Getting to Know Richard van Breemen

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Richard van Breemen

[The end of 2018 will mark the conclusion of Richard van Breemen’s first year as director of the Linus Pauling Institute at Oregon State University. Recently, the Pauling Blog sat down with Dr. Van Breemen to learn more about his scientific background, his career in research, and his vision for LPI.

Today’s post, which is part 1 of 3, focuses on his early years and his connections with Linus Pauling. The transcript that follows has been lightly edited for clarity and continuity.]

Early Years

Pauling Blog: Tell us about your earliest interests in science.

Richard van Breemen: I come from a family with a fairly substantial scientific background. My grandfather on my mother’s side came from a homesteader family in Iowa. He was the first in his family to go to college, and he went to the University of Iowa in Iowa City, stayed on there, got an early PhD in Physiology, became a faculty member, and eventually the department head of Physiology at the University of Iowa. My mother and father met each other at Iowa in graduate school; my father became a university professor as well. I moved around the country a little bit with him; he was at the University of Colorado and eventually became head of the Biology department at a state teacher’s college in Maryland called Salisbury University. So I’m a third-generation university professor.

So growing up, there was always science around the house. My mother got me and my brothers involved actively in the 4-H program in rural Maryland where we were, on the eastern shore. I had a county award-winning insect collection; I was learning about etymology at an early age. We had shell collections from coasts around the country. So there were lots of science projects going on around me; my parents made it a very rich environment in that sense. I’m very thankful to them.

PB: Can you tell us how this progressed? The progression of your scientific interests through your high school and undergraduate years?

RVB: In high school, I also developed an interest in music. I’ve found that quite a few scientists have also been interested in music over the years, so maybe there’s some part of the brain that is both music and science together. So I applied to colleges to be either an oboist, as an obo major, or as a physicist, a physics major. I chose Oberlin College because it offered both music conservatory and a strong science academic program.

I didn’t intend to major in chemistry, but I thought it was a good idea to take some first-year, maybe even second-year organic chemistry courses. Multiple times during my first semester of chemistry as an undergrad, Norman Craig, my teacher, said, “I’ll say this only once, because I hear some of you are still learning this in high school chemistry: this is 19th century and it’s wrong.” And every time he said that, that was exactly what I learned in high school chemistry. So I was intrigued by that.

By the end of my first semester, I was a chemistry major. So thereafter I talked with my advisor in school about a path to follow; what I was interested in doing. I wanted to merge chemistry with biology. Today we call that chemical biology, and there’s departments of this, like at Harvard and other schools around the country; departments of Chemical Biology. But that’s what I wanted to do back in the 1970s, and so I was steered towards a track – “maybe look into pharmacology or toxicology.”

PB: And then what happened?

RVB: Well, I went to the University of Iowa, where I had some family ties, and spent the summer as a junior working in a pharmacology laboratory. I was introduced to an analytical tool called a mass spectrometer and I was pretty much hooked on it from then on. Today, one of my hats is biomedical mass spectrometrist. So that was the beginning of that program.

So when it came time to apply to graduate school, I applied to schools of Toxicology and Pharmacology, and chose to go to Johns Hopkins University, in the Pharmacology program. At that time, and to this day, Pharmacology at Johns Hopkins has a very strong chemistry focus. I chose an advisor, Catherine Fenselau, who had been a student of Carl Djerassi at Stanford. Djerassi is a famous chemist, connected with the invention and early development of oral contraceptive pills. So what Catherine Fenselau did in Djerassi’s lab was to introduce him to the analytical tool of mass spectrometry, which he vigorously pursued for many years thereafter. Catherine moved from Stanford eventually to Johns Hopkins University, in Pharmacology, in 1967, and brought into that medical school, for the first time, mass spectrometry. I became her first graduate student at Johns Hopkins. So in a sense, I trace my lineage to Carl Djerassi; like my grandfather in graduate education.

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Carl Djerassi

So in that context, I learned about drug metabolism, analytical chemistry, in terms of how it can help solve chemical structures for new chemical entities, but also to follow how molecules change in the body. Mass spectrometry is also quantitative, and it shows you how much of a compound might be in blood or tissue. To this day, I use that as a tool for all of my research.

PB: The tool has changed a fair amount, I have a feeling.

RVB: In the 1980s, as a graduate student, mass spectrometry was a very exciting time. I tell the story to my students about how there have been three eras of mass spectrometry. The first one was the era of the physicists, using and inventing mass spectrometry to prove the existence of isotopes of the elements. Second era was the organic era, and that was championed by people like Carl Djerassi, Klaus Biemenn, and others who showed how mass spectrometers could be used to determine structures of organic molecules. At the end of each of these eras, professors were telling their students: “Don’t go into mass spectrometry, the field is done.” Physicists told their students back in the 1940s, “We’ve identified all the elements, all the isotopes. Don’t get involved in this field.” And then, by the end of the 1970s, organic chemists were telling their students, “Don’t get involved in mass spectrometry, because we know everything there is to know about the interpretation of mass spectrum that has application to organic molecules.”

Then, as a graduate student, new techniques were introduced to ionize macromolecules, to make proteins of sixty-thousand, a hundred-thousand molecular weight gas phase ions that could be manipulated in the vacuum of a mass spectrometer and measured, and the structures determined. So we’re still in that era of biomedical mass spectrometry, which has been the subject of Nobel Prizes for people like Koichi Tanaka and John Fenn, who shared the Nobel Prize for applying mass spectrometry to protein structure determinations and weighing them.

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John Fenn visiting the Oregon State University Libraries Special Collections storage stacks, 2012.

PB: What was your sense of Linus Pauling when you were a student?

RVB: Well, I was aware of Linus Pauling for that fabulous chemistry textbook that he had written for undergrads, but also for his work with the structure of proteins and the alpha helix and crystallography; with x-ray crystallography of protein structures. So the chemical bond, in his work, was structures of macromolecules.

And of course I grew up in an era where, in public school, we were told to hide under our desks or go into the hall in case there was a nuclear strike, and so Pauling’s work to stop the proliferation of nuclear weapons and halt the atmospheric testing of nuclear weapons was something I was very aware of in the early 1960s. And one could think of that as sort of the next stage of his career, when he became an activist in world peace.

Of course now, in the Linus Pauling Institute, I’m realizing that the last stage of his scientific career, where he was involved with how natural products – vitamins, minerals, micronutrients – can help maintain health and prevent disease; that’s something he was very active with from the 1970s until he passed away in the 1990s.

Meeting Linus Pauling

PB: You met Pauling, did you not? When you were at NC State?

RVB: Yes, I did. This was during my very first year, and in my first academic job as an independent assistant professor. The department of Physics at North Carolina State continues to have an endowed lecture program, and they invited Pauling to give a lecture in the fall of 1986, and I was lucky enough to not only attend this lecture but to go to a reception in his honor, to get a chance to talk to Pauling for five or six minutes on my own. I was mainly asking him about – he was passionate about teaching, educating new generations of young people, undergraduate teaching, as well as graduate education. I was teaching organic chemistry for the very first time, and some of my colleagues were skipping the chapter of organic chemistry books that deals with spectroscopic characterization and the identification of organic molecules – that includes mass spectrometry, as well as nuclear magnetic resonances, infrared spectroscopy, ultraviolets spectroscopy, and so on. It was optional.

So I wanted to teach it. Not all of my colleagues were, because they wanted to spend more time on the other chapters. We all had to start with the same textbook and the same chapter and finish by the end of the semester on the same chapter, but in between we were free to teach however we felt best. So I included that chapter on spectroscopy and the determination of organic chemical structures. Pauling said that was just fine and in his chemistry textbooks, he told me he had a chapter describing mass spectrometry too, so he thought that I should follow my heart on that one. I didn’t think to ask him about his Linus Pauling Institute. Of course I couldn’t have known where I would be all these years later, but if I had, I would’ve asked him more about that aspect of his career, and what he was doing in his Institute at that time. His lecture was actually about the structures of certain kinds of crystals-a physics lecture, in this particular case [on quasicrystals].

A Pauling Research Connection

RVB: With Norman Farnsworth, who has now passed away, but was a very esteemed, world-famous pharmacognosist, we founded the first NIH-funded botanical center for dietary supplements research in 1999. That grew out of the Dietary Supplement Health Education Act, known as DSHEA, of 1994. And here’s a Pauling connection.

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Norman Farnsworth

In the 1970s, when Linus Pauling got to being very active in research with vitamin C and cancer prevention, there was a move by the Food and Drug Administration, and by Congress, to regulate vitamin C and other vitamins as potential drugs or therapeutic agents. Pauling argued, testified before Congress, worked very diligently, to help keep vitamins and mineral supplements over-the-counter. He felt that that these compounds were so safe that it wasn’t necessary to make them prescription-only. First, he advocated for larger doses of Vitamin C than was necessary to prevent scurvy, but that’s the whole area of research that became the Linus Pauling Institute.

So he was successful, Congress only passed laws that helped regulate the amounts of certain nutrients and for the most part vitamins and mineral supplements remain over-the-counter…of course, there are prescription medicines for pregnant women who need extra vitamins during the prenatal period.

Skip ahead twenty years to the 1993-94 period of time, and Congress revisited whether dietary supplements should be regulated in a new and different way. This was towards the end of Linus Pauling’s career – or, his whole life – but he still weighed in on this. And I was just checking some of the facts and figures in this archive here at the Oregon State University Library, and Pauling did have written into the Congressional Record some of his opinions regarding the possible regulation or why dietary supplements should not be overly regulated, and I think he had another major effect because people listened to him in Congress.

And I think what came out of that period of Congressional hearings was the Dietary Supplement Health Education Act of 1994, which created a niche market for dietary supplements: they are neither drugs and regulated by prescription, nor are they foods, which has a whole different set of regulations. But it did authorize the Food and Drug Administration and the Federal Trade Commission to regulate what’s on the label, and to act if anything was being marketed that was harmful. The FDA has since issued a regulation that requires dietary supplements to be produced using good manufacturing practice. That wasn’t initially part of their regulations, but that has been added since.

So part of the DSHEA Act was to establish the Office of Dietary Supplements within the NIH – ODS – and gave them money by statute to investigate the safety and efficacy of botanical dietary supplements with the mission of protecting the health of the consumer. And by 1999, the very first grant out of that Office of Dietary Supplements was issued, and there were two grants funded that year, one to University of Illinois at Chicago, where I was, working with Norman Farnsworth, and the other to UCLA. That program has continued to this day, and when I left the University of Illinois at Chicago, I was the director of that botanical center. I wasn’t able to move it to Oregon State University, but the grant continues, and I continue to work with them, running a project in an analytical core to support the work that we began in 1999, looking at the safety and efficacy of botanical dietary supplements used by women.

So there’s a little overlap with Linus Pauling and the work I was doing in Chicago before coming here.

Pauling’s Enduring Legacy

PB: What is your sense of Linus Pauling’s legacy today?

RVB: Well, Pauling’s legacy, it continues in many, many ways. He, of course, received his first Nobel Prize for his work on the chemical bond, using a synthesis of theory and laboratory experiment to prove what the nature of the sigma bond is between atoms, like two carbons. All of chemistry today owes him a lot in that sense; he was extremely brilliant in many respects, he thought ahead. When I talked with him at that brief meeting during his lecture in North Carolina, he told me he was writing his next paper in the back of his mind as we were speaking. But he typically would write a paper, have all the aspects of it worked out in his mind, before sitting down with a typewriter.

He obviously had a lot of things going on at any one time. He was ahead of his time in his efforts to contain nuclear weapons – I think most of the world caught up later to realize how important that work was, in leading to the test ban treaty.

I think the work that began the Linus Pauling Institute was also well ahead of its time. He certainly received a lot of criticism. I think folks in biomedical research might’ve circled their wagons and said, “well, you’re a chemist, what do you know about cancer and cancer prevention?” But in many respects, he was ahead of his time there, and we now know, not only can vitamins prevent the diseases of malnutrition, but they do have benefits beyond simply keeping all of the biochemical pathways working. So to say that vitamin C has no benefits at all as supplements, of course, wouldn’t be true, because it prevents the disease of scurvy, and then there’s rickets and other vitamin deficiency diseases. So we definitely know that vitamins are essential for human health. The question is, what’s the optimum for human health? And that’s something that the Linus Pauling Institute began exploring and, to this day, we are continuing to work on that.

Pauling, Stanford and Research – Part 2

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Pauling in lecture at Stanford University, 1969. Photo by George Feigen.

[An examination of Linus Pauling’s tenure at Stanford University. This is part 5 of 7.]

Linus Pauling knew going into his appointment at Stanford University that grants and outside funding would of paramount importance to keeping his research afloat. In September 1972 – three years into his tenure – Pauling authored a memo describing his work for the chemistry department in which he explained that his Stanford salary was now coming exclusively from grants, and that he had no other assigned duties at the university besides heading research. He likewise noted that he was actively working to bringing in new sources of money as well. In particular, he had “negotiated” a sickle-cell anemia contract with NIH earlier in June, estimating that $92,000 would be necessary from the agency.

The previous year, in spring 1971, Pauling applied for a grant from the Department of Health, Education, and Welfare to build a field ionization spectrometer for use in his urine analysis diagnoses. This device had only recently become available, the result of new technological advances in instrument design. In his application, Pauling detailed the potentially profound impact that this piece of equipment would have on his work.

This device would make possible simultaneous quantitative analysis and identification of 500-1000 chemical substances in a human body fluid in a time period of a few minutes and with an expenditure of only a few dollars per sample.

Pauling requested $387,554 for the project. It appears from a later report on his activities that he received the grant.

While Pauling enjoyed a long track record of success in attracting funding for his work, it was not always enough. In August 1972, Perry West, an administrative officer at Stanford, wrote to Pauling’s colleague and lab-mate, Art Robinson, to inform him that the laboratory’s current NIH and NSF funds would only last until the end of the year, two months short of what they had been meant to cover. As it turned out, Pauling’s laboratory had been using more computer time than they had been allocated, and had “drastically overdrawn” one account which they needed reconcile for themselves. The group has also overdrafted a second computing account that West had been funding for them.


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In addition to finding money, establishing institutional support for his research was also important for Pauling as he began to push for something a bit more ambitious: the formation at Stanford of a new Department of Orthomolecular Medicine and Nutrition. In a pre-proposal written in August 1972, Pauling called for a revitalization of nutrition as an active field of research at the university. In that same memo he also defined orthomolecular medicine “as the preservation of good health and the treatment of disease by varying concentrations in the human body of substances that are normally present in the body and are required for health.”

A few months later, in January 1973, Pauling brought his proposal to William F. Miller, Stanford’s Vice President and Provost. In making his pitch, Pauling emphasized the potential for orthomolecular medicine to bring in “millions of dollars” of funding. He also described the ways in which interest in orthomolecular research had already been taking off. By way of evidence, Pauling noted several talks that he had given the previous fall, details of which had made their way into the press.

As became readily apparent in the years that followed, Pauling also saw potential for vitamin C to treat a number of maladies including cancer, skin diseases, schizophrenia, the common cold and other infections. To begin actively investigating these tantalizing possibilities, he wanted to establish research centers at both Stanford and the University of Chicago. Miller replied to Pauling that he would consider his proposal and discuss it with the Dean of the Medical School.


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

During this time, Pauling was also being encouraged by others reaching out to him, particularly Ewan Cameron, a surgeon and medical researcher at the Vale Leven Hospital in Scotland. Cameron shared with Pauling data related to his own successful use of vitamin C in treating bladder cancer patients. Pauling wanted to follow up on Cameron’s success and, in 1972, the two attempted to publish a paper in the Proceedings of the National Academies of Science on ascorbic acid as a treatment for cancer and other diseases. Their paper was initially rejected and, after Pauling resubmitted it, it was rejected again, an action that was described as “professional censorship” in an editorial published within the Medical Tribune.

Undaunted, Pauling continued to push his interests in developing orthomolecular medicine at Stanford and, in May 1973, proposed that the university consider building a new laboratory dedicated to the topic. In addition to the direct benefit of providing support for orthomolecular research, Pauling argued that a new laboratory would remove this work from the chemistry building, allowing it to emphasize its closer sympathies with medical research. Pauling again approached William Miller, telling him that a donor had already promised to give $50,000 for construction, which was estimated to be about half of the total cost. Pauling also expected other grants to come in as well.

Ultimately, Miller did not think it wise to pursue construction of Pauling’s orthomolecular facility. In rendering this judgement, Miller explained that Pauling had only been at Stanford for a short period of time and that his position was subject to annual renewals. This being the case, Miller did not want to “institutionalize” Pauling’s work unless Pauling was able to convince others in the chemistry and medical departments of its importance.

In effect, Pauling was told that, if he wanted his space, he would have to win over his colleagues first and convince them to initiate their own research programs in orthomolecular medicine. If this were to come about and more faculty with plenty of years ahead of them were to push for the idea, then Miller would be more open to considering a new capital project. Short of this, Miller suggested that donor funds be steered toward a more general purpose facility that would be made available to all chemistry faculty members.

Miller’s decision was important as it directly led to Pauling’s departure from Stanford University. Motivated to develop a space to pursue what he believed to be an exciting line of research, Pauling began to look for a laboratory facility off campus. This search led him to a building in Menlo Park near the Stanford Linear Accelerator. Not long after, the building became home to the Institute of Orthomolecular Medicine which, in 1974, was renamed the Linus Pauling Institute of Science and Medicine.

Intravenous Vitamin C: The Current Science

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Jeanne Drisko with Murray Susser. Both Drisko and Susser are past presidents of the American College for Advancement in Medicine.

[Part 2 of 2]

At her public lecture, “Intravenous Vitamin C: Does it Work?” delivered at the Linus Pauling Institute’s Diet and Optimum Health Conference in September 2017, Dr. Jeanne Drisko of the University of Kansas Medical Center, Kansas City, provided an overview of current research on the potential impact of intravenous vitamin C in treating disease.

She began this portion of her talk by reflecting on the factors that have continued to propel her own scientific interest in the topic, despite the headwinds generated by critics of the work. For one, Drisko has taken heart in the fact that intravenous vitamin C is used in many clinics around the world. Indeed, at a 2006 integrative medicine conference, Drisko and colleague Mark Levine took a survey of participants and found that some 8,000 patients had received intravenous vitamin C from doctors attending the meeting. Because Drisko maintains contacts in both conventional and alternative medical circles, she knows that naturopaths have been using intravenous vitamin C as well.

Drisko then pointed out that one barrier to more widespread acceptance of vitamin C as a cancer treatment is that, conventionally, it does not make sense to administer it in tandem with chemotherapy, since vitamin C is known to be an antioxidant and chemotherapy is a prooxidant. That said, Levine and Drisko’s colleague in Kansas, Qi Chen, have found that when vitamin C is given intravenously, it actually works as a prooxidant because it produces hydrogen peroxide. As such, it actually becomes a very good compliment to chemotherapy. Moreover, studies conducted by Drisko and others have found no evidence of conflict arising as a result of vitamin C dosages given alongside chemotherapy. On the contrary, researchers have reported a synergistic relationship in many cases.

In explaining why this is so, Drisko noted that when vitamin C is injected into a vein, it takes on the form of an ascorbyl radical, which she described as a “very promiscuous and active molecule that likes to interact with transition metals” like copper and iron. These interactions lead to the formation of hydrogen peroxide, which is quickly turned into water and oxygen by the enzymes glutathione peroxidase and catalase, such that levels of hydrogen peroxide in the bloodstream are promptly rendered as unmeasurable.

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However, when vitamin C gets into the extracellular fluid it also becomes hydrogen peroxide. The difference in this case is that glutathione peroxidase and catalase do not intervene and the hydrogen peroxide is not broken down into water and oxygen. Instead, the hydrogen peroxide diffuses throughout the extracellular fluid, bathing the cells.

While the presence of hydrogen peroxide in the cells might seem unsafe, Levine’s cell culture tests have found that hydrogen peroxide caused harm only to cancer cells. In reporting his results, Levine explained that the glutathione peroxidase and catalase enzymes are not as efficient in attacking cancer cells because they direct their activity towards reproduction rather than other processes. The fact that glutathione peroxidase and catalase are not active in the extracellular fluid renders vitamin C as a pro-drug and hydrogen peroxide as an actual drug.


Drisko’s research portfolio on the use of intravenous vitamin C includes the first randomized controlled trial involving ovarian cancer patients, work that was published in 2014. The trial studied two groups of patients: one group received standard care, which included carboplatin and paclitaxel chemotherapy for six cycles. The other group received this same care along with 75 to 100 gram doses of intravenous vitamin C.

The trial made clear that this form and dosage of vitamin C therapy is safe to administer. It also yielded a statistically significant improvement in how certain types of patients felt during their cancer treatment. Drisko called this a “feel good effect” which she believes is neurological. This same impact, however, was not observed in patients suffering from more advanced stage three and stage four cancers. Drisko is currently following up on these results by looking at the role that vitamin C might play in brain chemistry.

While her work has generated positive results, Drisko is also aware that vitamin C should not be used in all cases. Importantly, vitamin C is known to be potentially harmful when given in large doses under certain conditions. One such case is in individuals suffering from a deficiency of Glucose-6-Phosphate Dehydrogenase, or G6PD. On its own, G6PD can cause anemia, but when combined with high levels of vitamin C it leads to hemolysis, or the destruction of red blood cells. As a matter of standard protocol, Drisko checks her own patients for G6PD deficiencies, but she knows of others who have been unaware of this biological conflict and who have had to send patients to the emergency room.

Drisko will likewise opt against administering intravenous vitamin C when a patient reports a history of oxalate kidney stones, which can form as a result of excessive vitamin C intake. For individuals who have gone ten years or more since their last instance of oxalate kidney stones, Drisko administers vitamin C, but she does so cautiously, monitoring kidney functions and liver enzymes throughout the process.


Another barrier to studying intravenous vitamin C is that it is a difficult substance to measure since it is processed by the body so quickly. To get around this difficulty, Drisko developed a finger stick method that emerged from her interactions with a diabetic ovarian cancer patient. Over the course of these interactions, Drisko found cause to contact a glucometer manufacturer who told her that, because vitamin C and glucose molecules are so similar, the glucometer would indicate levels of both. Making use of this similarity, Drisko started taking finger stick glucose readings both before and right after her patients received their doses, and using this process she is now able to ascertain a rough estimate of how much vitamin C has been absorbed by the body.


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Qi Chen

In attempting to achieve greater certainty about appropriate dosage levels of vitamin C to administer, Qi Chen and Mark Levine have conducted experiments wherein they give intravenous vitamin C to mice and rats with tumors. This work is a follow-up to Levine’s original studies in the 1990s, which showed that vitamin C given orally could not be absorbed above a 10 millimolar concentration. In their more recent invesigations, Levine and Chen have found that blood concentration levels of 20 to 30 millimolar can be achieved as a result of intravenous application. They also found that the tumors in their mice studies would take up the vitamin C and that hydrogen peroxide formed in the tumors and subcutaneous tissue, but not in the blood.

Drisko gives her patients two to three infusions of vitamin C per week in advanced cases. Ideally, the vitamin C would be administered as the fluid loading dose for chemotherapeutic drugs, but it is often difficult to carry out both vitamin C and chemotherapy treatments on the same day because patients are already burdened by a busy treatment schedule and the facilities providing the two types of treatments are often not in the same location. (A new dosing device that attaches to the hip, developed by Channing J. Paller at Johns Hopkins, could help to get around some of these barriers.) Drisko’s treatment schedule uses a “stair-step” methodology wherein doses ranging from 0 to 100 grams are able to achieve 20 millimolar blood concentrations.

The appropriate duration of vitamin C treatment for cancer is still an open question. What is known is that it takes at least a couple of months before effects start to show. This stands in stark contrast to chemotherapy, which makes a much quicker impact.


Drisko concluded her talk by sharing the hopeful story of a woman who had participated in her ovarian cancer trial. This patient had been part of the group that had received the standard chemotherapy treatment only. She had subsequently relapsed very quickly and was believed to have only months to live. In her conversations with Drisko, the patient expressed a strong desire to live long enough to give her grandson a present at Christmas, and she requested that Drisko give her vitamin C in addition to her chemotherapy, since she was no longer part of the trial.

Initial CT-PET images showed that the woman was suffering from an accumulation of fluid, or ascites, full of cancer cells that were pushing against her organs. At the start of her intravenous vitamin C treatment in 2004, a second CT-PET scan showed both the malignant ascites as well as a residual tumor that could not be removed surgically.

Subsequent scans after Drisko began her treatment showed gradual improvement. In 2007, the pictures included fewer ascites and the tumor was somewhat smaller, trends that continued to be seen in 2012. By 2014, calcification appeared in the tumor and around the fluid, with further calcification showing in 2015. In essence, what the scans were revealing was an eight-year process of “turning her cancer into a scar.” While this is only a single example, it is a powerful one, and may prove to be harbinger of medical breakthroughs to come.

Intravenous Vitamin C: The Historical Progression

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Jeanne Drisko

[Part 1 of 2]

Jeanne Drisko, MD, Director of Integrative Medicine at the University of Kansas Medical Center, Kansas City, was a featured speaker during the public session of the Linus Pauling Institute’s Diet and Optimum Health Conference, held September 13-16, 2017.  She delivered a public lecture titled “Intravenous vitamin C and cancer treatment: Does it work?” Dr. Maret Traber, a principal investigator at LPI, introduced Drisko, describing her as a “leading expert on intravenous vitamin C.”

Drisko began her talk by tracing the history of vitamin C research, noting the ways in which previous studies had made her own research possible. The first person Drisko spoke of was Nobel laureate Albert Szent-Gyӧrgyi (1893-1986), who isolated ascorbic acid while working at Cambridge University and the Mayo Foundation between 1927 and 1930. Drisko then pointed out that, in the 1940s, vitamin C was used widely in clinical settings to treat pertussis, or whooping cough, along with other bacterial and viral infections. Importantly, these treatments were not administered orally. At the time, pharmaceutical preparations of vitamin C were not of a quality that could be administered intravenously, so they was injected into the muscles.

The use of vaccines was also on the rise during this period and Drisko pointed out that the development of the polio vaccine was particularly connected to the clinical fate of vitamin C. Albert Sabin (1906-1993), who had developed an oral polio vaccine, also carried out trials on the effects of vitamin C injections on primates. Sabin found no benefit and suggested that focus turn toward vaccines instead. It was at this point, Drisko explained, that the use of vitamin C injections went “underground,” drifting well outside of the medical mainstream.

One individual who remained interested in the promise of vitamin C was Frederick Klenner (1907-1984), who began using intravenous ascorbic acid at his North Carolina clinic in the 1940s. Drisko described Klenner as keeping “vitamin C use alive,” by administering both muscular and intravenous injections, while the broader medical community turned elsewhere. In particular, Klenner used vitamin C to treat children suffering from polio and found that even advanced cases could be approached successfully. During this time, Klenner also trained other practitioners in the methods that he was pioneering at his clinic.


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Ewan Cameron, Ava Helen and Linus Pauling. Glasgow, Scotland, October 1976.

Next, Drisko turned to Linus Pauling. To begin, Drisko noted that since Pauling was already well known, his interest in oral vitamin C was written off by many who were familiar with his prior work. Others, however, did look to Pauling as an authority, and among them was the Scottish surgeon Ewan Cameron (1922-1991), who contacted Pauling after reading some of his papers in the early 1970s. In his initial correspondence, Cameron informed Pauling that he had been giving about ten grams of vitamin C to cancer patients and had observed that they tended to live longer. As a result of their shared interest, Pauling and Cameron decided to collaborate on a series of papers investigating the potential clinical import of large doses of vitamin C.

As they delved deeper into this work, Pauling became convinced of the need to carry out more rigorous trials. Lacking the funds to do so, he instead turned to the National Institutes of Health. Fatefully for Pauling, Charles Moertel (1927-1994), an oncologist at the Mayo Clinic who was eager to debunk the effectiveness of vitamin C, agreed to lead the NIH investigation. Specifically, Moertel carried out a double-blind placebo-controlled trial in which ten grams of vitamin C were administered orally, and he found no benefit. (He was not aware that Cameron had been injecting vitamin C intravenously.) Moertel published his results in the New England Journal of Medicine and the press picked it up. Once the negative conclusion had been widely circulated, subsequent mainstream interest in the medical application of vitamin C suffered a near fatal blow.


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Mark Levine

Research on intravenous vitamin C began to re-emerge during the 1990s, led in part by NIH scientist Mark Levine. Levine’s nutrition experiments were novel, and did not emerge from the types of medical training that he could have been expected to received. For context, Drisko described her own education, wherein courses on nutrition were optional and held on Saturday mornings. She attended them because she was interested, but she also went along with the convention of the time; one emphasizing that nutrition was of lesser importance relative to other aspects of medical practice.

Levine, on the other hand, did not follow this line and decided to study vitamin C in depth. In the trials that he carried out at the National Institutes of Health, Levine tracked patients deprived of vitamin C and showed that they had indeed become vitamin C deficient. He followed this by administering oral doses of vitamin C, which demonstrated repletion. At the end of his trial, Levine also administered one gram of vitamin C intravenously. He was not allowed to administer a higher dose to his subjects, due to fears of toxicity, but it was his guess that ten gram doses would yield peak blood levels of vitamin C.

Ultimately, Levine demonstrated that oral vitamin C was not capable of yielding maximal vitamin C blood levels, because the body does not absorb oral doses well and excretes it very quickly. Intravenous administration, on the other hand, bypassed these metabolic processes, leading to higher blood levels. With Levine’s work in mind, Drisko summarized the difference between Cameron’s research and Moertel’s Mayo Clinic trial: “Cameron gave a drug and the Mayo Clinic gave a vitamin.”


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Hugh Riordan

Drisko’s mentor, Hugh Riordan (1932-2005), was another individual responsible for keeping vitamin C research alive. The founder of what is now known as the Riordan Clinic in Wichita, Kansas, Riordan belonged to a group of orthomolecular physicians who saw vitamins as providing restoration of a healthy baseline in all humans.

After Levine published his paper on vitamin C absorption, Riordan went to visit him in Maryland to convince him to continue following this path of inquiry. The two ultimately collaborated on several case studies and welcomed others into their fold, a progression that helped incubate today’s group of researchers investigating the use of intravenous vitamin C.

As of 2016, the intravenous vitamin C group included Qi Chen, who works on basic research at the University of Kansas with Drisko; John Hoffer at McGill University, who explores the effects of high doses of vitamin C on cancer; Garry Buettner and Joseph Cullen at the University of Iowa, who looks at the redox capacity of vitamin C in patients undergoing radiation therapy; and Ramesh Natarajan at Virginia Commonwealth University, who is researching the use of vitamin C in the treatment of sepsis.

Drisko noted that there are differences in the lines of research followed within the current group. On the one hand, her cancer trials use megadoses of vitamin C at 75 to 100 grams. Natarajan, on the other hand, only uses 4 or 5 grams in the ICU for sepsis.  For Drisko, these differences emphasize that there is still a lot of research to be done to understand exactly what is going on.


At present, attitudes toward vitamin C within the medical community can be mostly lumped into two categories. One is comprised of “early adopters,” as Drisko defines herself, who continue to carry out research to refine vitamin C treatments. The other consists of those who adhere more closely to the conclusions of the Moertel study, and who thus believe that claims supporting the effectiveness of vitamin C have been disproven. The distance between these two groups was characterized by Drisko as a “gulf of disapproval.”

However, current trends suggest that the gulf is being bridged. While some state medical boards still restrict the therapeutic use of vitamin C, Drisko and others have succeeded in garnering increasing levels of support from both colleagues and institutions. Shifts in funding opportunities are also beginning to emerge: though Drisko was unable to secure federal dollars for her work on ovarian cancer, the Gateway for Cancer Research non-profit stepped in to provide crucial support. With evidence of the efficacy of the treatment building from a growing number of trials, the possibility of obtaining federal grants is becoming more realistic. Likewise, drug companies are now looking at ways to patent vitamin C therapy, and some vitamin C treatment patients have succeeded in receiving reimbursement from their insurance companies.

Next week, we will provide an overview of the science underlying this renewal in optimism about the potential to fight disease with intravenous ascorbic acid.

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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Normal Expression of Human Beta-Actin (Cloned at LPISM) Acts as a Tumor Suppressor – A Novel Hypothesis

[Guest post written by John Leavitt, Ph.D., retired Senior Scientist at LPISM in Palo Alto CA from 1981 to 1988; living in Woodstock CT.]

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In 1980, Klaus Weber at the Max-Planck Institute and I published the amino acid sequence of human beta- and gamma-cytoplasmic actins. In 1981, after we completed this work, Klaus asked me “What are you going to do next?” I told him that I was moving to the Linus Pauling Institute of Science and Medicine in Palo Alto, California, and that I was going to clone the human beta-actin gene. My reason was that I had discovered a mutation in beta-actin that was associated with a tumorigenic human fibrosarcoma cell line. I wanted to test the hypothesis that this mutation contributed to the tumorigenic potential of this fibrosarcoma.

In 1984, I published the cloning of multiple copies of both the normal (wildtype) human beta-actin gene and multiple copies of the mutant gene. These actins are the most abundant proteins of all replicating mammalian cells and most other cells, down to yeast. (My story of meeting Dr. Pauling, moving from the National Institutes of Health to the LPISM, and our work on the role of this actin mutation in tumorigenesis in our model system was recounted in an article posted at the Pauling Blog in 2014.) In 2013, Schoenenberger et al. at the Biozentrum in Basel, Switzerland, reproduced all of our findings in a different cell system, a rat fibroblast model system, and extended our findings (see our review of their work).

A year ago, in June 2015, Dugina et al published a paper that proposed that altering the ratio of these two actins regulated either suppression or promotion of cancerous cell growth (more work needs to be done). I was very surprised by this idea – even though our work at LPISM had suggested this, I hadn’t thought of putting our observations into the language of “tumor suppression” and “tumor promotion.” Perhaps this was because, in the 1980s, hundreds of so-called “oncogenes” (tumor promoters) and tumor suppressor genes were being cataloged, and our findings were suggesting that a so-called “housekeeping” gene could do the same.

Indeed, Dugina and colleagues even stated this, somewhat simplistically, at the beginning of their Discussion section if their paper:

Until recently non-muscle cytoplasmic β- and γ-actins were considered only to play structural roles in cellular architecture and motility. They (the two isoforms) were viewed as products of housekeeping genes and β-actin was commonly used as internal control in various biochemical experiments.

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It didn’t go unnoticed by me that this paper failed to cite any of our papers, which had produced fundamental knowledge about human cytoplasmic actins. For example, instead of citing our 1980 paper on the amino acid sequences of human cytoplasmic beta- and gamma-actins, the Russian authors cited a paper on the sequences of bovine actins. Furthermore, these authors were apparently unaware of our discovery of actin mutations leading to tumorigenesis and several examples of null alleles of human beta-actin genes associated with tumors.

I communicated by email with the senior author of this paper, Pavel Kopnin at the Blokhin Russian Cancer Research Center in Moscow, not to complain about these omissions, but to tell him that I liked his hypothesis and to explain why. He thanked me and opined that he had had trouble persuading reviewers to publish the paper. I told him that our findings supported his hypothesis and would have made his argument stronger. He apologized for not citing our work and said that he had not reviewed the literature that far back, which amounted to twenty-eight years since our last paper from LPISM was published in 1987 (this made me feel old).

As early as March 1980, I had suggested in writing that altering the ratio of beta- and gamma-actins might contribute to the causation of cancer. This paper was published in the major journal, Journal of Biological Chemistry (see the figure below, last sentence of the abstract). If Dugina et al. were to consider filing a patent on this idea as an invention, our paper would have to, at least, be considered as invalidating prior art along with the rest of our work at LPISM up to 1987.

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Both our work at LPISM and Schoenenberger’s work in Basel indicate that the mutation in one of two alleles of the beta-actin gene produces a stable, but defective, form of beta-actin. If Dugina’s hypothesis is correct, it is tempting to suggest that the function of the mutation site in beta-actin controls suppression of tumor formation. I recommended to Pavel Kopnin that his lab pursue this and it is my impression that his lab will continue to work on this hypothesis.

In our model system, we isolated a derivative cell line from the original mutated human fibrosarcoma cell line that exhibited even faster tumor formation (Leavitt et al, 1982). In this second cell line, the mutant beta-actin gene had acquired two additional mutations that made the mutant beta-actin labile with a fast turnover rate in the cell (Lin et al, 1985). As the result of this change, the ratio of stable beta- to gamma-actin changed from approximately 2:1 to approximately 1:1. Furthermore, we found that the two remaining stable forms of beta- and gamma-actin up-regulated in synthesis to maintain a constant normal amount of actin in the cell.

In addition, when we transferred additional mutant human beta-actin genes into immortalized but non-tumorigenic human fibrosarcoma cells, we found that both beta- and gamma-actin from the endogenous normal genes were down-regulated to maintain a constant stable amount of actin in the cell. Thus, we found and reported that beta- and gamma-actin levels in living cells auto-regulated the activities of their own endogenous genes to maintain a constant level of actin in the cell along with a constant ratio of these actins as well (Leavitt et al, 1987a; and Leavitt et al, 1987b). This finding was later confirmed by other laboratories.

These final observations lend support to the idea that maintaining a normal ratio of fully functional cytoplasmic beta- and gamma-actins may be required for the maintenance of the normal, non-neoplastic cellular phenotype. By contrast, mutations and deletions that alter the ratio of functional cytoplasmic beta-actin to gamma actin could lead to tumorigenesis. Hopefully, Pavel Kopnin and others who are aware of our work at LPISM will explore further the role of cytoplasmic actins in maintenance of the normal, non-neoplastic state.

L-Plastin is One of 70 Signature Genes Used to Predict Prognosis of Breast Cancer Metastasis

[Guest post written by John Leavitt, Ph.D., retired Senior Scientist at LPISM in Palo Alto CA from 1981 to 1988; living in Woodstock, CT.  Leavitt has contributed several posts to the Pauling Blog in the past, all of which are collected here.]

John

John Leavitt

On August 24, 2016, the New York Times summarized the results of a Phase 3 clinical study of 6693 women with breast cancer. The outcome of this extensive clinical study was published in the New England Journal of Medicine on August 25, 2016. The clinical trial had been initiated ten years earlier on December 11, 2006 in Europe, (2005-002625-31) and on February 8, 2007 in the United States (NCT00433589). The study examined seventy select genes (seventy breast cancer “signature genes”) out of approximately 25,000 genes in the human genome that, when assayed *together* using a high density DNA microarray, predict the need for early chemotherapy.

In other words, the study asked which of the 6,693 tumors were “high risk” and likely to metastasize to distant sites within a five-year period, and which of these tumors were “low risk” and likely not to metastasize to distant sites in five years. One stated purpose of the study was to determine the need for chemotherapy, which can be very toxic and cause unnecessary harm to the patient, in treating breast cancer. The study found that a certain pattern of elevated or diminished expression of the seventy signature genes can predict a favorable non-metastatic outcome without chemotherapy for five years (while undergoing other forms of therapy such as surgery and irradiation).

One of the seventy selected genes is L-plastin (gene symbol “LCP1” and identified by the blue arrow in the figure below).

List of 70 signature genes

In 1985, my colleagues and I identified this protein in a cancer model system and named it “plastin” (Goldstein et al., 1985). We cloned the gene for human plastin while at the Linus Pauling Institute of Science and Medicine in 1987, and discovered that there were two distinct isoforms encoded by separate genes, L- and T-plastin (Lin et al, 1988). In 2014, in a piece published on the Pauling Blog, I described in some detail the discovery of L-plastin and its subsequent cloning.

A second figure, which is included below, summarizes information about L-plastin in a gene card published by the National Center for Biotechnology Information. This card shows that “LCP1: is the gene symbol for L-plastin and also identifies alternative names for L-plastin. Except for the inappropriate expression of L-plastin in tumor cells, this gene is only constitutively active in white blood cells (hematopoietic cells of the circulatory system). We used very sensitive techniques to try and detect L-plastin in non-blood cells such as fibroblasts, epithelial cells, melanocytes, and endothelial cells, but could not detect its presence in these normal non-hematopoietic cells of solid tissues.

Plastin Gene Card

The L-plastin gene card.

The clinical study reported on in the New York Times and New England Journal of Medicine shows that if L-plastin is not elevated in synthesis and modulated in combination with other signature genes, there should be little or no metastasis in five years. However, if L-plastin, in combination with other signature genes, is elevated in the early stage tumor, then the tumor is a high risk for metastasis and should be treated with chemotherapy.

plastin gels

The above figure consists of a pair of two-dimensional protein profiles that show the difference in expression of L-plastin and its phosphorylated form (upward arrows) between a human fibrosarcoma (left panel) and a normal human fibroblast (right panel).

My colleagues and I also found that L-plastin elevation is likewise a good marker for other female reproductive tumors like ovarian carcinoma, uterine lieomyosarcoma and choriocarcinoma (uterine/placental tumor), as well as fibrosarcomas, melanomas, and colon carcinomas. Abundant induction of L-plastin synthesis was likewise observed following in vitro neoplastic transformation of normal human fibroblasts by the oncogenic simian virus, SV40 (see Table IV in Lin et al, 1993).

The abundant synthesis of L-plastin that we found normally in white blood cells (lymphocytes, macrophages, neutrophils, etc.) suggested to me that the presence of L-plastin in epithelial tumor cells like breast cancer cells contributes to the spread of these tumor cells through the circulatory system to allow metastasis at distant sites. Indeed, both plastin isoforms have now been linked to the spread of tumors by metastasis, an understanding that is summarized in another Pauling Blog article from 2014 and, more recently, in other studies.