Alexander Fleming was an untidy worker. He left cultures stacked on his bench for weeks, partly because he was interested in what grew on them by accident, and partly because he could not be bothered to clear up. In August 1928 he went on holiday to Suffolk with his family and left a pile of petri dishes on a bench in the corner of his laboratory at St Mary’s Hospital in London.
He came back on 3 September. Going through the stack with a visiting colleague, he picked up one dish, looked at it, and said something to the effect that this was funny. A blue green mould was growing on the plate, and in a ring around the mould the colonies of staphylococcus had gone transparent and dissolved.
That plate is the founding object of the antibiotic era. It also did nothing at all for twelve years.
The Mould Should Not Have Been There
The likeliest explanation for the contamination is a laboratory one floor below, where a mycologist named Charles La Touche was working on moulds collected from the homes of asthma patients. Spores drifting up a stairwell are the standard version of the story.
What made the plate readable was the weather. London had an unusually cold spell at the start of that August, followed by a warm period. Mould grows well when it is cool and staphylococcus grows well when it is warm. The mould got its start first, established itself, and produced its inhibitory substance before the bacteria could overrun the dish. Reproducing the observation deliberately turned out to be surprisingly awkward, and later attempts had to imitate that temperature sequence.
Fleming was also unusually well prepared to notice it. Seven years earlier, with a head cold, he had let a drop of his own nasal mucus fall onto a bacterial culture and found that it dissolved the bacteria. He named the substance lysozyme, an enzyme present in tears, saliva and egg white, and spent years on it. It was a genuine discovery of a natural antibacterial agent, and it was medically useless because the organisms it killed were mostly harmless ones. But it meant that a clear ring around a contaminant was not, to Fleming, a spoiled plate. It was a phenomenon he had already spent years studying.
What He Did and What He Did Not Do
Fleming worked on the mould for about eighteen months. He identified it as a Penicillium, grew it in broth, and named the active substance in the filtrate penicillin. He showed that it killed staphylococci, streptococci, pneumococci, gonococci and the diphtheria organism, and left others untouched, which meant it could also be used to isolate the resistant ones from a mixed sample. He confirmed that it did not harm white blood cells, which was a good sign for toxicity.
He published in the British Journal of Experimental Pathology in June 1929. The paper is careful, correct, and reads mostly as a note about a useful laboratory tool.
What he could not do was get the substance out of the broth. Penicillin is unstable, present in tiny quantities, and it degrades under most of the obvious purification methods available in a hospital laboratory in 1929. Fleming was a bacteriologist, not a chemist. Two young chemists at St Mary’s tried and produced only crude extracts that lost their potency within days.
He also seems not to have pushed the idea of injecting it. He tried it on surface infections with mixed results, and the culture filtrate was too weak and too impure to do much. Without a purified compound there was no way to test it properly in an animal, and without an animal test there was no case for a drug.
So he moved on. The mould was kept alive and posted out to anyone who asked, and for a decade penicillin was a curiosity in the literature.
Oxford, 1938
The people who turned it into a medicine were a team at the Sir William Dunn School of Pathology in Oxford: Howard Florey, an Australian pathologist who ran the department, Ernst Chain, a biochemist who had left Germany in 1933, and Norman Heatley, whose job was to make the impossible production side work.
Chain came across Fleming’s paper while surveying antibacterial substances in the literature, and the group decided to look at three of them. Penicillin was chosen for chemical interest rather than medical promise. The work began in 1939 with the war starting and almost no money.
Heatley solved the extraction. He worked out that penicillin could be pulled from the broth into ether under acid conditions and then back into water, a technique he built as a continuous countercurrent apparatus out of glass tubing, milk bottles, a doorbell and parts of a bookcase. He also devised the assay used to measure potency, and the culture vessels, since nothing existed that gave enough surface area. The department eventually settled on hospital bedpans, and then had ceramic vessels made to the same shape.
On 25 May 1940 they infected eight mice with a lethal dose of streptococci and treated four of them. By the next morning the four untreated mice were dead and the four treated ones were alive. Florey’s comment was that it looked like a miracle.
The Policeman
The first human patient was Albert Alexander, a 43 year old Oxford policeman with a septicaemia that had begun as a small infection and had already cost him an eye. He was treated in February 1941 and improved dramatically within a day.
The supply ran out. The team recovered penicillin from his urine and re injected it, which bought a few days more, and then there was nothing left. He relapsed and died a month later.
The lesson taken from that case was that the science was settled and the problem was now manufacturing. Making enough penicillin to treat one adult required brewing and processing hundreds of litres of mould broth, and Britain in 1941 had no industrial capacity to spare.
Florey and Heatley flew to the United States in July 1941 with the mould culture, reportedly smeared into the linings of their coats in case the material was lost. At the government laboratory in Peoria, Illinois, two changes multiplied the yield: growing the mould in corn steep liquor, a waste product of the local starch industry, and switching to a better strain, found on a cantaloupe from a Peoria market. Deep tank fermentation replaced the flasks. By D Day in June 1944 there was enough penicillin to treat every Allied casualty who needed it.
Who Gets the Credit
The 1945 Nobel Prize in Physiology or Medicine went to Fleming, Florey and Chain. Heatley, who was not a professor and whose contribution was technical, received nothing at the time, and got an honorary doctorate of medicine from Oxford in 1990, the first in the university’s history awarded to someone who was not a physician.
Fleming became the public face of it, which he had not sought and did not entirely deserve, and he was consistently honest about it in interviews. The Oxford team resented the coverage for the rest of their lives.
There were earlier observations too. A French medical student named Ernest Duchesne wrote a thesis in 1897 on the antagonism between moulds and bacteria, including animal experiments, and the Institut Pasteur did not acknowledge receiving it. He died of tuberculosis at 37. The idea that moulds fight bacteria had been noticed by Pasteur himself, who observed in 1877 that anthrax bacilli died in the presence of certain airborne organisms.
The reason 1928 counts and 1897 does not is that a discovery in medicine is not the observation. It is the observation plus somebody able to turn it into a treatment, and that took a hospital bacteriologist who noticed, a department head who chose the problem, a biochemist who characterised it, a technician who built the apparatus, and an American fermentation industry with corn syrup to spare.
Fleming’s Warning
In his Nobel lecture in December 1945, Fleming spent a passage of it describing how easy it was to make bacteria resistant in the laboratory by exposing them to doses too small to kill, and pointed out that the same thing would happen in the body if patients took too little for too short a time.
Penicillin resistant staphylococcus appeared in hospitals within about four years. The organisms that Leeuwenhoek first saw through a glass bead in the 1670s, and that John Snow tracked without ever seeing at all, turned out to be able to evolve faster than the chemistry could be replaced.
The dish itself survives. Fleming preserved and photographed the original culture plate, and it is in the British Library. It is a small brown disc that does not look like much, and it is the reason that a scratch, a chest infection or a childbirth stopped being a plausible way to die.
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