1941-1950: Friedberg revises SBE deathwatch

In 1950 Dr Charles Friedberg told the readers of JAMA, one of the world's leading medical journals for frontline doctors, not to forget that SBE was now the easiest of the common heart diseases to cure.

They listened.

 Friedberg had quite literally wrote the book on SBE, back in 1941.

The, ahem, old book on SBE.

In that 1941 book, Friedberg and chief co-author Emanuel Libman had carefully surveyed 1200 cases of SBE in detail and said 'no cures' - at least no cures by the efforts of doctors.

 However three percent might expect a spontaneous cure.

Until the next and the next attack -  for SBE was a repeater disease and so really inevitably fatal - over the short medium term period.

Another researcher at the time was even less hopeful - finding  out of 249 of his SBE patients, maybe one had a temporary cure.

But now in 1950,Friedberg's 'invariable fatal SBE' had become Friedberg's 'the most curable common heart disease' !

The reason for this amazing turn about, Dr Martin Henry Dawson, had died a little earlier, back in April 1945.

But these amazing 1950 conclusions were due to his pioneering 1940-1945 efforts to prove up penicillin as an anti-biofilmic agent , able to penetrate SBE vegetations and kill the bacteria without killing the patient.

It was a mission carried on and brought to a spectacular conclusion by his assistant Thomas H Hunter, after the war.

DOCTOR MOM  now had one Sword of Damocles removed from over her head --- thanks to a doctor from Columbia University.

Just in time too.

Because another doctor from Columbia university, Harold Urey, PhD, had just given her a new Sword of Damocles.

During World War II, in one part of Columbia,
the former Lt Dawson,(winner of the Military Cross with Citation),was busy(illegally) curing "4F" SBE patients.

 Meanwhile, in another part of Columbia, Urey-The-Pacifist, with his crew of war-exempt healthy, young "1A" scientists, was busy inventing the Cold War's most fearsome weapon: the gaseous diffusion process for the extraction of uranium for the mass production of nuclear weapons.

As a result, 1950s kids, of which I was one, were the healthiest and the most scared generation of kids ever raised.

Thank you, Columbia.....

Why I claim Warren Weaver was 'naive' over penicillin

Some have objected that Warren Weaver,long time chief of the Rockefeller Foundation Natural Sciences Division was one of the most astute men in American science.

I say he was a math teacher, placed in charge of allocating millions in grants devoted to discerning the 'deepest secrets of biology' and what he did not know about the basics of biology and medicine would fill a library.

In particular, can you see the people in the medical side of the Rockefeller Foundation buying the Florey and Chain claim of 1939 that penicillin was an enzyme (ie a foreign protein) and yet, once purified ,it could be safely injected into a vein as a systemic medicine?

Aren't we also always told that Fleming's penicillin was too
unsafe to inject as a systemic medicine?

This because the mold was grown in a foreign protein medium and so was too deadly to inject into humans.

Though Fleming ,in fact, showed that neither penicillin juice or the medium juice seemed to affect mice when injected into them.

Weaver knew next to nothing medical, but he loved a good line.

The line he always loved best was that chemists, physicists and mathematicians  and other hard science types would quickly clear out the soft descriptive clinical types holding up true medical progress.

So he gave Florey and Chain all they asked for.... and more.

A good thing really - because Florey would never have given penicillin a moment's notice, if he hadn't a nice grant to do so.....

Mae Smith ; the real life DOCTOR MOM that gave us penicillin

Readers sometimes asked me if DOCTOR MOM was a real person.

I usually say "No, Dawson was trying to reach all the Doctor Moms in America , via his success in preventing all the deaths and all the worries caused by childhood Rheumatic Fever."

But I have reflected and maybe my readers are right - yes, there was was one specific Doctor Mom that Dawson reached - perhaps, indeed, only one that he reached.

But one can be more than enough.

Her real name was Mae Smith, though she is sometimes known as Mrs John l Smith or ,more accurately, as Mary Louise Smith.

MAE SMITH in 1954

Her husband owned 25% of the Brooklyn Dodgers baseball team and after his death, she held those shares.

More books have been written on these , the original "Boys of Summer", than any other team.

Many people seem to rate the day the team left Brooklyn as more significant in the decline of America than Watergate or Viet Nam.

The other Mary Louise Smith is also very important in this story : she was the Smiths' daughter.

John L grew up in a small seaport in Connecticut and he loved to sail more than almost anything and he loved his cottage in his old home town.

One day when the family was out in the cottage, far from big cities and big city high tech hospitals, young Mary Louise said she had a stiff neck. And a headache. And a fever. And that in fact, she generally wasn't feeling very good indeed.

That put her family in a real panic.

Not as much as it did the local doctors - it was obviously Spinal Meningitis - still a deadly, every-minute-counts-disease even today with antibiotics.

By the time they got her to a big hospital, it was too late to even stabilize her - though surviving a late case of spinal meningitis can be a very mixed blessing - it often leaves you physically and mentally challenged.

An immediate (and I mean like yesterday) massive needle full of Penicillin was the best cure then , as it still is today.

Penicillin had been discovered at the time of Mary Louise II's death, but had not yet been produced, let alone mass produced.

In 1941 and 1942 and in 1943, as Dawson always naggingly reminded any and all visitors from John L.'s firm, it still was not being mass produced.

"But if it had been developed back then and if it was a staple in the black bag of even the smallest backwoods doctor, Mary Louise would be alive today."

"How many more Mary Louises would have to die needlessly before the world got enough penicillin to make a difference?"

And on and on.

John L had heard this all too many times before - he felt that Dawson simply didn't understand the technical and economic issues that prevented his firm from taking the plunge.

"What risk ", said Dawson , "are you not planning to take the company public, and to do a stock split?  This war has made you guys even richer - give something back to the fighting man - and the fighting woman."

I bet John L would go home at night, get a stiff drink and unwind at his wife, all about what a nag that Henry Dawson was -- "why he even said this and he dared say that."

I don't think John L bought Dawson's line.

But to her credit, I think Mrs John L eventually did.

I bet, late at night, just when John L was trying to get some shuteye , she would softly bring up the question of 'why couldn't the firm take a little risk for once, do something extra for the war effort?'

I think it must have rubbed off eventually, because if his firm was cautious, John L was even more so.

But between late August 1943 till March 1944, that 'stiff little man' was like a man possessed, so determined was he to get a big new, NATURAL, penicillin plant on line as soon as possible.

(This was just at the very time that the Florey team at Oxford University were semi-secretly announcing that they had totally synthesised penicillin chemically and that to continue to rely on natural production by the mold was a 'retrograde' step - so John L was betting against the received opinion.)

But they went ahead anyway: shifts of crews building around the clock, lit by Klieg Lights and posters everywhere reminding employees that this was a "Race Against Death."

 "The quicker this building is done, the quicker penicillin can go out to the wounded boys at the front."

It paid off  because by D-Day Pfizer, his firm, was producing most of the world's penicillin---and the company has never looked back.

We never did get any of that wonderful 'Refined Penicillin' out of the chappies at Oxford - but 'Brooklyn Crude' pulled us through the war anyway.

And I like to think a lot of the credit for starting Pfizer on the road to becoming the world's biggest company should go to a quiet but persistent push from  "Doc" Mae Smith.....

DEMAND SIDE penicillin versus SUPPLY SIDE penicillin

Long ago, it was realized that a University Registrar could often be a high school teacher's best friend.

If, for example in Canada, the Registrar at a big provincial university like the University of Toronto held firm that no one would be admitted to any science undergraduate course without a suitable pass in German, then school board administrators all across the biggest Canadian province of Ontario would dig deeper to pay for properly qualified German language instructors.

Most other provinces, in turn, bowed down to Ontario's greater wisdom and followed suit.

 And even the kids,learning from negative feedback from older siblings and friends who failed to get into university because of poor German, knuckled down and learned the language.

But if the university regulations required German but the Registrar frequently ignored it, then a different sort of feedback got back to school boards, teachers , pupils and parents.

Dawson recognized this as a sort of Demand Side Economics: making penicillin ,like learning university science level German, was bloody difficult, and given any choice, drug companies , like high school kids everywhere, would much rather do something, anything, easier.

But if the paying customers was screaming, money in fist, demanding penicillin and willing to turn to anyone who had it --- even the most stubborn of old school drug firm chemist would reluctantly knuckle down and learn the new skills required - or face the alternative of the unemployment lines.

Dawson focussed on the ultimate customer - the Doctor Mom and offered her a solution to her number one fear in 1940 - Rheumatic Fever.

If he could only publicize his hopes and successes with natural (ie unpatentable) penicillin to her, the public, her demand would push the drug firms to learn that difficult art of growing natural penicillin  in massive quantities.

Members of the public yelling to doctors and druggists and government bureaucrats and the professionals and scientists yelling back is sooooo undignified, so Italian family at suppertime, so Operatic.

But it works and it works quickly - if not quietly.

Florey and his supporters took the exact opposite tack: Supply Side Economics.

"Don't, For God's Sake,tell the public we have had success with patients treated with penicillin - they'll only ask for it for their dying brood- and we haven't yet fully tested it in every imaginable disease and clinical situation."

" We haven't learned its full structure and particular molecular shape and so we haven't yet synthesized it."

"Keep everything secret until we can surprised a delighted and grateful public with fully determined, fully formed, fully patented-up-the-jing-yang artificial penicillin at their local drug store."

This would be the much slower, but much dignified, route - the professionals would appear fully professional - an act they can pull off fairly well, given enough time and money.

The public and the media would appear so supplicant and so grateful to the wonders of science - an act they too had learned very well.

So in 1943-1944, which side won; which form of economics worked the best ???

My ebook, MO goes PO, out October 16th, will tell which side actually got us the D-Day penicillin and which side was nothing but talk....

BROOKLYN CRUDE versus OXFORD REFINED

You remember all those wartime movies that tried to build a sense of unity within diversity , both among Americans and among Americans and their erstwhile Allies?

The platoon had to have a WASP for the Captain, but the rest of the enlisted men and Non-Coms were a bundle of ethnic and regional stereotypes.

The tough Sergeant  from Tennessee or Texas, the scared kid from somewhere in the milk-fed Mid West,the weedy smart Jewish kid, the Italian aleck from Brooklyn with an accent you could cut with a knife , sorry NOI-IF.

If our multi-ethnic infantry platoon meet anyone from the British army, all the British enlisted men men were short and stubby and talked in a broad sort of Cockney that you only really meet at the discharge door at Wormwood Scrubs - or on a theatre stage.

The officers were all tall and thin and talked in a plummy voice  redolent of Oxbridge or Whitehall.

It must have been something like that the day that John L first met Sir Howard Florey,FRS and offered to take him to see the Dodgers play.

This after Florey had spent an uncomfortable hour with Gladys Hobby watching the natural penicillin vials tumble off the Pfizer production line faster than an Oxford chemist could change their final, final formulation for their synthetic penicillin molecule.

Alec Fleming would have been delighted - Florey would just have turned stiffer than normal and said he had another urgent war-related engagement elsewhere and then would have gone off to the nearest washroom to change the pickle up his ass.

The duel between Brooklyn and Oxford was not just a difference of penicillin science between artificial chemistry and natural biology.

It has also a battle between two types of social classes and cultures - Brooklyn crude and Oxford refined.....

Milton Wainwright's thesis on whining Oxford postdocs

Mea Culpa.

I admit it, I originally dissed Dr Wainwright's theory that much of the anti-Fleming abuse really came from a small group of Florey's Oxford post-docs, unable to accept that the world did not rise and set in Oxford.

But I have changed.

As I followed the letters of  Florey and Heatley vetching for four years that all penicillin - to be worthy of the name penicillin - must measure up to the OXFORD STANDARD, my Canadian hackles rose.

My grandmother came from the suburbs of Manchester Lancashire and my granddad from Petley Bridge in Yorkshire -- they never spoke OXFORD ENGLISH and they promptly moved to a country where that sort of nonsense never mattered.

To read Florey telling A.N. Richards to keep secret any differences between Oxford and American penicillin - as if strep bacteria cared a toss - is to see a citizen of a nation who has lost the financial war  still acting like they ruled the world, that George Washington had never won, and that they could still lay down the rules on how everyone was to speak and assay penicillin.

Read Milton Wainwright , particularly on Fleming - he says a lot of interesting things and raises a lot of interesting points...

Why HEATLEY rather than Fletcher,Chain or Jennings ?

The attempt to make Oxford penicillin the "Received Pronunciation" of world penicillin....

OXFORD :"First we take Manhattan, then we take Berlin, Paris and Cape Town..."
                                        ************

Fletcher could have accompanied Florey to America to remind Americans that Britons had also ,me-too, used penicillin to treat patients... after Dawson did it first in America.

Chain could be there, to say penicillin was his idea and that Florey only got interested after it got promising - and to admit, yes, his own chemical work was not yet as advanced as Meyer and the Schering Corp was in America.

Jennings could have gone along to say that Britain did the first animal protection test (which Fleming didn't do) but that, yes, Dawson did the first human protection test, in America.

But Heatley-the-invisible, he'd never steal any glory from Florey.

And he was the assay man - the man who would act like the schoolmaster he looked like - checking every American firms' penicillin sample to measure it against the Oxford Standard, and docking marks for any firm that failed to measure up.

For just as nobody anywhere else spoke as good an English as OXFORD ENGLISH , so too nobody's penicillin would ever quite measure up to to the Oxford Standard, the Received Pronunciation  of penicillin, the only penicillin you could prescribe on the BBC or give to the King.

Two points: (1) the supposed standard, OXFORD PENICILLIN, was actually composed of 98% rubbish - and don't get me started about Oxford in general.

(2) There were in fact many many strains of penicillium producing many many different types of penicillin, depending on what they had to eat and how acidic their surroundings were etc. This is Reality at ground zero. But Florey spent the next 4 years denying and downplaying any existence of differences in types of penicillin.

His only chance at grasping the golden ring was to constantly maintain his claim that he was the first to purify penicillin - he couldn't have this claim disputed by people asking which of the twenty variants of penicillin did he ,ahem, first 'purify' exactly ?!

I don't know if Florey played chess - but he had the chess player's skill of always thinking six moves ahead of anyone he thought might possibly be his opponent as he clawed his way to the top of English Society.

And when he was a Baron and president of the Royal Society, you'd never guess he had been born in the Outback - his English was now far more RP than his penicillin ever became....

Thanks to DOCTOR MOM, "he (and she) will be coming home!"

Most wartime GIs who drank too much Schenley whiskey and ran their jeeps off the road and woke up in the hospital with a penicillin drip in their arm, never realized that not only did Schenley sell them the bite of a snake but they also sold them the cure.

That wartime penicillin might have come from Schenley Labs.

Their whiskey is still here  - but their penicillin is long gone.

But Schenley did have the satisfaction for having produced the most iconic image of the entire saga of early penicillin.

Printed in rich vivid glossy magazine color, this ad featured the realistic style painting of a medic putting penicillin in the arm of a wounded Marine in a place that looks to be Tawara, as photographed by Marine photographer Norman Hatch.

 Seventy years later, Hatch's photos remain the gold standard of 'you are there' combat photography.

This famous island battle first brought home to America just how bloody this war was going to be - particularly because of the casualty count.

 But mostly because Hatch's grim photographs were deliberately released, rather than censored, to toughen up Americans at home to the mounting death toll that lay ahead.

So the ad's painting immediately conjured up a grim backdrop to any magazine readers in 1943-1945.

But the cutline below was pure uplift : "Thanks to PENICILLIN...
he will come home !"

Often rendered in the retelling as "Thanks to Penicillin, he will be coming home !"

The combination of image and cutline basically assures home viewers worried about their relative overseas that "Despite the vicious fighting and the terrible jungle conditions, thanks to penicillin, he WILL be coming home !"

This ad went totally unremarked upon during the war.

 But in the 65 years since, it has grown by leaps and bounds in importance as almost every scholar today finds it to be the best single wartime expression of the sheer hope that grew in a world (bone tired of 15 years of Depression and War) that something good must lie ahead.

Usually, their subtext when recalling this ad is "Thanks to Big Science bringing us Penicillin, he will be coming home !"

I don't think this is true at all.

I believe that if left to their own devices (along with scads of our tax dollars) it would have been 1946 or later before enough penicillin would had been produced to help the soldier at the front , let alone the patient back home.

I think there were two competing strategies to speed up the production of wartime penicillin.

One was develop scientific evidence on a very wide and deep front ("Big Science") to convince scientists in universities, hospitals, corporate research labs and in bureaucratic offices that a small shift in international wartime priorities was justified to produce large amounts of penicillin as a supplement to the sulfa drugs for illnesses resistant to sulfa like those caused by staph bacteria.

But that only enough penicillin needed to be produced to aid the fighting men, at least until the war was finally won.

I hope you sense the contrast between a massive effort of "means" to secure a limited "end".

This was Howard Florey and his supporters' thesis.

The other strategy was proposed by just one man - a soon-to-be dying man - in  September 1940 and maintained by him until his death in April 1945.

Martin Henry Dawson.

He said penicillin had already been privately discovered, in 1928 by Fleming, but no one had been roused and no lives had been saved.

Penicillin had also been publicly discovered,( ie published in the scientific media) in 1929 by Fleming and again in 1940 by Florey but no one had really been roused and no lives had been saved.

Dawson proposed instead to have penicillin popularly discovered - by Doctor Mom.

It was a Man's World back in 1940 .

(It mostly still is, but not as bad as back then !)

But even in 1940 women voted, bought much of the family's purchases and they were the daughters, mothers, sisters and spouses of the prominent men who ultimately ran things.

If they got on the case of the men to bring them penicillin and they stayed on the case (as women are very good at doing - some dare call it 'persistent nagging') , even reluctant men will eventually give in and get moving.

So Dawson persuaded Meyer and Hobby and Chaffee, his entire team of 'little science', to refocus their primary aim of their newborn penicillin pilot project.

He said they should immediately and narrowly focus on curing  a single disease, Rheumatic Fever-induced Subacute Bacterial Endocarditis.

This disease was the one that all parents in the western world regarded as a constant Sword of Damocles over their heads ,at least until all their children had gotten safely into their early twenties.

Tuberculous might be the disease feared more by the poorest families and Diphtheria and Scarlet Fever  might have been feared more in grandma's day, but from about 1910 to 1960, Rheumatic Fever (RF) was the number one killer of school age kids .

In addition, the invariably fatal subacute bacterial endocarditis (SBE) it brought to many Rheumatic Fever 'survivors' was a big killer of youth and adults all along life's journey.

But the main point of the myth of The Sword of Damocles was not the pain of the instant the sword actually did fall and kill you but rather that the situation made you afraid all of your life, just waiting for the day the sword might fall.

Most parents never experienced their children getting RF or SBE but all dreaded it might happen someday.

RF starts with a child getting a sore throat or tonsillitis from strep bacteria.

Think about it - what child doesn't get tons of those, even today with antibiotics?

Before antibiotics, the kids might cure themselves.

But one attack did not bring immunity.Your children got them again and again  - like the common cold they were common, endemic ,ubiquitous.

Always the fear was that this strep throat attack will lead to something worse. Many kinds of worse, but the deadliest and the most common was Rheumatic Fever (RF).

Most times, nothing happened. But like Russian Roulette, for no good reason one strep throat attack or tonsillitis attack could lead to RF.

Now RF could kill your child outright, during the very first attack.

But in most cases, the child lived, even emerged unharmed.

But again it did not bring immunity.

Far from it, one incident of RF made a child more vulnerable to another and more severe attack of RF and so on and so on, ever downhill.

Now suppose the child survived all those severe repeater attacks but with a damaged heart - particularly damaged heart valves.

Now in their teens, the child was less likely to see RF ever again, but instead they faced the fact that ordinarily harmless tooth bacteria, swept into their blood stream by a single vigorous tooth brushing, could settle in on their damaged heart valves and lead to an 'invariably fatal' case of SBE.

They might , nevertheless, fight off a single bout of SBE - as perhaps as many as 10 to 20% did.

(The near 100% death rate for SBE as normally reported, was biased by only counting cases sick enough to end up in hospitals. But autopsy work often revealed hints of healed SBE scars on the valves of young traffic accident victims.)

But again, and I know I am a broken record, one cure of SBE did not prevent those tooth bacteria from settling in again on your valves - and the second bout was fatal.

RF induced SBE was a chronic ,invariably fatal, disease.

Dawson treated patients as young as 10 and as old as 60. After penicillin, patients were found to dying of RF mediated SBE into their seventies - deaths often disguised as a 'stroke' .

More bad news : the kind of strep throat bacteria that gives you RF grow more virulent by being passed back and forth repeatedly between humans in close contact.

If you had lots of children,  that meant that your chances that several would get RF and SBE was higher than the statistical average, even when corrected for the number of children you had.

That is if you had six kids and a small house, their chances that one
of them would get RF should be six times 3.3 per 100,000 ( ie 1 in 5,000) but in fact it was much higher than this - more like 1 in a 1,000.

Small houses and big families being more common among poorer families, they got hit the hardest, resulting in it being called The Polio of the Poor.

But no family was really immune.

Dawson knew that a report of a cure for either RF or SBE would grab the attention of every single DOCTOR MOM in the world.

And Doctor Mom, not Dad (in charge of the bread winning), was the person in charge of the entire family's health -- if she wanted penicillin , now, she would get it - or governments (even wartime governments) would tremble.

Drug companies would rush in to take her money.

This was Dawson's thesis.

He had a small crew - four people, no government or foundation funding, with curing a single disease as its sole thrust. But against those small 'means', look at its broad 'ends'.

Doctor Mom, said Dawson, would see to it that her entire family all got lots of penicillin, now, not after the war - penicillin enough for  both Frank on the battlefield on Tarawa and for little Susie in the Rhemuatic Fever ward in America.

Was he right - or did Florey's view prevail?

I will 'tell all' - on October 16th this year - in my e-book "MO goes PO".....

1941 penicillin:Porton Down GERM WARFARE yes, patients no

The Florey Archives at London's Royal Society has a Florey letter (HF/1/3/2/1/19 )(previously 98HF.35.1.19)  that didn't get shredded but probably was intended to be.

Dated December 4th 1941, it is addressed to Doctor "Cameron" at "Porton" and mentions scientists "Courtice" and "Gaddum".

Florey says ICI penicillin is at Porton and he is glad that Gaddum wants lots and lots of penicillin.

In December 1941, no one had much penicillin - certainly no patients in UK got any - and only Dawson's patients in the USA.

This must be some of the very first ICI penicillin ever produced - not for patients - but for 'Porton' .

One of Florey's very closest of his (very few) friends was Paul Fildes, very near the top of Britain's WWII Germ Warfare effort, which was centred at Porton Down.

That place has been for a century Britain's leading gas and germ warfare centre - in fact one of the top centres in the world for this highly secret activity.

Florey's first biographer, Bickel, indicated that in 1939, Florey had been asked by the War Office if he would be a consultant in 'poison gas research' (probably because of his proven skill in doing lethal experiments on small animals and his middle-aged chickenhawk attitude to the upcoming war.)

Florey had agreed.

I have always wonder if Florey's mystery month , mid July-mid August 1941, was somehow connected with him having informal talks on germ and gas warfare with various American researchers.

Certainly, Florey go top clearance for his trip to America from US and British officials - penicillin ,alone, seemed too unproven to warrant this kind of assistance.

Now Penicillin and Porton is like Jeckyll and Hyde to British audiences - no wonder this letter has never been mentioned in all the hagiography on penicillin and Florey.....

 GR - Gordon Roy- Cameron *
FC -Frederick Colin- Courtice *
JH -John Henry- Gaddum

* Part of Florey's power was his cultivation of a network among the sizable Aussie contingent working in the UK - these two are but a tiny part of this group. Florey also cultivated ex pat britons who had taught in Australia.

Fleming versus Dawson on Endocarditis

Hardly dueling Scots, though.

Fleming's  Cheadle Prize winning medical essay "DIAGNOSIS OF ACUTE BACTERIAL INFECTIONS" (the only time I know of that he seriously engaged the subject of endocarditis) was written in 1909 and published in the ST MARYS HOSPITAL GAZETTE (volume15 , pages 67-69,72-77).

Most biographers of Fleming felt this early essay nevertheless set out the course of his life's work - which extended for another 45 years - so it is well worth a close reading.

Dawson confounded the essay's conclusions on intravenous injections to treat endocarditis in March 1942, with his first success in reducing bacterial colonies in endocarditis patient's blood.

Critics of vaccines said endocarditis's constant shedding of small amounts of bacteria directly into the bloodstream should lead to a natural immunity against them but instead actually only led to death.

Fleming dosed himself with a staphylococcic vaccine via an intravenous injection directly into the bloodstream.

 (Staph was then a far less virulent bacteria than it is today.)

He lived, having only a slight headache and fever, but gained no increased resistance to staph.

Intravenous injections of vaccines gave maximum infectious effects and minimal increases in natural antibodies said Fleming.

Despite the fact that all of Fleming's considerable wealth came from his great skill in injecting the very dangerous drug Salvarsan directly into veins, he seemed dubious on 'systemic' or intravenous medications in general.

I think this is partially why he never tested penicillin as a systemic medicine in humans - or animals.

Not till 1940 did Dawson do so for humans and Florey for animals...

Dawson, Florey and the multiple suppliers

Dawson first turned down Pfizer and then a month later accepted their offer of penicillin extracts, at the same time his co-worker Meyer was working with a potential competitor of Pfizer called Schering and Co, while at same time  Dawson, Meyer, Hobby and Chaffee were producing their very own penicillin !

This was not unique.

Florey produced his own penicillin and was willing to ask for penicillin from any commercial firm and got commercial supllies from at least Merck, ICI and Kimball and Bishops, the latter two on a regular basis.

Why ?

And how were conflict of interests avoided?

I believe none of the commercial firms had a problem if a doctor wished to stick their penicillin (and that of all their competitors,) into patients.

 Even if the doctor(s) first concentrated the commercial liquid
extracts up to a minimal level necessary for therapy - say to a dried state of 30-50 units per mg.

None of this would affect the commercial interests of the firms.

But it would be unfair if a doctor used commercial extracts to improve extraction processes or to do chemical synthesis work on the firms' offerings.

The firms were spending lots of money on these sorts of activities and hoped to eventually profit from it.

They won't want the doctor get to the patent office first or pass on the information on to their favorite commercial firm.

So Dawson, who cared not for the chemical synthesis of penicillin, could treat patients with Pfizer penicillin, while Meyer the chemist used his own penicillin or that of Schering to do chemical studies.

Everybody happy.

Florey did likewise - using mostly ICI penicillin on his famous second series of treatments of patients but not using any of it for chemical studies, while his own team's penicillin mostly went to the team chemists to be destroyed in chemical studies.

It hardly jibs with the heroic image of either group now does it?

I can only say that very quickly, Meyer dropped synthesis studies and shifted to chemically altering penicillin into an ester so it worked better (ie worked slooooower) inside patients.

Morally, it is hard to fault this sort of chemical work.

Oxford claimed (ala LADs' PEN) that it produced 500 litres of penicillin a week between the Fall of 1940 till May 1944.

That is 400 million units of useful, injectable penicillin, in Duhig Units.

J V (James Vincent)  DUHIG

I feel sure than Duhig's first reaction would be the same as mine: "Bull feathers".

I bet a check of the published records will show that only 4 million units of Oxford-created penicillin ended up being used for patients in that period.

(To keep things in perspective, in 2010, 4 million units - 4 MegaUnits - is what you might receive as a daily dose, for an average serious infection. But in 1942, it should be enough to treat 40 patients with life-threatening illnesses.)

Gladys Hobby, quoting a ICI report on Oxford's efforts, says in 1941 they were producing 2 grams a week at 16-32 units a mg, ie 15,000 to 30,000 units a week or a maximum of 1 to 2 million units a penicillin a year at the outside best.

I have seen an estimated figure of 13 million units produced in total between 1938 till 1944, coming - it seems - from Norman Heatley, and that seems to match this report fairly well.

Trevor I Williams, in probably the best single book on the Oxford team ,"HOWARD FLOREY", says that even in 1942, half of the final Oxford penicillin went to the chemists.

I believe all, or almost all, went to the chemists from 1943 onwards.

Doctor Mom has a right to be skeptical about the Lads....

MARJORIE DAWSON , 

still in widow's weeds in 1946, at a film industry meeting

Mom's penicillin versus Lads' penicillin

That's 'DOCTOR MOM' by the way, and 'LADS' as in British Lad's magazines (a weak rendering in North American terms might be "its a guy thing" - a stronger rendering would be that Connie Kaldor song about "Jerks" .)

I have tried out various names for what I am now calling Doctor Mom's penicillin: pragmatic penicillin, patients' penicillin --- all share a common drive - to save lives , now.

Lads' penicillin can also be usefully be called prestige penicillin, purified penicillin, priority penicillin, scientific paper penicillin, scientific penicillin ,scientists' penicillin.

The goal here is "who can get 100% pure, stable, colorless penicillin crystals first - dam the poor yield and dam the poor patients, forget that there is a War on."

(And by the way I almost never call it "penicillin" when I am thinking about it or even when I talk about it - I call it simply
"PEN" rather as the British chemists called their reports, the PEN reports, and just as the paper tags on patients undergoing penicillin treatment during the war were also labelled PEN.)

(Yellowcake uranium (easily mistaken for early dried penicillin powder or dried mustard) together with the wartime 'products' derived from it, were also given prominent labels with black letters and symbols on a bright mustard yellow background.)

Mom's pen is expressed in a ratio of units of penicillin actually ready for use in human patients over a period of time.

As in :"Pfizer released 500 mg of dry penicillin, (the famous Lot #696) assaying at 50 units a mg, for Dawson to use on his patients in March 2nd 1942 - a total of 25,000 units of therapeutic penicillin."

Or : "Starting in October 1941,Pfizer released to Dawson a 5 gallon carboy of non-concentrated penicillin juice every week, the juice assayed at an average of 2 units a ml, so if injected immediately into a patient in the form of a drip IV, that was 160,000 units of therapeutic penicillin a month ." 

Lads' penicillin can be found described - ad nausem - throughout almost any account about penicillin.

Its boastful vagueness stands in for the most basic of basic arithmetic.

Here is one example, picked at random from the recent book on early penicillin:

We are told that the Royal Navy set up a 'small' production unit in 1942. Even if you follow the penicillin saga closely, this might be the first time you have read of this effort - it must have been small potatoes.

Apparently not so, for in the very next sentence we are told their weekly production was 200 million units.

To put this in context, Pfizer - the world's largest drug firm and a company you have heard of , said it produced 400,000 units of penicillin in March 1942.

(If you have a good memory, you will recall that not all of this ended up in patients' veins - Dawson seems to have only got 25,000 units and he was Pfizer's only clinician at this point.

 Most of this semi-purified dry penicillin was probably destroyed by Pfizer chemists trying to degrade it enough to guess at the building blocks of its assembly by the penicillium.)

In early 1943, it took two months for the entire American pharameutical industry to produce as much penicillin as the Royal Navy's little operation at Clevedon produced in a week.

Count me more skeptical of this story than Robert Bud is.

Another example, from Macfarlane's biography of Howard Florey.

It is the claim that production at Oxford had been 500 litres a week for a few months by January 1941.

Meyer to Durack: I started penicillin to get back at Chain

In 1981 Harcourt Brace Jovanovich published "Treatment of Infective Endocarditis" ,edited by Alan L Bisno.

You can read it on the stacks at your closest medical school library.

I suppose the most cited article is the first, a "Review of  Early Experiences in Treatment of Bacterial Endocarditis, 1940-1955", by David T Durack, M.B., D Phil.

 I first read it very early in 2005.

Durack is from Australia, came to Oxford as a Rhodes Scholar, and was soon regarded as one of the best young doctors around anywhere.

He did a very through review of his chosen subject, reading through the early articles closely.

 Quickly he saw something in Dawson's and Hunter's first article on SBE patients treated by penicillin that others writing about penicillin or endocarditis hadn't fully sensed .

The disease of endocarditis was in fact the very first disease to ever be treated by an antibiotic, in the modern sense of that word.

(And even perhaps cured by an antibiotic, if you want to go out on a limb - others have - but I hesitate.)

(In any case, an event that happened on October 16th 1940 - an anniversary seventy years old this year - hence my urgency in trying to finish this book as soon as I can.)

An antibiotic in the modern or common sense meaning of that word is a medication produced by microbes that is taken internally and that can save lives.

(By contrast, antiseptics are often man-made chemicals and are applied externally and are intended as a band-aid solutions for minor cuts and bruises.)

To doctors, this means an antibiotic is a systemic medication and in the case of the original penicillin (aka Penicillin G), one administrated by needle - ie parenterally.

All this fully met by Dawson's first needle of penicillin stuck into a dying patient seventy years ago next month.

Durack managed to personally contact the three key surviving members of Dawson's team and I feel he must have asked some very probing questions.

Hunter and Hobby added interesting tidbits to the historical record, but Karl Meyer dropped the biggest bombshell.

Well it was a bombshell to me anyway, because I have this thing  (call me a stickler) for exact dates and figures.

Hobby and Hunter weren't at Columbia in early September 1940 when the decision to begin the penicillin project was taken and Dawson never publicly spoke how it came about.

Karl Meyer had never publicly spoke out about his motives either---- until 1981, when he was 83.

 I rather doubt he ever told Dawson,Chaffee or Hobby about his motives back in 1940-1945.

His personal motives hardly seemed to mount a high moral plane that might bring others in help out.

Meyer had recently been incensed, says Durack, by an article from Ernst Chain on lysozyme that slighted Meyer's earlier work (in 1933-1936) on lysozyme.

Durack quotes Meyers as saying that when he read, in August 1940, the first Oxford article in LANCET on penicillin, he determined to quickly purify penicillin, before Chain could, to pay him back.

Durack then moves on to the matters more pertinent to the actual subject of his review.

I, on the other hand, had a much greater interest in this particular matter and as a result I had available a greater variety of other information to try and make sense of this 'claim' of Meyer.

First, I doubted that Meyer in New York could have read a copy of Lancet with a cover date of August 24th, much earlier than about September 7th in peacetime, let alone when Britain was at war.

Secondly, in an 1990s oral interview with Meyer's boss in 1940, (Phillips Thygeson), Dr. Thygeson describes Meyer as a rather typical type of chemist who is (rightfully) worried that others will steal their data.

In old fashioned mystery books circa 1880 to 1940s, the 'formula' stolen from the safe was always chemical--- not math or physics or biology.

Only in chemistry is something extremely valuable to the world outside Science reducible to a page or two of formulas and symbols.

The most famous modern chemist of them all, Robert Burns Woodward, liked to make public his total synthesis of yet another impossible-to-synthesis natural material in a brief announcement of not more than a page or two.

It was as a sort of 'guy thing' type bravado, common in male chemists involved in scientific pissing contests --- but it does mean than valuable chemical results are easily stealable.

I knew Meyer and Chain had known each other since their student days in Berlin and that both were young German Jewish emigres
 very insecure about their ability to avoid a wartime internment camp --- very eager to garner citation credits, if only for the sakes of their families.

And by mischance, both were interested in the same very ,very, very narrow area of science and so bound to trip over each others' feet.

A rivalry seemed a distinct possibility.

Only one problem ---a very very big one --- Chain only published one article on lysozyme, and it didn't even get submitted to the British editors till October 28th 1940, let alone get published and find it way to America.

The Columbia penicillin effort was begun about September 9th 1940, months before this ----so could Meyer read into the future?!

I had to put Meyer's 'claim' on the mental back burner.

Then in early 2010, I read Ronald Bentley's "Leslie A (Epstein) Falk, 1915-2004, and Penicillin production at Oxford", published in the JOURNAL OF MEDICAL BIOGRAPHY, Volume 15, May 2007.

Bentley mentions that in Chain's sole article on lysozyme (of which Epstein, not Chain, is the lead author), Epstein (LE) thanks "Dr K Meyer" for lab space and assistance.

So sometime between June 10th 1940 (Epstein's return to New York) and early October 1940, Epstein was in Meyer's lab and presumably mentioned (a) how Epstein planned to dis-credit Meyer's early work and (b) that Chain was now working on penicillin and that work was very,very fruitful and would soon be published.

Alerted and incensed about (a), Meyer was also alerted about (b) so as to watch all ports for an article---- and to start attracting Dawson and Hobby to see the virtues of penicillin as a research subject.

Meyer, Chaffee and Hobby would probably have remained content to just grow enough penicillin to try and purify it.

But Dawson saw its capabilities as a possible ABF agent (anti bio-filmic agent) and the rest...... is history.

Seven flasks became seven hundred flasks, etc....

Fleming proved penicillin "non toxic to animals, even in large doses", says Florey and Chain

Soldiers with guns. In our cities. We're not making this up.

Florey and Chain really did say that about Fleming, in their famous  penicillin grant application to the British Medical Research Council in September 1939.

It hardly squares with their claim for a place in the eternal scientific sun for finally doing the animal tests that Fleming didn't do.

 But it does explain why they didn't do any animal testing with  penicillin between Spring 1938 to Spring 1940 - and only then over Florey's loudly protesting dead body.

Why bother?

"Fleming's already done that."

But if the tests had been done in Spring '38, we might have had plenty of commercial penicillin by September 1939.... saving many,many lives...

Chain irks boss - puts snakes before lysozyme

When Ernst Chain was hired as the Dunn Pathology School's biochemist in the Spring of 1935, his new boss, Howard Florey only asked one specific thing of Chain.

Florey wanted him to determine the chemical action of Lysozyme, an enzyme that Florey thought might be the cause of ulcers (particularly his own ulcer!)

But Chain first turned to his own work on the chemical action of the enzyme that made some snake venoms so extraordinarily  and so quickly lethal in truly tiny amounts.

But now, in early 1936, he was made aware that someone he knew of very well indeed, a fellow German Jewish biochemist emigre he had met earlier in Berlin, Karl Meyer, had been and done up  Lysozyme already.

The papers had been submitted in late 1935 and a little research revealed that Meyer had already published on Lysozyme in the prestigious journal SCIENCE , based on work from 1933.


So Chain had to scramble - and from this date, he regarded Meyer as his biggest rival in studying lytic (dissolving) enzymes.


 What had happened was that both men, unaware of each other's interest, had settled on this same narrow area of science to base their life's work upon !


And since both men, plus plenty of others, mistakenly regarded penicillin as a lytic enzyme, a showdown was sure to come one day.


For both men, this 'guy thing' dueling over citation credit in a obscure backwater of science got badly away from them when it turned out penicillin had more than academic importance.


In the case of Meyer, he gave up the control of his penicillin project to his colleague Martin Henry Dawson.


He did so, when it became clear that powerful elements of the American and British governments were determined to see that Meyer was to play no role in the chemistry of penicillin.


 They indicated this by engaging in repeated acts of censorship of his publications and by firing his colleagues from the Schering Corporation of America.


Chain also lost his penicillin project to his boss Florey, when the animal studies of the substance suddenly got interesting.


(Florey was well known for letting you do all the heavy lifting on a project that you and him were supposedly jointly involved in, only to have him steal it from under you if something promising turned up.


 He got away with it, technically, because he was the senior investigator - but it hardly made him popular. 


And it explains why the lazy but likable Fleming got most of the credit for the Oxford team's work.)


But Florey had no interest in the clinical side of penicillin and quickly became just the administrator of the overall Oxford penicillin project, away from England almost more than he was home.


Now Chain could regain some control, by throwing himself into the 
work to purify and then totally synthesize penicillin - something Chain and the Oxford team did in February 1944.


But it turned out the yield was terrible and the process long , difficult and very expensive.


Meanwhile, Dawson had gotten his chosen corporate partner, Pfizer, morally committed to producing as much penicillin as possible as soon as possible.


That meant NATURAL (microbe-made) penicillin - the way we still produce all the various penicillins and beta lactam antibiotics.


In the end, Nature batted last and it batted long.


The supposedly simple, unchanging, (etc) creatures in the Domain of microbes vanquished the efforts of all the best PhDs in the human Domain of Chemistry.


Chain never returned to Lysozyme  - penicillin , even his failed 
synthetic efforts, still gave him a knighthood and a Nobel prize.


Why bother?


Meyer got no personal gain out of his four years of penicillin efforts - just personal heartaches.


But he had the quiet satisfaction that his personal efforts to save a few lives had moved Pfizer, the company that finally gave us the mass penicillin that saved millions of lives.


In 1946, the war over, Meyer turned back to Lysozyme, with his wartime research assistant on penicillin, Eleanor Chaffee ( now Hahnel) helping him.


Meyer kept up his work on Lysozyme and other lytic enzymes long past his formal retirement.


By then Chain, noticeably mellowing in his later years, had died.


Meyer , too, finally revealed his secret, the one he never told Chaffee, Dawson or Gladys Hobby.


He had originally embarked on penicillin merely to get back at Chain for failing to adequately credit him on his own Lysozyme work from way back in 1936.


This is truly Operatic Science - the way that Science all too often really works, if scientists would only admit it .....

how I got into this 'penicillin thing'

People are frequently curious how I got involved in this penicillin book.

 They ask "do you have a medical or science degree or something?"

I don't - particularly the 'something' .

All I can say is that all my life I have been badly bitten by the curiosity bug.

I have always been intensely curious - about anything and everything.

Like a dog with a bone.

Here , for example, is a picture taken on Vancouver's English Bay Beach in the Fall of 1960.

My parents treasure it :

I have just turned nine and while all other kids are running around playing in the sand, there I am sitting and reading a newspaper that some adult had thoughtfully/thoughtlessly left behind.

I don't know whether this curiosity is a gift from God or a curse from God, but there it is....

Michael Marshall, penicillin researcher, age nine, relaxing on  beach...

The Duel begins: October 1940

By October 1940, Ernst Chain knew he was in the race of his lifetime over penicillin - and while he had a MD colleague who plodded, his rival's MD colleague obviously moved like greased lightning.

By that October, Chain had a copy of Leslie Epstein's finished paper on the Lysozyme work that Epstein had done with Chain at Oxford.

The paper thanked Karl Meyer at Columbia University for the help and the lab space that Epstein had received from him.

Meyer had done similar research on Lysozyme (an enzyme that dissolves certain bacteria) - but 4 years earlier - so attribution of priority was going to be a touchy issue for all three individuals.

In fact, incensed by Epstein informing him that Chain did not plan to properly credit Meyer's earlier work, Karl Meyer was determined to extract revenge by purifying penicillin before his rival did !

Chain and Meyer, both Germans and Jews and both biochemists interested in enzymes that dissolve substrates, had known each other back in Berlin biochemical circles in the mid 1920s.

They had become serious rivals in the mid-1930s , both publishing on lysozyme and on the 'spreading factor' that dissolved hydraluronic acid, (including the hydraluronic acid found as part of some bacteria).

Each new published article became like another dueling scar on the cheeks of rival german students.

Now penicillin also looked to be another enzyme that dissolved bacteria - a new point of rivalry.

Both unlike the earlier two, it seemed to have the potential to cure life-threatening diseases - and bring world fame to the biochemist connected to the first team that did so.

Now Meyer's MD colleague,Martin Henry Dawson, had written Chain, asking for some penicillin spores (enclosing a $5 international money order) and informing Chain he planned to use it on SBE,endocarditis, the Mount Everest of infectious disease.

Serious stuff --- clearly Meyer's team had been fully informed about Chain's two and half years of work on penicillin by Leslie Epstein.

Meanwhile Chain's MD colleague, Howard Florey, hadn't yet even started scaling up to the pilot plant size of production needed to treat human patients.

Chain did send some penicillin spores - eventually - spores that never produced penicillin.

Perhaps an accident - perhaps deliberate.

Too late - Dawson mailed him a letter on October 28th 1940 : Dawson had already gotten Fleming's spores from an American researcher , grown it, tested it and injected concentrated penicillin into two SBE patients on October 16th 1940.

Beaten to the punch.

All Chain could hope to do was to avoid being blamed for Epstein telling Meyer about the secret penicillin project, by not telling anyone about the Dawson letters

 That and then try to light a fire under Florey to 'do the clinical' as soon as possible.

Unfortunately, Chain had come to realize that Florey never did anything quickly......

Florey's "Unfinished": the unfaithful Vassal #2

In 2002, Milton Wainwright published "Fleming's Unfinished" .

Fleming was not some obscure Scottish composer and the "Unfinished" was not a musical work cobbled together from unpublished musical sketches after the composer's death and based on a close study of his mature style.

In fact a famous composer is rather undone if no one cares enough about them to find something that can be hacked into shape, published and performed to acclaim.

Now Fleming ,that is Sir Alexander Fleming, as one of the most famous names of all, is hardly thought of as someone badly done by in the "fame" department .

But among scientists, he is damned by faint praise - faulted for dropping penicillin almost as soon as he picked it up - leaving millions to die needlessly.

Milton Wainwright (and Ronald Hare, Gynn Macfarlane and Kevin Brown) have all pointed to Fleming's extensive notes on penicillin from the Fall of 1928 to the Fall of 1940 as proof he didn't quickly give up totally on penicillin as an antiseptic agent.

Wainwright goes much further and claims that Fleming had hopes for penicillin as an antibiotic in the common sense - something taken internally to cure life-threatening diseases.

I, and almost every one else, disagrees that Fleming did see it that way... until August 1942 - making him penicillin's biggest Doubting Thomas.

Anyway, Wainwright implies that Fleming was just about to wrap up his 12 years of research on penicillin, when the Florey team's first article rendered it all moot. So Wainwright was going to try to finish it for him anyway.

 My belief is that Fleming had good cause to doubt penicillin's efficacy as a systemic, based on his lab work.

Fleming ,and the institute that he worked at, was never inclined 'to do the clinical' anymore than his nemesis, Howard Florey, was.

Both men avoided the wards, "preferring the deep,deep sleep of the laboratory bench to the hurly-burly of the hospital bed".

(And don't think that I haven't waited my whole life for a chance to misuse that quote in my writing...)

 Florey's father and his business was betrayed ,the Florey family claims, by an unfaithful servant - an accountant.

Certainly, Florey was notorious for acting like he trusted none of the scientists directly under his employ, while giving an unusually free hand to any researcher merely 'renting space' at his Institute.

Once bitten, twice shy, I guess.

Unfaithful Vassal #1, Ernst Chain, actually saved Florey's plodding bacon, when Chain broke ranks and broke protocol on the wide front/ slow moving penicillin project in March 1940.

This is because Unfaithful vassal #2, Leslie Epstein, didn't keep silent about the penicillin project when he returned to New York on June 10th 1940.

He talked it up to Dawson's teammate Karl Meyer that summer, along with the more unpleasant news that Chain meant to dish Meyer of some credit for the chemical meaning of Lysozyme.

 (This, the first big discovery of Fleming tied together Fleming and Florey and Chain and Epstein and Meyer and Dawson and Hobby.

 All, for different reasons, were keenly interested in its bacteria-dissolving nature and in anything (like penicillin) that looked to be similar.)

Now Chain and Meyer were both Jewish, German and unknown scientifically.

These two young bio-chemists knew they would soon end up in alien internment camps (as thousands like them eventually did) if they couldn't soon establish scientific reputations.

Every bit of citation credit helped - well worth fighting dirty over.

Meyer resolved to get revenge by beating Chain to the punch on the purification of penicillin - Chain's private baby.

He didn't start right away, but he planned to - even if Florey's team hadn't of published in August 1940.

Meyer had to wait till his team re-assembled in September 1940 after family vacations - he absolutely needed the services of a microbiologist and a clinician if he hoped to purify penicillin.

My version of Florey's "Unfinished" looks at what would have happened if Unfaithful Vassal #1, that is Chain, hadn't broke protocol on March 18th 1940 and had some of his penicillin powder stuck into two mice by the obliging Doctor John Barnes.

Florey hated doing anything twice - freely admitted hated doing routine clinical work.

(When you and I are dying of perfectly regular lobar pneumonia caused by perfectly regular Type II s. pneumococcus, that is "routine clinical work" to Florey - though possibly not to you and I !!!)

He always wanted to be the person to do something the first time - whether or not it had any meaning outside of that feat - the athlete of science.

I take some of that back - many things he disdained doing ever - first or otherwise.

He probably never ever gave a human a needle of penicillin - he had no privileges to do so but he didn't seek them either.

He was first and last a good animal experimenter.

Putting penicillin into mice was his job, not Chain's.

And Chain had agreed to it.

But to Chain , more than to Florey, penicillin was his project - a project to purify penicillin chemically.

The proof of any success he might think he had in purifying penicillin was dependent on demonstrating the material had biological activity.

For that, as Florey (and Fleming et al) could point out, testing it against bacteria in a petri dish was all that was needed - and Chain could do that, without having to gain a hard-to-get animal testing license.

The plan, the protocol, that Fleming and Chain had sold to the MRC and to the Rockefeller Foundation called for a methodical, through, step-by-step study of penicillin.

No rush - the Rockefeller grant was intended - unofficially - to run for years and the first payment wasn't even due till March 1st 1940.



So Florey might have felt that any animal testing was way too premature and could be held off till the Fall of 1940, when he might be less busy with his current, more important, research on shock and when Chain might be further along on the chemical side.

So animal protection tests on November 25th 1940, and publication in Lancet three months later, as planned - ie in late February 1941.

Too late to learn that Dawson has already announced his results at a public lecture at the NEW SCHOOL FOR SOCIAL RESEARCH on February 12th 1941 !

The wartime story of penicillin would then look very different.

If Florey's father was ruined by an unfaithful Vassal, Howard Florey can only be thankful that he was saved by an unfaithful Vassal....

Brotzu 'does the clinical' that Florey and Fleming didn't

You know the mantra if you have ever read a taxpayer-funded article from an academic historian about post-war science.

It was 1945's Manhattan Project and the Synthesis of Penicillin that led to the birth of Big Science.

 (All bow down and worship.)

It now takes lashings of taxpayers' money and large teams of scientists to lead to big breakthroughs these days, particularly in drug research.

Hard then to explain the actions of Giuseppe Brotzu, full time mayor and part time medical scientist of Cagliari Sardinia during the hot summer days of July 1945.

Sardinia was not then and is not today a hotbed of scientific research - in a word, it was as Non-U as a place could be.

Not the sort of place to attract the big money and big teams of Big Science.

Nevertheless, world-shaking research starts with big ideas, not big money or big name scientists.

Brotzu's big idea begins when he wonders if the relative resistance that his citizens display to endemic typhoid fever is because of something in the harbour water - specifically something in the water near the raw sewer outflow into that harbour.

His big idea pays off and he discovers the first of the (ever-expanding) cephalosporin family of antibiotics - a trillion dollar industry - even bigger than the original penicillin .

Our mayor gets turned down by the big scientists in Rome - wrong party, wrong ideas.

So he grows some of his sewer fungi  by using boiled placentas- from the maternity ward - as his medium, this is wartime Italy after all.

He then injects some of the raw liquid given off by this fungus into patients and finds it brings relief to people with typhoid fever.

Ie Brotzu does in 1945 what Fleming in 1928 and Florey in 1938 failed to do - he tests his discovery promptly , first via animal protection tests and then on real human patients.

Still no interest, so he creates a fake medical journal and gets a copy to Britain.

Florey's team, to its credit, is interested.

This, appropriately enough for a story set in Southern Italy, is truly "Operatic" Science and is not at all "Dignified" Science.

But our mayor's obvious agape love of his citizens led him to do some heroic things and he ended up helping to save millions of lives in the years since.

I think Martin Henry Dawson would have admired him very much....

UK universities continue to shed chemists as MO continues to go PO

In 1940, CHEMISTRY was the "Queen of Science" in the UK, the central science tying Physics to Biology to Engineering to Geology and Metallurgy and on and on.

ICI was one of the biggest employers in the UK and judged the most crucial single industrial firm in the country - as Du Pont and IG Farben were for its competitors , the USA and Germany.

But by 2010, mid-level University Chemistry Departments are rapidly disappearing across Great Britain and more and more chemist professors are going public about their fears that declining undergraduate interest in Chemistry in Britain and around the world was permanent.

By contrast, anything with the word 'bio-" in it seems to be what kids want to make a career in - while Chemistry remains associated with plastics that break and pollution that poisons.


Explaining what went wrong with Chemistry, 1940 -2010, is partly why I am writing MO goes PO....

was I too harsh on Eric Lax ?

Some have worried that I was.

But I don't agree and I hope that even Eric Lax will see why I argued as I did.

Almost anyone reading Lax's book on penicillin, "The Mold in Dr Florey's Coat", is struck by the fact that the emotional climax of the book is well forward in the overall Penicillin Saga - occurring in May 1940.

 I would have set the emotional climax much later - in August/September 1943 or in May/August 1944.

Lax's book builds steadily up to the (supposedly) crucial animal protection tests that Lax and almost all other penicillin authors chide Fleming for failing to perform in the Fall of 1928.

A check of Lax's own indexing confirms the large number of pages (in a shortish book) that are devoted to animal testing and the mouse protection tests.

He is also that rarity among the many penicillin authors in deciding to quote at length from John Fulton's letter to the Nobel Committee ,in which Fulton says that Florey deserves the Nobel because of his animal experiments with penicillin.

Surely an, ahem, unique viewpoint.

But in a perverse sort of way it does show some truth - Fulton and Florey loved to experiment on the bodies of animals far more than they did anything else in life.

Lax sets up the animal protection tests of May 1940 as the moral high ground of the entire penicillin story.

He even highlights the story of the Florey team deciding to smear their coats with the most widely available 'rare' mold on Planet Earth (thanks to Fleming !), all to keep it from the Nazis.

I merely say that what is good for the goose is even better for the gander.

Yes, Fleming should have needled the mouse back in '28, but why didn't Florey do the bog simple mouse test in early 1938, when peacetime drug firms might have been able to produce commercial penicillin, even before Hitler overran Poland ?

The usual biographer's apology for Florey waiting from Spring 1938 till Spring 1940 to test penicillin against an artificial illness (and until Spring 1941 before testing against a real human illness) is that he needed purified dry penicillin before he could do an injection.

Fleming's rebuttal would be "that since I never obtained any dry purified penicillin - according to Florey" - "then I was under no moral obligation to do the mouse protection test".

"Or if I should have done so anyway with wet penicillin in 1928,then Florey should have done ditto in 1938."

Duhig from Brisbane could also chime in with that blunt Australian manner, with "Look, Florey, I saved large adults from terminal illnesses with injections of weak,wet, penicillin - surely you could cure a diseased mouse with some of your 1938 wet penicillin if you had only tried ..."

In support of Duhig, Heatley says that the first penicillin used by Chain in March 1940 ( in a sort of toxicity test) had between 2 to 5 units of anti-bacterial activity per mg and that
a 20 gram mouse got 40 mgs - that is about 4,000 to 10,000 units per kg of body weight.

For a 80 kg adult human male that is the equivalent of a single dose of 320,000 to 800,000 units of injected penicillin - even today that is 'heroic medicine'  -and as a single dose in a series for animal protection it is about one hundred times too big.

But is also the liquid penicillin you would obtain, even in 1928 or 1938, from a single medium sized lab flask  - not exactly hard work to gather up.

But it is 40 mls of liquid penicillin to inject into a mouse - far too much even if done as a slow drip.

However, injecting .5 or 1.0 ml of raw crude wet penicillin at a time into a twenty gram mouse, as part of a series of injections, would be perfectly safe.

It would give , in human adult male equivalent terms, a single dose of about 4,000 to 16,000 units - which is about what a wartime adult male penicillin patient did get in a single dose in a series of shots (usually receiving 4 to 8 such shots in a twenty four hour day).

The technical claims against using crude wet penicillin in animal protection tests fails to stand up - but fails for Florey as well as for Fleming.

In talking about (Duhig's) raw, totally non-concentrated penicillin as being suitable for animal protection tests, I am deliberately worsening the case against Fleming.

In fact, while in 1940 Florey had a dry brown powder with 2-5 units of activity per mg, in 1929, Fleming had a brown gooey toffee with 2-5 units of activity per mg - once re-wetted with distilled water to inject into a mouse, both were as equal as can be.

 Neither were pure.

But both had been concentrated successfully enough to be highly useful therapeutic penicillin - if only that pair had had the guts to 'do the clinical' .

That was something that Dawson did , and did in a ' New York minute' .

Harsh on Eric Lax ?

I don't think so...

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....

a Penicillin Dictionary: the CHEMIST

A CHEMIST is someone who if asked to separate the wheat from the chaff and upon discovering that the chaff can be crystallized and that the wheat can't be, promptly crystallizes the chaff and throws away the wheat....

May 1944: MOdernity goes POstmodern

May 1944 is almost comically overdetermined as the Mensis Mirabilis of the wartime penicillin story.

Coghill, that unsinkable bureaucrat, pretending to admire billions and billions of units of natural penicillin intended for D-Day at Pfizer, while Hobby and John l barely stiffle wide grins.

Dawson in a triumphant re-match with Charlie at Columbia.

Florey destroys his Rube Goldberg penicillin setup at Oxford and then flies off to inspect Antipode universities' postwar educational demands.

Duhig saving lives at Brisbane with totally unpurified and totally un-synthetic penicillin in Brisbane.

 Robert B Woodward displaying his total synthesis of Quinine with the OSRD dying to go public about a similar feat for penicillin.

 Fleming ,not Florey or Dawson/John L, getting the cover of Time.

On and on and on.....

May 1940: our two protagonists enter stage left

The Penicillin Story had been underway for almost twelve years when our two protagonists, Howard Florey and Henry Dawson, first seriously entered the story in May 1940, Mensis Horribilis, and changed the Story's direction completely.

It is true that Ernest Chain, Leslie Epstein, and Norman Heatley had been working with penicillin at the Dunn Pathology Institute at Oxford University for about two years by that point.

But only when it became intensely and personally important to the Dunn's director, Howard Florey, (when he injected the first therapeutic doses for some artificially infected mice),did it gain some real momentum for the side of the war time penicillin story that I will call "Chemistry".

Dawson's team (Karl Meyer specifically) didn't display any interest in penicillin still sometime between June 10th 1940 and September 7th 1940 when he first heard of it from Leslie Epstein, newly arrived from Oxford and the Dunn.

Dawson didn't become directly involved in penicillin until he first heard of Florey's published results from Meyer, sometime around September 9th 1940.

But he was emotionally ready for committing to penicillin as his ABF agent (Anti BioFilmic agent) since a series of New York area symposiums on Rheumatic Fever and Subacute Bacterial Endocarditis (SBE) in April and May 1940, that had just been published in article form in August 1940.

After the development of the Sulfa drugs, bacterial diseases seemed passe to the ambitious medical researcher.

As a result, it was becoming clear that the victims of (middle class) virus diseases like Polio would soon occupy the emotional and charitable space once occupied by (working class) Rheumatic Fever patients.

But Rheumatic Fever/SBE was still the major killer of school age children and young adults, killing far more than Polio by at least ten to one.

Dawson was not employed by his hospital and university to worry himself over SBE, to put it mildly.

Endocarditis was generally thought of as a disease for heart specialists, while Dawson operated a day clinic for chronic arthritis - in 1940, about as low as you could go on status
ladder in an acute-life-threatening-disease-oriented teaching hospital.

But it seems he stepped in, early in September 1940 when he found no heart specialists felt penicillin could be the long sought cure and he found no drug company willing to make clinical penicillin for such a disease.

His heart drew him in.

But his head kept him there.

His lifelong hobby or personal research focus, as opposed to his day job, had always been the commensenality shared between humans and their live-in microbes, a sort of uneasy co-existence or cold war as we and they struggled to survive against the activities of the other side.

His two previous developments ( HGT/Q-Sensing for s. pneumoniae and Molecular Mimicry for s. pyogenes)  had profound implications for all Biology, not just Medicine.

Unfortunately, they had no immediate application for fighting back these two sometimes-deadly bugs.

But his instant and intense conviction that penicillin's combination of non-toxicity and extreme diffusability made it the perfect ABF tool for penetrating SBE vegetations ((biofilmic colonies) on heart valves would let him get three bugs for the price of one.

This was because it was s. pyogenes that caused our bodies to attack its own heart valves - damaged areas that later were colonized by s. pneumoniae or s. viridans - leading to  fatal acute or subacute endocarditis.

I will call this side of the wartime penicillin story, "Commensality" ....

Yet more SMART women scientists in pearls -Agnes Warbasse II

Thanks to Mo goes Po devotees, I am offering up more photos of SMART women scientists in pearls.

I have to dash off to work to fill in for a sick employee ,( remember what I said about not forgetting the impact of ordinary 'day job' demands on all the wartime penicillin participants?), so this will be very brief and I will expand it in a later blog.

Agnes Warbasse ,(Junior? or Second,/II ?- we seem to have no convention for mothers and daughters who share the same first name and who both become prominent), was the co-author on what I claim was Martin Henry Dawson's most important paper.

That it is among his least known and least cited doesn't change my argument - in fact I claim it was and isn't cited because of its revolutionary nature.

Agnes Warbasse married in the early 1930s ------and as most married women did then and frequently do today, changed her job to suit her husband's career path - so she left Dawson's lab.

But for two years, between late 1929 and mid 1931, she was Dawson's first research assistant.

Here is a photo of her from around that time period:

AGNES WARBASSE II

Here is a photo of Dawson's last female research associate, Gladys Hobby :

Gladys Hobby


I think it is the eyes that grab you in both shots - the two women seem to be to be intelligent and yet guarded or self-contained. Quietly self confident.

Now I must be off to work ...

impure to PATIENTS, pure to CHEMISTS

Many scholars have doubted Big Pharma kept its word back in the Fall of 1941, when a dozen of its firms each promised to brew up hundreds (or even thousands) of liters of penicillin juice every week , so  penicillin could start flowing into dying patients' veins.

Because all throughout 1942,one of the worse years of the war for the Allied cause, very very few patients or soldiers seemed to get any of the life-saving  stuff.

I may stand alone - even stand naive - in believing the drug companies' pledge.

But I admit that I also read the fine print in that promise - the drug companies would indeed seed all that raw penicillin juice flasks that they had promised, but not "all" of the resulting penicillin would go to the patients - only "some" of it would.

In April 1943, GLAXO patted itself on the back and said it was the largest penicillin producer in the world.

It probably was.

But NONE, zilch, zero, zip of that world-beating supply was going to the soldiers, sailors, airmen or civilians that month.

Let see, that meant no penicillin for all the burn victims of the HMS Dasher disaster or for the people crushed in the Bethnal Green Tube disaster and no penicillin for the American wounded in the Battle for Bougainville.

So where was all the penicillin going that was produced in Glaxo's Aylesbury and Greenford plants?

It was all off to the chemists at Glaxo and Wellcome, to be degraded and destroyed in their ongoing attempts to achieve total synthesis of penicillin.

I hear a lot of chat that "we couldn't get any penicillin for my mother during WWII because the military had it all" but this was never so.

The military at the frontline hospitals frequently made its own unofficial and unrefined penicillin when it got tired of the scientists back home trying to perfect artificial penicillin.

Pulvertaft did it for the British Army in Cairo - he taught the nearby Royal Air Force to do likewise and the Canadian Army in Italy took up his idea.

Back in Britain, the Royal Navy under Green set up its own unofficial penicillin plant using Gordon Gin bottles instead of Glaxo's Bonny Baby milk bottles - gin bottles of which they had a great deal of, for some reason ( joke !)

Out west in Utah, US Army major Frank Queen started trying to make his own penicillin.

 He was tired of seeing boys from Guadalcanal still lying about with rotting bone
infections, ten months after they were first wounded and evacuated, with sulfa drugs only making them vomit rather than killing off their infections.

The military always said and acted upon, "a bird in the hand today is worth a million birds in the hand tomorrow" - they were only interested in technology that could be mass produced for this war, preferable this year.

General Grove always insisted he had to be a brute, because if you give scientists a pile of money and equipment and no one to ride herd on them, they will always go for the most interesting scientific problems but not deliver anything 'good enough' in time to be useful.

In other words, the better the scientist, the worse the engineer - they are not deadline or budget oriented by nature - they need a firm hand.

The military finally did plump for natural penicillin - produced in mushroom farms if that got the job done - rather than wait for the chemists.

The military's decision to demand natural penicillin now,ironically, got badly needed penicillin into the veins of dying civilians as well.

I think all the firms were guilty of this.

 Florey was not alone in getting raw penicillin juice instead of semi-purified dry penicillin from one company he was cooperating with (Kemball-Bishop). That meant he had to purify the penicillin he needed for patient trials.

Dawson got penicillin juice from Pfizer, starting back in October 1941.

But not till five months later did he get semi purified penicillin from them.

When he asked, back in November 1941, he was told all the pure stuff Pfizer could produce and more was going to Pfizer's Doctor Walton J Smith - if Dawson wanted some pure penicillin ,he could purify it himself from the raw juice.

Doctor Smith was not an MD - he was a PhD in Chemistry - an organic chemist - he set about degrading and destroying the purest stuff that Pfizer could produce, while Dawson's patients got the impure stuff.

Kemball-Bishop, a partner of Pfizer, did the same to Florey in the fall of 1942.

Now Pfizer and Kemball-Bishop were fermentation experts, not really drug companies.

If they, the most biologically-oriented of any of the firms involved in penicillin, were hell-bent on creating synthetic penicillin from the very beginning, how much more so the chemically-oriented firms like Merck and Squibb and ICI ?

It is a Big Lie, in the most accurate sense of that word, to say the search for pure penicillin was done for the patients' benefit.

Many dying patients, in a frontline dugout or in a SBE ward, would have settled for any kind of penicillin now, over a promise of perfectly pure artificial penicillin for the lucky patients who came along long after they themselves died for lack of help.