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.

Excerpt from "The principles determining the structure of complex ionic crystals."

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.

"Outline of Experiments on Hemochromagen," pg. 1. June 25, 1935.

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.