Penicillin: More than a Moldy Petri Dish

The development of penicillin started – but definitely did not end – with the chance discovery of some mold in a petri dish. There is so much more to the story.

Research:

• Bernard, Diane. “How a miracle drug changed the fight against infection during World War II.” Washington Post. 7/11/2020. https://www.washingtonpost.com/history/2020/07/11/penicillin-coronavirus-florey-wwii-infection/
• British Library. “Inventor(s) of the month, Alexander Fleming and the story of Penicillin.” 7/28/2021. https://blogs.bl.uk/business/2021/07/inventors-of-the-month-alexander-fleming.html
• Chain, E. et al. “Penicillin as a Chemotherapeutic Agent.” The Lancet. Vol. 236, Issue 6104. 8/24/1940. https://doi.org/10.1016/S0140-6736(01)08728-1
• Fleming A. On the Antibacterial Action of Cultures of a Penicillium, with Special Reference to their Use in the Isolation of B. influenzæ. Br J Exp Pathol. 1929 Jun;10(3):226–36. PMCID: PMC2048009.
• Gaynes, Robert. “The Discovery of Penicillin—New Insights After More Than 75 Years of Clinical Use.” Emerg Infect Dis. 2017 May; 23(5): 849–853.. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5403050/
• Lee, Victoria. “Microbial Transformations.” Historical Studies in the Natural Sciences, SEPTEMBER 2018, Vol. 48, No. 4. Via JSTOR. https://www.jstor.org/stable/10.2307/26507225
• National Museums of Scotland. “Culture Vessel.” https://www.nms.ac.uk/explore-our-collections/stories/science-and-technology/culture-vessel/
• Quinn, Roswell. “Rethinking Antibiotic Research and Development: World War II and the Penicillin Collaborative.” American Journal of Public Health | March 2013, Vol 103, No. 3.
• Scibilia, Anthony Julius. “Being Prometheus in 1943:: Bringing Penicillin to the Working Man.” Pennsylvania History: A Journal of Mid-Atlantic Studies , Vol. 80, No. 3 (Summer 2013). https://www.jstor.org/stable/10.5325/pennhistory.80.3.0442
• Science History. “Alexander Fleming.” 12/5/2017. https://www.sciencehistory.org/historical-profile/alexander-fleming
• Science Museum. “How Was Penicillin Developed?” 2/23/2021. https://www.sciencemuseum.org.uk/objects-and-stories/how-was-penicillin-developed
• Shama, Gilbert. “’Déjà Vu’ – The Recycling of Penicillin in Post-liberation Paris.” Pharmacy in History , 2013, Vol. 55, No. 1 (2013). Via JSTOR. https://www.jstor.org/stable/23645718
• The Alexander Fleming Laboratory Museum, London, UK. “The Discovery and Development of Penicillin 1928-1945.” 11/19/1999. https://www.acs.org/content/dam/acsorg/education/whatischemistry/landmarks/flemingpenicillin/the-discovery-and-development-of-penicillin-commemorative-booklet.pdf
• Wainwright, Milton. “Moulds in Folk Medicine.” Folklore , 1989, Vol. 100, No. 2 (1989). https://www.jstor.org/stable/1260294
• Wainwright, Milton. “The History of the Therapeutic Use of Crude Penicillin.” Medical History, 1987, 31: 41-50.
• Williams KJ. The introduction of 'chemotherapy' using arsphenamine - the first magic bullet. J R Soc Med. 2009 Aug;102(8):343-8. doi: 10.1258/jrsm.2009.09k036. PMID: 19679737; PMCID: PMC2726818.
• Wood, Jonathan. “Penicillin: The Oxford Story.” Oxford News Blog. 7/16/2010. https://www.ox.ac.uk/news/science-blog/penicillin-oxford-story
• Zaffiri, Lorenzo et al. “History of Antibiotics. From Salvarsan to Cephalosporins.” Journal of Investigative Surgery, 25, 67–77, 2012.

 

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Episode Transcript

Speaker 1 (00:01):
Welcome to Stuff you Missed in History Class, a production
of I Heart Radio. Hello, and welcome to the podcast.
I'm Tracy V. Wilson and I'm Holly Fry. Holly, when
you were a kid that you learned the story of penicillin,

(00:23):
I feel like I didn't get it until later. Okay,
do you remember what you learned? Um? You know, accidental
grew on mold because there was a rumor at our
school that you could make your own antibiotics in your bedroom. Well,
we'll talk about something similar to that, and you better
believe my crafty little brain was like, could I could

(00:46):
I start a little apothec area out of my classes? Uh? Maybe?
Um so, I, like a lot of people learned this
very basic story about Alexander Fleming leaving a Petri dish
out and a getting taminated with mold, and then it's
just sort of presented as voila penicillin. He did it
all by himself. That is not remotely accurate. Like the

(01:13):
Petri dish and mold part, that part kind of accurate,
at least we'll talk more about it. But like it
was not suddenly he had invented penicillin by himself at all. Uh,
so that's one of the things we're going to talk
about in today's episode. Also, though, this was just inspired
by an email from listener Abbey, which we actually read

(01:35):
on the show recently, and Abby mentioned that after World
War Two there was a penicillin recycling project and I
was like, I need to know more about this, uh,
And I didn't talk about it a lot in that
listener mail segment because it is gross. So just as
a heads up, there is a lot of mold in

(01:58):
this episode and if a Phray is like mold Broth
bothers you, maybe this is not the episode for you.
That's your punk band, mold Broth were also just there's
a lot of bodily fluids. There's also some animal testing,
just you know, I know people can be squeamish about

(02:18):
particular things. Just a heads up on all of that. So,
like we just said, the development of penicillin started but
definitely did not end, with the chance discovery of some
mold in a petri dish. We're going to get back
to that. But the discovery of a seemingly miraculous treatment
made from mold piqued the interest of medical historians who

(02:40):
started looking for earlier uses of mold as a treatment
for wounds or diseases, and it turned out there were
actually a lot of them. Yeah, the people who had
been using these obviously already knew about them, but there
had not really been a systemic historical look at it. Uh.
The vast majority of the treatments involved using mold to

(03:02):
make a topical preparation for wounds. So this included using
moldy soybeans and China, and moldy bread in Egypt, and
cheese mold in Greece, with all of those dating back
roughly three thousand years or more. Aboriginal and indigenous peoples
all around the world have used molds medicinally as well.

(03:23):
There's also some evidence that more than two thousand years ago,
people in northern Africa consumed something that contained enough tetracycline
to leave evidence of that on their bones. Tetracycline actually
comes from bacteria, not from mold, but the bacteria and
question form these branching filaments that look enough like a

(03:47):
fungus that it was classified as a fungus for a
really long time. In more recent times, herbalists and apothecaries
in Europe described medicinal mold preparations all through the seventeen
and eighteen centuries, and researchers looking into the historical use
of mold in the twentieth century found that a lot
of full remedies using mold were still around. One biochemist

(04:09):
described traveling through Europe and finding that each home had
a moldy loaf of bread stored in the kitchen rafters,
which would be used to prepare dressings for cuts or
other wounds. Other oral accounts described people intentionally growing mold
on oranges or other fruit or substances, or collecting it
from meat as it was being cured. We don't really

(04:31):
have a lot of detail about how effective these treatments
actually were. There weren't clinical studies or things like that
to reference. But there are so many different medicinal uses
for molds to treat infections in so many different parts
of the world that some medical historians have concluded that
at least some of them probably did have some real

(04:52):
antimicrobial efficacy. Some of the folks that were interviewed about
their folk remedies after penicillin was developed and they learned
that penicillin was made out of mold, they were kind
of like Oh yeah, we've been doing that forever, and
by the time Fleming spotted that contaminated culture plate, it

(05:12):
was already established that various bacteria, molds, and other organisms
could inhibit one another's growth. The term antibiosis was coined
by the end of the nineteenth century to describe this
antagonistic effect that micro organisms could have on one another,
and there may have even been some work with penicillium

(05:32):
mold specifically before Fleming made his discovery. Joseph Lister may
have successfully treated a patient with a filtrait made from
Penicillium glaucum as early as eighteen seventy seven. Around the
same time, there were other doctors and scientists experimenting with
whether penicillium mold killed other micro organisms in a lab.

(05:56):
None of this is totally certain, though, the taxonomy for
molds and other fungi was not very robust yet, and
the people who were doing this work were not experts
in mycology. It's possible that they were working with totally
different molds that they were just calling penicillium, and then
aside from that, none of them published a thorough description

(06:17):
of their work, So a lot of this conclusion is
based on notes which we're not necessarily complete. You cannot
replicate an experiment to test it if you don't really
know what went down right. The early twentieth century saw
the development of the first drugs that killed specific bacteria.
In the eighteen seventies, German physician Paul Erlick had noticed

(06:40):
that chemical dies changed the color of some bacteria and
not others. This was a precursor to the Graham staining
method that is still used today to broadly classify bacteria
as gram positive and gram negative based on how they
respond to the stain. Erlick started to wonder if it
was also possible well to discover a substance that killed

(07:02):
some bacteria but not others. In nine researchers in Erlick's
lab discovered that the arsenic compound arsphenamine killed the bacteria
that caused syphilis. This drug was marketed as salver sand,
and it was also known as six oh six because
it was the six hundred and sixth preparation that had

(07:22):
been tested in Erle's lab. As part of this project.
Salver sand was found to be effective against other infectious
diseases as well. This was really the first effective treatment
for syphilis and the first modern antimicrobial compound. Erlick described
this use of a chemical to kill cells in the
body using the word chemotherapy, and he coined the term

(07:45):
magic bullet to describe the drug's ability to target pathogens.
Erly's lab had been systematically testing one arsenic compound after
another when it developed salversen. On the other hand, Alexander
Fleming's discovery of pennas sill in a little less than
twenty years later, was an accident. He was interested in
the anti microbial properties of the body's own fluids and secretions.

(08:09):
He coined the term licensign to describe a substance in
things like mucus, tears, and saliva that seemed to inhibit
bacterial growth. He reportedly made this discovery when he had
a cold. He cultured his own mucus in a petri
dish and then later discovered that the area around the
mucus wasn't growing bacteria. In some versions of this story,

(08:31):
his office was perpetually untidy, and this petrie dish had
sat there forgotten in some clutter for a couple of
weeks before he made the discovery. His discovery of penicillin
had some similarities. This time, he was studying staff bacteria,
and all of his petri dishes were supposed to be
in an incubator when he left for a two week

(08:53):
vacation in nineteen eight. One of them, though, was apparently
left on a lab bench by accident. When he got
back to the office on September three, he noticed the
misplaced Petrie dish that had been contaminated with mold, and
the area around the mold, he saw colonies of staff
bacteria that we're dying. We don't know exactly where the

(09:17):
mold contamination came from. One possibility is an open window,
and another is a mycology lab that was in the
same building. And this discovery was only possible because the
petrie dish was left out on a bench. If it
had gone into the incubator like it was supposed to,
the staff bacteria would have flourished, but the temperature would

(09:37):
have been wrong for the mold to grow. Beyond this,
other details are really hazy. Fleming did not take careful
notes about exactly what he was looking at when either
he or one of his assistants spotted this petrie dish.
His later descriptions about exactly how the mold and the
bacteria were interacting with one another could be contradictory. When

(09:59):
he published his discovery and the British Journal of Experimental
Pathology in June of nine, he made it sound as
though he routinely left his staff culture on plates on
the bench for extended periods, rather than that often repeated
story that this was one that was forgotten while he
was on vacation. He also described the mold as most

(10:21):
resembling Penicillium rubrum, and other researchers later corrected that identification
to penicillium notatam. That June paper describes various experiments Fleming
and his colleagues did with a filtrate made from the
broth the mold was growing in. He coined the term
penicillin to describe this fil trait because writing quote mold

(10:44):
broth filtrate over and over was apparently cumbersome. He did
some basic toxicity tests and small mammals by injecting them
with this fil trait, and it did not seem to
be toxic. But he doesn't seem to have tried injecting
animals with one of the bacteria that he knew penicillin
killed in a petri dish to see if that worked
in a living body as well. He did test penicillin's

(11:08):
activity against various microbes in a petri dish, including Staphylococcus, streptococcus,
and new Macoccus, as well as what was described at
the time as Basillus influenza and Basillus diph theory a
penicillin was particularly effective against all the pyogenic cocai, so
the ones that ended with caucus in that list, but

(11:31):
it wasn't as effective against the bassilla. So if he
had a petri dish that was growing both staff bacteria
and Bacillus influenza, he could use penicillin to kill only
the staff, leaving that Basillus culture in place. Side note.
Today Basillus influenza is known as Hemophilis influenze. It got

(11:52):
the influenze moniker when people thought that it caused influenza,
which it does not. Influenza is caused by a riss.
Just to keep things a little confusing for everybody. That
was one of the things about reading this paper was
then needing to go and look like, what did they
call that? Now? I don't think that's what they call
that now. Fleming didn't really have the skills or expertise

(12:15):
to try to extract this fil trait into a usable medicine.
His research students Stuart Craddock and Frederick Ridley both worked
on this, and both of them were credited at the
end of the published paper. Fleming also sent samples of
the mold to anyone who asked for it, but he
didn't really make any headway into turning penicillin into a medicine,

(12:36):
and he stopped working with it in ninety one. We'll
talk about how it did become a medicine after a
sponsor break. When Alexander Fleming was working with penicillin at
the end of the nineteen twenties, he was mostly approaching

(12:59):
it as something would have uses in a laboratory, such
as using it to isolate different cultures from one another
depending on whether they were sensitive to penicillin. One of
his students, Cecil George Payne, does seem to have successfully
used penicillin to cure eye infections in newborns in nineteen thirty,

(13:20):
as well as to treat a minor who had an
infected scratch on his cornea, but Pain did not publish
anything about this success, and he also does not seem
to have realized until much later that he had been
looking at something that could have revolutionized medicine. Meanwhile, in
nineteen thirty two, German bacteriologist Gerhard Domac was studying a

(13:42):
red dye that hadn't been in effective antibacterial in a
petri dish, but turned out to treat strip infections in
mice and staff infections in rabbits. This die was developed
into the drug Protonsal, the first sulfa drug and the
first drug used to treat and prevent a ray inache
of bacterial infections in humans. Unlike Salversen, which was primarily

(14:05):
used to treat civilist Protonsal could treat a variety of
grand positive bacteria. Do Mac was awarded the Nobel Prize
and Physiology or Medicine for this work in nineteen thirty nine,
but the Nazi Party had forbidden Germans to accept the
Nobel Prize. This was because the Nobel Peace Prize had

(14:25):
previously been awarded to German pacifist Carl von Ostiski in
nineteen thirty five. Do Mac accepted the prize anyway. Afterward,
he was arrested by the Gestapo and forced to write
to the Nobel Committee rejecting the prize. He wasn't able
to get his medal for having won the Nobel Prize

(14:45):
until after the end of World War Two, and he
never actually got the monetary award. As a side note,
we mentioned Paul Erlick earlier in the episode. The street
in Frankfurt where his institute was located was named after him,
but it was renamed to the Nazis came to power
because he was Jewish. Erlake was no longer living at
this point. He had died after a stroke in nineteen fifteen.

(15:08):
So the same year that Domac was awarded the Nobel
Prize for developing the first sulfa drug, researchers at the
Sir William Dunn School of Pathology at Oxford University started
studying penicillin. There had been a Department of Pathology at
Oxford for decades, but this school was almost brand new.

(15:29):
It had opened in nineteen thirty five after the university
received funds from the estate of the late Sir William Dunn,
which is what funded the new school. Australian pathologist Howard
Walter Florey had been appointed Professor of Pathology and the
research team he recruited included Ernst Chaine, who was a
Jewish biochemist who had fled to the UK from Germany

(15:51):
after the Nazi Party came to power. Floory, Chain and
others at Oxford had been inspired by Domac's success with
sulfa drugs, and in eight they started studying the enzyme lyssyme,
which Alexander Fleming had discovered. Chain also found Fleming's earlier
paper on the anti microbial effects of penicillium mold, and

(16:12):
Oxford already had a sample of Fleming's mold on hand.
The team started working with it in nine. Fleming and
his team at St Mary's had been mostly working with
small amounts of mold and a petri dish. Florian Chain,
on the other hand, we're trying to extract enough of
the active substance to test whether it could be used

(16:33):
as a medicine. Even though they were going to start
with mice, which are very small, this required a lot
of mold, so much more mold than Fleming had been
working with. Hospital bed pants turned out to be just
about the right size and shape to grow this mold in,
but most of the ones on hand were needed by

(16:55):
hospital patients, so the team at Oxford started repurposing what
her vessels they could scrounge up, jars and food tens,
milk churns, fuel cans, all kinds of things. I love
that it's a little hodgepodgy. It's very hodgepodgy. It was
also really a team effort. Over the course of the project,

(17:18):
six women were paid two pounds a week to tend
to the fermenting mold. They were Ruth Callo, Claire Eniot,
Betty Cook, Peggy Gardner, Megan Lancaster and Patricia mckegney, and
they were nicknamed the Penicillin Girls. Norman Heatley developed a
method to extract penicillin from the mold broth into amyl
acetate and then back into water. Edward Abraham developed techniques

(17:43):
to purify it, and on May nine, almost exactly ten
years after the British Journal of Experimental Pathology received Fleming's
paper on penicillin, they conducted an experiment involving eight mice.
All eight of the mice were injected with Streptococcus bacteria.

(18:03):
Then four of the mice were injected with penicillin and
the other four were left untreated. The four untreated mice
died but the other four who got penicillin all survived.
Other tests on animals followed, including studies on rats and cats.
They tested penicillin's efficacy against multiple bacteria. In addition to

(18:25):
strep and staff, there was Claustridium septicum, which can cause
gas gang green, and penicillin was dramatically effective against all
of them with little to no toxicity to their test subjects.
In August of nineteen forty, Chain, Floury, Heatley, and others
published Penicillin as a Chemotherapeutic Agent in the journal The Lancet,

(18:48):
detailing the basic findings of their research. It was clear
from this work that penicillin could potentially be a life
saving drug for human beings, and at this point, aside
from the medicines we have talked about in this episode,
there just weren't many effective options to treat bacterial infections.

(19:08):
That meant that minor illnesses like strep throat could lead
to much more serious problems like rheumatic fever. Life threatening
infections could develop an injuries that had seemed really superficial.
People like Ignace cell Vice and Joseph Lister had advocated
for things like hand washing and sterile surgical techniques to

(19:29):
cut down on the likelihood that a person would contract
an infection during childbirth or surgery, but infections could still happen,
and often there just was not much that could be
done about it SELFA drugs had been a huge step
forward in providing broadly effective treatments for bacterial infections, but
a lot of people were allergic to them, and most

(19:50):
of them could also cause a range of unpleasant side effects.
So figuring out whether penicillin could be a usable drug
in people and not just small mammals was a huge priority.
And since people are significantly bigger than mice, that meant
that the team needed to grow a lot more mold.
But at this point the UK was a war Germany

(20:12):
had invaded Poland on September one, nine and both the
UK and France had declared war on Germany two days later.
That meant that a lot of equipment and materials were
now dedicated to the war effort. For the sake of
time and expense, Norman Heatley designed a flat, rectangular pottery
vessel with a spout that was stackable and glazed on

(20:34):
the inside to make it watertight. The team eventually used
seven hundred of these vessels to produce about five hundred
liters of mold broth every week, but this was a
slow and cumbersome, kind of fiddly process. Even with all
seven hundred vessels in use, it took about four weeks

(20:54):
to make enough penicillin to treat one human patient, and
it took once for all seven hundred of those vessels
to be ready. At the end of nineteen forty, only
about ninety of them were all set and had been
seated with mold spores. The first attempt to treat a
person with penicillin made from all of this mold started

(21:15):
on February twelve, ninety one. That patient was Albert Alexander,
and there are multiple conflicting descriptions of how he became injured.
In some accounts, he cut himself shaving, In others, he
scratched himself while pruning roses, and still others he was
injured in a bombing during the Blitz. But regardless of

(21:38):
the cause, it is documented that he had a very
serious infection that was certain to be fatal if left untreated.
Alexander showed promising signs of recovery within twenty four hours
of being treated with penicillin, but because so little penicillin
had been made at this point, they had to collect
his urine and extract the pen sillin out of it

(22:01):
and then reuse it. So the body excretes penicillin really rapidly,
and roughly seventy percent of it comes out in the
urine unchanged, it could be more or less than that.
I saw numbers that were literally from one percent to
It's possible to recover half or more of that excreted

(22:21):
penicillin using the same basic method that was used to
extract it from the mold broth in the first place.
Even with the penicillin that had been reclaimed from his urine,
there wasn't enough to totally cure Alexander's infection. Eventually, the
team had given him all of the penicillin they had,
and after they ran out, his infection returned and he

(22:44):
died on March fift So it's clear that making enough
penicillin to do a clinical trial it was going to
be a huge challenge. With all this effort, they had
not made enough to successfully treat even one patient, Although
folk sing on treating children would have allowed the team
to use smaller doses. At this point, the priority was

(23:06):
really confirming the penicillin worked in adults, and then if
it did, supplying Allied troops with it. Infections were a
major major cause of death for wounded soldiers, and effective
treatments for bacterial illnesses could also allow six soldiers to
return to duty faster, but the prospects for doing that

(23:26):
in the UK were grim. Although there were British companies
that were interested in working with penicillin, most were dedicated
to critical wartime work involving drugs and other chemicals that
were already known to have a use. Plus British factories
were at risk of being bombed or otherwise attacked. Floor
and his team also understood that if Britain were invaded,

(23:50):
they might need to destroy their research work to prevent
it from being captured by the Germans. But they were
also really unwilling to risk loseing their penicillium mold entirely.
Norman Heatley suggested that several of them intentionally rub mold
into their coats so that if they had to flee,

(24:11):
they could just wear their samples with them undetected. Why
does everybody a miss on this transport? Smell weird? Smells well,
Musty in one, Floor and Heatley went to the United
States to try to find pharmaceutical companies that could help.
Work in the UK didn't stop at this point or

(24:33):
in other countries that had started experimenting with penicillium, but
the focus on mass producing penicillin shifted to the US,
and we'll talk more about that. After a sponsor break
in June of one, Howard Florey and Norman Heatley took

(24:56):
a series of flights to get from the UK to US.
These flights were paid for by the Rockefeller Foundation, which
had also done some of the funding for their research.
When they left, they had treated a total of six
patients with penicillin. In addition to Albert Alexander. One other

(25:17):
patient had died, but that patient died of a ruptured aneurysm,
not of the infection that the penicillin was treating. There
was just not enough penicillin to treat more people than that.
As Floor and Heatley were preparing to go, the Oxford
team was preparing and freeze drying as much penicillin as

(25:38):
possible for them to take with them. Floor was also
finishing a second paper titled Further Observations on Penicillin, which
went on to be published that August. There had been
a lot of debate about whether to publish this paper.
On the one hand, it contained a lot of information
that could save people's lives, but on the other hand,

(25:59):
there were scerns about Germany or its allies producing penicillin,
which could provide them with an advantage in the war,
and that paper would give them a lot more information
to do it. There were similar debates among the Oxford
team about whether to patent penicillin. A lot of them
found the idea of patenting any medicine to be just appalling,

(26:22):
while Ernst Shane argued that penicillin was their work and
it deserves to be protected. Chane also thought that their
ongoing struggles to get enough funding for their work would
be totally resolved if it could just be paid for
through licensing fees from a patent. Chane was also deeply
disappointed by not being part of this trip to the

(26:44):
United States, and this is something that seems to have
caused a huge rift between him and Floor since the
whole purpose of this trip was to try to get
manufacturing started, and Heatley was the person who had been
focused on manufacturing like it makes sense that Heatley would
be the person ago. They also wanted to minimize the
number of people going for the sake of secrecy. This

(27:06):
decision made sense, but Chain seems to have been incredibly
upset by it. The US had passed the Lend Lease
Act in March of ninety one, which established a framework
for the United States to provide the allies with things
like weapons, vehicles, materials, machinery, and facilities that would promote
the defense of the United States. The manufacturer of penicillin

(27:29):
seemed to fall under that definition, but Floury and Heatley
still had to find a pharmaceutical company that had the
interest and the ability to try to produce penicillin on
a commercial scale. They had a series of meetings and
disappointments and kind of stops and starts, and then Floury
and Heatley wound up at the Department of Agriculture's Northern

(27:50):
Regional Research Laboratory or n r r L and Peoria, Illinois,
which already had a fermentation division, which was very handy
since they grew penicillin by fromenting. Researchers there started working
on finding ways to grow penicillium mold. A lot faster
than it had been. They started on that work in July.

(28:13):
This was a multi step process. At Oxford, researchers had
been growing the mold in a broth in flat, rectangular
pottery vessels. In Illinois, researchers figured out that growing it
in corn steep liquor yielded about ten times more penicillin.
This was convenient because corn steep liquor is a byproduct

(28:34):
of the wet milling process and people were already trying
to find a practical use for it. Those vessels and
Oxford were also rectangular and flat, because the mold was
essentially growing as a flat surface layer, and researchers in
Peoria thought it would be more efficient to grow the
mold in a submerged medium, but this also required they're

(28:56):
finding a different strain of penicillium mold that would grow
really well while submerged and also produced the antimicrobial substance
that they need, because not all of the penicillium strains
really did that very well. This involved gathering mold from
all over the world, which they did with the help
of the Army Transportation Corps, and they tested all these

(29:18):
samples in the lab. They Eventually, though, found a sample
growing on a moldy cantelope that worked really well. This
find is usually credited to lab assistant Mary kay Hunt,
who was nicknamed Moldy Mary. She had found this cantelope
not in some far reaching place brought back by the
Army Transportation Corp, but at a local Peoria fruit market.

(29:42):
The strain of the mold, Penicillium chrysogenum, was about a
hundred times more productive than the other strains they tried.
Even as the research lab figured out ways to increase
the yield of penicillium mold, they still needed pharmaceutical or
chemical manufact ers to actually get a penicillin drug into production.

(30:03):
A group of pharmaceutical companies and the federal government met
in October of to coordinate both the production process and
information sharing. The goal was to first produce enough penicillin
for clinical trials, and then, if those were successful, to
scale up production to make as much as could be
needed for Allied troops. This was a huge and really

(30:27):
unprecedented level of cooperation that was also gonna be really tricky.
John L. Smith from Fieser had this to say about it, quote,
the mold is as temperamental as an opera singer. The
yields are low, the isolation is difficult, the extraction is murder,
the purification invites disaster, and the essay is unsatisfactory. So

(30:51):
the Office of Science, Research and Development helped coordinate information
sharing about methods and techniques to do this successfully. Along
with managing fifty seven different research contracts related to it,
The War Production Board also worked with twenty five different
companies to scale up production of penicillin. They narrowed it

(31:13):
down to those twenty five after investigating more than a
hundred seventy five different companies to determine whether they were
suitable or not. The first patient in the US to
be treated with penicillin was thirty three year old and Miller,
who had developed septicemia after a pregnancy loss. Her treatment
started on March fourteenth, ninety two, and it required half

(31:35):
the penicillin that was in existence in the US at
that point. Also in nineteen forty two, back in the UK,
Alexander Fleming got some penicillin from the Oxford Group, which
was still at work, used that to treat one of
his patients, and when that treatment was successful, he got
a huge right up about it in the times. This

(31:57):
article didn't actually mention Floory or any of the other
researchers at the Oxford team, though, and this really started
to build the perception that penicillin was solely Fleming's work.
Fleming also seemed willing to take that credit, and Flory
didn't want to talk to the press and also didn't
want the rest of the Oxford team to talk to

(32:19):
the press, just really starting the ball rolling on this
being just Alexander Fleming's own work and nobody else's. The
fact that all of this was happening during World War
Two came along with a number of ethical dilemmas. One
that we referenced earlier was how careful researchers should be
about making sure information about penicillin and penicillin production wasn't

(32:43):
available to Germany or its allies. Doctors and medical ethicists
generally agreed that if a patient needed penicillin and the
penicillin was available, they could have it, regardless of their
nationality or what army they fought for. But since access
to penicillin could also create a military advantage, people also

(33:04):
believe that information about how to make it or samples
of the mold itself should not be shared, not with Germany,
and not with any countries likely to cooperate with Germany.
There are a lot of articles discussing whether, in fact
somebody in Germany did or did not receive one of
Fleming's samples way earlier in this whole story, before the

(33:26):
hostilities started. Within the US, another ethical issue was access
to penicillin, because once clinical trials were complete, the penicillian
being produced was going to be reserved almost exclusively for
military use. At the same time, they were definitely going
to be civilians whose lives would be lost without it.

(33:49):
Dr Chester Kiefer was responsible for rationing penicillin to civilians
and was absolutely inundated with requests for it. This led
some people to figure out ways to make their own penicillin.
For example, on November tenth three, Julius A. Vogel, who
was the plants physician at a steel plant in Pennsylvania,

(34:12):
figured out how to make penicillin in his kitchen see
my plan as a kid was not completely because I
had the knowledge of a plant position. Vogel based his
work on an earlier discovery by George Robinson and James
Wallace at Singer Laboratory at Allegheny General Hospital in Pittsburgh, Pennsylvania.

(34:36):
On October eighth, n they reported that they had found
a way to make a topical treatment by soaking a
gauze pad and penicillium mold and then letting it grow
in a petri dish for four or five days. Vogel,
who had been disabled following a serious infection in his
knee as a child, built on this to turn his
kitchen into a miniature factory for treating similarly mold and

(34:59):
few used gauze. Vogel's wife, Unice, was a big part
of this process, making the auger for the petri dishes
and sterilizing the equipment between batches. As you can imagine,
all of this required a lot of careful planning to
keep a steady supply of mold that was the right
age to produce penicillin. Yeah, Vogel talked a lot about

(35:21):
how if penicillin had existed when he was a child,
he probably would not have almost died and then had
like a disability that affected him for the rest of
his life. Vogel presented his development at the Department of
Industrial Research on November eleven, and he got a lot

(35:42):
of criticism from the research community and from the companies
that were working on mass producing penicillin. There were some
understandable concerns about the potential for penicillin made at home
to be contaminated in some way, but Vogel reportedly used
these gauze pads that steel mills all over the area,

(36:04):
treating workers who had on the job accidents and otherwise
would have just not had access to any antibiotics at all.
Yet another ethical conundrum arose after Floory and Chain traveled
to Northern Africa in ninety three to test penicillin on
wounded soldiers and realized that it was also effective against gonaihea.

(36:26):
Before this point, penicillin had been envisioned as something that
would save the lives of soldiers who had been seriously
entered in battle or had contracted a serious illness like
bacterial pneumonia, but gonahea, especially in its early stages, is
more of a nuisance. Winston Churchill reportedly said that penicillin
should be used for the quote best military advantage, which

(36:49):
meant when supplies were limited, getting soldiers who had gonaha
back into peak condition, rather than treating seriously injured soldiers
who were going to be sent back home. I supplies
were not limited for that much longer, though. Fiser's first
plant for the commercial production of penicillin opened in Brooklyn,
New York, on March first, nineteen. By that point, clinical

(37:13):
trials had showed that penicillin was clearly beneficial against a
range of pathogenic bacteria. Refinements to the production process and
to the mold itself using things like X rays and
UV light continued to increase the yield. Meanwhile, Alexander Fleming,
who wasn't involved with any of this, was on the

(37:34):
cover of Time magazine on May fifteenth. By this point,
pharmaceutical companies in the U s we're trying to produce
enough penicillin to meet the needs of the D Day invasion.
Propaganda posters were hung on the walls of penicillin factories
reminding workers that they were doing it for the troops,
and production of penicillin in the US expanded rapidly. Twenty

(37:59):
one billion units of the drug had been made in
nineteen forty three, and in nineteen forty five it had
jumped to six point eight trillion. In March of nineteen
forty five, the US was able to lift rationing restrictions
on penicillin and make it commercially available to the public.
After the liberation of Paris in nineteen forty four, American

(38:21):
military hospitals throughout France started trying to extend the supply
of penicillin in the country, which is what inspired this episode.
The French military Penicillin Team was established, and starting in
January of nineteen forty five, the team collected urine from
patients to reclaim the penicillin in it. So if a

(38:43):
patient was being treated with penicillin, their bed was barked
with a placard to note that their urine should be collected.
Patients who are well enough to get up and go
to the bathroom themselves were instructed to urinate in flasks
that were just left around the wards for that purpose.
Officials were understandably a little concerned that these flasks that

(39:03):
people were peeing into could themselves become a source of infection,
so the penicillin team collected them all twice a day.
After the war, manufacturing methods for penicillin that had been
developed in the US were introduced in the UK, which
meant that the same researchers who had originally developed the
drug had to pay licensing fees to access American methods

(39:26):
to produce it. Although penicillin itself had not been patented,
some of the manufacturing methods had been new. Penicillin factories
were also established around the world as nations started making
their own supply or expanded production from research that they
had been doing is the war was going on. Alexander Fleming,

(39:46):
Earnsports Chain, and Howard Walter Floory were jointly awarded the
Nobel Prize in Physiology or Medicine in that same year.
The chemical structure of penicillin was confirmed by Dorothy Crowfort Hodgkin,
and that paved the way for synthetic forms of penicillin.
Penicillin's effect on medicine was massive, and many other antibiotics followed.

(40:12):
Stripped a mic in, which was the first truly effective
treatment for tuberculosis, was developed in nineteen three. We have
covered that and the controversy around who should be credited
with discovering it on the podcast in This is an
enormous advance in medicine, but by the nineteen fifties, some
bacteria were already becoming resistant to penicillin, including some strains

(40:36):
of staff bacteria and This was something that Fleming had foreseen,
and he warned about it in his Nobel Prize address, quote,
it is not difficult to make microbes resistant to penicillin
in the laboratory by exposing them to concentrations not sufficient
to kill them, and the same thing has occasionally happened
in the body. The time may come when penicilla and

(41:00):
can be bought by anyone in the shops. Then there
is the danger that the ignorant man may easily underdose
himself and by exposing his microbes to non lethal quantities
of the drug, make them resistant. This is obviously still
a problem. You have probably heard about it in your
day to day life at some point, and it's compounded

(41:21):
by the fact that most antibiotics in use today were
developed between the nineteen forties and the nineteen sixties, along
with the widespread use of antibiotics in agriculture. In the
World Health Organization warned that the world is nearing the
point of a post antibiotic era and currently describes antibiotic
resistance as one of the biggest threats to global health,

(41:44):
food security, and development. Yeah the use of penicillin after
and other antibiotics after the discovery and sort of the
Golden Age of antibiotics could be a whole other episode.
We're living through it. You have listener mail for us
I do. I have listener mail from Susan, and Susan says, hello,

(42:06):
I just finished listening to your episode on hypertension. I
enjoy your podcasts, and I wanted to say thank you
for that episode. Like Tracy, I have to monitor my
BP at home and so appreciated a detailed history of
the condition. I did not realize that dogs could be
affected by hypertension until one of my dogs was diagnosed
with a heart murmur. When he went in for his

(42:28):
e k G, his BP was to ten. The vet
said their readings should be like ours, when twenty is normal.
My sweet Baron has been on medication since then and
it has worked wonders. My other dog, Ramona, recently had
to have hers checked. Hers was one fourteen, so she's good.
I've always appreciated the work that vets and vet texts do,

(42:48):
but I can't imagine what it takes to read blood
pressure on a dog. I've attached pictures of the baby's
Ramona is pictured with cuttles the resident boss Lady. I
was fortunate enough to travel to Europe the summer. Having
listened to your episode on Margaret Cavendish, I made sure
to see your tomb at Westminster Abbey picture attached. My
day job is middle school science teacher, but I'm a

(43:10):
history buff and very much enjoy listening to your podcast.
Thank you for all you do season. Thank you so
much for this email. Season. One of the things that
crossed my mind in the many, many, many minutes that
I have spent taking my own blood pressure at home
is could my cats have high blood pressure? How would
we even find that out? I'm just gonna say probably

(43:32):
the answer is yes, if it can also occur in dogs.
Thank you so much for the email and the dog
pictures and the picture of Margaret Cavendish's tomb. I don't
remember if I looked up pictures of that when I
was researching that episode, but it was more ornate than
I had it in my head. So thank you for
all of that. If you would like to send us

(43:55):
a note about the sereny other podcast or history podcast
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(44:17):
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