Vitamin C and Heart Disease: An Open Question

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A note on LDL cholesterol and Lipoprotein (a) written by Pauling on his office chalkboard.

[An analysis of Linus Pauling’s research on vitamin C and heart disease, part 4 of 4]

In June 1992, Linus Pauling visited the Texas Heart Institute, after which he accepted an offer to write an editorial for the organization’s journal. He completed his short piece, “Can Vitamins Help Control Heart Disease and Strokes?” in March 1993, a little over a year before he passed away.

The Texas Heart Institute article turned out to be Pauling’s final public statement of consequence on the question of ascorbic acid and cardiovascular health. In his text, he argued once again that, although physicians had long known that arterial lesions cause heart disease, they had not yet accepted the evidence that lesions are brought about by low levels of vitamin C in the blood. This consensus had been maintained despite a widely accepted understanding that vitamin C is necessary to repair bodily tissues via collagen production.

Unfortunately for Pauling, the research required to clearly to shift scientific opinion was not forthcoming. Pauling realized that a major study needed to be funded to show a strong relationship between intake of larger doses of nutritional supplements (especially vitamin C) and even greater preventative or therapeutic health benefits for victims of cardiovascular disease. As the idea’s chief proponent, Pauling would have seemed to be a primary figure in attracting grant funds for such a study. However, in part because of the intense controversy over Pauling’s previous work with vitamin C and the common cold, and vitamin C and cancer, Pauling’s reputation had been badly marred within the medical mainstream, and research dollars had become very difficult for Pauling to source.

Partly as a result, his and Matthias Rath’s work stressing the importance of vitamin C as a key factor in combating heart disease was perhaps a case of too little, too late. Though the tandem had succeeded in establishing a general sense of the potential importance of vitamin C in heart disease prevention, the circumstances surrounding their work were not ripe enough for the duo to develop a more complete and lasting understanding of the types and levels of nutrients needed to ensure optimum heart health.


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Linus Pauling giving an interview at Deer Flat Ranch, September 1993.

Other material considerations further compounded the problem. For one, at precisely the same time that the cardiovascular work was gaining traction, the Linus Pauling Institute of Science and Medicine was in the depths of dire financial straits. Furthermore, Linus Pauling was now nearly 93 years old and in declining health. As he battled with the cancer diagnosis that would ultimately claim his life, Pauling realized that could no longer go on assisting Rath. Meanwhile, Rath’s relationship with others in the Institute had fallen into turmoil, and the Linus Pauling Heart Foundation, which Rath directed, was withering on a vine of financial insolvency.

Rath was ultimately asked to leave the Institute amidst a period of legal disarray, partly a result of his having never signed the Institute’s mandatory employee patent agreement. In the wake of his departure from the Institute, and following the death of Linus Pauling in August 1994, the Unified Theory of Human Cardiovascular Disease largely slipped into obscurity, though some echo of it has remained in the public consciousness.


In the years that followed Pauling’s death, the Institute’s cardiovascular program continued to investigate the role that nutrients like vitamin C, E, and B6 might play in limiting oxidative damage brought about by low density lipoproteins (LDL) in individuals suffering from atherosclerosis. Similar work is on-going today in multiple laboratories.

At present, the scientific understanding of the importance of vitamin C in preventing or treating heart disease remains somewhat mixed. Although vitamin C does not appear to directly lower blood cholesterol levels, evidence exists that it does significantly lower low density lipoprotein and Lp (a) levels, which in turn helps to protect arteries from blockage by these cholesterol-carrying molecules.

Total blood cholesterol may also lessen with increased vitamin C intake due to the fact that vitamin C is an HMG-CoA reductase inhibitor, meaning that if vitamin C levels are high, the body manufactures less cholesterol. Additionally, vitamin C’s benefits to the body as both a primary collagen producer and as an antioxidant contribute to what most studies agree to be a significant, though still not fully understood, protective effect against heart disease when taken in doses of 400 to 2,000 mg daily. As in Pauling’s era, this level of supplementation is far above the current Recommended Daily Allowance for adult men and women, which is 60 mg per day.

Likewise, the interaction between lysine and vitamin C that many of Pauling’s case study patients found to be highly therapeutic – with anecdotal reports of actual reversal of atherosclerosis in certain patients – has not been investigated further. And so it is that, more than twenty years after his death, Linus Pauling’s ideas on the impact that nutritional supplementation might make on heart health remain just as tantalizing and out of reach as they were when Pauling was alive and active.

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The Unified Theory of Human Cardiovascular Disease

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[An examination of Pauling’s research on vitamin C and heart disease, part 3 of 4.]

In early 1991, Dr. Howard Bachrach of Southold, New York informed Linus Pauling of experimental results indicating that lipoprotein (a) [commonly abbreviated as Lp(a)] binding to arterial walls could be suppressed through the use of supplemental lysine. In the weeks that followed, Bachrach continued to exchange information with Pauling and his colleague at the Linus Pauling Institute of Medicine, Matthias Rath, in hopes of determining if lysine, vitamin C, or some combination of the two might not only prohibit but actually reverse plaque accretion in vitamin C-deficient guinea pigs.

A breakthrough came about on February 28, 1991 – Linus Pauling’s 90th birthday – when Rath reported to his colleagues his finding that Lp(a), as synthesized in the liver, was in fact regulated in an unknown way by the amount of vitamin C present in the body.

Lp(a) was understood by Rath and Pauling to form from low density lipoprotein (LDL) and Apoliprotein A-1 [abbrevied apo(a)] in the liver in amounts largely determined by the rate of synthesis of apo(a). This rate of synthesis was increased by low vitamin C concentrations in the blood. Rath and Pauling published the finding in Medical Science Research, arguing that plaque formation was not caused by LDL cholesterol, as previously thought, but lipoprotein (a) instead. Crucially, high doses of vitamin C was identified by the authors as being central to reducing these dangerous lipoprotein (a) levels.


This discovery formed the basis for what Pauling and Rath would eventually call their Unified Theory of Human Cardiovascular Disease. Fundamental to this framework was Pauling and Rath’s belief that cardiovascular disease was a degenerative disease caused by vitamin C deficiency. The theory also put forth that humans’ inability to synthesize their own vitamin C drove the disease, though it was also aggravated by genetic defects and exogenous risk factors, such as free radicals introduced by cigarette smoke or oxidatively modified triglyceride-rich lipoproteins exerting a noxious effect on the vascular wall.

Further, lipoprotein (a) was put forth as an evolutionary surrogate for vitamin C in animals – like primates and guinea pigs – that no longer produced their own ascorbic acid. This collection of species shows much higher levels of Lp(a) in the blood, a characterstic seen by Pauling and Rath as serving as an ad hoc biological mechanism used by the body to repair damaged tissues through deposit on weakening arterial walls. Too much Lp(a), however, leads to plaque formation, causing angina, heart attack, and stroke. A lack of vitamin C thus leads indirectly to the deterioration of arteries.

From there, the researchers argued that this problem could be easily fixed if only the recommended doses of vitamin C were increased to levels many times larger than those prescribed by the federal government. Were the body enabled to make use of supplemental vitamin C to produce collagen – as all animals that synthesize vitamin C internally do – humans would be much more efficient at repairing damaged arterial walls. Indeed, vitamin C could function not only to strengthen arterial walls, but also to reduce the amount of Lp(a) being produced by the body and consequently – as a co-factor in the hydroxylation reaction that converts cholesterol to bile acids – lowering the amount of free cholesterol in the blood as well.


vitc-plaque

Published in the Linus Pauling Institute of Science and Medicine Newsletter, March 1992.

To Pauling and Rath, the logic supported their theory was clear. Critics, however, demanded large clinical studies to support the claims, and this was research that the Institute, which was struggling mightily for funds, did not have the resources to pursue.

It was at this point that other interested researchers took up the torch. One of them, Dr. James Enstrom at UCLA, led a 1992 study of over 11,000 human subjects. Enstrom’s work indicated that those individuals who regularly took supplements of vitamin C at federally recommended levels enjoyed significantly lower rates of heart disease than did those not subscribing to a supplementation routine. This data led Enstrom’s team to wonder – in tandem with Pauling and Rath – whether larger doses would achieve an even greater protective effect.

In 1993, hoping to add additional support to the hypothesis, Pauling published three case studies in the Journal of Orthomolecular Medicine. Each study focused on individuals who had suffered from severe cardiovascular disease and undergone surgical procedures, including heart bypass. The individuals in question had read Pauling’s papers with Rath and had decided to try adding lysine and vitamin C to their diet. In certain cases, members of the study group had already been taking fairly high doses of vitamin C and then added lysine.

The 1993 data clearly were not anything like controlled studies and were reported on anecdotally by Pauling. Further, the amounts of lysine and vitamin C ingested varied significantly between individuals, but was generally in the range of between 3 to 6 grams per day of each supplement. Many within the study group reported rapid relief and positive responses.

Though far from authoritative, the published case studies did help to bolster Pauling and Rath’s position, attracting increased interest in the work. However, the duo also received plenty of letters, some filled with irritation, from people who had incorporated supplementation and saw no positive change. Some correspondents, in fact, were getting worse.

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.


pauling-heart-foundation

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.

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.

The OSU Era

LPI Director Balz Frei, 2010.

LPI Director Balz Frei, 2010.

[A history of the Linus Pauling Institute of Science and Medicine, Part 7 of 8

Despite Linus Pauling’s death in August 1994, prospects were finally beginning to look up for the Linus Pauling Institute of Science and Medicine. By early 1995, finances had improved and, crucially, LPISM had decided to move from Palo Alto, California, to the campus of Oregon State University in Corvallis, Oregon.

Even though the reorganization of the Institute after Emile Zuckerkandl’s departure had shrunk its staff from 75 to 50, it was still determined that LPISM was too big to move to Oregon in its then-current size. For one, many of its development obligations would no longer need to be assumed by Institute staffers, as the OSU Foundation had agreed to lead fundraising efforts, and other staffing redundancies were quickly becoming apparent.

CEO Steve Lawson began to meet regularly with OSU’s Dean of Research, Dick Scanlan, the two carefully studying their staff lists, deciding who and what was most likely to succeed at OSU. Eventually it was agreed that LPISM would move to OSU with a skeleton holdover staff of five people: Steve Lawson, Conor MacEvilly (biochemist), Vadim Ivanov (cardiovascular disease researcher), Svetlana Ivanova (Ivanov’s wife and research partner), and Waheed Roomi (researcher focusing on the cytotoxic molaity of vitamin C derivatives) would come to Oregon.

LPI Staff and faculty affiliate investigators, ca. 1996. Left to right: (back row) Waheed Roomi, Barbara McVicar, Stephen Lawson, Donald Reed, George Bailey, Vadim Ivanov, Ober Tyus; (front row) Svetlana Ivanova, Rosemary Wander, Peter Cheeke, Conor MacEvilly; (not pictured) David Williams, Philip Whanger.

LPI Staff and faculty affiliate investigators, ca. 1996. Left to right: (back row) Waheed Roomi, Barbara McVicar, Stephen Lawson, Donald Reed, George Bailey, Vadim Ivanov, Ober Tyus; (front row) Svetlana Ivanova, Rosemary Wander, Peter Cheeke, Conor MacEvilly; (not pictured) David Williams, Philip Whanger.

In preparing for the move, Lawson worked closely with Scanlan and OSU president Dr. John Byrne to hammer out the specifics of how to integrate LPISM into OSU. In 1995 Linus Pauling Jr., Lawson, and incoming OSU president Paul Risser all signed a Memorandum of Understanding that laid out how everything would be transferred to OSU, and how LPISM would be legally dissolved as a separate entity. OSU promised to provide the Institute with administrative and laboratory space on the fifth floor of Weniger Hall, which had just been renovated. The university also pledged additional funding for salary lines, and to work toward eventually housing LPISM in its own building should it someday outgrow Weniger Hall.

The big move was made in July 1996. LPISM was able to bring with it an endowment of $1.5 million, which the state of Oregon agreed to match. As they moved, the remaining staffers purged much of their material: Lawson estimated that they filled two full-sized dumpsters per week immediately before, during, and after the move.

Upon arrival, the Linus Pauling Institute was created as a separate entity from LPISM, which continued to exist as a shell company for several years afterward. LPISM needed to continue to live as many bequests had been specifically made out to LPISM, and there was the issue of standing lawsuits from Matthias Rath and another former staffer who was suing LPISM for wrongful termination. Due to these legal reasons, and despite the fact that, by 1996, it had ceased to exist on anything but paper, LPISM was not finally dissolved until the mid-2000s.


Maret Traber, one of the world's leading experts on vitamin E.

Maret Traber, one of the world’s leading experts on vitamin E.

Once settled in Corvallis, the Institute’s fortunes continued to improve. For one, the financial problems which had plagued the Institute for all of its life basically vanished. Regular influxes of donations coupled with residence at OSU saved a fortune for LPI, which no longer had to pay rent or keep a fundraising staff on its payroll.

Next, after a long and thorough search, Balz Frei was hired as director of LPI in the summer of 1997, a position that he holds to this day. The Institute spent the rest of the late 1990s setting up its research agenda and recruiting new faculty. In 1998 LPI hired Tory Hagen, Maret Traber, and Rod Dashwood, all acclaimed scientists whom Lawson described as the “research backbone of the Institute.” (presently all three hold endowed professorships) Shortly afterward David Williams was hired from within OSU as another principal investigator; he ended up holding numerous positions at LPI and was very important to its success in the following years.

In 2000 LPI launched one of its most successful projects: the Micronutrient Information Center, which has proven to be a highly popular and dynamic outreach program. The resource, which continues to expand, provides information on dietary intake and encouragement for healthy living. While it still advises vitamin C doses much higher than that recommended by the FDA, the numbers involved are far from Pauling’s recommended megadoses of the 1970s and ’80s.

lpi-conference-2003

The year 2001 was another big one for the Institute, in part because of their hosting the first Diet and Optimum Health Conference that winter. As part of the conference, they presented the first Linus Pauling Institute Prize for Health Research to Dr. Bruce Ames, along with a $50,000 award. In the span of a decade, the Institute had gone from being hundreds of thousands of dollars in debt to being able to award a biennial prize of $50,000 – tangible evidence of a truly remarkable turnaround. That year LPI also hired Joe Beckman, who opened up a new area of research for LPI through his focus on amyotrophic lateral sclerosis, or Lou Gehrig’s disease.

The ensuing decade was refreshingly free of drama – certainly so by past LPISM standards – and saw unprecedented growth. In 2002 the general expansion of LPI’s research support staff continued and in 2003 the second Diet and Optimum Health Conference was held with the signature prize going to Dr. Walter Willett of Harvard University. The third, fourth, and fifth conferences were held in 2005, 2007, and 2009 with Drs. Paul Talalay, Mark Levine, and Michael Holick winning the awards at each event.  In 2011 the prize went to OSU alum Dr. Connie Weaver; this year the biennial conference is scheduled to take place in May, and another LPI Prize will be announced then.


Jane Higdon.

Jane Higdon, 1958-2006.

In an otherwise near-spotless decade of growth and good news, one tragic occurrence did befall the Linus Pauling Institute. On May 31, 2006, Jane Higdon, a prolific writer, well-known researcher, creator of the Micronutrient Information Center, and six-year veteran of LPI, was hit and killed by a logging truck while bicycling near her home in Eugene. In her honor, the Jane Higdon Foundation was established, the trucking company involved in the accident donated $1 million to bicycle safety programs, and LPI set up the Jane V. Higdon Memorial Fund. The Higdon Foundation’s goal is to create “scholarships and grants to encourage and empower girls and young women to pursue healthy and active lifestyles and academic excellence” and also to promote bicycle safety in Oregon’s Lane County. The Memorial Fund is largely dedicated to supporting the Micronutrient Information Center.

Buoyed by the success of its past outreach efforts, LPI decided to expand its education programs to include young people as well, launching the Healthy Youth Program in 2009. The Program is aimed at elementary- and middle school-age students, and promotes healthy lifestyles and nutrition.

At the same time, LPI responded to the “Physicians’ Health Study II on Vitamin C and E and the Risk for Heart Disease and Cancer.” Published in the Journal of the American Medical Association, the study claimed that vitamins C and E were useless in treating cardiovascular disease. LPI retorted that the research directly contradicted numerous other contemporary studies, that it failed to accurately measure vitamins in the bloodstream, and that a ten-year study isn’t adequate time to gauge the effect of vitamins on cardiovascular disease.  LPI’s public response was emblematic of its participation in public debate; presently the Institute is looked upon as a respected and valuable contributor to many conversations concerning, as Linus Pauling would have put it, “how to live longer and feel better.”

For the first time in its existence, things were going very smoothly for LPI. As the first decade of the new millennium came to a close, the future looked even brighter, a welcome change from the past.  Exciting news was not long at hand.

A Tough Start to a New Decade

LPISM staff assembled for a group photo.  To Pauling's right are Emile Zuckerkandl, Ewan Cameron and Richard Hicks.

LPISM staff assembled for a group photo. To Pauling’s right are Emile Zuckerkandl, Ewan Cameron and Richard Hicks. By 1992, none of these three crucial staff members would remain affiliated with the Institute.

[A history of the Linus Pauling Institute of Science and Medicine, Part 5 of 8]

For the Linus Pauling Institute of Science and Medicine, the difficult decade of the 1980s was one plagued by lawsuits, dramatic monetary problems, and the death of Ava Helen Pauling. Yet for all of its struggles, LPISM soldiered on as best as it could.

One who would help define the decade to come, Dr. Matthias Rath, was a charismatic, intelligent, young German physician who had a passion for vitamin C and cardiovascular health. He had met Linus Pauling on numerous occasions, and in 1989 Pauling invited him to join the LPISM staff. Rath was charming and popular with many of his colleagues. However Pauling’s oldest son, Linus Jr. – a long-time Institute board member – took caution, noting in a 2012 interview his concern that Pauling would offer a position of importance to somebody that he felt was very inexperienced.

Two other major events occurred in 1990: Pauling and Zelek Herman developed a new method to analyze clinical trial data, and the National Cancer Institute installed a new president by the name of Samuel Broder. Pauling immediately began corresponding with Broder, and eventually convinced him to reopen the case for vitamin C as a treatment and prevention for cancer. This resulted in an international conference held in Washington D.C. in 1991 and sponsored by the NCI. It was titled “Ascorbic Acid: Biological Functions in Relations to Cancer.” Pauling was the obvious candidate for keynote speaker and he later said of the conference, “It was great! A great affair! Very exciting!”

Participants in the NCI symposium on Vitamin C and Cancer, Bethesda, Maryland, September 1991

Participants in the NCI symposium on Vitamin C and Cancer, Bethesda, Maryland, September 1991

At this same time, Pauling created a new position at LPISM for Rath, who was named the first Director of Cardiovascular Research. With this, Linus Jr. became even more concerned. Increasingly, he began to question his father’s administrative acumen and began taking steps to assume a more active role in the management of Institute, despite the fact that he lived in Hawaii.

Another big change was on the horizon as well. The city of Palo Alto was planning to change their zoning laws in an effort to increase residency, and informed LPISM that they had three years to find a new home. The Institute realized that the time allotted them was insufficient, and they began a campaign to delay the eviction.  Staff set up card tables in front of businesses, disbursing flyers and circulating a petition to keep LPISM where it was.

The positive response that they received from the locals was staggering and gave the Institute some measure of leverage in their conversations with the city. At one point, Steve Lawson was called before the city council, and one member said that she didn’t want to read in the New York Times that Palo Alto had kicked LPISM out of town. Eventually the council informed LPISM that the zoning law changes were still going to go through, but that the Institute would be granted more time to plan and relocate.


On the research front, after almost two years of marketing Pauling’s superconductor domestically with no leads, Rick Hicks decided to look abroad for a buyer. He contacted parties all over Europe and Asia, and one day a man showed up at the office to inquire about superconductor sales. He identified himself as an employee of the Central Intelligence Agency, which had taken an interest as to why LPISM was trying to sell this research internationally, especially in Japan, instead of on the U.S. market.

Hicks was away from the office at the time, but other employees were able to explain how he had tried unsuccessfully to sell it domestically first. Steve Lawson later recalled the experience as having been a jarring one. Unfortunately for LPISM, they also failed to sell the superconductor abroad and, due to an oversight, misplaced the paperwork required to pay the royalty fee needed to maintain the patent, which they lost as a result.

rath

While this was going on, Pauling and Rath published a paper defining vitamin C deficiency as the major cause of cardiovascular disease. It immediately caused controversy, but the authors stood behind their work and continued on. Once again, concerns about Pauling’s infatuation with vitamin C began to resurge in the scientific community.

Another blow to the Institute’s fortunes was delivered on March 21, 1991, when Ewan Cameron died. His passing rocked the staff and morale plummeted. Shortly afterward, Pauling was diagnosed with prostate cancer and had to undergo surgery. On top of all of this, the fiscal report for the end of 1991 showed that LPISM was hundreds of thousands of dollars in debt. Workers remained loyal however, and numerous employees volunteered to suspend retirement contributions or work at reduced pay to keep the Institute afloat. Despite this, LPISM was still forced to cut their staff in half by early 1992.

Meanwhile, Pauling and Rath continued to promote vitamin C for cardiovascular disease prevention and treatment, and despite continuing doubts about their individual claims, they began to see more support as the medical community gradually realized that it had been underestimating the value of vitamin C for decades. As their work progressed, Rath’s connection to Pauling continued to grow.


In the spring of 1992, more change was clearly afoot when Emile Zuckerkandl’s contract with LPISM was not renewed. This was a controversial move, as Zuckerkandl was well-liked and respected by the staff. After his departure from LPISM, he founded his own institute, the Institute of Medical Molecular Sciences. He asked the Board of LPISM if he could lease space within LPISM for his new IMMS, a request that was granted.

Additionally, Zuckerkandl invited many of the LPISM staff who had been laid off to join IMMS. When he received news that Zuckerkandl was leaving, Rick Hicks, who by now was the Vice President for Financial Affairs, submitted his resignation as well. He had worked very closely with Zuckerkandl and wanted to follow him to other business ventures. The Board was surprised by Hicks’ resignation and the Institute didn’t want to lose its affiliation with him completely, so they elected him to the Board to keep him at least tangentially involved in LPISM. Happily, Hicks’ last act as an employee was to inform the Board that the estate of Carl L. Swadener had been bequeathed to the Institute and that it was valued at $2-3 million.

Linus Pauling Jr. was elected as the next Institute President, replacing Zuckerkandl. The organization that he took over was in grim shape, despite the windfall from the Swadener estate. As he assumed his new office, one of his top priorities was Matthias Rath. Amidst the recent shuffle, Linus Pauling had appointed Rath as Hicks’ replacement and at the same time the two had founded the Linus Pauling Heart Foundation, a separate and parallel organization to LPISM designed to focus on the Pauling-Rath cardiovascular disease research. These decisions were a source of concern to the Board and much of the staff, who were unsure if the Heart Foundation would be a competitor to the Institute, an arm of the Institute or a supporting organization to the Institute.

lawson-lpj

Overwhelmed by work, facing a serious illness and feeling his age, Linus Pauling officially retired from his leadership role at LPISM on July 23, 1992. In the wake of this announcement, the Board elected Steve Lawson as Executive Officer of the Institute, named Pauling its Research Director and Linus Pauling Jr. the Chairman of the Board. Linus Jr. immediately assumed a strong leadership role and, working closely with Lawson, aggressively pursued actions to solve the Institute’s numerous problems.

The two quickly decided that attaching LPISM to a university offered the best chance for its survival. At the same time, they realized that LPISM had become bloated and that they needed to pare back on the organization’s non-orthomolecular research, which had largely been created and expanded under Zuckerkandl’s leadership. While Linus Jr. and Lawson both agreed that the research was worthwhile, they also realized that the Institute simply lacked the funds to maintain it. Zuckerkandl had remained close to LPISM, and when almost all of his research programs were cut, he asked the researchers overseeing these programs to resign from LPISM and join IMMS, which many did.

While this was happening, tensions were mounting between Pauling, Linus Jr. and Matthias Rath. Pauling was informed that Rath had created an office for the Heart Foundation that was separate from LPISM, and that he had done so without permission and without even telling Pauling. He criticized Rath aloud for this decision, which only inflamed the situation.  From there, the speed with which the Pauling-Rath relationship soured was dramatic. In July, Rath was spending great amounts of time at Pauling’s home, and they frequently exchanged letters expressing a close friendship. By August they were hardly on speaking terms, and Rath was ultimately expelled from the Institute, asked to resign over a dispute involving intellectual property rights.

For all of the troubles of the 1980s, the ’90s were getting off to a rough start. The roller coaster ride would continue on in the time ahead, containing both the Institute’s darkest hours and its greatest triumphs.

Lipoprotein(a) Patents

Promotional literature for the Linus Pauling Heart Foundation, ca. 1992.

Promotional literature for the Linus Pauling Heart Foundation, ca. 1992.

[Part 2 of 2]

With the results of their Lipoprotein(a) [LP(a)] experiments in hand, Linus Pauling and Matthias Rath decided to create a treatment and try to patent it. Their treatment relied on three main ideas: First, that increased Vitamin C levels in the bloodstream would prevent the creation of lesions to which Lp(a) might bind. Second, that lipoprotein binding inhibitors would detach any plaque that had already built up. And lastly, that Vitamin C would then also help the body to filter out Lp(a). In this way, it could be used to both treat and prevent cardiovascular disease (CVD) and other related cardiovascular problems.

The duo also saw great potential use for their research in surgery – specifically angiopathy, bypass surgery, organ transplantation, and hemodialysis. Lysine or other similar chemicals naturally help to speed the healing process and also act as blood clotting agents, therefore reducing the risk of blood loss during surgery. Also, patients undergoing organ transplant surgery, bypass surgery, and hemodialysis often suffer strong recurrences of CVD, which Pauling and Rath felt was due to depleted Vitamin C levels from blood loss. Similarly, diabetics often suffer from both inhibited Vitamin C absorption and higher levels of Lp(a), leading Pauling and Rath to hope that their work could help to treat diabetes-related CVD as well.

When living patients were using their treatment, the mixture was designed to be taken orally in pill or liquid form, or injected intravenously. Pauling also wondered if the mixture could be taken subcutaneously (injected into the deepest level of skin), percutaneously (injected into internal organs), or intramuscularly (injected into the muscle). When being used as preparation for transplant surgery, the organs to be transplanted were to be soaked in the mixture. Later research done by other scientists showed that Vitamin C is not absorbed into the bloodstream like it was thought, and that there are specific Vitamin C carrier molecules in the digestive tract, therefore limiting the amount of Vitamin C a person can absorb when taken orally. As such, injection is a much more effective method of getting Vitamin C into the bloodstream.

Pauling and Rath’s work was polarizing, if not unprecedented. As far back as the early 1970s, enthusiastic support for Vitamin C by Pauling and others had been a point of extreme controversy. Now, even with this latest batch of research, many scientists and doctors seemed to think that their conclusions were grossly incorrect, and in some cases even dangerous for people. Pauling, Rath, and their supporters felt that the harsh criticism emerged, at least in part, from pharmaceutical companies concerned about losing revenue if people stopped buying their expensive medications and instead bought inexpensive, common Vitamin C. On the flip side, many of the people who felt that their research was correct were absolutely steadfast in their support.

The controversy surprised Pauling. He repeatedly expressed these feelings, pointing out that he was not the first to make claims about the benefits of Vitamin C nor even the most extreme, and yet he was viewed as a controversial figure espousing fringe medicine. The Pauling-Rath team was not the only organization researching and promoting the positive effects of Vitamin C. Other groups, such as that led by Dr. Valentin Fuster of Harvard Medical School, were conducting similar experiments. Pauling and Rath attempted to collaborate with them where possible, often with success. But more generally the duo had to rely heavily upon individual case histories to support their research, largely because they were unable to convince major American institutions to conduct their own studies or to sponsor the Linus Pauling Institute of Science and Medicine’s studies.

Figure 1 from Pauling and Rath's July 1990 patent application.

Figure 1 from Pauling and Rath’s July 1990 patent application.

On July 27, 1993, Pauling and Rath were awarded a patent for the application filed in April 1990. On January 11, 1994, they received a second patent for the application filed in July 1990. Shortly afterward, in March 1994, the two filed a third application, following similar grounds, titled “Therapeutic Lysine Salt Composition and Method of Use.” The compound they were patenting was a mixture of ascorbate, nicotinic acid (also known as Vitamin B3 or niacin) and lysine, or a lysine derivative. The mixture was to be combined at a ratio of 4:1:1, and include a minimum of 400 mg of ascorbate, 100 mg niacin and 100 mg lysine. The mixture functioned more or less identically to the previous two patents, the major difference being the inclusion of Vitamin B3 for its antioxidant properties. Pauling and Rath also encouraged the inclusion of additional antioxidant vitamins.

This was the last patent that Pauling and Rath would file together. Shortly afterward the two experienced a falling out and Rath left LPISM.  A few months later, on August 19, 1994, Linus Pauling passed away from cancer.

The third patent application was approved and awarded to Pauling and Rath in 1997. The two hadn’t made any profit off of the previous patents to speak of, and research that followed in the later 1990s and after 2000 showed that Vitamin C appeared to have no real effect on Lp(a). The discrepancy between the Pauling-Rath trials and subsequent tests seem to be attributable to the major differences between the two test subjects – humans and guinea pigs. However, other trials have shown that large doses of Vitamin C are useful in fighting cardiovascular disease – for reasons other than Lp(a) levels – and also work to combat stroke, decrease blood pressure and provide other health benefits.

Additional studies in the wake of Pauling and Rath have also revealed the complexity of Lp(a).  The compound is today regarded to be somewhat of a mystery in terms of function, as scientists aren’t very clear on what it does in the human body. Also, “normal” levels of Lp(a) vary massively on an individual basis, a trait that seems to trend along racial lines. As a result, choosing Lp(a) as a target for medication has proven to be extremely difficult.