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Florey, Chain and large scale productionWho were Howard Florey and Ernst Chain?Howard Florey was an Australian. From the 1920s onwards, he was Professor of Pathology at Oxford University, working in a well equipped and well staffed lab. One of his team was Ernst Chain, a brilliant Jewish biochemist who joined Florey's research team after he fled to Britain from Nazi Germany. Pinpointing penicillinIn 1938 Chain came across Fleming's original 1929 paper in the British Journal of Experimental Pathology. It interested him greatly and he began work using a culture which originated on one of Fleming's plates. There is some dispute about who was really responsible for the bulk of the work in Oxford on penicillin. Florey was in charge of the lab and oversaw and approved all the projects, whilst Chain seems to have been most active in the actual research. It was not a great vision for a miracle cure which motivated their research. As Chain said:
Chain managed to extract some relatively pure penicillin - more that Fleming had ever achieved. To show that this penicillin was effective he needed to inject it into mice already infected with bacterial disease. However Chain was not qualified to inject laboratory animals He claims to have asked Florey to set the experiment up for him several times, but that Florey showed little interest. In fact he apparently said to Margaret Jennings, another colleague:
Chain felt humiliated and asked another colleague, J M Barnes, to inject two mice with a bacterial disease and with penicillin for him when Florey was away. The mice recovered - and now Florey WAS interested! The next step was to inject 50 white mice with the deadly Streptococcus bacteria and then give half of them penicillin injections as well. All of the mice given penicillin recovered - all of the others died. Penicillin was beginning to show real promise in beating bacterial disease - but the next big step was to try the drug on humans. Human guinea pigsThe biggest problem was making enough penicillin - it was dreadfully difficult to extract penicillin from the mould where it was formed in tiny amounts. In 1940 Albert Alexander, a 48 year-old London policeman, was rushed to the Radcliffe hospital. He had a temperature of 105oF and had developed septicaemia (a bacterial infection that attacks the whole body) from a tiny cut he had made while shaving. When he was dying, Florey and Chain requested permission to try their new 'purified' penicillin and injections began. Five days later, as Albert was recovering from certain death, the supply of penicillin ran out. Florey and Chain were even extracting unused penicillin from the man's urine and reusing it in a desperate attempt to keep treating him - but to no avail. The poor policeman became ill again and died five days later. The penicillin had shown that it worked and that it wasn't harmful to the patient - but although the treatment worked, the patient died. When more penicillin had been collected it was used on a fifteen year old boy with blood poisoning and another 84 year old man. Both of these patients made full recoveries, although the fourth patient, a four year old boy, recovered from his infections but then died from a burst blood vessel. Then Alexander Fleming, who had maintained his interest in penicillin whilst stopping work on it, asked Florey for some penicillin and used it to save the life of an old friend of his, getting maximum press coverage for the story. By now, in 1941, most scientists acknowledged that penicillin was potentially enormously important for saving lives by defeating bacterial infections - but there simply wasn't enough of it. Yet in the middle of a war, with soldiers suffering from gangrene and other dreadful infections, it was more desperately needed than ever. A matter of scaleIf Chain had been the driving force behind the purification and use of penicillin in the lab, Florey came into his own when it came to manufacturing the amazing drug. All UK factories were taken up with the war effort - and what is more they might be bombed. However Florey had good contacts in the USA - the Rockefeller foundation funded his research - and so he went over to the States to see what could be done. Three big companies including Pfizer lent their resources and labs to the project. Corn steep liquor, made from the processing of maize provided lots of nutrients and increased the yield of penicillin. It wasn't really available in the UK at the time. The use of huge deep fermentation tanks provided with a good supply of air also made it possible to produce more of the wonder drug, because the mould could grow throughout the 25 000 gallon tanks instead of just on the top. However it eventually became clear that the type of Penicillium notatum, the penicillin mould first discovered by Fleming, would never give enough of the drug to be useful commercially. The hunt was on for other, better penicillin moulds. Army scientists sent back soil samples from all over and lab workers were asked to look in the fridges at home. In 1943 Mary Hunt, a lab worker in Peoria, brought in a canteloupe melon infected with a 'pretty, golden mould'. This turned out to be Penicillium chrysogeum, a mould which gave about 200 times as much penicillin as the original form. By using X-rays to cause mutation sand refining the whole process Florey and the teams in the US eventually produced a strain of mould which gave 1000 times the yield of penicillin from the original. From January to May 1943, only 400 million units of penicillin had been made; by the time the war ended, U.S. companies were making 650 billion units a month. Millions of lives were saved from the D-day landings onwards, and once the war was over the miraculous effects of this fungal based drug were available increasingly cheaply to everyone. For the first time in human history a reliable weapon against bacterial diseases had been found and produced on a large scale. No wonder Fleming, Florey and Chain each received a Nobel prize for the part they each played in this amazing story.
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The germ theory of disease
