11 May 2019

The true story of penicillin: Fleming, Florey, Chain and the team

It wasn't until the late C19th that scientific studies of anti-biot­ics began. French chemist Louis Pasteur discovered that infectious diseases spread by bacteria; he observed that mould inhibited the growth of an infectious animal disease, anthrax. British surgeon Joseph Lister noted that samples of urine contam­inated with mould didn't allow bacteria to grow, but he couldn't identify the substance in the mould. French medical student Ernest Duchesne successfully tested a substance from mould that inhibited bacterial growth in animals, but he died in 1912.

After WW1, Scottish scientist Alexander Fleming (1881–1955) was working at St Mary's Hospital in London. While conducting an experiment with bacteria, a tear fell from his eye into a Petri dish. He later noticed that a substance in his tear killed the bacteria, but was harmless to the body's white blood cells.

Years later, in 1928, Fleming was doing research on the flu. While he was away on holidays, some mould fell into a discarded Petri dish containing bacteria. When this messy scientist returned to his lab, he recognised the pattern from his previous experience. The mould was producing an antibiotic substance that he named Penicillin.

Thus the first anti­biotic used successfully to treat people with serious infectious diseases began with dumb luck. Bacteria reproduce by dividing into two new cells. They enlarge their size before the DNA chromosome is copied. The two new chromo­somes move apart and a cell wall forms between them. But if there’s penicillin, the new cell wall won't be able to form and the bact­eria can't reproduce, so the disease can't spread. Fleming noticed that mould had prevented the growth of bacteria in his lab but he couldn't extract the bacteria-killing substance. He wrote up his findings in the British J of Experimental Pathology (1929), got a cool response and moved on to other research.

So the main plot of the story inv­olves the re-discovery of pen­ic­il­lin 10 years later by an Australian scientist Howard Florey (1898-1968). Florey had been brilliant at school and sport, and studied Medicine at Adelaide Uni. He won a Rhodes Scholarship and went to Oxford University in 1921.

photo credit: Sandwalk

Florey gathered a team of specialist scientists at Oxford Uni in 1938. They commenced a careful investigation of the properties of anti-bacterial substances that are produced by mould.  German scientist Ernst Chain worked on purifying penicillin with Edward Ab­raham. Norman Heatley improvised methods for extracting penic­illin using ether and bedpans. AD Gardner and Jena Orr-Ewing studied how penicillin reacted with other organisms. Howard Florey looked with Margaret Jennings at the impact of penicillin on animals. Ethel Florey later worked with her husband on clinical trials of penic­il­lin. Indiv­id­ual members worked separately then got together to exchange ideas.

By May 1940 the work was urgent, so Florey's team tested penicillin on eight mice injected with a lethal dose of streptococci bacteria. Four of the mice were treated with penicillin, while four weren’t. Next day, the treated mice had recovered; the other mice were dead.

The results were so exciting Florey knew it was time to test the drug on humans. The first patient in 1941 had a terrible infec­t­ion and was given penicillin, and soon began to recover. But be­cause Flor­ey's team didn't have enough of the drug to see the pat­ient through to a full recovery, the patient died. Instead the team concent­rated on sick children, who required smaller quantities.

In 1943 Florey travelled to North Africa to test the effects of penicillin on wounded soldiers. Instead of amputating wounded limbs, the wounds were cleaned and sewn up, and the patients given penicillin.

Florey's team worked with a lack of funding and equipment, and needed drug companies to help produce the large amounts required. Companies in Britain were unable to help out on a large scale because of the war, so Florey and Heatley took a dangerous flight to the USA in a blackened plane. The trip was against the wishes of Ernst Chain, who wanted to first patent their ideas in Britain. This would have made the team very rich, but patenting medical discoveries in Britain that had used government funding would have been unethical.

Florey explained his penicillin-making methods in the USA, including in a Department of Agriculture laboratory looking for a new use for a by-product of the corn-milling process. When this liquid was used, 10 times the amount of penicillin was able to be produced. Then they found mould growing in cantaloupe was twice as successful again. By late 1943 mass production of the drug had commenced, a sign of Florey's persistence and determin­ation. Thanks to his team, the drug was available to treat Allied troops by D-Day 1944.

By the end of the war, many laboratories were making the drug eg Merck, Squibb and Pfizer Cos in the USA and the Commonwealth Serum Labor­atories in Australia. CSL made the drug available for civilian use.

The Discovery and Development of Penicillin 1928-1945, 
commemorative booklet of the National Historic Chemical Landmarks programme 
American Chemical Society, 1999.

However, several strains of bacteria became resistant to penicillin after a few years, through mutation of the cells. To overcome this, 1950s scientists made artificial penicillin by chemically changing natural penicillin; resistant bacteria multiply when non-resistant bacteria die. Hospitals in Australia etc saw the arrival of antibiotic-resistant bacteria due to the _overuse_ of antibiotics.

Fleming’s role as the leader of the scientists that developed penicillin won him the Nobel Prize in 1945 with Florey and Chain. He was knighted in 1944. He was the first Aus­tr­alian elected to the prestigious position of President of the Royal Society in 1960.

Penicillin G is the form that killed bacteria during Duchesne's work in 1896, Fleming in 1928 and Florey in 1939. There are now 60+ antibiotics, substances that fight bacteria and other microbes harmful to humans. Everybody knows of Alexander Fleming’s role in discovering penicillin. Alas Howard Florey’s vital role in the story is still largely unknown.

I thank and recommend The Discovery of Penicillin by Robert Gaynes and Sandwalk by Prof Moran.






8 comments:

Deb said...

One important outcome, but lots of very clever minds involved en route.

Hels said...


Deb

that was true for almost every "sudden" discovery in medicine and science. I will be looking at the same question in the fame derived by the discovery of the DNA, where only two names are familiar - Watson and Crick.

I realise only 3 people can win a Nobel Prize, even if there were more than 3 equal contributers in the medical or scientific team. The others should have published every finding in respectable academic journals, en route to the final discoveries. That way their names would not have been lost to history.

Parnassus said...

Hello Hels, This is a remarkable story of how the work of individual scientists, fueled by chance discoveries, coalesced into an important medical tool. Euell Gibbons, the naturalist, often noted that at the aboriginal or folk level, certain plants have been known for centuries to have antibiotic or antibacterial properties, even if they didn't recognize the mechanisms involved. Some of these have been tamed for medical use, but unfortunately many early discoveries were masked by the magic and nonsense of the period, such as the doctrine of signatures, which stated that, for instance, a plant with kidney-shaped leaves would be good for kidney complaints. I strongly recommend Gibbons' very readable book, Stalking the Healthful Herbs.
--Jim

Hels said...

Parnassus

Thanks for the reference. People have long known, or guessed, which plants had anti bacterial properties, even if they had no way of understanding the mechanisms involved. That is why scientists benefit individually... by working collectively. No one individual can have expertise across multiple scientific skills.

Hilary Melton-Butcher said...

Hi Hels - I didn't know the others associated with Penicillin ... so thanks for giving us the overview history ... Interesting to read about Florey - I wonder if he hadn't of got the Rhodes Scholarship to Oxford whether history would be different. Cheers Hilary

Hels said...

Hilary

True.. the Rhodes Scholarship to Oxford was a life saver for Florey. Although undergraduate degrees in Australia (and South Africa, Canada etc) were top quality, most parents had to get their children into paying jobs as soon as they graduated. Florey was one of 3 children, all of them needed university fees, accommodation, meals, clothes, books and transport until they were financially independent. The Rhodes Scholarship covered all costs, for at least 2 and sometimes 3 years.

Even more importantly, at Oxford Florey got to meet and work with the best scientific minds from all over the British world and beyond.

Andrew said...

Many heads worked on the project, but I think Florey is rightfully honoured here and should be overseas too.

Hels said...

Andrew

Baron Florey of Adelaide was given the same royal honour and the same Nobel prize as Lord Fleming, so the question becomes "how Australian was Florey?"

Florey was 23 when he left Australia, and wanted to live in Britain for the rest of his career. But he actively recruited young Australian scientists to Oxford, he visited an Australian science conference in 1944 and became chancellor of the Australian National University in 1965.