Remembering Frank Press

Frank Press

Linus Pauling’s colleague and friend, Frank Press, passed away last month on January 29, 2020 in Chapel Hill, North Carolina. Press was 95 and died of complications from a fall. Perhaps most widely known for his work as President Jimmy Carter’s chief science advisor and his twelve years leading the National Academy of Sciences, Press also collaborated with Pauling on multiple fronts, and the two ultimately grew close.

Press was born on December 4, 1924 in Brooklyn, New York. After earning his bachelor’s degree at City College of New York in 1944, Press went on to Columbia University where he earned a master’s (1946) and a Ph.D. (1949) in geophysics. During that time, Press married his high school sweetheart, Billie (nee Kallick), and the couple remained together until Billie’s death of heart failure in 2009.

After a few years teaching at Columbia, Press was offered a professorship at the California Institute of Technology, where he remained until 1965. Press left Pasadena for a position as chair of earth and planetary sciences at the Massachusetts Institute of Technology, and remained at MIT until he was asked to serve as President Carter’s science advisor and director of the Office of Science and Technology Policy.

Not long after Carter was voted out of office, Press was selected to serve as president of the National Academy of Sciences, where he remained until 1993. Following this, he took up a four-year fellowship with the Carnegie Institute as the Cecil and Ida Green senior research fellow in the Department of Terrestrial Magnetism. His fellowship concluded, Press remained on the Carnegie board for another ten years.


Press’ long and fruitful career brought him into contact with Pauling on many occasions. They first met at Caltech, but did not have cause to interact very frequently, owing to their different departmental affiliations and research agendas. The two began to find a bit more common ground through their shared interest in social justice issues concerning the United States and the Soviet Union. Like Pauling, Press pushed for both nations to sign the partial test ban treaty in 1963. Later, Pauling and Press spoke out to protest the USSR’s treatment of scientist and dissident Andrei Sakharov.

Indeed, shared interest in Sakharov seems to have prompted one of their first formal interactions, a 1983 telegram from Pauling informing Press that he had offered a job to their Russian colleague. Even though the offer did not appease the Soviets enough to release Sakharov, the telegram did catch Press’ attention. Perhaps influenced by Pauling’s actions, the National Academy of Sciences, led by Press, formally renounced the Soviet government’s mistreatment of Sakharov, and refused to participate in a joint US-Soviet scientific cooperation in 1984.


An example of the holiday cards that Frank and Billie Press routinely sent to Linus Pauling

Though Press and Pauling were not successful in securing Sakharov’s release, their shared effort on this issue created space for the two to form a friendship. As president of the National Academy of Sciences, Press sent Pauling a card nearly every year of his tenure, and Pauling become close to Billie Press as well. The friendship between the three was such that Billie often included her own note in the annual holiday card, at one point thanking Pauling for his gift of Florence Meiman White’s book, Linus Pauling Scientist and Crusader. When Pauling announced that he had cancer in 1992, the news shocked the Presses, though they were heartened to learn that he had been well enough to celebrate his 91st birthday with sixteen of his closest friends and family.

Pauling was also concerned with the well-being of the Presses, and it was here that friendship and current research intersected. As his work on orthomolecular medicine moved forward, Pauling was increasingly convinced that the Federal Recommended Daily Allowance (RDA) for certain vitamins, such as vitamin C, were far too low. Pauling believed the RDA should be much higher, and that a higher intake of vitamin C could drastically reduce the chance of developing cardiovascular disease, among other maladies.

Pauling was so convinced of this idea that he took pains to let his friends know that they could easily reduce their risk of heart disease by following the simple step of increasing their vitamin C intake. With this concern in mind, Pauling wrote to Press to urge him and Billie to have blood samples drawn so that their physician might determine the levels of lipoprotein (a) in their systems. Pauling specified that if either of their results came back elevated, “I strongly recommend that you begin a prophylactic regimen, that of taking some extra vitamin C and also perhaps 2 grams per day of L-lysin,” the latter because “the L-lysine interferes with the deposition of lipoprotein in the vascular wall.”

Pauling was also quite willing to review their results. “If the level is high,” he wrote, “there are orthomolecular measures that you should take. Let me know the results of the analyses, and I shall tell you what you ought to do.” Anticipating that the Presses might be nervous about vitamin C megadosing, Pauling wrote that a recent friend of his had used orthomolecular treatments to make a remarkable recovery after being bed-ridden following a third triple by-pass surgery. He signed the letter “Love From,” Linus Pauling.

From the correspondence, it appears as though Press trusted Pauling’s guidance. Shortly after receiving Pauling’s letter, Press replied that he would get his lipoprotein levels checked, and that he and his wife “appreciate[d] [his] interest in [their] well-being.” Press concluded the letter by noting the extent to which he and his wife “have admired you over the years.”


Several months later, in June 1992, Pauling asked Press for his help with an issue of mutual concern. Pauling’s request was spurred by an article that he had recently read titled “Reducing the Risk of Chronic Disease,” a summary of the National Research Council’s landmark, three-year study, “Diet and Health.” The aim of the study was to assist the public in making sound decisions related to their diet. (For one, the notion of “food groups” emerged from this study.)

Pauling called many of the study’s conclusions into question and, not surprisingly, took particular offense to a passage that read, “If you take a dietary supplement, do not exceed the U.S. Recommended Daily Allowance.” Because the statement was coming directly from the National Academy of Sciences, Pauling thought that he might be able to enlist Press’ support in revising its language. In his letter, Pauling was clear in his intent, writing that

I believe that this is an important matter – important to the health of nearly all Americans and other people. It seems clear to me that the members of the Food and Nutrition Board are biased against the optimum use of vitamins and are unwilling to consider the evidence. It is my duty as a member of the Academy to try and rectify this situation.

Pauling’s pleas did not fall on deaf ears. Shortly after receiving his letter, Press replied that he would pass Pauling’s concerns on to the Food and Nutrition Board (FNB) for their “thoughtful consideration” at their next meeting. Pauling’s timing could not have been better, Press explained, because the FNB had recently approved a study to look into nutrition requirements for older adults. As Press noted, this was partially due to Pauling’s inquiries into the “possible roles that antioxidant nutrients may play in preventing acute infections and chronic diseases.” Pauling passed away before the FNB had issued a verdict, but he surely took some degree of comfort at having been heard by his colleague and friend, Frank Press.

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.

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)

lpa

[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.

rath

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.