Linus Pauling and the Mystery of Anesthesia: Part II

Pastel drawing of Xenon Hydrate by Roger Hayward. 1964.

Pastel drawing of Xenon Hydrate by Roger Hayward. 1964.

[Part 4 of 5]

After nearly a decade of puzzling over the mechanisms of anesthesia, Pauling had finally developed a workable theory. By re-imagining molecular interactions, he had been able to produce an entirely new theory that not only explained the effects of general anesthesia but even demonstrated the reversibility of the process. In short, it looked as though he had solved a problem that had baffled scientists for more than a century. But, in order to prove the theory, he needed to begin the experimentation process. For that, he needed a lead researcher.

In the summer of 1959, Linus and Ava Helen Pauling traveled to central Africa and visited Albert Schweitzer’s famous medical compound in Lamberéné. There, they met Frank Catchpool, Schweitzer’s chief medical officer. Pauling found Catchpool to be both intelligent and engaging. The two men spent a great deal of time together, touring the compound and discussing a variety of medical and scientific problems. Thoroughly impressed with the young physician, Pauling suggested that he apply for a position at Caltech.  Shortly thereafter, in 1960, Catchpool became a researcher in the chemistry division under Pauling’s direction.

Dr. Albert Schweitzer. August 15, 1959.

Dr. Albert Schweitzer. August 15, 1959.

Upon Catchpool’s arrival in Pasadena, the two men discussed the problem of anesthesia. As they talked, Pauling began to formulate experiments for the new researcher to conduct. Before long, Catchpool and his assistants were hard at work attempting to verify Pauling’s theories. Success was not to be so easy, however – try as he might, Catchpool could not find a definitive link between microcrystals and anesthesia.  In a June 1960 letter to his son, Peter, Linus described the experimental anesthesia work in which he and Catchpool were engaged. He explained,

“Dr. Catchpool is just beginning a series of experiments on the effect anesthetic agents have in changing the brain waves of an artificial brain, made out of gelatin. I don’t know whether anything will come of this or not. I like the whole theory of anesthesia, but it is hard to think of good experiments to carry out in connection with it.”

Despite the obvious difficulties, Pauling was not to be deterred. Instead of trying to demonstrate the anesthetic effects directly, he decided to approach the problem tangentially. Rather than proving that hydrates were responsible for the anesthetic effect, he would prove that lower body temperatures (which would increase hydrate formation) would allow known anesthetics to act more quickly and with a stronger effect. In this way, he would be able to correlate high rates of hydrate formation with an increased anesthetic effect.

Seeking to experimentally verify this tangential approach, Catchpool and his assistants brought dozens of goldfish to the lab, each in its own temperature-regulated bowl. There, they mixed various anesthetic agents into the bowls. They hoped to find that the fish kept in lower temperature water would become more quickly anesthetized than those in warmer water. Unfortunately for the researchers, goldfish proved to be difficult test subjects. Much like Hans Horst Meyer’s tadpoles some sixty years before, the Catchpool group’s fish were almost impossible to observe objectively and the experiment quickly devolved into a guessing game. To make matters worse, Pauling’s colleagues were beginning to take notice of his strange experiments, leading to more than a few raised eyebrows.

Despite a string of failures in the laboratory, Pauling was unwilling to admit defeat. He felt strongly about the merits of his theory and was determined to publish it before another researcher had the chance. After a few preliminary lectures on the subject in early 1960, Pauling felt that he was ready to unveil it to a larger audience – with or without experimental evidence. He spent the spring and summer working on the paper, alternating between his office at Caltech and his home near Big Sur. A year later, in July of 1961, Pauling published “A Molecular Theory of General Anesthesia” [pdf link] in Science magazine. [134 (July 1961): 15-21]

Pauling and his team thought the paper would make a major splash in the medical world. As the first viable theory of anesthesia in decades, they expected chemists, biologists, and medical practitioners to be clamoring for details about his findings. Instead, the response was muted. A few anesthesiologists took note, but the scientific community as a whole remained unaffected. To make matters worse, another paper on anesthesia was published in the Proceedings of the National Academy of Sciences in the same month. The competing paper, published by Stanley L. Miller, a researcher at the University of California at San Diego, contained a theory similar to Pauling’s. Miller claimed that tiny “icebergs” formed around the gaseous anesthetic agents, preventing normal electrical oscillations and the flow of ions. And because Pauling’s paper was published just before his competitor’s, Miller had a chance to address Pauling’s findings. The following was added to Miller’s draft before publication:

Note added in proof.—Since this article was submitted, a paper by L. Pauling has appeared (Science, 134, 15 (1961)) in which a similar theory is presented. Pauling proposes that microcrystals of hydrate are formed during anesthesia, these crystals being stabilized by side chains of proteins. In spite of any possible stabilization of hydrate crystals by protein side chains, it appears doubtful that crystals could be formed. The gas-filled “icebergs” could be considered equivalent to Pauling’s microcrystals, except that the “icebergs” are much smaller and are not crystals in the usual sense.

Notes re: molecular medicine and anesthesia. November 23, 1964.

Notes re: molecular medicine and anesthesia. November 23, 1964.

Things were looking gloomy for Pauling. Not only had his theory gone almost completely unnoticed, but Miller’s idea was so similar to his own, and published so closely to it, that his work no longer looked entirely original. Over the next eighteen months, Pauling did his best to promote his theory. He gave a few speeches on his work and even tried to draw attention to the similarities between his and Miller’s publications in hopes of gaining credibility. Unfortunately, the scientific community simply wasn’t interested.

It is difficult to conjecture the exact reasons why Pauling’s theory was so effectively ignored. After all, he was a Nobel laureate, a prominent member of the international scientific community, and a well-known public figure. Moreover, he was presenting a novel solution to a problem that had troubled scientists since the mid-1800s. Today only a few individuals even remember that the hydrate microcrystal theory exists, much less that it was born in Pauling’s lab.

While it’s not easy to pinpoint the exact cause of the theory’s public flop, given the time period and events in Pauling’s personal life, it is possible to imagine some of the contributing factors. First, one must consider the impact of his political activities. Not only had Pauling sacrificed huge amounts of his time in the laboratory to lectures and peace demonstrations, he had also attracted the attention of the Senate Internal Security Subcommittee, a body designed to seek out and interrogate suspected Communist sympathizers. The Senate committee hearings, public appearances, and meetings with lawyers ate up much of his time during the first part of the decade, leaving Pauling with  little room for research or the promotion of his theory.

Moreover, Pauling was at odds with Caltech administrators during the early 1960s. His radical political activities and, to a lesser degree, his unconventional research projects had frayed his relationship with the Institute. Without the support of the university, it was much more difficult for him to access personnel and lab space, conduct research, and publicize his findings. This break between Pauling and the Caltech staff would result in his 1963 resignation from CIT and subsequent transfer to the Center for the Study of Democratic Institutions.

Lastly, and perhaps most importantly, was Pauling’s research philosophy. Pauling believed in what is known as the stochastic method. In principle, the stochastic method requires an individual to apply his or her knowledge of a given subject to a particular phenomenon with the intention of developing a hypothesis regarding the phenomenon, absent of any unique laboratory data, which might be generated later. In laymen’s terms, we might refer to the process as making an educated guess and then designing experiments to see if the guess is correct.

However, to suggest that Pauling simply guessed would be both unfair and inaccurate. Instead, he combined the available information about a subject with his considerable skill as a scientist to formulate what he saw as a viable, working theory. Then, he would hand his findings off to other researchers, leaving them to do the experimental work. In most cases, the arrangement worked well. While he was most interested in theoretical work rather than the tedious job of running experiments, most others lacked Pauling’s creative genius, and instead preferred the structured, hands-on time in the laboratory. Normally, this resulted in a sort of symbiotic relationship in the Caltech laboratories. Unfortunately, this also meant that not all of Pauling’s theories received the attention that they deserved. If no one chose to work with Pauling’s theories, or if the research methods proved unsuccessful, the theory was often left to gather dust in one of the Institute’s filing cabinets. It’s likely that the difficulty of conducting appropriate experiments had a hand in silencing Pauling’s hydrate microcrystal theory.

Whatever the reason, Pauling’s theory now stands as little more than a footnote in the history of anesthesiology. After its publication in 1961, it quickly faded out of the picture and the field was, yet again, left without a single agreed-upon theory. Luckily, it wasn’t to remain so forever. In our final post on Linus Pauling and anesthesia, we will explore the advances in anesthetic theory from the 1970s to the present.

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

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One Response

  1. Gerald Pollack’s “Cells, Gels and the Engines of Life” mentioned Pauling when outlining a new theory for the action potential. So Pauling’s theory is more than a footnote ;D.
    Thanks for this wonderful article!

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