Medicine's Wartime Wonder Drug and Its Production at Peoria, Illinois (2024)

Penicillin:
Medicine's Wartime
Wonder Drug and
Its Production at
Peoria, Illinois

John S. Mailer, Jr., and Barbara Mason
Historical Research and Narrative

The story of penicillin continues tounfold. Authors have written any number of books and articles on the subject, and while most begin with Sir AlexanderFleming's discovery in 1928 and end with SirHoward Florey's introduction of penicillin intoclinical medicine in 1941 or John C. Sheehan'sinorganic synthesis in 1957, broad differencesof opinion exist between and among the principal scientists, governments, laboratories, anddrug industries in Britain and the United Statesas to the details of this story. Over and abovethe microbiological and chemical achievementsin penicillin's discovery are to be found aspectsof competition between two nations and theirscientists; political and wartime intrigue; competition for academic and financial rewards;the formidable challenge of producing penicillinin quantities needed to support the military inWorld War II; the complexities of cooperationamong governmental, industrial, and academicentities; and human, legal, and national differences over patent rights and royalties in thepostwar years. Despite these issues, the storyof penicillin is one of scientific, medical, andindustrial triumph that made heroes and saviors of the men and women who were associated with its development and use. Furthermore,no other chemotherapeutic agent did more toraise the professional status of the doctor inWestern medicine.

Beginnings
Molds are kinds of plants, but they are likemushrooms and toadstools rather than like thegrasses and garden plants. They are fungi.The main difference is that they do not produceseeds in little pods like peas and beans butinstead release "spores," tiny dust-like particlestoo small to be seen by the naked eye. Thesefloat away from the parent molds, or fungi, untilthey find something suitable on which to grow.

Alexander Fleming at Work
Courtesy, St. Mary's MedicalSchool Hospital, London

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First portion of Alexander Flemings article of May 10, 1929

Reprinted from
The British Journal of Experimental Pathology,
1929, Vol. X, p. 226.

ON THE ANTIBACTERIAL ACTION OF CULTURES OF A
PENICILLIUM, WITH SPECIAL REFERENCE TO THEIR
USE IN THE ISOLATION OF B. INFLUENZAE.

ALEXANDER FLEMING, F.R.C.S.
From the Laboratories of the Inoculation Department, St. Mary's Hospital, London.

Received for publication May 10, 1929.

WHILE working with staphylococcus variants a number of culture-plates wereset aside on the laboratory bench and examined from time to time. In the examinations these plates were necessarily exposed to the air and they became contaminatedwith various micro-organisms. It was noticed that around a large colony of a contaminating mould the staphylococcus colonies became transparent and were obviouslyundergoing lysis (see Fig. 1).

Subcultures of this mould were made and experiments conducted with a view toascertaining something of the properties of the bacteriolytic substance which hadevidently been formed in the mould culture and which had diffused into the surroundingmedium. It was found that broth in which the mould had been grown at roomtemperature for one or two weeks had acquired marked inhibitory, bactericidal andbacteriolytic properties to many of the more common pathogenic bacteria.

CHARACTERS OF THE MOULD.

The colony appears as a white fluffy mass which rapidly increases in size and aftera few days sporulates, the centre becoming dark green and later in old cultures darkensto almost black. In four or five days a bright yellow colour is produced which diffusesinto the medium. In certain conditions a reddish colour can be observed in the growth.

In broth the mould grows on the surface as a white fluffy growth, changing in afew days to a dark green felted mass. The broth becomes bright yellow and thisyellow pigment is not extracted by CHCI₃. The reaction of the broth becomesmarkedly alkaline, the pH varying from 8-5 to 9. Acid is produced in three or fourdays in glucose and saccharose broth. There is no acid production in 7 days in lactose,mannite or dulcite broth.

Growth is slow at 37°C. and is most rapid about 20°C. No growth is observedunder anaerobic conditions.

In its morphology this organism is a penicillium and in all its characters it mostclosely resembles P. rubrum. Biourge (1923) states that he has never found P. rubrumin nature and that it is an "animal de laboratoire." This penicillium is not uncommonin the air of the laboratory.

IS THE ANTIBACTEBIAL BODY ELABORATED IN CULTURE BY ALL MOULDS ?

A number of other moulds were grown in broth at room temperature and theculture fluids were tested for antibacterial substances at various intervals up to onemonth. The species examined were : Eidamia viridiscens, Botrytis cineria, Aspergillusfumigatus, Sporotrichum, Cladosporium, Penicillium, 8 strains. Of these it was found

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We often see this green growth on jam, bread,and on fruit. If eaten, it is easy to detect andunpleasant to the palate.

One of these molds has for nearly sixtyyears saved the lives of many millions of sickand wounded. It is called penicillin, and itgrows in the shape of a tube or a pencil, henceits name. The man we have to thank for this isDr. Alexander Fleming, a bacteriologist whoworked in St. Mary's Hospital in London.Bacteriologists are scientists who study germsor bacteria. They grow them on glass-liddeddishes called culture plates or Petri dishes.In 1928, Fleming was growing staphylococci,a round-shaped bacteria, injurious to man.To study this under a microscope he had toremove the lids. Leaving one uncoveredenabled the airborne spores from a moldcalled Penicillium to settle in it and form alarge colony, which then spread out in a circleand set about dissolving the staphylococci.

This unexpected event led Fleming toinvestigate the mold that had so effectivelyattacked the bacteria. With the help of mycologists, it was named Penicillium rubrum, butlater it was correctly identified as Penicilliumnotatum. Fleming put spores from this moldonto another plate, where they were allowedto grow for four or five days. Various bacteriawere then added to the plate, some of whichgrew until they touched the penicillin mold andthen stopped. Other bacteria would not evengo near it. Scientists established that this moldwas an antibacterial material—an antibiotic—a microorganism capable of killing anothermicroorganism.

Nobody else seemed impressed withthese findings except Professor HaroldRainstrick of the London School of Hygieneand Tropical Medicine, who attempted to produce larger quantities of penicillin from 1929to 1932. He was unsuccessful in getting otherscientists interested in a common mold as amedicinal tool, and with the discovery of life-saving sulfonamide—sulfur drugs—in 1935,interest in other germ-killers waned.

As a laboratory scientist rather than aclinician, Fleming did not use his penicillin tokill infections in humans. Moreover, ten yearsafter Fleming's discovery, penicillin's chemicalstructure was still unknown, and the substancewas not available in sufficient amounts formedical research. In fact, few scientiststhought it had much of a future. But the outbreak of World War II changed that thinking byraising the treatment of battlefield wounds anddisease from one of academic research to thatof a national priority.

Source: Alexander Fleming,
"On the Antibacterial Action of
Cultures of a Penicillium, with
Special Reference to Their Use
in the Isolation of B. Influenzas"
The British Journal of
Experimental Pathology, (1929)
x: p.226.

In the years leading up to the discoveryand clinical use of penicillin, medical sciencehad been successful in identifying and generally classifying most of the major contagiousdiseases. There were also advances withvaccines, serums, and the diphtheria anti-toxins. Although researchers and doctors knewthe names and pathological effect of mostdiseases, and could observe their morphology,the practicing physician was powerless to combat deep-seated infections. The only recoursefor serious bacterial infections was to hope foran immunological response that would overpower the infection. Tragically, for millionseach year this never happened. For a brieffew years in the early 1930s, scientists thoughtthey had discovered the "magic bullet" in thewar against septic infection with the discoveryof the sulfonamide derivatives. But theantibacterial powers of the sulfonamidesproved disappointing as researchers learned oftheir ineffectiveness in killing staphylococci andpneumococci. They only stopped those germsfrom growing.

Interestingly historical records and folklorerefer to ancient Chinese and primitive peoplessuccessfully treating infections and boils withwarm soil and molds scraped from cheeses,and in England, bread poultices were the homeremedy for these up until penicillinbecame available. Unfortunately,no one made the connection.

At Oxford University inEngland, Dr. Howard Florey,Director of the School ofPathology Dr. Ernst B.Chain (who had fled fromHitler's pogrom against theJews in Germany), Dr.Norman G. Heatley, and Dr.Edward P. Abraham conductedexploratory research on howpenicillin could be used to treat infection. Dr. Fleming gave them some of his culture, and they grew more penicillin very carefully and found it indeed had remarkable curativeproperties.

The so-called Oxford Group publishedtheir work on animals in 1940 and their workon human clinical trials in January 1941. At

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the time, penicillin was in such short supplythat the scientists found it necessary to recoverthe unmetabolized drug from the patient's urinefor purifying and recycling into the patient. Partof the frustration that the Oxford group ofresearchers faced during these years was theirdifficulty in obtaining research funds to supporttheir work. Money was short and governmentsand the pharmaceutical industry continued tolook to the sulfonamides and their derivatives.

World War II and Peoria

The outbreak of World War II in 1939changed everything and, as it raged throughEurope, Asia, and Africa, soldiers and civiliansdied from ravaging staphylococcal, streptococcal, and pneumococcal infections (Gram-positive micro-organisms). The publication of theOxford report on the isolation of various typesof bacteria with penicillin coincided with theBattle of Britain and the beginning of the airwar that raged over the skies of Britain in 1940and 1941. People injured in air attacks weredying. Doctors wanted more effective methodsfor treating burns. Penicillin was badly needed,but the daily bombing raids over Britain madeits industries and laboratories vulnerable toGerman bombs.

The Rockefeller Foundation in New Yorkarranged for Florey and Heatley to come toAmerica in July 1941 to ask for help in makinglarge quantities of penicillin. They met with Dr.Charles Thorn, the U.S. Department ofa*griculture's chief mycologist. Convinced ofthe drug's potential in treating infection, theU.S. Office of Scientific Research andDevelopment and its Committee on MedicalResearch agreed to increase the production ofnaturally fermented penicillin. The Office ofScientific Research sought also to identify thechemical structure of the penicillin moleculeand to attempt a chemical or inorganic synthesis. Both projects of production and trying tomake a synthetic drug went forward concurrently. By 1941 thirty-nine separate drug laboratories in the United States had embarkedon the effort to synthesize inorganic penicillin.

This was not the first time that the penicillin-producing strain of Penicillium notatumhad reached the mycologists in America. In1930 some of Fleming's culture had been sentto Thorn to get his confirmation that it was P.notatum and not P. rubrum—the nameoriginally given to it. Thom distributed samplesto other mycologists who were interested, butapart from confirming the identity of the mold,nothing was done except some laboratory workby Dr. R.D. Reid, who confirmed and extendedFleming's findings.

In December 1941 the Japanese attackedPearl Harbor in Hawaii, and the United Statesentered the war. America now urgently needed penicillin to treat its own wounded. Whatelse could be done?

The place chosen to produce naturallyfermented penicillin was the Northern RegionalResearch Laboratory at Peoria, Illinois, locatedin the middle of the greatest corn-growingfarmland in the world and therefore very keento find new industrial uses for surplus farmproducts, including corn. At the time of Floreyand Heatley's visit, the Peoria laboratorieswere already involved in fermentation researchon corn-steep liquid, a by-product of the wetcorn-milling industry that produced corn starch.It was the liquid left after the corn kernel wasremoved from corn during soaking. This lactose liquid became the medium used in theculture of penicillin, and its use increasedpenicillin production by ten times, making possible the commercial production of the much-needed drug.

At first all the penicillin was made fromdescendants of the original molds that hadlanded on Fleming's plate in 1928. They hadbeen kept alive in various laboratories inEngland. However, they varied in their abilityto produce strong penicillin, so the Americanscientists kept looking for better kinds of molds.They were unsuccessful until 1943 when theyfound that the mold—Penicillium chrysogenum—discovered on ripe cantaloupes byMary Hunt from Peoria, was much more potentand thus ideal for their needs.

Scientists from Britain and the UnitedStates continued to cooperate closely, and asPeoria increased production, the valuable drugwas made available to Britain and other Allies.

Significant differences of opinion existedbetween the government scientists at Peoria,who preferred scientific disclosure of information, and the pharmaceutical industry's (principally Merck and Company, Charles Pfizer andCompany, E. R. Squibb and Sons, and AbbottLaboratories) insistence on the protection ofproprietary rights. In part, the drug

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companies were reluctant to share informationfor fear of prosecution under the Sherman antitrust laws. Despite those obstacles, work wentforward on the production of natural penicillinwith the goal of having ample stocks of thedrug available for General Eisenhower's invasion of Europe in the spring of 1944. By D-day, some 300 billion units of penicillin wereavailable to the armed services crossing thechannel.

In large measure, the success of thePeoria program was due to the efforts of AlbertL. Elder, coordinator of the penicillin programof the War Production Board of the U.S.Government and Robert D. Coghill, chief of thefermentation division of the Peoria Laboratory.By the war's end, twenty-one plants wereinvolved in the drug's manufacture.

The challenge of mass-producing the drughad been daunting. On March 14,1942, thefirst patient was successfully treated for strephtococcal septicemia with U.S.-made penicillin.Half of the total supply produced at the timewas used on that one patient. By June 1942there was just enough available to treat tenpatients.

Penicillin was first tested for military usein the spring of 1943, with pilot studies onsoldiers with chronic bacterial infections inBushnell General Hospital in Utah and HalloranGeneral Hospital in New York. By autumn,doctors were using antibiotic in combat zones,where it was limited to American and Allied military and to patients with life-threatening infections. The first U.S. wounded to directly benefitfrom the drug were the flight crews of theEighth Air Force stationed in Britain. Rationingwas necessary, as a single infection couldrequire 2 million or more units of the drug(single ampoules—sealed glass vessels holding solutions for hypodermic injection—contained 100,000 units). During the war, the armed forces received 85 percent of thenation's production, which amounted to 231billion units in 1943. With the implementationof successful mass-production techniques,1,633 billion units were produced in 1944 and7,952 billion units in 1945. Penicillin becamethe war's "wonder drug," and its remarkablemedical effects on infectious disease madeWorld War II different from any previous war.

Penicillin is now used all over the world.Thanks to the work of scientists and their staff,together with the Illinois farms and numerousdrug companies, the drug saved the lives ofhundreds of thousands of war victims duringWorld War II and has continued to shortenillness and save lives every day since.

By the early 1950s Pfizer was the largestproducer of natural penicillin. By then, however, it was no longer the only wonder drug.

Synthesizing Penicillin

The effort to synthesize penicillin duringthe war marks one of the most intensive undertakings in the history of inorganic chemistry.Unlike the natural fermentation process thatscientists successfully used to produce penicillin, the effort to produce a synthetic penicillinfailed. It is a story of frustration, bewilderingcomplexities involving the beta-lactam structure, and personal triumph, leading ultimatelyto the development of a family of antibioticsin the 1950s and 1960s.

After the war, academic chemist John C.Sheehan at the Massachusetts Institute ofTechnology, who had earlier been involved atMerck and Company in New Jersey with thedevelopment of the antibiotic streptomycin andvitamin B6, took up the challenge of producinga chemical synthesis of penicillin. He concluded that penicillin could be synthesized by arational chemical process but not by any of theknown techniques at the time. As a university

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researcher without the pressures of wartime,Sheehan made the decision in 1948 to directhis research efforts to the penicillin puzzle. Forthe next ten years he was without competitors,as most other organic chemists had concludedthat penicillin's synthesis was too difficult orunnecessary. In 1957 Sheehan synthesizedpenicillin and first used the term antibiotic.Research continues today in the penicillin andrelated beta-lactam antibiotics.

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