Widespread Penicillin Use In World War II
by
ANR
Penicillin was discovered in 1928 by Alexander Fleming, the Professor of Bacteriology at St. Mary’s Hospital in London. When Fleming returned from vacation on September 3, 1928, “Fleming began to sort through petri dishes containing colonies of Staphylococcus, bacteria that cause boils, sore throats and abcesses.”[1] In one Petri dish, he noticed that the surface was covered in bacterial colonies except for one area that was covered by a patch of mold. The space surrounding the immediate perimeter of the mold was free of Staphylococcus. Fleming concluded that the mold produced a substance that stopped bacterial growth. This substance was found to be a rare strain of Penicillium notatum, which kills “Gram-positive bacteria, including those that caused scarlet fever, pneumonia, gonorrhea, meningitis, and diphtheria.”[2]
The issue with this strain of Penicillium is that it had to be separated from the mold itself. Fleming also believed that the Penicillium would not work in humans, as he thought that the bacteria would not be able to stay in the body long enough to kill the harmful infections. In 1929, Fleming published an article on penicillin. About 10 years later at Oxford University, Ernst Chain found the article and “proposed to his supervisor, Howard Florey, that he try to isolate the compound. Florey’s predecessor, George Dreyer, had written Fleming earlier in the 1930s for a sample of his strain of Penicillium to test it for bacteriophages as a possible reason for antibacterial activity (it had none).”[3] The strain was still at Oxford, and Florey assembled a team of scientists, including Chain and the mycologist Norman Heatley. Heatley cultivated Penicillium in large amounts while Chain worked on purifying the bacteria from the mold. In February 1941, they tested penicillin on a policeman who had several infected abscesses. The supply ran out, however, and the policeman died a few weeks later. But, other patients were treated with the drug, and they recovered nicely. “The Oxford team then published their clinical findings.”[4]
Penicillin works by taking advantage of the bacteria’s natural cell cycle. When the bacteria prepares to divide, it creates “‘holes’ in its cell wall to allow for growth and separation of the daughter cells.”[5] Normally, a protein called PBP4 (Penicillin-Binding Protein 4) repairs the holes in the wall with peptidoglycans after the cell divides. “Penicillin kills bacteria by inhibiting the proteins which cross-link peptidoglycans into the cell wall.”[6] As a result, the PBP4 cannot repair the cell wall and the bacterial is flooded with water due to osmosis. Without any way to close the cell, the bacteria “ pop” under the pressure and undergoes necrosis (unprogrammed cell death). The necrosis also releases toxins into the bacteria’s environment, which damages the neighboring harmful bacteria.
The problem with penicillin being produced in England was that Great Britain was involved with World War II, so it could not use resources to mass produce the antibiotic. To help solve this problem, the British government turned to America to help this mass-production problem. Five companies volunteered to help, one of them being the pharmaceutical giant Pfizer.
At first, Pfizer tried to mass produce penicillin by using flasks and pans to try and cultivate the antibiotic in batches. When that proved to be slow, a lab assistant named Jasper Kane suggested using deep-tank fermentation, which was successful in producing gluconic acid. “Kane’s suggestion was risky for it meant Pfizer would have to curtail production of other, more profitable products while it concentrated on penicillin… In September 1943 it purchased the old Rubel Ice Plant on Marcy Avenue in Brooklyn, a nearby building that had the refrigeration equipment required, rebuilding it into the world’s first large-scale penicillin factory. ”[7] Upon its opening on March 1, 1944, it had 14 7,500-gallon tanks and produced about five times more penicillin than what was originally estimated. “The first large-scale human trials were conducted in military field hospitals”[8], and they were a success.
The production of penicillin first started with a penicillin mold, which was then bred in three-liter containers. These cultures were then placed in giant fermenter tanks that had “microbe fodder, chiefly corn steep liquor, milk sugar, salts and minerals. The mold was allowed to grow for two to four days. Although the whole process was difficult, the trickiest part was extracting penicillin from the broth, for penicillin was a very stingy “magic bullet:” only four parts drug per 10,000 parts broth.”[9] Then, the extracted penicillin was purified and carefully bottled in sterile rooms to avoid the possibility of contamination. After the penicillin was bottled, it was then frozen and dehydrated.
Penicillin and its related antibiotics are to be refrigerated if they are in liquid form. This would have complicated transport of the medicine considerably, as refrigerators on board the cargo ships would have to be kept constantly running. The penicillin would also have to be carefully packaged, as it was stored in glass bottles. Since the supply of penicillin was severely limited at first, “initial stocks were earmarked for military use.”[10] Howard Florey and an Australian consultant surgeon named Hugh Cairns tested penicillin on the British Army in North Africa in 1943.
The Allied invasion of Normandy, more commonly known as D-Day, would require millions of doses of penicillin if the Allies hoped to preserve the lives of men with infections. “Scientists working around the clock manufactured 2.3 million doses of penicillin in preparation for the D-Day landings on June 6, 1944.”[11] There is no good estimate of how many lives were saved in World War II due to penicillin, but the total deaths were around 60 million people.[12] Based on production speed and shipping time, it may be estimated that about 20 million lives were saved due to the administration of penicillin. Without penicillin, the total deaths in World War II may have been an estimated 80 million people.
[Image pending permission for use]
This poster appeared on the walls of fermentation plants producing penicillin during World War II.
Source: “Rethinking Antibiotic Research and Development: World War II and the Penicillin Collaborative,” NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673487/.
Source. Record Group 44, Records of the Office of Government Reports, 1932–1947, 44-PA-1505 “Penicillin Saves Soldiers' Lives! Every Minute Saved in Building This Plant Means a Life Saved on the Fighting Fronts. Give This Job Everything You’ve Got, 1941–1954,” National Archives, College Park, MD.
Glossary
Sources
Footnotes
[1] “Discovery and Development of Penicillin,” American Chemical Society, https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html
[2] Ibid.
[3] Robert Gaynes, “The Discovery of Penicillin—New Insights After More Than 75 Years of Clinical Use,” Centers for Disease Control and Prevention, May 2017, https://wwwnc.cdc.gov/eid/article/23/5/16-1556_article.
[4] Ibid.
[5]Audra Amasino, Dianna Amasino, Re-I Chin, Axel Glaubitz, Hsien-Yu Shih, Xiao Zhu, “How Penicillin Kills Bacteria (and How Bacteria Fight Back),” Milwaukee School of Engineering, http://cbm.msoe.edu/includes/pdf/smart2007/mwp2007.pdf
[6] Ibid.
[7] “Penicillin Production through Deep-tank Fermentation,” American Chemical Society, June 12, 2008, https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/penicillin.html
[8] Ibid.
[9] Ibid.
[10] Celia Henry Arnaud, “Penicillin: Purpose: Typical Antibacterial,” Chemical and Engineering News, June
20, 2005, https://cen.acs.org/articles/83/i25/Penicillin.html
[11] “Thanks to Penicillin… He Will Come Home!: The Challenge of Mass Production,” The National World
War II Museum, July 2017, https://www.nationalww2museum.org/sites/default/files/2017-07/thanks-to-penicillin-lesson.pdf
[12] “Research Starters: Worldwide Deaths in World War II,” The National World War II Museum,
https://www.nationalww2museum.org/students-teachers/student-resources/research-starters/research-starters-worldwide-deaths-world-war
The issue with this strain of Penicillium is that it had to be separated from the mold itself. Fleming also believed that the Penicillium would not work in humans, as he thought that the bacteria would not be able to stay in the body long enough to kill the harmful infections. In 1929, Fleming published an article on penicillin. About 10 years later at Oxford University, Ernst Chain found the article and “proposed to his supervisor, Howard Florey, that he try to isolate the compound. Florey’s predecessor, George Dreyer, had written Fleming earlier in the 1930s for a sample of his strain of Penicillium to test it for bacteriophages as a possible reason for antibacterial activity (it had none).”[3] The strain was still at Oxford, and Florey assembled a team of scientists, including Chain and the mycologist Norman Heatley. Heatley cultivated Penicillium in large amounts while Chain worked on purifying the bacteria from the mold. In February 1941, they tested penicillin on a policeman who had several infected abscesses. The supply ran out, however, and the policeman died a few weeks later. But, other patients were treated with the drug, and they recovered nicely. “The Oxford team then published their clinical findings.”[4]
Penicillin works by taking advantage of the bacteria’s natural cell cycle. When the bacteria prepares to divide, it creates “‘holes’ in its cell wall to allow for growth and separation of the daughter cells.”[5] Normally, a protein called PBP4 (Penicillin-Binding Protein 4) repairs the holes in the wall with peptidoglycans after the cell divides. “Penicillin kills bacteria by inhibiting the proteins which cross-link peptidoglycans into the cell wall.”[6] As a result, the PBP4 cannot repair the cell wall and the bacterial is flooded with water due to osmosis. Without any way to close the cell, the bacteria “ pop” under the pressure and undergoes necrosis (unprogrammed cell death). The necrosis also releases toxins into the bacteria’s environment, which damages the neighboring harmful bacteria.
The problem with penicillin being produced in England was that Great Britain was involved with World War II, so it could not use resources to mass produce the antibiotic. To help solve this problem, the British government turned to America to help this mass-production problem. Five companies volunteered to help, one of them being the pharmaceutical giant Pfizer.
At first, Pfizer tried to mass produce penicillin by using flasks and pans to try and cultivate the antibiotic in batches. When that proved to be slow, a lab assistant named Jasper Kane suggested using deep-tank fermentation, which was successful in producing gluconic acid. “Kane’s suggestion was risky for it meant Pfizer would have to curtail production of other, more profitable products while it concentrated on penicillin… In September 1943 it purchased the old Rubel Ice Plant on Marcy Avenue in Brooklyn, a nearby building that had the refrigeration equipment required, rebuilding it into the world’s first large-scale penicillin factory. ”[7] Upon its opening on March 1, 1944, it had 14 7,500-gallon tanks and produced about five times more penicillin than what was originally estimated. “The first large-scale human trials were conducted in military field hospitals”[8], and they were a success.
The production of penicillin first started with a penicillin mold, which was then bred in three-liter containers. These cultures were then placed in giant fermenter tanks that had “microbe fodder, chiefly corn steep liquor, milk sugar, salts and minerals. The mold was allowed to grow for two to four days. Although the whole process was difficult, the trickiest part was extracting penicillin from the broth, for penicillin was a very stingy “magic bullet:” only four parts drug per 10,000 parts broth.”[9] Then, the extracted penicillin was purified and carefully bottled in sterile rooms to avoid the possibility of contamination. After the penicillin was bottled, it was then frozen and dehydrated.
Penicillin and its related antibiotics are to be refrigerated if they are in liquid form. This would have complicated transport of the medicine considerably, as refrigerators on board the cargo ships would have to be kept constantly running. The penicillin would also have to be carefully packaged, as it was stored in glass bottles. Since the supply of penicillin was severely limited at first, “initial stocks were earmarked for military use.”[10] Howard Florey and an Australian consultant surgeon named Hugh Cairns tested penicillin on the British Army in North Africa in 1943.
The Allied invasion of Normandy, more commonly known as D-Day, would require millions of doses of penicillin if the Allies hoped to preserve the lives of men with infections. “Scientists working around the clock manufactured 2.3 million doses of penicillin in preparation for the D-Day landings on June 6, 1944.”[11] There is no good estimate of how many lives were saved in World War II due to penicillin, but the total deaths were around 60 million people.[12] Based on production speed and shipping time, it may be estimated that about 20 million lives were saved due to the administration of penicillin. Without penicillin, the total deaths in World War II may have been an estimated 80 million people.
[Image pending permission for use]
This poster appeared on the walls of fermentation plants producing penicillin during World War II.
Source: “Rethinking Antibiotic Research and Development: World War II and the Penicillin Collaborative,” NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673487/.
Source. Record Group 44, Records of the Office of Government Reports, 1932–1947, 44-PA-1505 “Penicillin Saves Soldiers' Lives! Every Minute Saved in Building This Plant Means a Life Saved on the Fighting Fronts. Give This Job Everything You’ve Got, 1941–1954,” National Archives, College Park, MD.
Glossary
- Mycologist: A scientist who specializes in fungi and, on a lesser scale, microbiology
- Necrosis: The process in which a cell undergoes unexpected cell death. Since this cell death is unexpected, enzymes that would normally carry away the remains of the cell do not appear. This means that the cell’s remains stay in the environment, acting as potentially toxic substances.
- Peptidoglycans: A substance that makes up the cell walls of bacteria
Sources
- Amasino, Audra, Dianna Amasino, Re-I Chin, Axel Glaubitz, Hsien-Yu Shieh, and Xiao Zhu. "How Penicillin Kills Bacteria (and How Bacteria Fight Back)." MSOE. http://cbm.msoe.edu/includes/pdf/smart2007/mwp2007.pdf.
- Arnaud, Celia Henry. "Penicillin." CEN RSS. https://cen.acs.org/articles/83/i25/Penicillin.html. "Discovery and Development of Penicillin." American Chemical Society. https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html.
- "Penicillin Production through Deep-tank Fermentation - National Historic Chemical Landmark." American Chemical Society.https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/penicillin.html.
- Quinn, Roswell. "Rethinking Antibiotic Research and Development: World War II and the Penicillin Collaborative." American Journal of Public Health. March 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3673487/.
- "Research Starters: Worldwide Deaths in World War II." The National World War II Museum. https://www.nationalww2museum.org/students-teachers/student-resources/research-starters/research-starters-worldwide-deaths-world-war.
- “‘Thanks to Penicillin…He Will Come Home!’ The Challenge of Mass Production." The National World War II Museum https://www.nationalww2museum.org/sites/default/files/2017-07/thanks-to-penicillin-lesson.pdf.
- "The Discovery of Penicillin-New Insights After More Than 75 Years of Clinical Use - Volume 23, Number 5-May 2017 - Emerging Infectious Diseases Journal - CDC." Centers for Disease Control and Prevention. April 14, 2017. https://wwwnc.cdc.gov/eid/article/23/5/16-1556_article.
Footnotes
[1] “Discovery and Development of Penicillin,” American Chemical Society, https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/flemingpenicillin.html
[2] Ibid.
[3] Robert Gaynes, “The Discovery of Penicillin—New Insights After More Than 75 Years of Clinical Use,” Centers for Disease Control and Prevention, May 2017, https://wwwnc.cdc.gov/eid/article/23/5/16-1556_article.
[4] Ibid.
[5]Audra Amasino, Dianna Amasino, Re-I Chin, Axel Glaubitz, Hsien-Yu Shih, Xiao Zhu, “How Penicillin Kills Bacteria (and How Bacteria Fight Back),” Milwaukee School of Engineering, http://cbm.msoe.edu/includes/pdf/smart2007/mwp2007.pdf
[6] Ibid.
[7] “Penicillin Production through Deep-tank Fermentation,” American Chemical Society, June 12, 2008, https://www.acs.org/content/acs/en/education/whatischemistry/landmarks/penicillin.html
[8] Ibid.
[9] Ibid.
[10] Celia Henry Arnaud, “Penicillin: Purpose: Typical Antibacterial,” Chemical and Engineering News, June
20, 2005, https://cen.acs.org/articles/83/i25/Penicillin.html
[11] “Thanks to Penicillin… He Will Come Home!: The Challenge of Mass Production,” The National World
War II Museum, July 2017, https://www.nationalww2museum.org/sites/default/files/2017-07/thanks-to-penicillin-lesson.pdf
[12] “Research Starters: Worldwide Deaths in World War II,” The National World War II Museum,
https://www.nationalww2museum.org/students-teachers/student-resources/research-starters/research-starters-worldwide-deaths-world-war