A Vision for the Future of the Linus Pauling Institute

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[An interview with LPI director Richard van Breemen, part 3 of 3. This is also our final post for 2018 — see you again in early January!]

Pauling Blog: When did the Linus Pauling Institute become something that was on your radar? Did you have any sense of it in the ’80s and ’90s, or was that far from your world?

Richard van Breemen: I don’t remember for sure, learning about the Linus Pauling Institute, until I visited the campus of Oregon State University. I visited here multiple times over the last twenty years. The very first time was as part of a site visit team for the National Institute of Environmental Health Sciences. They were funding a center here on the Oregon State campus led by George Bailey, who was a member of the Linus Pauling Institute, and Bailey was an expert in toxicology and environmental exposure to toxicants. And he developed a fish model – I think he was working with trout maybe at the time – and that legacy is continuing worldwide and on-campus here at Oregon State, and its led by Robert Tanguay, with the zebra fish model.

At the time we visited here it must’ve been in the 1990s, with George Bailey, and we reviewed his center, and of course it got renewed. And then after he retired – I think he retired from Oregon State around 2008 – it became directed by, for that particular grant, it was taken over by Joe Beckman, who’s also a Linus Pauling Institute investigator to this day. We made one other site visit. Today most NIH institutes have abandoned the site visit approach because of costs, but I’ve found it to be very enlightening. I didn’t know, at that time, much about fish models of toxicology and predicting effects, toxic effects, on animals and human health. But George Bailey was way ahead of his time in that model and it has been adopted, as I’ve said, worldwide.

I came back here to visit a few more times. Next visit would’ve been with the American Society of Pharmacognosy. I’ve mentioned that name before, and that Norm Farnsworth was a famous pharmacognosist; he was one of the founders of that organization. It was actually founded in 1959 in the Pharmacy School at the University of Illinois-Chicago, in the same lecture hall that I’ve lectured in many times. That same building was there in 1959, and that’s where my laboratory had been.

So the American Society of Pharmacognosy has its annual meeting, and it’s held in different places around the country. Oregon State has hosted that meeting at least three times and I’ve attended every one of the more recent ones in the last twenty years here on campus. The most recent one was just a year ago; that was in Portland though. It wasn’t specifically on the Oregon State campus, but several of them were held here, and I did attend one, and it was organized by mainly LPI investigators: Fred Stevens, with help from his colleagues in the LPI like Balz Frei. The next time I visited was at the invitation of Balz Frei, the previous director of the Linus Pauling Institute. He invited me to give a seminar at the LPI. So a few years later, when my telephone rang and my emails lit up with messages: would I be interested in applying to be the director of the Linus Pauling Institute?

So I knew exactly at this point what it was – I was very familiar, I’d been here before, I’d met the people. And it was an easy decision; I submitted my application.

PB: By invitation?

RVB: By invitation.

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PB: What are your goals for LPI, now that you are the director, for the next handful of years?

RVB: When I joined the group in Chicago, I was invited and recruited there because I complimented the team. There was a team of experts in pharmacognosy, in biochemistry, in medicinal chemistry, and I brought in certain skills that they didn’t have. But together we were very effective at competing for the National Cancer Institute grants to look for natural products for chemoprevention, the botanical center grant opportunity when that appeared in 1999, and others.

So I want to do all I can to build teamwork. We’ve got a lot of skilled, very talented researchers in the Linus Pauling Institute, but we have no center grants at this time. They have had them in the past, but at the moment there are none. So I’m coming in at sort of a lull and my immediate goal is to put together some teams and compete and hopefully win some external grants from the National Institutes of Health, maybe one from the National Cancer Institute, to look at chemoprevention again, of natural products. The grant I mentioned, that I’ve been a part of in Chicago, is no more. There’ll be a new competition in the next year for the botanical centers program; it would be wonderful if the Linus Pauling Institute could be the home of one of those.

The very next center grant that we will submit will be one that is focused on mass spectrometry, and that one I will submit in the first week of January in the new year, 2019. And the focus of that will be how to rapidly find active – that is, pharmacologically active – natural products and complicated mixtures. This is a question we ask every day in our research with botanical dietary supplements. If the dietary supplement made from a particular plant has an effect on cognition, on blood sugar levels, on estrogen levels and the like, how does it do that? And we can hopefully use mass spectrometry to more rapidly identify the active constituents?

This is something I started doing in Chicago, initially to compliment the field that was combinatorial chemistry. In the late 1990s, the pharmaceutical industry shifted from its more traditional approach to looking to nature to find inspirations to find new therapeutic agents, and they thought, “well, all we have to do is build libraries of chemicals, synthesize all we can, but put them into some storage, and then we screen all those compounds against a target, a pharmacological target, and that’ll be our way of discovering new things.” Some companies built libraries with as many as a million compounds and what they found was that it was very expensive but they didn’t find more compounds and they didn’t develop more drugs than they had before.

So I initially invented some mass spectrometry screening tools so we could look at pools of these combinatorial libraries, and within the pool of a hundred compounds, or five hundred compounds, in one step, identify any that interacted with the pharmacologic target, like an inhibitor of an enzyme. But then I quickly realized that would also be applicable to a plant extract, and if that plant was used by Native Americans, in ayurvedic medicine, in traditional Chinese medicine, for a specific purpose, then it might have a pharmacologic target. And I could take that target and test for compounds that interacted with it to identify them with mass spectrometry in a matter of, let’s say, hours at most, whereas it would take months of an individual’s effort to identify it by the conventional means.

So I want to use that approach, which I’ve been working on for twenty years, and there’s a mechanism at the NIH and the National Institute of General Medical Sciences to get a mass spectrometry center award, to teach other laboratories that do drug discovery and how to do this. Hopefully I’ll have some success, but that’ll involve some folks in the Linus Pauling Institute, like Fred Stevens. We’ll collaborate with the Center for Genome Research and Biology, led by Brett Tyler. That’ll be my first center grant application since arriving here on the Oregon State University campus.

Second will be our botanical center application in the middle of next year. Dave Williams, another LPI investigator, will hopefully submit – and this is something that we’re working on now – he’s putting together a team from the LPI to apply to the National Cancer Institute for funds to study natural products as possible chemoprevention agents. This is what we used to do in Chicago, in a grant that doesn’t exist anymore, and there’s very few research groups left in this country who are doing natural products drug discovery for cancer prevention, so I hope Dave is successful in his NCI application in the new year.

So those are my immediate plans, but it all depends on teamwork, drawing on the experts we have within the LPI, reaching out to other units on campus to build groups who have the breadth and depth of expertise to be competitive for these large grant awards. And, of course, I’m going to continue to do my best to get the word out about the Linus Pauling Institute and continue the philanthropy that Linus Pauling started, which helped build the Linus Pauling Institute in the beginning, as well as the grant proposal approach.

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PB: It’s a difficult balance to strike, being an administrator and a scientist at the same time.

RVB: Well, that’s part of the job. I wouldn’t have taken the job if this was going to be a strictly administrative post. I’m not ready to leave the lab, and I also enjoy, very much enjoy, as did Pauling, teaching. I was in a pharmacy school the last twenty-four years and lectured to some pharmacy students, but I spent most of my time training graduate students who either worked in my lab or in other laboratories.

Graduate education is something that we do exceptionally well in the United States; we have a great history of that, from the time our PhD programs were started roughly a hundred years ago. But we rapidly emerged as the world leaders in scientific research and scientific education for researchers. I’ve graduated over fifty PhD student and about twenty-five post-doctoral trainees and master’s students, and I’m continuing that. I brought five graduate students with me from Chicago and I’m looking forward to continuing that tradition. The first grant proposal I submitted once arriving at the Linus Pauling Institute this year was actually a training grant, which will train exclusively pre-doctoral students in natural products research. That’s still pending. I have my hopes up that we’ll get our award before the year is over; the National Institutes of Health training grant.


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The four men who have served as director of the Linus Pauling Institute at Oregon State University. From left: Don Reed, Balz Frei, Fred Stevens and Richard van Breemen.

PB: Any thoughts in closing?

RVB: I’m delighted to be here on the campus of Oregon State University. I’d like to say that the moment I heard, my bags were packed, but of course there was the national search, and I interviewed. The process first began on the telephone interview and then an in-person interview and then another follow-up visit, and all of it was most exciting. The more I learned about Oregon State, and the more I learn to this day, the more excited I am about being here. It’s a great environment, fabulous investigators, great resources.

I would like to not only enhance the external funding of the Linus Pauling Institute, but I want to enhance its international presence, its image. I think this is a gem that needs to be appreciated more outside of the walls of Oregon State, and across the state and beyond the state borders, throughout the country. And I think that the Linus Pauling Institute has a worldwide image. I’m going to do my best to enhance that in all the ways that I can.

Exploring the Possibilities of Mass Spectrometry: An Interview with Richard van Breemen

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[In part 2 of our interview with Linus Pauling Institute Director Richard van Breemen, we trace the evolution of his career in scientific research, first at North Carolina State University and later at the University of Illinois, Chicago. This transcript has been lightly edited for clarity and continuity.]

Pauling Blog: Was North Carolina State your first faculty position?

Richard van Breemen: I did a post-doctoral fellowship for a year at Johns Hopkins, with Robert Cotter, then moved immediately into a faculty positon, yes. So I was an assistant professor at North Carolina State in the Chemistry department.

PB: And you founded the Mass Spectrometry Lab for Biotechnology at NC State, is that correct?

RVB: That was the attraction. I was offered a position with a very appealing start-up package that would enable me to buy a state-of-the-art, high-resolution, high-performance mass spectrometer. As I mentioned [in part 1], this revolution had occurred in the 1980s which enabled us to ionize molecules much larger than anyone had ever imagined, and so this was a time when we were starting to look at peptides, various small proteins, oligonucleotides, expanding beyond the volatile compounds that had dominated organic chemistry and mass spectrometry up until that time.

Mass spectrometers were very adept at looking at anything that could be distilled as gas phase molecules, things that could be changed from a condensed phase to a gas phase, because ultimately you have to put them into a vacuum. The ions are formed and then the ions have to be manipulated in weight in that vacuum so they don’t contact any air or any molecules that could quench the ions. But no one had succeeded in changing very polar large molecules – like sugars, DNA, proteins, RNA – from that condensed phase into the gas phase. It was just not considered possible. So my interest in the North Carolina State job was to start a mass spectrometry center and apply it to biotechnology questions.

Well, we could now, for some of the first times ever, use mass spectrometry to look at large protein-like molecules in ways that we never could before and answer some interesting questions in the biotech world. I had written a grant proposal to the NIH to use mass spectrometry to help determine protein structures, whereby we would cleave the proteins into smaller pieces with trypsin, chymotrypsin and other endoproteases, and then measure those smaller pieces by mass spectrometry, and then put them all back together again to determine what the structure of that protein had been and if there were any changes in it, post-translational modifications, or maybe it got modified by a pharmaceutical agent or a toxin.

And the critique – I keep all of the old critiques which I get from my grant proposals, I have a file for them. We used to call them Pink Sheets, because the NIH would mail you pink carbon copies of the type-written critiques of your grant applications, and you always shuddered when the mail came and you knew that letter was there, and you didn’t want to open it because you didn’t know what the answer was.

This one said that mass spectrometers were incapable of measuring large molecules, and it was absolutely impossible for anyone to even think that mass spectrometry could be applied to the study of whole proteins. Today, we call that field proteomics. I didn’t pursue proteomics beyond about 1990-91, and by the time I left NC State to go to Chicago, I was looking at much more biomedical problems.

PB: So was that the prompt to move to Chicago, this new shift in your interests?

RVB: Well, partly. I abandoned the idea of what was to become proteomics and peptide-based therapies and protein-based therapies, which is something that I’d been very interested in for a while, and started to pursue something that some of my colleagues at NC State had originally suggested.

So in the Biotechnology program, I got to meet a lot of folks involved in botany, food science, forestry, all these departments that are found at state universities around the country. And some of these colleagues brought me interesting research problems which I just found quite intriguing and pursued in one way or another to this day.

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Mikhail Tsvet

One of my friends in food science, Steve Schwartz, brought me a set of carotenoids that he had purified by chromatography. Carotenoids and chromatography go all the way back to the beginning of chromatography, over a hundred years ago, when a Russian chemist, Mikhail Tsvet, found that he could take a glass column, fill it with diatomaceous earth and other solid-phase sorbents, pour an organic chemical solution – an extract from a plant – through it, and he would see bands as the liquids percolated through the column. He would see bands of color appear, and the bands would be chlorophylls and carotenoids.

So my colleagues in botany and food science brought me carotenoids and chlorophylls, and asked if I could determine their structures by mass spectrometry, which actually was fairly novel at the time. And so I had the tools – a very nice, high-performance tandem mass spectrometer, with absorption techniques, which enabled these molecules that really had been difficult with earlier mass spectrometry tools to ionize. I could ionize them with tandem mass spectrometry, which is literally: make the ion, break it into pieces in the gas phase, then measure the pieces with the next phase of mass spectrometry. You learn a lot about structure that way. I was able to get some very useful data for both chlorophyll identification and carotenoid identification. And that is where, at least in the carotenoid field, that I continued later.

There’s some other interesting stories of botanists. Wendy Boss came with a problem about signal transduction. Phosphatidylcholine, inositol, and other phospholipids were known to be messengers between human cells. She was asking the question, do plants also use these second messengers? Like phosphatidylinositols – P.I. – phosphoralated versions – PIP – and so on. And so I’ve collaborated with Wendy Boss for a while and helped establish that yes, some of the very same second messenger communications with phosphatidylinositols occur within plants – in particular, we used carrot cells – as happen in animals and humans.

So I moved out of the area of more biotechnology orientation towards more biomedical work, and then it was time for a change. I needed to be in a more biomedical environment, and an opportunity arose to move to Chicago to join a department in a Pharmacy school. I was trained in pharmacology, not strictly pharmacy, so I knew a lot about drug metabolism and receptors, and how drugs work, and a lot about mass spectrometry and looking at drug metabolism.

I joined a team there which had a long history and was one of the best pharmacognosy groups in the world. Pharmacognosy is an old name from the 19th century about the study of medicinal natural products from sources like plants, microbes; terrestrial or marine. And they needed somebody with my expertise who could use mass spectrometry to help them more quickly and efficiently identify new products that they were isolating, but also somebody who could help translate their discoveries into more of a biomedical application, towards the path of drug discovery. I joined a team lead by John Pizzuto, who was my department head at that time, who had been leading an NIH-funded center for natural products drug discovery; he called it “natural cancer prevention.” So these compounds that he envisioned would be useful in preventing the occurrence of disease and, in particular, cancer.

I remember the days when going to the doctor for an annual checkup wasn’t covered by insurance, because you weren’t sick, but the doctors had to check a box off to say that they were treating you for a cold or a throat infection or something, just so you could get health insurance to cover it. Those were the days before health insurance folks realized that – it’s the old Ben Franklin adage, “prevention is worth a pound of cure,” was true. It’s a lot cheaper to prevent cancer than to cure it. So today, I think, when health insurance does cover routine visits, it’s for annual checkups for the prevention of various forms of disease. But this was still an unappreciated, almost radical idea, even as recent as the 1990s.

So John Pizzuto had a program project grant from the NIH to screen, initially, botanical natural products – and later also marine natural products – for possible cancer prevention agents. And I helped identify those agents and then looked at their metabolism, bio-availability, pharmacokinetics; I started to move them towards clinical trial. And that group discovered molecules like resveratrol, which today are very famous as cancer prevention agents. Towards the end of the 1990s, I was still working as part of that team, but now it was time for me to start organizing some group efforts of my own.


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Van Breemen in his laboratory at UIC.

PB: Can you tell me about that phase of your work, from 1999 to 2017, the research that was being done?

RVB: As the very first botanical center funded by the NIH to look at the safety and efficacy of these products, we decided to focus on women’s health, because women were, and continue to be, the main consumers of botanical dietary supplements. If not for themselves, they sometimes buy these supplements for children and for the household, so they’re the main consumers. But as is evident from the NIH initiatives recently, women have been understudied in clinical trials, they’ve been understudied in the drug development programs. And historically – and not everyone who consumes dietary supplements are uniform, middle-aged, or young men, but basically those are the folks for whom these products were initially developed

So we focused on women’s health, and instead of trying to go to the jungles of the world or the oceans of the world to find new supplements that might be safe and effective, we have focused exclusively on dietary supplements that have already been used or are currently on the market. We look at the evidence for use, historical use, in the literature and in natural medicine – the ethnobotanical history of these products – and of course their current use in products that are on the market. So our first goal in this program is to make sure that the products that are being used by women are safe. And as funding permits, we carry our clinical trials to investigate their efficacy.

But at all times we investigate mechanisms of action; we want to identify the active compounds and figure out how to standardize these products to make them more reproducible. That’s the essence of science: to understand why something is happening but do it in such a way that, when you carry out an experiment, others can follow and reproduce your work. How can you reproduce a clinical trial if you don’t really know what species of plant had been used in a study?

So prior to the botanical center’s program, funded by the NIH, much too much published literature was not as reproduced as it should have been. They were not using products where they had a botanist identify the species of a plant, they didn’t carefully – sometimes – describe how that plant was harvested, extracted, prepared, put into pills or something like that; some form for a clinical trial. But in order to reproduce their work, one needs to be able to know all those things, and so we helped formulate an approach where byproducts could be standardized chemically so we know what their constituents are, at least the active constituents. Plant extracts and plant products are so complex, we don’t know all their constituents, but we know what the major ones are chemically, and then standardize the product also biologically through receptor-based assays. That’s the essence of pharmacology. Through animal studies, through human clinical trials even, we want a product that is biologically standardized as well as chemically standardized. I envision that the botanical supplements industry will eventually reach that point where the products have a body of literature behind them, so consumers can make a very safe choice about what to use and why to use it.

PB: So that standardization piece was the primary thrust then, of that program?

RVB: It was one of the early success stories of that program. I think more than anything my background in organic and analytical chemistry, that application – at least in our grant, in our studies – I think it’s become a paradigm that’s now standard in the industry, whereby, if a company wishes to market a botanical dietary supplement, they have to have evidence that shows they know what plant is going into that product. There have been a few unfortunate events where toxic plants were used by mistake and it’s caused some deaths worldwide. But if the producers are careful and follow good manufacturing practices, they can ensure that the materials that go into their products are carefully identified and standardized so they produce a safe product. And eventually the clinical trials of these products will be carried out so that we’ll also have evidence about their efficacy. But at present, there’s no – at least in the US – rules and regulations about dietary supplements; there’s no requirement that the product be efficacious. But if a producer wishes to label their product as having a specific health benefit, they have to have the evidence to show it.

And that’s, I think, the next phase of the botanical dietary supplements research field, is to not only continue to identify active compounds in botanical supplements – and not necessarily with the idea that we’ll discover new drugs, but people want to use these as mixtures, and mixtures certainly have different effects than individual substances do. Dietary supplements have been with us since the dawn of medicine, in one form or another. People have gone to nature to use medicinal plants and other sources around them to cure disease, to treat disease, to relieve pain. And so that’s the basis of the early field of medicine, of the drug industry, of pharmacology: looking at how natural products effect receptors, enzymes, health.


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Clive West

If I may digress a moment to another vitamin story, to give you an idea about why we don’t know what the optimum amount of vitamins are to this day, in many cases. In my early work with carotenoids, I applied mass spectrometry and was able to identify carotenoids in ways that really hadn’t been done before. I was presenting some of that work at an international conference in Leiden, Netherlands, at the International Carotenoids Society Conference being held there, when I was approached by a Dutch investigator, Clive West – Clive was originally from Australia, but he was a professor at Wageningen University, which is like the Oregon State of the Netherlands, an agricultural university there as well. And he said, “if I gave you a blood sample with this level of micromolar level of beta-carotene in it, could you measure it?” And I said, “sure.”

So we got to talking and he was interested in establishing the optimum amount of beta-carotene that one would need in their diet to prevent vitamin A deficiency. Vitamin A deficiency is the number-one cause of blindness in children worldwide and yet, if beta-carotene is such a good source of it, why should people from countries where they rely primarily upon fruits and vegetables and very little on meat for food suffer so much from vitamin A deficiency? So he thought that the recommended daily allowances and the minimum daily requirements that were listed in the WHO, and by the Institute of Medicine in the United States, needed revision.

I helped him on several clinical studies that were carried out in Indonesia and several in Europe, on the bioavailability of carotene, given orally, and its bioconversion to retinol, which is vitamin A. So it can be considered to be a pro-vitamin A molecule. It’s not active – beta-carotene is not a vitamin A molecule – but it can be converted by an enzyme in the human intestine, a dioxygenase, which cleans it into two molecules of vitamin A retinol. But people had overestimated the efficiency of that process.

So we did some studies with stable, isotopically labelled beta-carotene. Remember, mass spectrometers were invented by physicists to prove the existence of isotopes. Isotopes can be stable as well as radioactive, so mass spectrometry typically measures stable isotopes and uses them as a way to distinguish a molecule that’s heavier than another. We can distinguish the endogenous form of vitamin A from one that you might add as a supplement because we can put deuterium or carbon-13 – stable but heavy isotopes of hydrogen and carbon – into that molecule of retinol or beta-carotene, feed it to somebody, then measure, by mass spectrometry – the quantitative aspects of mass spectrometry – we can distinguish endogenous from supplemental heavy beta-carotene and retinol in the blood, and then determine how much of that oral dose got absorbed.

We did that on a study of children in Indonesia and sent the data to the Institute of Medicine in the United States, who rejected it, saying “it’s irrelevant for the health of Americans because it’s Indonesian children!” So Clive went back to the Netherlands and did a new study on graduate students at Wageningen University eating a western diet. I did all the measurements in Chicago, because he sent me the blood samples, and we published another study. Since then, the World Health Organization has revised the recommendation of the amount of beta-carotene necessary for vitamin A formation in the human body, but the Institute of Medicine in the United States has not. There’s also a difference that we explored about how the food matrix, containing beta-carotene, affects bioavailability.

Then we moved on to another study that had to do with folic acid; folic acid being another necessary nutrient, but it’s a pre- or a pro-nutrient. Folic acid is not active, but tetrahydrofolate, a metabolite of it, is. In the United States we supplement flour with folic acid to prevent, hopefully, neural tube defects, which is a birth defect caused by maternal deficiency in folic acid. The European Union doesn’t allow folic acid in their food; it’s considered an adulterant and it’s banned by law. So here we have the Europeans saying there’s no evidence that folic acid in the human diet can prevent folic deficiency and the US mandates it by law.

So we embarked on some clinical trials with labelled tetrahydrofolate, folic acid, and other forms of folic acid, to measure the bioavailability in orally administered supplements. We published some of that work and, unfortunately, Clive fell ill and passed away, and we only published the first two papers on folic acid. So that work hasn’t continued, but it does give you an example that, by anecdote, why we don’t know everything there is to know on vitamin supplements. So the work of Pauling is not over.

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.

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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Pauling in Memorium

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Linus Pauling Jr. speaking at his father’s memorial service, August 29, 1994.

[Part 4 of 4]

On August 29th, 1994, a memorial service planned by Pauling’s children and his long-time assistant Dorothy Munro was held at Memorial Church on the campus of Stanford University. Many people spoke, including Linus Pauling Institute of Science and Medicine administrator Steve Lawson, Oregon State University president John Byrne, and scientific colleagues Frank Catchpool and Verner Schomaker.

Remembrances were likewise offered by close friends and family. Pauling’s youngest son Crellin spoke movingly, while also offering comments written by his brother Peter, who was living in Wales at the time and was unable to travel to attend the memorial. Pauling’s daughter Linda, and eldest son Linus Jr., also gave their heartfelt goodbyes to their father. Steve Rawlings, the ranch hand who had cared for Pauling for the past several years, spoke of the bond that they had formed. Four of Pauling’s grandchildren – Cheryl and David Pauling, and Barky and Sasha Kamb – recalled fond memories of their Grandpa.

The memorial program featured a quote to remember Pauling by, one taken from his 1958 book, No More War. It read:

Science is the search for truth- it is not a game in which one tries to beat his opponent, to do harm to others. We need to have the spirit of science in international affairs, to make the conduct of international affairs the effort to find the right solution, the just solution of international problems, not the effort by each nation to get the better of other nations, to do harm to them when it is possible. I believe in morality, in justice, in humanitarianism.


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Linus Pauling Jr. speaking at the grand opening of the Linus Pauling Science Center, October 19, 2011.

With its director of research and namesake now gone, the reigns at LPISM were taken up by Linus Pauling Jr. In so doing, Linus Jr. sought mainly to secure his father’s long-term legacy by moving his beloved but financially unstable institute from its location in Palo Alto, and to associate it with a prestigious academic institution, where it might find new and greater successes.

Along with Lawson and the Institute’s Board of Trustees, Linus Jr. entered into conversations with a number of universities where they believed that LPISM’s orthomolecular mission might find support. At the same time, the Institute benefited greatly from a large number of memorial donations and bequests made in honor of Pauling. Ultimately, an agreement was struck between the Institute and Oregon State University, which offered to match those contributions.

This resulting endowment in hand, a new director, Balz Frei, was brought on board and, at its new home in Corvallis, the Linus Pauling Institute was reborn. While still able to engage in the orthomolecular research that Pauling had always envisioned, the move to OSU offered the Institute the opportunity to open up new lines of research in other areas of human health. When Linus Jr. gave the keynote address at the grand opening of OSU’s brand new Linus Pauling Science Center in 2011, he spoke of this evolution.

I’ve appreciated other people’s recognition of (my father’s) capabilities and endeavors, and done what I can to increase that appreciation and recognition. My whole investment in LPI was part of that too, recognizing my father’s contribution to society…and wanting to make sure in some way that he didn’t get lost in the sands of time. What has happened has pleased me. I don’t think there’s anything I can do to personally do more than I have done. I don’t think I’m going to try… I’m very appreciative of those who have dedicated themselves to the continuation of my father’s reputation. I feel that I can rest assured that he will not be forgotten.


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Linus Pauling’s humble marker at the Oswego Pioneer Cemetery, as photographed in 2009.

Before he died, Pauling made clear his wish to be cremated and to have his ashes, along with those of his wife, interred in Lake Oswego, Oregon at the Pioneer Cemetery where his parents were buried. In 1994, a cenotaph – which is a marker honoring a person whose remains are elsewhere – was placed in the family plot by Pauling’s sister, Pauline. Pauling’s ashes remained with Ava Helen’s among family in California until 2005, when they were finally moved to Oregon and placed alongside those of Pauling’s parents, Herman and Belle.

In 2013, an Oregon resident named Jean Crellin Ashby took her mother to see Linus Pauling’s grave at Pioneer Cemetery. Ashby is the granddaughter of Edward Webster Crellin, a mentor and colleague of Linus Pauling’s at Caltech, and the man after whom Pauling named his youngest son. Standing over Pauling’s marker, Ashby thought about how her grandparents were buried in Pasadena. Since she was unable to easily visit their graves, given the considerable distance, Ashby decided that honoring Pauling’s family in Lake Oswego would also serve to honor her own. Subsequently, Ashby contacted cemetery administrators and filed the appropriate paperwork to become the official caretaker for the Pauling plot, which she and her family still maintain today.


It is Pauling’s legacy that we honor on this, the twenty-second anniversary of his passing. And what better way to reflect on that legacy than to return to the diary entry that Pauling wrote when he began the history of his life at the age of 16. In it, Pauling said that his history was not intended to be merely a life’s story. Rather, it was to be a reflection on good times had in his passage through this “vale of tears”

Often, I hope, I shall glance over what I have written before, and ponder and meditate on the mistakes that I have made—on the good luck that I have had—on the carefree joy of my younger days; and pondering, I shall resolve to remedy my mistakes, to bring back my good luck, and to regain my happiness.

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Pauling’s Final Years

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Pauling posing at lower campus, Oregon Agricultural College, ca. 1917.

[An examination of the end of Linus Pauling’s life, part 1 of 4]

In 1917, at sixteen years of age, Linus Pauling wrote in his personal diary that he was beginning a personal history. “My children and grandchildren will without doubt hear of the events in my life with the same relish with which I read the scattered fragments written by my granddad,” he considered.

By the time of his death, some seventy-seven years later, Pauling had more than fulfilled this prophecy. After an extraordinarily full life filled with political activism, scientific research, and persistent controversy, Pauling’s achievements were remembered not only by his children, grandchildren and many friends, but also by an untold legion of people whom Pauling himself never met.

Passing away on August 19th 1994 at the age of 93, Pauling’s name joined those of his wife and other family members at the Oswego Pioneer Cemetery in Oregon. What follows is an account of the final three years of his life.


 

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Linus Pauling, 1991.

In 1991, Pauling first learned of the cancer that would ultimately take his life. Having experiencing bouts of chronic intestinal pain, Pauling underwent a series of tests at Stanford Hospital that December. The diagnosis that he received was grim: he had cancer of the prostate, and the disease had spread to his rectum.

Between 1991 and 1992, Pauling underwent a series of surgeries, including the excision of a tumor by resection, a bilateral orchiectomy, and subsequent hormone treatments using a nonsteroidal antiandrogen called flutamide. During this time, Pauling also self-treated his illness with megadoses of vitamin C, a protocol that he favored not only for its perceived orthomolecular benefits, but also as a more humane form of treatment than chemotherapy or radiation therapy.

Pauling’s interest in nutrition dated to at least the early 1940s, when he had faced another life-threatening disease, this time a kidney affliction called glomerulonephritis. Absent the aid of contemporary treatments like renal dialysis – which was first put into use in 1943 – Pauling’s survival hinged upon a rigid diet prescribed by Stanford Medical School nephrologist, Dr. Thomas Addis.  At the time a radical approach to the treatment of this disease, Addis’ prescription that Pauling minimize stress on his kidneys by limiting his protein and salt intake, while also increasing the amount of water that he drank, saved Pauling’s life and led to his making a full recovery. Though his famous fascination with vitamin C would not emerge until a couple of decades later, Pauling’s nephritis scare instilled in him a belief that dietary control and optimal nutrition might effectively combat a myriad of diseases. This scientific mantra continued to guide Pauling’s self-treatment of his cancer until nearly the end of his life.

Pauling also believed that using vitamin C as a treatment would, as opposed to chemotherapy, allow him to die with dignity. Were his condition terminal and his outlook essentially hopeless, Pauling felt very strongly that he should be permitted to pass on without “unnecessary suffering.” Pauling’s wife, Ava Helen, had died of cancer in December 1981. She too had refused chemotherapy and other conventional approaches for much of her illness, a time period during which Linus Pauling had helped his wife the only way he knew how: by administering a treatment involving megadoses of vitamin C. This attempt ultimately failed and, by his own admission, Pauling never really recovered from his wife’s passing.

Nonetheless, Pauling continued to lead research efforts to substantiate the value of vitamin C as a preventive for cancer and heart disease in his capacity as chairman of the board of the Linus Pauling Institute of Science and Medicine (LPISM). By the time of his own diagnosis in 1991 however, the Institute was in a desperate financial situation, several hundred thousand dollars in debt and lacking the funds necessary to pay its staff.


 

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In 1992, while he recovered from his surgeries and managed his illness, Pauling continued to act as chairman of the board of the LPISM. No longer able to live entirely on his own, he split his time between his son Crellin’s home in Portola Valley, California, and his beloved Deer Flat Ranch at Big Sur. When at the ranch, Pauling was cared for in an unofficial capacity by his scientific colleague, Matthias Rath. Pauling was first visited by Rath, a physician, in 1989, having met him years earlier in Germany while on a peace tour. Rath was also interested in vitamin C, and Pauling took him on as a researcher at the Institute. There, the duo collaborated on investigations concerning the influence of lipoproteins and vitamin C on cardiovascular disease.

Not long after Pauling’s cancer diagnosis, a professor at UCLA, Dr. James Enstrom, published epidemiological studies showing that 500 mg doses of vitamin C could extend life by protecting against heart disease and also various cancers. This caused a resurgence of interest in orthomolecular medicine, and it seemed that Pauling and Rath’s vision for the future of the Institute was looking brighter.

As it happened, this bit of good news proved to be too little and too late. LPISM had already begun to disintegrate financially, its staff cut by a third. The Institute’s vice president, Richard Hicks, resigned his position, and Rath, as Pauling’s protégé, was appointed in his place. Following this, the outgoing president of LPISM, Emile Zuckerlandl, was succeeded by Pauling’s eldest son, Linus Pauling Jr. Finally Pauling, his health in decline, announced his retirement as chairman of the board and was named research director, with Steve Lawson appointed as executive officer to assist in the day-to-day management of what remained of the Institute.

One day prior to his retirement as board chairman, Pauling signed a document in which he requested that Rath carry on his “life’s work.” Linus Pauling Jr. and Steve Lawson, however, had become concerned about Rath’s role at the Institute, and particularly on the issue of a patent agreement that Rath had neglected to sign. Adhering to the patent document was a requirement for every employee at the Institute, including Linus Pauling himself. When pressed on the issue, Rath opted to resign his position, and was succeeded as vice president by Stephen Maddox, a fundraiser at LPISM.

After this transition, Pauling met with Linus Jr. to discuss the Institute’s dire straits. Pauling’s youngest son, Crellin, had also became more active with the Institute as his father’s illness progressed, in part because he had been assigned the role of executor of Pauling’s will. Together, Crellin, Linus Jr., and Steve Lawson struggled to identify a path forward for LPISM. Eventually it was decided that associating the Institute with a university, and focusing its research on orthomolecular medicine as a lasting legacy to Pauling’s work, would be the most viable avenue for keeping the Institute alive. The decision to associate the organization with Oregon State University, Pauling’s undergraduate alma mater, had not been made by the time that Pauling passed away.

Vitamin C and Cancer: Rays of Hope

 

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[Part 4 of 4]

Ridiculed by the medical profession for two decades, the tide began to shift for vitamin C and cancer starting in 1992. That year, the New York Academy of Sciences voted to discuss high-dose vitamins and nutrients at its annual meeting, devoting several sessions to the antioxidant properties of vitamin C and its potential value at higher-than-dietary amounts in preventing lung, stomach, colon, and rectal cancers.

Oddly, throughout the proceedings, one prominent name had been missing from the conversation, a point noted by a professor from Alabama who finally spoke up, saying,

For three days I have been listening to talks about the value of large intakes of vitamin C and other natural substances, and I have not heard a single mention of the name Linus Pauling. Has not the time come when we should admit that Linus Pauling was right all along?


Since 1996 the Linus Pauling Institute, relocated from California, has continued work on cancer from it’s new home at Oregon State University. Basing these contemporary orthomolecular studies on the hard sciences of cellular biology, molecular biology, and organic chemistry, the Institute continues to explore the cutting edge of health and nutrition research.

Working under Dr. Balz Frei, the current director of the Institute, as well as former LPI principal investigator Dr. Roderick Dashwood (now director of the Center for Epigenetics and Disease Prevention at Texas A&M University), OSU student Matt Kaiser has spent time analyzing the benefits of vitamin C treatment for colorectal cancer, which remains the third leading cause of cancer related deaths in the United States. The Pauling Blog has interviewed Kaiser in the past, and we met with him again recently to gain a better sense of trends in the community of researchers interested in vitamin C and cancer.


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One primary question that begs further exploration is, why didn’t earlier studies find evidence of the value of vitamin C?

As it turns out, the problem appears to have been primarily located in the way that vitamin C was being administered. The 1979 Mayo studies to which Pauling so strongly objected had assumed that, since vitamin C was filtered out of the body after a certain point of blood saturation, higher doses need not be examined. This assumption – that excess vitamin C could not be absorbed and was simply excreted in the urine – was one of the most basic issues of contention that Pauling was never able to get past with the medical community. However, it now appears that the assumption applies only if vitamin C is taken as an oral supplement, a breakthrough that was first identified by Mark Levine, a Senior Investigator at the National Institutes of Health.

Matt Kaiser explains

Mark Levine realized in the 1990s that the way drugs are distributed and function in the body [pharmacokinetics] can drastically change the amount of vitamin C entering blood plasma. Eating vitamin C you can only get about 250 micromolar [a measure of vitamin C, or ascorbate— to use its chemical name— that can be concentrated in the blood stream]. With intravenous injection, the levels are much larger: 200 times. One millimole is a thousand micromoles, so 30 millimolar [of ascorbate in blood plasma] is a huge difference!

At these high pharmacological— or even super physiological— doses, Levine found that cancer cell populations dropped significantly. To understand why, it is important to know a bit about how cancer works.

Human DNA can wrap up tight (heterochromatin) or unwind into a loose, more open configuration (euchromatin). When it is wrapped up tight, the genetic information on the DNA cannot be expressed. This is because transcription, which is the process by which a cell reads and expresses the genetic code, requires access to DNA.

There are very specific times when DNA should be wrapped tight to maintain optimum health, and other times when one’s body needs to be able to use the instructions for cellular function that are contained in DNA. When DNA needs to be unwound, molecules called histone acetyltransferases (HATs) help to unwind it. When it needs to be wound up tight, the process is aided by histone deacetylases (HDACs).

HDAC overexpression is a hallmark of cancer cells, and hyperactive HDAC cells lead to messy, knotted DNA winding. This biological circumstance hinders the cell from reading important instructions found in DNA, which in turn prevents the production of important tumor suppressor proteins. At the same time, it leaves certain sections of the genetic code open that should not be expressed.

“Basically,” says Kaiser, “You remove the break from the car, and then you also step on the gas. And that’s cancer.”


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Matthew Kaiser.

The prevailing theory of how vitamin C acts on tumors is that it functions as a “prodrug,” meaning that it stimulates biochemical processes that allow something else to kill the cancer cell, rather than acting on it directly. In this case, the active agent is hydrogen peroxide, which is produced in saturated tissues by excess vitamin C. “Vitamin C acts as the Trojan horse that allows hydrogen peroxide to enter the tumor site,” Kaiser explains. “You can’t inject it straight in; your body will react too strongly. Hydrogen peroxide is a reactive oxygen species…it tears cells apart.”

However, since working on the project, Kaiser has found that this consensus on how vitamin C fights cancer isn’t necessarily the whole story. Pharmacological levels of ascorbate appear to selectively reduce the presence of proteins that regulate reactive oxygen species, like hydrogen peroxide, in cancerous cells. Some of these same proteins also happen to promote cell growth, which is not something that one would wish for cancer cells to do. In addition to producing hydrogen peroxide, ascorbate actually inhibits the runaway HDAC production that makes cancer cells so dangerous.

“What makes it really hard, really complicated,” Kaiser laments, “is that this might not work the same way for different types of cancer cells in different locations. There’s still so much to understand about how vitamin C is having this protective effect…That’s what’s lacking and that’s why we need studies like this.”


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And indeed, more studies are coming. In keeping with it’s mission to extend and promote what it calls “healthspan,” LPI hosts a bi-annual Diet and Optimum Health Conference, bringing together experts from around the world to talk about topics in orthomolecular medicine, among other fields. This year the conference, which was held at OSU in September, featured several speakers discussing vitamin C and cancer. One of them was Dr. Mark Levine, the NIH scientist who first showed the value of intravenous ascorbate.

Margreet Vissers and Anita Carr, of the University of Otago in New Zealand, also described their own advances on the subject. Vissers found in her studies that levels of 50 micromolar ascorbate in blood plasma (average dietary levels are between 40 and 80) had little to no protective effect against cancer. Doubling the amount to 100 micromolar, however, boosted a patient to the lowest level of the protective range. It would seem, then, that Pauling was right to suggest that mega doses might be important for optimum health.

Vissers also explained that, in animal models, ascorbate injected intravenously will peak after about twenty hours in both healthy tissue and in tumors. However, unlike the healthy tissue, tumor tissues hold onto the vitamin C and do not return to a natural baseline. This detail is important because it allows high doses of ascorbate to build up in tumor tissue, and these doses disproportionately kill cancer cells instead of healthy tissues for reasons that are still not fully understood.

Conversely, the dangers of using vitamin C, even in high intravenous doses, appear to be small. While some people harbor an enzymatic deficiency that can cause a severe negative reaction, most individuals simply cannot overdose on vitamin C. Even in the blood plasma, vitamin C usually reaches a saturation point and is filtered from the body.

At the LPI conference, Dr. Carr pointed out that this form of treatment also dramatically improves the quality of life of cancer patients as compared to chemotherapy. For one, vitamin C treatments involve significantly less pain, mental and physical fatigue, nausea and insomnia. As of March 2015, three clinical trials involving pharmacological levels of ascorbate have been conducted, all of them showing that it is well tolerated by patients and reduces chemotherapy-related toxicity.

Additionally, vitamin C at high doses is known to aid cognitive function, and these positive benefits work together to aid in social satisfaction for the patient. As Pauling pointed out in the 1970s, it is not only the disease that the doctor should be concerned about treating, but the patient as well.


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Pauling in 1989 – an extraordinary life. Photo by Paolo M. Sutter.

So is Linus Pauling vindicated when it comes to vitamin C and cancer? The answer is complicated.

On the one hand, it would appear that vitamin C can serve as an important preventative and treatment for cancer. However, the method that Pauling advocated— taking large supplemental doses orally— is pretty clearly not an effective form of application. Rather, contemporary research indicates that the levels of ascorbate that are required to slow or stop tumor growth are far greater than that which can be achieved naturally by ingesting vitamin C; they can be accomplished only by intravenous injections of ascorbate. Furthermore, it is likely that this form of treatment will not replace, but instead will augment, existing protocols including chemotherapy.

But the broader trend is optimistic and, one might argue, validating. And with the Linus Pauling Institute and many others around the world continuing to investigate the potential for vitamin C and other nutrients to help people live longer and feel better, exciting new studies on optimum diet and effective treatments for diseases like cancer would appear to be on the near horizon.