

Nutrients in Food and their bodily purpose I (Phenols)

Nutrients in Food and their bodily purpose II (Lignans, Triterpenes, Phytosterols, Carotenoids and Fats)

Nutrients in Food and their bodily purpose III (Phenolic acids, sulphur,sulphides,sulphoxides )

Nutrients in Food and their bodily purpose IV (Glucosinolates, Sulforaphane, Indole-3-Carbinol)

Nutrients in Food and their bodily purpose V (Lipid distribution, absorbed fats, Criciferous Veg)

Nutrients in Food and their bodily purpose VI (Nutrients required for Liver Detox)

Nutrients in Food and their bodily purpose VII ( Seeds and the Omega Fatty Acids)

Nutrients in Food and their bodily purpose VIII ( Nutrients required for cellular energy production)

Nutrients in Food and their bodily purpose IX ( Water I Properties and Body fluids)

Nutrients in Food and their bodily purpose X ( Water II Cellular Hydration)

Nutrients in Food and their bodily purpose XI ( Water III Fluid filtration, reabsorption, excretion)

Nutrients in Food and their bodily purpose XII ( Water IV Blood pressure, Blood volume regulation)

Nutrients in Food and their bodily purpose XIII ( Water V Body Fluid Dysfunction

Nutrients in Food and their bodily purpose XIV( Dental Nutrients)

Nutrients in Food and their bodily purpose XV(Nutrients involved in Methylation I)

Nutrients in Food and their bodily purpose XVI(Nutrients involved in Methylation II)

Nutrients in Food and their bodily purpose XVII(Nutrients involved in Methylation III)


References/Acknowledgments :

  1. Single Nucleotide Polymorphisms bgbunict.it
  2. MTHFR gene mutations are the root of all health problems and vaccines Skeptical Raptor 2017
  3. Human genetic variation, H19 gene, IGF2 gene, Caspase Wikipedia
  4. 5-S-cysteinyl-conjugates of catecholamines that induce cell damage, extensive DNA base modification and increase caspase-3 activity in the neurons. Spencer et al 2002 Journal of Neurochemistry
  5. Dopamine-or L-DOPA-induced neurotoxicity: the role of dopamine quinone formation and Tyrosinase in the model of parkinson’s disease Asanuma et al 2003 NCBI (Pubmed)
  6. Everything you need to know about using SAMe for depression 2018 Meryl Davids Landau  Tonic
  7. L-Methylfolate (5-MTHF): Your best read beginners guide Joe Leech dietician 2018    Diet vs Disease
  8. Genomic imprinting Learn. Genetics
  9. Dirty Genes 2018 Dr Ben Lynch
  10. Treating Methylation: Are we over-supplementing 2017 Chris Kresser
  11. Dubious MTHFR genetic mutation testing  2015 Jann Bellamy  Science based Medicine
  12. MTHFR: Hope or hype Heather Millar 2017 Genomemag.com
  13. Monty python and the Holy Grail scene 2 1974 Sacred-Texts.com

Author : Eric Malouin

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