Think Independently: Pauling’s Years at OAC

 

Linus Pauling on OAC graduation day, June 1922.

Linus Pauling on OAC graduation day, June 1922.

[Ed Note: Last Saturday, Oregon State University graduated its largest class ever.  In honor of the class of 2014, we're taking a quick look back at Linus Pauling's years as an undergraduate at what was then known as Oregon Agricultural College.]

It might be said that brilliant ideas start with reflections on problems of daily life. The undergraduate story of young Linus Pauling traces the growth of a remarkable talent emerging from an interest in tackling the familiar problems of ordinary life. Pauling enrolled in Oregon Agriculture College (OAC) at the young age of 16 in the Fall of 1917 and graduated from OAC with a B.S. in chemical engineering in June 1922. In those five years, he matured in a significant way, both socially and academically. In school, he not only earned A’s in all of his chemistry and mathematics courses, he also stoked his passion for science and even began to approach the burgeoning field of physical chemistry – a landscape of study that he would one day play a major part in defining.

At OAC and in the decades that followed, a main propellant of his growth and success was Pauling’s persistence in thinking independently. Years later, Pauling famously suggested to a crowd of young people that, “When an old and distinguished person speaks to you, listen to him carefully and with respect – but do not believe him. Never put your trust into anything but your own intellect.”  The kernel of that idea was apparent during young Pauling’s stint in Corvallis.

Pauling at the Oregon coast with his cousin Rowena, 1918.

Pauling at the Oregon coast with his cousin Rowena, 1918.

One quality shared by most successful scientists is that they love and excel at thinking. At an early age, Pauling started to show the signs of an independent thinker, always seeking to dig deeper into a question once he was drawn to it. Pauling’s grandparents lived in Oswego, Oregon close to the newly built Portland Cement Company. On weekend visits to his grandparents, Pauling, aged 14, frequently went to the cement plant’s laboratory and spent hours there bombarding the chief chemist with questions. Many years later, Pauling remembered this patient individual as “a man who was not very interested in chemistry, but who served as scoutmaster and who was willing to talk with me and to answer my questions.”

Pauling continued to pursue this interest during his college years. In the summer of 1919, mostly due to his need to earn money to pay for school but likely also motivated by his early contacts with the cement industry, Pauling secured a summer job in southern Oregon as a blacktop pavement inspector. His main task was to monitor the quality of the bitumen-stone mixes comprising the pavement. In June 1920, these activities were crystallized in his first scientific publication, “The Manufacture of Cement in Oregon,”  which appeared in The Student Engineer. In his three-page article, Pauling specified the process by which cement was produced, from crushers cutting large rocks as a first step to the kilns yielding the final, small round particles for cooling in the finishing mill.

Freshman fun at OAC, 1918. Photo by Linus Pauling.

Freshman fun at OAC, 1918. Photo by Linus Pauling.

Pauling’s digging into the cement industry was an indication of his ability to think independently and pursue a problem persistently, a set of traits that informed his academic work as well. His course reports from the metallography lab in the spring of 1921 also provide a nice glimpse into his scientific acumen and his growing confidence. The reports are not written in the formal and impersonal manner that one might to expect to find. Instead, quite often, Pauling used plain terms and interjected many of his own thoughts in the write-ups. From item to item, a personal voice is easily identified and the reports make for engaging reading. One interesting example is the concluding paragraph to Pauling’s report on “Preparation and Examination of Specimens” (April 25, 1921), which is typically lighthearted and even boastful.  Presumably addressing his professor, Pauling writes

I have made free use of technical terms throughout on the assumption that you would understand them, but in case you do not, I refer you to my experiment on metallography the first quarter of this year, in which complete definitions are given. I have also attempted to use words of one syllable to as great an extent as is practicable in order to prevent any mental strain. Let me repeat that, for a really good article, you should read my previous experiment.

When approaching a lab topic, Pauling early on developed the habit of consulting all of the relevant literature that he could find in developing a general picture of the status of current research on that topic. In his reports, he often gave his opinions of the literature in a very frank manner. See, for example, this aside included in a 1921 report titled “Heat Treatment and Tests of Specimen and Case-Carburizing.”

Quite often in reading, I wonder where people find all the things they do to write about. Just about as often I wonder what the idea of writing so much is, and why it is necessary to really do it. Then again I find the secret. It is this. All this writing is necessary because we are acquiring so much knowledge that we are behind in writing it down as it is, and there is still room for more books. I wish that someone would prepare (or rather, had already prepared) a short concise article on heat treating steels covering about five such pages as this. His work at least would be considered useful by me.

While sharpening his scientific toolkit at the theoretical level, the undergraduate Pauling also loved the mathematical rigor required by many technical tasks. In pursuing these tasks, he developed a stickler’s personality, one that reveals itself time and again in his correspondence over the years.

One such early example is dated March 15, 1920, in a letter from Pauling to Dr. George Smith, the author of a chemistry textbook.  In it, Pauling – who had just turned 19 years old – points out a tiny technical error. On page 11 of the textbook, Smith talked about errors in weight measurement. Using the tools of the day, Smith pointed out that weighing the same sample of a given substance twice would always yield two results which were very slightly different, meaning that there is always a built-in percentage error in weight measurements.

Smith went on to explain how observers calculated errors of this sort in weighing mixtures, using as an example the measurement of the weight of a sample clay which contained in it 0.2% of magnesium oxide. Here Pauling found a point of disagreement; he thought the calculation of the percentage error of the magnesium oxide was problematic. In his text, Smith stated that if the measuring error was 0.1% in total, then for the impurity in the sample, which was 0.2% of the total clay, the percentage error would be 0.0002%. Conversely, Pauling thought the error in the weight of the impurity should be compared with the impurity itself, and that the percentage error would thus be 0.1%, instead of 0.0002%.

Ready to take on the world. 1922.

Ready to take on the world. 1922.

A few days later, on March 22, Smith wrote back to his young correspondent in a very pleasant tone, saying that although he did not agree that this was an error, he admitted that the example was confusing and  needed further clarification. What’s more, at the end of the letter, Smith enthusiastically mentioned that he was looking forward to meeting Pauling at the upcoming meeting of the Pacific Division of the American Association for the Advancement of Science.

Before and during his years at OAC, Pauling thought independently about scientific problems, making every effort to find answers that were satisfying to him. He doggedly queried expert opinions, widely searched the available literature, and critically judged the information that he gathered. Only then would he put forward and test his own proposals. He was interested in industrial problems and theoretical questions alike. He was engaged with topics in the lab and gradually developed an acute scientific insight.  And by the time he left Oregon Agricultural College, he was well-poised to do great things as a scientist.

Pauling and Perutz: The Later Years

[Concluding our series on Max Perutz, in commemoration of the Perutz centenary.]

In 1957, Max Perutz and Linus Pauling wrote to each other again on a topic that was new to their correspondence. This time Pauling asked Perutz to sign his petition to stop nuclear weapons tests, a request to which Perutz agreed.

Signature of Max Perutz added to the United Nations Bomb Test Petition, 1957.

Signature of Max Perutz added to the United Nations Bomb Test Petition, 1957.

As the decade moved forward, the discovery of the double helical structure of DNA attracted ever more attention to the work of James Watson and Francis Crick. In May 1958, Perutz asked Pauling to sign a certificate nominating his colleagues Crick and John Kendrew to the Royal Society. Pauling agreed, though stipulated that Kendrew’s name be placed first on the nomination, as he expected that Crick would get more support. As with Pauling’s bomb test petition a year earlier, Perutz agreed.

At the beginning of 1960, William Lawrence Bragg wrote to Pauling about nominating Perutz, along with Kendrew, for the 1961 Nobel Prize in Physics. Pauling was hesitant about the nomination, thinking it was still early, as their work on hemoglobin structure had only recently been published. Pauling also felt that Dorothy Hodgkin should be included for her work in protein crystallography. Bragg thought this a good idea and included Hodgkin in his nomination.

By March, Bragg’s nominations had gone through and Pauling was asked to supply his opinion. After spending some time thinking about the matter, Pauling wrote to the Nobel Committee that he thought that Robert B. Corey, who worked in Pauling’s lab, should be nominated along with Perutz and Kendrew for the Nobel Prize in Chemistry instead. Pauling felt that if Perutz and Kendrew were included in the award, Corey should be awarded half, with the other half being split between Perutz and Kendrew. Pauling also sent a letter to the Nobel Committee for Physics, indicating that he thought that Hodgkin, Perutz, and Kendrew should be nominated for the chemistry prize. Pauling sent a copy of this letter to Bragg as well.

Pauling’s letter to the Nobel Committee, March 15, 1960. pg. 1.

Pg. 2

In July, Bragg replied to Pauling that he was in a “quandary” about Corey, as he was “convinced that” Corey’s work “does not rank in the same category with that which Mrs. Hodgkin or Perutz and Kendrew have done.” Perutz and Kendrew’s efforts, he explained, had theoretical implications directly supporting Pauling’s own work, whereas Corey’s research was not that “different from other careful analyses of organic compounds.” Once everything was sorted out, Perutz and Kendrew were awarded the Nobel Prize for Chemistry in 1962 (the same year that Watson and Crick, along with Maurice Wilkins, won in Physiology/Medicine, and Pauling, though belated for a year, won the Nobel Peace Prize) and Hodgkin received the Nobel Prize for Chemistry in 1964. Robert Corey never was awarded a Nobel Prize.


Linus Pauling, Max Delbrück and Max Perutz at the American Chemical Society centennial meeting, New York. April 6, 1976.

Perutz and Pauling corresponded very little during the 1960s, with Perutz writing only to ask for Pauling’s signature, once for a photograph that would be displayed in his lab and a second time for a letter to Italian President Antonio Segri in support of scientists Domenico Marotta and Giordano Giacomello, who were under fire for suspected misuse of funds.

In 1971 Perutz read an interview with Pauling in the New Scientist which compelled him to engage Pauling on scientific questions once again. Perutz was surprised to have read that Pauling had tried to solve the structure of alpha keratin as early as 1937 and that his failure to do so led him to study amino acids. Perutz wrote that had he known this in 1950, he, Bragg and Kendrew might not have pursued their own inquiry into alpha keratin. Pauling responded that he thought his efforts had been well-known as he and Corey had made mention of them in several papers at the time. Pauling explained that he had difficulties with alpha keratin up until 1950, when he finally was able to show that the alpha helix best described its structure. Perutz replied that he was aware of Pauling and Corey’s work and the alpha helix, but was surprised that Pauling’s early failure to construct a model led him to a more systematic and fruitful line of research.

Perutz also wondered whether Pauling had seen his article in the previous New Scientist, which reflected on Pauling and Charles Coryell’s discovery of the effect of oxygenation on the magnetic qualities of hemoglobin. Perutz saw this as providing “the key to the understanding of the mechanism of haem-haem [heme-heme] interactions in haemoglobin.” Pauling responded that he had not seen Perutz’s article but would look for it, and also sent Perutz a 1951 paper on the topic. Perutz took it upon himself to send Pauling his own article from the New Scientist.

A few years later, in 1976, Perutz again headed to southern California to attend a celebration for Pauling’s 75th birthday, at which he nervously gave the after dinner speech to a gathering of 250 guests. Before going to the event in Santa Barbara, Perutz stopped in Riverside and visited the young university there, which impressed him. Perutz wrote to his family back in Cambridge that he wished that “Oxbridge college architects would come here to learn – but probably they wouldn’t notice the difference between their clumsy buildings and these graceful constructions.”

Perutz also visited the Paulings’ home outside Pasadena, which elicited more architectural comments. Perutz described to his family how the Pauling house was shaped like an amide group, “the wings being set at the exact angles of the chemical bonds that allowed him to predict the structure of the α-helix.” Perutz asked Pauling, perhaps tongue in cheek as he thought the design somewhat conceited, “why he missed the accompanying change in radius of the iron atom.” Pauling replied that he had not thought of it.

Bertrand Russell and Linus Pauling, London England. 1953.

In preparation for his speech, Perutz also took some time to read No More War! which he concluded was as relevant in 1976 as when it was first published in 1958. Perutz saw Pauling’s faith in human reason as reminiscent of Bertrand Russell’s. Indeed, the many similarities between the two were striking to Perutz, and he included many of them in his talk, “except for their common vanity which I discreetly omitted.” In a personal conversation, Perutz asked Pauling about his relationship with Russell which, as it turned out, was mostly concerned with their mutual actions against nuclear weapons. Perutz was somewhat disappointed that “they hardly touched upon the fundamental outlook which I believe they shared.”


Perutz and Pauling were again out of touch for several years until April 1987, when Pauling traveled to London to give a lecture at Imperial College as part of a centenary conference in honor of Erwin Schrödinger. Pauling’s contribution discussed his own work on antigen-antibody complexes during the 1930s and 1940s, during which he shared a drawing that he had made at the time. Perutz was in attendance and noticed how similar Pauling’s drawing was to then-recent models of the structure that had been borne out of contemporary x-ray crystallography. Perutz sent Pauling some slides so that he could judge the similarities for himself.

Flyer for Pauling's 90th birthday tribute, California Institute of Technology, February 28, 1991.

Flyer for Pauling’s 90th birthday tribute, California Institute of Technology, February 28, 1991.

The final time that Pauling and Perutz met in person was for Pauling’s ninetieth birthday celebration in 1991. Perutz, again, experienced stage fright as he gave his speech. But he was encouraged afterwards, especially after receiving a compliment from Francis Crick who, according to Perutz, was “not in the habit of paying compliments.” Perutz told his family that the nonagenarian Pauling “stole the show” by giving one speech at 9:00 AM on early work in crystallography and then another speech at 10:00 PM on his early years at Caltech. Perutz found it enviable that Pauling stood for both lectures and was still getting around very well, though he held on to the arm of those with whom he walked. Without coordinating, Perutz and Pauling also found a point of agreement in their talks, noting that current crystallographers were “so busy determining structures at the double” that they “have no time to think about them.” This rush often caused them to miss the most important aspects of the newly uncovered structures.

Just as Perutz first encountered Pauling through one of his books, The Nature of the Chemical Bond, so too would Pauling’s last encounter with Perutz be through a book, Perutz’s Is Science Necessary? Pauling received the volume in 1991 as a gift from his friends and colleagues Emile and Jane Zuckerkandl. Pauling’s limited marginalia reveal his interest in the text’s discussions of cancer and aging research. Aged 90 and facing his own cancer diagnosis, Pauling was particularly drawn to Perutz’s review of François Jacob’s The Possible and the Actual which sought, but did not find, a “death mechanism” in spawning salmon. Pauling likewise highlighted the book’s suggestion that “like other scientific fantasies…the Fountain of Youth probably does not belong to the world of the possible.” And Pauling made note of particular individuals that he had known well, like John D. Bernal and David Harker. Pauling deciphered the latter’s identity from Perutz’s less-than-favorable anonymous portrayal.

Pauling also noted spots where Perutz wrote about him. While most of these references were positive and focused on topics like Pauling’s influence on Watson and Crick and his breakthroughs on protein structure, one in particular was not. Perhaps less cryptic than the reference to Harker, Perutz described how “one great American chemist now believes that massive doses of vitamin C prolong the lives of cancer patients,” following it with “even more dangerous are physicians who believe in cancer cures.”

While critical, Perutz really meant the “great” in his comment and he continued to repeat it elsewhere. After Pauling passed away in August 1994, Perutz told his sister Lotte that “many feel that he [Pauling] was the greatest chemist of this century” while also being “instrumental in the protests that led to Kennedy and Macmillan’s conclusion of Atmospheric Test ban.”  He reiterated this idea in the paragraph that concluded his obituary of Pauling, published in the October 1994 issue of Structural Biology.

Pauling’s fundamental contributions to chemistry cover a tremendous range, and their influence on generations of young chemists was enormous.  In the years between 1930 and 1940 he helped to transform chemistry from a largely phenomenological subject to one based firmly on structure and quantum mechanical principles.  In later years the valence bond and resonance theories which formed the theoretical backbone of Paulings work were supplemented by R. S. Mullikens’ molecular orbital theory, which provided a deeper understanding of chemical bonding….Nevertheless resonance and hybridization have remained part of the everyday vocabulary of chemists and are still used, for example, to explain the planarity of the peptide bond.  Many of us regard Pauling as the greatest chemist of the century.

Pauling and Perutz in the Golden Age of Protein Research

Max Perutz, 1987. Image Credit: Graham Wood.

Max Perutz, 1987. Image Credit: Graham Wood.

[Part 3 of our series celebrating the Perutz centenary.]

In 1939 Max Perutz’s girlfriend gave him a book token for Christmas. Working on finishing his dissertation on the structure of hemoglobin, Perutz used that token to purchase Linus Pauling’s recently published text, The Nature of the Chemical Bond.

In the obituary of Pauling that he wrote some fifty-five years later, Perutz described how the “book transformed the chemical flatland of my earlier textbooks into a world of three-dimensional structures” and “fortified my belief, already inspired by J. D. Bernal, that knowledge of three-dimensional structure is all-important and that the functions of living cells will never be understood without knowing the structures of the large molecules composing them.”  The purchase of Pauling’s book marked the beginning of a long, fruitful and sometimes contentious correspondence between the two men, working on separate continents but united by similar interests.


Not until 1946 did Perutz first write to Pauling, asking for assistance as he labored through his research on the structure of hemoglobin. The Cavendish Laboratory, where Perutz was located, did not have the latest equipment that was available to Pauling at Caltech. In particular, Perutz needed a Hollerith punch-card machine to carry out calculations of the three-dimensional Patterson-Fourier synthesis. Perutz knew that Pauling’s lab was already conducting calculations of this sort and that the work Perutz was doing “would have to be done sooner or later, if the molecular structure of the proteins is to be worked out.”

As such, Perutz hoped that someone in Pauling’s lab might do the calculations for him. Pauling was not moved enough by Perutz’s request to offer the labor of his own team, replying that enlisting someone do such work in a “routine way” could lead to confusion. Pauling did offer that Perutz come to Pasadena, or send a surrogate to do the work, if he could find the money. Perutz was unable to support such an undertaking and so ended that conversation.

Linus Pauling and Lord Alexander R. Todd. Cambridge, England. 1948.

Two years later, in 1948, Pauling was in England, enjoying a stint as George Eastman Professor at Oxford. It was during this time that he and Perutz met for the first time in person. Perutz described his first experiences of Pauling’s lectures, in which

he would reel off the top of his head atomic radii, interatomic distances and bond energies with the gusto of an organist playing a Bach fugue; afterwards he would look around for applause, as I had seen Bertrand Russell do after quoting one of his eloquent metaphors.

The two also found time to talk together about their own particular research projects.

Pauling’s work at Oxford touched directly on Perutz’s own program, in what would become a oft-noted story in twentieth century history of science. As Pauling lay in bed with a cold, he did not stop working, choosing to spend his time making planar peptide models with paper chains. From his paper folding exercises, Pauling, according to Perutz’s obituary, “found a satisfactory structure by folding them into a helix with 3.6 residues per turn.” (A story that Pauling relayed many times himself.) The structure would come to be known as the alpha helix.

After Pauling recovered from his illness, Perutz showed him his own model of a polypeptide chain which was part of his larger hemoglobin model and was similar to fibers described by William Astbury. To Perutz’s “disappointment, Pauling made no comment,” and gave no hint as to his own breakthrough, which he announced the next year in a “dramatic lecture.”  That later unveiling of the alpha helix gave rise to a famous Perutz anecdote, which later informed the title of a book of essays that Perutz published.

When I saw the alpha-helix and saw what a beautiful, elegant structure it was, I was thunderstruck and was furious with myself for not having built this, but on the other hand, I wondered, was it really right?

So I cycled home for lunch and was so preoccupied with the turmoil in my mind that I didn’t respond to anything. Then I had an idea, so I cycled back to the lab. I realized that I had a horse hair in a drawer. I set it up on the X-ray camera and gave it a two hour exposure, then took the film to the dark room with my heart in my mouth, wondering what it showed, and when I developed it, there was the 1.5 angstrom reflection which I had predicted and which excluded all structures other than the alpha-helix.

So on Monday morning I stormed into my professor’s office, into [William Lawrence] Bragg’s office and showed him this, and Bragg said, ‘Whatever made you think of that?’ And I said, ‘Because I was so furious with myself for having missed that beautiful structure.’ To which Bragg replied coldly, ‘I wish I had made you angry earlier.’

 


Once Pauling returned to Pasadena, he and Perutz fell into a minor quarrel. In December 1950, Perutz had heard that Pauling had been “annoyed” by Perutz and John Murdoch Mitchison’s paper, “State of Hæmoglobin in Sickle-Cell Anæmia,” which had been published in Nature that October. Pauling was upset that Perutz and Mitchison had suggested that crystallization caused cells to sickle without properly citing his own seminal work on the subject.

In a December letter, Perutz said he was “very disappointed” that Pauling was upset with the publication, not only because there was a reference to Pauling, et al. in its introductory paragraph, but “particularly because all the new experimental evidence we report seemed to fit in so beautifully with the basic ideas set out in” Pauling’s co-authored Science article, “Sickle Cell Anemia, a Molecular Disease,” published in November 1949. Perutz explained his position in more detail, noting,

There is perhaps a slight difference between our points of view. Whereas you regard the sickling as being due to an aggregation and partial alignment of hæmoglobin molecules by a lock and key mechanism, an interlocking of specific groups in neighbouring molecules, we regard the cause of the sickling as being simply a crystallization, due to abnormally low solubility of the reduced hæmoglobin. No specific interaction of the kind you mention need be involved in the second process, though it obviously may be…I am sorry that this misunderstanding between us should have arisen, particularly as I have spent much effort trying to convert unbelievers to your scheme.

Pauling waited until the following February to respond and explained his feeling that readers of Perutz’s article might conclude that Perutz was making an original proposal. Having made this statement, Pauling, in his own way, moved beyond the quarrel by telling Perutz about his more recent work showing that “hemoglobin is not crystallized in the sickle cells, but is only converted to the nematic [or liquid crystal] state.” The ice broken, Perutz quickly responded by inviting Pauling to take part in informal discussions about protein structure at the Cavendish Laboratory before an annual conference, to be held in Stockholm. Pauling, however, could not attend.

The next year, Pauling attempted to visit England, this time to speak at a conference about the alpha helix, but was delayed due to his passport renewal being denied on account of his political activities. Perutz wrote that Pauling’s “absence had a sadly damping effect on our meeting at the Royal Society, and it made the discussion rather one sided as there was no none to answer the various objections to the α-helix raised by the Astburites and Courtlauld people” since Pauling’s supporters were unprepared to defend Pauling’s position without him. Perutz was also keen to show Pauling his own progress, an eagerness that Pauling reciprocated. By July Pauling had cleared up his passport problems and was able to spend time in person discussing his and Perutz’s work.


By 1953 Perutz and Pauling were quarrelling again over proper citation, though this time it was Perutz suggesting that Pauling had not given Francis Crick enough credit regarding the coiling of alpha helixes. Pauling explained to Perutz that, while he was at Cambridge the previous summer, he had talked with Crick and John Kendrew at length. During that conversation, according to Pauling,

There was only brief discussion of α keratin at this time, and, if my memory is correct, only a few sentences were said about the coiled coil, as Crick calls it. We discussed the fact that the 5.15-Å meridional reflection offers some difficulties of explanations, and that also there seemed to be a discrepancy in the density of α keratin. The discussion was very brief. Then Mr. Crick asked me if I had ever thought of the possibility that the α helixes were twisted about one another. I answered that I had. So far as I can remember, nothing more was said on this point.

Pauling went on to emphasize that “the idea was not a new one to me then” and that his own description of it in Nature was different from Crick’s understanding. Perutz ceded this point, adding that Pauling’s differences with Crick “stimulated Crick to clarify his own” ideas on the coiling of alpha helixes. More generally, Perutz found that the competition that arose between the two labs as they worked on similar problems helped to push each forward, thus leading to positive advances.

The famous group photo of the Pasadena Conference on the Structure of Proteins, September 1953. Pauling stands front row, third from left. Perutz stands two rows behind Pauling. [Image credit: The Archives, California Institute of Technology]

That September, Perutz made his first visit to California in order to deliver a paper at the Pasadena Conference on the Structure of Proteins, at which were gathered all of the world’s major figures in the field, including Jim Watson and Francis Crick, newly famous for their double helical structure of DNA. Perutz told his wife, Gisela, that his paper was “well received.” Additionally, with all of the different perspectives presented, there was “an atmosphere of soberness, and a realization that no-one’s solution of the protein problem was complete, and every approach was still fraught with complications.” Perutz was also quite taken with the Paulings’ home and their hospitality, pointing out that Ava Helen had invited him “after one of the meetings for a swim in their garden.”

Correspondence between Perutz and Pauling dipped a bit after the conference, though Pauling did take a moment to congratulate Perutz on being elected to the Royal Society the following Spring. While the exchange was brief, it reflected the long relationship built up between the two over the preceding years and, in particular, a confluence of work that had boosted the esteem of both scientists.

Perutz had begun looking at the structure of wool proteins back in 1951, thinking that there might be similarities to hemoglobin. He became excited after finding Pauling’s work on alpha helixes in fibers, thinking that the structure might be present in wool as well. His initial studies resulted in disappointment, but after adjusting the angle at which he was taking his x-rays by 30 degrees, he compiled new data that confirmed Pauling’s alpha helix structure. After applying it to his own work on hemoglobin, Perutz told Pauling “the discovery of this reflexion in haemoglobin has been the most thrilling discovery of my life…there is no doubt that it is a universal feature at least of all fibers of the α type. Whether all crystalline proteins show it remains to be seen.” Not suprisingly, Pauling was also “very pleased” with this discovery.

This research opened the door for Perutz to be considered by the Royal Society. But it was his development of a technique for determining a three-dimensional view of structures derived from x-ray crystallography that assured his election. He did this be attaching mercury atoms to hemoglobin, which allowed him to figure out where the crest and trough of a given x-ray was in relation to the structure that appeared on the photos. Perutz later said that after he finished the work and published it in Nature at the end of 1959, he went skiing in the Alps, and by the time he returned he was famous, assuring his fellowship in the Royal Society.

Perutz’s Hemoglobin Breakthroughs and Later Work

Perutz with his hemoglobin molecule, 1959. Image credit: Life Sciences Foundation.

Perutz with his hemoglobin molecule, 1959. Image credit: Life Sciences Foundation.

[Part II of our survey of the life of Max Perutz, this time focusing on the years 1941-2002. Published in commemoration of the Perutz centenary, May 2014.]

Knowing that his parents were safe from Nazi persecution and able to return to the United States, circumstances began improving for Max Perutz. The Rockefeller Foundation reactivated his grant, allowing him to support himself while stateside as well as his parents in Cambridge, England. Perutz’s father was also able to find work as a laser operator during the war and afterwards qualified for a pension.

In September 1941, Perutz met Gisela Peiser, who was an accountant at the Society for the Protection of Science and Learning, an organization that assisted Jewish and other academic refugees fleeing from the Nazis. After a quick courtship, they were married the following March and, in December 1944, welcomed their daughter Vivien into the world. That same year, Perutz also found himself back in good stead with the British government and recruited to research ice strength for potential ice stations in the North Atlantic. The research did not work out, so Perutz returned to his work on hemoglobin at Cambridge. The next few years were spent trying to put together a secure source of income for him and his growing family. In the interim, he took out more loans and found a temporary fellowship.

Meanwhile, Perutz’s health continued to suffer. As his chronic gastrointestinal attacks became more unbearable, interfering with his daily activities more and more, Perutz began to seek out help. Most doctors he saw told him it was a psychological problem, but eventually one doctor recognized that the symptoms could be treated by a mixture of atropine and codeine. The remedy helped enough for Perutz to live more or less undisturbed by the problem for several years, though eventually that would change.


Perutz and John Kendrew, 1962. Image credit: Nobel Foundation.

Perutz and John Kendrew, 1962. Image credit: Nobel Foundation.

In 1947, the war now completed, Perutz, along with John Kendrew, was appointed to head the new Research Unit for the Study of the Molecular Structure of Biological Systems (Perutz later shortened the unit’s name to Molecular Biology Research) at the recently established Medical Research Council. Situated at the Cavendish Laboratory in the physics department, the group expanded on Perutz’s earlier application of x-ray crystallography to biological materials. Perutz, in this new administrative role, described his lab management as one where he would “leave people free to do what they wanted…if they were good scientists.”

One of the several student researchers that came through the lab was Francis Crick, who started work in 1949. Perutz had Crick look at the validity of his hemoglobin model, which was the culmination of roughly six years of research. Crick applied his mathematical training to show that the model was “nonsense.” Perutz accepted Crick’s assessment and later reflected that only in England at that time could a student be so critical of their principal investigator. Crick was eventually drawn away from hemoglobin research by James Watson, who came to the lab in 1951 to work under Kendrew on molecular structure, but his impact on the development of Perutz’s hemoglobin structure was long-lived.

Throughout the late 1940s, Perutz also continued his work on glaciers in the Alps and helped found the Glacier Physics Committee in 1947. Though he had trouble recruiting able assistants who could also ski (the first two broke their legs), the work gave Perutz and his family the opportunity to spend summers in the mountains. Perutz’s research led him to conclude that glaciers flowed faster at the surface than at the bottom.

Perutz’s digestive attacks began increasing in intensity in the early 1950s to the point where, in 1954, he was hospitalized for ten days. While there, doctors looked for possible causes but came up empty and could only prescribe bismuth, with little effect. What did help, for reasons Perutz did not understand, was visiting the Alps, and so he arranged for a trip after being released from the hospital. Unfortunately the attacks resumed as soon as he returned to Cambridge, pushing Perutz to his limits – he considered resignation and even contemplated suicide. In desperate straits, he arranged for another trip to the Alps that spring but, once there, continued to get worse and, as an added complication, came down with scurvy.

When he returned, Perutz sought out other doctors who might be able to help, eventually visiting Werner Jacobson, who was also at Cambridge. Jacobson thought Perutz’s symptoms sounded like those of Celiac disease. He suggested that his patient stop eating wheat, or more specifically gluten, which immediately improved Perutz’s condition. Whenever the symptoms appeared again, as they did in the early 1960s, Perutz could trace them back to gluten; he eventually stopped eating any form of bread, since even gluten-free flour contained small amounts of gluten that negatively affected his health.


Perutz in lecture. Image credit: Nature.

Perutz in lecture. Image credit: Nature.

Perutz’s improved physical condition coincided with the final years of his triumphant work on a determination of the structure of hemoglobin. After working out a solution to interpret x-ray diffraction photos of proteins three-dimensionally, Perutz came upon the structure in September 1959, submitting his findings to Nature before heading to the Alps to ski over the winter break. By the time he returned, he was famous.  It was quickly and widely acknowledged that his work comprised a major breakthrough for both chemistry and biology.  As Hugh E. Huxley wrote, in 2002

He was the first person to find out how to determine protein structure by X-ray crystallography, after many years of patient struggle, and he applied the technique to solve the structure of haemoglobin, the oxygen-carrying protein in blood….The results showed that it was possible to see, in the atomic detail necessary to understand mechanisms, the structure of the macromolecules that carry out many of the functions of a living cell. Such knowledge is basic to the revolution that has swept through biology in the past 50 years, and to modern medicine and biotechnology.

By Fall 1962 there were rumors that Perutz would be awarded the Nobel Prize for chemistry. As October arrived, he began receiving calls from the press, but did not quite trust them. As the calls continued, Perutz received a telegram and thought, along with the rest of the lab, that it may be from the Nobel committee. Alas, the message was only from Nature asking how many reprints of his article Perutz wanted. That afternoon however, Perutz received another telegram, the one he had been waiting for. The lab celebrated with a champagne party as Perutz and Kendrew had been awarded the Nobel Prize for Chemistry, and Watson and Crick, along with Maurice Wilkins, would receive the Nobel Prize in Physiology and Medicine.

Perutz continued to work on the hemoglobin structure after his rise to fame, next turning to the question of how the structure changed with the uptake of oxygen. His Nobel lecture described this continued research on the four subunits within hemoglobin that changed their structure as oxygen was taken up; the first description of how proteins changed in structure.

In the years that followed, Perutz focused more on why this change occurred. Aided by automated x-ray diffraction machines and able assistants, Perutz’s lab was able to turn out more measurements than ever before. But the measurements, as Perutz later related, did not make any sense. After one of his research assistants completed his postdoc, Perutz looked closer at his results and realized that the new x-ray instruments had not been calibrated correctly.

In 1967, with all the bugs fixed, Perutz and his team put together the first atomic model of hemoglobin, but Perutz’s questions about why the structure changed still were not answered. By 1970, the lab was able to construct an oxygen-free model, allowing Perutz to compare it with the oxygenated model. As Perutz later described “there came this dramatic moment when between them, the models revealed the whole mechanism.” What he was able to see was how a slight movement of the iron atom triggered a change in the whole molecule. Thus, Perutz felt he was able to explain “all the physiological functions of hemoglobin on the basis of its structure.” The results were published in Nature.

Within the field, objections to Perutz’s explanation were numerous and he spent much of the next two decades refuting criticisms and refining his own explanation. At the same time, his celebrity also rose among scientists as he was increasingly invited to give lectures all over Europe and North America. By 1975 Perutz’s fame outside of scientific circles had grown such that Queen Elizabeth II invited him to visit with her at Buckingham Palace. Afterwards, Perutz expressed his regrets to the Queen’s secretary that “she had made me talk away like an excited little boy about my own doings and that I never asked her anything about hers.” Nonetheless, Perutz did hope that the Queen would enjoy his gift, the autobiography of Charlie Chaplin.


Max Perutz with his hemoglobin model. Image credit: BBC.

Max Perutz with his hemoglobin model. Image credit: BBC.

By 1980 Perutz had begun to reach out to broader audiences more intentionally. Shortly after retiring from the chair of the Laboratory of Molecular Biology, Perutz wrote a memoir of his time there. This, in turn, inspired him to compile an account of his experiences during World War II and submit it to the New Yorker. Penned in 1980 but not published until 1985, “Enemy Alien” helped bring Perutz greater levels of fame, as he received more letters after its publication than he did congratulations for his Nobel Prize.

An Italian pharmaceutical company also approached Perutz in 1980 to give a lecture on the social implications of molecular biology. According to a 2001 interview, Perutz told the company that “molecular biology has no social implications,” but that he could talk about “science as a whole.” This spurred him to take more of an interest in broader scientific questions, ultimately leading him to adopt controversial stances combatting criticism of the Green Revolution, DDT use and nuclear power, among other issues in the headlines. It also evolved into an interest in philosophy – Karl Popper’s Open Society and its Enemies proved particularly impactful. By 1989, Perutz expanded his popular lectures into a book of essays, Is Science Necessary? which included writings that he had also done for the New York Review of Books as well as “Enemy Alien.”

While continuing to write for the New York Review of Books up to the end of his life, Perutz also pursued new research on proteins and hemoglobin, taking a particular interest in neurodegenerative diseases like Parkinson’s and Alzheimer’s. In 2001, right before he passed away, Perutz was still at the lab seven to eight hours a day (including lunch and tea), preparing a publication for the Proceedings of the National Academy of Sciences on the common structure of insoluble protein deposits in neurodegenerative diseases. He passed away at the age of 87, unable to reconcile his initial structure with x-ray diffraction photos which showed contradicting features that Perutz concluded arose from three different structures. The results were published in 2002, after Perutz had died, in two separate articles.

Max Perutz (1914-2002)

Max Perutz. Credit: Theresianische Akademie Wien.

Max Perutz. Credit: Theresianische Akademie Wien.

[Ed Note: We mark the centenary of Max Perutz' birth today with the first in a series of posts on his life and his associations with Linus Pauling. Today's post focuses on his life from 1914-1941.]

Max Ferdinand Perutz was born May 19, 1914 in Vienna, the third child and second son of Hugo and Adele Perutz.  His birth came little more than a month before the assassination of Archduke Franz Ferdinand and the subsequent start of World War I. Vienna was largely untouched by the war, but suffered mightily from the economic depression that followed. The Perutzes, who had accumulated a substantial fortune from family textile concerns, lost their savings to the rapid postwar inflation. Nonetheless, according to biographer Georgina Ferry, the family managed to maintain an income and “within a few years of the war’s end, they were living as well as before.”

In a 2001 interview with Katherine Thompson for the British Library, Perutz said that he remembered little of these early years. He did recall being a “very delicate child,” contracting pneumonia three times before he was six and a very serious fever at age nine. Fortunately, he was able to recover from the fever after his nanny took him to a resort in the Alps for the winter. After World War II, chest x-rays revealed that Perutz had suffered from tuberculosis, the likely cause of his fever.

Perutz’s physical delicacy affected his social life as well; he described himself as a “weakling at school” who had no friends early on since he was sick so often. Because of his condition, Perutz did not excel at most sports. But his many holidays in the Alps led him to develop a lifelong love of rock climbing and skiing. These skills eventually earned Perutz the respect of his peers after he won a prize for the school skiing team.

Perutz attended private primary schools until entering the newly organized Realgymnasium, which brought a shift in focus from classics to modern languages and the sciences. Perutz described his early years of schooling as “eight years of unbearable boredom.” This boredom began to wane as Perutz gravitated toward English literature, an interest enabled by his Anglophile father who saw that he was tutored in English in addition to the more common French. Perutz secretly read Charles Dickens and other British novelists under the bench while at school, later furthering this passion with his first girlfriend, who was from England. Perutz’s parents expected him to take over the family textile business once he was old enough, and were heartened by his developing intellectual prowess.

However, the business route never appealed to Perutz, especially after he was exposed to chemistry by an influential teachers, and at eighteen he began formal pursuit of his interest in chemistry at the University of Vienna. (Protests from his parents were soothed by the help of a friend of Perutz’s older brother, a chemist at Dow.) As with his primary schooling, Perutz was not very impressed by the education that he received at university. He described the curriculum’s lack of mathematical training and decidedly practical emphasis as “chemistry done by heart” because of the reading and memorizing he was forced to do in lieu of actual laboratory work. But ultimately he made it through and, in the process, cultivated a new attraction to physics which he would later fulfill as a graduate student in England.


Portrait of Perutz drawn by William Lawrence Bragg. Credit: MRC Laboratory of Molecular Biology

Portrait of Perutz drawn by William Lawrence Bragg. Credit: MRC Laboratory of Molecular Biology

From Vienna, Perutz moved on to Cambridge, where he hoped to work with Frederick Gowland Hopkins, the university’s first chair of biochemistry and recipient of the 1929 Nobel Prize in Physiology for his work on the relation between vitamins and growth. Since Perutz showed up without letting anyone know, he did not find out that he could not work with Hopkins until he actually arrived. Chastened, Perutz looked elsewhere and ended up in the Cavendish Laboratory of Physics doing x-ray crystallography. “Without knowing it,” Perutz later recalled, this “was one of the best things I could have done.”  Supported by £500 sent by his father, Perutz settled in and was able to take care of his own finances for the duration of his doctoral studies.  His health continued to suffer though – once in England, he began to experience frequent and painful digestive problems.

The first project that interested Perutz was identifying radioactive deposits dug out from the cliffs in Cornwall. Perutz measured the half-life of the material, but found that it did not correspond to any known elements. Excited that he may have discovered a new element, Perutz shared his findings with Cambridge luminaries Ernest Rutherford and J. D. Bernal, who helped him to determine that the substance was, in fact, radium. Bernal also encouraged Perutz to publish his findings and to present them at a Royal Society soiree. This led to his first publication, “The Iron-Rhodonite from Slag,” which appeared in Mineralogy Magazine in 1937.

At the end of his first year at Cambridge, Perutz spent his summer holiday back in Austria and thought about what he might do for his doctoral dissertation. Felix Haurowitz, then at Charles University in Prague, suggested focusing on hemoglobin, telling Perutz that he could get crystallized hemoglobin from Gilbert Smithson Adair at Cambridge. When he returned and acquired the hemoglobin, Perutz says he “immediately got a lovely x-ray diffraction picture,” which “thrilled” Bernal.

In the midst of his hemoglobin research, Perutz also agreed to assist a man who came to the Cavendish Laboratory looking for researchers to satisfy his own interest in glacier development. Perutz saw this as a perfect opportunity to spend more time skiing in the Alps. He published his work in the Proceedings of the Royal Society in 1939, describing how melting and the movement of water contributed to glacier formation and flow.

In March 1940, Perutz wrapped up his Ph.D., which described the structure of hemoglobin and the x-ray methods used to develop the model. Yet the looming threat and subsequent reality of war overshadowed his findings and began to color components of his world that were much more important than his research.


Credit: National Portrait Gallery, London.

Credit: National Portrait Gallery, London.

As World War II approached, the Perutz family, still in Vienna, looked for ways to get out. The Perutzes were ethnic Jews, but Max’s parents were non-observant and Perutz himself had been baptized Catholic. As a young boy, Perutz was very devout, a character trait that he abandoned after his prayers that the Italians not invade Ethiopia were not answered. While his baptism was meant to protect him from anti-Semitism, he claimed that his family “very rarely” experienced discrimination before the Anschluss. Once the Nazis assumed power, the Perutz family quickly left with Max’s brother and sister going to the United States and his parents coming to stay in Cambridge. Hugo and Adele Perutz, used to supporting themselves, lost their businesses and spent all their money leaving Vienna – according to their son, they “were traumatized by suddenly being poor.”

To get them to England, Max both had to prove that he could support them and was also required to pay a thousand pounds, compelling him to sell some of his mother’s jewelry and to borrow funds to cover the rest. Around this time, William Lawrence Bragg, winner of the 1915 Nobel Prize in Physics, came to the Cavendish. Bragg was very excited about Perutz’s work with hemoglobin and helped him to secure a grant with the Rockefeller Foundation in New York. The grant provided £275 per year, enough for Perutz to prove that he could support his parents. But soon the family would come into even more trouble.

In May 1940, just two months after he finished his Ph.D., Perutz was interned by the British government. He was first taken and held in a school at Bury St. Edmunds, east of Cambridge, for one week before being transported to Liverpool. By July, Perutz, along with roughly twelve-hundred others, was shipped across the Atlantic to a camp near Quebec City, Canada, where the residents’ status was upgraded from “internee” to “civilian prisoner of war,” a change that promised access to clothing and army rations. In a 1985 essay for the New Yorker, titled “Enemy Alien,” Perutz wrote,

To have been arrested, interned, and deported as an enemy alien by the English, whom I had regarded as my friends, made me more bitter than to have lost freedom itself. Having first been rejected as a Jew by my native Austria, which I loved, I now found myself rejected as a German by my adopted country.

Perutz’s friends were working on his behalf to have him released, unknown to him since he could receive no communications.

Meanwhile, in Quebec, Perutz tried to make the best of things and organized a “camp university.” Hermann Bondi, a mathematician also from Vienna, taught on vector analysis, while Klaus Fuchs, a student at Bristol who fled Hitler’s persecution for being a communist, taught theoretical physics. For his part, Perutz drew on past research of his own, explaining the atomic structure of crystals to all who might be interested.

The Rockefeller Foundation did not forget about Perutz and arranged a professorship for him at the New School for Social Research in New York City. Hearing rumors that his father had also been interned and worried that he would not be able to obtain a visa to travel once he had been established in the United States, Perutz was eager to go back to England to check on his parents. After several delays and transfers, Perutz arrived back in Cambridge in January 1941, finding his father already released and his friends happy to see him.

The Decline of Orthomolecular Psychiatry

Abram Hoffer and Linus Pauling at the symposium, "Adjuvant Nutrition in Cancer Treatment," Tulsa, Oklahoma, November 1992.

Abram Hoffer and Linus Pauling at the symposium, “Adjuvant Nutrition in Cancer Treatment,” Tulsa, Oklahoma, November 1992.

We have written before on both the orthomolecular psychiatry of Linus Pauling and the birth of orthomolecular medicine, which has its roots in nutritional (later called orthomolecular) psychiatry. This post delves further into how orthomolecular psychiatry came to be, as well as its marginalization out of the scientific mainstream.

It all began with Albert Hofmann, the Swiss scientist who, in 1938, famously synthesized LSD and discovered its psychedelic properties. After several trials, some on himself, Hofmann developed the hypothesis that LSD mimics the effects of psychosis.

Hofmann’s idea inspired two English psychiatrists, Dr. Humphry Osmond and Dr. John Smythies, to further his research in the late 1940s. Using mescaline (derived from the peyote cactus) as their basic compound, the duo took Hofmann’s work a step further, eventually conjecturing that schizophrenics suffered from an overdose of an endogenous (made in the body) toxin that was similar in structure to mescaline and LSD.

Finding no sympathy in England – at the dominated by Freudian thought – Osmond and Smythies took their work to Saskatchewan, Canada, relocating there in late 1951. Once in Canada, Osmond met Abram Hoffer, a fellow psychiatrist with whom he would collaborate for decades. Together, Hoffer and Osmond ran the psychiatric sciences and therapies divisions of the psychiatric hospital in Weyburn, Saskatchewan, which housed a number of schizophrenic patients.

Hoffer and Osmond eventually discovered the toxin that Osmond and Smythies had suspected was causing the psychoses present in schizophrenics: adrenochrome, a byproduct of the body’s metabolic oxidization of adrenaline and noradrenaline. The next step in helping their patients, the doctors felt, was to find some way to alleviate the psychoses brought about by schizophrenia. This led them to nicotinic acid, also known as vitamin B3 or niacin. Niacin, they learned, was known anecdotally to help patients with neuropsychiatric disorders. This fit with the fact that pellagra, a disease caused by a deficiency of niacin, sometimes presents with psychiatric symptoms.

Eager to test their theory that vitamin B3 could help alleviate mental disease, Hoffer and Osmond began experimentation, dosing their schizophrenic patients with large amounts of niacin by adding it to their daily diets in the first double-blind tests performed in psychiatry. Once the experimentation was finished, Hoffer and Osmond followed their patients for ten years, measuring the effectiveness of their added-vitamin therapy in terms of readmission rates and ability to find outside employment once released from the hospital.

In 1962 Hoffer and Osmond published the book Niacin Therapy in Psychiatry, the text that introduced Linus Pauling to the duo’s megavitamin work. The book revivified his interest in the biochemical basis of mental illness, which he had been studying for a decade, having previously learned that phenylketonuria is a molecular disease in much the same way as sickle-cell anemia.

By the time Pauling read the niacin book, anecdotes about megavitamin therapy, as it was then called, had begun to spread. Additionally, it had already been discovered that niacin could lower cholesterol levels. When added to his prior knowledge, these facts led Pauling to find the evidence presented in the book compelling enough to merit further investigation. The final ingredient to Pauling’s interest appeared the next year, when Dr. Irwin Stone introduced Pauling to the potential health benefits of large doses of Vitamin C. .

It wasn’t until 1967 that Pauling coined the term “orthomolecular,” using it in print for the first time in a paper titled “Orthomolecular Methods in Medicine.” In 1968 Pauling wrote his more famous paper on the subject, “Orthomolecular Psychiatry,” published in the journal Science. Pauling, of course, went on to found the Institute of Orthomolecular Medicine with Art Robinson in 1973, (soon after renamed the Linus Pauling Institute of Science and Medicine) and co-edit the book Orthomolecular Psychiatry: Treatment of Schizophrenia in the same year. Around this time, Pauling also began broadening his theory of orthomolecular medicine to include the whole body, not just the mind.


But what happened to Hoffer and Osmond? The answer to this question plays a part in understanding why many doctors today still refuse to consider orthomolecular medicine a legitimate form of treatment.

In 1967 Hoffer and Osmond formed both the Canadian Schizophrenia Foundation and the American Schizophrenia Association. The two doctors had recently been encountering a great deal of resistance to the publication of their ideas, so they started their own journal, the Journal of Schizophrenia, in the same year. They asked Pauling to serve on the editorial board; Pauling agreed, participating in that capacity for the rest of his professional life.

In 1973 orthomolecular psychiatry was dealt a serious blow by the American Psychological Association Task Force. That year, the group published a report titled “Megavitamin and Orthomolecular Therapy in Psychiatry,” condemning the practice as unsupported at best and “deplorable” at worst. Hoffer and Osmond were subjected to humiliation and orthomolecular psychiatry was deemed unworthy of study or application. The following year, Pauling responded to the report, pointing out a number of flaws, including errors in methodology, lack of research, confusion of focus, and bias:

Orthomolecular psychiatry is the achievement and preservation of good mental health by the provision of the optimum molecular environment for the mind, especially the optimum concentrations of substances normally present in the human body, such as the vitamins….The APA task force report Megavitamin and Orthomolecular Therapy in Psychiatry discusses vitamins in a very limited way (niacin only) and deals with only one or two aspects of the theory. Its arguments are in part faulty and its conclusions unjustified.

But Pauling, Hoffer, and Osmond’s expressions of outrage at perceived mistreatment by the APA weren’t enough to overcome further obstacles that lay ahead. For one, in the mid-1970s, orthomolecular psychiatry, rather than sticking to megavitamin doses, expanded to include diet in the treatment of mental health, as well as avoiding stimulants like nicotine. However, no consensus was reached within the community with regard to precise standards for the practice, so recommendations varied from doctor to doctor, making the efficacy of orthomolecular psychiatry difficult to evaluate.

The mainstream introduction of tranquilizers and the phasing out of electroconvulsive therapy in the treatment of mental illness also proved a barrier to the orthomolecular community. Tranquilizers, unlike megavitamins, were immediately successful in alleviating symptoms, making orthomolecular medicine, which took time to work, appear ineffective by comparison.

Eventually, whenever a patient would ask about megavitamin or orthomolecular therapy as an alternative treatment, many doctors would simply cite the APA report, claiming that it had disproven orthomolecular methods. After a while, most patients simply stopped asking.

The American Schizophrenia Association eventually became the Huxley Institute for Biosocial Research, still led by Abram Hoffer. Dr. Hoffer asked Pauling to serve on its board of directors but Pauling declined, by then more interested in pursuing Vitamin C in the treatment of cancer and colds.  The flagging in his energy for the discipline of orthomolecular psychiatry was indicative of the lack of momentum within the field, a situation that persisted for the remainder of Pauling’s life.

Humphry Osmond, the Original Psychedelic Psychiatrist

Humphry Osmond (front row seated, far left), with the Paulings and others at a gathering in Tulsa, Oklahoma. June 1972.

Humphry Osmond (front row seated, far left), with the Paulings and others at a gathering in Tulsa, Oklahoma. April 1972.

Dr. Humphry Fortescue Osmond, while never a direct collaborator of Linus Pauling’s, was nonetheless a professional influence in his life and a friend. Alongside Dr. Abram Hoffer, Osmond helped to establish orthomolecular psychiatry, the precursor to the larger body of work on orthomolecular medicine that consumed Pauling for close to three decades. Later in life, Pauling and Osmond wrote numerous letters back and forth, in which Osmond often shared interesting articles on the uses of vitamin C, schizophrenia, nutrition, and orthomolecular medicine.

Osmond is famous to both the medical community and to the public for related, yet separate reasons. In the field of medicine, Osmond, along with Abram Hoffer, is best known for his work in orthomolecular psychiatry. Working together, the two doctors performed extensive studies on schizophrenic patients in psychiatric hospitals in Saskatchewan, Canada, using niacin (vitamin B3) and ascorbic acid (vitamin C) as potential cures for the disease. Osmond is also known for his work with lysergic acid diethylamide, or LSD, in the treatment of alcoholism and as a way for psychiatrists and psychologists to experience something approximating what he believed to be the state that schizophrenics experience as they struggle with their illnesses.

To the public however, Humphry Osmond will forever be known as the man who coined the term “psychedelic” and the man who “turned on,” in the words of the famous LSD advocate Timothy Leary, acclaimed British author Aldous Huxley, a man with whom he developed a close friendship. In the early 1950s, Huxley approached Osmond after reading an article on his research with mescaline; Huxley expressed a desire for Osmond to run a human trial of the drug with Huxley as subject. Osmond wasn’t fond of the proposal, not relishing “the possibility, however remote, of finding a small but discreditable niche in literary history as the man who drove Aldous Huxley mad.” Despite his misgivings, Osmond dosed Huxley with 400 mg of mescaline in 1953.  The result was recorded in Huxley’s cult hit The Doors of Perception (1954), a book that both takes its name from William Blake’s poem “The Marriage of Heaven and Hell” and inspired the name of the legendary 1960s rock band, The Doors.

Later, when discussing his flight of hallucinogenic fancy, Huxley, writing to Osmond, penned this bit of verse:

To make this mundane world sublime, / take half a gram of phanerothyme.

The word phanerothyme, cobbled together from the Greek, translates roughly to “manifest spirit.”

In response Osmond wrote some poetry of his own, in the process coining a term that soon spread around the world:

To fathom Hell or soar Angelic, / just take a pinch of psychedelic.

Psychedelic – again from Greek etymology – translates to “mind-manifesting.” By 1957 Osmond had introduced the word to the medical community as a way to describe the euphoric, perception-altering, mind-expanding effects of hallucinogenic drugs like LSD, mescaline, DMT, and psilocybin. Previously the only well-known description of this concept was “psychotomimetic,” a mimicry of the symptoms of psychosis.


Humphry Osmond was born in July 1917 in Surrey, England, gaining his primary and secondary education from Haileybury, a long-established boarding school in Hertfordshire. After Haileybury, Osmond earned his medical degree from Guy’s Hospital Medical School, London, in 1942, and from there joined the Royal Navy, commissioning as a surgeon-lieutenant and training to be a ship’s psychiatrist.

After the Second World War concluded in 1945, Osmond returned home and accepted a position as a resident psychiatrist at St. George’s Hospital, Tooting. It was here that he met his future wife, Amy “Jane” Roffey, and his first major research partner, Dr. John Smythies. Together, Smythies and Osmond performed a number of studies in the late 1940s on the chemical composition and effects of the drug mescaline – a hallucinogenic derived from the peyote cactus – having been inspired by the work of Albert Hofmann, who had discovered the hallucinogenic properties of LSD a decade prior.

From their research, Smythies and Osmond hypothesized that because the experience of subjects on mescaline seemingly mimicked the symptoms of schizophrenia, and that because mescaline is structurally related to adrenaline, it could be possible that schizophrenics were over-producing a chemical related to both mescaline and adrenaline. They called this hypothesis, fittingly, the “M-hypothesis.” The idea, when presented to the British psychiatric medical community – which at the time was dominated by Freudian thinking – was not well received. Feeling isolated in the UK, in 1951 Humphry and Jane Osmond, along with John Smythies, immigrated to Canada, where Osmond had been offered a job as the clinical director of the psychiatric hospital in Weyburn, Saskatchewan.

"How to Live with Schizophrenia," by Abram Hoffer and Humphry Osmond, 1966.

“How to Live with Schizophrenia,” by Abram Hoffer and Humphry Osmond, 1966.

It was at Weyburn that Osmond met Dr. Abram Hoffer, director of psychiatry at the hospital, with whom Osmond would collaborate for the next decade. Working together with the patients at Weyburn and at neighboring hospitals, Osmond and Hoffer developed what became known as the “Hoffer-Osmond Adrenochrome-Hypothesis.” Using the M-hypothesis as their basis, Osmond and Hoffer claimed that it was adrenochrome, a byproduct of adrenaline that is structurally similar to mescaline and other hallucinogens, that schizophrenics were overproducing.  In theory, schizophrenics were suffering from their disease either as a result of their bodies producing too much adrenochrome or through an inability to properly metabolize adrenaline.

Working from this hypothesis, Osmond and Hoffer next searched for a way to reduce the overproduction of adrenochrome, hoping to find a cure for schizophrenia as well as additional evidence for their idea. Learning that niacin might limit the production of adrenaline, they decided to dose their schizophrenic patients with “megavitamin” amounts of B3, adding it to their diets in the first double-blind studies ever conducted in the field of psychiatry. The results were encouraging: according to their studies, the recovery rate for the schizophrenics that they treated over the next few years doubled from 35% to 75%.

In addition, the Osmond and Hoffer studies provided data that added to the finding that niacin could reduce cholesterol, a result that was replicated and confirmed by the Mayo Clinic in 1956. This finding is now globally accepted and niacin is presently used in the treatment of high cholesterol all over the world.


An example of Hoffer's "memos," October 1976.

An example of Hoffer’s “memos,” October 1976.

In 1967 Linus Pauling – who had learned of Hoffer’s work on niacin two years before – read the Osmond and Hoffer studies and, finding the subject interesting enough to pursue further, wrote to the duo asking for more information.  The data that he received was eventually included by Pauling alongside his own theories in his seminal paper, “Orthomolecular Psychiatry” (published in Science in 1968) as well as in the book that he co-edited with Dr. David Hawkins, Orthomolecular Psychiatry: Treatment of Schizophrenia (1973). Over time, Pauling expanded his orthomolecular theory from the study of the mind to include the whole body, thus creating the field of orthomolecular medicine.

This initial contact between Drs. Pauling and Osmond led to a nearly thirty-year correspondence between the two men, with Osmond regularly sending to Pauling selected copies of his “memos” – commentaries in which Osmond would paste a news article onto the left side of a sheet of blank paper, then cover the right side and the back with prodigious, elegant essays on the context, significance, and meaning of the article. (These memos were collected into a book, Predicting the Past, and published in 1981). Osmond made special effort to forward to Pauling those memos concerning ways in which orthomolecular medicine was being used around the world as well as any material on mental illnesses.

Exchanges between the two men were often personal as well as professional. For example, after learning of Ava Helen Pauling’s trouble with cataracts, Osmond sent Dr. Pauling any information that he could find on the ocular malady, of which Osmond was also a sufferer. Osmond also wrote letters filled with his thoughts on Pauling’s activism and increasing celebrity, including a letter in which he agreed with Pauling’s negative assessment of physicist Edward Teller, a major advocate for U.S. nuclear armament and the hydrogen bomb, as well as a letter congratulating Pauling on his 1977 appearance on NOVA.


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In 1961 Osmond was appointed Director of the Bureau of Research in Neurology and Psychiatry at Princeton University. While there, he continued his research into schizophrenia as a physical illness. In 1970, hallucinogenic drugs like mescaline, LSD, and DMT were declared controlled substances, and studies on the effects of these drugs on psychiatric patients was curtailed.

In 1971 Osmond resigned his position at Princeton and moved to Alabama, where he taught at the University of Alabama, Birmingham as a professor of psychiatry. He worked there alongside his old friend, John Smythies. Osmond also consulted at Bryce Hospital in Tuscaloosa, the oldest and largest in-patient psychiatric hospital in Alabama. He retired from the university and the hospital in 1992. A decade later, by then an octogenarian, Osmond granted an interview for a documentary on the history of LSD, titled “Hofmann’s Potion.” Not long after, in February 2004, Osmond died of natural causes at his daughter’s home in Appleton, Wisconsin. Abram Hoffer wrote an obituary on the event of Osmond’s passing, which was featured in the British newspaper, The Guardian.

Some of Humphry Osmond’s more well-known books include The Chemical Basis of Clinical Psychiatry (with Abram Hoffer, 1960); How to Live with Schizophrenia (with Hoffer, 1966); Psychedelics: The Uses and Implications of Hallucinogenic Drugs (with Bernard Aaronson, 1970); and Models of Madness, Models of Medicine (with Miriam Siegler, 1974). A complete bibliography of his works can be found here.

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