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.

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Farewell to Balz Frei

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Next week, a new school year will start here at Oregon State University. And with it, for the first time since 1997, the Linus Pauling Institute will enter into a fresh academic calendar without the leadership of its now emeritus director, OSU Distinguished Professor of Biochemistry and Biophysics, Dr. Balz Frei.  Last Spring, word of Frei’s retirement from LPI made its way into local headlines, and in this interview he confided that, in addition to relinquishing his administrative responsibilities, he will be closing down his research laboratory as well.

A native of Winterthur, Switzerland, Frei moved permanently to the United States in 1986, when he accepted a lengthy post-doctoral appointment in Dr. Bruce Ames’s lab at the University of California, Berkeley. Frei later moved on to a position in the Nutrition Department at the Harvard School of Public Health, and after four years at Harvard, he relocated to the Boston University School of Medicine. A widely respected scientist, Frei’s research has focused on the mechanisms causing chronic human disease, in particular atherosclerosis and cardiovascular disease, and the role that micronutrients, phytochemicals, and dietary supplements might play in ameliorating these diseases.

In 1997, Frei became the first and, until now, only director of the Oregon State University incarnation of the Linus Pauling Institute.  Founded in 1973 as the Institute for Orthomolecular Medicine, and renamed the Linus Pauling Institute of Science and Medicine a year later, the Institute struggled for much of its history in California, hamstrung in part by the intense controversy that it’s founder and namesake generated through his bold proclamations about vitamin C.

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Moving to OSU in 1996 helped to wipe the Institute’s slate clean, and the major progress that the Institute has enjoyed in the twenty years that have followed is a direct outcome of Frei’s vision, skill, and endeavor. Following Linus Pauling’s death in 1994, the Institute, crippled by funding problems and lacking a clear strategic vision, was nearly shuttered. Today, Frei leaves behind a thriving research enterprise that includes twelve principal investigators and a $10.2 million endowment.

We conducted a lengthy oral history interview with Frei in January 2014 and have included a few excerpts after the break.  The entire interview is worth a read as it details the life and work of a man who has made a true difference at our institution and within the fields of disease prevention and the quest for optimal health.

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Pauling’s Cancer

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Medical Tribune, September 10, 1992.

[An examination of the final years of Linus Pauling’s life. Part 2 of 4.]

In February 1992, Linus Pauling announced publicly that he had cancer. His critics responded with sentiments that were, at times, distinctly unsympathetic. In their view, since Pauling had been advocating vitamin C as a preventative treatment for cancer for years, his diagnosis undermined those decades of work. Pauling retorted that most elderly men develop hyperplasia or cancer in their prostates, often by age 70. Pauling believed it was quite likely, although not provable, that his high intake of vitamin C delayed the inevitable by decades.

As Pauling continued to struggle with the limitations that his illness placed upon him, his new caretaker, ranch-hand Steve Rawlings, became an important part of his life. Rawlings did a lot of the day-to-day work of providing for Pauling while he was ill, a time period during which Pauling increasingly sought out the solace and solitude of his isolated home on the Pacific Coast. Linus Pauling Institute of Science and Medicine (LPISM) administrator Steve Lawson would later reflect on the importance of Pauling’s Big Sur residence at Deer Flat Ranch during the last few years of his life. In a 2011 interview, Lawson explained,

When he was in Palo Alto, Pauling’s time was sought by many people for many different reasons: old friends, colleagues, the public, the media. When he retreated to Deer Flat Ranch, he removed himself from that. I think he really loved that time alone down there. I know that he liked to watch some programs on T.V., some serialized programs. He read quite a lot. He loved to read mystery books. He was a rare individual in that there was really no division between what he did recreationally and what he did professionally. He was a scientist through and through, and derived pleasure from working on scientific problems. Often times if you go into someone’s bathroom, you’ll find a Prevention magazine, a Reader’s Digest, or Entertainment Weekly, or Time, or the newspaper. Pauling’s bathroom was stacked with scientific journals. He wasn’t physically vigorous [by the early 1990s], but he certainly didn’t seem fatigued.

With his time becoming increasingly precious, Pauling’s coworkers, friends, and family all felt that he should do what he most wanted to do with his days, and this had always been to focus on science. Freed from the responsibility of running the LPISM’s day-to-day operations, Pauling continued to work at Deer Flat Ranch in spite of his worsening health problems.

Of particular interest was the fact that, stricken with cancer himself, Pauling’s scientific fascination with the disease only intensified. Rather than remove himself from ongoing cancer research as his disease advanced, he instead committed even more fully to this cause in his final years. In particular, Pauling became increasingly interested in non-toxic methods of cancer therapy; methods, in other words, that were far less stressful on the body than are radiation or standard chemotherapy regimens.

In a paper co-authored with Drs. David Knight and Abram Hoffer, he worked to determine survival rates among over 2,000 cancer patients receiving high doses of vitamin C and other nutrients. He even flew to Tulsa, Oklahoma in October 1992 for a conference on alternative treatments of cancer. He likewise continued to work to convince American physicians of the value of vitamin C and lysine in preventing and treating heart disease, a notion that was gradually beginning to gain small slivers of recognition in the medical community.


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Privately, Pauling was waging a personal war on his disease, exploring avenues of immunotherapeutic treatment that were unorthodox in the medicine of the time but which have, in recent years, begun to show great promise.

In a letter to medical writer and cancer consultant Ralph Moss, Pauling detailed a therapy involving autologous anticancer antigen preparation, or AAAP, of which he was somewhat skeptical but nonetheless interested in pursuing further. Working with friends and colleagues at Stanford Medical School to raise monoclonal antibodies against his prostate cancer cells, Pauling ultimately conducted what amounted to exploratory and self-experimental science to discern the potential value of AAAP.

Pauling’s first exposure to the idea of AAAP came from the work of Duncan McCollester, a medical doctor based in Irvington, New York, who advocated for a form of “Active Specific Immunotherapy.” This treatment involved the use of a manganese phosphate gel that was mixed with isolated portions of tumor tissue in which tumor antigens had been converted to a form capable of stimulating a cancer-destroying immune response in the patient upon re-administration on the forearm or thigh. McCollester dedicated a book on the subject to Pauling, even as he was struggling to receive FDA approval for the treatment.

David Stipp, a reporter for the Wall Street Journal, reported in August 1992 that a similar medical treatment had been developed by Cellcor, Inc. of Newton, Massachussetts. Cellcor offered customers a treatment for kidney cancer in which a patient’s own white blood cells were extracted, treated in such a way as to make them attack tumor cells, and then reintroduced into the patient’s cells. Known as autolymphocyte therapy, or ALT, the treatment had been available commercially in Atlanta, Boston, and Orange County, California since around 1990. However, at the time, medical officials disputed the efficacy of Cellcor’s anti-cancer therapy, arguing that not enough data had been collected to substantiate the company’s claims.


By July 1992, Pauling had decided to move forward with AAAP treatment, the ultimate goal being a vaccine that would combat his own illness while also providing useful data for the science of the future. Subsequently, a 1 gram section of cancerous tumor tissue that had been surgically removed from Pauling’s body was shipped to McCollester’s lab in New York. Upon entering the operation, Pauling’s surgeon had advised him that his entire tumor should be removed, rather than a small section. Pauling refused this request, arguing that a full resection would prevent him and others from observing the effectiveness of the AAAP treatment. In other words, rather than focusing on the fact that his own life was on the line, Pauling was still operating, first and foremost, in the mode of the scientist: he was running an experiment in which he himself was a test subject, and the stakes could not have been higher. In Pauling’s mind there were plenty of reasons for optimism.


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Pauling notes his first AAAP injection on October 23, 1992.

By October, scientists at Stanford University, led by Dr. Ronald Levy, had successfully boosted the immune systems of a small group of B-cell lymphoma patients using a vaccine that had been genetically engineered from the patients’ own tumor tissues. In two of these nine patients, tumors vanished completely.

In generating the vaccines for each individual patient, the Stanford scientists created clones of the cancerous B-cells from each subject, and then separated out specific proteins – known as receptors – from the outer coatings of the B-cells. Using genetic engineering techniques, the scientists then added other proteins that boosted the immune system and created a synthetic version of the engineered receptors. The result was a tailor-made vaccine created from the B-cell receptors that used each patient’s immune system to attack cancer cells.

Pauling’s confidence in his anti-cancer antigen treatment was likewise elevated by other immunotherapy techniques then being developed by a team at the National Cancer Institute, as headed by Dr. Steven Rosenberg, Dr. French Anderson, and Dr. Michael Blaese. However, these studies were all specific to skin cancer, and were carried out on patients already in remission and receiving chemotherapy, or on patients with very small tumors. Pauling, by contrast, was already afflicted with advanced prostate cancer by the time that his condition was discovered, and he had not yet accepted any form of radiation therapy.

From October 1992 on, Pauling almost exclusively used the AAAP vaccine and vitamin C to treat his cancer. The vaccine traveled from McCollester’s lab in New York to a willing physician in California who had agreed to administer Pauling with the suggested injections- anywhere from 0.2 to 0.65 ml of vaccine a few times monthly. Pauling continued to receive these injections, which routinely caused tenderness and swelling, until January 1994, about seven months before he died.

Pauling’s Final Years

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Pauling posing at lower campus, Oregon Agricultural College, ca. 1917.

[An examination of the end of Linus Pauling’s life, part 1 of 4]

In 1917, at sixteen years of age, Linus Pauling wrote in his personal diary that he was beginning a personal history. “My children and grandchildren will without doubt hear of the events in my life with the same relish with which I read the scattered fragments written by my granddad,” he considered.

By the time of his death, some seventy-seven years later, Pauling had more than fulfilled this prophecy. After an extraordinarily full life filled with political activism, scientific research, and persistent controversy, Pauling’s achievements were remembered not only by his children, grandchildren and many friends, but also by an untold legion of people whom Pauling himself never met.

Passing away on August 19th 1994 at the age of 93, Pauling’s name joined those of his wife and other family members at the Oswego Pioneer Cemetery in Oregon. What follows is an account of the final three years of his life.


 

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Linus Pauling, 1991.

In 1991, Pauling first learned of the cancer that would ultimately take his life. Having experiencing bouts of chronic intestinal pain, Pauling underwent a series of tests at Stanford Hospital that December. The diagnosis that he received was grim: he had cancer of the prostate, and the disease had spread to his rectum.

Between 1991 and 1992, Pauling underwent a series of surgeries, including the excision of a tumor by resection, a bilateral orchiectomy, and subsequent hormone treatments using a nonsteroidal antiandrogen called flutamide. During this time, Pauling also self-treated his illness with megadoses of vitamin C, a protocol that he favored not only for its perceived orthomolecular benefits, but also as a more humane form of treatment than chemotherapy or radiation therapy.

Pauling’s interest in nutrition dated to at least the early 1940s, when he had faced another life-threatening disease, this time a kidney affliction called glomerulonephritis. Absent the aid of contemporary treatments like renal dialysis – which was first put into use in 1943 – Pauling’s survival hinged upon a rigid diet prescribed by Stanford Medical School nephrologist, Dr. Thomas Addis.  At the time a radical approach to the treatment of this disease, Addis’ prescription that Pauling minimize stress on his kidneys by limiting his protein and salt intake, while also increasing the amount of water that he drank, saved Pauling’s life and led to his making a full recovery. Though his famous fascination with vitamin C would not emerge until a couple of decades later, Pauling’s nephritis scare instilled in him a belief that dietary control and optimal nutrition might effectively combat a myriad of diseases. This scientific mantra continued to guide Pauling’s self-treatment of his cancer until nearly the end of his life.

Pauling also believed that using vitamin C as a treatment would, as opposed to chemotherapy, allow him to die with dignity. Were his condition terminal and his outlook essentially hopeless, Pauling felt very strongly that he should be permitted to pass on without “unnecessary suffering.” Pauling’s wife, Ava Helen, had died of cancer in December 1981. She too had refused chemotherapy and other conventional approaches for much of her illness, a time period during which Linus Pauling had helped his wife the only way he knew how: by administering a treatment involving megadoses of vitamin C. This attempt ultimately failed and, by his own admission, Pauling never really recovered from his wife’s passing.

Nonetheless, Pauling continued to lead research efforts to substantiate the value of vitamin C as a preventive for cancer and heart disease in his capacity as chairman of the board of the Linus Pauling Institute of Science and Medicine (LPISM). By the time of his own diagnosis in 1991 however, the Institute was in a desperate financial situation, several hundred thousand dollars in debt and lacking the funds necessary to pay its staff.


 

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In 1992, while he recovered from his surgeries and managed his illness, Pauling continued to act as chairman of the board of the LPISM. No longer able to live entirely on his own, he split his time between his son Crellin’s home in Portola Valley, California, and his beloved Deer Flat Ranch at Big Sur. When at the ranch, Pauling was cared for in an unofficial capacity by his scientific colleague, Matthias Rath. Pauling was first visited by Rath, a physician, in 1989, having met him years earlier in Germany while on a peace tour. Rath was also interested in vitamin C, and Pauling took him on as a researcher at the Institute. There, the duo collaborated on investigations concerning the influence of lipoproteins and vitamin C on cardiovascular disease.

Not long after Pauling’s cancer diagnosis, a professor at UCLA, Dr. James Enstrom, published epidemiological studies showing that 500 mg doses of vitamin C could extend life by protecting against heart disease and also various cancers. This caused a resurgence of interest in orthomolecular medicine, and it seemed that Pauling and Rath’s vision for the future of the Institute was looking brighter.

As it happened, this bit of good news proved to be too little and too late. LPISM had already begun to disintegrate financially, its staff cut by a third. The Institute’s vice president, Richard Hicks, resigned his position, and Rath, as Pauling’s protégé, was appointed in his place. Following this, the outgoing president of LPISM, Emile Zuckerlandl, was succeeded by Pauling’s eldest son, Linus Pauling Jr. Finally Pauling, his health in decline, announced his retirement as chairman of the board and was named research director, with Steve Lawson appointed as executive officer to assist in the day-to-day management of what remained of the Institute.

One day prior to his retirement as board chairman, Pauling signed a document in which he requested that Rath carry on his “life’s work.” Linus Pauling Jr. and Steve Lawson, however, had become concerned about Rath’s role at the Institute, and particularly on the issue of a patent agreement that Rath had neglected to sign. Adhering to the patent document was a requirement for every employee at the Institute, including Linus Pauling himself. When pressed on the issue, Rath opted to resign his position, and was succeeded as vice president by Stephen Maddox, a fundraiser at LPISM.

After this transition, Pauling met with Linus Jr. to discuss the Institute’s dire straits. Pauling’s youngest son, Crellin, had also became more active with the Institute as his father’s illness progressed, in part because he had been assigned the role of executor of Pauling’s will. Together, Crellin, Linus Jr., and Steve Lawson struggled to identify a path forward for LPISM. Eventually it was decided that associating the Institute with a university, and focusing its research on orthomolecular medicine as a lasting legacy to Pauling’s work, would be the most viable avenue for keeping the Institute alive. The decision to associate the organization with Oregon State University, Pauling’s undergraduate alma mater, had not been made by the time that Pauling passed away.

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: Pauling vs. the Physicians

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Diary entry by Linus Pauling, 1980. The text reads: “L[inus] P[auling] / Found enzymes enthralling / He was filled with glee / By Vitamin C”

[Part 2 of 4]

As a double Nobel laureate, Linus Pauling’s recommendation that everyone ingest 1 to 4 grams of vitamin C daily developed into a media frenzy. And with time, the debate took on a distinctly political flavor, with the battle over vitamin C argued on talk shows and in press releases, rather than vindicated in the lab.

Pauling’s accusations that the medical establishment was ignoring the potentially profound benefits of vitamin C in part because of a mutually beneficial relationship with Big Pharma did not, as one might expect, go over well with many medical professionals. Indeed, his work with vitamin C was written off by many as a passing craze, and Pauling was increasingly referred to as a “kook” and a medical “quack.”


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Notes by Linus Pauling regarding vitamin C and the common cold, 1974.

As Pauling and the physicians went back and forth, the two sides sometimes found themselves citing the same data and producing opposite conclusions. Often Pauling argued that the studies under consideration – discarded by dissenting physicians for apparently showing negligible effects – actually suggested a real value to the use of vitamin C that would be amplified if only larger doses were used.

One study in particular, authored in 1942 by A.J. Glazebrook and Scott Thomson, found vitamin C to only slightly decrease the occurrence of colds and their symptoms in a sample of college students. For proponents, the work was heralded nonetheless as significant evidence in vitamin C’s favor. The problem, Pauling believed, was that physicians expected vitamin C to act like a drug, with a concomitant “tendency…to use relatively small amounts and look for big effects.” But vitamin C wasn’t a drug, it was a nutrient, and Pauling thought its effects would not be easily observed in a typical physician’s research paradigm.

In an effort to put the issue to rest, a University of Maryland study in which eleven prisoners were given 3 grams of vitamin C a day for two weeks found that, when inoculated with cold viruses, each subject became ill. While many considered this proof that Pauling was wrong, he dismissed this study as well. For one, it lacked a placebo control group and did not take the severity of symptoms into account. Pauling likewise suspected that the prisoners were infected with a cold virus potent enough to have overwhelmed any protective effect from vitamin C.

On and on the debate raged and, by the time of Pauling’s death in 1994, little consensus had been reached: Pauling stood firm in his beliefs and the physicians hadn’t from their position.


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Harri Hemilä

Today, while Pauling’s faith in and advocacy of vitamin C has endured in the public consciousness, it has not translated into concrete medical practice. Presently, the United States Food and Nutrition Board has set the Recommended Daily Allowance for Vitamin C at 120 mg at the highest (for pregnant women), nearly three times greater than the RDA in the 1970s, but still about 100 times lower than the levels that Pauling believed to be optimal.

So what does the research really show? Is there, in fact, zero evidence that Vitamin C prevents or cures colds, as the Food and Drug Administration once claimed?

Perhaps the best summation of the current state of affairs has been compiled by Dr. Harri Hemilä, a researcher in public health at the University of Helsinki. Hemilä, whose 2005 comprehensive study on the subject is cited by the National Institutes of Health, makes a number of intriguing points.

For one, Hemilä points out that, while the broad body of research seems to indicate that vitamin C supplementation does not decrease cold incidence in most individuals, it does significantly decrease incidence in marathon runners, skiers, and soldiers – all groups subject to consistent exposure to cold weather or physical stress – by as much as 50%. Daily supplements also appear to decrease the symptoms and duration of colds by a modest degree – observations of 14% in children and 8% in adults.

It is important to note that studies of this sort have used what Pauling would have considered to be minimum dosages for optimal health – 1 to 2 grams daily. To date, few investigations have looked into doses higher than 2 grams, presumably because it is known that, for oral doses of more than 1 gram, absorption rates fall below fifty percent. The operating idea then, is that for supplementation above 2 grams, most of the extra vitamin C is unused and excreted in one’s urine.

Yet there does exist some evidence of a more significant impact at higher dosage levels. Hemilä’s survey of the research concludes that, in some studies, doses larger than 2 grams do appear to provide some measure of therapy, if taken at the onset of cold symptoms.

Digging more deeply into the data, however, one finds conflicting results. In one study, taking 8 grams once at the onset of symptoms appeared to decrease symptoms and duration of colds. In another, 10 gram doses were given for three days during a cold, without impact.

Obviously, when trying to measure the impact of any therapy on the progression of an illness – particularly one as protean as the common cold – numerous co-factors can enter the equation. It would seem then that a thoughtful modern study of vitamin C – one that carefully considers the methodology of those conducted in the past – is still needed before we can be certain of its potential impact on the common cold.


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Had Pauling invested in proving his point in the lab after the publication of Vitamin C and Common Cold, perhaps we would have a better understanding of the immune function of this nutrient today. But Pauling felt vitamin C’s protective effects against the cold were not seriously debatable and that, for him, it was time to move on. The physicians, he believed, were set in their ways – a description he often used during the long argument over vitamin C – and it was pointless for him to spend too much of his time and energy trying to disprove them.

Indeed, in Pauling’s mind, there were more important issues to take into the lab than the common cold. Because Pauling wasn’t just busy arguing that vitamin C could cure the common cold. He believed that it might cure cancer, too.