Oxford Artificial versus Manhattan Natural

Howard Florey (along with Alexander Fleming and Winston Churchill's government) spend ten years before during and after WWII pursuing the chimera of totally artificial (patentable) penicillin --- to no avail.

As did Florey's supporters in America - Merck, Squibb and Vannevar Bush's all-powerful OSRD.

Set against then, on the opposite side of the Hudson River , was Dr Martin Henry Dawson and John l Smith , chemist and boss of Pfizer.

They saw possibilities in the fermentation of the (public domain - free for all to grow) natural penicillium to produce antibiotics.

This was despite its current yields being admittedly low: they felt as it was a totally new way of doing medicine , it might well improve drastically with more practise.

(I should mention that two other strong skeptics of the whole idea of the commercial viability of total synthesis of penicillin were also practising chemists : Glaxo boss Harry Jepcott and the WPB's penicillin czar Larry Elder.

 It was chemist manques like Florey and the OSRD's Dr Richards who were the most likely to feel that of course man-made Chemistry was always bound to be superior to Mother Nature.)

Today of course, with penicillin being produced at 50,000 times the levels of Fleming for the same cost in time labour and materials, the case against oxford Artificial seems clear - but it wasn't so throughout the war and beyond.

Long Island scientist Miloslav Demerec deserves a lot more credit than he ever gets (which is none !) for his major role in making our wonderful world of relatively cheap abundant antibiotics ....

Howard Florey saw potential enemies everywhere, but with "friends" like A N Richards and Robert Coghill, he hardly need bother looking any further

Howard Florey's correspondence twice notes that he has just received a higher yielding strain of penicillium from America.

The first, in November 1941 ,was obtained from Dr Rake at Squibb - a higher producing mutant from Fleming's original strain.

The second time in November 1943, some un-named strains were obtained from Robert Coghill of the NRRL , while he was visiting Oxford .

But in the two crucial years in between ?

I see bugger all evidence that Florey got the latest improvements in penicillium strains as they emerged at Peoria. (Prove me wrong, please) .

The mycologists at the NRRL research centre in Peoria had steadily improved and improved and improved again Rake's variant and their final version, NRRL 1249.B21 produced - via surface cultivation - most of the world's wartime penicillin until quite late in the war.

At that point, submerged strain NRRL 832, from a non-Fleming strain first found in Belgium, took over.

I believe that Merck's chief consultant and OSRD medical chief ( giant conflict of interest alert !) A N Richards, supposedly Florey's second closest American friend, using as an excuse that America was now at war, deliberately held back the giving these improved strains to Florey.

All to further America's ( sorry ! Merck's) post-war commercial opportunities.

Nicolas Rasmussen, in his article "Of  'Small Men', Big Science and Bigger Business", looks much closer than most historians at the day to day workings of the medical wing of the famous OSRD.

 He points to several examples where Richards authorizes the further spending of taxpayers' money, supposedly only for war weapons, on drug research that no longer had an obvious military use, because he claimed that keeping  American's edge in their development would definitely benefit the nation.

If not in this war, or any war, how would the drug's successful development benefit a nation at war - supposedly the sole purpose of the OSRD, whose mandate was set up to expire the moment peace was declared ?

Richards doesn't say.

So let me suggest a more sinister purpose , because Rasmussen does not.

I note that the two examples that Rasmussen gives where the OSRD spends taxpayers money on projects that no longer seemed to have a military need were pet projects of Merck, the firm that Richards advised.

The first was the chemical synthesis work on penicillin , carried on well past the point (say June 1944)  when biological penicillin was being produced en masse and cheaply.

The other was after mid 1943, when it was clear that cortisone would not help pilots fly higher longer - an important advantage for any nation's air force if proven so.

Merck got nothing for all the money it spent on synthetic penicillin but its finally successful efforts on cortisone was and is one of its biggest successes for both its scientific reputation and its pocketbook (the two of course being closely related).

First success with Cortisone would be an advantage to America as well as Merck, over European (Swiss) competitors --- but synthetic penicillin's success could only have come by crushing fellow American firm Pfizer and given the field to Merck.

How then would that serve America's interests, rather than merely Merck's?

Because Europe wasn't even in the running on biological penicillin in 1944.

Perhaps Richards, already a pensioner when he took on the job of heading the OSRD medical wing and with the rigidity of old age, still believed synthetic penicillin would better Pfizer's penicillin in price and yield.

Then Merck would beat their only European synthetic penicillin rival : Florey !

Normally, Vannevar Bush's OSRD - as in denying the British to atomic energy research - did a better job of using taxpayers' military-assigned money to screw America's European Allies' commercial chances after the war , without favouring any one American firm.

Richard's willingness to screw Pfizer and even his friend Florey, shows just how much further he was prepared to go to aid Merck.

But he needed pliant helpers  to succeed.

Luckily for him, the  NRRL's Robert Coghill seemed to have had a hard time accepting that research paid for by his employer , the US Department of Agriculture and ultimately the American public, belonged to the USDA.

And that this research shouldn't only go where a different agency's chief bureaucrat, A N Richards, wanted it to go - though he hadn't paid for it and had no statutory (legal) control over it.

However , I see Coghill, a misplaced chemist running a biological program, wanted in so badly on a "technically sweet" chemical problem (the synthesis of penicillin) that he sold out the farmers he had sworn to help.

Synthetic penicillin would only negate the ready market for  hundreds of thousands of tons of farm waste corn steep liquor, farm waste whey and farm waste crude brown sugar, all used in the natural fermentation of penicillin and other antibiotics coming along in the pipeline.

Coghill did publicly announce that he was giving the top two commercial strains of penicillium (presumably NRRL 1249.B21 and 832) to the entire world in November 1943, about the same time as Florey first mentions having them.

Why ?

I can only suspect because they were about to become obsolete, as synthetic penicillin seemed only months away.

By April 1944, that no longer seemed so and Coghill was back on the side of the biological angels, publicly praising Pfizer's biological penicillin and modestly claiming a role in their success.

Coghill's talents seemed rather wasted in democratic America - I can see him as the ultimate bureaucratic survivor in Stalin's Russia, adroitly changing sides as the situation shifted, moment by moment.....

Fleming's seminal 1929 article on penicillin is missing two words : impurities and crude

Fleming, in this extremely famous article, defines his "penicillin" as consisting of  one or more soluble solid active ingredients in a liquid nutritional  broth, no more and no less.

He makes it clear that "penicillin" is merely a useful shorthand for that cumbersome longer phrase.

He never once uses the word impurities or impure or crude: to him his active ingredient is perhaps ALL  of the soluble solids left behind when the water is evaporated .

Fleming says that this (mixture) of soluble solids and nutritional broth is non-toxic to the extent that it can be injected in a mass of one fortieth of body weight without harm.

(That is, this liquid mixture appears to be safely injectable in a mouse and a rabbit to the equivalent of  a single bolus of 1500 to 2000 cc into an average adult human.)

And Fleming isn't the only one never to use impurities or crude in describing penicillin in a scientific report, in the twelve years between 1928 and 1940.

Clutterbuck & Raistrick in 1932 do not use the words impurities or crude, nor does Roger Reid in 1934, or Elizabeth Pickering at Squibb in 1937 or Siegbert Bornstein in 1939.

But Howard Florey, the chemist manque , the anti-clinician, he sure does in 1940.

He might even ask his potential readers, "Purity : how many ways do you want it ?"

Despite being a very short article - almost more of a scientific note  in the style of letters to the journal Nature - Florey manages to inject the words "purify" , "not a pure substance", "impure" and "impurities" and talks constantly of his "penicillin preparations" as if they are something quite different and advanced from Fleming's liquid penicillin.

But, in fact, Florey has merely concentrated all the soluble solids by evaporating away the water, so that 4 tiny units of anti-bacterial activity are no longer in a gram of water and solubles, but in a milligram of solubles.

But two thirds of the scarce anti-bacterial activity has been lost in this totally unnecessary and expensive and complex effort : and in any case, this dry powder has to have water added back into it, to inject it for use !

Dawson, Pulvertaft, Duhig, Yermolieva , Berger (among a mere handful of all the world's doctors ---- maybe just .01% of them  thought this way) seemed to have picked up on Fleming's crucial point.

A point he quickly missed, because he publicly always said that the substance would have to be synthesized pure by chemists before it might be a useful antiseptic .

But his original point was true, nevertheless.

It was this : that regardless of whatever was the compound(s) with that mixture of soluble solids that had the anti-bacterial powers, the water and other solids had no harmful effect and needn't be laboriously purified out - or even concentrated by evaporation - at a tremendous loss of the anti-bacterial matter.

Dawson is at pains to introduce the word "crude" repeatedly in his 1941 article, but with a much different point that Florey's article a few months earlier.

Dawson wants to hammer home that despite the crudity of this mixture of the anti-bacterial activity and the other soluble solids, it was still non-toxic even when injected ( finally) into the human blood stream : life-saving does not have to wait until the chemist's apple has been polished to a 't' .

Dawson is , in a sense , "The James Lind of Penicillin".

Put in another way, James Lind said we don't know which compound (later determined to be vitamin c) it is in limes that prevents scurvy but that shouldn't stop us from using it - NOW ! - to save lives.

Almost two hundred years later, another Scottish (Canadian) doctor (Henry Dawson) said pretty much the same thing.

The lesson might be this : chemists, let the sleeping dogs of chemical perfection lie -----  while we clinicians get on with saving lives.....

Florey quickly flees the biology of NRRL Peoria for the chemical comforts of Merck

Howard Florey probably spent no more than a few hours of his whole life in the labs of the NRRL at Peoria, Illinois where most of the fruitful work that gave us the antibiotics revolution was actually done.

Within hours, he had dumped his sidekick Norman Heatley there to toil on the rural farmer-like task of growing penicillin, because Florey preferred much more the urban chemistry-oriented approach of firms like Merck and Squibb and ICL.

Florey was no country hick and disdained 'farming' penicillin

Florey after all had wanted to be part of the then most glamorous part of science( chemistry) and only took up medicine as the easiest way for an Australian to get employment in scientific research (as a medical "doctor" , he hated dealing with patients and in fact, hated dealing with people in general.)

He remained a chemist-manque all his life.

Hence why he avoided doing any hands-on research at NRRL Peoria on increasing the biological yield of penicillin .

He much preferred the chemical synthesis approach of Merck and of its chief scientific consultant, A N Richards, new head of the war  medicine section of the war weapon research organization, the OSRD....

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....

Was there a Parran-Hearst Telegram ? (You provide the penicillin, I'll provide the pictures)

"Operator, get me Washington, tell 'em I'm from Hearst..."

There is no firm evidence that Citizen Hearst ever sent that infamous telegram to the famous war artist Frederic Remington in Cuba.

We all know which telegram:  the one where Remington is sent out to illustrate the ongoing civil war in Cuba, but finds all is quiet and begs to go home.

Hearst supposedly telegraphs him to stay : "(If) you furnish the pictures, I'll furnish the war."


Hearst proceeds to puff up the accidental explosion on board the battleship The Maine as an act of sneaky warfare by the Spanish, ("Remember Pearl Harbour" 50 years ahead of schedule) and the rest is history: Yellow Journalism's finest moment.

Or is it ?

For a start, that particular telegram was apparently never sent.

But did the aging Hearst later intervene with US Surgeon General Thomas Parran in August 1943, to get penicillin to a dying baby girl in Manhattan ?

Was this Yellow Journalism's finest moment ?

The Pulitzer Committee apparently felt so - and it is worth noting that Pulitzer and Hearst were the most bitter of bitter enemies.

Consider what we know (or think we know).

Supposedly the whole thing started with a phone call from the distraught father (Lawrence J Malone) of a dying two year old girl called Patricia Malone, made to the city desk editor of the Hearst media empire's flagship newspaper, the New York Journal-American.

Actually Malone quickly fades back into the wallpaper , as do the nominal doctors for the baby girl.

Because in fact, Malone was set up for the call by a crippled Italian-American surgical resident named Dante Colitti, then working at the tiny Lutheran Hospital in upper Manhattan, about a mile from pioneering penicillin doctor Henry Dawson's hospital, Columbia Presbyterian.

The little girl was dying of blood poisoning and normally a surgical staffer - a mere resident at that - has no place in treatment decisions for that sort of illness.

But Colitti was raised right, with a good moral education and he couldn't stand by and let her die, when he knew that not a mile away, Henry Dawson was dragging babies like her back from the grave with his Floor G penicillin.

And Colitti had no cause to love the New York medical establishment which supported the limiting of penicillin to curing VD cases among the unfaithful husbands and boyfriends of the combat corps.

In the 1930s, he had been rejected from attending any New York medical school, by an informal quota system designed to keep out Catholics and Italians.

 (And Jews and Blacks and Asians and Women. Colitti's parents were recent immigrants to America).

Colitti had a permanently bent spine as a result of childhood TB and had to use crutches so it was probably the excuse given him for his rejection.

But Colitti knew that Henry Dawson, just a mile north of him, was working with a doctor who used crutches thanks to polio and another doctor who was missing an arm.

The only real difference was that these were Protestant men, with native-born parents.

Colitti paid a private medical college in Massachusetts to get his MD degree but no New York hospital would recognize any degree not granted by one of the quota-oriented establishment schools.

It was a closed loop.

But WWII led to a desperate shortage of medical staff and even New York's medical establishment had to let people like Colitti in to do the lowest medical jobs, at least until the war was over.

But the highly morally minded Colitti felt that if they had displayed no charity towards a cripple, that did not mean he would follow suit.

Hence his setting up of the phone call to the Hearst paper : he knew exactly who would cause the most noise.

The Journal-American photo-journalists were then world famous for their large, vivid, gripping front page photographs and a dying baby story was just made for their skills.

The Hearst editor got no where ( says the AP press agency) with the OSRD's Dr Richards or with the NAS Committee on Chemical Therapeutics.

But somehow or other the newspaper knew of the ongoing conflict between those who felt we could best win the war ("Hearts & Minds") through well publicized Social Medicine versus those that felt that secretive and rationed War Medicine would save more scarce resources for "Guns & Bullets".

Because the newspaper ultimately got the penicillin it needed from that supply reserved for the US Public Health Services (at that time, it only had a tiny amount of penicillin and it was only normally used for treating cases of VD among merchant seamen.)

Released by drug company Squibb upon the direct order of Thomas Parran, US Surgeon General and head of the US Public Health Services (then a relatively small and powerless body compared to its status today.)

Parran versus Weed over the fate of wartime penicillin

Parran was the de facto head of the Social Medicine forces, while the NAS's Lewis Weed was the voice of War Medicine.

Did Hearst or his senior staff know of this ongoing debate and approach Parran directly, dismissing his concerns about tackling the all-powerful OSRD and NAS by reminding him he had no love for the NAS's Weed anyway , and that if he would only provide the penicillin vials, Hearst photographers would provide the poignant pictures.

Yellow Journalism and the Yellow Magic then proceeded to make beautiful music together : because the Patty Malone Story ultimately spelled the end to the Age of Modernity ...

"Jabbing" BIG PHARMA awake

Good things happen when you quit the shilly-shalling and "do the clinical" - ie 'stick the needle in and see what happens'.

I have said before that it was in October 1940 - the same month that Martin Henry Dawson jabbed the very first needle of antibiotics in a patient - that the American Drug Companies and the American medico-scientific establishment (NAS-NRC) finally woke up and started smelling the coffee on penicillin.

Example ?

That very month, Squibb asked for a sample of Fleming's penicillin mold from the culture collection in Peoria.

They did the smartest thing that Squibb ever did in the entire Penicillin Saga - they threw the chemists out of the building and let the mycologists get down and into it.

Don't you wish all the other labs had done ditto?

 Alexander Fleming, unfortunately, seemed to really hate mycologists - and he rarely - in public anyway - disliked anyone

Thankfully, the result was a much improved strain from Fleming's original and it was eventually called NRRL 1249. (January 1942)

All praise to Dr Geoffrey Rake and his co-workers at Squibb who never get any thanks for giving us life-saving penicillin in time for D-Day.

Instead the big losers in the penicillin affair, the chemists, have written all the official histories, blowing smoke rings so we won't see how they failed to deliver on their promises.

Other claims to the contrary,history is usually written by the losers - at least "the losers with l'argent..." *

Mycologists take a bow : thanks to you , it was natural NRRL 1249 and its offspring , 1249.B21, (December 1942) that delivered most of the penicillin produced in World War II.

The chemists just delivered papers and articles instead....

* Canadian-anglophone-only joke --- Yanks and Brits/Anzacs etc can safely ignore it