Discover, Capture And Share, Penicillin!

Photo credit : www.gaurangimaitra.com
Memory tags: The - discover, capture, share - story, is a common thread that runs through all scientific discovery story lines. The story behind this first antibiotic is about one fungus, one world war, three decades, four Nobel laureates and a multitude of unsung heroes. And the poster session at the 96 ^th in Science Congress in NEHU Shillong.

THE MARKSMAN, THE TENNIS PLAYER, THE MUSICIAN AND THE BIOCHEMIST

It begins with Alexander Fleming (1881 – 1955) at St. Mary’s Hospital in London . He entered St. Mary’s Hospital in 1901 as a student and did well enough to become a surgeon in 1906.  Instead, he joined its research department on the request of the captain of the St. Mary’s rifle shooting club. Fleming was an excellent marksman having been an active member of the Territorial Army   since 1900.  His captain did not want to lose him! So the prospective surgeon became a researcher thanks to rifle shooting! And began to work with Almroth Wright an eminent immunologist and bacteriologist! Serendipity? If the first main player in this story entered partly due to rifle shooting, the second came in partly due to tennis! Howard Florey the youngest son of a boot maker from Australia, came to England on the Rhodes Scholarship, on the strength of his academic excellence and prowess at tennis! After a near dream run in academics he became Prof. of Pathology at the Sir William Dunn School of Pathology in 1938.

The third player in this story was a fine pianist who almost chose music over a scientific career. A Russian Jew immigrant escaping from Nazi Germany, Ernst Boris Chain   came to England complete with Chaplinesque Hitler moustache!  It was just three years since he had come to England.  At the time Florey was setting out to build his new team. Chain’s  excellent academic profile and  background  in physiology and chemistry made him one of Florey’s first recruits at Oxford

Among others Norman Heatley joined Florey’s team. This Englishman was an inspiring school teacher and a graduate in Natural History. He was an inventive genius with a love for the practical side of science. He was the most delightful 'old-fashioned gentleman': modest to a fault, courteous, kind, considerate and always looking for ways to help others; a team player, rather than a leader of men.

OF DISCARDED PETRIDISHES...
By 1928 Fleming had built up a reputation for brilliant thinking but casual, almost careless lab work. He was now Prof. of Bacteriology at the self same St. Mary’s Hospital! He did not; in today’s fashion have a gaggle of technicians, doctoral and post doctoral research fellows. He by his own admission was working alone. He tossed culture dishes left exposed during a holiday into a sink with disinfectant. Then suddenly faced with the prospect of showing evidence of on going lab work, to a visitor, he retrieved a half submerged dish! What the visitor’s reaction was we don’t know. But we do know that Fleming saw staphylococci colonies lysed by some agent. With mounting excitement he examined the agent! This was a chemical from the fungus Penicillium notatum which he obviously named Penicillin. In his Nobel Prize acceptance speech he attributes the lucky chance (serendipity) to the fact he was working alone. Team members would have probably thoroughly soaked and cleaned out the Petri dishes.  He suggested that discovery is probably personal intuition, but to capture and share, one needs a team.

AT OXFORD ...
The decision to work on Penicillin came in 1938.  At this point of time they were probably not consciously looking for a great curative agent but an academic screening of   certain antibacterial substances. Funding for the penicillin project came in from Britain's Medical Research Council and the Rockefeller Foundation in the US. Fleming had established its antibacterial activity, selective inhibition of the growth of certain bacteria and a measure of its non toxicity to the immune system. His failure at purification of this heat labile and elusive chemical left the job less than half done. As team Oxford stepped in, it was Norman Heatley who began refining the growth conditions.  Once the culture method was established, the work of extraction began. With some amount of workable penicillin extracted it was time for the next step. On 25th May 1940 the first trials on 8 mice began. Four mice (controls) received only the infective staphylococci, whereas the other four (experimental) received both staphylococci and penicillin.  Heatley recorded in his lab diary, their going to the lab after supper, with friends, continuing the timed and measured injections of penicillin   and then staying up till 3.45am, by which time all the four controls were dead! Penicillin could actually combat staphlococcus infection in vivo borne out by the fact that all the four experimental mice survived!

AUGUST 1940, THE PENCILLIN BOMBSHELL !!!
The Lancet edition of 24th August, 1940 dropped the penicillin bombshell on the research community in a war torn Europe . Only the completely blind would be unaware of its military potential to save lives. It was time now to run trial runs on humans. In the two cases tested in early 1941, Florey’s team was lucky that neither showed penicillin allergy. Otherwise, it would have been doomed at birth, to say nothing of the loss to humanity. A terminally ill cancer patient  volunteered to be given penicillin.  Unfortunately, its impurities gave her high fever and violent shivering. The second, Alex Alexander, a policeman suffering from an invasive infection, had his initial recovery reversed due to lack of purified penicillin. Florey was determined this would never happen again! He began looking around for pharmaceutical companies to whom he could outsource large scale penicillin culture. In England with every factory either given over to war work or destroyed by bombardment, there were few takers.

ACROSS THE ATLANTIC ...
In 1941, only ICL was interested; with Rockefeller being one of their financers it was only natural they looked across the Atlantic. Besides, America had yet not fully joined the war.   Timing was crucial in hind sight. Had they come four months later, would the curative powers of Penicillin been persuasive enough?
Pfizer and two other big companies lent their resources and labs to the project. Well aerated 25, 000 gallon deep fermentation tanks allowed the oxygen loving penicillin to grow throughout, feeding on rich nutrients provided by corn steep liquor. Corn steep liquor not available in the UK at the time and Heatley was able to harvest a higher yield.   Unfortunately, even this higher yield was far from satisfactory! Penicillium notatum, the penicillin mould first discovered by Fleming, would only give a low yield. This was not commercially viable.

MARY, Hunt!
And thus, a decree was sent out to all able bodied citizens to look for better varieties of penicillin. Soil samples and anything that vaguely looked like a mould came in for scrutiny. Finally,  in 1943 the golden pot turned up  at home ,in Peoria, brought in by Mary Hunt ! A cantaloupe melon had been infected by a golden mould,  Penicillium chrysogeum, which gave about 200 times as much penicillin as   original form !

Ernst Chain often walked down the street to Oxford. On one these jaunts he had met Dorothy Crowfoot Hodgkin, a talented crystallographer, over the typical English large cups of tea ( made from tea grown in India ?). He persuaded Dorothy to start working on  penicillin even before  they had crystallized it. The X- ray analysis of the molecule revealed the complete chemical structure of penicillin. Now its biosynthetic pathway was elucidated leading to its artificial synthesis, its mode of action, penicillin action spectrum, resistance, allergy   and  uses other  than medicinal   were worked in quick succession , making it the over the counter prescription drug it is today.  

If the human genome project is a mega project of our times, the penicillin project was a mega project of its times. This British-American collaboration involved thousands of people and some thirty-five institutions: university chemistry and physics departments, government agencies, research foundations, and pharmaceutical companies. Out of the evil that was the Second World War, came this tremendous effort, cutting across national boundaries spurred by the terrible war casualties, threatening to wipe out generations and the civilized world.

After Marie Curie’s decision not to patent radium it was Florey’s decision not to patent Penicillin that was to be one more boon. It was perhaps a single step for the scientists but a giant step for mankind.

Ernst Chain who lost his mother and sister in the holocaust, in his banquet speech    poignantly asks that a humane, integrated well informed society must balance the dividends of scientific creativity. You can almost hear him say may the holocaust and genocide never happen again. That most terrible of powers contained in a tiny atom seems to have held off a similar one till today at least. For both penicillin and the atom bomb are vintage world war II. Are we masters of the situation or mere pawns of some superior power ?

Main resources:

1. Encyclopedia Britannica
2. Wikipedia
3. https://www.nobelprize.org
4. https://www.path.ox.ac.uk