Campbell, Pressman, Pauling and the Binding of Antibodies

Drawings of the interaction between an antibody and azoprotein by Linus Pauling. 1940s.

Dan Campbell first collaborated with Linus Pauling on a fellowship at Caltech in 1940, during which time the duo tried to explain how antibodies are formed. At the time, Pauling believed that antibodies were proteins in-the-making that needed to bind to antigens in order to fold and complete their structure. If this principle was correct, Pauling thought, it might be possible to create artificial antibodies by simply denaturing proteins and allowing them to bind and refold in the presence of antigens.

Despite the fact that Campbell’s initial test results cast doubt on his collaborator’s theories, Pauling went ahead and published his ideas on how antibodies work, hoping that further research could support his paper. Thus began a lengthy study of antigen-antibody binding in which Pauling and Campbell attempted to develop a complete theory. Along the way, Dan Campbell’s research at Caltech would become very important to the Institute as well as to Pauling.

In 1943 a Caltech research fellow named David Pressman agreed to join Campbell and Pauling in their study of immunology. Starting with work that had previously been published, Pressman, Pauling and Campbell refocused their studies to explain how antigens and antibodies bind, a change in focus from Campbell and Pauling’s earlier inquiries into how antibodies and antigens are formed. The decision to focus on previous research was made after Pauling had mistakenly announced that antibodies had successfully been synthesized at the Gates and Crellin Laboratories. As it turned out, attempts to create synthetic antibodies using Pauling’s proposed methods were completely unsuccessful. Pauling thus decided to start from scratch by developing a theory of antigen-antibody binding, which he would use to further investigate the chemistry of this interaction.

In July 1943, the three men published “The Nature of the Forces Between Antigen and Antibody and of the Precipitation Reaction,” appearing in the journal Physiological Reviews. The paper attempted to make more educated predictions about antigen-antibody binding.  In doing so, the article begins by referencing the concept of structural complementarity, which posits that antigen-antibody binding is driven by the close complementary physical shapes of the two molecules, which fit together like two adjoining pieces in a jigsaw puzzle. Commonly referred to as “the lock and key mechanism,” this idea was developed in the early 1930s, and served as Pauling and Campbell’s starting point in their initial investigations.

The 1943 study also drew from outside theories, such as the framework theory of precipitation, to suggest that antigen-antibody binding results in the formation of a precipitate; that is, that the two structures react to form an insoluble compound. Using these points as their foundation, the three researchers developed a new theory of antigen-antibody binding.

Pauling and Campbell, 1943.

Pauling and Campbell, 1943.

Campbell, Pressman and Pauling’s breakthrough came by way of their proposal that structural complementarity is an especially important feature for reactions that depend on Van der Waals forces. Van der Waals forces are weak forces of attraction that bind together molecules located in close proximity to one another. The Caltech researchers believed that the close complementary geometry of antibodies and antigens was significant enough to enable these molecules to fit together using the weak Van der Waals attraction as a binding force. In other words, the summation of Van der Waals forces present along the binding site of an antibody worked to bind it to its antigen, specifically because the shapes of antibodies and antigens complimented each other so closely. This theory explained much of what had been observed by immunologists across the discipline in multiple investigations of antigen-antibody reactions.

From here, the three researchers also asserted that two propositions placed forth in Pauling’s 1940 paper should still be considered for further study: the multivalence of antigen-antibody interactions and the probability of hydrogen bonds acting between the two molecules. The trio also concluded that the antigen-antibody mechanism would require at least two supplementary types of forces: Coulomb attraction and polar attraction.

Of the conclusions published by Campbell, Pressman and Pauling in 1943, the multivalence of antigen-antibody interactions and the three proposed forces (Van der Waals, Coulomb and polar) between the two molecules are still considered to be contributing factors to the functioning of the human immune system. With this publication, Campbell, Pauling and Pressman also showed that the immune system relies heavily on both structural and chemical features to carry out its processes.

The important conclusions derived from research conducted by Campbell, Pauling and others established Caltech as a leader in the field of immunology. Over the years that followed, Campbell and Pauling continued to develop their theory of antibody formation, which remained widely accepted until the 1950s. Even when the duo’s work began to be disproven by findings in the genetics field, the understanding of antigen-antibody interactions suggested by research done at Caltech remained undisputed.

Dan Campbell and Linus Pauling went on to publish more than twenty articles relating to immunology, exchanging ideas on the topic until the end of Pauling’s tenure at Caltech in the early 1960s. The attention that their work brought to the Gates and Crellin Laboratories at Caltech prompted the creation of a separate department, one that was entirely dedicated to immunochemistry. (The first of its kind on the west coast.)

For thirty years, Campbell headed Caltech’s immunochemical research and his fame as an immunologist grew to the point where, in 1972, he was named president of the American Association of Immunologists. Two years later, in 1974, Campbell passed away at the age of 67, the victim of a heart attack.  Over the course of his career, he published more than 200 papers as well as several books, and he served on editorial boards of four scientific journals related to immunology.

The Arrival of Dan Campbell at Caltech

Dan Campbell, ca. 1940s.

Dan Campbell, ca. 1940s.

[Part 1 of 2]

As a scientist, Linus Pauling is remembered by many for combining his expertise in chemistry with other fields. Often times Pauling would start off thinking about a problem from a chemical perspective and end up learning about a field entirely new to him, like cellular biology or medicine. Though this sort of cross-disciplinary work is more commonplace today (partly because of the example that Pauling provided), in the 1930s it was fairly rare for scientists to combine different fields of study. This given, pioneers of the cross-disciplinary approach often found it difficult to identify like-minded researchers with whom to collaborate. Fortunately for Pauling, a man with a very wide network, other researchers often found him.

After delivering a talk about hemoglobin in 1936, Pauling was pleasantly surprised to be consulted by Austrian medical researcher Karl Landsteiner. For many years, Landsteiner had been trying to understand how antibodies in the immune system work, and he believed that Pauling’s knowledge of medicine and chemistry could help him in his investigations. An antibody is a disease-fighting macromolecule that targets and rids the body of unwanted foreign substances, such as viruses and incompatible blood types. Landsteiner wanted to know how antibodies can target specific foreign substances with such precision. This encounter drew Pauling’s attention to the field of immunology, which would eventually become an important part of his research and would remain so for many years to come.

Pauling’s communications with Landsteiner spurred an interest in looking into the chemistry of antibodies and their substrates, antigens. At the time, however, most of Pauling’s focus was necessarily occupied with finishing up his previous program of grant-funded research on protein structures. Furthermore, Pauling was not an immunologist and the demands on his time were such that he could do little more than keep immunology in the back of his mind.

It wasn’t until 1939 that Landsteiner once again brought Pauling’s full attention back to antigens when he used Pauling’s theory of protein structure in a discussion about antibodies. Reading Landsteiner’s article sparked several ideas for Pauling which quickly led to his drafting a rudimentary theory of antibody chemistry. Six months later he found the perfect opportunity to test some these ideas.


Image extracted from a glass plate display, “Pictures of Antibodies,” prepared for the First International Poliomyelitis Conference, New York, 1948. The caption accompanying this image reads: “…[An] antibody-antigen framework which may precipitate from a solution or be taken up by phagocytic cells.”


In January 1940, immunologist Dan Campbell first visited Caltech on a fellowship. Campbell was an Ohio native who had been trained at Wabash College in Indiana and George Washington University in St. Louis, before receiving a doctoral degree from the University of Chicago, where he was subsequently hired as an assistant professor. During his tenure at Chicago, Pauling invited Campbell to spend a fellowship period at Caltech.  Campbell was only scantly familiar with the Institute, but was aware of the reputation of its chemistry department and accepted Pauling’s offer largely on this basis.

Due to his unfamiliarity with the institution, by the time of his arrival in Pasadena Campbell had still not yet identified a research project on which to collaborate. Pauling advised Campbell to consider different researchers before making his final decision on where and with whom he might work. In the end, after asking around, Campbell chose to collaborate with Pauling on his theory of immunology.

This was a fortuitous decision, for several reasons.  First, in addition to immunology, Campbell had a background in biophysics and chemistry, which made him a perfect candidate to test and develop Pauling’s antigen theory. More importantly, as Campbell began his initial investigations, it became apparent that Pauling’s ideas were flawed and that Pauling’s knowledge of chemistry alone would not be sufficient to make further progress in immunological research.


Campbell and Pauling, 1943.

Pauling had alleged that antibodies were similar to denatured proteins; that is, a protein that has lost its secondary and tertiary structures and has unfolded into an amino acid chain. Pauling’s theory anticipated that antibodies were an unfinished protein that required specific antigens in order to fold into the proper secondary and tertiary structures.

According to this model, antibodies would only form hydrogen bonds and thus would coil around chemically complementary antigens. As such, the theory explained how antibodies are able to bind unambiguously to their complementary molecules. However, Campbell’s results did not support all of Pauling’s ideas. Though his research showed that antibodies were in fact proteins, their physical structure before and after binding to antigens remained unclear.

Pauling’s lack of evidence for his theory of antibody structure and composition limited him to publishing only a single theoretical paper in which he explained his ideas about antibodies. In July 1940 the Journal of the American Chemical Society featured Pauling’s “A Theory of the Structure and Process of Formation of Antibodies.” The article received much attention and, despite the lack of evidence, was widely acclaimed, though it failed to provide a definitive explanation for antibody structure.

After the publication of the piece, Campbell once again tested Pauling’s theory, and this time his results were much more confusing, to say the least. Initially, it appeared that Campbell had succeeded in creating artificial antibodies by simply denaturing beef globulins (a protein found in blood) and later allowing them to refold around an antigen.

Word of these results greatly excited Pauling, who began to envision the mass production of antibodies using Campbell’s method. Reality turned out to be not so simple; when students and postdoctoral fellows tried to replicate Campbell’s experiment, they were unable to obtain the same results. Looking back now, it seems most likely that Campbell’s research assistants had misinterpreted the results of his experiment.

Pauling knew that he would need more time with Campbell to refine his theory, but that could only happen if Campbell’s position at Caltech was secured. In 1942 Pauling arranged for the Institute to offer Campbell an assistant professorship, which he accepted. By 1950 Campbell had become a full professor.

Combining immunology and chemistry proved to be a commendable approach for tackling many health concerns of the time. Likewise, Campbell’s presence was crucial to the development of Caltech’s immunochemistry department, which over a span of five years grew from a single office (Campbell’s) to a space occupying most of the third floor of Caltech’s Church Laboratory. Students and professors alike flocked to the growing department to discuss questions and engage in research on immunology, using chemistry as the basis of their approach. From the outset, both Pauling and Campbell benefited from one another’s expertise while colleagues at Caltech, and their partnership would continue to yield fruit for many years.

The End of Artificial Antibodies

Illustration of bivalent antibodies attaching to complementary antigen molecules. Image extracted from a glass plate display, “Pictures of Antibodies,” prepared for the First International Poliomyelitis Conference, New York. The caption accompanying this image reads: “In vitro or in vivo bivalent antibodies may become attached to complementary portions of antigen molcules.”

[Part 3 of 3]

Though highly controversial, Linus Pauling’s claim that he had created artificial antibodies gave him a boost in funding. Many of his backers realized that if Pauling was correct he had just revolutionized modern medicine and they were just as eager as he was for his project to succeed. Since he now had more money, Pauling hoped he could expand his staff, though the war greatly prohibited this effort. Pauling lamented:

Unfortunately the amount of war work which is being done now here is so great that the usual seminars and informal discussions of science have decreased somewhat in number, but still a good bit of work in pure science is being carried on.

To help remedy this situation, Pauling corresponded frequently with William C. Boyd of Boston University’s School of Medicine, trying to persuade him to transfer to Caltech over the summer. Boyd refused, stating that he had too many other medical defense projects, though suggesting that “perhaps it will not be too late when the war is over, unless it goes on for 10 years or more, as some pessimistic writers predict.” Pauling also failed to hire two other well-known researchers, Henry F. Treffers, and A.M. Pappenheimer. Both declined because he was only able to offer a one year position. Indeed, from 1942-1943, Pauling actively tried to find staff for his lab, offering a $3,500 one-year position and draft deference. Despite this, most of the competent researchers he wanted were otherwise employed doing war work. He was able to hire Leland H. Pence in December of 1942, and in 1945 Frank Johnson visited from Princeton and worked at the lab in Caltech a bit. These individuals were, however, the exceptions, and Pauling was generally unsuccessful with his offers of employment.

Pauling was also facing other staff issues that were relics of the era. Among his group were two employees who were born and raised in the United States, but whose families were Japanese, Carol Ikeda and Miyoshi Ikawa. All too cognizant of the forthcoming policy of internment, Pauling began corresponding with Michael Heidelberg of Columbia University, hoping that he could temporarily trade employees as a method of getting Ikeda, at least, to a less hostile location. The plan did not work out, and Heidelberger ended one of his letters to Pauling bemoaning the fact that “…unfortunately a lot of wholly patriotic people are going to suffer.” Pauling was eventually able to get both Ikeda and Ikawa into graduate programs, though doing so took a substantial amount of work.


Dan Campbell and Linus Pauling, 1943.

Even though William Boyd had refused a job, he and Pauling continued to correspond frequently. Boyd was critical of Pauling’s theories on antibodies, warning his colleague that “preconceived notions evidently play a big role in the field [of immunochemistry.]” Boyd told Pauling to be careful with his research and his declarations, as he had often made arguments that he felt infallible only to have his colleagues inform him that they were unconvinced.

In August 1942, five months after issuing his controversial press release, Pauling finally published his research on artificial antibodies in an article titled “The Manufacture of Antibodies in vitro,” which appeared in the Journal of Experimental Medicine. As with the press release, Pauling’s paper was somewhat lacking in detail and many scientists found it hard to replicate his experiments. Those who did, such as Pauling’s valued colleague Karl Landsteiner, were unable to obtain the same results that Pauling had reported. Despite this, Pauling remained convinced that his research was valid and worth pursuing. However, Pauling’s collaborator Dan Campbell seemed to be the only one who could successfully produce the antibodies, and even those were weak and ineffective.

In early 1943 the Rockefeller Foundation assigned Frank Blair Hanson to assume some of the work that Warren Weaver had been conducting, and right away it was clear that Hanson was notably “less entranced than Weaver with Pauling’s work.” Despite the fact that he agreed to continue funding Pauling’s artificial antibody research, he was skeptical of its worth and began polling immunologists across the country to that end. They did not respond favorably – even Landsteiner believed that there was a less than 50% chance that Pauling had actually created artificial antibodies. As a result of these lackluster opinions, Hanson cut Pauling’s funding by half.

Pauling proceeded nonetheless, his enthusiasm still strong. His next move was to submit a patent application, “Process of Producing Antibodies.” The response that he received was not what he wanted to hear:

The claims are again rejected for lack of utility as no evidence has been presented to show that the antibodies alleged to be produced by the claimed have any utility at all… The claims are rejected as being too broad, functional, and indefinite…the claims are rejected for lack of invention…all the claims are rejected.

Pauling was disheartened by this response but still confident that he could salvage the project. However, shortly afterward he received a letter from the Rockefeller Foundation informing him that they did not approve of researchers using their funds to apply for medical patents. Because of the letter, and the general ineffectiveness of the research, Pauling opted not to pursue his patent application any further.

Illustration of the antibody-antigen framework. The caption accompanying this image reads: “…[An] antibody-antigen framework which may precipitate from a solution or be taken up by phagocytic cells.”

As 1943 progressed, Pauling continued to piece together a better understanding of how antibodies adhere to antigens. Later that year, he and Campbell published a paper in Physiological Review which further elaborated on their idea that shape was the primary determinant of antibody functions. They wrote that while many of their colleagues at other institutions felt that antibody formation adhered to a “lattice theory,” they did not, because their research showed that the structures created by antibody/antigen precipitation were not regular enough. Instead, they coined the phrase “framework theory” to describe their idea.

By the winter of 1943-1944, Pauling had at last concluded that the artificial antibody research was going nowhere. This was a difficult admission for Pauling because, despite the fact that progress in the research was still slow, he was convinced that he could make it work if given more time. Unfortunately for him, the war effort demanded quicker results and actively prohibited greater focus on antibodies. In the end, he decided to abandon the artificial antibodies research. Pauling never retracted his support for the work, though many years later Dan Campbell admitted that a laboratory technician had “shaded” the results to fit what he thought Pauling wanted to see.


The failure of the artificial antibodies project allowed Pauling to move on to more productive lines of research. He continued to build his ideas on how exactly antibodies function, and by 1945 he was able to prove that shape was indeed what caused antibodies to adhere to antigens. In Pauling’s description, the antibodies would fit to the antigens like a glove, at which point they adhered, not due to orthodox chemical bonds, but because of another weak, poorly understood force.

The force that causes antibodies to bind with antigens is called the van der Waal’s force. It is a very weak, almost imperceptible subatomic bond between two molecules existing in extremely close proximity. Historically, due to their weakness, van der Waal’s forces had been ignored as viable components of biochemical reactions. However, Pauling was able to show that the extremely tight fit between antibodies and antigens exposed a large surface area across which the van der Waal’s force could become a factor. The fit had to be precise, as even one or two atoms being out of place would effectively break the hold that the van der Waal’s force put into place. This concept, known variously as molecular complementarity or biological specificity, cast a great deal of light on a central mystery of molecular biology. With it, Pauling was additionally able to confirm his earlier hypothesis that antibodies are bivalent.

As World War II drew to a close, Pauling shifted his focus away from antibodies and back towards a more general study of the shape, creation, and function of proteins. Pauling’s focus on proteins was long lived, stretching at least twenty-five years from 1933-1958. His foray into antibodies was notably shorter, a nine-year interlude from 1936-1945. Yet in this time, he had managed to dramatically impact immunochemistry with his discovery that antibodies are bivalent and his insights into how they work. These accomplishments are made even more impressive when considering that Pauling was neither an immunochemist nor an immunobiologist by trade. As was so often the case during his life, he threw himself into the challenge with characteristic enthusiasm, and managed to make major contributions to the field.

The Tantalizing Prospect of Artificial Antibodies

Linus Pauling and Dan Campbell, 1943.

[Part 2 of 3]

By late 1939, Linus Pauling had thrown himself wholeheartedly into the study of antibodies, specifically how they work and how they are made. He’d already developed a few memorable and unique hypotheses, though by 1940 they were still yet to be proven correct or otherwise.

In January 1940, a researcher named Dan Campbell arrived at Caltech with the intent of working on problems in immunochemistry. He and Pauling began collaborating, and ended up co-authoring several papers together. Later in 1940, after a first, erroneous paper, Pauling published another in which he claimed:

all antibody molecules contain the same polypeptide chains as normal globulin, and differ from normal globulin only in the configuration of the chain; that is, in the way that the chain is coiled in the molecule.

In other words, shape was what determined the effect of antibodies. Pauling acknowledged the potential for flaws lying within his hypothesis, but adopted it because of his inability to otherwise “formulate a reasonable mechanism whereby the order of amino-acids residues would be determined by the antigen.”

Nobody knew about the genetic basis of amino acids at the time. As a result, while Pauling’s hypothesis on how antibodies worked eventually turned out to be correct, his coupled hypothesis on how they were formed was still wrong. Regardless, Pauling’s theory “ruled the roost amongst immunochemists” for almost 20 years. It wasn’t even until 1949 that people began to seriously question Pauling’s model, and when that finally happened, it was because the model failed to account for the development of immunity to antibodies.

In July a colleague at Caltech, Max Delbrück – a German researcher who had arrived in the US on a study abroad trip and never went home – showed Pauling a paper written by Pascual Jordan, another German scientist. Jordan claimed that identical molecules were attracted to each other, and opposite molecules repelled from one another, because of quantum mechanical resonance. Pauling declared the idea “baloney,” and decided to write a paper debunking Jordan’s theory. He asked Delbrück to co-author it, which he did with hesitation, as the young scientist was nervous about signing his name to a paper attacking the theories of the famous and well-respected Jordan. The duo finished the paper and published it in Science, but unfortunately for them, the work went largely unnoticed.


Since the start of the Battle of Britain in 1940, Pauling had been doing some side research on explosives, propellants, and other “war work” in anticipation of United States involvement in the war raging across Europe and the Asia. In 1941, U.S. engagement finally came about with the attack on Pearl Harbor. Pauling and his laboratory at Caltech switched their main priority to war work, as did just about every other research laboratory in the country. As part of this realignment of efforts, Pauling received a grant to begin a research project with the goal of creating gelatin-based blood plasma artificial antibodies, to be used for military medical purposes.

Pauling hypothesized that if a generic protein, such as beef globulin, was very carefully denatured, then placed in the presence of an antigen and revitalized, it would grow and mold itself to the antigen. If this worked, medical technicians would someday be able to create antibodies “made to order.” The potential import of the idea was clear: “the end result of a million years of evolution” would become available “by the quart.” Successful implementation would represent a massive breakthrough in medical technology, and Pauling was convinced that he was just the man to do it. He picked Dan Campbell and David Pressman to be his primary assistants and the group got to work.

The process was slow and complicated; it involved a mixture of 1-2% beef globulin, dissolved in 0.9% sodium chloride, then very slowly heated to 57˚F. Once at that temperature, alkali would be carefully added to bring the mixture to a pH of 11, before very delicately and slowly returning the mixture to pH 0. To further complicate issues, the process produced a large amount of nitrogen, which had to be removed, but the process of removing the nitrogen created carbon monoxide and other “undesirable substances.” The Pauling group tested their antibodies on rabbits, mice, and guinea pigs predominantly, as their labs lacked the space for more extensive animal research.

In March 1942, instead of submitting his ideas to a peer-reviewed scholarly journal, Pauling issued a press release to Science News, claiming that his lab had developed artificial antibodies.

Text of Pauling's artificial antibodies press release, March 1942.

Text of Pauling’s artificial antibodies press release, March 1942.

The scientific community was vexed by this highly unusual action. Numerous scientists questioned the strength of the data, saying that the reports released by Pauling and Campbell were vague and weak. Pauling asserted that while the data they had gathered was not definitive, it was strong enough to make the statement that artificial antibodies had been produced. Pauling said that his artificial antibodies, though weak, were still real, and that he was going to continue improving on them. Specifically, he claimed that the antibodies had been used to prevent mice from getting pneumonia.

Pauling’s reputation helped to coax certain colleagues in the direction of his arguments. And after some skillful debating, the Rockefeller Foundation offered $31,000 to continue the research, while the federal Office of Science Research and Development offered $20,000.

Despite the skepticism of his peers, Pauling was enthusiastic and eager to continue research on this line of work. He had the funding and the desire, and he was convinced it was only a matter of time before he could start mass-producing artificial antibodies. However, he was about to run into some issues outside of his laboratories.

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.

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 on the Homefront: The Development of Oxypolygelatin, Part 2

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

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.

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 1.

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

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.

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 1.

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

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

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

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.

Oxypolygelatin patent agreement, December 4, 1946.

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.