Men who have excessive faith in their theories or ideas are not only ill prepared for making discoveries; they also make very poor observations. Of necessity, they observe with a preconceived idea, and when they devise an experiment, they can see, in its results, only a confirmation of their theory. In this way they distort observation and often neglect very important facts because they do not further their aim….

Claude Bernard, An Introduction to the Study of Experimental Medicine

This article discusses our experience at the one-day Institute of Medicine workshop on vitamin D and calcium. Both of us had an opportunity to make comments before the committee. Here are Paul’s comments and slides and here are Amy’s comments and slides. Note that our 2009 paper in Autoimmunity Reviews discusses some of the science we allude to in further detail.

On the cab ride to the IOM committee meeting on whether to change the dietary reference intake (DRI) of vitamin D, Amy practiced her speech.

The cabbie had been silent for the whole ride, but broke character by talking to us. “So, let me ask you a question,” he said. “Do you take vitamin D?”

“Actually, no, we don’t,” Amy said. Amy explained briefly how our data suggests that the form derived from supplementation is immunosuppressive, meaning that while it may temporarily improve signs and symptoms of disease, we have found it may do so at the cost of long-term health.

We asked him if he took vitamin D. He said yes and explained that a few years back, he had a partially blocked artery. It scared him, so he searched the internet and found that high doses of vitamin D were being recommended for cardiovascular disease. He wasn’t clear about the evidence, but in his words, “I had to do something.”

Which brings us to this point in time. At least in the United States, rates of chronic disease are rising. One recent study predicted that if current trends continue, all Americans will be obese by 2040. Other studies have shown chronic disease is rising at rates faster than could otherwise be explained by an aging population and/or a general increase in population. One recent estimate says that by 2030, 171 million Americans will have a chronic disease. We have to do something, right?

A committee to evaluate the DRI of vitamin D is convened

The Institute of Medicine (IOM) is a non-profit organization that was first chartered in 1970. In 2008, IOM appointed a committee of experts whose charge is to reevaluate the DRI of calcium and vitamin D in light of recent research. The committee is expected to produce a report including these recommendations scheduled to be publicly released in May 2010.

An IOM committee with the same purpose last met in 1997 and set the current standard of 400 IU of vitamin D per day for adults. But none of the members of the previous committee are on the current committee despite, collectively, hundreds of MEDLINE citations to their names. Perhaps this suggests that the IOM was trying to exclude scientists who most vocally tout vitamin D’s benefits from the committee.

A great deal has happened since 1997. We learned that hormone replacement therapy (HRT) can cause disease (which led to thousands of premature deaths) even while early observational studies seemed to quite erroneously suggest the opposite. Also, evidence-based medicine has come of age.

For those who are not from this planet or from a Western country anyway, it’s hard to really express how enthusiastic the support for vitamin D supplementation is – at least in the popular media. A quick search of Google News for “vitamin D” has led us to conclude that the few articles that allude to vitamin D’s risks are vastly outnumbered by stories repeating the same unchallenged claims about vitamin D’s perceived benefits.

As part of their deliberation process, the IOM committee commissioned a report by the Tufts Evidence-based Practice Center. For this report, the Tufts group used a pre-existing set of criteria to identify only those studies meeting a certain standard of validity. Those studies that made the cut were independently analyzed.

According to the report’s abstract: “The majority of the findings concerning vitamin D, calcium, or a combination of both nutrients on the different health outcomes were inconsistent.” For a variety of diseases, the report repeatedly finds few or no controlled studies showing an association between vitamin D intake and disease.

Interestingly, Dr. Boullion, the sole speaker at the meeting from Europe (Belgium) conceded that he was confident that the European Union would not raise its recommendations regarding vitamin D intake based on vitamin D research to date.

The complete list of presentations including audio and slides is available on the IOM website.

Dr. Barry Kramer sounds an early note of caution

Arguably the most illuminating speech of the day came before lunch. Dr. Barry Kramer, MD, MPH, works in the Office of Disease Prevention, a division of the NIH. His speech was somewhat dryly titled, “Weighing Scientific Evidence” (PDF of slides) but might just as well have been titled, “Hey, wait a second.”

Invoking the work of Leon Gordis, PhD, Dr. Kramer discussed the “Levels of Decision Making,” and how the requisite amount of evidence for a non-conservative (our word) medical decision increases as the number of people it would affect increases. In other words, a person must make decisions for one’s family or even groups of patients with a different standard of evidence than he or she would when making decisions on behalf of the entire nation and possibly the world.

The evidence-based pyramid. Higher levels of the pyramid have higher levels of validity. Note that while Dr. Kramer’s evidence-based pyramid contains a section for ideas and opinions, many evidence-based pyramids make no such provision.

Dr. Kramer argued that some levels of evidence are not sufficient – at least not to make decisions on behalf of millions. The evidence must meet a minimum standard of validity: randomized controlled studies (RCTs), if not double-blind, placebo-controlled RCTs. According to Dr. Kramer, the history of research has shown in the cases of high-dose paclitaxel, encainide/flecainide, torcetrapib, and HRT, of course, that confounding variables have a way of compromising researchers’ most certain conclusions.

A good example of a confounding variable is smoking in alcohol’s relationship with lung cancer. Alcohol consumption is strongly correlated with lung cancer, but only because people who drink are also more likely to smoke. Another commonly cited example: Volvos may be involved in fewer accidents, but that’s probably because people who choose to drive them are generally older and more safety-conscious.

Dr. Kramer said in the case of observational studies with a relative risk of less than two, he could “spit them [confounding variables] out at the rate of one a second.” His slide lists a few obvious confounders for vitamin D studies: health consciousness, health insurance, and access to care.

Dr. Kramer also made what should be an obvious point: surrogate outcomes do not substitute for reductions in mortality or disease. A surrogate outcome is a variable that is a substitute for a “true outcome”, used because it is easier, quicker or cheaper to measure – and the most common one used in vitamin D studies is serum 25-D although bone mineral density, polyps, and PTH levels are also used. But Dr. Kramer said that none of these surrogate outcomes, in his words, “measure up.”

At the end of the speech Dr. Kramer showed the audience a classic Far Side cartoon, explaining, “Especially when you’re dealing with public health issues and millions of people, it pays you not to shoot first, because once you’ve shot, you can’t ask the questions any more, because your credibility is invested in your message. It pays to ask the questions before you shoot.”

We’re not sure if Dr. Barry Kramer heard our five-minute remarks (we never saw him after lunch), but we were, in essence, presenting a set of explanations for how his note of caution could later prove to be well-justified or even prescient.

Researchers affiliated with the Vitamin D Council drive the science on vitamin D

Inarguably the most forceful voices for increasing the DRI of vitamin D come from researchers affiliated with the Vitamin D Council, a California-based organization. At the one-day workshop, a total of seven speakers were affiliated with the Vitamin D Council (only Drs. Hollis and Grant are board members; the remainder are listed as “Vitamin D scientists” on the website), and the balance of other speakers could be fairly characterized as strongly sympathetic to their aims.

Many of the most influential papers on vitamin D are published by this group. We searched the online database, Web of Knowledge, for papers published since 2005 that mention “vitamin D” in the title or abstract, and then we sorted that list by number of times cited. The top four papers on that list are by researchers with the Vitamin D Council – as are a number more in the top twenty.

These researchers have a habit of wholeheartedly agreeing with one another; throughout the day, we would hear at least several times something to the effect, “I agree with my colleague.”

What does a bandwagon look like? If you search for the publications in MEDLINE on vitamin D since 2005 in GoPubMed.com and click on the statistics tab, you see how often Vitamin D Council researchers have co-authored each others’ papers. Below is an annotated screenshot (click for full-size PDF) of the professional collaborations in this relatively close-knit and like-minded group. Researchers affiliated with the Vitamin D Council are in red.

Despite a notable lack of data derived from RCTs, those researchers associated with the Vitamin D Council are pushing the IOM committee to raise the DRI of vitamin D by a huge increase – around 5-6 times the current DRI. To achieve this goal, the Vitamin D Council markets the form of vitamin D derived from food and supplements to the public as a nutrient. What harm can high levels of a nutrient cause, right?

Yet although we’re referring to it as vitamin D in this article so that you know what we are talking about, any molecular biologist would confirm that the two main forms of “vitamin” D are actually powerful secosteroids. The active form of vitamin D, 1,25-D, can also function as a hormone. We suspect that people would be less willing to take extremely large amounts of vitamin D if they were actually told, “We’re giving you high doses of a secosteroid that will adjust your hormonal and immune activity in ways not yet fully understood.”

Yet rather than trying to help the public understand these true properties of “vitamin” D, a number of prominent vitamin D researchers still seem content to refer to it as nothing more than the “sunshine vitamin,” some with impressive consistency.

Did our human ancestors really have extremely high levels of vitamin D?

Late in his talk, Dr. Robert Heaney, a researcher affiliated with the Vitamin D Council, said, “We all agree and it is well-established that humans evolved in equatorial East Africa wearing no clothes.” This assumption is repeatedly invoked to justify supplementation with vitamin D at levels that would leave the average American with a 25-D level similar to that of a present-day farmer who works near the equator.

We’re not sure anyone noticed, but in the next talk, Dr. Michael Holick would undercut this very argument. Dr. Holick said that according to his research, students of African descent need three to five times the exposure to ultraviolet light as Caucasians to “barely raise their blood levels” of 25-D. In short, their skin is “such a good sunscreen.” If ancient man had darkly pigmented skin, (according to a paper by Jablonski et al., man only evolved lighter skin pigment as he left the tropics) then why would he produce the copious levels of vitamin D referenced by Dr. Heaney?

What about climate change? That ancient man evolved in a consistently sunny and hot environment makes no provision for several extended ice ages, which corresponded to key periods in hominid evolution.

What about skin cancer? Say that early man did not hunt and gather at dusk like so many other animals – that early humans did evolve in an unforested environment with no caves, no clothing, and no thick body hair, whiling away his hours sizzling like a big piece of Paleolithic bacon. Why then would just a few burns before the age of 20 dramatically increase the risk of skin cancer? Did humans evolve to get skin cancer?

To clear up the confusion surrounding this issue, we recently contacted Dr. Peter Bogucki, an archaeologist at Princeton University, who is a leading expert on prehistoric man. We asked him to estimate how much sun prehistoric man actually got.

Dr. Bogucki responded, and I trust he won’t mind us quoting him, “You raise a very good question, but I don’t know that there’s a good answer. All we have is skeletal remains. There’s no elemental isotope to track sun exposure.” In the absence of such a marker, our understanding of how much vitamin D early man actually synthesized is complicated by several factors including climate variability, migration, and changes in skin pigment.

Dr. Richard Potts sums up the evidence or lack thereof for inferring how man evolved from specific environmental scenarios:

The study of human evolution has long sought to explain major adaptations and trends that led to the origin of Homo sapiens. Environmental scenarios have played a pivotal role in this endeavor. They represent statements or, more commonly, assumptions concerning the adaptive context in which key hominin traits emerged. In many cases, however, these scenarios are based on very little if any data about the past settings in which early hominins lived.

Dr. Richard Potts, Director of The Human Origins Program, Smithsonian Institution

At this point, it’s probably safe to say that we simply do not know how much sun early man got.

With this in mind, isn’t it a bit less plausible that, when it comes to the ability of the human body to naturally adjust its vitamin D levels for optimal health, current humans are a complete evolutionary bust and must be given truckloads of pills in order to remain healthy?

Dr. Michael Holick speaks on sunscreen and vitamin D

Dr. Michael Holick is a professor at Boston University, a medical doctor, and may be the world’s leading authority on vitamin D. Since 2005, he has authored or co-authored 59 publications appearing in PubMed on vitamin D (26 more than Dr. William Grant, who is second in that category and a frequent co-author) and he has the distinction of being quoted on vitamin D in nearly every magazine, newspaper, television show and website ever. In his 10-minute statement, Dr. Holick was critical of dermatologists, a group which he singled out for advising the public to avoid creating vitamin D by direct sun exposure. As it happens, Dr. Holick receives large amounts of funding from the UV Foundation, which is in turn sponsored by the Indoor Tanning Association.

Entitled The D-Lightful Vitamin for Health, Dr. Holick remarks sprinkled his speech with a number of pop culture references including mentions of Charlie Brown and Don King. And then there was the clip of Darth Vader telling Luke to come to the Dark Side. It has been a while since we have seen the Star Wars trilogy, but we don’t seem to recall Darth Vader’s evil stemming from his unnecessary prudence.

Dr. Holick went on to claim that sunscreen use blocks 99% of vitamin D production in the skin. This claim is a featured part of his argument, because there has to be a reason why what he views as vitamin D deficiency is so widespread. If there’s evidence to back up this statistic, then our search of the literature cannot find it.

What we did find were three small studies, one of which Dr. Holick authored himself.

One of these studies measured the vitamin D3 (a precursor of 25-D) levels of only eight subjects while another performed no intervention but simply measured the 25-D levels of 20 sunscreen users. The third put only 27 subjects into tanning beds rather than into the sun, which could easily introduce bias. All three are by the same lead author, Dr. Lois Y. Matsuoka.

As it happens, several reviews have refuted the idea that real-world use of sunscreen entirely halts cutaneous production of vitamin D. By real world, we mean people putting sunscreen on themselves for extended periods of time while exposed to the actual sun.

Dr. William L. Scarlett writes in his review, “Several large prospective studies have shown that vitamin D deficiency does not result from regular sunscreen use.”

A review by Drs. Wolpowitz and Gilchrest states, “There is no evidence that customary sunscreen use causes vitamin D deficiency or insufficiency in otherwise healthy individuals.”

One research team, studying patients with xeroderma pigmentosum, a genetic disorder in which patients are unable to repair damage caused by ultraviolet light, found that vitamin D levels are maintained even when patients practice at least six years of rigorous photoprotection and not supplementing with vitamin D beyond their normal dietary intake. Most importantly, the researchers also concluded that the clinical manifestations of vitamin D “deficiency” were absent.

In a 2007 review, Dr. Melanie Palm concludes real-world people tend not to consistently or repeatedly apply sunscreen. She writes: “Most people’s real-life experience with sunscreen is that despite its application, they still sunburn or tan after casual sun exposure.” Dr. Palm goes on to explain, “SPF [sun protection factor] is a strictly defined and Food and Drug Administration (FDA)-regulated measurement based on applying 2 mg/cm² of product. Studies have shown that most users apply insufficient amounts of sunscreen to meet this FDA standard, and the true SPF obtained is usually less than 50% of that written on the package.”

Dr. Holick also proudly informed the committee of the manner and amount of his vitamin D intake. If you ask us, this is irrelevant. It’s nice that Dr. Holick believes what he says enough to try it on himself, but this kind of data falls to the very bottom of Dr. Kramer’s evidence-based pyramid – the opinion level that should never be used to guide public health decisions.

In the remainder of his talk, Dr. Holick went on to say that no one living in a latitude north of Atlanta, Georgia can make vitamin D in their skin during the winter months. Based on everything else we have heard, maybe you can understand why we’re a bit dubious of this claim.

It seems that one of the unspoken rules of publishing a study on vitamin D is that you must cite Michael Holick – geez, even we have done it. But in light of the conflicting data related to Dr. Holick’s claims, we have to wonder why the man has been accorded that authority and why more people don’t second-guess some of his more definitive statements.

A concession: vitamin D is not for people with granulomatous disease

From our perspective, one positive statement Dr. Holick made was when he conceded, as actually many of the pro-vitamin D researchers will do, that vitamin D is not for everyone, specifically not for people with granulomatous diseases such as Crohn’s or sarcoidosis.

A granuloma is a ball-like collection of immune cells which forms when the immune system attempts to wall off substances such as bacteria. But it looks like patients with granulomatous diseases are going to have a tough time if Holick and his colleagues succeed in drowning us in vitamin D. Raising the DRI of vitamin D would inevitably mean that vitamin D would be added to another slew of foods.

When Dr. Holick et al. were questioned about the fact that some people have been shown to develop kidney stones after taking extra vitamin D or that people with granulomatous disease could easily ingest excess levels of vitamin D and become significantly more ill, they seemed ambivalent. In their eyes, if a certain number of people are harmed by taking vitamin D, it should not matter, so long as more people benefit. We find this risk-benefit analysis difficult to stomach having seen first-hand the suffering associated with granulomatous diseases.

Dr. Cedric Garland discusses vitamin D and cancer

Another member of the Vitamin D Council, Dr. Cedric Garland, spoke in his remarks about vitamin D and cancer. After his remarks, a committee member, Dr. JoAnn Manson challenged him on his claim that vitamin D is protective against cancer at high levels of intake. She asked him about the Women’s Health Initiative-led randomized controlled study which trended in the opposite direction when it comes to breast cancer among women who start out with high intakes of vitamin D.

Dr. Garland brusquely and repeatedly dismissed the cancer study, saying that the dose of vitamin D administered to subjects, 400 IU – which happens to be the current adult DRI – was “not even a placebo.” In other words he believes that 400 IUs of vitamin D has no biological effect whatsoever. Dr. Manson responded, “I don’t buy it.” Actually, neither do we. To put things in perspective, you’d have to consume 20 eggs or four glasses of vitamin D fortified milk a day in order to get 400 IUs of vitamin D.

Interestingly, when you take a look at the five most frequently cited papers on vitamin D published in the last five years, the first four are authored by researchers affiliated with the Vitamin D Council. But study #5 derives its conclusion based on data collected by the Women’s Health Initiative, the same research group whose data Dr. Garland suggested should have no implication on the IOM Committee’s decision-making. That other vitamin D researchers are more than inclined to analyze data from the Women’s Health Initiative suggests that, although Garland may seem like he is an expert speaking on behalf of the entire vitamin D community, not all vitamin D researchers share his views.

We have taken the liberty of annotating in red several of Dr. Garland’s slides to make points about the presentation of data especially as it pertains to vitamin D.

Below is Dr. Garland’s slide showing a strong and consistent increase in the rate of breast cancer since 1935, which he used as a general indication for why it is important to significantly increase the amount of vitamin D added to the food supply.

However, as you can see below, it is very easy to take that same data and “show” the opposite – that vitamin D consumption has led to a dramatic increase in breast cancer.

Another example: Dr. Garland didn’t mention this publication in his speech, but in a 2008 study, his group found a significant association between “low UVB irradiance and high incidence rates of type 1 childhood diabetes.”

Data derived in this observational manner could just as readily be used to show something else entirely.

As you can see in this graphic above, there is a strong apparent association between states that get more sun and teenage pregnancy. But does sun exposure actually cause teen pregnancy? We certainly hope not!

Obviously, you can try to control for confounding variables, as Dr. Garland did in his ’08 publication, but so too did researchers who repeatedly concluded that hormone replacement therapy was safe. According to Dr. Kramer: “There were literally scores, if not hundreds, of observational studies that showed almost beyond reasonable doubt that hormone replacement therapy would prolong women’s lives, if it were given routinely.”

In the words of Dr. David Ransohoff (who Dr. Kramer quoted in his talk), observational data are “guilty until proven innocent.”

When discussing vitamin D, Dr. Garland put up another thought-provoking chart on the effect of vitamin D and calcium on the development of kidney stones (derived from the Women’s Health Initiative).

Several things about Dr. Garland’s chart are of interest.

• Although the y-axis could easily have gone up to only 10%, it goes all the way up to 55%. This visually minimizes the apparent negative treatment effect of calcium and vitamin D and barely impresses on the viewer that if the trend observed in the study is accurate and significant, approximately 1.2 million Americans will develop kidney stones if they continue taking vitamin D and calcium.
• We probably should not be surprised that on this same slide, Dr. Garland opted to display absolute risk rather than relative risk. Absolute risk is a measure of what portion of a population have a disease in a given time period. Relative risk is that percentage increase divided by the risk in a placebo group, e.g. (2.5%–2.1%)/2.1%. In this case, patients who take calcium and vitamin D have an increased absolute risk of 0.4% of developing kidney stones but a relative risk of 19% of getting kidney stones. So by showing absolute risk, Dr. Garland again downplays the sheer number of people who could be negatively affected by taking extra vitamin D and calcium.

Dr. Reinhold Vieth speaks about safety

In his slot, Dr. Reinhold Vieth was asked to speak on whether there was a safe upper limit/level of vitamin D. As he has stated in at least one paper, his answer was no. In his words, “A prolonged intake of 250 mug (10,000 IU)/d of vitamin D(3) is likely to pose no risk of adverse effects in almost all individuals in the general population.”

Dr. Vieth’s comments echoed those of Dr. Garland, who had earlier concluded, “The benefit/risk ratio for 2,000 IU/day of vitamin D is infinite.”

Obviously, we disagree. We take no comfort in the fact that a person, as demonstrated in case reports, can accidentally take several thousand times the recommended dose of vitamin D and still seem healthy after only several months – which is the only data Dr. Vieth provided. Our attention is directed towards long-term outcomes, time windows which correspond to the slow growth of chronic bacteria and other pathogens that may play a role in causing chronic disease. Also, the full negative effect of immunosuppressants (recall that we have found that 25-D acts as an immunosuppressant) can often only be noted after decades.

25-D vs. 1,25-D and the long elusive search for biological plausibility

Most of the talks had us scratching our heads, trying to figure out why, when 1,25-D is the biologically active form of vitamin D and the sole vitamin D metabolite able to activate the Vitamin D Receptor (VDR), almost every speaker focused on research and recommendations pertaining to 25-D levels. For a brief discussion of the different forms of vitamin D see my (Paul’s) speech.

One of the points both of us tried to make in our own five minute presentations is that the levels of the different forms of vitamin D are jointly regulated by several feedback mechanisms. This means that if one alters the level of one form of vitamin D, levels of the other vitamin D metabolites will almost certainly shift to accommodate the change.

It seems prudent then, that if a study measures 25-D levels, it should measure 1,25-D levels as well. Without the ability to examine the relationship between the two main vitamin D metabolites, how can a researcher fully understand the spectrum of the changes that occur when vitamin D supplementation takes place? Over a decade ago, even the FDA suggested that “1,25-D should be measured in order to support claims of a drug’s osteoporotic activity.” Yet few researchers seem to have heeded this advice. Thus, we would venture to say that studies absent levels of 1,25-D should at least be regarded with less rigor than those studies that test both metabolites.

At some point in a discussion with the Committee, one of the experts mentioned how 1,25-D is difficult to detect. We hope that doesn’t serve as an excuse for not testing 1,25-D. Since most major laboratories – including Quest Diagnostics – can easily perform the test, we would expect any vitamin D researcher would be able to do so as well. The real reason 1,25-D might be “hard” to test is that the 1,25-D test costs more than the 25-D test. But we’re all trying to do the best possible research… right?

The potential significance of 1,25-D is suggested in a forthcoming study published in the Annals of the New York Academy of Sciences. In the study, Dr. Greg Blaney of Vancouver, Canada reported on the 25-D and 1,25-D levels of 100 patients with autoimmune disease.

While many of the subjects had very low levels of 25-D, even more of the subjects (approximately 85%) had levels of 1,25-D elevated above the normal range. Under these circumstances can those subjects with low levels of 25-D but elevated levels of 1,25-D truly be considered vitamin D deficient? They are certainly not deficient in the sole form of vitamin D that actually activates the VDR to transcribe approximately 913 genes, TLR2, and the antimicrobial peptides vital to the innate immune response.

When Dr. Heaney was asked to comment on 25-D’s actions by a member of the committee he admitted that he did not know, biologically speaking, how 25-D exerts any of the myriad beneficial effects that he claimed occur when it is elevated. All he could offer was that he knows that 25-D must be present in patients for them to get better.

Is this what passes for biological plausibility among pro-vitamin D researchers?

Later that afternoon, one committee member asked Dr. Cedric Garland, “Do you have a mechanism to explain the outcomes you’re reporting?”

Dr. Garland proceeded to offer his analysis for how supplemental vitamin D, in his words, “eradicates” cancer. Garland pointed to a stack of his papers and asked that it be passed out. When members of the committee seemed hesitant to do so, he went on to explain the details of his model anyway. Dr. Garland shared that he had developed a novel pathogenesis for cancer in which cancer is caused by gaps between cells, which, in simple terms, he believes form as a body becomes vitamin D deficient. This line of inquiry was clearly only in its infancy and had not yet passed muster with cancer researchers. But even if Garland’s model proves to be valid, one would have hoped he would expose it to great scientific scrutiny before using it as the basis for making unequivocal recommendations regarding vitamin D supplementation.

But as Dr. Garland went on to further describe what he believes are vitamin D’s cancer benefits (he was eventually cut off by a member of the committee), he provided a perfect example of the vitamin D expert that we have trouble following. The reason? He used the broad term “vitamin D” when making claims and by doing so, mixed up research that pertains solely to 25-D or 1,25-D. For example, Garland said that vitamin D is able to “upregulate tumor suppressor genes.” Most audience members probably thought he was referring to 25-D since that was the only vitamin D metabolite he ever mentioned. Yet, only 1,25-D is able to activate the Vitamin D Receptor to express Tumor Metastasis Suppressor 1 and other related genes.

Similarly, another talk that we believe should have discussed 1,25-D levels but did not was Dr. Stephanie Atkinson’s remarks on vitamin D in pregnancy. That is because researchers have realized for some time now that 1,25-D is over-expressed during pregnancy. Placental conversion was demonstrated in vitro in 1979, over-expression of 1,25-D in vivo in 1980, and the dysregulated vitamin D metabolism was described in 1981. If 1,25-D becomes elevated during pregnancy, then isn’t it only prudent that studies on vitamin D and pregnancy should measure it and its relationship to 25-D?

We find the relationship between 25-D and 1,25-D important, because it was by observing relationships between the two metabolites that our group was able to realize that in the majority of cases, when a subject’s 25-D level is low, their 1,25-D levels are actually high (AIDS is an exception because HIV completely co-opts the VDR). And it was these relationships that led to our alternate hypothesis for the low levels of 25-D observed in patients with chronic diseases such as cancer. We have found that when 1,25-D is high, the vitamin D feedback pathways naturally downregulate levels of 25-D. This means that what is now viewed as “deficiency” could simply be a result of the chronic disease process. Under such circumstances, allowing people to create extra 25-D by raising the DRI is not only useless but harmful. We believe that our alternative hypothesis at least deserves consideration by the committee, yet are worried that when they are not presented with data on both 25-D and 1,25-D, they will not be able to recognize the pattern that makes our model plausible.

Vitamin D and the evolving definition of autoimmune/inflammatory disease

We also find it problematic that none of the experts who spoke at the meeting seem to be aware that microbial metabolites have a profound effect on the activity of the Vitamin D Receptor (VDR). The US NIH now estimates that 90% of cells in the human body are bacterial in origin while only a mere 10% of cells in the body are truly human. Thus, many microbiologists now believe that humans are best viewed as superorganisms in which a plethora of bacterial gene products can effect the activity of our own receptors and genetic pathways. Indeed, independent research teams have found that Mycobacterium tuberculosis downregulates VDR activity by approximately 3.3 times. Active Borellia lowers VDR activity by about a factor of 50 and Epstein-Barr Virus by a factor of around 10. HIV completely shuts down VDR activity. It’s quite likely that other pathogens yet to be fully characterized have also evolved ways to decrease VDR activity because by doing so, they slow important components of the innate immune response that might otherwise render them dead. That the experts who spoke before the committee have failed to factor this knowledge into their study designs suggests that they cannot fully account for the actions of the various vitamin D metabolites in an in vivo environment.

Furthermore, no vitamin D researcher, of whom we are aware, makes provision for research which shows that the current view of autoimmune disease – in which the immune system is believed to attack itself – may be running its course. Many microbiologists now believe that at least some, if not all, of the inflammation that drives the autoimmune disease state is caused by the presence of chronic pathogens.

Inflammation is a clear potential link between infectious agents and chronic diseases.

Siobhán M. O’Connor

With this in mind, the claim by many vitamin D researchers that vitamin D can help patients with autoimmune disease by slowing an “over-active” adaptive immune response no longer jives with an emerging view in the microbiology/immunology community – that both the adaptive and innate immune systems should be kept active in autoimmune disease in order to allow the body to best target disease-causing microbes.

The possible presence of pathogens in autoimmune and other inflammatory disease states such as cancer and atherosclerosis makes our group’s findings on vitamin D’s actions more plausible. When the immune system is fighting a microbe, it continually releases inflammatory molecules in an effort to kill the pathogen. If the pathogen dies, endotoxins and cellular debris are generated. This leads to increased symptoms of malaise on the part of a person who harbors such microbes.

It follows that any substance that slows the innate immune response will decrease this battle between man and microbe, causing the patient to feel better. The more the immune response is slowed, the greater the decrease in inflammation and inflammatory markers. But while such measures can make the patient appear as if they are getting better for years, ultimately the bacteria causing their disease are able to spread much more easily and exacerbate the disease state over the long-term.

Our molecular and clinical data shows that 25-D, like the pathogens we describe above, binds the Vitamin D Receptor and slows its activity. Since the VDR largely controls the innate immune response, increasing 25-D levels could easily display the pattern of immunosuppression described above. This begs the question – is 25-D a miracle curative substance or simply an excellent palliative?

If we are correct and 25-D slows VDR activity then we have found that patients who are chronically ill benefit from decreasing their vitamin D intake. This is because their VDR activity already appears compromised by the pathogens they harbor. Yet this should not be interpreted to mean we think healthy people can’t consume vitamin D. However, our data suggest that healthy people can get the vitamin D they need by eating a well-rounded diet that does not include fortified foods and getting sun exposure similar to that of a person taking measures to avoid an increase in skin cancer risk.

Our speeches and the reaction to them

In our speeches, we raised the possibility that low levels of 25-D are caused by the inflammatory disease process and that taking vitamin D suppresses the immune response.

In total, the two of us spoke for 600 seconds, and we’re not sure we convinced anyone of anything. By all indications, a discussion of molecular mechanisms was outside the committee’s comfort zone. Most would probably say that they are uninterested in software emulations of molecular interactions, no matter how provocative or far-reaching the conclusions they imply. If we had to pin the members of the committee down on it, I think they would say that when it comes to our clinical trial, we needed better controlled data such as the kind we intend to generate as a part of our West China Hospital collaboration. For this reason, we opted for a more measured tone.

During Amy’s speech, a Dr. Holick sighting, seated in the front on the left.

During Paul’s speech, there was some tittering in the audience (not the committee). He saw one prominent researcher, who shall remain nameless, chuckling. For a moment, he thought he had spinach in his teeth or was trailing toilet paper from his shoe, and then he realized that, oh yes, he was telling 50 PhDs and MDs that their conclusions have the potential to be very misguided.

After the day’s business concluded, everyone began to file out. One woman though turned to us and said, “What a bunch of rebels!”

Glad we could liven up the workshop for you, ma’am.

Although during our speeches, we asked people to come by and ask us about our work, only Dr. Tony Norman did. He did not seem convinced, but did invite us to submit an abstract for a poster presentation at an upcoming vitamin D conference in Belgium.

Anticipating what is to come

If you ask most Vitamin D Council researchers, they would say that this is the “end game,” and there is already more than enough evidence to raise the level of vitamin D added to the food supply. During the question and answer sessions, some of these scientists such as Dr. Garland were dismissive of evidence to the contrary. It was as if many were saying, “Look – there is no downside here. It is demonstrably impossible that consumption of vitamin D can cause harm. If we don’t have all the requisite evidence, it doesn’t matter. Lives are at stake!” We suspect that even if the committee decides to maintain current vitamin D levels, there are other ways to convince the public to increase vitamin D intake.

But despite the media’s stampede to promote the “sunshine vitamin,” the evidence is ambiguous and the issue of biological plausibility – not knowing how 25-D exerts its claimed benefit – is troubling as well. Dr. Kramer said that the root of science is the art of thinking hard about how you could be wrong. Is this something the vitamin D research community is actively doing? Looking through everything that was presented throughout the day, how many confounding variables might Dr. Kramer have identified? How many surrogate outcomes could he point to?

It is difficult to anticipate exactly what decision the IOM Committee will arrive at. However, from this perspective, it would be hard to see how the group could raise the dietary reference intake in light of such an equivocal set of conclusions in the Tufts report – in spite of considerable pressure to do so.

Will an IOM committee ever emerge from this climate of consensus and consider research that would cause them to lower the DRI of vitamin D?

Here are a few possibilities:

• An evolution in the understanding of disease raises new concerns about the risks of using immunosuppressants. The Human Microbiome Project shows that bacteria are not confined to the surfaces of the body, i.e. skin, mouth, gastrointestinal tract, etc. As chronic disease is increasingly characterized as an infection or at least having infectious components, researchers seriously question if reducing the inflammatory response needed to kill chronic pathogens is in a individual’s long-term interest.
• After continuing to increase vitamin D consumption to historic levels, members of the public and some researchers begin to question the absence of the promised overall drop in rates of disease. In some respects, the decision of the IOM committee is immaterial. All indications are that the vitamin D “experts” are having a great deal of success communicating their message that it’s important to take 4-5 times or more the current DRI of vitamin D. People will take increasing amounts of vitamin D as food manufactures will add increasing amounts to their products. Many of the presenters at the Workshop essentially promised double-digit declines in disease. If this does not materialize, there will be questions. If we are right, this could be the hormone replacement therapy (HRT) saga redux, except with potentially broader ramifications.
• Well-controlled long-term studies show that vitamin D consumption increases incidence and severity of chronic disease. To most people – probably in excess of 95% of people at the workshop – this is not even a possibility, but the history of HRT use proves such unexpected results can emerge, eventually, from well-controlled studies.

Epilogue: The ride home

After the meeting adjourned, we were approached by a nattily attired man in his thirties, originally from Barcelona. He offered us a ride home to New York. His Mercedes SUV looked quite appealing, so we skipped the bus and took him up on his offer.

On the ride home, this fellow – who told us he had a PhD in oncology – told us he agreed with the sentiment of our remarks and expressed disappointment with the lack of rigor of the science presented. The word he used to describe the majority of presentations was “pseudoscience.” He told us that, based on what he saw, vitamin D was harmful and that it was only a matter of time before the hype surrounding vitamin D would fizzle.

Although we felt validated, we wondered why he had attended the conference in the first place. It turns out that he was an entrepreneur, had just bought the patent for a new formulation of calcium, and wanted the discussion at the IOM workshop to help him decide how much vitamin D to add to his product.

He seemed like a honest and honorable guy until, that is, he let us know that despite his negative view of vitamin D, he intended to add high levels of it to his supplement anyway, so long as the medical community and public viewed it as beneficial. Later on, he said, he planned to strategically remove it “just before the vitamin D bubble bursts.”

Well, isn’t that wonderful? Some reassurance about the people behind products aimed at “improving our health.”

In that vein, we couldn’t help remembering the short speeches delivered by members of the Dairy Council as well as a yeast company, whose goal in speaking before the Committee were simply to urge the Committee that, if more vitamin D is added to the food supply, it should be added to the food they market. This would give these interests the ability to claim more health benefits from their food and, of course, make more money.

In sum, our adventure in the nation’s capital left us with a bad taste in our mouths. We’d like to wash it away but we’re worried that by the time we do so, no drink won’t be fortified with vitamin D.

Parkinson’s disease (PD) is a degenerative condition affecting movement and balance in more than one million Americans each year: its prevalence is expected to rise in aging populations.

The men were followed for three decades. At that point, 128 men had developed Parkinson’s. But… cue drum roll… the risk of Parkinson’s disease increased as the amount of milk consumed each day rose. Heavy milk drinkers, who drank more than 16 oz a day, were 2.3 times more likely to develop Parkinson’s disease than those man who didn’t drink any milk. Milk was related to PD whether it was whole or skim.

One may ask, “Why?” The beautiful person with the milk mustache in the latest magazine add told me milk was good for me!

Perhaps it’s the calcium? Nope. The team, under Dr. Park, used careful statistical analysis to rule out the possibility that calcium could have caused the increased disease incidence. “In addition, calcium intake from non-dietary sources was not related to PD, further suggesting that a role for calcium in altering PD risk is absent,” states the paper, which was published in the March issue of the Journal of Neurology.

Total fat and protein also had no relation with the risk of PD. Park and team suggest that neurotoxins such as organochlorine, tetrahydroisoquinoline, and heptachlor may be to blame, but even they would concede that this explanation is speculative at best. In fact, according to the study’s authors, “Unfortunately, there are no clear explanations for the relation between milk intake and the risk of PD.”

What the researchers fail to even consider is that since the 1930′s, milk suppliers have been fortifying milk with vitamin D. According to, A. W. Norman in the book, Vitamin D: The calcium homeostatic steroid hormone, “There developed in the 1940′s, and continues to the present, a large business of industrial production of vitamin D3 used for the supplementation of foods for human consumption: milk (both homogenized and evaporated), some margarine and breads. Since the 1960′s vitamin D3 has been used also for the supplementation of farm animal and poultry food. In 1973 in the United States some 290 trillion (290 x 1012) International Units of vitamin D3 was manufactured and sold for over 3 million dollars. This vitamin D3 is the equivalent of approximately 8 tons.”

This strongly suggests that the men in the Honolulu heart study were drinking vitamin D fortified milk. With this in mind, the powerful secosteroid incorrectly labelled “vitamin” D seems like an extremely logical culprit for the rise in PD amongst subjects drinking higher amounts of milk. As described in this recent paper, vitamin D’s steroidal properties allow it slow the innate immune response. While this allows for palliation and symptom reduction in the short-term, it causes chronic bacteria that very likely contribute to the progression of PD to proliferate more easily.

When writing previously about vitamin D, I’ve argued that, “One of the abiding weaknesses of studies on vitamin D is that researchers do not follow subjects consuming the secosteroid for a sufficient period of time. Instead they track subjects over the course of weeks, months, or one or two years, during the period of time when study participants are usually feeling the palliative effects of the secosteroid. Researchers will rarely, if ever, track subjects over the course of decades, the length of time needed to begin to note the negative changes that chronic bacteria cause later in life.”

So hooray for the authors of the Honolulu Heart Study who spent the time and money to monitor subjects for 30 years after their dietary intake was reported. Clearly, when it comes to vitamin D, patience is needed for the negative impact of consuming the secosteroid to be noted.

Another clue that vitamin D likely caused the increase in PD risk among men drinking more milk in the Honolulu study was that consumption of cheese and ice-cream did not affect PD risk. The explanation? Although these products are made from milk, they are generally made from milk before it has been fortified with vitamin D.

That Park and team did not even consider the vitamin D in milk as a possible cause for the increase PD among men consuming more of the substance speaks to the incredible strength of the current consensus that fails to recognize the immunosuppresive properties of vitamin D. This is bound to change, but in the meantime, vitamin D fortified milk should at least come with the message, “Immunosuppressive steroid included at no extra charge!!”

Our group in front of the Karolinska Institute

The Marshall Protocol epitomizes translational medicine, which is why, in my opinion, our poster presentations at the Conference were, for the most part, viewed with great interest and optimism.

The researchers who filled the lecture and poster halls at DMM had travelled to Sweden from the most prestigious universities in the world. It didn’t take long to realize that many of them have spent their entire careers looking for faulty genes that might be able to cause mental illnesses such as autism or obsessive-compulsive disorder.

The problem with such research is that the genetic mutations found in people with mental illness can easily be attributed to the fact that, once inside the body, the Th1 pathogens mutate our DNA. Thus, as a person acquires a significant bacterial load, mutations become more common and can even be passed from generation to generation. This alternate hypothesis for genetic mutations in people with various mental illnesses has been largely ignored by mainstream medicine, a fact confirmed by the talks at DMM. Many researchers spoke of only 5 -10% correlations in the genetic mutations found among patients with a particular mental disease such as autism. As I sat through lectures that discussed such correlations, the reality that only pathogens can cause such a diverse array of mutations became increasingly clear.

One might think that researchers looking for a purely genetic cause of disease would have become discouraged by this point. After all, as one of the researchers who gave a talk admitted, back in 1990 geneticists were sure they would identify direct correlations between specific genes and specific diseases by 2000, allowing them to cure most forms of illness. But the researchers at DMM seemed determined not to see this as a sign of failure. Instead, they put forth a new philosophy – namely the idea that genetic research has failed to generate any successful treatments because it has proved to be much more complex than expected. So, based on this notion of complexity, the geneticists at the Conference have yet again pushed back the date at which they expect to find a way to treat mental illness using gene therapies. Those of us familiar with the MP realize the date will be pushed back endlessly until pathogens are finally recognized as the agents causing the complex mutations observed by so many researchers.

After a talk on the genetics of obsessive-compulsive disorder, I threw my arm up in the air. By that point, I had realized that I would be given one of the few opportunities to ask the researcher a question, only if I did some serious arm flailing. “Have you considered pathogens?” I asked. “Have you considered the fact that perhaps the reason you are finding such random genetic mutations among your study subjects is because the mutations are simply the result of active changes to the DNA created by bacteria?” Dr. Matthew State of Yale University, who had given the talk, was thoughtful in his response. He agreed that certain environmental factors could be contributing to cognitive disease, and that pathogens are among these factors. The audience seemed interested in his response. Perhaps, like me, they were wondering just how complex genetic research will have to get before they are given any concrete explanations from geneticists about how to treat so many severe cognitive diseases.

Much of the research presented at the Conference focused on mice, and how we could poke, prod, and medicate them towards becoming alternately quicker learners and more chipper. And what would a neuroscience conference be without mice running mazes? We were not let down, as many researchers at the Conference had created novel ways to test the cognitive abilities of their furry subjects. In fact, one researcher whose talk hadn’t focused on mice squeezed in some data on rodents at the end of his speech, joking that he wouldn’t be believed unless he verified his data on mice. Again, I found it difficult to see how the implications of such studies on rodents could be applied to human beings, particularly since I’m well aware of the fact that the rodent VDR and immune system is vastly different than that of humans.

All of the speakers gave concise, deliberate presentations, and I have a lot of respect for the sophisticated techniques they have mastered in order to conduct their research. It’s just that the DMM’s aim is to stress translational medicine. At a Conference that is supposed to demonstrate how basic research can drive clinical care, none of the data presented by geneticists can be used to actually help even one person with any type of mental illness.

While the lectures inside the grand auditorium at the Institute focused largely on genetics, three posters lingered in the poster hall that implicated pathogens, rather than genes, as the cause of chronic disease. These posters were, of course, the posters created by Dr. Marshall, Meg Mangin, and myself.

Dr. Marshall lucked out in the sense that his poster slot was #53 – meaning that, because of the way the posters were positioned, his poster was the first one every person saw as they entered the poster hall. Just around the corner from his poster were Meg and her poster. This provided an excellent atmosphere in which people could learn about the MP. First, researchers would wander over to Dr. Marshall’s poster where they would get an in-depth explanation of the molecular science behind the treatment. Then, they would turn the corner and Meg would explain the practical side of the science – the way it has been used to create a medical treatment in which patients are monitored over an open study site.

It didn’t take long for people who spoke with Dr. Marshall and Meg to realize that Autoimmunity Research Foundation was the only group at the conference truly exemplifying translational medicine. For this reason, his work attracted many visitors. It didn’t hurt that Dr. Marshall had two small video players velcroed to his poster that ran videos of L-form bacteria inside the blood of a patient with CFS. The blood, which is absolutely overtaken by long biofilm tubules with bacteria inside, was a rather large wake-up call to those researchers who incorrectly consider the blood to be sterile.

In fact, Dr. Marshall was an endless source of electronic gadgets at the Conference. Out of a meticulously packed suitcase came small video cameras, recording devices, computer cables, and essentially any other device that successfully allowed Paul Albert of Weill Cornell Medical College – who came down to help with the technical aspects of the conference – to videotape large segments of the Conference. If Paul was missing a device, be it a cord or tripod, all he had to do was ask, and Dr. Marshall inevitably had it on him. It’s clear that focusing on molecular biology has not prevented Dr. Marshall from keeping up with the latest electronic trends.

My poster

My poster was on board space #89, which was on the far side of the auditorium. I was glad that my poster was separated from Dr. Marshall’s and Meg’s posters because people who wandered down the left side of the auditorium would hear me speak first and my poster seemed to spark enough interest so that they would continue on down the line to Dr. Marshall’s.

But the hypotheses put forth on my poster interested people in their own right. For starters, I was pleasantly surprised that everyone whom I spoke with seemed to realize that Chronic Fatigue Syndrome is an extremely debilitating disease with a very serious mental component. Nancy Pederson, the associate dean at Karolinska Institute, made a point of coming over to my poster because she is actually studying Chronic Fatigue Syndrome in identical twins. She admitted that her group is not finding any significant genetic trends among their study subjects. So her team is considering pathogens, namely viruses. We proceeded to discuss how the viruses observed in some of her study subjects might just be co-infections, co-infections that are able to take advantage of the immunosuppression generated by bacterial blockage of the VDR. She seemed interested. In her case, and in the case of others, I found people constantly picking up my handouts, my brochures about Autoimmunity Research Foundation, and my business card for Bacteriality.

I discussed several topics that related to my poster, but women in particular seemed extremely interested in understanding why women often feel better during pregnancy, then relapse after giving birth. The reason being that during pregnancy the active vitamin D metabolite 1,25-D rises to extremely high levels, interfering with the activity of the nuclear receptors that control many families of antimicrobial peptides. Because the peptides are produced at a much lower rate during pregnancy, women experience much less bacterial die-off and subsequent relief during that time. However, because women with Th1 disease are immunocompromised during pregnancy, the Th1 pathogens they harbor spread easily, causing them to feel worse after giving birth when 1,25-D drops back into a lower range.

A lot of people admitted that what I was putting forth “just really made so much sense!” After hearing so many complex explanations about the genetics of mental diseases, I guess Dr. Marshall’s hypotheses seemed exceptionally logical. I spent a long time discussing the scientific topics on my poster with Dr. Yujiang Shi from Harvard. After he had absorbed the details of the Marshall pathogenesis, he literally turned to me and stated confidently, “You know, Dr. Marshall is going to win the Nobel Prize.” I said, “Yes, I know!”

The concept of the poster hall is a good one because food is served at the back of the hall, meaning that anyone who wants to eat has to walk by all the posters in the process. Then, they can take their plate of food and wander around looking for posters that catch their eye. I didn’t have time to eat. Before I could even reach for a plate of food, someone had come over to my poster and wanted an explanation. Dr. Karl Deisseroth from Stanford (who later presented an amazing talk about new technology his team has developed to track the action of neurons in the brain) again commented that he was very open to the idea that chronic inflammatory diseases might have a bacterial cause. I spoke to several doctors who seemed eager to try the MP on their patients, particularly doctors who worked with children with behavioral disorders. Most seemed amazed that we were actually putting forth a potential treatment backed by so much scientific data.

Every so often I would glance down the hall and see Dr. Marshall’s yellow shirt and red tie gleaming under his jacket. He seemed to be talking non-stop as well. On the first day, I actually lost my voice for a while because of the fact that I talked so much.

The poster right next to mine that detailed how to create an immunosuppressive drug

Because of its location, my poster was quite close to the poster of the researcher next to me. He was a researcher from Northwestern University who sadly was presenting data that might allow for the development of yet another immunosuppressive drug. I have to say that people walked right by his poster and over to my poster instead. At one point, a good natured older man appeared behind me and tapped my shoulder. He said, “Your poster is getting so much attention, it’s too bad that you’re standing between me and my money.” I realized that he had funded the research for the immunosuppressive drug and that the crowd looking at my poster was largely blocking the poster about the medication. I tried to move over to the side, but at that exact moment one of the deans of the Karolinska Institute barged right in front of the other scientist’s poster to ask about mine. The older gentleman sighed and walked away. Any feelings of sympathy were short-lived as I was happy to see that people were more interested in the MP than immunosuppressive drugs.

A researcher a few posters away had travelled to the conference from the Longevity Institute in Japan. He was working with VDR knockout mice. He was so excited about Dr. Marshall’s work that he spent more time by my poster than his own. At one point he even asked me if I would be willing to put my name on one of his papers. I told him that if I thought the paper was accurate, I would be happy to do so. I’ll see how that works out.

Some of the other talks at the Conference, those that didn’t focus completely on genetics, were actually quite interesting. A speech that focused on estrogen sparked Dr. Marshall’s interest. He was also extremely interested in a talk by Dr. Adriano Aguzzi from the University Hospital of Zurich about prions. Prions are small infectious agents made purely of protein that are believed to propagate by refolding abnormally into altered structures that accumulate in infected tissue, causing cell death and tissue damage. I’ll be writing more about prions in another article.

After the poster sessions and presentation ended on Friday, we had just enough time to return to the hotel, rest for about five minutes, and then get ready for a welcome reception at the Town Hall. The words “Town Hall” don’t spur thoughts of glorious architecture in my mind, but I soon realized that the Stockholm Town Hall is an exception. When we entered the gates, we found ourselves just steps away from the water with slim arches bending gracefully over our heads.

Upon entering the reception hall we were offered glasses of wine. The head of the Karolinska Institute gave an inspiring welcome speech, to which we all responded “Skål!”, which is an all-purpose Swedish toast. At that point I started to realize, “Hey, I’m really here. This is the place where the top minds in medicine get together to advance the understanding of medicine.” A little chill ran down my spine as I gazed out the window at the beautiful buildings across the water that were illuminated in the setting sun.

Next, we made our way along a table replete with a smorgasbord of food which unfortunately consisted of a large variety of delicious looking salmon and other fish. Luckily, there was a large platter of Swedish meatballs that saved me from starvation.

Soon, we were ushered on a tour of the entire Town Hall. Having failed to read anything about the Stockholm Town Hall, I was amazed to walk into a room in which the walls were literally made of gold and a massive image of the maternal figure symbolizing Stockholm gleamed on the opposite wall. After that, we entered the “Blue Hall,” the space in which the Nobel Prize banquet takes place on December 10th every year. We then proceeded to enter an ornate room where the Stockholm city council meets. Finally, we ended up standing at the bottom of a tremendous stone tower that is one of the city’s landmarks.

Dr. Marshall and me at the Andy Warhol exhibit

It was tough to leave and go back to the hotel, but I needed to sleep so that I could present my poster with zeal the following day. After another day of long and successful talks and presenting our posters, we were bused to the Museum of Modern Art. First, we were given a tour of the Museum’s Andy Warhol exhibit, which was very well done and included many multimedia effects in an attempt to create an atmosphere that mimicked Warhol’s lifestyle. Dr. Karl Deisseroth from Stanford alerted me to a video which showed a transvestite slowly eating a banana. We had a good laugh over how eccentric Warhol was. Since Warhol’s art clearly reflects the fact that he suffered from anxiety, depression, and other mental afflictions, I could almost see each scientist there trying to come up with their own explanation for his cognitive issues. My biases are more than a little obvious– I think Warhol was just suffering from a tremendous number of Th1 pathogens.

Dinner was served right on the waterfront with a view of the old Swedish city across the water. Towards the end of the meal, Dr. Kenneth Chen of Massachusetts General Hospital and Harvard Medical School, one of the conference organizers, stood up to give a toast. After his own short speech, he selected other important members of the audience to stand up and give a few words about the Conference. I was half-listening, half-eating my delicious piece of steak, when I heard him ask Dr. Marshall to give a short speech. Dr. Marshall has attended the DMM Conference for the last three years and is thus something of a veteran. Dr. Marshall spoke about the importance of translational medicine, which, of course, is the focus of his work. As his words blended with the clinking of wine glasses and the lights of the beautiful buildings across the river, I felt an immense sense of pride in Dr. Marshall. I admire his relentless drive to push forward his scientific discoveries, and to consistently attend conferences even when some researchers dismiss his work. Now, here he was, being given the same recognition as any other scientist at the event.

Paul and Liz passing through the entrance to the Warhol exhibit

During those rare moments of down time, I chatted with Meg, her husband Tom, and Dr. Marshall’s wife, Liz. I’ve known Meg for three years over the internet so it was great to finally meet her in person. She’s spunky, fun, and full of interesting stories. Her husband Tom took full advantage of being in Sweden. Instead of attending the Conference, he spent most of the time at an Irish pub where he made friends with several Swedish natives, one suspiciously named Jim Beam. In fact, both Meg and Tom love Irish pubs. Meg even has her own special toast, part of which Paul caught on video. We discussed how, to a great extent, there are two different Megs. There is professional Meg who must be very careful about adhering to FDA regulations on the study site, and then there’s fun, laid-back Meg who loves to travel and has eight adorable grandchildren. Tom told me about the fact that Meg answers questions on the MP Board from the moment she wakes up until the moment she goes to sleep. He does all the shopping and cooking. Even when they go out to eat, Meg takes her laptop along so that she can post on the study site during the time when they are waiting for the food to arrive.

The Conference was partially sponsored by Cell Press, a group that runs a number of medical journals. The staff from Cell Press didn’t seem very interested in the MP. For one thing, I think they simply weren’t prepared to hear an explanation for chronic disease that was so different from those explanations offered by the lion’s share of articles their journals feature these days. As Dr. Marshall has commented, the editors of medical journals are petrified of publishing something that may turn out to be wrong, and perhaps the MP seemed almost too good to be true.

Interestingly, the representatives from several drug companies were very interested in my poster. A man from AstraZenica asked me a lot of questions. I told him that if his company wants a heads up, they should start creating drugs that prevent the formation of L-form bacteria. He laughed, but it may not be that long before he realizes that I was completely serious. At the museum dinner, I sat across the table from several drug chemists who told me they were disappointed that none of the speeches had really given them any clues about how to create more effective drugs for mental disease.

Their comments reenforced my belief that, at the moment, the timing is ripe for acceptance of the MP. Drug companies have little to work with in order to create palliative drugs for mental illness or illness in general. Genetic researchers claim they need a few more decades before their work will be able to help patients. Meanwhile, doctors are getting restless. They are tired of telling patients, “I can’t explain your illness and I can’t help you get better.” These doctors are increasingly attracted to the MP, or at least they were at Karolinska. Presenting information about the MP in person made a big difference. It makes me wish that I could sit down with every doctor and give them a 15 minute talk on the MP.

Giving my lecture on the MP to a group of Swedish patients

The day after the Conference should have been a day of rest, but I had made a commitment to give a speech about the MP to a group of Swedish patients and doctors who were interested in the treatment. Aside from having a few difficulties when it came to balancing the microphone and my script in the same hand, it went well. Everyone seemed open-minded. One lady in particular, in the front row, kept nodding her head as I moved from concept to concept, as if all of a sudden her disease was starting to make sense. At the end of the presentation most patients seemed eager to do the MP. However, the Swedish government prevents them from doing any treatment that is not deemed “standard.” My message to the group – go to Norway, a country nearby that allows doctors to do the MP without a problem. I hope they follow my advice despite the obvious hardship such advice entails. I’ll be creating a video version of my speech that should be up on this site soon.

On Sunday, after the conference had finished, all of us took the bright red #47 bus down to the Stockholm Square. By that point, I had realized that everything in Sweden runs smoothly. The buses come exactly on time. There is no traffic, the streets are so clean that sometimes the buildings look as if they are part of a movie set. In Sweden, an elevator is called a “hiss”, a term which makes me smile. It took me a while to learn that in Sweden hiss doors do not open automatically, rather they must be pushed open by the people inside. Particularly during the first days of the trip, I would forget this fact and wait inside the elevator for the door to open, much to the amusement of the Swedish people around me.

The Square was lined with other architectural masterpieces. Again, we could gaze out over the water and watch boats dock into the harbor. I had been looking forward to seeing the Square. After all, it’s the place where almost 20 years ago Dr. Marshall realized that sunlight plays a role in exacerbating chronic disease. He had been told that people in Sweden barely ever get enough vitamin D, but while waiting for a walking tour of the Square, sun streamed down on his face, and he felt physically ill. It was at that point that he started to question whether the current dogma on vitamin D and latitude makes sense.

Paul Albert encouraged Dr. Marshall to re-enact his eureka moment, which he did while standing in nearly the exact same location he had decades before. As I watched him joke around with Liz in an effort to recreate the moment, I was struck by how far he has come in the 20 years since that walking tour. I was struck at how far all of us on the MP have come, in terms of being part of a movement that will change so many paradigms in the medical world. I also marveled about the implications of the Marshall pathogenesis and how the best is yet to come.

Below is a link to a video created by Paul that chronicles some of what I have described above:

Here is a link to a second video clip which contains “outtakes” that did not make it into the main video:

A few days ago, researchers at Stanford University released the results of a study that tracked the effects of a drug called Sutent on patients with kidney cancer or gastrointestinal stromal tumor (GIST). Sutent, which is widely being tested for the treatment of several other cancers, works by starving tumors — stopping them from growing blood vessels to feed themselves.

Fifteen percent of study subjects taking Sutent developed heart failure, a chronic condition in which the heart loses its ability to pump blood properly. Sutent, made under the generic name sunitinib by Pfizer, has also been shown to damage heart cells.

The study, presented at a meeting of cancer specialists, confirmed the results of previous studies, such as one published in the December issues of the Lancet, which found that half of 75 patients with GIST who took Sutent in a clinical trial developed high blood pressure, 8 percent developed heart failure, and two had heart attacks.

Nevertheless, the American Society of Clinical Oncology still encourages the use of Sutent in patients with GERT and kidney cancer. Why? Because as they stated at a recent meeting, the drug causes “risky” but “reversible” side-effects. Apparently the council feels that while heart failure is serious, it can be treated with a variety of yet more drugs – each of which elicits its own plethora of side effects.

How sad is the Society’s view on Sutent? The medical community’s ability to effectively treat patients with GERT and kidney cancer has sunk to such a low level that they are actually willing to give patients with the diseases a drug that will almost certainly destroy their cardiovascular system in the process of palliating their cancer. And cardiologists, the FDA, and the public actually accept this bleak reality, most without raising an eyebrow, because this is what we have come to expect from a medical world that fails to recognize bacteria at the heart of inflammatory diseases such as cancer.

The Stanford study on Sutent came out just a week after Merck and Co., the makers of Vytorin, a combination of the cholesterol-lowering drug Zetia and the statin called Zocor, failed to meet the primary goal that the company intended – to slow the accumulation of fatty plaques in the arteries more than either drug alone.

Similarly, a recent trial of Torcetrapib, a drug that both raises HDL and lowers LDL cholesterol, was halted midstream because the drug seemed to cause heart attacks and strokes rather than prevent them.

Of course, Merck and Co are continuing to defend and promote Vytorin. The alternative is financial ruin. But the tragic reality is that even if Vytorin, Sutent, Torcetrapib, or any of the other drugs made by major drug companies end up pulling in less of a profit, they will make other palliative drugs in their place: drugs that still fail to target the root cause of chronic disease.

When will mainstream medicine accept the reality that nearly all chronic inflammatory conditions can be treated with a selection of low dose antibiotics and one ARB? Few, if any side effects included.

Certainly not while companies like Merck and Pfizer avert their glance from studies implicating bacteria in chronic disease and continue to churn out drugs that may kill patients but put money in their pockets. It certainly doesn’t help that the medical community and the public continue to maintain such low standards about how a drug should work – accepting as normal the idea that in many cases, even the dangerous side effects of a particular medication must simply be endured.

Let’s start with the simple fact that they have both been wildly successful. Microsoft has 79,000 employees, global annual revenue in the year 2007 exceeding $51 billion, and has made more than 12,000 of its employees millionaires simply by increases in stock valuation. Additionally, Microsoft’s market share for the operating systems on desktop computers, by one 2003 estimate, is 90%. Not bad for a garage startup.

In the United States alone spending on medical research is at or near the $100 billion mark in the year 2007. That’s about $300 for every man, woman, and child and more than doubles what was spent just a decade ago. According to Dan Fox, president of the Milbank Memorial Fund, a philanthropic group that works on health policy issues, the data in a recent JAMA review makes it plain that “we are spending huge amounts of money, more than any other country, to develop new drugs and devices and other treatments.”

Not bad for a profession that used to do double duty as barbers.

But perhaps the strongest connection between the multinational and the medical profession may be that both are, in some very key respects, failures.

Anyone who has ever seen the dreaded “Blue Screen of Death” or had their computer infiltrated by spyware, adware, or other kinds of malware knows the shortcomings of Microsoft software. Maybe Microsoft is an easy target for the technorati, too easy it would seem. But let’s face it– Microsoft has over the past few decades consistently churned out software which costs more, has more bugs, and hogs more memory than comparable software. Right up to the present, new software releases have been slow in coming and devoid of groundbreaking features. Certain releases, namely Windows ME and Vista– some versions of which retail in excess of $350– have inarguably added very little if anything to previous releases. One prominent commentator, John C. Dvorak, in his colorfully titled column, “Vista Death Watch” has argued that the latest operating system, Windows Vista should be completely scrapped.

Modern medicine, specifically medical research, may be in the same boat. Let’s concede that we all are very pleased that medicine has advanced to the point that a burst appendix can be safely removed, catheters can spring open blood vessels, and that eliminating wrinkles surgically is just a series of injections away– and with a toxin no less!

When it comes to chronic illness, at least in its traditional form, medicine has largely failed. According to mainstream medicine, what causes Parkinson’s Disease? What causes cardiovascular disease? What about fibromyalgia? Lyme Disease? Crohn’s, cancer, bipolar disease, depression? The consensus among medical researchers has been, “We don’t know.”

Now, maybe these conditions are all too complicated to unravel over the course of mere decades even for a world that spends hundreds of billions on medical research annually. For that matter, maybe it’s the case that having stable software largely impervious to malware is no less a pipe dream.

Even if these explanations are mostly true, the absence of real solutions for chronic illness is not good enough– not for the hundreds of millions of patients watching the best part of their lives pass them by. For all the sound and fury of medical discovery we catch wind of these days in breathless press releases (Eureka Alert!), what chronic diseases have been definitively cured in the last few decades? You can count them on one hand: stomach ulcers and cervical cancer.

Few would argue that medical researchers aren’t highly intelligent and capable or that Microsoft’s software engineers are the same, or that both groups contain people who are quite possibly the most intelligent and the most capable at what they do. If a failure of smartness isn’t the problem, then what is?

This essay examines the Open Source Software (OSS) movement as a model for a more evolved, more effective system of medical research. We look at four lessons from the OSS movement and try to apply them to medical research. Also, we look at how one treatment protocol for chronic disease, the Marshall Protocol, incorporates many of these lessons and may represent a model for future medical research in more ways than one.

Lesson #1: Use open review.

One of the most influential works in the history of open source development is Eric S. Raymond’s, The Cathedral and the Bazaar. In this essay Raymond argues that there are two contrasting software development models– the cathedral and the bazaar. In the cathedral model, represented by Microsoft, software is available for all to use, but the ability to contribute to the code is restricted to an exclusive group of developers– wizards Raymond calls them– who work in “splendid isolation.” In the bazaar model, the code for a project is developed over the Internet in full public view, Linux and Wikipedia being excellent examples. In theory, anyone so inclined can contribute.

The cathedral model holds that the key to success of a software project is the judgment and experience of a limited group of well-vetted and talented experts. Most proprietary software is necessarily developed using the cathedral model. In contrast, the bazaar model says, “Let’s engage as many developers as are inclined and qualified to participate.” The theory here is that the mistakes and red herrings of inexperienced or confused contributors is more than counterbalanced by an ability to rapidly improve the code given the fact that, as Raymond puts it, “thousands of eager co-developers are pounding on every single new release.”

Which model is more effective in software development? Raymond explains his thinking: “I worked hard… at trying to understand why the Linux world not only didn’t fly apart in confusion but seemed to go from strength to strength at a speed barely imaginable to cathedral-builders.” For Raymond, the advantage of transparency and openness is simple: “Given enough eyeballs,” he writes, “all bugs are shallow.”

The track record of a number of large-scale projects like the production of an operating system such as Windows XP seems to support Raymond’s opinion. The day Microsoft released Windows XP, the company posted 18 megabytes of patches on its website: bug fixes, compatibility updates, and enhancements. Two patches fixed important security problems. Or actually, one of them did; the other patch didn’t work. Microsoft suggested that users back up critical files prior to installing the patches. Buyers of the home version of Windows XP, however, discovered that the system provided no way to restore these backup files if things went awry. As Microsoft’s online Knowledge Base blandly explained, the special backup floppy disks created by Windows XP Home “do not work with Windows XP Home.”

Though it’s certainly not the case with all closed or proprietary software projects, really big systems are forever in danger of the “tar pit” as Fred Brooks called it in his book The Mythical Man-Month. A tar pit– I would argue that that phrase is as apt a description as any to describe the state of research into chronic disease.

Is medical research a bazaar or a cathedral? At least when it comes to chronic illness, I think it’s pretty clear that it’s the latter– the reason being that the Academy is just not open enough to opposing ideas. The results, or lack thereof, speak for themselves.

“Not only are pulmonologists unwilling to consider infection as the cause of sarcoidosis, but many have actively suppressed publication of articles that are at odds with their points of view.”One need look no further than the field of pulmonology. Not only are pulmonologists unwilling to consider infection as the cause of sarcoidosis, but many have actively suppressed publication of articles that are at odds with their points of view. Biomedical researcher Trevor Marshall, PhD, head of Autoimmunity Research Foundation explains, “Dr. Om Sharma from USC Medical Center has kept the lid on bacterial pathogenesis when dozens of researchers have implicated pathogens in the disease.” Marshall says, “Dr. Sharma has discouraged discussion about patients who received organs from people with sarcoidosis also developed the disease – evidence which strongly supports an infectious cause.”

As is the case with a lot of these “experts,” Dr. Sharma has authored or co-authored over 500 journal articles, some 70 reviews and sits on the editorial board of all the key pulmonology journals. It’s this last line on Dr. Sharma’s resume that has allowed him to effectively act as a gatekeeper for new ideas about sarcoidosis. Yet, even now, there is growing evidence that Dr. Sharma is mistaken in the worst way. What provision does medical research have for reining in the myopia of the Dr. Sharmas of the world? Is it really acceptable for medicine to advance but one funeral at a time?

Or, take the work of Dr. Alan Cantwell who has photographed L-form bacteria in the cells of people with cancer for decades now. Dr. Cantwell’s research into the so-called “cancer microbe” is strong. He makes a number of claims worth further investigation or, at the very least, outright rebuttal. Yet, the medical community has largely marginalized his work such that it hasn’t even attracted a fraction of the attention it deserves.

According to Dr. Cantwell, most pathologists who saw his specimens would practically refuse to admit that what they were seeing was bacteria. Few, if any, were willing to co-author a paper to that effect. “For the most part,” Cantwell said, “they didn’t want to get involved.”

Why the cold shoulder from all corners of medicine? Is it because we have figured out the “true cause” of cancer? Well, that’s not the case. Though we certainly know how diet and heredity can effectively change the odds, we still have only the faintest understanding of what actually causes cancer. Or, is it true that it’s simply impossible that bacteria can exist in the size and shape described by Cantwell? No, there’s no reason to think that it’s not bacteria, specifically L-form bacteria, to blame. Entire textbooks, namely Lida Mattman’s Cell Wall Deficient Forms– Stealth Pathogens, now in its third edition, have been devoted to the culture and life cycle of L-form bacteria.

Dr. Cantwell was asked to explain his colleagues’ refusal to entertain the idea that bacteria may be involved in cancer. He responded, “I think it’s because finding bacteria in illnesses that are not [thought to be] attributed to infection is highly controversial, and most doctors shy away from controversy.” But if that’s what it takes to open up the dialogue, isn’t controversy exactly what sufferers of chronic disease need?

If you paid attention to your bulk mail announcing fundraisers, you’d think that the only reason diabetes or sarcoidosis or any number of other diseases have not been cured is a lack of funds for research. This, in spite of the fact that the National Institute of Health alone spends $28 billion annually on medical research.

“You could spend ten times as much money on medical research and without changes to the process of how ideas get considered, that money would be better used as wallpaper.”You could spend ten times as much money on medical research and without changes to the process of how ideas get considered, that money would be better used as wallpaper. One of the enduring lessons of open source software development is that the best way to tame complexity is to open up the discussion to as many people and ideas as possible.

Andrew S. Grove is founder of the computer chip maker Intel. Now Grove is suffering from Parkinson’s Disease and a medical system that continues to test drugs on rats in the laboratory but offers little, if any, medical options for human beings who suffer from Parkinson’s and other chronic diseases. Recently, Grove has been publicly critical of the biomedical establishment, particularly academic researchers, who while successful in getting NIH grants and publishing research papers, seem to have little regard for whether their work leads to ideas or treatments that can actually cure disease.

“The peer review system in grant making and in academic advancement has the major disadvantage of creating conformity of thoughts and values,” Grove told a correspondent from Newsweek. “It’s a modern equivalent of a Middle Ages guild, where you have to sing a particular way to get grants, promotions and tenure. The pressure to conform [to prevailing ideas of what causes diseases and how best to find treatments for them] means you lose the people who want to get up and go in a different direction. There is no place for the wild ducks. The result is more sameness and less innovation. What we need is a cultural revolution in the research community, academic and non-academic.”

It should be a no-brainer: medical research, particularly when it comes to chronic disease, ought to be more like a bazaar. You could start with peer review. Peer reviewers are often well-intentioned, but the fact that only two or three anonymous “experts” can act as gatekeepers for what gets published in prestigious journals severely limits the dialogue. Let’s allow increasing numbers of self-selected people– amateurs, volunteers, marginalized scientists– to critique work too. Let’s then publish all reviews, positive and negative, online. To the extent that we can make medical research less like a guild, let’s do that too. Too often grants are awarded on the basis of past success in winning a grant. Do we really want to continue to reward old ideas? Not when those old ideas are failures! Is that any way to foster new ideas and new approaches? After all, until a researcher succeeds in curing a chronic disease, he is neither an authority nor an expert.

Lesson #2: Write software for yourself.

In 2005, BMG Music Entertainment started selling CDs that came with copy protection software. Unbeknownst to users, this software contained an evil bit of code called a rootkit. Rootkits are a set of programs or instructions that effectively subvert control of an operating system from its legitimate users. They might allow a third party to install keyloggers monitoring bank account information or turn your computer into a zombie and have it send out thousands of spam email messages. According to security researcher Dan Kaminsky more than half a million machines were infected by the rootkit. Since then, Sony BMG has been the subject of numerous lawsuits and eventually had to settle in a national class action suit.

What would drive Sony BMG to include rootkits with their CDs to say nothing of notoriously restrictive copy protection software? It all has to do with the bottom line. The rootkit was Sony’s heavy-handed way of preventing users from copying songs they had purchased. For the multinational conglomerate, the bottom line was protecting the profitability of their music artists even if it meant trampling consumers’ rights.

But, if you’re an open source software developer, your bottom line is straightforward as can be: solving your own technical problems. Eric S. Raymond writes in The Cathedral and the Bazaar, “Every good work of software starts by scratching a developer’s personal itch…. too often software developers spend their days grinding away for pay at programs they neither need nor love.”

“What if everyone researching Crohn’s Disease had Crohn’s Disease? What if all those investigating bipolar had that illness? How would research change? ”The open source model has been successful time and again. AWStats, the excellent log analysis program, was written by developers who needed to know the makeup and characteristics of visitors to their websites. VLC Media Player was written by programmers who wanted to play back a range of audio and video codecs unrestricted in the way that Windows Media Player or even iTunes is. It’s laughable to think that any open source developer would include anything on par with Sony BMG’s 2005 fiasco.

So, what if everyone who studied a chronic disease had that chronic disease? What if everyone researching Crohn’s Disease had Crohn’s Disease? What if all those investigating bipolar had that illness? How would research change?

To paraphrase Samuel Johnson, nothing focuses the mind so much as a trip to the gallows. In sum, I think you would see a greater sense of urgency, a better openness to new ideas, and an increased willingness to do away with ideas that have gone long past their expiration date (more on this last one later).

The remarkable thing about being a researcher of chronic disease is that you can spend entire careers without actually contributing anything useful to the understanding of it.

It’s not the fault of researchers, necessarily. It’s the way these professionals are rewarded for their contributions. As it stands, developing and investigating bonafide cures for chronically sick patients can all too easily take a back seat to getting published, getting funded, and getting promoted– “time, tender, and tenure,” Thomas Goetz calls it. As it stands, you are more likely to get funded if you have gotten funded. As it stands, you are encouraged to publish research which has positive results, even with the most tepid, toothless conclusions, because positive results get published.

If there was the least bit of urgency, you might see the serious reconsideration of a variety of treatments, starting with the use of corticosteroids for sarcoidosis. The 2003 ACCESS study, which was funded by the NIH, shows that two-thirds of sarcoidosis patients do not get better on current treatments and those that do see improvement are in no way correlated to whether or not they received treatment.

Given all this, you would think researchers would be interested in any broad reconsideration of what causes sarcoidosis. One such idea that sarcoidosis is actually an infection has been posed by Trevor Marshall among others. In fact, since 2002 when the Marshall Protocol treatment was first published– open source style, online– many patients have claimed recovery on the antibiotic-based treatment. Strangely, the response from sarcoidosis doctors, primarily pulmonologists, has been lukewarm at best. “We’re not even on their radar,” Marshall has said of the pulmo doctors.

You would think that a new idea such as this one, which was backed by molecular data, would receive less of a chilly reception. You would think that this is exactly the kind of big idea sarcoidosis researchers should be looking for. If it was their own skin at stake maybe they would.

Lesson #3: Openly and honestly size up failure.

When it comes to chronic disease, there is no failure more categorical, more disastrous than the autoimmune model of illness. Autoimmunity is the idea that– contrary to the forces of natural selection or the dictates of basic common sense– the immune system *somehow* goes haywire and attacks the body.

One way to measure the worth of a theory in medicine is to gauge how that theory can functionally improve what should be everyone’s ultimate bottom line: patients’ health. In short, all the anti-inflammatory, immunosuppressive, and palliative medications given to those suffering from “autoimmune illnesses” are failures. If I were being paid by the word, I could list hundreds of first line anti-inflammatory, immunosuppressive drugs that don’t cure hundreds of chronic diseases. Corticosteroids do not cure sarcoidosis. Neither hydroxychloroquine nor cyclosporine cures lupus. Prednisone does not cure multiple sclerosis.

Of this class of drugs meant to treat autoimmune illness, prednisone is typical. Patients taking prednisone complain of weight gain along with any number of other symptoms including itching, increased sweating, irregular or absent menstrual periods, inappropriate happiness, and irregular heartbeat– and that’s just symptoms beginning with the letter I!

First proposed in more general terms by Paul Ehrlich more than 100 years ago (horror autotoxicus he called it), this theory of autoimmunity has had a lot of time to be tested and refined. Instead, further investigations have only rendered the concept of autoimmunity more flawed and more complicated. Wikipedia lists five theories about what causes autoimmunity: the clonal deletion theory, the clonal anergy theory, the idiotype network theory, the clonal ignorance theory, and the suppressor population theory. What do all these mean?… Does it matter? The point is, as an idea, autoimmunity is a failure.

A healthy sense of proportion– some would call it succumbing to realism– is much more common in the realm of programming especially of the open source variety. In fact, one of the colorful but enduring proverbs of the programming world, seen in a variety of forms is, “All software sucks.”

Ron Avitzur has said during the development of his groundbreaking piece of software called Graphing Calculator that if your software was exceptional, fellow engineers would simply say, “This sucks less.”

Maybe if the medical research community could be a bit more philosophical about failure, certain ideas that have gone long past their expiration, namely autoimmunity, could have been unceremoniously discarded long ago. Some would argue that any kind of operating system Microsoft produces is doomed to be underwhelming given its tens of millions of lines of “legacy code,” and maybe that’s not such a bad analogy for the concept of autoimmunity as they both share any number of fundamental flaws.

“Maybe if the medical research community could be a bit more philosophical about failure, certain ideas that have gone long past their expiration, namely autoimmunity, could have been unceremoniously discarded long ago.”The problem for medical research is that it has made little to no provision for failure. With certain notable exceptions (i.e. Journal of Negative Results in Biomedicine) journals tend not to publish negative results, a phenomenon known as publication bias. The media tend not to cover studies showing the absence of a connection.

If a negative result is based on good science, why confine it to obscurity? Why would we want to, in essence, encourage researchers to produce positive results even if those results make no significant contribution? You get what you ask for, and our system is, in essence, asking for such results.

One thing medicine might quickly discover if, as a whole, it better embraced failure is just how ineffectual old approaches to chronic disease have been.

Lesson #4: Seek to rapidly deploy multiple versions of software by iterating incrementally and openly.

While Andrew S. Grove was at Intel, the number of transistors on a chip has gone from about 1,000 to almost 10 billion. Over that same period, the standard treatment for any number of chronic diseases has remained unchanged: L-dopa is still the standard treatment for Parkinson’s just as it was nearly half a century ago.

“I picked the semiconductor [transistor] industry because it’s the one I know; I spent 40 years in it, during which it became the foundation for all of electronics. It has done a bunch of unbelievable things, powering computers of increasing power and speed,” says Grove.

So, twelve years ago, when Grove was diagnosed with prostate cancer he immediately jumped into the advocacy movement, with the expectation that quick, deliberate action could push scientists in the field of cancer research in the same way that a drive for innovation and knowledge had inspired his team at Intel. But nothing happened. “I got disappointed with the lack of real output,” says Grove. “Not much has changed 12 years later.”

In the last 20 years, there are only two common chronic illnesses for which the cause has been established. I’m thinking here about cervical cancer, caused by the human papillomavirus, and ulcers also found to be caused by bacteria. Is this pace acceptable?

In January of 2007, Scott Rosenberg wrote a piece about the debacle that is Microsoft Vista. First began in 2002, the development of Vista was beset by a series of problems. Microsoft developers were ultimately unable to execute the original grand vision, which included a complete file system overhaul. As a result, the new operating system came in much later than scheduled and lacked many of the originally promised features. Rosenberg’s analysis: without discipline “too often, software teams get lost in what are known in the field as ‘boil-the-ocean’ projects — vast schemes to improve everything at once.”

Where did Microsoft go wrong? Some of the failures of process are touched upon elsewhere in this essay, but I would suggest here one of those problems was an inability to iteratively build upon their project by harnessing the power of their natural community, their end users.

Those who follow software development are familiar with the idea of “perpetual beta,” or that certain software is always being added to and improved upon. Popular examples of software that have had the label of perpetual beta include Gmail, Google Maps, and del.icio.us. For many developers, “perpetual beta” is an attitude as much as anything. It starts with the assumption that software should be better. Changes are rapid, but incremental. Testing and assessment are done frequently.

Even those of us eager for cures to chronic disease recognize that magic bullets do not magically arise as if willed to exist. They need to be worked on, worked over, the subject of productive consideration. Dialogue is the order of the day.

Jean-Claude Bradley practices something he calls open notebook science, which he describes as making his online laboratory notebook freely available and indexed by common search engines. The underlying philosophy, Bradley says, is as pithy as it is bold: “No inside information.” On his UsefulChem blog he and his collaborators share and discuss chemistry problems and on his UsefulChem wiki observations from experiments in excess of 150 are described and logged.

What do third parties do with this data? Maybe nothing. But then again, perhaps a failed experiment or an unanswered question– the programming equivalent of a feature request made before the open source community– could spark progress. It could be the key to new advances and new understanding.

Bill Hooker on the excellent 3QuarksDaily blog writes that “From our current perspective we cannot predict more than a fraction of the ways in which openness will transform the culture and practice of science.” The advent of collaborative science and the openness that drives it has the potential to help us refine our understanding of medicine at increasing speed.

“We cannot predict more than a fraction of the ways in which openness will transform the culture and practice of science.”A prime example of this openness is the world of genomics. Right now, anyone anywhere can search NCBI’s online gateway Entrez and dig into any number of mRNA, genomic DNA and protein sequences using some thirty interconnected and all freely available databases. It’s easy to see how these kinds of resources made freely available can really allow researchers to rapidly and iteratively build knowledge.

Even in the field of chronic disease, we have seen promising developments where clinical data is posted online and made freely available for inspection. I’m speaking here about the Marshall Protocol site. As of December of 2007, the MP site has 5,000 members and 125,000 posts, the vast majority of which come in the form of self-reported statements of progress. When it comes to the sheer scale of open clinical experiments, the MP may be in a class of its own.

Patients suffering from a variety of chronic diseases including fibromyalgia, sarcoidosis, multiple sclerosis, even autism are on the Marshall Protocol, a novel antibiotic-based treatment for chronic diseases which is in some respects the original inspiration for this essay. Using instructions that can be downloaded from the web, patients work in conjunction with their prescribing physicians to put the Protocol into practice: avoiding vitamin D and taking low-dose pulsed antibiotics as well as Benicar, a Vitamin D Receptor agonist.

While the science behind the Protocol hasn’t changed much since 2002 when it was first made available to patients, the site is designed so that each patient reports symptoms and reactions to medications in a weekly progress report entry. Not only are these progress reports open to other patients who can ask questions about data, or on occasion offer advice, but they are also open to analysis by the FDA (who actively monitor the site) or any other health care agency, think tank or organization who wish view the data. Any doctor, scientist, or medical researcher can become a member of a special forum for medical professionals, which not only allows them to view progress reports, but gives them a place to actively engage in discussions about specific cases and share ideas about treatment and research.

Another indication of this study site’s uniqueness is the chance to get feedback on one’s progress from nurses and researchers including, often enough, from the originator of the Protocol, Trevor Marshall. In fact, this is very similar to the open source software community where end users can be in direct contact with the developers from whom they downloaded the source code.

This is in marked contrast to most other treatments where a patient’s reactions usually do not go much farther than the doctor’s office. Under such circumstances, each separate case history ends up in a different place, almost always at a metaphorical dead end. Such reports go hidden from the eyes of the public, other researchers, and medical professionals who might under many circumstances offer important feedback or learn something.

With open clinical data, such as the kind on display at www.MarshallProtocol.com, patients can discover a thing or two from researchers themselves but also from each other. How will I react to Benicar? Have patients who share my condition really experienced the telltale reaction to antibiotics? These are all questions that can be effectively and convincingly answered by fellow patients. Such insights make a tough treatment that much more manageable, and it’s the openness that allows it.

Who can use this study site? The science behind the MP has broad application, so a range of patients with different conditions can participate. Almost no one is turned away. This is quite different from other clinical trials in which participants are required to fit specific inclusion criteria with the aim of accumulating the most homogeneous group possible.

Had the Marshall Protocol followed that model, how much longer would it have taken to confirm that the Marshall Protocol works to treat other diseases besides sarcoidosis? Surely, since Marshall’s first model was based on sarcoidosis, any other clinical trial model would have carefully excluded patients with other diseases, ailments, and symptoms. But it was by allowing patients with a wide array of symptoms to join his open internet-based site that Marshall soon collected data demonstrating that symptoms other than those related to sarcoidosis respond to Benicar and antibiotic therapy – a reality that would have taken decades for a standard clinical trial to reveal.

A parting thought

If the research medicine were anything like the open source software movement, study sites like Marshall Protocol.com would be springing up left and right as other researchers jumped on the possibility that their data might also have a greater impact if freely available on the Internet. You might also see a greater number of bad ideas relegated to historical curiosity.

Medical research today has all the turning radius of an oil tanker. As a whole, it is too slow to accept and instigate positive change, and any sensible person would be right to lay a good chunk of that blame on the process itself.

Innovation: how can researchers better innovate in the field of chronic disease? I argue that when it comes to innovation, the open source software community is particularly inspired– and instructive.

For those of us who truly care to fight chronic disease, what lessons can we learn? Release early and often. Iterate. Practice openness to the point of promiscuity. Collaborate. Embrace failure. No failed or failing system has to be as it is. We can be worlds more productive. Let’s get to work.

Mice have been used in labs for decades.

The answers to the above questions are important for anyone who hopes to fully understand chronic inflammatory disease. “Unraveling the intricacies of human [Vitamin] D metabolism is often made extremely difficult by the intermingling of murine [mouse] and human biologies in the literature,” says biomedical researcher Trevor Marshall PhD. Armed with an understanding of the differences between humans and mice, we can better determine the accuracy of the studies we are presented with, and detect the flaws in studies that do not support the correct model of chronic disease.

In an article in the Journal of Immunology, Javier Mestas and team at the University of California describe how there are significant differences between the way the rat and human immune systems develop, which affect “activation, and response to challenge, in both the innate and adaptive arms [of the immune system].” Such differences should not be surprising as rats and humans diverged somewhere between 65 and 75 million years ago, and differ hugely in both size and lifespan. According to Mestas, “They have also evolved in quite different ecological niches where widely different pathogenic challenges need to be met – after all, most of us do not live with our heads a half-inch off the ground.” Consequently, he argues that, “There has been a tendency to ignore differences and in many cases, perhaps, make the assumption that what is true in mice is necessarily true in humans. By making such assumptions we run the risk of overlooking aspects of human immunology that do not occur, or cannot be modeled, in mice.”

Multiple studies have demonstrated that the immune systems of rats and humans are inherently different. Molecular modeling research has revealed that the activity of the human innate immune system is controlled by the Vitamin D Receptor. In humans, the Vitamin D Receptor performs several fundamental roles. Not only does it control the activity of the innate immune system, but it transcribes 913 genes, and new research points to the fact that it may actually transcribe 27,091. It also controls the production of many of the antimicrobial peptides. These peptides kill bacteria, viruses, and fungi by a variety of mechanisms including disrupting membranes, interfering with metabolism, and targeting components of the machinery inside the cell.

In contrast, the rat innate immune system is not controlled by the Vitamin D Receptor. It is dependent on a cascade of nitric oxide (an important signaling molecule) that functions in a manner yet to be fully understood. Rats do have Vitamin D Receptors, but they transcribe different genes than the human VDR. By using molecular modeling software, researchers at McGill University in Canada found many differences in the genes targeted by the rat and human Vitamin D Receptors. For example, the gene encoding a calcium binding protein called osteocalcin is “robustly” transcribed by the VDR in humans, but not in mice. In what proves to be a fundamental difference between mice and men, Manisha Brahmachary and team recently determined that the rat Vitamin D Receptor does not express the cathelicidin antimicrobial peptides (AMPs) – marking an important difference in the way the two species kill invading pathogens. This means that rats and humans respond differently to molecules or drugs that affect the VDR and subsequently the innate immune system.

The mouse’s innate immune system is not controlled by the Vitamin D Receptor.

Consider for example, the medication Olmesartan (the generic name for Benicar). Biomedical researcher Trevor Marshall has used molecular modeling software to demonstrate that when Olmesartan is administered to human subjects it binds and activates the Vitamin D Receptor. Yet when Olmesartan is administered to rats it has the opposite effect – it turns the VDR off. In fact, Olmesartan does not bind into the rat VDR in the same way that it binds the human VDR. The rat VDR lacks the ability to bind a protein that would allow Olmesartan to attach to the receptor. In contrast, Olmesartan can bind the human VDR directly, allowing it to activate the receptor. These differences can be observed in a video that Marshall presented at the 2007 Days of Molecular Modeling Conference.

Many of the genes that the VDR transcribes are known to be associated with the pathogenesis of cancer, including the breast cancer gene BRAC2. If the proteins that bind the human VDR are different from those that bind the VDR in rats, and the two animals don’t end up transcribing the same genes, how effectively can the data from cancer studies done on mice be applied to human beings?

As Marshall states, “The murine environment (the use of mouse models) is inadequate to accurately model drug carcinogenic activity in humans. Because the VDR affects the genes associated with cancer pathogenesis, good homology between human VDR, and the animal model VDR, is exceedingly important.”

Even in hamsters and rats, two animals that have quite a bit in common, Olmesartan affects their respective VDRs in different ways. During clinical trials aimed at testing the safety of Olmesartan, the drug’s manufacturer, Sankyo Pharmaceuticals, discovered that Olmesartan has possible carcinogenic activity in hamsters. Yet the carcinogenic activity was unable to be duplicated in rats. What accounts for this difference? The hamster VDR binds proteins in a different manner than the rat VDR, and controls different genes in each animal. In hamsters, Olmesartan appears to turn on genes that may negatively affect the pathogenesis of cancer – genes that the rat VDR may not transcribe.

“There is a laundry list of problems with mouse models of cancer. ”Bob Weinberg, based at the Whitehead Institute of Biomedical Research in Massachusetts, a pioneer of molecular cancer research, agrees. “There is a laundry list of problems with mouse models of cancer” says Weinberg. He first became acquainted with the limited applicability of murine models after trying to develop a mouse model for retinoblastoma, a childhood cancer of the retina. Retinoblastoma results from the loss of a gene called Rb, so Weinberg and team genetically engineered mice to lack the same gene. Instead, the mice developed tumors in their pituitary glands. “This planted seeds of doubt in my mind,” said Weinberg.

Besides the fact that the mouse and human VDRs transcribe different cancer-related genes, there are also substantial differences between the ways that mice and humans develop tumors. For one thing, most mouse tumors originate in different types of a mouse’s tissue than in a human’s, and, unlike in humans, healthy mouse cells can maintain the ends of their chromosomes, a key factor influencing which mutations tumor cells develop. What’s more, the technology used to create tumors in mice causes them to develop tumors early on, but human tumors develop later in adult life, following a stepwise series of mutations that turn a normal cell into a cancerous cell.

This may explain why of the potential anticancer drugs that give promising results in tests on mice, only about 11% are ever approved for use on people. It is also possible that drugs which might have helped humans battle cancer failed in preclinical mouse trials, although there is no way of knowing. There are also differences in the way humans and mice metabolize drugs. For instance, two human enzymes, CYP2D6 and CYP3A4, which together metabolize more than 70% of drugs on the market have markedly different activities compared with their rodent equivalents. The consequence is that mouse models may be of limited usefulness in predicting the effectiveness or toxicity of drugs in humans.

An increasing body of evidence is also pointing to the fact that bacteria are responsible for at least part of the pathogenesis of cancer. Since the VDR controls the innate immune system in humans but not in rats, the gap between how rats and humans fight cancer-causing bacteria is enormous. The same can be said for other diseases now known to be bacterial in origin. This situation has much wider implications than commonly understood. Many illnesses that are thought to be genetic, “autoimmune”, or of unknown cause are now known to be caused by bacteria, meaning that the immune system plays a greater role than expected in a wider array of illnesses. To make matters worse, numerous studies point to yet other aspects of the immune system that differ between mice and men.

The immune systems of both rats and humans use white blood cells called macrophages to kill bacteria and other pathogens. But rat macrophages are activated in different ways than human macrophages. In the book Immunology, Roitt explains that a chemical called INF-y can completely activate macrophages in rats, allowing them to successfully combat bacteria such as mycobacterium tuberculosis. However, when INF-y acts on human macrophages, it causes “at best, feeble inhibition of mycobacterium tuberculosis or, at worst, significantly increased growth.”

“Of the potential anticancer drugs that give promising results in tests on mice, only about 11% are ever approved for use on people”In addition, three papers published in the August edition of the medical journal Nature describe multiple differences between the way rats and humans form cells of the immune system called Th-17 helper cells – cells which play an important role in the inflammatory responses of the innate immune system.

Mestas and team at the University of California have detected multiple differences between how white blood cells called neutrophils affect the expression of defensins, proteins that assist the immune system in killing pathogens. In humans, neutrophils are a rich source of defensins, but these same defensins are not expressed by neutrophils in mice. In contrast, cells of the small intestine express over 20 defensins in mice but only two in humans. There are also differences in the processing of defensins, which Mestas feels are “likely reflecting different evolutionary pressures related to microorganism exposure through food intake.” The team goes on to describe over 20 differences in the pathways that control the innate and adaptive immune systems of rats and humans.

Clearly, rats target bacteria in a different manner than humans, and generalizing data from one species to another can result in inaccuracies. As Mestas argues, “While it is hard to draw global conclusions about the significance of differences between mouse and human immunology, it is worth considering the possibility that any given response in a mouse may not occur in precisely the same way in humans.”

Case in point: A study conducted by researchers at the Crash Trials Medical Center in London. The researchers analyzed the concordance between the effects of various medical treatments on rat and human subjects. When the researchers tested corticosteroid medications on humans with head injuries, they found that the drugs had absolutely no effect. Yet when corticosteroids were administered to rats with the same malady, the drugs demonstrated a beneficial effect. Similarly, drugs called antifibrinolytics, which are designed to reduce bleeding, worked successfully in human subjects but not in rats. A drug called Tiriiazad had a negative impact on humans with ischaemic heart disease, but when administered to rats, the medication had a beneficial effect on the activity of the heart. The researchers concluded that “Discordance between animal and human studies may be due to bias or to the failure of animal models to mimic clinical disease adequately.”

Experiments that target the rat genome can also yield inconclusive results. For example, Langui and team in France found that several genetic mutations that led to nervous system dysregulation in mice have no equivalent in man, causing them to conclude, “Introducing a human mutated gene in an animal does not necessarily trigger pathogenetic cascades identical to those seen in the human disease.”

“It is worth considering the possibility that any given response in a mouse may not occur in precisely the same way in humans.”Unfortunately, even animals which bear more resemblance to man such as apes and dogs have VDRs that differ substantially from the human VDR, meaning that many drugs cannot be successfully tested on these animals either. Several months ago, German biotech firm TeGenero conducted a trial on a drug designed to treat chronic inflammatory conditions and leukemia. When the drug, called TGN 1412, was tested on monkeys, no adverse reactions were observed. In fact, tens of thousands of initial phase 1 trials on TGN 1412 were conducted on animals without incident.

But when TGN 1412 was administered to six healthy human volunteers, it caused catastrophic systemic failure in the subjects, despite being administered at a dose of 0.1 mg per kg, some 500 times lower than the dose found safe in animals. All six volunteers were hospitalized, and at least four suffered from multiple organ dysfunction. One trial volunteer is said to be showing signs of cancer. According to representative of the pharmaceutical industry, problems arose due to “unforeseen biological action in humans.” TGN 1412 was intended to activate the immune system, but did so differently in humans than in apes.

The TGN 1412 story, albeit a medical disaster, confirms that differences in VDR homology detected by molecular modeling software do indeed generate variability among immune system responses observed in a clinical setting. In essence, we must cast a wary eye towards data derived from animal models.

“As therapies for human diseases become ever more sophisticated and specifically targeted, it becomes increasingly important to understand the potential limitations of extrapolating data from mice to humans. The literature is littered with examples of therapies that work well in mice but fail to provide similar efficacy in humans,” says Mestas. Of course these issues discussed above don’t mean that we should completely stop using rats in the laboratory. For one thing, mouse models can be very useful for determining the function of genes. Recently three researchers were awarded the Nobel Prize for developing precise methods that allow scientists to change mouse genes one by one. These discoveries led to the practice of deleting, or knocking out, specific genes in mice in order to discover their function – allowing scientists to create what are called “knock-out-mice.” “If for example, you see a little finger disappear, then you know that gene is important for making little fingers,” Mario R Capecchi, one of the researchers awarded the prize, said in a telephone interview.

Knock out mice can certainly offer valuable insights about disease. Studies that delete certain receptors from mice can give important clues about the role that the receptor plays in the body. For example, when mice are grown without beta thyroid receptors they are deaf. Glutocorticoid receptor knockout mice don’t even survive gestation.

Gene-targeting technology can knock out single genes to study development of the embryo, aging and normal physiology. So far 10,000 mouse genes, or about half of those in the mammalian genome have been knocked out. In theory, knock out mice can help researchers in the field of gene therapy identify faulty genes that could potentially be causing disease. It can also allow scientists to identify the function of a particular gene in mice. Although this research can generate hypotheses, the differences between mice and humans impose clear limitations – not to mention the fact that these studies may become less useful as medicine embraces the primary role of pathogens, rather than genes, in many unexplained chronic diseases.

Sometimes murine models cannot provide accurate data.

Other groups of scientists are attempting to inject mice with human cells, engineering genes that would allow mice to encode human enzymes, and finding ways to alter the expression of certain cell signals. For example, Glen Merlino at the National Cancer Institute in Maryland used one of these methods to better understand melanoma, a cancer affected by UV irradiation of the skin. Melanocytes, the pigment-producing cells that become cancerous in melanoma are found in the outermost layer of the human skin, but in mice they are confined to hair follicles, making it difficult to accurately study the disease in rodents. Merlino’s team was able to engineer mice to over-express a cell signal that causes melanocytes to be found in the outer layers of rodents’ skin, as in humans.

They went on to show that young, but not adult mice, exposed to UV radiation develop malignant melanoma, giving strong evidence to back up studies that have highlighted the potential dangers of sun exposure in children. “This is an example of the value of mouse models, – they are highly manipulable, for which there is no comparison in humans, says Tyler Jacks, a researcher who develops mouse models at the Massachussetts Institute of Technology in Cambridge.

But unfortunately, since none of these manipulations affect the rodent immune system, they still are of limited value. In situations where murine models cannot provide accurate data, how can we test medications that affect the immune system in a safe and effective manner?

The most logical solution rests in perfecting ways to collect data directly from human beings. Howard Finc of the National Cancer Institute (NCI) agrees, “The best study subject will always be the human,” says Finc. In an effort to better understand the pathogenesis of cancer, he is working on a project that collects and catalogues data on a wide range of human tumors. His team performs genetic and molecular analysis of samples of human brain tumors sent from patients around the world. The study is a pilot for the NCI’s larger cancer Biomedical Informatics Grid, which will provide a global network for researchers to input information and access bioinformatics tools for mining cancer data. The study currently has data for 700 tumors and will eventually contain information for 2,000 tumors.

Other possible solutions involve molecular modeling software, which can be used to elucidate the effects of a particular substance on the VDR and the immune system. Programs exist that allow a researcher to take a model of the human VDR and mathematically calculate how a drug will interact with the receptor and other pathways of the immune system.

If the mathematical data is carefully collected, it should be sufficiently reliable so that human subjects can be used to confirm the drug’s actions in a clinical setting. One such example is the Marshall Protocol, a treatment that uses low-dose antibiotics and Olmesartan, a medication that stimulates the immune system, to treat chronic disease. Subjects take medication as directed, while reporting symptoms and drug reactions in online progress reports. It is critical that the science community devote increasing amounts of energy towards research that examines how these types of studies can be conducted in the most effective way possible.

Another possibility is that studies could continue to be conducted in animals such as primates, whose VDRs more closely resemble that of man. If researchers continue to pinpoint the differences between the primate and human immune systems, then molecular modeling software, in some cases could correct for these differences and help clear up anomalies in the data.

The American Heart Association, the American College of Physicians, and the American College of Obstetricians and Gynecologists all agreed that a sufficient number of studies had been done to prove that HRT was unequivocally helpful in helping older women ward off heart disease and osteoporosis. By 2001, 15 million women were taking HRT, including 5 million elderly women.

Then, in 1998, a clinical trial concluded that estrogen therapy actually increases the likelihood that women with heart disease will suffer a second heart attack. It was followed by a trial in 2002 which concluded that HRT puts postmenopausal women at a greater risk for heart disease, stroke, blood clots, breast cancer and even dementia. Suddenly, It became painfully clear that HRT may offer a benefit to women who begin to use it early in life, but for those who start the treatment in their later years, it can be very dangerous.

Gary Taubes writes in The New York Times Magazine, “The question of how many women may have died prematurely or suffered strokes or breast cancer because they were taking a pill that their physicians had prescribed to protect them against heart disease lingers unanswered. A reasonable estimate would be tens of thousands.”

This HRT story, which Harvard epidemiologist Jeffrey Avorn calls the “estrogen debacle” and a “case study waiting to be written” is a glaring example of how even the most widely held medical beliefs can turn out to be wrong. The story is fraught with biased studies, overconfident clinicians, and researchers who failed to think critically.

Most alarming, however, is the fact that the medical community is currently oblivious to yet another public health disaster of epic proportions – one that is affecting the entire population. In an effort to curb chronic disease, well-intentioned researchers are promoting vitamin D, a substance that, according to recent molecular modeling research, can act as an immunosuppressive steroid. Studies which incorrectly interpret the reason for low vitamin D in patients with chronic disease have been seized upon by the media, and form the basis of massive advertising campaigns – which, along with ill-informed recommendations by doctors and researchers, have created a perfect storm of misunderstanding and bad advice.

What follows are fourteen pieces of a puzzle that, when complete, reveal a massive misunderstanding of the actions of vitamin D.

1. Vitamin D is not a vitamin; it is an immunosuppressive steroid.

Let’s start with this fact: the vast majority of doctors touting the benefits of vitamin D are not aware of discoveries made by researchers in the field of molecular biology, which have clearly shown that the “vitamin” D derived from diet and supplements is not a vitamin, but a steroid with immunosuppressive properties when elevated.

There are several forms of vitamin D. The form of vitamin D we get from food, diet, supplements and sun exposure is called D3. D3 is converted by the liver into 25-D, which functions as a steroid. 1,25-D, the activated form of vitamin D, functions as both a steroid and a hormone. It is produced inside various types of cells, including those of the immune system and the kidneys, as well as in response to sunlight. In healthy individuals, the kidneys continually convert 25-D into its active form, 1,25-D.

According to a paper published by the Institute of Biomedical Research in Birmingham, England, “The active form of vitamin D, [1,25-D] is a potent immunomodulatory seco-steroid” meaning that it is a steroid-like molecule which is able to control the activity of the immune system.”

Molecular modeling has shown that the hormonal 1,25-D form binds and activates the Vitamin D Receptor. The Vitamin D Receptor plays a fundamental role in the body. It transcribes 913 genes, and researchers at McGill University in Canada just released a paper saying it may actually transcribe 27,091. But, the Vitamin D Receptor also performs another critical function – it serves as a switch that regulates the activity of the innate immune system.

A molecular model comparing the structure of 25-D and of 1,25-D

According to recent molecular models, the steroid 25-D binds the Vitamin D Receptor and affects the activity of the immune system as well, but in a manner opposite to 1,25-D. When the steroid 25-D binds the Vitamin D Receptor, it decreases the activity of the receptor, causing the innate immune system to slow down and shut off. This effect begins around 20 ng/ml and gradually increases with higher levels of 25-D, until the VDR becomes completely blocked.

At the moment, most researchers understand that 1,25-D activates the Vitamin D Receptor. However, they are unaware of the models which demonstrate that 25-D has the opposite effect. Consequently, they do not understand that when people start to supplement with extra vitamin D (which is converted into 25-D) the Vitamin D Receptor begins to turn off, not on.

Most of these researchers are also unaware of a new understanding about the cause of many chronic diseases. As a person falls ill with a chronic disease, L-form bacteria begin to live inside the cells of the immune system and in various tissues. These bacteria create proteins that, just like elevated 25-D, are able to bind and block the Vitamin D Receptor. Together, elevated 25-D and bacterial proteins block the ability of the Vitamin D Receptor to turn on the immune system more than either substance alone.

Molecular modeling has also shown that the medication Olmesartan (called Benicar in the United States) is able to bind and activate the Vitamin D Receptor (VDR). Not only does Olmesartan activate the receptor, but, because its concentration can be controlled, it can reactivate the VDR even when it would normally be blocked by bacterial proteins or by excessive levels of 25-D. Olmesartan also binds a number of other receptors involved in the inflammatory response.

Long thin L-forms emerging from a cell as shown in a photo taken by Andy Wright

Patients on a medical treatment known as the Marshall Protocol are able to use Olmesartan, along with pulsed, low-dose antibiotics to slowly eliminate L-form bacteria over the course of several years. These patients also eliminate vitamin D from their diets and block sunlight in an effort to lower the amount of 25-D blocking the Vitamin D Receptor. Hundreds of patients on the Marshall Protocol, who are sick with a wide array of previously incurable chronic diseases, are reporting symptomatic improvement or complete resolution of symptoms. Their case studies, many of which are documented on the Marshall Protocol study site, confirm in a clinical setting the molecular models which show that elevated 25-D is immunosuppressive.

The Vitamin D Receptor also directly controls the expression of many of the antimicrobial peptides (AMPs). The AMPs are proteins that kill bacteria, viruses, and fungae by a variety of mechanisms including disrupting membranes, interfering with metabolism, and targeting components of the machinery inside the cell. When 25-D reaches the level at which it inactivates the receptor, the AMPs are no longer produced, and bacteria can spread more easily throughout the body.

People infected with L-form bacteria are particularly prone to the effects of 25-D on the Vitamin D Receptor. That is because their L-form bacteria have created proteins which have already bound and deactivated the Vitamin D Receptor to varying degrees. Extra amounts of the steroid 25-D only bind and shut down the receptor even more, further inhibiting the innate immune system, the transcription of thousands of genes, and the production of the AMPs.

“It is when L-form bacteria die that they begin to cause a major increase in symptoms for the host, since as they die they release a large amount of toxins and cytokines, proteins that generate pain and fatigue. ”The above scenario is all too familiar, since L-form bacteria are found everywhere in our environment, from soil, to water, to sperm, to inside the womb. Consequently, it seems that few people will remain free of them for long and most will acquire substantial levels of them as they age.

L-form bacteria have evolved mechanisms that allow them to live for long periods of time within the cells, and when alive, generally persist without generating too many symptoms.

It is when L-form bacteria die that they begin to cause a major increase in symptoms for the host, since as they die they release a large amount of toxins and cytokines, proteins that generate pain and fatigue. Furthermore, as L-form bacteria die, the cell that they have parasitized dies as well, and cellular debris is released into the bloodstream. These substances cause the tissues to become inflamed, resulting in what is known as “Th1 inflammation.”

As previously discussed, the innate immune system is responsible for killing L-form bacteria and is controlled by the Vitamin D Receptor (VDR). Elevated levels of the steroid 25-D and bacterial proteins bind and inactivate the VDR, causing the immune system to work less effectively.

As the immune system becomes increasingly inhibited, fewer L-form bacteria are killed. Furthermore, the Vitamin D Receptor is no longer able to transcribe the antimicrobial peptides, and fewer bacteria are killed by DNA fragmentation. As fewer bacteria die, fewer inflammatory cytokines are released, and fewer toxins and cellular debris enter the bloodstream. As the level of inflammation temporarily decreases, a patient will start to feel better.

This seeming wellness is illusory. Without the innate immune system and the antimicrobial peptides to keep L-form bacteria in check, the pathogens easily spread to new cells, new tissues, and new organs.

Many people who begin to supplement with vitamin D or spend extended periods of time in the sun only have a small or moderate amount of L-form bacteria in their bodies. Since these people’s immune systems are not yet severely compromised (their VDRs are not yet partially blocked by bacterial proteins), their bodies kill a fair share of the bacteria, resulting in minor aches and pains. But if 25-D rises to the level at which it inhibits their immune systems, less bacteria die, Th1 inflammation decreases, and their minor symptoms may be temporarily relieved.

Naturally, such patients feel that the extra vitamin D is helpful. It may take decades before their L-form bacterial load rises to the threshold at which they are diagnosed with an “autoimmune” illness, or have a stroke or heart attack. At this point later in life, they seldom make the connection between their current illness and the extra vitamin D they have been taking with no apparent ill effect for such a long period of time.

“If you think about it, it seems little wonder that vitamin D has become so popular. It’s basically an over-the-counter steroid.” It’s easy to see how people infected with even minor amounts of L-form bacteria tell their doctors that supplementation with vitamin D and increased exposure to the sun make them feel better. As Joyce Waterhouse, PhD, a researcher affiliated with Autoimmunity Research Foundation stated in a discussion of vitamin D in diseases caused by L-form bacteria, “If you think about it, it seems little wonder that vitamin D has become so popular. It’s basically an over-the-counter steroid.” Even the Vitamin D Council, a California non-profit agency who promote the use of vitamin D, say on their website that “vitamin” D is a steroid. Yet this group fails to question the full implications of their own statement.

Other steroids are commonly known to be immunosuppressive. Take the corticosteroid medication prednisone, a particularly effective immunosuppressant that affects virtually all of the immune system.

Prednisone is given to patients with diseases such as multiple sclerosis, rheumatoid arthritis, sarcoidosis, and lupus. Most doctors continue to think that these diseases are “autoimmune” in nature, and result when the body somehow mounts an immune response against its own cells and tissues. Hence, the desire to slow the immune system.

But when one understands that the diseases listed above are caused by L-form bacteria, the entire scenario becomes reversed. Prednisone, just like elevated 25-D, prevents the immune system from killing bacteria. Patients experience short-term relief and resolution of symptoms as the die-off slows down. But nobody would ever claim that prednisone actually cures “autoimmune” diseases. Instead, in the long run, patients taking prednisone generally become much more ill and require increasing amounts of palliative medication.

“At the moment there is a significant gap in communication between the molecular biologists who have realized that “vitamin D” is a steroid, and doctors who continue to think of it as a nutrient. ”At the moment there is a significant gap in communication between the molecular biologists who have realized that “vitamin D” is a steroid, and doctors who continue to think of it as a nutrient. But now that the actions of 25-D and 1,25-D have been confirmed by molecular modeling, it seems unlikely that doctors will be able to cling to the “vitamin” label for much longer.

As John Arbuthnot, author of Of the Laws of Chance states, “There are very few things we know which are not capable of being reduced to mathematical reasoning……and where a mathematical reasoning can be had, it’s as great a folly to make use of any other, as to grope for a thing in the dark when you have a candle standing by you.”

Of course, it’s only been over the past five years that biomedical researcher Trevor Marshall has revealed how L-form bacteria affect the Vitamin D Receptor, and exactly how 25-D affects the immune system. So clearly, before these very recent discoveries, researchers were forced to study vitamin D while missing vital pieces of the puzzle. However, it seems that in their enthusiasm to identify vitamin D’s benefits, many experts have not sufficiently absorbed the medical literature, literature that well before Marshall’s work revealed the complexities associated with the Vitamin D Receptor, the lynchpin of the innate immune system.

If researchers made themselves aware of work done by colleagues such as Dr. Tian Tian Wang at McGill University, they would know that when 25-D and 1,25-D bind the vitamin D receptor, they adjust the transcription of at least 913 genes. A search on the website Pubmed reveals that an average of one paper a day is published on the actions of the Vitamin D Receptor. Perhaps, armed with an understanding of this research, they would hesitate before recommending that the public take such high doses of the “vitamin.” It is only prudent that such a powerful seco-steroid and its transcriptional activity be understood to a far greater extent lest we all further subject ourselves to what is nothing short of an unofficial clinical trial of historic proportions.

Not surprisingly, the few researchers who understand the complexities of vitamin D seem concerned about supplementation. Recently, Professor Ronald M. Evans, a Fellow of the Salk Institute, delivered a seminar to the FDA about the public health policy on vitamin D. Given that vitamin D is seco-steroid rather than a vitamin, he indicated that he would advise his family against adding vitamin D to their diets.

Based on the above, it’s not surprising that researchers at Duke University found that elderly men and women who consumed higher levels of calcium and, in particular, vitamin D are significantly more likely to have greater volumes of brain lesions, indicating regions of damage that can increase risk of cognitive impairment, dementia, depression and death. The team found that vitamin D intake, (mean 341 IU and maximum intake 1014 IU), was the only variable that retained a significant correlation with the brain lesions when analyzed by a multivariate analysis.

Unaware of the latest research on the immunosuppressive properties of high levels of vitamin D, the researchers hypothesized that the calcium rather than the vitamin D was the main culprit in causing the lesions. They speculated that in patients given extra calcium, the calcium might be deposited inside the blood vessels of the brain rather than the bone. According to their theory, vitamin D would accelerate the process because it is involved in regulating calcium absorption and metabolism.

A much more likely explanation is that the lesions result when L-form bacteria in the brain cause the release of cytokines that damage the tissues. Sometimes the resulting inflammation damages blood vessels and promotes calcification, but it is the L-form bacteria, not the calcium that is the true culprit.

The connection between bacteria and calcification in heart disease has already been noted. Researchers at the Hospital Das Clinicas in Brazil found significantly higher concentrations of Chlamydia pneumoniae and Mycoplasma pneumoniae in calcified nodes of blood vessels throughout the body, including the heart and the aorta – causing them to suggest that “these bacteria may be associated with the development of calcification and inflammation.”

2. The vast majority of studies fail to account for the long-term effects of vitamin D.

The decrease in bacterial die-off among patients consuming a lot of vitamin D does mean that, at least in the short-term, less cytokines and toxins are released into the tissues and inflammation decreases. Since these substances damage the tissues, we frequently hear about studies stating that vitamin D can correct problems with the kidneys, parathyroid function, or resolve other maladies.

Although the decrease in toxins, cytokines, and overall inflammation may be helpful in the short-term, over longer periods of time, the negative consequences of L-form bacteria spreading throughout the body inevitably surpass any temporary beneficial effect created by a decreased level of toxins and cytokines, particularly since L-form bacteria have been implicated in such a vast array of diseases.

In April of 2000 a study published in the Archives of Internal Medicine by doctors at the State University of New York at Buffalo found that five patients confined to wheelchairs with severe weakness and fatigue were able to walk after supplementing with 300,000 IU’s of vitamin D (a huge amount!) over a period of six weeks. Sadly, the patients were not “cured”, and no follow-up study was done on the group. They were simply feeling the effect of a temporary decrease in cytokine and toxin release that resulted after the high levels of vitamin D completely shut down their innate immune systems. In fact, one of the patients actually died in the weeks during which vitamin D was administered.

“Instead, as in the Archives study, they track subjects over the course of weeks, months, or one or two years, during the period of time when study participants are usually feeling the palliative effects of the steroid.”One of the abiding weaknesses of studies on vitamin D is that researchers do not follow subjects consuming the steroid for a sufficient period of time. Instead, as in the Archives study, they track subjects over the course of weeks, months, or one or two years, during the period of time when study participants are usually feeling the palliative effects of the steroid.

Researchers will rarely, if ever, track subjects over the course of decades, the length of time needed to begin to note the negative changes that L-form bacteria cause later in life. In fact, L-form bacteria grow so slowly that researchers in the future will surely have to check back with their subjects at least 20-30 years after they begin supplementing with vitamin D in order to determine whether or not the steroid has contributed to the development of a chronic disease.

During the rare instances where researchers have tracked study subjects for decades, ingestion of vitamin D is rarely associated with improved health. Take, for example, a study recently performed by researchers from several institutions, including the University of Oulu in Finland and the Imperial College in London. The team found a clear association between high-dose vitamin D supplementation in infancy and an increased risk of atopy, allergic rhinitis, and asthma later in life. Those subjects given higher levels of vitamin D during infancy were found to suffer from higher levels of atopy, rhinitis and asthma, but not until the research team checked back with them at 31 years of age.

3. Chronically ill people are not deficient in vitamin D.

We are continually bombarded with studies claiming that patients with chronic disease are deficient in vitamin D. But this is not the case, and the misunderstanding comes from a misplaced focus on 25-D.

Numerous studies have demonstrated that the level of the hormone 1,25-D rises in patients with many chronic diseases. Chronically ill patients starting the Marshall Protocol sometimes have a level of 1,25-D exceeding five or six standard deviations above the “standard” value.

Sometimes called the body’s “master hormone”, 1,25-D directly controls the pathways that regulate the body’s other hormones including the thyroid, sex, and stress hormones. Consequently, elevated 1,25-D greatly contributes to the pathogenesis of chronic disease, since as a person’s level of 1,25-D rises to an unnaturally high level, the master hormone can no longer correctly regulate the above pathways.

A wide array of studies also point to the fact that 25-D is low in people with numerous chronic inflammatory diseases.

What explains these altered levels of 1,25-D and 25-D? (Note: If you find that the next few paragraphs seem complicated, hang in there! You will still be able to follow the rest of the article.)

As previously mentioned, in patients with chronic disease, L-form bacteria create proteins that affect the Vitamin D Receptor (VDR) in a manner similar to 25-D. They bind and inactivate the VDR, preventing it from transcribing a wide array of genes and enzymes.

In a paper recently published in BioEssays, “Vitamin D discovery outpaces FDA decision making,” Marshall describes how in healthy individuals, the VDR transcribes an enzyme called CYP24. CYP24 breaks down excess 1,25-D, ensuring that the level of 1,25-D in the body stays in the normal range. But in chronically ill individuals, the VDR (which is blocked by bacterial proteins) can no longer transcribe CYP24. The level of 1,25-D in the body becomes significantly elevated since there is no CYP24 to keep it in check.

1,25-D binds to the PXR receptor, a receptor that is involved in making another enzyme called CYP27A1. CYP27A1 is responsible for converting D3 into 25-D in the liver. Elevated 1,25-D affects the activity of the PXR receptor in a way that causes less D3 to be converted into 25-D, meaning that the level of 25-D in chronically ill individuals drops.

Yet another factor contributes to the low level of 25-D seen in patients with chronic disease. An enzyme called CYP27B1 normally regulates the amount of 25-D converted into 1,25-D. When more CYP27B1 is produced, conversion occurs at a greater rate.

L-form bacteria release cytokines, proteins that cause pain and fatigue. These cytokines activate a protein called Protein Kinase A (PKA). PKA in turn activates CYP27B1, causing more 25-D to be converted to 1,25-D. The level of 25-D in the body decreases, and the level of 1,25-D increases.

A study conducted by researchers at the University of South Carolina supports this scenario. The team gave healthy subjects high levels of 1,25-D and verified that it can indeed inhibit the conversion of vitamin D into 25-D. They found that this phenomenon also occurs in certain diseases in which patients naturally develop a high level of 1,25-D. Consequently, the low 25-D observed in patients with chronic disease is not a sign of vitamin D deficiency, but is an indicator of the disease process.

Similarly, researchers at the University of Tokyo found that VDR knock-out mice (mice grown without Vitamin D Receptors) showed a marked increase (10 times) in serum 1,25-D and a clear reduction – to almost undetectable levels- in serum 25-D. Such levels persisted at seven weeks until the mice eventually died.

While there are clear biological differences between humans and rodents, having a Vitamin D Receptor with no activity – because it is blocked by bacterial substances and 25-D – is analogous to having no VDR at all. So the Tokyo team’s data on VDR null mice also strongly supports the fact that a blocked VDR naturally leads to high levels of 1,25-D and very low levels of 25-D.

What happens when doctors and researchers take note of the low level of 25-D in patients with chronic disease? They all too often conclude that the low level of 25-D is contributing to or causing the disease. With such a mindset, doctors are all too eager to give patients oral supplements of 25-D in an effort to “remedy” the situation.

“Unfortunately the exact opposite is true. The level of 25-D in the body is not causing the illness, it is a result of the disease process.” Unfortunately the exact opposite is true. The level of 25-D in the body is not causing the illness, it is a result of the disease process, and as clear an indication as any that the patient is suffering from a significant degree of L-form bacterial infection. It’s similar to the connection between folic acid and heart disease – low levels of folic acid often lead to an increase in the amino acid homocysteine – a compound that at high levels has been linked to increased incidence of cardiovascular disease (CVD). Yet, extensive studies have revealed that giving patients with CVD folic acid supplements does not lower levels of homocysteine, and that high levels of the compound in patients with CVD is simply a result of the disease process.

Key to this misunderstanding are the doctors and researchers who fail to test the level of 1,25-D in patients with chronic disease. If they did, they might pick up on the fact that 25-D is low precisely because 1,25-D is elevated.

This certainly explains why a research team at the University of Wisconsin Osteoporosis Clinic, who did not test subjects’ levels of 1,25-D, seemed puzzled by the results of a study which revealed that some participants getting abundant sun exposure still displayed low levels of 25-D.

Or take for example, scientists at Musgrave Park Hospital in Belfast, Ireland, who published in 2006 the results of a study that tested the level of 25-D in 75 patients with fibromyalgia, but failed to test the subjects’ levels of 1,25-D. Surely the research team must have been perplexed by the fact that, although all of the subjects seemed to be consuming perfectly adequate levels of vitamin D, 69.3% were suffering from vitamin D “deficiency” because their serum levels of 25-D were considered to be too low.

As with most chronic diseases, fibromyalgia is an illness in which L-form bacteria create proteins that prevent the VDR from transcribing the enzymes needed to keep 1,25-D in the correct range. But since the researchers who conducted the study failed to test the level of 1,25-D in their subjects, they focused solely on the diminished level of 25-D and were, it seems, completely oblivious to the actual disease process. This led them to incorrectly conclude “Vitamin D deficiency is common in fibromyalgia and occurs more frequently in patients with anxiety and depression.”

In a similar study, published in 2003 in the Mayo Clinic Proceedings, researchers in Minneapolis tested vitamin D levels in patients suffering from chronic, non-specific, musculoskeletal pain: 93% of them turned out to be vitamin D “deficient.” If these studies’ authors can’t understand the process, it’s easy to understand how other researchers who look over their results would interpret the data to mean that patients with fibromyalgia need to consume even more 25-D, in order to correct the so called “deficiency.”

The failure to test for 1,25-D in subjects with chronic disease is as pervasive as it is troubling. The FDA continues to accept results from studies that do not bother to measure 1,25-D.

Naturally, when representatives of the FDA and other health agencies interpret the results of these studies they correlate chronic disease with vitamin D deficiency, and inevitably suggest that people should supplement with increased amounts of the “vitamin” in order to reverse or prevent chronic disease.

Of course, the media picks up on the conclusions of experts incorrectly attributing the low levels of 25-D in their patients to vitamin D deficiency. A recent article in US News and World Report states, “Research on vitamin D has flooded out over the past few months, linking a growing array of health ills to low levels of the nutrient.”

On the tanning website, tantoday.com, Jeffrey Dach, MD, laments in his article “Vitamin D Deficiency, the Ignored Epidemic” that the majority of people living in “sunny Florida” showed vitamin D deficiency (less than 20 ng/ml), or insufficiency (less than 40 ng/ml). This seems odd, considering the fact that if a person spends only 8-10 minutes in the sun they will obtain the entire RDA requirement for vitamin D even if they are not consuming foods with vitamin D or fortified products.

Citing published medical research, Dach goes on to report that vitamin D deficiency has been reported in 57% of 290 medical inpatients in Massachusetts, 93% of 150 patients with overt musculoskeletal pain in Minnesota, 48% of patients with multiple sclerosis, 50% of patients with lupus and fibromyalgia, 62% of the morbidly obese African American Women, 83% of 360 patients with low back pain in Saudi Arabia, 73% of Austrian patients with Ankylosing Spondylitis, 58% of Japanese girls with Graves’ Disease, and 40-70% of all Finnish medical patients.

What Dach doesn’t realize is that the opposite is true. The low 25-D measured in the above studies is a consequence, rather than a cause, of the disease process. In reality, the numbers cited are an indication that the diseases mentioned are caused by L-form bacteria.

An increasing body of research points to the fact that obesity is linked to certain species of bacteria in the gut. Sure enough, a study published in the Journal of Clinical Endocrinology and Metabolism by researchers at Tufts University found that subjects with the highest percentage of body fat had 20% lower blood levels of 25-D than those with the least body fat.

Michael F. Holick, one of the foremost vitamin D “experts” in the country, told the National Institutes of Health symposium “Vitamin D and Health in the 21st Century” that the nation faces “severe vitamin D deficiency” which, if not properly addressed, will have profound far-reaching health consequences. According to Holick and other “experts,” we are in the midst of a “silent epidemic of vitamin D deficiency.”

There’s no disputing the extent to which broad segments of the population have “low” levels of 25-D or that there is an epidemic of chronic disease and obesity. According to the CDC, seven of every ten Americans who die each year, or more than 1.7 million people, die of a chronic disease, and according to researchers at John Hopkins University, 75% of U.S. adults and 24% of U.S. children will be overweight or obese by 2015.

“Or, is this epidemic actually due to excess vitamin D consumption, and the immunosuppressive effects of 25-D on people infected with L-form bacteria?”Could it really be true that Professor Holick’s “silent epidemic” is one of vitamin D deficiency? Or is this epidemic actually due to excess vitamin D consumption and the immunosuppressive effects of 25-D on people infected with L-form bacteria?

To be fair, most researchers and “experts” who study vitamin D are well-intentioned. They are deeply concerned about the health of the public, and are trying their best to battle chronic disease.

But the failure of most doctors and experts to question the level of not just 25-D but 1,25-D in the subjects they examine shows a lack of understanding of the fundamental aspects of vitamin D metabolism. Given that this pair of metabolites is so closely tied to each other, wouldn’t any kind of understanding of the true nature of the vitamins D warrant measuring both?

Some claim that 1,25-D levels are not really important because they sometimes appear to fluctuate, and so do not measure them. Or, when they do measure 1,25-D, they automatically attribute a high 1,25-D combined with a low 25D to secondary hyperparathyroidism, a condition in which the kidneys produce more 1,25-D to compensate for inadequate calcium intake. Rather than recommend more calcium, such clinicians mistakenly recommend more vitamin D.

But secondary hyperparathyroidism can be ruled out by measuring parathyroid hormones, which researchers usually fail to do. More thorough studies on several inflammatory diseases specifically ruled out secondary hyperparathyroidism as a cause for the high level of 1,25D relative to 25D.

Furthermore, some researchers and physicians who test 1,25-D do not realize that the sample must remain frozen before analysis in order for the resulting reading to be accurate. With the limited data most researchers are habitually collecting, it’s easy to understand how they have made the mistake of interpreting the low levels of 25-D in their subjects as an indicator of “deficiency.”

4. Healthy people are not deficient in vitamin D and do not need to consume extra amounts of this steroid.

Based on the misunderstanding discussed above, researchers working with vitamin D and doctors administering the steroid seem fixated on the idea that more is always better. When a study about vitamin D presents inconclusive data, researchers inevitably suggest that the reason they didn’t generate a significant result was that their subjects should have taken more of the substance, which the public invariably understands as an endorsement of the idea that there is no limit to the amount of the vitamin D one should consume.

The prospect of identifying and distributing a substance of near universal benefit to the public’s health has always had an undeniable appeal to researchers, a fact which may have made them less careful about vitamin D. Janet Foutin, a board member of Autoimmunity Research Foundation writes, “There was a flurry of activity to discover vital substances early on, and in that rush, the various forms of vitamin D were confused with one another and have been since– causing regulatory agencies to base their recommendations on faulty assumptions.”

Researchers picked up on the feel-good, seemingly salutary, effects of vitamin D decades ago. It was on this basis that the FDA now encourages food producers to fortify their products with vitamin D, to the point where it is extremely difficult to find non-fortified milk in the United States.

In the United States, the FDA has determined that vitamin D can be added to breakfast cereals, grain and pasta products, milk, milk products such as cheese and butters, and soy milk. Canada goes so far as to require milk, evaporated milk, powdered milk, goat milk, and margarine to be fortified with vitamin D. The drive to supplement dairy products is as aggressive as ever. Even many developing countries currently fortify their milk with vitamin D.

Furthermore, vitamin D is a fat-soluble substance that is stored for weeks or even months inside cells of fatty tissues and the liver. Unlike water-soluble vitamins that need regular replacement in the body, fat-soluble vitamins are eliminated much more slowly than water-soluble vitamins, meaning that it’s relatively easy to maintain an adequate level of vitamin D in the body.

“ Consequently, over the past few years, the “healthy” range for 25-D obtained from bloodwork has been adjusted upward”Countries in Europe do not require that products be fortified with vitamin D, and although many food producers fortify their products anyway, a fair amount of people obtain fresh food from local markets and supermarkets. Many people are puzzled by “the French Paradox” or the fact that some Europeans are able to eat a diet high in fat and still maintain a normal weight, whereas Americans eating a diet high in fat tend to become obese. A recent study by Thorpe et al found that nearly twice as many Americans are obese compared to their European counterparts. Perhaps this difference can be attributed to the amount of vitamin D in the food supply.

But since the vast majority of the public still consume large amounts of fortified products, it is difficult to find people who have a truly natural level of vitamin D in their bodies. Consequently, over the past few years, the “healthy” range for 25-D obtained from bloodwork has been adjusted upward to reflect the fact that people consume fortified dairy products. The FDA now suggests that people maintain a level of 25-D between 30-32 ng/ml, which is in the range at which it becomes immunosuppressive. This means that the levels of 25-D in people eating a diet without fortified foods is inevitably considered to be too low, out of range, and ultimately a menace to their health.

With all the extra vitamin D we have added to the food chain, we no longer know what amount of 25-D the body would maintain under natural circumstances. Could it be that the people we call “Vitamin D deficient” actually have a normal level of 25-D? Studies which have tested the level of 25-D in people who live in countries where vitamin D is not added to the food chain prove this scenario to be true. A study which tested the level of 25-D in 90 “healthy, ambulatory Chilean women” showed that 27% of the premenopausal and 60% of the postmenopausal women had 25-D levels under 20 ng/ml. A study on healthy Bangladeshi women found that approximately 80% of the women had a level of 25-D under 16 ng/ml.

A molecular model showing capnine, a type of protein created by L-form bacteria bound into the Vitamin D Receptor.

Add to this mess the fact that the vast majority of people considered to be “healthy” already harbor L-form bacteria. These people can tolerate even less 25-D because their Vitamin D Receptors have already been deactivated by bacterial proteins.

Nevertheless, Dr. Holick has advised the FDA: “The 1997 daily recommended allowances for Vitamin D are totally inadequate to protect public health. New science supports a significant revision of the recommendation. Adults should be getting 1000 International Units (IU) of vitamin D a day, not the 200-600 (IU) that was recommended in 1997. Rewriting the recommended daily requirements as soon as possible should be a top priority.”

Similarly, Dr. Rainhold Vieth, another outspoken advocate for extra vitamin D, is adamant that the daily requirement of vitamin D should be in the range of 4,000 IU, or ten times the Recommended Daily Allowance. The FDA seem to be listening, considering that they are close to accepting a rule change that will amend one of the first health claims authorized in 1993 through the Nutrition Labeling and Education Act on the relationship between calcium and osteoporosis.

“The addition of even more vitamin D to the food supply will, without a doubt, continue to raise the average person’s level of 25-D well past the point at which it becomes immunosuppressive. ” They have proposed to change the claim by adding high levels of vitamin D into the equation, with calcium, for a reduced risk of osteoporosis. The addition of even more vitamin D to the food supply will, without a doubt, continue to raise the average person’s level of 25-D well past the point at which it becomes immunosuppressive.

According to Clarisse Douaud at NutraIngredients-USA.com, a news source for the food and supplement industry, “The proposal is likely to be welcomed by the vitamin industry – at both supply and finished product levels – since it communicates the importance of vitamin D. Moreover, it does not restrict the advice to just some demographics, which could help marketers target new sectors of the market more effectively.”

Should the FDA really get into the business of systematic immunosuppression any more than it already has?

5. The public does not require extra sun exposure in order to prevent vitamin D “deficiency.”

One of the complaints of vitamin D promoters is that people have been trained to cover up with sunscreen and heavy clothing due to concerns that they will get wrinkles or skin cancer. Many such promoters of vitamin D including Holick, who is the author of the book The UV Advantage, advise people not to wear sunscreen despite the elevated risk of skin cancer that might result. This is a major problem, considering the fact that exposure to sunlight greatly elevates the level of vitamin D in the body, which directly fuels the ability of L-form bacteria to dysregulate the immune system.

Holick told the New York Times, “I recommend that whatever your ethnicity or skin tone, you get outdoors without a sunscreen somewhere around 20 percent of the amount of time it would take to cause a sunburn, however long that might be.”

Holick stands by this advice despite the fact that in February he was rebuked and forced to resign from the dermatology department at Boston University’s medical school. Part of the reason given was that his work is partly funded, and actively promoted, by the Indoor Tanning Association, an industry group with obvious financial interests.

On the official website of the Vitamin D Council, a group that heavily promotes consumption of vitamin D, executive director John Jacob Cannell states, “We are saying that brief full body sun exposure may slightly increase your risk of skin cancer but it is a much smarter thing to do than dying of vitamin D deficiency. The only way to be sure you have adequate levels of vitamin D in your blood is to regularly go into the sun, or use a sun bed (avoiding sunburn).”

According to the Council, if you totally avoid the sun, “You need about 4,000 units of vitamin D a day, which means you can’t get enough vitamin D from milk (unless you drink 40 glasses a day) or from a multivitamin (unless you take about 10 tablets a day), neither of which is recommended.”

However, it’s been questioned whether sunscreen even blocks the majority of vitamin D production in the body. Scientists at the University of Melbourne took note of the level of 25-D and 1,25-D generated in two separate groups of study participants. One group wore SPF 17 sunsceen during the study period while the other group used a placebo.

They concluded that, “No person, including those aged 70 years and over, developed any vitamin D levels outside the normal reference range during the period of the study. The data suggest that over an Australian summer sufficient sunlight is received, probably through both the sunscreen itself and the lack of total skin cover at all times, to allow adequate vitamin D production in people who are recommended to use sunscreens regularly.”

“In my two decades of practice, I’ve never seen vitamin D deficiency caused by lack of sun exposure due to sunscreen use, yet the evidence that UV rays from the sun cause skin cancer is overwhelming.”The fact that people wearing sunscreen can still produce vitamin D has been confirmed by data collected from patients on the Marshall Protocol study site. Many patients on the Marshall Protocol are forced to avoid the sun in order to keep 1,25-D in the correct range, and experience an increase in symptoms when the metabolite is increased. Even when wearing heavy loads of sunscreen, patients still report symptom increase in response to light, suggesting that vitamin D can be created from the UVA rays which most standard sunscreens do not block adequately.

The American Academy of Dermatology says it is “deeply concerned” about the current claims about vitamin D and sun exposure put forth by Holick. “I am not aware of any scientific studies that support this claim,” said Dr. David J. Leffell of the Yale School of Medicine Department of Dermatology. “In my two decades of practice, I’ve never seen vitamin D deficiency caused by lack of sun exposure due to sunscreen use, yet the evidence that UV rays from the sun cause skin cancer is overwhelming.”

“I read better things in ladies’ magazines,” said Dr. Barbara Gilchrest, chair of the dermatology department at Boston University, and an authority on melanoma, the deadliest form of skin cancer. Holick’s book “is an embarrassment for this institution and an embarrassment for him.”

6. Vitamin D does not reverse osteoporosis.

Doesn’t vitamin D help reverse bone less? No. An increasing number of large, recent studies are demonstrating that this is not the case.

Instead, current research has demonstrated that osteoporosis and osteopenia are often the direct result of infection with L-form bacteria which produce inflammatory cytokines and inactivate the Vitamin D Receptor. The only way to achieve long-term reversal of bone loss is to kill the L-form bacteria driving the disease process.

An osteoclast

Osteoporosis and osteopenia result when the level of the hormone 1,25-D in the body rises above a certain range (above 43 pg/ml). Elevated levels of 1,25-D actually stimulate bone osteoclasts, cells that remove minerals from the bone.

Stimulated osteoclasts dissolve bone material, causing it to be reabsorbed into the bloodstream. Not only does this lead to osteoporosis, but it can also lead to calcium being deposited in the soft tissues of the body, including those in the lungs, breasts and the kidneys (where it forms kidney stones).

The elevated 1,25-D seen in people with osteoporosis is generally the result of L-form bacterial infection. As previously discussed, L-form bacteria create proteins that bind and block the Vitamin D Receptor, preventing it from transcribing the enzyme CYP24. Since CYP24 is needed to keep levels of 1,25-D in check, the level of 1,25-D becomes greatly elevated in individuals without the active enzyme.

Furthermore, in chronically ill individuals, the cytokine release stimulated by L-form bacteria activates the pathway which causes increased production of CYP27B1, the enzyme that converts 25-D into 1,25-D. As more conversion occurs, the level of 1,25-D in the body rises.

L-form bacteria inside a white blood cell, picture by Emil Wirotsko

If osteoporosis results in part from an increase in cytokines generated by L-form bacteria, then it would make sense that treatment to decrease cytokine release would, in the short term, reverse bone loss. Several studies have shown this to be true.

One of the inflammatory cytokines released as a result of infection by L-form bacteria is called TNF-alpha. A research team at the Rheumatoid Arthritis Center in Lyon, France found that a drug which blocks the production of TNF-Alpha led to an increase in the subjects’ spine and femoral bone mineral density (3.9% and 2.5% respectively). Another study, this one by researchers at the Kerckhoff Clinic and Foundation in Germany, on a different group of subjects, confirmed the results, this time finding a 2.7% and 13% increase in bone density of the spine and femur.

It should be noted that these TNF-alpha blocking drugs do not provide a permanent solution to osteoporosis, since L-form bacteria will continue to spread as the drug is administered. Also, TNF-alpha blocking medications are known to have serious side effects. However, the research is of interest since it confirms the importance of Th1 inflammation in osteoporosis.

So how can osteoporosis and osteopenia be reversed? Some clinicians have patients supplement with vitamin D and calcium in an attempt to reverse bone loss. To begin with, patients with chronic disease may obtain less of a benefit from calcium supplements since the calcium metabolism of patients suffering from chronic disease is different from that of healthy individuals.

Supplementation with vitamin D only exacerbates the disease process. Supplements are taken orally in the form of vitamin D which is converted to 25-D in the liver. 25-D further blocks the ability of the VDR to transcribe the enzymes which keep 1,25-D in the correct range. This results in greater bone loss as even more 1,25D is produced.

A problem with many studies on bone mass is that participants are given both calcium and vitamin D supplements at the same time. If participants demonstrate a small increase in bone density, which of the two supplements should be given credit for their improvement? Based on what we know about the actions of elevated 1,25-D, certainly the calcium, not the vitamin D, accounts for any positive changes in bone mass noted among study participants.

The largest meta-analysis of calcium and vitamin D trials in people over 50 was recently published in the Lancet. It combined the results of 29 randomized trials in which researchers had given participants supplements of calcium and vitamin D. The researchers state on page 663 of their paper that the “addition of vitamin D supplementation was not shown to offer additional risk reduction over and above the use of calcium alone.” They did find a small reduction in fracture risk (12%) correlated with calcium supplementation.

Similarly, a study by researchers at the Indiana University School of Medicine found that calcium supplementation (750 mg) improved bone density over a four-year period, whereas vitamin D supplementation (600 IU) had no effect. In fact, the effect of calcium on bone loss was blunted in subjects with the highest levels of vitamin D, causing the team to point out the danger of over-supplementation of the elderly with vitamin D if they are on an adequate calcium intake.

Another study, published in the Archives of Internal Medicine, also found that simply taking vitamin D as a supplement did nothing to improve bone health in black women. In the study, researchers randomly assigned 208 healthy black women, aged 50 to 75 years, to receive either 20 micrograms a day of vitamin D3 or a placebo. In addition, all the women received calcium supplements. After two years, the researchers increased the dose of vitamin D3 to 50 micrograms per day. All of the women underwent bone mineral density scans every six months during the three years of the study, to check for changes in bone health.

“There was really no difference in bone loss with vitamin D supplementation: our conclusion is that it does not need to be increased. ”According to the study’s lead author, “There was really no difference in bone loss with vitamin D supplementation: our conclusion is that it does not need to be increased. Raising vitamin D levels did not show an advantage in terms of bone health.” However, calcium supplementation did cause an increase in bone mineral density in both groups.

On the other hand, some large studies have demonstrated that both calcium and vitamin D supplements do nothing to help strengthen the bones. In 2005, researchers at the University of York in the UK published in the British Medical Journal a study on 3314 people aged 70 years and older who were at risk for hip fractures because of decreased bone mass. The women supplemented with 1000 mg of calcium and 800 IU of vitamin D over a period of 24- 62 months.

By the study’s end, there was no measurable change in the bone quality of any of the women. The researchers found “no evidence that calcium and vitamin D supplementation reduce the risk of clinical fractures in women with one or more risk factors for hip fracture.”

Another study published in 2005 in the The Lancet by researchers at the University of Aberdeen in the UK generated the same results. Yet a third study, this one published in 2006, conducted by the Women’s Health Initiative, came to the identical conclusion.

In the case of the above studies, it’s quite possible that calcium did have a positive effect on the bone mass of the study subjects. It’s just that the positive effects of calcium were probably offset by the negative effects of VDR blockage and elevated 1,25-D caused by consumption of the vitamin D supplements.

And then there are studies showing that vitamin D actually decreases bone mineral density. In 1999, researchers at Cedars-Sinai Medical Center in Los Angeles conducted a small study on patients with osteoporosis and hypercalciuria, a disease in which excessive calcium is excreted in the urine. The participants were taking supplements containing high levels of vitamin D. They were asked to stop taking the supplements for three years, and their bone mass was monitored during that period of time. After stopping the supplements, the level of 25-D in their blood returned to the normal range, the hypercalciuria resolved, and there were annual increases in bone density of all subjects involved.

The study’s authors concluded: “Occult vitamin D intoxication was detected in patients who were using dietary supplements that contained an unadvertised high level of vitamin D. Resolution of vitamin D intoxication was associated with a rebound in bone mineral density.” Their study is particularly valuable because their 3-year follow-up phase showed that the increase in bone mineral density persisted after initial recovery.

Similarly, researchers at the University of Science and Technology in Norway just released the results of a study that measured the forearm bone mineral density of 3,042 Norwegian women, aged 50 – 70 years old. They found that those women who had not taken cod liver oil (a substance that contains high levels of vitamin D) during childhood had higher bone mineral density compared to those who had ingested cod liver oil. Since the study compared childhood intake of vitamin D to bone density at least 4-5 decades after ingestion, it is a good example of how only those studies which track vitamin D intake over long periods of time are likely to pick up on the harm the secosteroid causes in the longterm.

“Resolution of vitamin D intoxication was associated with a rebound in bone mineral density.” In the long run, the best way to reverse the condition is to bring the level of 1,25D in the body back into a range where minerals will no longer be leached from the bones and the level of inflammatory cytokines can return to normal. In the meantime, getting the RDA of calcium from foods and supplements without vitamin D can be helpful.

Another misconception among some clinicians is the idea that vitamin D enhances the absorption of calcium. This is not the case. 25-D is a simple secosteroid which does not affect the genes responsible for calcium absorption. In contrast, the Vitamin D Receptor is a receptor that transcribes thousands of genes, some of which do affect the metabolism of calcium.

As biomedical researcher Trevor Marshall says, “In chronic disease the two things (vitamin D itself and the VDR) are NOT synonymous.” In patients with chronic disease, the VDR is unable to function properly. As previously discussed, this is due in large part to L-form bacteria that create proteins which inactivate the VDR, to a point where it can no longer correctly transcribe a wide array of genes, including some involved in calcium metabolism.

Once again then, it is only by killing the bacteria responsible for causing the disease process in the first place that the VDR can function properly, allowing the genes that affect the absorption of calcium to be turned on in the correct fashion. The mistaken notion that more vitamin D automatically means more activation of the Vitamin D Receptor, and hence greater calcium absorption, is probably the single greatest reason why vitamin D has been incorrectly identified as the solution to bone loss in people with chronic inflammatory disease.

In the same vein, low calcium in the bloodstream can lead to a condition called secondary hyperparathyroidism. The condition alters the level of Parathyroid Hormone in the body, which can result in bone loss. In patients with the disease, the kidneys try to compensate for the low level of calcium by increasing the conversion of 25-D to 1,25-D. Because the illness involves the vitamins D, many doctors mistakenly think that supplementation with the steroid might help the problem. However, the truth is that this condition is best corrected by bringing the level of calcium intake back into range.

Joyce Waterhouse, Ph.D. has recently described in detail a number of flaws in studies that use the relationship between low 25D and secondary hyperparathyroidism in order to estimate an optimal level of 25D. One problem is that they usually fail to ensure that subjects are consuming adequate calcium before assessing the relationship between 25-D and PTH. Thus, when researchers at Winthrop University Hospital in New York made sure that subjects consumed adequate calcium, they found that only a small percentage of patients with low 25-D actually had elevated levels of PTH, and that just 16 ng/ml of 25-D is usually enough to keep PTH in the correct range. This was confirmed by a recent study which found that PTH levels frequently remain normal even in patients with very low 25-D. The bone density of the elderly subjects in the study also remained the same as subjects taking higher levels of 25-D as long as their PTH remained normal.

When it comes down to it, 25-D accounts for only a very small percentage of variation in PTH levels, especially when subjects are taking adequate calcium. Several studies have shown that low magnesium, increasing age, or elevated serum phosphate and creatinine due to kidney disease also greatly contribute to the level of PTH, causing researchers at the University Hospital of New Norway to conclude that elevated PTH “is therefore probably a result of a combination of factors.” It’s not surprising then, that several studies have noted that giving vitamin D to patients with low levels of 25-D often does nothing to bring PTH back to normal levels.

In the end, it is perfectly possible that when calcium intake is adequate, most of what remains of the association between low 25-D and elevated PTH is simply part of the pathogenesis of chronic disease and osteoporosis. Just as the low 25-D seen in patients with chronic disease is the RESULT rather than the CAUSE of the disease process, elevated PTH in patients with low 25-D may simply be an indicator of inflammation caused by L-form bacteria.

7. Extra vitamin D does not reduce the risk of cancer.

The language of some studies, especially in the sections where researchers are asked to interpret their results, has suggested that supplementing with vitamin D might help people ward off cancer. Other research provides evidence that this is untrue.

In fact, the latest study by the National Cancer Institute – the first study to actually look at the relationship between measured vitamin D in the blood and subsequent total cancer deaths – failed to show an association between baseline vitamin D status and overall cancer risk in men, women, non-Hispanic whites, non-Hispanic blacks, Mexican Americans, and in persons younger than 70 or 70 years or older.

The findings, which appear in the Journal of the National Cancer Institute, are based on an analysis of data for 16,818 subjects who participated in the Third National Health and Nutrition Examination Survey. The subjects were at least 17 years of age when the survey was undertaken between 1988 and 1994 and they were followed through 2000. The researchers did find an association between vitamin D and colorectal cancer risk, most likely for reasons that will be addressed later in this section.

When asked by a correspondent from CBS News if vitamin D can reduce the risk of cancer, David Fishman, head of the National Ovarian Cancer Early Detection Program at New York University said, “I don’t believe vitamin D is the answer. I wish it was as simple as saying ‘If you take vitamin D, cancer will be cured. I don’t think it’s that simple.”

The Mayo Clinic’s website states, “It remains unclear if vitamin D deficiency raises cancer risk, or if an increased intake of vitamin D is protective against some cancers. Until additional trials are conducted, it is premature to advise the use of regular vitamin D supplementation to prevent cancer.”

L-form bacteria may be responsible for at least part of the pathogenesis of cancer. For one thing, L-form bacteria have been found in the tissues of patients with cancer. Some studies have found that people with certain types of cancer, such as prostate cancer, display the same dysregulated vitamin D metabolism observed in people with other chronic diseases now known to be bacterial in origin.

L-forms of various shapes and sizes inside the cells of a patient with breast cancer, photo taken by Alan CantwellSeveral forms of bacteria have already been linked to cancer. Researcher Alan Cantwell used acid-fast staining to identify L-form bacteria in patients with Hodgkin’s Disease, lymphoma, prostate cancer and other immunological diseases. Both gastric cancer and gastric MALT lymphoma (lymphoma of the mucosa-associated lymphoid tissue) have been associated with H. pylori bacteria, and the bacterium has been categorized as a group I carcinogen by the International Agency for Research on Cancer (IARC).

Other research has shown a link between a cancer of the eye, ocular adnexal lymphoma (OAL) and Chlamydia bacteria. In October, researchers at the San Raffaele H. Scientific Institute in Milan published, in Journal of the National Cancer Institute, the results of a study which demonstrated that the antibiotic doxycycline is proving to be an effective treatment for this form of cancer. “Our prospective trial revealed that doxycycline is a fast, safe, and active treatment for OAL, both at initial diagnosis and at relapse,” the study’s authors wrote.

In 2006, D.L. Mager and team published a review article in the Journal of Translational Medicine called, “Bacteria and Cancer: Cause, or Cure?” According to Mager, “An overwhelming body of evidence has determined that relationships among certain bacteria and cancers exist.” In the paper, Mager details how research teams around the world have implicated Salmonella typhi in gallbladder cancer, Streptococcus bovis and E.coli in colon cancer, and Chlamydia pneumoniae in lung cancer. According to Mager, the mechanisms by which bacterial agents may induce carcinogenesis include “chronic infection, immune evasion, and immune suppression.”

“Everybody knows inflammation induces cancer.” This suggests that, just as in other chronic diseases, long-term supplementation with vitamin D slows the immune system and facilitates the proliferation of L-form bacteria, ultimately driving the progression of cancer. Over time, L-form bacteria release more cytokines into the tissues, resulting in elevated levels of inflammation.

“Everybody knows inflammation induces cancer”, stated Francesco Marincola, MD, Senior NIH Investigator, at a recent conference. But how? According to biomedical researcher Trevor Marshall, “Th1 inflammation feeds the initial proliferative stage of cancer. Without Th1 inflammation the cancer cells can’t get adhesion to the ‘healthy’ cells and tissues, and can’t become proliferative. Then, as the cancer starts to metastasize, the inflamed stem cells are critical in enabling the spread of the inflammation, and the metastasis of the cancer.”

Furthermore, the Vitamin D Receptor is known to transcribe genes that work to prevent the spread of cancer. These include Metastasis Suppressor Protein, a protein that slows the creation of cancer cells, and Mitochondrial Tumor Suppressor 1 gene. But when too much 25-D and bacterial proteins bind and inactivate the Vitamin D Receptor these anti-cancer genes are not transcribed correctly.

A molecule of 25-D

Because inflammation induces cancer, it’s no surprise that research teams who follow their subjects for only a few years find that vitamin D seems to be “preventing” cancer. What they actually pick up on is the temporary decrease in cytokine production that results when 25-D slows the immune system and less L-form bacteria are killed. In the short term, as less bacteria die, less cytokines are released into the tissues, resulting in a temporary decrease in inflammation.

But in the long run, L-form bacteria will take full advantage of the subjects’ weakened immune systems. The bacteria will increase in number and spread to new tissues and organs. Decades later, the subjects will display higher levels of inflammation and higher rates of cancer and/or other chronic diseases, because even consistent immunosupression with vitamin D will no longer sufficiently prevent so many L-form bacteria, both alive and dead, from releasing cytokines into the tissues. Consequently, researchers who follow their study participants for the longest periods of time are often the ones to claim that supplementation with vitamin D offers no benefit when it comes to fighting the cancer.

Several months ago, researchers at Creighton University published the results of a study which found that vitamin D might lower the incidence of colorectal cancer. But Jacques Rossouw at the National Institutes of Health criticized the study. His group conducted a similar study that tracked the effects of vitamin D on 46,282 postmenopausal women with colorectal cancer and monitored the women over a longer period of time. “In our study we found absolutely no indication of an effect of calcium or vitamin D [on cancer] — zero,” he said. “And that’s over a seven-year period. It was a much larger study and a much longer study,” Rossouw told the press.

Dr. John Milner, chief of the Nutrition Science Research Group at the National Cancer Institute, agrees that skepticism is necessary. “We need to put this in the context of the entire diet and lifestyle and understand why we’re getting some effect,” Milner said. “I don’t want to minimize it, but let’s see a little bit more before we start jumping into public health policies.”

“In our study we found absolutely no indication of an effect of calcium or vitamin D [on cancer] — zero. And that’s over a seven-year period. It was a much larger study and a much longer study”Researchers at the Moores Cancer Center in California have published several disastrously misleading studies in which they incorrectly interpret the role of vitamin D in the pathogenesis of cancer. One study, published recently in Nutrition Reviews, combines data from researchers who tested the level of 25-D in subjects around the globe during the winter months. Not surprisingly, the researchers, who failed to question the subjects’ levels of 1,25-D, picked up on the fact that patients at a higher risk for colorectal and breast cancer had lower levels of 25-D. In reality, the low 25-D observed in the subjects resulted from the downregulation of 25-D under the influence of elevated levels of 1,25-D

The researchers incorrectly state that higher levels of vitamin D offer a “protective effect” against cancer. Their conclusion: supplementing with up to 2,000 IU’s of vitamin D daily could prevent an estimated 600,000 cases of cancer. Unfortunately, virtually the opposite is true. In reality, the “protective effect” they are picking up on is simply the point at which 25-D becomes immunosuppressive and a temporary decrease in cytokine release begins.

These studies are the equivalent of giving subjects prednisone and concluding that prednisone offers a “protective effect” against cancer because it slows the immune system, leading to a temporary decrease in bacterial die-off. In addition, no study to date has tested whether study participants given high doses of vitamin D later develop a wide array of other chronic illnesses such as diabetes, arthritis, and heart disease. Surely if they looked, they would pick up on a higher incidence of inflammatory disease in the groups of subjects taking vitamin D.

A particularly telling study on vitamin D and prostate cancer by researchers at the University of Tampere in Finland revealed that the highest rate of prostate cancer occurred when subjects’ levels of 25-D were either particularly low (under 8 ng/ml) or particularly high (over 33 ng/ml), giving a U-shaped curve.

It is very likely that the subjects with low 25-D were displaying the dysregulated vitamin D ratio (low 25-D, high 1,25-D) seen in patients with chronic disease, and that the patients with high 25-D were consuming very large amounts of vitamin D, amounts so large that the liver had no choice but to convert much of it into 25-D. These patients were sick indeed, since the high levels of 25-D suppressed their immune systems, disabling their ability to fight the progression of the cancer. Consequently, the researchers concluded that high levels of vitamin D might be associated with a higher risk of prostate cancer.

Similarly, a team of researchers at the National Cancer Institute in Rockville, Maryland conducted a study on men to determine the relationship between their levels of 25-D and pancreatic cancer risk. The researchers tracked the men for over 16 years. They found that in the long term, high 25-D levels greater than 26 ng/ml were associated with a three-fold increased risk for pancreatic cancer, suggesting that individuals consuming high levels of vitamin D were more likely to fall ill with the disease. Again, according to molecular modeling research, 26 ng/ml is near the range when 25-D significantly shuts off the Vitamin D Receptor, particularly when it is already partially blocked by bacterial proteins.

“Contrary to expectations, subjects with higher prediagnostic vitamin D status had an increased pancreatic cancer risk compared with those with lower status”They stated, “Contrary to expectations, subjects with higher prediagnostic vitamin D status had an increased pancreatic cancer risk compared with those with lower status…. Our results are intriguing and may provide clues that further the understanding of the etiology of this highly fatal cancer.”

Researchers at the Chinese Academy of Medical Sciences in China found a similar association between excessive vitamin D intake and esophageal and gastric cancers in men. Male subjects with levels of 25-D in the range of 48.7 ng/ml were much more likely to develop one of the two forms of cancer.

This same association between very high levels of 25-D (suggesting subjects are consuming large amounts of vitamin D) and higher rates of illness has also been observed in heart disease. A group of researchers at the Sree Chitra Tirunal Institute for Medical Sciences and Technology in India explored the relationship between elevated vitamin D (due to excessive sun exposure) and heart disease. The researchers tested the level of 25-D in 143 men with heart disease and 70 healthy control subjects. They found that the subjects with heart disease had much higher levels of 25-D in their blood, levels over 89 ng/ml, which is well beyond the level that causes the VDR to completely shut down.

Many people who hear about studies on cancer and vitamin D also don’t realize how easy it is for researchers to manipulate statistics in order to demonstrate positive associations.

Take, for example, a recent study published in the American Journal of Clinical Nutrition by Lappe et al, who gave study participants 1,100 IU’s of vitamin D over the course of four years (during the time when the short-term immunosuppressive effects of the steroid would be at its strongest). The researchers divided the participants into three groups. One group took no vitamin D, a second took calcium, and a third group took calcium and vitamin D. The team concluded that vitamin D significantly reduces the risk of cancer.

The study’s biggest flaw is that the researchers discarded the data of subjects who developed cancer during the first year of the study. Their excuse: cancers during the first year would have been present but undiagnosed at entry. Of the 50 people who developed cancer during the four-year study, 13 were removed based on this premise, and only 37 cases of cancer were actually analyzed. But the 13 people who developed cancer during the first year were likely to be the study participants with the highest loads of L-form bacteria. They would have been the people to suffer the most from the negative impact of elevated 25-D on the immune system. If data from the 13 participants would have been included in the study, the results would have reflected much less of a “benefit” from vitamin D. Even the researchers admit that “their conclusion was strengthened by both the observational, substantial improvement in risk reduction when cancers occurring early in the trial were excluded.”

Recall for a moment the study on breast cancer by the Women’s Health Initiative discussed earlier in this paper. The researchers concluded that vitamin D might offer a small benefit in preventing breast cancer. The story was picked up by the media and advertised ad nauseam. The authors’ inboxes were no doubt brimming with media requests.

“Neither use of supplemental calcium nor vitamin D intake was associated with [breast cancer] risk.” However, the media does not seem interested in broadcasting the results of other studies which have determined that vitamin D offers no benefit whatsoever in preventing breast cancer. A second study by the Women’s Health Initiative found no reduction in risk of breast cancer among postmenopausal women supplementing with 1000 mg calcium and 440 IUs of vitamin D. Researchers at the American Cancer Society conducted a study on 68,567 postmenopausal women and found that “neither use of supplemental calcium nor vitamin D intake was associated with [breast cancer] risk.” And researchers at the Northern California Cancer Center found no association between dietary vitamin D intake during adolescence and subsequent breast cancer risk.

Of course, since we know our picture of cancer remains relatively incomplete, we shouldn’t reject the possibility that vitamin D might offer some small benefit in preventing the disease. If L-form bacteria didn’t exist, then it might make sense to supplement with vitamin D in the hope that this might be true. But is it worth the risk when 25-D also slows the immune system, facilitating the spread of L-form bacteria into new tissues and organs, and also prevents the Vitamin D Receptor from transcribing the antimicrobial peptides and several anti-cancer genes? To say nothing of evidence which points to the probability that L-form bacteria and their subsequent dysregulation of the immune system are the ultimate cause of cancer in the first place.

Take, for example, 1,25-D. Several laboratory studies have shown that elevated 1,25-D may have a small anti-tumor effect. But elevated 1,25-D is also key in allowing L-form bacteria to spread unchecked from cell to cell. Elevated levels of 1-25-D leach calcium from the bones. High levels of 1,25-D affect muscle function, particularly the cardiac muscle. Studies which have detailed the intricate feedback pathways between the two forms of vitamin D have shown that elevated levels of 1,25-D are also immunosuppressive.

Consequently, any effect that 1,25-D might have in reducing tumors comes with a price – a price so large that it puts patients at much greater risk for Alzheimers, arthritis, diabetes, heart disease, strokes, and a vast array of other chronic diseases. And it may even have long term cancer promotion effects that cancel out any purported short-term benefit.

So, although elevated 1,25-D might possibly turn out to have a short-term beneficial effect on one small part of the complex disease process that is cancer, the effects on the L-form bacteria that also contribute to the illness mean that, in the end, it generates a plethora of negative consequences, consequences which contribute to more insidious, far-reaching and long-lasting aspects of the disease.

8. Vitamin D deficiency does not cause rickets.

Rickets is a softening of the bones that leads to fractures and deformity. The majority of cases occur among children in developing countries who suffer from severe malnutrition.

This child’s bowed legs are a symptom of rickets.

This past March a team of biologists at Harvard Medical School published the results of a study on rickets. The researchers engineered mice without vitamin D receptors (VDRs). Since vitamin D can have no effect on the body unless it can bind to the VDR, the mice could use no vitamin D whatsoever in their bodies. The researchers found that if the mice were given a diet high in calcium and phosphorous they did not develop rickets and their bones were just as strong as normal mice with active Vitamin D Receptors.

A second study, by the same research team, corrected rickets by replacing calcium and phosphate ions in the bloodstream of mice without Vitamin D Receptors, thereby confirming the results. The team concluded that rickets is not caused by a deficiency of vitamin D but instead results from hypophosphatemia, a condition where the level of phosphorous in the blood is too low.

Clearly, low calcium was part of the problem as well. Diminished levels of calcium cause an increase in Parathyroid Hormone, which subsequently causes the body to excrete too much phosphorous. This causes the level of phosphate in the body to drop, leading to the altered bone formation seen in rickets. Joyce Waterhouse, PhD, a researcher associated with Autoimmunity Research Foundation writes, “Low phosphorus is the proximate cause — but low calcium intake is generally the ultimate cause.”

In 2004, a study published in the American Journal of Clinical Nutrition by researchers from the Mayo Clinic, Oregon University School of Medicine, and other institutions confirmed that a low level of calcium can lead to rickets. The team assessed the absorption of calcium in 15 Nigerian children with active rickets. They found that all 15 children had resolution or improvement of rickets after six months of treatment with calcium supplements.

“Rickets in toddlers is a large problem in parts of Africa, especially Nigeria. It is not due to vitamin D deficiency but is caused by not having enough calcium in the diet.”Consequently, the US Department of Agriculture website clearly states “Rickets in toddlers is a large problem in parts of Africa, especially Nigeria. It is not due to vitamin D deficiency but is caused by not having enough calcium in the diet.” It’s certainly no surprise that children in Africa, who get copious amounts of sunlight, are not suffering from a disease caused by vitamin D deficiency.

In North America, too, the role of calcium is being reexamined. DeLucia et al emphasize that “Nutritional calcium deficiency may occur in North American infants and is not limited to the setting of developing countries.” Some attribute a recent small increase in rickets in North America to an increase in breast feeding, claiming that this is due to breast milk being low in vitamin D. However, breast feeding is also often accompanied by a diet low in calcium, particularly after weaning (e.g., juices rather than milk). Also, in recent years, more people have begun to avoid milk due to a greater awareness of lactose intolerance.

Marshall suggests that rickets may be related to Th1 inflammation, as a number of patients on the Marshall Protocol with Th1 illnesses and their close relatives report having had rickets as children. Vitamin D proponents claim that vitamin D added to the food supply was responsible for a historical decrease in rickets. But the history of rickets shows that a typical rickets case often had a history of smallpox, measles, or whooping cough. Plus, a 1997 study in Ethiopia found a high association between pneumonia and rickets. This provides more suggestive evidence that infection, either obvious and acute, or subtle and chronic, may play a role in the development of rickets and may exacerbate the effects of a low-calcium diet.

Does vitamin D come into the picture at all?

If a child with rickets is severely deficient in vitamin D, as well as in calcium and phosphorous, administering a small amount of vitamin D (which will be immediately converted into 1,25-D) can help by allowing the Vitamin D Receptor to turn on genes that affect the absorption of calcium. This probably explains why in the early 19th century, some children given high does of vitamin D were said to be cured from rickets.

However, if supplementation is continued, the level of the precursor form of vitamin D (25-D) in the body will soon reach the point at which it becomes immunosuppressive. With the negative effects of this situation in mind, it makes much more sense that patients low in calcium should simply be given extra calcium, which can remedy the situation without the need for vitamin D.

Thus, it goes without saying that the involvement of vitamin D in the above process does not justify the high levels of vitamin D currently added to the food chain in the name of “preventing rickets”, and that the health of the public would be much better served by regulations ensuring that they obtain adequate calcium and phosphorous rather than vitamin D.

9. Most researchers fail to consider the alternate hypothesis about vitamin D.

When it comes to studies about vitamin D, researchers simply do not consider the alternate hypothesis, the idea that additional supplemental vitamin D might be harmful or unnecessary, and that that low 25-D in many chronic diseases is a consequence of the disease process rather than a cause. At a recent conference on vitamin D organized by the American Cancer Society, Dr. Len Lichtenfeld, Deputy Chief Medical Officer of the organization, stated unequivocally, “There is no dispute among medical professionals that vitamin D is beneficial for our health.”

“This study is “not as ringing an endorsement of calcium and vitamin D as one might like.” If the results of a study show that vitamin D didn’t help the subjects involved, the study’s authors seem all too eager to explain away the results or discard the findings. Take the recent $18 million dollar study on vitamin D and calcium conducted by the Women’s Health Initiative. The study of more than 36,000 middle-aged and older women – the largest ever to test the health benefits of vitamin D – found that calcium and vitamin D had essentially no benefit on the bone density of the women involved.

After seven years of taking the supplements the group given supplements showed a 1% increase in hip-bone density but ranked no better statistically in avoiding fractures of all kinds. This study is “not as ringing an endorsement of calcium and vitamin D as one might like,” said one of the study’s authors, Dr. Norman Lasser at New Jersey Medical School. For one, the researchers might have considered whether the 1% increase in hip-bone density was due to the calcium, and not the vitamin D.

Nevertheless, the researchers who conducted the Women’s Health Initiative study tried to explain away the findings. An article about the study from the Associated Press stated, “Many experts downplayed the meaning of the negative finding. Dr. Bess Dawson-Hughes, a Tufts University vitamin expert who helped shape the dietary guidelines, said they should remain unchanged for now.” The article went on to state that, “Some researchers said the effect would have been clearer with higher doses of vitamin D, perhaps up to 1,000 units daily.” Furthermore, nearly every researcher, including the team who conducted the study, denied the implications of the findings, urging people to continue taking vitamin D despite the fact that the study showed it had no beneficial effect. About this, the article wrote, “Even so, experts are urging women to stick with government advice to keep taking the supplements anyway.”

In fact, the leader of the study, Rebecca Jackson at Ohio State University stated, “Based on our findings, women, particularly those over 60, should consider taking calcium with vitamin D for bone health and to guard against fracture.” Jackson’s advice is at odds with her own findings. It’s as if she is referring to data that doesn’t exist. It seems that researchers like Jackson are so prepared to say that vitamin D is beneficial that even when studies prove it isn’t, they say it’s helpful anyway.

Meanwhile, a second analysis of the same study group found that the supplements did not lower the women’s risk of colorectal cancer. Naturally, the researchers once again questioned the data. The San Diego Union Tribune wrote, “While the results were also disappointing, researchers speculated that a benefit might show up with more time.” No one bothered to comment on the finding that the women taking vitamin D had a 17% increased risk of developing kidney stones.

Perhaps the most recent example of researchers’ blindness to the implications of even their own results is on display in the August 25, 2007 issue of the Lancet. The largest such meta-analysis to date, Dr. Tang and team statistically analyzed a total of 29 studies involving 63,897 study participants with an eye towards definitively measuring the connection between fractures and bone loss, and vitamin D and calcium supplementation. Their abstract states clearly enough in the interpretation section, “We recommend minimum doses of 1200 mg of calcium, and 800 IU of vitamin D.”

“The addition of vitamin D to calcium did not change treatment effect significantly…. It was not significant.”This language is interesting in that it is just not supported by the substance of the findings. On page 661: “The addition of vitamin D to calcium did not change treatment effect significantly…. It was not significant.” On page 663: “Although addition of vitamin D supplementation was not shown to offer additional risk reduction over and above the use of calcium alone, a significant difference was observed between the effects of different vitamin D doses. This discrepancy could be due to statistical artifact.”

What is this “artifact”? “Our analysis was limited by the scarcity of vitamin D doses higher than 800 IU,” the researchers claim. “It is possible that vitamin D does have a beneficial effect when the dose is large enough (>800 IU).”

It’s also possible that these researchers are having it both ways, using ambiguous results to support two nearly opposite conclusions. In one breath (above), they blame the “scarcity” of vitamin D data at higher levels (>800 IU) for not being able to measure a significant effect. And then, in the abstract no less, they conclude that “treatment effect,” meaning fracture risk reduction, was better with “vitamin D doses of 800 IU or more than with doses less than 800 IU of vitamin D.”

A similar bias can be seen in a recent meta-analysis by researchers in Lyon, France, who concluded that subjects who began taking vitamin D were 7% less likely to die in the next few years than those who did not. In the paper, the team fails to mention that the benefit of vitamin D given alone, without calcium, was not statistically significant. Furthermore, four of the studies analyzed actually showed a greater rate of death among subjects taking vitamin D (though the death rate was only statistically significant in one of the studies). Two of these four studies were using a single injection with a very large amount (300,000 IU) of the steroid.

How can these contradictions be allowed to persist?

It seems that many researchers are under pressure to demonstrate that their data is statistically significant. Researchers obtain the money to conduct a study by applying for a grant, and inconclusive or insignificant results are not likely to impress the institutions in charge of distributing resources. It may be that many of the scientists who bolster claims of statistical significance have already received large grants and are eager to show that the money was spent on an analysis worthy of note.
The lockstep perception of the healthiness of ingesting vitamin D has even led some experts to downplay the effects of its toxicity. According to the school of nutrition at Colorado State University, “Because fat-soluble vitamins are stored for long periods, they generally pose a greater risk for toxicity than water-soluble vitamins when consumed in excess.” In excess, vitamin D is highly toxic. It causes calcification of soft tissues, and may cause calcified kidneys and kidney failure. Too much vitamin D may disrupt the level of calcium in the blood and produce fatigue and mental confusion.

In 1997, researcher Bernadette Marriott wrote an editorial in Annals of Internal Medicine entitled “Vitamin D Supplementation: A Word of Caution” in which she argues that vitamin D supplements be recommended with caution and care.

In a section on their website called “The Truth About Vitamin D Toxicity” John Jacob Cannell, the Vitamin D Council’s executive director tries to invalidate Marriott’s concerns by repeating the advice of vitamin D “expert” Reinhold Vieth, who feels that fear of vitamin D toxicity is unwarranted, and such unwarranted fear, bordering on hysteria, is rampant in the medical profession. Cannell himself states that “In fact, living in America today while worrying about vitamin D toxicity is like dying of thirst in the desert while worrying about drowning.”

And to whom is the NIH listening?

The National Institutes of Health held a recent conference that examined a range of scientific perspectives related to vitamin D and bone health across the life cycle. They invited Professor Reinhold Vieth, one of the most vocal advocates for very high vitamin D supplementation, to advise them on the issue of vitamin D toxicity. He was scheduled to give a speech about “Potential Adverse Outcomes of Vitamin D.” Although the transcripts of the conference are not yet publicly available, it would be reasonable to think he mentioned few, if any, causes for real concern.

10. When it comes to vitamin D, the current medical climate of consensus is hostile to new ideas.

Sir Isaac Newton once wrote, “If I have seen farther than others it is because I have stood on the shoulders of giants.” But even intellectual giants get it wrong from time to time. Many researchers today seem to regard the work of the most prestigious among them– at least in the field of vitamin D– as giants, and there is little room for questioning of basic assumptions.

“For many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias.” The fact that researchers seem so hesitant to say anything negative about vitamin D reflects the blanket assumption that vitamin D simply cannot be harmful. Arguments to the contrary are assumed to be untenable and entirely without merit. This is due in no small part to the reality that researchers today are overly committed to the idea of replication, the requirement that new findings must be supported by and stem from earlier research. As John P. A. Ioannidis writes in the Journal of PLOS Medicine, “For many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias.”

New research draws on the inferences of other studies conducted in the field, and it is required that conclusions be reviewed and accepted by peers who must share the same set of assumptions. If and when someone puts forth findings that turn an established area of medicine on its head, those findings are unceremoniously questioned and dismissed.

Janet Foutin, a staff member of Autoimmunity Research Foundation writes, “Even the most credible researchers must start upon a research foundation of previous empirical studies or it won’t be taken seriously in the community from which it springs. This consensus contamination is widespread and makes it very difficult to introduce process-or-content foundation-level changes.” In other words, when new medical research is always derived from previous work, fundamental changes to researchers’ assumptions are slow in coming.

The case of Barry Marshall and Robin Warren, the team of researchers who discovered that ulcers are caused by H.pylori bacteria rather than stress is particularly instructive. When that duo first put forth their findings, published in 1982, other doctors and researchers rejected their data and walked out of their lectures. It’s not as if published explanations of ulcers invoking stress and food intake weren’t internally consistent or validated in other peer-reviewed papers. Those papers just had one little problem: they were wrong. The medical community’s refusal to consider the alternative and, ultimately correct, explanation offered by Marshall and Warren lasted decades.

11. Research touting vitamin D’s benefits is often biased, methodologically weak, and ultimately misleading.

Studies about vitamin D can often be biased, methodologically weak, or both. Publication bias is the tendency of scientists to report findings that report statistical significance, but to bury examples that are inconclusive. The tendency towards publication bias is well-suited to prolonging any number of false positive conclusions, including the proposition that consumption of vitamin D is healthy.

An article published last September in the Wall Street Journal discussed how scientific journals are much more likely to publish studies which reveal positive qualities of a medication or supplement rather than those which demonstrate a negative or null effect.

For example, throughout the 1990s, publication bias gave the impression of a link between oral contraceptives and cervical cancer. But in reality, a 2000 analysis concluded that the studies finding no link between the two factors had seldom been published. In the end, the analysis found there was only “a spurious statistical connection” between oral contraceptives and cervical cancer.

In fact, another analysis, conducted in 1999, found that the percentage of positive studies in some fields routinely tops 90%. According to Lee Sigelman of George Washington University, “That is statistically implausible, suggesting that negative results are being deep-sixed.” As a result, “what we read in the journals may bear only the slightest resemblance” to reality. “You hear stories about negative studies getting stuck in a file drawer, but rigorous analyses also support the suspicion that journals are biased in favor of positive studies,” says David Lehrer of the University of Helsinki.

Various forms of bias may also be perpetuated by drug and supplement companies looking to make a profit. Several reports have revealed that some companies will even pay their own staff to help researchers write up the results of studies. The final papers eventually end up in scientific journals.

For example, in 2001, the American Journal of Kidney Diseases published an article that touted the use of synthetic vitamin D. Its author was listed as Alex J. Brown, an associate professor at Washington University in St. Louis.But recently, that same article was featured as a work sample by a different person: Michael Anello, a freelance medical writer, who posted a summary of it on his web site. Mr. Anello says he was hired to write the article by a communications firm working for Abbott Laboratories, which makes a version of the vitamin D product.

“Promotion has a different goal than publishing a legitimate research study”According to Anna Wilde Mathews, a staff reporter at The Wall Street Journal, “It’s an example of an open secret in medicine: many of the articles that appear in scientific journals under the bylines of prominent academics are actually written by ghostwriters in the pay of drug companies. These seemingly objective articles, which doctors around the world use to guide their care of patients, are often part of a marketing campaign by companies to promote a product or play up the condition it treats.”

Sabine Kleinert, an executive editor at The Lancet, says she makes a genuine effort to reject articles that have a marketing spin. “Promotion has a different goal than publishing a legitimate research study,” says Dr. Kleinert. She suspects companies sometimes influence medical writers “to write it up in a certain way to make a product sound more efficacious than it is.”

As opposed to research bias, methodological flaws are easier to identify– if one cares to look. So conditioned are we to hearing that vitamin D is helpful, when a study reveals the substance’s “benefits” few people take the time to analyze how the data was collected or ultimately interpreted. Because of this, the methods that researchers use to collect data on patients taking vitamin D rarely come under scrutiny.

Results from recent research attempting to demonstrate a protective effect of ingested vitamin D have been alternately inconclusive and lacking in sound methodology. Yet, all too often, researchers (and their colleagues and the media) conclude that such an effect exists. One such study, published in Annals of Internal Medicine in May of this year, claims as a part of its conclusion: “Findings from this study suggest that higher intakes of calcium and vitamin D may be associated with a lower risk of developing premenopausal breast cancer.” Before you run out and begin gulping down vitamin D pills as the local news anchor might have you do, what is the basis for this claim? Let’s take a look.

The study was conducted on 10,579 premenopausal women and 20,909 postmenopausal women by the Women’s Health Study Group. The women were asked to fill out baseline questionnaires about lifestyle, medical history, and were required to specify how often they ate certain foods. Participants self-reported whether they were taking vitamin D supplements, calcium supplements, and multivitamins. Then, the researchers followed up with the women over a ten-year time period to determine if they developed breast cancer.

The media took the results of the study and generalized the conclusion to all women despite the fact that in the results section of their paper, the researchers had clearly stated that among the postmenopausal women subjects, vitamin D intake was not inversely associated with breast cancer risk. There was also no association between calcium and vitamin D intakes and more aggressive breast cancer in postmenopausal women.

Furthermore, although the difference between those who ingested the highest and lowest levels of vitamin D did result in differing rates of breast cancer, those groups differed in other very substantial ways. Women in the group who consumed higher levels of vitamin D were 67% less likely to be a smoker, burned over 39% more calories doing physical activity, and drank about a fifth less alcohol. The researchers here assure us that they statistically controlled for these factors. But, if you have a purported effect of just a few percentage points, how strong can your conclusion be when you are studying two such substantially different groups?

This phenomenon is known as the “healthy-user bias.” Until the power of this effect is sufficiently and widely appreciated, researchers will continue to publish the results of studies that fail to account for a wide variety of lifestyle differences, many of which may be impossible to quantify.

Jerry Avron, a Harvard epidemiologist argues that when it comes to large epidemiological studies the healthy-user bias has the potential for “big mischief.” For example, in one large population studied by Elizabeth Barrett-Cinner, an epidemiologist at the University of California, San Diego, having gone to college was associated with a 50% lower risk of heart disease. Other studies have established a connection between a person’s income and a lower risk of heart disease. Considering all these factors, is it possible to isolate one single factor, such as vitamin D, as the reason for a small decrease in disease noted in a particular study?

“Women in the group who consumed higher levels of vitamin D were 67% less likely to be a smoker, burned over 39% more calories doing physical activity, and drank about a fifth less alcohol.” It wouldn’t so far-fetched to assume that women who take vitamin D are more likely to get better health care and be aware of prevailing health advice. After all, they’ve probably heard about studies like this one! Why else would they be consuming extra vitamin D? For a substance that ultimately is said to have a negative or absent net effect on the development of cancer, these circumstances represent an infinite loop of self-fulfilling prophecy.

In fact, even with a marginally significant correlation between vitamin D intake and a lesser risk of cancer in premenopausal women coupled with a study population, the enormity of which can only be described as a statistician’s dream, the 95% confidence interval was gaping: 0.42 – 1.00. You can think of confidence intervals as an indication of how reliable an estimate is. In this case, the answer would be not very reliable.

Compounding matters was the method used to gather food frequency data from study participants. No researcher’s first choice of gathering data is a survey. But, in this particular case, the data was gathered in an especially problematic way. Study participants were asked to remember back to what they consumed over the previous year, a method at which people appear to be notoriously poor.

A different group of researchers performed two simultaneous tests on the same participants. For one test, subjects were asked to recall the amount of vitamin D they had consumed in the previous year and for the second they were to fill out four one-week dietary records at regular intervals over the course of a year. The researchers found only a 0.35 correlation between the amount of vitamin D the subjects reported taking with the first method as compared to the second, meaning that the subjects had a very low tendency to correctly recollect the amount of vitamin D their food diaries suggested they were taking.

This methodological flaw is a problem and shows up from time to time in studies done in this manner, precisely because it magnifies the potential for systematic error. Once more, the problem with this particular survey is that the study participants who are more likely to engage in a wide range of known and unknown cancer-protective behavior by limiting alcohol intake, being more physically active, etc. are also more likely to know that researchers think they should be having more vitamin D and remember it that way. Therefore, it is probable that they over-reported their vitamin D intake. With the results of the study mentioned above showing that there was a very weak correlation between the amount of vitamin D participants reported taking over the course of a year and the amounts of vitamin D they reported consuming when given a weekly survey, it would be hard to argue otherwise.

Why would researchers use this kind of methodologically weak survey? The short answer is that their in-house statistician told them they needed the numbers– tens of thousands of participants. The one-year recollection survey is a crude instrument, but it is relatively easy to administer to a study cohort the size of a small city, and that is a minimum number you’ll need to demonstrate any statistical connection between vitamin D intake and cancer. Even with these numbers, this study, for the record, comes up just short on statistical significance in spite of its methodological flaws. Returning once more to the original concluding language of the Annals paper, it would seem like a stretch to conclude that if you’re a premenopausal woman, taking vitamin D has any demonstrable effect on cancer.

Even when researchers give their subjects vitamin D, they may fail to account for differences in lifestyle between women who carefully follow instructions and take supplements as directed and those who do not correctly follow the guidelines. This phenomenon is known as compliance effect. Avorn argues, “Girl Scouts in the group, the compliant ongoing users, are probably doing a lot of other preventative things as well.”

David Freedman, a statistician at the University of California, Berkeley, has written books on clinical trial design and analysis. Freedman says in The New York Times, “Women who take their pills as directed year in and year out are known to be different from ordinary women, so it is a mistake to generalize from them to the entire population.”

“Women who take their pills as directed year in and year out are known to be different from ordinary women, so it is a mistake to generalize from them to the entire population.”In fact, in an article in The New York Times Magazine, Gary Taubes puts forth Freedman’s findings, explaining that “whenever epidemiological studies compare people who faithfully engage in some activity with those who don’t – whether taking prescription pills, or vitamins, or exercising regularly or eating what they consider a healthy diet – the researchers need to account for the compliance effect or they will most likely infer the wrong answer. They’ll conclude that this behavior, whatever it is, prevents disease and saves lives, when all they are really doing is comparing two different groups of people who are, in effect, incomparable.”

Taubes explains, “No matter how well designed and how many tens of thousands of subjects they might include, they [observational studies] have a fundamental limitation. They can distinguish associations between two events. But they cannot inherently determine causation – the conclusion that one event causes the other. As a result, observational studies provide what researchers call hypothesis generated evidence – what a defense attorney would call circumstantial evidence.”

While no research methodology can be completely free of bias or methodological weakness, one potential bright spot, in certain cases, is that of molecular modeling. Increasing numbers of researchers are using molecular modeling to accompany or replace experiments using human volunteers. Molecular models display exactly how molecules in the body fit together. For example, software can take a virtual molecule of 25-D or 1,25-D and demonstrate exactly how they fit into the Vitamin D Receptor.

It was molecular modeling software that allowed a research team at McGill University to identify over 900 different genes transcribed by the Vitamin D Receptor. And it was molecular modeling that allowed biochemical researcher Trevor Marshall to discover exactly how 25-D binds and inactivates the Vitamin D Receptor, proving with inarguable precision that the molecule is immunosuppressive as it reaches higher levels. As Marshall says, “The primary difference between mathematical science and evidence-based medicine is that one is definitive and one is interpretive. As we enter the 21st century, the tools to reduce some important medical dilemma to mathematical precision are now available in Molecular Genomics.” And when molecular modeling evidence is combined with clinical data showing the reversal of many chronic diseases, the evidence is even stronger.

12. The dairy and supplement industries are intent on heavily promoting vitamin D.

In order to understand why we hear such unreservedly positive things about vitamin D, one must appreciate the extent to which supplement and food interest groups such as the one representing the dairy industry promote its use. Thanks in no small part to media campaigns sponsored by the dairy and supplement industries, vitamin D has become widely known as the “sunshine vitamin” and is touted to health-conscious individuals in an effort to make them feel that vitamin D is part of a responsible lifestyle.

Let’s start with the supplement industry, a syndicate which is certainly cashing in on vitamin D’s health “benefits.”

On the same online supplement retailer which lists how vitamin D can be used in connection with 21 different health conditions, we are offered oils and spreads, protein powders, breakfast bars, any number of other nutraceuticals, and some 40 different multi-vitamins, all of which contain the secosteroid. NEEDS, another online retailer, sells 37 different supplements with vitamin D and approximately 100 fish oils containing vitamin D, some priced over $30.00 a bottle.

If you think that vitamin D isn’t heavily promoted by the food and dairy industries, think again. Consider the recent marketing battles that have emerged after the FDA proposed a rule change in its guidelines about vitamin D. Within the next few months, the FDA is expected to smooth the way for manufacturers intent on adding “high” levels of vitamin D to a variety of food products.

According to an article in Packaging World Magazine by Stephen Barlas, ”It is predicted that this will set off a scramble by both milk, milk product, and juice marketers to redo their product labels and packaging in order to take advantage of the new guidelines.”

A petition from the Beverage Institute for Health and Wellness, which is funded by the Coca-Cola Co.— one brand of which is Minute Maid fruit juices and drinks— is petitioning the FDA to allow a broader claim about vitamin D to be made. At present, few product retailers choose to make the osteoporosis/vitamin D health claim because of the qualifications required to accompany it, such as noting that calcium only benefits “young adult white and Asian women who engage in regular physical activity.”

Minute Maid’s new line of Vitamin D-fortified products

Under the request advocated by the Beverage Institute, a food would have to be considered “high” in both calcium and Vitamin D before it could make an osteoporosis health claim. That would mean a product would have to contain at least 20% of the Daily Value (DV) of Vitamin D and/or calcium per reference amount customarily consumed. Minute Maid’s orange juice and some of its offshoots contain more calcium than the milk products now eligible to use the calcium/osteoporosis claim, and contain about the same level of Vitamin D. On April 25 Minute Maid introduced its Enhanced Juice line. It includes new Minute Maid Multi-Vitamin and Minute Maid Active variety, and a calcium-fortified orange juice offering: Home Squeezed Style + Calcium + Vitamin D.

But according to Barlas, “producers of reduced-fat, low-fat and fat-free milk and yogurts will also benefit from a more streamlined and expanded claim. Once the FDA decision is finalized, milk and fruit juice marketers will begin battling one another for new market share.”

Cary Frye, vice president of regulatory affairs for the Intl. Dairy Foods Assn. (IDFA), says, “It is certainly clear that the intent of the petition is to be able to make stronger claims for fortified orange juice in preventing osteoporosis, to compete with milk in that regard. But the new simpler claim will be available to all foods, and it will be up to the dairy industry to leverage its nutrient-dense foods so as to market milk as the superior beverage choice.”

Of course, companies such as Colombo, Dannon and Yoplait, all of which sell vitamin D-fortified yogurts, are unlikely to take the challenge sitting down. Tom Nagle, senior vice president of marketing for IDFA, stated, “Fortified juices have made progress in consumer perception, but it is our intention to protect our number-one position with consumers.” In order to remain competitive, these companies are predicted to add the vitamin D/osteoporosis claims to their products as well.

But don’t leave out the fishing industry. Vital Choices seafood company sends out an “official newsletter” with articles such as “Wild Salmon Affirmed as Top Vitamin D Source” and “Vitamin D May Lower Risk of Ovarian, Breast, Kidney, and Colon Cancers”, accompanied by a chart showing exactly which of their products are highest in vitamin D.

With vitamin D appearing in so many foods, and people eating them, often regardless of the total amount of the substance they are consuming, along with the additional amount produced by sun exposure, the danger of this trend becomes obvious.

The dairy industry generates millions off the claim that vitamin D increases the absorption of calcium, a claim to which more and more studies are taking exception. It’s no small secret that industry marketing campaigns have nothing to do with science and are all about generating a profit.

Not long ago, the National Dairy Council partially funded a small study to measure the effects of consuming dairy on weight loss. That study consisted of about 30 participants, only 11 of which were in the high dairy group. The subjects were instructed to follow a reduced-calorie diet, which many have argued was actually the key to their weight loss success.

An advertisement by the dairy industry touting milk’s supposed weight-loss benefits

On the basis of that suspiciously humble study, the Council mounted the “3-A-Day” campaign, a multi-million dollar marketing offensive spent on advertisements connecting milk to weight loss. In 2006 the milk producers even enlisted high-profile celebrities for their “Great American Weight Loss Challenge” and “Body by Milk” promotions.

The Dairy Council has persisted with their campaigns despite a number of research studies showing a contrary association, linking milk and dairy consumption to weight gain, and regardless of the fact that the Physicians for Responsible Medicine have filed a petition stating that the weight loss claims are misleading.

Now that an increasing number of studies are showing no association between vitamin D and osteoporosis, will the dairy and supplement industries persist with their campaigns involving vitamin D? If left unchecked, the answer is probably yes. And the public will continue to get information about vitamin D off the side of a beverage carton rather than from the molecular biologists who truly understand the actions of the steroid.

13. The media is neither well-informed nor objective about vitamin D.

There is no doubt about it— the media love vitamin D. Here’s a sample of articles that turn up on the web.

• Sunshine Vitamin D – Sunshine Vitamin Brightens Smiles
• The Sunshine Vitamin, The Crucial Need For Vitamin D
• Critics Now Accept the Sun as Your Healthiest Source of Vitamin D
• Vitamin D Deficiency, the Ignored Epidemic of the Developed World
• How The Sunshine Vitamin Zaps Disease
• Let the Sunshine Vitamin Brighten Your Day
• The Wonderful Healing Properties Of The Sunshine Vitamin D
• Sunshine: Don’t Leave Home Without It
• Vitamin D – The Sunshine Vitamin!
• Almost Everyone Needs More of the Sunshine Vitamin
• Shining a Light on the Health Benefits of Vitamin D
• Vitamin D Deficiency: the Silent Epidemic
• The Miracle of Vitamin D

It’s not as if the media is purposefully intending to deceive. The supposedly and unequivocally positive benefits of vitamin D make for good copy. The vitamin D story is one of the media’s rare opportunities to convey a positive message, and they seize it whenever possible. Consumers of media are weary of hearing about skyrocketing obesity, about the failure of once promising drugs like Vioxx. They are also scared of cancer. Nothing attracts viewer interest more than the promise that the information presented will offer some way to get an edge on chronic disease. Vitamin D as the freely available anti-cancer wonder drug fits the bill very nicely. What members of the media do not realize, just like researchers who don’t dig deep enough to seek out the alternative hypothesis, is that high-level vitamin D’s feel-good effects are due entirely to its immunosuppressive nature.

“The vitamin D story is one of the media’s rare opportunities to convey a positive message to their viewers, and they seize it whenever possible.”Just like the supplement industry, the media will often unknowingly take a small study about vitamin D and blow it completely out of proportion. Newspapers, magazines, TV shows, talk shows, radio programs – all pick up the same story and repeat it over and over again, until it seems as if twenty different studies have been published on the subject rather than one. And the language is often overly dramatic. In an article about vitamin D published in US News and World Report called “The ABCs of D, Almost Everyone Needs More of the Sunshine Vitamin”, the author states, “A single nutrient keeps bones strong, wards off diabetes, and protects against tuberculosis, cancer, colds, and the flu. Sound too good to be true? There’s more: It’s free. But you’re almost certainly not getting enough.”

So many articles about vitamin D end with copious amounts of advice about how to get more of the “vitamin.” We see tables, which are attempts to help the reader maximize D intake. The authors often chime in with advice, basing their statements on data that is already misleading and on biases already unchecked. The vitamin D publicity sequence: from data to interpretation to scientific publication to media generalization is not unlike the children’s game telephone, in which each subsequent interpretation is less accurate than the one that preceded it.

Not surprisingly, the media invites vitamin D “experts” to weigh in, communicating their mistaken views on vitamin D to a vast number of viewers. The following was taken from an interview with vitamin D expert Michael Holick that was published in The New York Times, “A visit to the office of Dr. Michael F. Holick in the Boston University Medical Center quickly conveys his enthusiasm for his favorite hormone, vitamin D. On the office walls are letters from sixth graders responding to a talk he gave.

”The important fact I learned from you yesterday is that most living things or persons need vitamin D,” one child wrote. Added another, ”Even frogs need vitamin D.” To advance his point he handed a reporter a copy of a paper he had recently written, ”Vitamin D: The Underappreciated D-lightful Hormone That Is Important for Skeletal and Cellular Health.”

Oh dear.

14. We must take immediate action to remedy the health crisis that has resulted from faulty conclusions about vitamin D in chronic disease.

When it comes to public health, a few false assumptions can have disastrous and far-reaching consequences. The failure of researchers to understand that the low levels of 25-D observed in their subjects is not the cause, but the result of chronic disease, has put the public at greater risk for developing diseases that range from Alzheimers, to diabetes, to cancer, and is directly feeding an epidemic of chronic disease. The chronic diseases caused by L-form bacteria are far more common than currently realized, and are often only noticed as subtle signs of aging, such as osteoporosis, obesity, fatigue and arthritis.

As I write, well-intentioned researchers striving to improve public health, are unknowingly touting a steroid that allows L-form bacteria to proliferate and spread. People taking extra vitamin D are not getting better. Instead, they are feeling a short-term palliative effect from a steroid that slows the immune system, preventing L-form bacteria from releasing the cytokines that result in Th1 inflammation.

It is critical that everyone from clinicians to medical researchers to policymakers understand that recent research has shown the immunosuppressive effects of 25-D and the transcriptional effects of 1,25-D. New research that has also revealed how to correctly activate the Vitamin D Receptor once it has already been turned off by proteins created by L-form bacteria. Given this research, it’s no less important that the various industries touting the benefits of vitamin D immediately stop those marketing campaigns.

“It is incumbent upon the FDA and every other food regulatory agency around the world to scale back and reverse plans to add even more vitamin D to the food supply.” Most importantly though, it is incumbent upon the FDA and every other food regulatory agency around the world to scale back and reverse plans to add even more vitamin D to the food supply. Given the FDA’s explicit mission “to protect the public health” and the balance of research which is rapidly accumulating against vitamin D, the agency will simply have no alternative.

Vitamin D is far more often a cause, and not a cure for disease. And that discrepancy makes a world of difference. It is the difference between advising the public to supplement with vitamin D and telling people to avoid supplementation at all costs. It is the difference between preventing a disease and speeding its progression, the difference between fighting an epidemic of chronic disease, and watching more and more people fall ill every day. And it’s a change that needs to happen right now.

In The Structure of Scientific Revolutions, Kuhn argues that, at first, a scientific revolution takes place slowly, and that changes in mentality happen gradually as serious thinkers reconsider ideas. He states that “If the paradigm is one destined to win its fight, the number and strength of the persuasive arguments in its favor will increase. More scientists will then be converted, and the exploration of the new paradigm will go on. Gradually the number of experiments, instruments, articles, and books based upon the new paradigm will multiply.”

But when it comes to vitamin D, there is no time for Kuhn’s incremental revolution.

It’s no secret that the scientific community is particularly resistant to the long-term harmful effects of vitamin D. Understanding its role in chronic illness will require a vast number of people to admit they have been wrong. Uttering a collective “oops” will not come easily to the medical profession. One can hope that the urgency of this health crisis will inspire doctors, researchers, experts, and everyone with a stake in vitamin D to swallow their pride and strive to make things right for the common good.

Along with the revolution in attitude towards vitamin D is the equally important acceptance of the role of L-form bacteria that block the Vitamin D Receptor, and the treatment that can eliminate them. Instead of using short term palliatives, like vitamin D supplements, there is evidence that these bacteria can be now be killed, meaning that many debilitating chronic diseases can now be cured.

It’s hard to say how this scientific revolution will pan out. One likely scenario is that those with the greatest stake in it, those most sickened by chronic disease, will simply demand that everyone – from the industry to the media to their doctors to medical researchers and regulatory agencies – take good note of the future of conventional wisdom about vitamin D.

This paper would not have been possible without the help of Joyce Waterhouse PhD and Paul Albert who spent extensive amounts of time informing me about research and editing my work.