Pauling, Rath, and Lipoprotein(a)

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[An examination of Pauling’s research on vitamin C and heart disease. Part 2 of 4.]

In 1989, a young medical doctor by the name of Matthias Rath began working at the Linus Pauling Institute of Science and Medicine. Rath had come from Germany, where he and his colleagues had uncovered evidence that the cause of plaque development in atherosclerosis (the hardening of arteries brought about by cholesterol deposits) was not a direct result of the presence of Low Density Lipoprotein (LDL), as had been previously thought. Rather, the Rath group found that LDL was synthesized in the liver into a new substance called lipoprotein (a), which binds to and carries cholesterol to sites throughout the bloodstream, building up on arterial walls in the process.

In moving to the Pauling Institute, Rath brought with him a specific interest in the potential relationship between vitamin C and lipoprotein(a), or Lp(a). He hoped that, in collaborating with Linus Pauling, he might be able to more fully explain the preventative effects of vitamin C on cardiovascular disease that had been observed in vitamin C-deficient animal models.

However, within the field, there existed significant skepticism as to whether vitamin C could actually affect Lp (a) levels in the blood, since these levels were not known to be modifiable by diet or drugs; – rather, the operating assumption was that the levels were genetically determined. Furthermore, concerns were raised that high doses of vitamin C might lead to an increased zinc-to-copper ratio in the blood, the end result being hypercholesterolemia and a concurrent increase in the risk of stroke or heart attack.

Skeptics also argued that an intense regimen of vitamin supplementation might spur the development of kidney stones, due to the acidification of urine in patients unable to take sodium ascorbate for health reasons. Additional fears were expressed that large doses of vitamin C, vitamin E, and other nutrients that act as blood thinners might interact dangerously with blood-thinning medications taken by many heart patients already.


Unsurprisingly, Rath and Pauling were hopeful that a solution could be found that would put to rest all of the naysaying. In this, the duo was driven by a belief that an optimum amount of vitamin C and other vitamins would mitigate any negative complications while simultaneously preventing a majority of heart disease.

By February 1990, Rath and Pauling were preparing to run experiments using vitamin C-deficient guinea pigs with induced atherosclerosis. These trials, according to Pauling, were devised by Rath and based on the idea that lipoprotein (a) synthesis in a small number of animals might be correlate with the inability to synthesize vitamin C. Pauling remained involved mostly as an eager and interested advisor and patron for Rath’s work on the subject.

In terms of their business arrangement, Pauling made it clear early on that Rath should not be held to the regular patent agreement for LPISM employees (25% royalties to the inventor, 75% to the Institute). Since Rath had developed the idea and foundational work outside LPISM, Pauling suggested a 50/50 split on the profits.

In addition to his scientific work, Rath was also a peace activist, an outspoken opponent of international corporate exploitation, and an advocate for the control of nuclear weapons, and as such he had followed Pauling’s political exploits with great personal interest for many years. Perhaps because of these shared qualities and the growing connection between the two, Rath refused the favorable 50/50 deal that Pauling had recommended. Instead, Rath communicated to Pauling that he believed the Institute should receive any and all profits, leaving Pauling to infer that Rath required no royalties for what he viewed, in principle, as an effort to decrease the amount of suffering endured by people with heart disease. In the end, Rath never signed the Institute’s patent agreement at all.


The first major paper to emerge out of Rath and Pauling’s collaboration was published in Proceedings of the National Academy of Science in December 1990 and titled “Immunological Evidence for the Accumulation of Lipoprotein(a) in the Atherosclerotic Lesion of the Hypoascorbemic Guinea Pig.” The publication reported on Rath’s study and showed that vitamin C protected arteries from fatty build-up at an intake of what would be about 5 grams a day in humans, as adjusted for weight. This dose stood in stark contrast to the much smaller Recommended Daily Allowance at that time, which was 50 mg.

With this paper, it appeared that Pauling had finally acquired a critical piece of evidence that he had been searching for ever since writing Vitamin C and the Common Cold in 1970: experimental proof that a widespread lack of vitamin C in the human diet was resulting in negative health consequences that ranged far beyond scurvy. Likewise, for Pauling, the Rath studies were a clear indication that the federally recommended dose, though sufficient to prevent scurvy, was by no means optimal. Rather, at 50 mg per day, humans were living in a state of chronic vitamin C deprivation and were suffering from a wide range of maladies as a result.


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From 1990 on, the connection between vitamin C and heart disease took center stage in Pauling’s life. Invigorated, he and Rath both saw the topic as a key new focus for research at the Institute, and a program that would pair well with growing national interest in orthomolecular medicine and in controlling health through diet.

To promote this vision, The Linus Pauling Heart Foundation was established as a non-profit agency that aimed specifically to raise money to support the clinical trials needed to determine the exact value of different doses of vitamins needed to prevent cardiovascular disease. In addition to the vitamin C work, the Foundation also sought to  generate funds that would support investigations into alternative heart therapies that used proline, lysine, and niacin.

Once it was established, Pauling named Rath as president of the Foundation, which operated separately from the Institute, but with some financial backing. To draw support for the Foundation’s work, Pauling made regular appearances on media outlets in the San Francisco Bay Area. Likewise, over the course of the next two years, he issued a steady stream of press releases arguing in favor of the use of vitamin C, vitamin B3, nicotinic acid, and lysine to prevent and even reverse the onset of cardiovascular disease. In these, Pauling also alluded to the notion that Lp(a) might be implicated not only in heart disease, but also in diabetes and cancer. No specific optimal vitamin intake was ever detailed in the news releases. Instead, readers were encouraged to make donations to the Foundation so that research to better understand the role that vitamins play in controlling heart disease might more rapidly progress.

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Vitamin C and Cardiovascular Disease: The Roots of Controversy

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Caricature of Linus Pauling created by Eleanor Mill and published in the Philadelphia Inquirer, May 1992.

[Part 1 of 4]

“People are not dying from too much fatty food, they’re dying from too little vitamin C.”

-Linus Pauling, Vitamin C and Heart Disease, 1977

Health-conscious readers of a certain age have likely experienced a frustrating back and forth in food trends over the past several decades, and especially in the 1980s and 1990s. First eggs were said to be bad for you because they are high in cholesterol, then it was learned that they didn’t increase cholesterol in the blood. Likewise, butter was believed to be a health risk because of its high levels of saturated fats, however, butter (especially from grass fed animals, and especially as opposed to margarine) is now argued to be a valuable source of vitamins, minerals, and fatty acids. Chocolate and red meat, too, were decried for being too fatty or, in the case of chocolate, also too sugary. Yet today, both are viewed as useful and even valuable sources of nutrition, so long as they are consumed in moderation.

These swings in consensus swept across the United States beginning in the 1970s largely in response to rising concerns over cardiovascular disease, or CVD. CVD includes a range of maladies such as angina, or heart attack, and many occur in conjunction with atherosclerosis, or the build-up of fatty plaques on arterial walls.

Today, CVD remains the leading cause of death in the United States, claiming over 600,000 lives every year. As health professionals have sought to provide guidance on balanced eating, ideas have flip-flopped on the potential dangers of many foods because, over time, it has become increasingly clear that cutting these foods out of one’s diet altogether had little to no impact on rates of CVD.

Linus Pauling was arguing in support of this point of view long before the data had been gathered to confirm it. Pauling believed that the trend toward removing eggs, red meat, and whole milk from American diets was an ill-advised scheme that restricted valuable sources of protein and nutrients from individuals who often could not afford substitutes for these staple foods. In Pauling’s view, it should have been clear to physicians and other health professionals that these dietary sources of cholesterol could not significantly impact total cholesterol levels in the blood, because cholesterol is synthesized, to a great extent, within the body due to its importance in the maintenance of cell membranes.

The real problem behind heart disease, then, was not a high-cholesterol diet. The problem behind heart disease, Pauling argued, was a widespread failure to ingest a substance that could limit the body’s natural production of life-threatening cholesterol: Vitamin C.


As early as the late 1950s and early 1960s, researchers were uncovering evidence that high vitamin C intake reduced cholesterol in vitamin C-deficient guinea pigs, rats, and rabbits. Perhaps most notably, in the 1950s a Canadian group of researchers led by Dr. G.C. Willis found that above-average cholesterol intake did not result in plaque deposits in non-human subjects’ arteries so long as the diet was paired with a high-dose vitamin C regimen.

Intrigued, Linus Pauling began a search for other champions of this view, and in 1972 he wrote to Dr. Donald Harrison at the Stanford Medical School of Cardiology inquiring into additional research that was being conducted on the interplay between vitamin C and a reduction in the risk of cardiovascular disease. Harrison responded that, although the results were not yet published, he had found lower levels of cholesterol in the livers of guinea pigs that had been fed non-trivial doses of vitamin C.

By 1976 many had come to accept that vitamin C played some role in the regulation of cholesterol metabolism and thus in the progression, or lack thereof, of atherosclerosis and CVD. In addition to Harrison’s studies at Stanford, preliminary work conducted by researchers at Pennsylvania State University found that ascorbic acid and ascorbic acid sulfate (two forms of vitamin C) significantly reduced atherosclerosis caused by cholesterol plaques in rabbits.

However, at about this time, other research projects had suggested the opposite, and indicated that increased intake of vitamin C might in fact increase the risk of heart disease by inhibiting the absorption of copper in the intestinal tract. As a result of this inhibited absorption, the ratio of zinc to copper in the blood would stray from what is ideal and ultimately result in hypercholesterolemia: an imbalance in zinc and copper metabolism that is implicated in coronary heart disease.

These findings created a scenario in which the Pauling camp was squared off against many physicians over the confusing and opposing views that large doses of vitamin C both reduced and increased one’s risk of cardiovascular disease.


Throughout the 1970s, Pauling’s broad argument in favor of the fundamental importance of vitamin C to optimum human health was based on the idea that when primates lost the gene for vitamin C synthesis about forty million years ago, systematic physiological imbalances arose that continue to carry negative health consequences for humans today.

Pauling was quick to point out that all animals require vitamin C to live and that most synthesize it naturally. Yet humans – primates who do not synthesize their vitamin C naturally – typically obtain far less of it in their diet (when adjusted for body weight) than do other primates and non-synthesizing animals like guinea pigs. In addition, animals of this sort, when fed moderate to low levels of vitamin C, showed increased risk for development of arterial plaques of cholesterol.

What was less clear was whether or not this same effect was occurring in humans. Physicians opposed to Pauling’s view based their arguments on the idea that humans are physiologically different in important ways from the animals used to model the effects of vitamin C deficiency in the laboratory. Pauling scoffed at this notion and firmly believed that vitamin C deficiency in humans was the true cause of CVD. But even he could not fully explain exactly why vitamin C should be directly related to heart disease.

Over a decade later, in 1989, when a scientist named Matthias Rath came to the Linus Pauling Institute of Science and Medicine, Pauling would finally find what he believed to be the key to explaining how and why vitamin C was so important to the well-being of the human heart.

Vitamin C and Cancer: Rays of Hope

 

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[Part 4 of 4]

Ridiculed by the medical profession for two decades, the tide began to shift for vitamin C and cancer starting in 1992. That year, the New York Academy of Sciences voted to discuss high-dose vitamins and nutrients at its annual meeting, devoting several sessions to the antioxidant properties of vitamin C and its potential value at higher-than-dietary amounts in preventing lung, stomach, colon, and rectal cancers.

Oddly, throughout the proceedings, one prominent name had been missing from the conversation, a point noted by a professor from Alabama who finally spoke up, saying,

For three days I have been listening to talks about the value of large intakes of vitamin C and other natural substances, and I have not heard a single mention of the name Linus Pauling. Has not the time come when we should admit that Linus Pauling was right all along?


Since 1996 the Linus Pauling Institute, relocated from California, has continued work on cancer from it’s new home at Oregon State University. Basing these contemporary orthomolecular studies on the hard sciences of cellular biology, molecular biology, and organic chemistry, the Institute continues to explore the cutting edge of health and nutrition research.

Working under Dr. Balz Frei, the current director of the Institute, as well as former LPI principal investigator Dr. Roderick Dashwood (now director of the Center for Epigenetics and Disease Prevention at Texas A&M University), OSU student Matt Kaiser has spent time analyzing the benefits of vitamin C treatment for colorectal cancer, which remains the third leading cause of cancer related deaths in the United States. The Pauling Blog has interviewed Kaiser in the past, and we met with him again recently to gain a better sense of trends in the community of researchers interested in vitamin C and cancer.


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One primary question that begs further exploration is, why didn’t earlier studies find evidence of the value of vitamin C?

As it turns out, the problem appears to have been primarily located in the way that vitamin C was being administered. The 1979 Mayo studies to which Pauling so strongly objected had assumed that, since vitamin C was filtered out of the body after a certain point of blood saturation, higher doses need not be examined. This assumption – that excess vitamin C could not be absorbed and was simply excreted in the urine – was one of the most basic issues of contention that Pauling was never able to get past with the medical community. However, it now appears that the assumption applies only if vitamin C is taken as an oral supplement, a breakthrough that was first identified by Mark Levine, a Senior Investigator at the National Institutes of Health.

Matt Kaiser explains

Mark Levine realized in the 1990s that the way drugs are distributed and function in the body [pharmacokinetics] can drastically change the amount of vitamin C entering blood plasma. Eating vitamin C you can only get about 250 micromolar [a measure of vitamin C, or ascorbate— to use its chemical name— that can be concentrated in the blood stream]. With intravenous injection, the levels are much larger: 200 times. One millimole is a thousand micromoles, so 30 millimolar [of ascorbate in blood plasma] is a huge difference!

At these high pharmacological— or even super physiological— doses, Levine found that cancer cell populations dropped significantly. To understand why, it is important to know a bit about how cancer works.

Human DNA can wrap up tight (heterochromatin) or unwind into a loose, more open configuration (euchromatin). When it is wrapped up tight, the genetic information on the DNA cannot be expressed. This is because transcription, which is the process by which a cell reads and expresses the genetic code, requires access to DNA.

There are very specific times when DNA should be wrapped tight to maintain optimum health, and other times when one’s body needs to be able to use the instructions for cellular function that are contained in DNA. When DNA needs to be unwound, molecules called histone acetyltransferases (HATs) help to unwind it. When it needs to be wound up tight, the process is aided by histone deacetylases (HDACs).

HDAC overexpression is a hallmark of cancer cells, and hyperactive HDAC cells lead to messy, knotted DNA winding. This biological circumstance hinders the cell from reading important instructions found in DNA, which in turn prevents the production of important tumor suppressor proteins. At the same time, it leaves certain sections of the genetic code open that should not be expressed.

“Basically,” says Kaiser, “You remove the break from the car, and then you also step on the gas. And that’s cancer.”


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Matthew Kaiser.

The prevailing theory of how vitamin C acts on tumors is that it functions as a “prodrug,” meaning that it stimulates biochemical processes that allow something else to kill the cancer cell, rather than acting on it directly. In this case, the active agent is hydrogen peroxide, which is produced in saturated tissues by excess vitamin C. “Vitamin C acts as the Trojan horse that allows hydrogen peroxide to enter the tumor site,” Kaiser explains. “You can’t inject it straight in; your body will react too strongly. Hydrogen peroxide is a reactive oxygen species…it tears cells apart.”

However, since working on the project, Kaiser has found that this consensus on how vitamin C fights cancer isn’t necessarily the whole story. Pharmacological levels of ascorbate appear to selectively reduce the presence of proteins that regulate reactive oxygen species, like hydrogen peroxide, in cancerous cells. Some of these same proteins also happen to promote cell growth, which is not something that one would wish for cancer cells to do. In addition to producing hydrogen peroxide, ascorbate actually inhibits the runaway HDAC production that makes cancer cells so dangerous.

“What makes it really hard, really complicated,” Kaiser laments, “is that this might not work the same way for different types of cancer cells in different locations. There’s still so much to understand about how vitamin C is having this protective effect…That’s what’s lacking and that’s why we need studies like this.”


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And indeed, more studies are coming. In keeping with it’s mission to extend and promote what it calls “healthspan,” LPI hosts a bi-annual Diet and Optimum Health Conference, bringing together experts from around the world to talk about topics in orthomolecular medicine, among other fields. This year the conference, which was held at OSU in September, featured several speakers discussing vitamin C and cancer. One of them was Dr. Mark Levine, the NIH scientist who first showed the value of intravenous ascorbate.

Margreet Vissers and Anita Carr, of the University of Otago in New Zealand, also described their own advances on the subject. Vissers found in her studies that levels of 50 micromolar ascorbate in blood plasma (average dietary levels are between 40 and 80) had little to no protective effect against cancer. Doubling the amount to 100 micromolar, however, boosted a patient to the lowest level of the protective range. It would seem, then, that Pauling was right to suggest that mega doses might be important for optimum health.

Vissers also explained that, in animal models, ascorbate injected intravenously will peak after about twenty hours in both healthy tissue and in tumors. However, unlike the healthy tissue, tumor tissues hold onto the vitamin C and do not return to a natural baseline. This detail is important because it allows high doses of ascorbate to build up in tumor tissue, and these doses disproportionately kill cancer cells instead of healthy tissues for reasons that are still not fully understood.

Conversely, the dangers of using vitamin C, even in high intravenous doses, appear to be small. While some people harbor an enzymatic deficiency that can cause a severe negative reaction, most individuals simply cannot overdose on vitamin C. Even in the blood plasma, vitamin C usually reaches a saturation point and is filtered from the body.

At the LPI conference, Dr. Carr pointed out that this form of treatment also dramatically improves the quality of life of cancer patients as compared to chemotherapy. For one, vitamin C treatments involve significantly less pain, mental and physical fatigue, nausea and insomnia. As of March 2015, three clinical trials involving pharmacological levels of ascorbate have been conducted, all of them showing that it is well tolerated by patients and reduces chemotherapy-related toxicity.

Additionally, vitamin C at high doses is known to aid cognitive function, and these positive benefits work together to aid in social satisfaction for the patient. As Pauling pointed out in the 1970s, it is not only the disease that the doctor should be concerned about treating, but the patient as well.


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Pauling in 1989 – an extraordinary life. Photo by Paolo M. Sutter.

So is Linus Pauling vindicated when it comes to vitamin C and cancer? The answer is complicated.

On the one hand, it would appear that vitamin C can serve as an important preventative and treatment for cancer. However, the method that Pauling advocated— taking large supplemental doses orally— is pretty clearly not an effective form of application. Rather, contemporary research indicates that the levels of ascorbate that are required to slow or stop tumor growth are far greater than that which can be achieved naturally by ingesting vitamin C; they can be accomplished only by intravenous injections of ascorbate. Furthermore, it is likely that this form of treatment will not replace, but instead will augment, existing protocols including chemotherapy.

But the broader trend is optimistic and, one might argue, validating. And with the Linus Pauling Institute and many others around the world continuing to investigate the potential for vitamin C and other nutrients to help people live longer and feel better, exciting new studies on optimum diet and effective treatments for diseases like cancer would appear to be on the near horizon.

Vitamin C and Cancer: Raising the Stakes

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Ewan Cameron, Ava Helen and Linus Pauling. Glasgow, Scotland, October 1976.

[Part 3 of 4]

By 1970, the year that Linus Pauling published Vitamin C and the Common Cold, the federal government’s “war on cancer” was soon to arrive. The National Cancer Act, passed in 1971, increased federal funding for treatment and prevention research, embracing cytotoxic treatment solutions like chemotherapy. That same year, Pauling began to push for investigations between nutrition and cancer, especially concerning vitamin C. Since the role of vitamin C in immune defense is arguably much less significant than Pauling supposed, the idea that intake of vitamin C should prevent or treat cancer seemed ludicrous to many physicians. Incredibly, evidence is now emerging that the opposite might be true.

In hindsight, there is a tendency for critics to see Pauling simply as a politically liberal proponent of alternative medicine; one who lashed out against a consumerist medical establishment that was firmly supported by conservative citizens, among others. However, proponents of alternative health and holism in the 1960s and 1970s prescribed to a broad range of political ideologies; Pauling was just one among many people who were searching for better preventative and alternative treatments.

In 1980, when Pauling was actively campaigning for a vitamin C treatment for cancer, Americans spent 13.1 billion dollars on cancer diagnosis and treatment. Five years later, a survey of over one-thousand individuals showed that a majority believed clinics using unorthodox cancer therapies should be permitted to operate in the U.S., and just over half said they would seek alternative treatment if seriously ill.

Pauling and his ideological positions are remembered now as having been central to the vitamin C “movement.” Perhaps this is because he was renowned in many arenas and easily attracted a great deal of media attention. Or perhaps, especially knowing his penchant for protesting against nuclear weapons testing and war, this was another issue on which Pauling was the most outspoken opponent of what he saw as a wrong to be made right.


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Table from “Ascorbic acid and cancer: a review”, co-authored by Pauling and Cameron, 1979.

For Pauling, the continuing suffering of cancer victims was unnecessary, since a useful treatment was already cheap and readily available. He argued that,

The involvement of ascorbic acid (vitamin C) in the natural defense mechanisms is now known to be so great that we hope that a really significant control of cancer might be achieved by the proper use of ascorbic acid.

Of the studies that Pauling found so convincing, none were as crucial as those conducted at the Vale of Leven Hospital, near Glasgow, Scotland. There, Dr. Ewan Cameron found that mega doses of vitamin C (10 grams daily or more) seemed to slow and even reverse cancerous growth in some patients. He wrote to Pauling in 1971, who eagerly responded that this “attack” on cancer was the most promising application of vitamin C that he knew of.  Pauling, who had been studying the role of dietary vitamin C in issues of orthomolecular psychiatry such as schizophrenia, now shifted his focus to cancer.

Far from being the flaky alternative health guru that many came to see him as, Pauling’s work with vitamin C— like all his research on the subject of orthomolecular medicine (a field that he spearheaded)— was consistent with a biomedical model of molecular disease. Since Pauling saw this work as fitting within the framework of molecular biology, it was frequently unclear to him why the medical community resisted what was, to him, a straightforward and significant scientific endeavor.

Further complicating matters was the fact that Stanford University, Pauling’s academic home at the time, rejected his request for additional lab space to pursue cancer research. Now the target of regular media pummelings, Pauling’s ideas were becoming a potential source of bad press for the university. Refusing to take no for an answer, Pauling and his young lab assistant, Arthur Robinson, solicited private funding to continue their work on vitamin C outside of the university setting. Raising $50,000 in donations from wealthy supporters of vitamin therapies, the duo helped to found the Institute for Orthomolecular Medicine in 1973, subsequently renamed the Linus Pauling Institute of Science and Medicine (LPISM) one year later.

From 1973 to 1976, Pauling published co-authored articles with Cameron, who continued to study the effects of vitamin C on cancer from his base in Glasgow. And in 1975, Pauling and Robinson secured additional funds to begin their own animal testing. Two years later, the collaborators began reporting their results in the Institute’s newsletter.  In 1979 Cameron and Pauling likewise published an extensive review article in Cancer Research that cited previous studies corroborating their own conclusions. The duo published their book, Cancer and Vitamin C, that same year.


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A sample of Pauling’s notes compiled in response to the Mayo Clinic trials, 1979.

Cameron and Pauling’s data seemed to show that vitamin C would be especially valuable for cancer patients. Whereas a daily intake of 10 g of vitamin C in a healthy individual would bring the vitamin C level in the blood to a saturation point that could not be exceeded by increasing or prolonging intake, cancer patients showed a different pattern. Known already to have abnormally low blood levels of vitamin C, the patients in fact achieved just over half the same level of vitamin C blood saturation found in healthy individuals subscribing to a daily intake of 10 grams. For those afflicted with cancer, it was seen as necessary to take 10 grams a day just to reach the normal level of vitamin C found in healthy individuals who did not take supplements at all.

To Pauling, this alone justified continued research on the matter. After persistently stating his case to Dr. Vincent De Vita, director of the National Cancer Institute, two rounds of trials were conducted through the Mayo Clinic to solve what the medical community perceived to be problems in Cameron’s studies. When the trials indeed failed to produce anything like Cameron’s results, funding effectively dried up for vitamin C research – a significant blow to LPISM’s functional well-being.

In response, Pauling and his supporters argued that the Mayo Clinic was missing the point. The Mayo trials had attempted to measure the effectiveness of vitamin C in a manner similar to drug treatments, because the advent of chemotherapy and antibiotics, and the biases of the pharmaceutical industry, had placed primary medical emphasis on the disease, and not on the patient. Pauling saw the results of the Mayo studies not as a definitive defeat, but as the triumph of a complex of interdependent federal and private organizations that held a vested interest in supporting the chemotherapy status quo.


Pauling had claimed that, with vitamin C, lifespan could be increased, tumors could regress, and even full recovery was possible. For many in the medical community, these were not only foolish assertions, they were dangerous as well.

Dr. Charles Moertel, chairman of the Department of Oncology at the Mayo Clinic, was particularly vocal in his rebuke, stating that

For such a message to be conveyed to desperate and dying people, with the endorsement of a Nobel laureate, the presumption must be that it is based on impeccable scientific methodology.

Moertel’s implication, of course, was that Pauling’s argument was instead based on unsound science and certainly lacked the scientific basis to challenge the use of chemotherapy.

Yet vitamin C retained a broad appeal because many saw the prevailing treatment, and its manifold side effects, as inhumane. John Cairn, head of the Mill Hill Laboratory of the British Imperial Cancer Research Fund, provided a voice to the other side the coin by calling out the survivorship data. To wit: in 1986, 200,000 patients were receiving chemotherapy and, by 1991, five year survival rates for colon cancer remained at just 53%. Cairn spoke for many in suggesting that, when it came to the prevailing course of treatment, “the benefit for most categories of patients has yet to be established.”


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Ava Helen Pauling, June 1981.

For Pauling, the debate turned from the public to the personal when, at the height of his study of vitamin C, his wife Ava Helen was diagnosed with stomach cancer. Following Ewan Cameron’s advice, she took 10 grams of vitamin C daily, and did not receive chemotherapy.  Throughout her treatment, Linus clung to the belief that mega doses of vitamin C would work for Ava Helen, just as it had for Cameron’s success stories in Scotland.

“Daddy was convinced that he was going to save her,” remembered Linus and Ava Helen’s daughter, Linda. “And that was, I think, the only reason he was able to survive… He said to me after she died that until five days before, he thought he was going to be able to save her.”

Ava Helen Pauling passed away in December of 1981. And though he was badly shaken by his wife’s death, belief in the value of vitamin C in the fight against cancer did not fade from Pauling’s mind. Suffice it to say, the medical community remained whole-heartedly unconvinced.

Vitamin C and the Common Cold: The Roots of Controversy

Detail from "The Perils of Pauling", National Observer, November 27, 1971.

Detail from “The Perils of Pauling”, National Observer, November 27, 1971.

[Part 1 of 4]

Growing up in the United States, many children today are told to drink plenty of orange juice to get their vitamin C, in part to avoid getting a cold. And indeed, vitamin C is now widely accepted as an important nutrient. Its antioxidant properties are valuable to cellular health and can protect against heart disease as well as the genetic damage that can lead to cancer and other dysfunctions. It aids the body’s production of collagen and other connective tissues, and is important for optimal healing from injury. It is also implicated in optimal neurotransmission (brain function), and stimulates the production of white blood cells important for immune health. This basic component of healthy living has been repeated so many times on television shows like “Sesame Street,” or in the classroom, or at home around the dinner table, that American children grow up recognizing vitamin C’s  importance as an obvious fact of life.

Perhaps surprisingly then, there is still little consensus in the medical community as to the ability of Vitamin C to significantly reduce the incidence, duration, or severity of the common cold. For Linus Pauling in 1971, it seemed so clear that Vitamin C was critical to human health that he felt compelled to publish his best-selling book, Vitamin C and the Common Cold, feeling that to withhold such simple and valuable information for the public’s general well-being would be negligent. His work sparked a vitamin C craze in America: after the book’s publication, consumption of vitamin C increased so much that bulk prices nearly tripled. The public certainly believed Pauling. Professional physicians, on the other hand, were highly critical.


While the full benefits of vitamin C are better known now than was the case in Pauling’s day, even in the 1970s no one argued against the vitamin’s fundamental importance. The real argument that emerged was about how much Vitamin C was enough, and why.

Oranges and other fruits and vegetables were known to prevent scurvy from at least 1753, when British naval physician James Lind reported on its effectiveness in treating this disease of nutritional deficiency. Vitamin C was first isolated in the early 1930s by Albert Szent-Györgyi, William Waugh, and Charles Glen King, and produced in the lab shortly after by Norman Haworth and Edmund Hirst. Unlike most mammals, human beings do not naturally synthesize vitamin C within our own bodies. Along with Guinea pigs, other primates, and fruit bats, we need to acquire the entirety of our vitamin C through our diet. The Federal Recommended Daily Allowance (RDA) was duly set at 60 mg each day – enough to keep one from falling prey to scurvy – by the time that Pauling arrived on the scene.


Irwin Stone. (Image by Oscar Falconi)

Irwin Stone. (Image by Oscar Falconi)

To Irwin Stone, “giving someone enough vitamin C to prevent scurvy was like feeding them just enough to keep them from starving.” Stone, a biochemist, published on Vitamin C as a food preservative beginning in 1935. In the course of this research, he discerned that a 150 lb human would need to ingest 4 to 10 grams of Vitamin C a day in order to match what a healthy rat produces on its own.

Stone met Pauling in 1966, not long after Pauling had delivered an acceptance speech for the Carl Neuberg Medal, awarded for Pauling’s assessment of sickle cell anemia as a molecular disease. In the speech, Pauling expressed his hope that he might live to see the medical advances that the next 15 years might bring. Afterward, Stone recommended that with vitamin C, Pauling (who was sixty-five years old at the time) might see the advances of the next fifty.  His interest piqued, Pauling began taking 1 gram of Vitamin C per day, and by the late 1970s, this increased to 10 or more grams daily. Around the same time, the RDA was lowered to only 45 mg. In other words, Pauling was now taking over one hundred and sixty times the daily dose of Vitamin C recommended by the government.


The concern in the medical community was, and continues to be, the potential for “overnutrition”; i.e., negative physical effects associated with consuming too much of a particular vitamin or mineral. As Pauling’s ideas gained increasing cultural currency, physicians began to warn that vitamin C consumed in such large doses might cause the development of kidney stones. Pauling countered that this was only likely in a small segment of the population – those with pre-existing hyperoxaluria – and that it could be entirely avoided by ingesting sodium ascorbate pills rather than ascorbic acid or natural sources. Pauling pointed out that, in fact, there were no health problems associated with high dose vitamin C intake other than potential stomach irritation and loose bowels – symptoms now known to occur with a daily intake of approximately two grams. For Pauling, the decision to take large doses in spite of these drawbacks seemed obvious.

But for many clinicians it was not. Leading nutritionist Dr. Victor Herbert attacked Pauling’s claims as unsupported, as did FDA head Charles Edwards, who denounced Pauling as spurring a national frenzy over vitamin C with no scientific basis. This backlash begged the question, if the benefits of Vitamin C were really medically obvious, then why would physicians mislead the public?

Medical Tribune, June 6, 1973.

Medical Tribune, June 6, 1973.

Pauling’s answer, as delivered through the media, provoked even greater controversy. Physicians were misleading the public, he said, because the reality of a cheap, safe alternative to expensive pharmaceuticals would prove economically disastrous for the medical industry. In other words, the physicians, in partnership with drug companies, had an economic interest against vitamin C. “Every day,” Pauling explained, “even every hour, radio and television commercials extol various cold remedies… I am convinced by the evidence now available that ascorbic acid is to be preferred to the analgesics, antihistamines, and other dangerous drugs that are recommended for the treatment of the common cold by purveyors of cold medicines.”

Pauling’s assertion was based in part on the opinion of Albert Szent-Györgyi, who had first isolated Vitamin C, and who told Pauling in a personal letter that,

…right from the beginning I felt that the medical profession misled the public. If you don’t take ascorbic acid with your food you get scurvy, so the medical profession said that if you don’t get scurvy you are all right. I think this is a very grave error. Scurvy is not the first sign of the deficiency, but a premortal syndrome, and for full health you need much more, very much more. I am taking, myself, about 1 gram a day.

Pauling was also drawing on the opinion of others in the medical field, such as Dr. Douglas Gildersleeve, who stated in a 1967 Fact magazine article that,

having worked as a researcher in the field, it is my contention that an effective treatment for the common cold, a cure, is available, that is being ignored because of the monetary losses that would be inflicted on pharmaceutical manufacturers, professional journals, and doctors themselves.

Pauling, in other words, wasn’t alone in staking out this controversial ground.

Continuing Work on Vitamin C and Cancer: An Interview with Matthew Kaiser

Matthew Kaiser.

Matthew Kaiser.

The blog recently had the opportunity to sit down with Matthew Kaiser, an Oregon State University undergraduate senior in microbiology from Salem, Oregon.  Kaiser, who hopes to pursue a career as an MD/Ph.D., has led an exciting research project on the potential treatment of cancer using intravenous vitamin C.  He also recently delivered a talk titled “Is Humanity Ready for an Upgrade?” at a recent TEDx symposium hosted by OSU.

What follows below is an edited excerpt of our interview with Kaiser in which he discusses the roots of his project, its potential application, and his experience of conducting and presenting high level research at a very young age.

The Roots of the Research Project 

The beginnings of this research project were more or less like most undergraduate project tend to start. Not all, but some tend to be these big black box projects, we call them, in that there are a lot of unknowns. It’s almost like, “we really don’t know a lot about this but hey, we’ll give it to an undergraduate to take a stab at it. Because even that way if it doesn’t work out, if we find out that there really is no story here, they get the research experience and then we don’t necessarily waste a graduate student’s time or post-doc’s time on a project that didn’t end up being published.”

But where this project started was, of course, back in the days of Linus Pauling who was among the first to suggest that high doses of Vitamin C could have an anti-cancer effect. But following his initial studies with Vitamin C, or ascorbate, there were studies that came out by the Mayo Clinic and other labs that showed that Vitamin C did not have a protective or anticancer effect. And so it was largely abandoned by the medical community for several years but it continued to be researched in kind of an alternative medicine environment. Through that, as our understanding of how Vitamin C is metabolized by the body developed, we were able to understand that if Vitamin C was delivered orally, it was completely different than how Vitamin C could be regulated if it was administered through an IV, because if you administer it through an IV you’re able to bypass all the digestive control and renal reabsorption in your small intestine. That normally would limit the amount of Vitamin C that gets into your bloodstream and then becomes vitally available.

So this project started kind of on the cusp of these exciting studies looking at the pharmacokinetics and, again, looking at the bioavailability of Vitamin C. And just to put it in perspective: so if you go home and eat fifty oranges, like all my friends like to try and do because they know I work on Vitamin C, they’re like “oh, Vitamin C and cancer, I can eat fifty oranges, right? And I can prevent cancer or cure myself or colon cancer?” And what we’re looking at in this project are doses that can only be achieved by IV because if you eat these fifty oranges, the maximum you can saturate your blood plasma level is about 220 micromolar. To put it in perspective, so if you can saturate your blood to a level of about 200 micromolar following oral ascorbate, if you go home and had an IV or you went to a clinic and you had an infusion of IV ascorbate, you can saturate blood plasma up to 30 millimolar. And there’s a thousand micromolars in one millimolar. So, extremely different doses can be achieved by these two different routes.

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Irwin Stone’s Impact on Pauling

Linus Pauling and Irwin Stone, 1977.

Linus Pauling and Irwin Stone, 1977.

[Part 2 of 2]

Four years after Irwin Stone first convinced Linus Pauling to start taking megadoses of vitamin C, Pauling decided to share with the world the successes that he had observed in his own improved mental and physical health.

In 1970 Pauling began to work on a book, Vitamin C and the Common Cold, and he wrote to Stone asking permission to dedicate it to him. He also sent Stone a copy of the manuscript to review. Stone wrote back praising the work.

The book is excellent and should go far to eliminate this thoroughly unnecessary and annoying condition, at least among your readers. The audience will increase over the years, especially if Medicine can eventually see the light.

Stone continued to encounter difficulty getting his own scientific articles about ascorbic acid published and he certainly did not have the funding to run his own clinical trials. Partly as a result, he too was writing a book about vitamin C and all of the many diseases that he thought were related to hypoascorbemia. A  major thrust of the book was its plea for large scale research on the topic. Stone hoped to get popular opinion on board with his ideas in order to place pressure on physicians and nutritionists to do research in this area.

Pauling’s Vitamin C and the Common Cold was a popular success. Many readers around the world were persuaded by his ideas and began to take vitamin C supplements to prevent and treat colds. Some of his acclaim rubbed off on Irwin Stone, who wrote to Pauling telling him that he too was finally receiving recognition from popular media sources, including NBC.

In 1971 Stone retired to San Jose, California and devoted the rest of his life to researching and promoting the need for high consumption of vitamin C by humans. That same year he finished his book, The Healing Factor: Vitamin C Against Disease, and asked that Pauling write a foreword for it. Pauling was glad to do so, calling it “an outstanding contribution to knowledge.”

Stone's inscription to Pauling in a first edition of The Healing Factor, 1972.

Stone’s inscription to Pauling in a first edition of The Healing Factor, 1972.

Despite their popular appeal, Pauling and Stone continued to encounter problems convincing medical practitioners and researchers to take their ideas about ascorbic acid seriously. Stone believed that this was so because vitamin C would be a much more inexpensive cure than the current treatments of the time, causing pharmaceutical companies and doctors to lose money.

One medical doctor, Ewan Cameron, did believe in the effectiveness of vitamin C against cancer and was treating his terminal cancer patients with megadoses of it in Glasgow, Scotland. He formed a trans-Atlantic research partnership with Pauling in 1971 and they began to collaborate on papers discussing the use of vitamin C against cancer, eventually publishing ten articles together.

Through his partnership with Pauling, Cameron also began to correspond with Stone about the implementation of vitamin C against cancer and their shared difficulties getting the medical community to accept their hypotheses.

Cameron maintained a unique viewpoint on the treatment of cancer and how ascorbic acid might fit into a clinical regimen. In December 1974, he explained his views to Stone.

It is completely contrary to all contemporary medical thought to even suggest that such a mundane substance as ascorbic acid could have any value in such a complicated disease as cancer. This is because cancer research is concentrating all its energies in searching for more and more sophisticated ways of selectively destroying cancer cells. The research is becoming so complex and so unproductive, that it is natural to assume that ‘the answer’ must be extraordinarily complex and almost beyond human comprehension….We would make much more progress if we accept that cancer cells are normal cells that merely happen to be behaving in an abnormal way. We would then accept that cancer cells have an equal right to live, and concentrate our energies in suppressing the abnormal behavior pattern.

Throughout their correspondence, Cameron described his successes treating cancer with ascorbic acid. But he also noted that a number of patients showed no improvement from it or, at best, their cancer was brought to a standstill. He was disappointed that his primary successes were mostly by way of increasing patients’ survival time, not in curing them. Cameron thought that the greatest success would be in prophylaxis – taking megadoses of ascorbic acid throughout one’s life in order to prevent cancer.


In 1978 Stone wrote a letter to the editor of Nutrition Today in response to the publication’s recent issue focusing on ascorbic acid. His letter shows how fervently he believed in hypoascorbemia.

I regard our most serious medical problem to be the dangerous complacency that the orthodox medical establishment exhibits toward Chronic Subclinical Scurvy and its refusal to do anything to correct and alleviate this potentially-fatal human birth defect. Chronic Subclinical Scurvy has killed more human victims, caused more disease and misery among Mankind than any other single factor in the past and is continuing this evil record in the present. I’m worried about the future, because that is where I’m spending the rest of my life.

Meanwhile, Stone and Pauling’s relationship continued to flourish. In 1977 Pauling invited Stone to become a member of the Board of Associates of the Linus Pauling Institute of Science, an offer that was accepted. Pauling also attended Stone’s surprise 70th birthday party that year. In 1981 Stone was unable to make it to Pauling’s 80th birthday, but he did pass along a message.

You will recall the promise I made you in 1966 of 50 more healthy years of life with Megascorbics. You thought I was exaggerating and said you would be satisfied with 15 years. Well the 15th year is now and I am looking forward to attending your 115th birthday party in 2016. Megascorbics makes you practically indestructible.

In response, Pauling wrote, “I am glad to express my thanks to you for having written to me in 1966. Your letter and the reprints of your papers changed my life.” While Pauling did not make it to 2016, he did live until 1994, passing away at 93 years of age.

The last letter that Pauling wrote to Stone concerned a joint award from the Academy of Orthomolecular Psychiatry and the Orthomolecular Medical Society that Stone was to receive. The Linus Pauling Institute of Science and Medicine was also going to surprise him with a second award. Pauling wrote,

For many years you have been an inspiration to me, because of your devotion to vitamin C and your conviction that a high intake of vitamin C has great value in improving the health of human beings. You have rendered a great service to the people of the world through your continued study of vitamin C over a period of fifty years.

Unfortunately, Dr. Irwin Stone died on May 4, 1984, at the age of 77, while in Los Angeles to receive the award. He died by choking on regurgitated food, the result of a constricted esophagus that had plagued him ever since his car accident many years prior.

Irwin Stone received two honorary doctorates, many additional awards, and 26 patents. He also published over 120 scientific papers throughout his life (at least 50 were about vitamin C) and wrote one book, The Healing Factor, published in 1972. He was father to one son, Steven, and was married to his wife Barbara for over 50 years.

In December 1986, two years after his death, Barbara Stone sent Pauling a card congratulating him on the publication of his latest book, How to Live Longer and Feel Better. She wrote “Irwin would have enjoyed reading it and noting the many references to him and other colleagues.” Pauling hadn’t exaggerated in his 1981 letter: Irwin Stone really did change his life and made a profound impact on the scientific legacy that Pauling leaves behind today.