Carol Ikeda and Miyoshi Ikawa

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Linus Pauling, 1942

[Ed Note: Parts 5 and 6 of our series detailing Linus Pauling’s work on the serological properties of simple substances both focus on the intriguing life stories of three individuals with whom Pauling worked on this program of research.]

Over the years, Linus Pauling forged close relationships with many of his graduate and doctoral students, offering guidance that, in numerous cases, changed the course of a student’s career. During World War II, he fought particularly hard for two of his research assistants, Miyoshi Ikawa and Carol Ikeda. In both cases, Pauling’s intervention prevented these colleagues from being forcibly interned. Instead, Ikawa and Ikeda each moved on to graduate studies and fruitful careers in science.


Miyoshi “Mike” Ikawa was born in California in 1919 to first generation immigrant parents. He pursued undergraduate studies at Caltech, where he was a member of the Chemistry Club and Tau Beta Pi, and competed on the Fleming House wrestling team. When he graduated in 1941, he was already working in Pauling’s lab, preparing compounds and helping with the first three serological papers. Pauling subsequently served as his graduate advisor.

Carol Ikeda came to Caltech from Texas in 1939, having started his education at Paris Junior College in Texas. He transferred to Caltech with the intent to study chemistry and become an organic chemist. At Caltech, he stood out among many other very bright students; Pauling described him as “one of the top men in the class.” Not one to give compliments lightly, Pauling recognized Ikeda’s potential not only from his performance in class, but also from his work in organic research labs on campus. Before Ikeda had even decided to continue onto graduate studies at Caltech, Pauling had recruited him for the serological project as an assistant in the Immunochemistry department. Indeed, it is especially noteworthy that Ikeda and Ikawa both are listed as co-authors for Pauling’s first three serological papers, given that the first two papers were published while Ikeda and Ikawa were still undergraduates.


Up until World War II, it appeared that Ikawa and Ikeda were each moving well down the path toward successful careers in immunology, organic chemistry, or biochemistry. This all changed when President Franklin Roosevelt issued Executive Order 9066 and declared Pasadena to be a military zone.

Even before the attack on Pearl Harbor, U.S. citizens of Japanese descent faced discrimination on the basis of race as well as suspicions that they would prove more loyal to Japan than to the United States even if they were second- or third-generation citizens. Acutely aware of the mounting tension faced by American-born Japanese, Pauling was determined to support students bearing this burden and to make sure that they could find positions at Caltech for which they were suitably qualified.

Pauling was likewise clear in his understanding that other universities did not share his point of view. In the recommendations that he wrote, he provided full disclosure and acknowledged potential discomforts regarding race, an issue that many administrators would have preferred be left unacknowledged. In one particular reply to a request for recommendations, Pauling wrote

…the two best men scholastically in our graduating class are American born Japanese, Ikawa, and Ikeda. Although one of them has, I think, a satisfactory personality for teaching work, I doubt that you would be interested in appointing him because of his racial handicap.

Some universities responded positively to recommendations of this sort; the University of Iowa, for one, confirmed that race wouldn’t be a problem at all. Rather, Pauling’s Iowa contact assured that the institution shared Pauling’s stance and was committed to considering the qualifications of their applicants regardless of race. The reply went on to state,

While we have not had any American-born Japanese on our teaching staff, I see no reason why they would not get along satisfactorily, if they have the necessary intelligence and ability.


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Miyoshi Ikawa, 1941

Ikawa and Ikeda had been working on the serological project for more than a year when Pasadena was declared a military zone. Cognizant of the need to help his assistants relocate to a safer area, Pauling had a relatively easy time finding Ikawa a position as a graduate student at the University of Wisconsin, where he worked under Karl Paul Link. This move ultimately changed the course of Ikawa’s career. Before receiving his doctorate, Ikawa, along with Link and Mark A. Stahmann, synthesized warfarin and obtained a patent for it to be used as a rat poison. By 1950, warfarin (now commonly referred to as Coumadin) was being used to treat blood-clotting disorders such as thrombosis, because it was a strong anticoagulant. It still serves this purpose today.

With the war over, Ikawa was free to return to the West Coast, where he conducted postdoctoral research at Caltech and UC-Berkeley, before moving on to the University of Texas. In the early 1960s, he settled down and became a professor at the University of New Hampshire, where he began focusing on marine biotoxins. In 1972, he and his colleagues established the Paralytic Shellfish Monitoring Program for the state of Maine, a course of action that followed the first evidence of a red tide in the southern Gulf of Maine. Ikawa taught at the University of New Hampshire for twenty years and then spent most of his later career advising technical panels and partaking in peer review committees for federal research grants. He passed away in 2006.


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Carol Ikeda, 1941

Pauling had a harder time finding a position for Ikeda. In February 1942, shortly after Roosevelt released his executive order, Pauling sent a letter to Robert Millikan – the chairman of the Caltech Executive Council – about Ikeda’s progress and position. In this, Pauling tried to make the case that, while his serological research wasn’t directly related to defense work, its results could be valuable for their medical application. He also pointed out that finding someone as competent as Ikeda to continue these studies would be nearly impossible.

As it turned out, this approach backfired for Pauling, because so many people were nervous about having American-born Japanese involved in any war effort. Consequently, Millikan asked Pauling to vouch for Ikeda’s loyalty in order to allow Ikeda to continue “to undertake, under special arrangement, research work which may involve defense matters.” Pauling vouched for Ikeda’s work, but hesitated to comment on his loyalty, because he felt that someone with a more personal working relationship with Ikeda could give a better answer. He also suggested that Ikeda could be transferred to a teaching position if the issue of loyalty could not be resolved to Millikan’s satisfaction.

As Millikan deliberated, Pauling began to feel that Caltech might not be the best environment for Ikeda, even if he was transferred to a teaching position. In short order, Pauling contacted Michael Heidelberger, a faculty member at Columbia University’s College of Physicians and Surgeons. In doing so, Pauling offered Heidelberger a quid pro quo of sorts, suggesting that Heidelberger accept Ikeda into his program at Columbia in exchange for Pauling hosting one of Heidelberger’s researchers in Pasadena. This plan broke down when the Columbia researcher that Pauling had in mind wrote back to say that he could not accept an appointment at Caltech and that he wished to stay on at Columbia instead.

The situation was not improved much by Heidelberger’s blasé attitude toward the internment camps. Recognizing that “wholly” patriotic people would be unjustly punished, Heidelberger remained unconvinced that there was much that he or Pauling could do to alleviate the issue, an opinion shared by many. As would later become the norm, Pauling stood out here as a lonely voice in the scientific community.

For Ikeda, things worked out at the last minute. In April 1942, just two weeks before Ikeda was assigned to report to a camp, Pauling managed to find him a graduate position at the University of Nebraska, where he completed his Ph.D. in 1945. In 1947, Ikeda accepted an offer of employment from DuPont in Delaware, and then later moved within the company to Philadelphia. In 1962, he received a patent for a resinous coating material that he developed while working for DuPont. He passed away in Phoenix, Arizona in 1996, having enjoyed a successful life and career.

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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.