Some Personal Thoughts on Vitamin C in the 1980s and Now

[Guest post written by John Leavitt, Ph.D., Nerac, Inc., Tolland, CT.]

The author in his laboratory at the Linus Pauling Institute of Science and Medicine. Originally published in Science Digest, June 1986.

The author in his laboratory at the Linus Pauling Institute of Science and Medicine. Originally published in Science Digest, June 1986.

During my daily work for pharmaceutical and biotech clients, I am continuously learning about developments resulting from my research at the Linus Pauling Institute of Science and Medicine in Palo Alto, CA in the 1980s. Likewise, I am regularly coming into contact with new medically related developments focusing on vitamin C, an interest of Linus Pauling in those years.

With regard to our research on human plastins, a gene family of proteins that we discovered, cloned, and characterized at the Pauling Institute, it has recently been reported that plastin (PLS3) is a marker of carcinoma cells circulating in the blood (for example Yokobori, et al.). Our hypothesis was that when this protein was inappropriately expressed in cells from solid tissues, as it is in many tumor types, (e.g. carcinomas, fibrosarcomas, etc.) these potential tumor cells become more like blood cells in that they are able to live and replicate in an anchorage-independent state, an essential property of metastatic tumor cells. It is metastasis that kills us when we get cancer. Thus plastins, discovered and characterized at the Pauling Institute, may turn out to be the “holy grail” of cancer research.

I often run across new information on the medical importance of vitamin C without looking for it. Back in the 1980s, we would receive an annual shipment of loose vitamin C from Hoffmann-La Roche, Inc. as a way of saying thank you to Dr. Pauling for his advocacy of the merits of vitamin C. We received no funding from Hoffmann-La Roche though. One year I recall that two dignitaries from the company visited us. Dr. Pauling, with me and several others, walked our visitors to lunch a few blocks down El Camino Real in Palo Alto to my favorite restaurant, the Captain’s Cabin.

Afterward, while walking back to the Institute, one of the guests asked Dr. Pauling if he thought the perceived benefits of vitamin C were due to the placebo effect. I was amused because I too had said something ill-advised like that to Dr. Pauling in my first few months at the Institute. I mentioned to him that I had a vitamin C-resistant cold to which he replied, “You’re not taking enough!” and told me that he takes 18 grams a day. No doubt he had calculated this number based on the amount of vitamin C that animals produce within themselves every day. He would stir 18 grams into a large glass of water and imbibe the glass with no great rush.

A few months ago I heard a physician state in the national media that taking supplemental vitamins is a waste of money. This bold assertion reminded me of the announcement of the discovery of cold fusion and another premature announcement of the discovery of a cure for AIDS. The progress of science is slow but relentless, like the new developments with plastins fifteen years after I left LPISM’s labs.

On October 31, 2013, Kim, et al. at Seoul National University in South Korea published their findings on a new strain of experimental mice. The researchers knocked out the mouse gene encoding the enzyme L-gulono-γ-lactone oxidase, known as gulo for short. This is the gene that is missing in humans and that keeps us from synthesizing our own vitamin C, unlike nearly all other animals. An extreme lack of vitamin C in our diet can lead to scurvy, caused by aberrant expression of collagen in our connective tissues because of starvation of vitamin C in our diet. In these mice the lack of this gene caused “vitamin C insufficiency” in an animal model – a model that can now be used to learn more about the importance of vitamin C.

As these mice matured they expressed known blood markers of liver damage. This damage, called fibrosis, is basically the scarring of the liver, sort of like the scarring of the skin that is caused by certain types of skin damage. Concomitantly, as the mice aged, reactive oxygen species (ROS) and lipid peroxides increased in the liver, as did activated hepatic stellate cells, which deposited abnormal collagen fibriles on the basement membrane of functional liver cells. There is a wealth of evidence that elevated ROS in the lungs, liver, and kidneys is associated with pulmonary, hepatic, and renal fibrosis. Elevated vitamin C in these tissues will quench ROS.

Currently in the United States, there are no drugs approved to treat any of these forms of fibrosis. Fortunately, Intermune’s drug, pirfenidone, is close to approval for treatment of pulmonary fibrosis and has already been approved in Canada, Europe, and Japan. This drug reduces ROS and inhibits other key targets that are suspected of playing a role in the development of fibrosis. So who is to say that supplementing your diet with vitamin C is of no consequence? It is certainly not toxic in any way. Oh, by the way, pulmonary fibrosis is worse than cancer – it kills you in three to five years once diagnosed. You basically die of asphyxiation.

In the last week I stumbled upon another interesting paper on the effects of vitamin C on humans. A 2011 paper by Juraschek, et al. at Johns Hopkins University Medical School reported the results of a significant meta-analysis (a systematic review of multiple clinical trials) of 13 randomized clinical trials involving 556 patients who took a median dose of 500 mg of vitamin C per day. (I take a full gram)

The purpose of the study was to examine the effects of vitamin C supplementation on uric acid levels in the blood. Elevated uric acid levels in the blood causes gout, because saturation of blood with uric acid causes urate crystals to form in the synovial fluids of joints (e.g. crystal arthritis). Drugs that lower uric acid in the blood are used to treat gout because lowering uric acid causes the urate crystals to dissolve to ameliorate the arthritic pain.

Admittedly gout is not as bad as cancer. But another systematic clinical review of multiple trials on humans published in 2012 by Lottmann, et al. at the IGES Institut GmBH in Germany has shown clearly that having gout is associated with both all-cause mortality and, in particular, cardiovascular mortality. So what could be worse than death by gout?

I think I will keep taking vitamin C.

Scenes from the 2014 Pauling Legacy Award Event

On Monday, April 21st, Dr. Zia Mian became the eighth individual to receive the Linus Pauling Legacy Award, granted every other year to an individual who has achieved in an area once of interest to Linus Pauling.

Mian’s talk, “Out of the Nuclear Shadow: Scientists and the Struggle Against the Bomb,” provided an informative and often sobering view of the history of anti-nuclear activism within the scientific community and the challenges that the world continues to face today as nuclear technologies become more widespread.  Mian’s talk, once transcribed, will be made freely available on the website of the Oregon State University Libraries Special Collections & Archives Research Center in the coming weeks.  We’ll be sure to pass along word as soon as it goes live.

In the meantime, here’s a glimpse of the event, which took place at the Oregon Historical Society Museum in downtown Portland.

Irwin Stone’s Impact on Pauling

Linus Pauling and Irwin Stone, 1977.

Linus Pauling and Irwin Stone, 1977.

[Part 2 of 2]

Four years after Irwin Stone first convinced Linus Pauling to start taking megadoses of vitamin C, Pauling decided to share with the world the successes that he had observed in his own improved mental and physical health.

In 1970 Pauling began to work on a book, Vitamin C and the Common Cold, and he wrote to Stone asking permission to dedicate it to him. He also sent Stone a copy of the manuscript to review. Stone wrote back praising the work.

The book is excellent and should go far to eliminate this thoroughly unnecessary and annoying condition, at least among your readers. The audience will increase over the years, especially if Medicine can eventually see the light.

Stone continued to encounter difficulty getting his own scientific articles about ascorbic acid published and he certainly did not have the funding to run his own clinical trials. Partly as a result, he too was writing a book about vitamin C and all of the many diseases that he thought were related to hypoascorbemia. A  major thrust of the book was its plea for large scale research on the topic. Stone hoped to get popular opinion on board with his ideas in order to place pressure on physicians and nutritionists to do research in this area.

Pauling’s Vitamin C and the Common Cold was a popular success. Many readers around the world were persuaded by his ideas and began to take vitamin C supplements to prevent and treat colds. Some of his acclaim rubbed off on Irwin Stone, who wrote to Pauling telling him that he too was finally receiving recognition from popular media sources, including NBC.

In 1971 Stone retired to San Jose, California and devoted the rest of his life to researching and promoting the need for high consumption of vitamin C by humans. That same year he finished his book, The Healing Factor: Vitamin C Against Disease, and asked that Pauling write a foreword for it. Pauling was glad to do so, calling it “an outstanding contribution to knowledge.”

Stone's inscription to Pauling in a first edition of The Healing Factor, 1972.

Stone’s inscription to Pauling in a first edition of The Healing Factor, 1972.

Despite their popular appeal, Pauling and Stone continued to encounter problems convincing medical practitioners and researchers to take their ideas about ascorbic acid seriously. Stone believed that this was so because vitamin C would be a much more inexpensive cure than the current treatments of the time, causing pharmaceutical companies and doctors to lose money.

One medical doctor, Ewan Cameron, did believe in the effectiveness of vitamin C against cancer and was treating his terminal cancer patients with megadoses of it in Glasgow, Scotland. He formed a trans-Atlantic research partnership with Pauling in 1971 and they began to collaborate on papers discussing the use of vitamin C against cancer, eventually publishing ten articles together.

Through his partnership with Pauling, Cameron also began to correspond with Stone about the implementation of vitamin C against cancer and their shared difficulties getting the medical community to accept their hypotheses.

Cameron maintained a unique viewpoint on the treatment of cancer and how ascorbic acid might fit into a clinical regimen. In December 1974, he explained his views to Stone.

It is completely contrary to all contemporary medical thought to even suggest that such a mundane substance as ascorbic acid could have any value in such a complicated disease as cancer. This is because cancer research is concentrating all its energies in searching for more and more sophisticated ways of selectively destroying cancer cells. The research is becoming so complex and so unproductive, that it is natural to assume that ‘the answer’ must be extraordinarily complex and almost beyond human comprehension….We would make much more progress if we accept that cancer cells are normal cells that merely happen to be behaving in an abnormal way. We would then accept that cancer cells have an equal right to live, and concentrate our energies in suppressing the abnormal behavior pattern.

Throughout their correspondence, Cameron described his successes treating cancer with ascorbic acid. But he also noted that a number of patients showed no improvement from it or, at best, their cancer was brought to a standstill. He was disappointed that his primary successes were mostly by way of increasing patients’ survival time, not in curing them. Cameron thought that the greatest success would be in prophylaxis – taking megadoses of ascorbic acid throughout one’s life in order to prevent cancer.

In 1978 Stone wrote a letter to the editor of Nutrition Today in response to the publication’s recent issue focusing on ascorbic acid. His letter shows how fervently he believed in hypoascorbemia.

I regard our most serious medical problem to be the dangerous complacency that the orthodox medical establishment exhibits toward Chronic Subclinical Scurvy and its refusal to do anything to correct and alleviate this potentially-fatal human birth defect. Chronic Subclinical Scurvy has killed more human victims, caused more disease and misery among Mankind than any other single factor in the past and is continuing this evil record in the present. I’m worried about the future, because that is where I’m spending the rest of my life.

Meanwhile, Stone and Pauling’s relationship continued to flourish. In 1977 Pauling invited Stone to become a member of the Board of Associates of the Linus Pauling Institute of Science, an offer that was accepted. Pauling also attended Stone’s surprise 70th birthday party that year. In 1981 Stone was unable to make it to Pauling’s 80th birthday, but he did pass along a message.

You will recall the promise I made you in 1966 of 50 more healthy years of life with Megascorbics. You thought I was exaggerating and said you would be satisfied with 15 years. Well the 15th year is now and I am looking forward to attending your 115th birthday party in 2016. Megascorbics makes you practically indestructible.

In response, Pauling wrote, “I am glad to express my thanks to you for having written to me in 1966. Your letter and the reprints of your papers changed my life.” While Pauling did not make it to 2016, he did live until 1994, passing away at 93 years of age.

The last letter that Pauling wrote to Stone concerned a joint award from the Academy of Orthomolecular Psychiatry and the Orthomolecular Medical Society that Stone was to receive. The Linus Pauling Institute of Science and Medicine was also going to surprise him with a second award. Pauling wrote,

For many years you have been an inspiration to me, because of your devotion to vitamin C and your conviction that a high intake of vitamin C has great value in improving the health of human beings. You have rendered a great service to the people of the world through your continued study of vitamin C over a period of fifty years.

Unfortunately, Dr. Irwin Stone died on May 4, 1984, at the age of 77, while in Los Angeles to receive the award. He died by choking on regurgitated food, the result of a constricted esophagus that had plagued him ever since his car accident many years prior.

Irwin Stone received two honorary doctorates, many additional awards, and 26 patents. He also published over 120 scientific papers throughout his life (at least 50 were about vitamin C) and wrote one book, The Healing Factor, published in 1972. He was father to one son, Steven, and was married to his wife Barbara for over 50 years.

In December 1986, two years after his death, Barbara Stone sent Pauling a card congratulating him on the publication of his latest book, How to Live Longer and Feel Better. She wrote “Irwin would have enjoyed reading it and noting the many references to him and other colleagues.” Pauling hadn’t exaggerated in his 1981 letter: Irwin Stone really did change his life and made a profound impact on the scientific legacy that Pauling leaves behind today.

Irwin Stone: An Influential Man

Irwin Stone. (Image by Oscar Falconi)

Irwin Stone. (Image by Oscar Falconi)

[Part 1 of 2]

Dr. Irwin Stone was a biochemist and chemical engineer who maintained a particular interest in and enthusiasm for vitamin C. Stone was the person who first raised Linus Pauling’s interest in vitamin C, leading to Pauling’s extensive program of research on vitamin C and its uses for the prevention and treatment of disease. Pauling’s contributions to the field are one of the big reasons why many people believe in taking vitamin C for the prevention and treatment of colds today.  But for Pauling, it all started with Irwin Stone.

Stone was born in 1907 and grew up in New York City. He attended the College of the City of New York and then worked at the Pease Laboratories, a well-known biological and chemical consulting lab, from 1924 to 1934. Stone started out as a bacteriologist, but was promoted to Assistant to the Chief Chemist and then to Chief Chemist.

In 1934 the Wallerstein Company, a large manufacturer of industrial enzymes, recruited Stone to set up and direct an enzyme and fermentation research laboratory. Ascorbic acid, or vitamin C, had just been identified and synthesized by a Hungarian research team led by Albert Szent-Györgyi, who later won the 1937 Nobel Prize in Medicine for his work. Stone pioneered processes for implementing the antioxidant properties of ascorbic acid in industrial settings. One specific application that Stone developed was the use of ascorbic acid as a preservative for food – an innovation that landed him three patents.

Stone’s interest in vitamin C lasted throughout his life. He began to study scurvy intensely and by the late 1950s he had formulated a hypothesis that scurvy was not merely a dietary issue, but a flaw in human genetics. (He called it “a universal, potentially-fatal human birth defect for the liver enzyme GLO.”) Stone considered the amount of vitamin C that nutritionists recommended in a healthy diet – the Recommended Daily Allowance (RDA) – to be far from sufficient. In 1968 that recommendation was 55 mg for women and 60 mg for men. The current standard is slightly increased at 75 mg for women and 90 mg for men, with higher recommendations for pregnant and lactating women. But none of these figures are anywhere near Stone’s recommendations.

Stone believed that humans suffer from “hypoascorbemia,” a severe deficiency of vitamin C, caused by our inability to synthesize the substance the way that virtually all other mammals do. Most other mammals synthesize vitamin C in large quantities relative to body weight; proportionately, humans theoretically should be taking between 10-20 grams daily. Stone suggested that about 25 million years ago the primate ancestors of human beings lived in an environment in which they were able to consume relatively massive amounts of ascorbic acid, compared with what we get from our diets today. These material circumstances created an environment in which a genetic mutation occurred that allowed these human ancestors to stop synthesizing the substance. In present day, Stone noted, these amounts of ascorbic acid are not readily available in our diets, so humans may only be getting 1-2% of what they need.

This hypothesis initially led Stone to propose a vitamin C intake of 3 grams for optimal health, 50 times the RDA, and as he further researched ascorbic acid, he recommended increasingly higher doses. He was convinced that taking less than the amount that he recommended would cause “chronic subclinical scurvy,” a state of lowered immunity that increased susceptibility to a variety of illnesses. He felt that large doses of ascorbic acid should be used to prevent and treat infectious and cardiovascular diseases, collagen breakdown, cancer, SIDS, birth defects, AIDS, and health problems normally associated with aging.

Practicing what he preached, Stone and his wife began taking megadoses of vitamin C and they found that it greatly improved their overall health. When the couple both incurred injuries from a serious car accident, they treated themselves in part with large doses of vitamin C and reported a swift recovery. Stone attributed their rapid healing to the large doses of vitamin C.

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

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

In March 1966, Linus Pauling gave a speech on the occasion of his receiving the Carl Neuberg Medal for his work in integrating new medical and biological knowledge. In the speech, Pauling – who was 65 years old at the time – mentioned that he hoped to live for another fifteen years so that he might see several advances of science in medicine that he anticipated to be emerging during that time period.

Irwin Stone was in the audience at this lecture and, on April 4, 1966, he wrote Pauling a fateful letter in which he noted

You expressed the desire, during the talk, that you would like to survive for the next 15 or so years….I am taking the liberty of sending you my High Level Ascorbic Acid Regimen, because I would like to see you remain in good health for the next 50 years.

Pauling was initially skeptical of Stone’s advice, but he had recently learned about other uses of megavitamin therapy and their successes, so he decided to give the regimen a try. It was at that point that Linus and Ava Helen Pauling began taking 3 grams of vitamin C a day.

In July Pauling wrote back to Stone: “I have enjoyed reading your paper and manuscript about hypoascorbemia. I have decided to try your high level ascorbic acid regimen, and to see if it helps me to keep from catching colds.”

Pauling, as it turned out, was impressed by the results. For most of his adult life, he had suffered from severe colds several times a year and had taken a daily dose of penicillin off and on from 1948 to the early 1960s. Pauling thought that the penicillin doses were his primary defense against colds but, in all likelihood, he was probably just killing off his good bacteria and making himself more susceptible to colds through his overuse of antibiotics. Once the Paulings started taking vitamin C, they reporting a noticeable uptick in their physical and emotional energy, and seemed to suffer from fewer colds.

Two years after their initial communications, Stone noticed that Pauling had cited him in a recently published journal article. Stone described his difficulties in getting his research published and the backlash that he was experiencing from physicians. He also asked about Pauling’s health.

The last time I wrote you in 1966, you mentioned that you were going to try my high level ascorbic acid regimen to see if it would help prevent your catching colds. How did it work? At the time you also had a broken leg. I know from personal experience [a reference to his car accident] that it is excellent in bone healing.

Pauling replied

I can report that both my wife and I have been less troubled by colds during the last two years, during which we have been taking 3 to 5 grams of ascorbic a day, than we had been before beginning your regimen.

He also asked about Stone’s research on ascorbic acid and leukemia.

During the late 1960s, Pauling did not make a point of promoting vitamin C megadoses, though he did support the use of megavitamin therapy for the treatment of schizophrenia. But by 1969, he was finally fully convinced of Irwin Stone’s arguments as well as his own personal successes with vitamin C, and he began to promote vitamin C publicly.

Alejandro Zaffaroni, 1923-2014

Alejandro Zaffaroni. (Life Sciences Foundation image)

Alejandro Zaffaroni. (Life Sciences Foundation image)

In a 1997 interview with Jill Wolfson and Tejinder Singh, Alejandro Zaffaroni shared what it was like for him growing up in Montevideo, Uruguay, where he was born on February 27, 1923. He described himself as “kind of a sick child” with asthma severe enough to keep him isolated from his peers. As a boy he spent his time alone outdoors playing, exploring, and thinking about what he found. And when not playing outside, he attended a Jesuit school where he rebelled against the strict disciplinary regime. Zaffaroni described this as an opportunity to “think a lot about all kinds of strategies,” a skill that came in handy in his adult life.

As Zaffaroni transitioned into a public school at the age of twelve, his mother passed away. His father, a banker, began to spend more time with the boy, exposing him to the cultural life of Montevideo through the symphony, opera, and other outings. Encouraged by his father to develop his own interests, Zaffaroni found chemistry and, with the help of a friend who had a much better grasp of the content than the rest of the class, found a subject he could excel in. Unfortunately, just five years after his mother had done so, Zaffaroni’s father also passed away. Yet his example continued to inspire his son.

As a pre-med student at the University of Montevideo, Zaffaroni encountered biochemistry, a subject he pursued further as the first Uruguayan to enroll in a biochemistry Ph.D. program in the United States. In July 1945 he headed to Rochester University which Zaffaroni chose over other options, including Harvard, because of the promise of freedom to follow his own research path in endocrinology, with a focus on steroids. After finishing his doctorate in 1949, he continued his work with steroids with the support of a grant from the National Institutes of Health and published his first article, “Adrenal Cortical Hormones,” in Science with Robert B. Burton and E. Henry Keutmann.

Finished with his education and ready for the next step, Zaffaroni had his pick of offers from several universities and private labs. Harvard again appeared to be a possibility, one that briefly brought him to the attention of Linus Pauling. In 1953, George. B. Kistiakowsky of Harvard wrote to Pauling for advice on a list of candidates for a new biochemistry professorship that included “Alessandro Zaffaroni.” Pauling underlined two names, Frank H. Westheimer, which he annotated with “best,” and Zaffaroni, which he annotated with “never heard of him.” Zaffaroni chose another path as Westheimer ultimately got the position, delaying further contact between Zaffaroni and Pauling for another fifteen years.

Continuing to follow his father’s earlier directive that he seek out what interested him most, Zaffaroni also turned down a position at the newly established Sloan-Kettering Institute which, according to a 2012 article in Life Sciences Foundation Magazine, had “one of the world’s top steroid labs.” Expanding on an established relationship with George Rosenkranz at Syntex, Zaffaroni chose instead to head to Mexico City to work for the smaller company, where he felt he would have fewer restrictions on his own research. At this time, in 1953, Zaffaroni also received his first patent, which concerned the extraction of adrenal hormones from bovine and porcine adrenal glands.

At Syntex, Zaffaroni worked on synthesizing steroids using a phytoestrogen extracted from yams. When he noticed that the quality of the yams interfered with the process, he went to the supplying yam farm himself and reorganized harvesting and transportation while also increasing its worker’s wages. Zaffaroni’s efforts were noticed by Charles Allen, who bought Syntex in 1956 and gave the young researcher a promotion. Zaffaroni and Rosenkranz quickly built the company into a major supplier of topical corticosteroids.

In 1962 Zaffaroni was named president of Syntex’s subsidiary in Palo Alto, California, and given the specific charge to gain access to the US pharmaceutical market. The company entered the nascent birth control pill market in 1964 and started creating offshoot companies to take advantage of Syntex’s various lines of research. This led to the creation, in 1966, of the Syva Corporation, which produced diagnostic equipment, as well as the pest control company, Zoecon, incorporated in 1968.

In addition to his executive duties, Zaffaroni also began thinking about new methods of drug delivery, but the culture at Syntex was not supportive of this work. So, funded by $3 million of his own money, Zaffaroni started ALZA in 1968 to focus on this new path of research. ALZA’s main products included an ocular insert designed to administer glaucoma medication, an intrauterine device for birth control medication, and transdermal patches, each of which incorporated timed release mechanisms. Though ALZA’s products were innovative, the pharmaceutical market was hard to move as eye drops, pills, and injections maintained their dominance.

The creation of ALZA, Inc., based in Palo Alto, coincided with Linus Pauling’s move to Stanford University in 1969. In March of that year, Zaffaroni introduced himself to Pauling, writing that he was “extremely pleased” that Pauling would soon be nearby and noting his eagerness to talk with Pauling in person about the burgeoning field of orthomolecular psychiatry. By enclosing some company literature, Zaffaroni also got Pauling interested in ALZA. The two met in April as Linus and Ava Helen were in the midst of their house hunting. The meeting was especially fruitful for Pauling as Zaffaroni provided him with a $100,000 grant to be divided over his next four years at Stanford.

For the next few years the two maintained an informal relationship by visiting each other, sharing ideas, and extending invitations to social gatherings. In 1974 Pauling brought a formal element to their relationship by asking Zaffaroni to become a member of the Board of Associates of the Linus Pauling Institute of Science and Medicine, at that point still in its infancy. Zaffaroni told Pauling in November, “I have been approached by many groups to participate in directorships of various worthwhile organizations, and have been forced to decline. But because of my great admiration for you and for your accomplishments, I am prepared to accept.” He warned Pauling that his busy schedule might interfere at times and in reply Pauling promised that he would not make too many demands. Zaffaroni’s fundraising experience quickly became central to his activities as an associate and he began a correspondence with Art Robinson – at that time LPISM’s Assistant Director – concerning the development of a prospectus for potential donors.

In the summer of 1975, Pauling asked Zaffaroni to extend his relationship with the Institute by joining its Board of Trustees. Again, Pauling promised that Zaffaroni’s duties would be minimal. Zaffaroni made one stipulation in his acceptance: that the Institute revisit the operation of its fledgling medical clinic. Zaffaroni told Robinson that the psychiatric research going on at the clinic needed a better review system. Robinson responded by suspending all outpatient services at the clinic. By November, with the changes in place, Zaffaroni agreed to join the Board.

In his new capacity, Zaffaroni continued his involvement in helping Robinson with fundraising. Their first outreach effort involved “two popular appeals,” one in Prevention and the other in Executive Health. The Institute published an article in both publications and placed a request for donations at the end of each one. Robinson reported to Zaffaroni in March 1976 that the Prevention article had generated 183 donations worth $5,101.50 while the Executive Health article received 103 donations worth $8,031.50.

(Life Sciences Foundation image)

(Life Sciences Foundation image)

Besides running ALZA and serving on the Board at LPISM, Zaffaroni continued his own scientific work. This included “Special requirements for hormone releasing intrauterine devices,” published in Acta Endocrinologica in 1974, and “Contraception by intrauterine release of steroids,” which appeared in the Journal of Steroid Biochemistry in 1975. He also received patents for his transdermal bandages in 1974 and 1976, and patents for controlled release tablets in 1976 and 1977. The following year he published an article, “Therapeutic Systems: The Key to Rational Drug Therapy,” in Drug Metabolism Reviews, that described some of his new developments.

Pauling tried to tie in his own interests to these drug delivery systems. In March 1979, Pauling wrote to Zaffaroni about a study on the improvement of patients with anorectal cancer who were given time released capsules of ascorbic acid. Pauling saw the improvement as being due to topical effects and shared his idea for a similar “slow release” capsule for stomach cancer, which was then afflicting Ava Helen. Pauling’s capsule would “spring into the shape of a sphere, which would cause it to be retained in the stomach” as the ascorbic acid was released into the stomach and afterwards broken down and digested. Zaffaroni responded that ALZA was already at work on something similar to what Pauling described and that he was eager to talk more about it. By 1986 ALZA had released a “once-a-day” Vitamin C supplement utilizing its controlled-release technology.

Amidst the biotech boom of the early 1980s, Zaffaroni’s business practices came under closer examination. In 1982 Time highlighted Zaffaroni’s recent start-up, DNAX, as one of the genetic engineering companies “having trouble living up to their early billing” as one of the “hottest companies on Wall Street.” The article pointed out that to start the company Zaffaroni had “easily raised $5.5 million,” but was now “spending nearly $4 million annually on research, and…does not expect to see any profits for at least another six or seven years.” Other sources in the popular press were often more critical, focusing on Zaffaroni’s commercial, rather than scientific, performance.

In August 1985, Zaffaroni decided to resign from LPISM’s board. He felt that his work was done, telling Pauling that the Institute “has now attained worldwide recognition” and that, with Pauling’s “guidance it will continue to evolve in many positive directions.” He continued

My pattern, as you know, has been to participate in the founding of various enterprises and, once they are established, to go on to new ones. That is because I believe that what is done initially counts more than anything else. Thus, my focus has generally been on contributing innovative concepts at the outset rather than remaining permanently associated with any particular endeavor. That pattern enables me to do what I do best and to keep from becoming stale. It also leaves room for others to follow with fresh insights and new concepts. Thus, I believe it serves everyone well.

I am sure that you know, without my saying it, that the main inducement to my acting as Trustee has been the opportunity it gave me to work with you. That association has brought me great personal pleasure, intellectual challenges, and a keen appreciation of your many gifts of heart and head. You may be sure that I stand ready to help you at any time in any way I can, should the need arise.

Zaffaroni did, however, remain on the Institute’s Board of Associates until 1996 and maintained his connections to LPI into the 2000s when he met with longtime administrative officer Stephen Lawson in Palo Alto to discuss the Institute’s collaborative research on ALS and peroxynitrite in Uruguay.

Congratulatory note from Pauling to Zaffaroni on the occasion of Zaffaroni being honored by the Weizmann Institute of Science, November 1989.

Congratulatory note from Pauling to Zaffaroni on the occasion of Zaffaroni being honored by the Weizmann Institute of Science, November 1989.

After leaving LPISM, Zaffaroni also stepped down as ALZA’s CEO to seek out new endeavors. In 1988 he asked Pauling to become the Honorary Scientific Advisor for the newly forming Affymax Research Institute. As part of the deal, LPISM received 25,000 shares of stock in the company. By June 1990, Zaffaroni told Pauling that Affymax was “moving from an early stage ‘start-up’ to a successful development stage pharmaceutical company.”

The press continued to be somewhat cautious. The following year, the New York Times still referred to Affymax as a promising start-up, but was concerned with Zaffaroni’s avoidance of investment bankers by relying on his many contacts to raise his own funds. The Times followed up with questions as to how Affymax “burned through over $20 million so fast” and by noting that its central product -VLSIPS, short for Very Large Scale Immobilized Polymer Synthesis, which were biological compounds produced on silica chips developed by the semiconductor industry – was not selling well. Zaffaroni was not concerned with Affymax’s profitability at all, informing Pauling in May 1991 that he had raised $26 million and was ready for the company to “aggressively pursue our scientific and commercial goals” as well as move into their new research facility. By the end of the year, Affymax began offering public stock.

At the end of the 1990s, Zaffaroni began attracting more praise in the press, particularly for his founding, in 1995, of Smyx, a company focusing on the applications of combinatorial chemistry in the development of drugs. But he was also running up against new criticism echoing that issued in the early 1980s about the viability of DNAX. This time those fears were directed at Affymetrix, which had been spun off from Affymax in 1992 to focus on VLSIPS. An article in Forbes reported that the chips, though potentially “a godsend to medicine,”  may not be a “godsend…to Affymetrix’s bottom line.”

Zaffaroni soon had more direct problems to deal with. In 1995 he organized the sale of Affymax to Glaxo for $533 million. Some of Zaffaroni’s friends and family members began trading shares of Affymax just before the sale was announced publicly, which drew the attention of the Securities and Exchange Commission. Charged by the SEC with insider trading, Zaffaroni and six others agreed to pay fines of $1.85 million and immediately tried to move on. According to the New York Times, Zaffaroni’s lawyer stated that his client wanted “to devote his time to science and charity rather than litigation.” And that’s just what he did as he continued to produce more patents related to drug delivery and VLSIPS.

The 2000s saw Zaffaroni open up another line of research, this time for a drug delivery system that used the cigarette as a model. In 2000 Zaffaroni started Alexza to focus on this research and, before too long, he, along with Joshua D. Rabinowitz and Dennis W. Solas, produced patents for delivering insomnia, anti-inflammatory, antipsychotic, pain relieving, and several other drugs through inhalation. Unlike other inhalation drugs, these relied on the slight heating of the drugs before delivery. Zaffaroni and others described their research in “Fast Onset Medications through Thermally Generated Aerosols” for the Journal of Pharmacology and Experimental Therapeutics in 2004. In 2012 Alexza’s first product, aimed at schizophrenia and bipolar disorder, was ready for market. That same year, at the age of 89, Zaffaroni was inducted into the National Inventors Hall of Fame.

Zaffaroni passed away this past March 1st from complications related to dementia. When asked in 1997 how he wanted to be remembered, Zaffaroni said

Well, the one thing that was always very important in my life is human relations. So in looking at candidates for any of the jobs that I had, I wanted to have people who shared my value system, in addition to being the kinds of capable individuals that I needed to have.

Perhaps drawing on his father’s support and encouragement of him as a youth, Zaffaroni continued,

It is tremendously important in building this company that I create a very, very warm caring environment, so that people have an opportunity to do the best of their work. One of the key things to success is never to worry about failing. Many people do not do a lot of the things that could be done because they do not want to have a negative result. If you don’t go for the new breakthrough, if you are going just to stay in the areas which we all know, we are stationary.

Now on the other hand, if you make a huge effort with a new idea and you don’t succeed, the big companies don’t see that as a good thing. So why take risk, if there is no opportunity to be rewarded by the effort?

In my view, the only thing attractive in life is continually to move forward, to be looking for new opportunities, and to support people and let them fail safely.

Rebecca Mertens, Resident Scholar

Rebecca Mertens

Rebecca Mertens

Rebecca Mertens of Bielefeld University, located in northwest Germany, is the latest visitor to complete a term as Resident Scholar in the Oregon State University Libraries Special Collections and Archives Research Center.  A Ph.D. candidate in the philosophy and history of science, Mertens spent a month stateside, visiting both the OSU Libraries as well as the Caltech Archives.

During her stay she braved both a major (and unusual) snow event in Corvallis as well as torrential rains in southern California.  Despite these obstacles, Mertens enjoyed a fruitful visit to the west coast as she pursued her research on Linus Pauling’s contributions to the lock-and-key model of biological specificity and the influence that this model imparted upon the sweep of modern biochemistry.

The conditions that awaited Mertens upon her arrival at OSU.

The conditions that awaited Mertens upon her arrival at OSU.

An outgrowth of his research on antibodies and antigens, Linus Pauling’s work on biological specificity comprised a major contribution to contemporary thinking on biochemical topics.  Pauling biographer Thomas Hager gives us this primer on what is meant by by the term, “biological specificity.”

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.

In her Resident Scholar presentation, Mertens described the thrust of her research, which focuses on how one should interpret the contributions that Pauling made in this particular arena.

In the course of his research on antibodies, Linus Pauling postulated that the complementary structure of two molecules or two parts of a molecule determined the specificity of reactions in the living organism. However, the idea that molecular complementarity and biological specificity are deeply connected was already mentioned by Emil Fischer at the end of the 19th century. Thus, Pauling’s novel contribution was not the initial articulation of the model, but rather his emphasis on the importance of molecular complementarity for all biological phenomena.

Through examination of the Ava Helen and Linus Pauling Papers, as well as the institutional records held at Caltech, Mertens is pursuing the idea that “Pauling’s interdisciplinary reputation, his public presence and his engagement in the organization of scientific institutions led to the popularity of the lock-and-key model and to its standardization in the second half of the twentieth century.”  These forces of Pauling’s status and personality in turn made an impact on questions of “financial support, networking and science popularization within the administration of scientific projects.”


Beyond uncovering and detailing the history of Pauling’s role in the development of the lock-and-key model, Mertens is also using her research to “suggest an approach to the study of analogical models that considers social and political factors on successful model usage…[and] the formation and consolidation of model-based research programs.” Mertens returned to Germany with a large volume of content to sift through and absorb as she continues to develop her thinking on these issues.

Now entering its seventh year, the Resident Scholar Program at OSU Libraries provides research stipends of up to $2,500 to support work conducted in the Special Collections and Archives Research Center.  Applications for the 2014 class of scholars are being accepted now – the deadline for entry is April 30, 2014.  For more details, please see the program homepage.

An Interview with Zia Mian

Dr. Zia Mian, who will be traveling to Oregon in April to accept the 2014 Linus Pauling Legacy Award, was kind enough to give us a bit of his time not long ago for an interview.  In it he discussed a whole range of topics including the development of his socio-political consciousness, his admiration for Pauling and his thoughts on healing old wounds in South Asia.  The transcript of our conversation is presented below.

For a more technical perspective on Mian’s thinking with particular respect to the Comprehensive Test Ban Treaty, see the embedded video above.  An excellent profile of Mian, published by his home institution, Princeton University, is likewise available here.

Pauling Blog: You studied physics in graduate school. Were you already interested in socio-political issues? Or did you experience an awakening of sorts, as happened to Pauling with Hiroshima and Nagasaki?

Zia Mian: I’m of a generation of people that were growing up during the period of the late 1970s and the early 1980s, what has come to be called the Second Cold War, where President Reagan and the United States, and I believe it was Western Europe, moved new nuclear missiles into Western Europe as a response to new Soviet missiles that had been developed. And so there was a great risk of nuclear war again and peace movements across Europe and in the United States became very active. We had some of the largest demonstrations by these groups that had ever been seen in New York and London and other cities. And the presence of such a large and determined and active social movement raises questions for all kinds of people, such as “what do I think about this issue? What does this mean? How does this impact society and what is my role in what’s going on?”

And so as a young physics student it became obvious that nuclear weapons were something that I had to think about and to try and understand what I thought about them and what they might mean. And so as a consequence I think that it wasn’t so much like a calling of having a Hiroshima or Nagasaki type moment, but the existence of a large and determined peace movement raising the issue to people across the world, that this is an issue you have to take seriously and come to a position on. That led me to think about what nuclear weapons meant and how I felt about them.

PB: With Pauling and several other scientists at the beginning of the nuclear age, they could understand the science behind nuclear weapons as well, and that seemed to lend itself toward their activism, in the sense that they could understand how they worked and the amounts of energy they could release. Did that play in for you as well?

ZM: At the beginning of the nuclear age certainly many scientists, including ones who had worked on the Manhattan Project, realized that the public and policy makers needed to understand the new dangers that nuclear weapons and nuclear materials posed to the world. And having a technical background made it easier to understand some of the things that nuclear weapons mean, without having to know secrets. Because the science was sufficiently clear that you could make this understanding of what was going on. What you have to remember is that lots of other people came to a similar understanding about nuclear dangers without being scientists. One thinks of Mahatma Gandhi writing about the danger of nuclear weapons soon after Hiroshima and Nagasaki, or the French writer and philosopher Albert Camus or the English writer George Orwell or the American writer Lewis Mumford. All of them, within months or the first year or so after Hiroshima, tried to explain to people that these nuclear weapons posed a profound and unimaginable new danger, without being scientists themselves.

But the scientists—being experts gives you a somewhat privileged position to debate, because people have a tendency to look to scientists as being people who can understand and explain some of the more detailed factual and technical basis of what nuclear weapons and their production and use mean, rather than just talking about the politics of what nuclear weapons mean or the ethics and morality of what nuclear weapons mean. But I can’t emphasize strongly enough that many of the early scientists like Pauling and others, as well as writers like Mumford and Bertrand Russell and Albert Camus and George Orwell who wrote about nuclear weapons, combined both a technical understanding and a political understanding and a moral and ethical sensibility about what these weapons would mean. And it was only by taking them all together that one can see what kind of intervention they made in helping people understand the nuclear danger.

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