The Fate of Oxypolygelatin

An original container of 5% Oxypolygelatin in normal saline. 1940s.

During World War II, Linus Pauling, along with Dan H. Campbell and Joseph B. Koepfli, created a blood plasma substitute which they dubbed “oxypolygelatin.” This new compound seemed to be an acceptable substitute for human blood, but needed more testing to be approved by the Plasma Substitute Committee. Unfortunately when Pauling asked for additional funds to carry out more testing in 1945, he was denied by the Committee on Medical Research, which had been funding research up until that point.

By the time Pauling received more funding the war had almost come to a close, and it ended before oxypolygelatin got off the ground as an acceptable blood substitute. Likewise, the need for artificial blood was less pressing after the conclusion of the war. More information on the creation and manufacture of oxypolygelatin can be found in our blog posts “Blood and War: The Development of Oxypolygelatin, Part 1,” and “Pauling on the Homefront: The Development of Oxypolygelatin, Part 2.” Today’s post will focus on the patenting, ownership and uses of oxypolygelatin after World War II.

Pauling seemingly gave up on the project after 1946, mostly because widespread blood drives organized by the Red Cross and other organizations lessened the demand for artificial blood. In 1946 Pauling, Campbell and Koepfli decided to file for a patent on oxypolygelatin and its manufacturing process, which they then transferred to the California Institute Research Foundation with the stipulation that one of the inventors would be consulted before entering into any license agreement. They also noted that the Institute should collect reasonable royalties for the use of the invention, but only so much as was needed to protect the integrity of the invention.

The “Blood Substitute and Method of Manufacture” patent was filed December 4, 1946, and the Trustees of the Institute agreed to take on ownership of oxypolygelatin and the patent application in early 1947.

Notes by Linus Pauling on a method for producing oxypolygelatin. July 23, 1943.

Although it would appear that Pauling gave up on the oxypolygelatin project with the transfer of ownership, he still pushed for its manufacture years later. In October 1951, he wrote to Dr. I. S. Ravdin of the Department of Surgery at the University of Pennsylvania Medical School to inform him that oxypolygelatin was not being considered seriously enough by the medical world as a blood substitute.

Pauling insisted, “…that it is my own opinion that Oxypolygelatin is superior to any other plasma extender now known.” He likewise noted that it was the only plasma extender to which the government possessed an irrevocable, royalty-free license, so he could not understand why it was not being stockpiled and utilized.

As far as Pauling knew, only Don Baxter, Inc., of Glendale, California, was manufacturing oxypolygelatin. At this point the rights to oxypolygelatin were owned by the California Institute Research Foundation, not Pauling, and the Institute was not authorized to make a profit from it. Consequently, Pauling’s insistence on the production and usage of his invention can only be explained by a concern for humanity, coupled perhaps with an urge to see the compound succeed on a grander scale.

Later in 1951, Pauling continued to push for the usage of his invention, arguing in a February letter to Dr. E.C. Kleiderer that oxypolygelatin was superior to the plasma substitutes periston and dextran. In Pauling’s opinion “the fate of periston and dextran in the human body is uncertain…these substances may produce serious injuries to the organs, sometime after their injection.”

Oxypolygelatin, on the other hand, was rapidly hydrolyzed into the bloodstream and would not cause long-term damage. It was also a liquid at room temperature, unlike other gelatins, and was sterilized with hydrogen peroxide to kill any pyrogens (fever-inducing substances) while many other gelatin preparations failed because of pyrogenicity. One of the only problems with oxypolygelatin was that the chemical action of glyoxal and hydrogen peroxide could potentially produce undesirable materials, but the matter could be cleared up with further investigation.

It appears that Pauling’s interactions with Ravdin and Kleiderer did not result in the mass manufacture or marketing success of oxypolygelatin, but this did not deter Pauling from pursuing the matter many years later. In 1974, after visiting Dr. Ma Hai-teh in Peking, China, he sent Ma his published paper on oxypolygelatin, and discussed the possible production of the substance in China. He wrote to Ma, “I hope that you can interest the biochemists and pharmacologists in investigating Oxypolygelatin. I may point out that no special apparatus or equipment is needed.”

In reply, Ma expressed interest in oxypolygelatin and said that he had passed Pauling’s paper on to a group of biochemists, but that he was personally more interested in Pauling’s work on vitamin C. The rest of their correspondence focused primarily on the benefits of vitamin C, especially in the treatment of psoriasis.

In a 1991 interview with Thomas Hager, author of the Pauling biography Force of Nature, Pauling claimed, “I patented, with a couple of other people in the laboratory, the oxypolygelatin. I don’t remember when I had the idea of making oxypolygelatin. Perhaps in 1940 or thereabouts.” He added that it was not approved by the Plasma Substitute Committee, so it was not usable for humans, but was manufactured instead for veterinary use.

At the time of the interview, Pauling believed that oxypolygelatin was still being manufactured in some places, but was unsure of the details since there were many rumors floating around. According to him, the Committee on Plasma Substitutes did not approve his oxypolygelatin because it wasn’t homogenous; meaning that, on the molecular level, it included a range of weights. Pauling, however, believed that the range in molecular weights should not matter, since naturally occurring blood plasma includes serum albumin and serum globulin, whose molecular weights fall in a wide range anyway.

Joseph Koepfli

In 1992 Hager also interviewed Joseph Koepfli, one of the co-inventors of oxypolygelatin. Koepfli claimed that oxypolygelatin was at one time used by motorcycle officers around L.A. because they were the first to the scene of accidents. He also remembered that, in the early 1980s, Pauling had told him that oxypolygelatin was used for years in North Korea, but that no one was ever paid any royalties.

These and a few other rumors about oxypolygelatin circulated, but evaluating their worth is virtually impossible due to the secrecy surrounding wartime scientific work, as well as the scarcity and ambiguity of the surviving documentation. Judging from Pauling’s opinions though, what can be said is that perhaps if it had been pursued more vigorously, oxypolygelatin could have benefited the war effort and proven successful on a commercial level.

Travels in China, 1973

Ava Helen and Linus Pauling at the Great Wall of China, 1973.

In March 1973, little more than one year after Richard Nixon’s historic visit, Linus Pauling received a letter inviting him to travel to China for three weeks in the coming summer. He was invited by Wu Yu-hsun, Vice President of the Scientific and Technical Association of the People’s Republic of China, who informed Pauling that his accommodation and transportation would be provided by the Association. “It is my belief that your visit will contribute to the promotion of the traditional friendship and scientific exchanges between the scholars of China and America,” Wu wrote.

Following Wu’s instructions for obtaining a visa, Pauling wrote to the Embassy of the Chinese People’s Republic in Ottawa, Canada, on April 4, requesting visas for him and Ava Helen. (At that time, there was no Chinese embassy in the United States as diplomatic relations between the two countries had not yet been formalized.) Two months later, he received a reply from the embassy, accompanied by applications for the two visas.  On August 8 Pauling wrote to Vice President Wu to let him know that the trip details had been finalized and informing him that he and Ava Helen would arrive in Hong Kong on Sunday, September 16, and leave Monday, October 8.

In his letter, Pauling mentioned his book Vitamin C and the Common Cold, stating his belief that vitamin C not only decreases the severity and instances of the common cold, but does the same for other diseases. As such, he expressed a desire for both himself and Ava Helen to engage with relevant Chinese medical authorities and members of the Ministry of Public Health about this matter. Pauling also communicated his interest in talking with physicians and scientists about Oxypolygelatin, a blood plasma substitute that he had developed during World War II, as well as his desire that he and Ava Helen see his former student, Chia-si Lu, a chemist and crystallographer, and also their friend Professor Tsien, an authority on rockets whom they knew from Caltech. On August 9, Pauling returned the visa applications along with a letter stating that “I do not travel without my wife, and I have assumed that the invitation includes her also.”

After finally receiving their visas, the Paulings departed San Francisco for Hong Kong on Friday, September 14, 1973. They spent that night in Honolulu, and arrived in Hong Kong on Sunday, September 16.

Much of what we know now about the Paulings’ visit to China comes from Linus’ travel log.  The log is very detail-oriented – so much so that one wonders how much detail is owed to Pauling’s insatiable scientific appetite, and how much to his knowledge that the U. S. government was historically suspicious of his every move, and likely maintained a particular interest in his activities while traveling through communist China.

The Paulings arrived in Hong Kong on Sunday night, stayed an extra day, and went by train to Canton on Tuesday. They spent Tuesday night at a guest house in Canton, where Pauling noted that it was “very hot during the day, very humid, and humid and hot during the night, too.” After visiting Sun Yat Sen University and having lunch, the couple flew to Shanghai, where Pauling judged the humidity to be less oppressive. They visited the Shanghai Industrial Exhibition on the morning of September 20, and the Institute of Biochemistry in the afternoon. In his travel log, Pauling recorded the details of research being conducted by an Institute staff member who was working on nucleotides and nucleosides. One investigation in particular focused on the effectiveness of nucleotides in increasing the yields of different plants such as rice. Pauling also spoke with Mr. Kung who, in 1965. was among the first scientists to synthesize insulin, and a man named Lee, who was conducting work on liver cancer.

Pauling was particularly interested in a screening of 150,000 people in Shanghai that was described to him by Mr. Lee. In the screening, 158 people were found to have an embryonic globulin in their blood which is manufactured in large amounts by people who have liver cancer. All of these 158 subjects either already had cancer or developed it later. Pauling suggested that the people who tested positive for this embryonic globulin be given 10 g of vitamin C per day, in an effort to stave off further development of the cancer.

While in Shanghai, the Paulings frequently saw members of the Philadelphia Philharmonic at mealtimes, since they were staying at the same hotel. Pauling noted that he and Ava Helen had tickets to hear the orchestra on September 21. But before that, in the morning, he visited the Peking Institute of Organic Chemistry of the Academia Sinica, where he saw the laboratories and learned about the Institute’s work on steroids. Meanwhile Ava Helen went shopping and visited the zoo, where, Pauling’s record shows, she saw “three giant pandas and several small ones.”

In the afternoon, the Paulings toured a commune. This commune was likely one of many established by Mao Zedong in the late 1950s with the aim of turning China into an industrialized nation. At the commune, Pauling took note of the work and lifestyle of its 24,000 inhabitants, who mostly made tools or did farm work.

Ava Helen and Linus Pauling with hospital staff members, Shanghai, China. 1973.

On Saturday, September 22, Linus and Ava Helen visited the Shanghai Institute of Pharmacology and later the Shanghai Psychiatric Hospital, where they observed a wide array of treatments being given to patients, including acupuncture. Pauling presented the director of the hospital with a copy of his book Orthomolecular Psychiatry, and discussed megavitamin therapy with the hospital’s staff. Afterwards the Paulings watched an acrobatics performance, and the next day they continued to enjoy China’s culture by visiting the Children’s Palace and the Palace of History.

When the Paulings went on a sightseeing tour down to the banks of the Hwang-ho with Chia-si Lu, Pauling’s former Caltech student, Chia-si told them of the hardship that had existed before China’s “liberation.” By liberation, Pauling’s student was referring to the Chinese Revolution in which Mao Zedong and his supporters took over China’s government and installed communist rule in 1949. According to Chia-si, who had been in the U.S. for five years during the 1940s, only about ten percent of the money that he periodically sent home to his wife and son would actually reach them; the rest was taken by the Bank of China, which, according to Chia-si, was the bank of T.V. Soong at the time. For a few years Chia-si’s wife and son were close to starvation, along with many other people in China. However, after the revolution, the new Maoist government controlled the price and distribution of food and, in Chia-si’s estimation, the quality of life improved. (It is important to note that this perspective is contrary to other more contemporary analyses of Chinese food security under Mao.)

Although a few days are excluded from his travel log, Pauling wrote notes in his diary about activities related to hemoglobin and orthomolecular medicine on September 24, and a trip by train to Hangchow that evening, where he and Ava Helen did some sightseeing. Their tourism included the Ling Yin Temple, the Tiger Spring, the Jade Fountain, a tea ceremony, a boat ride on West Lake and a visit to a brocade factory. They attended another in a long string of banquets, and saw the Dragon Well Spring before leaving by train.

Pauling next wrote in his journal on Friday, September 28, to record his and Ava Helen’s tour of a petroleum refinery. The day before, on Thursday, they had visited the big bridge across the Yangtze, after which Pauling gave a lecture on vitamin C and good health at Nanking University. On Thursday night, the Paulings went to a dancing and singing performance staged by children of the district of Nanking. That weekend, the Paulings attended the National Day banquet in Beijing in the dining room of the Hall of Ten Thousand, to which 1,000 guests were invited by the Minister of Foreign Affairs. Before the banquet, the Paulings had visited the Forbidden City once in the morning, and again in the afternoon.

Linus and Ava Helen Pauling with three unknown individuals at a statue of Mao Zedong. China, 1973.

Pauling’s log does not contain entries any further than September 30, which leaves the next few days until his departure on October 8 unaccounted for. However, other documents indicate that the Paulings did get their desired opportunity to speak with scientists Dr. Ma Hai-teh and Rewi Alley on the subject of oxypolygelatin. Pauling wrote to Dr. Ma a few months later, in February 1974, to tell him about further work being conducted on the substance. In his letter, Pauling intimated that he had the idea that the properties of gelatin as a plasma extender would be improved if the long thin gelatin molecules could be tied together into rosettes using hydrogen peroxide, such that the molecules would not escape into the dilate urine through pores in the glomerular filter. This would improve the substance’s time of retention in the body. Pauling also pointed out that oxypolygelatin is non-antigenic, while other proteins are antigenic, meaning that they cause the body to produce antibodies.

Linus and Ava Helen’s first trip to China was a good experience both culturally and scientifically; one in which they were able to appreciate the historical and artistic aspects of the country while likewise engaging in scientific dialogue with Chinese scientists. While there, Pauling was able to spread the word about the benefits of vitamin C and orthomolecular psychiatry, and also to learn about research being conducted in China, including an unlikely exchange of ideas on oxypolygelatin, a substance that he hadn’t touched in some thirty years.

Hydrogen Peroxide

Linus Pauling in the laboratory. 1940.

“I am planning to carry out during the next few days some experiments on the resistance of concentrated peroxide to shock by detonators and by rifle bullets, and I shall let you know the results of the experiments.”

-Linus Pauling, letter to T. K. Sherwood, November 14, 1940.

Beginning in early 1940, Dr. Paul A. Giguere, a visiting researcher from Laval University, began a study of the properties of concentrated hydrogen peroxide at the Caltech labs. Under Pauling’s watch, Giguere spent several months performing electron diffraction analyses on samples of hydrogen peroxide and hydrazine. By November, the testing had been completed and the two men wrote a brief report on their findings. Pauling, already deeply involved in the development of the oxygen meter for the National Defense Research Committee (NDRC), felt that his and Giguere’s work might net the Institute another war research contract.

On November 14 he sent Thomas K. Sherwood, his primary NDRC contact, an enthusiastic letter detailing the initial findings. One early indication of Guigere’s work was that hydrogen peroxide might be used to absorb shock from explosives or rifle bullets. He also thought it possible to develop a means of controlling the evolution of hydrogen peroxide, suggesting that it could be used to produce oxygen for respirators. The laboratory intended to begin shock resistance tests immediately so that a clean set of data might be prepared, pending Sherwood’s response.

Pauling received an encouraging reply from Sherwood, but it is unclear at what point further work on the hydrogen peroxide project began. Fully two months after the initial correspondence exchange, Sherwood sent a letter to Caltech requesting a progress report from Pauling. In response, Pauling appears to have sent two letters: one detailing work on the oxygen meter and the other containing information on the hydrogen peroxide project. Unfortunately, it seems Pauling’s archives are incomplete as only the first letter remains extant. Whatever information may have been included in the second letter is lost, though we do know that Sherwood responded positively and sent Pauling data on hydrogen peroxide as a chemical fuel for combustion engines.

Thomas K. Sherwood, ca. 1960s. National Academy of Sciences image.

Bizarrely, following this last communication from Sherwood, no further mention of the hydrogen peroxide problem appears in Pauling’s papers until February 1943, in the form of a letter from Giguere demanding to know why Pauling’s article – presumably on his hydrogen peroxide research – had never been published. In response, Pauling reported that he and Dr. Verner Schomaker had only recently completed the manuscript and would send it on to Giguere shortly. Interestingly, this report too appears to be absent from the archives. What’s more, only a single page of hydrogen peroxide research remains in Pauling’s research notebooks.  This page details the decomposition of hydrogen peroxide in blood – a tantalizing entry that gives little indication of the nature of his research.

It is surprising that Pauling, who maintained comprehensive records of his scientific activities, possessed so few notes on his work with hydrogen peroxide. One might speculate that perhaps certain of the materials related to this project were turned over to higher authorities within the government, as has been confirmed with other projects in which Pauling was engaged.

Whatever the cause may have been for this lapse in the record, it seems plausible that Pauling’s early hydrogen peroxide work did have some long-term consequences.  In 1942 Pauling began work on a war research project on the development of a plasma substitute eventually known as oxypolygelatin. This work was spawned from his private Caltech-based research into bovine gamma-globulin, possibly the cause of Pauling’s initial experiments with blood and hydrogen peroxide. It may have also been this initial investigation that led Pauling to use hydrogen peroxide in the creation of oxypolygelatin.

Unfortunately, without letters, reports or laboratory data to review, it is impossible to know exactly what Pauling’s hydrogen peroxide research entailed or how it affected his later research. It seems then, that this particular project will remain one of many small mysteries in Pauling’s life.

Penicillin

Linus Pauling and Dan Campbell in the laboratory, California Institute of Technology. 1943.

In early 1942, Merck & Co. began producing penicillin with the intention of making it available for soldiers in the field. Up to that point, the company was able to produce only tiny amounts of the drug, making it a precious commodity. They needed a way to mass produce penicillin.

While chemists and biologists worked frantically to devise a better production method, Linus Pauling began to consider a completely different approach to the problem: What if smaller quantities of penicillin were needed to treat a patient?

From his oxypolygelatin experiments, Pauling knew that one of the biggest issues with conventional gelatin-based plasma substitutes was that they typically left the bloodstream at a rapid rate, requiring multiple injections. Pauling and Dan Campbell‘s process for treating gelatin in the oxypolygelatin program had caused molecular chains to form and required more time to cycle out of the blood. In thinking about this new problem, Pauling theorized that, by pairing a penicillin molecule with a protein molecule, the substance would remain in the bloodstream for a longer period of time, greatly increasing its effectiveness.

Pauling first presented his and Campbell’s idea for penicillin in the fall of 1943, generating positive feedback from Office of Scientific Research and Development (OSRD) officials and Committee on Medical Research (CMR) staff. And after conducting more experiments with oxypolygelatin, Pauling had enough evidence to move forward.

In May 1944, he sent a proposal and contract request to the CMR. The proposal was accepted and in September he received 1,000,000 units of penicillin for use in experimentation. By this time, the drug had emerged from novelty status to that of a major medical landmark, adding importance to Pauling’s research. A.N. Richards, the chairman of the CMR, seemed particularly interested in the work, noting in one letter that his request for additional information was “simply a suggestion which emerges from my interest and curiosity.”

Portrait of A. N. Richards, ca. 1940s. National Academy of Sciences image.

Unfortunately, all of the enthusiasm that Richards, Pauling, and Campbell could muster wasn’t enough to make the project succeed. One major deterrent to success was the fact that at the time of the experiments, the molecular structure of penicillin was still classified, forcing Pauling to make guesses as to the way the molecule could combine with gelatin. As a result, what should have been a well-planned series of experiments instead became a game of guess-and-check.

By late December 1944, Pauling was ready to submit his first report and the results were not promising. Pauling and Campbell had treated the penicillin samples with urea, alkaline chemicals, and high temperatures – each a denaturing agent meant to break down the penicillin and reform it with the gelatin. On the contrary, these treatments appeared to cause the penicillin to deactivate. Instead of causing the penicillin to bond with the gelatin, the denaturing agents were destroying it.

Pauling and Campbell provided Richards with a one-page report accompanied by a two-sentence cover letter. The investigation was going nowhere and there were other projects to be looked after. What the researchers didn’t say, however, was that Howard Florey and his team at the University of Oxford had, in the meantime, discovered a method to mass produce penicillin and were in the process of creating a large cache for military use. The need for augmented penicillin was gone.

After the informal update was delivered to Richards, no other mention of the penicillin project appears in the Pauling Papers. It seems that the project was quietly discontinued without so much as the traditional final report to the CMR.

Pauling’s Early Development as a Peace Activist

Linus Pauling, 1940s.

Before America’s involvement in World War II, Linus Pauling was openly in favor of intervention to stop the spread of fascism, a menace that he considered dangerous to the stability of world peace. He was horrified by stories emerging from Europe, some pertaining to the treatment of well-respected scientists. He later received pleas from colleagues who were unable to attain visas and thus escape to the United States, and was disturbed and saddened by his inability to aid acquaintances that desperately sought his help.

Throughout the ensuing military engagement, the U.S. government financed research at levels unheard of in previous times. Linus Pauling and many others at Caltech gladly aided the war effort in their own way, and benefited greatly from generous war time funding in the process. Several divisions of the Institute changed dramatically as a result, responding to the growing needs of the armed forces.

Pauling oversaw the development of several devices and innovations, mostly medical in nature, that were meant to be used for the war effort. Near the beginning of the war, he co-manufactured an apparatus that could measure oxygen levels in submarines using a magnetic field. Towards the war’s end, he was developing an artificial substitute for blood plasma, which received substantial attention from the press. He also spent a considerable amount of time examining and testing combustible powders at Caltech’s rapidly expanding powder-research facilities. As the war was drawing to an end however, Pauling began shifting his research focus from federally funded war projects to Rockefeller-oriented protein work.

Though Pauling was mildly active in political affairs before the onset of the war, he tended to keep such views private. He was often too caught up in his work to spare much attention for such things, but he also valued principles of neutrality and objectivity, qualities that stemmed from his scientific research and academic training. Pauling began to change his mind however, when faced with a growing mix of racism, extreme nationalism and atomic peril. Among other stimuli, including countless discussions with Ava Helen, two particular events affected Pauling’s willful political silence during the course of the war.

The first incident involved a talented Japanese-American student. Caltech resided in a zone that required all Japanese and Japanese Americans within to move to internment camps. Realizing the seriousness of his plight, the student turned to Pauling for help. After a difficult search, Pauling finally found him a job on the east coast, but the injustice of the affair caused Pauling some discomfort.

A second event involved George H. Nimaki, a returned Japanese-American evacuee, who was temporarily employed by the Paulings as a gardener at their home. One morning in March of 1945, the Paulings woke up to graffiti on their garage door. Some one had painted, in bright red, “Americans die but we love Japs – Japs work here Pauling” alongside an image of the rising sun flag. Pauling was appalled, and equally appalled by subsequent threats made against him and his family after he spoke out in condemnation of the incident.

These two events began to shift Pauling towards a more active and open involvement in public affairs.  Another would soon cement this attitude.

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On August 6th, 1945, the United States dropped an atomic bomb on Hiroshima, Japan. Another bomb was dropped on Nagasaki a few days later. Among other less apparent ramifications, the use of the bombs signaled the end of the war. The day after the first bomb was dropped on Nagasaki, a day he never forgot, Pauling read of the story in a local newspaper. He was immediately interested in the physics of the bomb, but did not share in the euphoria that was sweeping the nation.

During the war Pauling had been offered a spot at the chemistry division of the Manhattan Project, where the atomic bomb was developed, but he had had little personal interest in the opportunity. Following the bombings in Japan, groups of concerned scientists that had accepted the Los Alamos offer began discussing the effects of their work. The devastation which resulted from the use of atomic weapons began to weigh heavily on many of them. Consequently, they began distributing  information about the role that atomic weapons might play in a rapidly changing world.

Linus Pauling speaking in Tampa, Florida. 1950s.

Pauling received much of this material, and began to attend informal and formal meetings where issues, such as civilian control of atomic weapons and technology, were the main topic of discussion. As Pauling increased his involvement with the growing movement, his political views began to surface more readily. After hearing what many other scientists had to say, and reflecting on his own beliefs, Pauling became openly supportive of sharing atomic secrets with Russia, and of increased cooperation generally. While on a trip in September, Pauling wrote to Ava Helen about his growing concerns, noting that

[Samuel] Allison has made a strong public statement against keeping the A-bomb secret from Russia. . . I think that Union now with Russia is the only hope for the world.

Pauling learned more and more about the science of the bomb, and began giving talks around southern California, his first at the Rotary Club in Hollywood. As time went on, he began to incorporate international relations and politics into his talks, but most people found his non-science discourse dry and unconvincing. After one of these early speeches, Ava Helen told Pauling that he should stop discussing war and peace. He later wrote that her comments changed his life. Pauling struggled with the advice, plagued by inner turmoil.

I thought ‘What shall I do? I am convinced that scientists should speak to their fellow human beings not only about science, but also about atomic bombs, the nature of war, the need to change international relations, the need to achieve peace in the world. But my wife says that I should not give talks of this sort because I am not able to speak authoritatively. Either I should stop, or I should learn to speak authoritatively.’

From this point on, Pauling devoted half of his time to peace and the abolition of war. He began to read about international relations and law, treaties, history and other information related to the peace movement. Pauling tackled social science much the same way that he approached chemistry, focusing on function, frameworks and the interests that motivated different groups of people within certain circles of debate. His new speeches were often concerned with world union and peace with other nations. He shared Ava Helen’s opinion that a single world government would make war unnecessary, and thus safeguard against the use of nuclear weapons. He believed in the ability of basic human connections to overcome political disagreements, as can be seen in this excerpt from a speech that he gave to the Russian-American club in November 1945:

We must all strive for that great goal of world union – of perpetual unity between nations . . . all that remains now is for the final steps to be taken. The steps that lead to union of the great powers. And the world will be safe forever, and we shall see the beginning of a new era of continuing peace and happiness.

In the years following the end of the war, Pauling maintained a great faith in the possibility of world peace. As a result, he became involved with a number of organizations and issues that would later be subjects of  substantial controversy.

Early in his new-found political advocacy, Pauling enjoyed a minor victory in the form of the defeat of the May-Johnson Bill. According to its opponents, the bill would likely have given the military near-complete control over atomic weapons and technology, though ostensibly with the cooperation of scientists and civilian board members. The victory was short lived however. A fast-growing political movement that was both pro-nuclear and exceedingly anti-communist began to overwhelm members of organizations that valued peace and international cooperation. The following years would test Pauling’s commitment to the peace movement, as well as his personal and social convictions.

Pauling on the Homefront: The Development of Oxypolygelatin, Part 2

Dan Campbell and Linus Pauling in a Caltech laboratory, 1943.

“Science cannot be stopped. Man will gather knowledge no matter what the consequences — and we cannot predict what they will be. Science will go on — whether we are pessimistic, or are optimistic, as I am. I know that great, interesting, and valuable discoveries can be made and will be made…But I know also that still more interesting discoveries will be made that I have not the imagination to describe — and I am awaiting them, full of curiosity and enthusiasm.”
Linus Pauling, October 15, 1947.

After developing a promising blood plasma substitute during World War II, Pauling found his funding cut and his contract with the Office of Scientific Research and Defense coming to an end. Rather than abandon the project, the Caltech researchers chose to forge ahead.

Frustrated with the lack of progress, Pauling and his team scraped together enough residual funds to allow for one more series of experiments. Pauling began injecting mice and rabbits with his synthetic plasma, carefully monitoring their health and examining blood samples to determine the effects of the treatment. The results were satisfactory but not enough to put the project back in the good graces of the Committee on Medical Research. Pauling knew that the only way to stimulate interest (and funding) for the project was to prove that his substance could be used in humans. In September of 1944, twelve patients at Los Angeles General Hospital were injected with Oxypolygelatin, all exhibiting favorable reactions. Pauling had the results he needed.

Letter from Linus Pauling to B. O. Raulston, September 19, 1944.

Statement of Work Carried Out Under Contract OEMomr-153, 1944. Page 1.

Statement of Work Carried Out Under Contract OEMomr-153, 1944. Page 2.

In a final effort to save the project, Pauling submitted one last application, noting the success of his experiments with both animal and human patients. To aid his cause, Pauling attempted to find support at the source, sending individual letters to key members of the CMR.

In October of 1944, the CMR responded to his requests for aid, providing a $10,000, nine-month grant. The CMR had previously assured Pauling that the Committee would arrange any necessary physiological tests that could not be completed at Caltech and, upon the renewal of the Oxypolygelatin contract, they reaffirmed this promise.

While Pauling waited for the CMR to complete arrangements for testing, he and his team continued to refine the production process, ironing out wrinkles that had developed in the course of frantic experimentation. During the early months of the Oxypolygelatin program, Pauling had corresponded often with Robert Loeb, a researcher at the College of Physicians and Surgeons in New York. In a 1943 letter to Loeb he wrote,

It looks as though our method of preparation is not well enough standardized to give a uniform product – the osmotic pressure varies from preparation to preparation. With some evidence from the ultracentrifuge as to how the distribution in molecular weight is changing, we should be able to improve the method.

The lack of uniformity in the substance was a problem for Pauling and his team. In order to locate the irregularities, the researchers needed results from a series of physiological tests. Unfortunately, the CMR had yet to arrange for the promised tests and Pauling’s grant was about to expire.

Letter from Linus Pauling to Robert Loeb, August 17, 1943.

By the spring of 1945, Pauling had virtually given up on the project. He had resigned his post as responsible investigator and allowed Campbell to take his place. With the rest of Caltech still knee deep in war research, Pauling had no trouble finding other projects to attract his attention. As a result, his Oxypolygelatin work was relegated to correspondence with gelatin manufacturers and a few curious scientists. In a letter to Chester Keefer of the Committee on Medical Research, Pauling stated,

I feel that the development of Oxypolygelatin has been delayed by a full twelve months by the failure of the CMR to arrange for the physiological testing of the preparation, despite the assurances to me, beginning July 24, 1943, that this testing would be carried out under CMR arrangement. I feel that I myself am also to blame, for having continued to rely upon the CMR, long after it should have been clear to me that the promised action was not being taken and presumably would not be taken.

Letter from Linus Pauling to Chester Keefer, March 12, 1945. Page 1.

Letter from Linus Pauling to Chester Keefer, March 12, 1945. Page 2.

Letter from Linus Pauling to Chester Keefer, March 12, 1945. Page 3.

The project was dead. The CMR had lost interest and no lab in the country was either willing to or capable of performing the tests Pauling required. Even worse for the project, Germany was on the brink of surrender and Japan was losing ground in the Pacific; the war would be over soon and with victory would come the closure of war research programs all over the country.

The team quietly disbanded, each member returning to old projects or starting up fresh lines of research. In 1946, Pauling, Koepfli and Campbell filed for a patent for Oxypolygelatin and its manufacturing process which they immediately transferred to the California Institute Research Foundation.

Oxypoly-gelatin patent agreement, December 4, 1946.

In 1947, the American Association of Blood Banks was founded and in 1948 the American National Red Cross began widespread blood donation campaigns. The genesis of the two programs allowed for large supplies of fresh blood to be dispersed throughout U.S. hospitals on a regular basis, virtually eliminating the need for a plasma substitute during peacetime.

While Pauling was the source of many scientific breakthroughs during his career, in the end Oxypolygelatin was a failed project. Over the following years, he would occasionally discuss his blood plasma work with an interested scientist or mention it at a symposium address, but he never returned to the Oxypolygelatin problem.

For more information on Pauling’s Oxypolygelatin research, read his 1949 project report or view this 1974 letter regarding the development of Oxypolygelatin production in China. For additional Pauling content, visit Linus Pauling: It’s in the Blood! or the Linus Pauling Online portal.

Blood and War: The Development of Oxypolygelatin, Part 1

An original container of 5% Oxypolygelatin in normal saline.

“On the basis of the information available to me, I have formed the opinion that oxypolygelatin solution…may well be a thoroughly satisfactory blood substitute, which could be manufactured cheaply in large quantities. It is probably superior to gelatin itself with respect to fluidity of solution, retention in blood stream, and osmotic pressure.”
Linus Pauling, March 14, 1944

In 1941 Linus Pauling began a limited program of study on bovine and human γ-globulin, a project stemming from his interest in the manufacture of antibodies. Pauling initiated experimentation with the preparation of antisera – blood sera containing defensive antibodies – and in the process quickly became an authority on the chemistry of human blood and hemoglobin. Following the Japanese attack on Pearl Harbor and subsequent U.S. entrance into World War II, the federal government issued a national call for research with wartime applications. Thanks to his ongoing immunological work, Pauling was already a step ahead of his fellow scientists.

In April 1942, Pauling submitted a contract proposal to the Committee on Medical Research (CMR) of the Office of Scientific Research and Development (OSRD). Entitled “The Chemical Treatment of Protein Solutions in the Attempt to Find a Substitute for Human Serum for Transfusions,” the proposal outlined a plan to develop a gelatin-based substance which could be used as a plasma substitute. The project, if successful, would produce a synthetic material that would take the place of donated human blood plasma in transfusions, aiding Allied soldiers when America’s peacetime blood reserves ran low.

The Committee on Medical Research accepted Pauling’s proposal and within two weeks Pauling had assembled a group of researchers, including doctors J.B. Koepfli and Dan Campbell, an immunology expert. After securing materials from Edward Cohn and other American-based scientists, the team was ready to begin.

Linus Pauling to A.N. Richards, May 12, 1942

Linus Pauling to Edward Cohn, May 21, 1942, page 1.

Linus Pauling to Edward Cohn, May 21, 1942, page 2.

Pauling’s idea for a plasma substitute was not an unfamiliar one. Gelatin was already in use as a plasma replica during the late 1930s and early 1940s, but its viscosity and tendency to gel at room temperature made it a poor candidate. The U.S. military needed something quick and efficient that could be used in field hospitals with minimal preparation. The Caltech team, however, was not yet ready to discard gelatin as a potential candidate. Pauling hoped that, through chemical processes, he might be able to transform standard commercial-grade gelatin into a workable substance.

Between June 1942 and May 1944, Caltech received approximately $20,000 from the CMR in support of the project. During that time, Pauling and his team were able to successfully develop a possible plasma substitute through the polymerization and oxidation of gelatin.

Notes by Linus Pauling re: the production of oxypolygelatin, July 23, 1943.

This substance, first referred to as polyoxy gelatin and eventually known as Oxypolygelatin, was superior to its unmodified counterpart in several ways. Because it was a liquid at room temperature, Oxypolygelatin did not require the same pre-injection heating that previous substitutes required, allowing it to be used quickly and without the help of heating implements. Furthermore, thanks to the creation of large chain-like molecules during the preparation process, oxypolygelatin was retained in the bloodstream for longer periods, allowing the patient’s body more time to manufacture natural plasma. Finally, where gelatin contained pyrogens (fever-causing substances), Oxypolygelatin did not – a property that was due to the addition of hydrogen peroxide, a substance capable of destroying pyrogens.

To a chemist’s eye, Oxypolygelatin appeared to be an acceptable substitute for human plasma. Unfortunately, Pauling knew his own tests were not enough to convince the CMR of the substance’s viability. What he really needed was a medical expert’s stamp of approval. Pauling called on Dr. Thomas Addis – a kidney expert whom history now credits with curing Pauling’s near-fatal case of glomerular nephritis – to analyze the effects of Oxypolygelatin on human organs. Addis accepted the challenge, bringing fellow researcher Dr. Jean Oliver to the project as well. Over the next two years, Addis and Oliver would subject Oxypolygelatin to a battery of tests, eventually confirming its potential as a plasma substitute.

Despite Pauling’s enthusiasm and Addis’ promising results, the CMR did not believe Oxypolygelatin to be sufficiently superior to the pre-existing gelatin substance and, in the spring of 1944, the committee refused Pauling’s request for a renewal of contract. Surprised by the committee’s decision, he submitted a second request, asking that his contract be renewed for the period of four months, with no additional funding from the OSRD. His request was granted but, due to empty coffers, no progress was made. Pauling applied again in June, this time requesting extra resources for the project. Again, he was denied.

Linus Pauling to A.N. Richards, June 14, 1944.

The future of Oxypolygelatin research looked bleak, but Pauling and his team refused to abandon the project. Instead, they began making preparations for one final assault on the problem.

Please check back on Thursday for the conclusion to this series. In the meantime, for more information on Pauling’s Oxypolygelatin research, read his 1949 project report or view this 1974 letter regarding the development of Oxypolygelatin production in China.  For additional Pauling content, visit Linus Pauling: It’s in the Blood! or the Linus Pauling Online portal.

Carleton Gajdusek, Doug Strain and Richard T. Jones

Before settling completely in to 2009, we would like to take a moment to note the 2008 passing of three men who had, in various ways, inhabited the Pauling orbit.

D. Carleton Gajdusek died on December 12, 2008 at the age of 85.  Gajdusek was a former graduate student of Pauling’s who received international acclaim – culminating in the 1976 Nobel Prize for Medicine –  for his research on a disease called kuru.

Gajdusek built his scientific reputation studying indigenous peoples throughout Asia and South America, in all cases seeking out unique diseases specific to small and isolated populations.  Kuru was a fatal disease that plagued the Fore tribe of New Guinea.  Sufferers of kuru experienced declines into madness before death, and their autopsies revealed that the disease had ravished their brains, shooting it through with holes.  Gajdusek’s breakthrough, and its resulting impact, is summarized nicely by Donald G. McNeil, Jr. in his excellent New York Times obituary of the Nobel laureate:

In 1957, Dr. Gajdusek…realized that the victims had all participated in “mortuary feasts” in the decades before the custom was suppressed in the 1940s by missionaries and the Australian police.

The Fore, who lived as they had in the Stone Age, cooked and ate the bodies of tribe members who had died, and smeared themselves with the brains as a sign of respect for the dead.

The disease confounded explanation because the mashed brains of the victims, injected into chimpanzees’ brains, produced no symptoms. All known disease-causing bacteria, viruses and parasites produced symptoms within days or weeks. But when the chimps developed kuru two years later, Dr. Gajdusek theorized that a slow-acting virus was at work, somehow not producing the expected immune reactions.

One of his assistants found “scrapie-affiliated particles” — fibrils resembling those in the brains of sheep with scrapie. But it was Stanley B. Prusiner who identified them as tangles of normal proteins that had misfolded and clumped, “teaching” other proteins to follow; he named them prions. They are now recognized as the cause of kuru, scrapie, human Creutzfeldt-Jakob disease and bovine spongiform encephalopathy, better known as mad cow disease. Dr. Prusiner won his own Nobel in medicine for that work in 1997.

McNeil’s obituary also describes Gajdusek as “difficult and eccentric,” in no small part because he was an admitted pedophile, convicted in 1997 of molesting one of the at least-fifty indigenous children that he adopted, raised and financially-supported over the course of his life.  Much more on this component of Gajdusek’s biography is spelled out by Thomas H. Maugh II in his Los Angeles Times obituary.

Pauling and Gajdusek were decades-long friends.  It is uncertain, though in our opinion unlikely, that Pauling was aware of Gajdusek’s personal proclivities.  On the contrary, the final communication from Pauling to Gajdusek that is contained in our files – dated December 28, 1993 –  indicates that Pauling hoped to appoint Gajdusek for five years as a staff member at the Linus Pauling Institute of Science and Medicine.  Likewise, the FBI’s investigation and subsequent arrest of Gajdusek did not take place until 1996, two years after Pauling’s death.

Letter from Linus Pauling to Carleton Gadjusek, December 28, 1993.

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Douglas C. Strain passed away on November 15, 2008, at the age of 89.  A Caltech undergraduate who had occasion to take classes from Pauling, Strain went on to found Electro Scientific Industries, Inc., a pioneer of Oregon’s now-thriving technology sector.

Strain was raised in the Quaker tradition.  A conscientious objector during World War II, he was sympathetic to Linus and Ava Helen Pauling’s perspective on issues of peace and civil liberties. (This older post of ours, titled “An Outspoken Man,” relies heavily on Strain’s recounting of Pauling’s response to the anti-Japanese hysteria that arose in the immediate aftermath of the Pearl Harbor attack.)

A success in business, Strain was also an accomplished philanthropist who generously supported education at a number of institutions in both Oregon and California.  Strain’s intersecting interests in Pauling and in education culminated in his support of the OSU Libraries Special Collections — our reading room is named in his honor.

Though their contacts were limited following Doug’s graduation from Caltech, Strain remained a keen observer of Linus Pauling’s life and career.  In a 1995 oral history interview, Strain offered these perceptive thoughts on Pauling’s talents and multi-facted persona.

He was always off on his own ideas.  He was not a team player.  He would not, I don’t think, work well in a scientific team.  He was really an original guy and you either went along with Pauling or you weren’t there, that sort of thing.  But he was very stimulating because he was so openly enthusiastic about his ideas and always tried to be very intellectually honest about what he believed.  I mean, a lot of experimentation, a lot of proof.  He expected everybody else to do the same.  He was a very tough taskmaster for his graduate students.  I know for a fact.

The Oregonian has published an obituary of Doug Strain and also covered his memorial service.

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Richard T. Jones was an Oregon Health Sciences University biochemist who passed away on February 26, 2008, aged 78.  Jones was both a Caltech undergraduate as well as a graduate student of Pauling’s in the late-1950s and early-1960s, who contributed to Caltech’s sprawling program of hemoglobin research.  One important component of Jones’s hemoglobin work was his introduction to the group of a technique called “molecular fingerprinting,” which Pauling and a third colleague, Emile Zuckerkandl, used to develop their influential theory of the molecular evolutionary clock.

Pauling was frequently asked to provide recommendations of his students for various positions around the world, and he had no trouble in relaying brutally-honest opinions, some of them rather starkly negative.  It is clear, however, that Pauling was a fan of Jones’s work.

Letter of recommendation for Richard T. Jones, written by Linus Pauling, December 12, 1959.

Following his tenure at Caltech, Jones went on to chair the biochemistry department at the University of Oregon before relocating to OHSU, where he worked for thirty years, including a short term as acting University President.  Interestingly, one of Jones’s primary research interests during his time in Oregon was the study of blood substitutes, to some degree echoing Pauling’s work on oxypolygelatin during World War II.

One month before his death, OHSU honored Jones by renaming its Basic Science Building in his honor.

Pauling in the ROTC

ROTC Cadet Linus C. Pauling, 1918.

As most of our readers are no doubt aware, this past Tuesday was Veterans’ Day in the U.S. and Remembrance Day in many other parts of the world.  In honor of this global occasion, we thought it appropriate to discuss a component of Linus Pauling’s story that may come as a surprise to many — his involvement in the Reserve Officers’ Training Corps.

At the time of Pauling’s arrival in Corvallis for the beginning of his studies at Oregon Agricultural College, two years of ROTC service were required of all male students physically-able to participate.

[Indeed, compulsory ROTC remained a feature of university life at Oregon State until 1962.  OSU’s proud tradition of military training is documented nicely by our colleagues in the University Archives in the Historical Note to this finding aid.]

Pauling, decades away from the peace activism that, for many, continues to define his legacy, participated with typical vigor.  His marks for military drill were consistently stellar, and near the end of his freshman year Pauling received first runner-up in the Best Soldier competition at OAC’s Military Inspection Day.

Pauling's OAC report card, October 1918. The usual good grades in military drill, the sciences and math; a highly-unusual A+ in P.E.; and more-typical struggles in Mechanical Drawing.

Pauling’s commitment to service did, at least on one occasion, come at a cost:  in his Pauling Chronology, biographer Robert Paradowski notes an unhappy incident befalling the young undergraduate at the beginning of his second term.

After going home for his Christmas vacation, Pauling returns on January 7 to the OAC campus for the Winter Short Course. His financial problems become severe during this time. He is also asked to leave the boardinghouse because he makes too much noise tramping up the stairs in his heavy military boots. During the winter and spring, he goes through several changes of address, sometimes rooming with friends, other times taking whatever he can find.

Nonetheless, Pauling’s heart seemed fully in tune with the ROTC mission.  Biographer Thomas Hager, in the early pages of his Force of Nature, writes

Following his freshman year, in the early summer of 1918, Pauling and Mervyn Stephenson, along with a number of other OAC cadets, were sent to the Presidio in San Francisco for six weeks of intensive officers’ training.  Pauling and Stephenson spent the rest of the summer helping build wooden-hulled freighters in a shipyard on the coast of Oregon.  Whatever Pauling’s opinions about war later, during World War I he was in full support of the government’s actions.  Stephenson would later remember that Pauling was a strong supporter of the war effort, “100 percent for it.”

Military training at the Presidio, San Francisco, California, Summer 1918.

Having completed the required two years, Pauling chose to remain active in ROTC for the duration of his time as an undergraduate, adding classes in camp cookery to his compulsory drilling.  By the time of his movement on to graduate work at the California Institute of Technology, Pauling had risen to the rank of Major within the Training Corps.

In later years, Pauling would answer the call to service again by engaging in an ambitious program of scientific war research on behalf of the Allied effort during World War II — the human blood plasma substitute oxypolygelatin, new types of rocket propellants, invisible inks and an oxygen meter for use in aircraft and submarines all arose out of this fruitful period.

For his efforts, Pauling received a number of awards from the U.S. government including a Naval Ordnance Development Award, a certificate of recognition from the Office of Scientific Research and Development, a certificate of appreciation from the Rocket Development Program and, most importantly, the Presidential Medal for Merit.

Though the later Pauling was, without question, a vocal and, at times, incendiary critic of U.S. military policy, one would be hard-pressed to make the argument that he was anti-soldier.  To Pauling, war was the greatest of all immoralities, but his criticism was always pointed at the world’s larger actors — the governments and war profiteers — rather than the men and women working in service to their countries.

On the contrary, service to a larger cause was clearly important to Pauling, to the point where he and his wife, Ava Helen, once pledged themselves as willing “Hostages for Peace,” offering to travel to North Vietnam to serve as human shields for Vietnamese citizens and U.S. prisoners of war endangered by the U.S. aerial raids being conducted in the early 1970s.

Clearly, amidst all the accusations and noise surrounding his alleged “anti-Americanism” or “communist ties,” Linus Pauling’s remarkable willingness to sacrifice, much like his earlier ROTC service, was an important but frequently-overlooked component of a terrifically-complex story.

Thinking Between Disciplines: Immunological Interests and Beyond

“I believe that chemistry will play a very important part in the golden age of biology that is now beginning.”
– Linus Pauling, “Molecular Structure and Biological Specificity,” July 17, 1947.

One of the reasons why Linus Pauling enjoyed such a prolific and diverse scientific career was his ability to combine and draw inspiration from rather disparate interests and research questions.

Indeed, structural chemistry – the discipline with which Pauling is most commonly associated – appealed to Pauling in part because it allowed him to consider the physical causes underlying the chemical nature of certain biological phenomena in concert with known principles of chemical interaction.  In other words, Pauling viewed structural chemistry as the avenue by which he could best utilize the tools not only of chemistry, but of physics and biology as well.

Many of Pauling’s laboratory experiments rested on knowledge and methods borrowed liberally from biology, medicine, chemistry and physics. In a 1946 proposal for a program of fundamental research in biology and medicine at Caltech, Pauling emphasized that the long-established cooperation of the Institute’s divisions of Biology, Chemistry, and Chemical Engineering were resulting in a vigorous and successful “attack” on the “great fundamental problems of biology and medicine.” As he sought to justify the expansion of these interacting programs, Pauling wrote that the “primary features” of their organization were “the presence of a group of men rigorously trained in the exact sciences and interested in attacking…broad problems.”

Of nearly-equal importance was an “unusual spirit of cooperation.” Such ‘unusual cooperation,’ in Pauling’s opinion, could be expected to produce work that was at once “sound but imaginative,” and indebted to “the transfer of ideas among different fields…ranging from quantum mechanics to animal physiology.” Pauling’s ideas on the nature of hemoglobin and sickle cell anemia were two of the ‘sound but imaginative’ ideas that arose out of the broader culture of interdisciplinary laboratory research.

In the 1930s Pauling came under the influence of a prominent immunologist, Karl Landsteiner, who helped to turn his attention and interest towards the mechanism of immunological response. To Pauling, the fundamentals of immune response in the body seemed reminiscent of the folding of hemoglobin in the presence of iron. Both mechanisms underscored the importance of the physical structure of a molecule in influencing its chemical interactions.

Pauling’s work on both the nature of hemoglobin as well as the immunological reaction to antigens and foreign proteins were linked practically, as well as conceptually, to his hemoglobin research. As he came to learn more about immune response, Pauling applied some of this knowledge to increasing the practical value of his work on the development of Oxypolygelatin, a blood substitute created as part of the Pauling’s contributions to the Allied effort during World War II.

An original container of 5% Oxypolygelatin in normal saline. Developed by Linus Pauling as part of his scientific war work research program, mid-1940s.

This project, which was not completed to fruition until 1949, was vexed by certain problems having much to do with the nature of blood in the human body. In a handwritten note from 1945, Pauling suggested that foremost among his concerns vis-a-vis the creation of a suitable blood alternative were both a “lack of toxicity,” and a lack of “antigenicity.”

Pauling’s ideas on the nature of hemoglobin, sickle cell anemia and the blood substitute Oxypolygelatin were all born of his ability to fruitfully-combine the methods of several different disciplines with the expertise of his colleagues and fellow researchers. Even moreso, this remarkable body of work constitutes a clear example of the important place that interdisciplinarity can assume in scientific research.

To learn more about Pauling’s research on hemoglobin, immunology and Oxypolygelatin, please visit the website It’s in the Blood!  A Documentary History of Linus Pauling, Hemoglobin and Sickle Cell Anemia.