The Public Response to The Nature of the Chemical Bond

Pauling lecturing on valence and molecular structure, 1957.

[Celebrating the 75th anniversary of The Nature of the Chemical Bond. Part 6 of 6.]

Not all of the responses to The Nature of the Chemical Bond that Linus Pauling received were from academics; some came from students.  Lois Joyce was one such respondent.  Working her way through graduate school at the University of Illinois, she began contacting Pauling in May 1939 in hopes that she could study with him at Caltech.  She told Pauling how she was much more interested in his focus on molecular structure than on the analytical chemistry that she was studying at Illinois.  By July, after bringing her case before the Division of Chemistry and Chemical Engineering at Caltech, Pauling was compelled to tell Joyce that he could not bring her aboard due to Caltech’s restriction on women without Ph.Ds working in their labs.  Pauling encouraged Joyce to continue on and get her doctorate at the University of Chicago, after which point she might be able to join him.

A month later, Pauling received a letter from Joyce’s mother asking for an autographed copy of what she could only remember as “The Strength of the Chemical Bond” for her daughter’s birthday.  She told Pauling how Joyce thought Pauling to be “one of the greatest men in the world” and that even though “it’s a strange career for a girl” her daughter was “deeply interested in X-ray research and willing to give up all pleasure in life to succeed,” often studying “until two and three in the morning.” Pauling obliged by signing and sending a copy of his book through special delivery, as Joyce’s birthday was only days away.  Joyce was overjoyed when she received the gift, telling Pauling that she was glad her mother “bothered” him to send a copy and that she was “never so thrilled.” Joyce still regretted that she was unable to work with Pauling however, telling him again that the only topic she wanted to study was molecular structure.


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Scholarly reviews of The Nature of the Chemical Bond did not start appearing until 1940, the year following its publication.  Many of the reviews offered soaring praise not only for the book, but for Pauling as well.  They also included more technical criticism than had been contained in the letters that Pauling had received earlier from his colleagues.

The Transactions of the Faraday Society published a review, identifying the author as L. E. S., which played off the assumption that Pauling was already so well-known as to need little in the way of an introduction.  L. E. S. noted, “All who have researched in the field of molecular structure have long awaited this book.” According to the review, Pauling’s account mostly focused on “the structure of individual molecules…with problems centering around relatively normal covalent bonds.”  It also included a “delightful chapter” on the hydrogen bond and two “succinctly but excellently discussed” chapters on the structure of crystals.

Similar praise came from John E. Vance in the American Journal of Science and George B. Kistiakowsky in the Journal of the American Chemical Society, who both lauded Pauling’s non-mathematical style.  Kistiakowsky added that Pauling’s presentation was “by and large…lucid, and a student with little more preparation than the four basic courses in chemistry should be able to digest most of the contents.” Indeed, even novices might be interested and find the text “stimulating.” The reviews from Germany echoed these sentiments, though one author in the Zeitschrift des Vereins Deutscher Chemiker was disappointed that Pauling, like most English chemists, ignored the German literature on the subject.

As the reviewers continued, they brought in a handful of criticisms of Pauling’s work.  L. E. S. found that Pauling had oversimplified his discussion and gave it a “premature happy ending.” According to L. E. S., these flaws emerged from Pauling having written such a broad survey and resulted in assumptions along the lines of “the electric dipole moment of a purely covalent link is small or is zero,” a suggestion presented without any proof.  L. E. S. wrote that Pauling’s certainty in his own understanding came “partly from this simplification and partly from tricks of style.”

Kistiakowsky made a similar observation, calling attention to Pauling’s “pontifical style” and “his advocacy of the doctrine of infallibility of Pasadenean research,” before concluding that this was “understandable and should not be taken amiss.”

A more serious criticism came from Vance, writing in December 1939,  who complained that Pauling ignored a large stream of the chemical discourse then current, and in particular found it “remarkable that no mention of the Hund-Mulliken treatment of chemical bonds,” based on molecular orbitals, appeared in the text.  Such an inclusion, Vance thought, surely would have increased the “usefulness of the book.” He was not the only person who felt this way.


Robert Mullikan, 1929.

In June 1940, Robert S. Mulliken – himself a rising scientific star and future Nobel Prize winner whose atomic structure work was sometimes at odds with Pauling’s theories – published his own review in the Journal of Physical Chemistry.  Mulliken initially took a generous tone, calling Pauling’s book a “clearly written survey of the nature of the chemical bond,” before adding the critical clause, “from the viewpoint of the atomic orbital method.”  This viewpoint, Mulliken ceded, was most suited to combining wave mechanics with the “traditional ideas” of chemical bonds and therefore had “wide appeal and usefulness among chemists,” but it was not the only perspective in play: Mulliken’s molecular orbital model, developed with Friedrich Hund, was a competing body of work that Pauling largely ignored.

Mulliken suggested that Pauling’s failure to include a molecular orbital perspective, except for a brief “aside,” was misleading, especially for the “unfamiliar reader.”  “Most authorities,” according to Mulliken, “would feel that for a deeper understanding of the electronic structures of molecules a knowledge of both methods is necessary, and that for many problems the MO [molecular orbital] method is the simpler and more intelligible.” Despite this criticism, which became more common over the years, Mulliken ended on an upbeat note, echoing his earlier comment on the volume’s usefulness and recognizing that “the book is a landmark in the history of valence theory.”


While criticism, like Mulliken’s, urging Pauling to add another theoretical perspective to The Nature of the Chemical Bond may not have been exactly what Pauling was looking for from the public response to his book, he would not be able to incorporate any of this new feedback into the next edition anyway.  After he had received his requested interleaved copy from W. S. Schaefer of Cornell University Press back in October 1939, Pauling quickly got to work on making revisions.  By December he was already sending in the first three chapters to Schaefer and by May 1940 the second edition was out, published one year after the first edition and one month prior to Mulliken’s review, also of the first edition.  The opportunity to incorporate new suggestions was not completely lost, however, as Pauling began working on yet another version of his landmark text just one year later, in 1941.

Pauling's interleaved copy, full of notes for future revisions.

Pauling’s interleaved copy, full of notes for future revisions.

Promoting and Reacting to The Nature of the Chemical Bond

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[Celebrating the 75th anniversary of The Nature of the Chemical Bond. Part 5 of 6.]

Once all of the hindrances to getting The Nature of the Chemical Bond printed had finally been overcome, Linus Pauling looked to the next phase – promoting his book.  He started by compiling a list of people to whom he wanted to send the text, a list that included those who had helped him along way,  journals that would review it, previous Baker Lecturers, and chemistry professors who, Pauling thought, would be interested in using it in their courses.  Pauling ultimately came up with a list of sixty-one people, not counting journals.

Cornell University Press chief W. S. Schaefer responded that the press’s policy was to allow for only six free copies, but he could send the book to those on Pauling’s list at a thirty-three percent discount.  Pauling explained that he had drafted the list based on previous experiences with McGraw-Hill, which was much looser in doling out free copies. He had Schaeffer remove sixteen individuals from the list, paid for four copies, and claimed that the remaining individuals would most likely use the book in their courses and so should get a copy as a promotional offer.  Schaefer agreed to this arrangement, charging the bulk of the books to the advertising budget.

Once The Nature of the Chemical Bond was officially released in May 1939, Cornell did its part in getting the word out.  The press sent out an order form addressed to “Students of Chemistry and Molecular Structure” in chemistry departments across the country, alerting them to the opportunity for a ten percent educational discount.  The form summarized the material found in The Nature of the Chemical Bond as including “the structure of molecules and crystals, and the nature of the chemical bond,” and emphasized the book’s grounding in quantum mechanics without relying on “mathematical argument in demonstrating the conclusions reached.”  It went on to describe how

Early chapters discuss the theoretical basis and the nature and properties of isolated bonds between pairs of atoms.  Then complex ions, molecules, and crystals are considered; the extensive illustrative material is drawn about equally from organic and inorganic chemistry.  There are complete chapters on such important subjects as the hydrogen bond, ionic crystals, and metals.

The methods used by the author in exploring the nature of the chemical bond include the resonance concept and the techniques of diffraction of electrons by gases and vapors and of X-rays by crystals, the determination of electric and magnetic moments, and various kinds of thermal measurements.

The Press also produced an advertising brochure that expanded upon the information contained in the order form.  In addition to noting the book’s basis in quantum mechanics, the brochure promised an “especial emphasis on the resonance phenomenon, including the new concept of resonance of molecules among alternative electronic structures.”  It also suggested that The Nature of the Chemical Bond was “of unusual importance for chemists and mineralogists,” quoting from a glowing write-up in the August 1939 Scientific Book Club Review, which declared that “the publication of this book is literally epoch making.” The journal also described how Pauling’s final chapter, which he added at the very last minute, dealt “with the future development and application of the concept of resonance” and “will probably prove to have been truly prophetic.”

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By June and July, readers began corresponding with Pauling about the book.  The initial responses, mostly from academics, thanked Pauling for sending a complimentary copy and were generally positive in their evaluation.  Many mentioned how they, or someone in their department, planned to use Pauling’s book in an upcoming course.   Earl C. Gilbert of Oregon State College, for example, told Pauling that the text would “be very successful and fill quite a need” and found Pauling’s account of hydrogen bond properties in particular to be a “convincing treatment” in comparison to Jack Sherman and J. A. A. Ketelaar’s application of quantum mechanics to the carbon-chlorine bond.

Joseph E. Mayer of Columbia University was more effusive in his praise, writing, “It’s the first book that I’ve read through for years!” C. P. Smyth issued a similar response, telling Pauling in mid-October

As evidence of my interest in it I can cite the fact that it is the first scientific book which I can remember reading during the course of a fishing trip, although I have carried many with me in the past.

G.N. Lewis, ca. 1930.

Pauling also received encouragement from a former mentor, Gilbert N. Lewis at Berkeley, who wrote in August,

I have returned from a short vacation for which the only books I took were a half a dozen detective stories and your ‘Chemical Bond’.  I found yours the most exciting of the lot.

Pauling appreciated the responses and was particularly glad that Lewis was happy. He had dedicated the book to Lewis and explained “that I had you in mind continually while it was being written, and I have been hoping that my treatment would prove acceptable to you.”

Along with the praise, Pauling also received constructive advice, which he was eager to incorporate into a second edition.  Joseph Mayer mentioned that the book needed some work regarding its discussion of metals.  Gerold Schwarzenbach of the University of Zurich was also appreciative, but Pauling responded to his note by saying that he “hoped to give proper discussion of” Schwarzenbach’s findings on acid strengths “in a revised edition of my book.” Pauling likewise pressed others for deeper input. He asked Oliver Wulf, who earned his Ph.D. from Caltech in 1926 and would return to Pasadena in 1945, for suggestions on the hydrogen bond spectra, Wulf’s area of interest.

By mid-October, buoyed by all of the responses he was receiving, Pauling began to suspect that he might have a hit on his hands. Curious about sales numbers, he wrote to Schaefer at Cornell University Press for an update and also asked for an interleaved copy which he could use to plan out the next edition.

The Nature of the Chemical Bond Goes to Press

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[Celebrating the 75th anniversary of The Nature of the Chemical Bond. Part 4 of 6.]

Once Linus Pauling began to send in the manuscript chapters of The Nature of the Chemical Bond to the Cornell University Press, the next step was to get the text formally approved by the Press’s board of directors and to find a printer. As it turned out, these tasks were not simple ones to achieve.  First Pauling needed to deliver a complete manuscript that could be approved by the board.  Pauling’s Caltech colleague Eddie Hughes helped him by staying in Ithaca, serving as an intermediary with the Press and making last minute changes to the manuscript, as directed by Pauling from Pasadena.

Hughes was finally able to hand over a finished product to W. S. Schaefer at the Cornell Press on July 5th, 1938. A quick turnaround to print looked dicey however as, according to Hughes, “it was the seventh book they’ve had ready for press in the past three weeks.”   Schaefer promised Hughes that “the typescript would be in the printer’s hands at least before August 15,” but “it will be impossible to have the book before November 1 at the very earliest.”  This timeframe was further interrupted in late July when Schaefer broke his knee and needed to be hospitalized.  Hughes, for his part, had done all that he could and so made his way to Pasadena at the end of August.

It didn’t take long for Pauling to get anxious.  On September 9th he wrote to both Schaeffer and his other main Cornell contact, Jacob Papish, asking for any word on his book’s progress, as he wanted to use it for one of his courses in the upcoming academic year.  Schaefer responded apologetically, informing Pauling about his knee and how “the manuscript was received too late for publication this fall” because, over the summer when the book had arrived, “it was no longer possible to assemble our Committee on Publication.”  The committee was scheduled to meet within the next week, and Schaefer assured Pauling that he would “rush” publication as much as possible.

Pauling did not take this news well, and he immediately wrote back to Schaefer that he had only just heard of this delay due “to the failure of your Committee on Publication.” Pauling was even more forthright with Papish, blaming Schaefer for “still holding up the printing until this Committee meets” and calling the potential two and a half month delay “inexcusable.” Overlooking his own earlier delays in getting the manuscript compiled, Pauling wrote, “if I had known at the beginning of the summer that this delay was contemplated, I might have done something about it.”

Papish tried to direct Pauling’s ire away from Schaefer, telling him “the [delay] was not due to inefficiency or procrastination on the part of Mr. Schaefer but to the organization of the University Press” which, being composed of professors, “is not very active during the summer.”  With this, Pauling seems to have accepted the book’s fate, as he adjusted his own course schedule to incorporate the delayed publication. He also began explaining to others that his book might not be out until January, a date that, as it turned out, he would have to continually push back.


Eddie Hughes in 1957. Hughes played an important role in the publication of the Nature of the Chemical Bond and became a valued colleague of Pauling's in the years that followed.

Eddie Hughes in 1957. Hughes played an important role in the publication of the Nature of the Chemical Bond and became a valued colleague of Pauling’s in the years that followed.

With the book in press by the first half of November 1938, Pauling began to send in revisions to Schaefer since “the unexpected delay of three months has caused the book to be somewhat out of date in places.”  Schaefer was glad to include them, telling Pauling that doing so would delay the galley proofs somewhat, but that this loss “will be made up later.” Pauling started receiving, correcting, and returning the galleys to Schaefer by the end of December.  After getting through the first four chapters, Schaefer suggested that Pauling send the corrected galleys directly to the printer in Wisconsin, in order to speed things up.

In January 1939, with the process moving along, Pauling began receiving more and more inquiries on the whereabouts of his book.  Pauling had to tell sellers looking to stock his book and professors looking to use it in their courses that they would all have to wait – the initial word was that it would be ready in March, which quickly became April. During this time, Pauling also decided to add a twelfth chapter, (“A Summarizing Discussion of Resonance and its Significance for Chemistry”) suggesting to Schaefer that he prepare it for print without sending him the galleys to correct.  Pauling still hoped to have the book ready for at least part of his course.

Since all of the galleys had been returned by the end of January, Pauling was expecting the page proof to arrive by the end of February.  When this did not happen, Pauling began to get agitated again, reminding Schaefer that he was “being inconvenienced this year in teaching my class here because of lack of the book.”  The page proofs started to arrive at the end of March and order arrangements were made for the Caltech bookstore, but interferences kept arising – now an influenza epidemic had rendered the printer short-handed.  Schaefer told Pauling that “they are doing their utmost to complete your book,” but they did not want to “risk using inexperienced men for this difficult task.”  As Schaefer’s letter was en route, Pauling, responding to an earlier request to shorten his preface, had the Press add Eddie Hughes to the list of individuals thanked for helping him put the book together.  In this same letter, Pauling asked Schaefer to remove the printer from those so acknowledged.


The first edition office copy of The Nature of the Chemical Bond, containing Peter Pauling's (age 8) typed annotation.

The first edition office copy of The Nature of the Chemical Bond, containing Peter Pauling’s (age 8) typed annotation.

In mid-April, Pauling returned the final proofs, correcting any leftover spelling mistakes, and soon followed up with author and subject indices.  Pauling also wanted to negotiate the price of the book.  Forgetting that he had earlier expected it to sell for one cent per page, Pauling suggested that the 430-page book be priced at three dollars, but no more than three dollars and fifty cents.  Schaefer told Pauling that this price was not possible, partly due to the special mathematical and chemical notation required by the book.  Additionally, previous books in the Baker Lecture series had been published through the chemistry department at Cornell which had “rather lush” funding.  The series was now fully under purview of the University Press and, as such, the selling price needed to cover production costs.  Schaefer suggested four dollars and fifty cents, knowing that the Press would not garner the full price on most sales because of discounts afforded to educational organizations, booksellers, and foreign distributors.  Pauling accepted Schaefer’s suggestion of four dollars fifty cents; mostly he was anxious to get the book printed.

On May 8th, Schaefer wrote to Pauling that, at last, the day had come – The Nature of the Chemical Bond was finally being printed, nearly six months after the original date proposed. Nonetheless, the books that Pauling ordered for his students did not reach Caltech until May 29th.  Pauling told Schaefer this “was during the last of my lectures for the year, so that it turned out that the students were not able to use it very much in connection with my course.”

The same first printing containing Pauling's notes for revision.

The same first printing containing Pauling’s notes for revision.

Returning to Pasadena and Finishing the Manuscript

Segment of Pauling's draft manuscript for The Nature of the Chemical Bond, ca. 1936.

Segment of Pauling’s draft manuscript for The Nature of the Chemical Bond, ca. 1937.

[Celebrating the 75th anniversary of the Nature of the Chemical Bond. Part 3 of 6.]

While Linus Pauling, temporarily settled at Cornell as George Fischer Baker Lecturer, used his absence from his family to fuel his work and writing, he also ran into several obstacles and courted various diversions.  An early obstacle came by way of his left wrist.  Not long after Ava Helen left, Pauling’s letters home begin to describe mounting soreness in the wrist.  On November 11, 1937, Pauling’s main Cornell contact, Jacob Papish, intervened directly by calling a doctor “who said (without looking) for me to get it baked out at the hospital with a short-wave apparatus and bandaged. This was done.”

Pauling was not too impressed – later in the day he reported “I am carrying my arm in a sling – it hurts when I use it, and I find myself using it if it is free. I think it will be well soon, though. If it isn’t I’ll go to a doctor – not Papish’s.”  From the sounds of it though, the treatments started to work.  By the fifteenth Pauling told his wife that “it still hurts, but only once in a while, and I can use my hand if I am careful.”  But a few days later his voluminous writing began to catch up with him as he began experiencing cramps in his right hand and developed a callous on his pinky finger.  By the 24th, with most of his wrist pains behind him, Pauling finally remembered how he had hurt himself in the first place, recalling that he was “at Maury’s office” and “fell over backward in his chair – flat on the floor – and I’m sure that I fell on my wrist.  Isn’t it strange that I forgot that?  I’m rather tired of writing.”


Pauling also found a few diversions to break up his otherwise relentless pace of writing and lecturing while at Cornell.  For one, he took advantage of the opportunity to sit in on various campus lectures.  On November 11, for example, Pauling “listened to a long talk” that was “rather boring” but still boasting an interesting point or two – on the sweet-potato starch industry.”  Pauling also engaged in some reading, including Edwin C. Kemble’s The Fundamental Principles of Quantum Mechanics with Elementary Applications.  He likewise found time to read for pleasure, most commonly the Sunday paper and Time magazine.  He included a bit of space for fiction, including two short stories by Thomas Mann and Christopher Morley’s The Trojan Horse, which he found “very amusing” and useful for “put[ting] me in the mood (Liny’s word) for sleep.”  Alas, the technique didn’t work too well, because the next day a weary Pauling wrote to Ava Helen that he was going home early to finish the book and go straight to bed.

These diversions, it would seem, were not enough to slake Pauling’s loneliness and he continued to seek out ways to be together with Ava Helen.  At Thanksgiving Pauling wrote to his wife,

I am working hard now so that if you do come back with me in January I’ll have more time to play with you. We would have fun going to Princeton and Yale (also Buffalo – we would go to Niagara Falls again). I liked having you in the Lab. with me, but I did get worried about you, thinking that you were bored while I was trying to work. If you come back with me I’ll work in my/our room and you can read or go to bed. We used to do that in Munich. You have forgotten what it is like to have Paddy with you working.

Though Ava Helen initially protested the idea of going back to Ithaca, she gradually warmed to the suggestion.  For it to happen, they needed their helper Lola Cook to take care of the four Pauling children, including Crellin, still an infant.  This may not have been too difficult to arrange since Ava Helen had told Linus earlier, on November 11th, that Lola “said she wants to take care of the baby!”  On December 2, Ava Helen wrote, “I’d leave Lola with the baby I think and get someone to do the work.  I’m hoping that after three weeks at home you will want to return to Ithaca alone.  That would be simpler and less expensive.”  Those three weeks, as it turned out, were not enough, and Ava Helen returned to upstate New York with her husband in January.

The Paulings and Yvonne Handy at Niagara Falls, January 1938.

The Paulings and Yvonne Handy at Niagara Falls, January 1938.



As the time came closer for him to return to Pasadena for the Christmas holiday, Pauling began to run out of steam.  On December 3rd, he told Ava Helen, “I’m afraid that I’m getting stale – I’ve written only a few pages today.”  A few days later he repeated how “stale” he had become, telling his wife, “I need you to play with me and love me and make me happy again.”  Ava Helen responded the same day, though presumably to his December 3rd letter, telling him, “Of course you can’t write more on your book because you’ve worn yourself out.”  Luckily for Pauling, his plan to make a quick exit from Cornell for the winter break was successful and he was on his way home in early December.  Riding the train back to Pasadena, Pauling continued to work on his book, telling Ava Helen, “I haven’t anything to read” and, as a result, had “been planning out the last chapters of the book.”

Once Linus and Ava Helen were back together, first in Pasadena and later in Ithaca, progress on The Nature of the Chemical Bond slowed considerably – it would take several months to match the productivity of Pauling’s one month alone at Cornell, during which time he had written half of his book.  On February 10, 1938, Pauling, now back in Pasadena for good, wrote to Papsish at Cornell to let him know that he had just received his manuscript by mail and “shall now settle down to work on it with the hope of completing it before long.”  Over a month later, on March 18, Pauling told his Caltech colleague Eddie Hughes, who had stayed at Cornell to help push the book through the university’s press, “I haven’t done very much toward completing the chemical bond book, but I hope to get to work on it soon.”  The following month, when Pauling was away from Ava Helen again, he told her that he was working on the book “for a while (correcting old chapters).”

Ava Helen and Linus peeking through a train window, Spring 1938.

Ava Helen and Linus peeking through a train window, Spring 1938.



By May contacts at Cornell were inquiring into the whereabouts of Pauling’s book, but the author still had one chapter left to write.  On May 10 he told Hughes, “I am indeed anxious to get my book finished, but I am having trouble in finding time to work on it.”  Pauling decided to begin sending it in sections and told Hughes that he would finish it by the end of June, at which point Hughes could make his way back to Pasadena.

While he had not yet begun sending the manuscript to Cornell, Pauling resumed his correspondence with Papish to discuss a second edition; according to Pauling, “the field is progressing so rapidly…[a second edition] probably should be prepared in about two years.”  A month later Pauling began sending chapters one-by-one, telling Hughes that he was mostly finished “except for two or three odd sections” and “some of the figures.”  Pauling would find that his delay in getting a final manuscript to Cornell would only cause trouble and interfere with his plans to use the book in his classroom the following year.

The George Fischer Baker Lectureship and the Beginnings of the Manuscript

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[Celebrating the 75th anniversary of The Nature of the Chemical Bond. Part 2 of 6.]

While Linus Pauling attempted throughout the 1930s to sit down and compose a book-length treatment of his ideas on chemical bonding, he was seemingly destined not to complete it. Burdened, in a sense, by his own and other’s rapid advancements in understanding, early attempts at what would become The Nature of the Chemical Bond quickly went out-of-date if they were even briefly set aside.

A window opened at the end of 1936, when Pauling began to receive offers to serve as visiting fellow at two different institutions on the East Coast. One offer came from the Institute for Advance Study in Princeton, New Jersey, and the other from Cornell University in Ithaca, New York, to give the chemistry department’s George Fischer Baker Lectures. Pauling quickly saw the latter option as a chance to give himself both the time and structure necessary to write his book. The Baker Lectures appeared to Pauling to provide the best circumstances to accomplish this, since every year’s lectures were followed by a publication.

Pauling promptly tried to figure out how his writing of The Nature of the Chemical Bond could fit in with the Baker Lectures. In November 1936, he asked Jacob Papish, who was arranging the fellowship, if an expanded text based on his lectures was possible and how much the book might cost. Pauling wanted the price to be set as low as possible to have a “good sale,” and based his expectations on the one-cent per page cost of previous books published in the series. Royalties were also of interest as Pauling was already planning additional editions and expansions of his yet unwritten book. Papish welcomed Pauling’s idea and suggested (very correctly, as it turned out) that his book would be one of the most successful of the series. However, all royalties for the first edition would go to the Cornell University Press, while royalties for any subsequent editions belonged to Pauling.

With everything seemingly arranged by December, Pauling only needed approval to take leave. The death in June of Caltech chemistry head Arthur A. Noyes created some hesitation in the minds of those around Pauling; as he told Papish, “the authorities of the Institute” questioned whether it was appropriate for him to take leave. The matter was quickly resolved however and Pauling began to plan for his trip the following autumn.


The Pauling family, summer 1937.

The Pauling family, summer 1937.

Initially Pauling hoped that his whole family, including Ava Helen, Linus Jr., Linda, and Peter, could join him in Ithaca, where they would all stay together in a house. But the family was growing and, in June 1937, Ava Helen gave birth to the youngest Pauling child, Crellin. Linus Pauling, most likely relaying the results of his failed attempts to convince Ava Helen that the whole family make the trip, had told Papish a month before the birth that it would most likely only be him. Ava Helen did end up joining her husband on the train and staying with him for about a month, leaving the children and their dog Tyl in the care of Lola Cook, who lived with the Paulings to assist with childcare and household chores.

Preparations related to Pauling’s work responsibilities were also necessary. Pauling told E. Bright Wilson, Jr. that he planned to stay in Pasadena “until the last possible moment” so he could help the new lab workers settle in and prepare for the coming months without him. Pauling also arranged for a graduate student to work under him while at Cornell, choosing Philip A. Shaffer, Jr. from Harvard rather than someone from Caltech. Shaffer’s assistance was sufficient to merit a mention by Pauling in the preface to The Nature of the Chemical Bond. Two research fellows, however, did accompany Pauling from Caltech: G. C. Hampson, who continued his research on crystal structures, and H. D. Springall, who continued his work on electron diffraction. Both also earned Pauling’s gratitude in the preface.

The Paulings arrived in Ithaca during the last week of September 1937. Their date of arrival gave Linus one week to settle affairs before the start of his duties, which included giving the Baker Lectures on Tuesdays and Thursdays and leading a weekly Wednesday seminar. The couple selected the Telluride House, which housed students, as their residence while in Ithaca, and Pauling wound up staying there for the duration of his lectureship. It didn’t take long for Pauling to make an impact: during the third week of his visit, he gave a public lecture to an audience of 100 that drew the attention of the Cornell Daily Sun and the Ithaca Journal. The town newspaper described Pauling as building “his story around the statement that ‘Structure is the basis of all chemistry,'” a story that was subsequently detailed in the Baker Lectures and The Nature of the Chemical Bond.

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At the beginning of November, once living arrangements had been fully ironed out, Ava Helen returned to Pasadena. The separation was difficult for them both. By writing to each other several times a week, they salved their heartache and kept up to date on the everyday activities that occupied them and those around them. Ava Helen kept her husband informed on how Peter was beginning to read, how Linus Jr. was learning to pronounce “competitor,” and how Crellin was being “such a good baby” who “literally never cries.” Though Pauling missed the children, he longed for Ava Helen most of all and told her several times how lonely he was and that working was the only thing that was keeping his emotions together. On November 20, he wrote

I love you, my own dear Ava Helen, with every bit of me. Life doesn’t mean anything while you are away – I live in a sort of daze, with nothing worthwhile. The only thing I can stand to do is to work.

At least in part, it would seem then that it was out of a motivation to suppress his longing to be with his wife and children that Pauling wrote the bulk of The Nature of the Chemical Bond while he was at Cornell.

Pauling’s Cornell correspondence with Ava Helen also chronicles how hard he pushed himself to progress through his writing, to the point where he eventually wore himself out. Handwriting anywhere from ten to forty-plus pages per day of manuscript, Pauling often stayed late at the lab, sometimes until three or four in the morning. This upset his wife, who repeatedly admonished him for working himself too hard. On November 27th she wrote,

You are an awful boy to try to work all night. Your Wednesday (really Thursday) letter came today and I’m mad – hopping mad as Peter says. I told Mrs. Crellin that you worked until 4:10 a.m. (She took us all riding in her electric car this morning for an hour) She said you were shortening your life and that you owed it to your family to take care of yourself. It is wonderful that you were able to get so much done but I do worry about you.

Pauling was indeed able to get a lot done, finishing more than half of the chapters for his first book draft early in December, only a month after Ava Helen had left.

The Story of “The Nature of the Chemical Bond”: Coordinating Research & Funding

[Ed. Note: This year marks the 75th anniversary of Linus Pauling's publication of his landmark text, The Nature of the Chemical Bond.  For the next six weeks we will take a detailed look at the creation, release and impact of a book that changed the scientific world.]

Linus Pauling’s The Nature of the Chemical Bond, first published in 1939, was the product of over two decades of diligence, sacrifice, and collaboration among a broad range of actors that included Pauling’s family, research assistants, professional colleagues and a variety of institutions. Pauling’s prefatory remarks to the book – “For a long time I have been planning to write a book on the structure of molecules and crystals and the nature of the chemical bond” – give an indication of the extent to which this was a long-term objective for Pauling, despite his being only 38 years old.

Looking back at his process, Pauling’s application for a grant from the Carnegie Institute in February 1932 provides a more detailed affirmation of his ambitions. In it, Pauling relayed how his undergraduate research in crystal structures at Oregon Agricultural College between 1917 and 1922 had laid the foundation for his current work by bringing him into contact with contemporary questions in structural chemistry. As a graduate student at Caltech, Pauling began to search for answers to those questions in the newly developing field of quantum mechanics.

In pursuit of those answers, Pauling and his wife Ava Helen, with the support of a Guggenheim Fellowship, left their one-year-old son, Linus Jr., with Ava Helen’s mother in Portland and traveled to Europe in 1926 to study quantum mechanics at its source. There, Pauling deepened his understanding and immersed himself even more by beginning to apply the new physics directly to chemical bonding.

J. Holmes Sturdivant

Upon returning to Caltech in 1927, Pauling began to seek funding so he could continue what he had begun. Let down by the National Research Fund, Pauling supported his work with funding from Caltech and the National Research Council, money which allowed him to hire a full time assistant, J. Holmes Sturdivant, who focused on x-ray crystallography and continued to work with Pauling for many years. Pauling also brought aboard Boris Podolsky for nine months to assist him with the more detailed technical components of connecting quantum mechanics to chemical bonding.

In 1932 Pauling expressed a hope that, with help from the Carnegie Institute, he could expand his work by funding more assistants and purchasing equipment like an “electric calculating machine,” a “specialized ionization spectrometer,” and a microphotometer. The Carnegie Institute was not interested. Luckily for Pauling, the Rockefeller Foundation came through with a general grant of $20,000 per year over two years, to be split between the physics and chemistry departments at Caltech. This allowed Pauling to keep Sturdivant on staff while adding George Wheland, Jack Sherman, and E. Bright Wilson, Jr. to his research team.

This scramble to secure funding and bring new people into the lab came amidst the publication of Pauling’s first four “Nature of the Chemical Bond” articles for the Journal of the American Chemical Society, proof positive that Pauling’s work was bearing fruit. Once the funding was secured and Sherman and Wheland began producing results, Pauling wrote – with Sherman and Wheland as co-authors – three more “Nature of the Chemical Bond” articles the following year, published in the newly established Journal of Chemical Physics. Wheland also worked with Pauling on a monograph discussing the application of quantum mechanics to organic molecules. Wheland finished his part of the book by 1937, but Pauling never got around to his portion: his desire to write a book length treatment of chemical bonds began, more and more, to take center stage.

Warren Weaver

In order to keep the funding coming in through the lean years of the Great Depression, Pauling was compelled to follow the lead of his patrons, the Rockefeller Foundation. Warren Weaver, Director of Natural Sciences for the foundation, told Pauling in December 1933 that the organization was “operating under severe restrictions” and that funding would go to projects “concentrated upon certain fields of fundamental quantitative biology.” That Pauling’s work had “developed to the point where it promises applications to the study of chlorophyll, haemoglobin and other substances of basic biological importance” was key to his potential receipt of continued dollars.

The commitment of Caltech’s chemistry department to continue pursuing the line of research suggested by Weaver helped Pauling to secure funding for the following year. A three-year commitment came after that, providing the Caltech group with a reliable source of support into 1938. Pauling thanked Weaver in February of that year for his direction, writing,

I am of course aware of the fact that our plans for organic chemistry not only have been developed with the aid of your continued advice but also are based on your initial suggestion and encouragement; and I can forsee that I shall be indebted to you also for the opportunity of carrying out on my own scientific work in the future to as great an extent as I have been during the past six years.

Secure funding allowed Pauling to maintain a research group consisting of graduate students and post-doctoral fellows. In his preface to The Nature of the Chemical Bond, Pauling expressed his gratitude to several of these individuals, including Sherman and Sturdivant. Another, Sidney Weinbaum, earned his doctorate under Pauling and continued on afterwards, helping Pauling with quantum mechanical calculations and molecular structures.

Fred Stitt worked as research fellow with Pauling and assisted him in teaching his graduate course on the applications of quantum mechanics to chemistry – an exercise, no doubt, that helped to shape Pauling’s own thoughts on the subject, crystallizing them in preparation for the book.

Charles Coryell and Linus Pauling, 1935.

Charles Coryell and Linus Pauling, 1935.

Charles Coryell worked as a research fellow at the Caltech lab with Pauling on the topic of magnetic susceptibilities, which were central to investigating chemical bonds.  (Coryell also later helped Pauling to construct a magnet for the Caltech labs, based on one already in place at Cornell.)

Edwin H. Buchman, according to a 1985 oral history interview, was self-supporting due to royalties from his synthesis of vitamin B1. Buchman told Pauling in May 1937 that he would assist Pauling “on any problem in which an organic chemist could be useful and for which extra space could be had.”

Once assembled, Pauling’s team helped him to refine his understanding of chemical structures and bonding as the time approached when he could produce a book-length treatment on the subject.

Research Completed at LPISM in 1988 – Reproduced and Extended in 2014

The author in his laboratory at the Linus Pauling Institute of Science and Medicine. Originally published in Science Digest, June 1986.

The author in his laboratory at the Linus Pauling Institute of Science and Medicine. Originally published in Science Digest, June 1986.

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

In 1987, my colleagues at the Pauling Institute in Palo Alto, colleagues at Stanford and I published a paper that clearly demonstrated that expression of a charge-altered mutant human beta-actin (glycine to aspartic acid substitution at amino acid 245; G245D) caused non-tumorigenic, immortalized human fibroblasts to form aggressive tumors in nude mice (Leavitt et al, 1987a). When these tumor-derived cells were examined, we discovered that they exhibited further elevated expression of the mutant beta-actin and these tumor-derived cells formed tumors even more rapidly – observations that were consistent with the role of this mutation in the tumorigenic phenotype. Furthermore, over-expression of mutant beta-actin was associated with down-regulation of three abundant tropomyosin isoforms in a well-documented transformation-sensitive manner (Leavitt et al, 1986; Leavitt et al, 1987a and Ng et al, 1988). These final papers were the culmination of research conducted at the Linus Pauling Institute of Science and Medicine (LPISM) from December 1981 to March 1988.

Normally when a scientific observation is never repeated it is usually not worth remembering. In this case, twenty-six years after our 1987 publication, a study was published by Schoenenberger et al. at the Biozentrum in Basel, Switzerland, that reproduced our findings in a different cell system, a rat fibroblast model (provided to them by LPISM in 1986). Furthermore, these investigators extended our findings by characterizing new aspects of abnormal behavior of the mutant beta-actin and cells that express this aberrant protein, which help to explain its potential role in cancer such as enhancement of tumor cell motility and invasiveness.

In addition to enhancement of tumor growth and alteration of cell shape, the Swiss investigators presented the following findings to clarify and support the oncogenicity of this mutation:

  1. The mutant actin stimulated formation of ruffles at the cell periphery as shown by staining of cells with an antibody that bound specifically to the mutant epitope of the mutant beta-actin (left image below)
  2. The mutant actin concentrated primarily in these ruffles (palloidin staining reveals the location of filamentous actin in stress fibers; right image below)
  3. The expression of mutant actin inhibited the tropomysin binding to filamentous actin and tropomysin did not accumulate in the ruffles
  4. Mutant actin colocalized with Rac1 (a GTPase mediator of membrane ruffling) and beta1-integrin (adhesion protein) in the ruffles

ruffles

Back-tracking several years, the discovery of this actin mutation was made in a mutagenized cell line isolated by Takeo Kakunaga at the National Cancer Institute (NCI) in 1978. During the month that his paper was published, I walked over to NCI from my lab across the street at the Bureau of Biologics (FDA) to have a chat with Takeo about using his in vitro transformed Syrian Hamster cells as a model system to identify changes in protein expression that correlated with neoplastic transformation. After describing what I wanted to do, he seemed agreeable but then casually mentioned that he had succeed in transforming human fibroblasts into tumor forming cells. I nearly fell off my chair because human cells had never been transformed in vitro before, a major problem for cancer researchers at that time.

I blurted out that we should do the work that I had proposed in his human cell model system, comparing protein expression by the transformed neoplastic cells with their normal precursor cells. My hypothesis was that this comparison would allow identification of proteins that were turned on or turned off in expression by comparing protein profiles of the most abundant 1,000 proteins expressed in these cells and resolved by high-resolution 2-D gel separation (protein profiling). My plan was to look for charge-altering mutations in proteins that might govern neoplastic transformation and tumorigenesis. A fall-back goal was to define the pattern of qualitative and quantitative changes in protein synthesis to try and get a handle on the mysterious mechanism of human cancer development. A summary of the global changes in gene expression of neoplastic human fibroblasts was published from LPISM in 1982 (Leavitt et al, 1982).

Within two weeks, in May of 1978, I was metabolically labeling the total cellular proteins (with the amino acid S-35 methionine) of the normal fibroblasts and three strains of cell lines derived from the normal culture which were immortalized, only one of which formed subcutaneous tumors in nude mice. After four hours of labeling, I prepared extracts of S-35 methionine labeled proteins from each of the four cultures and loaded 25-microliter aliquots of each sample onto the top of clear noodle-like isoelectric focusing gels (7-inch long urea-polyacrylamide gels with the thickness of thin spaghetti) which separated the complex mixture of total cellular proteins by their net charge (isoelectric point). These gels were subjected to isoelectric electrofocusing of the proteins overnight. The next morning I harvested the spaghetti-like gels, and incubated them in a detergent that would bind to the proteins to help separate them by their molecular weights in a second dimension. So, these proteins were first denatured and separated by their net charge and then, in a second dimension, separated by their size on a thin rectangular slab gel.

After about five hours of separation in the second dimension, I was soon to learn that I had separated more than 1,000 denatured protein subunits (polypeptides) by their differing charges and molecular weights. The final step before autoradiography, which revealed the full protein profile, was to fix and stain the gels to get a glimpse of the resolution of these peptide patterns. The staining of these rectangular gels revealed only the most abundant architectural cellular proteins, the largest number of which were cytoplasmic beta- and gamma-actin, at a ratio of about 2:1 in abundance, respectively. The figure below shows what quickly appeared as the gels were de-stained. In the one tumorigenic cell line, instead of seeing a 2:1 ratio of beta- to gamma-actin, a new abundant protein at about one unit charge more negatively charged (more acidic), and half of the normal beta-actin was lost. The pixilation of these three radioactive “spots” immediately suggested to me that one of the two functional genes (alleles) encoding beta-actin had mutated, possibly due to the replacement of a neutral amino acid with a negatively charged amino acid. This prediction was no mystery to me as I had demonstrated this type of electrophoretic shift in another protein a year earlier at Johns Hopkins.

mutant actin further annotated

A number of experiments were done to build the case for the beta-actin mutation, and then I wrote a letter to Klaus Weber at the Max-Planck Institute in Goettingen, Germany, asking for his help in sequencing these actins. His lab was the only one in the world sequencing actins, e.g. the four muscle forms of actins. It only took Klaus two weeks to respond affirmatively, an indication to me that he was eager. I provided him with the actin proteins from this cell line and it took a postdoctoral fellow, Joel Vandekerhkove, and Klaus a little over a year to determine the complete amino acid sequences of the mutant beta-actin and both the wildtype beta- and gamma-actins, to define the mutation that had occurred. We published the result shown above in the top journal Cell in December 1980. Four years later, my colleagues at Stanford and I published my cloning of the mutant and wildtype human beta-actin gene, and the experiments that formally proved the mutation at the level of the gene (Leavitt et al, 1984). Three years after that, we published the experiments that demonstrated the tumorigenic effect of this mutation in immortalized human fibroblasts.

The dramatic nature of this discovery was never fully appreciated, perhaps, because no other actin mutations had been reported and it took Scheonenberger, et al. twenty-six years to complete the work published in September 2013. In another recent related development, Lohr et al. reported reoccurring beta-actin mutations in a panel of tumor cell samples from patients with diffuse large B-cell lymphoma.

One interesting piece of information that came out of our initial sequencing of these actins was the degree of evolutionary conservation of human beta- and gamma-actin. These two actins differ by only four amino acids at the N-terminus, whereas the four muscle-specific human isoforms are more divergent. Comparing the sequence of actin cloned from Saccharomyces cerevisiae (yeast) with these human sequences (sequences stored at the National Center for Biotechnology Information; NCBI) reveals that yeast and human cytoplasmic actins are 92% identical in their sequences (differing by only 31 amino acids out of 375) and most of these amino acid exchanges are conservative replacements both structurally and thermodynamically. This makes these actins the most highly conserved proteins (on a par with histones H3 and H4) among the 20,000 or so known human protein sequences. This fact presents an argument for the fundamental importance of non-muscle cytoplasmic actins in eukaryotic life. It turns out that among actin sequences of all species, no replacement of the Glycine 245 has ever been documented as a result of species divergence or mammalian isoform divergence.

When we introduced the mutant beta-actin gene into a non-tumorigenic immortalized fibroblast strain by gene transfer (Leavitt et al, 1987a), we isolated a transfected clone in which the ratio of exogenous mutant beta-actin to wildtype beta- + gamma-actin was 0.88 – a 76% higher level of expression than the mutant actin in the original mutated cell line in which the mutation arose (0.5 ratio). When we isolated and cultured the cells from a tumor formed by this cell line, the ratio of exogenous mutant beta-actin to wildtype beta- + gamma-actin had increased to 1.95, indicating that about 64% of the total cytoplasmic actin was the mutated beta-actin. Whereas the initial transfectant cell line produced visible tumors at about six weeks, the tumor-derived transfectant cells expressing 64% mutant actin formed visible tumors at about 1.5 weeks. Thus, expression of this mutation was not inhibitory to cell growth.

The other surprising finding was that cell lines expressing the transfected mutant actin gene did not have higher levels of cytoplasmic actins in them because the two endogenous wildtype beta- and gamma-actin genes were coordinately down-regulated (auto-regulated) so that the relative rates of total actin synthesis remained around 30% compared to S-35 methionine incorporation into 600 surrounding non-actin polypeptides in the protein profile (Leavitt et al, 1987b). This auto-regulation phenomenon was reproduced by Minamide et al. (1997) ten years later.

Cytoskeletal rearrangement of actin microfilaments, as well as changes in composition of tropomyosin isoforms and other actin-binding proteins, have long been associated with neoplastic transformation. However, before our study, causal mutations in a cytoplasmic actin had apparently not been considered. It is perhaps consistent then that Ning et al. (2014) have recently described genetically inherited polymorphisms in the actin-bundling protein, plastin (also discovered and cloned at LPISM), that significantly affect the time of tumor recurrence in colorectal cancer after resection and chemotherapy.

During my tenure at the Pauling Institute, I felt that Dr. Pauling understood and appreciated this work and its relevance to the fundamental nature of cancer development. Progress can be slow, but ultimately true understanding of cancer will emerge from this type of research…and I predict that cytoplasmic actins and actin-binding proteins that regulate actin organization and function in the cytoskeleton will be understood to play a central role in the manifestation of the tumorigenic phenotype.

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