Pauling’s Best Friend: Lloyd Jeffress

Photo of Lloyd Jeffress, extracted from Physics Today, December 1977.

As a child, Linus Pauling had relatively few friends. After moving from Condon, Oregon to Portland, the death of his father and subsequent poverty forced him to work when not in school. The remainder of his time was consumed with studying and household chores, leaving little room for companionship. Pauling, even as a boy, was also exceedingly introspective and self-reliant, capable of quietly entertaining himself without supervision. Nevertheless, even the busiest and most independent children need friends.

In 1913, while walking home from school, Pauling began talking with another young boy, Lloyd Jeffress. The two quickly discovered a mutual interest in science and natural phenomena, and Lloyd invited Linus to his home to view a chemistry experiment. Pauling readily agreed and, within the hour, Lloyd was performing a series of basic chemical reactions that bubbled, fizzed and smoked, transfixing the young Pauling. It was on this day, in Lloyd Jeffress’ little Portland bedroom, that Pauling decided to become a chemist.

From that point on, the two boys were inseparable. When not at school or work, they were performing crude, and sometimes dangerous, experiments in the makeshift lab that Linus built in the Pauling basement. Using donated or pilfered chemicals, the boys created noxious gases and exploding powders while dreaming of getting rich as corporate chemists.

Video Link: Watch Pauling recount his and Jeffress’ early chemical experiments

As an adult, Linus Pauling often told a story of Lloyd Jeffress to friends and interviewers. At the age of fifteen, Pauling had imagined himself as a chemical engineer, working for one of the United States’ major companies. When Pauling told his grandmother this, Lloyd chimed in saying, “No, he is going to be a university professor.” Jeffress’ words proved prophetic, as Pauling spent more than thirty years as a professor at the California Institute of Technology.

Following high school, Linus and Lloyd both attended Oregon Agricultural College, where Pauling studied chemistry and Lloyd majored in electrical engineering. Jeffress, however, developed an interest first in physics and later in the medical field, eventually graduating from the University of California with a Ph.D. in psychology, while Pauling, of course, took at job as a chemistry professor at Caltech. Despite the divergence in their interests, the two stayed in intermittent contact for the following sixty years.

Lloyd Jeffress served as best man at Pauling's wedding. Linus and Ava Helen also gave their second-born son the name Peter Jeffress Pauling.

With Pauling at Caltech and Jeffress at the University of Texas in Austin, it was difficult for the men to meet. They visited one another as regularly as their schedules would allow, sometimes engaging in the tomfoolery of their youth. In a short manuscript written after Lloyd’s death, (see below) Pauling recounts their deceiving the guests at an academic event with Lloyd’s “mind reading” abilities, a hoax successfully planned and orchestrated by the pair. He also tells readers of Lloyd’s wedding, a hurried affair conducted by an unknown minister in Linus and Ava Helen Pauling’s small California apartment with only the Paulings to act as witnesses.

Jeffress, like Pauling, was a highly successful member of the academic community. Though his career began slowly, the breadth and depth of his research expanded considerably as he aged, with the vast majority of his papers being produced after his 50th birthday. As an expert in experimental psychology, focusing on psychoacoustics, he served as the chairman of the University of Texas psychology department, and even worked with various military-based programs.

Additionally, his longstanding interest in physics led him to take over some physics classes while serving in the university’s psychology department. Perhaps more surprising, his experience with wave transference resulted in work on mine-detecting devices for the United States military. Over the course of his career, Jeffress earned a series of awards and commendations for his excellence as an educator and for his contributions to the field of psychoacoustics. Pauling personally took great pride in his friend’s successes, expressing special interest in his scientific papers.

Following Lloyd’s death, Pauling was asked to write a brief narrative of their relationship as part of a tribute. In it, Linus described their meeting as boys and their lifelong friendship. In closing, he stated “I have many friends, but I continue to think of Lloyd Alexander Jeffress as my best friend.”

For more on the life of Lloyd Jeffress, please see Pauling’s typescript below, as well as this lengthy memorial resolution (PDF link) prepared by members of the University of Texas faculty.  For more on Pauling’s links with Oregon, check out our continuing Oregon150 series.

“Life with Lloyd Jeffress,” by Linus Pauling, June 5, 1986.

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Thingums from Roger Hayward: A Few Sketches

We are very pleased to announce that the Roger Hayward Papers are now part of the OSU Libraries Special Collections.  To commemorate the occasion, here are three sketches from Hayward’s notebooks.

Gothic sketches commissioned by Cram and Ferguson, 1926.

In 1925, Hayward moved to Cram and Ferguson, a well-known Boston architectural firm specializing in gothic design. Cram and Ferguson were working on the New York cathedral, St. John the Divine, and Roger did a number of architectural designs and renderings of the north face.  He also did similar artistic renderings for the two World War I military cemeteries in France at Aisne-Marne and Oise-Marne for which Cram had commissions. Ralph Cram sent Roger and his wife Betty to Europe in 1926 to examine and sketch many classical buildings and to see “real Gothic structure”. During the trip, Roger filled sketchbooks with his carefully-rendered drawings and color studies.  This “inspection trip” would be valuable in developing ideas for many of the later California architectural projects. Although his trip was confined to Italy, France and England, one of the sketch books opens with a watercolor drawing of the Hagia Sophia in “Constantinople.”

-extracted from Roger Hayward (1899-1979): Architect, Artist, Illustrator, Inventor, Scientist

"Commercial Radio Ads," undated.

"Chaperone?," undated.

Roger worked “for the fun of it”. He was a curious individual and was satisfied when he discovered or exhibited something new. In this regard he was a true dilettante, but a brilliant one.

-extracted from Roger Hayward and Linus Pauling

Much more on Roger Hayward is available here.

Stuck on a Cliff

New York Herald Tribune, February 1, 1960

On the morning of January 30, 1960, Linus Pauling told his wife Ava Helen that he would be out checking the fence lines along the boundaries of their ranch near Big Sur, California. A little before 10:00AM, Ava Helen watched as Linus walked towards the coast south of their cabin but did not notice – as Pauling mistakenly believed she had – as he veered away from the fence line and toward Salmon Cone, a small mountain in the Santa Lucia chain near the Pauling home. Linus was dressed comfortably, wearing slacks, a light jacket, and his characteristic beret. He and Ava Helen had planned to meet for lunch and thought that a friend would perhaps stop by around noon, both expecting Pauling to be back by that time.

For several years Pauling had been interested in finding the mouth of nearby Salmon Creek. He got the idea that the mouth was around China Camp area instead of Salmon Cone, and climbed several ledges that allowed him to walk east to investigate his theory. After a time he found and followed a deer path up several hundred more feet. The deer trail came to an end, but Pauling thought that he saw a spot twenty or thirty feet above him where the path picked up again and began trying to make his way to it over loose rocks. Unable to move east as he had hoped, Pauling was unable to retrace his steps back down or go further up the slope safely. A sickening realization washed over him – he was stuck.

A map included with the Herald Tribune article.

The ledge on which he was perched was about three feet by six feet. Loose rocks, leaves, and sticks covered the ledge; behind him was a sheer rock face. Pauling sat on the ledge for several hours thinking that Ava Helen would walk along the beach and see him stranded on the ledge but, as afternoon moved into evening, came to realize that he might have to stay the entire night perched on the little cliff. Having reached this conclusion, he began to dig a little hole with his walking stick in which he could sit. He dug until he had made the hole two feet by three feet and about a foot deep. He then used the extra dirt to create an eighteen-inch mound around the hole. His resting area completed, Pauling intently pondered a route off the ledge, only to become too frightened to continue on his own. Soon it was dark.

Pauling did not want to fall asleep during his long night on the cliff because, for one, he was afraid he would not hear the calls of searchers. More importantly, Pauling was very concerned that, in the midst of sleep, he might roll off of the precipice and into the crashing ocean below. In order to remain awake, Pauling engaged in a variety of mental tasks. For a while he lectured to the waves about the nature of the chemical bond. He also listed the various properties of the elements of the periodic table. As the night dragged on, Pauling counted as high as he was able in as many languages as he could – German, Italian, French and eventually English. He even used his walking stick to try to tell time based on the positions of the constellations. In an effort to stay warm as well as awake, Pauling tried to move one limb or another at all times.

Moving his arms and legs was only part of Pauling’s process of keeping warm on this January night. Earlier in the evening, having decided that it would be necessary and prudent to remain on the cliff in the small hole that he had dug, Pauling began pulling up some of the bushes that were located near his little ledge. He broke them up into smaller pieces and placed them on the damp bottom of the hole. He then laid some of the intact branches over himself. He was not happy with the results, however, as he had to constantly pull out small leaves and twigs from inside his clothes – eventually he just broke the bushes into twigs, which he used as both mattress and blanket. Still wishing to be a bit warmer, Pauling unfolded the map that he had brought with him and laid it over himself. He later told his family that the map helped immensely although, luckily, it was not as cold a night as could have been the case.

Notes by Ava Helen Pauling. January 30, 1960.

As Linus was settling in for the night, Ava Helen had sprung into action to find him. When he missed their lunch date, Ava Helen had assumed that he had simply lost track of time and did not worry too much. But when 4:15 PM rolled around and there was still no sign of her husband, she went to the nearby ranger station for help and to call her son-in-law Barclay Kamb. As it turned out, a ranger came close to Pauling’s ledge near Salmon Cone but Pauling was unable to attract his attention and the ranger moved on to search other areas. At 11:30PM, a deputy sheriff from Monterrey called off the search for the night. The weather conditions were not conducive to a search – intermittent clouds and fog enshrouded the area from early evening until well-after Pauling had been rescued.

Undeterred, Barclay Kamb reached the ranch around 2:30AM and began searching for an hour and a half in the direction that Ava Helen had last seen Pauling…the wrong direction. At 6:00AM, he began searching in the same area again. Just before 10:00AM, Pauling finally heard another one of the searchers – a man named Terry Currence who was walking along the beach below the ledge. Pauling called to him and Currence scrambled in Pauling’s direction. Terry then called to the deputy sheriff, who maneuvered to a spot a little ways above Pauling. Currence was sent by the deputy sheriff to tell Ava Helen that Pauling had been found alive and well, and to send some rope back. While waiting for the rope, Pauling and the sheriff made their way off of the cliff using one of the paths that Pauling had been afraid to follow unassisted.

New York Times, February 1, 1960.

Pauling was in good spirits as he was led back to his cabin, even joking with the rescue team. Upon returning home, Pauling had lunch and some coffee. Ava Helen shooed-away the reporters who had assembled and thanked everyone who had helped to find her husband. The two packed up their car and the following day drove back to Pasadena. On Tuesday, Pauling went to his Caltech laboratory to give a lecture. When he reached his office, he walked past the small party that his office had put together to welcome his return and went into his office without saying a word. He locked his office and shoved a note under the door requesting that his day be cleared. His staff was unsure of what to do so they called in Barclay Kamb. Barclay came to Pauling’s office and drove him home.

Once home, Ava Helen put him to bed and called the doctor. Pauling had gone into mild shock and was told to rest in bed for several days. He was likewise afflicted with a severe case of poison oak, an unfortunate side effect of his bedding on the ledge. Pauling remained in bed and barely spoke; he cried at the sight of his grandchildren when Linda brought them over for a visit. The emotional and physical exhaustion that he suffered from his night on the cliff forced Pauling to take a much-needed rest and to finally let out some of the emotions that he had been bottling up for so many years of relentless work as a scientist and activist. The trauma was relatively short-lived though, and two weeks later he was not only talking and responding to letters but also honoring speaking engagements again.

The media response to Pauling’s plight on the cliff was swift and rampant. By 9:30AM on Sunday, news of Pauling’s disappearance had spread across the radio, and a half hour later, at 10:00AM, an overzealous reporter told San Francisco Bay area residents that Linus Pauling was dead. Two of Linus’s children, Linda and Crellin, were informed of the radio broadcast and for an hour were unable to discern otherwise – they thought their father was dead. After Pauling was found, news reports of the past weekend’s events were spread around the world, from Oregon to Massachusetts, India to Australia. Over the coming month Pauling received well wishes from colleagues, friends, family, and even strangers who had heard of his ordeal. One such telegram read as follows:

Dear Dr. Pauling, Will you be so kind as to stay off precipitous cliffs until the question of disarmament and atomic testing is finished? A needy citizen. [Signed] Marlon Brando.

For more on the life and times of Dr. Pauling, see the Linus Pauling Online portal.

A Prominent High School Dropout

Linus Pauling posing with his honorary high school diploma, 1962.

Interviewer: Where did you go to high school at in Portland?

Pauling: I went to Washington High School for 3 ½ years, so that my whole high school career was there. It was on the east side of Portland.

Interviewer: How come they wouldn’t give you a diploma?

Pauling: Well, I didn’t finish the requirements. I started in February and by June of 1917, I had completed, essentially, the high school course. I hadn’t taken a one year course in American History. I planned to have it in my last semester. But there was a rule that said you couldn’t take the second half of a course simultaneously with the first half. So, I just wasn’t allowed to take American History. I didn’t return to high school in the fall, but was admitted to Oregon Agricultural College in 1917. I came down [to Corvallis] then.

-Oral history interview, Oregon State University, May 20, 1980.

Linus Pauling, as might be expected, developed an interest in learning at a very early age. By age six, he had already reached the second grade of the elementary school in Condon, Oregon. At eight, he developed an interest in ancient civilizations, and by age nine he had read almost every book in the Pauling household, including works such as Darwin’s On the Origin of Species. In February of 1914, right before his 13th birthday, Linus entered Washington High School in Portland, Oregon, having finishing an accelerated grade school program.

East Portland High School, the second oldest in Portland, was renamed Washington High School in the early 1900s. It was later rechristened Washington-Monroe High School, and eventually closed in the early 1980s because of declining enrollment. In its prime, however, WHS was a great school and, for a young boy keen on learning all he could, there was no better place to be.

In his first semester, Linus took a standard course load consisting of elementary algebra, English, Latin, and gym. After the summer, he returned to WHS for the full year and took his first actual science course, physiography. In this course, Linus was taught about minerals, which he found very interesting. Subsequently, he began a rock collection, and although it never grew to be very large, he enjoyed analyzing and classifying his specimens.

Before long, Linus was taking a course load of above-average difficulty. On top of his normal classes, he continued with Latin and began taking every science and math course he could. Mathematics and the sciences quickly became his favorite subjects, because, as Linus later remembered it:

It’s like the story of the little boy who, when his teacher asked him, ‘Willie, what is two and two?’ answered, ‘Four.’ And she said, ‘That’s very good, Willie.’ And he said, ‘Very good? It’s perfect!’ I liked mathematics because you could be perfect, whereas with Latin, or in studying any language, it’s essentially impossible to be perfect.

As his high school career progressed, Linus easily maintained his challenging schedule and still managed to find time outside of school for other activities. In fact, high school never presented any sort of challenge to him. This was fortunate, because he needed every minute of his free time to work his various jobs, and also to feed his ever-growing appetite for chemistry, which he had developed around the same time he entered high school.

Although chemistry quickly became Linus’ main interest, he wasn’t able to take many classes on the subject. He took first-year chemistry as a junior, which was the only chemistry course that was offered at WHS. Fortunately, the teacher of the course took a liking to Linus, and he was allowed to stay after class to work on additional problems during both his junior and senior years.

W.V. Green was an important early mentor of Linus Pauling. This annotated extract is from Pauling's W.H.S. yearbook, ca. 1917.

In his last semester of high school, Linus took his first physics course. The instructor of this course impressed Linus, and specifically emphasized the importance of the use of precise language in the sciences. One of the main points that Linus took from high school was the importance of the careful use of language, not only in the sciences but in all aspects of education. Linus even tried his hand at fiction writing, which resulted in his English teacher encouraging him to write a novel. Linus’ appreciation for languages and reading would be a great help to him throughout his career.

At the end of his seventh semester at WHS, Linus had run out of math and science classes to take. He had also completed all of the requirements for graduation, except for the year of senior-level American history required by the state of Oregon. Upon learning of this requirement, Linus decided to return to WHS for his last semester after summer break, with the intent of taking the two required history courses simultaneously. This decision was quickly vetoed by the principle, and although Linus had been impressed with the thoroughness of his high school education, he decided to attend Oregon Agricultural College (now Oregon State University) in the fall without a high school diploma – none was required by OAC at the time.

Although this was a natural decision for Linus, it soon provided him with a fair amount of anxiety. The following, written on September 5, 1917, is an excerpt from his diary.

Yesterday and today the feeling has often come to me that never more will I go to school. I think of all the other students beginning their studies, I imagine how I am [sic] member of the graduation class, would appear at Washington, I remember the enjoyment I got out of my studies and school life in general, and I sometimes poignantly regret that I have decided to go to college without graduating from high school. I covet every term of education that I have, and would gladly have more. College still seems so dim and far away that I often forget all about it. In a month and a day from now I will be in Corvallis. I try not to think of College, because of the way it affects me. Why should I rush through my education the way I am?

Despite his nervousness, Linus stuck with his decision and did not return to WHS. He left for college in early October and ended up thriving at OAC. He would eventually go on to have an extremely long and distinguished career as one of the most influential scientists in history. And finally, in 1962, he was awarded an honorary diploma from Washington High School.

For more information about Linus Pauling and his relationship with Oregon, please visit the Linus Pauling Online portal or check out the previous posts in our Oregon150 series.  For those interested in the history of Washington High School, have a look at this great alumni website.

Many Years…

The Pauling and Miller families on Linus and Ava Helen's wedding day. Salem, Oregon. June 17, 1923.

I just saw a statement by Dr. Joyce Brothers about vacation, who said, you can never plan to go with your companion for longer than three days on vacation, because people can’t stand being with one another for more than three days.  She just doesn’t know anything!  Thirty years ago, we were in our cabin here, and my wife said to me, ‘Do you know, we’ve been married for about thirty years now, and this is the first time you and I have been alone for a week without seeing another single human being?’  Well, we were happy being by ourselves, without seeing another human being for a week, to say nothing about living together for 59 years; and rarely being away – years went by before we were ever away from one another a single night.  Many years.

-Linus Pauling, 1990.

Linus Pauling Online

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

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

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.

[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.

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.

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.

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

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

[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 18^th 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] .

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[CN1]http://pauling.library.oregonstate.edu/

[CN2]http://osulibrary.oregonstate.edu/specialcollections/