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.”

Remembering Jack Roberts

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Jack Roberts

On October 29, 2016, John D. “Jack” Roberts, renowned scientist, professor, and pioneer in organic chemistry, died of a stroke at the age of 98. Roberts was a colleague of Linus Pauling’s at Caltech during the 1950s and early 1960s, and a friend until Pauling’s death in 1994. During a career at Caltech that spanned more than sixty years, Roberts served as chairman of the chemistry department as well as Institute vice president, provost, and dean of faculty. As a scientist, Roberts pioneered techniques in organic and physical chemistry and nuclear magnetic resonance spectroscopy (NMR). He also expanded the range of interdisciplinary study within the chemical sciences, focusing in particular on the application of experimental techniques of physical chemistry to organic molecules.

Jack Dombrowski Roberts was born in 1918 in Los Angeles, “where the freeways cross,” as he said in a 2007 interview. He developed an interest in science at an early age, and was particularly captivated by Einstein’s theory of relativity, taking advantage of his location to attend open houses held at Caltech while Einstein was a visiting professor. These events, as well as the opportunity to see Caltech’s impressive high voltage lab, made a deep impression on him growing up. Thus inspired, he and a cousin conducted frequent experiments in a home-built lab, sometimes resulting in accidents or explosions that warranted a visit to the doctor.

Although he wanted to attend Caltech, Roberts chose UCLA because of financial considerations. Even so, he worked six days a week at a bakery to pay for his tuition up until his sophomore year, when he accepted a research position. Because UCLA didn’t have a Ph.D. program in chemistry at the time, Roberts was enlisted to work as a lab assistant, a position that would have ordinarily gone to a doctoral candidate. (As a sophomore, Roberts learned the techniques of glass blowing so that he could make his own equipment.) In later years, Roberts reflected on this time fondly, recounting with a laugh some of the eccentricities of his lab mates, classmates, and UCLA professors. Indeed, he attributed most of his future success to the unique opportunities and relationships with faculty that he enjoyed during this time. Of particular note was his connection with Professor William G. Young, who became a close friend, and for whom Roberts wrote a biographical memoir when Young died in 1980.

Following a brief foray into graduate work at Penn State, the attack on Pearl Harbor called Roberts to return to UCLA. Once back, he worked on war projects related to oxygenation and deoxygenation.  On July 11, 1942, he eloped with his high school sweetheart, Edith Johnson, and the pair settled happily in L.A. Edith had attended UC Berkeley for one and a half years before going into the insurance business to help support her family. While he was working on his thesis, Jack would wake up early with Edith and usually be the first person in the lab. Often Edith would come to his lab after work and fix dinner over a Bunsen burner. They were married for sixty-eight years, until Edith’s death in 2010

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Jack and Edith Roberts

After completing his thesis in 1944, Roberts began lecturing at UCLA as a post-doc and pursuing his own research projects on cyclopropyl chloride. He enjoyed the position and the opportunity to exchange ideas with colleagues and students alike. One particular colleague, Paul Bartlett, made such a strong impression on him that he applied for and received a year-long National Research Council Fellowship to work with Bartlett at Harvard University. While there, Roberts continued his work on cyclopropyl chloride and began a new inquiry into metalation.

Roberts accepted a position at MIT after his fellowship, buoyed by the support of Arthur Cope, chair of the MIT Chemistry department. As chair, Cope was intent on changing the dynamic at MIT by inviting new professors to the campus and reinstating a strong research focus. Once settled, Roberts immersed himself in resonance theory and quantum chemistry. By then, Roberts had realized that quantum mechanics was slowly outranking more classical research practice, and he wanted his classes to reflect this shift, despite his relative inexperience with the subject. In order to do so, he taught himself the basics almost overnight, thus challenging himself nearly as much as his students.

While he was at MIT, Roberts also worked as a consultant for DuPont and became involved with research on molecular orbital theory, on which he published a few papers as well as a successful book. He incorporated these ideas into his lectures as well, and his students responded enthusiastically. Importantly, a colleague, Richard Ogg, introduced the concept of NMR to Roberts while he was affiliated with DuPont, but it was a few more years before the ideas really took told for Roberts.

Roberts recalled his time at MIT as fruitful, yet troubled. While he won more space for the chemistry department and enjoyed the motivated students with whom he worked, the department’s older faculty – those who dated to the era before Arthur Cope had become chair – held both Cope and Roberts in low regard. As such, when Ernest Swift offered him a job at Caltech in 1952, Roberts was quick to accept. Once arrived, he became acquainted with a number of extraordinary scientists, including Linus Pauling. Friends and former colleagues of Roberts expressed concerns that Pauling tended to overshadow the scientists with whom he worked, but Roberts and Pauling quickly established a mutual respect for one another. Roberts especially appreciated Pauling’s multidisciplinary exploration and his attention to teaching and inclusivity.

Their shared commitment to that last characteristic was demonstrated by the case of Dorothy Semenow, the first female graduate student at Caltech, whose enrollment Pauling and Roberts were instrumental in bringing about. In his later years, Roberts said that this milestone in Caltech’s history, was “clearly the best thing I have done at Caltech in the sixty years I’ve been here.” Semenow received her degree in chemistry and biology in 1955 and, after her admittance, Caltech relaxed its policies regarding gender, agreeing to accept female students who exhibited “exceptional” aptitude and who could prove that they were of the same high caliber as the Institute’s male students. Caltech went completely co-ed in the 1970s.

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Roberts in lecture, 1962.

As he became more deeply involved with spectroscopy, Roberts garnered support from Pauling to bring NMR technology to Caltech, arguing that the the investment would give Institute chemists a powerful new structural tool to study organic compounds. Roberts had clearly chosen the right ally; not only did Pauling secure funding, he also assigned space for Roberts and his team to work in the newly constructed Church lab. In addition to the research that he conducted using the machine, Roberts was also responsible for maintaining it and expanding the scope of its use, tasks which proved alternately frustrating and rewarding.

Later on, space arose as a different sort of issue, when a disagreement arose over laboratory allocations for Pauling’s orthomolecular research. In 1963, newly appointed as chairman of the chemistry department, Roberts approached Pauling about giving up two of his rooms in order to fulfill promises that the department had made to newly appointed faculty. The issue was debated for weeks, with Pauling pushing for a different approach in which he would give up one room and share others, thereby yielding the same square footage while, in his view, using the spaces that he did have more efficiently.

Roberts rejected some of Pauling’s suggestions and accepted others in what he later remembered to be a reasonable and civilized resolution. Pauling saw the matter differently, claiming that Roberts had expressed little regard for his orthomolecular research. Though the issue of space allocation was ultimately passed on to a committee that came to a compromise requiring Pauling to give up less space than initially proposed, the conflict was one of many reasons why, at the end of 1963, Pauling ultimately decided to seek opportunities elsewhere.

When Pauling decided to leave Caltech, Roberts was the second person that Pauling told, the first being Ava Helen. Shortly after Pauling resigned, Roberts offered him an honorary position of sorts, as a research associate. Pauling accepted, with the caveat that he not have an office, a salary, or duties. But Pauling’s continuing involvement with Caltech was important to Roberts, who valued Pauling’s scientific legacy and never took issue with the political stances that had led to soured relationships with so many others in Pasadena. Reflecting specifically on Pauling’s work as an activist, Roberts said

It seems to me that, in the long run, you do better to be known as a bastion of integrity than as a weather vane, responsive only to the directions whence the money winds blow.

Though no longer close scientific colleagues, Pauling and Roberts continued to exchange letters and Christmas cards for the rest of Pauling’s life.

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Roberts family holiday card, with accompanying diagram. 1993.

Meanwhile, Roberts was writing extensively. In 1959, he published Nuclear Magnetic Resonance, an influential text which included his own color illustrations. In 1977, he and Marjorie Caserio, one of his post-doctoral fellows, co-authored Basic Principles of Organic Chemistry, the manuscript of which Pauling had helped to edit. Roberts spoke with pride of sending his four children to Stanford by giving them the copyright to another successful book, Organic Chemistry: Methane to Macromolecules, which he co-authored with Ross Stewart. Roberts was also very active with the National Science Foundation, evaluating projects and grant proposals.

In 1980, Roberts received the Linus Pauling Medal from the Puget Sound and Oregon sections of the American Chemical Society, a distinction rewarding contributions to chemistry that have attracted national and international recognition. In 1987, Roberts received an even more prestigious decoration, the Priestley Medal, which is the highest honor bestowed by the American Chemical Society and an award that Pauling himself had received three years prior. In his acceptance speech, Roberts praised Caltech as having been “the ideal place” for him to pursue his scientific career. He likewise affirmed Pauling’s scientific work and his political activism as well, stating

I am glad that Linus is also associated with Priestley, not only for his contributions to chemistry, but even more for his adherence to the same high moral and social principles. Chemistry – indeed the world – needs more men and women with not only the ideas of Priestley and Pauling, but also with the same willingness to work to establish those ideals in a far-from-perfect world.

From 1980-1983, Roberts served as Caltech’s provost, vice president, and dean of faculty. He officially retired in 1988, but continued to mentor students well into his nineties as part of the Summer Undergraduate Research Fellowship at Caltech, providing the same inspiration and encouragement that he himself had received at the Institute’s open houses during his youth. Roberts also reveled in the achievements of his children and his students, writing, in his autobiography, “One does not achieve in a vacuum—people are needed, not only to help, but to appreciate. 

At the time of his death, Roberts had taught at Caltech for over sixty years and had earned honorary degrees from the University of Notre Dame, the University of Munich, and Temple University. In 1998, he was named one of the seventy-five most influential chemists of the last seventy-five years. He later received the National Academy of Science Award for Chemistry in Service to Society (2009) and the American Institute of Chemists Gold Medal (2013). He will be remembered as a pioneer in physical organic chemistry, an extraordinary scientist, and an invaluable mentor.

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

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

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

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

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

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

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

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

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

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

andy

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

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

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

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

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

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

John

John Leavitt

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

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

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

List of 70 signature genes

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

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

Plastin Gene Card

The L-plastin gene card.

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

plastin gels

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

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

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

Ahmed Zewail, 1946-2016

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Earlier this month, on Tuesday, August 2, Ahmed H. Zewail, a world renowned Nobel laureate chemist and Caltech’s Linus Pauling Professor of Chemical Physics, died at 70 years of age. As a major figure in the field of chemistry and a personal friend to Linus Pauling, Zewail’s passing is honored and mourned here at Oregon State University.

Zewail was born and raised in Egypt, where he received his bachelor’s and master’s degrees at Alexandria University before going on to attain his PhD at the University of Pennsylvania. After completing his doctorate in 1974, Zewail joined the faculty at the California Institute of Technology, where he remained for the next forty years.

During his tenure at Caltech, Zewail’s team became the first to directly observe the breaking and formation of atomic bonds, also known as transition states. This was initially accomplished in 1987, but the team’s technique had a long way to go before it could be considered revolutionary, to say nothing of routine. Nonetheless, Caltech saw the potential for greatness in Zewail’s work and, in 1990, it named him the first Linus Pauling Professor of Chemical Physics, a newly endowed chair. Upon receiving this accolade, Zewail wrote to Pauling immediately, confiding, “You are one of my personal heroes in science, and I am honored to be holding your chair.” Zewail remained in this position until his passing, frequently stating that it was an honor just to be compared to Linus Pauling, and that he hoped to do justice to that comparison. Important above all else, however, was that Linus Pauling considered him a friend.


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Zewail and Pauling at the 90th birthday event, Caltech, February 1991.

Zewail played a major role in revitalizing the relationship between Caltech and Pauling during the 1980s and early 1990s. Pauling had left the Institute in 1963 amidst increasingly strained circumstances surrounding his work for peace and his stance against nuclear testing. From 1986 through 1993, Zewail was in regular contact with Pauling, helping to arrange his visits to the Caltech campus for a variety of lectures dedicated to Pauling’s work and time there. In 1986, Caltech’s eighty-fifth birthday “Salute to Linus Pauling” afforded Zewail the opportunity to present Pauling with a portrait depicting his face on the body of a Pharaoh, captioned “King of Kings of Chemistry.”

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“King of Kings in Chemistry”

Later events in which Zewail was involved included Caltech’s first Linus Pauling Lecture in 1989, a second Linus Pauling lecture in 1991, and an additional 1991 symposium on the chemical bond that was held to mark Pauling’s 90th birthday. A year later, Zewail produced an edited volume of the papers presented at this conference, The Chemical Bond: Structure and Dynamics, a work which was the source of much pleasure for Pauling in his final years.

Over time, the two became close friends. Christmas cards were routinely exchanged and Zewail even sent Pauling an announcement on the occasion of the birth of his son. In 1992, Zewail likewise provided Pauling with a manuscript documenting his team’s first successful recording of ultrafast electron diffraction from molecules, a breakthrough that enabled increasingly accurate “pictures” of transition states that had never before been observed by chemists. Pauling responded with praise: this was “a fine piece of work” that would make possible the exploration of previously inaccessible frontiers in the fields of chemistry, physics, and biology.

Zewail won the Nobel Prize for Chemistry in 1999. In continuing to seek out methods to observe transition states, he had pioneered a technique that used laser pulses akin to strobe lights to record the colors of light emitted and absorbed by molecules. This technique was termed “femtosecond spectroscopy.” While chemistry had hitherto inferred specifics of reactions based on the material input and output of a given chemical reaction, Zewail’s work now enabled scientists to see specific changes at the molecular level for the first time.


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Crellin and Linus Pauling with Lynne Martinez and Ahmed Zewail, 1991.

To fully appreciate Zewail’s contributions, one must understand that the breaking and shifting of chemical bonds that he worked to observe typically occur in a space of 10-100 femtoseconds, each femtosecond being a millionth of a billionth of a second. Zewail explained the scale of these observations as follows:

Here is the journey in time… 12 or 15 billion years of the Big Bang, and then you come down to our lifespan, which is about 100 years or so – your heart beats in one second. But to go from here [present day] to there [Big Bang] is about 1015, and I am going to take you from the heart into a molecule inside the heart, or eye specifically, and you have to decrease by 15 orders of magnitude to see the beats of this molecule, as you see the beats of your heart. The timescale is fast… if you go from this age of the universe, and you count back from the age of the Earth to the human lifespan to your heart (1 second), and then you go to the microscopic world (sub-second), into how molecules rotate, vibrate, and how the electrons move… In this whole microscopic world here, we reach 10-15 or so seconds, where on the opposite end you reach 1015.

This is the end of time resolution for chemistry and biology, because if you look here, even molecules that are linking undergo collisions on a time scale of 10-14 seconds. A molecule can break a bond and make a bond on this time scale as well. The eye has a molecule called rhodopsin which divides and allows you to see, and that happens in 200 femtoseconds. The way we get photosynthesis to work, and the electron to transfer inside the green plant, is on the order of femtoseconds. So this is the fundamental time scale, and if we were to understand the dynamics of the chemical bond we must understand this time scale.

In other words, the timespan of one heartbeat is to the age of the universe as the timespan of one molecular bond breaking is to the length of an elderly human’s lifespan; the time required by the event is so infinitesimal as to be practically nonexistent. Yet Zewail found that it was at this scale – the “one heartbeat” of a single bond breaking or forming – upon which our entire reality is formed from its molecular foundations up. Zewail showed that events occurring in femtoseconds are the basis for all the occurrences that we take for granted in everyday life.

The ability to observe these events created a new field of study called femtochemistry. And while femtoscopic experiments provide a method for researchers to determine the amounts of energy that hold together different types of chemical bonds, their impact is not limited to chemistry alone. Since the time of Zewail’s breakthroughs in the 1980s and 1990s, many practical applications have emerged from femtoscopic research, including a better understanding of the mechanics of human vision and of the properties of photosynthesis in plants.  Today, most femtosecond lasers are sold not to chemists or physicists, but to hospitals, because of their ability to image very fine tumors. Likewise, in the technology sector, femtosecond pulses can be used to lift material on the micron scale without dissipating heat into a microchip.


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In more recent years, Zewail was named Director of the National Science Foundation’s Laboratory for Molecular Sciences, and was nominated by President Barack Obama as both the first United States Science Envoy to the Middle East as well as a member of the President’s Council of Advisors on Science and Technology. In February, Caltech held a symposium titled “Science and Society” to celebrate Zewail’s 70th birthday. At the event, the honoree spoke of his efforts to expand scientific research initiatives in his native country and stressed the importance of holding to a scientific vision. Advocating as he was for education and peace across international borders, Zewail’s message was, without doubt, one that would have made Linus Pauling proud.

On February 28, 2001, on what would have been Linus Pauling’s one-hundredth birthday, Zewail delivered the keynote address at the Linus Pauling Centenary Celebration, a day-long symposium organized and hosted by Oregon State University. In his talk, “Timing in the Invisible,” Zewail reflected on the rapid changes that had arisen in the field of chemistry as a result of breakthroughs in femtoscience. In 1950, when asked what he thought chemists would be studying fifty years on, Pauling responded: “We may hope that the chemists of the year 2000 will have obtained such penetrating knowledge of the forces between atoms and molecules that he will be able to predict the rate of any chemical reaction.” Zewail’s work, in effect, accomplished this ambition. It has given chemists insight into the dynamics of chemical bonding, and thus greater predictive knowledge of the forces and rates of these dynamic changes.

Dr. Ahmed Zewail, who held the Linus Pauling chair at the California Institute of Technology for so long, was indeed the right scientist to carry Pauling’s legacy forward. Now, as that chair sits empty, Zewail is remembered and missed for all that he accomplished as a scientist, as an advocate for social change, and as a friend.