Thursday, January 31, 2013

First person to ever read Fleming's 1929 penicillin article, REALLY READ IT, was Henry Dawson, in October 1940...

Very early in his investigation of  the antibacterial qualities of the liquid beneath a penicillium mold , probably by October 1928, Alexander Fleming came to a truly startling conclusion.

And it is not what you - or he - or any other doctor or scientist might have expected.

Finding unknown substances that kill bacteria was and is a commonplace.

Finding a substance that kills bacteria without also killing the patient is a distinct rarity.

But the chances of finding a unknown substance that kills bacteria  while (a) not killing the patient AND (b) while being a part of about two dozen other unknown compounds in a bath of 97% water ?

Well, sir, that simply is an event that has mathematic odds well beyond the calculating.

Let us label the Alec Fleming of this startling conclusion, "Fleming I" , because six months later he had - confusingly - become both Fleming I and "Fleming II", depending on his mood.

Fleming II consistently insisted, for the next fifteen years, that penicillin would not become a useful medication until chemists had purified it, discovered its chemical structure and recreated it as an artificial synthetic. Even then, it would only be good as an external antiseptic.

Talk about a parent praising their latest offspring with faint dams !

But while Fleming II's team had actually started down the chemists' path  and had produced a much more concentrated (and semi-purified) material, he totally and abruptly abandoned this effort and never wrote it up in his seminal 1929 article.

He never even used this highly concentrated material  (a thousand times more concentrated than original his liquid mixture) in any biological experiment.

It could just be that the businessman-bacteriologist Alexander Fleming, a frugal Scot, had more native arithmetic in him than almost all the doctors and scientists who followed him into penicillin - certainly more native arithmetic ability than almost all the writers I have read on the penicillin saga.

Because the two dozen unknown compounds swirling about together hadn't eliminated the anti-bacterial activity or caused a toxic reaction, removing them by purification was a 50/50 shot at  improving- or reducing - those two valuable qualities.

Remember that : let me repeat it : purification might actually reduce the bacterial activity or increase toxicity. Synergy, working together, does many mysterious things.

In fact, Dawson's co-worker, Gladys Hobby ten long years later was only one of many who were convinced that crude impure penicillin worked better than the equivalent amount of units of pure penicillin did all by itself.

Balancing these unknowns, it wasn't mathematically likely that purifying penicillin 100% was actually going to make it a better medicine.

In fact, since with 1929 levels of original mold juice and the then current state of extraction technology, 100% pure penicillin was probably going to require losing 99% or more of the original anti-bacterial substance, 99 patients would now die so that 1 might receive 100% pure penicillin.

Let me go further, and recall some of the economics lesson professor John Graham taught me too many years ago.

Graham had a way of bringing economic jargon down to ground level, perhaps never more so than in explaining the term  "opportunity cost".

I'd like to think that this is the way he'd explain Fleming I's decision to refute Fleming II's progress :

It is not just that purifying the penicillin juice to 100% results in so little penicillin output that 99 potential patients must die so one patient can be treated with 100% penicillin - that has no more medical efficacy than the original un-purified juice.

Because devoting all of your incredible amounts of labour, stress, time, expense, lab space to this purification effort, means your team can't find the time and space to simply produce more absolute units of the original penicillin, with the production technology they already have.

Nor can they find the time, energy and money to improve the biological yield of that original strain of penicillium mold.

In the real world of limited time and resources, when you open one door, you close many others.

Now Fleming II didn't actually go very far down the path of this (pointless) path of purification.

But his team did find success in the much easier and much more potentially useful concentration of penicillin juice ; aka simply removing most of the harmless water, as we do with concentrated orange juice.

If water is the one compound in the mixture known to be harmless, why bother ?

Fleming's strain of penicillium was actually a very potent producer of penicillin on (not in) water : eventually it produced 200 units of activity per ml of liquid in painstaking experiments in the lab, and routinely got at least 40 units in day to day industrial efforts.

But Fleming didn't know how to grow penicillium right to produce its potential in penicillin - and why should be ?

But he also didn't bother to try to find out, from other fungus farmers, how to grow it better.

He was a medical bacteriologist and he grew it as if it was a medically important bacteria.

The results were a disaster : he was lucky to get one unit of activity per ml of liquid.

But even the most careful technique of safely injecting large amounts of liquid by IV drip wasn't going to find a way to get anti-bacterial activity that diluted into the blood stream to cure really life threatening blood poisoning.

Success by this method, as several bold and brave doctors discovered in 1943-1944, wasn't actually that far off : in those early days, even massive infusions of 10 units per ml of liquid would save lives ,and at 40 units per ml of liquid all but the toughest infections could be beat back then.

So if Fleming II concentrated his original liquid down to a thick syrup, he'd have concentrated it enough to inject into patients --- without losing too much of the original scant penicillin in the process  OR consuming all his team's limited energy, time and money in the process.

But at this point, another set of experiments convinced Fleming II completely (and totally wrongly) that penicillin would not work at all as a systemic - concentrated, purified or not.

If only he had injected his syrup, mixed with a little bit of saline solution, into a dying mouse, the mouse would lived.

 And penicillin would have been in wide clinical use by December 1929, repeating the rapid pattern of Banting's insulin, but this time in spades.

However, Fleming I never put Fleming II's work or conclusions into his 1929 paper - only repeating his conclusions in private conversations , if pushed.

He found, (and so told hundreds of hospital bacteriologists all over the world) , that easy to make, 100% recovery , liquid penicillin worked well as a routine lab clearing agent and for use as an a non-toxic human antiseptic.

Now to October of 1940 , exactly 12 years after Fleming's original startling discovery about 'the non toxicity of impurity'.

 Henry Dawson is waiting impatiently for his co-worker Karl Meyer to purify some of Fleming's penicillin up to what the team imagined was the level of purity acceptable to their famous teaching hospital's quality standards.

And to the level they imagined the deliberately vague but purity-obsessed Howard Florey had claimed he had achieved before safely injecting his penicillin into infected mice in the summer of 1940, saving their lives.

Suddenly, while impatiently waiting and pacing the floor, Dawson was presented with a truly Solomon's Dilemma.

He had expected to treat a single patient with SBE, provided the young man didn't die of the invariably fatal disease before Meyer had purified the penicillin to an acceptable level.

Now he suddenly had two young men dying of SBE.

Re-reading Fleming's original article gave him his solution : if purifying merely lent losing half or more (much more) of the limited material available, without making the resulting medicine any less toxic, why bother ?

Merely quickly concentrate the liquid penicillin, so most of the harmless impurities are left in, while the harmless but burdensome excess of water was left out - and you would be quickly left with enough penicillin to treat two patients - and all this could happen before the two men died.

So the spirit of Fleming I , not Fleming II, was guiding Dawson's hand when he injected the world's very first antibiotics , months ahead of schedule, into BOTH Aaron Alston AND Charles Aronson on October 16th 1940.

Fittingly, in this act of inspired charity, Matthew 20:16 was again fulfilled as the Last became the First to receive this healing balm.

(Alston was almost certainly black and Aronson almost certainly Jewish and in 1940s America both were hardly among the truly favoured peoples.)

After Dawson, a few others others would re-read Fleming's paper as if for the first time, and decided to prefer large amounts - today ! - of highly impure but non toxic penicillin, over small amounts of highly purified but no more non toxic penicillin, maybe, tomorrow.

I suspect their grateful patients, plucked back from the grave, more than agreed with their re-reading of Fleming 1929.

A case of Jam Today , indeed .....

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