It’s been said that one reason the Allies
won WW2 in Europe was that they had Penicillin, and the Germans didn’t… well - in the autumn of 1942, the Allies start
testing Penicillin on large scale - but is this really the drug that will win the war? I’m Spartacus Olsson, welcome to a World
War II in real-time special, this time looking at the development of penicillin. The discovery of penicillin occurs almost
by chance in September 1928. Alexander Fleming, a professor of bacteriology,
returns from a two-week holiday to his workplace at St Mary’s Hospital in London. Known for his somewhat careless nature, he
has left a petri dish containing a bacterial culture of Staphylococcus on his lab bench,
rather than in its rightful place in the incubator. During his absence, the culture has become
contaminated, and a mold is growing on the surface. Fleming notices that the bacteria around the
mold have been weakened and killed. After further examinations, he determines
that the mold, a strain of Penicillium, secretes a liquid toxic to several strains of bacteria. He publishes his findings in June 1929 and
successfully treats one of his lab staff for an eye infection in 1932. However, the time and effort needed to extract
and purify usable amounts of the liquid limit its utility. In 1935, Harold Raistrick, a leading expert
on bacteria and fungi, claims “the production of penicillin for therapeutic purposes is
almost impossible". And why should it be a priority to develop
a new antibiotic, when they already exist? These are known collectively as the Sulpha
drugs - based on the compounds sulphonamide and sulphanilamide. One of these drugs, Prontosil, achieves high-profile
success in 1936 when it is used to treat a serious throat infection in FDR’s son, Franklin
Delano Roosevelt Jr. And Sulpha are standard issue in most modern
militaries. Wounded Germans are given sulphapyridine by
mouth and Sulphanilamide powder at the location of a wound, and the British War Office recommends
that all wounds likely to become infected should be treated with sulphonamides for forty-eight
hours. During the war, Sulpha drugs will save huge
numbers of servicemen and women, and civilians on all sides. But they have some downsides. There’s a chance of allergic reaction, they
damage white blood cells over long-term use, can cause blockage in the urinary tract, and
oral administration frequently causes vomiting. In addition, because of such widespread use,
bacteria are starting to become resistant. An Allied study carried out later in the war
will estimate that 60% of cases of the sexually transmitted infection Gonorrhoea are resistant
to Sulpha. Moreover, resistance to one Sulpha drug gives
resistance to them all. So there is good reason to find new alternatives. So, in 1939, a team at the University of Oxford
are given a grant of $25,000 from the Rockefeller Foundation in America to study the antibacterial
action of molds. The team is lead by the Australian Howard
Florey, who sees potential in Fleming’s earlier work, and penicillium as a good starting
point. He recruits the British scientist Norman Heatley
and the German-Jewish Ernst Chain – a refugee from the Nazis who had arrived in 1933. The Oxford team manage to perfect the purification
and extraction of penicillin. The mold is grown in fermenting beakers, feeding
on a liquid broth. It is into this broth which it releases its
vital bacteria-killing liquid. After a long process involving acids, crystallization,
and granulation, Florey and his team refine the broth into powdered penicillin, which
can be injected into a subject. Not yet pure enough for use in humans, the
first tests are conducted on mice on the night of May 25th, 1940. Eight are injected with Streptococcus bacteria. Four receive penicillin, and four are untreated. By the early hours of the next morning, the
untreated mice are dead. The next day, Florey comments that the results
are “quite promising”. Chain is less reserved and proclaims it “A
miracle.” After further tests on a range of animals,
results are published in The Lancet in August. An article in the Lancet means that the news
travels the medical world, including when German authorities learn of penicillin development
through an article in The Lancet that eventually makes its way to them via neutral Sweden. But so far there is little military interest
in the research - after all these test are limited to animal tests, and the method for
extraction and purification is not yet scaled up - and as Florey says “Treating and curing infections in mice
was one thing, but humans are roughly 3000 times bigger and would need 3000 times more
penicillin.” So they will need a bigger boat - a method
that allows to to an industrial scale of growing mold, extracting the drug, and purifying the
drug. For that the war now stands in their way as
public and private funds for research are seen to have other priorities. Especially when there are already are working
antibiotics. So the researchers have to resort to their
creativity to soldier on. Ideally they would move to a pharmaceutical
lab, and expand the research team. Instead they recruit a team of six “penicillin
girls” and put them to work in a university classroom. Clad head to toe in protective equipment,
they are paid £2 a week to cultivate the fungus in special containers modelled from
hospital bedpans. Week by week they laboriously extract vital
milligrams of usable penicillin powder from hundreds of liters of fermenting broth, or
as they call it “mould juice”. By February 1941, they have a product suitable
for human use that can theoretically be made at large scale. The first patient, a policeman named Albert
Alexander infected with staphylococcus and streptococcus, initially recovers. But, despite going to great lengths, even
recycling penicillin from his urine, supplies are exhausted, and he dies in March after
a relapse. However, four more patients with life threatening
infections are treated over the next few months, three survive, with one dying of an unrelated
brain hemorrhage. In the meantime, the war rages on and on. For British troops fighting in North Africa,
Sulpha drugs seem to still be doing the job. Injured troops get injections in the field,
and intravenous drips in hospitals to stave off gangrene. Burnt tissue, extremely vulnerable to infection,
is treated with Sulpha, allowing plastic surgery and skin grafts to be performed. Venereal diseases are kept in check, although
antibiotic resistance is developing, and the arrival of the new American drug sulphaguanidine
helps to treat dysentery. But the Oxford team are confident that penicillin
will do the job even better. Their August 1941 Lancet article states that
it is far more effective against the coccus bacteria, streptococci, staphylococci, etc.
than the Sulphas, but is also far less toxic to white blood cells. Again, copies of this article make their way
to Germany. As well as the Oxford team’s results, it
includes details of the medium in which the mold is grown, and crucially the new method
of extraction. But non of the warring nations, including
Britain have extra resources to launch for large-scale trials or mass production, of
what is still seen as an experimental drug. In Germany there is even less interest. The Nazi authorities have limited distribution
of the Lancet - which they view as a Jewish publication. So most actual scientists will only hear of
the new drug in about a year.. In fact, right now, one of the few people
who can get their hands on them is Hitler’s physician, Theodor Morell, something of a
quack, who we have covered in our episode about Hitler’s drug dependces - link at
the end of the video. Moreover, German pharmaceutical conglomerate
IG Farben actually received a culture from Fleming before the war – the general opinion
at IG Farben is that the sulpha drugs are good enough, and that opinion seems validated. One might note, perhaps cynically, that this
opinion fits very well with the massive income IG Farben and other pharmaceuticals are generating
form the sale of Suplha drugs. So the researchers look to America, still
at peace and with vast resources. After obtaining more Rockefeller funding,
Florey and Heatley travel to New York in early July. Worried about losing or breaking their test
tubes of penicillium, they have smeared samples of the mold on the inside of the jackets for
safekeeping. It is then on to Washington DC for a meeting
with the National Research Council who direct them to the Department of Agriculture, in
Peoria, Illinois. The Department of Agriculture has lots of
experience with fermentation and quickly points towards an important innovation. Corn steep liquor – a syrupy waste product
from local corn mills. When they start using the rich in nitrogen
liquor yields increase by nearly 2000%. While the European belligerents are hard pressed,
or unable to see the potential benefits of a new, better antibiotic, the Americans are
not. America’s entry into the war now puts urgency
into the research. Only ten days after Pearl Harbour, a meeting
is convened of the Committee on Medical Research (CMR) a sub-division of the Office of Scientific
Research and Development (OSRD). Present are the heads and research directors
of the pharmaceutical companies Merck, Pfizer, and Lederle. They, along with Eli Lilley, had been courted
by Florey earlier in the year. At the time they were concerned that scaling
up the fermentation process was an issue, and the windfall of a new drug would be wiped
out if a commercially viable synthetic form of penicillin came to market. Informed of the success of the corn starch
innovation, and with the government promising substantial support the pharmaceutical giants
agree to lend their weight. This is the beginning of a project that will
eventually see twenty-one companies working together to develop the antibiotic at a total
cost of about $14 million, around a quarter of a billion dollars in 2021. The resources of the big corporations yield
fast improvements, especially on the industrialization of the process, but still the challenges facing
the coalition are huge, as John L. Smith, a chemist at Pfizer puts it; "The mould 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 assay is unsatisfactory." By June 1942, only enough penicillin has been
produced under the OSRD to treat eleven patients. However, the Department of War pushes the
project relentlessly, and large-scale trials are soon planned for the following year. Around the same time, seeing potential problems
with Sulpha after all, the Germans at IG Farben also start looking into the drug. They quickly discover that the penicillium
held by IG Farben is so old that it is no longer viable though. Searching for alternatives, they look to the
occupied countries. A culture held in Holland is found to be from
a poor producing strain, and the Pasteur Institute in Paris, and the University of Copenhagen,
cleverly ensure that their cultures stay out of German hands. Once the Germans do manage to find a usable
strain, they are faced with the same challenges of low yields, and with harvesting, and purifying
the mixture. Unlike the Americans, the German government
do not devote significant resources of funding or manpower to the project until much later
in the war. In 1942, IG Farben’s facility in Frankfurt
counts less than ten employees on the job. They will not implement the industrial scale
fermentation processes until 1944, so will be stuck with pathetically small quantities
of penicillin until then. British intelligence even continue to permit
press reporting on penicillin because they are so confident that the Germans will never
catch up. But maybe there’s another reason they don’t
censor news about the drug. Everyone understands that penicillin might
save more lives, but Sulpha is still doing at least part of that job. Sure, you might get some wounded back in action
faster, but it’s not turning around some of the wounded soldiers faster that will win
the war. Not a wonder drug, but logistics, military
strategy and economic might is what they believe should be the main focus. That said, we shouldn’t diminish the effect
that the creation of penicillin will have. In the last year of the war the Allies will
have managed to stockpile massive amounts of the drug, and it turns out that it does
work much better than Sulpha. So thanks to penicillin, tens of thousands
of GIs and Tommies who would probably have died from infections, will instead go home
to their friends and families. But no, penicillin will not win the war, the
impact will be too small for that, and come at a time when things are decided anyway,
It will however definitely save lives - and after the war it will change human life for
ever. The most common causes of death before penicillin,
even with Sulpha - bacterial infection, will be treatable and most often survivable - at
least until bacteria also start to develop resistance to penicillin. I mentioned Hitler’s Drug use. We also did a special about the “wonder
drug” the German Wehrmacht used liberally to stay alert and fighting, especially at
the beginning of the war, sometimes with catastrophic effects - meth amphetamine. Links to the two videos are here beside me
- You”ll also see Indy looking like a mad pharmaceutical researcher there. Make sure we can continue keeping the knowledge
growing at an industrial scale by joining the TimeGhost Army at Patreon, or timeghost.tv Never Forget.
