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.

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Anesthesia Today: Building a Modern Theory

Nicholas P. Franks, Ph.D.

[Part 5 of 5]

Following the discrediting of Meyer and Overton and the less than stellar debut of Pauling’s theory, anesthesiologists were again left without a central working theory of anesthesia. While Pauling still supported his own work, his fellow scientists remained uninterested and he gradually disappeared from the scene altogether.

Fortunately, the problem was not forgotten for long. Beginning in the mid 1970s, Nicholas P. Franks and William R. Lieb, researchers at the Imperial College in London, began work on a new theory of anesthesia. They suggested that anesthetics are, in fact, similar to conventional pharmaceuticals. They theorized that anesthetic molecules are able to bond to protein receptors in the brain and, in doing so, manipulate specific ion channels. Like the hydrate theory, the protein theory suggests that, by affecting the brain’s ion channels, the anesthetics would have the ability to disrupt brain functions and result in unconsciousness.

Franks and Lieb spent several years testing the effects of various liquid anesthetics on isolated, lab-grown proteins. In 1984, they published “Seeing the Light: Protein Theories of General Anesthesia.” The paper introduced the protein theory to a wider audience and suggested that, through extensive testing, scientists might be able to identify the correlations between specific anesthetics and binding sites. This, in turn, would allow researchers to predict the effects of a given anesthetic and eventually develop improved synthetic chemicals.

In order to positively demonstrate the relationship between anesthetics and protein receptors, researchers in the

Generation PSP94-knockin mice

Generation PSP94-knockin mice

United States and Switzerland began developing genetically modified mice. These test subjects, known as knockin mice, lacked specific proteins thought to be affected by a given anesthetic. By using the anesthetic on the supposedly immune mice, the researchers were able to pinpoint correlations between anesthetics and proteins. With improved technology, the researchers were eventually able to minimize the necessary genetic changes by altering amino acids within the proteins. This allowed the researchers to avoid eliminating any macromolecules within the knockin mice, creating a more authentic testing process.

The results from the knockin mice experiment proved monumental. Through extensive testing, researchers were able to locate and identify specific interactions between anesthetics and protein receptors. For the first time in over a century of studying anesthesia, scientists were finally able support theoretical claims with conclusive experimental data.

Unfortunately, this breakthrough did not solve the mystery completely. Anesthetics in gaseous form, which are commonly used to induce general anesthesia, do not necessarily adhere to the same principles as injected anesthetics. Inhaled anesthetics do not seem to bind as tightly as their injected counterparts, and instead pass over a huge number of receptors rather than triggering a single one. Though a great deal of disagreement exists among scientists, it is widely believed that gaseous anesthetics affect anywhere from three or four types of receptors to over one hundred. To further complicate this issue, there is disagreement whether every receptor affected by the gas contributes to the anesthetic effect.

Knockin Mouse

Knockin Mouse

Currently, several teams around the world are engaged in determining receptors for inhaled anesthetics. The process, however, will be long and tedious. Each knockin mouse must be genetically altered so that its significant receptors are modified to match a given anesthetic. This process is one of trial and error and provides an amazing challenge for scientists.

From Ernst von Bibra to Pauling to Franks and Lieb, the theory of anesthesia has had a bumpy ride. But, with each researcher and each breakthrough, we have moved a little closer to a better understanding of our biological selves. With a little luck and a lot of hard work, the next decade will yield even more progress and, undoubtedly, more questions.

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.

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.

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.

The Meyer-Overton Theory of Anesthesia

overton

Charles Ernest Overton

[Part 2 of 5]

In 1896, Hans Horst Meyer, a German pharmacologist and Director of the Pharmacological Institute at the University of Marburg, became interested in Ernst von Bibra’s theory of anesthesia. Meyer hypothesized that anesthetics were hydrophobic (repelled by water) and in turn attracted to other hydrophobic molecules. Lipids, the fatty molecules in brain cells, are also hydrophobic as evidenced by the separation of lipid-based substances (such as vegetable oil, grease, and butter) in water. Meyer believed that this mutual hydrophobia led anesthetics to bond to and dissolve the lipid molecules in brain cells.  His hypothesis  further argued that increasingly-hydrophobic anesthetic molecules were capable of forming stronger bonds with lipids, thereby bonding more readily and increasing the potency of the anesthetic effect.

In order to test his hypothesis and expand upon von Bibra’s work, Meyer began a small-scale research program on anesthetics, using his position at the University of Marburg to acquire the necessary assistants and apparatus for his experiments. His intention was to demonstrate some degree of correlation between a substance’s ability to bond with fatty substances and its anesthetic power.

As a means of assessing interactions between anesthetics and lipids, Meyer measured the solubility of known anesthetics (including, but not limited to, ketones, alcohols and ethers) in olive oil, which was meant to represent the fatty molecules in brain cells. He then tested the same anesthetics on tadpoles, measuring the quantity of anesthetic agent required to induce what he defined as abnormal behavior. Though his use of tadpoles as experimental subjects led to imprecise and often subjective observations, he was able to positively correlate lipid solubility with anesthetic potency. By equating lipid solubility with anesthetic affect, Meyer was able to offer experimental support for von Bibra’s hypothesis. In 1899, Meyer published his theory on the anesthesia-lipid relationship in his paper “Zur Theorie der Alkoholnarkose,” Arch. Exp. Pathol. Pharmacol. 42: 109–118.

In 1901, Charles Ernest Overton published his own theory of anesthesia independently of Meyer’s. He too had found a positive correlation between lipid solubility and potency. Moreover, he had discovered that the power of an anesthetic was unrelated to the method by which it had been delivered. In other words, Overton was able to show that lipids in the brain were affected by anesthetic agents regardless of whether they had been administered in a liquid or gaseous form.

Because Meyer and Overton, both established researchers, came to the same conclusions using different experimental methods, their work gained traction in the scientific world and quickly became known as the Meyer-Overton theory of anesthesia. In its simplest form, the theory claims that once an anesthetic agent reaches a critical level in a lipid layer, the anesthesia molecules bond to target sites (sometimes known as receptors) on the lipid molecules, in the process dissolving the fatty part of the brain cells affected by the anesthetic agent. In response to the dissolution of the lipid layer, the brain reaches an anesthetized state and the patient is rendered unconscious.

To much of the early twentieth-century scientific community, the theory seemed to adequately describe the well-established relationship between anesthetics and lipid solubility that seemed to underlie the anesthetic effect. The theory had been substantiated by multiple experimental tests and, in the end, was the best existing explanation of the phenomenon. Meyer and Overton seemed to have decoded the mystery behind a major medical practice.

As is common with major discoveries, however, the Meyer-Overton discovery eventually succumbed to scientific scrutiny. Nearly six decades after Meyer’s and Overton’s original publications, researchers were finally able to identify a key flaw in the lipid theory:  namely that anesthetics interacted with lipid-free proteins in the same way that they interacted with lipids. This suggested that anesthetics did not require lipid target sites for binding, but could instead bind to other sites with the same resulting anesthetic effect. This discovery greatly reduced the perceived importance of lipids in the anesthesia-brain interaction.

Moreover, researchers found that as anesthetics in a given series of tests became increasingly hydrophobic (through the lengthening of the carbon chain), their potency did not increase indefinitely. Instead, molecules appeared to reach what is known as a “cutoff point” where otherwise-effective anesthetics lose their ability to anesthetize the brain. According to the Meyer-Overton theory, the loss of anesthetic effect would imply an inability to bond with lipids. Scientists, however, found that long-chain anesthetics continued to bond with lipids despite the loss of anesthetic ability, further strengthening the argument that anesthetic-lipid bonds are not responsible for the sensory-altering effects of anesthesia.

With these breakthroughs, the Meyer-Overton theory was crushed. If anesthetics could be effective without bonding with lipids, and could be ineffective when bonded to lipids, the original Meyer-Overton theory could no longer be considered valid.

Click here to view our previous posts on 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.

A Look at Anesthesia: The History of a Puzzle

Engraving of Ernst von Bibra by August Weger ca. 1888

Engraving of Ernst von Bibra by August Weger ca. 1888

[Part 1 of 5]

Anesthetics have been used throughout much of human history as tools for relieving pain and shielding the body. They have played a major role in human health and medicine from prehistory to the present. In our blog series “Linus Pauling: The Mystery of Anesthesia,” we will examine Linus Pauling’s intriguing theory of anesthesia and the science and history that surrounds it.

Until the 18th century, anesthetics were typically concocted from the local flora by herbalists and chemists. Opium, for example, is thought to be one of the oldest prepared anesthetics, distilled from poppy flowers farmed by Sumerians as early as 4000 BC. In the late 1760s, however, the great British scholar Joseph Priestley discovered the anesthetic power of nitrous oxide in its gaseous state, thus rendering as outdate most conventional herbal anesthetics. Following Priestley’s discovery, the international scientific community launched a number of small-scale investigations into potential anesthetics, eventually resulting in the medical use of ether, chloroform, and other gases. In 1803, Friedrich Wilhelm Sertürner distilled morphine from pure opium, creating yet another wave of interest among researchers.

Despite this pronounced early-19th century interest in anesthesia, little was known about the properties of anesthetics. Researchers wondered, what caused the numbness and unconsciousness? Why were the effects of anesthesia reversible? What made some anesthetics more powerful than others?

A few intrepid anesthesiologists suggested that anesthetic gases formed a sort of fog in the brain, or that they caused the nerves or brain matter itself to coagulate. Unfortunately, without access to advanced medical and chemical techniques, and lacking a sophisticated understanding of brain functioning, scientists harbored little hope of uncovering the precise mechanisms behind anesthesia.

In 1847 the German polymath Ernst von Bibra decided to tackle the problem. In his previous chemical work, von Bibra had specialized in the study of intoxicants and poisonous plants and, as a result, had accumulated a great deal of experience with the various medicinal compounds derived from flora. Von Bibra’s idea was that anesthetics might dissolve fats in human brain cells, resulting in a temporary loss of consciousness and normal brain activity. He further theorized that at some point after the anesthetized state had been induced, the anesthetic would eventually cycle out of the brain, thus permitting the brain’s cells to steadily return to their natural rate of functioning.

Von Bibra realized that, if true, his theory would explain the temporary yet reversible unconsciousness induced by anesthesia and, in the process, revolutionize the scientific understanding of how the brain works. Unfortunately, his research was largely ignored for a half-century, in part due to the limitations of mid-nineteenth century technology. However, in the late 1800s, von Bibra’s theory resurfaced and attracted the attention of several researchers who would go on to revolutionize the study of brain chemistry.

All of our posts on the theory of anesthesia will be collected here.  For more information on Linus Pauling’s life and work, visit the Linus Pauling Online Portal or the OSU Special Collections homepage.

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Anesthetics have been used throughout much of human history as tools for relieving pain and shielding the body. They have played a major role in human health and medicine from prehistory to the present. In our blog series Linus Pauling: The Mystery of Anesthesia, we will examine Linus Pauling’s intriguing theory of anesthesia and the science and history that surrounds it.

Until the 18th century, anesthetics were typically concocted from the local flora by herbalists and chemists. Opium, for example, is thought to be one of the oldest prepared anesthetics known to man, distilled from poppy flowers farmed by Sumerians as early as 4000 BC. In the late 1760s, however, Joseph Priestley discovered the anesthetic power of nitrous oxide in its gaseous state, rendering most conventional herbal anesthetics outdated. Following Priestley’s discovery, the international scientific community launched a number of small-scale investigations into potential anesthetics, eventually resulting in the use of ether, chloroform, and other gases. In 1803, Friedrich Wilhelm Sertürner distilled morphine from pure opium, creating another wave of interest among researchers.

Despite a great deal of medical interest in anesthesia during the early 1800s, little was known about the properties of anesthetics. What caused the numbness and unconsciousness? Why were the effects of anesthesia reversible? What made some more powerful than others? A few intrepid anesthesiologists suggested that the anesthetic gases formed a sort of fog in the brain, or that they caused the nerves or brain matter itself to coagulate. Unfortunately, without access to advanced medical and chemical technologies, or an understanding of brain function, scientists had little hope of uncovering the mechanisms behind anesthesia.

In 1847, Ernst von Bibra, decided to tackle the problem. As a chemist, he specialized in the study of intoxicants and poisonous plants and had a great deal of experience with the various medicinal compounds derived from flora. He suggested that anesthetics might dissolve fats in human brain cells, resulting in the temporary loss of consciousness and normal brain activity. He theorized that after the anesthetized state had been induced, the anesthetic would eventually cycle out of the brain, allowing brain cells to return to their natural state. von Bibra realized that, if true, his theory would explain the temporary yet reversible unconsciousness induced by anesthesia and revolutionize the scientific understanding of brain function. Unfortunately, his work was largely ignored for a half-century, in part due to the limitations of mid-nineteenth century technology. However, in the late 1800s, von Bibra’s theory resurfaced and attracted the attention of several researchers who would revolutionize the study of brain chemistry.

For more information on Pauling’s life and work, visit the Linus Pauling Online Portal[CN1] or the OSU Special Collections homepage[CN2] .

Happy (Almost) Birthday Linus Pauling!

Cross-posted at Ether Wave Propaganda

Pauline, Linus and Lucile Pauling, 1908.

Pauline, Linus and Lucile Pauling, 1908.

Linus Pauling was born in Portland, Oregon on February 28, 1901, meaning that this coming Saturday will mark the 108th anniversary of his birth. (He died on August 19, 1994 at the age of 93)

Over the years, one of our annual habits around here has been to reflect back upon Pauling’s life at the time of his birthday anniversary, usually by highlighting his activities 100, 75, 50 and 25 years ago.

Looking back in segments of twenty-five years is admittedly rather an arbitrary observance, but it can oftentimes prove to be very revealing. By choosing to study the effectively-random dates of, in this instance, 1909, 1934, 1959 and 1984, one is compelled to sample a broad period of time in Pauling’s life and, in the process, gain a sense of his remarkably-wide variety of interests. It is our belief that, as much as anything else, these broad horizons define Pauling’s legacy.

1909: Age 8

The Pauling family begins this year in Condon, Oregon, a small and isolated farming community some 150 miles east of Portland. Four years previous, Linus’s father, Herman, had moved the family to the dry side of the state in search of business opportunities. A drug store operator, Herman has been able to make a living meeting the pharmaceutical needs of the region’s farmers, ranchers and cowboys.

Neither Herman nor his wife, Belle, particularly care for the area, and in September, following a fire that guts the Condon store, the family decides to return to Portland. By the time the family settles, Linus has transferred into his third fourth-grade class of the term. A rather withdrawn little boy, by 1909 Linus has already developed keen interests in the scientific world. He is particularly enamored of insects and minerals, and will soon develop and classify collections of both. He is also a voracious reader with a particular taste for ancient history.

1934: Age 33

Dr. Linus Pauling is a full professor at the California Institute of Technology, a recipient of the A.C. Langmuir Prize (awarded by the American Chemical Society to the best young chemist in the nation) and a married father of three. He has already published a set of papers that revolutionized the modern understanding of structural chemistry and is now turning his attentions to biological topics, including the structure of hemoglobin. The hemoglobin work will prove to be of major importance and will eventually receive hundreds of thousands of dollars of funding support from the Rockefeller Foundation.

Jack Sherman and Linus Pauling, 1935.

Jack Sherman and Linus Pauling, 1935.

Pauling has not, however, lost his passion for more traditional structure determinations. In 1934 he and Maurice L. Huggins publish an important paper on the atomic characteristics of crystals containing electron-pair bonds. Pauling also supervises investigations of enargite, binnite and calcium boride. His collaborator in the calcium boride work is a young Ph.D. named Sidney Weinbaum who, sixteen years later, will be imprisoned for having perjured himself during a loyalty hearing.

1959: Age 58

He does not know it yet, but Pauling is nearing the end of his long association with the California Institute of Technology. The recipient of the 1954 Nobel Prize for Chemistry, Pauling has made a decision to devote roughly half of his time to the world peace movement, a trend that proves increasingly troublesome to the Caltech regents.

In 1959 he delivers dozens of speeches on the perils of nuclear testing, the social ramifications of Cold War hysteria and the great immorality of war. He and his wife, Ava Helen, also spend the year traveling widely. They visit Dr. Albert Schweitzer at his medical compound in French Equitorial Africa; they contribute to the Fourth Pugwash Conference on Science and World Affairs in Baden, Austria; and they help draft the “Hiroshima Appeal,” issued in Japan by the Fifth World Conference Against Atomic and Hydrogen Bombs.

Linus and Ava Helen Pauling working on the United Nations Bomb Test Petition, 1957.

Linus and Ava Helen Pauling working on the United Nations Bomb Test Petition, 1957.

Pauling’s first love is and always shall be science, and amidst his flurry of peace activism he is still able to make time for work in the laboratory. One of his more novel pursuits is a theory of anesthesia, which he begins researching in April 1959. Running a series of experiments that involve goldfish, among other subjects, Pauling theorizes that anesthetic agents form hydrate “cages” with properties similar to ice crystals. Owing to the nature of their molecular structure these “cages” serve to impede electrical impulses in the brain, thus leading to unconsciousness.

1984: Age 83

Pauling’s fascination with vitamin C is in full bloom and by now he has written and lectured on the subject widely — one of his seventeen publications issued in 1984 is a book chapter on the topic of vitamin C and pregnancy.

Two years removed, Pauling likewise continues to struggle with the death of Ava Helen, his wife of fifty-eight years. Increasingly he turns to highly theoretical scientific pursuits as a method for occupying his mind and coping with his grief. In tandem with his orthomolecular work, publication titles the likes of “Evidence from bond lengths and bond angles for enneacovalence of cobalt, rhodium, iridium, iron, ruthenium, and osmium in compounds with elements of medium electronegativity” come to dominate his curriculum vitae.

In 1984 Pauling receives the American Chemical Society’s most prestigious award, the Joseph Priestley Medal. That same year he and three other Nobel laureates (Adolfo Perez Esquivel, George Wald and Betty Williams) sail to Nicaragua to promote peace and democracy in Central America. Never one to mince words, Pauling tells an interviewer aboard the “Peace Ship” that “the people of the United States need to know what great immorality the Reagan government has been committing, through the CIA and by direct subsidy of the forces that are trying to overthrow the government of Nicaragua by force and violence.”

Linus Pauling in Nicaragua, 1984.

Linus Pauling in Nicaragua, 1984.

Celebrate Pauling’s 108th birthday by visiting the Linus Pauling Online portal.