Has Big Pharma Gone Bonkers?

Big Pharma has gone bonkers! That is the only way I can explain the most recent developments in the quest to destroy cholesterol synthesis in the body. The recent FDA mandate to label every statin prescription with warnings of increased risk to diabetes and cognitive impairment has not phased them in the least! With their extraordinary marketing schemes, the industry has managed to convince the doctors, the media, and the general public that there is no number below which LDL becomes pathologically low; no number above which HDL becomes pathologically high. If you happen to fall outside of a strict range, you have no doubt that you are sick – you need to take at least one drug for the rest of your life to whip those numbers into shape. Never mind that you feel just fine. Never mind that you are a child with a maturing brain or a young woman about to start a family. In fact, some are now suggesting that anyone over 50 years old should be automatically put on a statin, without even bothering to check their cholesterol levels [1].

The industry has now decided that it is not enough to offer an HMG coenzyme A reductase inhibitor (statin) that interferes with the mevalonate pathway at its root – a pathway that is essential to the survival of the cell. Now they are scheming with two new drug classes, one of which promises to knock your LDL cholesterol down by 75%, and the other of which promises to drive your HDL sky high, to levels never seen in nature. Can they be serious? Can they have any credibility left after the fiasco that will surely develop once these new toxins are widely disseminated?

NARC-1 Inhibitors

It turns out that, if you take a statin drug, your body tries desperately to get around the toxic effect of the statin by greatly increasing the synthesis of the enzyme, HMG Coenzyme A reductase, that the statin drug inhibits. This alone ought to tell us that the body needs this enzyme! But furthermore, your body will also increase its synthesis of an extraordinarily powerful high level controlling element, called NARC-1 (also known as PCSK9), one of only a handful of so-called protein convertases, which are still today poorly understood, but which surely have far reaching implications for the homeostasis of the body. NARC-1 is unusual among the protein convertases in that, unlike all the others, it does not require calcium uptake to be activated [2]. Furthermore, it is sulfated at two highly conserved tyrosine residues as it leaves the ER ready for prime time. I find both of these observations highly significant in light of the research I have been conducting on the importance of sulfate and the pathology associated with calcium uptake.

One of the known effects of NARC-1 is to decrease the reuptake of LDL by the liver, which is a good idea in order to allow the LDL (now in scarce supply) to linger longer in the blood so that it can deliver its goods (triglycerides, antioxidants, fat-soluble vitamins, and cholesterol) to the tissues. The industry, in all its wisdom, has now come up with a new injectable drug which interferes with the synthesis of NARC-1 [3], and the hope is that people who are not happy with their LDL numbers even after statin therapy can use this drug to drive their LDL down to as close to zero as possible. The two people who won the Nobel prize for their research on cholesterol back in the 1980’s are now working for one of the companies that is marketing a version of this new drug. These agents apparently can get your LDL down to levels you won’t see even if you’re taking the highest dosage of a statin drug [4, 5].

What NARC-1 stands for is “neural apoptosis-regulated convertase 1,” which is, to say the least, a confusing name, but with the word “neural” in there you ought to be worried about the concept of an inhibitor of this protein. Studies on zebrafish have shown that NARC-1 is expressed in neurons in the cerbral cortex and in the cerebellum in association with neurogenesis. Suffice it to say that, if you render NARC-1 inactive in a zebrafish embryo, the embryo dies after just 3 to 4 days of development with its midbrain and hindbrain blended together in a confusing array of disorganized neurons [6]. This is not a protein that I would care to mess with! Yet the industry is currently getting its rocks off thinking about the kachink of the cash register if it can successfully market this drug, as a way to further reduce your LDL number beyond the already too-low values achievable through statin therapy.

CETP Inhibitors

The other new drug, Torcetrapib, that had everybody excited [7] until the phase III trial results came in, is in a class called “CETP” (cholesterol ester transferase) inhibitors, and it works by inhibiting a protein that allows all the various lipoproteins (HDL, LDL, IDL, VLDL) to equilibrate their supplies of cholesterol and fatty acids by making trades. A quote from a recently published article on a phase III trial involving 15,000 people sums up the current situation: “Hopes have been running high that treatments aimed at raising HDL levels would soon help to reduce the large burden of cardiovascular disease that remains in patients at high risk of CHD who are now treated with statins. The unexpected and premature termination of the ILLUMINATE study has dashed those hopes.” [8] p. 257.

After 82 people died in the treatment group, as against only 51 in the placebo group, they called an early halt to the trial, and scrambled to regroup. As well as a substantially increased death rate, increases were observed in the treatment group in heart failure, angina, and revascularization procedures [8].

Why they could possibly think this drug was a good idea is beyond me! CETP is critically important for getting the fatty acids from the factory to the table. In diabetes, the skeletal muscles are insulin resistant, which means that they don’t like glucose as a fuel. The fat cells have assumed an awesome responsibility in maintaining fat stores that can be delivered to the muscles to keep them well fed. The delivery mechanism is interesting – kind of like the truck taking the goods to the dock where they’re piled into a containiner that’s loaded onto the cargo ship for long-distance transport. The HDL particle is the truck, and the VLDL particle is the ship. HDL takes up the fatty acids from the fat cell, and, as a consequence of now having a cargo load, it picks up an apo signature called “apo-CIII” which tells the liver not to recycle this particular particle (because it still has valuable goods to deliver). What it’s supposed to do next is to hand over its goods to a VLDL particle, along with the apo-CIII sign, and to pick up more cholesterol in return, so that it can now support a new load of fatty acids (the fatty acids need adequate cholesterol to wrap them and protect them from oxidative damage during transport). But with a CETP inhibitor at work, this exchange of goods can’t take place, so the HDL particle is stuck with a load it can’t deliver. The muscle cells don’t get fed, and the HDL particle is essentially converted into an LDL particle that can never be recycled. Your HDL numbers are high, but you should be thinking of them as LDL numbers! HDL containing apo-A1 is the healthy kind of HDL, but these fat-laden HDL particles can no longer reconvert themselves into apo-A1 versions, due to the fact that CETP isn’t working. In an in vitro study, it was shown that apo-CIII is handed over along with fatty acids when the exchange takes place. And HDL particles containing apo-CIII, i.e., burdened with fatty acids, are even worse than LDL containing an apo-CIII signature in terms of cytotoxicity to cells [9].

People with metabolic syndrome or diabetes tend to have an excess of free triglycerides in their blood, which have been released by fat cells to supply fatty acids to skeletal muscle cells for fuel. So their HDL particles are often overloaded in fatty acids relative to their cholesterol content, particularly in the context of a statin drug which has assured that cholesterol is in short supply. The CETP inhibitor prevents them from trading their excess triglycerides for some cholesterol with a VLDL particle, and therefore they are stuck with a situation where they can’t protect the fats they’re carrying from attack by oxidizing agents, and they can’t unload them. So, when you take this drug, you end up with a wonderfully high number of HDL particles in your blood, laden with dangerous undeliverable goods, because these oxidized fatty acids will launch a reaction cascade to create further damage to any biologically important molecules that intersect their path.

Statin Drugs

Now I want to reexamine the effects of statin drugs on muscle cells, in the light of some new information I have recently uncovered from the literature. It appears to me that statins offer the possibility of a nasty reaction cascade that would lead to an escalating pile of toxic cell debris accumulating in the skeletal muscles. This would go a long ways towards explaining all the muscle pain and weakness associated with statin therapy. As I’ve said before, statins interfere with the mevalonate pathway at its root. What I have come to realize lately is that, despite the fact that cholesterol is vitally important to the cell’s well-being, it may be the effect that statins have on another branch of the mevalonate pathway that is even more significant. This is because this other branch, involving G-proteins, is critical to the ability of the cell to communicate with other cells [10], something that is particularly important when the cell is distressed. Such communication turns out to be essential in order for the cell to die graciously. Why might the cell be distressed? Well, with insufficient cholesterol in its membrane, it’s going to be subjected to excess ion leaks, as I’ve discussed before. To solve this problem, it will switch from potassium to calcium (a bigger molecule) as a positively charged electrolyte to help it maintain its ion buffering and its charge balance. Having switched to calcium, it also has to switch its eNOS molecules from producing sulfate to producing nitric oxide. If the cell is a muscle cell, it depends on calcium transport between cellular compartments to generate the contractions that will support mobility. However, excess calcium in the cytoplasm provides background noise that weakens the signal and therefore the contraction strength. Furthermore, nitric oxide nitrosylates a critical protein that pumps calcium back into the sarcoplasmic reticulum to restore initial conditions after the contraction has completed [11]. So the cell becomes less and less able to perform its function, and at some point the best option is to die.

In such a situation, ordinarily a cell would send out a signal using G-proteins and this would draw the attention of a nearby neutrophil, which would arrive on the scene, ready and waiting to clean up the debris left behind after the cell dies with dignity. The neutrophil actually sends a reply signal that initiates a programmed cell death process called apoptosis, such that the cell can die in an orderly fashion, much like initiating a controlled computer “shutdown” rather than just pressing the power button [12, 13]. The SOS signal is called ”Fas” and the neutrophil’s response signal is called “Fasl.” The complex response initiated in the cell is aptly named a “death-inducing signaling complex” (DISC).

But with statins suppressing the mevalonate pathway, both the cell in trouble and the neutrophil are depleted in G-proteins [14] and are thus impaired in their ability to initiate the Fas-Fasl signaling that would allow the cell to shut down gracefully. Neither one can carry out its half of the signaling handshake, so instead the cell dies a messy unorchestrated death by necrosis, spilling its guts out into the intercellular space. One of the really toxic substances that shows up as debris when a cell dies an “unnatural” death is D-ribose, a glycating agent that is much worse than fructose, which in turn is much worse than glucose. So now we have a reaction cascade taking place where neighboring cells also die untimely deaths as a consequence of the toxicity of D-ribose, and a necrotic pile of cell debris accumulates. I would imagine that an accumulation of necrotic cell debris would also show up in the atherosclerotic plaque, because neutrophils are unable to respond to SOS signals sent out by distressed cells in the plaque. Indeed, what you typically see in statin therapy is a decrease in the overall number of heart attacks (and I think this may also be attributable to the shutdown of cell-cell communication channels), but an increase in the number and size of big heart attacks that are much more likely to kill you.

But the bigger problem, in my view, with these necrotic deaths, is that it has the effect of globally increasing the body’s cells’ exposure to advanced glycation end products (AGEs). Some have argued that AGEs should be equated with aging: that aging can best be defined as the accumulation over time of more and more AGE products. These AGEs are the biggest health problem associated with diabetes. They cause impaired function for all cells and blood proteins that come in contact with them. This accumulation of D-ribose from debris from dead cells is, in fact, I think, the key reason why statin drugs accelerate the rate at which you grow old. And I think that is the best way to characterize statin drugs.

An Exciting New Book

Finally, I want to shamelessly promote a book that has just been released called, “How Statin Drugs Really Lower Cholesterol and Kill You One Cell at a Time.” I just got a copy of this book [15], and I have been devouring it! The technique the authors use of showing snippets from papers written by the major players in the early promotion of statin drugs is stunning. If you do nothing else this summer, read this book! It will change forever your view of the medical establishment and the FDA.

Here, I just want to talk about one key paper referenced in the book [16]. This paper, written in 1980, discusses the core problem with statins addressed by the book, namely, that they interfere with the cell cycle and therefore prevent cells from being able to replicate their DNA. It’s another branch of the mevalonate pathway besides the cholesterol branch that leads to the key enzyme that is necessary for cell replication, and this is why statins interfere with the cell’s ability to multiply. Many cell types depend upon such cloning to maintain healthy tissues, such as in the skin, and most certainly a fetus, which probably explains why they’re labelled class X for pregnancy. But the really disturbing thing, to me, that this paper points out is that tumor cells exhibit a near universal pathology which is uncontrolled, unregulated, synthesis of mevalonate, the precursor to the reaction that is blocked by statin drugs. Since stressors induce tumorigenesis, and since the mevalonate pathway is highly stressed when a cell is bathed in statin drugs, I would expect that statins would be highly tumorigenic. But the key reason why they don’t actually lead to tumor growth is that statins interfere with the new tumor cell’s ability to clone itself. My prediction is that, when people who have been taking a statin for a long time go off of it (which they will surely do in droves if they read this book!), they will be primed for runaway cancer, because the statins are probably causing many cells to become malignant, but these cells have been trapped in a limbo state because of the suppression of DNA replication by statins.

References

[1] R. Smith, “All over 50s should be taking statins,“ The Telegraph, May 17, 2012. Accessed May 17, 2012.

[2] S. Benjannet, D. Rhainds, R. Essalmani, J. Mayne, L. Wickham, et al., “NARC-1/PCSK9 and Its Natural Mutants: Zymogen Cleavage and Effects on the Low Density Lipoprotein (LDL) Receptor and LDL Cholesterol,” J. Biol Chem 279(47) Nov. 19, 2004.

[3] R. Huijgen, S. M. Boekholdt, B.J. Arsenault, W. Bao, et al., “Plasma PCSK9 Levels and Clinical Outcomes in the TNT (Treating to New Targets) Trial A Nested Case-Control Study,” J Amer Coll Cardiol 59(20):1778-1784, 2012.

[4] D. Holmes, “Hopes soar as cholesterol plummets with new drug class,” http://www.nature.com/nm/journal/v18/n5/full/nm0512-633.html; accessed May 13, 2012.

[5] R.A. Vogel, “PCSK9 Inhibition: The Next Statin?” J. American College of Cardiology 59(25), 1-2, 2012.

[6] S. Poirier, A. Prat, E. Marcinkiewicz, J. Paquin, B.P. Chitramuthu, D. Baranowski, B. Cadieux, H.P. J. Bennett, and N.G. Seidah, “Implication of the proprotein convertase NARC-1/PCSK9 in the development of the nervous system,” J. Neurochem. 98:838850, 2006.

[7] M.E. Brousseau, E.J. Schaefer, M.L. Wolfe, L.T. Bloedon, A.G. Digenio, R.W. Clark, J.P. Mancuso, and D.J. Rader, M.D., “Effects of an Inhibitor of Cholesteryl Ester Transfer Protein on HDL Cholesterol,” New England Journal of Medicine 350(15):1505-1515, Apr. 8, 2004.

[8] The Failure of Torcetrapib : Was it the Molecule or the Mechanism? Alan R. Tall, Laurent Yvan-Charvet and Nan Wang Arterioscler Thromb Vasc Biol 2007, 27:257-260

[9] M.K. Jensen, E.B. Rimm, J.D. Furtado and F.M. Sacks, “Apolipoprotein C-III as a Potential Modulator of the Association Between HDL-Cholesterol and Incident Coronary Heart Disease,” J Am Heart Assoc 1:1-10, 2012.

[10] N. Wettschureck and S. Offermanns, “Mammalian G Proteins and Their Cell Type Specific Functions,” Physiol Rev 85:1159-1204, 2005.

[11] R.I. Viner, T.D. Williams, and C. Schöneich, “Nitric Oxide-Dependent Modification of the Sarcoplasmic Reticulum Ca-ATPase: Localization of Cysteine Target Sites,” Free Radical Biology and Medicine 29(6):489-496, 2000.

[12] M.-C. Lee, G.-R. Wee, and J.-H. Kim, “Apoptosis of Skeletal Muscle on Steroid-Induced Myopathy in Rats,” J Nutr.135(7):1806S-1808S, Jul. 2005.

[13] M. Bennett, K. Macdonald, S.-W. Chan, J.P. Luzio, R.Simari and P. Weissberg, “Cell Surface Trafficking of Fas: A Rapid Mechanism of p53-Mediated Apoptosis,” Science 282(5387):290-293, Oct. 9, 1998.

[14] L.M. Blanco-Colio, B. Muñoz-García, J.L. Martín-Ventura, C. Lorz, C. Díaz, G. Hernández and J. Egido, “3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Decrease Fas Ligand Expression and Cytotoxicity in Activated Human T Lymphocytes,” Circulation 108:1506-1513, 2003.

[15] G.B. 14]Yoseph an H.Y. Yoseph, How Statin Drugs Really Lower Your Cholesterol and Kill You One Cell at a Time. Hannah Yoseph, Publisher, March 12, 2012.

[16] V.Q. Huneeus, M. H. Wiley, and M.D. Siperstein, “Isopentenyladenine as a mediator of mevalonate-regulated DNA replication,” Proc. Natl. Acad. Sci. 77(10) 5842-5846,Oct. 1980.

Can Bacteria Help Us Metabolize Sulfur and Rescue Us from Crisis?

Over the past year or so, I have been furiously reading the research literature, while simultaneously brainstorming on a fanciful story about how the human body might maintain good health in the face of severe deficiencies. I am going to try to piece certain parts of this story together here, in the hopes that someone else who knows more about biology than I do will pick up on it. I admit that what I write here is full of speculation, so please take it with a grain of salt. But if I am right about even some of what I say, I think it is very important for my message to get out to the world, because it means that the way we currently go about treating illness is all wrong.

In the 1800’s, Louis Pasteur framed illness in terms of infectious diseases, and his message has dictated how we treat disease today. Our aggressive administration of vaccines has greatly reduced the incidence of childhood diseases like measles and chicken pox, but at what cost? We need to seriously ask ourselves whether the alarming increases in autism, Tourette’s syndrome, ADHD, asthma, allergies, and childhood depression are a fair bargain in return. Antibiotics are clearly reaching the end of the line, with runaway MRSA (methicillin-resistant Staphylococcus aureus) leaving people terrified to spend time in a hospital, and no clear path towards new antibiotics in the pipeline to rescue us from disaster.

A little-known contemporary of Louis Pasteur, Antoine Béchamp, had an opposing point of view on the driver behind all disease, and I think he got it more right than Pasteur did. His focus was on the stability of the blood [1], and he felt that diseased states came about when the blood was chemically imbalanced. Béchamp’s most well known quote is probably, “The primary cause of disease is in us, always in us.” Certainly this seems to be more and more true over time, as modern noninfectious diseases like diabetes and Alzheimer’s replace the infectious diseases of yesteryear.

My studies, beginning with autism, have led me to the bold hypothesis that cholesterol sulfate deficiency is the most significant factor in modern diseases, ranging from arthritis to GERD (gastrointestinal reflux disease) to heart disease and Alzheimer’s. As I have discussed in previous posts, the troubles begin in many cases in the womb, where the mother’s deficiencies in the supply of cholesterol sulfate to the fetus predispose that child to future autism. Postnatally, the child continues to be deprived of dietary cholesterol, fat, sulfur, zinc and magnesium. In parallel, overexuberant application of sunscreen containing both aluminum and vitamin A leads to a direct suppression of cholesterol sulfate synthesis in the skin, an effect which may well continue even after the sunscreen has been washed off.

The dangers of insufficient cholesterol sulfate supply are manifested most poignantly in the blood stream. Without enough sulfate, the glycocalyx, which is the term used to describe the complex mesh of glycosaminoglycans (GAGs) lining the walls of the blood vessels, becomes incompetent in its function of maintaining low viscosity/surface tension in the capillaries. While this may sound unimportant, it is absolutely crucial for the ability of blood to flow smoothly through the capillary. A fascinating paper [2] has shown, using physical arguments, how a capillary will flush all of its blood out towards both the arteries and the veins, whenever its pressure is greater than the pressure in the arteries and veins. Since pressure is inversely related to the diameter of the vessel, the pressure in capillaries will automatically be higher than that in arteries, unless the capillaries maintain a very low viscosity to offset the smaller radius. This viscocity trick will work because pressure is directly related to viscosity.

I propose that the capillary achieves this goal through populating its glycocalyx with sulfate anions. This has the effect of creating a ’gel-like’ region along the interior of the capillary wall, which encloses all the dangling proteins and sugar molecules that are attached to the endothelial cells in the wall. Thus, a smooth “frictionless” surface, like the surface of jello, surrounds the interior of the capillary, preventing turbulent flow, and therefore lowering the viscosity. Due to their anionic kosmotropic property, the sulfate ions each surround themselves with a field of structured water, an exclusion zone of nearly pure water that behaves almost like a crystalline solid; i.e., that stays in place and does not join the flowing water in the middle of the capillary [3].

If there isn’t enough sulfate in the capillary wall, then the gel will turn into mush, and the viscosity will go up, as this part of the stream starts to participate in the flow. A crisis will be reached if the pressure in the capillary gets too high. This may well be the key reason why people develop hypertension – the arterial pressure must necessarily be raised through vasoconstriction of the artery wall in order to keep the pressure there higher than the pressure in the capillary. Otherwise the capillary will collapse. An alternative solution is to lower the viscosity in the capillary by depolymerizing the glycocalyx [4, 5]. Depolymerization (breaking down into smaller sized units) will significantly decrease the viscosity as well, and this can be achieved by attacking the wall with reactive oxygen species (ROS), a characteristic feature of heart disease. Thus the glycocalyx will be stripped away into little pieces, and the effective capillary diameter will grow. However, ROS can do a lot of collateral damage to the neighboring cells, which is why such inflammation is in general a bad idea. And the exposed capillary wall is now highly vulnerable to attack by things like maurauding microbes.

When the capillaries are in a fragile state due to inadequate sulfation, any disruption of the status quo could lead to a crisis, where the capillaries collapse and the affected organs are no longer supplied with oxygen. In my opinion, this could be a precipitating cause of both sudden infant death syndrome (SIDS) and sudden adult death syndrome (SADS), both of which are alarmingly on the rise. Since the aluminum in vaccines is known to deplete sulfate, vaccines would only increase a vulnerable child’s susceptibility. And endotoxin, which is the active ingredient in vaccines, is known to cause the heparan sulfate in the glycocalyx to erode [6].

The body responds to such a crisis with a remarkable reaction cascade that attempts to avert disaster, which I believe explains the extreme adverse reactions ot vaccines that result in anaphylactic shock and encephalitis, which I have previously discussed. A new insight that I have developed concerning encephalitis is the possible role that bacteria play in renewing critical nutrients, especially sulfate. It is very interesting to me that, in encephalitis, bacteria are literally invited into the brain. And I hypothesize that this is because they are useful to the brain in some way. Encephalitis is characterized by a leaky blood brain barrier [7], and this allows microbes to gain easy access to the brain. Heparan sulfate has been shown to be essential to maintain the epithelial barrier in the intestines [8], which is also known to be impaired in autism. So the bacteria can easily cross the gut wall as well as the BBB.

I have found a paper that describes how many bacteria, including E. coli, a common source of infection, can produce sulfate from taurine, using an enzyme called taurine alpha-ketoglutarate dioxygenase (TauD) [9]. The reaction also converts alpha-ketoglutarate to succinate, and converts oxygen to carbon dioxide. I am now thinking that this could be the key reason why bacteria are allowed into the brain during an acute crisis of the blood. In encephalitis, alpha ketoglutarate would likely be abundantly available, as it is easily derived from glutamate, which is known to be released by astroyctes in response to the swelling associated with encephalitis [10]. Astrocytes routinely store an abundance of taurine, which is also released along with glutamate [11]. And the neutrophils that follow the bacteria into the brain and that will eventually kill them also harbor taurine. So all the ducks are lined up to allow the bacteria to save the blood stream by resupplying the glycocalyx with sulfate derived from taurine.

The carbon dioxide that is produced by the bacteria as a by-product could be the key trigger of the hyperventilation and coma that often appear with acute encephalitis. Excess carbon dioxide in the blood leads to an acidosis condition that can easily be fatal if left unchecked. The brain stem responds by producing serotonin, which triggers a cascade reaction inducing spontaneous hyperventilation, associated with general anxiety [12]. By breathing faster and deeper than normal, the excess carbon dioxide could be expelled, thus averting the crisis. Rett syndrome, a rare condition affecting exclusively girls but with many similarities to autism [13], is associated with a charateristic hyperventilation behavior that highly suggests excess serotonin in the brain stem [14]. And the anxiety associated with autism [15] can be explained the same way, as the serotonin induces a state of anxiety and high alertness appropriate for the impending crisis. This idea is further supported by the fact that the serotonin system appears to be disturbed in autism [16]. A subsequent coma arises if the condition becomes so acute that the brain must shut down in order to rescue itself from potential extensive brain damage due to rampant exposure to carbon dioxide and to neuroexcitatory agents like glutamate.

Acidosis is a serious problem, since an increase in the blood concentration of free protons by as little as 0.1 M is fatal. It has been proposed that a defective serotonergic system might explain increased susceptibility to sudden infant death as well as panic disorders and the anxiety associated with autism [17]. I propose that such an impairment could arise due to a chronic exposure to excess carbon dioxide in the brain from the reaction carried out by the bacteria to extract sulfate from taurine. If true, this shows the critical importance of sulfate to the health of the blood system.

Now I want to abruptly change the topic to talk about algae, and you will soon see why this is relevant to the larger picture I am painting. A must-read book written by Elizabeth Plourde, called “Sunscreen Biohazard” [18] has a lot to say about the dangers of sunscreen, not just to us but to the fish, algae and coral in the sea. One of the key topics she covers is the destruction of coral reefs by sunscreen. Think of all the visitors who douse themselves in sunscreen before going snorkling over the coral reef. It turns out that sunscreen is extremely toxic to the algae that live in symbiosis with the coral and that supply the coral with critical nutrients for its survival.

I have dug up an article on algae that might explain not only how sunscreen destroys algae but at the same time how it interferes with the sulfur cycle in humans. In other words, the biochemical method that algae use to metabolize sulfate, in the presence of sunlight, may well be happening in human skin as well. It’s even possible that we exploit bacteria residing in our skin to provide critical enzymes to help us perform this feat, since common bacteria, such as E. coli, can also metabolize sulfate. And the sunscreen applied to the skin could be interfering with the process in the bacteria on the surface of the skin. According to the article [19], algae, when exposed to light, can extract sulfate from a molecule called APS (similar to PAPS that humans use as an activated form of sulfate), and reduce it to sulfide. It may be a long shot to propose that sunscreen interferes with the same process in algae and in humans, which is the reduction of sulfate to sulfide, but it would be remarkable if this were true. And it would mean that we have a complete sulfur cycle functioning in our bodies, utilizing sunlight as a source of energy.

References

[1] A. Béchamp, “The Blood and its Third Element,” Paperback edition, Review Press, 2012.

[2] I.A. Sherman, “Interfacial tension effects in the microvasculature,” Microvascular Research 22(3) Nov 1981, 296-307.

[3] G.H. Pollack, X. Figueroa and Q. Zhao, “Molecules, Water, and Radiant Energy: New Clues for the Origin of Life,” Int. J. Mol. Sci. 10:1419-1429, 2009.

[4] M.S. Baker, S.P. Green, and D.A. Lowther, “Changes in the Viscosity of Hyaluronic Acid after Exposure to a Myeloperoxidase-Derived Oxidant,” Arthritis & Rheumatism, 32(4):461467, Apr 1989.

[5] F.E. Lennon and P.A. Singleton, “Hyaluronan regulation of vascular integrity,” Am J Cardiovasc Dis 2011;1(3):200-213.

[6] P. Colburn, E. Kobayashi, and V. Buonassisi, “Depleted level of heparan sulfate proteoglycan in the extracellular matrix of endothelial cell cultures exposed to endotoxin,” J Cell Physiol 159: 121130, 1994.

[7] H.E. De Vries, J. Kuiper, A.G. De Boer, T.J.C. Van Berkel and D.D. Breimer, “The Blood-Brain Barrier in Neuroinflammatory Diseases,” Pharmacological Reviews 49(2):143-155, 1997.

[8] L. Bode, C. Salvestrin, P.W. Park, J.-P. Li, J.D. Esko, Y. Yamaguchi, S. Murch, and H.H. Freeze, “Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function,” J. Clin. Investig. 118(1):229-238, Jan. 2008.

[9] K.P. McCusker and J.P. Klinman, “Facile synthesis of 1,1-[2H2]-2-methylaminoethane-1-sulfonic acid as a substrate for taurine a ketoglutarate dioxygenase (TauD),” Tetrahedron Letters 50:611-613, 2009.

[10] V. Parpura, T.A. Basarsky, F. Liu, K. Jeftinija, S. Jeftinija and P.G. Haydon, “Glutamate-mediated astrocyteneuron signalling,” Nature 369:744-747, Jun 30, 1994.

[11] H.K. Kimelberg, S.K. Goderie, S. Higman, S. Pang, and R.A. Waniewski, “Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures,” J Neurosci. 1990 May;10(5):1583-91.

[12] Brashear, R.E., “Hyperventilation syndrome,” Lung 161(1) 257-273, 1983.

[13] B. Olsson and A. Rett, “Autism and Rett syndrome: behavioural investigations and differential diagnosis,” Dev Med Child Neurol 29:429-441, 1987.

[14] D.P. Southall, A.M. Kerr, E. Tirosh et al, “Hyperventilation in the awake state: potentially treatable component of Rett syndrome,” Arch Dis Child 63:1039-48, 1988.

[15] J.A. Kim, P. Szatmari, S.E. Bryson, D.L. Streiner, and F.J. Wilson, “The Prevalence of Anxiety and Mood Problems among Children with Autism and Asperger Syndrome,” Autism 4(2):117-132, Jun. 2000.

[16] E.H. Cook and B.L. Leventhal, “The serotonin system in autism.” Curr Opin Pediatr. 8(4):348-54, Aug. 1996.

[17] G.B. Richerson, “Serotonergic Neurons as Carbon Dioxide Sensors that Maintain pH Homeostasis,” Nature Reviews 5:449-461, 2004.

[18] E. Plourde, “Sunscreens Biohazard: Treat as Hazardous Waste,” New Voice Publications, 2012.

[19] A. Schmidt, “On the mechanism of photosynthetic sulfate reduction,” Archives of Microbiology 84(1) (1972), 77-86.

Cholesterol Sulfate and the Sulfur Cycle

It seems to me that now is a good time to recapitulate what I have learned about cholesterol sulfate in my studies over the past several months, summarizing its roles, according to my understanding, and explaining the resulting pathology that arises when levels are depleted. I’m going to make this blog post as short and succinct as possible, in the hopes that people who may be getting lost in the details of the biology will be able to follow these high level arguments presented, I hope, in plain English.

Back when people spent a significant amount of their time outdoors, and hadn’t heard of sunscreen, they got plenty of sun exposure to the skin, and this allowed the eNOS in cells close to the surface layer of the skin to produce sulfate from sulfide and attach it to cholesterol. Some of the cholesterol sulfate got released into the blood stream, probably getting picked up by HDL-A1, and some of it ended up in the outer layer of the skin, where it plays a very important role in barrier function (keeping the skin water-tight and keeping out pathogenic bacteria). eNOS normally produces cholesterol sulfate not only in cells in the epidermis but also in cells that roam the blood, like platelets and RBCs. All of these cells contain functioning eNOS, and all of them produce cholesterol sulfate, which I do not think is a coincidence.

Today, due to our dietary avoidance of foods high in cholesterol and sulfur, and due to our sun avoidance and liberal use of sunscreen, we don’t get enough cholesterol sulfate supply, and this has huge ramifications everywhere. It’s most obvious, in my opinion, in the autism epidemic. In addition to their cognitive and social issues, autistic children have several characteristics that can be directly explained by cholesterol sulfate deficiency, namely, eczema, asthma, digestive problems, and increased susceptibility to infection.

I think preeclampsia (toxemia), a condition that now affects 6-8% of American pregnancies, and is rapidly increasing, is due to an insufficient supply of cholesterol sulfate for the fetus. To start with, cholesterol sulfate plays an essential role in fertilization. Furthermore, I believe that the fetus gets its entire supply of both cholesterol and sulfate from the cholesterol sulfate molecule, which can penetrate the placental barrier, unlike cholesterol. It has been shown that cholesterol sulfate shows up in profuse amounts in the placental villi in the last trimester of pregnancy, the same time during which preeclampsia develops. Preeclampsia is a very strong risk factor for future autism in the fetus.

In looking at heart disease, I think atherosclerosis develops as an alternative method to produce cholesterol sulfate, since the normal method through sunlight exposure to the skin has failed. As I’ve discussed before, the macrophages take up cholesterol from LDL and hand it over to HDL-A1, and the platelets combine the cholesterol from HDL-A1 with sulfate derived from homocysteine thiolactone (a process which requires superoxide and therefore ROS – reactive oxygen species) to produce cholesterol sulfate and release it to the blood.

What does the cholesterol sulfate do that’s so important? It supplies both cholesterol and sulfate to all the tissues. I cannot think of a more important thing to do! Sulfate plays an important role in the glycocalyx, which is a thick layer of attached glycosaminoglycans that decorate the artery wall, in keeping the blood and its suspended contents from seeping out into the tissues. Sulfate, a kosmotrope, pairs with sodium, a chaotrope, in the blood stream to maintain the appropriate kosmotrope/chaotrope balance that keeps proteins (and cells!) from salting-out/salting-in. What this means in plain English is that sulfate is needed to stabilize the blood. It’s clear from the research literature that cholesterol sulfate hangs out in the outer membrane of red blood cells, and it plays an important role in protecting them from falling apart.

I believe that RBC’s hand off cholesterol sulfate to the tissues (especially the heart, skeletal muscles, and neurons) as they pass through the capillaries. I further believe that muscles and neurons are able to process glucose in the caveolae of their cell membranes, using ferrous sulfate as a catalyst to help in the reaction converting glucose to pyruvate. Hydrogen peroxide is also required, and insulin will not induce GLUT4 to go to the membrane unless hydrogen peroxide is present. The reduction of the sulfur in sulfate to sulfide is a decoy exploiting the reducing power of glucose, to protect the cell’s proteins from glycation damage. The sulfur is first attached to pyruvate to form 3-mercaptopyruvate, and is then released from the pyruvate and easily passed into the blood stream as hydrogen sulfide, a signaling gas that has all the good properties of nitric oxide but none of the bad properties. The oxygen released from the sulfate anion is handed over to myoglobin in muscle cells or alpha-synuclein in neurons, and delivered to the mitochondria (safe oxygen transport).

When there isn’t enough cholesterol and sulfate to supply this process, the muscle cells become impaired in their ability to process glucose. This is the “insulin resistance” that is becoming a steadily increasing problem in modern society. Unlike the skeletal muscles, the heart muscle is protected from it, but only because the plaque is doing its job delivering a private stash of cholesterol sulfate to the heart.

The hydrogen sulfide that is produced by metabolizing glucose in the caveolae is eagerly taken up by the mitochodria of all the tissues (they prefer it over glucose as a source of energy!). The mitochondria convert hydrogen sulfide to thiosulfate, producing ATP in the process (this is well established). The thiosulfate is the source of sulfur that feeds into eNOS to produce two molecules of free sulfate from one molecule of thiosulfate (at least that’s my current model). This completes the sulfur cycle. Thus, hydrogen sulfide is oxidized to sulfate in the skin upon sun exposure (capturing the energy in sunlight), and then the sulfate is reduced back to sulfide in the caveolae of muscles (and probably also neurons), using glucose as the reducing agent.

When an individual becomes so deficient in cholesterol and sulfur and sunlight exposure that they can no longer maintain the sulfur cycle, their body converts to a nitrogen-based oxygen transport mechanism. This has the advantage that it doesn’t depend on cholesterol, but the disadvantage that nitrate does not hang out in the extracellular matrix proteins the way sulfate does. So I think it has to be continually produced and excreted through the urine. Eventually, sources of nitrogen become depleted, and the person ends up with cachexia, a muscle-wasting disease.

When you switch to nitrogen-based oxygen transport, you also have to adjust the cations to reflect the fact that nitrate is a chaotrope instead of a kosmotrope. This is why calcium entry into a cell causes eNOS to switch from producing sulfate to producing nitrate. Calcium is a kosmotrope, whereas potassium is a chaotrope. So you have the following possible pairs in the cell:


potassium-sulfate: chaotrope-kosmotrope
calcium-nitrate: kosmotrope-chaotrope


I think the system is rather elegant, because, when the cell becomes depleted in cholesterol, it starts leaking small ions through its membrane, such as potassium and sodium. It will exhaust itself, consuming all of its ATP, in trying to keep these ions on the right side of the fence. So, instead, it converts to calcium-nitrate instead of potassium-sulfate, because calcium is a much bigger ion and won’t leak. It has to switch the anions in order to balance the kosmotrope/chaotrope situation.

So, another thing that happens when you switch from sulfur-based to nitrogen-based oxygen transport is that calcium gets leached from the bones, so that it can buffer the nitrates in the blood and in the cells. Arteries become calcified (”hardened”) and heart valves become calcified, while the person simultaneously develops osteoporosis.

People’s bodies react differently to these deficiencies depending on their genotype. Many people develop a condition that reflects an attempt to raid sulfate from one or more sites in the body, in order to be able to stay with sulfur-based oxygen transport rather than switching to nitrogen-based oxygen transport. Some people develop arthritis, which raids sulfate from the ligaments surrounding joints. Other people develop digestive problems like

Crohn’s disease and colitis, which raids sulfate from the stomach lining. Other people get multiple sclerosis, raiding sulfate from the myelin sheath in axons in neurons. Other people end up with destroyed beta cells in the pancreas (type 1 diabetes) due to a depletion of heparan sulfate in the pancreas.

To summarize, I believe that cholesterol sulfate deficiency is behind many if not all of the chronic diseases facing us today. The solution to the problem is incredibly simple: eat more foods that are rich in cholesterol and sulfur, and get more sun exposure to the skin.

What do Preeclampsia, Heart Disease, and Adverse Vaccine Reactions have in Common? Cholesterol Sulfate Deficiency!

What do Preeclampsia, Heart Disease, and Adverse Vaccine Reactions have in Common? Cholesterol Sulfate Deficiency!

Those of you who have read my previous blog posts know by now that I am a big fan of cholesterol sulfate. The more I study, the more I come to realize that, more than any other factor, cholesterol sulfate deficiency is behind most of the conditions/diseases we face today. Perhaps the single largest factor contributing to cholesterol sulfate deficiency is inadequate sun exposure to the skin, combined with the interference effect of the chemicals in sunscreen.

Recently, I have been trying to learn everything I can about preeclampsia, in part because I think it is the most compelling example I have of cholesterol sulfate deficiency. Preeclampsia, also known as toxemia, is a serious condition now affecting 6-8% of pregnancies in the United States. Furthermore, a preeclampsic pregnancy is a significant risk factor (P=-0.0001) for future autism in the fetus [14]. Despite much study, the underlying cause of preeclampsia remains elusive. It begins innocently enough as elevated blood pressure and excess protein in the urine (proteinurea), but can quickly cascade into a remarkably divese set of alarming symptoms, sometimes terminating in the death of either the mother or the fetus or both.

Preeclampsia typically develops in the last trimester of pregnancy, the same period during which the placenta normally stocks up on cholesterol sulfate [11], as I have discussed previously. Is this a mere coincidence? I don’t think so! Proteinurea comes about because the glomeruli of the kidney allow large blood proteins like albumin and globulin to sneak past the sieve of their filter. An enlightening article published in the year 2000 [18] showed that such defective filtering in the kidneys is a consequence of both a decreased production of heparan sulfate and an increased breakdown of heparan sulfate by both reactive oxygen species (ROS) and active enzymes like heparanase. In my interpretation, the glomeruli are sacrificing their sulfate supply for the sake of the fetus, and this leads to a pathology in their function. In the extreme case, it can result in kidney failure, and this is one of the conditions that leads to death of the mother in severe preeclampsia.

Common Grounds in Preeclampsia and Cardiovascular Disease

There are remarkable similarities between preeclampsia and cardiovascular disease. First of all, women who develop preeclampsia are at a greater risk to cardiovascular disease later in life [20]. Secondly, the serum markers for preeclampsia and cardiovascular disease are identical – high levels of small dense LDL particles and reduced serum HDL [21], elevated blood pressure, and high serum homocysteine [13]. Finally, preeclampsia is associated with a vascular disease in the arteries of the placenta that eerily resembles the defects in the arteries supplying the heart associated with cardiovascular disease – thickening of the artery wall, smooth muscle cell proliferation, and the appearance of fatty deposits in foam cells derived from macrophages [7,10].

Since I know that the placenta needs to accumulate a huge supply of cholesterol sulfate during the third trimester, I hypothesize that the purpose of the activities in the artery wall of the diseased placenta might be to produce cholesterol sulfate. This is further supported by two of the most effective treatments for preeclampsia: heparin and magnesium sulfate injections. While it is generally believed that it’s the magnesium in magnesium sulfate that’s important, I think it could well be that the sulfate is as well. And heparin, as I’ve said before, is the most highly sulfated molecule known to biology. Interestingly, heparin is also used as a treatment for infertile women who have become pregnant through in vitro methods.

Since cardiovascular disease has been much more thoroughly studied, I turn to the cardiovascular disease literature to answer my question – I seek evidence that cholesterol sulfate is being produced in the atheroma, and, by analogy, I suggest that this is also the reason for the disturbances in the artery wall of the placenta in preeclampsia. By deduction, I propose that the need to synthesize cholesterol sulfate is the underlying cause of both conditions.

The most significant evidence comes from the known association of both conditions with elevated serum homocysteine. Homocysteine is a sulfur-containing amino acid, and, when its level is elevated in the blood, much of it gets converted to homocysteine thiolactone, which then enters the artery wall in the atheroma and attaches itself to the matrix proteins [15]. A chemical reaction requiring superoxide (ROS) as a catalyst can oxidize the sulfur atom in homocysteine to produce sulfate. This reaction is catalyzed by vitamin C, which has been shown to reduce risk to preeclampsia when used as a supplement [5] [because it would enhance the supply of sulfate and hence solve the core problem]. Reaction with ATP then produces a molecule awkwardly called 3’-phosphoadenosine 5’-phosphosulfate (PAPS) [24], which is basically an energized sulfate molecule.

Platelets, also residing in the plaque, can synthesize cholesterol sulfate from cholesterol and PAPS. Experiments conducted in vitro have shown that platelets increase their synthesis rate of cholesterol sulfate 300 fold when they are provided with PAPS [24]. Red blood cells play an important role as well, because they provide ATP to the artery wall [23]. Cells are stimulated to produce ROS when they are exposed to externally supplied ATP, and I think this is because the ATP provides the oportunity to produce PAPS, but the ROS are needed first in order to derive sulfate from homocysteine thiolactone.

Platelets are also choosey about who can deliver the cholesterol to combine with the sulfate. In fact, they will only use cholesterol provided by HDL-A1 [24]. Reduced serum HDL, as well as reduced cholesterol content in serum HDL, are strong risk factors for cardiovascular disease. I therefore think that HDL is the bottleneck in the production of cholesterol sulfate. The macrophages in the plaque perform a vital function in extracting cholesterol from damaged small dense LDL particles, buffering it internally within fatty deposits, and later exporting it into HDL-A1, whenever the opportunity presents itself [9].

Since low cholesterol in HDL is a significant risk factor for atherosclerosis, how is HDL supposed to be supplied with cholesterol normally? Fibroblasts in the skin are an important supplier, mediated by ATP-binding Cassette A1 (ABCA1), and defective ABCA1 is associated with a substantially increased risk to atherosclerosis, along with decreased efflux of cholesterol from these peripheral cells [2]. I believe that cholesterol sulfate may be an intermediary that allows cholesterol to easily migrate from the cell wall of a fibroblast to the HDL monolayer. It has been demonstrated that cholesterol sulfate moves much more freely from one lipid membrane to another than does cholesterol, largely due to its increased solubility in water (i.e., blood) [19]. Fibroblasts are among the cell types that contain eNOS, and I have argued previously that eNOS can synthesize sulfate in the presence of sunlight. So I firmly believe that sunlight exposure to the skin would help fibroblasts fill the coffers of HDL containers with cholesterol. It follows that insufficient sunlight exposure would therefore lead to depleted cholesterol supplies in HDL, and therefore increased risk to cardiovascular disease and to preeclampsia.

Nitric Oxide, Cobalamin Destruction and Pernicious Anemia

In a moment, I will show you some results I obtained by investigating adverse reaction reports from the VAERS (Vaccine Adverse Event Reporting System) database. In browsing the data, I was struck by the number of symptoms that were common in extreme vaccine reactions that are also associated with pernicious anemia. These include diarrhea, constipation, fatigue, light-headedness, appetite loss, pale skin, shortness of breath, swolen tongue, depression, loss of balance, and numbness/tingling. Pernicious anemia is due to a severe cobalamin (vitamin B12) deficiency, usually due to impaired uptake from the gut. However, cobalamin can be stored for a long time in the liver (up to a year), and so impaired uptake takes considerable time before it manifests as severe disease. In adverse vaccine reactions the symptoms come on very quickly, so it is likely to be due to a destruction of the cobalamin already present in the blood rather than to an impaired uptake.

Therefore, I sought papers that might explain how cobalamin could be destroyed. I came across several papers that discussed interactions between various oxides of nitrogen and cobalamin [8, 3, 16]. It seems that nitrous oxide (N2O), nitric oxide (NO) and peroxynitrite (ONOO−) all react with cobalamin to form various oxidized or nitrosylated derivatives. Since nitric oxide is the gas that’s produced by eNOS in the endothelium, it is the most likely candidate for our purposes, although the other two molecules will also be present as derivatives when NO is in high concentration in the blood.

Profuse nitric oxide synthesis is an expected reaction in the vasculature to exposure to endotoxins from pathogens, which are the “active ingredients” in vaccines. Furthermore, aluminum, added as an adjuvant, has also been shown to stimulate nitric oxide synthesis in the artery wall, likely due to its imitation of calcium, a well-established inducer of the reaction. A very enlightening paper [4] showed that anaphylactic shock (equivalent to an extreme adverse reaction to vaccines) can be induced in mice by exposing them to endotoxin and aluminum hydroxide. The paper elegantly demonstrated that it was eNOS (endothelial NOS, the constitutive form), not iNOS (the inducible form that macrophages produce to fight infection) which produced the profuse amounts of nitric oxide that led to anaphylactic shock. The anaphylactic shock reflects a sudden dramatic drop in blood pressure, brought on by the excess nitric oxide – a well known vasodilator. The journal editors, in an article introducing the above article [12], suggested that “agents that inhibit NOS or that scavenge NO might prove useful in treating life-threatening anaphylactic shock.” I maintain that one such agent is cobalamin!

A direct quote from a 1996 paper on nitric oxide and cobalamin says it better than I could ( [3], p. 1863): “Based on spectroscopy of urine samples, they believed that nitrosylcobalamin was formed in vivo in the mice overproducing NO as a result of endotoxin injection [34], and that the nitrosylcobalamin was being eliminated in the urine. Thus, it appears the H2O-Cbl [water-cobalamin complex] may bind NO and quench its effects both in vitro and in vivo.”

Thus cobalamin performs a useful role as a scavenger of excess nitric oxide, but then the reaction product is eliminated through the kidneys, and this will deplete the supply of cobalamin to the body. For someone who is deficient in cobalamin, this could then lead directly to a physiological state that’s indistinguishable from pernicious anemia.

Studies on the VAERS Database

I have done a number of studies of different subsets of the VAERS (Vaccine Adverse Event Recording System) database, which very nicely reveal a common thread among severe vaccine adverse reactions, autism, pernicious anemia and preeclampsia. My approach was to produce the following two datasets:

1. “Autism set:” A subset of all cases where the word “autism” or the word “autistic” show up.

2. “Anemia set:” A subset of all cases where any of the following symptoms show up: diarrhea, fatigue, light-headedness, loss of appetite, shortness of breath, swollen tongue, and numbness. These are all known symptoms of pernicious anemia.

The “autism” set consisted of 1323 events, and the “anemia” set was much larger, with over 50K events. I could then create another two sets, which I call “not-autism” and “not-anemia.” These were randomly drawn from the remainder of the (over 340,000) events, so as to maintain the same age distribution as the corresponding available sets for autism and anemia.

Now, what can be done is to count word frequencies for each of these pairs: Autism/Not-autism and Anemia/Not-anemia. Words that show up statistically significantly more frequently in the autism set or in the anemia set become words of interest, representing, collectively, other characteristics associated with the people who experienced these adverse reactions.

First of all, it’s reassuring that the word “anemia” was highly associated with the Anemia set (p=0.00074). Since we didn’t select on “anemia” itself, what this tells us is that the symptoms of anemia associate with anemia itself, as would be expected. Furthermore, the Anemia set is also an excellent predictor of autism (p=0.00066). What this tells us is either that autistic children are more likely to develop this anemia-like reaction to vaccines than other children, or that this group of symptoms is more likely to lead to autism. We can’t identify the cause-and-effect relationship, only the correlation, but it is very strong.

Another very interesting result we observed is that all of the symptoms that showed up with increased frequency in the Autism set were also highly overrepresented in the Anemia set. These include “anxiety,” “eczema,” “asthma,” “premature,” “pneumonia.” and “infection.” Thus, the Anemia set is a much larger set than the autism set which however captures the same set of conditions as the autism set, suggesting that the autism group of children are a small subset of a profile that is characterized by this anemia-like reaction to vaccines. The advantage of the Anemia set over the Autism set is that it is much larger, and therefore has a lot more statistical power in uncovering other related features.

So now, the interesting part comes when we look at additional symptoms/conditions that are over-represented in the Anemia set, beyond those present in the Autism set. I show these in Tables 1 and 2. Table 1 shows all the symptoms that are both highly overrepresented in the Anemia set and characteristic symptoms of preeclampsia. These include highly specific things like “blurry vision,” “facial swelling,” and “sensitivity to light,” as well as “pulmonary disease.” Table 2 shows additional symptoms that are over-represented in this set, which are cause for alarm, words like “seizure,” “death,” “paralysis,” and “heart failure.” These represent the final stage in a cascade reaction in the blood, when it is unable to right itself in time, following exposure to the toxins in the vaccine. They are also the extreme symptoms that show up in final stages of severe preeclampsia.

Table 1: Symptoms that occur with enhanced frequency in the anemia data set, compared with the control set, which are also known to be highly common in preeclampsia.

Reaction	Count Anemia	Count Control	P-value
Nausea	8817	3088	4.2E-14
Headache	4495	1839	9.5E-10
Abdominal Pain	945	146	8.3E-7
Anxiety	1720	728	6.7E-6
Pulmonary Disease	453	113	0.00016
Vision Blurred	420	129	0.00042
Visual Impairment	258	54	0.00069
Facial Swelling	288	162	0.015
Eye Irritation	119	50	0.022
Sensitivity to Light	70	11	0.011
Bilirubin	66	26	0.042

So all these analyses lead me to a bold generalization as follows: both preeclampsia and extreme adverse reactions to vaccines are a consequence of a profuse over-production of nitric oxide by eNOS in the artery wall. This excess nitric oxide reacts with cobalamin, which helps to neutralize its effects, but also gets taken down in the process. The blood enters a severe state of crisis following the sudden depletion of cobalamin, leading to the symptoms of pernicious anemia. eNOS is prevented from producing sulfate, and it may well be the sulfate depletion that is at least as big a problem as the overproduction of nitric oxide.

But, if you’re paying attention, you should be asking the question at this point, “How does preeclampsia end up with exuberant synthesis of nitric oxide?” I was puzzled, too, by this question, but the parallels in the symptoms make me think it must be true. I suspect it has something to do with progesterone. As you can see from the figure [25], progesterone levels shoot way up in the last trimester of pregnancy. Progesterone has a remarkable ability to prevent cells from storing cholesterol in private stores [6]. Excess progesterone in the blood would therefore cause the endothelial cells lining the artery wall to give up their cholesterol for the greater good. As we’ve seen from my previous blog post, insufficient membrane cholesterol leads to runaway leaks of small ions, and a rapid influx of calcium, which stimulates eNOS to switch from synthesizing sulfate to synthesizing nitrate. This idea has strong support from the literature [17, 22], where it has been shown that excess nitrates in the blood are associated with preeclampsia, and the amount of nitrate correlates with the severity of the disease.

Table 2: Other symptoms that were identified as highly signficantly over-represented in the anemia data set, besides those specifically associated with autism or preeclampsia.

Reaction	Count Anemia	Count Control	P-value
Sleep Disorder	534	140	0.0001
Seizure	1144	632	0.0005
Nerve Injury	69	0	0.004
Disorientation	112	32	0.01
Chest Pain	1366	278	2.0E-7
Heart Rate Irregular	963	279	1.0E-5
Heart Failure	64	8	0.01
Myalgia	981	416	0.00001
Paralysis	384	71	0.0001
Dysphagia	353	96	0.0005
Loss of Consciousness	832	447	0.001
Death	180	74	0.01

The whole point of it might simply be to spare the consumption of cholesterol and sulfur by these cells so that the fetus can have more. Such problems would only arise when there isn’t enough cholesterol sulfate to go around. Interestingly, Triton X-100, a surfactant ingredient found in the flu vaccine, has the same property as progesterone in interfering with cholesterol homeostasis in cells.

A Role for Seizures

You might imagine that preeclampsia is a precursor to eclampsia, and, if so, you would be right. You may have also noticed that “seizures” was one of the conditions that showed up with a highly significant bias (p= 0.00047) in the Anemia data set compared to the control. In rare cases, preeclampsia turns into eclampsia, a condition that is defined by the appearance of seizures. This to me is extremely intriguing, because it leads me to hypothesize that the purpose of the seizures is to generate sulfate anions. I believe this because I believe that sulfate deficiency is the root cause of preeclampsia.

How might a seizure produce a sulfate anion, and where might it come from? I think the answer is taurine! Taurine is a very unusal amino acid, the only sulfonated amino acid, and it is believed to be basically inert – an end product that happens to be stored in high concentrations throughout life in the heart, brain, and liver. These are arguably the three most important organs for survival in an emergency. I can’t imagine that these organs maintain an abundant store of a molecule that they find useless except possibly for reacting to osmosis imbalances by moving it around between cells and the blood stream. I believe instead that taurine is brought into play under conditions of extreme stress; in particular, under conditions where severe sulfate deficiency would result in a melt-down of the blood if not immediately corrected.

The sulfur in taurine is in a +5 oxidative state. It needs to be in a +6 oxidative state in order to happily live in a sulfate anion. That is, it needs to give up an electron. One thing that an electric current is very good at is pursuading molecules to give up electrons. A seizure induces an electric current! Oxygen molecules (O2) will be happy to pick up electrons given up by other molecules, thus turning into superoxide, a highly reactive molecule. I’m imagining that, in the context of an electric current, a superoxide anion steals a sulfur along with two oxygen molecules from taurine, leaving behind acetaldehyde in its wake. The sulfur atom, now at a +6 charge, is very happy to double-bond with the superoxide, magically yielding a sulfate anion! And this helps solve the brain’s crisis involving insufficient sulfate buffering. So, if this argument is right, there is a silver lining in seizures, in that they can replenish sulfate in the brain.

Summary

This blog post turned out to be a lot longer than I was expecting when I set out to write it. I’ve hit upon a number of topics, all closely intertwined in somewhat subtle ways. I started by showing the remarkable parallels between preeclampsia and cardiovascular disease, and I argued that the activities going on in cardiovascular plaque are the same as those going on in the arteries of the placenta in preeclampsia, and that both serve the purpose of producing cholesterol sulfate for their host: the heart in the one case and the fetus in the other.

My second topic was the relationship between pernicious anemia and severe adverse reactions to vaccines. Pernicious anemia is a direct result of extreme cobalamin deficiency, and in this section I showed how cobalimin would likely be destroyed if there was an overabundance of nitric oxide in the blood. This overabundance would be due to the stimulation of eNOS to produce nitric oxide in the context of both endotoxin and aluminum in the vaccine. In the case of preeclampsia, the trigger to synthesize abundant nitric oxide is brought on by a depletion of membrane cholesterol in the endothelial cells lining the artery wall. This in turn is caused by progesterone, which is well-known as an agent that leaches choesterol from cell walls, and which rises to high serum levels towards the end of pregnancy.

In the next section, I developed an argument based on studies of the VAERS database, where I showed remarkable links among autism, extreme adverse reactions to vaccines, preeclampsia, and pernicious anemia. I believe that all four of these conditions are attributable to a deficiency in cholesterol sulfate, which results in a dramatic switch from sulfate to nitrate as the anion of choice to maintain electrolyte balance in the blood. An instability brought on by the rapid depletion of cobalamin leads to the symptoms of pernicious anemia. But I think the severe depletion of sulfate in the blood may cause the disturbing symptoms that show up in extreme cases, such as paralysis, seizures, and death.

The final section addressed specifically the topic of seizures, and proposed a novel theory for a positive role seizures may play in allowing taurine to free up its sulfonate and convert it into sulfate. This is of course a critical step in recovery from the event, and so, if I’m right about this speculation, seizures likely are an important part of the solution in such situations.

References

[1] U. Acharya, J.-T. Gau, W. Horvath, P. Ventura, C.-T. Hsueh and W. Carlsen, “Hemolysis and hyperhomocysteinemia caused by cobalamin deficiency: three case reports and review of the literature,” J Hematology and Oncology 1:26, Dec. 18, 2008.

[2] A.D. Attie, J.P. Kastelein and M.R. Hayden, “Pivotal role of ABCA1 in reverse cholesterol transport influencing HDL levels and susceptibility to atherosclerosis,” J. Lipid Res 42:1717-1726, 2001.

[3] M Brouwer, W Chamulitrat, G Ferruzzi, DL Sauls and JB Weinberg, “Nitric oxide interactions with cobalamins: biochemical and functional consequences” Blood 88:1857-1864, 1996.

[4] A. Cauwels, B. Janssen, E. Buys, P. Sips, and P. Brouckaert, “Anaphylactic shock depends on PI3K and eNOS-derived NO,” J. Clin. Invest. 116:2244-2251, 2006.

[5] L.C. Chappell, P.T. Seed, A.L. Briley, F.J Kelly, et al., “Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial,” The Lancet 354:810-816, Sep 4, 1999.

[6] P. Debry, E.A. Nash, D.W. Neklason and J.E. Metherall, “Role of Multidrug Resistance P-glycoproteins in Cholesterol Esterification,” J. Biol Chem 272(2):1026-1031, Jan 10, 1997.

[7] J.S. Gilbert, M.J. Ryan, B.B. LaMarca, M. Sedeek, S.R. Murphy and J.P. Granger, “Pathophysiology of hypertension during preeclampsia: linking placental ischemia with endothelial dysfunction,” Am J Physiol Heart Circ Physiol 294:H541-H550, 2008.

[8] H. Kondo, M.L. Osborne, J.F. Kolhouse, M.J. Binder, et al., “Nitrous Oxide Has Multiple Deleterious Effects on Cobalamin Metabolism and Causes Decreases in Activities of Both Mammalian Cobalamin-dependent Enzymes in Rats,” J.Clin.Invest. 67:1270-1283, May 1981.

[9] P.T. Kovanen, “Atheroma formation: defective control in the intimal round-trip of cholesterol,” Eur Heart J 11 (suppl E): 238-246, 1990.

[10] Helen Kay, MD, D. Michael Nelson, MD, Yuping Wang, MD., Ed., The Placenta: From Development to Disease, Blackwell Publishing, Ltd., 2011.

[11] B. Lin, K. Kubushiro, Y. Akiba, Y. Cui, K. Tsukazaki, S. Nozawa and M. Iwamori, “Alteration of acidic lipids in human sera during the course of pregnancy: characteristic increase in the concentration of cholesterol sulfate,” Journal of Chromatography B, 704, 99-104, 1997.

[12] C.J. Lowenstein and T. Michel, “What’s in a name? eNOS and anaphylactic shock” J Clin Invest. 116(8): 2075-2078 Aug 1, 2006.

[13] G. Makedos, A. Papanicolaou, A. Hitoglou, I. Kalogiannidis, A. Makedos, V. Vrazioti, and M. Goutzioulis, “Homocysteine, folic acid and B12 serum levels in pregnancy complicated with preeclampsia,” Arch Gynecol Obstet (2007) 275:121-124.

[14] J.R. Mann, S. McDermott, H. Bao, J. Hardin and A.Gregg, “Pre-eclampsia, birth weight, and autism spectrum disorders.” J Autism Dev Disord. 40(5):548-54, May 2010.

[15] K.S. McCully, “Chemical Pathology of Homocysteine. V. Thioretinamide, Thioretinaco, and Cystathionine Synthase Function in Degenerative Diseases,” Annals of Clinical and Laboratory Science, 41:4, 300-313, 2011.

[16] R. Mukherjee and N.E. Brasch, “Kinetic Studies on the Reaction between Cob(I)alamin and peroxynitrite: Rapid Oxidation of Cob(I)alamin to Cob(II)alamin by Peroxynitrous Acid,” Chem. Eur. J. 17:11723-11727, 2011.

[17] N. Pathak, H. Sawhney, K. Vasishta and S. Majumdar, “Estimation of Oxidative Products of Nitric Oxide (nitrates, nitrites) in Preeclampsia,” Australian and New Zealand Journal of Obstetrics and Gynaecology, 39(4):484-487, Novr 1999.

[18] C.J.I. Raats, J. Van Den Born, and J.H.M. Berden, “Glomerular heparan sulfate alterations: Mechanisms and relevance for proteinuria,” Kidney Int 57:385-400, 2000.

[19] W.V. Rodrigueza, J.J. Wheeler, S.K. Klimuk, N. Kitson and M.J. Hope, “Transbilayer Movement and Net Flux of Cholesterol and Cholesterol Sulfate between Liposomal Membranes,” Biochemistry 34, 6208-6217, 1995.

[20] N. Sattar and I.A. Greer, “Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening?” BMJ 325(7356):157-160, 2002.

[21] N. Sattar, A. Bendomir, C. Berry, J. Shepherd, I.A. Greer, and C.J. Packard, “Lipoprotein subfraction concentrations in preeclampsia: Pathogenic parallels to atherosclerosis,” Obstetrics and Gynecology 89:3 403-408, Mar 1997.

[22] A.Smarason Jr., K.G. Allman, D. Young and C.W.G. Redman, “Elevated levels of serum nitrate, a stable end product of nitric oxide, in women with pre-eclampsia,” BJOG 104(5):538-543, May 1997.

[23] R.S. Sprague, A.H. Stephenson, E.A. Bowles, M.D. Stumpf and A.J. Lonigro, “Reduced Expression of Gi in Erythrocytes of Humans With Type 2 Diabetes Is Associated With Impairment of Both cAMP Generation and ATP Release,” Diabetes 55:12, 3588-3593 Dec. 2006.

[24] H. Yanai, N.B. Javit, Y. Higashi, F. Hirotoshi and C.A. Strott, “Expression of Cholesterol Sulfotransferase (SULT2B1b) in Human Platelets,” Circulation 109:92-96, 2004.

[25] From “Progesterone Levels during Pregnancy,” Center for Reproductive Immunology and Genetics; http://repro-med.net/repro-med-site2/index.php?option=com content&view=article&id=25&Itemid=12

Sodium-Potassium ATPase Dysfunction: The Key Initiator of All Chronic Diseases?

I discovered an article [1] this morning that really excites me, because I think it gets at the core problem in most of the chronic diseases of aging, although its focus is on the nervous system. The article is titled, “Na⁺,K⁺-ATPase: functions in the nervous system and involvement in neurological disease.” The article maintains, and, happily, I had recently been reaching the same conclusion, that impairment in sodium-potassium ATPase (Na⁺,K⁺-ATPase) is the key early marker of neurological diseases like Parkinson’s and multiple sclerosis.

What is Na⁺,K⁺-ATPase and why is it important? This protein is called an “integral membrane protein” because it is tightly integrated in the membrane of the cell. It is crucially present in all cells, and its main job is to make sure that there’s lots of potassium (K⁺) inside the cell, and that sodium (Na⁺) is mostly outside the cell. It also has the arduous task of making sure the cell interior is appropriately negatively charged relative to the outside world. It essentially assures that there is a voltage gradient (like a battery) across the cell membrane, with the interior of the cell being the anode. It can do this by operating the pump, because it pumps out three sodium ions for every two potassium ions that it pumps in. Since both potassium and sodium have a charge of +1, the net effect is to charge the battery: push out a +1 charge every time it pulls in two potassiums and ships out three sodiums.

This article claims that cells expend most of their energy operating this pump! Who would have guessed that? Impairment in the pump comes about when the cell runs low on ATP, the energy currency of all life. Every time it runs the pump, it uses up ATP. If the mitochondria (the powerhouses of the cell) can’t keep up with the supply, the cell battery starts losing charge, and then “all hell breaks loose.”

So the article puts the blame squarely on mitochondrial dysfunction. Over time, mitochondria suffer oxidative damage from dangerous reactive molecules like peroxynitrite (ONOO⁻), which can destroy the iron-sulfur clusters the mitochondria depend upon for electron transport. However, I believe an earlier problem, preceding mitochondrial damage, is at play. The problem is that the cell is suffering from an excessively leaky cell membrane – a membrane that too easily allows sodium ions and potassium ions (which are unfortunately very small) to sneak back across the membrane in the wrong direction, i.e, to “leak.”

Why would the cell membrane be leaky? The answer is easy – an impoverished supply of cholesterol sulfate! Both cholesterol and sulfate play essential roles in maintaining a healthy membrane function. I refer you to an excellent article written by Thomas Haines [2], which points out very clearly that cholesterol, by intermingling with the polyunsaturated fatty acids that form the bulk of the membrane, causes the fatty acids to configure themselves more tightly and more regularly, such that it becomes much more difficult for small ions like sodium and potassium to pass through. When cholesterol is deficient in the membrane (due to the depleted supply of cholesterol sulfate), sodium and potassium can much more easily leak across the membrane.

The other problem is insufficient sulfate, and to better understand this aspect you need to read some of the papers by Gerald Pollack [3, 4], who has made a tremendous contribution in revitalizing interest in questions about the structure of water, which makes up roughly 70% of the human body. So now I need to digress a bit and explain in simple terms the Hofmeister series. Ions – both cations (positive) and anions (negative) can be arranged along a continuous scale according to the Hofmeister series. At one extreme you have the strong kosmotropes (sulfate is an example) which are called “structure making” with respect to water. At the opposite extreme are the chaotropes (potassium is an example) which are “structure breaking.” Kosmotropes and chaotropes can be either negatively or positively charged, and their charge has a different kind of effect on the cell (increasing or decreasing its battery strength), which is also very important. Kosmotropes (structure making) cause the water surrounding them to become almost like a liquid crystal. And, due to the orderly arrangement of the water molecules, they effectively create a shield around them that keeps other ions away.

You can perhaps now see why sulfate would be important to a cell. I have spoken before in this blog about the importance of sulfate in the extracellular matrix proteins of all cells. I have mentioned that sulfate keeps bacteria out because of the repellent property of two negatively charged “particles.” But sulfate can also keep the small ions out, by forming a crystalline structure around itself – something that Pollack refers to as an “exclusion zone.” Interestingly, as an aside, the exclusion zone around a sulfate molecule grows much bigger when the water is exposed to light, especially infrared light (IR). Pollack claims that the exclusion zone grows by a factor of four when a kosmotrope is exposed to IR [3].

So when the supply of cholesterol sulfate to a cell has been inadequate for a long time, the cell begins to find itself in a very difficult state, where there isn’t enough sulfate sprinkled around its walls to maintain a proper exclusion zone, and there isn’t enough cholesterol in its cell membrane to keep the fats from allowing small ions to cross. Now it has to expend much more energy pumping ions, and this leads to a great deal of stress, as it requires the cell to consume much more fuel and oxygen, and excess metabolism is risky business due to all the reactive oxygen species it generates.

Coming back to the Na⁺,K⁺-ATPase article, a very enlightening paragraph describes succinctly what happens as the pump begins to fail [1], p. 287:

“The inability to maintain transmembrane Na⁺,K⁺ gradients results in collapse of the membrane potential; impaired activity of glutamate transporters; secondary Cl⁻ and water influx, and thus intracellular swelling and accumulation of intracellular Ca⁺²... This triggers downstream enzymatic cascades leading to injury of the gray and white matter.”

There is a lot packed into the above paragraph, all of which is important. But, clearly, the cell is in trouble! I will have to return to this paragraph in a later blog post about taurine, because the entry of chloride (Cl⁻) and water into the cell have important consequences to taurine metabolism. But for now I want to focus on the implications of the subsequent calcium entry. And for this we have to return to the discussion on kosmotropes and chaotropes. Calcium is a significantly bigger molecule than either sodium or potassium, and therefore it’s much less prone to leak, which can make it an attractive molecule for maintaining ionic balance. However, it is very different from potassium on the Hofmeister series: instead of being a chaotrope, it is a kosmotrope. This is a huge difference – recall that sulfate is also a kosmotrope, and if the cell continues happily synthesizing sulfate it is going to have too many kosmotropes and not enough chaoptropes on its hands.

As I’ve said before, when calcium enters a cell that contains eNOS, the calcium binds with calmodulin, and this calmodulin-calcium complex then causes eNOS to detach from the cell membrane and start producing nitric oxide (nitrate) instead of sulfate. There’s an enzyme called nNOS (neuronal nitric oxide synthase) in neurons, and it too will start producing nitrate when it sees calcium entering the cell. Why is this? Well, my best guess is because nitrate is a chaotrope, like potassium. Chaotropes and kosmotropes have to be balanced to prevent proteins from either precipitating out (too many kosmotropes) or dissolving (too many chaotropes). Furthermore, I think an individual cell has to make a commitment to producing either potassium sulfate or calcium nitrate as the ionic mix to balance both their electrolytes and their chaotrope/kosmotrope ratio. It can’t be on the fence about this.

There’s a very compelling reason for this: eNOS produces superoxide as a precursor to sulfate and it produces nitric oxide as a precursor to nitrate. So, if some of the eNOS molecules were producing sulfate and others were producing nitrate, there would be a mixture of nitric oxide and superoxide gases simultaneously present in the cell. This is very dangerous, because these two gases react to form peroxynitrite (ONOO⁻), the highly reactive gas that will destroy the mitochondria’s ability to produce ATP. So we’ve come full circle here! Switching back and forth between nitrate and sulfate synthesis leads to an excess burden of peroxynitrite, which causes mitochondrial damage. Eventually, the cell has no choice but to permanently switch to a calcium-nitrate solution, because there isn’t enough energy to keep on pumping sodium and potassium ions back to where they belong. Cells live under a lot of constraints, and it’s truly remarkable that they perform as well as they do most of the time!

Now I want to turn, once again, to aluminum. Recall that aluminum is an adjuvant that is added to vaccines, and that the aluminum burden our nation’s children are exposed to through vacines has been steadily growing over the past 15 years. Aluminum is a much more potent kosmotrope than calcium, and it binds to calmodulin with an affinity that’s an order of magnitude stronger than that of calcium [5]. So, if even a small amount of aluminum gets into a cell, it will bind to calmodulin, mimicking calcium, and stimulate eNOS to detach from the cell membrane and start making nitrate instead of sulfate. This is very wise, because it turns out that aluminum sulfate is a reagent that is used in chemistry for precipitating out proteins from a cell. You should think about amyloid beta and tau protein plaque at this point: these are proteins that have precipitated out! And their accumulation in the brain is a hallmark of Alzheimer’s disease.

So, in summary, here’s the situation as I see it. The cell suffering from too little cholesterol in its membrane and too little sulfate in its surround is stuck with a huge problem because sodium and potassium are leaking across its membrane at an unacceptably high rate. It has to burn a lot of energy (generate ATP) to keep the pump going to restore the wayward ions. After a point (probably when the ATP starts to run out) it “decides” that the better option is to forget about trying to maintain a high potassium content, and instead use calcium as a cationic buffer. But calcium is a kosmotrope instead of a chaotrope, so the NOS (eNOS or nNOS) has to switch from producing sulfate to producing nitrate, to compensate. When a cell is suddenly confronted with an onrush of aluminum (due to a vaccine), it has no choice but to quickly switch to nitrate production, to avoid a catastrophic precipitation of its proteins. And the really disturbing thing is that aluminum can gain entry more readily when sulfate supply is impoverished in the cell’s extracellular matrix.

As people get older, they often suffer from osteoporosis – the leaching of calcium from the bones. They also tend to build up calcified plaque in the arteries (“hardening of the arteries”) and calcified heart valves. I think this is a direct consequence of insufficient cholesterol sulfate in the artery wall and in the heart. The calcium is leached from the bones in order to supply it to these other cells, which would die if they can’t maintain their charge gradient. They’re willing to turn into bone if that’s what it takes to protect them from a certain death.



References

[1] E.E. Benarroch, “Na⁺, K⁺ ATPase: Functions in the nervous system and involvement in neurologic disease,” Neurology 76:287-293, Jan 18, 2011.

[2] T.H. Haines, “Do sterols reduce proton and sodium leaks through lipid bilayers?” Progress in Lipid Research 40:299-324, 2001.

[3] G.H. Pollack, X. Figueroa and Q. Zhao, “Molecules, Water, and Radiant Energy: New Clues for the Origin of Life,” Int. J. Mol. Sci. 10:1419-1429, 2009.

[4] G.H. Pollack, Cells, Gels and the Engines of Life, Ebner and Sons, publisher, Seattle, WA, USA., 2001.

[5] N. Siegel and A. Haug, “Aluminum interaction with calmodulin. Evidence for altered structure and function from optical and enzymatic studies,” Biochim Biophys Acta 744(1):36-45, Apr 14, 1983.

Cholesterol and Statins: Who’s the Hero? Who’s the Villain?

The statin drugs, known more technically as HMG Coenzyme A reductase inhibitors, are the biggest blockbuster drug class of all times. Now that Lipitor, the number one selling drug in history, has gone off patent, we can expect the price to drop precipitously, and even more people will be able to afford this wonder drug that promises to keep heart attacks at bay.

Statins’ claim to fame is that they reduce serum levels of cholesterol, that villainous moleclule that clogs up our arteries and leads to an early death. Statins work remarkably well – most people who adopt statin therapy quickly see their measures of serum LDL drop dramatically.

Beyond their ability to delay heart attacks, statins have also been credited with a large and growing number of “off-label” benefits – you can find articles on the Web claiming that they protect form Alzheimer’s disease, osteoporosis, multiple sclerosis, cancer, and infection, among others. Some are even advocating, not necessarily tongue in cheek, that statins should be added to the drinking water.

A good example is the article that just appeared on the Web on the subject of statins and influenza. The headline claims that statins may improve your chances of surviving the flu, but a couple of points in the article lead me to suspect that instead statins are increasing the risk of healthy people catching the flu. As will become clear later in this article, cholesterol is an important weapon against infection and statin drugs disturb the immune response in ways that would be expected to increase susceptibility to infection. This idea is borne out by the fact pointed out in the article that a greater percentage of the statin users had gotten a flu vaccine, but nonetheless acquired the infection. Furthermore, fully one third of the infected people were on statins, a number that is surely significantly larger than the frequency of statin use in the general population; i.e., statin use is associated with increased risk of infection. Finally, the statin users had an increased incidence of chronic lung disease, something that I have argued previously would be promoted by long-term statin therapy, and something that would likely increase the risk of infection from exposure to influenza. If the serum cholesterol levels of the people who died had been measured, it would probably have been found that their levels were low and falling, as has been shown to be the case for people with sepsis who fail to recover [24]. In fact, these authors wrote: “In patients who died, final cholesterol levels fell by 33% versus a 28% increase in survivors. ... New therapies directed at increasing low cholesterol levels may become important options for the treatment of sepsis.” A paper published in 1997 revealed an inverse association between cholesterol levels and pneumonia hospitalization [20], suggesting that high cholesterol is protective against pneumonia as well.

Curiously, despite aggressive campaigns to get people vaccinated against the flu, morbidity and mortality from flu has steadily gotten worse in recent years. Besides the ineffectiveness of vaccines, I suspect this increased mortality is due in large part to the ever increasing use of statin therapy. My personal belief is that it will eventually be shown that not only susceptibility to infection, but every one of the claimed off-label benefits of statins is actually a benefit derived from cholesterol, and that statins are actually eroding that benefit by steadily depleting the supply of cholesterol to the tissues. Furthermore, I predict that it will eventually be shown that the depletion of cholesterol supply to the plaque caused by statin drugs leads to heart failure down the road, due directly to the cholesterol deficiency brought on by the statin drug.

How can my bold claim possibly be true? Below, I will examine several of these alleged off-label benefits, and show how statin drugs have been able to systematically play a devious game that results in stealing credit from cholesterol and falsely giving it to themselves.

Cancer

It is not easily shown that statins increase risk to cancer, because it takes considerable time for cholesterol to become depleted in the tissues as the supply line to replenish worn out cholesterol is reduced, and then more time for this depletion to lead to cancer due to genetic mutations. However, low cholesterol is a risk marker for cancer [15], and, despite the fact that statin trials are usually too short to reveal the trend towards increased cancer risk, several statin trials have resulted in observable differences between treatment and control groups, with treatment groups faring worse. In the first two trials on simvastatin, non-melanoma skin cancer was more prevalent in the treatment group, a result that becomes statistically significant if the data from the two trials are combined. In the CARE trial, which involved exclusively women, 12 women in the treatment group developed breast cancer, as against only one in the control group, a result that was highly significant (p = 0.002). Two other trials, both PROSPER and SEAS, also showed statistically significant increases in cancer incidence in the treatment group compared to the control group.

The story, in my view, for how statins increase your risk to cancer, involves a number of players and some complexity regarding mechanism. But it’s a very logical step-by-step progression, taking place steadily over an extended period of time. To understand the story, you first have to know something about vitamin B12 (cobalamin), a key player in the story. Vitamin B12 catalyzes a great number of reactions that require methionine, an essential sulfur-containing amino acid, as substrate, extracting the methyl group from methionine and adding it to some other molecule. One of the key molecules that benefits from such reactions is DNA. Methylation of DNA protects it from damage due to exposure to carcinogens or oxidation or radiation.

Methionine can also be degraded via a different pathway, and it’s an either-or situation here. This alternative fate results in the production of homocysteine, which later becomes substrate for the synthesis of sulfate. So, logically, if sulfate is in short supply, then methionine would get side-tracked down the homocysteine pathway, and less of the DNA would get methylated. Eventually, this would manifest as an increased risk to cancer.

Why might sulfate supply be deficient? This is something I have already discussed in previous blog posts, and one way it could happen is if the cells in the epidermis didn’t have enough cholesterol. This is because they need cholesterol in order to produce cholesterol sulfate, upon exposure to sunlight. The cholesterol sulfate is then shipped out via the blood stream to all the tissues, which eagerly take it up to resupply themselves with both cholesterol and sulfate.

The cells in the skin can synthesize their own cholesterol, but statin therapy would interfere with this process. As a result, they would not be able to spare cholesterol to ship out. What happens first is that, due to cholesterol deficiency in their membranes, they start leaking potassium at an excess rate, and an energy burn they can’t afford ensues, to pump the potassium back in. This becomes untenable, so calcium is brought in to replace some of the potassium as a positively charged electrolyte. Being a much bigger molecule, calcium doesn’t leak out nearly so easily. Its presence has a dramatic effect, however, on the eNOS molecules that had been responsible for synthesizing sulfate. They detach from the cell membrane and start making nitric oxide (−→ nitrate) instead. Unfortunately, this also results in some nasty side products like peroxynitrite and superoxide, which are potent oxidizing agents.

One of the first molecules that gets oxidized is cobalamin [1]. This drives the cobalt atom in cobalamin to a +3 charge, which inactivates the molecule, meaning that it will no longer support the methylation of the vulnerable DNA, thus increasing the risk to cancer. This is interesting from a biological standpoint, because it means that the methionine will naturally shift towards producing sulfate, a good idea since the skin is no longer going to be able to keep up with the supply.

One of the other molecules whose synthesis is catalyzed by cobalalmin is coenzyme Q10, probably the most important antioxidant in the mitochondria. The mitochondria are the chambers where sugars and fats are oxidized to produce ATP, the energy currency of the cell. Mitochondria are the organelles in the cell that suffer the greatest exposure to oxidizing agents, because oxidative metabolism takes place there. They contain their own separate mitochondrial DNA, now highly vunerable to attack.

To add insult onto injury, statins also interfere with the synthesis of coenzyme Q10, so this potent antioxidant is now in very short supply in the mitochondria of any cell in the skin that has been hit hard by a statin drug. The cells in the skin are now poised to develop cancer: they’ve got an extra burden of oxidizing agents, an increased vulnerability in their DNA to susceptibility to damage due to the demethylation process, and a decrease in the agents that would mop up extra free radicals. It’s not at all surprising that skin cancer is where the increased risk to cancer with statin therapy was first noted.

Another cancer which I suspect is increasing in incidence directly due to statin therapy is prostate cancer, which is the most common cancer by far in men. A very interesting recently noted observation is that prostate cancer tumors actually are producers of cholesterol sulfate! [3]. It has been suggested that this feature might be useful as a more reliable indicator of prostate cancer than the PSA test. I suspect in fact that this is a positive role they play, to try to correct a severe deficiency in this vital molecule, as cholesterol sulfate plays an essential role in fertilization [6]. Unlike women, men normally remain fertile throughout life, but not if cholesterol sulfate is insufficient. I would predict that surgery to remove a prostate tumor, beyond rendering a man infertile, will lead to an increase in various medical problems related to cholesterol sulfate deficiency.

Infection

Population-based observational studies have suggested that statins may reduce the risk to infection and improve recovery following infection. I find this idea astonishing, because there are numerous ways in which cholesterol protects from infection, so the reverse should actually be true. Very recently, articles have begun to appear that have questioned this benefit. A meta study looking at the results of several placebo-controlled studies relating statins to infection showed no benefit [22]. So, once again, the benefit goes away when the study is done properly.

Beatrice Golomb, a professor at UC San Diego, argues that the idea that statins protect from infection is likely to be completely spurious, being mainly attributable to what has been called the “healthy user” effect – people who take statins are also more conscientious about their health, by exercising, losing weight, eating healthier foods, and quitting smoking [5]. More than this, Golomb also argues for publication bias, where studies that come out favorably towards statins get published, and the ones that don’t don’t. For example, only 11 of 632 statin trials were included in the meta analysis that showed no benefit for statins in infection [22]. Tellingly, none of the other trials provided data on infection, which could well be because those data would show statins in a bad light. I think another important factor is that people who take statins have had high serum cholesterol for a long time prior to taking the statins, and therefore their tissues are, ironically, better supplied with cholesterol, at least in the short term. Of course the statins are steadily eroding this benefit.

A study trying to determine how statins might protect against infection discovered a remarkable effect of statins on macrophages and on phagocytes [2]. Phagocytes are the immune cells that are supposed to engulf bacteria and subsequently kill them, a process referred to as phagocytosis. Statins had a bizarre effect on both macrophages and phagocytes, which was to turn them into suicide bombers: instead of ingesting bacteria, they intentionally kill themselves (apoptosis), simultaneously releasing a potent toxin called “extracellular trap,” intended to do harm to the bacteria. Contrary to the idea that statins might increase the activity of the standard immune reaction, it was found that statins reduced both oxidative burst and phagocytosis. All of these effects were found to be due directly to statins’ ability to reduce the bioavailability of cholesterol.

Due to their interference with an early step in the mevalonate pathway, statins wreck a great number of pathways in the cell. One of the affected signaling pathways is the activation of NF-kβ, normally happening in macrophages (immune response white blood cells) in response to exposure to toxins from pathogenic bacteria. As a consequence of the production of NF-kβ, macrophages synthesize inducible nitric oxide synthase (iNOS), resulting in the production of a burst of nitric oxide, which is toxic to the invading bacteria. Experiments have demonstrated conclusively that statins weaken this immune response of macrophages to endotoxin [11], and this effect is explained as being due to their inhibition of the synthesis of farnesyl pyrophosphate, a mevalonate metabolite that plays a critical role in cell signaling.

Now I would like to take a look at the science behind how cholesterol protects from infection, and what effect that might have. Let’s start with the skin, an important interface with the world where bacteria might gain entry. A case-control study has shown that statin users are more susceptible to bacterial infection through the skin [7]. A key protein in the skin that keeps bacteria out is filaggrin, which maintains a healthy epithelial barrier [14]. The synthesis of its precursor, profilaggrin, is catalyzed by cholesterol sulfate [8]. Since statins interfere with cholesterol production in the skin, they would deplete the cholesterol sulfate supply, which would then interfere with the maintenance of filaggrin, and bacteria would more readily gain entry.

Once bacteria have managed to gain entry into the blood stream, they need to break through an individual cell’s defenses in order to actually infect the cell. Here, the presence of sulfate anions in the extracellular matrix proteins of the cell affords an invisible shield, due to the negative charge field that now surrounds the cell. The bacteria have a similar negative charge field, and so the two negatively charged “particles” will repel one another. If the cell becomes depleted in sulfate, it will become easier for bacteria to gain entry. Since the major supplier of the sulfate is cholesterol sulfate, produce by cells in the skin, by red blood cells and platelets, and by endothelial cells lining the artery walls, suppressed cholesterol synthesis induced by statin therapy will render the cells more susceptible to infection by the bacteria that gained entry due to the imapired skin barrier, also attributed to cholesterol deficiency.

Finally, LDL, the lipid particle whose serum concentration dramatically drops with statin therapy, is a powerful antibacterial agent. LDL has been shown to bind to the endotoxin (lipopolysaccharide) produced by pathogenic microbes and literally deliver it to the macrophages, so that they can properly dispose of it. Mice that have been engineered to have low levels of apoB, the signature apolipoprotein of LDL, are more susceptible to infection by Staph aureus, the microbe responsible for the MRSA epidemics now taking place in hospitals throughout the Western world [12]. In fact, it has been suggested that increased statin use may be a factor in the rapid increase in meth resistant Staph infections [4, 17].

Alzheimer’s Disease

The way the numbers game has been played in Alzheimer’s disease is a great example of how the truth can be hidden from view without actually falsifying the data. Luckily, one group not beholden to the statin industry decided to look at the numbers in a slightly different way, and that is how it becomes clear what is really going on.

Several studies have shown that, if you look at people currently taking statins and those not currently taking statins, the ones taking statins have a slightly reduced incidence of Alzheimer’s disease. Such observational studies were the basis for exalted claims that statins might protect from Alzheimer’s, such as this 2003 Newsweek article.

At face value, this result seems compelling, but you have to remember that people taking statins have enjoyed elevated cholesterol levels for much of their life, and this may be the true source of their reduced Alzheimer’s risk. Much has been made of a study that showed that elevated cholesterol levels in midlife lead to increased Alzheimer’s risk three decades later [19], but this study explicitly stated that they did not have access to information on whether their subjects were taking statins in the intervening years. You can be sure that if it had shown statins in a favorable light, they would have been granted access to those data. In fact, what has become clear is that it’s a drop in cholesterol levels that increases risk, to Alzheimer’s disease, and I think that drop is likely due to statin therapy.

In the study I alluded to earlier that looked at the data in a slightly different way, the researchers first showed, as have others, that that there were proportionately fewer cases of Alzheimer’s among people currently tkaing statins, compared to those who were not [16]. But then they took the group who were not, and asked them the simple question: “Have you ever taken a statin drug?” Turns out that the ones who answered “yes” to this question were two and a half times as likely to have Alzheimer’s, compared to those who said “No.” The easy answer is that the doctor takes you off the statin when you first complain of memory problems, a known side effect of statin drugs. This puts you on the other side of the fence. It’s not that statins protect from Alzheimer’s, but rather that Alzheimer’s protects from statins.

There’s a consistent pattern with these claims that statins protect from some condition – early observational studies seem to show that statins help, and this idea is widely publicized, but then later placebo cotrolled studies get a contradicting result, and this result is buried. The placebo controlled studies are the only ones that count, because people are chosen randomly to receive drug or placebo, and you don’t run up against biases due to other factors such as the “healthy user” effect that distinguish the two populations being observed. A randomized placebo-controlled study funded by Pfizer [18] showed not only that statins did not slow the decline of Alzheimer’s patients, but that the patients on statins actually showed more mental decline than the ones not on statins. The results were not statistically significant, but, on the other hand, any patients whose caretaker decided to take them out of the trial prematurely were left out of the data. These people were likely declining even faster than the ones who stayed in the trial.

In a study comparing cholesterol levels among patients with Alzheimer’s disease (AD) and healthy controls, the authors wrote [13], p. 117: “Serum cholesterol, LDL-C , and HDL-C levels were significantly lower in all patients with AD than in healthy subjects... Patients in the late stage of disease had significantly lower cholesterol, HDL-C, LDL-C and TG levels than healthy controls and significantly lower cholesterol and LDL-C levels than patients in the middle stage of disease.” In other words, healthy people had more cholesterol than Alzheimer’s patients, and late-stage Alzheimer’s patients had lower cholesterol than early stage patients. This observation flies in the face of the argument that lowering cholesterol with statin drugs would improve your odds against developing Alzheimer’s disease.

References

[1] M Brouwer, W Chamulitrat, G Ferruzzi, DL Sauls and JB Weinberg “Nitric oxide interactions with cobalamins: biochemical and functional consequences,” Blood 88: 1857-1864, 1996.

[2] O.A. Chow, M. von Köckritz-Blickwede, A.T. Bright, M.E. Hensler, A.S. Zinkernagel, A.L. Cogen, R.L. Gallo, M. Monestier, Y. Wang, C.K. Glass and V. Nizet, “Statins Enhance Formation of Phagocyte Extracellular Traps,” Cell Host and Microbe 8:445454, Nov. 18, 2010.

[3] L.S. Eberlin, A.L. Dill, A.B. Costa, D.R. Ifa, L. Cheng, T. Masterson, M. Koch, T.L. Ratliff and R.G. Cooks, “Cholesterol Sulfate Imaging in Human Prostate Cancer Tissue by Desorption Electrospray Ionization Mass Spectrometry,” Anal Chem. 82:9, 34303434. May 1, 2010.

[4] M.R. Goldstein, L. Mascitelli and F. Pezzetta, “Methicillin-resistant Staphylococcus aureus: A link to statin therapy?” Cleveland Clinic Journal of Medicine 75:5 Letter to the Editor, May 2008.

[5] B.A. Golomb, “Do statins reduce the risk of infection? Observational evidence of a benefit is now refuted by randomised trials,” BMJ, Nov. 29, 2011.

[6] C. Iribarren, D.R. Jacobs, Jr, S. Sidney, A.J. Claxton Gross, M. Sadler and H. Blackburn, “Serum total cholesterol and risk of hospitalization, and death from respiratory disease.” Int J Epidemiol 26:11911202, 1997.

[7] J.Langlais, M. Zollinger, L. Plante, A. Chapdelaine, G. Bleau and K.D. Roberts, Biochemistry 78:12, 7266-7270, Dec. 1981 Localization of cholesteryl sulfate in human spermatozoa in support of a hypothesis for the mechanism of capacitation

[8] A.P. Liappis, V.L. Kan, C.G. Rochester and G.L. Simon, “The effect of statins on mortality in patients with bacteremia,” Clin Infect Dis 33:13521357, 2001.

[9] H. Nakae, O. Hanyu, H. Fuda and C.A. Strott, “Novel role of cholesterol sulfate in gene regulation during skin development,” The FASEB Journal 22:782.2, March, 2008.

[10] T. Neale, Senior Staff Writer, “Statins May Protect Against Flu-Related Death,” MedPage Today, Dec. 14, 2011; http://www.medpagetoday.com/InfectiousDisease/URItheFlu/30214

[11] D. Noonan, “You Want Statins With That?” Newsweek, Jul 27, 2003; http://www.thedailybeast.com/newsweek/2003/07/27/you-want-statins-with-that.html

[12] K. Pahan, F.G. Sheikh, A.M.S. Namboodiri, and I. Singh, “Lovastatin and Phenylacetate Inhibit the Induction of Nitric Oxide Synthase and Cytokines in Rat Primary Astrocytes, Microglia, and Macrophages,” J. Clin. Invest. 100:11, 26712679, Dec. 1997.

[13] M. M. Peterson, J.L. Mack and P.R. Hall, A.A. Alsup, S.M. Alexander, E.K. Sully, Y. S. Sawires, A.L. Cheung, M. Otto, and H.D. Gresham, “Apolipoprotein B is an Innate Barrier Against Invasive Staphylococcus aureus Infection” Cell Host Microbe.4(6): 555566, Dec. 11 2008.

[14] P. Presecki, D. Mück-Seler, N. Mimica, N. Pivac, M. Mustapic, T. Stipcevic and V. Folnegovic Smalc, “Serum Lipid Levels in Patients with Alzheimers Disease,” Coll. Antropol. 35 (2011) Suppl. 1: 115120

[15] R.B. Presland, “Function of Filaggrin and Caspase-14 in Formation and Maintenance of the Epithelial Barrier,” Dermatol Sinica, 1-14, 2009.

[16] U. Ravnskov, K.S. McCully and P.J. Rosch, “The statin-low cholesterol-cancer conundrum,” QJMed, Advance Access published December 8, 2011.

[17] T.D. Rea, J.C. Breitner, B.M. Psaty, A.L. Fitzpatrick, O.L. Lopez, A.B. Newman, W.R. Hazzard, P.P. Zandi, G.L. Burke, C.G. Lyketsos, C. Bernick and L.H. Kuller, “Statin Use and the Risk of Incident Dementia: The Cardiovascular Health Study,” Arch Neurol 62:1047-1051. Jul 2005.

[18] S.J. Rehm, “Staphylococcus aureus: the new adventures of a legendary pathogen,” Cleve Clin J Med 2008; 75:177192.

[19] M. Sano, K.L. Bell, D. Galasko, J.E. Galvin, R.G. Thomas, C.H. van Dyck, et al. “A randomised, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease,” Neurology 77:55663, 2011.

[20] A. Solomon, M. Kivipelto, B. Wolozin, J. Zhou, and R.A. Whitmer, “Midlife Serum Cholesterol and Increased Risk of Alzheimer’s and Vascular Dementia Three Decades Later,”Dementia and Geriatric Cognitive Disorders 28, 75-80, 2009.

[21] C.S. Valente Barbas and L.B. Kawano-Dourado, “What is the real role of statins in community-acquired pneumonia and sepsis?” Crit Care Med 2011 39: 8, 1998-1999.

[22] H.L. van den Hoek, W.J. W. Bos, A. de Boer and E.M.W. van de Garde, “Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials,” BMJ, Nov. 29, 2011.

[23] M.L. Vandermeer, A.R. Thomas, L. Kamimoto, A. Reingold, K. gershman et al., “Association Between Use of Statins and Mortality Among Patients Hospitalized With Laboratory-Confirmed Influenza Virus Infections: A Multistate Study,” J Infect Dis. 2011.

[24] R.F. Wilson, J.F. Barletta and J.G. Tyburski, “Hypocholesterolemia in Sepsis and Critically Ill or Injured Patients,” Critical Care 7:413-414, 2003.

[25] S. Yende, E.B. Milbrandt, J.A. Kellum, L. Kong, R.L. Delude, L.A. Weissfeld and D.C. Angus, “Understanding the potential role of statins in pneumonia and sepsis,” Crit Care Med 2011 39:8, 1871-1878.