Thursday, December 15, 2011

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.


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.


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.


[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;

[11] D. Noonan, “You Want Statins With That?” Newsweek, Jul 27, 2003;

[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.

Sunday, October 30, 2011

Do Statins Destroy Red Blood Cells?

Although statin drugs, otherwise known as HMG-coenzyme A reductase inhibitors, are very effective in reducing the serum levels of LDL, the so-called “bad” cholesterol, it is not clear that this is the reason why they reduce the incidence of heart attacks. Over the last decade or so, there has developed among the research community a strong opinion that statins prevent heart attacks via a so-called pleiotrophic effect unrelated to their ability to reduce serum LDL [7]. Recently, the idea that this pleiotrophic effect is tied to statins’ observed ability to increase the production of nitric oxide by endothelial cells lining the artery walls has gained considerable traction [1, 12, 14]. It’s been argued that nitric oxide has a lot of benefits in terms of relaxing the artery wall, as well as anti-proliferative and anti-migratory properties, which are considered to be protective features in cardiovascular disease in vessels [4].

Armed with this knowledge, I became interested in finding other examples from the literature of mechanisms that increase the production of nitric oxide. I stumbled upon an article on a rare disease called paroxysmal nocturnal hemoglobinurea (PNH) [13], first described in the literature in 1986 [8], only a few years after statins began to be widely prescribed.

This condition immediately caught my attention, because the health issues associated with it fit well with a set of side effects I had learned were associated with statins, such as difficulty swallowing, abdominal pain, and erectile dysfunction. Furthermore, the condition is caused by a genetic defect in a protein called PIG-A [2], which is essential to orchestrate glycosylphosphatidylinositol (GPI)-anchoring of proteins to cell membranes. Statins also interfere with GPI-anchoring, directly through their obstruction of the mevalonate pathway, by inhibiting the synthesis of isoprenoids, which, in turn, are essential for the GPI-mediated membrane attachment of signaling molecules like Rho GTPases [12].

PNH results in two major direct effects, one related to red blood cells (RBCs) and the other to platelets. The RBCs depend on the impaired protein to protect them from hemolysis – a breaking apart of their membrane and a spilling of their contents into the blood stream. Platelets depend on the same protein to protect them from forming blood clots.

RBCs have an important role and a difficult job in transporting a highly toxic element – oxygen – to all the tissues. Once they’ve picked up oxygen, the resulting oxyhemoglobin is a strong oxidizing agent. It is therefore very important that RBCs sequester hemoglobin within their walls to protect blood proteins and fats from oxidative damage. RBCs ordinarily produce an abundance of coenzyme Q10 (ubiquinone) to protect their own membrane from oxidation damage, and statins interfere with the production of coenzyme Q10 [11]. The genetic disease, sickle cell anemia, is associated with an excess of oxidizing agents in the blood and therefore the sickled RBCs maintain far more coenzyme Q10 than normal RBCs [9]. Statins’ known ability to deplete the supply of Coenzyme Q10 would result in excess oxidation damage to RBC membranes, which would further increase their vulnerability to hemolysis. This may mean that blacks, who have a much higher incidence of sickle cell anemia (due to the protection it affords against malaria), may also have a greater susceptibility to statin side effects.

What does all of this have to do with nitric oxide? It turns out that hemoglobin is an avid scavenger of nitric oxide – it binds strongly to the gas and disables its ability to signal arterial relaxation. Furthermore, RBCs contain a protein, L-arginase, that actively degrades the substrate for NO synthesis, L-arginine. As a consequence of hemoglobin and L-arginine now roaming freely in the blood stream, spilled out from the destroyed RBCs, there will be severe arterial constriction unless the endothelial cells greatly increase their production of nitric oxide. The mechanism is mediated by the protein erythropoietin (epo) which both stimulates the production of replacement RBCs from stem cells in the bone marrow and acts as a signaling agent to induce NO production in the artery wall [5]. So I would like to suggest that statins increase the production of nitric oxide as a compensatory mechanism to its active destruction by hemoglobin and its reduced substrate supply due to L-arginase.

I also found a series of articles on a fascinating breed of genetically engineered mice, which produce excessive human epo and therefore have too many RBCs in their blood serum [15, 10, 5]. These mice also dramatically overproduce NO. They don’t fare well, however; they develop paralysis in their hind legs and die young.

Statin drugs also interfere with mobility – many of the web side effect reports written by people who have taken statin drugs talk about muscle weakness, difficulty walking, and decreased mobility. These phrases all came up as highly significantly over-represented in statin reviews compared to age-matched reviews in our studies on statin side effects. Comparing the collective count of a number of phrases associated with “difficulty walking” in reviews on statin drugs vs other drugs yielded a skewed distribution with a p-value less than 0.0005.

Another indicator that I am on the right track with this idea comes from the observation that statins induce an increased synthesis of heme oyygenase in macrophages [3]. Macrophages typically produce heme oxygenase in order to break down hemoglobin into bilirubin and carbon monoxide, thus detoxifying the hemoglobin. So this is a strong indication that statins induce excess free hemoglobin in the blood, with the most plausible source being wrecked RBCs. The macrophages in atherosclerotic plaque have been shown to avidly take up hemoglobin and break it down with heme oxygenase, with the resulting accumulation of iron deposits in the plaque. It is believed that this iron is a significant contributor to the inflammatory processes in the plaque [6].

The really disturbing part of this story for me is the link between PNH and deep vein thrombosis – half of the deaths associated with PNH are due to venous thrombosis [13]. We have been hearing a lot more lately about deep vein thrombosis, with a warning issued regarding long airplane rides and massive prescriptions of blood thinners like Coumadin (i.e., rat poison!) to attempt to avert it. In PNS, deep vein thromobosis is a consequence of the platelets’ increased potential to form blood clots, due to the defect in GPI-anchoring of proteins, and I suspect that the leg paralysis in the mice is a consequence of suppressed circulation in the legs due to the excess risk of thrombosis. Might statin therapy be a direct contributor to the increased incidence of this highly critical condition?

PNH also leads to pulmonary hypertension, which in turn leads to increased risk to heart failure. This is hypothesized to be a direct consequence of the scavenging of nitric oxide by hemoglobin, which then induces increased pressure in the blood vessels supplying the lungs, putting excess strain on the heart [13]. It’s another one of those biological cascades that makes sense in that oxygen supply needs to be suppressed when there is so much free hemoglobin, because the hemoglobin is far more destructive to cell membranes and proteins when it is oxidized. Our studies showed a significant (p<0.05) increased risk to heart failure associated with statin therapy. Whether this occurs directly due to the depletion of coenzyme Q10 and cholesterol in the heart muscle, or indirectly due to the cascade from erupted RBCs to artery constriction in the lungs to inadequate oxygen supply to the heart is anybody’s guess. I suspect both paths contribute.

So now we must go back to the question of the pleiotrophic effect of statins that results in a reduced incidence of heart attacks. Experts are in agreement that statins don’t actually reduce the plaque, despite the fact that they interfere with the supply of cholesterol and fat. I don’t personally believe that nitric oxide synthesis is the right answer, as it would be more than cancelled out by the scavenging of NO by free hemoglobin. My own best guess at the moment is that statins interfere with the cells’ communication lines directly through their disruption of G-protein signaling mechanisms. I believe the consequence is that the little heart attacks don’t happen, because the cells can’t orchestrate a coordinated plan. As a result, the big heart attacks are more deadly. This idea is analogus to the consequences of preventing the small forest fires and watching the large ones rage out of control. Another analogy is with earthquakes – when the little ones don’t happen, the pressure builds up and the big one is highly destructive. This would explain why statins don’t consistently show improvement in mortality rates due to cardiovascular disease, despite their significant reduction in the frequency of heart attacks.


[1] P. Balakumar, S. Kathuria, G. Taneja, Sanjeev Kalra, and Nanjaian Mahadevan, “Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins?” Journal of Molecular and Cellular Cardiology, To Appear, 2011.

[2] M. Bessler, P.J. Mason, P. Hillmen, T. Miyata, N. Yamada, J. Takeda, L. Luzzatto and T. Kinoshita, “Paroxysmal nocturnal haemoglobinuria (PNH) is caused by somatic mutations in the PIG-A gene,” The EMBO Journal 13(1):110-117, 1994.

[3] F. Gueler, J-K Park, S. Rong, T. Kirsch, C. Lindschau, W. Zheng, M. Elger, A. Fiebeler, D. Fliser, F.C. Luft, and H. Haller, “Statins Attenuate Ischemia-Reperfusion Injury by Inducing Heme Oxygenase-1 in Infiltrating Macrophages,” The American Journal of Pathology, 170(4):1192-1199, Apr. 2007.

[4] D.G. Harrison, “Endothelial control of vasomotion and nitric oxide production a potential target for risk factor management,” Cardiol Clin 14:115, 1996.

[5] K. Heinicke, O. Baum, O.O. Ogunshola, J. Vogel, T. Stallmach, D.P. Wolfer, S. Keller, K. Weber, P.D. Wagner, M. Gassmann and V. Djonov, “Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration,” Am J Physiol Regul Integr Comp Physiol 291:R947-R956, 2006.

[6] W. Li, L.H. Xu, and X.M. Yuan, “Macrophage hemoglobin scavenger receptor and ferritin accumulation in human atherosclerotic lesions,” Ann N Y Acad Sci. 1030, 196-201, Dec 2004.

[7] James K. Liao, and Ulrich Laufs “Pleiotropic Effects of Statins,” Annual Review of Pharmacology and Toxicology 45: 89-118, 2005.

[8] J.T. McCarthy, B.A. Staats, “Pulmonary hypertension, hemolytic anemia, and renal failure: a mitomycin-associated syndrome,” Chest, 89:608-611, 1986.

[9] P. Niklowitz, T. Menke, T. Wiesel, E. Mayatepek, J. Zschocke, J.G. Okun , and W. Andler, “Coenzyme Q10 in plasma and erythrocytes: comparison of antioxidant levels in healthy probands after oral supplementation and in patients suffering from sickle cell anemia,” Clin Chim Acta. 326(1-2):155-61, Dec. 2002.

[10] O.O. Ogunshola, V. Djonov, R. Staudt, J. Vogel, and M. Grassmann, “Chronic excess erythrocytosis induces endothelial activation and damage in mouse brain,” Am J Physiol Regul Integr Comp Physiol 290: R678-R684, 2006.

[11] G. de Pinieux, P. Chariot, M. Ammi-Said, F. Louarn, J.L. LeJonc, A. Astier, B. Jacotot, and R. Gherardi, “Lipid-lowering drugs and mitochondrial function: effects of HMG-CoA reducase inhibitors on serum ubiquinone and blood lactate/pyruvate ratios.” Br. J. Clin. Pharmacol. 42: 333-337, 1996.

[12] Yoshiyuki Rikitake, James K. Liao, “Rho GTPases, Statins, and Nitric Oxide,” Circulation Research 97:1232-1235, 2005.

[13] R.P. Rother, L. Bell, P. Hillmen, and M.T. Gladwin, “The Clinical Sequelae of Intravascular Hemolysis and Extracellular Plasma Hemoglobin: A Novel Mechanism of Human Disease,” JAMA, 293(13): 1653-1662, Apr 6, 2005.

[14] M. Sata, H. Nishimatsu, E. Suzuki, S. Sugiura, M. Yoshizumi, Y. Ouchi, Y. Hirata, and R. Nagai, “Endothelial nitric oxide synthase is essential for the HMG-CoA reductase inhibitor cerivastatin to promote collateral growth in response to ischemia.” The FASEB Journal 15(13):2530-2532, Nov 1, 2001.

[15] C. Wiessner, P.R. Allegrini, D. Ekatodramis, U.R. Jewell, T. Stallmach, and M. Gassmann, “Increased Cerebral Infarct Volumes in Polyglobulic Mice Overexpressing Erythropoietin,” J Cereb Blood Flow Metab, 21(7):857-864, 2001.

Monday, September 19, 2011

Is it Time to Reevaluate Vaccination Policy in America?

Up until a few months ago, I held the majority view that a well maintained vaccination program is one of the hallmarks of a highly developed country. The U.S. leads the world with 24 requiredk vaccinations before the end of the baby’s first year: DTaP (3), polio (3), Hib Titer (3), hepatitis B (3), pneumonia (3), rotavirus (3) and influenza (2). We don’t however lead the world in infant mortality rates. Thirty three countries have lower infant mortality rates than we do, and there is a highly significant linear relationship (p < 0.0001) between infant mortality rates and the number of vaccine doses routinely given to infants [1]. Counterintuitively, nations that require more vaccines have higher infant mortality rates.

The autism community has long held the view that vaccines are contributing to their children’s autism. This is something that the vaccine industry vigourously denies. However, the incidence of autism is sharply on the rise over the last decade, and there are now several research articles pointing to a clear correlation between vaccination rates and autism [2, 3]. A 2011 article compared vaccination compliance records from the 50 states in the U.S., and found that a 1% increase in vaccination rates was associated on average with an additional 680 children having autism or speech and language delay in that state [4].

One might argue that, even if it’s true that vaccines cause autism, the price is still worth it – the childhood diseases that these vaccines protect from also carry a significant risk of permanent damage or even death. But supposing it’s also the case that vaccines are the major contributor to the alarming increases we’ve recently seen in food allergies [5], in asthma [6], in sudden infant death syndrome (SIDS) [7], and even in the E. coli epidemics? What if vaccines are a major contributor, not only to autism, but also to attention deficit hyperactivity disorder (ADHD), depression, manic depression, schizophrenia and Alzheimer’s disease? Would it still be worth it? What exactly is the cost to society of preventing the inconvenience of a childhood illness like chicken pox or measles that used to be a right of passage?

My recent studies have led me to believe that we have all been duped by the vaccine industry for a very long time. While Americans for the most part never even question the merit of a vaccination program, population studies have led some experts to argue that diseases can be kept in check more effectively by simply providing clean sanitation and better nutrition. It is not fair that the vaccine industry is not required to prove that its product is “effective.” Fear tactics are enough to convince most people that vaccination is absolutely necessary; that dire consequences would follow if we suddenly terminated the vaccination program.

This quote from the Natural News site’s Mike Adams aptly sums up the dismal situation we all face, with a wry sense of humor [8]:
(Mike Adams on MMR) : ”In layman’s terms, this is what’s known as a ‘scientific circle jerk’ where one group of bought-off scientists quotes another group of bought-off scientists as ‘authorities’ even though they all parrot the same medical quackery of their masters – the pharmaceutical companies.” Mike Adams was referring to the just-released Institute of Medicine (IoM) report which once again declares that the MMR (measles, mumps and rubella) vaccine is not linked to autism. Mike Adams begs to differ, and offers substantial support for his opinion drawn directly from the IOM report itself.

I am going to focus on Gardasil, the ”new kid on the block” in the vaccine arsenal. The story of the making and marketing of Gardasil is a triumph for both the National institutes of Health (NIH) and Merck, the company that brought the vaccine to market. Researchers at NIH, who patented their ideas and then handed them over to Merck for productization, have already gained enormous financial rewards, as well as formal recognition and high praise for their scholarly achievements.

The vaccine, touted as the first “anti-cancer” vaccine, immunizes against HPV (human papillary virus). The vaccine was rushed through the FDA approval process, and heralded as a magnificent example of what can be accomplished when government and industry work together towards a common, lucrative, goal. Heavy advertising was directed at the general public, priming them to be receptive when the vaccine became available. The governor of Texas, Rick Perry, wasted no time making it mandatory for preteen girls in his state. Mothers are lining up to get their 11 year old daughters vaccinated, hoping to give them one less thing to worry about health-wise in the future. California is even putting into law a bill called AB 499 [9], which would waive parental consent: young girls can make the decision for themselves whether they want to be vaccinated against HPV.

But the fairy tale is beginning to turn into a nightmare. A number of girls in the prime of their life, following a Gardasil vaccine, turned up dead from extremely rare conditions for their age group, like heart failure, deep vein thrombosis, and ALS (Lou Gehrig’s disease).

Mark Blaxill, who manages the “Age of Autism” web site, has written an astonishing 3-part article [10] detailing the dirty secrets behind Gardasil, and the much larger story of how the government, the media, and the drug companies have established an incredibly profitable revolving door arrangement that makes sure that only the public at large loses out. What amazes me most is the naivety of both the general public and the medical practioners, and their unfounded faith in the idea that vaccines are safe and effective, given the obviously huge confict-of-interest problems in the vaccine approval process. In the second installment of his article, Blaxill points out the audacity that the industry exhibits in designing severely flawed safety trials and getting by with it. A glaring loophole is that the so-called “placebo” administered to the control group does not have to be inert, and often the details of the contents of the placebo are not even revealed to the public, or are kept hidden in a terse description on page 303 of a long and wordy document. But Blaxill was able to discover that the placebo used in four out of five Gardasil trialscontained aluminum, as did the vaccine itself. And in these same fourtrials, the placebo group had many more adverse reactions than the one placebo group without the aluminum. Since Gardasil had only slightly more adverse reactions than the “placebo,” it was considered safe. Left unstated was the fact that the placebo itself was unsafe.

One admirable move that the U.S. government has done is to make the reports of vaccine adverse reactions available to the public for automatic download from the Web. The U.S. Centers for Disease Control have posted a large database of adverse events related to vaccines dating back to 1990, and I have downloaded this database and studied some of its characteristics [11]. It contains over 330,000 instances of recorded events, with information about which vaccine(s) were administered, the age of the person at the time, the symptoms encountered, relevant history, and whether death was an outcome.

I have thus been able to take a look for myself at Gardasil, comparing the frequency of various adverse reactions to the frequency observed in an age-matched control group of people receiving all other vaccines. It is mathematically very straightforward to use a log-likelihood ratio computation to determine the likelihood that a given count distribution could have occurred by chance [12].

Selected results we obtained, shown in Table 1 below, are astonishing. Some really severe reactions like seizure, loss of consciousness, and death, as well as a spontaneous abortion (miscarriage) for pregnant women obtaining the vaccine, are far more likely in the Gardasil data than in the random comparison set. Cynthia Janak, a freelance journalist, has produced a compellinganalysis of the dangers of Gardasil on the website, Renew America .

Table 1: Counts of the number of adverse events where the vaccine was Gardasil, compared to a sampled age-matched control set of events where the vaccine was not Gardasil, along with the associated p-value, indicating the likelihood that this distribution could have occurred by chance.
Seizure 538 150 0.00010
Loss of Consciousness 393 119 0.00046
Depression 109 11 0.0029
Fatigue 351 167 0.0042
Miscarriage 97 12 0.0044
Anxiety 170 56 0.0058
Asthma 142 49 0.0095
Death 35 7 0.040

She too points out the dangers of the aluminum in the vaccine, which contains 225 mcg of aluminum as amorphous aluminum hydroxyphosphate sulfate adjuvant. I was able to find several web pages providing detailed accounts of the ingredients in various vaccines, such as this one, and I then did a study on the VAERS data comparing all thealuminum-containing vaccines I could confidently identify with vaccines that don’t contain aluminum, i.e., generalizing the experiments with Gardasil to include additional data: males as well as females, and over a much broader age range, since the flu vaccine, administered typically to the elderly, contains aluminum. Several of the adverse reactions that are statistically significantly associated with Gardasil are also statistically significantly associated with the other aluminum-containing vaccines that I identified, namely, DTaP, Hepatitis A and B, PREVNAR, and ANTHRAX. Some of the most significant adverse reactions showing up in all aluminum-containing vaccines are shown in Table 2.

Table 2: Counts of the number of adverse events where the vaccine contains aluminum, compared to a sampled age-matched control set of events where the vaccine does not contain aluminum, along with the associated p-value, indicating the likelihood that this distribution could have occurred by chance.
Seizure 2965 2161 0.0009
Depression 231 85 0.0050
Fatigue 1435 745 0.00016
Death 464 284 0.012

It’s not as though it’s not known that aluminum is toxic to health. No known biological system makes use of aluminum for any purpose. People with end-stage kidney disease suffer from severe dementia after sufficient accumulation of aluminum in their brain, accidentally supplied to their blood stream from aluminum-containing water in the dialysis fluids [13]. If you ingest aluminum, only a quarter of a percent of it actually gets through the lining of the gut. But if you inject it in a vaccine, 100% goes directly into the blood stream.

You must be asking yourself at this point why on earth they’d be putting aluminum into vaccines in the first place. The vaccine industry is, quite frankly, caught between a rock and a hard place. Either they use live (weakened) pathogens in the vaccine (such as in MMR) or they use dead pathogens, but add some so-called ”adjuvants” to disrupt the immune response and make sure that the body will react sufficiently well for the vaccine to ”take.” With live pathogens, the vaccine can and does cause actual disease in susceptible individuals – it infects the person with the disease it’s trying to vaccinate against. But, with adjuvants like aluminum, you can get by with dead viruses, and you can get by with a lot fewer dead viruses in each vaccination, thus increasing the yield and saving money. However, and this is a huge consideration, the vaccine can add to an accumulated aluminum build-up in the brain, directly contributing to autism and Alzheimer’s disease.

It seems that the industry is well aware that they had better not combine both aluminum and live pathogen in the same vaccine, as the resulting adverse reactions would probably keep the vaccine from ever making it through safety trials. However, they don’t seem to mind injecting children with two vaccines simultaneously – one containing aluminum and the other containing live toxin. This is exactly the situation with DTaP and MMR, where DTaP contains aluminum and MMR contains live pathogens for measles, mumps and rubella. I suspect the combination wreaks havoc on the system of the immune-compromised child.

If you think that aluminum in vaccines is not a big deal, then you should read the paper called, simply, ”Aluminum Vaccine Adjuvants: Are they Safe?” by Tomljenovic and Shaw [14], which appeared just this year in the journal, Current Medicinal Chemistry. It is an eye-opener! They point out that the number of officially scheduled vaccines for U.S. children has increased sharply from 10 in the 1980s to 32 in the late 2000s, and that 18 of these vaccines contain aluminum adjuvants. Newborns in the U.S. and other developed countries receive 14.7 to 49 times more than the FDA safety limits for aluminum, just through their mandatory vaccines. They point out the very clear association between aluminum exposure and dementia in dialysis patients that I already mentioned earlier. In experiments with mice, injections of vaccine aluminum adjuvants showed up in the brain tissues a couple of days later, demonstrating that aluminum can cross the blood-brain barrier. Rabbits given aluminum phosphate experienced nerve degenration and neurofibrillary tangles similar to those that are characteristic of Alzheimer’s disease. Animals given dietary aluminum routinely show learning and memory deficits, along with confusion and repetitive behaviors, similar to those in autism. This is despite the fact that dietary aluminum is so poorly absorbed through the gut. These authors also reference several articles where vaccine safety tests were conducted by doping the so-called placebo with aluminum, sometimes in amounts in excess of the amount in the vaccine itself.

Although aluminum is probably the biggest problem with vaccines, it is not the only problem. I came across a web page proposing that the egg and peanut allergies, currently affecting 1-2% of the U.S. population, might be caused by vaccines, and then I started to explore all the other foods that show up in vaccines, finding, to my astonishment, that every one I checked had extensive hits in a web search in association with allergies. I then came upon an article written by Barbara Feick Gregory , who had done a far more extensive search than I had done, confirming much more exhaustively what I had suspected. The reason that small amounts of food in vaccines cause an intense allergic reaction is that the body develops a memory of the food in association with the toxin that’s also in the vaccine. The body is fooled into believing that the egg that the flu vaccine pathogen is grown in is somehow part of a strange new species, and it develops a response to the egg as well as, or perhaps even instead of, to the flu virus.

So this then explains the adverse reaction report #403192, which described the child’s reaction as follows: “Large welts and extreme itching in skin from the waist down, which are the typical reaction that he receives when he eats eggs.” This report concerned a5-year-old autistic child’s reaction to a flu shot. It was surely an earlier vaccine that had primed him for this kind of reaction. It’s surprising how many foods besides eggs and peanut oil show up in vaccines, including gelatine, lactate, yeast, glycine (soy), and lectin (wheat). It’s possible that most of these are intentionally added precisely because they are substances to which the body can build an immune response – this may make them useful as adjuvants toincrease the likelihood of the creation of a permanent memory of the pathogen, i.e., a protective response.

The recent major E. coli epidemic in Europe has led me to wonder whether these E. coli epidemics might also be due directly to vaccination. E. coli epidemics were unheard of until vaccines started to be routinely administered. If the body can overreact to foods in vaccines, then it stands to reason that it might also overreact to E. coli infection as a consequence of previous exposure to E. coli membranes in vaccines. E. coli cell membrane fragments are in fact another substance that is often put into vaccines, as a well-known effective adjuvant. E. coli are essential bacteria in our guts, helping with digestion and generally not causing any trouble. But I can easily imagine that our bodies can be fooled into believing that certain strains are toxic if they’re injected directly into our blood stream thoroughly mixed in with some severely toxic pathogen. While I was unable to trace the strain that caused the recent European outbreak directly to a vaccine adjuvant, I did determine that several strains of E. coli have been added to vaccines for the sake of their adjuvant properties, including strains known as 0111, 0127, 026, 055, and F583 (Vaccine Adjuvants) . Several mentions of an outbreak related to strain 0111 can be found on the web, such as this one in Oklahoma .

In closing, I want to return to Gardasil, to mention yet another severely problematic aspect of this vaccine that has just become public knowledge. Recently, it has been discovered that Gardasil contains contaminants in the form of HPV recombinant DNA, even though the vaccine label states clearly that it does not. A young girl developed juvenile rheumatoid arthritis the day after she received her last Gardasil vaccination, and the vaccine batch she received was then analyzed for contaminants. The Milford Hospital pathology laboratorywhere the tests were conducted found the recombinant DNA, and then tested several other batches of the vaccine from around the world, finding the contaminant to be present in every batch they tested. Dr. Sin Hang Lee, a pathologist at the Milford Hospital laboratory, has this to say about recombinant HPV: “Based on medical literature and some of the FDA/Mercks own publications, adventitious(coming from an outside source) DNA in an injectable protein-based vaccine may increase the risk of autoimmune disorders and gene mutation which may lead to malignancies.” [15] So these are just some other health problems we can look forward to as we increase our bodies’ vaccine load.

It is long past the time when we should be taking a hard look at the American vaccination program, to rigorously assess the risks and benefits of vaccines in the same way that we routinely do for drugs. It may be expedient to simply trust the industry; to blindly believe that the down side of vaccination is more than adequately offset by the up side. But this is not good science. Canadians have walked down this new path already, as eidenced by a thoughtful and rational article discussing a risk/benefit analysis for Gardasil [16]. Vaccines are costing us a great deal more pain than we realize, and it’s time to take stock.


[1] N.Z. Miller and G.S. Goldman, “Infant mortality rates regressed against number of vaccine doses routinely given: Is there a biochemical or synergistic toxicity?” Human and Experimental Toxicology, published online 4 May, 2011.

[2] A.J. Wakefield, “MMR vaccination and autism,” The Lancet 354:9182 949-950, Sep 11 1999; doi:10.1016/S0140-6736(05)75696-8

[3] O.M. Gallagher and M.S. Goodman, “Hepatitis B vaccination of male neonates and autism diagnosis, NHIS 1997-2002,” J Toxicol Environ Health A. 73(24):1665-77, 2010.

[4] G. DeLong “A Positive Association Found Between Autism Prevalence and Childhood Vaccination Uptake across the U.S. Population,” Journal of Toxicology and Environmental Health, Part A, 74:903916, 2011; DOI: 10.1080/15287394.2011.573736.

[5] allergy.htm


[7] A.M. Walker, H. JICK, D.R. PERERA, R.S. Thompson, and T.A. KNAUSS, “Diphtheria-Tetanus-Pertussis Immunization and Sudden Infant Death Syndrome,” AJPH 77(8):945-951, Aug 1987.

[8] P.F. Louis, “BMJ had secret financial ties to Merck during publication of articles attacking Wakefield,” NaturalNews, Wednesday, September 07, 2011; BMJ financial ties.html


[10] Mark Blaxill, “Rick Perry and the Conflicts of Government Licensed Corporate Profit: Merck and Gardasil,” Age of Autism Web site:

[11] CDC. Surveillance for safety after immunization: Vaccine Adverse Events Reporting System (VAERS)United States, 19912001. MMWR Surveill Summ. 52:124, 2003.

[12] T. Dunning,”Accurate methods for the statistics of surprise and coincidence,” Computational Linguistics 19(1):6174, 1993.

[13] M.R. Wills and J. Savory, “Water Content of Aluminum, Dialysis Dementia, and Osteomalacia” Environmental Health Perspectives 63:141-147, 1985.

[14] L. Tomljenovic and C.A. Shaw, “Aluminum Vaccine Adjuvants: Are they Safe?” Current Medicinal Chemistry 18:2630-2637, 2011.

[15] L.C.Botha, “SANE Vax Inc. Discovers Potential Bio-hazard Contaminant in Mercks Gardasil HPV 4 Vaccine,”

[16] A. Lippman, R. Melnychuk, C. Shimmin and M. Boscoe, “Human papillomavirus, vaccines and womens health: questions and cautions,” CMAJ, 177(5):484-487, 2007.

Thursday, July 7, 2011

Is Autism Caused by Sulfate Deficiency and Excess Aluminum Exposure?

My best friend’s son was recently diagnosed with autism spectrum disorder, and this has inspired me to do some research on autism. Vast amounts have already been written on the subject, yet it seems that we are still far from understanding the elusive cause(s). The experts clearly believe there is a strong genetic component, yet they have been frustrated in their diligent efforts to identify those genetic causes [8]. At the same time, it is now pretty much indisputable that the incidence of autism, particularly in the U.S., has been steadily on the rise over the last few decades, now estimated to be over one in a hundred, an astonishing number.

Despite the fact that the vaccine industry has built a strong case that vaccines don’t cause autism, the autism community persists in claiming that they do. My research has led me to believe that the aluminum in vaccines plays a contributory role, as does the aluminum often found in sunscreen. Aluminum is a very common metal, yet it has never been incorporated into any biological system, and is clearly toxic to neurons, a subject I will return to later.

But I also believe that other environmental factors play probably a larger role than aluminum. Or, to say it another way, certain nutritional deficiencies predispose a child to be especially vulnerable to aluminum. My investigative research has led me to consider cholesterol [11] and vitamin D [3] deficiencies as prime candidates.

The brain represents only 2% of the total body mass, yet it houses 25% of the body’s total cholesterol. Because of the current obsession in the U.S. against dietary cholesterol and saturated fat, I was led to explore the question of cholesterol supply to the fetus during pregnancy. I was richly rewarded, and initially left baffled, by an article with a very surprising revelation [17]. Women with high serum cholesterol typically give birth to children with low serum cholesterol who already at birth have developed fatty streaks in their arteries, and are predisposed to developing heart disease much later in life. There seemed to be an inverse relationship between the mother’s and the fetus’s cholesterol levels!

Given the importance of cholesterol to the nervous system, remarkably little research has been done to characterize the mechanisms by which the fetus supplies itself with cholesterol. It had been hypothesized that the fetus synthesizes all of its own cholesterol supply, which would be surprising, given that cholesterol synthesis is a complex twenty-five step process that might be difficult for a fledgling organism to carry out. However, the biological machinery that would be necessary to transport cholesterol across the placental barrier to the fetus did not seem to exist [18].

I believe I have found the answer in a 1997 article by a team of Japanese researchers [14]. These authors were inspired to look at the concentration of cholesterol sulfate in the placenta and in the mother’s blood, as a function of time throughout pregnancy. They discovered that cholesterol sulfate concentrations in the mother’s blood rose from 1.85 to 2.23 to 3.09 over the course of the three trimesters of pregnancy, whereas non-pregnant women had a serum level of only 1.56. However, the more remarkable observation was the increase in cholesterol sulfate noted in placental villi, hairlike projections from the placenta that provide lots of surface area for contact with fetal blood supply. The concentration of cholesterol sulfate here went up from 3.93 to 18.35 to 23.75 over the course of the three trimesters, a six-fold increase from the first trimester to the third trimester! It might have been anticipated that cholesterol sulfate is important to the fetus, as it is in fact critically involved in the sperm decapitation stage that allows the sperm to fertilize the egg [13].

I am inclined to hypothesize (somewhat boldly) that certain mothers (and, more generally, certain people) have high cholesterol to compensate for the fact that their cholesterol sulfate level is deficient. Their fetus has low cholesterol because of inadequacies in the supply chain, obligatorily mediated by cholesterol sulfate. I might also boldly add that high cholesterol, a risk factor for cardiovascular disease in both the mother and the child, is, by deduction, an indicator of low cholesterol sulfate, and therefore that cholesterol sulfate protects from cardiovascular disease. I will need to revisit this topic in a later post!

Cholesterol sulfate is an interesting and elusive molecule. It is synthesized in the skin upon exposure to sunlight, alongside vitamin D3 sulfate [10, 2] and so this might be the connection between autism and vitamin D deficiency. It could well be that the sulfated form of vitamin D3 can substitute for cholesterol sulfate to some extent in supplying the fetus with sulfate. And it might then be supposed that sulfate is a critical nutrient that is in short supply in fetuses destined to later develop into autistic children.

This idea gains strong support from an article in Press in the timely subject of sulfate in fetal development [5]. From several studies on humans with rare genetic disorders and on animal models involving genetically engineered defective genes, it is abundantly clear that sulfate is absolutely essential to healthy fetal development. Furthermore, sulfate plays an important role in detoxifying drugs that might damage the fetus or the infant, such as acetaminophen, the active ingredient in tylenol. In fact, an interesting review article proposes that vulnerability to damage by Tylenol given subsequent to a vaccine-induced fever may have been a risk factor for autism [6]. Further support for a sulfate deficit in autism comes from a study showing, with a highly significant p-value of ¡ .00002, that severely autistic kids are unable to sulfate (and therefore detoxify) toxic chemicals [1].

Another really remarkable thing about cholesterol sulfate is that, in part because of its negative charge, it is “amphiphilic”: soluble in both water and fat. This means that it can travel freely in the blood stream (does not have to be packaged up inside LDL particles), and easily enters cell walls (ten times as agile as cholesterol itself in penetrating cell walls) [19]. I suspect these unique properties make it also much easier for cholesterol sulfate to get across the placental barrier than would be the case for cholesterol. Furthermore, cholesterol sulfate plays an important role in the outer skin, in protecting the body from invasion by pathogens [16]. A deficiency in cholesterol sulfate in the skin might explain the fact that autistic children often have skin problems and are more prone to infection.

I’d like to now return to the subject of the supposed genetic component to autism, which has been justified in part because an identical twin is much more likely to also have autism given that his twin has autism than is the case for fraternal twins. However, there is a further interesting observation that even fraternal twins are much more likely to both have autism than two siblings who are not twins. The genetic distance between fraternal twins is the same as that between brothers, and therefore genes can not explain this phenomenon. Furthermore, just being a twin is a risk factor for autism [7]. It would seem to me that all of these observations can be nicely explained if the assumption is that inadequate supply of a scarce resource (e.g., cholesterol sulfate) is the source of the problem. Twins would place double the demand on the mother’s limited supply. And identical twins often share a single placenta, which means that the villi would have to be twice as proliferous to fully supply two fetuses simultaneously, an unlikely feat. This could account for the increased risk in identical twins, without involving genetics at all.

Finally, I would like to return to the subject of aluminum, by discussing a fascinating article involving an experiment with aluminum exposure to pregnant mice, followed by an investigation of the properties of neurons harvested from the brains of the offspring. But first I should mention a couple more facts about features of autism. One novel characteristic of the autistic brain is that it actually is larger than the non-autistic brain at the age of two or three [9]. This is a time when ordinarily the brain goes through a massive pruning process, to weed out neurons that have failed to build up sufficient synaptic connections to be worthy of survival.

Two biological molecules that pair up on either side of the synapse to promote the memory of synaptic stimuli are neurexin and neuroligin. Several of the rare genetic defects that sometimes show up in connection with autism are related to either neurexin [12], on the input side of the synapse, or neuroligin [21] on the output side, where these two work together synergistically to coordinate transmission of the neurotransmitter glutamate. Glutamate plays an important role in wiring up the brain during early development, and this function has been hypothesized to be disturbed in autism. Glutamate is also intimately involved in the stage where neurons are pruned due to the fact that they received little input and are thus deemed extraneous. Furthermore, cholesterol, through a scissors mechanism, has been shown to play a crucial role in greatly increasing the ability of two neurons to make contact at a synapse [20]. In line with this observation, in-vitro studies have shown that cholesterol deficient neurons exhibit impaired glutamate transport, causing excess glutamate to accumulate outside the neuron [3].

In this light, the experiment on the mice that were exposed to aluminum prenatally was highly relevant. One of the important roles glutamate carries out is to signal to an unworthy neuron that it should die: that it should commit “programmed cell death” or “apoptosis” during the massive pruning stage. The mouse experiment [15] showed that neurons taken from the brains of mice prenatally exposed to aluminum responded abnormally to glutamate exposure that should have led to apoptosis. Whereas the number of neurons in the petri dish harvested from control mice sharply decreased upon exposure to glutamate, the aluminum-exposed neurons were quite happy to keep on growing, effectively ignoring the glutamate signal. This seemed to be exactly the same thing that the neurons in the autistic brains were doing when they weren’t pruned!

In summary, it seems to me that a possible explanation for the recent steady and alarming increase in the rate of autism in the U.S. is the confluence of a number of factors leading to a perfect storm. The problem centers on the two American obsessions of avoiding dietary fat and cholesterol and overprotection from the sun. The problem is further compounded by the relentless increase in the number of vaccinations against a multitude of childhood diseases, increasingly mandated by the U.S. government. These environmental influences conspire to produce children who are grossly deficient in cholesterol sulfate, which leads to impaired neurotransmission in the brain and impaired immune systems. The infiltration of aluminum into the brain compounds the problem, by further disrupting the already impaired glutamate transmission. The aluminum toxicity builds up due to the combination of exposure to both vaccines and sunscreen applied far too frequently to the skin, in the context of sulfate deficiencies that impair natural detoxification processes. It seems that some major changes in the American attitude towards what constitutes healthy living will need to take place before this epidemic can be brought under control.


[1] A. Alberti, P. Pirrone, M. Elia, R.H. Waring and C. Romano, “Sulphation deficit in ’low-functioning’ autistic children: a pilot study,” Biol Psychiatry, 46(3):420-4, 1999.

[2] M. Axelson, “The cholecalciferol sulphate system in mammals,” J. Steroid Biochem. 26(3), 369-373, 1987.

[3] T. Borisova, N. Krisanova, R. Sivko and A. Borysov, “Cholesterol depletion attenuates tonic release but increases the ambient level of glutamate in rat brain synaptosomes,” Neurochem Int. 2010 Feb;56(3), 466-78, 2010.

[4] J.J. Cannell, “Autism and vitamin D,” Med Hypotheses, 70, 750-9, 2008.

[5] P.A. Dawson, “Sulfate in fetal development,” Seminars in Cell and Developmental Biology in Press, 2011.

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