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.

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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.