Saturday, September 26, 2015

"4Fs, Slime and a Cracked Pot"

Re-reading Hotchkiss and Dubos's various 1940 era papers on their quick "small science" success at extracting, crystallizing and analyzing high yields of gramicidin, an early (unfortunately deadly) antibiotic exuded by microbes, one is struck by the apparent ease of the whole project.

By contrast, penicillin, another antibiotic exuded by another microbe, was extremely difficult to successfully handle - in every single aspect of it --- from growing the microbe to the ultimate failure to commercially synthesize penicillin itself.

This despite a multi-nation effort that eventually rivalled the Manhattan atomic Project for "Big Science" funding and skilled manpower levels.

But biochemist Dr Karl Meyer was not to know this in September 1940 when he recruited his co-worker, bacteriologist Dr Martin Henry Dawson, to "just" grow a little bit of the fungus microbe, for a "little while".

A seemingly small request, for a short period of time, that cost Dawson his life but also ended up changing our entire world, for the better, forever.

Dawson then only needed to test tiny amounts of its raw penicillin (and the breakdown products and synthesis attempts from Dr Meyer) for their anti-bacterial effects on a few bacteria isolated upon small microscope slides.

A Piece of Cake, I promise !

Like all other would be penicillin synthesizers, Meyer had absolutely no plans to develop a simultaneous clinical program of treating patients with his naturally grown penicillin.

Not only would that would require producing vastly bigger amounts of penicillin and delivered on a reliable timetable, it would also absorb scarce penicillin that he really needed to destroy, as part of his destructive analysis process.

Meyer had a long and close relationship with Schering, a big (chemically sophisticated) drug company, and if he had any success at all in penicillin synthesis, they would quickly take over the process.

Schering would then mass synthesis the drug from off the shelf standard chemical reagents, in quantities at least large enough for a large collective clinical effort to test it out on first animals and then various human patients suffering different diseases.

I hope the impression I have given you of Meyer's initial project was how small it was and how leisurely it could proceed.

This is perhaps the total opposite to the set of conditions that Dawson's fellow Canadian Dr Banting imposed upon himself.

Banting's small team are busy trying to learn how to extract large amounts of fairly pure (natural) insulin consistently, while scores of dying children awaited that insulin in the hospital next door as the eyes of the entire world are rapt upon their heroic efforts.

No pressure !

I have written many times before how Dawson decided to aid the war effort not by attacking the bully Hitler but rather to attack Allied bystander hypocrisy, in the difference between the Allies' public war aims of helping the small and their actual inactions (or worse) on that front.

So he decided, in late September, to irk the Allied medical authorities the most offensive way he could think of, by deliberating inviting two of the Allied cultures' most worthless beings into his wartime Big Tent of all possible talents.

Patients with invariably fatal SBE had already been written off as "life unworthy of scarce wartime medicine" and were 'the 4Fs of the 4Fs' on the bottom scale of wartime medical priority.

That the first two patients invited to introduce the new Age of Antibiotic were a working class Black and a Jew added an extra frisson to his lateral move.

Next, he decided to buck a twelve year long world wide medical taboo against injecting fungoid growth metabolical waste (aka natural penicillin) directly into the temple of the human blood stream.

The medical consensus was that it was better to let patients die than inject patients with this highly effective and totally non-toxic lifesaver, before 'the chemists' synthesized it as totally artificial and totally pure, to paraphrase Alexander Fleming.

Along with all the doctors, many others among the educated, among them A Hitler and HP Lovecraft, shared this characteristically Modern irrational fear of fungoid growths.

Dawson would attempt to save the lives of the worthless '4Fs of the 4Fs' with the yellow poop/pee of the worthless fungoid slime !

Immediately, Dawson was into 'Doing a Banting', hijacking Meyer's tiny leisurely project, but doing a worse Banting, if that could be possible.

It was.

Few places feared fungus molds more than 1940s hospitals, home to the excessively house proud nursing fraternity, in an age when their excessive cleanliness was almost the only defence against hospital-spread infection.

Dawson would have to grow his penicillium in a very busy hospital itself, unlike Hotchkiss or Banting and resistance to his efforts from his bosses could be expected to be fierce.

Particularly as he would be growing 700 two litre flasks of the stuff on a regular two week turn cycle !

That amount, 50 US gallons of extraction liquid every two weeks, was the amount engineers mean when they talk about industrial 'pilot plant' levels.

This would have been a big undertaking for any drug company in 1940, let alone for a tiny team of four part time staffers, working in a hostile hospital, trying to keep up with their busy fulltime day jobs.

This was because the yield of penicillin, in 1940, from penicillium was incredibly low - one part in a million extracted as final 'medicine' output from one million parts of 'food' input.

And even in treating ordinary patients, penicillin presented unique difficulties that made its clinical use require larger than expected amounts of this miracle drug.

This despite the fact that tiny amounts of penicillin were highly effective bacteria killers - that is worked in tiny amounts was one of the many reasons why penicillin was so extraordinarily non toxic in the human body.

Just as well - because another reason it was so non-toxic was that it didn't get to hang about inside us - the kidneys excreted it all in a very rapid manner - as fast as in one half hour.

Frequent new injections were needed to maintain it at an effective germ killing level in the blood serum.

Wait !

it gets worse, much much worse.

SBE was - and is - considered the Mount Everest of all infectious diseases for any number of reasons.

This disease of the vital and very delicate heart valves is one that usually returns again and again, each time further weakening the valve while also providing a better place (a sturdy biofilm then know as vegetations) for the infectious bacteria to hide and survive drug attacks, until the patient dies.

But the real difficulty is the fact that the valves are literally a case of "blood, blood everywhere but not a drop to drink" - though all of the blood inside us flows through them repeatedly, ironically they themselves are basically not supplied with any tiny blood capillaries and hence no blood.

Drugs that arrive via the traditional capillary route trickle in slowly and leave slowly, making a little drug go a long way.

Instead the drug that could impact heart valves had to fill the entire blood system at a clinically effective level and yet only brush by the valves for a fraction of a second as the blood supply is at its very fastest being pumped through the valves.

Dawson's history-making first ever injections of an antibiotic into a patient, technically were fully internal systemic in nature but then acted rather like an internal antiseptic being dabbed on the outside of a cut !

The only good news was that penicillin readily killed the particular bacteria of SBE infections and because it was so non-toxic, the entire body could be safely filled with the drug to kill an infection in only a tiny part of the body.

In addition, Dawson noted that the drug seemed readily diffusible - meaning it could better penetrate deep into the SBE vegetations than most other drugs.

The problem for the highly moral upright Dawson, was that once he committed to trying to save SBEs when they came forth in the new admissions mix to the single ward he effectively controlled, he would have to keep producing the penicillin until the current patient died or was cured.

And then the same for the next SBE patient and so on.

Until penicillin was (a) mass produced and (b) authorized to be given to the written-off SBEs.

This didn't happen for four more years.

Dawson created for himself a moral and physical treadmill he couldn't climb off of.

The initial stress quickly gave him a case of MG, a dangerous auto immune disease, and the continuing stress finally made it fatal four years later.

No wonder that most in the medical world considered him a crackpot.

But I consider him a cracked pot ---- in the full biblical sense of that term....

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