Molecular Architects, Atomic Blueprints and Medical Progress

The Gibbs Award dinner, June 1946

[An exploration of Linus Pauling’s popular rhetoric on the potential for science following World War II. This is part 2 of 5.]

Modern structural chemistry.” [Acceptance speech for the Willard Gibbs Medal, awarded June 14, 1946 by the Chicago Section of the American Chemical Society] Chemical and Engineering News, July 1946.

In 1946, Linus Pauling was awarded the prestigious Willard Gibbs Medal by the Chicago section of the American Chemical Society for his work in structural chemistry. In thinking about his acceptance speech, Pauling ultimately chose to frame it as an overview of the history of modern structural chemistry.

Pauling began his talk with Lucretius who, in the first century BCE, began thinking about the properties of matter. Lucretius hypothesized that honey was made up of “smooth, round molecules which roll easily over the tongue, whereas wormwood and biting centaury consist of molecules which are hooked and sharp.” From there, Pauling rolled through the work of more contemporary greats including Lomonosov’s explanations of the properties of molecules in solid, liquid, and gaseous states; Dalton’s work on the weight relations of chemical reactions; and Avogadro and Cannizarro’s breakthroughs on chemical bonds.

Next up in the whirlwind tour were Frankland, Couper, and Kekulé’s theory of valence; Kekulé’s subsequent writings on the structure of the benzene molecule; and van’t Hoff and le Bel’s explanation of the right and left-handedness of substances. Rounding out the history lesson were Werner’s work on the spatial arrangement of chemical bonds, and Lewis’ identification of the chemical bond as a pair of electrons shared between two atoms. One outcome of all of these advancements was that the discipline of structural chemistry had moved firmly in the direction of the quantitative as opposed to the qualitative judgments that had permeated Lucretius’ analyses of taste and mouth-feel.

Pauling then noted that some of the most exciting and important developments in the history of modern structural chemistry had occurred during his lifetime. It was, for example, only during the early years of his career that methods for accurately measuring interatomic distances had been developed. Subsequent breakthroughs in methodology had included molecular spectroscopy, x-ray and electron diffraction, and applied quantum mechanics, among others techniques. More recently, new knowledge had been produced about moments of inertia, oscillational frequencies, the elucidation of molecular structures for specific substances including sex hormones and vitamin D, and the discovery of the β-lactam configuration of penicillin. In surveying this work, Pauling was particularly quick to praise the usefulness of x-ray diffraction as a powerful tool.

As he looked ahead, Pauling expressed a belief that the most promising application of modern structural chemistry would be its ability to explain the physiological activity of chemical substances. Previous research in this area had produced few results of importance, but Pauling felt sure that the structures of numerous molecules would soon be elucidated, thus laying the groundwork for new insights into physiological activity and, eventually, medical research on diseases like cancer and cardiovascular illness.  


Molecular Architecture and Medical Progress.” Radio talk broadcast on the New York Philharmonic-Symphony Radio Program and sponsored by the U. S. Rubber Company, October 13, 1946.

The ideas expressed by Pauling in Chicago were taken up again in this radio broadcast, which Pauling used to further explore the relationship between molecular structure and physiological activity. In attempting to make this relationship more understandable to his lay audience, he opened with the example of Penicillin G, a molecule commonly recognized as a powerful antibiotic.

Despite penicillin’s widespread application in medical contexts and its acknowledged significance to human life since its discovery in 1928, the molecule’s physiology, at the time of Pauling’s radio talk, was not well-understood. This circumstance was likewise true of other molecules that had become household names, including DDT, morphine, ether, and adrenaline. While scientists understood their uses and functions, the chemical activity that generates and determines those functions remained out of grasp.

Pauling believed that these connections, and the answers that they might provide, lay in what he called “their molecular architecture.” More specifically, were scientists able to determine the structures of specific molecules, they might then turn their attentions to the structures of the biochemical forms with which the molecule interacts. In the case of the household names molecules – penicillin, morphine and the like – these forms might include enzymes, nerve fibers, and tissues with which the molecules interact to produce a desired effect, such as killing bacteria or numbing pain.


Interatomic distance is one important aspect of molecular structure that Pauling took pains to emphasize to his audience. In order to convey a sense of the scale at which atomic distances are measured, Pauling created a hypothetical world where perspective was shifted in the direction of the commonplace. He began by stating that a single Angstrom – the unit used to measure interatomic distances – is equal to 1/254,000,000th of an inch. In other words, when magnified by a factor of 254 million, one scaled-up Angstrom unit would be equivalent to one inch.

With proportions thus shifted, the average human being in Pauling’s hypothetical world would be about 250,000 miles tall, and a wineglass would be as big as the Earth. Importantly, were this gargantuan wineglass full of liquid chloroform, each individual chloroform molecule would be a mere seven inches across. A molecule of chloroform is made up of one carbon atom, three chlorine atoms, and one hydrogen atom, and on this scale, the carbon atom would be the size of a walnut, each chlorine atom the size of a small orange, and the distance between the walnut and each orange would be 1.76 inches. Scaled back down to its actual size (that is, a wineglass-sized wineglass), that distance would be 1.76 Angstrom units.

Pauling’s point in developing this hypothetical was that, in part because they are both small and complicated, the structures of organic compounds were poorly understood. “This then is the great problem of modern chemistry,” Pauling suggested, “the determination of the molecular architecture of the proteins and other complex constituents of the living organism.”

Indeed, Pauling believed that progress in medicine was particularly dependent upon an improved understanding of molecular structure and physiology. By extension, he saw the future role of the “medical research man” as being equivalent to a “molecular architect.” Armed with an understanding of the molecular structures underlying physiological reactions, this new style of architect would have the ability to create “atomic blueprints” for pharmacological compounds designed specifically to treat particular illnesses.

A Post-War Vision for Science

Linus Pauling, 1946

[Ed Note: Today and in the four posts that will follow, we will be examining a series of popular articles and lectures that Linus Pauling delivered from 1946-1951 that outline his vision for what science might become in world no longer dominated by war.]

Introduction

Linus Pauling believed that the enormous scientific innovation characterizing World War II had resulted in a landscape where science was more relevant than ever to people’s daily lives. As such, in his post-war (defined here as 1946-1951) popular lectures and articles, he tended to focus on spaces where science intersected with everyday life, be it in medical research, education, or even popular culture.

Pauling’s vision for the future of science was optimistic and premised on the notion that the scientific community would build upon its war-time achievements and thrive in an environment defined by free exchange and ample resources no longer constrained by military imperatives. Major themes that he turned to during this period included the need for the creation of a National Science Foundation and subsequent provisions for large-scale funding of scientific research; the intersection of structural chemistry with biological and biomedical chemistry; and the imperative that scientific research and education be made accessible to the general public.

Pauling also frequently made mention of promising developments in medicine. Citing current breakthroughs in structural chemistry, Pauling predicted a ten to twenty year period of rapid advancement in medical research that would contribute to a sophisticated molecular understanding of disease and facilitate the synthesis of chemotherapeutic compounds tailored to specific illnesses. In pushing forward these ideas, Pauling once again emphasized his concern for the health and well-being of society, and his fundamental belief in the value of improving one’s understanding of the world around them.


Molecular architecture and biological reactions,” Chemical and Engineering News, May 1946

In this 1946 critique, Pauling made the argument that contemporary research on the nature of physiological reactions was falling short of the mark because of a lack of understanding about molecular structure, and a lack of emphasis on the connection between structure and function.

According to Pauling, prior research on physiological reactions had attacked the problem from the wrong direction by surveying the chemical reactivity of molecules. (e.g., the tendency of molecules to break their chemical bonds, the strength of bonds between atoms, and the formation of new chemical bonds.) Pauling instead put forth a different approach that would focus on the size and shape of molecules, and the nature of the interactions between molecules as opposed to within them.

Bolstered by this alternative framing, Pauling believed that researchers would soon arrive upon major new advancements, and that vexing questions would begin to be answered. “The next twenty years,” he predicted, “will be as great years [sic] for biology and medicine as the past twenty have been for physics and chemistry.” At the time that Pauling wrote this, scientists had developed only a rudimentary concept of the structure of proteins, a research topic of keen importance to his own lab. But Pauling believed that without a strong basis in molecular structure, it would be near impossible to gain a complete understanding of protein structures, to say nothing of the physiological processes to which they are fundamental.


Pauling next provided a brief summary of the progress that had been made over the previous forty years on structural questions across the sciences, citing the development of the electron microscope as being particularly crucial.

There was still work to be done though. For Pauling, the molecular world was a “dimensional forest,” and he believed that a particular ecosystem between 10 and 100 Å (or 10-7 and 10-6 cm) was home to tantalizing clues about the nature of growth processes, duplication mechanisms for genes and viruses, and enzyme activity. But the technology of the day had not yet caught up; no method had been developed that could enable scientists to view that unknowable part of the “forest.” As Pauling explained, the era’s electron microscopes could get close, and other instruments could go even smaller, but no tool was quite sophisticated enough to illuminate processes and substances within that size range.

To make this specific issue more comprehensible for a non-scientific audience, Pauling likened the situation to that of a scientist in space, attempting to study the Earth from thousands of miles away. With microscopes, diffraction units, and other scientific technology also appropriately scaled up, such a scientist might be able to “…distinguish Central Park, the rivers, and such aggregates of sky scrapers as Rockefeller Center…,” but would not be able to discern individual skyscrapers.

From there, using chemical methods, they would be able to identify “substances” moving across the surface of the Earth that they could not necessarily see, such as cars, buses, and ships. With an electron microscope, they could uncover information about the size and shape of objects to within ten feet, and through x-ray and electron diffraction, they would be able to study in detail the structure of objects smaller than one foot in diameter. But there was no tool that could handle objects in between these sizes, so the scientist’s understanding of life on Earth would necessarily be tempered by their lack of ability to see anything within that range of focus. Scaled back down to the molecular level, this was the situation in which structural biologists found themselves in 1946.

In order to overcome these difficulties, Pauling advocated for a greater allocation of resources to advance work in structural biology. He also argued that knowing the shapes and sizes of molecules would shed light on their physiological activities, as more and more evidence was suggesting that physical properties – as opposed to chemical properties – determined a great many molecular activities. (This was clearly the case with enzymes: catalysis reactions, it had been shown, only occurred in instances where two pieces of a molecule fit together like pieces of a puzzle.)

With the war now over, buoyed by ample funding, and following his suggestions on the most fruitful lines of inquiry, it was Pauling’s belief that the sky was the limit. “[P]recise information will rapidly accrue,” he suggested, “including ultimately detailed structures of fibrous proteins, respiratory pigments, antibodies, enzymes, reticular proteins of protoplasm, and others.”

Pauling’s First Paper on the Nature of the Chemical Bond

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Linus and Ava Helen Pauling in Munich, with Walter Heitler (left) and Fritz London (right), 1927.

[An examination of Linus Pauling’s first paper on the nature of the chemical bond, published in April 1931. Part 2 of 2.]

In 1928 the German physicists Walter Heitler and Fritz London published a paper that appeared to have beaten Linus Pauling to the punch in its application of quantum mechanics to the theory of chemical bonding. As with Pauling, the duo was interested in Erwin Schrödinger’s wave function, and in their paper they applied it to the simplest bond: that formed by two hydrogen atoms. In so doing, Heitler and London did indeed become the first scientists to publish an application of this type.

The German colleagues also incorporated Werner Heisenberg’s ideas on exchange energy. Heisenberg had theorized that the electrons of two given atoms would find themselves attracted to the positively charged nuclei of their atomic pairs. As such, a chemical bond, according to this theory, consisted simply of two electrons jumping back and forth between two atoms, belonging simultaneously to both and to neither.

Heitler and London extended this idea, proposing that chemical bonds sourced their lengths and strengths from the amount of repulsion extant between two positively charged nuclei. The balance between the electrons’ attraction to these nuclei, coupled with the quantifiable repulsion existing between the two nuclei, ultimately served to create the bond.


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Pauling on the precipice of greatness, 1928.

Invigorated by the promise of competition, Pauling set to work applying Heitler and London’s theory to more complex molecules. In part to motivate himself, but also to ensure that he received recognition for his research, Pauling announced in the Proceedings of the National Academy of Sciences that he believed he could solve the tetrahedral binding of carbon using the ideas put forth by quantum mechanics.

This declaration piqued significant interest throughout the scientific community, striking a nerve for chemists and physicists alike, both groups of whom had been puzzling over this specific structure in different ways. On one hand, physicists believed that carbon should have a valence of two because, of its six electrons, four were located in two different subshells. Both sets of two would then be expected to pair off with each other, leaving only two electrons logically available for bonding. On the other hand, chemists found in the laboratory that carbon typically offered four electrons for bonding in nature. In essence, both theory and experiment indicated that neither party was completely right, but so too could neither point of view be completely wrong. Pauling believed that quantum mechanics could illuminate the paradox.

In addition to his theoretical study, Pauling’s extensive graduate training in x-ray crystallography strengthened both his interest in and his flair for atomic structure. By 1928, after a busy year of research, he had established five principles for determining the structure of complex covalent and ionic crystals, later dubbed “Pauling’s Rules.” He used these rules to predict models for particular molecular structures, and then worked backward from the theoretical model to develop a more concrete picture based on x-ray data. When a colleague remarked that this technique resembled the Greek stochastic method – an approach based largely on applied guess work – Pauling offered a correction, stating that

Agreement on a limited number of points cannot be accepted as verification of the hypothesis. In order for the stochastic method to be significant, the principles used in formulating the hypothesis must be restrictive enough to make the hypothesis itself essentially unique.

In other words, Pauling was relying on his knowledge of chemical principles to develop meticulous and educated hypotheses that he could go back and prove. And as he would hasten to add, he placed very little stock in luck or guesswork.


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As work moved forward, Pauling added his rules to three others that had been established by G.N. Lewis – and then expanded and formalized by Heitler and London – concerning the electron pair bond. These rules set parameters for the circumstances in which an electron would be theoretically available to form a chemical bond.

Though equipped with a solid toolkit of his and others’ making, it ultimately took Pauling almost three years to solve the carbon tetrahedron, with his big breakthrough coming in December of 1930. Inspired by the work of MIT physicist John C. Slater, Pauling found a way to reduce the complexity of the radial wave function, a component of bond orbital theory the application of which had been giving him some trouble. With this solution in hand, the math required for solving further steps of the carbon puzzle became significantly more manageable.

Pauling’s subsequent equations led him to develop a model for the structure that consisted of four equal orbitals oriented at the angles of a tetrahedron. Using these equations, Pauling further discerned that the strength of the bonds within the structure increased in accordance with greater degrees of orbital overlap between two atoms. The overlap, Pauling found, produced more exchange energy and this in turn created a stronger bond.

Pauling sent his paper to the Journal of the American Chemical Society (JACS) in February 1931. In it, Pauling detailed three rules governing eigenfunctions that complemented G.N. Lewis’ rules about electron pairs. Pauling used this collection of guidelines to explain relative bond strength, finding that the strongest bonds occurred on the lowest energy level and where orbitals overlap. He also developed a complete theory of magnetic moments and ended the paper stressing the important role that quantum mechanics had played in his formulation of the rules and theories expressed in the work.

The paper, titled “The Nature of the Chemical Bond: Application of Results Obtained from the Quantum Mechanics and from a Theory of Paramagnetic Susceptibility to the Structure of Molecules,” was accepted and published in record time. The subject matter was so new and the ideas so fresh that Arthur Lamb, the editor of JACS at the time, had trouble finding a group qualified enough to review it. Even so, he scheduled the article for the April issue and in so doing published Pauling’s paper a mere six weeks after he had received it.


In 1926, whether he knew it or not, Linus Pauling embarked down a path toward the transformation of chemistry and the way that it would be studied for generations to come. The ideas that he began developing during this time gradually became the standard model for those studying chemistry while simultaneously launching Pauling to dizzying heights. His April 1931 paper, the first in a series of seven, also became the basis for his 1939 book, The Nature of the Chemical Bond, which was almost immediately recognized as a classic of twentieth-century scientific writing.

Largely on the strength of the April JACS article, Pauling also received the 1931 Langmuir Prize from the American Chemical Society, and used the money that came with the prestigious award to further his research. Now that he was interested in molecular structure, he saw it’s promise everywhere within a rapidly expanding research program. In fact, the chemical bond work of the late 1920s and early 1930s laid the foundation for his subsequent program of hemoglobin research, which in turn led to his sickle cell anemia discovery almost twenty years later. In hindsight, it is easy to see how Pauling could have looked back on the achievements of early 1931 as being “the best work I’ve ever done.”

“The Best Work I’ve Ever Done”

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Linus Pauling, 1931.

[An examination of Linus Pauling’s first paper on the nature of the chemical bond, published in April 1931. This is part 1 of 2.]

“It seems to me that I have introduced into my work on the chemical bond a way of thinking that might not have been introduced by anyone else, at least not for quite a while. I suppose that the complex of ideas that I originated in the period of around 1928 to 1933 – and 1931 was probably my most important paper – has had the greatest impact on chemistry.”

-Linus Pauling, 1977

One of the major film documentaries chronicling Linus Pauling’s life was produced for the long-running NOVA series in 1977. By that point, when asked to look back over the decades of significant work that he had done, Pauling still singled out his insights into the chemical bond as being his most significant contribution to chemistry.

Pauling’s initial 1931 paper in particular marked the first time that he published his revolutionary point of view related to the chemical bond, and reflecting on that period Pauling went so far as to call the article “the best work I’ve ever done.” Indeed, the paper marked the first instance in which Pauling began to spell out the ways in which the burgeoning field of quantum mechanics might be applied to fundamental questions in chemistry. And though first in a lengthy series, Pauling placed major significance on this one paper because it profoundly changed the course of his career and set into motion a period of heavy influenced on the trajectory of an entire discipline.


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G.N. Lewis, ca. 1930.

While an undergraduate at Oregon Agricultural College, Pauling had been taught – and went on to teach his own students – the “hooks and eyes” theory of chemical bonding. In this model, each atom was presumed to have a certain number of hooks or eyes that determined how and to what other atoms it could connect. Though it prevailed at the time, the model was deemed to be outdated and insufficient by many of Pauling’s contemporaries, some of whom were concurrently searching for a more satisfactory replacement.

That said, “hooks and eyes” did serve as a useful precursor to the later concept of valence, because it correctly assumed that each atom possessed a concrete number of electrons to contribute to the formation of bonds with other atoms. The theory also suggested that there were rules governing how chemical bonds worked and how likely it was that two or more atoms might form a bond.

While Pauling was still a student in Oregon, he avidly read G.N. Lewis’ ideas about electron structure and also studied Irving Langmuir’s theory of valence, a tutelage that helped propel his own nascent interest in chemical bonding and atomic structure. Lewis proved to be particularly important. A chemist at the University of California, Berkeley and a future mentor of Pauling’s, Lewis proposed that eight electrons provided a maximally stable environment for a molecule, a tenet known today as the octet rule. Working from this idea, Lewis hypothesized that an atom containing, for example, seven electrons would bond more readily with an atom containing nine electrons, and that the bond that was formed consisted of the electron shared between the two atoms.

Lewis wasn’t the first to chase the nature of the chemical bond. Indeed, the problem had been under attack for a few decades. In 1911, Ernest Rutherford created the first modern atomic model, but ran into trouble because it wasn’t compatible with classical physics. Niels Bohr then updated this model. Less than twenty years after J. J. Thompson had discovered the electron, Bohr suggested that electrons orbited the nucleus in a predictable way, emitting quanta when they moved into lower orbits.

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Arnold Sommerfeld, 1928.

From there, others sought to fill gaps in Bohr’s model. In 1915, Arnold Sommerfeld, a physicist with whom Pauling eventually worked, helped to devise what came to be known as the Sommerfeld-Wilson quantization rules. These guidelines provided an explanation for angular momentum by describing electron orbits as ellipses rather than perfect circles.

At the same time, Werner Heisenberg, Erwin Schrödinger and Max Planck (among others) were rapidly embracing a new way to look at physics, expanding the theory and mathematics behind involved in this innovative approach. In 1925, a year before Pauling began an influential trip to Europe, Heisenberg had authored his “Quantum Theoretical Reinterpretation of Kinematic and Mechanical Relations,” which many point to as the true beginning of quantum mechanics. Schrödinger then completed his wave function in 1926. By contrast, the Lewis and Langmuir models were part of an old system that – as soon Pauling discovered – was in the process of being discarded.


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Linus Pauling at the Temple of Neptune, Paestum, Italy, during his legendary Guggenheim trip to Europe. This photo was taken by Ava Helen in April 1926.

An admirer of Sommerfeld’s work, Pauling traveled to Europe on a Guggenheim fellowship to learn as much as he could about quantum mechanics, which at the time was referred to as “new physics.” He was especially keen to learn more about Schrödinger’s equation and to dig into the ways in which the wave function might be applied to a more sophisticated understanding of the chemical bond. Though impressed by Heisenberg, Pauling gravitated toward Schrödinger because he saw more potential for practical application of the wave function, as opposed to Heisenberg’s matrix mechanics. In a note penned during his travels, Pauling wrote specifically that

I think that it is very interesting that one can see the [psi] functions of Schrödinger’s wave mechanics by means of the X-ray study of crystals. This work should be continued experimentally. I believe that much information regarding the nature of the chemical bond will result from it.

These thoughts proved prophetic, as we will see in part 2 of this series.


Pauling returned to Pasadena in the fall of 1927, bursting with new ideas. While he was away, Caltech chemistry chief A.A. Noyes had sent word that a unique position had been created for his promising young faculty member, one that lined up nicely with Pauling’s new interests. Upon his re-arrival at Caltech, Pauling was to begin working under the title of Assistant Professor of Theoretical Chemistry and Mathematical Physics.

Although Noyes eventually dropped the physics course from the appointment, Pauling liked the idea of hybridizing his interests into one name. It was at that point that he began referring to himself as a quantum chemist.

Pauling and the Rockefeller Foundation

 

Rockefeller Foundation administrator Warren Weaver.

Rockefeller Foundation administrator Warren Weaver.

We are … particularly gratified that the Institute has found it possible to make a substantial contribution which will enable you to direct a larger proportion of our aid to the study of the substances of fundamental biological importance.”
– Warren Weaver to Linus Pauling, December 27, 1934.

It is obvious from much of his scientific work that Linus Pauling possessed a brilliant and uncanny ability to think across and between disciplines. Pauling was also a pragmatic and often business-like researcher who understood the necessity of securing financial support for his projects. The long and fruitful relationship Pauling maintained with the Rockefeller Foundation – and, in particular, a Rockefeller administrator named Warren Weaver – made possible much of Pauling’s most groundbreaking work on hemoglobin and structural chemistry. The full force of this intellectually-fruitful relationship reveals both the importance of interdisciplinarity in scientific work as well as the essential nature of active and timely funding.

Pauling received his first grant from the Rockefeller Foundation in 1932 for a program of research in structural chemistry. Shortly thereafter, in the fall of 1933, Pauling applied for and later received a three-year grant from the Foundation to support his experimental researches.  Pauling’s proposal was bolstered by his recent work in electron and X-ray diffraction, and held great promise of continued theoretical development in the study of the electronic structures of molecules.

In 1934 Pauling received more funding from the Rockefeller Foundation, this time in support of his hemoglobin research. He proposed to study hemoglobin in part because he understood that a great deal of general interest lay in the biomedical application of theoretical chemistry.

It is also clear that Pauling was, at least to a degree, shifting his research focus to match the lines of inquiry that the Foundation was interested in funding. In 1986, Pauling would note

…I’d had one elementary course in organic chemistry and no biochemistry. Didn’t know much about these things. I was getting support from the Rockefeller Foundation. Warren Weaver said to me, “Well it’s alright. We’ve been giving you some money to determine the structure of the sulfide minerals. But the Rockefeller Foundation isn’t really interested in the sulfide minerals. We’re interested in biological molecules and life.” So I said, “Well, I’d like to study the magnetic properties of hemoglobin and see whether the oxygen molecule loses its paramagnetism when it combines with the hemoglobin molecule.” So they said, “Alright, we’ll give you more money.”

And so it was, more or less, that Pauling’s hemoglobin work received Rockefeller support on the order of $70,000 per year circa 1940.

Listen: Pauling discusses the roots of his relationship with the Rockefeller Foundation

Pauling not only sought and gained special assistance from Rockefeller funds, but Rockefeller personnel also contributed to the development of his hemoglobin work throughout the 1930s. Alfred E. Mirsky, a professor in cell biology at the Rockefeller Institute for Medical Research, was one of the first individuals with whom Pauling discussed potential hemoglobin research. Pauling quickly developed a personal friendship with Mirsky and clearly held his colleague in very high regard as a scientist. In a 1944 letter recommending Mirsky for a position at the Carnegie Institution of Washington, Pauling wrote

I do not know any one who is so keenly interested in the development of the field of science involving the applications of chemistry and physics to borderline problems of biology, and especially of genetics, and who has such a penetrating understanding of the work which has been done. I find that every conversation which I have with Dr. Mirsky gives me some valuable idea. He has a masterly ability to coordinate results into a significant whole.

 

Alfred E. Mirsky

Alfred E. Mirsky

Indeed, over the years Pauling gave a number of lectures at the Rockefeller Institute and continued to benefit from a wide array of academic and personal relationships that began with the Foundation. The Foundation also continued to fund Pauling’s work well into the 1950s, contributing mightily to the “big science” phenomenon that helped define academic research following World War II.

The Rockefeller Foundation was pioneering in its recognition of the importance of supporting interdisciplinary work; in particular, it actively sought to foster research between biology and chemistry. In many ways, Pauling with the prototype scientist that the Foundation was looking to support. Looking back, few can deny the impact that this partnership made on the history of twentieth century science.

For more information on Pauling’s relationship with the Rockefeller Foundation, see the website It’s in the Blood! A Documentary History of Linus Pauling, Hemoglobin, Sickle Cell Anemia. We also strongly recommend the book The Molecular Vision of Life: Caltech, the Rockefeller Foundation, and the Rise of the New Biology (1993), written by the late Dr. Lily Kay.

Pauling’s Methodology: X-ray Crystallography

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

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.

Thinking Structurally: The Roots of Pauling’s Hemoglobin Work

Pastel drawing of Hemoglobin at 20 angstroms, 1964. Drawing by Roger Hayward.

Pastel drawing of Hemoglobin at 20 angstroms, 1964. Drawing by Roger Hayward.

Linus Pauling is one of that select group of individuals whose lives have made a discernible impact on the contemporary world. His contributions to molecular chemistry have been substantial and fully deserving of the recognition that he received in the form of a Nobel Prize in chemistry….Pauling continued to do productive scientific work throughout his lifetime, making a second outstanding contribution in his discovery of the molecular processes involved in sickle-cell anemia. This discovery, if made by anyone who was not already the only person to receive two unshared Nobel Prizes, might well have merited a third prize in medicine.
– Ted Goertzel. “Linus Pauling: The Scientist as Crusader.” Antioch Review, 38 (1980): 371-382. 1980.

Two of Linus Pauling’s greatest scientific discoveries, his work on the nature of the chemical bond and the discovery of molecular disease, both hinged on his distinctly structural approach to scientific problems.

Having written a doctoral dissertation on the determination of the molecular structure of inorganic compounds in crystalline state, Pauling chose hemoglobin as an object of study in part because he knew that it was hemoglobin’s changing structure that allowed it to carry oxygen to the tissues of the body. While Pauling like to joke that he chose to work on blood because it was easy to obtain, the intellectual challenge of explaining the sigmoid curve of oxygen saturation in hemoglobin profoundly sparked Pauling’s scientific interest.

Later, upon learning about the disease sickle-cell anemia, Pauling came to recognize that the potentially molecular and structural basis of the disease could facilitate a deeper investigation into structural studies of the molecule. Hemoglobin, in part because of its association with the bonding and transport of iron atoms, demonstrated extremely changeable magnetic charges and suggested, even from a preliminary acquaintance, the importance of structural changes in chemical function.

By 1934, when Pauling suggested hemoglobin as the organic molecule of choice for his particular research program, he had already laid out a general plan of research that relied heavily on investigations into the structural and electrically-charged nature of organic molecules. In May of 1935, Pauling wrote in his research notebook

At this time I have analyzed the oxygen equilibrium data to make plausible the idea that in hemoglobin the four hemes are arranged at the corners of a square on one side of the globin, being interconnected along the edges of the square, and that in the hemochromogens the hemes are independent of one another; and I have outlined a general program of investigation, consisting mainly of magnetic studies and x-ray studies (anomalous dispersion, radial distribution about iron atoms).

In a way, Pauling had always been thinking structurally about the nature of the hemoglobin molecule, its ability to bind oxygen molecules and, later, its particular pathology in the case of sickle-cell anemia.

In 1937, Pauling delivered an inaugural lecture for the Sigma Xi society of Corvallis, in which he asserted both the importance and the relatively-recent arrival of structural chemistry as a discipline. For Pauling structural chemistry involved “the determination of the structures of molecules – the exact location of the atoms in space relative to one another – and the interpretation of the chemical and physical properties of substances in terms of the structure of their molecules.”

This lecture, entitled “Hemoglobin and Magnetism,” addressed the “new branch of chemistry, modern structural chemistry” through a discussion of some of Pauling’s most recent work on hemoglobin’s magnetic properties.

The Guggenheim Trip, Part III: Unexpected Colleagues

Walter Heitler, Fritz London, and Ava Helen Pauling in Europe. 1926.

Walter Heitler, Fritz London, and Ava Helen Pauling in Europe. 1926.

The paper of Heitler and London on H2 for the first time seemed to provide a basic understanding, which could be extended to other molecules. Linus Pauling at the California Institute of Technology in Pasadena soon used the valence bond method. . . . As a master salesman and showman, Linus persuaded chemists all over the world to think of typical molecular structures in terms of the valence bond method.” – Robert Mulliken. Life of a Scientist, pp. 60-61. 1989.

After Linus Pauling’s publication of “The Theoretical Prediction of the Physical Properties of Many-Electron Atoms and Ions,” he was ready for an even greater challenge – the problem of the chemical bond was a tantalizing enigma for Pauling, and he wanted more time in Europe to work on it. In the winter of 1926, he applied for an extension of his Guggenheim fellowship and with the help of a particularly complementary cover letter from Arnold Sommerfeld, Pauling was granted six more months of support.

Boosted by this news, he quickly began planning visits to Copenhagen and Zurich, both cities boasting of some of Europe’s finest research facilities. His first stop was Copenhagen, where he hoped to visit Niels Bohr’s institute and discuss ongoing research with the renowned scientist. Unfortunately, he had arrived uninvited and found it almost impossible to obtain a meeting with the physicist. Bohr, with the help of Werner Heisenberg and Erwin Schrödinger, was deeply engaged in research on the fundamentals of quantum mechanics, and was specifically attempting to root out the physical realities of the electron, in the process developing a theory which would eventually be termed the “Copenhagen Interpretation.”

Pauling did, however, did make one valuable discovery in Denmark — that of a young Dutch physicist named Samuel Goudsmit. The two men quickly became friends and began discussing the potential translation of Goudsmit’s doctoral thesis from German to English. Their work did eventually get them noticed by Bohr, who finally granted Pauling and Goudsmit an audience. Unfortunately for the pair, Bohr was neither engaging nor encouraging. Nevertheless, the two continued to work together, their cooperation eventually culminating in a 1930 text, The Structure of Line Spectra, the first book-form publication for either scientist.

In 1926 though, frustrated by his unproductive time in Copenhagen, Pauling departed, stopping briefly at Max Born’s institute in Göttingen before traveling to Zurich where other advances in quantum mechanics promised an interesting stay. Unfortunately, the man Pauling was most interested in, Erwin Schrödinger, proved to be just as unavailable as Bohr. The quantum mechanics revolution was consuming the time and thoughts of Europe’s leading physicists and Pauling, a small-fry American researcher, simply wasn’t important enough to attract the interest of men like Bohr and Schrödinger.

Fritz London

Fritz London

As a result, Pauling chose to converse and work with men of his own status in the scientific community. Fritz London and Walter Heitler, acquaintances of the Paulings, had spent the past several months working on the application of wave mechanics to the study of electron-pair bonding.

Heitler and London’s work was an outgrowth of their interest in the applications and derivations of Heisenberg’s theory of resonance, which suggested that electrons are exchanged between atoms as a result of electronic attraction. Heitler and London determined that this process, under certain conditions, could result in the creation of electron bonds by cancelling out electrostatic repulsion via the energy from electron transfer. Their work on hydrogen bonds likewise agreed with existing theories, including Wolfgang Pauli’s exclusion principle and G.N. Lewis’ shared electron bond. The Heitler-London model was well on its way to contributing to a new truth about the physics of the atom

Walter Heitler

Walter Heitler

Pauling used his time in Zurich to experiment with the Heitler-London work. While he didn’t produce a paper during his stay, the new model made a great impression on him and he returned to Caltech with a renewed sense of purpose. He was preparing to tackle the problem of atomic structure, in all its manifestations, and make history as one of the greatest minds of the twentieth century.

For more information, view our post “Linus Pauling and the Birth of Quantum Mechanics” or visit the website “Linus Pauling and the Nature of the Chemical Bond: A Documentary History.”

The Guggenheim Trip, Part II: The Growth of a Scientist

Linus Pauling, Werner Kuhn, and Wolfgang Pauli traveling by boat in Europe. 1926.

Linus Pauling, Werner Kuhn, and Wolfgang Pauli traveling by boat in Europe. 1926.

My year in Munich was very productive. I not only got a very good grasp of quantum mechanics — by attending Sommerfeld’s lectures on the subject, as well as other lectures by him and other people in the University, and also by my own study of published papers — but in addition I was able to begin attacking many problems dealing with the nature of the chemical bond by applying quantum mechanics to these problems.”
– Linus Pauling. The Chemical Bond: Structure of Dynamics, Ahmed Zewail, ed. 1992.

After his and Ava Helen’s stay in Italy, Linus Pauling was itching to return to the lab. The couple arrived in Munich in the last week of April and the first item on Pauling’s agenda was a meeting with Arnold Sommerfeld.

Sommerfeld, in association with Niels Bohr, was responsible for the Bohr-Sommerfeld model of the atom, a precursor to modern quantum mechanical ideas on atomic structure. At the time of Pauling’s European trip, Sommerfeld was serving as the director of the Institute of Theoretical Physics in Munich. He had spent the past decade building Germany’s community of physicists, nuturing many of Europe’s best scientists on a steady diet of cutting edge research. His lectures, famous by the time Pauling reached Europe, were known for their new and innovative content. As Thomas Hager, a Pauling biographer, explains, “[Sommerfeld] knew everyone in theoretical physics, had collaborated with many of them and corresponded regularly with the rest.” He knew exactly what was happening in his field and made sure his students did too.

Pauling’s first Munich meeting with Sommerfeld was something of a disappointment for the young scientist. Rather than being allowed to continue the work he had begun at Caltech, Sommerfeld chose to assign Pauling mathematical research relating to electron spin – an area that held little interest for him.

After a spell of half-hearted devotion to the electron spin problem, Pauling convinced Sommerfeld to allow him to study the motion of polar molecules. Pauling believed he could clarify portions of the Bohr-Sommerfeld model by introducing the effects of a magnetic field to the existing equations. This caught Sommerfeld’s attention and Pauling was subsequently instructed to continue his research under the stipulation that he provide Sommerfeld with the details of his work for presentation at an upcoming conference in Zurich. Pauling did so, and a few days after Sommerfeld had departed for the conference, he received an order to appear in Zurich to discuss his work.

Once at the conference, Pauling found himself surrounded by the leading physicists of Europe. Wolfgang Pauli, a young German physicist famous for his development of the revolutionary Pauli Exclusion Principle, was among those in attendance. On a whim, Pauling approached his colleague and began explaining his recent work on the Bohr-Sommerfeld model. Pauli was unimpressed. The paradox-riddled Bohr-Sommerfeld model, and Pauling’s work supporting it, was on its way out with the new ideas of quantum mechanics soon to take its place. Pauling’s research was too late to be of any value and Pauli was not shy about telling him so.

After finishing his summer vacationing with Ava Helen in Switzerland, Pauling returned to Munich for the fall semester. It was at this time that Pauling really began to prove himself, developing a reputation for his extensive knowledge and concentrated enthusiasm. Pauling’s most important accomplishment, however, was not his ability to make friends. Instead, it was gaining both the attention and the esteem of Arnold Sommerfeld. Pauling did so by discovering a mathematical error in the work of Gregor Wentzel, a protégé of Sommerfeld. The discovery and correction of this mistake garnered Pauling a great deal of respect in Sommerfeld’s eyes.

As it turned out, Pauling’s discovery of Wentzel’s error resulted in more than just Sommerfeld’s acclaim. It allowed Pauling to apply Wentzel’s work to the calculation of energy levels, which in turn provided the platform for a series of calculations on the energy values for complex atoms. This was a totally new approach to deriving atomic properties and Pauling took full advantage of his discovery, publishing his findings in a paper titled “The Theoretical Prediction of the Physical Properties of many-Electron Atoms and Ions.”

In a matter of months, Pauling had evolved from a star-struck young American to a legitimate player in the European field of quantum mechanics. Fortunately for him, his rise to scientific prominence had only just begun.

Read about Arnold Sommerfeld in “The Duelist” or learn more about this entire story on the website “Linus Pauling and the Nature of the Chemical Bond: A Documentary History.”

Linus Pauling and the Birth of Quantum Mechanics

Linus and Ava Helen Pauling in Munich, with Walter Heitler (left) and Fritz London (right), 1927.

Linus and Ava Helen Pauling in Munich, with Walter Heitler (left) and Fritz London (right), 1927.

My year in Munich was very productive. I not only got a very good grasp of quantum mechanics — by attending Sommerfeld’s lectures on the subject, as well as other lectures by him and other people in the University, and also by my own study of published papers — but in addition I was able to begin attacking many problems dealing with the nature of the chemical bond by applying quantum mechanics to these problems.”
– Linus Pauling, 1992

In the spring of 1926, funded by a Guggenheim Fellowship, Linus and Ava Helen Pauling embarked on their first trip to Europe, scientific tourists beginning a journey that would revolutionize modern chemistry and physics.

The Paulings travelled through the continent, stopping at the famed institutes of modern science in Munich, Göttingen, and Zurich, among others, and meeting with scientific giants including Arnold Sommerfeld, Max Born and Erwin Schrödinger. It was at this time that quantum mechanics, the branch of science devoted to the study of the atom’s physics, was being revolutionized by the ideas of Schrödinger and Werner Heisenberg. It wasn’t until Pauling left Germany for Switzerland however, that he was introduced to a ground-breaking idea – the combination of Schrödinger’s wave mechanics with the study of structural chemistry.

In Zurich, the German researchers Walter Heitler and Fritz London explained to Pauling the concept of “electron resonance” as developed by Heisenberg. At its core, the theory suggested that electrons could be attracted to one another, to the point where they would eventually switch back and forth between two given atoms. This exchange of electrons would, in turn, release energy, in the process drawing the two atoms together and creating a chemical bond. This revolutionary concept agreed with certain known principles of the hydrogen atom – the atom on which Heitler and London were conducting their calculations – and appeared to support the Pauli exclusion principle which, as Pauling later put it, “states that no two electrons in the universe can be in exactly the same state.”

After his return to Caltech in September of 1927, Pauling worked on several projects, including his first published book and a class on the Heitler-London work. In the process of defining his research program as a young member of the Caltech faculty, Pauling decided that, rather than continuing to dabble in theoretical physics, he would instead return to his roots in chemistry. With that, he set out to combine what he had learned in Europe with his continuing interests in structural chemistry.

He began his work on the chemical bond, figuring calculations and comparing his results to existing experimental data. He affirmed that Heitler and London’s work meshed comfortably with G. N. Lewis‘ theory of the shared electron pair and he published articles on the subject, in the process introducing many chemists to the notion of using quantum mechanics as a tool for the study of non-physics problems. In early 1928, he suggested that quantum mechanics could answer the question of carbon bonding – a revolutionary idea at the time. Unfortunately, while the preliminary mathematics were promising, the sheer mathematical computing power required did not exist for Pauling to fully solve the problem.

In 1930 M.I.T. physicist John C. Slater succeeded in simplifying Schrödinger’s mathematical description of the types of changes experienced by any quantum system over time — an important mathematical model known as the Schrödinger Wave Equation. By slightly restructuring Slater’s set of simplified equations, Pauling was able to utilize the concept of wave functions to describe new orbitals that matched the known traits of the carbon-tetrahedron bond. Not only did these new methods allow Pauling to calculate the data for basic tetrahedral bonds, they also provided stable footing for detailing the precise structures of a series of complex molecules. This was the genesis of valence-bond theory — a hugely important marriage of quantum physics and structural chemistry.

In early 1931, Pauling released a paper detailing six rules, later known as “Pauling’s Rules,” that dictated the basic principles governing the molecular structure of any given molecule. He presented his findings in the simplest language possible, avoiding complex mathematics in order to make the concepts accessible to his fellow chemists. This paper, of course, was titled “The Nature of the Chemical Bond” and would serve as the basis for his immensely popular textbook of the same name.

In 1954 Pauling won the Nobel Prize in Chemistry “For research into the nature of the chemical bond and its application to the elucidation of complex substances.” The award was granted in recognition of the work that began during his first trip to Europe and blossomed in the decade that followed. Pauling’s innovative application of quantum mechanics had resulted in his receipt of the highest possible scientific honor and the subsequent worldwide recognition of his talents.

Learn more about this story by visiting the website “Linus Pauling and the Nature of the Chemical Bond: A Documentary History.”