Back

The Penicillin Myth

201 points2 monthsasimov.press
glenstein2 months ago

In my opinion, we're possessed by a cultural epidemic of think pieces doing rich and nuanced science history, but wrongly framed in the form of correcting "myths" that, in their substance amount to quibblings over narrative emphasis. It's easy to get taken in by the framing because it truly is enlightening, and the argument goes down so smooth because its embedded in a rich, curious, and fascinating scientific history that otherwise embodies best practices I would happily celebrate.

But the key details about the story of penicillin are that a moldy plate showed bacteria-free clearing, Fleming saw it, isolated the mold, proved its germ-killing filtrate and published the finding, which is the heart of the story and which is not a myth.

I'm sure it's true enough that St Mary's windows were usually kept shut to keep pathogens in and contaminants out, that London's August 1928 cold snap would have slowed staph growth, that Fleming's first notes Or 8 weeks later than the actual event, and that a modern plate seeded with bacteria first will not produce the celebrated halo unless the mold is given a head start. The article makes much of the fact that today’s researchers cannot reproduce the famous halo if they add staph first, yet that difficulty rebuts a sequence Fleming never claimed to have used.

These points are significant, even fascinating, yet the article inflates them into a strobe-lit "MYTH" banner, turning normal human imprecision about times and temperatures into evidence of wholesale fiction, which abuses the ordinary friction of any retrospective account and punishes the story for the very human messiness that makes it instructive.

The window quibble, the incubator gap, and the replication protocol do not touch the central, uncontested fact that chance contamination plus observational curiosity gave medicine its first antibiotic.

awkward2 months ago

It's a myth in the most literal way. Fleming published and promoted his results despite a lack of reproducibility. By the time he won the Nobel Prize, he had backformed or misremembered a folksy story about an open window. That's textbook mythmaking.

It can both be fine to have a glib story to tell schoolkids and important to recognize that the actual intellectual process is messier and more complex.

pcrh2 months ago

I have now actually read Flemming's 1929 manuscript that first described penicillin [0]. It is a careful and well documented scientific report describing the action of penicillin on various species of bacteria, how to produce it, and some of its chemical properties. It describes how penicillin can kill bacteria isolated from the throats of nurses, and shows that it has low toxicity in mice, and is possibly safe for use in humans: "Constant irrigation of large infected surfaces in man was not accompanied by any toxic symptoms, while irrigation of the human conjunctiva every hour for a day had no irritant effect."

It is far from having a "lack of reproducibility" and in fact allowed others to quickly and accurately replicate his discovery.

https://pmc.ncbi.nlm.nih.gov/articles/PMC2048009/

somenameforme2 months ago

The path to his discovery may have been difficult to replicate, but the fact that the mold could kill other bacteria was not, and was immediately replicated.

It just wasn't seen as relevant because, at the time, few people imagined its internal use in humans and it was instead seen more as a tool for other microbiologists and the like. The jump to "And then I see the disinfectant, where it knocks it out in a minute. One minute. And is there a way we can do something like that, by injection inside or almost a cleaning?" took quite some time.

kieranmaine2 months ago

> The window quibble, the incubator gap, and the replication protocol do not touch the central, uncontested fact that chance contamination plus observational curiosity gave medicine its first antibiotic.

This is the same conclusion as the article. IMO, the importance of challenging the myth is that it has hisotrically taken precendence over your (and the article's) conclusion.

FTA

> Fleming’s 1929 penicillin paper may have been written as a linear process, but that’s almost certainly not how the discovery occurred. And by eliminating these complicated twists and turns, Fleming inadvertently obscured what may be one of the most important lessons in scientific history: how combining a meticulous research program with the openness to branch out into new directions led him to Nobel Prize-winning success. Neither rigid plans nor the winds of chance are enough on their own; discovery requires both.

NetMageSCW2 months ago

I think that the author had the conclusion wanted before picking the story that supported the desired conclusion as best. To me that story overlooks too many documented facts as well as human behavior. They complain that it requires lottery odds for the first story to happen while ignoring that one win is documented - there was a cold snap exactly when Fleming we t on vacation. Both stories require the winning odds of the mold contaminating a culture - the mold wouldn’t have needed to be identified if Fleming was deliberately experimenting with a known mold from his colleague. So the only undocumented luck left would be the use of that contaminated culture just before vacation.

And which is more likely - Fleming imagining the initial discovery happening right as he returned from vacation or that he remembered those important details but forgot more minor ones?

irjustin2 months ago

> The window quibble, the incubator gap, and the replication protocol do not touch the central, uncontested fact that chance contamination plus observational curiosity gave medicine its first antibiotic.

Personally for me, while less important, I really appreciate the investigation into the narrative.

I agree that the science is more important and the results don't care about the story.

The balance is that we don't need to go around correcting everyone, but knowing more about the details of the story is worth my time in reading this piece. I think the article strikes the right tone.

somenameforme2 months ago

To be anal about being anal, the article doesn't preclude Fleming's account. It argues that it's unlikely, but countless highly improbable things are happening every second. On this topic somehow Ancient Egyptian poultices (and in cultures onward - though they are the oldest recorded account) even used moldy bread to treat bacterial infections, somehow stumbling onto genuine antibacterial aspects for an absurdly counter-intuitive treatment that has a real effect. However it was initially discovered back then, let alone replicated and confirmed, must have been through an unimaginably improbable series of events. Yet it happened. That's rather the story of humanity.

quesera2 months ago

Definitely worded for clicks, but remember that "myth" doesn't mean "false story", it just means "story".

lazide2 months ago

Myth absolutely implies false (or at least exaggerated) story elements. If it wasn’t, we’d call it history.

And you can tell - ‘the history of penicillin’ implies a very different thing than ‘the myth of penicillin’ eh?

quesera2 months ago

That's an incorrect conclusion to draw, though.

A mythology is just a system of stories and beliefs. Nationalism, religion, fandom, etc. All mythologies based on a shared set of stories. Some are more true (and/or complete) than others, but that's not the important part of being a mythology.

Note also that we do call mythology "history". It's just a matter of where you inhabit on the contextual spectrum. I'm sure you can think of several trivially-refuted examples, and I'm also sure that you realize that your preferred narrative is equally refuted by others.

You're correct of course, and they are not. But also the converse.

+1
lazide2 months ago
IAmBroom2 months ago

myth /miTH/ noun 1. a traditional story, especially one concerning the early history of a people or explaining some natural or social phenomenon, and typically involving supernatural beings or events. 2. a widely held but false belief or idea.

You can redefine words if you want, but don't pretend your definitions are useful for clear communication with others.

quesera2 months ago

You can find definitions that suit your needs if you like, but it does not change the meaning of the word.

A mythology is not necessarily untrue, although they do have a tendency toward expansiveness, which has a coincident trend toward favored interpretations.

But the ultimate truthiness (if it can be measured at all) is neither requirement nor disqualification, vis a vis being a mythology.

17186274402 months ago

A myth != mythology. Other people were discussing myth, you started talking about mythology. The words of course have a common origin.

arjie2 months ago

Oh I really enjoyed this one.

Got a quick insight about how penicillin works: interferes with cell-wall building which is a destroy and recreate process by preventing the recreate part.

Got a quick view into the scientific process and communication: Fleming focused on the insight - penicillium kills staphylococcus - and left out the circuitous detail. This is important so that the big win here is very clear.

And got an insight into human nature and memory: Fleming didn’t tell the accidental contamination story until much later. It could possibly be even an idea someone else might have come up with which then took root in his mind (ironic haha!)

The communication aspect reminds me of Mendel’s far too perfect ratios for his pea plants. That kind of “repeat till difference clear” statistics would be decried today but perhaps that was to communicate rather than to determine.

And finally, I really enjoy reading about human process innovation because I think it’s a big factor in how Humanity grows. The lab notebook has to be some kind of star performer here - Fleming’s notes allow us to look back like this.

When I experiment with things, I naturally lean to keeping notes on my test protocol, observations, and results. But not because of some personal genius. It’s just the standard way I was taught as a child in our science labs.

I won’t claim to the rigor of a microbiology lab but even just the process notes help a lot, which is useful since I’m just testing molecules on myself.

stevenwoo2 months ago

If you are not familiar with more of Mendel or plant biology, he got extremely lucky in picking a two chromosome species. The next plant he picked had more than two chromosome types so he spent the rest of his life hitting his head against the wall - obvious to us but him not having a theory and expertise with microscopes to explain his pea results hampered him greatly beyond his initial pea plant studies.

dexwiz2 months ago

What do you mean by a two chromosome species? A quick google says pea plants have 14 chromosomes. I only looked because I had never heard of a species only having two chromosomes. Do you mean the traits he was selecting for only had two alleles?

dekhn2 months ago

The traits he picked- hope I get this detail pedantically correct: had only two alleles, each allele had an obvious phenotype controlled mostly by that gene, the two phenotypes were binary (no intermediate "half-wrinkled-half-smooth"). and all segregated independently (different chromosomes, or far enough that the linkage was extremely weak). I remember my high school teacher speculating he inspected many different phenotypes and then reported his results on the final ones he picked where the results were nice.

Unfortunately, most modern genotypes and phenotypes in humans don't follow these patterns, and over the years, genetics devloped an entire vocabulary and physical model to explain them, although at a fairly abstract level. None of it made any sense to me so I follow the biophysics/molecular biology approach which tends to consider many more underlying physical details

There's a related story, https://review.ucsc.edu/spring04/bio-debate.html and https://review.ucsc.edu/spring04/twoversions.html which shows how different fields think about the genotype/phenotype relationship. Grinding up steering wheels to figure out how they work...

dexwiz2 months ago

Yeah that was my understanding. Most things have multiple genes controlling them. Like there is no single eye or hair color gene.

ahazred8ta2 months ago

Diploid. Peas have 7 pairs of chromosomes. Many types of plants have multiple (polyploid) copies of each chromosome, and you will not discover the classic Mendelian dominant-recessive pattern by studying them. Mendel lucked out by studying a diploid species. https://duckduckgo.com/?q=polyploid&ia=web

stevenwoo2 months ago

Right, my bad for wrong terminology as biology nor botany is not my speciality either. I was thinking along the lines of XY for humans, then the ordinary two row, two column chart used to teach the basics of Mendel with pea plants and dominant/recessive non polygenic traits in introductory biology classes.

kcexn2 months ago

It's a shame that Fleming misremembered his process of discovery and created a myth of accidental discovery.

I like the Root-Bernstein narrative more. That in the monotonous execution of routine experiments for something unrelated an unusual observation 'forced' them to discover penicillins antibacterial properties.

Not an accidental discovery by good fortune in a serendipitous sense. An accidental discovery of a brute force exhaustive search. The narrative of we spent months meticulously examining hundreds of samples is less romantic, but is one that supports the importance of funding scientific inquiry.

We won't make progress by hoping people leave culture plates out on window sills. We make progress when we fund meticulous exhaustive efforts of discovery.

Joker_vD2 months ago

> Mendel’s far too perfect ratios for his pea plants.

"Remember, if you flip a coin 200 times and it comes heads up exactly 100 times, the chances are the coin is actually unfair. You should expect to see something like 93 or 107 instead".

fainpul2 months ago

Isn't 100 / 100 the most likely outcome for a fair coin? Sure it's unlikely that you hit exactly that result, but every single other result is even less likely.

What I'm trying to say: if you get 100 / 100, that's not a sign of an unfair coin, it's the strongest sign for a fair coin you can get.

shakow2 months ago

> every single other result is even less likely.

But the summed probability of the “not too far away results” is much higher, i.e. P([93, 107]\{100}) > P([100]).

So if you only shoot 100/100 with your coin, that's definitely weird.

+1
tshaddox2 months ago
+2
fainpul2 months ago
grraaaaahhh2 months ago

>But the summed probability of the “not too far away results” is much higher, i.e. P([93, 107]\{100}) > P([100]).

That's true of every result. If you're using this to conclude you have a weird coin then every coin is weird.

Joker_vD2 months ago

Well, yes. But the expected deviation from the mean is still ≈7.07. And the probability that the outcome will be either 93/107 or 107/93 is (slightly) higher than the outcome being exactly 100.

+3
fainpul2 months ago
eviks2 months ago

Why not go one abstraction further and go expected deviation from deviation? Probably the word "expected" plays a mind trick? "Expected" doesn't mean the probability increases, the easiest way to understand it is just by looking at the probability distribution function chart for coin tosses - you'll immediately see that mean has the highest chance of happenning, so exactly 100 is the most likely outcome

voakbasda2 months ago

I would guess that a single trial of 200 flips can be treated as one event, so getting 100/100 is but one outcome. It may be the most likely individual outcome, but the odds of getting that exact result feel less likely than all of the other possible outcomes. The 100/100 case should be seen the most over repeated trials, but only marginally over other nearby results.

Intuitively, this seems right to me, but sometime statistics do not follow intuition.

ptrl6002 months ago

Low kolmogorov complexity equals suspicious

dooglius2 months ago

"fair coin" refers to both the probability of heads and tails being equal (which is still justified) as well as the trials being independent (unlikely with 100/200; more likely the "coin" is some imperfect PRNG in a loop)

+2
tshaddox2 months ago
buildsjets2 months ago

A truly fair coin would never land heads or tails. It would land standing on it's edge, every single time.

munchbunny2 months ago

The chance of exactly 100 heads from 200 fair coin flips is approximately 5-6%. Qualitatively, that's not particularly strong evidence for an unfair coin if you did only one trial.

You could also argue that 100 out of 200 on a fair coin is more likely than any other specific outcome, such as 93/200, so if the argument is that the coin is "too perfect", you then also have to consider the possibility that the coin is somehow biased to produce 93/200 much more often than anything else, vs. 100/200.

nearbuy2 months ago

There is also no way to weight a coin that makes it more likely to get 100/200 than a fair coin.

n1b0m2 months ago

In a real-world scenario, if you saw a result significantly far from 100 (like 150 heads), you might suspect the coin is unfair. However, seeing exactly 100 heads gives no reason to suspect the coin is unfair; it's the result most consistent with a fair coin.

awkward2 months ago

So many other good details that get to how impossibly multivariate biology research is, like the need to have several days at the exact temperature.

It's not uncommon for results in biology to have this kind of snag in reproducibility even now. Sometimes it's due to attributing variations to something like "steady hands at the bench", but other times it can even be a deliberate attempt to prevent rivals from duplicating a process before it can be patented and privatized.

microtherion2 months ago

cf The Harvard Law: "Under controlled conditions of light, temperature, humidity, and nutrition, the organism will do as it damn well pleases."

jjk1662 months ago

Hare's theory predicts that there would need to be a cold snap at just the right time, and lo and behold there was. Probability isn't an issue if the only reason you are considering the probability is because the event already happened. Indeed the low probability of such an event transpiring goes a long way towards explaining why the discovery was not made earlier.

Root-Bernstein's theory makes no such testable predictions, and it solves the issue of an incomplete record on September 3rd with incomplete or inaccurate records elsewhere. It seems to me extremely plausible that fleming did not record the results of a botched, uncontrolled experiment but still recognized it as an indicator of something interesting that warranted follow-up. If I were in his position I would preserve the random dish for comparison to the more rigorous follow up experiment. I certainly don't put any stock into the argument that if the story had gone as Root-Bernstein describes it would have been too circuitous for scientific publishing, if anything it would be much more harmonious with standard scientific writing than the chance observation story.

PoignardAzur2 months ago

Yeah, I don't see the huge improbability here.

Given that we know that:

- Fleming lived next door to an unsecure mycology lab.

- The temperature during the time period was low enough that if Fleming had left a contaminated culture unattended and non-incubated, he would have had a very high chance of getting the results he became famous for...

Well, given that the probability of discovering penicillin in those conditions is pretty high (say, if he forgot/neglected to incubate one out twenty batches, a 5% chance), and the prior probability of discovering penicillin any other way is extremely low (otherwise other scientists would have found it), bayesian calculus says the stroke of luck hypothesis is probably correct.

NetMageSCW2 months ago

Plus it seems probable that the forget/neglect to incubate odds went up since he was about to go on vacation.

jonny_eh2 months ago

> I would preserve the random dish for comparison to the more rigorous follow up experiment

This would also explain why the dish was treated with formaldehyde for preservation, and why the dish still exists today.

pcrh2 months ago

Preserving biological/medical specimens with formaldehyde so that they may be re-examined later is a common practice that still occurs today. So it isn't surprising here.

The alternative would be to freeze the specimens, but that is more cumbersome than stacking formaldehyde-fixed plates on a shelf, and specimens may alter upon repeated freezing and thawing.

NetMageSCW2 months ago

The surprising part (or the smart part) is preserving a dish that was randomly contaminated with an unknown mold instead of throwing it out.

+1
pcrh2 months ago
alexpotato2 months ago

One of my favorite "myths" about the discovery of stainless steel:

Metallurgist is trying out all kinds of steels looking for a particular attribute. He would dutifully record each recipe + test in a notebook but if a particular batch didn't have the attribute, he would throw it out a window into an outdoor scrap pile.

Several months go by and he's cleaning up the pile and notices that one of the blocks has no rust or corrosion. He knows that the pile is six months old but doesn't know which of the recipes this block was connected to.

So he repeats ALL of the block recipes from the last 6 months but labels each block so he can figure out which recipe led to the "stainless" steel.

(Probably not the real story but always loved this telling of it. Actual Wikipedia history is here: https://en.wikipedia.org/wiki/Stainless_steel#History)

commandlinefan2 months ago

I recall reading that the microwave oven was invented by a physicist after he walked by a radiation chamber and the chocolate bar in his pocket melted... makes me wonder if there was any historic license taken in that case as well.

jonny_eh2 months ago

That one I could totally believe. Radar equipment + chocolate bar = very likely to occur.

Izkata2 months ago

The main problem with that one is chocolate bar + body heat also leads to melting.

+2
jdub2 months ago
IAmBroom2 months ago

Any reasonable person could distinguish between a chocolate bar that melted in a pocket, and one that is fresh from a microwave heating.

mordae2 months ago

Hmm, sounds like the spores must have come from the outside. Otherwise he'd be saying his colleague has contaminated the building with improperly stored fungal colonies and he himself let those spores contaminate his lab. So yeah, definitely from the outside.

mandevil2 months ago

Best take on serendipty versus effort in the history of science is, naturally enough, from Monty Python:

https://www.youtube.com/shorts/1Hu0f_ti9EQ

Text from http://montypython.50webs.com/scripts/Series_3/99.htm

"Presenter[John Cleese]: Penguins, yes, penguins. What relevance do penguins have to the furtherance of medical science? Well, strangely enough quite a lot, a major breakthrough, maybe. It was from such an unlikely beginning as an unwanted fungus accidentally growing on a sterile plate that Sir Alexander Fleming gave the world penicillin. James Watt watched an ordinary household kettle boiling and conceived the potentiality of steam power. Would Albert Einstein ever have hit upon the theory of relativity if he hadn't been clever? All these tremendous leaps forward have been taken in the dark. Would Rutherford ever have split the atom if he hadn't tried? Could Marconi have invented the radio if he hadn't by pure chance spent years working at the problem? Are these amazing breakthroughs ever achieved except by years and years of unremitting study? Of course not. What I said earlier about accidental discoveries must have been wrong. "

niemandhier2 months ago

This stood out to me:

“Despite this close professional association, however, Hare claims to have played no part in the discovery or original research on penicillin nor to have discussed them with Fleming”

It’s nice to see that the bickering about who stole whose research does not affect all old discoveries.

dooglius2 months ago

Is it common in cases for someone with no involvement at all to claim involvement? Usually disputes I've heard of are when multiple people are involved, and they're arguing about who played a crucial vs minor role.

jjk1662 months ago

It's common for people who have close associations to have events that could be construed as involvement, and when someone does believe they are involved in something important, they tend to claim their involvement was important. It would be so easy to inflate a random conversation or a little common courtesy assistance as something more. It takes some genuine humility to take stock of all your interactions and conclude that you had nothing to do with one of the most important discoveries in history, and more still to admit that you thought nothing of it at the time.

pickledoyster2 months ago

imo, this paragraph covers the essence of a good chunk of the article: https://en.wikipedia.org/wiki/Discovery_of_penicillin#Replic...

johnyzee2 months ago

That was a lot of words to get to the point that Fleming probably misremembered the sequence of events when he retold the story 15 years later. He even mentioned this possibility at the time. Interesting article but not much of a mystery.

dj_gitmo2 months ago

The Hare theory is a better story, regardless of whether it is true. I am surprised that it hasn't seeped into pop science lore.

keepamovin2 months ago

Tangentially related: doxycycline helps improve muscle and tendon tear recovery by enhancing the performance of matrix proteins that form "scaffolding", by inhibiting factors that break them down. "By inhibiting MMPs, doxycycline helps preserve and remodel the ECM, accelerating repair and improving biomechanical strength (e.g., tensile strength and reduced creep/strain)". Crazy. I'm a big fan off high-ROI off-label uses of well-tolerated, cheap, out-of-patent "WHO essential medecines list" pharmas. There's much to be found there.

Another tidbit: inderol (propranolol, beta-blocker) can aide PTSD recovery by reducing the emotional potency of traumatic memories when taken in a therapeutic replay.

catlikesshrimp2 months ago

Not a mention of Clorito Picado?

https://en.wikipedia.org/wiki/Clodomiro_Picado_Twight

The contest is cold, but it deserves at least a fleeting hint

Peteragain2 months ago

The Flemming/Florey story is actually an interesting bit of science history, but it's about popular media and the romance of science v.s. how real science is done with patience, selfless dedication and a literature search. When Chain joined the Oxford lab, a literature search turned up 6 candidate "penicillins" which they went on to investigate. Fleming smoked a pipe, got to the office about 10, and was accessible (being in London). This version of the story admittedly comes from a Howard Florey biography I read 10 years ago..

ggm2 months ago

If it's the Leonard Bickel one, it's excellent.

Fleming is a folk hero. Florey and Chain (and Du Pont, for industrialisation) did the real work.

lynguist2 months ago

For me the biggest plot hole of the popular penicillin discovery myth is clearly the open window story, including its multiple side plots with meteorological events.

And that that story exists and has PREVAILED despite the fact that everyone knows that the same building was housing a mycology laboratory only a flight of stairs away, and that it was the mycology colleague La Touche who identified the penicillin.

fn-mote2 months ago

I wish this story were not framed as a “myth”. Far fewer people would read it if they knew the (presumed) truth - a small deviation from the story.

tetris112 months ago

(Off-topic:) Scrollbars, and their non-existence.

jasonjmcghee2 months ago

It's not the best implementation, but it's there (you just have to scroll a bit to get it to show).

mandevil2 months ago

The cartoon 60% of the way down the article definitely feels like an "artists barely concealed fetish" thing.

dooglius2 months ago

Can someone with more experience in scientific writing comment on

> It’s too circuitous and indirect for a scientific report

The preceding paragraph does not seem unreasonable to me--maybe a bit too glib, but nothing that couldn't be touched up.

paddleon2 months ago

in scientific writing, you need to take

100 articles at 6 pages each

and condense them to 1 article of 6 pages

And add how your method/insight moves the conversation forward, along with describing your method/insight.

The reason why scientific writing can be hard to read from the outside is the 100:1 compression. Decompression of that can require some knowledge of the field.

Also, some people are just bad at writing.

advisedwang2 months ago

The goal of a paper is to write up the actual discovery, not to tell a story or explain irrelevant background. The steps he wrote there would confuse rather than elucidate the actual discovery.

tolerance2 months ago

Writing like this does not belong on Substack.