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Just got the book - A Blockbuster!

 
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PostPosted: Thu Oct 21, 2004 3:50 am    Post subject: Just got the book - A Blockbuster! Reply with quote

I ordered your book from Amazon over the weekend and got it today! I started reading it, and was amazed at some things, and not at all shocked at others. GM, I know you refrain from criticizing the so-called "scientists" at Detrick, but I don't have to, and I won't. I find Bruce Ivins (especially) and the others who, in publication after publication, year after year, pushed adjuvants with squalene as a primary ingredient, to be the primary and original culprits in this whole sorry episode. It was his, and their, work that was principally responsible for the military's apparent testing of a squalene-containing anthrax vaccine in our troops. That's nothing short of hideous. The American people deserve the whole story, and the Department of Defense, from its scientists to its generals, needs to be brought to a full accounting. This is a superb book that Americans need to read!!!
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PostPosted: Thu Oct 21, 2004 4:22 am    Post subject: Reply with quote

I also got my copy today and I'm loving it. The beginning about Sverdlovsk is superbly written - I felt as if was almost there. I would like to ask one question. I admit I did some "look ahead" reading and found the squalene concentration steps very convincing. But what about DoD's contention on their website that squalene can be found at much higher concentrations in any normal blood sample?
Is this true?
It would have been helpful if GM had included some of this data (I may have missed it by not reading enough yet). If one were to draw blood from any normal person (not vaccinated) would much greater than 80 parts per billion of squalene be detected, as DoD contend?

Remember that the human blood system contains several litres of blood, so that injecting a few ml of vaccine with 80 parts per billion of squalene would only lead to a few parts per trillion in total in the entire vascualr system.

I'm just curious about this. If normal persons always carry several hundred parts per billion already, how could a few extra parts per trillion make any diference?
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Sjogrngrl
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PostPosted: Thu Oct 21, 2004 5:31 am    Post subject: Reply with quote

It's the source of the squalene that matters. Yes, we all have it naturally occurring in our bodies, but squalene injection from a foreign source--as I understand, even in trace amounts, will cause problems. It's all in there--you just have to read more of the book. It's a learning experience I never wanted to have, but I'm sure glad to be getting.
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PostPosted: Thu Oct 21, 2004 5:59 pm    Post subject: Reply with quote

I will keep reading and see if I can resolve this. Another question that arises is this: If squalene already occurs naturally in human blood at several hundred parts per billion, how come normal people don't have the squalene antibodies? Is the squalene in the vaccine actually a different chemical than the natural squalene in blood?
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Gary M - Author
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PostPosted: Sun Oct 24, 2004 7:26 am    Post subject: Reply to Guest 3 Reply with quote

Dear Guest 3: Under normal circumstances, the immune system ignores the body's own molecules. Immunologists call this phenomenon "tolerance." If our immune systems did not tolerate our own constituents, we would all perish. Tolerance can be broken by injection. As immunologists will also tell you, "route of administration" is key. By the oral route, ingestion, the body tolerates squalene, possibly even benefits from its potentially salubrious effects. By injecting squalene, the immune system sees these molecules in a novel way, and acts, in an apparent surprise to the scientists who have been injecting it into humans, as though these squalene molecules were an invading germ. The same phenomenon can occur following open heart surgery or an injury to the eye. When cardiac surgeons slice into the pericardium (the fibrous sac surrounding the heart), they expose previously non-reactive molecules (called antigens) in the pericardium to the immune system. These normally "sequestered" antigens now encounter immune cells that they would not otherwise see, possibly resulting in the autoimmune inflammation of these tissues, which is called postcardiotomy pericarditis. Injury to the eye can break tolerance to previously sequestered antigens found in the lens crystallin, for instance. An autoimmune inflammation of the lens can occur, resulting in ocular disease. So the fact that there might be several hundred parts per billion of squalene in the bloodstream (this is another unsupported assertion made by the Department of Defense) is not evidence of its safety. To the contrary, it explains why squalene is so perilous to inject. If you initiate an immune response to otherwise tolerated squalene molecules through injection, immune cells will then attack these molecules, wantonly and indiscriminately, wherever they're found in the body. If they're in the bloodstream, an autoimmune response to squalene could result in vascular disease. If these molecules are in the nervous system and the brain, and they are, an autoimmune response to squalene can result in irreversible neurological damage. To reiterate the gun analogy that I use in my book, injecting squalene is like pulling the trigger of a gun. Pull that trigger (through injection) and it is immune cells, and other products of the immune system, that do the damage. No laboratory has published data identifying the lowest dose of squalene capable of eliciting such a response. Chiron Corporation, which makes MF59 - the squalene-in-water adjuvant developed in close cooperation with the Army and the NIH - has published data showing that animals respond to low parts per billion doses of injected squalene. Tulane's data is evidence that a mere ten parts per billion concentration of squalene in anthrax vaccine, when injected into humans, not only induces an immunological response to squalene, it induces chronic and debilitating disease. To answer your second question, squalene processed from shark liver oil or other non-human sources should be the same thirty carbon atom, fifty hydrogen atom molecule found in the human body. However, the structure or "conformation" of biological molecules can be slightly different in vitro ("in glass" outside the body) than they are in vivo (inside the body). I have not seen any data showing structural differences between endogenous squalene (the squalene that our bodies make), and exogenous squalene (the artificial stuff that is added to vaccines).
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PostPosted: Sun Oct 24, 2004 1:53 pm    Post subject: Reply with quote

Thanks for your response. Since I hadn't yet thoroughly read the book I was a bit early with my first questions. Later on Dr Asa or yourself pretty much cover all these questions. The before and after testing of the 4 military personnel is the smoking gun. Before they were vaccinated they didn't have antibodies - afterwards they did. What could be more clear than that?
Surely any commission (and let's hope there will be one) should test EVERY vaccinated soldier for antibodies - and then the results should be correlated against which batch of vaccine they received.
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PostPosted: Sun Oct 31, 2004 11:43 am    Post subject: Reply with quote

Exclamation In attempting to receive a waiver from the current anthrax vaccine, I've learned that perhaps the quickest way to receive a discharge from the military (probably not honorable) is to refuse the innoculation. I wonder how the Pentagon would react if that attitude were taken by our "all volunteer military" currently serving overseas AND at home.
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Dan Leggett
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PostPosted: Mon Dec 06, 2004 5:59 pm    Post subject: squalene concentrations Reply with quote

First, I want to thank Mr. Matsumoto for this important and disturbing book. As a retired chemist, I'm not entirely convinced by the explanation of why squalene injected at ppb levels, which become ppt levels whan diluted in the blood stream, induce an immune response while normal blood levels or small amounts ingested as food do not. It seems to me once squalene molecules are in the blood, one molecule is like another. As a natural product squalene must be ubiquitous in nature, and as a component of edible oils, 'normal' people must be ingesting varying amounts without adverse health effects. Not everything ingested gets into the blood, but certainly trace amounts of squalene must enter the blood via food, and it is hard for me to believe that nanogram amounts introduced through vaccines would substantially raise blood levels. Now I raise the possibility that the doses of squalene in vaccine that were associated with the occurrence of autoimmune disease were actually much higher than the figures quoted in the book. There is also some confusion there where vaccine squalene concentrations in ppb are compared with adjuvant contents reported as mg. These units are not compatible in the absence of a reference to volume, e.g. 1ppb = 1ng/mL = 1mg/1000L. Clearly a study of blood squalene concentrations of unvaccinated controls and individuals known to have received contaminated vaccine should be conducted and would help resolve the etiological issue.
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Gary M - Author
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PostPosted: Fri Dec 10, 2004 3:20 pm    Post subject: Reply to Dan Leggett, RE: squalene concentrations Reply with quote

Dear Mr. Leggett: Thank you for your interest in VACCINE A. Because you are a chemist, my response to you will be more technical than one I would ordinarily write for lay people.

The purportedly large quantity of free squalene molecules in the bloodstream, assuming that one exists (DOD provides no evidence to support this assertion), has no bearing on whether or not a nanogram concentration of injected squalene can induce autoimmunity. This is a matter of anatomy and how different systems in the body (digestive system vs. immune system; lymphatic system vs. circulatory system) function, not chemistry alone.

THE ANATOMY OF THE PROBLEM: In rats, Finnish scientists have demonstrated that when ingested squalene molecules pass through the walls of the small intestine, they are enveloped in a lipoprotein for transport through the body. This envelope is called a chylomicron (something akin to a liposome). Squalene molecules transported through the body in these chylomicrons disappear from circulation in less than four minutes. The body cyclizes them into methyl sterols and cholesterol, as well as biliary and fecal sterols and bile acids (Tilvis RS, Mietennen TA, Fate of intravenously administered squalene in the rat, Biochim Biophys Acta, 1982 (712), pgs. 374-81).

Squalene molecules made in the body are equally transient, and are biosynthesized inside of cells. So, based on the available data in animals, squalene molecules aren't bobbing around in high concentrations in the bloodstream as asserted by DOD.

Even if that were the case, it wouldn't matter. Under normal circumstances, the immune system "tolerates" endogenous or "self" molecules. You can break this natural tolerance for "self" by "presenting" a molecule that the immune system might otherwise ignore to immune cells in the lymphatic system. In other words, to get an immune response to a molecule - whether it is self or foreign (endogenous or exogenous) - you have to get the immune system's full attention. This can be done by injection.

The act of injecting something into the body martials the body's defenses to repel this assault. This response is called inflammation. The soreness and redness at the injection site (which some vaccine designers consider undesirable because the resulting discomfort makes patients dislike vaccination), is actually a sign that a vaccine is doing what it was designed to do. The introduction or "presentation" of foreign material into the body (e.g., a microbe or pieces of one) recruits highly specialized immune cells to the injection site.

The first to arrive are called phagocytes, which actually gobble up microbes, digest them, and then display bits of the devoured microbe on the cell's surface. Other immune cells then react to these bits. B cells, for instance, make antibodies to them.

The body's counterattack occurs where the breach in the outer walls (the skin) first occurs. The invaders, or what's left of them, are transported by immune cells (not chylomicrons) through the lymphatic system (not the bloodstream) to the lymph nodes for further processing by still other immune cells (there are more than two dozen types that each perform a different function).

By presenting squalene to the body in this manner, through injection, immune cells encounter squalene molecules in an unnatural way. They aren't inside of cells or chylomicrons. What's more, microdroplets of squalene in a vaccine adjuvant emulsion are "carriers" or little "vaccine delivery vehicles" for what is supposed to be the vaccine's chief ingredient - the germ or the bits of a germ, or "subunits," which current vaccine designers are trying to use instead. It stands to reason, then, that squalene's natural immunogenicity (its ability to elicit an immune response specific to itself) would be further enhanced by its conveyance of a germ or a germ product (e.g., the protective antigen protein secreted by Bacillus anthracis, which is the core ingredient in anthrax vaccine). This, in reality, is a classic oil emulsion formula - germ (e.g., killed mycobacteria) + oil and water, which has proven toxic in experiments dating back to 1916.

So the amount of squalene in the bloodstream, whether increased by injection or not, has nothing to do with their effect. How a molecule enters the body, and is transported through it, makes all the difference. Immunologists refer to this phenomenon as "route of administration." Lots of squalene in the bloodstream, even if it is indeed there as DOD claims, is, based on the functioning of the body's different systems, irrelevant.

A LITTLE BIT GOES A LONG WAY: Infinitesmally small quantities of an antigen (a substance that can initiate immune responses, which occur at the molecular level), can activate immune cells or affect other systems in the body. This is why, when dose-ranging, pharmacologists routinely test biologically active molecules in the nanogram (parts per billion) range, and sometimes in the femtogram (parts per trillion) range. When testing for biologically active, and potentially harmful substances in the evironment, scientists analyze samples of ambient water, for instance, in the picogram range, which is parts per quadrillion. They do this with a test called gas chromatography/mass spectrometry.

In New Mexico, for instance, scientists are conducting a "surveillance" of sewage, groundwater, well water and surface water (e.g., rivers like the Rio Grande) for parts per trillion residues of common drugs like ibuprofen (Advil) and acetominophen (Tylenol); antibiotics like amoxicillin, penicillin and ciprofloxacin; and anti-depressants like Prozac. Why? Because even these infinitesimally small concentrations of drugs, parts per trillion, can affect fish and other wildlife.

Parts per trillion concentrations of a substance can be absorbed by humans through the skin and mucosal surfaces. How much greater, then, is the risk when injecting substantially higher parts per billion concentrations directly into muscle?

The body is ultra-sensitive; it responds to mere molecules of a substance, not tablespoons of it. This is why pharmacologists test for a lower threshold of a drug's activity in nanogram or femtogram concentrations.

When Chiron added MF59 (a squalene-in-wate emulsion) to its European-licensed flu vaccine, Fluad, it used a much large amount of squalene than the nanogram concentrations found by the FDA in anthrax vaccine. This was due, in part, to the fact that Chiron not only added microdroplets of MF59 to Fluad as an immunostimulant, each microdroplet was also a carrier or vehicle. They were a means to convey the vaccine's flu particles into the body. So Chiron used lots more squalene in Fluad than the FDA found in anthrax vaccine because Chiron used this oil to perform two distinct functions: the microdroplets are a "vehicle" for the antigen as well as an immunostimulant.

Chiron did not use the minimum amount of squalene necessary to induce an immune response. It did not use the minimum because it needed a lot more squalene microdroplets to transport the antigen (the microbe, or bits of it) into the body, and through it.

NO CONFUSION: There was no confusion in VACCINE A when I compared the twofold serial dilution of squalene (in nanograms), which was detected by the FDA in anthrax vaccine, and the twofold serial dilution (in micrograms) employed by Chiron in a clinical trial with Fluad. I was comparing ratios, not amounts, and I clearly stated this in the book.

Chiron's dose ranging in the microgram range to determine the optimal dosage to generate a desirable antibody titer to influenza virus particles has zero bearing on the safety of nanogram amounts of squalene. Efficacy and safety are entirely different issues that repeatedly conflated by DOD.

RE: CONTROLS: Tulane has already compared unvaccinated controls to patients immunized with nanogram concentrations of squalene. Unvaccinated control patients did not have antibodies to squalene and did not suffer from autoimmunity. According to Tulane's data, a very high percentage of patients injected with nanogram quantities of squalene in anthrax vaccine consquently developed anti-squalene antibodies, in addition to autoimmunity.

UNSAFE IN ANY AMOUNT: Scientists have proven that femtogram amounts (parts per trillion) of a substance can induce allergic responses that can cause anaphylactic shock and death.

What might seem intuitive in ordinary chemistry and toxicology, does not apply in immunochemistry. Again, this is a matter of anatomy. A poison wreaks its destruction in the body by different means. That is one reason why, with poisons, quantity matters. With immunogenic substances, extremely minute quantities of antigen can elicit an immune response. If you elicit such a immune response to a "self" molecule like squalene (immunologists have known about the dangers of doing this for decades), you can break, with mere molecular quantities of antigen, the body's tolerance for its own constituents. When this occurs, the immune system becomes self-destructive. The immune system does the damage, not the substance itself.

In immunology, you are in "molecular world." Ordinary, household measurements, or even common laboratory measurements, do not apply here. Mere molecules of a substance can trigger an immune response to "self." Once that occurs, its the immune system that does the damage, not the amount of squalene. So in immunology, less is indubitably more.

Squalene is found throughout the nervous system and the brain. Hence, a breach of tolerance for this "self" molecule can induce severe neurological damage. Squalene-induced neurological injury has been clearly demonstrated in animals.

Squalene by itself is non-toxic. It's safe to eat; it's safe to rub on your skin. Injecting it presents this molecule to a different system in the body that operates according to different rules. What you can ingest, you can't inject.

Once tolerance to squalene is broken, the body's continual biosynthesis of this oil means perpetual immunostimulation by it. The body, thusly, administers self-boosters to squalene, in perpetuity.

The overall confusion here can be cleared up by recognizing something as simple as this: chemistry is not immunology, and one mustn't assume the principles of one apply to the other.

Thank you for giving me this opportunity to re-state elementary principles in immunology that clearly need reinforcing with vaccine designers at USAMRIID, WRAIR and the NIH.

Sincerely,
Gary Matsumoto
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Dan Leggett
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PostPosted: Sat Dec 11, 2004 3:00 am    Post subject: squalene and autoimmunity Reply with quote

Gary, thank you for your extended response to issues raised in my post. In reading further in your book, I found words to the effect that in 1990 the anthrax vaccine antigen concentrations were increased 100-fold due to a change in the in filtration process. In other words, more stuff was getting through the filters. This may have had a significant impact on the immunogenic response to the vaccine apart from or synergistically with the squalene adjuvant.

The gist of your tutorial on immunology(and I congratulate you for digging this out) is that immunology and chemistry are different and we shouldn't rely on chemistry to explain what is happening in these cases. Well, I would say yes and no. But fundamentally I disagree with this assertion. Immunology is biochemistry on a molecular level but it is still chemistry. Given that squalene occurs naturally in human nerve tissue and liver, which we know is true, then there is a research question that needs to be investigated. That is, why do trace amounts of squalene injected into the blood elicit an immune response? It is not intuitively obvious, apparently even to working immunologists.

Since this can only be answered by research, we don't know the answer. I will offer some speculation in the vein of physical chemistry, because I reject the notion that immunochemistry is fundamentally different: (1)Vaccines containing squalene emulsions or micelles introduce large clusters of molecules(~ billion molecule aggregates). These may behave differently from squalene in its normal molecular or sequestered form. (2)Squalene and anthrax antigens may also form complexes in the vaccine that behave differently from natural squalene in the body when injected.

I think what we know is that certain vaccines containing squalene cause an autoimmune response when injected. I don't think it's 100% certain that squalene is the reason, although there is much research to suggest that squalene is immunogenic. I believe many of those trials were carried out with much higher concentrations, however. The immunoassay for squalene, even if quite specific, does not rule out other co-contaminants in the vaccines as being causitive agents.

Again, your book is a marvelous piece of detective work and expose of government bioresearch. Kudos.

Regards,
Dan Leggett
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Gary M - Author
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PostPosted: Sat Dec 11, 2004 8:49 pm    Post subject: Reply to Dan Leggett, RE: squalene and autoimmunity Reply with quote

Dear Dan: I drew a sharp distinction between immunology and chemistry because they are distinct disciplines with unique vocabularies and knowledge bases. In immunology there is undeniable overlap with chemistry. Most immunologists learn chemistry because it is necessary (many of the patriarchs of immunology like Austria's Karl Landsteiner were immunochemists), but the reverse is not true. I have met very few chemists who have training in immunology.

ANATOMY VS. CHEMISTRY: But mainly, I drew a distinction between anatomy and chemistry (not immunology and chemistry applied in this particular discussion without regard for a system in the body, the lymphatic system, which presents antigen to immune cells). Antigen presentation is not a function of the circulatory system. This unique phenomenon does not occur in the bloodstream, so the amount of endogenous squalene in the bloodstream, is moot. Also, as previously explained, squalene in the bloodstream is sequestered in lipoprotein envelopes called chylomicrons, and not exposed as a raw squalene molecule.

Without specific knowledge of the lymphatic system, and the complexly choreographed process of antigen presentation by various cells in the lymphatic system, I do not believe it is possible to extrapolate through chemistry alone why an endogenous molecule is non-immunogenic in the bloodstream, but immunogenic when presented to immune cells through injection.

FYI: I did not dig out this information expressly to answer your posting in this forum. The "tutorial" I offered on immunology is, in fact, in VACCINE A. What I wrote in the book is less technical because it was written for a general audience; the response I wrote to you was for a chemist. But the information is nonetheless in the book, albeit communicated in less detail.

I disagree with your assertion that:

Quote:
Given that squalene occurs naturally in human nerve tissue and liver, which we know is true, then there is a research question that needs to be investigated. That is, why do trace amounts of squalene injected into the blood elicit an immune response? It is not intuitively obvious, apparently even to working immunologists.

Since this can only be answered by research, we don't know the answer.


IMMUNOLOGISTS SHOULD KNOW BETTER: All immunologists should know that nanogram or femtogram quantities of antigen can elicit an immune response. It was theorized as far back as the 1940s (though not proven) that a single molecule can elicit such a response. This assertion was, in part, based on the fact that antibodies form against a single region on a single molecule called an epitope or antigenic determinant. So to an immunologist, it should be intuitively obvious that nanogram quantities of antigen can do the job.

WHAT APPEARS TO BE A LITTLE IS REALLY A LOT: It is misleading to call nanogram quantities of antigen "trace" quantities as the FDA and DOD have done, because in immunology they nanogram concentrations are, in fact, substantial. As I reported in VACCINE A, various scientists calculated the number of molecules in a 10 parts per billion concentration of squalene in a 0.5 ml of water. About a half a dozen Ph.D.s performed this calculation for me and the answers did not all agree. However, even with the lowest number of squalene molecules calculated to be in 0.5 ml of water (which is the volume dose in a vial of anthrax vaccine) was 1.67 trillion molecules. If, based on the aforementioned immunological theory (which has never been disproven) that a single molecule can elicit an immune response, then 1.67 trillion molecules should be more than sufficient to generate that response.

After the clonal priming of immune cells with the initial injection with squalene, any subsequent boosters with squalene amplifies the anamnestic or memory response in certain immune cells. So each booster amplifies the magnitude of immune response to subsequent antigen challenge. Conservatively, each B-cell creates roughly 20,000 clones of every antibody it make. So multiply 1.67 trillion x 20,000 and you get the approximate number of antibodies to squalene produced by one B-cell. Subsequent boosters will push the number of antibodies to squalene into the range of 10^23 molecules. That's huge. Tulane estimates that by the third shot, the effective dose of squalene in nanogram concentrations (as measured by the concomitant immune response) would be somewhere in the vicinity of 265 grams; not milligrams, grams.

Tulane's immunologists are hardly alone in understanding this. Dr. Dorothy Lewis of Baylor University College of Medicine, and a consultant in immunology to the NIH, wrote a letter to Congressman Jack Metcalf (R-WA) in 2000, stating that the low concentrations of squalene detected by the FDA in anthrax vaccine could, in fact, be immunogenic. Metcalf released the letter in an appendix to a report that he issued in September 2000, which demanded more answers from DOD about the presence of squalene in anthrax vaccine.

That nanogram and femtogram quantities of antigen can be immunogenic is fundemental to my assertion that the low nanogram concentrations of squalene, detected in a twofold serial dilution in specific lots of anthrax vaccine, constitute evidence of a de facto clinical trial to determine squalene's lower threshold of biological activity by a dose ranging/dose escalation study in military personnel.

WHY SQUALENE'S STILL THE CHIEF SUSPECT: I know this is obvious from the book that I have written, but please let me re-state, redundantly and didactically, that I believe the presence of squalene is the chief reason why certain lots of anthrax vaccine induce autoimmunity, but not others. This is based on several facts already demonstrated by laboratory research:

(1) Squalene is an endogenous molecule that is pathogenic when injected. Scientists affiliated with 10 laboratories around the world have demonstrated this phenomenon in 4 species of animals. If you give any credence to Tulane's work (DOD does not), then you can include a fifth species: man. The data has been published in nearly thirty peer-reviewed papers between 1974 and 2004.

(2) A so-called "chemical" vaccine against anthrax, made from the protective antigen protein (PA) secreted by Bacillus anthracis, has been around in various forms since the early 1950s in both the United States and Britain. In a half century's worth of research with PA in both the U.S. and the U.K., autoimmunity has never been observed in either animals or humans as a sequela to immunization with PA.

(3) Military personnel injected with anthrax vaccine not proven to contain squalene, but administered after 1990, do not form antibodies to squalene, or get sick.

(4) Both Tulane and Walter Reed Army Institute of Research (WRAIR) have proven that the immune system responds specifically to squalene by forming antibodies to it. Thus, injecting squalene, can break tolerance for a self-molecule found in the liver and the nervous system.

WHY YOUR QUESTIONS ARE NOT ONLY EXCELLENT BUT ESSENTIAL: I do not know with any certainty, based on your postings, whether you have specific training in immunology. I suspect you do not. You are - as a chemist, however - asking entirely logical questions that must be asked, and must be answered, in order to clarify matters that are no more intuitively comprehensible than the Serbo-Croatian language is to speakers of English.

For this reason alone, it is critical that scientists such as yourself challenge the assertions in VACCINE A; especially, if, after reading it, you feel that I have failed to clarify issues that are fundamental to the book's argument. Either I am capable of clarifying them, in which case their exposition or re-exposition can only be helpful to readers of the book, or I am incapable of it, in which case, there may be holes in the argument that require filling, or flaws in it that require correcting.

ROUTE OF ADMINISTRATION, AGAIN: The body's natural reluctance to attack its own constituents is the chief reason why endogenous squalene molecules get ignored by the immune system. "Route of administration" is the chief reason why exogenous squalene, when injected, activates an immune response specific to the material injected. That is the whole point of immunization.

But I have the following observations that are in some cases consistent with your theories on why squalene introduced into the body by injection is immunogenic/pathogenic and why native squalene is not (that is, until tolerance is broken).

(1) It is quite possible that squalene forms micelles in an adjuvant emulsion that may enhance squalene's immunogenicity, and consequent pathogenicity. Tulane is investigating that possibility right now.

(2) It is also possible that squalene, which is a relatively unstable molecule, oxidizes when exposed to air and water as a result of incorporation in a vaccine. This could alter the conformation of the molecule, creating a squalene peroxidase, or something like that. Tulane is also investigating this possibility.

(3) I would speculate that squalene is probably no more toxigenic when presented to the immune system with protective antigen, because science has already demonstrated that squalene alone can induce autoimunity. Animals injected with squalene, and nothing else, have developed autoimmune disease. This has been shown by the Karolinska Institute in Sweden, the Royal Adelaide Hospital and University of Queensland in Australia, and the Polish Academy of Sciences (Department of the Ultrastructure of the Brain) in Poland.

I think it is quite possible that coupling squalene, a molecule of relatively low molecular weight, with an immunogenic protein like PA could create a de facto hapten with uniquely toxic properties. But, again, it has been demonstrated over and over again that squalene does this job very well all by itself. The immune system even forms antibodies to it. So, in practice (not theory), squalene does not require the assistance of a protein or lipopolysaccharide to be toxigenic.

The issue, I believe, really boils down to route of administration. Deliver squalene via the gut, or rub it on intact skin, and you don't have a problem. Rub squalene on a break in the skin or inject it, and you get a different result because, by these means, the molecule then gets presented to the immune system.

WHY IT IS UNLIKELY THAT CONSTITUENTS OF ANTHRAX VACCINE CAUSE ILLNESS, LET ALONE AUTOIMMUNITY: I cannot rule out the possibility that other constituents of anthrax vaccine might induce disease, but I consider it unlikely because this vaccine has not been demonstrated to cause disease prior to 1990. Also, pathology is only associated with certain lot numbers.

Although the ardent opponents of anthrax vaccine allege that the clinical trials supporting its eventual licensure were inadequate to prove safety, I would challenge that. There were 7,000 textile workers in the 1962-1974 CDC trial with BioThrax, which, I believe, was more than enough to reveal a vaccine problem. Here's why. The recorded number of serious adverse reactions in this trial that observed patients over a 22-year period amounted to 0.06%. According to the CDC, even the serious adverse reactions recorded over those 22 years were negligible and transient. There were, on the other hand, about 3,000 BioThrax recipients at Dover AFB between 1998 and 2000, and all sorts of serious illnesses manifested in this patient population, which was less than half the size of the one in the CDC trial. Also, the problems manifested almost immediately (some patients literally collapsed after their shots). The CDC did not records a single instance of this happening over 22 years of observation.

If the problem is the licensed vaccine's core ingredient, protective antigen, which I must confress to finding a very dubious proposition, then why didn't that problem show up prior to 1990 in the thousands of people who received the vaccine at textile mills; and in hundreds of military personnel injected with the vaccine at Fort Detrick? Why would more PA be more toxigenic?

My provisional answer to the first question is that after 1990, the Army's second generation anthrax vaccine with squalene was selectivley introduced into the military vaccine supply.

The answer to the latter question, with specific regard to autoimmune disease, is that there is zero evidence that more PA would be more toxigenic. To induce autoimmune disease, immunologists have long proposed that tolerance must be broken for a self molecule by activating an immune response to said molecule. In theory, this can be done by a foreign molecule that has a correlary in the body. Group A Beta-hemolytic streptococci , for instance, share amino acid sequences that constitute several epitopes that cross react with cardiac myosin, a protein in heart muscle. Thus, a specific immune response to these epitopes in a cross-reactive strain of Streptococcus will generate lymphocyte clones that will attack cardiac myosin, inducing myocardial damage long after a strep infection has resolved. This is one reason why physicians intervene so aggressively with antibiotics to treat strep. Note here, the high specificity of the immune responses in question. An epitope is smaller than a molecule. It is a region on a molecule. This region is generally no larger than an 8-9 amino acid sequence. That is way beyond small. It is also phenomenally discriminating.

All immunologists are familiar with this concept. In fact, Army immunologists are familiar with it. In the January 2002 issue of the peer-reviewed journal, Opthamology, Army immunologist Renata Engler, and physicians at the Air Force's Wilford Hall Medical Center in San Antonio, reported two cases of the autoimmune disease optic neuritis in military personnel following anthrax immunization. (Kerrison JB, Lounsbury D, Thirkill CE, Lane RG, Schatz MP, Engler RM, Optic neuritis after anthrax vaccination, Ophthalmology, 2002 Jan;109(1): pgs. 99-104. When Engler & Co. tried to determine the cause of this disease - and this is what's relevant to this particular discussion - they looked for "cross-reactive epitopes" between anthrax vaccine and the retina/optic nerve. So an Army immunologist, and even Air Force opthamologists, undeniably get this concept.

Now, here's the rub in these two optic neuritis cases. Engler & Co. did not find cross-reactive epitopes, yet concluded anthrax vaccination could possibly induce optic neuritis. How? Well, what is potentially instructive here is what Engler & Co. leave out of their discussion. They do not identify the vaccine lot numbers given to the two optic neuritis patients discussed in their paper. Did those lots contain squalene?

SQUALENE'S IMMUNOGENICITY IS PROVEN: I must challenge your characterization of data on squalene's immunogenicity as suggestive. It is not suggestive; it is proven. Squalene injection causes antibodies and cell-mediated immune responses that are specific for squalene. The concentrations used by the Army to induce autoantibodies experimentally in animals were, indeed, much higher. But as Tulane's data shows, the concentrations that induced anti-squalene antibody production and autoimmune disease in humans were as low as 1-9 parts per billion, which I think bears reminding, constitutes a multi-trillion molecule dose of squalene - a substantial immunological challenge in anyone's book (that is, except for the agencies of government accused of covert experimentation on troops).

If anyone wants to link disease with anthrax immunization, they must first identify the disease the vaccine is supposedly causing. Only then, can a potential causative agent be proposed. This is especially important with anthrax vaccine, as no disease has been associated with it during the forty some-odd years of its use prior to 1990. If the proposed disease causing agent is protective atigen, why would more of it (which is what scientists have been deliberately trying to do: add more PA to anthrax vaccine; thus increasing the antigenic load) cause disease? And what disease? This protein has never been demonstrated to cause disease in either animals or humans. There is no known association with PA and autoimmunity.

The immune system is very discriminating. Its responses are highly specific; atomically specific, in fact. The difference of a single atom can prevent an antibody to one molecule from cross-reacting to another. If the immune system is the causative agent for disease in military personnel receiving anthrax immunizations; then the following questions must be answered: what constituents of this vaccine is breaking tolerance for a self-molecule? And which self-molecule?

My answer to both question is squalene.

Again, identifying the pathology narrows the field. If the pathology is autoimmune, an immunologist/pathologist would routinely look for a cross-reactive epitope(s) that could induce autoimmunity through immune responses to the identical structure on both a foreign and self molecule, or a similar structure on both, in which case the phenomenon would be called "molecular mimicry." With squalene there are no shared epitopes or molecular mimicry; the molecule is identical.

If anyone proposes other unidentified contaminants in anthrax vaccine (the FDA complaints cite contaminants found on tabletops and other work surfaces, but not in the vaccine), as a source of disease, then, again, the question that must be answered first is this: which disease? The second question is what are the alleged pathogenic contaminants correlating to fully diagnosed illnesses in recipients of anthrax vaccine? Association is not causation. And pathology must be established before etiology. These are principles dating back to the mid-19th century.

Thank you for reading the book and caring enough about its contents to make logical, thought provoking and constructive criticisms, which I felt required highly detailed responses.

Sincerely
Gary Matsumoto
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Dan Leggett
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PostPosted: Sun Dec 12, 2004 2:22 am    Post subject: Reply with quote

Dear Gary,
Thank you once again for your very patient and thorough post. No I do not have training in immunology or immunochemistry, but thanks to you I'm getting a short course. I simply meant that at the molecular level chemical forces and principles would still apply to to immuno-phenomena, though I'm not sure you agree. The problem is we don't have a detailed mechanism for exactly what is happening yet. Obviously my first attempt to understand was flawed by assumptions which aren't valid for the problem at hand, such as solution chemistry, perfect mixing, etc. You are quite right about the number of molecules presented in a single injection of vaccine. My quick boe calculation gave ~8 trillion squalene molecules/0.5 mL. When you think about it this is a massive number to stick into a particular locus all at once. No wonder it jolts the system to respond, as I assume injecting it im(sc?) would bring it into contact with the lymphatic system rather quickly, long before the micelles or emulsified squalene particles had a chance to disperse, dissolve, transport in blood, etc. My guess is this route would largely circumvent the squalene>lanosterol>cholesterol pathway which I believe you said eliminates squalene very rapidly. This must be true since ingestion of even fairly massive doses of squalene(pure squalene as shark liver oil is sold over the counter as an immune system booster!) do not trigger an overwhelming immune response, although maybe a small, beneficial one. Thank you again for clarifying these issues for me.
Regards,
Dan
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Gary M - Author
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PostPosted: Mon Dec 13, 2004 3:17 pm    Post subject: Reply to Dan Leggett Reply with quote

Dear Dan: You are correct. Anyone who knows anything about immunology knows that at the molecular level immunology is chemistry; a molecule's conformation and charge distribution, for example, are factors that affect a molecule's immunogenicity. So I don't dispute this particular point you've made. But I am saying that what applies this particular problem is a very specific type of chemistry that involves metabolic processes that are unique to the immune system. How this system operates cannot be deduced from a general knowledge of molecular biology, cellular and solution chemistry or toxicology.

I appreciate the considerable effort that you are making to understand this. As a chemist you are educated in a field that would, in theory, enable you to grasp this material a lot more readily than scientists from other disciplines. But in some ways, it also makes this material more problematic for someone like you, because long-held assumptions from your considerable experience in chemistry do not necessarily apply in ways you might expect in immunochemistry and immunohistochemistry. I suspect the autotoxicology of squalene-induced autoimmune disease would be counterintuitive, or least not obvious to someone in, say, physical or analytical chemistry.

If I might draw an imperfect analogy, learning differences between analytical chemistry and immunochemistry are like the differences between learning the Latin and Japanese languages. If you know Latin, learning Italian, Spanish or French is a lot easier. If you know Italian, you can practically read Spanish without studying the language. Not so with Japanese. Japanese is character-based. You have to learn, through rote memorization, thousands upon thousands of pictographic characters. It seems to me, then, that learning immunology is somewhat analogous to learning Japanese. A knowledge of molecular biology or molecular chemistry won't enable a person to deduce how the immune system operates; though once you start learning immunology, there will be many things, as a chemist, that you will grasp far quicker than a lay person like me.

I have to disagree with your assertion that "we do not have a detailed mechanism for exactly what is happening yet." I also disagree with the assumption that injected squalene will "disperse, dissolve or transport in the blood."

The journey that squalene molecules make through the immune system is actually fairly well mapped. Chiron Corporation has published papers showing that injecting MF59 (sans vaccine) recruits phagocytic cells like macrophages to the injection site, and then induces further macrophage trafficking, which facilitates the processing of squalene by the immune system. Macrophages endocytose squalene, then migrate to the draining lymph nodes. Once in the nodes, macrophages undergo apoptosis; they die. Chiron scientists believe that through cell death, macrophages then present squalene molecules to dendritic cells resident in the nodes. Dendritic cells internalize MF59 for presentation, probably to T cells, for further processing. Molecules of MF59 (squalene-in-water) have been observed in the nodes 48 hours after injection.

So, once introduced into this particular system of the body, the immune system, squalene molecules get "metabolized" only in the narrow sense that cells will process these molecules. But this particular process is vastly different from the one that operates in the digestive system, which appropriates nutrients for the body's benefit. In general, the gut tolerizes, appropriates and eliminates. It does not immunize.

Squalene's journey through the immune system has been traced through fluorescence labelling, and documented with electron-micrography.

FYI: The standard method for injecting recombinant vaccines with an oil adjuvant is IM, not SQ.

Yes, "the squalene-lanosterol-cholesterol pathway eliminates squalene very rapidly," but not when injected. Injected squalene, as noted above, is processed differently from self-produced squalene.

I am not a scientist. I am a reporter who has reported what scientists have said or have done ... or have published. Because of the inflammatory nature of the VACCINE A investigation, I have immersed myself in the scientific literature related to squalene and its use in adjuvants. Based on that, here's what I'm confident in saying:

There is no evidence that I am aware of to support the assumption that ingesting squalene can induce an immune response to squalene. Experiments in mice (conducted in Finland) have shown otherwise. The but enables the body to tolerate and appropriate foreign materials. The function of the immune is just the opposite. It is a system by which the body rejects materials that it recognizes as foreign; this includes endogenous molecules are in the wrong place at the wrong time.

There is also no evidence that I am aware of to support the assumption that there is such a thing as a "small, beneficial" immune response to squalene. In fact, all evidence is to the contrary. The immune response to squalene is significant and self-destructive. An immune system primed through vaccination to respond to squalene will then attack this molecule, indiscriminately and relentlessly, wherever it is found in the body. This leads to all kinds of problems. Squalene is found in the liver and the nervous system. An autoimmune response to squalene would explain the neurological and rheumatologic injury in military personnel injected with it.

As you have now caculated, a 10 ppb concentration of squalene is actually a significant antigenic load when thinking of that load in terms of its molecules, instead of a more conventional unit of measurement. The calculations I received from Ph.D.'s and M.D's were all over the place. On the high end, two Ph.D.'s - one of them working for a U.S. National Laboratory - came up with 367 trillion squalene molecules. On the low end, an M.D. immunopathologist and member of the American Mathematical Society came up with 1.67 trillion molecules. You got ~8 trillion. I'm not sure who's right here. I can, however, say this with certainty. The dose of squalene molecules in a 10 ppb concentration of this oil is in the 10^12 range. That's a whopping dose.

Although DOD, FDA and NIH officials dispute this, the fact that injecting squalene induces autoimmunity in animals is undeniable; the means by which squalene does this is also well documented. The Karolinska Institute in Stockholm has even identified the gene(s) that triggers autoimmunity by injection with oil adjuvants, including squalene.

The level of proof for this is greater than anything I have witnessed in more than 23 years in journalism. To prove that an infectious agent causes a disease in an animal, scientists must fulfill Koch's Postulates: (1) isolate the pathogen from a diseased animal; (2) culture the pathogen in vitro; (3) introduce the artificially grown organism into a healthy animal; and by this means, (4) reproduce the disease.

There is an autoimmune version of Koch's Postulates called Witebski's Criteria. Immunologist Ernest Witebsky suggested that:

Quote:
"an autoimmune response "should be considered as the cause of a human disease if (1) it is regularly associated with that disease; (2) immunization of an experimental animal with the antigen from the appropriate tissue causes it to make an immune response (form antibodies or develop allergy); (3) associated with this response the animal develops pathological changes that are basically similar to those of the human; (4) the experimental disease can be transferred to a nonimmunized animal by serum or by lymphoid cells."


All of Witebsky's Criteria have been fulfilled with squalene.

And for military personnel that's a damn shame.

Sincerely,
Gary Matsumoto
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Dan Leggett
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PostPosted: Mon Dec 13, 2004 4:02 pm    Post subject: counting 'squalenes' Reply with quote

Thanks, Gary,

You wrote:

As you have now caculated, a 10 ppb concentration of squalene is actually a significant antigenic load when thinking of that load in terms of its molecules, instead of a more conventional unit of measurement. The calculations I received from Ph.D.'s and M.D's were all over the place. On the high end, two Ph.D.'s - one of them working for a U.S. National Laboratory - came up with 367 trillion squalene molecules. On the low end, an M.D. immunopathologist and member of the American Mathematical Society came up with 1.67 trillion molecules. You got ~8 trillion. I'm not sure who's right here. I can, however, say this with certainty. The dose of squalene molecules in a 10 ppb concentration of this oil is in the 10^12 range. That's a whopping dose.

You didn't say whether the PhDs were chemists. I hope not:-). I might forgive the M.Ds and immunologist. I redid the calculation more carefully and got 7.3 trillion squalene molecules per 0.5 mL of a 10 ppb(10 ng/mL) solution.

Regards,
Dan
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Gary M - Author
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PostPosted: Wed Dec 15, 2004 4:38 am    Post subject: Reply to Dan Leggett, RE: "counting 'squalenes'" Reply with quote

Dear Dan: Thank you very much for performing the calculation. It is reassuring to know that everyone who has crunched these numbers so far has determined, without exception, that the number of squalene molecules in a 10 ppb concentration of squalene in 0.5 mL of vaccine is in the trillions. There may not be a consensus among the people I've consulted on how many trillion, but 10 ppb is undeniably a whopping dose of squalene molecules.

The other PhDs who worked on this problem were mainly molecular biologists; there were also a couple of immunologists, one MD one MD/PhD immunopathologist whose undergraduate degree was in chemistry. This last fellow is also a member of the American Mathematical Society.

Thanks again.

Sincerely,
Gary Matsumoto
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