Pauling, Rath, and Lipoprotein(a)

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

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

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

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

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


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

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

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

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


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

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


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

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

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

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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.

Experimenting with Lipoprotein(a)

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[Part 1 of 2]

In the late 1980s into early 1990, Linus Pauling and a colleague, Matthias Rath, worked intensively on the health benefits of Vitamin C and Lipoprotein(a) binding inhibitors. In 1990 they applied for two patents related to that research. The first, applied for in April, was titled “Use of ascorbate and tranexamic acid solution for organ and blood vessel treatment prior to transplantation.” The second, submitted in July, was titled “Prevention and treatment of occlusive cardiovascular disease with ascorbate and substances that inhibit the binding of lipoprotein (A).”

The technique that Pauling and Rath were attempting to patent in April was both a method and a pharmaceutical agent designed to prevent and treat fatty plaque buildup in arteries and organs and also prevent blood loss during surgery by introducing into a patient (or organ) a mixture of ascorbate and lipoprotein(a) [Lp(a)] binding inhibitors, such as tranexamic acid.

Tranexamic acid is a synthetic version of Lysine, and ascorbate is the shortened name for L-ascorbic acid, or more commonly, Vitamin C. Lp(a) is a biochemical compound of lipids and proteins which binds to fibrin and fibrogen in the walls of arteries and other organs, which causes plaque buildup, which in turn often results in atherosclerosis – the thickening and embrittling of arterial walls – and cardiovascular disease (CVD), one of the most common causes of death in the United States. The second patent described effectively the same method, but focused more on CVD and less on surgery.

Pauling and Rath noticed that humans and a select few other animals are the only creatures that suffer from heart attacks and other issues associated with the buildup of plaque in the circulatory system. One common link between all of these creatures is the fact that they do not naturally produce Vitamin C, and therefore must obtain it solely through diet. The duo hypothesized that the cause of Lp(a) buildup was due to a lack of Vitamin C, and that if Vitamin C intake was increased, it would help the body filter out Lp(a) and therefore decrease the amount of Lp(a) in the bloodstream. They decided to run tests on Hartley guinea pigs, since they are one of the few other animals that don’t synthesize their own Vitamin C.

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The first test was run on three female guinea pigs, each about a year old and weighing 800 grams. The animals were all fed a diet devoid of ascorbate (e.g., a hypoascorbate diet), and given an injection daily of ascorbate so that Pauling and Rath could easily monitor and control their intake. The first pig was given ascorbate at a ratio equivalent to 1 mg per kilogram of body weight (1 mg/kg BW). The second pig was given 4 mg/kg BW, and the third was given 40 mg/kg BW.

The experiment only lasted three weeks, because Pauling and Rath didn’t want to inflict scurvy upon the guinea pigs. Creatures deprived of Vitamin C for prolonged periods develop scurvy, an incredibly painful condition where the victim becomes lethargic and begins to suffer skin color and texture changes, easy bruising, brittle and painful bones, poor wound healing, neuropathy, fever and eventually death.

The guinea pigs had their blood drawn at the start of the test, then once again after ten days. At the end of three weeks, the animals were anesthetized and euthanized, then dissected. Their results showed that the hypoascorbate guinea pigs had noticeably higher plaque buildup and general amounts of Lp(a) in their bloodstream. Upon closer analysis of the organs and the arterial wall, the researchers discovered that the guinea pigs had also developed lesions along the walls of their arteries, to which Lp(a) was binding even more than normal.

Pauling and Rath then ran a more expansive second test, with a test time of seven weeks and a test group of thirty-three male Hartley guinea pigs, each approximately five months old and weighing 550g. At the outset, the subjects were split into multiple groups. Group A consisted of eight guinea pigs and was given 40 mg/kg BW of ascorbate daily, while Group B consisted of 16 guinea pigs given 2 mg/kg BW daily. At five weeks all of Group A was euthanized and studied, as was half of Group B. The second half of Group B then had their daily dosage increased to 1.3 g/kg BW for two weeks before being euthanized.

Once again, it was observed that the hypoascorbate guinea pigs had developed lesions in their arterial walls and organs, as well as increased plaque buildup and Lp(a) levels. On the same token, the second half of Group B showed decreased levels of Lp(a) in their blood and decreased amounts of plaque after their ascorbate intake was dramatically increased.

Pauling and Rath felt that their research was confirming their hypothesis, and wanted to see how it would function on humans. Their method here was to obtain post-mortem pieces of human arterial wall. They cut the pieces into smaller sections, and for one minute placed a piece weighing 100 mg into a glass potter containing 2.5 ml of a mixture of ascorbate and tranexamic acid. Compared to the other pieces, the portions in the mixture released sizable amount of Lp(a).

This promising data in hand, Pauling and Rath then began to think about patenting and marketing their work.