segunda-feira, 17 de junho de 2013

Como se fez a penicilina

How to discover an antibiotic: a historian's guide

Given our pressing need for new antibiotics, or a whole new class of antibiotic-like drugs, perhaps we ought to try learning lessons from the history of penicillin (it might even help someone win the new Longitude Prize!)
Female researcher taking notices while she is using a microscope.
Can history teach us how to make new discoveries?. Photograph: Radu Razvan /Alamy
Historians of science and medicine are often terrible killjoys when it comes to great stories about discovery and genius. We've been quick to point out that the apocryphal story of Fleming discovering penicillin mould 'by accident' when it blew in through a window and landed on a discarded petri dish is, well, apocryphal. We're less unanimous about the way penicillin became a drug. Although the 'Oxford Group', lead byHoward Florey and Ernst Chain developed the chemical extract as far as clinical trials, in the end it was American agricultural, pharmaceutical and military researchers who produced the first useful quantities of purified antibiotic, and who subsequently made the biggest profits from it. Scientists and historians will tell you that this shows what happens when British science is underfunded, or that it warns us how much war can retard or skew scientific research, or (as politicians at the time argued) that it shows how British scientists lack the crucial competitive commercial edge and/or that the Americans are unscrupulous and underhand profit-hunters.
You can hear very similar arguments made today about funding, commercialization and patenting, so maybe we can learn something useful about drug discovery from the history of penicillin?

Hints from History

1. Use a public/private partnership.
This might seem like an unlikely suggestion from the Guardian, but theAlmroth Wright Laboratory that Fleming worked in would probably be a sort of public/private enterprise today. It was based at the St Mary's hospital, a voluntary - that is charitable - hospital which largely served the working classes. The laboratory earned its keep by making commercially viable vaccines, sometimes using the pus and bacteria from staff and patients. In 1914 Fleming himself produced a rather expensive vaccine against acne, costing £1 5s for just 25cc.
At almost every stage penicillin was developed by mixed interest groups - from Universities, the Medical Research Council and private pharmaceutical companies in the UK, to the complicated mix of government, private, military and agricultural funding that eventually produced antibiotics in the USA.
2. Buy your vegetables locally.
Agricultural scientists at the US Department of Agriculture's Northern Regional Research Laboratory (based in Peoria, Illinois) decided to hunt out a more productive strain of penicillum mould. They initiated a global search. The most promising new strain was Penicillium chrysogenum. And where was it found? On a melon, in a vegetable market. In Peoria.
3. Concentrate on pressing contemporary problems
The death rate from wound infections for those treated on the front lines in World War One was about 12-15%. For World War Two that figure was just 3%, due in large part to penicillin. With thousands of young men being injured the pressure to reduce deaths from raging infections in otherwise non-life-threatening injuries was huge (not to mention the men who were being invalided out with venereal disease). The military support for penicillin research was crucial, not only for financing, but also facilities and human guinea pigs.
From the first grant bid to the Medical Research Council onwards, those working on antibiotics repeatedly and explicitly linked their research – whether 'basic' or 'applied' – to the immediate contemporary needs for infection control, particularly in wartime.
4. Ignore pressing contemporary problems
Why didn't Fleming 'invent' antibiotics? Possibly because he was too busy concentrating on immediate contemporary needs. Fundamentally, he was interested in vaccines. It's how he made his living, after all. His 1929 paper on the mould was titled: 

What was useful about Penicillin was not just that it killed bacteria; it was that it killed most bacteria but not influenza. B. influenzae was already immune to the mould's action. This meant that researchers could use the mould to kill off other contaminating bacteria, while letting the rather fussy B. influenzae grow on a petri dish, making it much easier to study this temperamental bug in the laboratory. It also improved the sensitivity of culture tests for influenza; it seemed that in many cases 'flu infections were missed because the bacteria in a sample were outcompeted by more robust bugs, and so never grew into identifiable colonies on a petri dish.

Although the deaths from infected wounds in World War One were shocking, this was nothing to the incredible death toll of the Influenza pandemic that followed. Fleming's understandable focus on tools to study and understand influenza and make vaccines may have stopped him seeing the other potential uses of penicillin.
5. Be imaginative and spontaneous
Sometimes you have to use something in a way its inventors never intended. The Oxford team showed great imagination in making the leap from what penicillin was (a chemical tool useful for some experiments) to what it could be (an incredible drug); they also showed great creativity with their equipment, with Norman Hartley suggesting they try usinghospital bedpans as growing tanks.
6. Be plodding and systematic (and read a lot).
There was no guarantee that the Oxford Group would ever find Fleming's 1929 paper: today researchers are swamped with publications, and even digital indexing and open access doesn't mean that the 'right' paper will find the 'right' researcher. A lot of careful, methodical reading might be necessary to find the unexpected connection in papers that don't, at a glance, seem relevant. Fleming wasn't the first, after all, there was John Tyndall's 1875 papersuggesting Penicillum acted as an antibiotic, and Ernest Duschesne'swork in the 1890s curing guinea pigs of typhoid with the cheese mouldPenicillum glaucum was waiting to be exploited...
7. Get lucky
In the 1940s, while the USA concentrated on trying to grow the mould and harvest penicillin, British researchers tended to think that the antibiotic chemical itself could be cost-effectively synthesized. If this particular type of bacteria-destroying mould had no easy-grow variant (or if that melon had never been bought in Peoria), or if the chemical produced had been easier to synthesize, then the story of the Antibiotic Wonder Drug could have been very different - with Britain the first country to successfully produce industrial quantities, not the USA. So, most importantly, remember to season your hard work with lots of lucky choices.
Vanessa tweets as @HPS_Vanessa and has learnt from the history of penicillin that a messy desk increases the chance of serendipitous discoveries.

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