John Kendrew (1917-1997)

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

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

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

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

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John Kendrew and Max Perutz, 1962.

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

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

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

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

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

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Peter Pauling, 1954.

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

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

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

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

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

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

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

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

Pauling replied kindly, but did not include any recommendations.

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

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

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

Wall of Honor at the European Molecular Biology Laboratory.

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

Pauling and Perutz in the Golden Age of Protein Research

Max Perutz, 1987. Image Credit: Graham Wood.

[Part 3 of our series celebrating the Perutz centenary.]

In 1939 Max Perutz’s girlfriend gave him a book token for Christmas. Working on finishing his dissertation on the structure of hemoglobin, Perutz used that token to purchase Linus Pauling’s recently published text, The Nature of the Chemical Bond.

In the obituary of Pauling that he wrote some fifty-five years later, Perutz described how the “book transformed the chemical flatland of my earlier textbooks into a world of three-dimensional structures” and “fortified my belief, already inspired by J. D. Bernal, that knowledge of three-dimensional structure is all-important and that the functions of living cells will never be understood without knowing the structures of the large molecules composing them.”  The purchase of Pauling’s book marked the beginning of a long, fruitful and sometimes contentious correspondence between the two men, working on separate continents but united by similar interests.

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Not until 1946 did Perutz first write to Pauling, asking for assistance as he labored through his research on the structure of hemoglobin. The Cavendish Laboratory, where Perutz was located, did not have the latest equipment that was available to Pauling at Caltech. In particular, Perutz needed a Hollerith punch-card machine to carry out calculations of the three-dimensional Patterson-Fourier synthesis. Perutz knew that Pauling’s lab was already conducting calculations of this sort and that the work Perutz was doing “would have to be done sooner or later, if the molecular structure of the proteins is to be worked out.”

As such, Perutz hoped that someone in Pauling’s lab might do the calculations for him. Pauling was not moved enough by Perutz’s request to offer the labor of his own team, replying that enlisting someone do such work in a “routine way” could lead to confusion. Pauling did offer that Perutz come to Pasadena, or send a surrogate to do the work, if he could find the money. Perutz was unable to support such an undertaking and so ended that conversation.

Linus Pauling and Lord Alexander R. Todd. Cambridge, England. 1948.

Two years later, in 1948, Pauling was in England, enjoying a stint as George Eastman Professor at Oxford. It was during this time that he and Perutz met for the first time in person. Perutz described his first experiences of Pauling’s lectures, in which

he would reel off the top of his head atomic radii, interatomic distances and bond energies with the gusto of an organist playing a Bach fugue; afterwards he would look around for applause, as I had seen Bertrand Russell do after quoting one of his eloquent metaphors.

The two also found time to talk together about their own particular research projects.

Pauling’s work at Oxford touched directly on Perutz’s own program, in what would become a oft-noted story in twentieth century history of science. As Pauling lay in bed with a cold, he did not stop working, choosing to spend his time making planar peptide models with paper chains. From his paper folding exercises, Pauling, according to Perutz’s obituary, “found a satisfactory structure by folding them into a helix with 3.6 residues per turn.” (A story that Pauling relayed many times himself.) The structure would come to be known as the alpha helix.

After Pauling recovered from his illness, Perutz showed him his own model of a polypeptide chain which was part of his larger hemoglobin model and was similar to fibers described by William Astbury. To Perutz’s “disappointment, Pauling made no comment,” and gave no hint as to his own breakthrough, which he announced the next year in a “dramatic lecture.”  That later unveiling of the alpha helix gave rise to a famous Perutz anecdote, which later informed the title of a book of essays that Perutz published.

When I saw the alpha-helix and saw what a beautiful, elegant structure it was, I was thunderstruck and was furious with myself for not having built this, but on the other hand, I wondered, was it really right?

So I cycled home for lunch and was so preoccupied with the turmoil in my mind that I didn’t respond to anything. Then I had an idea, so I cycled back to the lab. I realized that I had a horse hair in a drawer. I set it up on the X-ray camera and gave it a two hour exposure, then took the film to the dark room with my heart in my mouth, wondering what it showed, and when I developed it, there was the 1.5 angstrom reflection which I had predicted and which excluded all structures other than the alpha-helix.

So on Monday morning I stormed into my professor’s office, into [William Lawrence] Bragg’s office and showed him this, and Bragg said, ‘Whatever made you think of that?’ And I said, ‘Because I was so furious with myself for having missed that beautiful structure.’ To which Bragg replied coldly, ‘I wish I had made you angry earlier.’

 

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Once Pauling returned to Pasadena, he and Perutz fell into a minor quarrel. In December 1950, Perutz had heard that Pauling had been “annoyed” by Perutz and John Murdoch Mitchison’s paper, “State of Hæmoglobin in Sickle-Cell Anæmia,” which had been published in Nature that October. Pauling was upset that Perutz and Mitchison had suggested that crystallization caused cells to sickle without properly citing his own seminal work on the subject.

In a December letter, Perutz said he was “very disappointed” that Pauling was upset with the publication, not only because there was a reference to Pauling, et al. in its introductory paragraph, but “particularly because all the new experimental evidence we report seemed to fit in so beautifully with the basic ideas set out in” Pauling’s co-authored Science article, “Sickle Cell Anemia, a Molecular Disease,” published in November 1949. Perutz explained his position in more detail, noting,

There is perhaps a slight difference between our points of view. Whereas you regard the sickling as being due to an aggregation and partial alignment of hæmoglobin molecules by a lock and key mechanism, an interlocking of specific groups in neighbouring molecules, we regard the cause of the sickling as being simply a crystallization, due to abnormally low solubility of the reduced hæmoglobin. No specific interaction of the kind you mention need be involved in the second process, though it obviously may be…I am sorry that this misunderstanding between us should have arisen, particularly as I have spent much effort trying to convert unbelievers to your scheme.

Pauling waited until the following February to respond and explained his feeling that readers of Perutz’s article might conclude that Perutz was making an original proposal. Having made this statement, Pauling, in his own way, moved beyond the quarrel by telling Perutz about his more recent work showing that “hemoglobin is not crystallized in the sickle cells, but is only converted to the nematic [or liquid crystal] state.” The ice broken, Perutz quickly responded by inviting Pauling to take part in informal discussions about protein structure at the Cavendish Laboratory before an annual conference, to be held in Stockholm. Pauling, however, could not attend.

The next year, Pauling attempted to visit England, this time to speak at a conference about the alpha helix, but was delayed due to his passport renewal being denied on account of his political activities. Perutz wrote that Pauling’s “absence had a sadly damping effect on our meeting at the Royal Society, and it made the discussion rather one sided as there was no none to answer the various objections to the α-helix raised by the Astburites and Courtlauld people” since Pauling’s supporters were unprepared to defend Pauling’s position without him. Perutz was also keen to show Pauling his own progress, an eagerness that Pauling reciprocated. By July Pauling had cleared up his passport problems and was able to spend time in person discussing his and Perutz’s work.

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By 1953 Perutz and Pauling were quarrelling again over proper citation, though this time it was Perutz suggesting that Pauling had not given Francis Crick enough credit regarding the coiling of alpha helixes. Pauling explained to Perutz that, while he was at Cambridge the previous summer, he had talked with Crick and John Kendrew at length. During that conversation, according to Pauling,

There was only brief discussion of α keratin at this time, and, if my memory is correct, only a few sentences were said about the coiled coil, as Crick calls it. We discussed the fact that the 5.15-Å meridional reflection offers some difficulties of explanations, and that also there seemed to be a discrepancy in the density of α keratin. The discussion was very brief. Then Mr. Crick asked me if I had ever thought of the possibility that the α helixes were twisted about one another. I answered that I had. So far as I can remember, nothing more was said on this point.

Pauling went on to emphasize that “the idea was not a new one to me then” and that his own description of it in Nature was different from Crick’s understanding. Perutz ceded this point, adding that Pauling’s differences with Crick “stimulated Crick to clarify his own” ideas on the coiling of alpha helixes. More generally, Perutz found that the competition that arose between the two labs as they worked on similar problems helped to push each forward, thus leading to positive advances.

The famous group photo of the Pasadena Conference on the Structure of Proteins, September 1953. Pauling stands front row, third from left. Perutz stands two rows behind Pauling. [Image credit: The Archives, California Institute of Technology]

That September, Perutz made his first visit to California in order to deliver a paper at the Pasadena Conference on the Structure of Proteins, at which were gathered all of the world’s major figures in the field, including Jim Watson and Francis Crick, newly famous for their double helical structure of DNA. Perutz told his wife, Gisela, that his paper was “well received.” Additionally, with all of the different perspectives presented, there was “an atmosphere of soberness, and a realization that no-one’s solution of the protein problem was complete, and every approach was still fraught with complications.” Perutz was also quite taken with the Paulings’ home and their hospitality, pointing out that Ava Helen had invited him “after one of the meetings for a swim in their garden.”

Correspondence between Perutz and Pauling dipped a bit after the conference, though Pauling did take a moment to congratulate Perutz on being elected to the Royal Society the following Spring. While the exchange was brief, it reflected the long relationship built up between the two over the preceding years and, in particular, a confluence of work that had boosted the esteem of both scientists.

Perutz had begun looking at the structure of wool proteins back in 1951, thinking that there might be similarities to hemoglobin. He became excited after finding Pauling’s work on alpha helixes in fibers, thinking that the structure might be present in wool as well. His initial studies resulted in disappointment, but after adjusting the angle at which he was taking his x-rays by 30 degrees, he compiled new data that confirmed Pauling’s alpha helix structure. After applying it to his own work on hemoglobin, Perutz told Pauling “the discovery of this reflexion in haemoglobin has been the most thrilling discovery of my life…there is no doubt that it is a universal feature at least of all fibers of the α type. Whether all crystalline proteins show it remains to be seen.” Not suprisingly, Pauling was also “very pleased” with this discovery.

This research opened the door for Perutz to be considered by the Royal Society. But it was his development of a technique for determining a three-dimensional view of structures derived from x-ray crystallography that assured his election. He did this be attaching mercury atoms to hemoglobin, which allowed him to figure out where the crest and trough of a given x-ray was in relation to the structure that appeared on the photos. Perutz later said that after he finished the work and published it in Nature at the end of 1959, he went skiing in the Alps, and by the time he returned he was famous, assuring his fellowship in the Royal Society.

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.

An Era of Discovery in Protein Structure

Linus and Ava Helen Pauling, Oxford, 1948.

[The Paulings in England: Part 4 of 5]

Though metals were consuming a good portion of his time during his fellowship at Oxford, Linus Pauling’s other projects never strayed far from his thoughts.  High on the list were the mysteries of proteins, whose structures and functions were slowly starting to be unraveled.

Pauling’s interest in proteins was spurred in the mid-1930s when the Rockefeller Foundation began to look most favorably upon the chemistry of life when deciding where their grant money would go. Early on, Pauling set out to tackle hemoglobin and though his affair with the molecule lasted for the remainder of life, Pauling certainly didn’t limit himself to the study of just one protein.

At a time when most were looking at proteins from the top down, trying to sort out the complicated data produced by an x-ray diffraction photograph of an entire protein, Pauling was working from the bottom up, in the process determining the structures of individual amino acids – the building blocks of proteins.

A specific protein that kept coming back into view over the years was keratin. In the 1930s, the English scientist William Astbury had studied the structure of wool, which along with hair, horn, and fingernail is made up primarily of this enigmatic protein, keratin. Astbury proposed that the structure was akin to a flat, kinked ribbon, but Pauling disagreed. “I knew that what Astbury had said wasn’t right,” Pauling recalled, “because our studies of simple molecules had given us enough knowledge about bond lengths and bond angles and hydrogen-bond formation to show that what he said wasn’t right. But I didn’t know what was right.” Pauling attempted to construct a model at the time, but could not match his structure to the measurements dictated by Astbury’s blurry x-ray diffraction images. Pauling wrote the project off as a failure and continued pursuing other interests.

In 1945 Pauling found himself seated next to Harvard medical Professor William B. Castle on a railroad journey from Denver to Chicago. Castle was a physician working on the nature of sickle cell anemia and the conversation that he shared with Pauling planted a seed in Pauling’s mind about the cause of this debilitating disease.

In the bodies of those suffering from sickle cell anemia, red blood cells assume a sickled shape when they are in the deoxygenated venous system but retain their normal flattened disk shape in the oxygen-rich arterial system. Noting this, Pauling suggested that perhaps the source of the problem could be a defect in the oxygen-carrying protein itself: hemoglobin.

Amidst his travels in Europe, Pauling continued to act on this idea as maestro from afar, directing the scientists in his Caltech laboratory to continue searching for differences in the hemoglobin of normal and sickled cells. In the meantime, he sought out and communicated new ideas gleaned from meetings such as the Barcroft Memorial Conference on Hemoglobin, held at Cambridge in June 1948. Pauling’s research team, in particular Harvey Itano and S. Jonathan Singer, were able to show experimentally that his hunch had been right, and less than a year after his return to Pasadena a paper was published that established sickle cell anemia as the first illness to be revealed as a truly molecular disease.

Linus and Peter Pauling at the model Bourton-on-the-water, England. 1948.

While in England, Pauling had occasion to interact closely with a number of scientific greats.  Among these were his close friend Dorothy Crowfoot Hodgkin, who is credited as a pioneer in the development of protein crystallography and was the winner of the 1964 Nobel Prize for Chemistry.  Likewise, Pauling conversed with Max Perutz, a protege of Sir William Lawrence Bragg‘s at the Cavendish Laboratory at Cambridge, who would go on to discover the structure of hemoglobin and receive the Nobel Prize for Chemistry in 1962.  While fruitful in many respects, these interactions served to increase Pauling’s feelings of urgency as concerned the race to determine the structure of proteins.

Bragg shared the 1915 Nobel Prize in Physics with his father for their early development of X-ray crystallography, and though there existed a long-standing scientific rivalry between Pauling’s and Bragg’s laboratories, it wasn’t until Pauling saw, with his own eyes, the work that was being done that he admitted he was “beginning to feel a bit uncomfortable about the English competition.” As he wrote to his colleague Edward Hughes back at Caltech

It has been a good experience for me to look over the x-ray laboratory at Cambridge. They have about five times as great an outfit as ours, that is, with facilities for taking nearly 30 x-ray pictures at the same time. I think that we should expand our x-ray lab without delay.

This realization prompted Pauling to get researchers in his lab started on work with insulin – an arduous and complicated process that required sample purification and crystallization prior to x-ray investigation. In relaying research findings from English scientists working on insulin to his partners back in Pasadena, Pauling intimated that

It is clear that there is already considerable progress made on the job of a complete structure determination of insulin. However, there is still a very great deal of work that remains to be done, and I do not think that it is assured that the British school will finish the job. I believe that this is the problem that we should begin to work on, with as much vigor as possible, under our insulin project.

Little did Pauling know that, while laying in bed, using little more than a piece of paper, a pen and a slide rule, he would soon make a major breakthrough in protein chemistry on his own.

The Crystal Structure of Brookite

Brookite model, side view.

Brookite, TiO₂ (titanium = grey, oxygen = red).  An orthorhombic unit constructed by an octahedron of oxygen ions arranged about a single titanium ion. Each octahedron shares three edges with adjoining octahedra.

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After returning from a trip to Europe in 1927, Linus Pauling was appointed to the position of Assistant Professor of Theoretical Chemistry at Caltech, and reinitiated his study of crystal structures in Pasadena. During this time, Pauling was focusing his attention on the crystal structures of silicate minerals. He and other scientists were utilizing X-ray analysis for crystal structure determinations, but the limitations of the technique were becoming more and more apparent as it was applied to increasingly complex crystal structures.

To overcome these difficulties, Pauling formulated a new theory which helped him to determine the structure of brookite, topaz and a number of other complex ionic crystals. The theory, and the work that resulted from it, comprised an important step in the development of his most cited and most used crystal structure work.

Pauling’s new development was called coordination theory, and served as a method for predicting the possible structures of ionic compounds. Pauling contrasted the new theory with another method used previously by crystallographers for similar crystal structure determinations. The previous method involved testing and eliminating all but one of the possible arrangements in order to determine the atomic arrangement of particular crystals. Pauling noted that this method was both very certain in its results, and extremely labor intensive, making it difficult to apply to more complex compounds.

Brookite model, top view.

Pauling’s new method utilized sets of rules to both dismiss unlikely potential chemical structures and to hypothesize an atomic arrangement that would likely match the crystal structure of the compound being examined. Pauling and his associates would then compare the hypothesized arrangement to experimental observations. The new theory closely resembled an earlier technique formulated by William Lawrence Bragg, which applied a method called close-packing. (In this letter, Pauling discusses his crystal structure work with Bragg, including his research on the structure of brookite.)

Pauling first used his extended version of the technique to successfully determine the structure of brookite.  Brookite, or titanium oxide, is a minor ore of titanium and a polymorph with two other minerals. It shares a number of similarities with the minerals rutile and anatase, having the same chemistry but a different structure.  The variety of similar structures largely results from exposure of the basic chemical components to different temperature variations. As such, when exposed to higher temperatures, brookite reverts to the chemical structure of rutile.

J. Holmes Sturdivant, 1948

In their examination of brookite, Pauling and J. Holmes Sturdivant used spectral photographs to determine the dimensions of the possible unit cells, and Laue photographs to determine the smallest possible unit and space group symmetry criteria. Using Pauling’s new coordination theory, they predicted two possible structures for brookite. One of these hypothesized structures turned out to have a space-group symmetry and unit cell matching the spectral and Laue photograph observations. From there, Pauling and Sturdivant were able to determine that the basic unit of arrangement in brookite was that of an octahedron of oxygen ions around a titanium ion.

Following his examination of brookite, Pauling later used coordination theory to determine the structure of topaz. After these successful examinations, he was compelled to develop a set of principles which governed the structures of complex ionic crystals. The principles were described in a set of compiled documents known as the Sommerfeld festschrift papers, and would later be known as “Pauling’s Rules”. Pauling used his examinations of brookite and topaz, as well as the principles developed in their determinations, to write a paper that detailed this work. “The Principles Determining the Structure of Complex Ionic Crystals,” [J. Am. Chem. Soc. 51 (April 1929): 1010-1026.] published in 1929, became the most cited and most used of all of Pauling’s crystal structure papers.

For more on Pauling’s achievements in structural chemistry, see Linus Pauling and the Nature of the Chemical Bond:  A Documentary History.

The Crystal Structures of Corundum and Hematite

Corundum model, side view.

Corundum, Al₂O₃ (aluminum = silver; oxygen = red). A hexagonal (rhombohedral) crystal system constructed of aluminum atoms that are each surrounded by six oxygen atoms. The oxygen atoms are not bonded at the corners of a regular octahedron.

Hematite model, side view.

Hematite, Fe₂O₃ (iron = orange; oxygen = red). A hexagonal (rhombohedral) crystal system constructed of iron atoms surrounded by six oxygen atoms not at the corners of a regular octahedron.

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In 1925 Linus Pauling and Sterling Hendricks published a paper detailing the crystal structures of corundum and hematite. It was the fifth crystal structure analysis that Pauling had undertaken. During the early years of his research, Pauling had a tendency to correct the work of others, and the determination of hematite and corundum’s crystal structures was not an exception.

In 1917 the British father and son duo of William Henry and William Lawrence Bragg had studied the structure of ruby using X-rays. Citing this data, they hypothesized in 1924 that each aluminum atom in ruby is equidistant from six oxygen atoms, and that each oxygen atom is equidistant from four aluminum atoms. The Bragg’s used this hypothesis in their later work on theories of birefringence (the refraction of a ray of light into two slightly different and unequal rays) and to explain the intensity of X-ray reflections, in terms of temperature variation, from the faces of ruby crystals.

Hendricks and Pauling were not certain of the Bragg’s methods, and wrote in their analysis of corundum, “an exact knowledge of the arrangement of the constituent atoms in ruby would make the arguments of these papers much more convincing.” (J. Am. Chem. Soc., 47 (1925), p. 781)

Corundum is a gemstone whose varieties include ruby and sapphire. It is an aluminum oxide, and the second hardest mineral known to science after diamond. This property is generally attributed to the strong and short bonds which pull oxygen and aluminum atoms close together, making the crystal unusually hard and very dense.

Corundum model, top view.

Hematite comes in many varieties, each having their own unique name and composition. Hematite is an iron oxide, and very important as an ore of iron. It is also used as a pigment and is collected as a mineral specimen. It is blood red in powdered form, but can be gray, black, red or brown in its solid form. It is also used in jewelry, either as a set stone, or as a piece itself.

Pauling and Hendricks used Laue and spectral photographs, as well as the theory of space groups, to analyze the crystal structures of hematite and corundum. They found that, contrary to the Braggs’ hypothesis, the spacing of atoms in corundum’s atomic structure was not equidistant. Though they confirmed the Braggs’ ratio of oxygen to aluminum atoms, they found that instead of forming the corners of a regular octahedron around aluminum atoms, three of the six oxygen atoms were closer to the aluminum atom than were the other three. Similarly they found that instead of forming the corners of a regular tetrahedron around oxygen atoms, two of the aluminum atoms surrounding each oxygen atom were closer than the other two.

Sir William Lawrence Bragg

Pauling and Hendricks disproved the Braggs’ hypothesis of a constant aluminum-oxygen distance, and found that the Braggs’ value for the distance between aluminum and oxygen was also incorrect. The publication of the Pauling-Hendricks findings and the professional implications of their critique were not missed by the Braggs. Pauling was later told that Lawrence Bragg resented his “intrusion” into the fields of crystallography and mineralogy, and that he considered Pauling to be a competitor. Consequently, many of Pauling’s initial publications, often critiques of the work that others had done, led to the start of what would become a long lasting rivalry between himself and the Braggs.

Pauling later claimed that his view of their relationship was very different, both at the beginning of his academic career and the end of it.   According to Pauling, the work that was initiated to correct the Braggs’ early hypotheses was done in order to strengthen the validity of their subsequent claims. In regards to the influence of atomic arrangements on birefringence, this work was successful.

Pauling had perceived the early relationship between himself and W. L. Bragg as that of professor and student, respecting the work that the Braggs had done, and acknowledging that it had enabled him to study crystallography and chemical bonds upon his entrance to Caltech. In reference to the rivalry perceived by the Braggs, Pauling wrote “I did not think of my own scientific work as being competitive; I found it engrossingly interesting for its own sake.” Overall it seems that Pauling and the Braggs were not merely separated by an ocean, but also by an unfortunate misunderstanding of motives.

Pauling research notebook entries on the structures of corundum and hematite.

More on Pauling and Hendricks’ determination of the structures of corundum and hematite can be found in Pauling’s Research Notebook 4.   The larger story of Pauling’s structural chemistry work, including his relationship with the Braggs, is told in Linus Pauling and the Nature of the Chemical Bond: A Documentary History.

The Paving Inspector Job

Linus Pauling (second from right) with a highway work crew, Sutherlin, Oregon. Summer 1922.

A unique chapter of Linus Pauling’s life played out over the summers of his undergraduate years at Oregon Agricultural College. A theme that had shadowed much of his young adult life – problems with finances – would continue to follow him into his graduate studies. The absence of a steady source of income, as well as short periods of more intensified financial hardship, significantly shaped the transition years between his start as an undergraduate and the beginning of his rigorous studies at the California Institute of Technology.

Pauling worked odd jobs on campus to make ends meet during the school year, but during most summers he was employed by the Oregon State Highway Commission as a paving plant inspector, living in a tent and charged with monitoring the quality of the bitumen-stone mixes used in the building of roads. His employment at the highway commission would stretch from the end of his sophomore year to the beginning of his doctoral studies. Over this course of time, particularly his final summer, distinguishing themes and aspects of Pauling’s professional life began to blossom.

Though it was not glorified work, and at times very boring, Pauling did enjoy his time working outdoors. He wrote of his love for the sun, and the benefits of spending a substantial portion of the year outside of a laboratory. Though Pauling would go on to work three additional summers for the highway commission, his first year was not without conflict. At this time he worked under the partial jurisdiction of a man named E.W. Lazell, a chemical and efficiency engineer stationed in Portland. A series of letters and reprimands from Mr. Lazell, as well as consultations with third parties, became common toward the end of Pauling’s first summer at the commission. In early September Pauling replied to department official Leland Gregory, apparently in regard to a complaint lodged against his handling of paving material temperatures. The “misinformed informant,” as Pauling referred to the unnamed complainant (Lazell), could apparently have been better informed had he referred to Pauling’s reports.

At the end of his first season with the commission, Pauling’s mother Belle informed him that she had been forced to use the money he had been sending her over the summer. The money had been meant to pay his school expenses for the following year, and with no additional funds at his disposal, Pauling chose to continue working into the fall.

Luckily, in late autumn of the same year, Pauling was offered a job by the chemistry department at O. A. C. Though it entailed a $25 per month pay cut, Pauling returned to the college as a full-time assistant instructor in quantitative analysis. The following summer he began work once again for the highway commission, and saved enough money to continue his studies as an undergraduate.

As has been well-documented, it is during Pauling’s stint as “boy professor” that he met Ava Helen Miller, his future wife, while teaching chemistry to her and twenty-four other home economics students. The two began dating toward the end of the school year, and the exchange of letters between them during Pauling’s last summer as a paving plant inspector gives one of the clearest and most intimate views of the future Nobel Prize winner’s advancing train of thought. All in all Pauling received 94 letters over the summer from Ava Miller, and replied in kind every day, sometimes two or three times.

You are my own darling girl, and your love is my only priceless possession. I shall try to make my life perfect in order that it may be good enough for you. I love your beautiful big blue eyes, your dainty little ears, your adorable own darling self. I love you.

-Linus Pauling to Ava Helen Miller, June 14, 1922.

The elements that generally defined Pauling’s correspondence with his future wife were a) their wish to be engaged, and b) the strong opposition to marriage that the two faced from their respective families. Always the romantic, Pauling was accused by some of Ava’s friends as being consistently “too mushy,” and indeed there is much written between the two about marriage, children and love.

However, over the course of their exchanges, Pauling likewise discussed much of his evolving personal philosophy. Both suggested reading materials to one another, with the bulk of the books suggested by Ava generally being metaphysical or philosophical in nature. As a result, Pauling discussed, in great detail, his perceptions of the soul, his conflicted feelings between animism and materialism, and his predisposition towards pacifism.

Money, a common theme for the duration of his undergraduate experience, also makes its presence felt throughout their correspondence. At times Pauling secretly mailed money to Ava to help finance trips to see him. He also devoted a substantial portion of his energies to trying to acquire the funds that would allow the two to marry after the summer’s end, with or without help from their parents.

Through youthful confessions, bouts of jealousy, and bold declarations, much can be gleaned about the budding relationship between Pauling and his wife-to-be. Other precursors such as Ava’s influence on Pauling’s diet, as well as his developing fascination with fruits, hint at patterns that would come to define important periods of his future life.

Hand-tinted photo of Pauling at the Sutherlin work site, 1922.

Pauling also read from his own selection of books, and took quite a liking to David Copperfield among others. Far and away, however, a major defining characteristic of his summer evenings was the time that he spent working through proof sheets of the first nine chapters of a newly revised chemistry textbook, Chemical Principles, sent to him by Arthur Amos Noyes, the head of the Division of Chemistry and Chemical Engineering at the California Institute of Technology.

Worked while stationed near the Pacific Coast at Astoria, Pauling devoured all 500 of the listed problems. After discussing his other interests with Noyes by mail, Pauling also began reading books on x-ray crystallography, a new technique being used to study the structure of crystals.  (One of these texts was X-rays and Crystal Structures by W. H. and W. L. Bragg, the latter of whom would eventually become a chief scientific rival of Pauling’s.)  Having completed his reading, and prompted by some nudging from Noyes, Pauling would begin his career as an x-ray crystallographer under the direction Professor Roscoe Dickinson at Caltech the following year.

It is clear by the end of his final summer with the highway commission that Pauling had grown weary of his summer occupation. (In an August 1922 letter to Ava Helen he writes: “I really hate working in a paving plant.  I do it just because I earn more than I would elsewhere.”) Bored, lonely and finished with the problem sets given to him by Professor Noyes, it appears that Pauling was left in an ideal state of mind to begin his graduate studies, and start what would become a brilliant career as an academic, a scientist and an activist for peace.

For more information on Linus Pauling in Oregon, check out our Oregon 150 series. For general information on Linus Pauling, please visit the Linus Pauling Online portal.

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.

Pauling’s Methodology: X-ray Crystallography

X-ray apparatus at Linus Pauling's desk, Gates Laboratory, California Institute of Technology. 1925.

“I was very fortunate in having A.A. Noyes suggest to me, or tell me, that I was to work with Roscoe Dickinson on x-ray crystallography, determination of the structure of crystals by x-ray diffraction. This technique gave for the first time detailed information about how atoms are related to other atoms in a crystal and how far apart they are from the other atoms.”
– Linus Pauling, 1988.

As a graduate student, well before Pauling began to research hemoglobin in earnest, he spent a great deal of his time using the technique of X-ray crystallography to determine the crystalline structure of a number of inorganic compounds. Pauling recalled that at that time X-ray crystallography “was a new technique, ten years old when I began. Quite a number of structures had been determined but there was a tremendous field open, a tremendous amount of work that could be done.”

Listen: Pauling discusses the importance of X-ray crystallography to his early structural chemistry research

The young Pauling obviously reveled in the excitement of being able to use a new and powerful technology. “We have a pretty extensive collection of apparatus” he once wrote to William Lawrence Bragg, the senior author of a 1922 textbook that started Pauling on X-ray crystallographic research. Any one of Bragg’s student’s, Pauling remarked, “no matter how physical his training,” need not “be frightened at coming to a chemical laboratory” so well-stocked with mechanical apparatus.

Initially Pauling used the technique of X-ray diffraction to determine the structures of fairly simple inorganic compounds, but later, as his own expertise grew and as he discovered new sources of funding, Pauling oriented this new technology toward complex organic compounds, including hemoglobin.

What was ultimately important to Pauling was not what X-ray crystallography could tell him about the size, structure, or relative placement of atoms within a molecule, but rather, what broader theories that information could then be used to support. His growing allegiance to structural chemistry, his developing ideas about the nature of the chemical bond, and his still nascent interest in biochemical interaction were all fed by his experience of rigorously determining molecular structure through new technological methods.

Pauling’s manuscript notes concerning his early experiments with hemochromogen, for instance, indicate the wide spectrum of experimental results he had to assimilate in order to create a coherent picture of the hemoglobin molecule.

The difficulties presented by the need to combine the information he had obtained from x-diffraction with information from other kinds of experimentation, including solubility and more traditional experimental methods, are readily apparent in Pauling’s notes.  Indeed, the impressive new technology of X-ray crystallography is relegated to just one entry in a list of experimental results.

Ultimately it wasn’t the technology at Pauling’s disposal that helped him become such a successful researcher, but rather his attitude in approaching technology and his ability to use the results it gave him to construct more broadly-applicable and intellectually-powerful theories.

To learn more about Linus Pauling’s use of x-ray crystallography, see the websites Linus Pauling and the Nature of the Chemical Bond: A Documentary History and It’s in the Blood!  A Documentary History of Linus Pauling, Hemoglobin and Sickle Cell Anemia.