Pauling, Zuckerkandl and the Molecular Clock

Dr. Emile Zuckerkandl, 1986.

In 1963, a year after first publishing their ideas on the study of molecules as indicators of evolutionary patterns, Emile Zuckerkandl and Linus Pauling continued to explore what they felt to be a very promising thread of inquiry.

Specifically, the two joined in arguing that the molecular clock method – as they had since termed it – might be used to derive phylogenies (or evolutionary trees) from essentially any form of molecular information. This position was further explicated in “Molecules as Documents of Evolutionary History,” an article published in Problems of Evolutionary and Industrial Biochemistry, a volume compiled in 1964 on the occasion of Soviet biochemist Alexander Oparin’s 70^th birthday.

Zuckerkandl and Pauling’s most influential work on this subject was first put forth that same year, in a paper that they presented together at the symposium “Evolving Genes and Proteins,” held at the Rutgers University Institute of Microbiology. The talk, formally published a year later and titled, “Evolutionary Divergence and Convergence at the Level of Informational Macromolecules,” classified molecules that occur in living matter into three groups. Each of these groups was identified according to new terms that the pair had developed that were based on the degree to which specific information contained in an organism was reflected in different molecules. These three categories were:

1.Semantophoretic Molecules (or Semantides), which carry genetic information or a transcript of it. DNA, for example, was considered to be composed of primary semantides.

2. Episemantic Molecules, which are synthesized under control of tertiary semantides. All molecules built by enzymes were considered episemantic.

3. Asemantic Molecules, which are not produced by the organism and do not express (directly or indirectly) any of the information that the organism contains. In their discussion, Zuckerkandl and Pauling were quick to point out that certain asemantic molecules may shift form. Viruses, for example, can change form when integrated into the genome of the host; so too can vitamins when used and modified anabolically.

Semantides were considered most relevant to evolutionary history, but the term never caught on in biology, paleontology, or other allied fields relevant to the study of evolution. Nonetheless, whatever the nomenclature, the “semantides” that Zuckerkandl and Pauling wanted to investigate – DNA, RNA, and polypeptides – proved indeed to be precisely the treasure trove of information on evolutionary history that the duo had hoped would be the case.

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A figure from the French translation of Zuckerkandl and Pauling’s 1964 paper.

Fundamentally, Zuckerkandl and Pauling aimed to elucidate how one might gain information about the evolutionary history of organisms through comparison of homologous polypeptide chains. In examining these substances, the researchers sought specifically to uncover the approximate point in time at which the last common ancestor between two species disappeared. In essence, it is this approach that we speak of when we use the terms “molecular clock” or “evolutionary clock.”

Zuckerkandl and Pauling argued that, by assessing the overall differences between homologous polypeptide chains and comparing individual amino acid residues at homologous molecular sites, biologists and paleontologists would be better equipped to evaluate the minimum number of mutational events that separated two chains.

With this information in hand, researchers would thus be empowered to exhume the details of evolutionary history between species, as inscribed in the base sequences of nucleic acids. This set of data, they believed, would hold even more useful information than would corresponding polypeptide chain amino acid sequences, since not all substitutions in the nucleotides would be expressed by differences in amino acid sequence.

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A table from Zuckerkandl and Pauling’s 1965 Bruges paper.

As their work moved forward, Pauling and Zuckerkandl published another paper, 1965’s “Evolutionary Divergence and Convergence in Proteins.” This publication appeared in Evolving Genes and Proteins, a volume that emerged from a conference that the two had attended in Bruges, Belgium.

By this point, the duo’s idea of the molecular clock, or “chemical paleogenetics,” had elicited opposition from organismal evolutionists and taxonomists, as well as some biochemists. Now referring to their “semantides” simply as informational macromolecules, Zuckerkandl and Pauling used the 1965 meeting to argue strongly against their skeptics. Zuckerkandl chided

Certainly we cannot subscribe to the statement made at this meeting by a renowned biochemist that comparative structural studies of polypeptides can teach us nothing about evolution that we don’t already know.

Pauling likewise added that

Taxonomy tends, ideally, not toward just any type of convenient classification of living forms (in spite of a statement to the contrary made at this meeting).

Directly challenging those present who were attempting to discredit the idea of the molecular clock, the pair insisted that taxonomy tended toward a phyletic classification based on evolutionary history. Since the comparison of the structure of homologous informational macromolecules allowed for the establishment of phylogenetic relationships, the Zuckerkandl-Pauling studies of chemical paleogenetics therefore had earned a place within the study of taxonomy. This, they argued, was true both as a method of reinforcing existing phyletic classifications and also of increasing their accuracy. Specifically, the two claimed that

The evaluation of the amount of differences between two organisms as derived from sequences in structural genes or in their polypeptide translation is likely to lead to quantities different from those obtained on the basis of observations made at any other higher level of biological integration. On the one hand, some differences in the structural genes will not be reflected elsewhere in the organism, and on the other hand some difference noted by the organismal biologist may not be reflected in structural genes.

Indeed, it was these early observations, coupled with additional work conducted by those scientists who took their ideas seriously, that allowed for the development of a successful measure of rates of evolutionary change over time. Without these data, modern paleontologists, physical anthropologists, and geneticists would not be able to accurately determine evolutionary histories. Today, this technique has been systematized and specialized in the field of bioinformatics, which is now foundational to many studies in both biology and medicine.

The taxonomic purpose of the molecular clock, however, was only a byproduct of Zuckerkandl and Pauling’s main ambitions in studying paleogenetics: to better understand the modes of macromolecular transformations retained by evolution; to elucidate the types of changes discernible in information content; and – most importantly for Pauling – to identify the consequences of these changes for a given organism.

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Linus Pauling, 1992.

Despite its considerable potential, the work of Zuckerkandl and Pauling, though conducted at such a critical juncture in a nascent field, was largely forgotten as recently as the early 1990s. In fact, in Allan Wilson and Rebecca Cann’s 1992 article, “The Recent African Genesis of Humans,” it was implied that the concept of the molecular or evolutionary clock was first developed and employed by a Berkeley anthropologist, Vincent Sarich. Sarich had collaborated with Wilson in 1967 to estimate the divergence between humans and apes as occurring between four to five millions years ago.

Pauling was still alive in 1992, and seeing this article he duly wrote to the editor of its publisher, Scientific American, pointing out that that, in fact, he and Zuckerkandl had, in 1962, issued their own estimate of the disappearance of the last common ancestor of gorilla and man. Zuckerkandl and Pauling’s calculations had yielded a divergence at about 7.6 million years before present, which Pauling pointed out was much closer than Sarich’s figure to the more recent estimates of divergence determined by Sibley and Ahlquist in 1984 and 1987. Notably, Pauling and Zuckerkandl’s estimate continues to remain closer to more contemporary notions of 8 to 10 million years.

Today, Emile Zuckerkandl and Linus Pauling are remembered as having first championed the notion of the molecular clock, even if many of the details now deemed as fundamental still needed to be ironed out by an array of scientists who followed. Regardless, as in so many other areas of science, Pauling proved once more to be on the ground floor of a new discipline. This was an academic venture that continued also to serve the younger Zuckerkandl well, as he continued on through a prolific career in science that concluded with his passing in 2013.

Molecules as Documents of Evolutionary History

Linus Pauling and Emile Zuckerkandl, 1986.

[Part 1 of 2]

“Of all natural systems, living matter is the one which, in the face of great transformations, preserves inscribed in its organization the largest amount of its own past history. We may ask the question: Where in the now living systems has the greatest amount of their past history survived, and how it can be extracted?”

-Linus Pauling and Emile Zuckerkandl, 1964

Austria-born Emile Zuckerkandl fled to Paris with his parents to escape the Nazi occupation of his homeland when he was only sixteen. Twenty years Linus Pauling’s junior, this extraordinary scientific mind was nurtured through the study of the biological sciences at the University of Illinois in the United States, and the Paris-Sorbonne University in France. During the course of these studies, Zuckerkandl developed a particularly keen interest in the molecular aspects of physiology and biology, and is now regarded to have been a major contributor to both fields.

Zuckerkandl first met Linus Pauling in 1957, a time period during Pauling himself was spearheading the new study of molecular disease, following his earlier, groundbreaking discovery of the genetic basis of sickle cell anemia. Two years later, Zuckerkandl joined Pauling as a post-doc in the Chemistry and Chemical Engineering Division at the California Institute of Technology. Once arrived, Zuckerkandl was encouraged by Pauling to study the evolution of hemoglobin, a research project that was informed by a basic and crucial assumption that the rate of mutational change in the genome is effectively constant over time.

This assumption was something of a hard sell for biologists at the time, due to the prevailing belief within the discipline that mutations were effectively random. Undaunted, Pauling and Zuckerkandl moved forward with their project and ultimately created a model that, over time, ushered in major changes to the conventional wisdom.

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The Pauling-Zuckerkandl project was first revealed to the world in a co-authored paper that appeared in 1962’s Horizons in Biochemistry, a volume of works written and dedicated to the Nobel winning physiologist Albert Szent-Györgyi. The paper, titled “Molecular Disease, Evolution, and Genic Heterogeneity,” is regarded today as a foundational work in its application of molecular and genetic techniques to the study of evolution.

At the time that Pauling and Zuckerkandl wrote this first joint paper, Pauling was, as the title of the work might suggest, very interested in molecular disease; so much so that he was thinking about molecular disease and evolution as occupying two sides of the same coin. Defining life as “a relationship between molecules, not a property of any one molecule,” Pauling believed that disease, insofar as it was molecular in basis, could be defined in exactly the same way. Since both evolution and molecular disease were merely expressions of relationships between molecules, the distinction between the two became blurred for Pauling, who felt that the mechanism of molecular disease represented one element of the mechanism of evolution.

In their paper, Pauling and Zuckerkandl outlined their point of view as follows:

Subjectively, to evolve must most often have amounted to suffering from a disease. And these diseases were of course molecular. …[T]he notion of molecular disease relates exclusively to the inheritance of altered protein and nucleic acid molecules. An abnormal protein causing molecular disease has abnormal enzymatic or other physicochemical properties. Changes in such properties are necessarily linked to changes in structure. The study of molecular diseases leads back to the study of mutations, most of which are known to be detrimental. A bacterium that loses by mutation the ability to synthesize a given enzyme has a molecular disease. The first heterotrophic organisms suffered from a molecular disease, of which they cured themselves by feeding on their fellow creatures. At the limit, life itself is a molecular disease, which it overcomes temporarily by depending on its environment.

These assertions – in particular that “life itself” was a molecular disease – were so strange and seemingly outrageous that many biologists dismissed the paper outright. However, the basic idea that the pair was considering simultaneously sparked the interest of many other scientists who willing to entertain the consequences of this mode of thinking. If Pauling and Zuckerkandl were right, then every vitamin required by human beings stood as a witness bearing testimony to the molecular diseases that our ancestors contracted hundreds of millions of years ago. These “diseases” would manifest negative symptoms only when the curative properties of the nutrients gained from our natural environment through food and drink proved insufficient to dampen their effects.

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This line of reasoning provided the impetus for Pauling and Zuckerkandl to begin examining differences between the genetic code as a tool to better understand evolutionary history. Though they did not call it “the molecular clock” at the time, the concept served as the foundation for the genetic analysis of species over long periods of evolutionary history.

Fundamental to Pauling and Zuckerkandl’s argument was the notion that there was no reason to place molecules at specific points “higher” or “lower” on an evolutionary scale. Horse hemoglobin, for example, is not less organized or complex than is human hemoglobin, it is simply different. The same is true for the genetic information contained in the hemoglobin of humans as compared to other primates, such as gorillas.

As Zuckerkandl examined differences of these sorts, he was not surprised to find that the peptide sequences of a gorilla were more similar to a human’s than a horse’s were to either. He and Pauling then began to consider how these sequences must be indicative of the millions of years of separate evolution that had passed since the disappearance of the last common ancestor linking horses and primates.

While compelling in its own right, for Pauling the chief purpose of understanding these differences was to discern crucial information about the human condition and to define the parameters of optimal health. Indeed, Pauling fundamentally believed that an improved understanding of the transitions that the genetic code had undergone would ultimately reveal new and effective treatments for molecular diseases.

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Table I from Pauling and Zukerkandl’s 1962 paper.

To demonstrate the efficacy of their methodology, Pauling and Zuckerkandl calculated the number of genetic differences that exist between the alpha and beta chains of hemoglobin peptide sequences in horses, humans, and gorillas, which they then used to determine the time that had elapsed since the erasure of the last common ancestor linking these species. In seeming support of their claims, the authors found that their figures matched pretty closely with data uncovered by paleontologists.

Despite this, the impact of Pauling and Zuckerkandl’s paper dissipated pretty quickly. For other established figures in the field, Pauling and Zukerkandl had failed to prove the essential assumption that evolution should proceed with relative uniformity over time. Lacking a clear reason to accept that genetic change occurs at a constant rate, there was no compelling reason to believe that Pauling and Zuckerkandl’s molecular clock should give an accurate picture of evolutionary history.

Nonetheless, the idea of the molecular clock found a degree of traction among biologists who valued its potential to corroborate and increase the accuracy of existing phylogenetic assignments. And as we’ll discuss in our next post, Pauling and Zuckerkandl continued to explore their ideas, eventually building a body of work that came into far greater favor a few decades later.

The 1980s at the Linus Pauling Institute – A Wonderful Place to Be

John Leavitt

[Ed Note: This is part one of a two part series of guest posts written by John Leavitt, Ph.D., Nerac, Inc., Tolland, CT.]

There was an article about Linus Pauling in Time magazine in early 1981 about the fact that at the age of 80 he was still seeking a grant from the National Institutes of Health (NIH) to fund his research on ascorbic acid for treating diseases. This news caught my attention and I looked into the possibility of joining Dr. Pauling’s institute. Toward the end of the summer I was invited to visit the Pauling Institute in Palo Alto, CA to give a seminar on my research at NIH.

In late August Koloman Laki, an aging scientist at NIH, called me up and invited me over to his lab in NIH Building 10, a short walk across the campus from my lab in NIH Building 37. He was interested in talking to me about my recent discovery of mutations in human non-muscle cytoskeletal actin that was published in Cell in late 1980. This protein is the major architectural protein of all eukaryotic cells and we had shown that it was the most highly conserved protein in evolution of the species from yeast to humans. This fact made these mutations even more interesting.

Koloman was a protege of the Hungarian Nobel Prize winner Albert Szent-Györgyi who, I later learned, was much admired by Dr. Pauling because he had discovered both vitamin C and actin. Koloman described how Szent-Györgyi discovered muscle actin. When I mentioned that I was to visit the Linus Pauling Institute in late September, he told me about Emile Zuckerkandl’s and Dr. Pauling’s work on the ‘biological clock,’ which provided evidence in support of Charles Darwin’s theory on divergence of the species.

In the last week of September I flew to Oakland, CA and was picked up at the airport by Emile who was President of the Linus Pauling Institute of Science and Medicine. The next morning I stood up in front of Dr. Pauling and the institute staff to tell them about my discovery of a mutant human beta-actin and my speculation on its involvement in neoplastic transformation. The evidence suggested that I had actually discovered at least two mutations in the same gene, each of which caused a progression to a higher malignant state.

Linus Pauling was in the front row and was all smiles. He asked me if I knew who discovered actin. I was prepared to answer that question thanks to Koloman Laki. In the afternoon I met with Emile who offered me a Senior Scientist position at the Institute, which I accepted. At the time it would be me and Dr. Pauling with separate research interests. Nevertheless, Dr. Pauling could appreciate my discovery as, 32 years earlier, he had described the molecular basis for sickle cell anemia, which predicted that mutations in hemogloblin governed the sickled shape of red blood cells which caused the disease, sickle cell anemia. Likewise, human cancer cells exhibit altered shapes.

So I resigned my secure job-for-life at NIH and moved to Palo Alto to join the struggling Linus Pauling Institute. My technician, Patti Porecca, hired from Bob Gallo’s lab at NIH, would follow me to the Pauling Institute.

Cloning of the Human Beta-Actin Gene

After I arrived at the Pauling Institute, two of my colleagues at NIH and I published a comprehensive study of the changes in protein expression between normal and neoplastic cells in Carcinogenesis using high-resolution computerized microdensitometry to analyze the complex protein patterns (my first paper from the Pauling Institute). This was the first time that such a study had been published, e.g. the comparative profiling of expression of a large number of proteins in neoplastic cells. It was a study of the 1,000 most abundant proteins in normal and neoplastic human cells which revealed potential biomarkers and causative genetic events for human cancer. At the time it was staggering to view these patterns but perfect for my dyslexic brain and mind’s eye. In addition, we published another paper in Cell that described, for the first time, the progression of a neoplastic human cell to a higher malignant cell following a second mutation in the same beta-actin gene. Early in 1982, Steve Burbeck and Jerry Latter at the Institute set up the same computerized microdensitometry platform I had exploited at NIH.

Jerry Latter gave a stirring talk at Argonne Labs in Chicago demonstrating that computerized microdensitometry of protein profiles could be used to determine the identities of unknown proteins based upon determining their amino acid compositions in situ in protein profiles. This paper was published in Clinical Chemistry in 1984. At the same meeting, Steve Burbeck described a truly innovative invention that could measure beta-particles emitted from radioactive protein profiles to produce a direct image of the protein profile pattern. As a group we had entered an exciting period of discovery and innovation at the Linus Pauling Institute.

When I got to Palo Alto in December 1981, I called Professor Larry Kedes at Stanford and we embarked on a collaboration to clone the human beta-actin gene. His impressive postdoctoral fellow, Peter Gunning, taught me some basic recombinant DNA techniques, and I was off to the races. The difficulty was to identify the functional gene in a sea of actin pseudogenes (sometimes referred to as junk DNA). I used an elegant method of homologous recombination developed in Tom Maniatis’ lab at Harvard that had never been used before to clone a novel gene (In fact, cloning of human genes was just getting started at the time). This was smart because Professor Maniatis would be the chairman of the NIH study section that reviewed my first grant proposal submitted from the Pauling Institute. I did not know it at the time but within a month or two I had cloned the functional beta-actin gene a week before Christmas in 1982.

I developed a scheme to identify the correct gene among 300-400 clones of pseudogenes that Patti and I had cloned and the strategy worked. We gave Dr. Sun-Yu Ng the task of sequencing the DNA clone that we were betting on. Rather quickly we determined that we had cloned the functional human beta-actin gene because the DNA sequence that Sun-Yu determined from our candidate clone accurately encoded the amino acid sequence of human beta-actin protein that I had published in Cell in 1980 (with Klaus Weber). Quite coincidentally another lab discovered a rat oncogene that was a fusion of part of an actin gene with a tyrosine kinase gene. I sent this information off to the study section that was reviewing my grant in January 1984 as added evidence that the actin gene was in some way relevant to neoplasia.

My colleagues and I at the Pauling Institute and Stanford published our successful isolation of both the mutant and wildtype human beta-actin genes in Molecular and Cellular Biology in October 1984. As shown below, we had given Armand Hammer’s name to our cancer research program because of his generosity in helping to fund the Linus Pauling Institute.

In January 1984 I was awarded a grant of about $110,000 a year for two years from the American Cancer Society…what a relief. Later in the spring I received word from Professor Maniatis’ NIH study section that our program would also be funded in June by a grant of about $150,000 a year for 3.5 years from the National Cancer Institute for the same work. I was able to hire Dr. Ching Lin from Iowa State University and Dr. Ng (Sun-Yu) from Kedes’ lab. By 1985 Sun-Yu finished the complete DNA sequencing of the human beta-acid gene and Ching sequenced the copy of the beta-actin gene that had two mutations to formally prove the mutations at the level of the gene. Everything that we had learned about the genetic code and amino acid sequences of proteins made our findings predictable. I had learned from my own research how Darwin’s theory of evolution and natural selection worked.

This was the year I finally successfully transferred in recombinant gene inside a cell in culture. I transferred the mutant human actin gene into a rat fibroblast cell line to show that I had cloned the functional gene which could abundantly express its protein the way the natural endogenous beta-actin gene worked (shown in a protein profile below).

At this point I had a brief meeting arranged by Emile with Alex Zafferoni, founder and CEO of Alza Corporation, a block away on Page Mill Road. Zafferoni recommended Bert Roland as a patent attorney. I arranged a meeting with Roland, also a block away, for that afternoon to discuss patenting the human beta-actin gene promoter because of its strong constitutive nature (the engine of the gene that drives its expression). I told Bert that this was a collaboration with Peter Gunning and Larry Kedes at Stanford. Roland was famous for filing Boyer’s and Cohen’s genetic engineering patent which created Genentech and eventually funded Stanford with hundreds of millions of dollars.

We published Sun-Yu’s work on the sequence, structure, and chromosomal location (chromosome 7) of the human beta-actin gene in Molecular and Cellular Biology and we published Ching’s work locating three mutations in this gene in the Proceedings of the National Academy of Sciences, sponsored by Linus Pauling. A patent was filed on the beta-actin promoter and over the years it was licensed to about 15 biotech companies by Stanford University. This patent was prosecuted for the full 17 years (the life of a patent) but never issued. The Institute’s first royalty check was about $10,000 in 1986, but most of the royalties were earned by Stanford’s patent attorneys.

Peter, Larry and I published a paper in PNAS on the use of the human beta-actin gene promoter for expression of other genes. This vector was distributed to anyone who asked for it – and many did – and to those companies that licensed the invention. At last count this paper had more than 1,000 reference citations.

Our paper popularized the actin promoter as a strong constitutive promoter of foreign gene expression. Soon the rice actin promoter would be used to make Round-up Ready crops by DeKalb Genetics and Monsanto, and giant tilapia fish would be engineered with growth hormone under the control of the fish beta-actin promoter. There were even fluorescent mice running around in Japan created with firefly luciferase expressed by the beta-actin promoter (which I called “the cat’s meow”). Since cytoplasmic actins are the most abundant proteins in most cells you could use the promoter to abundantly express foreign genes in most cells of any animal.

In 1987 we also published the culmination of my research on the mutant beta-actin gene in Molecular and Cellular Biology. When I introduced this gene into non-tumor forming immortalized human fibroblasts they became tumorigenic. The results showed that the more abundant the expression of the mutant beta-actin, the more tumorigenic the non-tumorigenic cells became and the cells that came out of the tumors were enhanced further in the level of mutant beta-actin expression. This was a sensational finding that was the goal of research which began with the discovery of the mutant beta-actin in 1978 at NIH.

Emile Zuckerkandl, 1922-2013

Pauling and Zuckerkandl in Japan, 1986.

We close out our posting schedule for the year on a melancholy note with this remembrance of the life of Emile Zuckerkandl, who passed away on November 9th at the age of 91.

Zuckerkandl was born in Vienna, Austria on July 4, 1922. His family was of Jewish descent and active in the scientific, artistic, and political culture of the time. His father, Frederick, was a biochemist and his mother, Gertrude, was a portrait and landscape artist whose father, Wilhelm Stekel, was an anatomist. His paternal grandfather, Emil Zuckerkandl, was also an anatomist – one of great prominence – whose wife, Berta, was a journalist and art critic. Berta also hosted salons in Vienna attended by all manner of literary, musical and artistic figures.  She likewise used her position to speak out against Nazi occupation and militarization, a stance that forced the Zuckerkandls to flee from Austria into France in 1938 and to later to Algiers.

The family’s flight from Vienna briefly disrupted educational pursuits for Emile, who was attending high school at the time. He finished school in Paris before going to university in Algiers where he studied medicine. While there – as he would relate in a 1996 interview with Gregory Morgan at the Dibner Institute – “I came to understand that it was biology that I was interested in, more than medicine.” He was soon expelled however, a victim of the Vichy’s anti-Jewish laws that extended to colonial Algiers. By this point, the only schooling still available to him was at the music conservatory, where he studied piano.

Emile and Berta Zuckerkandl, ca. 1930. Image courtesy of the Austrian National Library.

While the family had escaped the dangers of residence in Austria and France, Emile’s outspoken grandmother was still not completely safe and so she sought to go to the United States. During this time, Albert Einstein took an interest in the young Zuckerkandl and helped him to obtain a scholarship to study in the U.S. The Zuckerkandls ultimately did not need to come to the United States as the Nazis were soon defeated, thus rendering France safe for the family once again. Nonetheless, Emile spent one year at the Sorbonne in Paris before taking advantage of the scholarship that Einstein had helped him to obtain.

Once stateside, Zuckerkandl attended the University of Illinois where, in 1947, he obtained a master’s degree in physiology, spending summers researching at the Marine Laboratory at Woods Hole in Massachusetts. He returned to the Sorbonne afterwards and earned his PhD in biology. Following that, he spent ten years at the Roscoff Biological Station in western France – the country’s largest marine laboratory – where he carried out biochemical research.

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Emile and Jane Zuckerkandl, October 1970. Image courtesy of the Esther M. Lederberg Collection.

In 1958, while in Paris, Zuckerkandl arranged to meet with Linus Pauling. The two had been introduced through Alfred Stern, an Austria-born professor of philosophy at Caltech and a friend of the Zuckerkandl family. The following year Pauling recommended Zuckerkandl for a post-doc position at Caltech, stressing his relationship with Stern as well as with Charles Metz, who had received his PhD in biology from Caltech and was the brother of Emile’s wife, Jane.

Buoyed by Pauling’s initial recommendation and continued support, Zuckerkandl spent the next five years at Caltech. While there, Zuckerkandl propelled important work on what would become known as the molecular clock. The project was spurred by a suggestion that Pauling made to Zuckerkandl; that he compare the hemoglobin protein sequences of humans and gorillas to trace their evolutionary development. As Zuckerkandl told Morgan, “When Dr. Pauling made this suggestion to me, I was not too happy,” as he wished to continue his own line of research. But “later I understood how right Dr. Pauling was… At first I did not know how lucky I was!” Indeed, the molecular clock and molecular evolution would form the foundation of much of Zuckerkandl’s scientific career.

In 1961 Zuckerkandl, on Pauling’s recommendation, began working in Walter A. Schroeder’s lab, one of the few in the world researching protein sequences at that time. Zuckerkandl proposed that Schroeder coauthor the publication of his evolution work, but Schroeder refused due to his own creationist views. Pauling came to the rescue by suggesting that he coauthor with Zuckerkandl instead, but stipulated that they “should say something outrageous” since the piece was slated to appear in a prominent collection honoring the birth of Albert Szent-Györgyi.

The result was a classic 1962 paper, “Molecular Disease, Evolution and Genetic Heterogeneity,” in which Zuckerkandl and Pauling first postulated the idea of the molecular clock. As Zuckerkandl told Giacomo Bernardi in 2012, Pauling was more focused on his peace work at the time and his involvement with the paper was relatively tangential. Burdened by a crush of other obligations, Zuckerkandl’s coauthor agreed that he would “make some changes that would be moderate, and then the paper would come out as I conceived it.”

Morgan described the basics of the paper and its impact in a 2001 essay.

The molecular clock hypothesis, as it came to be known, proposed that the rate of evolution in a given protein molecule is approximately constant over time. More specifically, it proposed that the time elapsed since the last common ancestor of two proteins would be roughly proportional to the number of amino acid differences between their sequences. The molecular clock, therefore, would not be a metronomic clock – that is, its ‘ticks and tocks’ would not be uniform – but would instead be a clock based upon random mutation events. In practice, a molecular clock would allow biologists to date the branching points of evolutionary trees.

The molecular clock hypothesis, while rarely cited among Pauling’s most important discoveries, has proven to be very influential. The UC Berkeley biologist Alan Wilson claimed that the molecular clock is the most significant result of research in molecular evolution. In his book Patterns of Evolution, Roger Lewin describes the molecular clock as ‘one of the simplest and most powerful concepts in the field of evolution.’ Francis Crick, co-discoverer of the structure of DNA, called the molecular clock a very important idea that turned out to be much truer than most thought when it was proposed.

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For the remainder of his time in Pasadena, Zuckerkandl continued to develop his ideas, and in this was assisted in the laboratory by his wife, Jane. Yet he was also eager to return to France, fueled in part by continued uncertainty surrounding his funding at Caltech. Pauling tried to help by recommending Zuckerkandl for a position in the anthropology department at the University of California – San Diego and by bringing back to Zuckerkandl contact information for scientists in Europe. Upon returning to Europe for a conference in 1962, Zuckerkandl wrote to Pauling, “It was as exciting, after three years of life in California, to rediscover Europe as it had been to first discover America.” Soon afterwards, he obtained a position at a new research facility in Montpellier, France – the only hitch was that he needed to wait three years for it to be built. In the meantime, Zuckerkandl expressed worry to Pauling that his work on gorilla hemoglobin would soon “be out of date” because of the interruption posed by his return to France.

Once Zuckerkandl and his research materials had finally arrived in Montpellier in 1965, new problems arose. He told Pauling, “I did not foresee the particular kind of obstacles that I find in my way. Bureaucracy is taking over the direction of our laboratory.” (In a 1971 letter, when asking how Pauling had been such a “great fighter” for peace and science, Zuckerkandl concluded that it could only have been because Pauling had “not tried to found a research department in France.”)  This manner of struggle proved a defining feature of Zuckerkandl’s years at Montpellier and it was not long before he and Pauling began seeking out avenues to reunite, both through short visits and Zuckerkandl’s standing invitation for Pauling to come to Montpellier as a visiting researcher. A bright spot occurred in 1970 as Zuckerkandl was offered the editorship of the new Journal of Molecular Evolution by Conrad Springer.

Zuckerkandl with Ewan Cameron, New Years Day, 1979. Image courtesy of the Esther M. Lederberg Collection.

Zuckerkandl eventually decided to leave France and return to the United States. In 1975 Pauling offered Zuckerkandl lab space at the Linus Pauling Institute of Science and Medicine, but by then he was already at Woods Hole where he hoped details might get resolved at his old position and he could return to Montpellier. A bit later, when Zuckerkandl decided to take Pauling up on his offer, Pauling had to turn him down due to the Institute’s mounting financial problems. Zuckerkandl stayed at Woods Hole and had assumed a visiting professorship at the University of Delaware when, in 1976, Pauling offered him a year-long non-resident fellowship.

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LPISM Newsletter, 1977.

Zuckerkandl quickly moved up the ranks at the Institute. At the end of his fellowship, Pauling recommended that he be sponsored for a two year visa and become Vice Director of the organization. By 1979 Zuckerkandl held the additional positions of Vice President and Research Professor, assuming responsibility for carrying out his own work on vitamin C and cancer while also helping Pauling with administrative duties. By the end of the year, Zuckerkandl was taking on even greater administrative responsibilities from Pauling, including budgeting, fund raising, and finding a new home for the Institute.

During this period, Zuckerkandl’s management skills came to the fore. He immediately set out to establish priorities for research, setting a “cutting off point” in time after which any new projects would be “provisionally abandoned.” He also dealt with the storm of controversy caused by the firing of Institute President Art Robinson and Robinson’s statement in Barron’s that high doses of ascorbate led to tumor development in mice. (In a memo to Pauling, Zuckerkandl noted that “the data do not appear to authorize Art’s statement’s” which were most likely based on a “scatter of the experimental points” and nothing more definite.)

The following year, Zuckerkandl was made President and Director of the Institute. Funding continued to be a problem, with each advance seemingly countered by a setback. Typically, at about the same time that the Institute agreed to pay a settlement to Robinson, Zuckerkandl also oversaw the opening of the Armand Hammer Cancer Research Center, with support from its namesake. In 1985, to show his dedication to the Institute, Zuckerkandl deferred a raise that he had been offered until it could be afforded.

However, in 1992 Zuckerkandl’s contract was not renewed. By then the Institute was in a dire financial position and needed to make some very difficult decisions concerning staffing and programs. Nonetheless, Zuckerkandl remained in the building through a lease agreement between LPISM and his new Institute of Molecular Medicine. He also invited many LPISM staff, some of whom had also been laid off, to join him in his fledgling enterprise.

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Emile Zuckerkandl, 1993.

When not managing a research institute, Zuckerkandl continued to produce work on molecular evolution. In 1997 and 2007, continuing a career-long debate over the relationship between molecular evolution and natural selection, Zuckerkandl addressed molecular diseases and “junk DNA” to argue against the neutral theory of molecular evolution. Beginning in the late 1960s, Motoo Kimura, Jack King, Thomas Jukes, and others had used the molecular clock idea to suggest that evolutionary change occurs not because of natural selection, but due to neutral random mutations and allele drift. Zuckerkandl disagreed, arguing that natural selection and the molecular clock were compatible.

Zuckerkandl not only argued against what he saw as misapplications of his own ideas, but also against broader cultural attacks on science. Beginning in the late 1980s, he began to speak out against creationists, telling Pauling in a 1991 memo that “since in this country they seriously threaten education and culture, a response to them needs to be made.”  As Zuckerkandl saw it, the threat was not only cultural but also involved the health of humanity and of the Earth. In a 1991 draft titled “Genetic and Esthetic Winter,” which he shared with Pauling, Zuckerkandl proposed the need for more control of population growth to curb human impact on the environment, an imperative that he saw as being impeded partly by religious beliefs.

Zuckerkandl also turned his gaze toward enemies within the academy, attacking the application of social constructivism to science. In a 2000 paper, he argued that while scientific discoveries may be socially determined, the “mature” results that lead to practical applications, especially in technology and medicine, is “evidence for independence” of science from similar influences.

But Zuckerkandl did not maintain a strict scientism. In “Genetic and Esthetic Winter,” he described the resilience of science, but also its limitations. When speaking about threats to environmental stability, he stated,

In this situation, curiously, scientific culture is perhaps the least threatened province of culture. Yet knowing and knowhow are not enough. Perceiving and feeling cannot be replaced by engineering. We can’t be satisfied with preparing a future in which the environment will be enriching only for the vocation of engineers.

Zuckerkandl’s health steadily deteriorated as he advanced in age. Over time, a troublesome back proved to be especially problematic. He died on November 9, 2013 in Palo Alto, California, the victim of a brain tumor.

A Tough Start to a New Decade

LPISM staff assembled for a group photo. To Pauling’s right are Emile Zuckerkandl, Ewan Cameron and Richard Hicks. By 1992, none of these three crucial staff members would remain affiliated with the Institute.

[A history of the Linus Pauling Institute of Science and Medicine, Part 5 of 8]

For the Linus Pauling Institute of Science and Medicine, the difficult decade of the 1980s was one plagued by lawsuits, dramatic monetary problems, and the death of Ava Helen Pauling. Yet for all of its struggles, LPISM soldiered on as best as it could.

One who would help define the decade to come, Dr. Matthias Rath, was a charismatic, intelligent, young German physician who had a passion for vitamin C and cardiovascular health. He had met Linus Pauling on numerous occasions, and in 1989 Pauling invited him to join the LPISM staff. Rath was charming and popular with many of his colleagues. However Pauling’s oldest son, Linus Jr. – a long-time Institute board member – took caution, noting in a 2012 interview his concern that Pauling would offer a position of importance to somebody that he felt was very inexperienced.

Two other major events occurred in 1990: Pauling and Zelek Herman developed a new method to analyze clinical trial data, and the National Cancer Institute installed a new president by the name of Samuel Broder. Pauling immediately began corresponding with Broder, and eventually convinced him to reopen the case for vitamin C as a treatment and prevention for cancer. This resulted in an international conference held in Washington D.C. in 1991 and sponsored by the NCI. It was titled “Ascorbic Acid: Biological Functions in Relations to Cancer.” Pauling was the obvious candidate for keynote speaker and he later said of the conference, “It was great! A great affair! Very exciting!”

Participants in the NCI symposium on Vitamin C and Cancer, Bethesda, Maryland, September 1991

At this same time, Pauling created a new position at LPISM for Rath, who was named the first Director of Cardiovascular Research. With this, Linus Jr. became even more concerned. Increasingly, he began to question his father’s administrative acumen and began taking steps to assume a more active role in the management of Institute, despite the fact that he lived in Hawaii.

Another big change was on the horizon as well. The city of Palo Alto was planning to change their zoning laws in an effort to increase residency, and informed LPISM that they had three years to find a new home. The Institute realized that the time allotted them was insufficient, and they began a campaign to delay the eviction.  Staff set up card tables in front of businesses, disbursing flyers and circulating a petition to keep LPISM where it was.

The positive response that they received from the locals was staggering and gave the Institute some measure of leverage in their conversations with the city. At one point, Steve Lawson was called before the city council, and one member said that she didn’t want to read in the New York Times that Palo Alto had kicked LPISM out of town. Eventually the council informed LPISM that the zoning law changes were still going to go through, but that the Institute would be granted more time to plan and relocate.

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On the research front, after almost two years of marketing Pauling’s superconductor domestically with no leads, Rick Hicks decided to look abroad for a buyer. He contacted parties all over Europe and Asia, and one day a man showed up at the office to inquire about superconductor sales. He identified himself as an employee of the Central Intelligence Agency, which had taken an interest as to why LPISM was trying to sell this research internationally, especially in Japan, instead of on the U.S. market.

Hicks was away from the office at the time, but other employees were able to explain how he had tried unsuccessfully to sell it domestically first. Steve Lawson later recalled the experience as having been a jarring one. Unfortunately for LPISM, they also failed to sell the superconductor abroad and, due to an oversight, misplaced the paperwork required to pay the royalty fee needed to maintain the patent, which they lost as a result.

While this was going on, Pauling and Rath published a paper defining vitamin C deficiency as the major cause of cardiovascular disease. It immediately caused controversy, but the authors stood behind their work and continued on. Once again, concerns about Pauling’s infatuation with vitamin C began to resurge in the scientific community.

Another blow to the Institute’s fortunes was delivered on March 21, 1991, when Ewan Cameron died. His passing rocked the staff and morale plummeted. Shortly afterward, Pauling was diagnosed with prostate cancer and had to undergo surgery. On top of all of this, the fiscal report for the end of 1991 showed that LPISM was hundreds of thousands of dollars in debt. Workers remained loyal however, and numerous employees volunteered to suspend retirement contributions or work at reduced pay to keep the Institute afloat. Despite this, LPISM was still forced to cut their staff in half by early 1992.

Meanwhile, Pauling and Rath continued to promote vitamin C for cardiovascular disease prevention and treatment, and despite continuing doubts about their individual claims, they began to see more support as the medical community gradually realized that it had been underestimating the value of vitamin C for decades. As their work progressed, Rath’s connection to Pauling continued to grow.

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In the spring of 1992, more change was clearly afoot when Emile Zuckerkandl’s contract with LPISM was not renewed. This was a controversial move, as Zuckerkandl was well-liked and respected by the staff. After his departure from LPISM, he founded his own institute, the Institute of Medical Molecular Sciences. He asked the Board of LPISM if he could lease space within LPISM for his new IMMS, a request that was granted.

Additionally, Zuckerkandl invited many of the LPISM staff who had been laid off to join IMMS. When he received news that Zuckerkandl was leaving, Rick Hicks, who by now was the Vice President for Financial Affairs, submitted his resignation as well. He had worked very closely with Zuckerkandl and wanted to follow him to other business ventures. The Board was surprised by Hicks’ resignation and the Institute didn’t want to lose its affiliation with him completely, so they elected him to the Board to keep him at least tangentially involved in LPISM. Happily, Hicks’ last act as an employee was to inform the Board that the estate of Carl L. Swadener had been bequeathed to the Institute and that it was valued at $2-3 million.

Linus Pauling Jr. was elected as the next Institute President, replacing Zuckerkandl. The organization that he took over was in grim shape, despite the windfall from the Swadener estate. As he assumed his new office, one of his top priorities was Matthias Rath. Amidst the recent shuffle, Linus Pauling had appointed Rath as Hicks’ replacement and at the same time the two had founded the Linus Pauling Heart Foundation, a separate and parallel organization to LPISM designed to focus on the Pauling-Rath cardiovascular disease research. These decisions were a source of concern to the Board and much of the staff, who were unsure if the Heart Foundation would be a competitor to the Institute, an arm of the Institute or a supporting organization to the Institute.

Overwhelmed by work, facing a serious illness and feeling his age, Linus Pauling officially retired from his leadership role at LPISM on July 23, 1992. In the wake of this announcement, the Board elected Steve Lawson as Executive Officer of the Institute, named Pauling its Research Director and Linus Pauling Jr. the Chairman of the Board. Linus Jr. immediately assumed a strong leadership role and, working closely with Lawson, aggressively pursued actions to solve the Institute’s numerous problems.

The two quickly decided that attaching LPISM to a university offered the best chance for its survival. At the same time, they realized that LPISM had become bloated and that they needed to pare back on the organization’s non-orthomolecular research, which had largely been created and expanded under Zuckerkandl’s leadership. While Linus Jr. and Lawson both agreed that the research was worthwhile, they also realized that the Institute simply lacked the funds to maintain it. Zuckerkandl had remained close to LPISM, and when almost all of his research programs were cut, he asked the researchers overseeing these programs to resign from LPISM and join IMMS, which many did.

While this was happening, tensions were mounting between Pauling, Linus Jr. and Matthias Rath. Pauling was informed that Rath had created an office for the Heart Foundation that was separate from LPISM, and that he had done so without permission and without even telling Pauling. He criticized Rath aloud for this decision, which only inflamed the situation.  From there, the speed with which the Pauling-Rath relationship soured was dramatic. In July, Rath was spending great amounts of time at Pauling’s home, and they frequently exchanged letters expressing a close friendship. By August they were hardly on speaking terms, and Rath was ultimately expelled from the Institute, asked to resign over a dispute involving intellectual property rights.

For all of the troubles of the 1980s, the ’90s were getting off to a rough start. The roller coaster ride would continue on in the time ahead, containing both the Institute’s darkest hours and its greatest triumphs.

LPISM in the 1980s

Linus Pauling Institute of Science and Medicine staff portrait, 1989.

[A history of the Linus Pauling Institute of Science and Medicine, Part 4 of 8]

In the spring of 1980, amidst a swirl of funding difficulties and legal actions, Emile Zuckerkandl was named President and Director of the Linus Pauling Institute of Science and Medicine. He quickly began working to expand LPISM into a more wide-ranging organization with a particular focus on cellular research. His leadership style was very different from the Institute’s previous presidents, but the staff liked him and generally supported his initiatives.

By this point, born of need, Linus Pauling’s relationship with the Institute began to assume a somewhat Faustian character. Pauling was contacted by, and began regularly meeting with, a man named Ryoichi Sasakawa to discuss future collaboration plans and possible donations. Sasakawa was a world-renowned philanthropist and famous businessman who had single handedly introduced and popularized motorboat racing in Japan. Sasakawa was also very controversial. An avowed fascist, he was an admirer of Benito Mussolini and a political strongman who had been charged with war crimes for his activities in support of the Japanese government during World War II.  He was also very wealthy and Pauling’s connection to Sasakawa would grow over time.

The summer and early fall of 1980 were largely preoccupied with the Art Robinson suits and fundraising. In August LPISM finally received some good news: the National Science Foundation had awarded the Institute a grant of $40,000 a year for two years to support research on the structure of molecules and complex ions containing transition metals. This provided a much needed financial boost, as finances were suffering greatly from the Mayo trials and the ongoing legal wrangling with Robinson.

The year ended somewhat stressfully when, in December, LPISM was forced to move from Menlo Park to 440 Page Mill Rd. in Palo Alto. The landlord of their building in Menlo Park had evicted all of his tenants while he was making structural repairs to the facility. Once completed, he decided not to welcome LPISM back, instead inviting more profitable companies to take their spot. The new building in Palo Alto was dramatically bigger and less expensive; it was also quite a bit shabbier, in part because it was made out of cinderblocks.  Employee Alan Sheets was able to help save the Institute a lot of money during the transition, as his father was a professional mover. As such, the Sheets family helped LPISM move itself instead of hiring the process out to a company.

Extracted from the LPISM Newsletter, Winter 1980.

The dawn of 1981 brought with it major financial relief for LPISM. After eight failed tries over eight long years, the National Cancer Institute finally agreed to fund a component of LPISM’s program – a two-year grant for $204,000 to research the effects of vitamin C on breast cancer in mice. At about the same time, Sasakawa’s company, the Japanese Shipbuilding Foundation, pledged $5 million to the Institute over the following ten years. As part of the deal, LPISM began working with Sasakawa to create the Sasakawa Aging Research Center, which was set up as a satellite facility on Porter Drive. Later in the 1980s, the building at Porter Drive suffered a major roof leak which destroyed thousands of pages of research and documentation. Thomas Hager, one of Pauling’s biographers, notes that LPISM successfully sued the landlord for neglecting to maintain the building.

Despite this influx of new cash, the close of 1981 proved to be an awful time for Linus Pauling and LPISM. In August, Ava Helen Pauling’s recurrent stomach cancer was declared inoperable and on December 7, after struggling with cancer for five years and three months, Ava Helen died. Linus Pauling was absolutely devastated, and the LPISM staff was greatly saddened by the loss as well. Pauling understandably did not cope well with the passing of the woman who was his wife for nearly 60 years, and he effectively ceased to be involved in LPISM except in the most cursory of ways, choosing instead to spend much of his time alone at his ranch in Big Sur, California.

The year that followed was, unsurprisingly, a tough one. Pauling remained in mourning and didn’t really contribute to LPISM, the Robinson suits dragged on, and the Institute’s fundraisers still struggled to cope with the fallout from the Mayo Trials. The NCI and Sasakawa donations helped to keep operations running, as did some of the revenue from Pauling and Cameron’s book, Cancer and Vitamin C. In the summer of 1982, Pauling took a trip throughout the Pacific Northwest where he visited many of his and Ava Helen’s favorite spots, as well as the cemetery where his maternal grandfather Linus Wilson Darling rested. The trip brought him closure and by the fall he became active at the Institute again.

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In February 1983, the lawsuits with Arthur Robinson finally ended, with LPISM paying an out of court settlement of $575,000. The Institute adamantly maintained no wrong doing, instead acknowledging the fiscal prudence of settling as opposed to prolonging the court battle, which was nearly five years old by that point.

Their legal problems resolved, LPISM fundraisers redoubled their efforts to regain their financial momentum, as the lawsuits had drained them of resources. Past fundraising techniques were unable to generate much steam, so Rick Hicks began cultivating relationships with individual, extremely wealthy donors, notably Armand Hammer, Ryoichi Sasakawa and Danny Kaye. As a part of this strategy, LPISM began annually awarding individuals – typically major donors – the Linus Pauling Medal for Humanitarianism. Sasakawa was its first recipient.

In November 1983, LPISM researchers announced that they had discovered a new type of chemical bond that mimicked the bond believed to exist between bulk metals. This was a fairly important discovery, and also helped restore some measure of favorable public opinion as people saw the good work that LPISM was doing. The announcement also reminded folks that LPISM wasn’t just about vitamin C research. The next year, in 1984, Pauling received the extremely prestigious Joseph Priestley Medal from the American Chemical Society for his lifetime of work and dedication in the field of chemistry.

However, the controversy over vitamin C was never far from the Institute and more arrived in a hurry when, on January 2, 1985, the Mayo Clinic released the results of its second set of trials. The Institute was given no warning of the release or chance to read the results in advance. This infuriated Pauling who saw it as an obvious insult levied by the study’s principal investigator, Charles Moertel.

Pauling Note to Self, January 14, 1985.

Perhaps unsurprisingly, Moertel announced that the study had reaffirmed his earlier assertion that vitamin C was useless in cancer treatment. Upon reading the report though, Pauling deduced that Moertel hadn’t actually examined Ewan Cameron’s papers, the very studies he was supposed to be replicating. Among other deviations, the amount of vitamin C used in the Mayo trials was lower than in Cameron’s studies, the amount of time that patients had been given vitamin C was shorter and patients were given vitamin C orally instead of intravenously. Both Pauling and Cameron publicly branded the Mayo report as “fraudulent” and angrily decried the false assertion that Moertel had closely replicated their work.

Many journals and newspapers refused to publish Pauling and Cameron’s rebuttals, or published them months after they were submitted such that the responses were no longer relevant. As a result, LPISM suffered still more financial hardships as public opinion once again swung away from the Institute and many people stopped donating. The direct-mail appeals that had been so successful in years past were only bringing in 25% of what they had a few months previously.

By 1986 LPISM was struggling with funding and also public awareness – the second Mayo Clinic trial seemed to have largely sealed public opinion on vitamin C research. But Pauling was still convinced that vitamin C had more merit than was being considered, and in support of this cause he published How to Live Longer and Feel Better. The book was well-received by critics and sold well.

For the Institute, its successes were manifold, as it provided a morale boost to LPISM staff, brought in sorely needed funds and dramatically raised awareness of the organization and its activities. Shortly afterward, Cameron and fellow LPISM employee Fred Stitt found themselves swamped with phone calls and letters to the Institute about health questions and recommendations. They quickly developed a standardized health information packet which they would mail out to people making more generic inquiries.

Nonetheless, as always, controversy was hovering over the Institute like a thunderhead. In 1987 Institute staffer Raxit Jariwalla began to research the effect of vitamin C on HIV/AIDS treatment. After a short period of time, Pauling became interested in the research and eventually Cameron did as well. Pauling began advocating increased usage of vitamin C in treating what seemed to be an incurable disease; the response was immediate and dramatic. Local donations increased, as the Bay Area was particularly sensitive to the hazards posed by HIV/AIDS. However, at the very same time, other sources of funding dropped as numerous groups and individuals pulled their support, stating that HIV/AIDS was a “moral disease.”

Through it all, the Institute continued to follow Zuckerkandl’s lead in expanding its research into areas outside the realm of orthomolecular medicine. In 1987 researchers began extensive work on protein profiling and the effect of phytic acid in cancer prevention, a program that was more or less entirely supported by a philanthropist based in New York.

The Institute also began working on superconductivity in 1988.  In particular, Pauling hoped to develop a room-temperature superconductor which he could then market as a stable revenue source for the Institute. Zuckerkandl, Steve Lawson, Pauling and even Cameron began working on this project, which utilized a material made out of borosilicate glass and tin. The process involved using a blowtorch and an inverted bicycle with its tires taken off the wheels. Pauling would often come down to the labs and help with the physical research and experimentation – it was the last research project he actively participated in. The process worked and the material was developed according to Pauling’s specifications. He received a patent for it early in 1989, and immediately began trying to market it, though ultimately without success.

The decade of the 1980s drew to a close on a mixed note for LPISM. The organization was, as always, struggling with controversy and financial problems. However, research was progressing well, popular support was increasing, and Pauling had come to terms with the death of his wife. The decade had seen its ups and downs, and what lay ahead would be no different.

The Departure of Art Robinson and Fallout from the First Mayo Clinic Study

Art Robinson, 1974.

[A history of the Linus Pauling Institute of Science and Medicine, Part 3 of 8]

By late 1978, the Linus Pauling Institute of Science and Medicine had reformed its fundraising strategy, an action which proved to be quite successful. As a result, for the first time in its five years of existence, LPISM was not struggling to keep its head above water.

This wave of good fortune carried with it unforeseen negative consequences. In particular, Rick Hicks and Art Robinson began to come into conflict over the best way to invest this sudden surplus. Robinson suggested that LPISM move to Oregon – which had recently announced “Linus Pauling Day” in honor of its native son – and build a campus of its own. The idea was not popular with many staff, most of whom did not want to leave the Bay Area.

At the same time, Robinson began cultivating ties with the Orthomolecular Research Institute in Santa Cruz, California, which was headed by Arnold Hunsberger. Linus Pauling was not pleased with this idea, as he felt Hunsberger’s research hypotheses to be off the mark. Pauling had also met Hunsberger and had said that his impression was “not a very favorable one.”

Robinson continued to press for closer ties between LPISM and ORI, a source of growing tension between him and Pauling. In particular, Pauling was angered when he learned that Robinson had begun to tailor experiments in accordance with Hunsberger’s ideas without first consulting Pauling. When confronted, Robinson defended his decision and redoubled his arguments for collaboration. Their relationship continued to sour and morale at LPISM plummeted as the tension between Pauling and Robinson mounted.

In June 1978, Pauling issued a memorandum to Robinson, ordering him to consult the Executive Committee – comprised of Pauling, Robinson, and Hicks – before making “any important decisions.” Robinson responded by immediately firing Hicks. Pauling responded in turn by overruling the termination and demanding Robinson’s resignation within thirty days. He then proceeded to issue a memorandum informing Institute staff that he had stripped Robinson of his position, and that the staff was to disregard all further instructions from Robinson. The next day, the staff arrived at work to find a second memorandum from Robinson, declaring that he was still the president, that neither Pauling nor Hicks had the authority to relieve him of his duties, and that he would not resign.

Pauling memorandum of July 10, 1978.

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The Board of Trustees met in mid-July to try and settle the dispute. They decided to place Robinson on a thirty day leave of absence, empowered Pauling with all executive authority and told him to resolve the issue. On August 15, with Robinson’s leave expired, Pauling was elected President and Director of LPISM. On August 16, Pauling promptly informed Robinson that he was taking over all of Robinson’s research, Emile Zuckerkandl was being appointed Vice-Director, and that Robinson was fired.

Now that Robinson was gone, LPISM attempted to consolidate and return to normal. Pauling asked Steve Lawson to assume a portion of Robinson’s research agenda, a request to which Lawson consented. Over the course of 1978, Lawson had steadily become less involved with the financial arm of LPISM and more involved with its scientific work. Zuckerkandl also tasked Lawson with setting up a cell culture facility where the two would conduct research on the differences between primary and metastic cancer cells, as revealed by protein profiling. Lawson worked closely with UC-San Diego, University of Colorado, and SRI International. He was later joined on that project by Stewart McGuire, Eddy Metz, and Mark Peck, all fellow employees at LPISM.

Robinson, however, did not take his firing lightly and on August 25, LPISM was informed that Robinson was suing the organization for $25.5 million, alleging a breach of contract and unlawful termination among other charges. LPISM’s lawyers began gearing up for a serious legal battle, standing firm in their conviction that the Institute had done nothing wrong.

Meanwhile, the Institute’s vitamin C research continued on despite the added burden of the Robinson lawsuit. In early October 1978, Pauling convinced Ewan Cameron to accept a one-year appointment to LPISM while the two worked on a book about vitamin C and cancer. Additionally, Pauling, Cameron, Lawson, and their coworker Alan Sheets began an experiment to determine the effects of vitamin C on chemotherapeutic drugs. The research took the form of a toxicology experiment in which multiple groups of fish were subjected to chemotherapeutic agents in their water, after which various groups were given different amounts of vitamin C while the research team observed the results.

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The year 1979 started with good news. LPISM was informed by Hoffmann-LaRoche, the world’s largest producer of vitamin C, that they had seen sales more than double during the 1970s, and they fully recognized that Pauling was the cause. As a thank you, they had decided to donate $100,000 a year to the Institute.

The happy days were not to last long. In April, LPISM received an advanced release of the results of the major Mayo Clinic study on the treatment of cancer with ascorbic acid. Its primary investigator, Charles Moertel, had concluded that vitamin C did absolutely nothing to help cancer patients. Pauling was stunned and immediately began writing to Moertel to discuss the study in detail.

Then, over the summer, Art Robinson filed six more charges against LPISM and Pauling, bringing the total number of suits to eight and the total requested damages to $67.4 million. The year-long and highly publicized suit was greatly hurting LPISM’s reputation, and the Institute noticed a subsequent decrease in the donor funds flowing their way.

“Vitamin C Fails as a Cancer Cure,” New York Times, September 30, 1979.

Things then went from bad to worse when, on September 27, the New York Times published the Mayo Clinic study, definitively stating its conclusion that vitamin C was useless in treating cancer. Pauling immediately responded by pointing out that the patients involved in the test were undergoing cytotoxic chemotherapy, which he felt crippled their immune system. He also asserted that the trial was not conducted for long enough to develop accurate results.

Pauling’s response to the New York Times article, October 24, 1979.

Charles Moertel returned fire, defending his results and questioning Pauling, implying that he was fanatical in his zeal for vitamin C and refused to acknowledge the truth. Pauling and Moertel began exchanging volleys in public, writing articles and giving interviews that attacked the research and competence of the other. Unfortunately for Pauling, he took the worst of it, as many people began to agree with Moertel, thinking Pauling to be too enamored with vitamin C to see any negatives. Funding plummeted as donations shrank and LPISM began finding large numbers of grants rejected outright with no chance for an appeal.

Pauling refused to give up. Shortly after the New York Times article was released, he and Cameron published their book, Cancer and Vitamin C. Pauling personally bought 16,000 copies of the publication and mailed them to every member of Congress and to countless other physicians and researchers. This action helped Pauling’s cause significantly as many of the recipients read the book, or at least glanced through it. And even those recipients who didn’t read the text were made more aware of Pauling and his research. Likewise, in the marketplace the book sold well despite the bad reception it received from professional reviewers – the public seemed interested in Pauling and Cameron’s ideas.

In light of this, National Cancer Institute head Vincent DeVita agreed to a second round of trials. However, in doing so DeVita once again chose the Mayo Clinic to host the trials and chose Moertel to lead them. Pauling was furious with these decisions, an understandable point of view considering that he and Moertel had spent the past few months publicly accusing one other of being incompetent.  Pauling was also now without his co-author: their book completed, Ewan Cameron returned to Scotland to fulfill his duties at Vale of Leven Hospital. Before leaving, he was appointed a Research Professor at LPISM for a period of five years.

With a new decade approaching, the easier times of the mid-1970s were clearly gone and by early 1980 the future was once again uncertain. While the tensions evident during the Art Robinson era were now history, his lawsuits and the Mayo Clinic trials severely detracted from the future prospects of LPISM. Unfortunately for the Institute and Linus Pauling, their immediate future was not going to be a happy one.

Important New Hires and Battles with the National Cancer Institute

Art Robinson and Rick Hicks with LPISM visitors, 1977.

[A history of the Linus Pauling Institute of Science and Medicine, Part 2 of 8]

By the end of 1975, the Linus Pauling Institute of Science and Medicine found itself teetering on the brink of financial collapse. Linus Pauling was donating his entire salary and even personal funds from his bank account to LPISM, and every employee had taken meaningful pay cuts. Everyone involved realized that the organization could not hope to succeed if business was to continue as usual.

An important change came in March 1976, when Richard Hicks was hired to help with fundraising. This move proved to be a windfall as Hicks interjected new energy and ideas into the search for additional income. One of the Institute’s most important employees for many years, Hicks rather quickly utilized his talents to help alleviate the extreme financial problems of 1975.  With Hicks on board, the Institute was only treading water, but the imminent threat of drowning had lessened.

Later in 1976, Pauling published Vitamin C, the Common Cold, and the Flu, an updated version of his earlier book Vitamin C and the Common Cold. The book sold reasonably well and managed to bring some much needed cash in to LPISM, though not as much as the organization had hoped. Additionally, Ewan Cameron and Pauling published another paper on vitamin C and cancer, which stated that terminal cancer patients lived longer and enjoyed a higher quality of life when given supplemental vitamin C.

Just as conditions were starting to improve, the Institute suffered another major setback when investigators from the National Cancer Institute visited LPISM to check on the progress of its hairless mice skin cancer study. In their report the investigators frowned upon the Institute’s tiny staff, what it deemed to be bad management by its administrators, and Pauling’s frequent absences. Their harsh judgement helped to “sink the Institute’s future grant requests” for many years afterward, thus forcing LPISM to redouble its efforts to secure new sources of private funding.

On the research front, Art Robinson began working with Kaiser-Permanente to set up a national sample bank with tens of thousands of blood and urine samples that LPISM could utilize for better research. The collaboration was moving along smoothly until Kaiser realized that the bill for the project would be in the neighborhood of $5.8 million, at which point Kaiser decided to scrap the deal in a most expedient fashion. In 1977, a year after negotiations had started, Robinson was informed that the plan was rejected because it was too ambitious and vague.

Robinson wasn’t the only one receiving that response. Pauling had been seeking grant funding from the NCI from the moment that its investigators’ report had been released. He reasoned that if the NCI was complaining that LPISM was too small, then they should give him more money to expand. By 1977 he had been turned down four times by the organization, each time under the auspices of his proposals being too ambitious and vague.

In light of the bad press that accompanied the NCI’s dismissals, Pauling sent copies of his proposals and rejection letters to twenty-four members of Congress, including the senators heading the committees on health and nutrition, Ted Kennedy and George McGovern respectively. He received no response, and in turn asked his lawyer if he could sue the NCI for bias. His lawyer advised him that there was no legal precedent for such a case, and that the chances of successfully suing a federal agency were “less than slim.”

Linus Pauling and Emile Zuckerkandl, 1986.

In early 1977, LPISM hired two people, both of whom ended up making major contributions to the Institute. First they hired Emile Zuckerkandl to lead their research on genetics. Zuckerkandl brought a different type of personality to the Institute. He and his family had fled Austria shortly before the onset of World War II, as they were wealthy and Jewish. In fleeing they had managed to bring with them some of their rare artwork collection, which Zuckerkandl would show to his coworkers at LPISM from time to time. A renowned scientist, Zuckerkandl had worked previously with Pauling at Caltech, collaborating and co-developing a theory of molecular evolution.

The second person of note to be hired was Stephen Lawson, who was brought on board to assist with direct-mail solicitations for fundraising. Lawson’ s position was very much at the entry level.  When he was hired he was not associated with the Institute in any way, and his only concrete knowledge of Linus Pauling harkened back to a chapter during his student days at Stanford University, when he saw Pauling protesting the firing of a tenured instructor.

About this time, the NCI also brought someone in: a new head named Vincent DeVita. He was more open-minded about Pauling and his vitamin C work, and was aware of how much public support Pauling had accumulated. As a result he consented to speak with Pauling and, after a multi-hour meeting, agreed to set up a conclusive clinical trial on vitamin C and cancer. When asked about the apparent reversal of the NCI’s opinion of Pauling’s work, DeVita responded that Pauling “can be a very persuasive man.” By March DeVita had arranged for the trials to be carried out at the prestigious Mayo Clinic, headed by the esteemed Dr. Charles G. Moertel. Pauling and DeVita met again in April to discuss the details of how the trial would be conducted.

Vincent DeVita, 1999.

On the eve of the Moertel study, circumstances appeared to be improving across the board for the Institute. With more apparent support for his research, Pauling expanded his program and in 1977 began a new series of tests designed to determine the effect of vitamins on tumor growth. The tests utilized 600 hairless mice as subjects. Additionally, LPISM managed to acquire enough funds to hire a professional direct-mail company for fundraising, and was able to place a number of successful advertisements in major financial periodicals including Barron’s and the Wall Street Journal. With these changes, LPISM saw a hefty boost in its incoming funds.

Buoyed by the success of the direct-mail strategy, LPISM began focusing its fundraising on this type of marketing. The move proved to be very effective and non-governmental donations increased from 50% of LPISM’s funding to 85% -the organization received almost $1.5 million in private donations in 1978 alone. For the first time in its short history, LPISM wasn’t suffering from financial hardships.

Pauling’s Superconductivity Patent

Linus Pauling, 1988.

[Part 2 of 3]

Until the late 1980s, the generally accepted theory of electric superconductivity of metals was based on an understanding of the interaction between conduction electrons and electrons in crystals. The critical temperature of superconductivity was thought to be below about 23 degrees Kelvin (roughly -418 degrees Fahrenheit), but in the late 1980s, it was discovered that superconductors could have critical temperatures above 100 degrees K, which threw the theoretical understanding of the subject into confusion and controversy. The discovery also spurred an effort to find new materials with an even higher Tc, or temperature of superconductivity; perhaps as high as room temperature.

The process of developing a superconducting product that Linus Pauling and his associates thought might be viable took several months and much collaboration, beginning in early 1988. Along with Pauling, other members of the Linus Pauling Institute of Science and Medicine, including Zelek Herman, Emile Zuckerkandl, Ewan Cameron and Stephen Lawson, worked on the project. When the researchers finished the task, Pauling was ecstatic and invited Herman and Lawson to his home, giving them large mineral crystals as gifts and offering to inscribe their copies of General Chemistry to commemorate the occasion.

Their invention aimed to form a composite structure in which superconducting materials assumed the form of fine strands embedded in a wave-guiding matrix. The matrix restricted the superconducting current to a linear motion; however, the strands did not need to be straight, but could also be bent or interconnected into a network. This matrix would be built of a non-conducting material such as glass.

Pauling notes on superconductivity, 1988.

Once the superconducting material was mounted with the help of the matrix material, the entire set-up was stretched to minimize the diameter of the superconductive strands, in the process maximizing the critical temperature. Optimum strand diameters were thought to lie in the range of 50-2000 angstroms – a unit of measure that is one-ten billionth of a meter and is denoted by the symbol Å. For its part, the matrix material needed to be easily drawn into fine strands and not be superconducting. Pauling believed that

by selecting the best superconducting and matrix materials and the optimum strand diameter, it should be possible to obtain a composite superconductor with critical temperature above room temperature, critical magnetic field above 100 tesla, and critical current density above 108 amperes per square centimeter.

In the group’s patent description, a few variations on this technique were listed that were thought to increase its effectiveness.  One variation involved the embedding of two types of superconducting materials into the matrix instead of one. A suitable composite structure of this type could include strands of lanthanum and tin embedded in glass with a softening temperature of about 950˚C.

The description also noted a couple of different ways that the matrix material and superconducting material could be joined together. In one variation, the matrix was constructed as a tube and the superconducting material poured in and afterwards “drawn,” or stretched. Then several of these tubes containing superconducting material were joined together and stretched simultaneously, over and over, the same way Italian millefiori glass beads are made. Another variation utilized the filling of a porous matrix with a liquefied superconductor, whereupon the whole apparatus was heated and stretched.

The group admitted to problems with these methods, but Pauling thought up solutions. One obstacle was that the melting point of glass might be lower than that of the superconducting material, which would make it impractical to draw glass or other material with the superconductor. Pauling’s method of solving this problem was to add a powder made up of the superconducting material to the glass in order to reinforce it.

Despite all the work that Pauling and other scientists were accomplishing, a New York Times article published October 16, 1988, declared that the U.S. was falling behind Japan in the race to commercialize superconductors. The author predicted that “major uses of the new materials are considered to be at least ten years away” but that “scientists envision superconductors that could eventually be used to make computers that operate at blazing speeds, highly efficient electric generators and transmission lines, and high-speed trains that would be suspended above their tracks by superconducting magnets.”

The article continued that the new superconductors could conduct electricity at temperatures as high as -235 degrees Fahrenheit, whereas previously it had been thought that superconductivity could occur only at about -420 degrees Fahrenheit. The new temperature, the article concluded, would be much easier to achieve in laboratories.

Pauling notes on superconductivity, January 1989.

Richard Hicks, Vice President of LPISM at the time, wanted to license Pauling’s invention, “Technique for Increasing the Critical Temperature of Superconducting Materials,” to U.S. companies, but was met with little positive feedback. As such, he instead attempted to license the invention to Japanese companies after hearing that Japan was also interested in the commercialization of superconductors. No Japanese companies showed interest either, but the CIA did come calling to ask why the Institute wanted to license a patent to Japan. Over the course of their interview, the CIA representative showed extensive knowledge and interest in the project. In explaining the Institute’s position, Steve Lawson clarified that no American companies had been interested in the purchase, so LPISM was compelled to look to other countries.

In 1988, the same year that the LPISM research group had begun work on the high-temperature superconductor, Pauling, Hicks and Zuckerkandl set up the Superbio Corporation to administer the business side of the invention. Initially Pauling assumed the role of Chairman of Superbio and Richard Hicks was President. Pauling believed it would be successful and invested in the company, owning 300,000 shares in Superbio, Inc. by the end of August. On August 12, 1988, Superbio entered into discussions with the Du Pont Company, which wanted to evaluate Superbio’s information on superconductivity with a view to “possible business activity.” In turn, Du Pont Co. was sworn to secrecy regarding Superbio’s research.

Rick Hicks and Linus Pauling, 1989.

Not long after, on August 31, 1988, Pauling and IBM drew up a draft agreement in which IBM agreed to purchase the patents and/or patent applications for high temperature superconductivity from Pauling for the sum of $10,000. The document described Pauling’s invention in detail, stating that it “provides a technique for increasing the critical temperature, critical magnetic field, and maximum current density” of superconducting materials. In addition, IBM was to pay Pauling “a royalty of five percent of the manufacturing cost of the patented portion of any apparatus made.” The patent would become fully paid when IBM had compensated Pauling to the tune of $2 million.

In early 1989, Superconductor News affirmed the fears voiced by the New York Times in October 1988 that the U.S. was falling behind Japan in the race to commercialize superconductors. Their January/February issue included a report on presentations given by the United States Superconductor Applications Association (the SCAA), which included Japanese developments in “SC power transmission, SC magnetic energy storage, SC generators, SC electromagnetic ships, SC electronics and computers, and the SC linear motor car (maglev).” Superconductor News also discussed the possibility of impending confirmation of superconductive materials that could operate at room temperature (Ambient Temperature Superconductors, or ASCs). Potential uses for room temperature avionics applications were listed as thermoelectricity, solid state synchron sources for x-ray lithography, and applications for earth and planetary sciences, medicine, biology, and physical sciences with Extra Low Frequency (ELF) magnetometry.

In response, the Exploratory Research and Development Center in Los Alamos, New Mexico, was set up to boost the U.S.’s superconductivity research infrastructure. The Center was interested in collaborating with Pauling after he sent them a letter in July 1989 in which he mentioned his patent application on high-temperature superconductivity, which by that point had been turned over to Superbio. Pauling’s faith in the company was evident – by the end of November 1990, he owned 900,000 shares of common stock with Superbio. Bolstered by the seeming momentum of Superbio, the interest of other companies in Pauling’s superconductivity invention, and a patent in the works, the future for this work looked promising.

Five More Years of Pauling

We are pleased to announce the release of five new years of the Linus Pauling Day-by-Day project, which attempts to document every day of Pauling’s life. With this release, thirty-seven years of Pauling’s activities, interactions and travels have been meticulously recorded in our online calendar, a mammoth resource now featuring an amazing 188,027 activity listings and supplemented with 2,299 scanned documents and 2,942 full-text transcripts. The transcripts include family letters as well as selected documents (mostly correspondence) used as illustrations for the Day-by-Day project and for the various Pauling Documentary Histories.  As with the first Nobel year, 1954, we have attempted to provide an illustration for every day of 1963, while other years receive an illustration for every week.

Our most recent addition is comprised of the years 1963-1967, a particularly tumultuous time for Pauling. In 1963 Pauling received the Nobel Peace Prize for his work in petitioning against the testing of nuclear weapons. Internationally, Pauling was celebrated for his activism, while at home in the United States he was attacked by for his leftist politics – a phenomenon that, in part, led to his move from the California Institute of Technology to the Center for the Study of Democratic Institutions.  The tumult of the era also led to his participation in several libel lawsuits filed against an array of American media outlets.

Pauling did not, however, allow the trouble at home to distract him from his activism. Instead, he used the fame afforded by the Peace Prize to draw attention to the question of nuclear disarmament. He traveled extensively through North America, Scandinavia, Western Europe, Australia, Latin America and India, lecturing on the need to achieve global nuclear disarmament and lasting peace, and cementing his relationships with fellow peace activists.

In the years following his receipt of the Peace Prize, Pauling returned to theoretical chemistry and, in 1965, he announced his close-packed-spheron theory of the structure of atomic nuclei. In the mid-1960s he also collaborated with Emile Zuckerkandl on a study of proteins as records of molecular evolution, published a revised and abridged edition of The Nature of the Chemical Bond, and continued serving as an informal bridge between the general public and the scientific community.

While naturally documenting the important moments in Pauling’s life, the Day-by-Day calendar also serves as a window into Pauling as a person – one which documents the strain of conflicting political pressures, the effects of age on him and his wife, and his ever-exacting personality.

Begun in 1999, Linus Pauling Day-by-Day is an ongoing project with work on 1968-1970 already well underway. For a detailed look at past milestones as well as the technical mechanics of this ambitious undertaking, please see our series of past writings on the project.