martes, 4 de junio de 2013

Nobel Prize 1945: Fleming’s Series of Fortunate Events

ORIGINAL: OxBridge Biotech
by: Kate Campbell
3rd June 2013
Petri dish from Fleming’s discovery
The Story of Penicillin’s Beginning in Medicine
Serendipity – or chance meeting the prepared mind – has famously long been a part of scientific discovery, producing Newton’s theory of gravity, dynamite and the microwave to name a few. But by any standards, the discovery of penicillin relied to an improbable degree on a series of fortunate events…

The bright but blighted beginning
One September Friday morning in 1928, in a laboratory belonging to St Mary Hospital, London, an airborne fungal spore without planning or purpose landed on a bacteria-containing petri dish, left open by its owner, Alexander Fleming. Fleming, meanwhile away from work on holiday, as a consequence had unwittingly allowed time for the fungal spore, Penicillium notatum, to develop in his dish of bacteria. The fungus grew into a considerable sized growth amongst the bacterial (-‘Staphylococcal’-) colonies, but strangely contained a clear bacteria free area or ‘halo’ surrounding itself. What followed from this unknowingly fortuitous event indeed changed the course of medicinal history. On his return, Fleming observed this phenomenon and concluded that the mould must contain properties which inhibited bacterial activity by either suppressing growth or killing (-‘lysing’-) the cells.

The Scottish microbiologist consequently began work statim on isolating the mysterious molecule able to lyse the surrounding bacteria, so he could ascertain its spectrum of activity. In other words, if this fungal agent was releasing something into the surrounding environment to kill off one type of bacteria, how many other bacteria types could also be affected? What benefited enormously Fleming’s investigation was his ability to use the many techniques he had applied years earlier when he discovered another antibacterial- ‘lysozyme’- also by chance. Fleming’s experiments thrillingly confirmed that the fungus secreted a metabolite able to kill bacteria that had cell walls with sugar chains connected to short proteins –‘peptidoglycan’- on their outer surface, known as gram-positive bacteria, responsible for such deadly infections as scarlet fever, pneumonia and meningitis. He called this new metabolite ‘penicillin’.

His findings published in the ‘The British Journal of Experimental Pathology’ one year later, only attracted little attention, and after a few years of further investigation, Fleming abandoned work on the molecule. As one man, neither a specialist in chemistry nor clinical biology, Fleming was unable to overcome problems with penicillin’s isolation, stability and yield nor could he prove beyond reasonable doubt that penicillin had any medicinal value. It seemed that progress on penicillin was about to reach a premature demise. 10 years after the initial discovery was made though, by an act of fate or simple chance, Fleming’s work attracted the attention of an English biochemist at Oxford, Dr Howard Florey. By 1939 Florey had convinced his co-workers, including Dr Ernst Chain, collectively known as the ‘Oxford Group’, to work on penicillin with serious determination. By another stroke of luck, their work coincided with the beginning of the Second World War. What resulted from these two simultaneous happenings, led to penicillin only a few years after its revival, attaining the spotlight on a world-wide stage, in the form of an antibiotic viable for use by man.

The wintry war and the champion cantaloupe

By 1941 Florey and Chain had moved on from animal clinical trials to human, the Oxford Group were striving hard to transform penicillin into an effective drug for man, with sufficient strength and minimal toxic side effects. At the same time, America had entered World War II upon Japan bombing Pearl Harbour. With war-time economics in full swing, the cost of penicillin research no longer became a setback, furthermore with US and UK governments seeing penicillin’s potential to treat soldiers, suffering from possibly fatal infections such as gangrene, penicillin production became national priority.

Problems to be overcome, however, were by no means trivial. The structure of penicillin was still unknown, consequently chemical synthesis of the candidate drug was exceedingly challenging. For example, penicillin for clinical trials was in such short supply that that which had not been metabolised had to be recovered from the patient’s urine to be reused for remaining treatment. Victories quickly ensued though from untiring efforts on both sides of the Atlantic. Florey and Chain succeeded in concentrating penicillin to enhance its activity and stability. Additionally, with the collaboration efforts of the US Department of Agriculture, one of the unsung heroes of the Oxford Group, Norman Heatley, and several biopharmaceutical giants like Pfizer, large scale penicillin manufacturing methods got underway with alacrity to conquer the production bottleneck.

A world wide search had also begun to find a new strain of penicillium, able to grow faster and produce more penicillin than Fleming’s original P. notatum. The search remained elusive until 1943 in Peoria, Illinois, when a laboratory assistant Mary Hunt, forever after named as ‘Mouldy Mary’, discovered mould on a supermarket cantaloupe and brought it into work. The mould she found, P. chrysogenum, was considerably more potent than Fleming’s original strain and was subsequently used for further penicillin development to great avail. With most problems solved, except for elucidating the structure (done so eventually in 1945), the modern era of large scale antibiotic production had truly begun. By 1944, enough penicillin could be successfully prepared in quantity to treat wounded Allied forces during the Normandy invasion, D-day. Undeniably affecting the outcome of total war casualties, it did not take long before penicillin was nicknamed the war’s ‘wonder drug’. One could even argue the fortunate timing of penicillin’s discovery and development may indeed have helped secure the Allies win for the war overall.

The endless end…
In 1945, almost 20 years after Fleming first noticed mould growing in his open petri dish in London, and thanks in part to a war that had catalysed scientific discovery, Fleming, Florey and Chain were awarded the Nobel Prize for their work on penicillin. Since its medicinal inception, penicillin has saved millions of lives and revolutionised health care across the world. However the effect of ever increasing levels of antibiotic resistance should not be underestimated. Even Fleming himself had a sense of foreboding about the discovery stating, ‘The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily under dose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.’ Due to the historic incorrect and excessive use of antibiotics, today modern science is consequently fighting a new war; that against bacterial infections, such as MRSA, resistant to the armoury of antibiotics designed to eliminate them. This shift in the arms race between man and pathogen is seemingly leading to a new era of healthcare, one that doesn’t include antibiotics as we know. To successfully negate the long term effect of antibiotic resistance and navigate towards a new method of treatment, future generation scientists will undoubtedly require extreme perseverance, endless innovation and maybe just a little bit of luck.

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