Robert Corey’s Fellowship and the Roots of an Argument

Robert Corey

[Pauling and the Guggenheim Foundation]

In 1949, as the John Simon Guggenheim Memorial Foundation tested out its new style of fellowships for established researchers, scholars, and artists, Linus Pauling put forth his California Institute of Technology colleague Robert B. Corey as an ideal candidate for funding. Corey was researching the crystal structure of amino acids, peptides, and proteins, and wanted to develop more refined molecular models to supplement his experimental work; Pauling estimated he would need about $3,500 to do so. Corey did not make it into the first group of new fellows for that year, but Pauling suggested him again the following year and he was approved.

Corey’s accepted project had grown from the year before. A Dr. Palmer, who worked under F. O. Schmitt at Caltech’s Department of Agriculture Regional Laboratory in Albany, California, had been taking x-ray photographs of lysozyme, the bacterial protein found in tears. Palmer no longer had the time to continue the work, but he and Corey thought a trained assistant could come in and continue taking the photos. These would then be brought back to Pasadena for analysis and interpretation in the Corey lab. Pauling wrote to Guggenheim administrator Henry Allen Moe that this was a “very important job” that fit nicely within Caltech’s broader program of protein structure determinations.

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When Corey’s case came before the Committee of Selection, evaluator E. B. Wilson suggested that Corey struck him as being a good candidate for Office of Naval Research funding, and as such he would not need Guggenheim support. Upon hearing this, Pauling clarified in a letter to Moe that the circumstances were not quite so straightforward.

As Pauling explained, after Corey applied for the Guggenheim Fellowship, the Office of Naval Research had indeed approached him about a potential collaboration. Pauling followed up by submitting an application for funding, but he had yet to hear back about final approval. He had, however, been informed that the funds, if granted, would come in at $25,000 less than requested. Furthermore, both Pauling and Corey did not like the idea of all their work being backed by the Navy. (By then, Pauling had already made the decision for himself that he would refuse to accept any armed forces funding.)

More importantly, Pauling told Moe that the progress made at Caltech in the last three years was the “greatest advance in the protein field” since Emil Fischer’s discovery that proteins were polypeptides, some fifty years prior. Pauling’s letter was persuasive and the Committee granted Corey $15,000 over two years.

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Corey knew that Moe wanted to meet each fellow in person, and so when he was in New York shortly after the beginning of his fellowship in September 1951, he stopped by the Guggenheim Foundation offices. Moe was not there, but Associate Secretary James F. Mathias was available, and the two enjoyed a pleasant conversation. During that trip, Corey needed to go to Connecticut for a week and decided he would try again to meet with Moe afterwards. This time he called first to see if Moe was in the office, and was told that Moe would not see anyone unless it was very important. Because of the brusqueness of the reply, Corey decided against attempting to arrange any future introductory meetings with Moe.

Over a year later, Pauling suggested that Corey stop to visit Moe while on a different swing through New York. Corey was hesitant to do so, explaining what had happened the first time around and adding a new complaint about Moe’s failure to reply to a letter from Corey about his income taxes. Pauling immediately wrote to Moe to find out more from the secretary’s perspective.

Letter from Josephine Leighton, October 27, 1952

Unbeknownst to Pauling, at that time Moe and Mathias were in the midst of answering a questionnaire issued by the House of Representatives Select Committee to Investigate Tax-Exempt Foundations and Comparable Organizations, also known as the Cox Committee. Moe’s assistant, Josephine Leighton, responded to Pauling and, while misunderstanding the exact circumstances, attempted to address his concerns by explaining that Moe had just been too busy, working up to eighteen hours a day on the Cox response. Leighton assured Pauling that Moe wanted to meet in person with all the fellows, but simply could not fit it into his schedule at this time.

Pauling clarified that he was describing an event from the previous year, but did not want to bother Moe any further with the matter and told Leighton that it could wait. Nonetheless, Leighton dug deeper and figured out that Moe had been in Washington when Corey had originally visited. She could not, however, explain the unpleasant telephone call, as the expectation was that no one in the office would act that way. She also could find no record of Corey’s letter about his income taxes.

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After a few more weeks had passed, Pauling assumed that Moe had finished up his work responding to the Cox Committee and wrote Moe about concerns that he had regarding the public’s perception of the foundation. In particular, it was Pauling’s impression that the granting organization was no longer seen as significant among the most able of scholars, scientists, and artists. This was mainly due to the foundation giving out comparatively smaller amounts than had been the case when Pauling was a fellow in the mid-1920s.

When he received his award, Pauling noted, he was granted $3,500, which was about $1,500 more than the sums offered by National Research Fellowships or the post-doctoral salaries then available at Caltech. By the time of Pauling’s 1952 letter, Caltech’s post-doctoral salaries had reached $4,000 to $4,500, and the pharmaceutical company Merck was providing grants of $6,000 plus travelling expenses. To keep up with this competition, Pauling thought Guggenheim Fellowships should generally average out to $6,000 plus travelling expenses.

Pauling sent a copy of his letter to Louis B. Wright, chair of the Committee of Selection. Wright agreed with Pauling’s point of view, noting that, increasingly, only scholars and scientists from wealthy schools equipped to grant sabbaticals were able to accept Guggenheim Fellowships. Wright, like Pauling, enjoyed the privilege of an extensive Guggenheim stay in Europe in 1928-1929, a trip that would only last six months in 1952 and not much longer were the person to stay at home. Given the choice, Wright felt it better to reduce the number of fellows and increase stipend sums granted.

Moe could not reply to either letter as he was still too tied up with his response to the Cox Committee. He would eventually address Pauling’s concerns, but first the two would need to resolve what developed into a major argument over how the Foundation had handled the Cox Committee questionnaire.

Pauling and Perutz: The Later Years

[Concluding our series on Max Perutz, in commemoration of the Perutz centenary.]

In 1957, Max Perutz and Linus Pauling wrote to each other again on a topic that was new to their correspondence. This time Pauling asked Perutz to sign his petition to stop nuclear weapons tests, a request to which Perutz agreed.

Signature of Max Perutz added to the United Nations Bomb Test Petition, 1957.

As the decade moved forward, the discovery of the double helical structure of DNA attracted ever more attention to the work of James Watson and Francis Crick. In May 1958, Perutz asked Pauling to sign a certificate nominating his colleagues Crick and John Kendrew to the Royal Society. Pauling agreed, though stipulated that Kendrew’s name be placed first on the nomination, as he expected that Crick would get more support. As with Pauling’s bomb test petition a year earlier, Perutz agreed.

At the beginning of 1960, William Lawrence Bragg wrote to Pauling about nominating Perutz, along with Kendrew, for the 1961 Nobel Prize in Physics. Pauling was hesitant about the nomination, thinking it was still early, as their work on hemoglobin structure had only recently been published. Pauling also felt that Dorothy Hodgkin should be included for her work in protein crystallography. Bragg thought this a good idea and included Hodgkin in his nomination.

By March, Bragg’s nominations had gone through and Pauling was asked to supply his opinion. After spending some time thinking about the matter, Pauling wrote to the Nobel Committee that he thought that Robert B. Corey, who worked in Pauling’s lab, should be nominated along with Perutz and Kendrew for the Nobel Prize in Chemistry instead. Pauling felt that if Perutz and Kendrew were included in the award, Corey should be awarded half, with the other half being split between Perutz and Kendrew. Pauling also sent a letter to the Nobel Committee for Physics, indicating that he thought that Hodgkin, Perutz, and Kendrew should be nominated for the chemistry prize. Pauling sent a copy of this letter to Bragg as well.

Pauling’s letter to the Nobel Committee, March 15, 1960. pg. 1.

Pg. 2

In July, Bragg replied to Pauling that he was in a “quandary” about Corey, as he was “convinced that” Corey’s work “does not rank in the same category with that which Mrs. Hodgkin or Perutz and Kendrew have done.” Perutz and Kendrew’s efforts, he explained, had theoretical implications directly supporting Pauling’s own work, whereas Corey’s research was not that “different from other careful analyses of organic compounds.” Once everything was sorted out, Perutz and Kendrew were awarded the Nobel Prize for Chemistry in 1962 (the same year that Watson and Crick, along with Maurice Wilkins, won in Physiology/Medicine, and Pauling, though belated for a year, won the Nobel Peace Prize) and Hodgkin received the Nobel Prize for Chemistry in 1964. Robert Corey never was awarded a Nobel Prize.

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Linus Pauling, Max Delbrück and Max Perutz at the American Chemical Society centennial meeting, New York. April 6, 1976.

Perutz and Pauling corresponded very little during the 1960s, with Perutz writing only to ask for Pauling’s signature, once for a photograph that would be displayed in his lab and a second time for a letter to Italian President Antonio Segri in support of scientists Domenico Marotta and Giordano Giacomello, who were under fire for suspected misuse of funds.

In 1971 Perutz read an interview with Pauling in the New Scientist which compelled him to engage Pauling on scientific questions once again. Perutz was surprised to have read that Pauling had tried to solve the structure of alpha keratin as early as 1937 and that his failure to do so led him to study amino acids. Perutz wrote that had he known this in 1950, he, Bragg and Kendrew might not have pursued their own inquiry into alpha keratin. Pauling responded that he thought his efforts had been well-known as he and Corey had made mention of them in several papers at the time. Pauling explained that he had difficulties with alpha keratin up until 1950, when he finally was able to show that the alpha helix best described its structure. Perutz replied that he was aware of Pauling and Corey’s work and the alpha helix, but was surprised that Pauling’s early failure to construct a model led him to a more systematic and fruitful line of research.

Perutz also wondered whether Pauling had seen his article in the previous New Scientist, which reflected on Pauling and Charles Coryell’s discovery of the effect of oxygenation on the magnetic qualities of hemoglobin. Perutz saw this as providing “the key to the understanding of the mechanism of haem-haem [heme-heme] interactions in haemoglobin.” Pauling responded that he had not seen Perutz’s article but would look for it, and also sent Perutz a 1951 paper on the topic. Perutz took it upon himself to send Pauling his own article from the New Scientist.

A few years later, in 1976, Perutz again headed to southern California to attend a celebration for Pauling’s 75th birthday, at which he nervously gave the after dinner speech to a gathering of 250 guests. Before going to the event in Santa Barbara, Perutz stopped in Riverside and visited the young university there, which impressed him. Perutz wrote to his family back in Cambridge that he wished that “Oxbridge college architects would come here to learn – but probably they wouldn’t notice the difference between their clumsy buildings and these graceful constructions.”

Perutz also visited the Paulings’ home outside Pasadena, which elicited more architectural comments. Perutz described to his family how the Pauling house was shaped like an amide group, “the wings being set at the exact angles of the chemical bonds that allowed him to predict the structure of the α-helix.” Perutz asked Pauling, perhaps tongue in cheek as he thought the design somewhat conceited, “why he missed the accompanying change in radius of the iron atom.” Pauling replied that he had not thought of it.

Bertrand Russell and Linus Pauling, London England. 1953.

In preparation for his speech, Perutz also took some time to read No More War! which he concluded was as relevant in 1976 as when it was first published in 1958. Perutz saw Pauling’s faith in human reason as reminiscent of Bertrand Russell’s. Indeed, the many similarities between the two were striking to Perutz, and he included many of them in his talk, “except for their common vanity which I discreetly omitted.” In a personal conversation, Perutz asked Pauling about his relationship with Russell which, as it turned out, was mostly concerned with their mutual actions against nuclear weapons. Perutz was somewhat disappointed that “they hardly touched upon the fundamental outlook which I believe they shared.”

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Perutz and Pauling were again out of touch for several years until April 1987, when Pauling traveled to London to give a lecture at Imperial College as part of a centenary conference in honor of Erwin Schrödinger. Pauling’s contribution discussed his own work on antigen-antibody complexes during the 1930s and 1940s, during which he shared a drawing that he had made at the time. Perutz was in attendance and noticed how similar Pauling’s drawing was to then-recent models of the structure that had been borne out of contemporary x-ray crystallography. Perutz sent Pauling some slides so that he could judge the similarities for himself.

Flyer for Pauling’s 90th birthday tribute, California Institute of Technology, February 28, 1991.

The final time that Pauling and Perutz met in person was for Pauling’s ninetieth birthday celebration in 1991. Perutz, again, experienced stage fright as he gave his speech. But he was encouraged afterwards, especially after receiving a compliment from Francis Crick who, according to Perutz, was “not in the habit of paying compliments.” Perutz told his family that the nonagenarian Pauling “stole the show” by giving one speech at 9:00 AM on early work in crystallography and then another speech at 10:00 PM on his early years at Caltech. Perutz found it enviable that Pauling stood for both lectures and was still getting around very well, though he held on to the arm of those with whom he walked. Without coordinating, Perutz and Pauling also found a point of agreement in their talks, noting that current crystallographers were “so busy determining structures at the double” that they “have no time to think about them.” This rush often caused them to miss the most important aspects of the newly uncovered structures.

Just as Perutz first encountered Pauling through one of his books, The Nature of the Chemical Bond, so too would Pauling’s last encounter with Perutz be through a book, Perutz’s Is Science Necessary? Pauling received the volume in 1991 as a gift from his friends and colleagues Emile and Jane Zuckerkandl. Pauling’s limited marginalia reveal his interest in the text’s discussions of cancer and aging research. Aged 90 and facing his own cancer diagnosis, Pauling was particularly drawn to Perutz’s review of François Jacob’s The Possible and the Actual which sought, but did not find, a “death mechanism” in spawning salmon. Pauling likewise highlighted the book’s suggestion that “like other scientific fantasies…the Fountain of Youth probably does not belong to the world of the possible.” And Pauling made note of particular individuals that he had known well, like John D. Bernal and David Harker. Pauling deciphered the latter’s identity from Perutz’s less-than-favorable anonymous portrayal.

Pauling also noted spots where Perutz wrote about him. While most of these references were positive and focused on topics like Pauling’s influence on Watson and Crick and his breakthroughs on protein structure, one in particular was not. Perhaps less cryptic than the reference to Harker, Perutz described how “one great American chemist now believes that massive doses of vitamin C prolong the lives of cancer patients,” following it with “even more dangerous are physicians who believe in cancer cures.”

While critical, Perutz really meant the “great” in his comment and he continued to repeat it elsewhere. After Pauling passed away in August 1994, Perutz told his sister Lotte that “many feel that he [Pauling] was the greatest chemist of this century” while also being “instrumental in the protests that led to Kennedy and Macmillan’s conclusion of Atmospheric Test ban.”  He reiterated this idea in the paragraph that concluded his obituary of Pauling, published in the October 1994 issue of Structural Biology.

Pauling’s fundamental contributions to chemistry cover a tremendous range, and their influence on generations of young chemists was enormous.  In the years between 1930 and 1940 he helped to transform chemistry from a largely phenomenological subject to one based firmly on structure and quantum mechanical principles.  In later years the valence bond and resonance theories which formed the theoretical backbone of Paulings work were supplemented by R. S. Mullikens’ molecular orbital theory, which provided a deeper understanding of chemical bonding….Nevertheless resonance and hybridization have remained part of the everyday vocabulary of chemists and are still used, for example, to explain the planarity of the peptide bond.  Many of us regard Pauling as the greatest chemist of the century.

Pauling and Proteins: The Final Five Publications

Linus Pauling showing a molecular model to a young boy. 1950s.

[Part 3 of 3]

On March 31, 1951, Linus Pauling and numerous associates published seven revolutionary papers in a single issue of the Proceedings of the National Academy of Science. The research had been funded by the Rockefeller Foundation and carried out at the Gates and Crellin Laboratories of Chemistry, at Caltech. The first two articles: “The structure of proteins: Two hydrogen-bonded helical configurations of the polypeptide chain” and “Atomic coordinates and structure factors for two helical configurations of polypeptide chains,” have been discussed by us in the two weeks prior to this one. The remaining five will be described here in much shorter detail, as they are technical in the extreme.

The third article was titled “The structure of synthetic polypeptides,” and was written by Pauling and Robert B. Corey. The article claimed that the gamma helix and alpha-helix protein structures had forms that were also assumed by synthetic polypeptides. The authors discussed how the fibers of synthetic polypeptides had been analyzed using x-ray and infrared spectroscopy, which allowed them to determine the shape of the synthetic structures. Other scientists had also proposed the shapes of such structures, but Pauling and Corey rejected their hypotheses, as the structures the other scientists had proposed would have been “inherently unstable.” They concluded that their structure was the superior idea, and that while other structures potentially existed, they would be extremely difficult to measure due to their size.

The fourth article was more crucial to the narrative of protein structure that Pauling and his collaborators were weaving. The title was self-explanatory, and somewhat less technical than the others: “The pleated sheet, a new layer configuration of polypeptide chains.” In it, Pauling discussed how it had been long-believed that polypeptide chains are fully stretched and bound to adjacent, lateral chains of protein. He proposed instead a new idea, the so-called “pleated sheet.” In his suggested structure, the chains formed planes and certain bonds were arranged perpendicular to the planes of the chain, instead of coincidental with them. As a result, the chains are staggered and scrunched, instead of stretched in long, parallel lines. The rest of the article was devoted to the mathematics that Pauling had used to develop and explain the shape.

Feathers – specifically the atomic structure of feathers – was the topic of the fifth article, titled “The structure of feather rachis keratin.” The piece was written once again by Pauling and Corey and it analyzed rachis – a term with many meanings, but in this context referring to the central shaft of a feather – and keratins, which are structural proteins. The authors wrote that x-ray analysis of feather rachis keratin had shown the patterns of the polypeptide chains to be extremely complex, and notably shorter than expected. The rest of the article was spent explaining how the concept of the pleated sheet was mathematically relevant to feather rachis keratin.

Second to last was an article called “The structure of hair, muscle, and related proteins,” written by Pauling and Corey. In it, the authors pointed out that it had been many years since R.O. Herzog and Willie Jancke, in 1926, had made important x-ray photos of hair, muscle, nerve and sinew. Pauling and Corey felt that these photos, though revolutionary, were no longer adequate. Yet despite this deficiency, few modern attempts had been made to take better photographs. Two scientists named Lotmar and Picken had tried in 1942, but Pauling felt that their pictures were likewise not detailed enough. The Caltech researchers determined that their lab had found enough data though, and proposed structures for hair, muscle and “related proteins.”

This article differed from the other six in that it had an addition dated April 10, 1951. Written by Verner Schomaker, the addition revealed that subsequent research had shown that, while its basic premise was correct, the argument outlined on the piece’s first two pages was in fact wrong, and that the rest of the article hoped to amend that. Pauling and Corey argued that relaxed muscle was configured as a sheet, while contracted muscle formed an alpha-helix. The sheet configuration was inherently unstable relative to the alpha-helix, which made it easy for the hydrogen bonds holding the muscle in a sheet to break. This breakage allowed the polypeptide chains to coil and in turn made the muscle contract. The mechanism to prevent a chain reaction that might result in the sheet ripping itself apart during contraction was not understood, though Pauling had some ideas for that as well. The rest of the article was spent analyzing the amounts of energy released in frog muscle contractions to provide hypothetical amounts of energy expenditure and size for contractions in human muscle.

Representation of the collagen-gelatin molecule. April – May 1951.

The final article was “The structure of fibrous proteins of the collagen-gelatin group.” In it, Pauling wrote of his particular fascination with the protein in question:

Collagen is a very interesting protein. It has well-defined mechanical properties (great strength, reversible extensibility through only a small range) that make it suited to the special purposes to which it is put in the animal body, as in tendon, bone, tusk, skin, the cornea of the eye, intestinal tissue, and probably rather extensively in reticular structures of cells.

Another intriguing feature of collagen-gelatin was that it provided similar x-ray photos regardless of the source. In his article, Pauling noted that twenty-six samples, ranging from demineralized mammoth tusk to sheep gut lining, were all photographed by a scientist named Richard Bear and each resulted in remarkably similar images. Pauling compared them to a photograph of raw kangaroo tendon taken by Corey and Ralph W. G. Wyckoff, which also provided a view of what appeared to be the same structure. Pauling wrapped up the article discussing how three molecular chains wrapped into a distorted coil, and how the correlations between collagen-gelatin proteins and hydrogen could affect the structure.

The proteins work published by Linus Pauling and his Caltech colleagues in 1951 shook the scientific community and only added to Pauling’s growing fame. However, as time passed, evidence began to mount that his proposals regarding the gamma helix, muscle, and feather rachis were, in fact, wrong. Additionally, J.D. Bernal‘s lab found that the alpha helix, while fitting Pauling’s structural model, actually played a much smaller role in globular proteins than Pauling had suggested. However, Pauling’s media savvy and undeniable charisma won the day, at least in the short term. And so it was that, in the fall of 1951, (quoting Thomas Hager)

the 5 million readers of Life opened their new issues to find an enormous photo of Pauling, a big grin on his face, pointing to his space-filling model of the alpha helix. The headline read, ‘Chemists Solve a Great Mystery.’

Pauling and Proteins: Helices in the Air

Mounted models of the gamma helix and alpha helix, as housed in the Special Collections & Archives Research Center, Oregon State University Libraries.

[Part 2 of 3]

Linus Pauling sent shock waves through the scientific community when he published seven articles relating to the structure and function of proteins in the April-May 1951 issue of the Proceedings of the National Academy of Sciences. The first article of this volley was titled “The structure of proteins: Two Hydrogen-Bonded Helical Configurations of the Polypeptide Chain.” The second article was written by Pauling and Robert B. Corey, and was called “Atomic Coordinates and Structure Factors for Two Helical Configurations of Polypeptide Chains.” This paper was much more technical than was the first, and introduced two new important models developed by the Pauling group: the Gamma-helix and the Alpha-helix.

The article began by explaining in great detail Pauling’s idea for what he called the Gamma-helix (γ-helix). The γ-helix was the name assigned to the 5.1-residue helical configuration that Pauling, Corey, and Herman Branson had described in the first PNAS proteins article. The main difference between the γ-helix and the other configurations that they had proposed was that the bond angle between the C-N-C connection had been changed from 123˚ to 120˚. The authors explained that this small adjustment in the bond angle resulted in a miniscule change in the interatomic distances between various hydrogen bonds, but that these changes were significant enough to notably affect the number of residues per turn present within the structure.

(It is worth noting that the unit used to measure the distance between molecules is the Angstrom (Å). One Å equals 10^-10 m, or one ten-billionth of a meter. Considering the truly tiny sizes being measured, it is likewise worth noting that the changes between hydrogen bonds that Pauling was talking about were often measured in the thousandths of an Angstrom or ten-trillionths of a meter. One trillionth of a meter is known as a picometer.)

The article stressed that differences as small as 10 picometers could notably change bond angles, which would then change the number of residues per turn, thus dramatically affecting the shape of the helix. Next, the authors elaborated upon the likely arrangements of molecules within the helix due to symmetry or lack of symmetry in certain molecular bonds. Pauling and Corey further noted that they had used x-ray crystallography to validate their arguments and determine the crystal structures in question. From his earliest days as a scientist, Pauling had established himself as a major figure in x-ray crystallography, a technique by which an operator fires x-rays at a substance in question, then measures the way that the x-rays have deflected off of the substance. By analyzing these deflection patterns, researchers were then able to develop models of the shapes of molecular structures.

Once the γ-helix had been explained, the article moved on to discuss the Alpha-helix (α-helix). The group explained that the γ-helix and the α-helix were similar in terms of how the hydrogens bonded with other molecular groups, and how the residues fit under those configurations. They also detailed the exact interatomic distances between hydrogen and various other molecules in the structure, while pointing out that the distance between carbon and its other bonds determined the number of residues per turn. The number of turns, however, was variable; the smallest possible angle of 108.9˚ resulted in a residue of 3.6, while the largest possible angle of 110.8˚ resulted in a 3.67 residue.

William Lawrence Bragg, an internationally famous scientist and proteins researcher of great import, was impressed by the α-helix, though he felt his rival Pauling to be overly excited about it. The α-helix was not a complete protein, except in a few cases including fibers, hair, and horn.  The structure also did not explain the functioning of proteins. As such, Bragg felt the paper to be an important first step – no more, no less. The rest of the scientific community was more enthusiastic than was Bragg and his team. Pauling received a Nobel Prize in 1954 in Chemistry “for his research into the nature of the chemical bond and its application to the elucidation of the structure of complex substances,” the α-helix being among the most famous of these “complex structures.” The National Science Foundation even named a research vessel The Alpha Helix in honor of the discovery.

Bragg was even less generous regarding the γ-helix. Though in his very carefully worded congratulatory letter to Pauling he did not say so, he felt the γ-helix to be far-fetched, perhaps existing only in Pauling’s imagination. While this was not the case, the γ-helix ultimately made less of an impact on the scientific community.

Regardless, the import of Pauling’s work was felt throughout the profession.  Though Francis Crick would write that the alpha helix did not give him and Jim Watson the idea that DNA was a double helix, he did suggest that “helices were in the air,” at the time “and you would have to be either obtuse or very obstinate not to think along helical lines.”

Pauling and Proteins: The Beginnings of a Revolution

Linus Pauling and Robert Corey examining models of protein structure molecules, ca. 1951.

[Part 1 of 3]

An article with the somewhat cumbersome title “The Structure of Proteins: Two Hydrogen-Bonded Helical Configurations of the Polypeptide Chain” appeared in the April-May, 1951 edition of the Proceedings of the National Academy of Sciences. The article was written by Linus Pauling, Robert B. Corey and Herman R. Branson, working collaboratively at the Gates and Crellin Laboratories of Chemistry at the California Institute of Technology and communicated to PNAS on Pauling’s fiftieth birthday. The article is immediately notable in that it is first of seven written by Pauling and his collaborators on the nature of protein and published in that single issue of PNAS.

And as it turns out, these seven articles were revolutionary. While the very act of mailing in all seven at once was audacious, their contents solved riddles that many researchers “believed would not be solved for decades.” Max F. Perutz, a competitor of Pauling’s in the field of biochemistry, read all seven papers in one morning, after which he immediately raced to his lab. Utilizing Pauling’s predictions, he was able to conduct experiments that validated the hypotheses proposed by the papers. He wrote to Pauling that

The fulfillment of this prediction and, finally, the discovery of this reflection in hemoglobin has been the most thrilling discovery of my life.

“The Structure of Proteins: Two Hydrogen-Bonded Helical Configurations of the Polypeptide Chain” was presented as the lead article in the April-May 1951 PNAS. The main question asked by the paper was: What is the structure of polypeptide chains – the backbones of proteins? Pauling, Corey, and Branson claimed that the best way to determine the answer to this question was to acquire an “accurate determination of the crystal structure of amino acids, peptides, and other simple substances related to proteins.” By determining the attributes of these components, which acted as the building blocks of polypeptide chains, the researchers could then make reasonable estimations of what the finished product would look like. Pauling’s group was specifically searching for the interatomic distances between molecules, the bond angles of the chemical bonds, and “other configurational parameters” fundamental to the structures.

Pauling and his colleagues felt that their work answered these questions and that they had determined the parameters satisfactorily. They then used their data to determine that their basic shape was a hydrogen-bonded, helical configuration. They wrote that “An amino acid residue (other than glycine) has no symmetry elements…” (In biochemistry, “residue refers to a specific monomer,” which is “a molecule that may bind chemically to other molecules…”) Because the residues lacked symmetry elements which would force the polymer chain into a symmetrical pattern, “…the only [possible] configurations for a chain…are helical configurations.”

Figures from “The Structure of Proteins: Two Hydrogen-Bonded Helical Configurations of the Polypeptide Chain,” 1951.

Furthermore, the group determined that, based on their calculations of bond angles, there were five possible angles for the helical turns; 165°, 120°, 108°, 97.2°, or 70.1°. Of these, only two, 97.2° and 70.1°, were “reasonable” potential configurations for the polypeptide chain, based on observed interatomic distances. Hydrogen, carbon, oxygen and nitrogen are the elements that make up the polypeptide chain. The chemical bond between C-O and C-N are both double bonds (they have four electrons instead of two). These tight bonds, along with the measured interatomic distances of other components, indicated that the interatomic distances for the chain would have to be small, otherwise the chain would very quickly become unstable. This is the reason that only the 97.2° and 70.1° configurations were acceptable. The other three angles were unstable and would have unraveled because the N-H bonds had too much space between them. Whether the helix turned at a 97.2° or a 70.1° rotation depended on the number of residues per turn in the chain. Pauling and his associates proposed either a 3.7-residue helix or a 5.1-residue helix.

The article ended by explaining why competing hypotheses on the shape of polypeptide chains were incorrect. The article specifically pointed out three hypotheses authored by William Astbury and Florence Bell, William Lawrence Bragg, John Kendrew, and Max Perutz, and Maurice Huggins as being inferior. The Caltech group asserted that each of their models assumed a set number of residues in the polypeptide chains instead of potential variables, and only gave rough estimates of interatomic distances and bond angles. While they all agreed that a helix was the correct shape, the specifics of all other helix models were incorrect because of these deficiencies.

This first paper was just a piece of the larger argument that Pauling was making. Each article was in itself useful, but only when considering the larger sum of the full publication bloc could the full import and implications of Pauling’s work be made visible. Pauling’s thinking proved to be revolutionary and controversial, as such ideas often are. William Lawrence Bragg, a key competitor of Pauling’s, was especially critical. He felt numerous of the Caltech group’s ideas to be outright false, and even the most solid of Pauling’s assertions to be just baby-steps rather than major breakthroughs. Pauling, naturally, disagreed.

Linus Pauling and the Structure of Proteins: A Documentary History

Today is Linus Pauling’s birthday – he would have been 112 years old.  Every year on February 28th we try to do something special and this time around we’re pleased to announce a project about which we’re all very excited: the sixth in our series of Pauling documentary history websites.

Launched today, Linus Pauling and the Structure of Proteins is the both latest in the documentary history series and our first since 2010’s The Scientific War Work of Linus C. Pauling. (we’ve been a little busy these past few years)  Like Pauling’s program of proteins research, the new website is sprawling and multi-faceted.  It features well over 200 letters and manuscripts, as well as the usual array of photographs, papers, audio and video that users of our sites have come to expect.  A total of more than 400 primary source materials illustrate and provide depth to the site’s 45-page Narrative, which was written by Pauling biographer Thomas Hager.

Warren Weaver, 1967.

That narrative tells a remarkable story that was central to many of the twentieth century’s great breakthroughs in molecular biology.  Readers will, for example, learn much of Pauling’s many interactions with Warren Weaver and the Rockefeller Foundation, the organization whose interest in the “science of life” helped prompt Pauling away from his early successes on the structure of crystals in favor of investigations into biological topics.

So too will users learn about Pauling’s sometimes caustic confrontations with Dorothy Wrinch, whose cyclol theory of protein structure was a source of intense objection for Pauling and his colleague, Carl Niemann.  Speaking of colleagues, the website also delves into the fruitful collaboration enjoyed between Pauling and his Caltech co-worker, Robert Corey.  The controversy surrounding Pauling’s interactions with another associate, Herman Branson, are also explored on the proteins website.

Linus Pauling shaking hands with Peter Lehman in front of two models of the alpha-helix. 1950s.

Much is known about Pauling’s famously lost “race for DNA,” contested with Jim Watson, Francis Crick and a handful of others in the UK.  Less storied is the long running competition between Pauling’s laboratory and an array of British proteins researchers, waged several years before Watson and Crick’s breakthrough.  That triumph, the double helix, was inspired by Pauling’s alpha helix, discovered one day when Linus lay sick in bed, bored and restless as he fought off a cold. (This was before the vitamin C days, of course.)

Illustration of the antibody-antigen framework, 1948.

Many more discoveries lie in waiting for those interested in the history of molecular biology: the invention of the ultracentrifuge by The Svedberg; Pauling’s long dalliance with a theory of antibodies; his hugely important concept of biological specificity; and the contested notion of coiled-coils, an episode that once again pit Pauling versus Francis Crick.

Linus Pauling and the Structure of Proteins constitutes a major addition to the Pauling canon. It is an enormously rich resource that will suit the needs of many types of researchers, students and educators. It is, in short, a fitting birthday present for history’s only recipient of two unshared Nobel Prizes.

Happy birthday, Dr. Pauling!

The Alpha Helix

Space-filling model of the alpha helix.

[The Paulings in England: Part 5 of 5]

It has been said that sometimes blessings come in disguise, and so it may be that we have the damp English spring to thank for the elucidation of the alpha-helix structure of alpha-keratin – a fundamental and ubiquitous secondary structure pattern found in many proteins.

Linus Pauling was plagued by sinusitis for much of his time in England, and for three days in March 1948 it had become severe enough to put him in bed (as he was fond of saying over the years, this was before his vitamin C days). After a day spent devouring mystery novels, Pauling asked Ava Helen if she would bring him some paper and his slide rule, at which point he started trying to figure out how polypeptide chains might fold up into a satisfactory protein structure.

Pauling’s canvas was just an ordinary 8 1/2 by 11 inch sheet of paper. His first step was to draw the correct bond angles and distances onto the sheet, as determined from previous x-ray crystallographic work on polypeptides. Next he folded the sheet along parallel lines into a sort of squared-off tube. Doing so allowed him to add in representations of hydrogen bonds, which the impromptu model suggested would form between amino acid residues and, as a result, hold the turns of the polypeptide together.

The model made sense and pretty quickly it was clear that Pauling had discovered something important.  As he later wrote, his folded creation “turned out to be the structure of hair and horn and fingernail, and also present in myoglobin and hemoglobin and other globular proteins, a structure called the alpha-helix .”

Reconstruction of the alpha-helix paper model. Drawn and folded by Linus Pauling, 1982.

Pauling kept this idea to himself until his return to the United States because something didn’t match up quite right with the current laboratory data. Specifically, the turns of Pauling’s helix didn’t mirror the 5.1 angstrom repeat found in all of William T. Astbury‘s x-ray patterns. Pauling’s structure came close, but made a turn every 5.4 angstroms, or every 3.7 amino acid residues.

After his return home, with the assistance of colleagues Robert Corey and Herman Branson, Pauling continued refining his alpha helix structure and developing others, including the beta sheet. Simultaneously, the Caltech group’s chief British rivals at the Cavendish Laboratory published a paper titled “Polypeptide Chain Configurations in Crystalline Proteins.” The paper promised more than it delivered though, and while it listed many possible structures, Pauling found none of them to be likely. The competition was still on.

Pauling was finally convinced to publish when he received word that a British chemical firm called Courtaulds had created a synthetic polypeptide chain that showed no sign of Astbury’s 5.1 angstrom reflection in x-ray diffraction images. This was enough evidence for Pauling to decide that the 5.1 angstrom repeat was, perhaps, not a vital component of all polypeptide chains.  And so it was that in April 1951 Pauling, Corey and Branson published “The structure of proteins: Two hydrogen-bonded helical configurations of the polypeptide chain,” in the Proceedings of the National Academy of Sciences.

After devouring the Pauling group’s results shortly after their publication, Max Perutz headed to the Cavendish lab at Cambridge to check the data himself. Having confirmed the structure in images of horsehair, porcupine quill, synthetic polypeptides, hemoglobin and, for good measure, some old protein films that had been tucked away, Perutz wrote to Pauling, “The fulfillment of this prediction and, finally, the discovery of this reflection in hemoglobin has been the most thrilling discovery of my life.” He then published an analysis of his own data, concluding, “The spacing at which this reflexion appears excludes all models except the 3.7 residue helix of Pauling, Corey and Branson, with which it is in complete accord.”

Video Link: Pauling Recounts His Discovery of the Alpha Helix

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It wasn’t until a year later that the mystery of Astbury’s 5.1 angstrom reflection was finally solved. In 1952, on a visit to the Cavendish, Pauling met Francis Crick, the then-graduate student who would go on to play a huge part in the discovery of the structure of DNA. The two maintained similar interests and during a taxi ride around Cambridge found themselves discussing the matter of the alpha helix. “Have you thought about the possibility,” Crick asked Pauling, “that alpha helixes are coiled around one another?” Whether Pauling had or had not considered this possibility remains a point of contention, but Pauling remembered replying that he had, because he had been considering a number of higher-level schemes for his helixes, including some which wound around each other.

Regardless, Pauling returned to Caltech and both he and Crick set to work on the problem. With help from Corey, Pauling discovered a means by which the alpha helixes could wrap around each other in a coiled-coil to produce the problematic 5.1 angstrom found in Astbury’s pictures of natural keratin.  Crick, in the meantime, was conducting a very similar study.  Pauling and Crick, independent of one another, ultimately submitted the solution to this puzzle for publication within days of each other, and at first there was a bit of grumbling as to whom the credit should be awarded. Though Crick’s note was published first, the Cavendish camp eventually conceded that Pauling’s paper included considerably more detail of consequence, and it was finally settled that both scientists had independently come to the same general conclusion.

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Pauling receiving his honorary degree from the University of Paris, 1948.

After Pauling’s two fruitful terms as Eastman Professor at Oxford were up in July, the family split their remaining time between travels in Amsterdam, Switzerland and Paris. Pauling rounded off the trip by receiving yet another honorary degree from the University of Paris, and on August 25, 1948, the Paulings set sail once more on the Queen Mary.

His eight months in Europe had been productive and enlightening, but Pauling was ready to return to Pasadena where he could share the myriad ideas he had generated and gathered during his time away from Caltech. As we have seen, he was especially eager to get back to work on proteins, writing shortly before his departure that “I have continued to work on my theory of metals, and have been doing nothing about proteins. However, I am looking forward to being back home, and to thinking about that subject again.”

DNA: The Aftermath

Pastel depiction of the DNA base pairs by Roger Hayward.

The solving of the double helix structure of DNA is now considered to be one of the most important discoveries in modern scientific history. The structure itself suggested a possible mechanism for its own replication, and it also opened up a huge window of opportunity for advances in multiple fields ranging from biology to genetics to biochemistry to medicine. Almost immediately after James Watson and Francis Crick announced their structure, new research began based on the structure’s specifications.

An Early Idea from George Gamow

The Pauling Papers contain an interesting example of research done on the structure of DNA mere months after its discovery. On October 22, 1953, the Russian-born physicist (and founder of the “RNA Tie Club“) George Gamow sent a letter to Linus Pauling that mentioned some work he had been doing with DNA. Gamow explained that he had found a manner by which the twenty amino acids that make up proteins could be related to different combinations of the four nucleotides found in DNA.

At this time, it wasn’t known that the DNA strands unwind during replication, and Gamow assumed that protein synthesis occurred directly on the double helix. He suggested that a “lock and key relationship” might exist between each amino acid and that the “holes” formed between each complementary base pair in the DNA chain. Science is now aware that this is not the case, but Gamow’s letter is nicely demonstrative of the innovative research ushered in by Watson and Crick’s solving of DNA.

Excerpt from Gamow's letter to Pauling, October 22, 1953.

Click here to view Gamow’s entire letter, and here to read Pauling’s response.

RNA

As the buzz around DNA started to die down, scientists began to move toward the next logical step: RNA. By then, Watson and Crick’s structure was widely accepted, and it had been clear for some time that DNA was the site of the gene. So, then, how did DNA transfer its information to RNA, and finally on to proteins?

Gamow’s above suggestion was a possibility, but it didn’t even involve RNA. Watson spent some time playing with the matter, but was not able to equal his luck with DNA. Unfortunately, it would be quite some time before this mechanism was elucidated. Even now, some of the finer details of how this is accomplished are not completely understood.

Four members of the RNA Tie Club, 1955. Clockwise from upper left: Francis Crick, Leslie Orgel, James Watson and Alexander Rich. Founded by George Gamow, the RNA Tie Club met twice a year in pursuit of greater understanding of RNA.

Eventual Honors

Unsurprisingly, as time went on, Watson and Crick began to accumulate awards for their work with DNA. On December 15, 1959, Linus Pauling responded to a previous letter sent to him by Sir William Lawrence Bragg soliciting Pauling’s support of the nomination of Watson and Crick for the Nobel Prize. In this letter, Pauling stated that he would indeed be willing to write the requested letter of support. However, contrary to Bragg’s suggestion that they be nominated for the prize in chemistry, Pauling stated his belief that a prize in physiology or medicine would be much more fitting.

Several months later, on March 15, 1960, Pauling finally sent his letter to the Nobel Committee.  By the time of its authorship, Pauling’s feelings about the importance of Watson and Crick’s work had become even more tepid.

While acknowledging that “the hydrogen-bonded double-helix for DNA proposed by Watson and Crick has had a very great influence on the thinking of geneticists and other biologists,” Pauling notes that their work was, at least to some degree, “stimulated” by his and Robert Corey’s incorrect triple-helix structure, and abetted by Maurice Wilkins‘ x-ray photographs.  Pauling also points out that Wilkins, Corey, Karst Hoogsteen and himself had already tweaked the Watson-Crick model a bit, “which suggests the possibility that a further change in the structure of nucleic acid may be found necessary.”

In the end, Pauling couldn’t bring himself to go through with the promised nomination.

It is my opinion that the present knowledge of the structure of polypeptide chains in proteins is such as to justify the award of a Nobel Prize in this field in the near future, to Robert B. Corey for his fundamental investigations of the detailed molecular structure of amino acids and the polypeptide chains of proteins or possibly divided between him and Kendrew and Perutz. On the other hand, I think that it might well be premature to make an award of a Prize to Watson and Crick, because of existing uncertainty about the detailed structure of nucleic acid. I myself feel that it is likely that the general nature of the Watson-Crick structure is correct, but that there is doubt about details.

Pauling’s hesitations served only to delay their inevitable receipt of a Nobel Prize for a short time. In 1962, Francis Crick, James Watson, and Maurice Wilkins shared the award in Physiology or Medicine “for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material.”

The discovery of the structure of DNA was clearly one of the most important discoveries in the modern scientific era. Not only was it a huge breakthrough in itself, but it also opened the door for major advances in numerous other science-related fields. For more information on DNA, check out the rest of the posts in our DNA series or the website on which they are based, “Linus Pauling and the Race for DNA: A Documentary History.” For more information related to Linus Pauling, please visit the Linus Pauling Online portal.

Letters to Peter

Linus and Peter Pauling at Warwick Castle, England. 1948.

“You know how children are threatened ‘You had better be good or the bad ogre will come get you.’ Well, for more than a year, Francis and others have been saying to the nucleic acid people at King’s ‘You had better work hard or Pauling will get interested in nucleic acids.’”

–Peter Pauling. Letter to Linus Pauling, January 13, 1953.

Normally, when Linus Pauling became interested in something, he would dive headlong into it. Hours and hours of his time, over weekdays and weekends, would be committed to research in pursuit of fleshing out every last useful detail. This arduous process is best illustrated by his work on the nature of the chemical bond, work which would later win him a Nobel Prize in Chemistry.

Pauling’s experience with DNA, however, was not an example of this typical approach.

First, it should be noted that Pauling did not have years to spend working on DNA. Its importance was fully realized in the summer of 1952, less than a year before Watson and Crick elucidated its structure, and although Pauling actually began studying nucleic acids as early as 1933, he wasn’t able, or willing, to spend a significant amount of time on a molecule that was perceived to be relatively unimportant.

Even after learning of the importance of DNA, Pauling still didn’t make time for it. As emphasized in earlier posts on Linus Pauling and DNA, Pauling remained very much preoccupied with his work on the nature of proteins.

An examination of Pauling’s correspondence with his son Peter – a man uniquely positioned in the middle of the DNA story – reveals that other matters, many of them trivial, also took precedence over Pauling’s pursuit of the structure of DNA.

In the fall of 1952, Peter Pauling, an aspiring crystallographer and the second oldest of the four Pauling children, began his graduate studies at the University of Cambridge. Coincidentally, James Watson and Francis Crick were also at Cambridge at this time, and not long after his arrival, Peter had met them, become an office-mate, and was spending off-hours time with the duo.

Because Linus Pauling and the Watson-Crick tandem were both attempting to solve the structure of DNA, Peter’s arrival at Cambridge gave his father an excellent opportunity to keep tabs on the work being done by his competitors in England. A close examination of the voluminous father-son correspondence from this era suggests, however, that DNA was far from a pressing topic in Pasadena.

Also, as to your curtains: will you check the dimensions and let us know. You say in your letter two windows 6’ 6” high, 50” and 37” wide respectively, in other words four curtains each 48” wide. Mama thinks that you probably mean four curtains each 36” wide. It would be hard to get the wider material.

Also, would you write us as to the exact points between which the vertical dimensions are measured. What is the distance from, say, the top of the window frame (or some other exactly specified locus) to the floor, and also to the bottom of the window frame? Mama thinks that probably the curtains should reach all the way to the floor, but in any case they should extend from the top of the window frame to the bottom of the window frame (if you have window frames), or from a point a little below the opening at the bottom. She suggests that one of your old curtains might serve for one of the windows, and that she would then have to make only a pair for the larger window.

I sympathize with you about the bed. I remember sleeping on a bed which had a two by four across under my ear; it was not very comfortable.

-Linus Pauling, letter to Peter Pauling, October 22, 1952.

Linus first wrote to Peter in England on October 22, 1952. By this time, the elder Pauling was well aware of the importance of DNA, but had not yet devised a structure. Watson and Crick, on the other hand, had developed a structure for DNA a year earlier. Although their model turned out to be incorrect, the two men continued their work with nucleic acids. Clearly, for Watson and Crick, DNA was becoming extremely important. For Pauling this did not appear to be the case – although Watson and Crick were both mentioned in this first letter, DNA was not.

As it turns out, other subjects – including, but not limited to, curtains for Peter’s new apartment, recent travels and upcoming travel plans, finances, and, of course, cars – were much more prevalent than was DNA in the Paulings’ early correspondence.

As time went on, nucleic acids naturally became a slightly larger topic, though never did they assume center stage. Take, for example, this letter sent from Linus to Peter on February 4, 1953. By the time of its authoring, Linus Pauling had completely developed his structure, and had also sent off his manuscript for publication, a development which merited one paragraph worth of description. The rest of the letter is used to discuss, in great detail, Pauling’s plans to travel to England and also his keen interest in purchasing a new Riley from the U.K.-based International Motors. (Being something of a family obsession, cars were a very popular subject in many of the letters between Linus and Peter.)

In another letter from Pauling to Peter written on March 10, 1953, DNA plays a much larger role. This time, about half of the three-page document is dedicated to discussing various aspects DNA; the remainder focuses on travel plans and automobiles.

Peter Pauling, December 1954.

The other letters follow this same trend. Clearly, Linus and Peter’s lengthy discussions on subjects such as cars, traveling, curtains, and other aspects of science suggest that Pauling wasn’t interested in DNA on the level of certain other scientific pursuits.

Another interesting aspect of the correspondence between Linus and Peter Pauling is the opportunity that it provides for tracking the evolution of the consensus response to Pauling’s structure.

As might be expected, Peter’s reaction stayed upbeat throughout all of their letters. However, as time progressed, it is clear that Peter became less-confident that his father had solved DNA. For example, in a few of the earlier letters, Peter mentions that Watson and Crick earlier devised and discarded a structure similar to the Pauling-Corey triple helix, but that the opinion at the Cavendish Laboratory is that Pauling’s structure is a good one, albeit “pretty tight.”

From that point on though, Peter begins talking less about Pauling’s structure, and more about work being done by Watson, Crick, and Rosalind Franklin. One might deduce that, although Peter didn’t specifically issue a disagreement with his father’s structure, he did develop a certain degree of skepticism as time progressed. Peter also does not often mention other opinions of his father’s structure, most likely because, upon further examination, it was not well-received by the English contingent.

Peter Pauling Discusses His Father’s Strengths and Personality

For more information on DNA, please visit the Race for DNA website. For more information on Linus Pauling, check out the Linus Pauling Online portal.

The Pauling-Corey Structure of DNA

Today, the structure of DNA series is continued with the model proposed by Linus Pauling and Robert Corey in 1953. As a result of insufficient data and an overloaded research schedule, Pauling’s structure turned out to be incorrect. However, it is interesting to see the ways in which one of the world’s leading scientists went wrong with his approach to the structure of this hugely-important molecule.

Linus Pauling played around with nucleic acids as early as 1933 when he hypothesized a structure for guanine, a base ring. In the summer of 1951, he again became interested in DNA when he heard that Maurice Wilkins at King’s College had developed a few good photographs of nucleic acids. Unfortunately for Pauling, Wilkins was unwilling to share his research. In November of that same year, a structure of nucleic acids was proposed and then published by Edward Ronwin. Pauling could tell almost immediately that Ronwin’s structure wasn’t correct, but it did contain a few good ideas that got him thinking about other possible structures. Pauling hypothesized that DNA was likely helical in shape, with the large base groups facing out and the phosphate groups stacked in the core. At this juncture, however, Pauling was again distracted by other research and let the project drop.

Until 1953 nucleic acids weren’t considered to be very important. At the time, proteins, rather than DNA, were considered by most scientists to be the carriers of genetic material. Partly because of this, Pauling’s attention was focused on proteins, not DNA. In May of 1952, Pauling was scheduled to attend a special meeting of the Royal Society where he would address questions pertaining to his protein structures. This trip would also give him an opportunity to discuss DNA with Rosalind Franklin, who was Maurice Wilkins’ assistant. She had recently developed an especially clear photograph of DNA which likely would have saved Pauling from making some key mistakes when determining the structure of DNA.

As a result of his very-public anti-war and anti-nuclear activities, Pauling’s initial request for a passport was denied, though he was granted a limited passport only ten weeks later. However, when Pauling arrived in England, he did not visit King’s College. He was preoccupied with his protein research and he assumed that Wilkins still wouldn’t be willing to share his data.

Soon after his visit to England, Pauling was granted a full passport and traveled to France. Here he was informed, through an experiment performed by Alfred Hershey and Martha Chase, that DNA was in fact the genetic master molecule. Upon learning this, Pauling decided that he would solve the structure of DNA. However, when he returned to California, he continued to work primarily with proteins. It wasn’t until November 25, 1952 that Linus Pauling would make a serious attempt at the structure of DNA.

Unfortunately, when Pauling did decide to put in some time with DNA, he still had insufficient data to correctly deduce its structure. Using only a few blurry x-ray patterns done by William Astbury in the 1930s and a photograph published by Astbury in 1947, Pauling decided that DNA was indeed a three-chain helix with the bases facing outward and the phosphates in the core.

Astbury's 1947 photographs of DNA.

However, it was immediately clear that making room for so many phosphates in the center of the molecule would be quite a task. Pauling spent a great deal of time manipulating his model, and eventually produced a satisfactory representation. He then asked Robert Corey, his chief assistant at Caltech, to perform detailed calculations on the proposed atomic positions. Corey’s calculations proved that, despite Pauling’s efforts, there still wasn’t enough room for all of the atoms. Pauling, refusing to consider the possibility that his structure was incorrect, resorted to further manipulation. (In fact, Pauling refused to concede even after a colleague pointed out that there was no room for sodium ions in the core of his model, a feature that is essential in the creation of sodium salts of DNA.) Convinced that the finer details would later fall into place, Pauling and Corey spent the last week of the year writing up their structure, and on the last day of 1952, they submitted “A Proposed Structure for the Nucleic Acids” to the Proceedings of the National Academy of Sciences.

Diagram of the Pauling-Corey structure for DNA, as published in PNAS.

The paper was uncharacteristic of Pauling. Instead of his usual confidence, he stated that the structure was “promising” but also “extraordinarily tight.” Pauling likewise noted that the model accounted only “moderately well” for the x-ray data, and that the atomic positions were “probably capable of further refinement.” As it turned out, Pauling wasn’t seeking perfection with his structure. In reality, he wanted to be the first to publish a roughly correct structure of DNA. Rather than having the final say, he wanted the first.

Once the article was published in February of 1953, it became more and more apparent that Pauling’s structure wasn’t even roughly correct. By this time, Pauling had already moved on to other projects, and was surprised at the fact that his paper was received so poorly. Once he caught wind of the talk surrounding his structure, he decided to return to the topic of DNA. Despite the negative reaction, Pauling still believed that his structure was essentially right. However, he soon received better nucleotide samples from Alex Todd, an organic chemist at Cambridge, and began a more rigorous approach to determining the structure of DNA.

Unfortunately, by this time it was too late. Upon the publication of Pauling’s unsatisfactory model, James Watson and Francis Crick were given the green light to pursue their own model of DNA. Before long, Pauling saw that the work they were doing was very promising. A few days after first seeing their structure, Pauling received an advance copy of the Watson and Crick manuscript. At this point, he still retained a fair amount of confidence in his own model, but acknowledged that there was now another possible model. In a letter to Watson and Crick written on March 27, 1953, Pauling noted

I think that it is fine that there are now two proposed structures for nucleic acid, and I am looking forward to finding out what the decision will be as to which is incorrect.

However, he had still not seen Rosalind Franklin’s data; Watson and Crick had. (Interestingly enough, Robert Corey had traveled to England in 1952 and viewed Franklin’s photographs. It is unknown whether or not he purposely failed to provide Pauling with the details of the images.)

This fact would soon change. In April of 1953, Pauling was to attend a conference on proteins in Belgium. On his way, he stopped in England to see the Watson and Crick model of DNA as well as Franklin’s photographs. After examining both, Pauling was finally convinced that his structure was wrong and that Watson and Crick had solved DNA.

Linus Pauling, although disappointed with the results, accepted his defeat graciously. He gave Watson and Crick full credit for their discovery and assisted them in tying up a few loose ends with their model. For Pauling, this event was a single failure in a sea of successes. In fact, the very next year, he would win the Nobel Prize in Chemistry – the first of his two Nobel Prizes. Despite his embarrassing mistakes, Pauling was to remain in good standing with the scientific community.

Please check back on Thursday for the conclusion of the DNA structure series – an examination of the correct structure deduced by Watson and Crick. For more information on DNA, please visit the website Linus Pauling and the Race for DNA. For more information on Linus Pauling, visit the Linus Pauling Online Portal.