The concept of “one mutation, one disease” originated in 1948, when the Nobel Prize laureate, Dr. Linus Pauling, began a new age in biomedical science with his historic work on sickle cell anemia. Pauling was the first person to characterize a disease at a molecular level illustrating that a mutation in a particular gene could cause an identifiable disease. A cause and effect; he had identified the “diseased gene” responsible for sickle cell anemia. The finding of a single gene for an individual disease sparked the hope and imagination of scientists and researchers. The knowledge of the gene involved could be used to diagnose and treat disease; the implication was that disease-causing genes could be found for every imaginable condition. And so began the equivalent of the “California gold rush” in pursuit of human genes. This would lay the groundwork for the Human Genome Project (the defining of the complete human genetic code) and today’s DNA based genetic tests. What was not understood at the time was the “one gene one disease” relationship is only applicable in certain instances. Many genes have multiple functions and other environmental and infectious components that can impact upon the ability of a genetic defect to ultimately manifest as disease. Yet at the time it seemed as if we had the explanation not only for infectious diseases but also for genetic diseases. Armed with this knowledge it would pave the way for therapeutic treatments for even inherited disorders.

How naïve we were. The fact that in 1953, the actual structure of DNA, as the material comprising our genomes, was first elucidated should have been an inkling that we were at the beginning of a long journey rather than at its end. It was not until 1968 that the notion of RNA as an “information molecule” was first proposed. Different types of RNA in the cell were first identified thirty years ago and concepts for manipulating RNA to influence gene expression have only emerged since the 1980’s. We are living in an exciting time from the standpoint of medical breakthroughs. Just as the computer has evolved from a 943 cubic foot giant to a laptop unit that can be carried in a backpack, so too the fields of molecular medicine and nutrigenomics have first begun to evolve.

In single gene disorders a mutation or defect exists in one gene, which results in the faulty production of its protein product. This would be analogous to having a defective concrete mixture that was used to pour the foundation for your new home. Every bag of concrete mix that was received from the cement factory contains this “mutation” such that it would be impossible for us to find a single bag that does not contain our “concrete mutation”. The end result of this faulty concrete mixture would be a foundation with holes or cracks or air pockets, your home’s version of a “faulty protein product” based on a defective gene, the “concrete mix gene”. This one defective component thus affects the stability of the entire new home, which is to be built upon the unstable foundation.

A classic example of what has been perceived to be a single gene disorder is the case of cystic fibrosis. If an individual carries particular CFTR gene SNPs they are likely to have the disease. The following quote illustrates that things are not always as simple as they might seem in terms of treatment, even when the genetic defect is well characterized. “Back in 1989, a giddy optimism swept over researchers, patients, and the public when the cystic fibrosis (CF) genome and its abnormality – a single error in a quarter of a million genetic letters – became one of the first discovered. The NIH made CF a priority, and researchers at various institutions and pharmaceutical companies moved quickly on the news. One year later, two excited research teams corrected CF cells in the lab by adding normal copies of the gene, and high expectations reigned for a drug that would replace the defective gene. However, the CF protein turned out to be too complex, unwieldy, and toxic to be made into a drug. Moreover, vectors that triggered the body’s natural immune system slowed any progress in a gene therapy approach. Fourteen years later, the hoped–for genetics cure is still considered close to 10 years away” (Richards, L., Modern Drug Discovery, June, 2004).

This was written a decade ago, and we are still far from a definitive molecular treatment for cystic fibrosis. Yet from this quote we can begin to see the logic and thinking behind the molecular medicine approach to disease. Methods used by standard medicine to isolate appropriate drugs may not be well suited to address the multifactorial nature of many of these diseases. “…the most significant problem in relation to target (drug) discovery is the multifactorial nature of the chronic diseases that are presently the focus of many pharmaceutical and biotechnology companies” (Lindsay, Nature Reviews Drug Discovery).

In comparison, recent findings in the field of nutrition suggest that answers to some of these complex diseases may lie in the use of natural supplements. Supplements may be helpful for genetically well-defined conditions even if we do not understand the precise mode of action of these nutritional supplements.

The use of the nutritional supplement glutathione has shown initial promise in helping to curb the severity of cystic fibrosis (Richards, L., Modern Drug Discovery). Preliminary trials using glutathione in cystic fibrosis patients demonstrated that the glutathione was able to significantly lower the level of oxidative stress in these individuals (Roum,J., Journal of Applied Physiology). As Valerie Hudson states with respect to glutathione, “Though not a “cure” for CF (as the underlying genetic defect remains), and though not a “panacea” for all CF-related ills (for some of those ills are not caused by GSH deficiency), it is nevertheless a therapeutic approach that calls for serious clinical investigation” (Hudson, V., Free Radical Biology and Medicine).

Recently, a second supplement, the herb curcumin has emerged as a potential tool to help offset some of the symptoms of this genetic disorder. In animal models curcumin supplementation was able to have a positive impact on symptoms of cystic fibrosis (Egan,Science). In this study the curcumin treated mice regained nearly normal nasal function. Additional research in the past year has shown that utilizing curcumin packaged in a special manner enhances delivery and expands the applicability of this approach (Cartiera, Mol Pharm).

So in spite of the genetic defect, we are able to add a component that alters the expression or manifestation of the mutation. If we go back to our “defective concrete gene” example this would be equivalent to adding a hardening agent to the defective cement mixture that allows us to overcome the mutation and have a more solid foundation.

This points to what many scientists have observed, that having a particular gene is not a guarantee that you will express the associated trait regardless of the “one gene/ specific disease” scenario. The ability to turn on or off genes also plays an important role in what we observe. This is what is known as epigenetics. “Epigenetics is to genetics as the dark matter in the universe is to the stars; we know it’s important, but it’s difficult to see…What we’re thinking now is that, in addition to genetic variation, there may be epigenetic variation that is very important in human disease” (Andrew Feinberg, Johns Hopkins School of Medicine).

You have about 25,000 genes all of which may have SNPs or mutations that impact their function. The body is a beautiful organism and has a system in place to help correct or compensate for mutations in our DNA. This system uses methylation to turn on and turn off genes by a mechanism called epigenetics. The reason I focus on the Methylation Cycle and the reason that the nutrigenomic test I use looks solely at genes in this pathway is that mutations in these genes not only affect the function of the genes carrying those mutations, they also affect the global editing function that the body relies on to help to compensate for issues in the remainder of the 25,000 genes. Having the Methylation Cycle function optimally and bypassing SNPs in this pathway allows the global editing function in your body to help to correct issues with any number of other genes in the system. THIS is why this pathway is so critical for health and wellness.

“With the completion of the Human Genome Project, we have a nearly complete list of the genes needed to produce a human. However, the situation is far more complex than a simple catalogue of genes. Of equal importance is a second system that cells use to determine when and where a particular gene will be expressed during development. This system (DNA methylation) is overlaid on DNA in the form of epigenetic marks that are heritable during cell division but do not alter the DNA….The importance of DNA methylation is emphasized by the growing number of human diseases that are known to occur when this epigenetic information is not properly established and/or maintained…”(Keith Robertson, Nature Review Genetics).

The Methylation Cycle is the system the body uses to edit and correct problems with other genes. Regardless of how many other SNPs there are in the 25,000 or so other genes in the body, since those genes are regulated by methylation, then having your Methylation Cycle in balance gives you the tools you need to help to turn on or off those other genes. This process is called epigenetics. While your DNA will not change over your lifetime, your epigenetics can change. The prefix “epi” literally means “over or attached to”. When it comes to epigenetics this means attaching a group to your DNA. Again, your DNA will not change, but the groups that can be attached to your DNA can change, and more importantly can influence the function of your DNA. Epigenetics serve as an editing function that helps to turn on and off your other genes. Epigenetics gives your body a way to compensate for problems in the DNA that you have inherited. Epigenetics is literally defined as “heritable changes in gene expression patterns that occur without changes in DNA sequence”.

In my opinion, the reason the pathway that we focus on, the ‘Methylation Cycle’ is so critical to health and well-being is that SNPs or mutations in this portion of your DNA affect your editing function as well as that portion of the DNA itself. This is such an important concept that I want you to be sure you really understand the magnitude of this situation.

While the term may seem intimidating, a methyl group is actually just a group of small molecules, similar in size to a water molecule (H2O). Water is a key to life as are methyl groups critical for health and well-being. Methyl groups are simply “CH3″ groups; they contain ‘H’ like in water and a ‘C’ like in coal or diamonds. However, these very basic molecules serve integral functions; they are moved around in the body to turn on or off genes.

One way to look at the role of methyl groups is that they serve as your own personal mechanic for your body, helping to repair and direct functions in your body. If we think about your body like a car then let’s assume that you have just one car that you need to maintain over the course of your life, with the help of your own personal mechanic. The longer you have that car the more outdated it will become. Over the course of a lifetime the car body will accumulate rust and can rot out. Tires may wear out and the engine may need an overhaul.

Alternatively the problems may be less complicated such as the need for more wiper fluid or simply to keep the car filled with gas and to regularly change the oil. In any case your personal mechanic ensures that your car keeps running, that it can stay on the road…in this case on the road to health. However, if your mechanic is unable to function, then all of these issues will start to accumulate over the course of the lifetime of your car. The rust may get so bad that car components fall off like your muffler or the tires become so worn that it is impossible to navigate a turn without the fear of blowing a tire. In the absence of your mechanic you have no way to repair all of the large and small problems that arise with your car to the point where your car can no longer function.

I truly want to be certain that you understand this critical concept of the global editing function of the Methylation Cycle. Another analogy that helps to illustrate the crucial role of this pathway is to view the function of methyl groups as analogous to the editing function on your computer. If we think about your body like a computer then you have just one computer that you need to maintain over the course of your life. The longer you have that computer the more outdated it will become. Over the course of a lifetime many of the keys may become stuck or broken. You may drop the computer and damage its function or spill your coffee on it. However, the editing function of the computer remains intact and compensates for these broken keys, misspelled words, and sticky space bars due to accidents of wear and tear. In the absence of this editing function, assume that these ‘misspells’ are accumulated in your body over the course of your life. If the editing function is impaired then you have no way to get around these misspelled words and other issues that affect your ability to function. Over your lifetime you will accumulate so many misspelled words, missed keys, etc. that at a certain point it would be impossible to read a ‘document’ amidst all of these mistakes.

You can start to see why the proper functioning of the pathway that serves to direct your genes is so important. In addition to the editing of genes, this pathway also serves more direct roles in your body and is thus critical for overall health. While there are several particular sites in this pathway where blocks can occur as a result of genetic weaknesses, thankfully supplementation with appropriate foods and nutrients can help to bypass these mutations to allow for restored function of this pathway.

By testing to look at mutations in the DNA for this Methylation Cycle it is possible to draw a personalized map for each individual’s imbalances which may impact upon their health. Once the precise areas of genetic fragility have been identified, it is then possible to target appropriate nutritional supplementation of these pathways to optimize the functioning of these crucial biochemical processes. There are specific places in the cycle where support can be added. This support helps to bypass mutations in the pathway in a similar manner to the way you might take a detour on a highway. We can look at mutations in this pathway as analogous to a collision that has totally shut down traffic going in one direction on a highway. Support to bypass mutations in this pathway is like taking an alternate route to avoid the accident on the highway. Thus, the use of key nutrients or foods can aid in helping to bypass methylation cycle mutations and help restore function to this pathway

It does not mean that every individual with mutations in this pathway will have one or more nonideal health condition. It may be a necessary but not a sufficient condition. Most health conditions in society today are multifactorial in nature. There are genetic components, infectious components and environmental components. A certain threshold or body burden needs to be met for each of these factors in order for multifactorial disease to occur.

A key component to charting your personal Roadmap to health is understanding the importance of the Methylation Cycle for overall health and wellness. Understanding that mutations in the group of genes involved in this cycle can not only impair a specific gene’s function but also have the ability to impair our global editing system. The Methylation Cycle is our fall back system that helps to compensate for mutations in our DNA in general.

Next Chapter:

Inheritance and Ancestry

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