Pauling, Zuckerkandl and the Molecular Clock

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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 70th 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

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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.


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.


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.

Remembering Richard Marsh

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Richard Marsh, 1960. Credit: Caltech Archives.

At the beginning of this year, on Tuesday, January 3rd, the highly accomplished crystallographer Richard E. Marsh passed away at the age of 94. During his impressive sixty-six-year career at Caltech, Marsh was influenced greatly by Linus Pauling’s work in crystallography, and eventually collaborated with him throughout the 1950s and early 1960s. Colleagues and admirers alike knew Marsh for his rigorous standards in investigating atomic structure, a discipline that resulted in his determination of over one-hundred crystal structures throughout his career and the improvement of at least that many more.

In a Caltech tenure that spanned more than six decades, Marsh also inspired generations of graduates and undergrads alike, teaching valuable techniques in crystallography and instilling in his students the rigor of his own research practice. His course “Methods of Structural Determination” was among the most popular graduate offerings in the Institute’s Chemistry division for a great many years. He leaves behind an impressive legacy for the crystallographers of today.


Marsh, who went by Dick, was born in 1922 in Jackson, Michigan. By the time that he arrived at Caltech as an undergraduate in 1939, Pauling had already helped to established the Institute as among the premiere destinations for budding young crystallographers around the world. In particular, Pauling’s newly published Nature of the Chemical Bond had transformed crystallography from arcane to fundamental.

Though Pauling was certainly well known on campus when Marsh was an undergraduate, it would be another eleven years before Pauling and Marsh formally crossed paths. As a student, Marsh had identified an interest in chemistry, but hadn’t narrowed to a particular focus. He commented later that a technical drawing course at Caltech served as a precursor to his interest in crystallography. He graduated with his BS in applied chemistry in the midst of World War II (1943) and, upon graduation, enlisted in the US Navy, spending the next two years degaussing ships in New Orleans. This is where he met his wife Helena Laterriere, to whom he remained married for nearly seventy years.

Following his discharge, Marsh enrolled in graduate school at Tulane University so that he might remain in close proximity to his fiancée. Most of the courses that he needed were already full at the time of his enrollment, so Marsh signed up for an X-ray crystallography class at the nearby Sophie Newcomb College for women. It was there that he met the teacher who changed his life and cemented his interest in crystallography.

That teacher, Rose Mooney, had previously attempted to enroll at Caltech for graduate studies only to be turned away when she arrived in Pasadena and the administration realized that she was a female. Pauling himself stepped in at this point, giving her a temporary position in his laboratory until she was accepted into the graduate program at the University of Chicago. Her lab at Sophie Newcomb College was quite modest, containing only a Laue film holder and one x-ray tube, but for Marsh it was enough. Inspired, his course was set from then on, though he’d have to travel across the country to continue it.

After marrying Helena on August 11, 1947, Marsh enrolled at UCLA. He later called the 2,000-mile move across the southern United States the beginning of their honeymoon, joking that it was a wedding present to his new bride. At UCLA, Marsh studied crystallography under Jim McCullough and earned his Ph.D. in 1950. Caltech subsequently offered him a post-doctoral research appointment, and he remained at the Institute for his entire career, always in a non-tenured position until his retirement in 1990, when he named an emeritus professor.


In the years immediately following World War II, Caltech was still very much the place to be for crystallographers. Thanks largely to Pauling, who returned to structural chemistry after his own war projects had wrapped up, scientists from all over the world travelled to Pasadena to conduct research and solve structures.

Marsh finally became associated with Pauling in 1950, when he arrived at the Institute as a post-doc. He published his first paper with Pauling, “The Structure of Chlorine Hydrate,” in 1952. A year later, the duo published “The crystal structure of β selenium,” which marked the first time that Marsh issued a correction of someone else’s work. Indeed, over the course of his career, Marsh became increasingly focused on policing the field for errors, always striving for maximum accuracy and precision. Pauling engaged in this work himself from time to time, although the various demands on his attention kept him too busy to make a full-time habit out of it.

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Marsh at the famous Caltech Proteins Conference in 1953. To his right is Francis Crick.

Pauling and Marsh continued to collaborate on a number of other publications related to atomic structure between 1952 and 1955, at which point their interests began to diverge. Nonetheless, the two retained a degree of professional closeness throughout the following decades, often writing to compliment one another on various accomplishments, solicit advice, or suggest future projects. In one instance, Pauling provided the kernel of an idea that resulted in Marsh’s 1982 paper on N, N-Dimethylglycine hydrochloride. Likewise, Marsh helped pave the way for Pauling to publish one of his own articles in Acta Crystallography, where Marsh served as an editor for seven years.

In 1975, presented with the problem of solving of a compound that generates hydrazine from molecular nitrogen, Marsh devised and shared a method for determining the structure. This solution influenced the direction of study into hydrazine formation, creating the opportunity for further study. And although Marsh continued to solve structural problems in the years that followed, he also devoted countless hours – over half his career – to the pursuit and correction of published errors, usually pertaining to inaccurate space groups in important crystal structures. Pauling later described Marsh as the “conscience of crystallography.”

With time, he gained such a reputation that his colleagues in the field were perpetually anxious that they would be “Marshed,” or taken to task, for their errors. Marsh held his colleagues accountable to their calculations and believed firmly in checking a computer’s work, rather than the other way around. He is remembered today as having been responsible for many refinements in crystallographic discipline and for the high standards that make future refinements possible.


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Marsh in 2012. Photo by Rafn Stefansson.

In terms of organizational involvement, Marsh joined the American Crystallographic Association (ACA) shortly after starting at Caltech. Over the duration of his career, he became increasingly active in the group, and ultimately served as its president in 1993. He was also co-editor of Acta Crystallography from 1964-1971.

Marsh’s classroom lectures and his relationships with students were at least as influential as were his publications in crystallography. One colleague, B.C. Wang, recalled that Marsh summoned crystallographers of all stature – be they students, professors, or visiting scientists – to a group coffee at 10:30am every day, to encourage discussion and advancement within the field. Students also remembered him as critical but encouraging, his commitment to student success serving as an inspiration for their own hard work.


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Marsh and Pauling in 1986. Credit: Caltech Archives.

When queried by CRC Press in the early 1990s for his input on future publications, Pauling suggested that the press solicit a monograph from Marsh on the crystal structures that he had corrected thus far, arguing that a volume of this sort might help future crystallographers to avoid these errors. Pauling then wrote to Marsh, inquiring about the total number of crystal structures that Marsh had indeed corrected. Pauling had guessed that Marsh had published fixes for 25 to 30 structures and was surprised to learn that the actual number was between 110 and 120.

Although Marsh didn’t publish this proposed monograph, Pauling’s idea evidently inspired him. In 1995, he authored a substantial article on the subject, titled “Some thoughts on choosing the correct space group.” In the piece, Marsh discussed common types of errors as well as preferable techniques and methodology, including a few tables that documented space group revisions over time.

While at Caltech, Marsh worked closely with Verner Schomaker, another of Pauling’s graduate students. In 1991, the two teamed up to put together a festschrift honoring Pauling’s early work on crystallography. Pauling, a man who, by then, had received basically every award that a scientist can get, was immensely pleased and grateful for this honor.

In 2003, Marsh received the inaugural Kenneth Trueblood Award from the American Crystallographic Association for his outstanding achievements in chemical crystallography. Few other awards could be more fitting for a crystallographer of Marsh’s caliber and commitment. In announcing the prize, the chair of the selection committee identified Marsh as a “rare individual among crystallographers, an outstanding teacher and researcher who has greatly influenced so many students and faculty.” He will be remembered and missed for this indefatigable integrity, dedication, and mentorship.

John Kendrew (1917-1997)

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John Kendrew building a model of myoglobin. Credit: MRC Laboratory of Molecular Biology.

[Ed Note: Today we remember Sir John Kendrew, who would have turned one-hundred years old on March 24th.]

The Cavendish Laboratory at Cambridge University was an exciting place to be in the 1950s. While James Watson and Francis Crick worked themselves into a frenzy in their race with Linus Pauling to discover the structure of DNA, lab-mate John Kendrew worked quietly alongside another future Nobel laureate, Max Perutz, as they too competed with Pauling in another arena: the molecular structure of various proteins.

For Kendrew however, this pursuit was not considered to be a competition against Pauling. Rather, he felt his corner of the laboratory to be working in tandem with researchers at Caltech in their joint pursuit of a common goal. For Kendrew, whoever got there first was beside the point. Indeed, when Perutz and Kendrew received the Nobel Prize for Chemistry – one year prior to Pauling’s receipt of his Peace Nobel – Kendrew credited Pauling as having been a source of inspiration and direction for his work on the atomic structure of myoglobin.


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John Kendrew and Max Perutz, 1962.

Sixteen years Pauling’s junior, John Cowdery Kendrew was born in Oxford, England on March 24, 1917. He received an appointment for study at Cambridge in 1939 and was working on reaction kinetics before the outbreak of World War II called him away to support the Allied effort.

By the time that he had reached the rank of Wing Commander in the Air Ministry Research Establishment, Kendrew had developed relationships with several important scientific contacts. Perhaps chief among these colleagues was the crystallographer J.D. Bernal, who also influenced Pauling’s protein work in the late 1930s. Bernal encouraged Kendrew to contact Max Perutz at the Cavendish Laboratory once his military service was completed. After receiving similar advice from Pauling, Kendrew began working with Perutz in 1945. His early research at the lab was conducted in support of his Ph. D. thesis – an x-ray diffraction study of hemoglobin in fetal and adult sheep.

In the late 1940s, Kendrew and Perutz established the Cavendish MRC Unit for the Study of the Molecular Structure of Biological Systems, and together they attacked the chemical structure of proteins using X-ray crystallography, with a particular interest in whale myoglobin. Although the research excited Kendrew, he was sometimes perplexed by the cross-disciplinary nature of what he was trying to accomplish. In a later interview with the Journal of Chemical Education, he remembered, “one of the problems was the lack of professional label. By profession, I was a chemist working on a biological problem in a physics lab.”

Nonetheless, Kendrew and Perutz were avidly pursuing the structure of keratin when the Pauling family visited the Cavendish in 1948. Pauling himself had done some preliminary work on the protein about ten years earlier, but after failing to build a satisfactory chain, he had abandoned the effort and moved on to other structures. Seeing the steady progress that Kendrew and Perutz were making reignited his own interest in the structure. Not long after, while lying in bed with a severe sinus infection, he worked on a rough sketch of a keratin model, which eventually inspired his signature proteins breakthrough: the alpha-helix.

Shortly after Pauling published his landmark 1951 paper, “The Structure of Proteins: Two Hydrogen-Bonded Helical Configurations of the Polypeptide Chain,” in which he introduced the alpha and gamma helixes, Pauling invited Kendrew to visit Pasadena and lecture at Caltech. Kendrew, impressed and eager to discuss Pauling’s findings, made preparations to stop in southern California as part of an already scheduled trip to San Francisco and Seattle. The visit proved thought-provoking for both scientists, and Kendrew returned to the Cavendish brimming with fresh ideas.


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Peter Pauling, 1954.

In their early exchange of correspondence, Pauling’s communications (as was typical) were usually formal and brief. On the contrary, Kendrew’s enthusiasm about both his and Pauling’s work is spelled out in long, detailed paragraphs. In due time, Pauling’s writing broadened not only in length, but in a personal dimension as well.  Importantly, between a letter dated October 8, 1956 and another written on November 22, 1957, Pauling switched from referring to his correspondent as “Dr. Kendrew” to “John,” and Kendrew responded in kind.

Without doubt, one catalyst for this shift was Kendrew’s mentorship and guidance of Linus’ second-oldest son, Peter Pauling, a budding crystallographer who was pursuing his doctorate at the Cavendish. Despite his promise and pedigree, once Peter had settled in, many scientists at Cambridge had begun to express concern about his level of commitment to and interest in his work.

Amidst a flurry of letters from Peter’s Cambridge professors that ranged from outright condemnation of his behavior to genuine concern for his future, a 1953 letter from Kendrew comes across as amiable but firm. In it, he expresses serious doubts about Peter’s ability to attain a Ph.D. unless he undergoes “a considerable revolution during the summer.” The message also urges the elder Pauling to alter other travel plans and come to England to address the matter in person. Ultimately, Pauling declined to do so and, fortunately, Peter initiated the revolution for which Kendrew had expressed hope. A year later, Kendrew penned another letter in which he assured Pauling that he had observed in Peter’s work both a genuine interest and a more stringent ethic.

Kendrew was not merely a fair-weather supporter of Peter’s endeavors. When Peter ran into serious personal trouble at Cambridge in 1955, Kendrew proved invaluably resourceful. Most notably, he helped Peter transfer his fellowship and remaining doctoral research to the Royal Institution of London, where former Cavendish chief Sir Lawrence Bragg was now directing the Davy-Faraday research lab.  Kendrew and Bragg later assisted Peter in moving yet again – this time to University College, London – when he could not complete his dissertation in the requisite amount of time allotted by the Royal Institution.

In a number of letters, Pauling repeatedly expressed his gratitude to Kendrew for so carefully tending to Peter’s well-being and educational progress, choppy though it was. These circumstances only served to cement a friendship between the two; one that developed alongside the great professional respect with which they had always extended to one another.


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Kendrew posing at a proteins conference held at Caltech, 1953.

On the other hand, Caltech and the Cavendish regularly found themselves to be in professional competition with one other, and this did lead to occasional friction between friends. In one instance, Kendrew sought out Pauling’s assistance with a rather complicated labor shortage that had partly been caused by Pauling himself. Shortly after Peter’s departure from Cambridge and Bragg’s resignation from his leadership post in the Cavendish, Kendrew wrote to Pasadena, asking for assistance. The gravity of the moment was especially amplified for Kendrew, who was presumably a tad annoyed by Pauling’s having convinced a mutual colleague, Howard Dintzis, to leave the Cavendish for Caltech the previous year. In his letter, Kendrew made a request:

I am writing to ask whether you would be good enough to let me know if you hear of any good man who would like to come to work on the myoglobin project in the near future. As you may have heard from Howard Dintzis, owing to a continuation of unforeseen circumstances I shall be totally without collaborators from January onward.

Pauling replied kindly, but did not include any recommendations.


In 1957, Kendrew succeeded in delineating the atomic structure of myoglobin. Two years later, Max Perutz successfully mapped the structure of hemoglobin. When Lawrence Bragg approached Pauling with the idea of nominating Kendrew for the Nobel Prize in Chemistry, Pauling suggested that the award be split three ways between Kendrew, Perutz, and Robert Corey, a colleague of Pauling’s at Caltech. Bragg disagreed and instead nominated the British chemist Dorothy Crowfoot Hodgkin, a pioneer in X-ray crystallography. Ultimately, Pauling’s final nomination of Kendrew and Perutz in 1962 included Hodgkin as well. As it turned out, Kendrew and Perutz split that year’s prize, and Hodgkin took the 1964 award for herself.


The remainder of Kendrew’s career was spent working less directly on scientific research and more intently on public policy. Like Pauling, Kendrew believed that scientists bore an obligation beyond scientific research and discovery. As he expressed in a 1974 interview

[Scientists] have special knowledge, and their most important responsibility is communication; because it is bad enough to try and foresee the effects of some scientific or technological advance given all the facts, but without them it is impossible…it is all the more important for scientists to communicate and make what they are doing understood at the government level and publicly through the media.

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Wall of Honor at the European Molecular Biology Laboratory.

In the same year that he gave that interview, Kendrew helped to establish the European Molecular Biology Laboratory in Heidelberg, where he acted as director until his retirement in 1981. The lab has since created the John Kendrew Award to recognize and honor outstanding contributions made by the laboratory’s alumni.

Ilya Prigogine: The Poet of Thermodynamics

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[Celebrating the one-hundredth anniversary of the birth of Ilya Prigogine]

“The attitude of Einstein toward science, for example, was to go beyond the reality of the moment. He wanted to transcend time…for him science was an introduction to a timeless reality beyond the illusion of becoming. My own attitude is very different because, to some extent, I want to feel the evolution of things. I don’t believe in transcending, but in being embedded in a reality that is temporal.”

Nobel laureate Ilya Prigogine (1917-2003) is best known today for his work in thermodynamics and especially for his focus on the concepts of irreversibility and dissipative structures. He was a champion of non-equilibrium thermodynamics, compelled by a lifelong fascination with biology’s apparent denial of the principals of physics, and his work is often described as having attempted to marry thermodynamics – particularly the concept of entropy – to biological evolution.

At first glance, notions of entropy and biological evolution seem irreconcilable: one states that the universe trends to disorder and the other suggests that organisms continue to become more ordered as they evolve. Partly because of this, Prigogine’s theories were unpopular within the scientific community for a number of years as they ran counter to traditional schools of thought within physics and thermodynamics.

In developing his thinking, Prigogine worked within the framework of Arthur Eddington’s “arrow of time” concept, which describes time’s asymmetrical, one-way direction. Prigogine was specifically interested in exploring its role in irreversible systems.  Although dismayed by his contemporaries’ lack of interest in challenging accepted concepts of time, Prigogine nevertheless persisted in his research and was eventually awarded the 1977 Nobel Prize in Chemistry for his work on dissipative structures.

Prigogine’s ideas have since been adapted for many purposes. The U.S. Department of Transportation, for one, has used the work in developing predicative tools for traffic patterns. Biologists have likewise used it to deepen their understanding of the glycolytic cycle.

But perhaps most notably, Prigogine is often cited as offering an alternative to the view that the universe will end in “heat death.” On the contrary, Prigogine believed just the opposite to be true, that our universe will continue to become more and more ordered to the point of becoming self-aware. Although many of his theories eventually gained widespread recognition, his speculations where the universe was concerned remained a matter of debate.

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The irreversibility of time is the mechanism that brings order out of chaos.”

Ilya Romanovich Prigogine was born into a Jewish family in Moscow on January 25, 1917, just months before the Russian Revolution. Repulsed by the new communist regime, his family left Moscow in 1921 and travelled Europe for a few years, staying first in Lithuania, then in Berlin. The family eventually settling in Brussels, where Prigogine spent his formative years. His mother, a conservatory student, spent a great deal of time teaching music to Prigogine and his older brother. She noted later that her younger son could read music before words and, as a child, that Ilya proved himself a talented pianist who aspired to become a concert pianist.

As he grew a bit older, Prigogine attended Ixelles Athenaeum, a school known for its rigorous curriculum focusing on the classics. It was likely there that Prigogine developed an appreciation of and interest in classical literature and philosophy. He was particularly taken with the philosophy of Henri Bergson, whom he later credited with shaping the direction of his early research.

After he turned seventeen and entered the Université Libre de Bruxelles, he decided to focus his studies on criminology. In preparation, Prigogine embarked on a mission to uncover the inner workings of a criminal’s mind. This led to a preoccupation with studying the chemical composition of the human brain and his fascination with the subject ultimately compelled him to change his major to chemistry.

In his fourth year at the university, Prigogine began studying under Théophile de Donder. The pair focused their efforts on transforming the “classical” view of thermodynamics that gave privilege to near equilibrium systems. Specifically, they argued that in practical applications, phenomena that are very far from equilibrium and produce minimum entropy are the most common. Such phenomena had been largely excluded from classical thermodynamics on the basis that they were transitory or parasitic.

As his research moved forward, the question of non-equilibrium consumed Prigogine’s interest, because he saw it as vital to explaining a variety of processes in living organisms. By 1945, a mere four years after obtaining his doctorate at the Université Libre, he had formulated a theorem of minimum entropy production to account for non-equilibrium states. At the time, this was not a widely respected theory, and years later Prigogine could still recall the disdain with which some of his colleagues had treated his interest in the subject.

In 1950 Prigogine accepted a position at the Université Libre, where he worked with his colleague Paul Glansdorff on research that eventually arrived at dissipative structures in the late 1960s. In 1967 Prigogine accepted a professorship in physics and chemical engineering at the University of Texas at Austin, and from then on he split his time between Texas and Brussels. Shortly after this appointment, he and René Lefever proposed what is now known as the Brusselator, a model of chemical reactions with oscillation.

Named the director of the International Solvay Institutes in Brussels in 1959, Prigogine was still working in this capacity when he sought to organize the 1987 Solvay conference in Austin. In the months leading up to this conference, he contacted Linus Pauling in the hopes that Pauling would approve of his idea to form a joint physics and chemistry meeting on the subject of surface phenomena. Pauling responded enthusiastically and told Prigogine of his own recent work with icosahedral and decagonal quasicrystals. Prigogine extended an invitation to Pauling to attend the conference, but Pauling was unable to attend due to commitments in Washington D.C. that ran concurrent with the conference. Beyond this, Pauling and Prigogine maintained little in the way of a correspondence.

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From the 1987 Solvay Conference in Austin, Texas. Prigogine is pictured in the bottom right. Pauling was unable to attend this conference.

Science for the benefit of humanity is only possible if the scientific attitude is deeply rooted in the culture as a whole. This implies certainly a better dissemination of scientific information on the side of the public, but also on the other a better understanding of the problems of our time by the scientific community.

After spending decades receiving little to no recognition for his work, Prigogine was informed that he would receive the 1977 Nobel Prize in chemistry. In a speech of introduction at the Nobel ceremonies, Prigogine was praised not only for his research and its significant impact, but also for the eloquence that had inspired his nickname, “the poet of thermodynamics.”

In his own banquet speech, Prigogine refrained from delving too deeply into his research and instead emphasized the need for cooperation between the scientific community and the surrounding culture. In interviews conducted after he received the Nobel Prize, Prigogine expressed his long-running dissatisfaction with the classical scientific treatment of time, and cited this as the spark that had driven his interests in subjects like thermodynamics, irreversibility, entropy, and dissipative structures.

Prigogine was also a proponent of the principle of “self-organization” or the process through which order arises between local components of a disordered system. Prigogine called this phenomenon “order through fluctuations,” sometimes translated as “order out of chaos” because of its association with entropy production. He proposed that these fluctuations eventually led to a state of irreversibility that could go in two directions: evolution or disorder. For Prigogine, the nature of these fluctuations served as the link between biological evolution and thermodynamics that he had sought to uncover for his entire career.

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The future is uncertain…but this uncertainty is at the very heart of human creativity.

By the time of his death in May 2003, Ilya Prigogine had written or co-authored eight books. In addition to his Nobel Prize, he received fifty-three honorary doctorates and won a bevy of awards including The Descartes Medal, the Imperial Order of the Rising Sun, and the Swedish Academy’s Rumford Gold Medal. He belonged to sixty-four national and professional organizations, including the National Academy of Sciences and the American Academy of Arts and Sciences. In 1989, the king of Belgium bestowed upon Prigogine the title of Viscount, an especially significant honor for someone who had not been born in Belgium.

In 2003, shortly before his death, Prigogine signed the third Humanist Manifesto, pledging, along with twenty-two other Nobel Laureates, to “lead ethical lives of personal fulfillment that aspire to the greater good of humanity.” In this, as in his undaunted and hugely creative pursuit of scientific truth, Prigogine was among Linus Pauling’s scientific brethren.

Pauling and Asimov: Playful Needling, Mutual Respect

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[Part 2 of 2]

By the late 1980s, Linus Pauling had expanded his editorial quest with his old friend Isaac Asimov. No longer content to just correct more current publications, Pauling was now dredging up Asimov’s old errors. In this, one is able to intuit a certain playfulness on Pauling’s part, as if correcting these past inaccuracies served mainly as fodder for continuing the banter between two long-time acquaintances.

Specifically, in 1989 Pauling wrote to Asimov about a 1982 article that he had published in Fantasy and Science Fiction. Erroneously, but perhaps seeking to needle his correspondent a bit, Pauling opened this particular note by saying that

The mistake that I’m writing to you about today is, I think, only the second one that I have noticed in your writings. Perhaps it gives me some pleasure to think that you are not infallible.

In the piece under retrospective review, Asimov had claimed that a double bond was weaker than a single bond, which Pauling assured him was all wrong. One of the world’s foremost authorities on the subject, Pauling conveyed to Asimov that, by various criteria, a double bond is found to be about twice as strong as a single bond.

“What you are really thinking about, but not clearly,” he went on, “is that a double bond is sometimes weaker than two single bonds between atoms of the same two kinds.” In his text, Asimov had claimed that a double carbon-oxygen bond was weaker than a carbon-oxygen single bond, but Pauling clarified that what he probably meant was that the double bond energy of carbon-oxygen in some molecular structures might be a little less than the energy of two single carbon-oxygen bonds.

One can easily imagine Asimov shaking his head a bit as he penned his response. “Chalk up one more mistake I’ll never make again. Unfortunately, I keep thinking up brand new mistakes.” He then added, perhaps with a tinge of sarcasm, “How fortunate I am to have you as a friend!”


Throughout the remainder of his years, Pauling continued to provide these apparently good natured criticisms, announcing on another occasion that he was “pleased to report” that he had found another place where the great science fiction writer had slipped up.

This time, in yet another recent issue of Fantasy and Science Fiction, Asimov discussed the Doppler effect. In it, he explained that sound waves are closer together when emanating from an approaching train than they would be if the train had been standing still and, as such, that the wave length upon approach is thus longer and the pitch lower. Pauling pointed out that, in fact, the opposite was true: the wave length was shorter and the pitch higher as the train was approaching.

In his retort, Asimov excused this particular error on the grounds that, “the damned typesetter left out a line or two.”

“I don’t mind making a mistake and being corrected,” he continued, “but it does bother one to have someone else make the mistake and make you look like a fool – but it happens to all of us.”


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As 1990 rolled around and Linus Pauling stepped down as director of the Linus Pauling Institute of Science and Medicine, he perhaps had a bit more spare time on his hands; time which he could dedicate to writing more helpful letters to his pen pal Isaac Asimov!

By now Pauling was reciting inaccuracies from memory, in one instance having apparently lost the article under consideration and unable to clearly recall what it was even about (“I think, cold fusion…” Pauling mused, though remaining unsure). On less stable footing that usual, Pauling offered an editorial olive branch of sorts, praising Asimov for so “rarely” making mistakes before nonetheless correcting yet another error, this one having to do with dideuterium molecules and their protons and electrons.

In case that wasn’t enough, Pauling’s concern for Asimov’s writing soon went beyond its scientific content. In a 1991 letter, Pauling criticized Asimov’s usage of the word “escapees” in a recent article. Pauling defended his stance with an appeal to the adjudicators of such things: “I join with authorities on the English language,” he argued, “Fowler’s Modern Usage, Second Edition, 1965 says ‘Escapee is a superfluous word that should not be allowed to usurp the place of escaper. One might as well call deserters ‘desertees.'”


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Though on the surface it may not always have appeared to be so, a strong bond of mutual respect was nestled within what sometimes came across as a rather pedantic relationship between one of the great scientists and one of the great science fiction writers in human history. Delighted as he was to spot an error, Pauling confessed to Asimov that, for years, he had admired his very broad knowledge of science and his ability to present it in an accessible and exciting way to a general group of readers. He likewise added that he greatly appreciated Asimov’s excellent use of English, stray use of “escapee” not withstanding.

After Asimov passed away in April 1992, Pauling sent a heartfelt letter to his widow, Janet Jeppson Asimov. “I am sure you know that I was very fond of Isaac,” he told her. “I read his articles with much pleasure and some profit (he occasionally presented facts that were new to me). From time to time, too, I had the pleasure of corresponding with him.”

Indeed, Pauling respected Asimov not only as an author and a purveyor of general scientific knowledge to the public, but also as an advocate for social change. Isaac Asimov had been president of the American Humanist Association from 1985 until his death, and in that time the organization operated throughout the United States and internationally as an agnostic ministry and educational outreach organization that hoped to teach others to do good and to preserve peace and prosperity for humanity regardless of religious creed. With such a list of accomplishments to his name, it is easy to see why Pauling gravitated to Asimov. As Pauling said in his final letter to Janet Jeppson Asimov, “He was a truly remarkable person.”

Letters to Asimov

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Isaac Asimov

[Part 1 of 2]

If you were to explore Linus Pauling’s extensive personal library, which covers everything from ancient philosophy to the life and times of Joseph Priestley to novels authored by John Grisham, you would find a large and dog-eared section dedicated to science fiction. Pauling was an avid reader of the genre and one of his favorite authors was Isaac Asimov, whose Foundation Trilogy and Pebble in the Sky were left a little weak in the binding by Pauling from repeated reads. Pauling was so taken with these and other sci-fi works that he even briefly considered writing a novel himself, though he never found the time amidst all of his other pursuits.

Pauling’s connection to the world of science fiction remained especially tied to a periodical called Fantasy and Science Fiction, which he read thoroughly and often, and in which Isaac Asimov frequently published. Initially through this joint association with the periodical, Pauling and Asimov developed a robust correspondence that lasted for many years. The duo’s relationship evolved accordingly, with Pauling often serving as a volunteer editor, a sometimes royal “pain in the Asimov,” and always a steadfast friend.


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Ever watchful and equipped with a critical eye, Pauling regularly expressed qualms with multiple science fiction writers, including some of his favorites, like Asimov. Pauling’s correspondence with Asimov began in 1959 with a fan letter of sorts, which Asimov later praised for, “the gracious way in which [it] referred to my work,” as well as the pride that it had bestowed upon him to feel that he had, “however tangentially and distantly,” been an inspiration to Linus Pauling.  Asimov considered Pauling to be one of the greatest scientists alive, and in 1963 he listed him in Fantasy and Science Fiction as being among the top 72 scientists of all time.

Naturally, Pauling was pleased to be viewed in this way and quickly wrote to Asimov to thank him for the plaudit. However, being something of a perfectionist, he also suggested a slightly altered description of his work for increased accuracy, in the event that Asimov might use the sketch for future publications.

Pauling’s “first round of edits” on Asimov’s work didn’t stop there, as he had noticed a far more egregious error in Asimov’s list of great scientists: namely, quantum theorist Louis de Broglie was listed as having died, but Pauling assured Asimov that de Broglie was most definitely still alive. In his reply, Asimov identified the source of his error: he had accidentally looked up Louis’ brother Maurice, who had died in 1960, in a careless perusal of Webster’s Biographical Dictionary. “I am quite embarrassed at having mistakenly killed poor de Broglie,” Asimov wrote, adding, “I can assure you that I have unkilled him.”


Their correspondence continued, and a year later Pauling wrote with more corrections on some calculations that Asimov had published concerning the mass of electrons replacing the sun and the mass of electrons replacing the Earth – proportional to the true masses of the sun and the Earth – required to produce a force of electrostatic repulsion equal to the gravitational force of attraction between the sun and the Earth at the same distance. Pauling explained that, upon review, he found the two masses that Asimov had given to be rather a bit too small:

The factor needed to correct each of them is a large number: it is 1 followed by 21 zeros. From time to time teachers and students write to me to point out errors in my books College Chemistry and General Chemistry. So far, I think, no one has reported an error in these books quite so large as this one.

Asimov replied that the figures had seemed small to him as well but that, in writing the original piece, he had gone over the mathematics and, believing the reasoning to be sound, had convinced himself that common sense and intuition on the matter were irrelevant. He admitted

when I got your letter, my heart sank for I knew I was wrong if you said I was. Thank you, Professor Pauling, for taking the trouble and time to save me from my own stupidity… For heavens’ sake, please don’t stop reading my articles. I need someone to catch these points.

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In retrospect, it would appear that Asimov had opened Pandora’s Box as, after inviting Pauling to pay close attention to his science fiction writing, the letters correcting his work became far more frequent.

A characteristic example came about by way of a 1978 submission to Fantasy and Science Fiction. In it, Asimov claimed that the French scientists Guillaume Amontons and Joseph Louis Gay-Lussac had observed that if a gas at the freezing point of water was decreased in temperature to -1 C, then both the volume and the pressure of the gas would decline by 1/273 of the temperature. Pauling declared in no uncertain terms that, “This statement and the rest of the discussion on this page are wrong.”

What Asimov should have said, Pauling explained, was that if the volume is constant, the pressure decreases by 1/273. Likewise, if pressure is kept constant, then volume decreases by 1/273. As such, “if for some reason the fractional decrease in volume were kept the same as the fractional decrease in pressure, each of them would be 1/546.”

Asimov responded courteously. “It is always with mingled pride and apprehension that I realize you have your eye on me,” he wrote. “You remain my favorite scientist, and may you continue to flourish for seven more decades at least.”


Pauling did indeed continue to flourish, and even as he neared the twilight of his life the letters to Asimov still showed up. To wit: in a 1986 piece, Asimov had claimed that the curvature of the Earth was 0.000012 miles to the mile. This, Pauling alerted him, would make curvature dimensionless. “The usual definition of curvature is that it is the reciprocal of the radius of curvature, which for the earth is 4,000 miles,” he corrected. “Accordingly, the curvature of the earth is 0.00025 reciprocal miles.”

The quantity that Asimov gave for the curvature, according to Pauling, yielded the correct answer only by ignoring his error in dimensions and only at a distance of 3.3 miles from a given point on the surface of the Earth, but not at any other distance. Asimov replied with dismay: he had done some “quick back of the envelope calculations and was, of course, egregiously wrong.”