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ARTICLE SUMMARY
• A historic trial against Monsanto that linked glyphosate to non-Hodgkin’s lymphoma recently settled in favor of the
plaintiff. Regulatory agencies are revisiting glyphosate as a potential carcinogen.
• Human and animal studies show that glyphosate causes oxidative damage and chromosomal aberrations, which are two well-known precursors to cancer.
• Thyroid cancer and liver cancer are both rising dramatically in the U.S. population, in lockstep with the rise in glyphosate usage on core crops. It is extremely unlikely that this could have occurred by chance.
• Autoimmune disease, including celiac disease, is on the rise and is a strong risk factor for non-Hodgkin’s lymphoma. Both celiac disease and the increased cancer risk could be directly due to glyphosate poisoning.
• Glyphosate sets up a perfect storm in the gut to induce autoimmune disease through its severe disruption of the
gut microbiome. In the context of exposure to glyphosate, gut exposure to pathogens will lead to a poor immune
response to infection and an increased likelihood of developing autoimmune disease.
• A protein called activation-induced deaminase (AID) plays an essential role in the development of B-cell lymphomas such as non-Hodgkin’s lymphoma. Glyphosate can affect AID and another protein called Nup98, triggering a number of “out-of-control” changes that include mutations in other proteins. Some of the affected cells begin endlessly cloning themselves and become tumor cells.
• Glyphosate induces excessive calcium uptake in multiple cell types, which can trigger runaway processes involving
NF-kappa-B (a powerful signaling molecule) that also contribute to mutations and tumor cell proliferation.
• Glyphosate has a uniquely destructive ability to function as an amino acid analogue of glycine (an important protein building block). When glyphosate gets incorporated in place of glycine, it has enormous disruptive consequences on protein behavior.
• In addition to cancer, the runaway processes set into motion by glyphosate’s substitution for glycine could be responsible for increases in sudden death and heart failure in both the young and the old.
• The “willy-nilly” displacement of glycine with glyphosate, which occurs in a random and unpredictable fashion, will
have complex and confusing consequences, which may explain the varied metabolic disruptions now being traced
to glyphosate exposure.
• Glyphosate uptake in utero can lead to rare genetic mutations and rare birth defects in the next generation.
We have all long awaited the day when a trial against Monsanto, linking glyphosate—the main ingredient in the herbicide Roundup—to cancer, would result in a large settlement in favor of the plaintiff. That day has finally arrived. Those of us who have been asserting (against popular belief) that glyphosate is very harmful to humans are all rejoicing in the outcome, which represents the first time anyone has succeeded in a lawsuit claiming that glyphosate causes cancer.
Dewayne “Lee” Johnson, a California schoolyard groundskeeper who routinely used a glyphosate formulation to control weeds, was diagnosed with non-Hodgkin’s lymphoma a few years after being exposed topically to glyphosate due to a faulty sprayer. Prior to the diagnosis but after the accident, he developed a nasty skin rash all over his body. He tried to contact Monsanto personnel to ask them if he should be concerned about the glyphosate in connection with the rash, and also with respect to potential harm to the school children. He never heard back from the company.
The trial went on for over two weeks, documented in colorful detail by, among others, a woman who calls herself “Glyphosate Girl.”1 Del Bigtree of HighWire2 also did a wonderful interview with two of the key lawyers in the case, an interview showcased in an article published by Dr. Joseph Mercola.3 The two lawyers are Robert F. Kennedy, Jr. and Brent Wisner, and both of them were clearly overjoyed with the outcome and very optimistic that a steady stream of lawsuits numbering in the thousands will follow.
Key information from secret emails among Monsanto employees, obtained by the counsel, revealed blatant schemes to get prominent experts in the field to put their names on papers ghostwritten by Monsanto—papers “showing” that glyphosate is safe—in exchange for a handsome monetary reward. There were also open admissions that Monsanto never was going to do the experiments that were suggested to the company by researchers who revealed potential issues with glyphosate needing to be validated through larger studies. At the same time, Donna Farmer, a Monsanto executive, was quoted as saying, “You cannot say that Roundup is not a carcinogen.”
On August 10, 2018, the jury awarded Johnson two hundred and eighty-nine million dollars, with most of that amount (two hundred and fifty million) slated for punitive damages. This unexpectedly high award produced a number of important follow-on effects. First, the stock price of German conglomerate Bayer—the company that recently bought out Monsanto—plummeted, losing over ten billion euros in value in the week after the verdict.4 Next, activist groups like the Environmental Working Group (EWG) made mainstream news headlines with reports of high levels of glyphosate in common breakfast cereals like Cheerios.5 France engaged in a more aggressive debate about legislation to restrict glyphosate.6 And, as predicted, thousands of new cases accusing glyphosate of causing non-Hodgkin’s lymphoma are being brought to the attention of lawyers around the country. Those of us who have long been warning of the dangers of glyphosate to human health are starting to feel that this might be the long-awaited “tipping point.”
THE EVIDENCE
Despite the large win, one weakness of the trial was an inability to explain exactly how glyphosate could cause non-Hodgkin’s lymphoma. However, there is plenty of evidence, from both human and animal studies that glyphosate causes oxidative damage and chromosomal aberrations—two well-known precursors to cancer.7-11
Standardized tests that assess the DNA damage often associated with cancer cells can imply carcinogenic potential for a chemical. For example, one can examine exposed cells under a microscope looking for easy-to-spot features such as micronuclei and binucleated cells. During the normal process of cell division or mitosis, a “parent” cell splits to form two identical “daughter” cells, including duplication of its chromosomes. Micronuclei are small nuclei that form whenever a fragment of a chromosome is not properly incorporated into one of the daughter nuclei during cell division. This can be caused by DNA hypomethylation (i.e., altered DNA methylation affecting gene expression) or by unrepaired or incorrectly repaired DNA breaks. Binucleated cells are cells with a pair of conjoined nuclei. These are commonly seen in tumors, occurring when the normal process of cell division is arrested early, and a cell essentially becomes a set of Siamese twins.
An expert witness in the glyphosate trial discussed two scientific studies—one based in Ecuador7 and one from Colombia8—both of which showed an association between increased exposure among human populations to glyphosate and increased numbers of micronuclei and binucleated cells in blood samples. One of the major sources of exposure in these studies was the widespread use of glyphosate to kill coca crops in the “war on drugs.”
Statistically, farmers have a higher rate of non-Hodgkin’s lymphoma than the general population, but it is not easy to tease out exposure to glyphosate as distinct from exposure to the many other toxic chemicals that farmers routinely use. It’s increasingly clear, however, that there is a glyphosate-related “smoking gun.” Although the powerful chemical industry lobby has made it difficult to sway regulators to change their policy regarding glyphosate, the World Health Organization’s International Agency for Research on Cancer (IARC) declared glyphosate to be a “probable carcinogen” in 2015.12 This has caused many regulatory agencies to revisit glyphosate as a potential carcinogen.
AUTOIMMUNE DISEASE AND NON-HODGKIN’S LYMPHOMA
The success of Mr. Johnson’s lawsuit has inspired me to try to figure out a mechanism by which glyphosate could cause non-Hodgkin’s lymphoma. One significant observation is that autoimmune disease, which is alarmingly on the rise in industrialized nations, is a strong risk factor for non-Hodgkin’s lymphoma.13 In the series of six papers linking glyphosate to various diseases that Anthony Samsel and I have published, the second one focused on glyphosate and celiac disease.14 In people with celiac disease, ingestion of gluten provokes an immune response that damages the small intestine. A growing practice among farmers involves spraying glyphosate on wheat just before harvest as a desiccant, and we argued in our paper that glyphosate contamination is what is making wheat so allergenic.
In the paper, we also pointed out that people with celiac disease generally have a shortened life span—and this is due mainly to an increased risk of cancer, particularly non-Hodgkin’s lymphoma. We referenced papers showing a link between non-Hodgkin’s lymphoma and glyphosate in population studies based in Canada,15 the United States16 and Sweden.17 As reproduced here in Figure 1 (next page), the alarming rise in the prevalence of celiac disease matches up very well with the rise in glyphosate usage on wheat crops.
One characteristic feature of the dysfunctional immune response that typifies celiac disease is a massive overproduction of immunoglobulin A (IgA) autoantibodies by specialized B cells in the gut.18 IgA is an antibody that plays a crucial role in the immune function of mucous membranes. In celiac disease, undigested gluten peptides cross the epithelial barrier and, following modification by the enzyme transglutaminase, are transported by dendritic cells to local lymphoid tissues, inducing a strong proinflammatory T-cell response, and a subsequent B-cell antibody response. These activated immune cells then infiltrate the gut lining and cause an inflammatory autoimmune attack against not only transglutaminase but also against actin, collagen and other proteins, inducing the intestinal discomfort associated with celiac disease.19
As celiac disease induces a state of chronic inflammation, this results in oxidative stress, which in turn causes DNA damage and an increased risk of genetic mutations due to impaired repair mechanisms. Over time, these genetic mutations, along with alterations in DNA methylation status, can cause a cell to revert to an immortal stem-cell-like phenotype called a “cancer stem cell.” These cells become more mobile and are obsessed with cloning themselves endlessly, leading to tumor growth and metastasis.20 Non-Hodgkin’s lymphoma tumor cells emerge out of an original population of B cells in the immune system.
The increased risk of cancer that is the main factor leading to a statistically shortened life span for people with celiac disease is not limited to non-Hodgkin’s lymphoma but also includes adenocarcinoma of the small intestine and squamous cell carcinomas of the esophagus, mouth and pharynx, as well as melanoma.21 It seems likely that both the celiac disease and the increased cancer risk could be directly due to glyphosate poisoning.
In the sixth paper in our series on glyphosate pathways to modern diseases, Anthony Samsel and I described how glyphosate could cause autoimmune disease through its severe disruption of the gut microbiome and the digestive system.22 In that paper, we reported on high levels of glyphosate contamination for porcine trypsin, pepsin and lipase (from the glyphosate-contaminated feed given to pigs). These digestive enzymes are produced by the pancreas and are essential for digesting proteins (trypsin and pepsin) and fats (lipase). Another enzyme that is essential for digesting gluten is called prolyl aminopeptidase, and it, too, is likely to be disrupted by glyphosate. As proposed in our paper (and in later sections of this article), we can expect glyphosate to suppress the activity of all of these enzymes, due to glyphosate’s insidious ability to get inserted into proteins by mistake in place of the coding amino acid glycine.22
Anthony and I proposed that glyphosate sets up a perfect storm in the gut to induce autoimmune disease. Glyphosate’s disruption of digestive enzymes leaves proteins undigested, and this induces a leaky gut,23 which allows the foreign (undigested) proteins to enter the gut-associated lymphoid tissue (GALT) and induce an intense B-cell antibody response. A process called “molecular mimicry” can cause these antibodies to attack native proteins that have peptide sequences resembling those in the foreign proteins. This can lead to a long list of autoimmune diseases besides celiac disease, including Hashimoto’s thyroiditis, multiple sclerosis, Sjögren’s syndrome, rheumatoid arthritis and systemic lupus erythematosus. Many of these conditions are also risk factors for non-Hodgkin’s lymphoma.13
IMMUNE SYSTEM DYSFUNCTION AND LYMPHOMA
B cells are a type of white blood cell that originate from the bone marrow. The gut houses at least 80 percent of the body’s B cells,24 many of which are localized to the GALT and the regional lymph nodes. B cells become “mature” through a transformation process that takes place in the thymus during infancy. A process that involves massive mutations in the immunoglobulin proteins results in many different varieties of these proteins, which can then be empowered to recognize different specific foreign proteins, called antigens (with gluten being one example).
Later, when a foreign protein (antigen) is identified at a place in the body where it should not be found, T cells release signaling proteins that are detected by specific B cells whose immunoglobulin profile happens to be sufficiently well “matched” to the offending antigen. These unique B cells, localized to “germinal centers” within the lymph system, then become even more specialized, perfecting their match to the antigen via a second stage of gene modification of their immunoglobulins, resulting in so-called “high affinity antigen binding sites.”25,26
Under normal circumstances, these now perfectly matched immunoglobulins will have become very specific antibodies that will stick around for a long time as “memory B cells” and will jump into action the next time the body encounters that same foreign protein, tagging the foreign antigen for clearance by macrophages (white blood cells that specialize in clearing cellular debris and foreign substances).
When all goes well, this system is amazing. It allows the immune system to immediately pounce on a viral infection when it sees it a second time, because the memory B cells recognize it immediately and mark the virus particles for clearance by patrolling macrophages. For example, if the foreign protein is the haemagglutinin protein synthesized by the measles virus, this is the elegant and sophisticated process by which a measles infection leads to permanent immunity against the measles (and it is the reaction hoped for in response to a measles vaccine).
Both the development of immature B cells in the thymus and the maturation of B cells in the germinal centers, as well as their survival following maturation, all depend critically on a nuclear signaling protein called “nuclear factor kappa-light-chain-enhancer of activated B cells” (NF-κB).27,28 In the absence of a matching infection, quiescent B cells have very little to do, and they mostly just wait around for a signal coming from a T cell that will cause them to jump into action. Upon a T-cell receptor response, a B cell launches what is called a phosphorylation cascade, initiated by NF-κB. NF-κB is normally kept sequestered in the cytoplasm by a specialized protein that tethers it in place. However, phosphorylation of the tether (in response to the T-cell signal) causes it to let go, and the liberated NF-κB can now get into the nucleus and start activating expression of a large number of proteins, many of which are kinases. Kinases are proteins that add phosphate ions to other proteins, changing their behaviors.
Two incredibly powerful proteins that are affected in interesting ways by phosphorylation are activation-induced deaminase (AID) and nucleoporin 98 (Nup98). AID is the master protein that initiates the genetic mutations in the immunoglobulins that will eventually lead to the creation of antibodies that perfectly match the offending antigen. This allows the B cell to then differentiate into one of those perfected memory cells. An infection induces migration of native B cells into germinal centers,29 where they undergo upregulation of AID mediated by NF-κB.30
Like NF-κB, AID is usually held securely in the cytoplasm by a specialized tether protein that will also let go once it is phosphorylated, in response to signaling consequent to an infection or other stressor. Even when it is freed up, AID can’t easily get into the nucleus, because the nucleus has a membrane around it that only allows small molecules to cross over. This membrane, however, is chock full of holes that are big enough for the large molecules, but the holes are then plugged with gelled water that is maintained in the gelled state by proteins called nucleoporins, one of which is Nup98.31 Importantly, when Nup98 gets heavily phosphorylated, it breaks apart from its partners in the pore and the gel disintegrates, leaving the pore wide open such that both AID and NF-κB can now freely enter the nucleus.32
In addition to the proteins that tether AID and NF-κB in the cytoplasm, there are also specialized escort proteins called importins that can bind to AID or NF-κB and hand-carry them across the gelled pores right into the nucleus. These proteins are only able to work under the special conditions that follow the signaling that alerted the B cell of the marauding viral attack. Other proteins hand-carry them back out of the nucleus once their job is done, because it’s too dangerous to let them continue their nuclear activities over an extended period of time. However, if Nup98 is heavily phosphorylated, these escort proteins are no longer necessary because AID and NF-κB can now enter or leave the nucleus any time they want. In particular, they can get in the nucleus and then become bound to the nuclear DNA and continue their unchecked activities with abandon.
Studies have shown that AID plays an essential role in the development of B-cell lymphomas.33 Non-Hodgkin’s lymphoma cells are very peculiar.34 First of all, they express AID at a very high level, and the AID tends to hang out in the nucleus rather than in the cytoplasm where it is normally sequestered. Secondly, their AID proteins are highly phosphorylated, and phosphorylation changes AID’s behavior in shocking ways, such that it starts putting mutations into lots of other proteins besides the immunoglobulins. As a result, many so-called “oncogenes” (genes that can transform a cell into a tumor cell) are hypermutated in association with B-cell lymphomas.35 AID also strips the cell’s DNA of its methyl groups;36 this is important because a cell with demethylated DNA will revert to a pluripotent stem-cell-like form where it refuses to differentiate and just keeps on cloning itself endlessly—that is, it becomes a tumor cell.37 Non-Hodgkin’s lymphoma cells also often have rogue versions of kinases that are “constitutively” expressed, meaning that they just keep on phosphorylating other proteins in an out-of-control fashion.38
In addition, lymphoma cells often have constitutively active versions of NF-κB, which helps to keep the phosphorylation cascade going in a runaway fashion. Both the AID and the NF-κB also stick around in the nucleus rather than getting escorted back out to the cytoplasm. NF-κB launches a runaway phosphorylation cascade that causes both rogue proteins to gain free access to the nucleus because of hyperphosphorylation of Nup98, and AID has a field day in the nucleus, mutating genes right and left and stripping off methyl groups until the cell turns into a pluripotent cancer stem cell (that is, a lymphoma cell).
EXCESSIVE PHOSPHORYLATION AND ALTERED DNA METHYLATION
How does a phosphorylation cascade get started? One common way is through excessive calcium uptake by the cell, which can trigger NF-κB expression and subsequent phosphorylation cascades, mutagenesis and tumorigenic proliferation. Calcium uptake is an early response of B cells following exposure to antigen.39 Glyphosate has been found to induce excessive calcium uptake in both in vitro and in vivo experiments in multiple cell types: Sertoli cells in the testes,40 neurons41 and cardiac muscle cells.42
NF-κB is a powerful signaling molecule that induces expression of a large number of proteins associated with cell survival and proliferation, including many kinases. It is activated in response to tumor necrosis factor alpha (TNF-α) signaling, which, in turn, is induced by multiple cellular stressors. As previously discussed, NF-κB is secured in the cytoplasm by inhibitor κB (IκB), and its release is dependent on expression of a kinase that phosphorylates IκB.
The cytokines interleukin 1 beta (IL-1β) and TNF-α are commonly expressed under stress conditions, and studies have shown that they are upregulated in tissues following glyphosate exposure.43,44 A study on carp exposure to glyphosate showed increased expression of TNF-α in liver, kidneys and spleen.43 TNF-α, IL-1β and NF-κB expression levels were all significantly increased in the livers of rats exposed to glyphosate at fifty mg/kg daily for thirty-five days.44 Experiments have shown that these cytokines tend to stimulate calcium uptake by various cell types. TNF-α induces calcium uptake in vascular smooth muscle cells,45 and it also induces NF-κB expression in neurons.46 IL-1β has been shown to induce calcium uptake in pancreatic islets.47
Glyphosate causes excitotoxicity in neurons through excessive stimulation of the N-methyl-D-aspartate (NMDA) receptors in the hippocampus, leading to excessive calcium uptake.41 It is well established that calcium uptake in hippocampal neurons induces expression of NF-κB.48 Glyphosate activates voltage-dependent calcium channels, in part by acting as a glycine analogue at the receptor site for glycine,41 and it also activates the serine-threonine kinase protein, calmodulin-dependent protein kinase II (CaMKII). This in turn launches a flurry of activities that ultimately result in hyperphosphorylation of a large number of proteins in the cell.
Glyphosate also has been shown to induce alterations in methylation patterns in the genome that are consistent with progression toward cancer. A 2018 study conducted in Poland showed that glyphosate exposure at a relatively low dose (0.25 millimolar, 40mg/L) induced significant modifications in the methylation pattern on the DNA of white blood cells.49 DNA was globally hypomethylated (less than normally methylated) in the presence of glyphosate, and, as we’ve seen, this can lead to a transformation into a pluripotent tumor-like state. Glyphosate also caused hypermethylation of the promoter region of TP53, a well-known tumor suppressor gene. Such hypermethylation has the effect of suppressing expression of the gene—that is, enhancing the likelihood of cancer. A combination of global hypomethylation along with hypermethylation of the control elements of tumor suppressor genes is a pattern that is commonly observed in cancer cells.50
Methionine and folate are essential for DNA methylation. Glyphosate’s adverse effects on gut microbes can be predicted to lead to deficiencies in both nutrients.51 Human cells are unable to synthesize methionine from inorganic sulfur and so we rely on our gut microbes to provide this essential amino acid for us, but glyphosate suppresses the multiple enzymes needed by E. coli to synthesize methionine.52 A study on carrot cells showed that both methionine and the aromatic amino acids become deficient following glyphosate exposure.53
GLYPHOSATE AS A GLYCINE ANALOGUE
The main effect by which glyphosate kills essentially all plants except those genetically engineered to resist it is through disruption of a key enzyme in the so-called “shikimate pathway.” This pathway is crucial in plants and in many microbes, but human cells do not have the pathway, and this is why—Monsanto argues—glyphosate is harmless to humans. What Monsanto overlooks is that our gut microbes depend on this pathway to produce the three essential aromatic amino acids: tryptophan, tyrosine and phenylalanine. These amino acids are “essential” precisely because our cells don’t have this pathway. They are among the twenty-two “coding” amino acids that are the building blocks of proteins, and they are also precursors to many biologically critical molecules such as the neurotransmitters serotonin, melatonin, dopamine and epinephrine; thyroid hormone; the B vitamin folate; and the skin tanning agent melanin. All of these can be expected to be deficient in the context of chronic glyphosate exposure to the gut microbiome.
Make no mistake about it: glyphosate is special. Researchers have examined over one thousand different “glyphosate analogues” that have much in common with glyphosate in terms of the general molecular shape, the charge distribution and the biophysical properties—yet none of them work nearly as well as glyphosate does to kill weeds via disruption of the shikimate pathway.54 It appears that very minor perturbations in the structure result in dramatically reduced potency. What is it that sets glyphosate apart from all these other molecules?
I think the answer is obvious: only glyphosate is an amino acid analogue of glycine. Glycine is one of the twenty-two coding amino acids that are assembled as peptide sequences to produce proteins according to the famous DNA code. Glycine is in fact the simplest of the amino acids, having no side chains on its carbon atom. Glyphosate is a complete glycine molecule, and, like glycine, it has no carbon atom side chain. However, what distinguishes glyphosate from glycine is the methylphosphonyl group that is attached to its nitrogen atom. This bulky, negatively charged side chain attached to glyphosate’s nitrogen atom does not prevent it from hooking up into the amino acid chain that forms a peptide sequence, but it does have enormous consequences in terms of disrupting the way a protein folds and the protein’s activity level.
Glyphosate’s main mechanism of toxicity is through suppression of the activity of the enzyme EPSP synthase, a critical enzyme in the shikimate pathway. It is astonishing to me that toxicology experts know that multiple species of microbes and multiple species of plants have “figured out” how to get around glyphosate’s toxicity to the shikimate pathway by mutating the code for EPSP synthase, yet it does not seem to occur to any of them that this could mean that glyphosate can get mistakenly incorporated into protein synthesis in place of glycine. Specifically, there is a highly conserved glycine residue at the site where the substrate phosphoenolpyruvate (PEP) fits snugly. All of these species have independently acquired immunity to glyphosate by changing the DNA code such that it codes for alanine instead of glycine. This is a very minor change, introducing one extra methyl group, but it makes all the difference in the world because glyphosate only substitutes for glycine, not alanine. Change the code, and you acquire complete immunity to glyphosate’s effects on this protein.52
It’s not as if researchers are not aware that this kind of thing happens in biology. There are probably over a thousand non-coding amino acids that are produced naturally by biological organisms, and a few of them are known to be able to substitute by mistake for specific coding amino acids, generally causing extremely debilitating disease as a consequence.55 One of these is another herbicide, glufosinate, which works by substituting for glutamate during protein synthesis.56 Glufosinate is naturally produced by certain bacteria. There is also a toxin produced by cyanobacteria, called β-methylamino-Lalanine (BMAA), that is an analogue of serine, and it causes a debilitating neurological disease similar to ALS and Parkinson’s disease.57,58
Another toxin produced by sugar beets under stress conditions substitutes for proline and causes multiple sclerosis and swayback in lambs.59,60 L-canavanine is an amino acid analogue of L-arginine, and it was probably responsible for the death of Christopher McCandless, the protagonist of the book Into the Wild by John Krakauer.61 However, there is no naturally produced amino acid known to mankind that substitutes for glycine. Glyphosate, only present because it is synthesized in the chemistry lab, is unique in this ability, and this is what makes it so demonic.
In addition to inducing expression of kinases via calcium uptake, glyphosate can also be expected to cause them to become hyperactive, through substitution for glycine during protein synthesis. In our first paper on glyphosate acting as a glycine analogue (fifth paper in our series),62 Anthony Samsel and I explained how glyphosate substitution for glycine at critical spots in kinases would be predicted to cause them to become overactive, and how glyphosate substitution in phosphatases (proteins that remove phosphates) would suppress them. For example, protein kinase CK2 is able to phosphorylate more than one hundred and sixty substrates, and it is involved in the cell cycle and cell proliferation. It contains a glycine-rich loop (GXGXXG) (where “X” stands for a “wildcard,” i.e., any amino acid), as do many other protein kinases. Experiments have shown that substitution of one of the glycines in this region, G48—which is conserved in 99 percent of protein kinases—with a negatively charged amino acid leads to increased activity.62-65 Glyphosate is negatively charged.
Both AID and Nup98 can be expected to be susceptible to something called “pseudophosphorylation” if glyphosate were to substitute for one or more of their glycine residues by mistake. Strikingly, there is a novel version of AID synthesized by zebrafish that does not have the serine residue at location 38 that normally gets phosphorylated to convert AID into a dangerous protein that causes random genetic mutations. However, zebrafish AID has been shown to induce genetic mutations nonetheless. Researchers have proposed that the presence of a negatively charged amino acid nearby has caused the protein to behave as if it is permanently phosphorylated.66 Substitution of glyphosate for a nearby glycine residue would very likely have a similar effect, with glyphosate’s phosphonate ion being a close approximation to a phosphate ion negative at typical cellular pH.
A remarkable experiment with transgenic mice, where the mouse DNA was modified to include a constitutively expressed version of AID, demonstrated the destructive capabilities of AID if left unregulated.67 The mice developed large numbers of point mutations in genes for a number of oncogenic proteins (proteins that induce cancer). They later developed multiple types of cancer, including lymphoma but also adenomas and carcinomas in the lungs. Nup98 induces a collapse of the pore plug in response to excessive phosphorylation on multiple serine residues within a segment known as a “phenylalanine-glycine domain” (FG domain) because it contains many FG pairs (phenylalanine linked to glycine) within this segment.68
Nup98 has eleven sites in this FG domain that can be phosphorylated. In an experiment where all of these sites were replaced with so-called “phosphomimetic” (i.e., negatively charged) amino acids, this modification caused Nup98 to act as if it were permanently phosphorylated.69 Substitution of many of those glycines with negatively charged glyphosate in this FG domain can be expected to have a similar effect. A schematic layout of a sequence of phenylalanine-glycine pairs with glyphosate substituting for two of the glycines is illustrated in Figure 2, where the blue sections represent the benzene rings of phenylalanine and the grey sections are the glyphosate molecules. Note the negative charge on the phosphonate ions in the glyphosate molecules.
Either phosphorylation or pseudo-phosphorylation causes Nup98 to detach from the nuclear pore, and disintegration of the pore then launches the cell into mitosis, inducing cell division and proliferation. Of course, this also allows access to the nucleus for both NF-κB and AID, further promoting a phosphorylation cascade as well as an opportunity to strip off the methyl groups and mutate oncogenic genes, eventually inducing lymphoma in B cells. The process is schematized in Figure 3 (next page), which shows a breaching of the nuclear pores by NF-κB and AID as a consequence of pseudo-phosphorylation of Nup98 by glyphosate. AID, also activated through phosphorylation and pseudo-phosphorylation, then launches a chemical reaction cascade that leads directly to damage to the DNA in the nucleus and transforms the B cell into a cancer cell.
CALCIUM CHANNEL DYSREGULATION AND HYPERPHOSPHORYLATION IN HEART FAILURE
If glyphosate can substitute for glycine during protein synthesis, reactive oxygen species (ROS) and excessive calcium entry can cause a runaway phosphorylation cascade with devastating consequences in multiple cell types beyond the B cells of the immune system. Calcium uptake is normally carefully controlled in the heart through multiple signaling mechanisms that are likely to misbehave in the presence of glyphosate contamination. Disruptions due to glyphosate uptake into proteins could be responsible for the alarming increase we are seeing today in sudden infant death, sudden death among our youth and heart failure among the elderly.
The fight-or-flight response can be deadly in the context of chronic glyphosate poisoning. As discussed in detail in a paper published in 2012,70 dysregulation of the signaling molecule CaMKII can lead to cardiac arrhythmias, heart failure and sudden death. Catecholamines (adrenalin and dopamine), aldosterone and angiotensin II are all capable of upregulating CaMKII via a sympathetic nervous system response. Its activity is increased both through oxidation and phosphorylation. As we’ve seen already, glyphosate-based formulations induce oxidative stress and they also induce excess calcium uptake. This launches the phosphorylation cascade that causes increased activity of CaMKII and subsequently a large number of other proteins, eventually inducing calcium overload and arrhythmias such as tachycardia and atrial fibrillation. These in turn can cause heart failure and sudden cardiac arrest. We currently face an unexplained epidemic in heart failure and sudden death.
An overexuberant response of both the calcium channel and the phosphorylation cascade can be predicted in the context of glyphosate substituting for glycine during protein synthesis. The net effect is that once a phosphorylation cascade gets started, it is very difficult to shut it down if glyphosate is being actively incorporated into the proteins being synthesized.
Unfortunately, the situation is potentially even worse than this. The L-type calcium channel pumps calcium into cells, and it, too, is likely to be overactive in the presence of glyphosate. Calcium entry triggers the phosphorylation cascade. If the calcium channel refuses to shut down, it will pump an excessive amount of calcium into the cell, depolarizing it and throwing it into a state that easily induces arrhythmias, especially long QT syndrome (LQTS), further aggravated by the excessive phosphorylation that is happening simultaneously.
The most common mutation leading to Timothy syndrome involves a substitution of arginine for the usual glycine residue at location 406 of the peptide sequence of exon 8A of the caveolin 1.2 L-type calcium channel gene.71 This is a gain-of-function mutation, which results in a remarkably prolonged action potential in the heart, manifested as LQTS, because the mechanisms that normally shut off the influx of calcium following sympathetic stimulation are disrupted. Another glycine mutation to arginine at location 402 is also linked to Timothy syndrome.73 Glyphosate poisoning in humans has been shown to induce life-threatening cardiac arrhythmias, including LQTS.74
Timothy syndrome represents an extreme case where every instance of the L-type calcium channel is defective due to a missing glycine residue. In the case of glyphosate, only some percentage of the calcium channel proteins would be defective, so the consequences would be a much milder version of a Timothy-like syndrome. Simultaneously, however, many other proteins would also have glyphosate residues displacing glycines willy-nilly in some random and unpredictable fashion. The consequences would be complex and confusing, which is probably part of the reason it has taken us so long to figure out what is going on in these metabolic disruptions caused by glyphosate insinuation into various proteins.
BEYOND NON-HODGKIN’S LYMPHOMA
Cancer is induced through genetic mutations in the cell line that eventually becomes a tumor. De novo mutations are changes in the DNA that are present in a child but not in its parents. That is to say, the germ cell that became the egg or sperm mutated. The new movie, “Genetically Modified Children,” proposes that glyphosate exposure in utero resulted in de novo DNA mutations that led to severe genetic diseases. The children featured in the film live in a farm community in northern Argentina where GMO Roundup-Ready tobacco is the core crop. The rates of cancer and congenital abnormalities are much higher than normal in this community.
A recently published paper exposed rats to low doses of glyphosate during pregnancy and lactation.75 Although the rats and their direct offspring suffered little damage, the second-generation offspring had an exceptionally high rate of rare genetic diseases. The female fetus develops her ovaries and eggs very early in pregnancy. AID, the protein that drives genetic mutations when it is defective or phosphorylated, is highly expressed in germ cells in the developing ovaries. Thus, glyphosate uptake by germ cells in utero can lead to rare genetic mutations and rare birth defects in the next generation!
The TNF-α, NF-κB and AID activation sequence—launched in response to environmental stressors in B cells and leading over time to tumorigenesis and non-Hodgkin’s lymphoma—is not a process that is unique to B cells. Thyroid cancer and liver cancer are both rising dramatically in the U.S. population, in lockstep with the rise in glyphosate usage on core crops.76 It is extremely unlikely that the match in the rise in glyphosate usage and the rise in the two cancers could have occurred by chance; the probability values or “p-values” for thyroid cancer (p < 0.000022) and liver cancer (p < 0.000054) are dramatically lower than the p=0.05 level that represents statistical significance. A study conducted on a population in Buenos Aires, Argentina, found a significant recent increase in thyroid cancer, particularly among men, and suggested that an environmental factor, such as the heavy use of glyphosate in the surrounding GMO corn and soybean fields, could be a factor in the increase.77
NF-κB expression has been shown to play a critical role in autoimmune thyroid diseases such as Hashimoto’s as well as in thyroid cancer.78 Stimulation by TNF-α in liver cells induces AID expression mediated through NF-κB, leading to liver cancer.79 I predict that it will turn out to be the case that all of the cancers that are being caused by glyphosate are occurring through aberrant expression of the TNF-α/NF-κB signaling pathways, leading to both hyperphosphorylation and pseudo-hyperphosphorylation of AID and Nup98.
Besides its important role in cancer development, AID also is essential for the maturation of the immune system. Disruption of the processes that take place in the thymus gland in the first year of life can be predicted to lead to a weakened immune system due to defective maturation of the B cells. Exposure to pathogens—especially in the gut—will lead, in the context of glyphosate exposure, to aberrant perfection of the antibody response to antigenic agents, causing both a poor immune response to the infection and an increased likelihood of developing autoimmune disease through molecular mimicry. Moreover, children’s responses to vaccination can be expected to be impaired, such that the vaccine fails to “take” and/or leads to autoimmune diseases such as thyroiditis, asthma, eczema and type 1 diabetes. Perhaps these disruptions caused by glyphosate are directly related to many of the immune deficiencies and autoimmune conditions so prevalent among U.S. children today. For sure, more research is needed to verify these ideas.
SIDEBARS
HOW TO PROTECT YOURSELF AND YOUR FAMILY
Glyphosate is pervasive in our environment. It’s been found in the water supply and rain, in tampons and other
cotton products, in vaccines and, especially, in the food supply. Glyphosate usage on core crops has been going up
exponentially over the past two decades, and people use it routinely in their yards to control weeds. It’s also in the air, especially if you live near agricultural fields where it is routinely applied. It may be released into the air on highways as well, since we now require 10 percent ethanol added to gasoline, and the ethanol is derived from either GMO Roundup-Ready corn or sugar cane sprayed with Roundup right before harvest as a ripener. It’s likely present in cigarettes, since tobacco is a genetically engineered glyphosate-resistant crop. Glyphosate is stable even at high temperatures.
What this means is that it is impossible to avoid glyphosate completely. However, there are simple steps you can
take to help reduce your body burden:
1. Stop using glyphosate/Roundup in your yard, and try to convince your neighbors to do the same. There are alternative methods to kill weeds, such as pulling them by hand or using a vinegar-soap-salt mixture.80
2. Buy organic cotton clothing, organic tampons and, if you are a smoker, organic cigarettes. I hope these options
will become more widely available in the future.
3. Test your water supply for glyphosate contamination. If necessary, install a reverse osmosis filter to remove it.
4. Choose only certified organic foods when you shop at the grocery store. This is possibly the most important thing
you can do. We are very fortunate that the certified organic label exists; one of its clear restrictions is that glyphosate cannot be used on organic crops. This can make a significant difference in your exposure level, because many foods are highly contaminated with glyphosate and ingesting it means a direct hit to your gut microbiome. You
can become aware of exactly which foods are most problematic by reading Tony Mitra’s book, Poison Foods of
North America. Tony convinced the Canadian government to test over eight thousand food items for glyphosate,
and his book provides detailed tables showing the amounts detected in various foods imported into or grown
in Canada.81 Some surprises were the very high levels found in non-organic lentils and chick peas, as well as significant contamination of oat- and wheat-based products, such as oatmeal and pasta. None of these crops are
GMO, but all are often sprayed with glyphosate as a desiccant right before harvest. Mexican imports generally
had significantly lower levels of glyphosate than foods grown in the U.S. or Canada. In fact, Mexico’s levels were more comparable to those found in European produce. So choosing produce grown in Mexico is probably a good
strategy if you can’t find a certified organic source.
5. Regularly consume fermented foods, such as kimchi, apple cider vinegar, sauerkraut, kombucha and kefir. Although Monsanto claims that glyphosate passes through the body mostly unmodified, and that nearly all of it is excreted either through the kidneys or the feces, the company knows that a certain percentage goes into the tissues and accumulates there—as they have clearly shown in unpublished experiments where they used traceable radio-labelled glyphosate. There are only a few species of microbes that can fully metabolize glyphosate, and one of them
is Acetobacter.82 For this reason, I recommend consuming fermented foods, which typically contain Acetobacter.
6. Eat a lot of herbs, spices and colorful fruits and vegetables, which are rich in polyphenols and flavonoids. This
is another strategy that should help to protect from glyphosate damage. Polyphenols in honey,83 turmeric84 and resveratrol (found in grapes, red wine, peanuts and mulberries)85 have all been shown to inhibit NF-kappa-B expression, and this may be a key factor in their beneficial effects.
7. Make a conscious effort to consume mineral-rich foods such as organic eggs and seafood. Glyphosate’s chelation
of many minerals makes them less available to the body.
8. There are now several products on the market that claim to help treat glyphosate poisoning, and these are often
based on probiotics, organic matter from the soil (humic acid and fulvic acid) and mineral supplements. A study
done on cows exposed to glyphosate showed that a combination of sauerkraut juice, activated charcoal, humic
acid and fulvic acid was beneficial for removing glyphosate and helping to ease disease symptoms.86 Humic acid was also used successfully to treat glyphosate damage in chickens.87
Two studies have revealed that glyphosate can be broken down nonenzymatically by simple highly oxidizing molecules such as ozone, chlorine dioxide and hypochlorite.88,89 Ozone therapy and Miracle Mineral Supplement (MMS) therapy may be successful therapeutic options in part because they help to reduce glyphosate burden in the body. However, these should be used with caution because their oxidation properties make them damaging to tissues as well.
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This article appeared in Wise Traditions in Food, Farming and the Healing Arts, the quarterly journal of the Weston A. Price Foundation, Winter 2018
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In 2009 my husband was diagnosed with Mantle Cell lymphoma and died Two months later, after just two chemo treatments. Two years later 2011 I was diagnosed with Waldrensons lymphoma. Two years later I was diagnosed with two different types of breast cancer in my right breast, Five years later I was diagnosed with a different type again, in my left breast. I have not taken any medical treatment for my cancers, but I do used CBD and THC as well as I take one AHCC capsule every day. The other herbal treatment I take is Essiac. I am 75 years of age and otherwise is very good health and still run my business, which is a Market, Garden Center, Bakery, and home decor.
Curious if you would have any comment on my situation.
“There were open admissions that Monsanto never was going to do the experiments….”
Where is “there”? Do you mean in the court room, or in the e-mails?