Linus Pauling and the Mystery of Anesthesia: Part I

Linus Pauling holding models of the structure of water. 1960s.

[Part 3 of 5]

Throughout his career, Linus Pauling’s inquisitive nature was widely recognized as a defining trait, second only to his legendary self-confidence. Indeed, it was his curiosity and analytical thinking style that made him the ideal problem solver. As a child, he spent his free time experimenting with pilfered chemicals, reading books on the manufacture and workings of machinery, studying scientific tables and categorical charts (searching for anomalies, one presumes) and devising logical explanations for the real-world phenomena he witnessed. In his later years, he read hundreds of mystery novels and compulsively reviewed newspaper and magazine articles for grammatical and factual errors. And, somewhere along the way, he managed to revolutionize the modern understanding of chemistry, in the process becoming one of the greatest scientists in history.

Because of his love for puzzles and conundrums, and his confidence in his own ability to find reason in chaos, Pauling was always on the lookout for new and difficult projects. It was this desire for a challenge that led him to synthesize chemistry and physics, research the structure of DNA, and eventually discover disease-causing molecular mutations. And, in 1952, it caused Pauling to take an interest in anesthesia.

During the late 1940s and early 1950s, Pauling served as one of twelve scientists on the Scientific Advisory Board for Massachusetts General Hospital. In accordance with his duties, in December 1951, Pauling attended a meeting of the advisory board in Boston. During this meeting, Henry K. Beecher, an anesthesiologist later known for his work in medical ethics, gave a talk on xenon as an anesthetic. Pauling was baffled by Beecher’s findings because he knew that xenon, due to its full electron shell, is highly unreactive. According to conventional logic, xenon should have had virtually no biological effect because of its atomic stability.

Following the conference, Pauling took the problem to one of his sons, Peter, an aspiring chemist in his own right. Peter, however, was unable to shed any light on the problem. Still curious, Pauling began to think about the problem in earnest, using his free time in the evenings to meditate over the dilemma. For several weeks, he considered the problem, turning over the implications in his mind. Despite the effort, he simply couldn’t tease out the answer with what little information he had on hand.

Notes RE: Anesthesia, ca. January 1960.

In 1952, Pauling became interested in methane hydrates and chose to begin a small-scale research program to study the properties of related compounds. He assigned Dick Marsh, a graduate student at Caltech, to the problem of manufacturing and studying chlorine hydrates. By combining chlorine with chilled water, Marsh was able to create the hydrates which he then subjected to x-ray photography.

The results were interesting. The chlorine molecules formed an ice-like tetrahedral cage around the water molecules, effectively trapping and freezing the entire unit. Pauling realized that, like chlorine, xenon was capable of forming hydrates. It followed that, if xenon hydrates were created in the brain, they would block the flow of ions through their lipid channels, essentially freezing all communication in the brain and rendering the subject unconscious. The brain tissue itself is approximately 78% water, providing more than enough liquid to allow for hydrate formation. Pauling estimated that as little as 10% of the water in the brain would need to be incorporated into hydrate molecules to result in insensitivity to pain and unconsciousness.

As promising as this hypothesis seemed, it possessed one glaring flaw:  A xenon hydrate becomes unstable and deteriorates at only two or three degrees above the freezing point of water. The human body’s native temperature is approximately three times that necessary to decompose xenon hydrates. Because of this, Pauling realized that hydrates couldn’t possibly explain xenon’s strange effect on the body.

Pauling was forced to accept that, without undertaking his own research program on noble gases, he would be unable to develop a solution to the xenon predicament. He laid the problem aside, assuring himself that he would return to it in due time.

Linus Pauling and King Gustav VI, Nobel Prize ceremonies, Stockholm, Sweden. 1954.

Linus Pauling and King Gustav VI, Nobel Prize ceremonies, Stockholm, Sweden. 1954.

In 1954, Pauling was awarded the Nobel Prize in Chemistry and his life became a whirlwind of activity. Overnight, he became a staple on the university lecture circuit, gave scores of interviews, and began applying his new-found fame to the peace movement. What time he had left was spent supervising graduate students and applying for grants at Caltech, leaving little opportunity for scientific research.

Nevertheless, the xenon question was not forgotten. In 1957, Pauling gave three lectures on the chemical bond which were filmed by the National Science Foundation and distributed to institutions around the country. In his second lecture, Pauling enumerated a revision of his 1952 theory on xenon hydrates, suggesting that they might be stable up to ten degrees above the freezing temperature of water. Even still, the revision wasn’t enough to make hydrates viable at body temperature. What Pauling needed was a breakthrough, something that would fundamentally change how he thought about the hydrate-temperature interaction.

According to Pauling, that breakthrough came in April of 1959 while he was reading a paper on alkylamonium salt, a crystalline hydrate resembling the protein side chains found in the brain. The paper claimed that alkylamonium salt, a clathrate similar to the xenon hydrates, was stable up to 25º C (77º F). Pauling realized that the dodecahedral chambers contained within the alkylamonium hydrate structure were strikingly similar to those formed in xenon hydrates. He hypothesized that xenon atoms introduced into the bloodstream could become trapped in the alkylamonium hydrate, thereby stabilizing the structure and raising its heat tolerance to approximately 37º C (98.6º F), thus preventing the hydrate from decomposing at body temperature.

Pauling suggested that once the alkylamonium hydrate crystals had formed with the xenon, they would prevent normal electrical oscillations and block the flow of ions in the brain, inducing anesthesia. Furthermore, the hydrates would gradually dissipate, in the process allowing the anesthetized brain to resume normal functioning. In short, Pauling had found the key to a new, seemingly workable hypothesis which would soon be referred to as the “Hydrate Microcrystal Theory of Anesthesia.”

Click here to view our previous posts on Linus Pauling and the theory of anesthesia. For more information on Pauling’s life and work, please visit the Linus Pauling Online Portal or the OSU Libraries Special Collections homepage.

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One Response

  1. [...] the 1950s Linus Pauling postulated that some substances dissolved in water will form clusters of molecules called hydrates. [...]

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