The Manhattan (natural penicillin) Project : Googling up a Ghost

How an amateur historian in a small city used the new Google Search tools to recover the lost story of wartime penicillin

 

I first fell upon the lost story of wartime penicillin way back in the Dark Ages --- late in 2004.

Merck has credible excuses for being beaten on D-Day penicillin by Pfizer - but none whatsoever for being crushed by Commercial Solvent

Merck, the OSRD, Florey's Oxford team (all part of the synthetic penicillin obsession) continue to have many defenders among academia.

Yes, one academic excuse goes, yes Merck failed to deliver much penicillin to the D-Day beaches - that was left to Pfizer, which had been a major partner of Merck and Squibb in the three year long effort to produce commercial amounts of penicillin.

But, the excuse went, Pfizer had 20 years of highly successful fermentation experience before late 1941and the commercial penicillin project's beginnings.

But how then to explain the huge success of Commercial Solvents  in producing medical grade penicillin from a cold start in January 1944 to levels twice that of Merck in just four months and then levels six or seven times higher than Merck in just three more months after that?

True, Commercial Solvent had 30 years of success in industrial grade fermentation in making bulk acetone but had never done anything even remote to pharmaceutical levels of purity and cleanliness.

But there it was - passing an increasingly demanding FDA testing requirements with its tens of billions of units of injectable penicillin.

Clearly, the supposedly-arcane craft could be learned fairly quickly, if a corporate culture demanded it.

Even Squibb redeemed itself by well beating Merck's output, by late 1944 .

Merck lost the race for one reason only : hubris.

It thought that since it had synthesized a few 300 molecular weight molecules that all 300 weight biological molecules were a piece of cake.

Tell that to  penicillin with a weight of 334 and still not commercially synthesized.

Or tell it to quinine , molecular weight 324, and 200 years after Man-The-Almighty first started to synthesize it, still without a commercially viable synthesis technique at hand....

Roy S Koch "shows me the money" on wartime penicillin

In December 1944, a very youthful looking economist named Roy S Koch was heading up The Biologicals and Parenteral Solutions Unit, hitherto an unimportant sub-section of a sub-section of a sub-section, buried deep somewhere in the bowels of the powerful War Production Board in wartime Washington.

Then , overnight in August 1943, penicillin became one of those parenterally delivered biologicals and nothing was ever quite the same.

One of Koch's jobs was tallying the actual amounts, month by month, firm by firm, of medical grade penicillin that passed from the FDA's approval into the military or civilian supply chain.

In those excited anxious days with American families's sons, brothers and fathers dying left (Pacific) and right (Atlantic) in record numbers, all eyes and ears were on the progress reports on penicillin production.

Everyone, in their own way, was pitching in to help American industry finally deliver the goods, 15 years later but better late than never.

Above all the American taxpayer was working overtime to pay for that promise of expanded production.

 Paying for the government building of private-firm-run buildings, paying through extra personal taxes for the shortfall caused by the writing off of excess corporate taxes, paying for military and civilian expeditors, paying to aid to university researchers who were in turn aiding corporate coffers - on  and on and on.

 So a corporate failure to make good on a public promise to deliver a lot of penicillin, with the help of lots of taxpayers' money, was going to seem tantamount to committing an act of treason.

Hence Koch's carefully collected figures had to remain a closely guarded secret : American corporations may fail to deliver all the time, but the American public is never ever to know.

But in 1958, about 55 years ago and almost 15 years after the figures were first collected, a muckraking US government inquiry into price-fixing in the antibiotic business did reveal the figures --- even put it in a public domain documents so all the world could quote them freely.

But I have never seen anyone do so and I have read an awful lot on wartime penicillin : so if I am wrong, please email me at my email on this blog.

Anyway, the figures are posted above and you can access the report  ("Economic Report on Antibiotics Manufacture" )  online --- this chart is from the appendix, page 331.

In January 1944, the Hare side of the race to make - and define - wartime penicillin was feeling pretty good : Merck had produced some actual therapeutically-effective penicillin by human synthesis (take that you nasty mold !), a result soon confirmed by the Oxford Hares and by other American Hares.

Yields were much lower than the mold-made penicillin and the impurities both more abundant and much more lethal than in the naturally-made penicillin , but the chemists (hundreds of the best chemists in the world) were working on it.

Soon the pesky Tortoises of  wartime penicillin, mostly obscure johnnies come lately, could be kissed off - their brand new plants just so yesterday, so very obsolete : growing mold like some rural farmer and then making things by fermentation.

 In this Modern Age !

Really, the nerve !

Still, in January 1944, some of the leaders in the secret effort to make penicillin by synthesis are still putting up a good front in aiding the build-up of penicillin supplies for the widely expected opening of the Second Front (D-day) in the late spring or early summer.

Their production of natural penicillin was quite good - compared to even a few months earlier.

The all-mighty Merck (leader, along with Howard Florey in Oxford England, of the penicillin Hares) delivered 3.1 billion units that month, about as much as some obscure mushroom farmer (Reichel) did , buried somewhere out in the backwoods of rural Pennsylvania.

Merck wasn't going to really go all out to produce a lot of natural penicillin for the boys overseas, not when they were about to blow the world away with their very own "technically sweet" synthetic penicillin.

But the boss, George W Merck, was still determined to be patriotic none the less, "do his bit".

Pfizer, another part of the New York area Hare triad, led the production, just barely, with 3.98 billion units.

Squibb ,the third of that triad, was not pulling its weight - even the War Production Board could barely contain their anger , as the folks at Squibb laying back on the oars --- producing just .61 billion units.

The Mid-West group of Hares hadn't done as well, but they hadn't been at it as long : Abbott did .71 billion, Lilly .43 , Upjohn .07 , Parke Davis .03.

Let us jump to April 1944.

Synthetic penicillin yields are still so low that they were a joke - making even Fleming's small amounts that he produced in 1928 look enormous in comparison.

But almost everyone's natural penicillin output has improved --- it was getting close, after all, to make the deadline to get into the pipeline to Kansas City's big depot and then out again to Southern England for the D-Day medical supply loadings.

Every drug CEO wanted to boast later in ads that it was his firm's penicillin that had won the day in the invasion of Nazi Europe.

Reichel had fallen way back below its January output and Merck hadn't even doubled its output.

But Squibb had increased its supply by 10 times , albeit from a low base and Abbott had done almost as well.

(Commercial Solvents had increased its output by 300 times, from a very low base - but it was a real newcomer.)

Pfizer switches sides and kills Modernity ...

But Pfizer wasn't playing fair, for it had turned from being a Hare into a Tortoise : it had increased its natural penicillin output by 10 times, from a very high base and doubled it again in May : producing more than the entire world's penicillin plants combined.

By July, Merck was almost producing less than it had in January, while Pfizer was producing 25 times as much as it had in January.

Still no early sign of synthetic penicillin production and Pfizer was on its way to producing enough penicillin for the entire world,naturally, with or without Merck's 'technically sweet" synthetic stuff .

Modernity had just taken a fatal shot to the base of the neck and deep down, everyone knew it....

For Howard Florey's mausoleum of an institute, penicillin's therapeutic value was incidental to putting paying bums on seats

Howard Florey's discovery that impure natural penicillin could cure experimentally induced infections in mice was incidental to his number one concern : getting enough paying guests in his mausoleum of an institute, to pay its annual heating bills.


And also accidental , in the sense that Chain only poured all of the penicillin hitherto made by Chain' own methods into two healthy mice in March 1940, out of spite.

Florey had just told him the day earlier, during a very heated argument, that Norman Heatley would be making the crude penicillin from now on and by Heatley's method.

Chain was determined to establish his (or any) penicillin was in fact very non-toxic , though he should have put his brew into infected mice as he then would have really made his mark in history for sure.

But, Chain's spite at least jumped the gun on whatever decade Florey was originally planning to interrupt his precious personal research long enough to test penicillin on infected lab animals. (If that was even ever to come about in the original project -- mice cost money.)

He had at least forced Florey to put penicillin into some infected mice (the next stage in the process) or risk forever losing a claim to be the first to ever do it in history ----- and Florey liked nothing better than getting the glory of doing something first, even if his minions had to do all the hard work forever afterwards.

Much to Florey's surprise, the mice lived !

Florey - to his dying day - hated clinicians and clinical work : hated patients in fact

Now Florey was almost forced to try it on humans in an attempt to save their lives ---- which he did , almost exactly twelve months after the first mouse experiments  ----------never one to rush into clinical, live-saving, work was our Dr Florey,MD.....

Sir Robertson's curious letter and curiouser claim

Late August and early September 1942 saw a furious burst of letters to the editor directed at The Times of London, provoked by an August 27th editorial in paper concerning penicillin.

The three hundred word effort echoed an earlier editorial from The Lancet , and supported their claim that the drug was non toxic and more active than sulfa drugs and that its production should be greatly expanded and quickly.

Since penicillin looked to be a real comer with much 'moral capital' accruing to the companies or institutions that best claimed the laurels for first developing it, naturally all the major bodies involved had to elbow their way forward to stake their claim -  the current 'all-for-one' war effort not withstanding.

(A note to errant historians and authors: the drug companies' penicillin research arm, the TRC,were actually the first to gave themselves credit. Only then did St Mary's Hospital step in to also seek some glory.)

Sir Robert Robertson, the world famous Oxford chemist , spoke for the Oxford team.

Some of what he claimed were mere weasel words.

Dawson published the results of his treatment of 12 patients by May 1941, Florey his results on ten patients in August 1941.

Both were admirably cautious in assessing what if anything penicillin had done for their patients.

Dawson was actually the first to treat a patient and see that patient go home from his deathbed --- so Robertson was content to use weasel words that Florey was the first to "demonstrate the value
(of penicillin) clinically."

'Demonstrate' is a subjective term - in the eyes of the beholder - and Robertson knew it.

So, he had as well admitted that Fleming discovered penicillin and that Dawson had been the first to use it clinically as a life-saving systemic antibiotic.

What credit left for Oxford?

Robertson then told the bare-faced lie that toxic materials were produced by the penicillium mold, along with penicillin.

 Florey was therefore to be praised for being the first to separate the unsafe impurities from the safe pure penicillin so that it could be at last safely used on humans. (But wasn't, not by Florey - at least not right away ...!)

Nobody who ever worked with penicillin-producing penicillium , starting with Fleming in 1928 and carrying right on through twenty years later, ever saw enough of anything harmful, at levels enough to be toxic.


All made a point to note that the raw penicillin juice was not toxic even when injected in huge quantities by normal medical standards.

Foremost among these supporters of the use of  semi-purified or raw penicillin was one Howard Florey.

He publicly marveled that in hundreds of IM injections, no damage was ever seen at the site of the needle - not even in babies. The impure preparations he rated at 10% pure at the max (actually 3% pure) yet their impurities ( 97% of the dose) were non toxic - even when given in huge dosages.

It is hard to imagine a better test for proving the impurities were NOT toxic --- I can not,myself, imagine one.

What was going on then - in the mind of Professor Robertson and his chemist-manque Dr Florey ?

If Robertson and Florey had made any headway on synthesizing penicillin, I am sure this would have been their sole claim to glory.

But they hadn't.

So what can chemists do?

They can separate substances, even if they can't synthesize them, and even if the substances didn't need separating !

A nice meal does not improve when a chemist burns it all and then pours acid over the remains, to separate it into its constitute elements.

Penicillin juice - as Australian Dr James Vincent Duhig demonstrated in Brisbane in the Fall of 1943, doesn't need to be separated from its impurities at all, in order to save lives safely.

When it comes to questions of health, trust Duhig,MD over chemist Robertson PhD.

I don't expect Oxford University's academics to ever set the scholastic record straight about what Oxford did and didn't do with penicillin.

Claiming a leading role in developing the best lifesaver the world will ever know is simply too much of a money spinner for Oxford and the entire Thames Valley community.....

FLOREY's biggest mistake : Spring 1938-May 1940

Two wrongs can never make a right.

Millions of lives, literally, might have been saved if Alexander Fleming had only run a quick animal protection test with a mouse, a bit of staph bacteria and a needle full of his wet penicillin juice , back in October 1928.

It wasn't until about ten years later that sulfa drugs began to be universally available and regularly used - and even then they didn't work as well as penicillin.

The lives needlessly lost in that period have to be laid at Fleming's door.

Howard Florey and his entire Oxford University team never stopped criticizing Fleming for this elemental failure - as most people would have a full right to do.

But Florey and his team do not have that right.

For they failed to do the same thing they criticized Fleming for not doing,that bog simple animal protection test with wet penicillin juice, something they neglected to do from early Spring 1938 till May 1940.

They had the wet penicillin, the mice and the skill to do the test.

If they had done that test, we might have seen penicillin development work started in earnest by British drug firms in 1938, before the Munich Crisis, long before the fall of France in June 1940.

In which case the exciting wartime penicillin story might have ended happily before it even began.

Not until they had accomplished their  real goal - concentrating Fleming's impure 2-5 units per mg penicillin sticky brown toffee into a 2-5 units per mg dry brown powder - and claiming it was highly purified penicillin, did the Oxford University think about the all important animal protection test.

All the evidence is that while Ernest Chain was anxious to do it, Florey didn't think they had gone far enough along the so called purification route to move into stage two animal trials.

Chain had to force the issue - making Florey so angry that Chain never ever regained Florey's trust.

Here was Britain about to be invaded, civilization tottering in the balance and Florey was plodding through every scientific experiment in his rulebook, instead of cutting to the chase on a drug that might save many Britons lives.

He was thinking like a scientist ,not like a patriot - fair enough - a common failing among scientists - even during a war crisis.

But most scientists who think like that don't have the nerve to turn around and very publicly blame a colleague for failing to do what they themselves also failed to do.

It is things like this that make it very hard for me to stomach Howard Florey as a whole - though there are many things I do admire about the man.

And don't think I let Florey's many admiring biographers off any more lightly - how in the name of all that is holy do they justify admiring Florey for delaying that critical wet penicillin animal protection test  for more than two years?

The recent British television movie on Florey criticizes Fleming for never doing the animal test, but remains silent on why on earth Florey waited until well into the Battle of Britain crisis to 'poke the mouse'.

Fleming deserves to be blamed for some of his failings.

Fair enough.

But Florey needs to be held to the same high standard - I only wish Eric Lax and others had done so....