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- The development of penicillin
- Testing and production of penicillin
- British-American penicillin effort
- Synthesising and commercial production of penicillin
- Florey and Chain’s later projects
Key Facts And Information
Let’s know more about Florey and Chain!
- In 1928, Sir Alexander Fleming's discovery of the antibiotic property of penicillin opened the door to the therapeutic possibilities of antibiotics. However, his discovery failed to gain enough interest to cause immediate pursuit by other scientists. Until in 1940, when Howard Florey, Ernst Boris Chain and a team of researchers worked on penicillin research at the Sir William Dunn School of Pathology, University of Oxford.
- The team successfully made progress in isolating the purified compound which resulted in the testing, mass production and medical application of penicillin. This scientific breakthrough earned Florey and Chain the 1945 Nobel Prize in Physiology or Medicine shared with Fleming.
The development of penicillin
- In 1928, Alexander Fleming discovered that the 'mould juice' from an accidentally contaminated staphylococcus culture plate was capable of killing a wide range of harmful bacteria but found it difficult to isolate pure penicillin. Interest in penicillin kept going, albeit fruitless. It was the team of researchers and technicians headed by Howard Florey and Ernst Chain that developed the potential of penicillin from being a laboratory curiosity into a life-saving drug.
Who were Florey and Chain?
- Born in Adelaide, Australia in 1898, Howard Florey had shown a keen interest in science, especially chemistry.
- He studied medicine at the University of Adelaide and obtained a Rhodes scholarship from Magdalen College, Oxford.
- He attended the University of Cambridge in 1925, then the Rockefeller Foundation sent him to the United States where he worked in many laboratories.
- Returning to England, he came across Fleming’s work in 1929. In 1935, he was appointed a professor of pathology at Oxford.
- It was a top institute, with much better laboratories, and had, in particular, a biochemistry laboratory.
- Ernst Boris Chain was born in Berlin in 1906 to a Russian father and a German mother.
- His father's profession (an industrial chemist) influenced him to choose a scientific course of studies, and he graduated in chemistry and physiology from Friedrich Wilhelm University in Berlin in 1930.
- He completed his degree and worked at the premier German research institute at the Kaiser Wilhelm Institute for Physical Chemistry and Electrochemistry and then in the chemical department of the Pathology Institute at Charité Hospital in Berlin, where he obtained his doctorate.
- When the Nazis came to power in 1933, Chain left for England.
- He worked successively in London then was accepted as a PhD student at Cambridge University under the direction of Sir Frederick Gowland Hopkins.
- In 1935, he became a lecturer at Oxford University, where he worked on a range of research topics.
- It was in 1939 that Chain joined Florey in investigating natural antibacterial agents produced by microorganisms, among them penicillin.
- With the help of a fellow biochemist, Edward Penley Abraham, Chain found a successful technique for purifying and concentrating penicillin.
- The process further improved with the input of Norman Heatley.
- This enabled the increased extraction of penicillin and the removal of impurities in the samples.
Testing and production of penicillin
- The Oxford scientists had penicillin finally concentrated, stable and purified. In 1940, they proceeded to test the therapeutic action of the sample of penicillin on animals.
- On 25 May 1940, a crucial experiment was carried out on eight mice infected with hemolytic streptococci. Half of these were subsequently injected with measured and timed doses of penicillin.
- The result showed that the four mice injected with penicillin survived, but the untreated ones died.
- This led to further testing involving hundreds of mice.
- Florey and Chain reported their findings in The Lancet in August 1940, which attracted numerous research groups seeking cures for bacterial diseases.
- In 1941, Florey began to try penicillin treatments on human infections.
- A young woman suffering from cancer agreed to be administered with the drug to test penicillin’s toxicity.
- She was the first English patient to be tested on but unfortunately had an adverse reaction to the treatment due to the impurities present in the drug.
- The first patient with an infection, a police officer, was then administered with penicillin.
- The required dosage and length of treatment was not yet established at this time.
- The police officer's condition improved initially but worsened as the penicillin supply faced a shortage.
- Due to the unfortunate result of the trial, Florey vowed to ensure that enough penicillin would be available to complete a treatment.
- Several other patients were treated successfully afterwards.
- Penicillin production became of principal importance and soon, more personnel had to be hired and all manner of vessels were used to grow Penicillium mould in the Dunn laboratory, outgrowing the space assigned to the research team.
- The laboratory became a fully functional penicillin factory.
- Chain urged to seek a patent on penicillin, a common practice in German research institutes, but Florey declined to go into a commercial agreement, which annoyed Chain.
- Florey approached various British pharmaceutical firms to help with the production.
- Most firms were already managing the manufacturing of other drugs essential for the military and civilian population, and some facilities had been damaged because of the war.
- It was only the Imperial Chemical Industries who took on the challenge to increase penicillin supply.
- Since England in 1941 was under constant shelling, the production of penicillin in industrial quantities was deemed impossible.
- Florey and Heatley had to find more assistance for research and manufacture. In 1941, they left for the United States.
British-American penicillin effort
- Florey and Heatley met up with old colleagues to help them obtain assistance for the penicillin production in the US.
- They were directed by an American colleague to the US Department of Agriculture's Northern Regional Research Lab (NRRL) in Peoria, Illinois, where fermentation processes were being actively studied.
- Apart from the NRRL, Florey visited another colleague, A.N. Richards who had become chair of the Committee on Medical Research in the Office of Scientific Research and Development (OSRD).
- Trusting Florey's judgement and cause, Richards decided to advance integrated action on penicillin.
- The programme of the joint penicillin effort consisted of thousands of people and some 35 institutions including university chemistry and physics departments, government agencies, research foundations and pharmaceutical companies.
- Heatley remained at the NRRL and moved to New Jersey to work on scaling up penicillin production.
- The NRRL turned out to be a key contributor to the large-scale production of penicillin as they found the most efficient method of growing the mould and the most productive penicillin-producing strains which happened to be a mouldy cantaloupe from a Peoria fruit market.
- On the other hand, the OSRD encouraged pharmaceutical companies such as Merck, Squibb, Lilly and Pfizer to pursue penicillin production.
- By March 1942, the OSRD was able to produce enough penicillin to treat the first American patient in New Haven, Connecticut, followed by ten more cases by June 1942.
- All patients were treated with penicillin supplied by Merck.
- Florey's trip to the US was a resounding success whilst the team under the direction of Chain continued with their work amidst the bombings that damaged the laboratories.
- Florey returned to England to head the clinical trials, which eventually took him to North Africa and the Soviet Union.
Synthesising and commercial production of penicillin
- To synthesise penicillin, it is believed that it was imperative to understand its structure first. At Oxford, Chain, Abraham and Robert Robinson were assigned to determining penicillin's structure.
- By 1943, research teams at Oxford and Merck had proposed two varying structures for the atomic groupings central to the penicillin molecule.
- In 1946, Chain and Abraham's deduction was confirmed and validated by Dorothy Crowfoot Hodgkin.
- Hodgkin's work came too late in the Second World War to be used in devising a synthesis for penicillin.
- Even after 1957, when a synthesis was developed, fermentation remained to be the most efficient method in the commercial production of penicillin and related antibiotics.
- However, the structural knowledge discovered during the war was vital in creating penicillin-like antibiotics which were more effective and had fewer side effects.
- The war effort aided in the production and appreciation of the importance of penicillin.
- The demand for the drug increased but supplies remained limited as priority was given to military use.
- Penicillin significantly helped reduce the number of deaths and amputations of troops during the war.
- It was only in 1945 that the 'miracle drug' became available to consumers.
- The work of both Florey and Chain was instrumental in the production of penicillin, allowing its extensive availability which saved many lives.
- This specific work by both scientists earned them the prestigious Nobel Prize in Physiology or Medicine, shared with Fleming in 1945.
Florey and Chain’s later projects
- After the Second World War and the Nobel Prizes awarded to Florey and Chain, the scientists continued their research work but headed in separate directions.
- Florey stayed leading the Dunn School lab and accomplished the development of cephalosporin C in 1954. He immediately urged its patenting.
- Then he went on to hold the world's most prestigious scientific position from 1960 to 1965, the presidency of the Royal Society.
- Furthermore, he helped organise the Australian National University in Canberra as a postgraduate-level university, becoming its chancellor in 1965.
- Chain parted ways with Florey at Oxford.
- He effectively combined a biochemical research department and a fermentation pilot plant at Istituto Superiore di Sanita in Rome.
- In 1957, the isolation of the atomic groupings central to the penicillin molecule was successful with the contribution of a group of scientists from the Beecham Group.
- This outcome was significant in the commercial production of all kinds of semisynthetic penicillins, such as penicillin V and ampicillin.
- In 1964, Chain left for England to head a new biochemistry department at Imperial College, London, which he specified would include a fermentation pilot plant as one of its facilities.