Nutrigenomics, the Methylation Cycle and
the Dawn of Personalized Medicine
by Dr Amy Yasko Ph.D., NHD, AMD, HHP, FAAIM
Today we stand at the dawn of the age of personalized medicine.
We have the technology and knowledge—now. We are able to look at crucial nutritional pathways and examine their underlying genetics—now.
With the mapping of the genome, we now know that there are approximately 25,000 genes in the human organism, but thus far they have yet to be sufficiently well characterized. With extensive expertise in biochemistry and molecular biology, I was a principal of a biotechnology company and pursued research in this arena for over fifteen years.
I know that over time, as we map the genome, we will learn more about the properties and functions of each and every gene. We can look forward to the day when we are able to identify risk factors throughout the entire human genome in order to optimize health and prevent adverse health conditions. However, since that work is already underway, why not put into practice what we know now?
Through genetic testing of genes, we are able to identify the specific genetic mutations, also called “single nucleotide polymorphisms” (SNPs—pronounced snips) within each individual. People with specific health conditions or risk factors seek this information to more accurately target treatments and preventive strategies based on their test results.
More than ten years ago, I began to research the genetics of neurological inflammation, the physiological precursor to a number of adult health ailments, such as chronic fatigue syndrome (CFS), Parkinson’s disease and MS. At that time, it was not my plan or design to work with children with autism, but as chance or destiny brought me the first children with whom I worked, I began to recognize that, just like these other neurological ailments, the condition we call autism arises from underlying neurological inflammation and therefore can benefit from approaches similar to those I offered to my adult clients.
One contributor to neurological inflammation is the overexcitation of neurons in the nervous system and brain, leading to misfiring, exhaustion, and death of these nerves. As I looked more deeply into the biochemical factors that mediate and/or contribute to neurological inflammation, both ground-breaking research and clinical results demonstrated that one particular biochemical pathway is key. As a result, I’ve concentrated my efforts on forging a more complete understanding and characterization of that pathway: the methylation cycle
There are a vast number of different and distinct biochemical pathways in the body that interact to perform all the many complex functions that are going on all the time without our awareness. So what makes this particular pathway so unique? First of all, I know from analyzing thousands of tests that an extraordinarily high percentage of children with autism have one or more mutations in this pathway, compared to the rest of the population. Secondly, I believe that the proper functioning of this pathway is critical to overcoming any form of neurological inflammation. This does not mean that every individual with mutations in this pathway will develop autism; problems with the methylation pathway may be a necessary but not a sufficient condition for autism.
What I refer to throughout this book as the methylation cycle is actually a combination of four interrelated biochemical cycles, including:
- The methionine cycle
The folate cycle
The BH4 (biopterin) cycle
The urea cycle
To my knowledge, no other clinician has traced the interactivity of these four cycles or emphasized their function for clinical practice as much as I have, although the folate and methionine cycles are widely regarded as interactive. To describe and evolve a program based on what I am calling the methylation cycle required combining divergent pieces of information not previously connected in order to recognize and find approaches to address the synergistic functioning of these four cycles. It’s by considering them all together as the “methylation cycle” that we create a solid foundation for addressing critical dysfunction.
The New Science of Nutrigenomics
Over time, I’ve evolved a holistic approach for bypassing genetic issues in the methylation pathway through the use of the budding science of “Nutrigenomics.” Nutrigenomics is a hot new area of research that you may have read about, based on the understanding that, while we cannot change our genes, we can change the way our genes act. For example, certain foods or supplements prompt our genes to act in healthy or unhealthy ways. Through the study of Nutrigenomics, scientists are learning what to eat (or to avoid) to promote healthy vs. unhealthy “genetic expression.” Using Nutrigenomics, labs compare the genomes of a large sample of individuals to determine which genetic “print-outs” represent “normal” vs. mutated variations.
Genetic expression = How our genes act
For example, a man—let’s call him Hal—may have a slight tendency to be irritable. Let’s say that is part of his disposition, his basic makeup. Nevertheless, overall he’s a solid, well-intentioned man—until a hot summer’s day at a family picnic, when he gets a bit too much sun. Next, Hal eats spicy chili and drinks a few martinis. Before you know it, his teenage son does something that annoys Hal, and his temper flares. Another person with less of a tendency to become inflamed and angry might react differently. But for Hal, staying out of the sun, perhaps drinking mint tea, and eating a salad would help manage his innate tendencies. In just the same way, by knowing more about our genetics we can help our genes to respond favorably, rather than flare and cause an undesirable reaction.
The goal of Nutrigenomics is to supply the body with the specific nutritional ingredients it needs for healthy functioning on a daily basis. Most of us have genetic mutations of some kind.
Nutrigenomics is genetically targeted supplementation.
These mutations impair our ability to perform all the biochemical actions necessary for ideal function. As a result, we may produce too much or too little of something, creating biochemical imbalances that lead to dysfunction and ultimately to health problems. Through supplying the missing nutritional ingredients that the body requires but cannot adequately produce itself due to genetic mutations, Nutrigenomics helps us to, in effect, “bypass” the genetically induced decrease in function, and restore proper functioning.
Why Do We Need Methylation?
Why have I singled out this particular pathway? What functions does it perform in the body? Why do we care about methylation at all?
Going forward in this chapter, I’ll explain the key functions of this pathway and describe why we need it for so many key bodily processes. In addition, I’ll briefly review some of the key functional areas that are impacted by inadequate methylation, as well as highlight a few of the issues that can manifest when the methylation cycle is not doing its job well.
Methyl groups are the body’s messengers and movers and shakers. They join with other compounds to “jump-start” a reaction (such as turning a gene on or activating an enzyme). When the methyl group is “lost” or removed, the reaction stops (or a gene is turned off or the enzyme is deactivated), OR when a methyl group is lost a gene is turned on (for example, a gene related to cancer) when it is not ideal to have it turned on.
When the methylation pathway performs well, it produces various byproducts, including biochemicals needed to perform other tasks. For children with autism, as for adults with neurological and other conditions, the healthy byproducts of methylation do many essential things, which you will be introduced to in this chapter. On the other hand, when the methylation pathway is not well functioning, there are two principle results:
A wide range of key bodily functions will not be performed effectively.
The byproducts of this pathway can lead to inflammation, a precursor to various conditions ranging from autism to Alzheimer’s to cardiovascular disease.
By characterizing the effects of genetic polymorphisms at key areas of the methylation pathways, it’s possible to create a personalized map of specific, individual imbalances that can impact your child’s or your own health. When we identify these precise areas of genetic fragility via Nutrigenomic testing, it is then possible to target appropriate nutritional supplementation to optimize the functioning of these crucial biochemical processes.
Why have I elected to focus on the methylation pathway? Because both the research literature, as well as my own clinical work, have revealed its centrality to a number of significant bodily processes.
What makes the methylation cycle so unique and so critical for health is that mutations in this pathway can have an impact on all of these factors. Picture each mutation as an accident causing a traffic tie-up. One accident will slow down the flow of vehicles on the highway. A second or third will snarl things even more. Through targeted supplementation, we are in effect creating a way for a vehicle to bypass the sites where the accidents have occurred, take a detour, and move further toward its destination. In the case of the methylation highway, these bypasses permit us to move beyond the blockades caused by mutations to produce and deliver the methyl groups that are key to a wide range of bodily functions.
Each methyl group consists of a carbon atom bonded to three hydrogen atoms, CH3. But since a carbon atom can bond with four other atoms, each methyl group has one more available bond, which constantly attaches to and detaches from numerous other molecules in the process known as methylation.
It is their ability to connect and create a new process that makes methyl groups so important.
Methylation Is the Message
Methylation is involved in almost every reaction in your body and occurs billions of times every second in your cells. To give just a few examples—and you will encounter many more throughout this chapter—without proper methylation, there is increased vulnerability to viruses, impaired attention span, and less efficient nerve transmission. We can get a basic idea of the impact of methylation on the nervous system by looking at the effects of coffee and the drug Ritalin. Coffee has a large number of methyl groups, which is why it causes such a sudden improvement in focus. And because Ritalin is a methyl donor, children on Ritalin may also experience improved focus.
Methylation is central to such critical reactions in the body as:
- Repairing and building RNA and DNA
Immune function (how your body responds to and fights infection)
Digestive Issues DNA silencing Neurotransmitter balance Metal Detoxification
Inflammation Membrane fluidity Energy production Protein activity Myelination Cancer prevention
Because it’s involved in so many processes, inefficient function or mutations along the methylation pathway can result in a wide range of conditions, including the following:
- Aging Allergic reactions Alzheimer’s Anxiety Arthritis Autism Bipolar disorder Bowel dysfunction Cancer CFS/FM Chronic bacterial infections Chronic viral infections Cytoskeletal breakdown Diabetes Down’s syndrome Heart disease Herpes Huntington’s disease Language and cognition impairment Leaky gut syndrome Metal toxicity Miscarriage Mitochondrial disease Neural tube defects Pneumonia Psoriasis Renal failure Rett’s syndrome Schizophrenia Seizures Sleep disorders Systemic Lupus Erythematosus (SLE) Thyroid dysfunction
Let’s look at a sampling of the issues arising from inadequate methylation.
Repairing and Building DNA
One extremely crucial function of methylation is its role in the synthesis of DNA. DNA carries the blueprint, or genetic coding, needed to build the components of living organisms. Every time your body needs to repair the gut lining, or create an immune cell to respond to an immune threat, or to heal when you have cut yourself, you need to synthesize new DNA. But without a functioning methylation cycle, your DNA is not going to replicate properly. Why?
DNA is composed of building blocks called nucleotides, chemical compounds that contain four bases—cytosine, guanine, adenine, and thymidine. Several of the enzymes involved in the creation of these bases are a part of the methylation cycle. For instance, one gene has the very long name of methylenetetrahydrofolate reductase (commonly abbreviated as MTHFR). As you can see from the beginning of its name, MTHFR contains a methyl group. That is why a mutation in the gene responsible for making this enzyme may impair the ability to make the necessary elements for DNA. As we will see later, the base most affected by the lack of methylation is thymidine.
Undermethylation is also responsible for what is known as “trinucleotide repeat disorders.” The bases are arranged on our genes in sequences of three, or “trinucleotide repeats.” But unless those three-base sequences are methylated, they will repeat themselves as much as a thousandfold, creating various serious conditions, such as Friedreich’s ataxia, Fragile X and Huntington’s disease, depending on which sequences are repeated. When there is insufficient methylation and these three-base sequences repeat themselves into very long sections, they also attract the limited number of methyl groups that are available, increasing the risks for these disorders.
Very similar to DNA is RNA, which is crucial to building proteins, transferring the information carried by your DNA and regulating your genes. In fact, RNA is even more abundant in your body than DNA. Just to keep your DNA constant—without even mentioning the amount of nucleotides we need for RNA, the body requires enormous amounts of nucleotides, the building blocks of DNA and RNA. One reason I suggest the use of RNA and nucleotides as supplements is to take some of the burden off the body, so that instead of the body needing to utilize the methylation cycle to make so many of its own building blocks, we supply some of those building blocks, leaving methyl groups for some of the other important roles we have mentioned. For example, when certain cells can’t make enough of the bases adenine and guanine on their own to keep up with the body’s needs, we are able to take some of the burden off the system by supplying RNA. Later in this book I’ll discuss the special RNAs (and nucleotides) we use to support the body.
The use of RNAs and other supplements can help to provide the body with what it needs even in the presence of mutations. Nearly all children with autism have impaired function (the blockage on the highway) caused by the genetic mutation in MTHFR along with mutations in other genes in this pathway. Now, suppose that a child also has had environmental exposure to thimerosal, a mercurycontaining preservative used in many vaccines, which can also interfere with methylation. When both things occur together, they interact and further weaken the body’s ability to perform key functions.
Here’s another example: Another one of the enzymes critical to methylation, methionine synthase (MTR), requires an active form of vitamin B12 in order to function properly. The body’s ability to supply B12 can also be impeded by the MTHFR mutation. Further, research has shown that mercury adversely affects this reaction, and so it can impede DNA methylation. With both the mercury present in the thimerosal and the MTHFR mutation you now have two accidents (the MTHFR mutation and mercury exposure) on the highway, causing a roadblock (impaired MTR function.) It’s going to be that much harder to clear two accidents and a roadblock than it would be to clear just one accident in order to restore adequate methylation function. The end result? Greater difficulty in creating the building blocks for DNA.
Methylation also plays a key role in the ability of our immune system to recognize foreign bodies or antigens to which it needs to respond. Whenever there is an assault on the immune system, the body must synthesize new T cells, which belong to your white blood cells. These cells help fight viral and parasitic infections, and are also needed to help to control B cells, which produce antibodies. Due to mutations in the methylation pathway, you may lack the ability to produce the methyl groups necessary for making new T cells. When that occurs, there is an increased tendency to produce B cells, which may therefore result in an autoimmune disorder. When I and my practitioner colleagues look at the blood work of many of the children, we often find these kinds of imbalances—they have too many auto-antibodies, not enough of a T-cell response, and too much of a B-cell response. I have seen several cases in which the level of auto-antibodies has declined after proper methylation cycle supplementation.
Methylation of DNA also regulates immune cells. Immune receptor DNA is initially in the “off” state and remains that way until the immune cells need to differentiate in order to respond to an intruder. As you will learn in greater detail below, at that time the DNA loses its methyl groups in a regulated fashion and the DNA is turned “on.”
As we have just seen, methylation is generally correlated with the silencing of genes. But research has also shown that when genes are not methylated at specific points, the immune system can be tricked into reacting against itself.
So, to sum up, methyl groups help turn your genes on and off. They also help determine the ways your immune system reacts. Unless methylation is operative, the immune system may react when it’s not needed, creating autoimmune disorders, or fail to respond to actual threats when it is needed.
The functional areas impacted by improper methylation are in a dynamic relationship with one another—that is, they are mutually interactive. So it is with the relationship of your immune cells to digestive issues. Since many of your immune cells reside in the digestive tract, there’s a close relationship between methylation, immunity, and such digestive problems as leaky gut, allergies, and various forms of digestive distress that the children commonly experience. Briefly, if methylation is low and T cell production is low, then histamine levels tend to be high. Histamine is linked to inflammation, a contributing factors to leaky gut as well as allergies.
 Methylation  T Cells  Histamine  Inflammation
With the underactivity of T cells, B cell activity can take over, which can lead to autoimmune issues like allergies and food sensitivities. That’s why so many children with autism benefit from a gluten-free, casein-free diet. While some practitioners working with children with autism recommend this type of diet, knowing the underlying biochemistry helps explain why it often proves helpful.
Methylation is critical to what we call “gene expression.” Although your genes never change, they can be active or inactive, as we saw earlier in this chapter. The body turns on (expresses) a gene, or turns off (silences) a gene. Whether it’s preferable for the body to either express or silence a gene depends on its role.
How does this work? To regulate our DNA, to help to turn it on and off, the body adds methyl groups to the DNA strands. If you think of your DNA as a charm bracelet, it’s as if the methyl groups are hanging off the bracelet at different points. Wherever there is a methyl group on the bracelet, those genes will be silent, and wherever the methyl group is removed, those genes will be expressed. A lack of proper methylation means that DNA that should be quiet can be expressed, and this may cause specific changes in the body. For example, many children change hair color as they grow older. A child with blonde hair may change into a brunette. This is because the gene for brown hair, which was switched off, becomes switched on. Lactose intolerance is another example. You may be able to easily digest milk as a child, but once your gene for lactase, the enzyme for digesting milk, is switched off, you no longer can.
Of course, gene expression or silencing can have far more significant consequences than hair color or lactose intolerance. Take the measles, mumps, and rubella (MMR) vaccine as an example. When viruses (such as those contained in this vaccine) are inserted into your genome, it’s not healthy for those viruses to be “turned on” and become active. However, without adequate methylation, that’s exactly what can happen. Unless you have adequate methyl groups that attach themselves to the viruses to silence them, they can become active.
What occurs if these genes are activated? Instead of evoking an immune response that grants resistance to measles, mumps, and rubella, as they are supposed to, these vaccines can produce an entirely different, unwanted effect. The recipient of the vaccine can become subject to chronic infection from these activated viruses that now, like a Trojan Horse, have taken up residence in the body. In a similar way, methylation plays a role in carcinogenesis, the growth of cancer cells. If, due to inadequate methylation, DNA isn’t regulated properly, then it doesn’t send the right signals, and cell division can become uncontrolled, resulting in cancerous growth.
When there is improper methylation, not only will the DNA bracelet lack the methyl groups that can turn your genes on and off, but the bracelet itself, the actual DNA links on the bracelet, will not be as stable.
~Extracted from Chap. 2 of Autism: Pathways To Recovery
~Edit by Fintan Dunne