July 11, 2026 • 42 mins
This 2022 episode covers the development of penicillin, which started – but definitely did not end – with the chance discovery of some mold in a petri dish.
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Speaker 1 (00:02):
Happy Saturday. After this week's episodes on Dorothy Crowfoot Hodgkin,
including our work determining the structure of penicillin, Today's Saturday
Classic is on the discovery of penicillin. This episode originally
came out on September fifth, twenty twenty two. Enjoy Welcome
to Stuff You Missed in History Class, a production of iHeartRadio. Hello,
(00:32):
and welcome to the podcast. I'm Tracy V. Wilson and
I'm Holly Frye. Holly, When you were a kid, did
you learn the story of penicillin? I feel like I
didn't get it until later. Okay, do you remember what
you learned? You know, accidental grew on mold because there
(00:52):
was a rumor at our school that you could make
your own antibiotics in your bedroom. Well about something similar
to that, and you better believe my crafty little brain
was like, could I could I start a little apothecary
out of my closet? Uh? Maybe so, I, like a
(01:14):
lot of people learned this very basic story about Alexander
Fleming leaving a Petrie dish out and it getting contaminated
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 petri dish and mold part,
(01:35):
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 Abby,
which we actually read on the show recently, and Abby
(01:57):
mentioned that after World War Two there was a penicillin
recycling project and I was like, I need to know
more about this, yes, 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 this episode, and if a
(02:19):
phrase like mold broth bothers you, maybe this is not
the episode for you. That's your punk band mold broth, Yeah,
mold broth. We're 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 particular things. Just a heads
(02:40):
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 gonna get back to that. But the discovery of
a seemingly miraculous treatment made from mold peak the interest
of medical historians who started looking for earlier uses of
(03:03):
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. The vast majority of these treatments
involved using mold to make a topical preparation for wounds,
(03:25):
so this included using moldy soybeans in 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. There's also some evidence that more
than two thousand years ago, people in northern Africa consumed
(03:51):
something that contained enough tetracycline to leave evidence of that
on their bones. Tetracycline actually comes from bacteria, not from mold,
but the bacteria in question form these branching filaments that
look enough like a fungus that it was classified as
a fungus for a really long time. In more recent times,
(04:12):
herbalists and apothecaries in Europe described medicinal mold preparations all
through the seventeenth and eighteenth centuries, and researchers looking into
the historical use of mold in the twentieth century found
that a lot of folk remedies using mold were still around.
One biochemist described traveling through Europe and finding that each
home had a moldy loaf of bread stored in the
(04:35):
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 have a lot of detail about how effective
these treatments actually were. There weren't clinical studies or things
(04:58):
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 antimicrobial efficacy. Some of the folks that were
interviewed about their folk remedies after penicillin was developed and
(05:21):
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 was already established that various bacteria, molds, and other
organisms could inhibit one another's growth. The term antibiosis was
(05:42):
coined by the end of the nineteenth century to describe
this antagonistic effect that microorganisms could have on one another,
and there may have even been some work with penicillium
mold specifically before Fleming made his discovery. Joseph Lister may
have successfully treated a paya with a filtrate made from
Penicillium glaucum as early as eighteen seventy seven. Around the
(06:06):
same time, there were other doctors and scientists experimenting with
whether penicillium mold killed other microorganisms in a lab. 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.
(06:27):
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 of their work,
so a lot of this conclusion is based on notes
which were not necessarily complete. You cannot replicate an experiment
to test it if you don't really know what went
(06:49):
down right. The early twentieth century saw the development of
the first drugs that killed specific bacteria. In the eighteen seventies,
German physician Paul Erleck had noticed that chemical dyes changed
the color of some bacteria and not others. This was
a precursor to the gram staining method that is still
used today to broadly classify bacteria as GRAM positive and
(07:13):
gram negative based on how they respond to the stain.
Erlick started to wonder if it was also possible to
discover a substance that killed some bacteria but not others.
In nineteen oh nine, researchers in Erlick's lab discovered that
the arsenic compound arsphenamine killed the bacteria that cause syphilis.
(07:34):
This drug was marketed as saliversan and it was also
known as six oh six because it was the six
hundred and sixth preparation that had been tested in Erlick's
lab As part of this project. Salversan was found to
be effective against other infectious diseases as well. This was
really the first effective treatment for syphilis and the first
(07:55):
modern antimicrobial compound. Erlick described this use of a chem
to kill cells in the body using the word chemotherapy,
and he coined the term magic bullet to describe the
drug's ability to target pathogens. Rlick's lab had been systematically
testing one arsenic compound after another when it developed Salversen.
(08:17):
On the other hand, Alexander Fleming's discovery of penicillin a
little less than twenty years later, was an accident. He
was interested in the antimicrobial properties of the body's own
fluids and secretions. He coined the term lysizyme to describe
a substance in things like mucus, tears, and saliva that
seemed to inhibit bacterial growth. He reportedly made this discovery
(08:40):
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, 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 disas discovery.
(09:01):
His discovery of penicillin had some similarities. This time, he
was studying staff bacteria, and all of his Petrie dishes
were supposed to be in an incubator when he left
for a two week vacation in nineteen twenty eight. One
of them, though, was apparently left on a lab bench
by accident. When he got back to the office on
(09:22):
September third, 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 were dying. We
don't know exactly where the mold contamination came from. One
possibility is an open window, and another is a mycology
(09:43):
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 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
(10:06):
looking at when either he or one of his assistants
spotted this patri dish. His later descriptions about exactly how
the mold and the bacteria were interacting with one another
could be contradictory. When he published his discovery in the
British Journal of Experimental Pathology in June of nineteen twenty nine,
he made it sound as though he routinely left his
(10:29):
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 resembling Penicillium rubrum, and other
researchers later corrected that identification to Penicillium notatum. That June
(10:50):
nineteen twenty nine 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 filtrate because writing quote mold broth filtrate over
and over was apparently cumbersome. He did some basic toxicity
tests in small mammals by injecting them with this filtrate,
(11:13):
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 petrie
dish to see if that worked in a living body
as well. He did test penicillin's activity against various microbes
in a petrie dish, including Staphylococcus, streptococcus, and Newmacoccus, as
(11:36):
well as what was described at the time as Bacillus
influenzae and Basillis diphtheria. Penicillin was particularly effective against all
the piogenic cacci, so the ones that ended with caucus
and that list, but it wasn't as effective against the basilla.
So if he had a petrie dish that was growing
(11:56):
both staff bacteria and Basillis influenza, he could use penicillin
to kill only the staff, leaving that Basillis culture in place.
Side note. Today Basillis influenzae is known as Hemophilis influenzae.
It got the influenzae Moniker when people thought that it
caused influenza, which it does not. Influenza is caused by
(12:19):
a virus. 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 do
they call that now? I don't think that's what they
call that now. Fleming didn't really have the skills or
expertise to try to extract this filtrate into a usable medicine.
His research students, Stuart Kradack and Frederick Ridley both worked
(12:43):
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,
and he stopped working with it in nineteen thirty one.
We'll talk about how it did become a medicine after
a sponsor break. When Alexander Fleming was working with penicillin
(13:16):
at the end of the nineteen twenties, he was mostly
approaching it as something that 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 Pain, does seem to have
successfully used penicillin to cure eye infections in newborns in
(13:38):
nineteen thirty as well as to treat a miner 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 bactiter peiologist Gerhard Domac was
(14:02):
studying a red dye that hadn't been an effective antibacterial
in a petri dish, but turned out to treat strep
infections in mice and staff infections in rabbits. This die
was developed into the drug protonsil, the first sulfa drug
and the first drug used to treat and prevent a
range of bacterial infections in humans. Unlike Salversen, which was
(14:24):
primarily used to treat syphilists, Protonsil could treat a variety
of Gram positive bacteria. Domac was awarded the Nobel Prize
in 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
(14:45):
previously been awarded to German pacifist Carl von Ossietsky in
nineteen thirty five. Domac accepted the prize anyway. Afterward, he
was arrested by the Gestapo and forced to write to
the Nobel Committe rejecting the prize. He wasn't able to
get his medal for having won the Nobel Prize until
(15:06):
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 after the Nazis came to power
because he was Jewish. Erlick was no longer living at
this point. He had died after a stroke in nineteen fifteen.
(15:29):
So the same year that Dolmach 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.
(15:49):
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 Chane, who was a
Jewish biochemist who had fled to the UK from Germany
(16:11):
after the Nazi Party came to power. Flory, Chain and
others at Oxford had been inspired by Domok's success with
sulfa drugs, and in nineteen thirty eight they started studying
the enzyme lyszyme, which Alexander Fleming had discovered. Chain also
found Fleming's earlier paper on the antimicrobial effects of penicillium mold,
(16:32):
and Oxford already had a sample of Fleming's mold on hand.
The team started working with it in nineteen thirty nine.
Fleming and his team at Saint Mary's had been mostly
working with small amounts of mold and a Patriot dish
Flori and Chane on the other hand, were trying to
extract enough of the active substance to test whether it
(16:52):
could be used as a medicine. Even though they were
going to start with mice, which are very small, this
record wired a lot of mold, so much more mold
than Fleming had been working with. Hospital bedpans turned out
to be just about the right size and shape to
grow this mold in, but most of the ones on
(17:14):
hand were needed by hospital patients, so the team at
Oxford started repurposing whatever 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.
(17:34):
It was also really a team effort. Over the course
of the project, six women were paid two pounds a
week to tend to the fermenting mold. They were Ruth Callo,
Claire Niant, Betty Cook, Peggy Gardner, Meghan Lancaster, and Patricia mckagney,
and they were nicknamed the Penicillin Girls. Norman Heatley developed
(17:55):
a method to extract penicillin from the mold broth into
ammial acetate and then back into water Edward Abraham developed
techniques to purify it, and on May twenty fifth, nineteen
thirty nine, almost exactly ten years after the British Journal
of Experimental Pathology received Fleming's paper on penicillin, they conducted
(18:16):
an experiment involving eight mice. All eight of the mice
were injected with Streptococcus bacteria, 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
(18:38):
studies on rats and cats. They tested penicillin's efficacy against
multiple bacteria. In addition to Strep and staff, there was
Claustridium septicum, which can cause gas gangreen and penicillin was
dramatically effective against all of them, with little to no
toxicity to their test subjects. In August of nineteen ten,
(19:00):
forty Chain, Flory, Heatley, and others published Penicillin as a
chemotherapeutic agent in the journal Blancet, 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
(19:22):
talked about in this episode, there just weren't many effective
options to treat bacterial infections. That meant that minor illnesses
like strep throat could lead to much more serious problems
like rheumatic fever. Life threatening infections could develop in injuries
that had seemed really superficial. People like Ignot Celeweiss and
(19:43):
Joseph Lister had advocated for things like hand washing and
sterile surgical techniques to 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 a it SELFA drugs
had been a huge step forward in providing broadly effective
(20:06):
treatments for bacterial infections, but a lot of people were
allergic to them, and most 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
(20:26):
needed to grow a lot more mold. But at this
point the UK was a war. Germany had invaded Poland
on September first, nineteen thirty 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
(20:46):
time and expense, Norman Heatlely designed a flat, rectangular pottery
vessel with a spout that was stackable and glazed on
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 and kind of fiddly processed. Even with
(21:10):
all seven hundred vessels in use, it took about four
weeks to make enough penicillin to treat one human patient,
and it took months 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 seeded with moldsbores. The first attempt to treat a
(21:32):
person with penicillin made from all of this mold started
on February twelfth, nineteen forty 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. In still others, he was
(21:54):
injured in a bombing during the blitz. But regardless of
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
(22:15):
had been made at this point, they had to collect
his urine and extract the penicillin out of it 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
ninety nine percent. It's possible to recover half or more
(22:40):
of that excreted 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 pennacilin they had, and after they ran out, his
(23:02):
infection returned. He died on March fifteenth, nineteen forty one.
So it was clear that making enough penicillin to do
a clinical trial was going to be a huge challenge.
With all this effort, they had not made enough to
successfully treat even one patient, Although focusing on treating children
would have allowed the team to use smaller doses, at
(23:24):
this point, the priority was really confirming that 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
(23:45):
the prospects for doing that 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. Flori and his team also understood
(24:08):
that if Britain were invaded, 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
losing their penicillium mold entirely. Norman Heatly suggested that several
of them intentionally rub mold into their coats so that
(24:30):
if they had to flee, they could just wear their
samples with them undetected. Why does everybody a miss on
this transport smelt weird? Smells a little musty. In nineteen
forty one, Flori and Heatly went to the United States
to try to find pharmaceutical companies that could help whek
(24:51):
in the UK didn't stop at this point or in
other countries that had started experimenting with penicillium, but the
focus on mass producing penicillin shift did to the US,
and we'll talk more about that. After a sponsor break
(25:13):
in June of nineteen forty one, Howard Flory and Norman
Heatley took a series of flights to get from the
UK to the 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
(25:35):
Albert Alexander. One other 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 Flory and Heatley
were preparing to go, the Oxford team was preparing and
(25:56):
freeze drying as much penicillin as possible for them to
take with them. Flori 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,
(26:18):
but on the other hand, there were concerns 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
(26:40):
medicine to be just appalling. While Ernst Chane argued that
penicillin was their work and it deserved to be protected.
Chaine 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.
(27:00):
Chain was also deeply disappointed by not being part of
this trip to the United States, and this is something
that seems to have caused a huge rift between him
and Flory. Since the whole purpose of this trip was
to try to get manufacturing started, and Heatlely was the
person who had been focused on manufacturing like it makes
sense that Heatly would be the person to go. They
(27:21):
also wanted to minimize the number of people going for
the sake of secrecy. The decision made sense, but Chain
seems to have been incredibly upset by it. The US
had passed the Lend Lease Act in March of nineteen
forty one, which established a framework for the United States
to provide the allies with things like weapons, vehicles, materials, machinery,
(27:42):
and facilities that would promote the defense of the United States.
The manufacture of penicillin seemed to fall under that definition,
but Flory and heat Ly 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
(28:04):
and starts, and then Flory and Heatly wound up at
the Department of Agriculture's Northern Regional Research Laboratory were NRRL
in Peoria, Illinois, which already had a fermentation division, which
was very handy since they grew penicillin by fermenting. Researchers
there started working on finding ways to grow penicillium mold
(28:27):
a lot faster than it had been They started on
that work in July of nineteen forty one. 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
(28:51):
convenient because corn steep liquor is a byproduct of the
wet milling process, and people were already trying to find
a practical use for it. Those vessels in 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
(29:11):
a submerged medium, but this also required they're 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,
(29:34):
which they did with the help of the Army Transportation Corps,
and they tested all these 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
(29:54):
found this cantelope not in some far reaching place brought
back by the Army Transportation Corp, but at a local
Peoria fruit market. The strain of the mold, Penicillium chrysogenome,
was about one 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
(30:17):
needed pharmaceutical or chemical manufacturers to actually get a penicillin
drug into production. A group of pharmaceutical companies and the
federal government met in October of nineteen forty one to
coordinate both the production process and information sharing. The goal
was to first produce enough penicillin for clinical trials, and then,
(30:39):
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 unprecedented level of cooperation. It
was also going to be really tricky. John L. Smith
from Pfizer had this to say about it, quote, the
mold is as temperamental as an opera singer. The yields
(31:01):
are low, the isolation is difficult, the extraction is murder,
the purification invites disaster, and the assay is unsatisfactory. So
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,
(31:25):
the War Production Board also worked with twenty five different
companies to scale up production of penicillin. They narrowed it
down to those twenty five after investigating more than one
hundred and 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
(31:46):
Anne Miller, who had developed septocemia after a pregnancy loss.
Her treatment started on March fourteenth, nineteen forty two, and
it required half 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
(32:06):
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 write up about it
in The Times. This article didn't actually mention Flory or
any of the other researchers at the Oxford team, though,
and this really started to build the perception that penicillin
(32:27):
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 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
(32:49):
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 available to Germany or its allies.
Doctors and medical ethicists generally agreed that if a patient
(33:10):
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 believed that information about how to make it
or samples of the mold itself should not be shared,
(33:31):
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 hostilities started. Within the US, another ethical issue
(33:51):
was access to penicillin, because once clinical trials were complete,
the penicillin being produced was going to be reserved almost
most exclusively for military use. At the same time, there
were definitely going to be civilians whose lives would be
lost without it. Doctor Chester Keefer was responsible for rationing
(34:13):
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, nineteen forty three,
Julius A. Vogel, who was the plant physician at a
steel plant in Pennsylvania, figured out how to make penicillin
(34:34):
in his kitchen. See my plan as a kid was
not completely not now because I had the knowledge of
a plant physition. Vogel based his work on an earlier
discovery by George Robinson and James Wallace at Singer Laboratory
at Allegheny General Hospital in Pittsburgh, Pennsylvania. On October eighth,
(34:57):
nineteen forty three, they reported that they had found away
to make a topical treatment by soaking a gauze pad
and penicillium mold and then letting it grow in a
petrie 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 infused gauze. Vogel's wife, Eunice,
(35:23):
was a big part of this process, making the augur
for the petrie 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 how if penicillin had existed when
(35:44):
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 eleventh night,
eighteen forty three, and he got a lot of criticism
from the research community and from the companies that were
(36:06):
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 at steel mills all over the area, treating workers
who had on the job accidents and otherwise would have
(36:28):
just not had access to any antibiotics at all. Yet
another ethical conundrum arose after Flory and Chain traveled to
Northern Africa in nineteen forty three to test penicillin on
wounded soldiers and realized that it was also effective against gonorrhea.
Before this point, penicillin had been envisioned as something that
(36:49):
would save the lives of soldiers who had been seriously
injured in battle or had contracted a serious illness like
bacterial pneumonia, but gonorrhea, especially in its early set stages,
is more of a nuisance. Winston Churchill reportedly said that
penicillin should be used for the quote best military advantage,
which meant when supplies were limited, getting soldiers who had
(37:12):
gonorrhea back into peak condition, rather than treating seriously injured
soldiers who were going to be sent back home. Those
supplies were not limited for that much longer, though. Pfizer's
first plant for the commercial production of penicillin opened in Brooklyn,
New York, on March first, nineteen forty four. By that point,
(37:33):
clinical 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
(37:54):
cover of Time magazine on May fifteenth of nineteen forty four.
By this point, pharmaceutical companies in the US were 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
(38:16):
expanded rapidly. Twenty 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
(38:39):
forty four, American 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.
(39:03):
So if a patient was being treated with penicillin, their
bed was marked with a placard to note that their
urine should be collected. Patients who were 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 people were peeing into could themselves
(39:26):
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 to produce it. Although penicillin
(39:49):
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 as the
war was going on. Alexander Fleming Ernst Boris Chain and
Howard Walter Florey were jointly awarded the Nobel Prize in
(40:12):
Physiology or Medicine in nineteen forty five. That same year,
the chemical structure of penicillin was confirmed by Dorothy Crowfoot Hodgkin,
and that paved the way for synthetic forms of penicillin.
Penicillin's effect on medicine was massive, and many other antibiotics followed. Streptomycin,
(40:33):
which was the first truly effective treatment for tuberculosis, was
developed in nineteen forty three. We have covered that and
the controversy around who should be credited with discovering it
on the podcast in twenty thirteen. This is an enormous
advance in medicine. But by the nineteen fifties, some bacteria
were already becoming resistant to penicillin, including some strains of
(40:57):
staff bacteria, and this was something that fled had foreseen,
and he warned about it in his Nobel Prize address
quote that 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 penicillin
(41:20):
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've probably heard about it in your day
to day life at some point, and it's compounded by
(41:42):
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 twenty fourteen,
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,
(42:05):
food security, and development. Yeah, the use of penicillin and
other antibiotics after the discovery and sort of the golden
age of antibiotics be a whole other episode. We're living
through it. Thanks so much for joining us on this Saturday.
(42:26):
If you'd like to send us a note, our email
addresses History Podcast at iHeartRadio dot com, and you can
subscribe to the show on the iHeartRadio app. Apple podcasts,
or wherever you listen to your favorite shows.
Happy Saturday. After this week's episodes on Dorothy Crowfoot Hodgkin,
including our work determining the structure of penicillin, Today's Saturday
Classic is on the discovery of penicillin. This episode originally
came out on September fifth, twenty twenty two. Enjoy Welcome
to Stuff You Missed in History Class, a production of iHeartRadio. Hello,
(00:32):
and welcome to the podcast. I'm Tracy V. Wilson and
I'm Holly Frye. Holly, When you were a kid, did
you learn the story of penicillin? I feel like I
didn't get it until later. Okay, do you remember what
you learned? You know, accidental grew on mold because there
(00:52):
was a rumor at our school that you could make
your own antibiotics in your bedroom. Well about something similar
to that, and you better believe my crafty little brain
was like, could I could I start a little apothecary
out of my closet? Uh? Maybe so, I, like a
(01:14):
lot of people learned this very basic story about Alexander
Fleming leaving a Petrie dish out and it getting contaminated
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 petri dish and mold part,
(01:35):
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 Abby,
which we actually read on the show recently, and Abby
(01:57):
mentioned that after World War Two there was a penicillin
recycling project and I was like, I need to know
more about this, yes, 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 this episode, and if a
(02:19):
phrase like mold broth bothers you, maybe this is not
the episode for you. That's your punk band mold broth, Yeah,
mold broth. We're 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 particular things. Just a heads
(02:40):
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 gonna get back to that. But the discovery of
a seemingly miraculous treatment made from mold peak the interest
of medical historians who started looking for earlier uses of
(03:03):
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. The vast majority of these treatments
involved using mold to make a topical preparation for wounds,
(03:25):
so this included using moldy soybeans in 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. There's also some evidence that more
than two thousand years ago, people in northern Africa consumed
(03:51):
something that contained enough tetracycline to leave evidence of that
on their bones. Tetracycline actually comes from bacteria, not from mold,
but the bacteria in question form these branching filaments that
look enough like a fungus that it was classified as
a fungus for a really long time. In more recent times,
(04:12):
herbalists and apothecaries in Europe described medicinal mold preparations all
through the seventeenth and eighteenth centuries, and researchers looking into
the historical use of mold in the twentieth century found
that a lot of folk remedies using mold were still around.
One biochemist described traveling through Europe and finding that each
home had a moldy loaf of bread stored in the
(04:35):
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 have a lot of detail about how effective
these treatments actually were. There weren't clinical studies or things
(04:58):
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 antimicrobial efficacy. Some of the folks that were
interviewed about their folk remedies after penicillin was developed and
(05:21):
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 was already established that various bacteria, molds, and other
organisms could inhibit one another's growth. The term antibiosis was
(05:42):
coined by the end of the nineteenth century to describe
this antagonistic effect that microorganisms could have on one another,
and there may have even been some work with penicillium
mold specifically before Fleming made his discovery. Joseph Lister may
have successfully treated a paya with a filtrate made from
Penicillium glaucum as early as eighteen seventy seven. Around the
(06:06):
same time, there were other doctors and scientists experimenting with
whether penicillium mold killed other microorganisms in a lab. 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.
(06:27):
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 of their work,
so a lot of this conclusion is based on notes
which were not necessarily complete. You cannot replicate an experiment
to test it if you don't really know what went
(06:49):
down right. The early twentieth century saw the development of
the first drugs that killed specific bacteria. In the eighteen seventies,
German physician Paul Erleck had noticed that chemical dyes changed
the color of some bacteria and not others. This was
a precursor to the gram staining method that is still
used today to broadly classify bacteria as GRAM positive and
(07:13):
gram negative based on how they respond to the stain.
Erlick started to wonder if it was also possible to
discover a substance that killed some bacteria but not others.
In nineteen oh nine, researchers in Erlick's lab discovered that
the arsenic compound arsphenamine killed the bacteria that cause syphilis.
(07:34):
This drug was marketed as saliversan and it was also
known as six oh six because it was the six
hundred and sixth preparation that had been tested in Erlick's
lab As part of this project. Salversan was found to
be effective against other infectious diseases as well. This was
really the first effective treatment for syphilis and the first
(07:55):
modern antimicrobial compound. Erlick described this use of a chem
to kill cells in the body using the word chemotherapy,
and he coined the term magic bullet to describe the
drug's ability to target pathogens. Rlick's lab had been systematically
testing one arsenic compound after another when it developed Salversen.
(08:17):
On the other hand, Alexander Fleming's discovery of penicillin a
little less than twenty years later, was an accident. He
was interested in the antimicrobial properties of the body's own
fluids and secretions. He coined the term lysizyme to describe
a substance in things like mucus, tears, and saliva that
seemed to inhibit bacterial growth. He reportedly made this discovery
(08:40):
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, 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 disas discovery.
(09:01):
His discovery of penicillin had some similarities. This time, he
was studying staff bacteria, and all of his Petrie dishes
were supposed to be in an incubator when he left
for a two week vacation in nineteen twenty eight. One
of them, though, was apparently left on a lab bench
by accident. When he got back to the office on
(09:22):
September third, 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 were dying. We
don't know exactly where the mold contamination came from. One
possibility is an open window, and another is a mycology
(09:43):
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 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
(10:06):
looking at when either he or one of his assistants
spotted this patri dish. His later descriptions about exactly how
the mold and the bacteria were interacting with one another
could be contradictory. When he published his discovery in the
British Journal of Experimental Pathology in June of nineteen twenty nine,
he made it sound as though he routinely left his
(10:29):
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 resembling Penicillium rubrum, and other
researchers later corrected that identification to Penicillium notatum. That June
(10:50):
nineteen twenty nine 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 filtrate because writing quote mold broth filtrate over
and over was apparently cumbersome. He did some basic toxicity
tests in small mammals by injecting them with this filtrate,
(11:13):
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 petrie
dish to see if that worked in a living body
as well. He did test penicillin's activity against various microbes
in a petrie dish, including Staphylococcus, streptococcus, and Newmacoccus, as
(11:36):
well as what was described at the time as Bacillus
influenzae and Basillis diphtheria. Penicillin was particularly effective against all
the piogenic cacci, so the ones that ended with caucus
and that list, but it wasn't as effective against the basilla.
So if he had a petrie dish that was growing
(11:56):
both staff bacteria and Basillis influenza, he could use penicillin
to kill only the staff, leaving that Basillis culture in place.
Side note. Today Basillis influenzae is known as Hemophilis influenzae.
It got the influenzae Moniker when people thought that it
caused influenza, which it does not. Influenza is caused by
(12:19):
a virus. 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 do
they call that now? I don't think that's what they
call that now. Fleming didn't really have the skills or
expertise to try to extract this filtrate into a usable medicine.
His research students, Stuart Kradack and Frederick Ridley both worked
(12:43):
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,
and he stopped working with it in nineteen thirty one.
We'll talk about how it did become a medicine after
a sponsor break. When Alexander Fleming was working with penicillin
(13:16):
at the end of the nineteen twenties, he was mostly
approaching it as something that 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 Pain, does seem to have
successfully used penicillin to cure eye infections in newborns in
(13:38):
nineteen thirty as well as to treat a miner 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 bactiter peiologist Gerhard Domac was
(14:02):
studying a red dye that hadn't been an effective antibacterial
in a petri dish, but turned out to treat strep
infections in mice and staff infections in rabbits. This die
was developed into the drug protonsil, the first sulfa drug
and the first drug used to treat and prevent a
range of bacterial infections in humans. Unlike Salversen, which was
(14:24):
primarily used to treat syphilists, Protonsil could treat a variety
of Gram positive bacteria. Domac was awarded the Nobel Prize
in 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
(14:45):
previously been awarded to German pacifist Carl von Ossietsky in
nineteen thirty five. Domac accepted the prize anyway. Afterward, he
was arrested by the Gestapo and forced to write to
the Nobel Committe rejecting the prize. He wasn't able to
get his medal for having won the Nobel Prize until
(15:06):
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 after the Nazis came to power
because he was Jewish. Erlick was no longer living at
this point. He had died after a stroke in nineteen fifteen.
(15:29):
So the same year that Dolmach 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.
(15:49):
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 Chane, who was a
Jewish biochemist who had fled to the UK from Germany
(16:11):
after the Nazi Party came to power. Flory, Chain and
others at Oxford had been inspired by Domok's success with
sulfa drugs, and in nineteen thirty eight they started studying
the enzyme lyszyme, which Alexander Fleming had discovered. Chain also
found Fleming's earlier paper on the antimicrobial effects of penicillium mold,
(16:32):
and Oxford already had a sample of Fleming's mold on hand.
The team started working with it in nineteen thirty nine.
Fleming and his team at Saint Mary's had been mostly
working with small amounts of mold and a Patriot dish
Flori and Chane on the other hand, were trying to
extract enough of the active substance to test whether it
(16:52):
could be used as a medicine. Even though they were
going to start with mice, which are very small, this
record wired a lot of mold, so much more mold
than Fleming had been working with. Hospital bedpans turned out
to be just about the right size and shape to
grow this mold in, but most of the ones on
(17:14):
hand were needed by hospital patients, so the team at
Oxford started repurposing whatever 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.
(17:34):
It was also really a team effort. Over the course
of the project, six women were paid two pounds a
week to tend to the fermenting mold. They were Ruth Callo,
Claire Niant, Betty Cook, Peggy Gardner, Meghan Lancaster, and Patricia mckagney,
and they were nicknamed the Penicillin Girls. Norman Heatley developed
(17:55):
a method to extract penicillin from the mold broth into
ammial acetate and then back into water Edward Abraham developed
techniques to purify it, and on May twenty fifth, nineteen
thirty nine, almost exactly ten years after the British Journal
of Experimental Pathology received Fleming's paper on penicillin, they conducted
(18:16):
an experiment involving eight mice. All eight of the mice
were injected with Streptococcus bacteria, 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
(18:38):
studies on rats and cats. They tested penicillin's efficacy against
multiple bacteria. In addition to Strep and staff, there was
Claustridium septicum, which can cause gas gangreen and penicillin was
dramatically effective against all of them, with little to no
toxicity to their test subjects. In August of nineteen ten,
(19:00):
forty Chain, Flory, Heatley, and others published Penicillin as a
chemotherapeutic agent in the journal Blancet, 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
(19:22):
talked about in this episode, there just weren't many effective
options to treat bacterial infections. That meant that minor illnesses
like strep throat could lead to much more serious problems
like rheumatic fever. Life threatening infections could develop in injuries
that had seemed really superficial. People like Ignot Celeweiss and
(19:43):
Joseph Lister had advocated for things like hand washing and
sterile surgical techniques to 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 a it SELFA drugs
had been a huge step forward in providing broadly effective
(20:06):
treatments for bacterial infections, but a lot of people were
allergic to them, and most 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
(20:26):
needed to grow a lot more mold. But at this
point the UK was a war. Germany had invaded Poland
on September first, nineteen thirty 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
(20:46):
time and expense, Norman Heatlely designed a flat, rectangular pottery
vessel with a spout that was stackable and glazed on
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 and kind of fiddly processed. Even with
(21:10):
all seven hundred vessels in use, it took about four
weeks to make enough penicillin to treat one human patient,
and it took months 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 seeded with moldsbores. The first attempt to treat a
(21:32):
person with penicillin made from all of this mold started
on February twelfth, nineteen forty 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. In still others, he was
(21:54):
injured in a bombing during the blitz. But regardless of
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
(22:15):
had been made at this point, they had to collect
his urine and extract the penicillin out of it 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
ninety nine percent. It's possible to recover half or more
(22:40):
of that excreted 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 pennacilin they had, and after they ran out, his
(23:02):
infection returned. He died on March fifteenth, nineteen forty one.
So it was clear that making enough penicillin to do
a clinical trial was going to be a huge challenge.
With all this effort, they had not made enough to
successfully treat even one patient, Although focusing on treating children
would have allowed the team to use smaller doses, at
(23:24):
this point, the priority was really confirming that 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
(23:45):
the prospects for doing that 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. Flori and his team also understood
(24:08):
that if Britain were invaded, 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
losing their penicillium mold entirely. Norman Heatly suggested that several
of them intentionally rub mold into their coats so that
(24:30):
if they had to flee, they could just wear their
samples with them undetected. Why does everybody a miss on
this transport smelt weird? Smells a little musty. In nineteen
forty one, Flori and Heatly went to the United States
to try to find pharmaceutical companies that could help whek
(24:51):
in the UK didn't stop at this point or in
other countries that had started experimenting with penicillium, but the
focus on mass producing penicillin shift did to the US,
and we'll talk more about that. After a sponsor break
(25:13):
in June of nineteen forty one, Howard Flory and Norman
Heatley took a series of flights to get from the
UK to the 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
(25:35):
Albert Alexander. One other 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 Flory and Heatley
were preparing to go, the Oxford team was preparing and
(25:56):
freeze drying as much penicillin as possible for them to
take with them. Flori 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,
(26:18):
but on the other hand, there were concerns 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
(26:40):
medicine to be just appalling. While Ernst Chane argued that
penicillin was their work and it deserved to be protected.
Chaine 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.
(27:00):
Chain was also deeply disappointed by not being part of
this trip to the United States, and this is something
that seems to have caused a huge rift between him
and Flory. Since the whole purpose of this trip was
to try to get manufacturing started, and Heatlely was the
person who had been focused on manufacturing like it makes
sense that Heatly would be the person to go. They
(27:21):
also wanted to minimize the number of people going for
the sake of secrecy. The decision made sense, but Chain
seems to have been incredibly upset by it. The US
had passed the Lend Lease Act in March of nineteen
forty one, which established a framework for the United States
to provide the allies with things like weapons, vehicles, materials, machinery,
(27:42):
and facilities that would promote the defense of the United States.
The manufacture of penicillin seemed to fall under that definition,
but Flory and heat Ly 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
(28:04):
and starts, and then Flory and Heatly wound up at
the Department of Agriculture's Northern Regional Research Laboratory were NRRL
in Peoria, Illinois, which already had a fermentation division, which
was very handy since they grew penicillin by fermenting. Researchers
there started working on finding ways to grow penicillium mold
(28:27):
a lot faster than it had been They started on
that work in July of nineteen forty one. 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
(28:51):
convenient because corn steep liquor is a byproduct of the
wet milling process, and people were already trying to find
a practical use for it. Those vessels in 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
(29:11):
a submerged medium, but this also required they're 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,
(29:34):
which they did with the help of the Army Transportation Corps,
and they tested all these 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
(29:54):
found this cantelope not in some far reaching place brought
back by the Army Transportation Corp, but at a local
Peoria fruit market. The strain of the mold, Penicillium chrysogenome,
was about one 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
(30:17):
needed pharmaceutical or chemical manufacturers to actually get a penicillin
drug into production. A group of pharmaceutical companies and the
federal government met in October of nineteen forty one to
coordinate both the production process and information sharing. The goal
was to first produce enough penicillin for clinical trials, and then,
(30:39):
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 unprecedented level of cooperation. It
was also going to be really tricky. John L. Smith
from Pfizer had this to say about it, quote, the
mold is as temperamental as an opera singer. The yields
(31:01):
are low, the isolation is difficult, the extraction is murder,
the purification invites disaster, and the assay is unsatisfactory. So
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,
(31:25):
the War Production Board also worked with twenty five different
companies to scale up production of penicillin. They narrowed it
down to those twenty five after investigating more than one
hundred and 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
(31:46):
Anne Miller, who had developed septocemia after a pregnancy loss.
Her treatment started on March fourteenth, nineteen forty two, and
it required half 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
(32:06):
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 write up about it
in The Times. This article didn't actually mention Flory or
any of the other researchers at the Oxford team, though,
and this really started to build the perception that penicillin
(32:27):
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 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
(32:49):
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 available to Germany or its allies.
Doctors and medical ethicists generally agreed that if a patient
(33:10):
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 believed that information about how to make it
or samples of the mold itself should not be shared,
(33:31):
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 hostilities started. Within the US, another ethical issue
(33:51):
was access to penicillin, because once clinical trials were complete,
the penicillin being produced was going to be reserved almost
most exclusively for military use. At the same time, there
were definitely going to be civilians whose lives would be
lost without it. Doctor Chester Keefer was responsible for rationing
(34:13):
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, nineteen forty three,
Julius A. Vogel, who was the plant physician at a
steel plant in Pennsylvania, figured out how to make penicillin
(34:34):
in his kitchen. See my plan as a kid was
not completely not now because I had the knowledge of
a plant physition. Vogel based his work on an earlier
discovery by George Robinson and James Wallace at Singer Laboratory
at Allegheny General Hospital in Pittsburgh, Pennsylvania. On October eighth,
(34:57):
nineteen forty three, they reported that they had found away
to make a topical treatment by soaking a gauze pad
and penicillium mold and then letting it grow in a
petrie 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 infused gauze. Vogel's wife, Eunice,
(35:23):
was a big part of this process, making the augur
for the petrie 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 how if penicillin had existed when
(35:44):
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 eleventh night,
eighteen forty three, and he got a lot of criticism
from the research community and from the companies that were
(36:06):
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 at steel mills all over the area, treating workers
who had on the job accidents and otherwise would have
(36:28):
just not had access to any antibiotics at all. Yet
another ethical conundrum arose after Flory and Chain traveled to
Northern Africa in nineteen forty three to test penicillin on
wounded soldiers and realized that it was also effective against gonorrhea.
Before this point, penicillin had been envisioned as something that
(36:49):
would save the lives of soldiers who had been seriously
injured in battle or had contracted a serious illness like
bacterial pneumonia, but gonorrhea, especially in its early set stages,
is more of a nuisance. Winston Churchill reportedly said that
penicillin should be used for the quote best military advantage,
which meant when supplies were limited, getting soldiers who had
(37:12):
gonorrhea back into peak condition, rather than treating seriously injured
soldiers who were going to be sent back home. Those
supplies were not limited for that much longer, though. Pfizer's
first plant for the commercial production of penicillin opened in Brooklyn,
New York, on March first, nineteen forty four. By that point,
(37:33):
clinical 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
(37:54):
cover of Time magazine on May fifteenth of nineteen forty four.
By this point, pharmaceutical companies in the US were 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
(38:16):
expanded rapidly. Twenty 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
(38:39):
forty four, American 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.
(39:03):
So if a patient was being treated with penicillin, their
bed was marked with a placard to note that their
urine should be collected. Patients who were 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 people were peeing into could themselves
(39:26):
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 to produce it. Although penicillin
(39:49):
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 as the
war was going on. Alexander Fleming Ernst Boris Chain and
Howard Walter Florey were jointly awarded the Nobel Prize in
(40:12):
Physiology or Medicine in nineteen forty five. That same year,
the chemical structure of penicillin was confirmed by Dorothy Crowfoot Hodgkin,
and that paved the way for synthetic forms of penicillin.
Penicillin's effect on medicine was massive, and many other antibiotics followed. Streptomycin,
(40:33):
which was the first truly effective treatment for tuberculosis, was
developed in nineteen forty three. We have covered that and
the controversy around who should be credited with discovering it
on the podcast in twenty thirteen. This is an enormous
advance in medicine. But by the nineteen fifties, some bacteria
were already becoming resistant to penicillin, including some strains of
(40:57):
staff bacteria, and this was something that fled had foreseen,
and he warned about it in his Nobel Prize address
quote that 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 penicillin
(41:20):
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've probably heard about it in your day
to day life at some point, and it's compounded by
(41:42):
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 twenty fourteen,
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,
(42:05):
food security, and development. Yeah, the use of penicillin and
other antibiotics after the discovery and sort of the golden
age of antibiotics be a whole other episode. We're living
through it. Thanks so much for joining us on this Saturday.
(42:26):
If you'd like to send us a note, our email
addresses History Podcast at iHeartRadio dot com, and you can
subscribe to the show on the iHeartRadio app. Apple podcasts,
or wherever you listen to your favorite shows.
Stuff You Missed in History Class News
Hosts And Creators
Holly Frey
Tracy Wilson
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