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.

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.....

Spores and Wartime Secrecy : can they actually co-exist ?

You might think I am going to talk about Anthrax spores and asymmetrical terrorist germ warfare.

But you are wrong, wrong, wrong.

I want to talk instead about wartime penicillin, and a part of it that is never ever discussed.

Its inherently asymmetrical medical nature.

Which appropriately enough, then  "drifts over" into its inherently asymmetrical military potential.

So lets start.

And lets start talking about just how the intellectually mis-guided (as well as seriously morally misguided) were the prolonged attempts by the medical establishment in both America and Britain to regard penicillium spores as something  that really could remain Top Secret medical military weapons.

And not just the wartime medical establishment, for recently author Eric Lax and his publishers felt they had a real winner in an exciting clock and dagger title for their book on wartime penicillin : "The Mould in Doctor Florey's Coat".

There was always something faintly Walter Mittyesque about Florey anyway - never more so than in the incident that gave this book its title.

Dunkirk was underway just as Florey at long last accepted that ole Flem's penicillin just might be priceless after all.

But how to save penicillin for the rest of the Allied cause, if Britain fell to the Germans ?

'Let's all rub penicillium spores in the inner seams of our clothing - so even if only one of us gets away, the precious fire of penicillin research can still be re-lit elsewhere'.

But none of these Oxford naifs seemed to have dared ask the boss (Florey) just how they came to possess these incredible spores in the first place.

Henry Dawson's first big scientific effort was in promoting the concept of HGT (Horizontal Gene Transfer) ,the instant transfer of genes between different species and even different families of Life, when its initial discoverer seemed reluctant to even publish his work.

Today it is believed that soil bacteria created the first beta lactam antibiotics about ten million years ago and  - via HGT - gave it to soil molds who modified it slightly and made it penicillin.

So, sometime in 1928, a particularly productive penicillin producer strain of penicillium mold blow into a fancy home in London.

Alexander Fleming's colleague John Freeman was an expert on allergies,  with many rich and powerful patients.

In 1928, Freeman heard a Dutch specialist claim that basement mold spores were the cause of many allergies.

 Freeman got his rich London patients (or more likely their scullery maids) to scrape molds off their basement walls to be tested by his most recent hire, Irish-born mycologist Charles La Touche, towards seeking  ways to gradually desensitize the patients against their particular household mold allergens.

La Touche had no high tech ways to keep spores inside his lab alone - not that I think in the long run a spore or two doesn't get out of the most secure modern facility.

There are many more fungus than us and they have and will be on the Earth a lot longer than us primarily because of their spores.

Their spores are incredibly tiny examples of temporarily suspended Life - Dried-up Life - inside a very hardy and bumpy package.

Tiny is the key here - so tiny they float anywhere and everywhere on the gentlest of breezes - down the hall and around the world.

Being bumpy but tiny and light doesn't hurt either - they can cling to almost any surface - like a human and its luggage bound for Australia, for example.

However if that surface is the tiniest bit damp and the tiniest bit tasty (they seem willing to eat almost anything faintly organic), they spring back into active slimey life.

One of La Touche's spores drifted out of his room and along the stairs to Fleming open Petri dish.

The rest actually wouldn't have been "legend", if Fleming hadn't promptly taken a sub culture of the resulting "spoiled" petri dish, and carefully and correctly preserved it.

Fleming did little to promote the medical use of penicillin in curing disease but he did vigerously promote it as a useful way for busy hospital labs to easily isolate the so called flu bacteria (sic) .

Dozens of labs world wide got a sample from him - they then gave samples of their samples to at least dozens of others.

That is how Florey got his penicillium spores he was so busy stuffing down his coat - from a sub culture Fleming had sent to the previous director of Florey's Dunn Institute.

The Free World beyond Britain had lots of  sub cultures of penicillium spores of the rare - right - type, even without Florey's belated act of charity.

In theory they didn't really need Fleming's spores, only his public article - but in practise, until 1943, they really did need his spores.

Examples of Fleming's spores were actually everywhere - some even better penicillium producers than his original un-mutated version as well.

But they could only be found by teams of researchers seeking hundreds of the right looking blue-green mold on walls and spoiled fruit, and then testing all for their possible anti-bacterial qualities.

Until miracle cures got rumoured about, no one in the world was willing to go to that much effort , just to test a troublesome possible antiseptic.

But by 1943, the miracle cure stories were out amongst the clinical doctors everywhere - and I do really mean everywhere.

Everywhere that Florey went, Egypt, Iran, Russia he had to endure local doctors thrusting excellent producing strains of penicillin molds in his face that they had found locally !

The Axis were just as quick off the mark - Japan got its strain by merely looking about locally.

And the clever Japanese correctly guessed - from one badly reproduced photo in an Egyptian picture magazine - just how best to produce the stuff !

The atomic bomb was effectively secret even if the US had proclaimed it was making one from the rooftops in 1942.

Uranium was everywhere - like penicillium spores - but a bomb from it takes the world's largest, most expensive, building ever built merely to get started on separating pure U-235 from the more abundant U-238.

And without 90% pure U-235,  no working bomb. No nothing.

Tons and tons of scarce money, time and effort kept the A-Bomb an American secret, even from the British and Canadians , let alone the Axis and Neutrals.

But by late 1943, popular magazine articles cheekily showed how one could make penicillin at home, on a kitchen top, for about $5 in equipment and growth mediums.

One didn't even need to go out searching for those semi-rare penicillin-producing strains by then.

In a surprising - even shocking - total volt face, the NRRL's Coghill and Raper had released the top two strains of penicillium.

 That's right, the top two strains that were then producing most of the Allies' military-bound penicillin - to the public American mold type collection in Washington where, as they told the readers of  JAMA worldwide, "anyone" can get some at a "nominal charge".

!!!!!!!!

Didn't they know there was a war on ?

No word if Argentina's Washington DC based scientific attache quickly took a cab over, got some samples and sent them off to his friends in Germany.

Clearly, penicillin was never a viable secret military medical weapon - Florey and Richards were both , to put it kindly, completely deluded to ever think so.

Deluded by utopian visions of near-total purity.

Because unlike the Atomic Bomb and U-235, penicillin's starting material (the spores) were both common worldwide AND its production fully successful even in a highly impure (aka low tech) state.

This was what Fleming had discovered in 1928 but never acted upon - this was the key insight that Henry Dawson brought to the penicillin story, starting on October 16th 1940....

A full two years after Florey arrives at Peoria, the NRRL starts looking for new sources of penicillin strains..."Soon" ?

Penicillin: II. Natural Variation

and Penicillin Production in

Penicillium notatum and

Allied Species

If pollyanna historians says two years - in the middle of a war - is "soon" , then I guess it must be so.

"Howard Florey arrives in Peoria in early July 1941 and "soon" planes of the American Air Transport Command are delivering moldy earth samples from the four corners of the world.... and that is why we have abundant penicillin today."

I always knew this story had to be bunk : the Air Transport Command won't even be in the four corners of the world for another year or two or three.

Ken Raper, the man at NRRL who directed that search and should know best says (in the1945 peer reviewed article at the top of this post) that the search started in June 1943.

Ie, after the OSRD stepped back from two years of navel fluff removal and the OPRD got involved in its typically no nonsense way.

If the OSRD's infamous AN Richards wasn't so hell-bound on a chemical synthetic solution, the NRRL would have gotten money and encouragement a lot earlier to search for higher producing strains than those held already by the NRRL  --- and these strains were key to the final successful chapter in the long penicillin saga...

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....