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Why Your Brain Craves PQQ


Reproduced from original article:
https://articles.mercola.com/sites/articles/archive/2019/12/02/pqq-for-brain-health.aspx

Analysis by Dr. Joseph MercolaFact Checked
December 02, 2019
pqq for brain health

STORY AT-A-GLANCE

  • Pyrroloquinoline quinone (PQQ) is particularly important for the health and protection of your mitochondria. It also helps regenerate new mitochondria
  • PQQ has been shown to improve the function of beta amyloid-damaged brain cells — a hallmark of Alzheimer’s disease — and prevent the formation of alpha-synclein proteins associated with Parkinson’s disease. It can even help prevent neuronal cell death in cases of traumatic brain injury
  • Studies show PQQ improves mental processing and memory. It also works synergistically with CoQ10, producing better results than either of these nutrients alone
  • PQQ lowers C-reactive protein and interleukin-6, which are inflammatory biomarkers, and upregulates Nrf2 expression — a biological hormetic that upregulates beneficial intercellular antioxidants
  • PQQ has also been shown to boost the activity of primary life span extension transcriptional factors, which led the researchers to surmise that PQQ may play a role in longevity

While your diet is one of the most important tools you can use to take control of your health, certain supplements can be helpful, especially when it comes to improving your mitochondrial function. One particularly powerful supplement in this regard is pyrroloquinoline quinone (PQQ),1 which has been shown to promote the growth of new mitochondria (mitochondrial biogenesis).

Your mitochondria also require PQQ to catalyze energy producing reactions, and it’s critical in protecting your mitochondria from damage. Your mitochondria are the tiny energy producers inside your cells, which is why mitochondrial dysfunction is at the heart of just about all chronic diseases, old age and death.

In order for your body to function properly, it needs sufficient energy and, for that, you need well-nourished, well-functioning mitochondria. PQQ is an important player in this regard.2 As noted by Dave Asprey, founder of Bulletproof and author of books on energy, life span and brain power:3

“Anti-aging starts at the cellular level and PQQ is an easy way to protect your cells, all while helping to improve the most mitochondrial-dense parts of your body like your brain and heart.”

PQQ Enhances Mitochondrial Density and Function

PQQ is relatively unique in its ability to enhance mitochondrial biogenesis, i.e., the creation of new, healthy mitochondria in aging cells, which is the basis of so many of its health benefits. As reported by Better Nutrition magazine:4

“In addition to improving energy production, this characteristic of PQQ shifts some of the aging process into reverse gear. In a study5 at the University of California, Davis, researchers gave a small group of men and women PQQ supplements and tested the effects 76 hours later.

Using blood and urine tests, researchers found that PQQ improved mitochondrial performance and reduced chronic inflammation. The effective dose was 0.3 mg of PQQ per kilogram of body weight — 20 mg of PQQ for a 150-pound person, as an example.”

One mechanism by which PQQ lowers inflammation, improves mitochondrial function and stimulates mitochondrial biogenesis is by upregulating Nrf2 expression — a biological hormetic that upregulates intercellular antioxidants such as superoxide dismutase and catalase.

PQQ has also been shown to boost the activity of primary life span extension transcriptional factors, which led the researchers to surmise that PQQ may play a “novel role” in longevity.6 Indeed, it modulates a variety of signaling pathways, including mTOR, which plays a role in aging and cancer,7 and helps repair DNA,8 all of which suggests it may help you live longer.

PQQ also enhances NADH,9 which is converted to NAD+ as food is broken down into energy.10 When DNA damage is repaired, NAD+ is used up, and if you run out you can’t repair the damage, which is likely the central cause for most of the diseases we are seeing in the modern world now.

How PQQ Protects and Benefits Your Brain

PQQ’s ability to shield your brain cells and their DNA from harm also suggests it can be a powerful preventive aid against neurodegenerative diseases. Mitochondrial DNA is quite prone to damage from free radicals and pro-oxidants. Most of the free radicals in the body are produced within the mitochondria themselves, which is why they’re so susceptible.

Free radicals are an unavoidable artifact of converting food into cellular fuel, and your food is ultimately metabolized in your mitochondria. PQQ has been shown to protect against this kind of damage. It also activates your mitochondria’s built-in repair and replication mechanisms.

In your brain, the practical end result is an overall improvement of neurologic function,11 including improved cognition, learning and memory,12 and a reduced risk of neurodegenerative diseases. Research13 has shown PQQ protects and improves the survival of neurons by stimulating the synthesis of nerve growth factor (NGF) in certain glial cells found in your central nervous system.

It’s also been shown to improve the function of beta amyloid-damaged brain cells14 — a hallmark of Alzheimer’s disease — and prevent the formation of alpha-synclein proteins associated with Parkinson’s disease.15

According to a 2012 study,16 PQQ can even help prevent neuronal cell death in cases of traumatic brain injury. According to the authors of this study, “PQQ may play an important role in recovery post-TBI.”

Adding CoQ10 Provides Synergistic Benefits

Both animal and human studies using doses between 10 and 20 milligrams (mg) of PQQ have demonstrated improvement in mental processing and memory on its own, but combining it with Coenzyme Q10 could potentially be even more beneficial.

One study found PQQ in combination with CoQ10 produced better results than either of these nutrients alone, so there appears to be some synergistic effects. I recommend using the reduced form of CoQ10, called ubiquinol, as it is more readily available for your body.

Both CoQ10 and PQQ are fat-soluble, so they’re best taken with a small amount of fat in your meal rather on an empty stomach. In addition to being a powerful antioxidant in its own right, CoQ10/ubiquinol also facilitates the recycling (catalytic conversion) of other antioxidants, so when taken in combination with PQQ, you’re really turbocharging your body’s antioxidant capacity.

PQQ Is a Powerful Antioxidant and Immune Booster

Another reason why PQQ is so beneficial has to do with its powerful antioxidant activity. It’s capable of undergoing upward of 20,000 catalytic conversions. A catalytic conversion is when an antioxidant neutralizes a free radical. In other words, PQQ is a remarkably efficient antioxidant. For comparison, vitamin C can only go through four catalytic conversions before it’s used up.17,18

Research has shown PQQ lowers the inflammatory biomarkers C-reactive protein and interleukin-6 in humans at doses between 0.2 mg and 0.3 mg per kg.19

PQQ also supports your immune function and PQQ deficiency has been linked to immune dysfunction.20 In one study,21 PQQ supplementation increased the responsiveness of B- and T-cells (white blood cells that play central roles in your immune response) to mitogens (proteins that induces cell division or mitosis).

PQQ Activates Metabolic Master Switch

The list of potential applications for PQQ is extremely long, as its metabolic effects go well beyond improving mitochondrial function. For example, it helps activate adenosine monophosphate-activated protein kinase (AMPK), which is an important molecular target for metabolic health.

AMPK is an enzyme inside your body’s cells. It’s sometimes called a “metabolic master switch” because it plays an important role in regulating metabolism. As noted in the Natural Medicine Journal:22

“AMPK induces a cascade of events within cells that are all involved in maintaining energy homeostasis … AMPK regulates an array of biological activities that normalize lipid, glucose, and energy imbalances.

Metabolic syndrome (MetS) occurs when these AMPK-regulated pathways are turned off, triggering a syndrome that includes hyperglycemia, diabetes, lipid abnormalities, and energy imbalances …

AMPK helps coordinate the response to these stressors, shifting energy toward cellular repair, maintenance, or a return to homeostasis and improved likelihood of survival.

The hormones leptin and adiponectin activate AMPK. In other words, activating AMPK can produce the same benefits as exercise, dieting, and weight loss — the lifestyle modifications considered beneficial for a range of maladies.”

With age, your AMPK level drops naturally, but poor diet can reduce AMPK activity at any age. This enzyme plays a major role in body fat composition, inflammation and blood lipids, so boosting its activity can go a long way toward improving blood sugar control, reducing visceral fat and lowering LDL cholesterol.

AMPK also stimulates mitochondrial autophagy (mitophagy) and mitochondrial biogenesis, as well as five other critically important pathways: insulin, leptin, mTOR, insulin-like growth factor 1 (IGF-1) and proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α).

It is important to note that PQQ will not likely work well, if at all, if you are eating around the clock, as elevated insulin levels will activate mTOR and inhibit AMPK, thus limiting PQQ’s ability to increase it.

Other Benefits of PQQ

PQQ has also been linked to several other health benefits, including:

  • Improved reproductive outcomes in animals23 (PQQ deficiency has been linked to abnormal reproductive performance24)
  • Reduced risk of nonalcoholic fatty liver disease in offspring when given to obese mouse mothers during pregnancy and lactation25
  • Improved sleep (by modulating the cortisol awakening response)26

As you can see, the list of PQQ’s health benefits is quite long. And, while PQQ is found in foods such as natto, parsleygreen pepperspinachpapaya, kiwi and green tea,27 the amounts you get from your diet are likely to be insufficient if you want to reap all of its beneficial health effects.

When taking a PQQ supplement, you’ll know within a few weeks whether the brand and dosage is working for you. Overall, you should feel better, with greater energy and clearer thinking.

– Sources and References

Gene-Editing Unintentionally Adds Bovine DNA, Goat DNA, and Bacterial DNA, Mouse Researchers Find

© 6th November 2019 GreenMedInfo LLC. This work is reproduced and distributed with the permission of GreenMedInfo LLC. Want to learn more from GreenMedInfo? Sign up for the newsletter here www.greenmedinfo.com/greenmed/newsletter
Reproduced from original article:
www.greenmedinfo.health/blog/gene-editing-unintentionally-adds-bovine-dna-goat-dna-and-bacterial-dna-mouse-res


Originally published on www.independentsciencenews.org

The gene-editing of DNA inside living cells is considered by many to be the preeminent technological breakthrough of the new millennium. Researchers in medicine and agriculture have rapidly adopted it as a technique for discovering cell and organism functions. But its commercial prospects are much more complicated.

Gene-editing has many potential uses. These include altering cells to treat human disease, altering crops and livestock for breeding and agriculture. Furthermore, in a move that has been widely criticised, Chinese researcher He Jiankui claims to have edited human babies to resist HIV by altering a gene called CCR5.

For most commercial applications gene-editing’s appeal is simplicity and precision: it alters genomes at precise sites and without inserting foreign DNA. This why, in popular articles, gene-editing is often referred to as ‘tweaking’.

The tweaking narrative, however, is an assumption and not an established fact. And it recently suffered a large dent. In late July researchers from the US Food and Drug Administration (FDA) analysed the whole genomes of two calves originally born in 2016. The calves were edited by the biotech startup Recombinetics using a gene-editing method called TALENS (Norris et al., 2019). The two Recombinetics animals had become biotech celebrities for having a genetic change that removed their horns. Cattle without horns are known as ‘polled’. The calves are well-known because Recombinetics has insisted that its two edited animals were extremely precisely altered to possess only the polled trait.

However, what the FDA researchers found was not precision. Each of Recombinetics’ calves possessed two antibiotic resistance genes, along with other segments of superfluous bacterial DNA. Thus, apparently unbeknownst to Recombinetics, adjacent to its edited site were 4,000 base pairs of DNA that originated from the plasmid vector used to introduce the DNA required for the hornless trait.

The FDA finding has attracted some media attention; mainly focussed on the incompetence of Recombinetics. The startup failed to find (or perhaps look for) DNA it had itself added as part of the editing process. Following the FDA findings, Brazil terminated a breeding program begun with the Recombinetics animals.


An animal research facility

But FDA’s findings are potentially trivial besides another recent discovery about gene-editing: that foreign DNA from surprising sources can routinely find its way into the genome of edited animals. This genetic material is not DNA that was put there on purpose, but rather, is a contaminant of standard editing procedures.

These findings have not been reported in the scientific or popular media. But they are of great consequence from a biosafety perspective and therefore for the commercial and regulatory landscape of gene-editing. They imply, at the very least, the need for strong measures to prevent contamination by stray DNA, along with thorough scrutiny of gene-edited cells and gene-edited organisms. And, as the Recombinetics case suggests, these are needs that developers themselves may not meet.

Understanding sources of stray DNA

As far back as 2010 researchers working with human cells showed that a form of gene-editing called Zinc Finger Nuclease (ZFN) could result in the insertion of foreign DNA at the editing target site (Olsen et al., 2010). The origin of this foreign DNA, as with Recombinetics’ calves, was the plasmid vector used in the editing process.

Understanding the presence of plasmid vectors requires an appreciation of the basics of gene-editing, which, confusingly, are considerably distinct from what the word ‘editing’ means in ordinary English.

Ultimately, all DNA ‘editing’ is really the cutting of DNA by enzymes, called nucleases, that are supposed to act only at chosen sites in the genome of a living cell. This cut creates a double-stranded break that severs (and therefore severely damages) a chromosome. The enzymes most commonly used by researchers for this cutting are the Fok I enzyme (for TALENS type editing), Cas9 (for CRISPR), or Zinc Finger Nucleases (for ZFN).

Subsequent to this cutting event the cell effects a repair. In practice, this DNA repair is usually inaccurate because the natural repair mechanism in most cells is somewhat random. The result is called the ‘edit’. Researchers typically must select from many ‘edits’ to obtain the one they desire.

Like virtually all enzymes these nucleases are proteins. And like most proteins they are somewhat tricky to produce and relatively unstable once made. Typically, therefore, rather than produce the DNA cutting enzymes directly, researchers introduce vector plasmids into target cells. These vector plasmids are circular DNA molecules that code for the desired enzyme(s). (vector plasmid DNA may also code for the guide RNA that CRISPR editing techniques require). What this means, in practice, is that TALENS, Cas9 and the other cutting enzymes end up being produced by the target cell itself.

Introducing DNA rather than proteins is thus much easier, research-wise, but it has a downside: non-host (i.e. transgenic) DNA must be introduced into the cell that is to be edited and this DNA may end up in the genome.

Plasmid vectors are not simple. As well as specifying the nucleases, the vector plasmid used by Recombinetics contained antibiotic resistance genes, plus the lac Z gene, plus promoter and termination sequences for each of them, plus two bacterial origins of replication. Each of these DNA components comes from widely diverse microbes.

As Olsen et al. and the FDA showed, using both TALENS and ZFN types of DNA cutters can result in plasmid vector integration at the target site. In 2015 Japanese researchers showed that DNA edits made to mouse zygotes using the CRISPR method of gene editing are also vulnerable to unintended insertion of non-host DNA (Ono et al., 2015).

Since then, similar integrations of foreign DNA at the target site have been observed in many species: fruitflies (Drosophila melanogaster), medaka fish (Oryzias latipes), mice, yeast, Aspergillus (a fungus), the nematode C. elegans, Daphnia magna, and various plants (e.g. Jacobs et al., 2015Li et al., 2015Gutierrez-Triana et al., 2018).

Other sources of stray DNA

The vector plasmids themselves are not the only source of potential foreign DNA contamination in standard gene-editing methodologies.

Earlier this year the same Japanese group showed that DNA from the E. coli genome can integrate in the target organisms’ genome (Ono et al. 2019). Acquisition of E. coli DNA was found to be quite frequent. Insertion of long unintended DNA sequences occurred at 4% of the total number of edited sites and 21% of these were of DNA from the E. coli genome. The source of the E. coli DNA was traced back to the E. coli cells that were used to produce the vector plasmid. The vector plasmid, which is DNA, was contaminated with E. coli genome DNA. Importantly, the Japanese researchers were using standard methods of vector plasmid preparation.

Even more intriguing was the finding, in the same paper, that edited mouse genomes can acquire bovine DNA or goat DNA (Ono et al., 2019). This was traced to the use, in standard culture medium for mouse cells, of foetal calf serum; that is, body fluids usually extracted from cows. This serum contains DNA from whichever animal species it happened to have been extracted from, hence the insertion in some experiments of goat DNA (which occurred when goat serum was used instead of calf serum).

Even more worrisome, amongst the DNA sequences inserted into the mouse genome were bovine and goat retrotransposons (jumping genes) and mouse retrovirus DNA (HIV is a retrovirus). Thus gene-editing is a potential mechanism for horizontal gene transfer of unwanted pathogens, including, but not limited to, viruses.

Other potential sources of unwanted DNA also exist in cell cultures used for gene editing. In 2004 researchers observed that when cells from a hepatoma cell line were caused to have DNA breaks, some of these breaks were filled by hepatitis B virus sequences (Bill and Summers, 2004). In other words, pathogens contaminating the foetal serum, such as DNA viruses, should also be a source of concern.

Furthermore, the insertion of superfluous DNA from other species is likely not restricted to the intended target site. As is becoming appreciated, gene-editing enzymes can act at unwanted locations in the genome (e.g. Kosicki et al., 2018). Accidentally introduced DNA can also end up at such sites. This has been shown for human cells and also plants using CRISPR (Kim and Kim 2014; Li et al., 2017; Jacobs et al., 2015). There is every reason to suppose that the more exotic DNAs mentioned above can integrate there as well, but this has not been specifically tested for.

Implications of superfluous DNA in edited cells

In summary, the new findings are very simple: cutting DNA inside cells, regardless of the precise type of gene editing, predisposes genomes to acquire unwanted DNA. The unwanted DNA may come from inside the edited cell, or it may come from the culture medium, or it may come from any biological material added to the culture medium, whether accidentally or on purpose. Therefore, it is not hard to imagine, for instance, gene-edited animals becoming the breeding stock that leads to the development or spread of novel or unwelcome viruses or mycoplasmas.

Stuart Newman of New York Medical College is a cell biologist, a founding member of the Council for Responsible Genetics, and Editor-In-Chief of the journal Biological Theory. According to him, the addition of DNA originating from cell culture “is something that has not been broached in the discourse around safety of CRISPR and other gene modification techniques.”

In the case of gene-editing intended to generate altered living organisms, cell culture media “contain genes that could cause developmental problems if reincorporated by CRISPR/Cas9 into the zygote genome in extra numbers and uncontrolled chromosomal sites.” says Newman.

“I have little doubt E. coli DNA has been inadvertently incorporated into many CRISPR targets, and it is likely to cause problems, as it has in the horned cattle.”

Similar concerns apply to human applications. The incorporation of DNA from other species has not publicly been raised in connection with the gene-edited human babies of researcher He Jiankui. Clearly, it should be. From what cell types, for example, did He Jiankui purify the proteins he presumably used to edit the CCR5 gene? Rabbit cells? Insect cells? Those, at least, are the standard methods.

The second important conclusion, and what the Recombinetics case exemplifies, is that researchers are often not looking for stray DNA. If they were to look, many more examples would likely be reported. We can conclude this because the research cited above used standard methods of gene-editing. The only untypical aspect was the extra effort put towards detecting superfluous DNA.

Gene-editing versus GMOs

What these recent findings also highlight is a more general, but little-discussed, aspect of gene-editing. Although the goals of gene-editors and genetic engineers are assumed to be very different, their standard methods are, in practice, virtually indistinguishable.

Consider crop plants, which are where much of the immediate commercial interest in gene-editing resides. To edit plants, DNA, in the form of vector plasmid, is introduced into plant cells. In contrast to methods of animal gene-editing, this vector plasmid is necessary (and not optional) since proteins cannot penetrate plant cell walls. This vector plasmid must access the cell interior, which requires either a gene gun or infection with the DNA-transferring bacterium Agrobacterium tumefaciens. Lastly, in-vitro cell culture is used to regenerate the edited cells into whole plants.

Gene guns, tissue culture, and A. tumefaciens are all standard genetic engineering methods for crops. They also all create mutations. That is, they damage DNA. Depending on the specifics of the method used, such as the length of time in tissue culture, the collective result can be ten thousand mutations per genome (Wilson et al., 2006Latham et al., 2006). For gene-editing of crops this means that one on-target mutation may be dwarfed by thousands of off-target ones.

The other necessary comparison with GMOs is their track record of being found, long after commercialisation, to have unintended foreign DNA present in their genomes. Cornell’s virus-resistant papaya, released in Hawai’i, turned out to contain at least five (and possibly six) separate fragments of transgenic DNA. Cornell had previously told regulators its papaya contained two transgenes (Ming et al., 2008). Monsanto’s Roundup Ready Soybean, by then grown on 96% of US soybean acres, was found by independent researchers to have substantially more foreign DNA than Monsanto had claimed (Windels et al., 2001).

So, if one only listened to the rhetoric contrasting ‘precise’ ‘tweaks’ of gene-editing with ‘messy’, ‘random’ genetic engineering one would hardly suspect that, when it comes to plants, and often to animals as well, there is little difference between the reality of gene-editing and that of genetic engineering.

Are there solutions to the presence of superfluous DNA?

Solutions to the presence of superfluous DNA (at or distant from the editing site) come in two basic forms: prevention or detection followed by removal.

An obvious preventive step is to avoid the use of vector plasmids and undefined culture media (undefined media are those containing fluids or extracts from living organisms). Another is to explicitly breed (backcross) gene-edited animals and plants to remove superfluous DNAs. A third is to sequence their whole genome, compare it to the parent genome, and select only unaltered lines, if they can be found (Ahmad et al., 2019).

However, these remedies are effortful. They are time-consuming and costly, or not yet fully developed, or only available for some species. These are also solutions that nullify the advantages of speed and ease that are often the stated reasons for editing in the first place.

The requirements for expertise and effort do much to explain the second major problem, which is that the industry, and not just Recombinetics, is not showing much interest in self-examination. Far greater even than the GMO industry before it, there is a cowboy zeitgeist: blow off problems and rush to market. Thus most gene-editing companies are reluctant to share information and consequently very little is known about how, in practice, many of these companies derive their ‘gene-edited’ products.

Many countries are at present formulating regulations that will go a long way to determining who benefits and who loses from any potential benefits that gene-editing may have. But in any event, these results provide a compelling case for active government oversight.

It is not just regulators who need to step up, however. Investors, insurers, journalists, everyone, in fact, should be asking far more questions of the scientists and companies active in gene-editing. Otherwise, boom is likely to stray into bane.


References

Ahmad, Niaz Mehboob-ur Rahman, Zahid Mukhtar, Yusuf Zafar, Baohong Zhang (2019) A critical look on CRISPR-based genome editing in plants. J. Cellular Physiology.

Bill, Colin A. and Jesse Summers (2004) Genomic DNA double-strand breaks are targets for hepadnaviral DNA integration. PNAS: 101 (30) 11135-11140.

Gutierrez-Triana, Jose Arturo, Tinatini Tavhelidse, Thomas Thumberger , Isabelle Thomas, Beate Wittbrodt, Tanja Kellner, Kerim Anlas, Erika Tsingos, Joachim Wittbrodt (2018) Efficient single-copy HDR by 5′ modified long dsDNA donors. eLife 2018;7:e39468.

Thomas B Jacobs, Peter R LaFayette, Robert J Schmitz & Wayne A Parrott (2015) Targeted genome modifications in soybean with CRISPR/Cas9. BMC Biotechnology 15: 16.

Kim, J. & Jin-Soo Kim (2016) Bypassing GMO regulations with CRISPR gene editing. Nature Biotechnology 34: 1014-1015.

Kosicki, M , K. Tomberg and A. Bradley (2018) Repair of double-strand breaks induced by CRISPR-Cas9 leads to large deletions and complex rearrangements. Nature Biotechnology 36: 765-771.

Norris, Alexis. L., Stella S. Lee, Kevin J. Greenlees, Daniel A. Tadesse, Mayumi F. Miller, Heather Lombardi (2019) Template plasmid integration in germline genome-edited cattle. doi: https://doi.org/10.1101/715482

Olsen, P.A., Gelazauskaite, M., Randol, M. & Krauss, S. (2010) Analysis of illegitimate genomic integration mediated by zinc-finger nucleases: implications for specificity of targeted gene correction. BMC Mol Biol 11, 35.

Latham, Jonathan R., Allison K. Wilson and Ricarda A. Steinbrecher (2006) The Mutational Consequences of Plant Transformation. The Journal of Biomedicine and Biotechnology (2006) 7 pages doi:10.1155/JBB/2006/25376

Li, Zhongsen, Zhan-Bin Liu, Aiqiu Xing, Bryan P. Moon, Jessica P. Koellhoffer, Lingxia Huang, R. Timothy Ward, Elizabeth Clifton, S. Carl Falco, A. Mark Cigan (2015) Cas9-Guide RNA Directed Genome Editing in Soybean. Plant Physiol. 169: 960-970.

Li, Rong Sheng Quan, Xiaofang Yan, Sukumar Biswas, Dabing Zhang, Jianxin Shi (2017) Molecular characterization of genetically-modified crops: Challenges and strategies. Biotechnology Advances 35:s 302-309.

Ming, R., S Hou, Y Feng, Q Yu, A Dionne-Laporte (2008) The draft genome of the transgenic tropical fruit tree papaya (Carica papaya Linnaeus). Nature 452: 991-996.

Windels, Pieter, Isabel Taverniers, Ann Depicker, Erik Van Bockstaele and Marc De Loose (2001) Characterisation of the Roundup Ready soybean insert. Eur. Food Res. Technol. 213:107-11.

Ono, Ryuichi, Masayuki Ishii, Yoshitaka Fujihara, Moe Kitazawa, Takako Usami, Tomoko Kaneko-Ishino, Jun Kanno, Masahito Ikawa & Fumitoshi Ishino (2015) Double strand break repair by capture of retrotransposon sequenc es and reverse-transcribed spliced mRNA sequences in mouse zygotes. Scientific Reports 5: 12281.

Ryuichi Ono, Yukuto Yasuhiko, Ken-ichi Aisaki, Satoshi Kitajima, Jun Kanno & Yoko Hirabayashi (2019) Exosome-mediated horizontal gene transfer occurs in double-strand break repair during genome editing. Communications Biology 2: 57 https://www.nature.com/articles/s42003-019-0300-2.pdf?origin=ppub

Wilson, Allison K., Jonathan R. Latham, and Ricarda A. Steinbrecher (2006) Transformation-induced mutations in transgenic plants: analysis and biosafety implications. Biotechnology and Genetic Engineering Reviews 23.1 : 209-238.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of GreenMedInfo or its staff.

How Functional Genetics Can Help You Take Control of Your Health

Analysis by Dr. Joseph Mercola  – Fact Checked – May 12, 2019

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Story at-a-glance

  • Functional genetics looks at the single nucleotide polymorphisms (SNPs, pronounced “snips”) of genes
  • When you have SNPs (genetic variants or defects on the genes), enzymes may not be working effectively, or the gene may be upregulated or downregulated
  • While traditional genetics often looks for potential disease states, functional genetics looks for potential impairment of function and helps find the best nutritional intervention to bring your body back into balance
  • People with genetic weaknesses that hamper detoxification who are exposed to high amounts of environmental toxins can be struggling with health due to their limited ability to detoxify
  • NutriGenetic Research Institute is devoted to functional genomic testing, training health professionals to help people understand the results and how to apply it to improve their health

Functional genomics is a gene testing modality with enormous value that many are completely unaware of. Bob Miller1 is a certified traditional naturopath specializing in genetic-specific nutrition. He’s the founder of the NutriGenetic Research Institute,2 devoted to testing and helping people understand the results of their functional genetic testing and how to apply it to improve their health.

“As a traditional naturopath, we’re not licensed medical doctors, so we don’t diagnose, treat or prescribe,” Miller explains. “We look at the functional approach of, ‘How is the terrain off in the body?’ … [W]hen the body is toxic or inflamed, that’s when pathogens have a better opportunity to thrive.

Many years ago, I learned about how homocysteine has pathways that clear it that may be impaired by genetic variants. I became very fascinated by it. I started looking at the enzymes that clear it, and then the genetics behind it.

My whole naturopathic and holistic practice is [now] dedicated to helping clients measure their functional genomics, which is quite a bit different than traditional genetics that looks for disease patterns, and trying to find out how we can make interventions to bring the body back into balance …

Our goal is to be able to make a contribution to functional practitioners, so they can do their job a lot better and improve the lives of those who are suffering with some of those things that nobody can seem to figure out …

To sum up what we’re finding is that those with genetic weakness in detox pathways are exposed to environmental factors we weren’t dealing with 50 to 75 years ago; their ability to detox is overwhelmed. I think this is a whole new paradigm that we have to look at in wellness.

Those who don’t have a specific disease, so to speak, but are just totally overwhelmed by all of the epigenetic factors, such as pesticides, electromagnetic fields (EMFs) … excess iron … plastics … mold … [and] sometimes even oversupplementation with things like folate and glutamine … that no matter what they try, it doesn’t work …

That’s why we need to move to personalized care, based upon the individual. Fortunately, we now have tools to do that.”

What Is Functional Genetics?

Certain genes are known to predispose you to, or raise your risk of, certain diseases. That’s not what we’re talking about here. Functional genetics looks at the single nucleotide polymorphisms (SNPs, pronounced “snips”) of genes related to function.

You’ve probably seen representations of the DNA ladder. On the end of each rung is a molecule from each of your parents. These molecules can either make your DNA optimal or, if you have a SNP, meaning a defect, that gene will not work at optimal efficiency. Miller explains:

“To make this simple, we eat fats, carbohydrates and proteins. We drink water, breathe air and are exposed to sunlight. What an absolute miracle it is that all of that turns into us: our blood, our skin, our nails, our organs and our thought processes. All of that is one enzymatic process after another.

So, an enzyme takes substance A; pulls in what we call cofactors and makes substance B. That continually happens throughout your body — one process after another. It’s your genetic makeup that [provides] the instructions on how to make these enzymes.

When we have genetic variants, SNPs, on the genes, sometimes those enzymes either aren’t as effective … or might be upregulated or downregulated. Therefore, that substance A to substance B [conversion] may not occur as it should.

Now, people get all excited about whether they have genetic variants or not, but there’s something else just as important. That’s the cofactor. Remember, substance A plus cofactors turns into substance B. You could have absolutely perfect genetics, that enzyme is made perfectly, but if you’re missing the cofactors, that A to B [conversion] is not going to work …

Where people really get hit hard is when they’ve got genetic weakness and cofactor weakness. Then there’s a third piece. Sometimes there are things that interfere. For example, lead, mercury and other things may suppress that enzymatic function …

Now, interestingly, we have all kinds of backups. One pathway may not be working, but another one might kick in. But what we’re observing … is that those who are struggling usually have multiple pathways blocked. Plus, they get multiple epigenetic exposures … When you get those epigenetic and genetic factors going together, that’s when things really start going awry.”

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The Relationship Between mTOR Pathway and Autophagy

Autophagy means “self-eating” and refers to your body’s process of eliminating damaged and defective cellular parts that are targeted for lysosome, which then digests them. The mammalian target of rapamycin (mTOR) is a molecular signaling pathway responsible for either growth or repair, depending on whether it is stimulated or inhibited.

I’ve often stated that to upregulate maintenance and repair (which will boost longevity and reduce your risk for cancer), you need to suppress the mTOR pathway. One of the most efficient ways to do this is to limit your protein intake, but it’s not the only way. Autophagy and mTOR are two processes that work together, but are inverse to each other. Miller likens mTOR to a construction crew, whereas autophagy refers to the cleanup crew.

“One of the ways you can tell if your autophagy is not working is when you get those age spots, sun spots, liver spots, whatever you’d like to call them,” Miller says. “That’s when the old cell is not cleared away and it becomes oxidized, it becomes senescent. It actually becomes a free radical-giving reactive oxygen species.

Now, we need a balance between [mTOR and autophagy]. We need a time to build and we need a time to clean. One of the things our research institute [found] in some of our studies on those with chronic Lyme disease [is] that we are being exposed to more epigenetic environmental factors that stimulate mTOR … ”

Factors That Activate mTOR Versus Those That Support Autophagy

Examples of environmental factors that activate mTOR include:

Xenoestrogens (chemicals in plastic) EMFs
Insulin Excess protein
Excess iron Excess folic acid, folate or methyl folate
Excess glutamate Amino acids such as leucine, isoleucine and valine

When mTOR is activated, it inhibits autophagy and, according to Miller, many of the health challenges people face these days appear to be related to excess mTOR activation.

This is also one way by which a cyclical ketogenic diet helps improve your health, as it inhibits mTOR and activates autophagy. When mTOR is chronically activated, it will not only inhibit autophagy but also impair apoptosis (cell death), and if that’s impaired, your risk for cancer will significantly increase as well.

“We have identified the genes that are involved with autophagy,” Miller says. “They’re called Unc-51 like autophagy activating kinase 1 (ULK1), serine/threonine-protein kinase (ULK2), 5’ AMP-activated protein kinase (AMPK) and AuTophaGy related 1 (ATG1).

Those all stimulate autophagy. We’re finding that when people have a lot of genetic variants, especially when they inherit it from both parents, this is where their autophagy’s weakened. They’re 45 years old and covered with age spots. They can’t detox.

Ketogenic diet, intermittent fasting and nutrients [such as] lithium and berberine support autophagy. Resveratrol and curcumin slow down mTOR.

When you put the three together — the caloric restriction mimetics (CRM) [editor’s note: supplements that mimic the antiaging effects of calorie restriction] … along with the keto diet, along with some form of intermittent fasting — you’re able to bring balance to mTOR and autophagy.”

If Ketogenic Diet or Intermittent Fasting Fails for You, This Could Be Why

While intermittent fasting is an excellent strategy for a majority of people, it doesn’t work as expected for everyone. As explained by Miller, members of his research team have discovered having a functional heme pathway is extremely important when you’re on a ketogenic diet and/or intermittently fasting.

Heme protein is created through an eight-step process beginning with succinyl coenzyme A (succinyl CoA), glycine and amino acids. Heme protein in turn is a component of hemoglobin, but it’s also involved in the making of nitric oxide, catalase, superoxide dismutase (SOD) and sulfite oxidase (SUOX), which is your sulfide to sulfate conversion.

“It’s involved in so many processes that I didn’t even realize until we started to research,” Miller says. “This [heme] pathway may be impaired by … glyphosate [which impacts glycine] … lead … and genetic variants in the heme pathway.

If any of those happen, you don’t make adequate heme, so you’re going to be a very poor detoxer. Now, what’s interesting … [is that] if porphyrins [glycoproteins responsible for pore formation in cell membranes] are not transferred one to another, they will block the gamma-aminobutyric acid (GABA) receptor sites. GABA is the ‘Don’t worry. Be happy. Sleep. Relax’ [neurotransmitter]. Clearly, there are problems with anxiety in the world today.

If this heme pathway gets disturbed, people oftentimes crave carbohydrates. If they try to go keto, it doesn’t work. If they try to do intermittent fasting, it doesn’t work … It’s a small amount of people, but for some individuals who just crave carbohydrates, they’ll get hangry if they don’t have their carbohydrates. They’re actually feeding that heme pathway.

If someone’s ever tried keto and is like, ‘This just does not work for me,’ there’s a potential that the heme pathway could be impaired. You have to keep those carbohydrates coming in on a regular basis to feed it, or else you feel horrible. I remember in the past people telling me, ‘Whenever I try to eat healthy, I feel horrible. When I eat junk, I feel better.’

I used to think, ‘Yeah. I’m not sure I buy that.’ But now that you understand this heme pathway and how carbohydrates and simple sugars can feed it, it starts to make sense that that is a potential scenario for some people.”

Even if You’re Anemic, You May Be Overabsorbing Iron

As mentioned earlier, iron stimulates mTOR. Clearly, iron is crucial for optimal health. Without sufficient amounts of iron, you cannot make sufficient amounts of hemoglobin, which carries oxygen through your body. However, in excess, iron is incredibly destructive.

“Here’s one of the interesting things we found through our research. There are many people who have genetic predisposition to overabsorbing iron, yet they’re told all their life they’re anemic. It just seems like such a dichotomy; how can you be anemic if you’re overabsorbing iron?

One of the things that we … find in many who are struggling and can’t get answers anywhere else is that they overabsorb iron. There’s an enzyme called ferroportin, [which] is what takes iron out of the cells. SNPs there, or genetic defects, inhibit the removal of the iron. Through something called the Fenton reaction … iron may combine with hydrogen peroxide to make hydroxyl radicals.

This can then go on to make another nasty free radical called peroxynitrite. Consequently, the person is anemic because they are measuring what’s in the blood, but the iron can be in excess and inside the cells, causing massive inflammation.

As that iron bangs around inside the cell, it creates fatigue, because the mitochondria are having a hard time making energy. These are the people who if someone gives them iron, many times, they feel considerably worse, because they’ve just fed the fire.

In our consulting, one of the things we probably do the most is identifying the Fenton reaction going on and taking remedial action to, for example, help turn the hydrogen peroxide into water through an enzyme called catalase; supporting enzymes and antioxidants called glutathione and thioredoxin that turn the hydrogen peroxide into water, [and] using homeopathics to make the iron behave itself.”

Hydrogen water can be helpful here, Miller notes, because it helps decrease the excess hydroxyl radicals. “Quite simply, H2O2 plus iron equals hydroxyl free radical (OH-), which is one of the most highly reactive and damaging free radicals,” Miller explains.

I’ve previously interviewed Tyler LeBaron, one of the leading experts on molecular hydrogen, and he believes the benefits may be related more to the upregulation of antioxidant pathways, such as the nuclear factor erythroid 2-related factor 2 (Nrf2). Either way, whatever the mechanism, it seems clear hydrogen water has the ability to neutralize free radicals.

Situations in Which NAC or Methyl Folate May Backfire

I’ve previously written about the benefits of N-acetyl cysteine (NAC), the rate-limiting factor for glutathione, which is a master antioxidant made by your body. However, in order for this to work, you must have the required enzymes. What’s more, if you have an iron problem, the cysteine you take can combine with the iron to create hydroxyl radicals — essentially worsening your situation.

“It goes back to the fact that we’ve got to get away from the cookie cutter, ‘Oh, you’re inflamed. Take NAC.’ NAC can be the perfect thing for you, or it can make you worse, depending on your genomic make up,” Miller says.

Miller has developed a hierarchical pyramid of different variables and his approach to treating them. Interestingly, many who superficially look at functional genomics think that the methylation defect is one of the most important. It is important, but according to Miller there are many others that supersede it in terms of importance.

nutrigenetic hierarchical pyramid

“[Methylation] is about how we take folic acid or folate from our diet and turn it into methyl folate, which is a very important molecule. For a woman who’s pregnant, you’ve got to have it for a good pregnancy. We’re not saying it’s not a good thing … Now, one of the interesting things about methyl folate is you need it for pregnancy because it supports mTOR.

If someone’s already in mTOR dominance and they take methyl folate, they’re going to get more anxious and more inflamed. I’ve talked to so many people who’ve said, ‘Oh, yeah. I have MTHFR. Somebody put me on methyl B12, methyl folate. I felt great for two weeks, and then I crashed.’

The reason they may have crashed is because they started to stimulate mTOR, weakening their autophagy even more, driving more inflammation … As we dug deeper, we realized that methyl folate is important, but it has to be done at the right time. That’s why I developed my pyramid.

At the very bottom we have things we have to address first, such as, is iron becoming a free radical? Is hydrogen peroxide not being cleared? Is there nitric oxide synthase (NOS) uncoupling? — where rather than making nitric oxide, we make more peroxynitrite.

And then we look at how we’re making antioxidants. How’s our glutathione pathways? How’s our superoxide dismutase? How are we making NADPH? … For the most part, I believe that when people are massively inflamed, you need to address that first.

If someone is massively inflamed, if their iron is creating hydroxyl radicals, if they have weakness in their antioxidants … and you throw methyl folate in there … there’s a very good chance it will make the situation worse.

By and large, if someone’s massively inflamed, I’d like to think about methyl folate six to eight months down the road, two to three days a week. We tend to think, ‘If a little’s good for us, a lot must be good for us.’ I’m now thinking need to be pulsing things.”

I totally agree pulsing is a key component that should not be overlooked, whether you’re taking supplements, fasting or doing a ketogenic diet. It’s important to go through cycles of buildup and tear-down.

For example, during a partial fast, you’re stimulating autophagy through caloric restriction. At that time, you would not want to take anything that stimulates mTOR (such as methyl folate or any of the other items listed above), as by stimulating mTOR you effectively interrupt the autophagy process.

Mast Cells Could Be Wreaking Havoc With Your Health

Glutathione rapidly loses electrons, making it useless unless recharged by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH). As explained by Miller, the “NADPH steal,” a term he coined, may also be at play in many of the health issues people face today.

It’s becoming more widely known that you can have excess mast cells. Miller estimates about 80 percent of his clients have excess mast cell activation triggering histamine reactions. One of the signs of this is redness of the face due to heat intolerance. Sensitivity to touch is another, as are frequent, red, raised rashes.

Mast cells are white blood cells that come to the rescue when there’s a pathogen or a foreign invader that needs to be eliminated. While overfiring mast cells can cause problems, they’re not inherently bad, and strategies that inhibit them can backfire. Instead, Miller recommends determining why your mast cells are overactive.

His team presented research at the International Lyme and Associated Diseases Society’s 19th Annual Conference in November last year, identifying epigenetic factors that stimulate mast cells. He explains the relationships between mast cells, NADPH, NOX and glutathione:

“In simple terms, glutathione … has one chance to give a free radical an electron. Once it does that, it becomes oxidized. Then we need to donate that electron back. There’s this substance called NADPH that donates that electron back.3 It takes that oxidized glutathione and turns it back into reduced. That’s a good thing.

Now, NADPH has a dual role. There’s also an enzyme called NOX (NADPH oxidase). Its only purpose is to take this NADPH and turn it into a free radical … Now, they’ve done studies on animals. When they knock out that NOX enzyme, the animal dies from infection because it doesn’t have the ability to kill the pathogen.

Again, NOX and free radicals are not bad. But there are multiple factors that are now overstimulating NOX. One of them is sulfite. Sulfite needs to turn into sulfates. If we have deficiency of heme, we may not turn sulfites in sulfates … If sulfites don’t turn into sulfates, the sulfites may tell the NOX enzyme, ‘You need to make inflammation.’

Dopamine stimulates it [NOX], so stress will cause it. Glutamate stimulates it. Iron stimulates the NOX enzyme, and so does excessive mTOR … The NADPH steal is when NADPH gets stolen away from recycling glutathione, recycling thriodoxine, making nitric oxide, and potentially making excess mast cells.

There are a lot of people struggling with excess mast cells firing. They’re really sick. They don’t know what to do … Mold will also stimulate mast cells …

To sum it up, NADPH is critical for recycling your antioxidants. I believe the nicotinamide adenine dinucleotide (NAD+) and the NADPH are some of the most important things we can have adequate levels of for longevity and good health. We’re using up a lot of it because we’re exposed to so many toxic substances. Then, if another set of substances are stealing it to stimulate NOX to make mast cells, then we’ve just doubled the problem.”

Molecular hydrogen serves a role here as well, as studies have shown molecular hydrogen is an effective inhibitor of NOX,4 and can increase your concentration of NADPH. Curcumin also inhibits NOX, as does luteolin, apigenin and olive leaf. Aldosterone, on the other hand, stimulates NOX, Miller says.

More Information

This interview is quite loaded with information, not all of which has been covered in this article. For even more side notes and fascinating tangents, I recommend listening to the interview in its entirety.

Health practitioners interested in learning more about functional genomic analysis and how to apply it in your own practice, see the NutriGenetic Research Institute’s website, where you can sign up for their 30-hour, 14-module online certification course to become a nutritional genetic consultant.

Webinars for health practitioners are held every other Thursday. They also hold an annual conference in Hershey, Pennsylvania. The next one is scheduled for November 2019. In September, they’re also holding a seminar on environmental toxicity, detoxification and methylation mapping.

Patients interested in more information are directed to the yourgenomicresource.com which includes a listing of doctors who have completed the training and are qualified to provide nutritional guidance based on your SNPs. Up until last year, Miller could guide patients based on the genetic data provided by companies such as 23andMe. Now, he has developed his own DNA testing, which is capable of identifying some 300,000 SNPs.

Importantly, NutriGenetic Research Institute will never sell your private DNA or health data to anyone, which is one of the reasons why 23andMe is so inexpensive — they make their money by selling your DNA results to drug companies.

“I have pledged to everyone in writing that this data will never be sold to anyone. The other thing people can do, if they’re still worried, you can just change your name. Just come up with a fake name. It doesn’t matter. We don’t care. You just have to remember what it is,” Miller says.

“The [DNA] data from Brooks at Rutgers gets loaded into my software, which is in Chambersburg, Pennsylvania — a huge database. Then it crunches the data and gives a report, including the pyramid …

If you’re sick, you’ve been everywhere and you’re not getting better, this is certainly an option … Our whole goal is to help people get well. And to make a little bit of a dent in functional medicine — to help functional practitioners have tools that they can help, because functional medicine doctors see the tough cases. We want to give them some tools so that they can do a better job …

One of my favorite sayings is, ‘Genetics is never a diagnosis, but it tells you where to start looking.’ It’s like shining a light. ‘Think about looking here. Investigate whether this is a problem.’ Sometimes the SNPs show a problem, sometimes they don’t, but it can really give you clues to look where you may never have thought to look before.”

Sources and References