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.

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Blood and War: The Development of Oxypolygelatin, Part 1

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

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 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 1.

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

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.

the production of oxypolygelatin, July 23, 1943.

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.

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.