Pauling110

Linus Pauling. Lecturing at the Concepts of Chemical Bonding Seminar, Oslo University, Oslo, Norway. 1982.

Today marks the 110th anniversary of Linus Pauling’s birth, which occurred in Portland, Oregon on February 28, 1901. As has become tradition on the Pauling Blog, we are celebrating this occasion by looking back at Pauling’s life in increments of twenty-five years.

1911

At the tender age of ten, young Linus was already at a crossroads in his life. First and foremost, his father Herman had died of a perforated ulcer the previous summer, thus throwing the Pauling family into something akin to chaos. Herman was a pharmacist and businessman of middling success, and his death was a source of major financial concern for his widow Isabelle and their three children, Linus, Pauline (age 9) and Lucile (age 7). From this point on, Linus’s childhood was certainly informed, if not dominated, by the continual need to contribute to the household income. His mother’s only asset of consequence was the family home, which she boarded out on a regular basis in an attempt to make ends meet. But as time passed and Belle’s own health faded, her only son was frequently called upon to assist with the family finances, leading Linus to assume any number of odd jobs, from delivery boy to film projectionist to grocery clerk.

Young Linus, ca. 1910s.

It was at this same time that the boy’s interest in science was beginning to flower. The previous year Herman had written a letter to the Portland Oregonian newspaper indicating that his son was a “great reader” keenly interested in ancient history and the natural sciences. In 1911 Pauling’s scientific impulses continued to flourish in the form of an insect collection that he maintained and classified using books checked out from the Portland library. Not long after, as with many scientists of his generation, Linus would develop an interest in minerals and begin compiling a personal collection of classified stones that he found.

1936

By the age of thirty-five, Pauling had already established himself as among the world’s pre-eminent structural chemists and was well on his way to making a major impact in the biological sciences. In 1936 Pauling met Karl Landsteiner of the Rockefeller Institute, a Nobel laureate researcher best known at the time for having determined the existence of different blood types in human beings. In their initial meeting, Pauling and Landsteiner discussed Landsteiner’s program of research in immunology, a conversation that would lead to a fruitful collaboration between the two scientists. Importantly, his interactions with Landsteiner would lead Pauling to think about and publish important work on the specificity of serological reactions, in particular the relationship between antibodies and antigens in the human body.

Linus Pauling, 1936.

The year also bore witness to a major change at the California Institute of Technology: in June, Arthur Amos Noyes died. Noyes had served as chairman of the Caltech Chemistry Division for some twenty-seven years and was among the best known chemists of his era. His death ushered a power vacuum within the academic administration at Caltech, by then an emerging force in scientific research. Three of Pauling’s colleagues cautiously recommended to Caltech president Robert Millikan that Pauling be installed as interim chair of the department. Millikan agreed and offered the position to Pauling, but was met with refusal. At the time of the proposal,  Pauling was the object of some degree of criticism within the ranks at Caltech – certain of his peers felt him to be overly ambitious and even reckless in his pursuit of scientific advance – and the suggestion that Pauling assume division leadership was hardly unanimous. Millikan’s terms likewise did not meet with Pauling’s approval; in essence he felt that he would be burdened with more responsibility but would not gain in authority. The impasse would not last long however, as Pauling would eventually accept a new offer in April 1937 and begin a twenty-one year tenure as division chief.

1961

A busy year started off with a bang when the sixty-year-old Pauling was chosen alongside a cache of other U.S. scientists as “Men of the Year” by Time magazine. By this period in Pauling’s life his peace activism was a topic of international conversation and early in the year Linus and Ava Helen followed up their famous 1958 United Nations Bomb Test Petition with a second “Appeal to Stop the Spread of Nuclear Weapons,” issued in the wake of nuclear tests carried out by France. As a follow-up, the Paulings organized and attended a May conference held in Oslo Norway, at which the attendees (35 physical and biological scientists and 25 social scientists from around the world) issued the “Oslo Statement,” decrying nuclear proliferation and the continuation of nuclear tests.

Group photo of participants in the Oslo Conference, 1961.

While Pauling’s attentions during this period were increasingly drawn to his peace work, he did make time for innovative scientific research. Of particular note was his theory of anesthesia, published in July in the journal Science. Pauling’s idea was that anesthetic agents formed hydrate “cages” with properties similar to ice crystals. Owing to the nature of their molecular structure, these cages would impede electrical impulses in the brain, thus leading to unconsciousness. In a review article published one year later, the pharmacologist Chauncey Leake described the theory as “spectacular,” though for reasons that are still unclear it failed to gain traction with the larger scientific community.

1986

By age eighty-five, Pauling’s interests centered largely upon his continuing fascination with vitamin C. Having already published monographs focusing upon ascorbic acid’s capacity to ward of the common cold and the flu, Pauling was ready to put his thinking together into a general audience book that would discuss the path to happier and healthier lives. The result was How to Live Longer and Feel Better, a modest critical and commercial success that helped bolster the reputation and the finances of the struggling Linus Pauling Institute of Science and Medicine.

Pauling at 85.

Many of the recommendations that Pauling made in How to Live Longer… were fairly typical of most health promotion books: a sensible diet, regular exercise and no smoking. The major exception to this moderate approach was the famed author’s stance on vitamin supplementation. In biographer Thomas Hager‘s words

Pauling was now advising between 6 and 18 grams of vitamin C per day, plus 400-16,000 IU of vitamin E (40-160 times the RDA), 25,000 IU of vitamin A (five times the RDA), and one or two ‘super B’ tablets for the B vitamins, along with a basic mineral supplement.

This staunch belief in the value of megavitamins would stay with Pauling until his death eight years later, in August 1994.

Pauling’s Methodology: Electrophoresis

Diagram of a Tiselius electrophoresis apparatus.

[Electrophoresis image extracted from the published version of Arne Tiselius' Nobel lecture, December 13, 1948.  A digitized version of this lecture is available here courtesy of the Nobel Museum.]

“The item of $7,500 for apparatus, supplies, animals would permit us to use the large number of animals required for some of our projected researches, and should permit also the construction of a Tiselius apparatus for the electrophoretic separation of antibody fractions by the suggested method of combination with charged haptens, and for other investigations.“
- Linus Pauling, budget request letter to Warren Weaver. January 2, 1941.

Though, by the late 1930s, X-ray crystallography had become important to Linus Pauling’s research on the structure of complex organic proteins, the newly developed technique of electrophoresis eventually became the technology that defined his work on sickle cell anemia.  Indeed, Pauling was one of the first in a generation of scientists to effectively use the technique of electrophoresis to explain a biological phenomenon.

Lying at the core of Pauling’s interest in sickle cell disease was this question: What really made normal hemoglobin and the hemoglobin from someone suffering from sickle cell anemia different? Though Pauling and his fellow researchers theorized that the answer lay in differences between the structures of the hemoglobin molecules themselves, and also figured that magnetic properties somehow played a role, they had yet to find or develop a method suitable for testing their ideas.

As it turned out, Pauling and his colleagues had to do both: they found and they developed.

The Pauling group seized upon the new technique of electrophoresis but manipulated it considerably to fit their own research agenda. Pauling attributed the idea of using electrophoresis in the first place to one of his graduate students, Harvey Itano. Later Pauling and Itano sought advice, assistance and collaboration with others who were also using the technique, including Karl Landsteiner and Arne Tiselius, both accomplished researchers and close colleagues of Pauling’s. After the construction at Caltech of an electrophoretic machine, Stanley Swingle, a general chemistry instructor at the Institute, developed a number of mechanical improvements while Harvey Itano and Seymour Jonathon Singer conducted research using the apparatus.

After much trial and error, electrophoresis emerged as one of the more important experimental methods used to determine the difference in electrical charge between normal hemoglobin and sickle cell hemoglobin.

Listen:  Pauling discusses the evolution of electrophoresis work at Caltech

The results of Pauling’s electrophoretic experiments, reported in his group’s groundbreaking 1949 paper, “Sickle Cell Anemia, a Molecular Disease,” promoted the argument that sickle cell anemia was not only a pathology resultant of differential protein folding patterns, but that it was also inherited in a simple Mendelian pattern. In other words, sickle cell anemia was both ‘molecular’ and ‘genetic,’ and by seeing it as such, Pauling suggested certain therapies that directly addressed both the structural and the genetic components of the disease.

Even as late as the 1960s Pauling was still looking for ways to use electrophoresis in his research. He mentions, in a handwritten note, that of the ‘likely developments’ in biology, control of molecular and genetic diseases could possibly be obtained through the “electrophoresis of sperm.”

Notes by Linus Pauling: "Biology - what are the likely developments?" 1960s.

(Though the idea may sound strange today, Pauling was an advocate for the controversial notion of positive eugenics — that is the planned and controlled production of healthy offspring, primarily through genetic counseling. We’ll talk more about this component of Pauling’s thinking in a later post.)

In more ways than one, electrophoresis was a new technology that required the coordinated effort of a number of trained individuals. Though it took several years to fine-tune both the method and the instruments, the results were well worth the wait.

To learn more about Linus Pauling’s use of electrophoresis, please visit the website It’s in the Blood!  A Documentary History of Linus Pauling, Hemoglobin and Sickle Cell Anemia.

Thinking Between Disciplines: Immunological Interests and Beyond

Hand-drawn figures used in "A Theory of the Structure and Process of Formation of Antibodies." July 27, 1940.

“I believe that chemistry will play a very important part in the golden age of biology that is now beginning.”
- Linus Pauling, “Molecular Structure and Biological Specificity,” July 17, 1947.

One of the reasons why Linus Pauling enjoyed such a prolific and diverse scientific career was his ability to combine and draw inspiration from rather disparate interests and research questions.

Indeed, structural chemistry – the discipline with which Pauling is most commonly associated – appealed to Pauling in part because it allowed him to consider the physical causes underlying the chemical nature of certain biological phenomena in concert with known principles of chemical interaction.  In other words, Pauling viewed structural chemistry as the avenue by which he could best utilize the tools not only of chemistry, but of physics and biology as well.

Many of Pauling’s laboratory experiments rested on knowledge and methods borrowed liberally from biology, medicine, chemistry and physics. In a 1946 proposal for a program of fundamental research in biology and medicine at Caltech, Pauling emphasized that the long-established cooperation of the Institute’s divisions of Biology, Chemistry, and Chemical Engineering were resulting in a vigorous and successful “attack” on the “great fundamental problems of biology and medicine.” As he sought to justify the expansion of these interacting programs, Pauling wrote that the “primary features” of their organization were “the presence of a group of men rigorously trained in the exact sciences and interested in attacking…broad problems.”

Of nearly-equal importance was an “unusual spirit of cooperation.” Such ‘unusual cooperation,’ in Pauling’s opinion, could be expected to produce work that was at once “sound but imaginative,” and indebted to “the transfer of ideas among different fields…ranging from quantum mechanics to animal physiology.” Pauling’s ideas on the nature of hemoglobin and sickle cell anemia were two of the ‘sound but imaginative’ ideas that arose out of the broader culture of interdisciplinary laboratory research.

In the 1930s Pauling came under the influence of a prominent immunologist, Karl Landsteiner, who helped to turn his attention and interest towards the mechanism of immunological response. To Pauling, the fundamentals of immune response in the body seemed reminiscent of the folding of hemoglobin in the presence of iron. Both mechanisms underscored the importance of the physical structure of a molecule in influencing its chemical interactions.

Pauling’s work on both the nature of hemoglobin as well as the immunological reaction to antigens and foreign proteins were linked practically, as well as conceptually, to his hemoglobin research. As he came to learn more about immune response, Pauling applied some of this knowledge to increasing the practical value of his work on the development of Oxypolygelatin, a blood substitute created as part of the Pauling’s contributions to the Allied effort during World War II.

An original container of 5% Oxypolygelatin in normal saline. Developed by Linus Pauling as part of his scientific war work research program, mid-1940s.

This project, which was not completed to fruition until 1949, was vexed by certain problems having much to do with the nature of blood in the human body. In a handwritten note from 1945, Pauling suggested that foremost among his concerns vis-a-vis the creation of a suitable blood alternative were both a “lack of toxicity,” and a lack of “antigenicity.”

Pauling’s ideas on the nature of hemoglobin, sickle cell anemia and the blood substitute Oxypolygelatin were all born of his ability to fruitfully-combine the methods of several different disciplines with the expertise of his colleagues and fellow researchers. Even moreso, this remarkable body of work constitutes a clear example of the important place that interdisciplinarity can assume in scientific research.

To learn more about Pauling’s research on hemoglobin, immunology and Oxypolygelatin, please visit the website It’s in the Blood!  A Documentary History of Linus Pauling, Hemoglobin and Sickle Cell Anemia.