Farewell to Balz Frei


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.


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.]


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.


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.


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 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.

Pauling’s Final Years


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.



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.



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.

Remembering Henry Taube


Four Nobel Prize-winning chemists with a connection to Stanford University. From left, Arthur Kornberg, Paul Flory, Henry Taube, and Linus Pauling. This photo was taken in 1983 on the day that Taube received notification of his having been awarded the Nobel Prize in Chemistry.

[Ed Note: This is our final post for 2015.  Thanks for reading and please check back in early January for more!]

This month marks the 32nd anniversary of Henry Taube’s Nobel Prize in chemistry, awarded for ‘Electron Transfer between Metal Complexes.’ His seminal paper on the subject was 30 years old when he received the Nobel Prize, but the correlation that he described in it remained the predominant theory at the time of his receipt of the Nobel medal. Taube would have turned 100 this past November 30th , 2015. He died in 2005 in his home in Palo Alto, California at 89 years old.

Linus Pauling, for many years a friend of Taube, wrote to him in 1983 to congratulate him on his prize, calling it a “fine honor.” Pauling also kept a newspaper clipping announcing Taube’s Nobel in a collection of his personal memorabilia. In it, Taube attributed his success in Stockholm to a “domino theory” of scientific awards: once they started coming, you just seemed to get more of them. “I have to pay for it by giving a speech,” Taube said.  And indeed, Taube received numerous other decorations, including the Priestley Medal in 1985.

Born in the small town of Neudorf, Saskatchewan, Henry Taube was the youngest of four boys. The son of German immigrants who moved from the Ukraine and settled in Canada in 1911, Taube reflected fondly on his experiences growing up, noting

Certainly, there is nothing about my first 21 years in Saskatchewan, taken in the context of those times, that I would wish to be changed. The advantages that I enjoyed include: the marvelous experience of growing up on a farm, which taught me an appreciation of nature, and taught me also to discipline myself to get necessary jobs done.

Two years after the completion of his PhD at UC Berkeley in 1940, Taube became a naturalized citizen of the United States. As a young academic, he began studying the chemistry and photochemistry of non-metallic oxidants such as ozone, hydrogen peroxide, and halogens, and their reactions with a variety of inorganic and organic substances. Taube also worked on the subject of electron transfer in chemical reactions for most of his professional life, stating in his Nobel lecture that,

by an accident of history, I was a graduate student at the University of California, Berkeley, about the time the first natal stirrings of [this] subject occurred, and at a place where those stirring were most active.

His interest in the measurement of the rates of self-exchange reactions was shared by many, but not reflected in research or development for years to come. Students who might have harbored plans to carry out such experiments, Taube later pointed out, became engaged in war-related activities instead.

Taube’s first academic appointment was as an assistant professor at Cornell, where he engaged in the study of oxidation-reduction reactions, or redox reactions. In 1943 he began his correspondence with Linus Pauling, asking him to visit Cornell and deliver a lecture on antibody reactions, one of Pauling’s areas of specialty at the time. Pauling declined, stating that he would not be traveling in the vicinity of Ithaca any time soon. Taube tried again to meet with Pauling while on a trip to UCLA in 1949, but Pauling was out of his office.

It is something of an irony that Taube, anxious to connect with such an eminent figure in chemistry, would become the chair of a department where Pauling would work later in life. While the pair did not have much luck connecting in the 1940s, forty years later they would regard one another as close companions.


As an associate professor at the University of Chicago, Taube studied charge transfer complexes, describing metal-ligand bonds in terms of molecular orbital language. As a result, the new field of mixed-valence compounds began to develop. Taube’s continued study in this area united the divergent disciplines of classical coordination chemistry and organometallic chemistry, bringing inorganic chemistry into a more modern age.

Taube’s contributions were notable as confusion between thermodynamic and kinetic stability of coordination compounds had plagued coordination chemistry for decades, hindering theoretical advancement in the field. Classical coordination chemistry was created by Alfred Werner in 1893, with little groundbreaking work in the area come to pass in the four decades following. At this same time, organic and biological chemistry were progressing in exciting ways, in no small part due to work being conducted by Linus Pauling. Indeed, in organic chemistry, Pauling’s influence is ubiquitous: the mechanisms of organic substitution reactions, the discovery of biochemical cycles and molecular disease, the role of vitamins and antibiotics – all were touched by his genius. But for inorganic chemistry, even Pauling’s valence bond theory did not prompt advancement. This all began to change with Henry Taube.

By shifting focus from classical coordination chemistry toward the mechanisms of redox reactions, Taube affected an important shift that revitalized inorganic chemistry. Specifically, Taube established a dichotomy between inert and labile complexes, using valence bond theory to frame the definitions of these metal ions. The effect on inorganic chemistry was so monumental, it has since been dubbed by some as the “Taube Revolution.” Published in 1952, Taube’s “Rates and Mechanism of Substitution Reactions in Inorganic Complexes in Solution” is a foundational work. This was an important personal year for Taube as well; it was the year that he married his wife, Mary. They would have four children; Karl, Heinrich, Linda and Marianna.

By the early 1970s, Taube was chairman of the Chemistry Department at Stanford University, where Pauling too was a faculty member. When Pauling was reclassified as an emeritus member of the faculty in 1972, a memo from Taube to Calvin Quate, the associate dean of humanities and sciences at Stanford, made his opinion of Pauling’s situation clear: “Linus Pauling’s contributions to our department are much valued,” Taube clarified for Quate. “It is the intention of the Executive Committee to recommend reappointment on a year-by-year basis for as long as he continues to be effective in supervising a research program.”

The following year, Pauling wrote to Taube to express concern about his position. In his response, Taube pointed out that, though now classified as a professor emeritus, the administration’s action did not change Pauling’s current appointment as regular faculty, which would remain in force until 1974. After that time, as indicated by Taube in his memo to Quate, Pauling would continue to be reappointed as long as he remained “productive in scientific work.” Taube added, “I feel confident that the change in nominal status next fall will not interfere with your scientific program.”

Over the years, the two men enjoyed a lively correspondence on many issues related to work and pleasure. Taube sent Pauling reprints of his papers, and asked Pauling just before receiving his Nobel Prize, “When you first formulated your ideas on back bonding, did you have any inkling of what its ramifications might be?” (in this, Taube was referring to his own work with redox reactions in metal complexes.) Taube added, “After things settle down, post-Stockholm, Mary and I hope to get together with you again socially.”

Taube also referred to Pauling as the living person whom he most admired, and the two saw eye to eye on many issues. In particular, Taube used his position as a Nobel laureate to argue for educational reform and nuclear disarmament, which he saw as the country’s most important issues in the 1980s. “I’m appalled not that the general public tends to be rather ignorant,” Taube explained, “but they don’t even care about the scientific issues.” All informed citizens, Taube thought, needed to know the basics, and in this he agreed with Pauling. “The training that science teachers get simply isn’t adequate for the job in the elementary schools,” he said. “The solution is to improve science teaching for teachers, and pay them a wage commensurate with their responsibilities.”

taube in lab

Though in many ways Taube is to inorganic chemistry what Pauling was to the organic side, Taube’s work has also been described as setting the stage for electron transfer studies in organic areas, including peptides, proteins, and other complex biomolecules –  all areas of study crucial to many of Pauling’s interests. This is presumably one reason why Pauling recruited Taube to support the Linus Pauling Institute of Science and Medicine.

The connection between Taube and the Institute began very early on, in 1972, when Pauling suggested to him that some of Taube’s graduate students might be interested in also working on orthomolecular studies with either himself or his assistant, Arthur B. Robinson. Twelve years later, in 1984, Pauling wrote to Taube asking him to join the Institute’s board of associates. Taube accepted, despite the fact that the Institute was involved in a very public battle with the Mayo Clinic, one based on what Pauling described in his letter as, “a thoroughly misleading account of [the Institute’s] work.”

In 1987 Pauling asked his friend to become even more involved, writing that he was pleased to tell him that the Board of Trustees had authorized him to ask Taube to join their rank and file. Taube accepted this position as well, but ultimately resigned in 1989, stating that he could “provide little help in solving the kind of [largely financial] problem that the Institute faces,” and that he believed he was “usurping an opportunity for service which others, of greater influence in financial or medico-scientific circles, could better fill.” Pauling was disappointed and disagreed with the decision, but responded simply that it would not otherwise impact Taube’s connection to the Institute.

Henry Taube’s love of chemistry and the impact that he made on the field seemed sometimes unbelievable to the man himself. Humble by nature, Taube offered in his Nobel lecture that he had only, “focused rather narrowly on electron transfer reactions between metal complexes.”

While Pauling and many others recognized and cited the importance of his work in developing a general principle of electron transfer, Taube remained much more cautious in his assessment. The principles that he had derived, Taube pointed out, manifested differently in different materials and reactions. Consequently, the descriptive chemistry of such relationships could be quite different.

Nonetheless, Taube saw these differing manifestations as an exciting challenge, describing them in his Nobel lecture as “the fabric of chemistry.”  In this love of scientific inquiry and the quest for a better understanding of the natural world, Taube was once again reunited with his close friend, Linus Pauling.


An Interview with Balz Frei, Director of the Linus Pauling Institute

Balz Frei

Balz Frei

Oregon State University is turning 150 years old in 2018, and already several projects are being developed to mark the occasion.  One of them is a major oral history initiative that is capturing the stories of a wide array of alumni, faculty, staff, administrators and friends of OSU.

Several months ago, the project conducted an interview with Dr. Balz Frei, who has led OSU’s Linus Pauling Institute since 1997.  A Swiss native, Frei worked under Bruce Ames at UC-Berkeley before moving on to Harvard, the Boston University School of Medicine and, ultimately, Oregon State.

Frei’s research has always focused on the processes fundamental to human health. During his time in Berkeley, Frei became interested in vitamin C and met Linus Pauling. His later work has focused on oxidative stress and the role that it plays in atherosclerosis. He has also investigated arterial function and potential dietary compounds – including vitamin C – that might help prevent oxidation of LDL cholesterol.

Under Frei’s leadership, the Linus Pauling Institute has stabilized its funding base, hired several principal investigators and made substantial contributions to the published literature on subjects relating to nutrition and optimal human health.

In 2011 the Institute celebrated a major milestone with the completion of the Linus Pauling Science Center. This 105,000 square foot facility, built for $62.5 million, is the largest academic facility project in OSU history. Now housed in this new space, LPI continues to conduct research on cardiovascular and metabolic diseases, healthy aging, and cancer chemoprotection, and engages in public outreach through its Micronutrient Information Center and Healthy Youth Program.

Excerpts from Frei’s oral history interview, including his memories of meeting Pauling, his sense of Pauling’s vitamin C work, and his vision for the future of LPI, are included below the cut.

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The Discovery of Human Plastin at the Pauling Institute

Milestones in Plastin Research

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

In 1985 my lab at the Linus Pauling Institute of Science and Medicine (LPISM) in Palo Alto, California started to work on an abundant protein of white blood cells (lymphocytes, macrophages, etc.) that mysteriously appeared in human tumor-derived cells of solid tissues (carcinomas, fibrosarcomas, melanomas, etc). I had noticed this phenomenon a few years earlier while at the National Institutes of Health. I also noticed that this protein appeared in oncogenic virus-transformed (SV40 virus) human fibroblasts, but the protein was not expressed in the normal fibrolasts.

I was intrigued by the fact that a major protein of circulating blood cells would be induced during solid tumor cell development because it is well known that solid tumor cells become more anchorage-independent and can circulate like white blood cells to metastasize to other organs. My colleague, David Goldstein, took the lead in examining the expression of this mysterious protein in different cell types of fractionated white blood cells. At the time this protein was assigned only a number (p219/p220) corresponding to its position in two-dimensional protein profiles. We found that this protein was abundantly expressed in all normal white blood cell types that we examined but it was not expressed in normal cells of solid tissues (Goldstein et al, 1985).

When David’s paper was submitted to Cancer Research, the reviews came back positive and the paper was accepted for publication, but one reviewer asked that we give the protein a name. I was thrilled by the thought of naming a protein and its gene which would immortalize our work, so I took on the serious task of coming up with a name that had lasting meaning. My theory was that this cancer marker contributed in some then-unknown way to the plasticity of the cytoplasm in solid tumor cells because of its normal presence in circulating white blood cells. Also, I had seen the great movie, The Graduate, with Dustin Hoffman and recalled that amusing scene depicted in the picture included below. So I named the protein “plastin” – the greatest new thing since sliced bread. 🙂

The Graduate

That same year, I met Steve Kent from Caltech at a meeting in Heidelberg, Germany. After hearing my talk, Steve suggested that we collaborate. He mentioned that a postdoctoral fellow in Leroy Hood’s lab, Dr. Ruedi Aebersold, was trying to develop a more sensitive protein sequencing method for purposes of determining snippets of amino acid sequences from small amounts of unknown proteins eluted from two-dimensional gels (protein profiles) like the gels that we used to characterize plastin in David’s paper. If we could get an accurate partial sequence of plastin, we could devise a nucleic acid probe based on the genetic code that could be used to clone a plastin “copy DNA” from a cDNA library. If the plastin cDNA was cloned, we could then define the protein and perhaps its function by determining the nucleic acid coding sequence in the clone.

Madhu Varma.

Madhu Varma.

I gave Dr. Madhu Varma at LPISM the arduous task of isolating the plastin polypeptide “spot” for sequencing. Madhu cut out the stained spot from 140 two-dimensional gels, in effect purifying enough protein for sequencing by Ruedi at Caltech. Madhu succeeded and Ruedi produced eight short peptide sequences that could be used to develop short nucleic acid probes that would hybridize to the plastin cDNA clone isolated from a tumorigenic human fibroblast cDNA library.

Ching Lin.

Ching Lin.

Dr. Ching Lin at LPISM took one of the nucleic acid probes and immediately attempted to screen a tumorigenic fibroblast cDNA library. If we identified any clones that bound this probe, then we would perform a quick test to determine that we had cloned the plastin coding sequence. But science is full of surprises and we found that the first clone he isolated detected a gene product that was not in lymphocytes but only in normal human fibroblasts – in other words, it failed the test. This is where Ching’s brilliance took over. He was convinced that this first clone he had isolated was indeed a plastin coding sequence so he used this clonal DNA as a new probe against the tumorigenic fibroblast cDNA library. He isolated a new clone that passed the test and detected a gene that was expressed in lymphocytes and tumorigenic fibroblasts but not in normal human fibroblasts.

We performed other experiments that proved that we had cloned two different isoforms of plastin: L-plastin, expressed in lymphocytes and solid tumor-derived cells, and T-plastin that was expressed in normal solid tissues and co-expressed with L-plastin in tumor cells from solid tissues (Lin et al, 1988; Lin et al, 1990). Ultimately this work led to the complete characterization of the human plastin multigene family and verification that both isoforms were aberrantly expressed in various types of human tumors.

The figure at the top of this post maps the progression of discovery that followed our research, which began at the Pauling Institute in 1985. Our publications are shown in red in the graph and research published by other labs is shown in the blue bars.

Here are several plastin milestones discovered by other researchers:

  • T-plastin is abundantly induced in Sezary lymphomas, a lethal T-lymphocyte cancer (Su et al, 2003);
  • L-plastin induction in solid tumors contributes to invasive cancer growth and metastasis (Klemke et al, 2007);
  • Mutations in T-plastin play a role in the genetic disease Spinal Muscular Atrophy (Oprea et al, 2008); and
  • Most recently mutations in both L- and T-plastin promote re-growth of colon carcinomas following surgical resection of these tumors and chemotherapy (Ning et al, 2014).

These developments are more or less typical of the way science works. Progress in understanding complex phenomena like human cancer is the work of many scientists that builds on the observations of other scientists. This is just one example of the productive contributions in biomedical research that came about through early discovery research at LPISM in the 1980s.