Wartime penicillin's six year odyssey : from secret war weapon to widely publicized beacon of hope

Without really meaning to, we tend to reify World War Two from a six year long process into a single event ("the war"), when we say things like "millions of women went to work in factories for the first time in their lives in WWII".

An event is like my last birthday ---- where I either did or did not have a birthday cake.

But a very long, quasi-total-war spread over an entire world is bound to see seemingly universal processes like "war-time rationing" or "women's war-factory work" actually break down into a huge number of situations happening at different times, to different extents , in different places.

Wartime penicillin was neither a top secret military weapon or a widely publicized beacon of hope but rather both and more - depending upon the time, the place and the institutions and individuals involved.

Wartime penicillin was a six year long debate on the nature of what it is to be human 

Defining the exact nature of wartime penicillin was a six year long debate , a very feisty debate between many people, that probed the deepest questions that humans can ask.

This is why I  continue to write about it, 75 years after the events....

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....

Like Admiral Byng, but in reverse, AlexanderFleming was given a Nobel prize "pour encourager les autres"

Alexander Fleming pursued, preserved and publicized a foolish observation that turned out to be.... not so foolish after all.

His personal Nobel Prize was really to encourage other future scientists to also publicize their oddball observations because they too might be all important.

New scientific breakthroughs are often delayed because the scientifically powerful are older and no longer open to an new ideas any newer than the new breakthroughs of their youth.

A person bold enough to bring forth oddball ideas is likely to face a lot of bricks and catcalls from these powerful personages who control grants and tenure and publication in big journals. (Big shout out to Dr Milton Wainwright !)

So the thought that a possible future Nobel Prize might lay in the offing if one faces the bricks and the catcalls , does tend to give all of us a little dutch courage.

Fleming was badly wrong about penicillin on two key counts.

It did not need to be synthetic to be useful and it was not limited to only local antiseptic use, but he argued these points from a reasoned position and did not attempt to weasel away from these positions when he was proven badly wrong by the mid-1940s.

And when I say wrong, I mean being highly visible wrong (as Fleming had become the most famous single person on earth).

Wrong ,wrong, wrong before the eyes of every single scientist in the world.

Fleming accepted he had been wrong and didn't fudge it

That took more than a little courage --- it is a pity than none of the rest of the penicillin pioneers who also advocated synthetic penicillin research to well past its due date were not as open in admitting their similar error......

That 'ever-climbing' Aussie Howard Florey: year by year his listed degrees got longer and longer

While we all know the differences between a BA, MA and PhD , few of us can fathom the distinctions between a BM/MB, and DM/M.D. in the field of medicine --- even when our life literally depends on it.

Most of us today, particularly in North America, tend to regard as the only real medical doctor someone who not merely has a degree of some sort from a medical school, but who has also passed an internship at a hospital (if not a residency), in addition to passing a local medical society's entry exams and gaining some hospital admitting privileges.

We tend to think , in other words, that the only real medical doctor is a full MD in the lay sense of that technical term, who is licensed to deal directly with acutely ill patients , giving them all forms of narcotics and IV needles,  can perform minor outpatient operations and is able to admit them to nearby large general hospitals.

In the British Commonwealth (outside of Canada), rather than a doctorate in medicine (M.D.) being the first medical degree, it is one reserved for medical researchers doing a PhD thesis in medicine. (DM=PhD in medicine= MD.)

One gets an initial BM/BS (BM=MB) and then goes off for various internships, residencies, local medical society and or speciality society exams, hospital admitting privileges etc just as brand new MDs do in North America.

Interestingly, none of the many people included in the Oxford team that Howard Florey assembled to develop penicillin were full MDs, in that lay sense of the word, including Florey himself.

(So Dr Florey was licensed, but only to do  operations on research animals but not licensed to deal with humans in the local general hospital..... Dr Chain wasn't even licensed to give needles to research animals !)

But in 1944, his old university in Adelaide gave Florey an honorary M.D. degree and he used it for the rest of his life with pride, as he did all of his honorary degrees.... without indicating their honorary nature.

His first well-known article (on penicillin) in 1940, lists him only as having a M.B.

By 1941 with his second article on penicillin, he could and did add a FRS to that.

By 1949 he is listed ,as chief author of the two volume history called simply "Antibiotics", with a MA, MD, PhD and FRS : that old oddball MB is forgotten history.

By, contrast Henry Dawson's rival penicillin effort had a much smaller team of just four people, but both he and Dr Meyer had M.D.s ---- an important distinction in 1940s American research hospitals, where by contrast with today, the PhD was a low degree indeed.

(His other team members ? Hobby had a PhD in bacteriology and Chaffee a BSc in chemistry.)

Obscure degrees, in author listings DO matter ...

Florey's team was oriented by their training and hence personal inclination , to fundamental research on on the nature of penicillin and away from saving individual lives.

Dawson's team was dominated, by training and hence personal inclination, to saving individual lives with therapeutic penicillin .

This matter of obscure degrees after researchers' names then turns out to matter greatly ...

Howard Florey, Henry Dawson,Penicillin and the NEW YORK TIMES : how then-tiny Pfizer became the biggest drug company in the world

"Giant Germicide" article changed history ...

Myth much to the contrary, Howard Florey went to America in 1941 not looking for a way to save lives, but for a way to save Allied military lives without having to save Axis, Neutral or Allied civilian lives : he was looking for a top secret medical bomb, a weapon of war.

Since publicity and top secret war weapons don't mix , this explains why when the New York Times sought to interview him upon his arrival on July 3rd 1941, fresh off the Pan Am Clipper, he curtly declined their kind offer and said nothing at all.

(Imagine : the most influential newspaper in the world offering to be your conduit for telling all of America's political and business leaders about penicillin's potential and you toss it aside like an used condom ! )

Perhaps as a result of his playing hard to get, Florey never did get the kilogram of pure penicillin that he sought so hard on this trip, because he had no public pressure backing his private appeal.

By way of contrast, Dr Henry Dawson did take his belief in penicillin's "unlimited potential" (his words) to a huge public medical conflab, attended by many of the world's science and health journalists, and got lots of publicity (as far away as South Africa) about his expansive belief in penicillin.

The New York Times article that changed history ...

Among the media who reported Dawson's comments was the New York Times , which splashed his optimistic views ("Giant Germicide") near the business section of the paper.

Next morning, some busy-- important---executive at then-tiny Pfizer chanced to read about a potential drug he had never heard of over his breakfast table ..... and the rest is history.

That same history reminds us that 90% of the penicillin that landed on the D-Day beaches in the first crucial mass clinical trial of penicillin came from Pfizer and Pfizer alone.

The one drug company in America that Florey had NOT visited on his search for his kilo.

The one drug company that Dawson did approach, ironically because he was merely seeking to help the churlish Florey.

So : "the stone the builder rejected", redeemed by an article in the New York Times.

That is the power of journalism, of publicity and of the New York Times.....

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....

Wartime Penicillin was a race between a Tortoise and a Hare,unexpectedly the Tortoise won but the Hare got to phone-in the results...

People invariably find the story of wartime penicillin fascinating because 75 years after the earliest events, it still remains a real puzzler with lots of inexplicables and unanswered questions.

The story of wartime penicillin is actually quite clear.... but it is its history that seems so full of holes and silences.

A great Russian poet once voiced the thought that lovers only sing love songs when they are far apart --- when they are together they have much better things to do.

So too with the winners in the race  to define and provide wartime penicillin.

The selfless nature of the objectives of those who won the race suggests that they might be equally self-effacing in the moment of triumph : just glad that penicillin was being made available to all, at a reasonable price, and before the six year long war ended.

The losers in the penicillin race were grasping and ambitious and  lost so dramatically and so unexpectedly , and so it would seem natural for them to seek a form of physic revenge by re-writing the history of wartime history.

The losers were, in part, from the government side of the race and they had lots of taxpayers money to write and publish huge official histories.

Even after that, they held most of the solid documentation (which they thoughtfully marked as "secret" during the war) in their official archives.

The same governments that , after the war, offered to generously fund all academic researchers and research projects - that they approved of .

The losers were also Big Pharma , who held much of the unpleasant details in their closely guarded archives but who were willing to fund researchers and open their archives in a limited fashion to them, provided the drug executives had reason to feel the researchers were sympathetic to their view point.

And all the secondary researchers ever since have had to scramble from pillar to post to get any sort of firm information about the winning side of the race for penicillin , while information from the losers comes at them by the trainload in war friendly well light archives in Washington and London.

How balanced an account can we expect even the most dispassionate author to provide under those circumstances ?

My job , as I see it , is not to be dispassionate but rather a partisan for the winning side : but not to be a partisan for anybody on the winning side.

I will seek to establish a firm , fact-based chronology when things did happen (and more importantly, did not happen) and try to follow the money trail : ignoring talk and claims and promises for cold hard cash (and again : more importantly, lack of evidence of cold hard cash.)

I will review all contemporary claims of penicillin yields to judge if they were credible-- and few were.

Above all, I will separate clearly when the contemporary numbers refer to absolute amounts and when they refer to relative amounts of penicillin : for this is one of the widest failings in all accounts about penicillin and one that is at the very core of the muddle about wartime penicillin.

The winning side wanted larger and larger absolute amounts of penicillin --- to help those dying of infection, in all countries, as soon as possible.

The relative purity of those absolute units of therapeutic penicillin interested them not in the slightest : greater and greater production of absolute units of therapeutic penicillin was their only concern.

Four daily injections of 500 cc of crude penicillin juice , with about 2 units of penicillin per filtered ml of medium, (4000 units of absolute penicillin per day , in total) was judged useful to Australian Jimmy Duhig because it saves a mother's live , even though that material (in relative terms of purity) was only 1 part per million of the medium !

 By way of pointed contrast, his fellow Australian Howard Florey was very proud in getting a single milligram of solid penicillin from the same amount and strength of penicillin juice, because it assayed at 450 units per mg, ie 25% pure.

Duhig's yield of therapeutic penicillin was 100% because he lost nothing trying to purify it - and the impurities in his penicillin juice caused his patient no more than temporary discomfort.

Florey's yield was 12% , because his repeated attempts to purify his penicillin juice resulted in huge losses and huge destruction of the basic penicillin ---- and it introduced toxic chemical contaminants worse than the natural impurities it sought to get rid of !

A patient receiving this material as medicine would get much less penicillin and probably find it more painful to boot.

But thankfully , patients didn't usually get this sort of penicillin from Florey.

His patient-directed penicillin was only purified to about 40 units per mg, and while nominally 'dirtier' , was actually probably safer than the early 'pure' variety : and certainly the yield was much higher and so the patient got more absolute units of germ killing power.

(Bacteria are only killed by absolute amounts of penicillin not by its relative purity : after all, the greatest diluter of penicillin - by far - is not the original pint of medium fluid but rather the quarts of blood fluid in the human body !)

No, the "pure" (high relative purity) penicillin was a holy grail sought for only one reason : we need pure penicillin to determine its chemical nature for then Man can hope to artificially synthesize it and push Mother Nature out of the picture entirely.

Millions of patients died, needlessly, during the 15 plus years of this fruitless quest.

Wouldn't you also want to cover your tracks in this shameful episode of your life....