Farewell to Balz Frei

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

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

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

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

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

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The Decline of Orthomolecular Psychiatry

Abram Hoffer and Linus Pauling at the symposium, "Adjuvant Nutrition in Cancer Treatment," Tulsa, Oklahoma, November 1992.

Abram Hoffer and Linus Pauling at the symposium, “Adjuvant Nutrition in Cancer Treatment,” Tulsa, Oklahoma, November 1992.

We have written before on both the orthomolecular psychiatry of Linus Pauling and the birth of orthomolecular medicine, which has its roots in nutritional (later called orthomolecular) psychiatry. This post delves further into how orthomolecular psychiatry came to be, as well as its marginalization out of the scientific mainstream.

It all began with Albert Hofmann, the Swiss scientist who, in 1938, famously synthesized LSD and discovered its psychedelic properties. After several trials, some on himself, Hofmann developed the hypothesis that LSD mimics the effects of psychosis.

Hofmann’s idea inspired two English psychiatrists, Dr. Humphry Osmond and Dr. John Smythies, to further his research in the late 1940s. Using mescaline (derived from the peyote cactus) as their basic compound, the duo took Hofmann’s work a step further, eventually conjecturing that schizophrenics suffered from an overdose of an endogenous (made in the body) toxin that was similar in structure to mescaline and LSD.

Finding no sympathy in England – at the dominated by Freudian thought – Osmond and Smythies took their work to Saskatchewan, Canada, relocating there in late 1951. Once in Canada, Osmond met Abram Hoffer, a fellow psychiatrist with whom he would collaborate for decades. Together, Hoffer and Osmond ran the psychiatric sciences and therapies divisions of the psychiatric hospital in Weyburn, Saskatchewan, which housed a number of schizophrenic patients.

Hoffer and Osmond eventually discovered the toxin that Osmond and Smythies had suspected was causing the psychoses present in schizophrenics: adrenochrome, a byproduct of the body’s metabolic oxidization of adrenaline and noradrenaline. The next step in helping their patients, the doctors felt, was to find some way to alleviate the psychoses brought about by schizophrenia. This led them to nicotinic acid, also known as vitamin B3 or niacin. Niacin, they learned, was known anecdotally to help patients with neuropsychiatric disorders. This fit with the fact that pellagra, a disease caused by a deficiency of niacin, sometimes presents with psychiatric symptoms.

Eager to test their theory that vitamin B3 could help alleviate mental disease, Hoffer and Osmond began experimentation, dosing their schizophrenic patients with large amounts of niacin by adding it to their daily diets in the first double-blind tests performed in psychiatry. Once the experimentation was finished, Hoffer and Osmond followed their patients for ten years, measuring the effectiveness of their added-vitamin therapy in terms of readmission rates and ability to find outside employment once released from the hospital.

In 1962 Hoffer and Osmond published the book Niacin Therapy in Psychiatry, the text that introduced Linus Pauling to the duo’s megavitamin work. The book revivified his interest in the biochemical basis of mental illness, which he had been studying for a decade, having previously learned that phenylketonuria is a molecular disease in much the same way as sickle-cell anemia.

By the time Pauling read the niacin book, anecdotes about megavitamin therapy, as it was then called, had begun to spread. Additionally, it had already been discovered that niacin could lower cholesterol levels. When added to his prior knowledge, these facts led Pauling to find the evidence presented in the book compelling enough to merit further investigation. The final ingredient to Pauling’s interest appeared the next year, when Dr. Irwin Stone introduced Pauling to the potential health benefits of large doses of Vitamin C. .

It wasn’t until 1967 that Pauling coined the term “orthomolecular,” using it in print for the first time in a paper titled “Orthomolecular Methods in Medicine.” In 1968 Pauling wrote his more famous paper on the subject, “Orthomolecular Psychiatry,” published in the journal Science. Pauling, of course, went on to found the Institute of Orthomolecular Medicine with Art Robinson in 1973, (soon after renamed the Linus Pauling Institute of Science and Medicine) and co-edit the book Orthomolecular Psychiatry: Treatment of Schizophrenia in the same year. Around this time, Pauling also began broadening his theory of orthomolecular medicine to include the whole body, not just the mind.


But what happened to Hoffer and Osmond? The answer to this question plays a part in understanding why many doctors today still refuse to consider orthomolecular medicine a legitimate form of treatment.

In 1967 Hoffer and Osmond formed both the Canadian Schizophrenia Foundation and the American Schizophrenia Association. The two doctors had recently been encountering a great deal of resistance to the publication of their ideas, so they started their own journal, the Journal of Schizophrenia, in the same year. They asked Pauling to serve on the editorial board; Pauling agreed, participating in that capacity for the rest of his professional life.

In 1973 orthomolecular psychiatry was dealt a serious blow by the American Psychological Association Task Force. That year, the group published a report titled “Megavitamin and Orthomolecular Therapy in Psychiatry,” condemning the practice as unsupported at best and “deplorable” at worst. Hoffer and Osmond were subjected to humiliation and orthomolecular psychiatry was deemed unworthy of study or application. The following year, Pauling responded to the report, pointing out a number of flaws, including errors in methodology, lack of research, confusion of focus, and bias:

Orthomolecular psychiatry is the achievement and preservation of good mental health by the provision of the optimum molecular environment for the mind, especially the optimum concentrations of substances normally present in the human body, such as the vitamins….The APA task force report Megavitamin and Orthomolecular Therapy in Psychiatry discusses vitamins in a very limited way (niacin only) and deals with only one or two aspects of the theory. Its arguments are in part faulty and its conclusions unjustified.

But Pauling, Hoffer, and Osmond’s expressions of outrage at perceived mistreatment by the APA weren’t enough to overcome further obstacles that lay ahead. For one, in the mid-1970s, orthomolecular psychiatry, rather than sticking to megavitamin doses, expanded to include diet in the treatment of mental health, as well as avoiding stimulants like nicotine. However, no consensus was reached within the community with regard to precise standards for the practice, so recommendations varied from doctor to doctor, making the efficacy of orthomolecular psychiatry difficult to evaluate.

The mainstream introduction of tranquilizers and the phasing out of electroconvulsive therapy in the treatment of mental illness also proved a barrier to the orthomolecular community. Tranquilizers, unlike megavitamins, were immediately successful in alleviating symptoms, making orthomolecular medicine, which took time to work, appear ineffective by comparison.

Eventually, whenever a patient would ask about megavitamin or orthomolecular therapy as an alternative treatment, many doctors would simply cite the APA report, claiming that it had disproven orthomolecular methods. After a while, most patients simply stopped asking.

The American Schizophrenia Association eventually became the Huxley Institute for Biosocial Research, still led by Abram Hoffer. Dr. Hoffer asked Pauling to serve on its board of directors but Pauling declined, by then more interested in pursuing Vitamin C in the treatment of cancer and colds.  The flagging in his energy for the discipline of orthomolecular psychiatry was indicative of the lack of momentum within the field, a situation that persisted for the remainder of Pauling’s life.

The Founding of the Institute of Orthomolecular Medicine

The Institute of Orthomolecular Medicine, 2700 Sand Hill Rd. Menlo Park, CA.

The Institute of Orthomolecular Medicine, 2700 Sand Hill Rd. Menlo Park, CA.

[Ed Note: 2013 marks the fortieth anniversary of the founding of the Linus Pauling Institute, known variously over time as the Institute of Orthomolecular Medicine and the Linus Pauling Institute of Science and Medicine.  For the next several weeks, the Pauling Blog will be celebrating LPI’s anniversary by publishing an in depth history of the organization.  This is post 1 of 8.]

In 1969 Linus Pauling was given his own laboratory at Stanford University for his work on schizophrenia, where Art Robinson, a colleague and fellow researcher, joined him. By 1972 Pauling and Robinson had decided that their Stanford facility no longer afforded the space necessary to continue their research, and in May of that year Pauling requested that the university construct a new building to house an expanded lab for him to use.

The institution hesitated in responding, as its administration was somewhat wary of Pauling at that time, given the controversy that surrounded both his scientific interests and political activism.  Pauling had recently co-authored controversial work with the Scottish physician Ewan Cameron about vitamin C and its usefulness in treating cancer, research which alienated him from much of the medical community. For its part, Stanford was very unsure about the wisdom of giving him a new lab to further that research.

Likewise, Pauling was working hard and visibly for global peace in the middle of the Cold War, activities which had long caused many people to suspect that he harbored communist sympathies. Almost as if to verify that accusation in their minds, he had been awarded the Lenin Peace Prize by the Soviet Union in 1970. Pauling was a harsh and public critic of the war in Vietnam, President Richard Nixon, US nuclear policy, and US foreign policy, which only served to legitimize some people’s doubts about Pauling’s loyalty to the United States. And if that wasn’t enough, Pauling had also publicly protested Stanford’s firing of a tenured professor known to have leftist, anti-war leanings. Stanford took these numerous activities into consideration, and decided to deny his request.

In response, Robinson suggested that Pauling step down from the Stanford faculty and move their research off campus, which they did, relocating in early 1973 to a building that Robinson had found nearby. Their new home was at 2700 Sand Hill Rd. in Menlo Park, across the street from the Stanford Linear Accelerator building. The space was in an office building shared with Kemper Insurance, a location never designed to accommodate scientific research. Nonetheless, Pauling and Robinson adapted, figuring out how to fit their lab into a footprint of less than 20,000 square feet – an area designed to hold desks and chairs instead of wet labs.

An Institute employee working at the Sand Hill Rd. facility, 1974.

An Institute employee working at the Sand Hill Rd. facility, 1974.

Freed from their affiliation with Stanford University, Pauling, Robinson and Keene Dimick – a biochemist who agreed to help pay the rent for their new quarters – decided to form a brand new institute. On May 15, 1973, the Institute of Orthomolecular Medicine was founded as a California non-profit research corporation with the stated goal of researching biology and medicine.

(In late 1973, Pauling decided to sever all of his professional ties with Stanford, equally annoyed with the university as it seemed to be of him. However, he still retained a number of good friends amongst the faculty there, with whom he maintained close ties and corresponded frequently.)

Immediately the Institute began trying to solve a problem which would plague it for most of its existence: funding. Pauling and Robinson began by lobbying all of their friends and associates for money, trying to entice them in part by offering them largely honorific positions on the Board of Associates of their new Institute. Over thirty people agreed to help, including Francis Crick, Maurice Wilkins and a number of other Nobel laureates. The funds generated weren’t princely, but they were enough to get the Institute standing.

On the research end, the Institute began by continuing the program that Pauling and Robinson had been conducting at Stanford – mostly work on vitamin C and metabolic profiling. The new labs contained a large number of animal experiments, which took up a great bulk of the very limited space, as did the Volcano Source Field Ionization Mass Spectrometer, a new device that was being developed by Bill Aberth, a recent hire who had previously worked for SRI International.

Pauling wanted to help people with his research on vitamin C, and in 1974 he opened a small outpatient clinic which was run by John Francis “Frank” Catchpool, a doctor whom Pauling had met in 1959 while visiting Albert Schweitzer’s medical hospital in Africa. Unlike Schweitzer’s venture, the Institute’s clinic was immediately beset with major problems – liability was too high and funding was too low. Additionally, because vitamin C was cheaper than other medication, the clinic often found itself overwhelmed by destitute patients. The staff often ended up working for free, as people would arrive who were too poor to pay anything, but Cameron and other staff would still help out of sympathy and a desire to do good. Due to severe limitations on resources, the clinic closed in 1975, eight months after it opened.

Interior view of the Sand Hill Rd. facility, 1974.

Interior view of the Sand Hill Rd. facility, 1974.

As 1974 progressed, the Institute’s funding problems became increasingly ominous, exacerbated by the fact that Robinson was one of the only people on staff who was adept at fundraising. In July the Board decided to start addressing the problem by renaming the Institute of Orthomolecular Medicine. They came to the conclusion that the term “orthomolecular” was not only too difficult to explain to most potential donors, but that the term had been tainted by a recent barrage of attacks on vitamin C by the American Psychological Association. They also decided that having Pauling’s name attached to the Institute would help with funding, due to his international fame and respect.

On July 26, the Institute was renamed the Linus Pauling Institute of Science and Medicine (LPISM). The Board’s choice proved to be a good one, and more funding began to come in. Even still, it wasn’t enough, and for much of 1974 LPISM was kept afloat through financing from Pauling and Robinson’s personal accounts. Unsurprisingly this too proved to be insufficient and by early 1975 LPISM was in danger of succumbing to bankruptcy. Desperate, the Institute’s administrators were forced to exact pay cuts for all employees, but did so on a sliding scale designed to minimize the impact on workers with already low salaries.

It was at this point that Robinson confronted Pauling, accusing him of neglecting his work as president. Pauling had in fact been neglecting daily duties, boasting to the press at one point: “I don’t waste time on needless details.” Unfortunately, many of these details weren’t needless, and his administrative inattention was harming the Institute. Pauling asked Robinson if he thought he could do better, to which Robinson replied that he could. Pauling responded by making Robinson President and Director of LPISM. Still the financial issues became worse: Pauling donated 75% of his income to LPISM for the first half of 1975, and then 100% of his income in the second half of the year.

In the meantime, the Institute staff began experimenting on hairless mice. For a week before the tests, they would feed the mice food full of vitamins C and E. Next they began irradiating them with ultraviolet light to produce skin cancer and observed the effects of the high-vitamin diet on cancer growth. As a result of this research, Pauling developed a cocktail of vitamins, which he put into a single dose that he called the “Linus Pauling Super Pill.” The Institute considered marketing the pill to raise additional funds, but that plan fell through and the Pauling Super Pill was relegated to a formula in a filing cabinet.

The Institute found itself in a bad place by the end of 1975; saddled with massive financial problems, it was uncertain if it would survive. And amidst this struggle, fortunes were about to get both better and worse for the Linus Pauling Institute of Science and Medicine.

A Somber Return to China, 1981

The Paulings in Tianjin, June 1981.

In the summer of 1981, Linus Pauling participated in the First International Conference on Human Nutrition, which took place in Japan and China. The conference lasted from May 31 to June 8, and was sponsored by the China Medical Association and the Foundation for Nutritional Advancement, the latter of which Pauling was president. The conference took place in Tokyo, Japan and Tianjin, China, travels to which would comprise the first part of a trip that would also take the Paulings to Germany and to London. Their daughter Linda and her husband Barclay accompanied Linus and Ava Helen to the Orient.

Pauling made the opening remarks at the beginning of the conference in Tokyo on June 1. After the Tokyo sessions were completed three days later, the Paulings flew to Peking, traveled in an official vehicle to Tianjin (a “red flag limousine,” as recorded by Pauling in his journal) and stayed in the State Guest House in the same suite used by Richard Nixon during his iconic 1972 trip to China.  From June 4-8, Pauling participated in the conference, which was jointly planned by the FNA and Professor Chou Pei-yuan, the President of the University of Beijing. This was the second and last time Pauling was to visit China.

A day after arriving in China, the Paulings toured Tianjin Medical College, Tianjin Hospital and Tianjin Children’s Hospital before attending a formal reception given by Li Xiannian, who eventually became the Chinese Head of State in 1983. The conference in China formally opened on June 6, again with Pauling delivering the opening remarks. In them, he discussed the roots of his interest in the field of nutrition, and also reflected upon the early years of his scientific career beginning with his focus on minerals and later interest in the nature of life, which arose in 1929 largely because of the presence of Thomas Hunt Morgan (who had discovered the concept of the gene) at Caltech.

An unidentified individual, Arthur Sackler, the Chinese Minister of Health and Linus Pauling, June 1981.

In his talk, Pauling explained that he had decided to learn more about organic chemistry in order to understand how molecules are built and how they interact with each other, beginning with hemoglobin. During this time, Pauling also studied antibodies, immunology, sickle cell anemias, and other heretic anemias. In 1954 he decided to look at other groups of diseases to see if they could be classed as molecular diseases, and chose to study mental illness over cancer, because he felt that many people were working on cancer already. After researching mental illness for ten years, he became interested in vitamins.

According to Pauling, his interest in vitamins came about when he learned that the Canadian scientists Abram Hoffer and Humphry Osmond were treating schizophrenia patients with large amounts of niacin. Simultaneously, Gerald Milner had been giving large amounts of ascorbic acid to mentally ill patients, with positive results. Pauling later observed that vitamin C had value in the control of cancer, so he became involved with cancer. Near the end of his address, Pauling remarked, “As I look back on my life, I see that I have enjoyed myself very much and a good bit of this enjoyment has come from the continued recognition of something new about the universe.”

Other talks given over the course of the Tianjin conference included “Vitamin C and Cancer,” delivered by Pauling; “Extending Life Span of Patients with Terminal Cancer Using High Doses of Vitamin C,” given by Dr. Akira Murata from the Department of Agriculture at Saga University, Japan; and “A Study on Fortified Foods with Ascorbic Acid Phosphate,” given by Professor Chou Deqin, from the Chinese Institute of Military Hygiene.

The conference closed on Monday, June 8. The next day, the Paulings took part in a sight-seeing tour of the Great Wall and the Ming tombs. Later that week, Pauling gave a talk on chemical bonds in transition metals at Peking University, and continued to give lectures and meet with various scientists throughout the rest of his time in China.

Photo of Ava Helen Pauling taken in China, six months prior to her death.

The trip took a dramatic turn for the worse when, in the afternoon of June 19, Ava Helen had a heart attack and was taken to the hospital. Though she left the hospital the next day, she remained medicated and too sick to travel for a few days after, causing the Paulings to change their plans. She remained weak for the rest of their time in China, though recovered enough to complete their planned itinerary through Germany and London.

When the couple returned to California and Ava Helen underwent exploratory surgery, it was determined that she was facing a recurrence of stomach cancer, from which she had been suffering for the past five years. Her cancer was deemed inoperable and only a few short months later, on December 7, 1981, Ava Helen would pass away, three weeks shy of her 78th birthday.

Vitamin C, the Common Cold and Controversy

By Tom Hager

[Part 3 of 3. For the full text of this article, originally presented as a lecture sponsored by Oregon Health Sciences University, please see this page, available at http://thomashager.net]

Portuguese edition of Vitamin C and the Common Cold, a book that was translated into nine different languages.

Pauling’s reading of the literature convinced him that the more vitamin C you took, approaching megadose levels, the lower your chances of getting sick, and the less sick you got.  It was at this point that Pauling made what I consider to be a fundamental mistake. He decided to publish his ideas without peer review, in the form of a popular book.

He did not feel he could wait. He had, he thought, good evidence that a cheap, apparently safe, easily available nutrient could prevent at least an appreciable fraction of a population from suffering through an affliction that made millions of people miserable. And there might be even greater results. Pauling had read of small villages, snowbound in the winter, where no one got colds because there was no reservoir of respiratory viruses to pass around. When visitors arrived in the spring, they would bring colds with them, and everyone would suffer. What if, through the use of vitamin C, a great many more people strengthened their resistance to colds? The two hundred or so cold viruses rampant in the world would have many fewer places to replicate themselves. The spread of colds would lessen; the population of cold viruses would decrease. “If the incidence of colds could be reduced enough throughout the world,” Pauling thought, “the common cold would dis­appear, as smallpox has in the British Isles. I foresee the achievement of this goal, perhaps within a decade or two, for some parts of the world.” Vitamin C, properly and widely used, might mean the end of the common cold.

Packaging for commercial cold remedies pasted by Pauling into his research notebook, July 1970.

This, of course, would not only greatly lessen the amount of suffer­ing in the world; it would increase the fame of Linus Pauling. He was nearing seventy years of age. It had been nearly twenty years since he had captured international attention for his scientific work with proteins, and won the Nobel Prize for chemistry. His efforts had gone to politics in the years since, and none of his recent scientific work had had much impact. Science was moving on without him. He was becoming a historical figure.

Pauling did not feel like one. He was not ready for emeritus status, trotted out at honorary occasions, shunted aside while the young men made the discoveries. He was still strong, still smart, still a fighter. Or­thomolecular medicine was the newest of his grand plans, and no one had shown that his ideas about creating an optimal molecular environ­ment for the body and mind were wrong. The evidence he had uncov­ered about ascorbic acid and colds, evidence that showed human health could be improved by increasing the amount of vitamin C in the body, was the strongest indication yet that he was right. Bringing it to the public’s attention would not only be good for the public; it would be a striking example of the correctness of his general theory.

Pauling’s book Vitamin C and the Common Cold, written in his usual clear, well-organized, straightforward style, presented the results of his literature search. He discussed the findings of five controlled trials that supported his idea, several anecdotal instances of physicians who had treated colds with vitamin C, and evidence that ascorbic acid was safe in large doses. Pauling felt confident that a several-gram daily dose would do no more harm than to cause loose stools, that vitamin C was safe, especially compared with potentially toxic, commonly avail­able over-the-counter medications such as aspirin. The rest of the book was a summary of his orthomolecular thinking and Irwin Stone’s ideas about evolution. A good deal of space was devoted to the topic of bio­chemical individuality, which resulted in a wide personal variation in the need for vitamin C and other nutrients.

On November 18, 1970, prepublication galleys were released to the press, and an unprecedented public roller-coaster ride began. The next day, the New York Times quoted Pauling as saying that humans needed between 1 and 4 grams of vitamin C per day to achieve optimal health and prevent colds. Pauling also took the occasion to slam the medical establishment – from drug companies to medical journals and physicians – for attempting to quash the evidence in favor of ascorbic acid. Why would they do that? the reporter asked. Look at the cold-remedy industry, Pauling said: It was worth $50 million per year, and that bought a lot of advertising space in medical magazines.

This quickly alienated both physicians and the editors of medical journals, neither of whom liked the implication that profits were more important than health. The medical establishment felt it necessary to respond, and respond quickly, once they saw how Pauling’s idea took off.

The book sold wildly, and so did vitamin C.  Pauling’s timing, at least on the public side, was superb. The 1960s had seen a resurgence of interest in “natural” health based on a holistic attitude that said body, mind, and soul were one. Many streams fed into this alternative health movement: a back-to-the-land, organic-foods orientation; a fas­cination with yoga, acupuncture, meditation, and other Eastern health practices; the rediscovery of the lost Western arts of naturopathy and homeopathy. Pauling’s message about vitamin C resonated with mil­lions of people who were reacting against corporate, reductionistic, paternalistic medicine, with its reliance on drug therapy, with people taking a renewed responsibility for their own health and trying to do it naturally. It was delivered just as natural food stores were popping up on corners in every town in America, each one stocked with a section for herbal remedies, a rack for magazines on alternative health regi­mens, and plenty of shelf space for vitamins.

The publication of Pauling’s book triggered a nationwide run on vitamin C. Sales skyrocketed, doubling, tripling, quadrupling, within a week of its appearance. Druggists interviewed in newspapers across the nation told of people coming in to buy all the vitamin C they had. Wholesale stocks were depleted. “The demand for ascorbic acid has now reached the point where it is taxing production capacity,” said a drug company spokesman less than a month after Pauling’s book ap­peared, adding, “It wouldn’t pay to increase production capacity since we’re sure it’s just a passing fad.”

The reaction was swift. The physician-head of the Food and Drug Administration (FDA), Charles C. Edwards, announced to the press that the national run on vitamin C was “ridiculous” and that “there is no scientific evidence and never have been any meaningful studies in­dicating that vitamin C is capable of preventing or curing colds.” The FDA, Pauling found, had proposed in 1966 that no vitamin C tablets over 100 mg be available without a prescription, and he responded to Edwards with sarcasm. If the FDA had its way and he wanted to take 10 grams of vitamin C to fight off a cold without going to a physician for a prescription, Pauling said, he would have to take 100 tablets. “I think I would have as much trouble swallowing all these tablets as I would swallowing some of the statements made by the Food and Drug Ad­ministration in proposing these regulations,” he said.

The medical press was equally critical of Pauling. The American Journal of Public Health said that Pauling’s book was “little more than theoretical speculation.” The Journal of the American Medical Association said of Pauling’s book, “Here are found, not the guarded statements of a philosopher or scientist seeking truths, but the clear, incisive sentences of an advertiser with something to sell. . . . The many admirers of Linus Pauling will wish he had not written this book.” The Medical Letter launched the harshest attack yet, saying Pauling’s conclusions “are derived from uncontrolled or inadequately controlled clinical studies, and from personal experience” and pointing out that there was no good evidence that vitamin C was safe when taken over a long period of time in large doses.

The controversy over Pauling’s book arose from a simple fact: He had not made his case. The book was a combination of his interesting but unproven speculations about orthomolecular medicine and the human evolutionary need for ascorbic acid, coupled with a select handful of studies that indicated that vitamin C could prevent or ame­liorate colds in a fraction of a population. That might make an inter­esting conference paper, but it was little reason to advocate a wholesale change in the dietary habits of a nation. His critics pointed out that he had no clear theory of how vitamin C exerted it powers and that there was no good study – no study at all – establishing that the long-term ingestion of megadoses of vitamin C was safe. The current dogma in the medical profession was that vitamins were needed only in the small amounts provided by a well-balanced diet. Taking grams of vitamin C every day might cause everything from gastric upset to kid­ney stones, and who knew what else?

The way he had gone about publicizing his ideas, sidestepping the normal channels of scientific peer review to publish a popular book, also fueled criticism. He was behaving like a health faddist, not a scien­tist. In the eyes of most physicians – generally conservative about new therapies, disdainful of the holistic health movement, trained to be­lieve that vitamin C was needed only to prevent scurvy – Pauling looked like a nutritional quack, a vitamin pusher who was essentially prescribing without a license.

Typically, Pauling fought back. To pursue his ideas, in 1973 he cofounded (with Arthur Robinson, a young colleague who later moved to Oregon and this year ran for Congress) the Institute of Orthomolecular Medicine in Palo Alto, California.

He went on to publish more books, adding the flu as another disease vitamin C could fight, then Vitamin C and Cancer, and finally compiled all his ideas into How to Live Longer and Feel Better.

Anecdote published in Chemtech, September 1994.

Criticism from the medical community has never let up. A general belief still exists in most – although not all – of the medical community that Pauling went off his rocker.

However, despite what many physicians believe, the jury is still out. A significant amount of active biomedical research research continues to examine the effects of micronutrients on a variety of conditions. For instance the Linus Pauling Institute at Oregon State University (successor to Pauling’s Orthomolecular Institute) maintains a highly successful research program in 12 laboratories funded with millions of dollars of competitive grant funding. The Institute’s head, Balz Frei, believes that Pauling’s basic approach remains sound – but that his arguments with physicians might have caused as much damage to the study of nutritional science as they did good. In my own view, by putting personal controversy ahead of reasoned consensus both Pauling and his critics polarized the public into groups that still have trouble communicating with each other.

Pauling’s work helped give birth to today’s booming market in nutritional supplements. Vitamin C remains the world’s largest-selling supplement. A large number of advocates strongly believe that ingesting vitamins in amounts far above the RDA can help optimize human health, especially by preventing chronic disease. There is a growing understanding that the key in these studies – as Pauling pointed out long ago – is not to look for vitamins to act like pharmaceuticals, exerting significant effects at low doses, but more like nutrients, with less dramatic effects that accumulate at much higher doses.

Linus Pauling himself lived an active life well into his nineties, performing useful research until the end. He was taking many grams of Vitamin C every day.

Will the controversy he started ever end? Was he a genius, or a crank?

The Birth of Orthomolecular Medicine

By Tom Hager

[Part 2 of 3.  For the full text of this article, originally presented as a lecture sponsored by Oregon Health Sciences University, please see this page, available at http://thomashager.net]

Linus Pauling and Irwin Stone, 1977.

The concept of orthomolecular medicine was Pauling’s grand theory of human health.

His approach was chemical, and viewed the body as a vast laboratory buzzing with chemical reactions: enzyme-substrate reactions, energy-producing reactions, antibody-antigen reactions, the chemical interactions that resulted in genetic duplication, and electrochemical reactions in the brain and nerves. Health, in this view, resulted when the lab was well-run and reactions were moving ahead properly; disease resulted if the proper reactions were hindered or stopped. Optimal health could be achieved by perfecting reaction conditions and making sure that the body maintained the proper balance of chemicals (nutrients, catalysts, and products).

After thinking about this balance for years, he coined a term to describe it: orthomolecular, meaning “the right molecules in the right amounts.”

He first used the term in print in 1967 in relation to psychiatric therapy. He had by then become convinced that conditions such as schizophrenia could be treated with nutrients such as niacin (an approach developed by Abram Hoffer and Humphrey Osmond). However, his theory of orthomolecular psychiatry was either ignored or criticized by the medical community.

Then came Vitamin C.


 

In March 1966, in a speech Pauling gave after receiving the Carl Neuberg Medal – awarded for his work in integrating new medical and biological knowledge – he men­tioned to the audience that he wanted to live another fifteen or twenty years in order to see the wonderful new medical advances that would surely come. A few days later, he received a letter from Irwin Stone, a gregarious Staten Island biochemist he had met briefly at the Neuberg dinner.

Stone told him how much he appreciated his talk and then wrote that asking for twenty more years of life was asking for too little. Why not live another fifty years? It was possible, if Pauling listened to his ad­vice.

Letter from Irwin Stone to Linus Pauling, April 4, 1966. This is the communication that spurred Pauling's interest in vitamin C.

He then told him about vitamin C.

Irwin Stone had been interested in vitamin C since 1935, when he began publishing papers and taking out patents on the use of ascorbic acid, or ascorbate (both synonyms for vitamin C), as a food preserva­tive. Over the years his interest grew as he read a series of scattered re­ports from around the world indicating that ascorbate in large doses might have some effect on treating a variety of viral diseases as well as heart disease and cancer. Convinced of its health-giving power, Stone and his wife started taking up to 3 grams of the vitamin per day- many times the daily dose recommended by the government.

Stone felt better as a result, but it took a car crash to make him a true believer. In 1960 Stone and his wife, driving in South Dakota, both nearly died when they were hit head-on by a drunk driver. They not only survived the crash, however, Stone told Pauling, but healed with miraculous rapidity. This he attributed to the massive doses of vitamin C they took while in recovery.

He emerged from the hospital ready to convince others about the value of ascorbate. He began to read widely, noting that among mam­mals, only man, closely related primates, and guinea pigs were unable to synthesize their own vitamin C internally because they lacked an en­zyme critical in producing the vitamin. As a result, humans had to ob­tain it through their diet. If there was none available, the result was scurvy, the dreaded ailment that had killed thousands of sailors before a British physician discovered it could be prevented by providing lime juice or fresh oranges. The U.S. government had duly set the mini­mum daily requirement for vitamin C at a level just sufficient to pre­vent scurvy.

But Stone believed that it was not enough. Scurvy was not a simple nutritional deficiency, it was a genetic disease, the lethal end point of an inborn error of metabolism, the loss of an enzyme that robbed hu­mans of the ability to produce a needed substance. And it appeared from animal studies that simply preventing scurvy might not be enough to ensure optimal health. Only one good biochemical assess­ment of ascorbic acid production in another mammal had been done, on rats, and it indicated that on a weight-adjusted basis, a 150-pound adult human would need between 1.4 and 4 grams of vitamin C per day to match what rats produced to keep themselves healthy. Stone was convinced that taking less than this amount could cause what he called “chronic subclinical scurvy,” a weakened state in which people were more susceptible to a variety of diseases. In a paper he had writ­ten- and which had already been rejected by six medical journals – he concluded,

This genetic-disease concept provides the necessary rationale for the use of large doses of ascorbic acid in diseases other than scurvy and opens wide areas of clinical research, previously inadequately explored, for the therapeutic use of high levels of ascorbic acid in infectious diseases, collagen diseases, cardiovascular conditions, cancer and the aging process.

In other words, to Stone, giving someone enough vitamin C to pre­vent scurvy was like feeding them just enough to keep them from starv­ing. Full, robust health demanded more. He advised that Pauling start with about one and a half grams per day. It was especially good, Stone said, for preventing viral diseases like colds.

“I didn’t believe it,” Pauling later said jokingly of Stone’s letter. After all, Stone was no physician, nor was he a nutritionist exactly or a professional medical researcher.

Pauling's response to Stone's letter of April 4, 1966. Written in July 1966.

But Pauling was interested enough to try taking more vitamin C himself. He discovered that it helped him fight off the colds that had frequently afflicted him. He felt better. He took a little more. Then more.

But he told few people about it. He remained generally silent about ascorbic acid and its benefits through the late 1960s, limiting his few comments to ideas about how it might be used, along with other nutrients, in the treatment of schizo­phrenics. In late 1969, however, convinced by the theoretical argu­ments of Irwin Stone and impressed by his own success in preventing colds, Pauling began expanding his comments to include the subject of ascorbate and general health, noting in a speech he gave to physi­cians at the Mt. Sinai Medical School his success with the use of vita­min C as a cold preventive. His comments were reported in the newspapers.


Cartoon of Linus Pauling in the laboratory, by Sidney Harris. 1985.

That is how it began. Then, two things happened. First, he received a “very strongly worded” letter from Dr. Victor Herbert, a leading clinical nutritionist and a man who helped set the U.S. recommended daily allowances (RDAs) for vita­mins, who assailed Pauling for giving aid and comfort to the quacks who were bleeding the American public with unsupported claims about the benefits of vitamins. Where, Herbert asked, were the care­fully controlled clinical studies to prove that ascorbic acid had a real effect on colds?

Pauling was taken aback. He had not, in fact, carefully reviewed the literature on vitamin C, limiting his reading to a few of the cita­tions in Irwin Stone’s original papers. But now, “sufficiently irritated by this fellow Herbert,” he began a typically comprehensive tour of the scientific journals.

Second, a writer for Mademoiselle magazine contacted Pauling to get his comments on vitamin C for an article on its health benefits. Pauling offered the reporter the general observation that “optimal amounts of vitamin C will increase health and intelligence” and re­ferred readers to his paper on orthomolecular psychiatry. When the article appeared in November 1969, he found his statement rebutted by Frederick Stare, a professor of nutrition at Harvard, who said Paul­ing “is not an authority on nutrition” and that there was no evidence that increased C helped prevent the common cold; in fact, just the op­posite was true. A large-scale study done with five thousand students in Minnesota twenty years earlier, Stare said, had proven definitively that vitamin C had no effect on colds.

Stung, Pauling quickly tracked down the study and decided that Stare had gotten his facts wrong. The 1942 University of Minnesota study involved 363 student subjects who had been given either a placebo or some extra ascorbic acid over a period of twenty-eight weeks. It was true that the authors had concluded in their summary that there was no “important effect” of vitamin C on infec­tions of the upper respiratory tract. But when Pauling took a closer look at their data, he decided they were wrong. Despite what Pauling considered the very low dose of vitamin C given the students – an aver­age of 180 mg per day compared to the 3,000 mg Pauling was now tak­ing – the researchers had in fact seen an effect:  Subjects receiving the extra vitamin had 15 percent fewer colds, and the colds they got were 30 percent less severe than those receiving the placebo. Vitamin C was not a preventive or cure, but the results were, Pauling estimated, statis­tically significant.

It was confusing, especially when Pauling saw the same thing hap­pening in other reports he found on vitamin C and colds: Partial ef­fects were discounted. The physicians who ran the studies seemed to be looking for total cures, not an indication of an effect. The doses they used were low (150-250 mg was common in these early studies –  several times the current RDA but many times lower than what Pauling and Stone considered a protective dose), and the effects they looked for were too strong.

The problem, Pauling decided, was that the researchers were look­ing for vitamin C to act like a drug. In traditional drug testing, small differences in dosage could have tremendous effects, and overdoses were deadly. The tendency was to use relatively small amounts and look for big effects.

Pauling research notebook entry on Gunther Ritzel's 1961 study. Notes dated February 22, 1971.

But to Pauling, vitamin C was a nutrient, not a drug. When the medical researchers saw a small effect, he thought the logical next step should have been to follow up with larger doses. His literature search uncovered at least one study that showed what might happen if they did. In 1961 a Swiss researcher named Gunther Ritzel had given half of a group of 279 skiers 1,000 mg per day of vitamin C – more than five times the Minnesota dose – and the other half a placebo. Ritzel found that those skiers receiving ascorbic acid had 61 percent fewer days of illness from upper respiratory tract infections and a 65 percent decrease in the severity of their symptoms compared to the placebo group.

This, Pauling thought, was very strong evidence in favor of his ideas. Plot the dose of vitamin C along the bottom of a graph and the effects on colds up the side and you could draw a straight line from the Minnesota results (a small effect with small dose) to the Swiss findings (a larger effect with larger dose). He found a few other papers in which the results fit the pattern. True, some of the research he looked at showed no effect at all – most of these studies, Pauling estimated, were flawed because they used too low doses, too short duration, shoddy oversight, or improper blinding – but the important thing was that a small group of careful clinical studies existed that supported Pauling and Stone’s general theory of vitamin C and health: The more C you took, approaching megadose levels, the lower your chances of getting sick, and the less sick you got.

The Medical Research of Linus Pauling

By Tom Hager

[Ed Note:  In October 2010, Pauling biographer Tom Hager delivered a talk sponsored by the Oregon Health Sciences University which detailed and discussed the various contributions that Linus Pauling made to the medical sciences, including the controversy over his strong interest in orthomolecular medicine.   With the author’s permission, excerpts of this talk are being presented on the Pauling Blog over the next three posts.  The full text of Hager’s OHSU lecture is available here.  Those with an interest in learning more about Hager’s work, including his latest research on food issues and world hunger, are encouraged to visit his blog at http://thomashager.net.]

[Part 1 of 3]

Oil portrait of Linus Pauling, featuring a model of the alpha-helix in the foreground. 1951. Portrait by Leon Tadrick.

By 1939, at the age of 38, Linus Pauling was a full professor and head of the chemistry division at Caltech, as well as the father of four children (three sons, Linus, Jr., Peter, and Crellin; and a daughter, Linda).

He was also beginning to turn his considerable talents toward understanding the complicated molecules inside the human body. He started with proteins.

The Molecules of Life

Determining the structure of proteins at this time was a gigantic problem. Most were difficult to purify, easily degraded, and hard to characterize. Proteins appeared to be not only gigantic, comprising hundreds or thousands of atoms – much too large to solve directly with x-ray crystallography – but also relatively fragile, losing their function (denaturing) after even slight heating or mechanical disturbance. No one at the time was even sure that they were distinct molecules – one popular theory held that proteins formed amorphous colloids, gels that did not lend themselves to molecular study.

Studying them at the molecular level seemed an impossible task with the tools available in the late 1930s. But Pauling took on the challenge. He started with the building blocks of proteins, the amino acids, and directed his growing lab team toward pinning down their precise structures. Then he set himself to figuring out how they formed protein molecules, often building models out of wood, wire, and paper.

He based his approach in part on the ideas of the German biochemist Emil Fischer. Like Fischer, Pauling came to believe that proteins were long molecular chains of amino acids linked end-to-end. Working with Alfred Mirsky in the mid-1930s, Pauling discovered that the denaturing of proteins resulted from breaking weak bonds, called hydrogen bonds, that pinned these chains into specific shapes. Between the early 1930s and early 1950s he made a string of important discoveries about hemoglobin, antibodies (including the most sophisticated work at the time into the structural relationship between antibody and antigen), enzymes, and other proteins.

Foldable paper model of the alpha-helix protein structure published in the Japanese journal Chemical Field, 1954.

In May 1951, he put everything he knew into a celebrated series of seven papers detailing the structures of a number of proteins at the level of individual atoms, including the structure of the single most important basic form of protein, the alpha helix (a hydrogen-bonded helical chain that is a structural component of almost every protein). It was an astounding breakthrough, and it opened the door for an understanding of biology at the molecular level. Within two years, Watson and Crick had used his approach to decipher the structure of DNA.

Biological Specificity

But structure was not everything. Pauling realized that life resulted not from individual molecules, but from the interactions between them. How did organisms make offspring that carried their specific characteristics? How did enzymes recognize and bind precisely to specific substrate molecules? How did antibodies recognize and bind to specific antigens? How did proteins, these flexible, delicate, complex molecules, have the exquisite ability to recognize and interact with target molecules?

It all fell under the heading of biological specificity at the molecular level. Pauling directed much of his attention here during through the 1940s, performing a great deal of careful work on the binding of antigens to antibodies.

Drawings of antibodies and antigens made by Linus Pauling in the 1940s.

His findings were surprising. Pauling demonstrated that the precise binding of antigen to antibody was accomplished not by typical chemical means – that is, through covalent or ionic bonds — but solely through shape. Antibodies recognized and bound to antigens because one fit the other, as a glove fits a hand. Their shapes were complementary. When the fit was tight, the surfaces of antibody and antigen came into very close contact, making possible the formation of many weak links that operated at close quarters and were considered relatively unimportant in traditional chemistry — van der Waals’ forces, hydrogen bonds, and so forth. To work, the fit had to be incredibly precise. Even a single atom out of place could significantly affect the binding.

Having demonstrated the importance of complementary structure with antibodies, Pauling extended his idea to other biological systems, including the interaction of enzymes with substrates, odors with olfactory receptors, and to the possibility of complementary structure in genes.

Pauling’s idea that biological specificity was due in great part to complementary “fitting” of large molecules to one another proved to be essential in the development of molecular biology. His research now formed a coherent arc, from his early work on the chemical bond as a determinant of molecular structure, through the structures of large molecules (first inorganic substances, then biomolecules), to the interactions between large biomolecules.

He carried out much of this research during World War II, when he also worked on synthetic plasma substitutes and a fruitless search for ways to produce artificial antibodies.

He had already earned a place among the nation’s leading researchers in the medical applications of chemistry. But his greatest triumph was still to come.

Sickle-Cell Anemia

Toward the end of World War II, Pauling’s reputation was great enough to earn him an invitation to join a national committee that was brainstorming the best structures for postwar medical research. This committee’s work led to the foundation of the National Institutes of Health.

Pauling was the only non-physician asked to join the committee.

At a dinner with other members one night, talk turned to a rare blood disorder called sickle-cell anemia. One of his dinner companions described how red blood cells in the victims were twisted into sickle shapes instead of discs. The distortion appeared to hinder the blood cells’ transport through capillaries, resulting in joint pain, blood clots, and death. The disease primarily affected Africans and African Americans. What caught Pauling’s attention most, however, was one odd fact: Sickled cells appeared most often in venous blood, rather than in the more oxygenated blood found in the arteries.

Pastel drawing of sickled Hemoglobin cells, 1964. Drawing by Roger Hayward.

He thought about this during the next few days. From his previous work with blood, he knew that red cells were little more than bags stuffed with hemoglobin. He had also shown that hemoglobin changed its shape slightly when it was oxygenated. If the red cells were changing shape, perhaps it was because the hemoglobin was altered in some way. What if the hemoglobin molecules in sickle-cell patients were changed in some way that made them clump, stick to one another, as antigens stick to antibodies? Perhaps something had changed that made the hemoglobin molecules complementary in shape. Perhaps adding oxygen reduced the stickiness by changing the molecules’ shape.

He presented his ideas as a research problem to Harvey Itano, a young physician who was then working on his Ph.D. in Pauling’s laboratory. Itano, later joined by postdoctoral fellow John Singer, worked for a year trying to see if sickle-cell hemoglobin was shaped differently from normal hemoglobin. They found no detectable differences in any of the tests they devised. But they kept at it. Finally, in 1949, using an exquisitely sensitive new technique called electrophoresis that separated molecules by their electric charge, they found their answer: Sickle-cell hemoglobin carried more positive charges on its surface.

This was an astounding discovery. A slight change in the electrical charge of a single type of molecule in the body could spell the difference between life and death. Never before had the cause of a disease been traced to a molecule. This discovery – to which Pauling attached the memorable title “molecular disease” – received widespread attention. Itano and Singer’s followup work demonstrated the pattern of inheritance for the disease, firmly wedding molecular medicine to genetics.

Medical Chemistry

It was a great triumph – there was talk of a Nobel Prize in Medicine or Physiology for Pauling – and it led Pauling to make greater efforts in the medical field. He encouraged M.D./Ph.D. candidates, hired physicians to work in his laboratory, and began focusing his own research on medical problems, including developing a new theory of anesthesia.

He was ahead of his time. An example of what the atmosphere was like: Pauling noted that as he went around in the late 1940s seeking funds for a comprehensive marriage of biology and chemistry to attack medical problems, people at funding agencies were telling him that they found the term “medical chemistry” to be “a disturbing description.”

In the late 1950s, Pauling extended his concept of molecular disease to the brain. After reading about phenylketonuria (PKU) – a condition in which a mental defect can be caused by the body’s inability to metabolize an amino acid, phenylalanine, leading to a buildup of that substance and others in the blood and urine – Pauling theorized that the problem might be caused by a defect in an enzyme needed to break down phenylalanine. PKU, in other words, might be another molecular disease. Now interested in the possibility that there might exist a range of molecular mental defects, Pauling visited a local mental hospital, saw other patients whose diseases seemed hereditary, and decided to seek support for an investigation into the molecular basis of mental disease. The Ford Foundation in 1956 awarded him $450,000 for five years’ work – a vindication of Pauling’s approach and a tribute to his reputation. The grant, however, yielded little in the way of immediate results, with much of the funding going toward testing his (ultimately found to be mistaken) theory of anesthesia.

The long-term results were more significant. Pauling’s immersion in the field, thanks to the Ford grant, led him to read widely in psychiatry and general health, always on the lookout for another molecular disease that might lend itself to new therapy. By the mid-1960s he was coalescing his findings into another overarching theory, this one combining much of what he knew about chemistry and health. He called his new idea “orthomolecular” medicine.