Tuesday, August 31, 2010

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....

Monday, August 30, 2010

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....

Sunday, August 29, 2010

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...

Saturday, August 28, 2010

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....

Thursday, August 26, 2010

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....

Wednesday, August 25, 2010

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" ....

Monday, August 23, 2010

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:


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 ...

Friday, August 20, 2010

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.

more HOBBY more PEARLS

GLADYS HOBBY in 1971, chairing the editorial board of the scientific journal she founded

Of course, people wanted more pictures of Gladys Hobby.

Well there is one color one, Hobby with Fleming, but it is all too common on the web already for me to add another copy.

But here are a few more, with pearls, natch.

I haven't put out any photos of  Meyer or Hunter or Odlum as they are well represented on the web.

But women always get short shrift, in photographs as well as in life in general.

I would really like to see a photograph of Eleanor Hahnel (of GAF industries in the 1960s) aka Eleanor Chaffee, (grad of the University of Connecticut 1937).

Or a photo of Miriam Olmstead (girlfriend of Robert Goddard of rocket fame), aka Miriam Lipman, spouse of artist Michael Lipman, aka a woman who did much to make Rheumatoid Arthritis and all auto immune diseases more understandable, if not yet much more treatable.

If you can help, leave me a comment below.

Until then, enjoy a few more pictures of Gladys Hobby:

Hobby in a formal pose , age about 75

From a picture taken of Hobby with Dr Ethel Florey, the clinician-wife who rode around on her bike in the rain collecting penicillin from patients' urine while her husband ,Howard Florey, played 'find the salami' with his mistress back in his apartment-like office at the DUNN ---- and then got most of the credit for Ethel's clinical penicillin work...ain't it always the way ?

Hobby finally gets her due

Today the best known member, at least among the general public, of the tiny Columbia University team that did the most to bring penicillin to the public as soon as possible (and did so over Columbia's dead body) is Gladys Hobby.
GLADYS LOUNSBURY HOBBY          Nov 19 1910 -July 4 1993

It is a fame she never enjoyed while still active in antibiotics.

The terminally ill Henry Dawson gets most of the credit for providing the moral energy and drive to the Columbia penicillin effort - something that Hobby and Meyer were always forthright in reminding people.

Karl Meyer lived the longest of the main foursome and lived long enough to see his lifelong scientific interest, hyaluronic acid, become a virtual growth industry.

The fourth member ,Eleanor Evelyn Chaffee (aka Mrs Eleanor Hahnel?), will emerge from the shadows, if it is the very last thing I do.

Thomas Hunter first saw fame for finishing Dawson's proof that penicillin could cure the incurable - SBE. Then he became a medical school dean best known for promoting medical education in the third world.

The fairy godfather of the team, Floyd Odlum, is probably best known today for displacing Howard Hughes at RKO.

Miriam Olmstead is today best known as a former girlfriend of the Rocket man, not Elton John, but rather Robert Goddard.

There were a few others, not as invisible as Chaffee ,but rarely connected today to this pioneering penicillin effort.

Hobby after penicillin went on to discover and prove up other big antibiotics and then take leadership roles in science organizations when few women were permitted to do so.

As a result we get many bare bones bios of her - celebrating what she did but not why.

The best - by far - of these is Elizabeth Moot O'Hern's "WOMEN SCIENTISTS" .

It is based on a 1977 interview with Hobby and includes some rare photos of Hobby - most other accounts re-cycle the photograph of Hobby shepherding Fleming about on his tour of South America.

{{What I really want is a photo of Hobby without her pearls - she always wore them - particularly at work in the lab - she was someone that people of my mother's generation would call a 'looker' because of her sharp dress and make-up.

Note the pearls ....

Perhaps this was a survival technique for daring to work above her station  in a very male-dominated world.

But those pearls ----I bet the woman wore them in the bath and to bed !

Perhaps not to church though - a true 'old skool' Presbyterian...}}

But O'Hern's admirable account fails to explain the 'why' in Hobby's four year struggle to bring penicillin to the public, over the opposition of many powerful forces.

I think Professor Jeremy Greene, from Harvard's History of Science Department, does a great job with the 'why' in his brief bio of Hobby in "NOTABLE AMERICAN WOMEN" edited by Susan Ware et al.

He focuses on her very first articles to explain how she came to hold a unique bridge role between the biological and chemical approaches to defeating bacterial infections.

Greene says she defends the validity of studying non-pathogenic bacteria .

(This was a real career-loser between 1870 and 1960 in medical science.)

Dawson's entire career - again opposed to his day job - was also devoted to exploring non- pathogens and pathogens as equally interesting and equally viable ways for commensal bacteria to survive in the human body.

This bonded Hobby to Dawson.

 A deep commitment to seeing new research put to work saving lives, even if it hadn't been all explained in scientific terms, was what bonded Meyer to Hobby.

Meyer was the rarest of 1930s biochemists - he was clinically oriented.... aka he was face to face people-oriented.

Dawson's team was very small and not well supported by his university --- but having two such unusual people to work with him (Hobby and Meyer) helped make up for this....

Thursday, August 19, 2010

STALIN lives? at the DUNN ?

I sometimes think that atheists have taken over Oxford University and that they now worship scientists (provided their 'tough minded' enough) instead of God.

Sometimes this means that Oxford have to apply some of Stalin's favorite photographic techniques for making Commissars vanish.

Stalin excelled at first the bullet to the back of the head and then a generous application of photographic varnish to the front of the head ,applied to whatever official photographs that couldn't be tossed.

Wilson Baker was a harmless little man, a devout Quaker peace activist and a darn fine chemist - he's dead but not by any bullet to the head.

But the photo vanishing varnish does apply - he's been erased from the official portrait of the moment of Oxford's University greatest triumph - the (failed) effort to synthesize penicillin during World War Two.

Baker's fault was that his mere presence in an iconic photograph interfered with the Sir William Dunn School of Pathology's panty lines when it came to exalting their best known director, Baron Sir Howard Florey.

Florey is himself dead but he still a real little money maker for the Dunn, Oxford University, Oxford City and the whole bio-med-crazy rich and rapidly growing "Thames Valley".

The original iconic photo is in Britain's National Portrait Gallery, taken in 1944 by Wolfgang Suschitzky at the Dunn in Oxford as part of a a ICI-funded film on Britain's role in penicillin:

I have shamelessly taken this from Robert Bud's book on Penicillin, together with his caption and credit line.

Now here is another almost exactly similar photo, taken this time from Eric Lax's book on penicillin, with its caption and credit line to the Dunn Pathology School.

I don't know about Pathological, but I find this all definitely creepy:

I have made these photos very small ,to save bandwidth, but they sure look alike---- aside from the tighter crop of the Dunn version.

But now look closer at the figure of Florey from the Dunn version:

It sure looks like a bad "insert" job ala Joe Stalin's technique.

And doesn't our Florey's pose look very very familiar , in fact ,iconic to cliche-worthy familiar ?

Ah yes, Florey had no license to inject people.

 The stand-in shot of him using a needle of his famous live-saving penicillin, in lieu of something more heroic, has become a posed-up shot of him and his aide, Jim Kent, needling a mouse in May 1940.

 I think its a law that it must be used in every book and article on Florey,Oxford and penicillin.

Here it is,also from Lax's book, and again provided by the Dunn people:

What do you think ?


During World War II, from July 1944 till 1946, the Canadian Army in Europe produced an ordinary-soldier-oriented newspaper called The Maple Leaf.

Sort of a pale version of the American Stars and Stripes.

Its June 29th 1945 edition has an interesting story datelined Vancouver and entitled "PENICILLIN GROWN IN ITALY'S FIELDS".

Newly demobbed Private Donald MacRae, working in a BC logging camp as the first aid medic, is now free to tell an interesting operatic science tale that the highly dignified medical scientists had kept under cover till then.

It was March 1944 before penicillin was flowing freely through conventional channels to the Canadian military in Italy.

(Thank you Pfizer !)

Till then, the Canadian doctors in some hospitals grew unofficial penicillin from spores sent to them from Cairo - ie from Robert Pulvertaft - one of my heroes in the whole penicillin saga.

Nice to know a few lives were saved or helped by this effort.

The instructions certainly sound like Pulvertaft's style - cut a lot of unpeeled potatoes in two, throw in a bucket of warm water with the top exposed to airborne microbes, leave out and about.

Twenty four hours later, put the potatoes in a stew and enjoy.

But the water they soaked in, with the addition of a few mineral salts, was now just about perfect to grow a good brew of yellow penicillin juice in about 6 days, if kept in a cool dank basement.

Call it the poor man's corn steep liquor --- !!!!

(If keeping the potatoes from spoiling before reaching Italy was a priority, we can assume these potatoes might have come from Prince Edward Island via a Halifax convoy.)

A chemist could grow old and die before they figured out why the mold preferred this rather foul smelling mess rather than their pure and expensive 'defined mediums' with added amino acids.

But an ecologist- or a housewife - could explain it in an instant.

Basically the potatoes were being deliberately put on the road to spoiling and rotting for 24 hours before being cooked and eaten.

For millions of years the fungi had adopted themselves to eating half rotted food - not simple amino acids nor complex proteins either - but rather half digested proteins etc.

Sloppy Seconds, as it were.

Andy Moyer knew what he was about when he told all visiting British researchers that they needn't think the NRRL's farm surplus corn steep liquor was the only thing that would make penicillium grow penicillin - almost any complex dirty -and dirt cheap- farm cast off might work.

"Go look about at what the British breweries throw out, " he said.

POWs and civilian prisoners have always known that potatoes make great contraband brew - now we see it saves lives too !

#3 in an occasional series of articles about morally resolute individuals and food and unofficial penicillin uniting to save lives when the medical establishment, governments and drug companies fell flat.

(#1 Duhig,unofficial penicillin and Vegamite saves lives in Brisbane.)

(#2 Dawson, unofficial penicillin and Jack Frost brown sugar save lives in New York.)

Wednesday, August 18, 2010

a patient died with every Alumina run

During the thick of the fiercest combat in WWII, the entire US Navy got the same amount
of scarce purified patient-ready penicillin as did just nine American Drug Companies , "for their own use".

I've read this statement in dozens of penicillin accounts without asking - "why so much patient-ready penicillin for just nine companies and what on earth did they need it for?"

After all, other patient-ready penicillin was being allocated for clinical trials run by a separate organization, the NAS-COC - the drug firms had no hand in it.

Their routine testing for anti-bacteria activity took incredibly tiny amounts of penicillin - about one millionth the amount allocated to them.

What these accounts have elided out of their story is that all of this patient-ready penicillin was being destroyed in experiments to totally purify and totally synthesis penicillin, at a time when patients were dying because of lack of penicillin.

"The Chemistry of Penicillin", a massive monograph released by Hans Clarke of Columbia University in 1949, was the official history of the six year long unsuccessful effort to synthesis penicillin in commercially-salable quantities, an effort that involved thousands of chemists and technical workers, millions of dollars and the best university and industry teams in the Allied countries.

In every way, it was a parallel effort to the Columbia University-based portion of the Manhattan Project.

 Not just in its scale but also in the fact that it too started with a yellow powder consisting of a mixture of substances that were 99.99% alike and could only count itself successful when it ended up with one shiny clear crystal that was 100% pure.

The Bomb would have dropped on Hiroshima with or without success from Columbia's chemists --- but the Cold War wouldn't have happened if they had failed.

All the Cold War Bombs, on all sides, were built with molecule-separation technology perfected at Columbia during WWII.

By contrast, the molecule-separation technology that gave us pure crystals of penicillin came from the Wool Institute of Northern England in 1938 and proved useful enough to win a Nobel prize for its two developers.

And if you hear me once, you'll hear me a million times - their work was not peer-reviewed-grant-based research  - (ie,it wasn't DIGNIFIED SCIENCE  but OPERATIC SCIENCE  to use my own terms).

The origins of this technique (chromatography) are even more interesting - they came from a Russian botanist and were long ignored by chemists because, (a) well he was a botanist after all and (b) it was all way too easy.

Chemists adhere to the notion that if you aren't in pain after you exercise, you haven't done it enough - every chemist's scientific papers are a testosterone-rich tale of endless amounts of back-breaking effort and mounds of chemical reagents used up to achieve the end result.

But chromatography worked so well it is now one of the most widely used chemical techniques - it relies on the fact that even molecules that almost totally alike are still absorbed onto other molecules at ever so slightly different rates.

(Note that in separating the two types of almost similar uranium for the Bomb, it was known they had slightly different weighs and sizes and so it was hoped they would tend to go through tiny holes at slightly different rates .)

They did, but sooooooooo slowly that some molecules put into the production line in the mid-1940s were still inside the same production line 40 years later when the Cold War ended !

Now it is true that this is a physical process ,not a chemical process, in the final analysis but the effort to make it all happen was really a physical chemist's type of work, rather than something a regular physicist would excel at.

In Dutch, the word for Chemistry is Scheikunde - "the art of separation" - a very good way to describe much of chemistry - and frequently the part of it judged most useful/most profitable to industry and society.

Back to the process by the Wool Institute's Synge and Martin, as applied to penicillin.

In this process, during each run of the process, 5 to 7 grams of patient-grade penicillin  (that is between 2.5 and 25 million units of penicillin depending on the year the work was done) was poured down a column of alumina or silicon gel, and the penicillin separated itself out into various colored bands.

These different colored bands of sticky wet alumina were carefully cut apart with a knife
and then the biologically most active colors were used in further tests to get almost pure samples of various types of penicillin.

Think about how those chemists must have felt as they performed each run- they weren't heartless men and women.

They knew that each run used up and destroyed enough patient-grade penicillin to save the life of  six children with blood poisoning or one young adult with SBE (sub acute bacterial endocarditis). Sulfa drugs weren't working - so no penicillin meant death.

The Chemistry of Penicillin describes many of these runs and the specific amounts of penicillin used in each run.

I love facts and figures and dates and prices (up to a point) and hate the fact that most accounts of penicillin either avoid them - or worse - screw them up by factors of one thousand or more ( mistaking grams for milligrams is routine, for example).

The facts and figures in this massive tome of a book look reliable to me and I feel that it -and they - are underused resources.

Even more useful are the facts and figures that are not there.

The firm (Pfizer) that produced most of World War II's penicillin, the firm that was the first to make patient-ready penicillin, a firm early into the blessed circle of synthesis research, is almost totally absent from this book in any meaningful way.

It had a vast amount of experience, having worked with penicillin almost longer than anyone else and it was making lots of money and taking on lots of talented staff during the war.

It even got the second or third largest allocation of penicillin to play with.

Yet with all these advantages, it produced almost nothing remotely useful towards the synthesis of penicillin.

This isn't just me (a totally non-chemist) saying this.

Accounts years later that tend to give an summary overview of the road to synthetic penicillin, written by penicillin chemists with no axe to grind, see nothing in Pfizer's work to highlight. Even very minor penicillin players get more attention than Pfizer.

So where did all that Pfizer experimental penicillin go then, if not into useful synthesis work?

John L -(John L Smith ,head of Pfizer's penicillin efforts) -care to explain ?

"I secretly broke my solemn signed agreement with my government and diverted the penicillin away from synthesis to give to patients dying of SBE, patients that that very same government had refused to treat."

Why ?

"Because I had just bet the farm and Pfizer's entire fate on the guess that my biologists on this side of the Hudson could make deep tank penicillin successfully - and make it better and quicker than Merck's chemists could make artificial penicillin on their side of the Hudson. I was betting that soon there would be more penicillin than we would know what to do with - plenty for Second Front soldiers AND SBEs here at home."

"Was I right; was I right ?!"

Yes, you were. And some SBE patients and their families are very grateful you bucked your wartime government and diverted penicillin towards dying SBE patients.

"Well, I must say I learned how to divert penicillin and 'buck' from the best - Henry."

Dawson ?

"Yes,the old stubborn mule, Henry Dawson ..."

Monday, August 16, 2010

"4Fs and WOMEN and the GRACE of GOD"

The Official History of Vannevar Bush's famous wartime science agency the OSRD, home to World War Two's 'elitist science' , is called "ORGANIZING SCIENTIFIC RESEARCH FOR WAR" and was written by Dr Irvin Stewart.

In discussing penicillin and the medical section of the OSRD, Stewart claims that "Laboratories cannot be run by 4-Fs or Women or by the Grace of God alone." (Page 107).

Well, I know a great book or movie title when I see one and so I took up Irvin Stewart's intended insult to 4Fs and Women (and God) with relish.

Two 4F doctors called Dawson and Hunter together with three women scientists called Hobby,Chaffee and Olmstead could run a lab very well indeed ------and did more than anyone else to bring us NATURAL penicillin in time for the D-Day beaches and all those wounded young soldiers.

And the Grace of God no doubt came in handy a lot....

the Coghill versus John L race

In October 1943, a committee of three chemists, including the head of the US Agriculture Department division of NATURAL Fermentation, said that SYNTHETIC penicillin would a reality in six months - in April 1944.

" Bet the farm on it ! "

That was a mighty good deadline for synthetic penicillin true believers to aim for .

Because April 1944 was about the last possible date for any sort of penicillin to enter the US Army supply pipeline, be transported to the  Kansas City Kansas central army medical supply depot and then be shipped all the way back again to the East Coast and shipped
across the Atlantic to the Southern England ports, to be loaded on hospital ships bound for D-Day's beaches.

If this chemist (Robert D Coghill) had been proven right, he would have put his own Division out of business - so he had a conflict of interest about a mile wide and mile deep.

A conflict of interest between his natural chemist's fetish to achieve the complete synthesis of anything and everything and the duty he owned to his employers at the Agriculture Department.

But across town, another chemically-oriented key mover and shaker, was having a change of heart.

John L (John Lawrence Smith, the head of Pfizer) was leading one of the firms heavily involved in synthesising penicillin.

But moved by the plight of a child so like his own daughter that he had earlier lost to meningitis, he was secretly breaking the spirit of the wartime laws governing penicillin.

 Scarce amounts of penicillin that he should have been devoting to chemical synthesis John L was instead giving to doctors (under the table) to save the lives of people dying of SBE, a traditionally always-fatal form of endocarditis.

John L was also busy backstopping his own private bet that he could produce billions of units of NATURALLY-brewed by the April 1944 deadline.

He did this by having his crew work night and day under powerful Klieg Lights with posters reminding his employees that every delay would cost lives.

And he did this be accepting the second-best as more than good enough : he didn't build a brand new shiny factory like all his competitors were doing.

He took over a ice making plant (a sort of milk plant, in many senses) and adapted it quickly to produce deep tank penicillin.

Coghill and the other synthesis believers were working just as quickly, in labs all over America and Britain, fueled by lots of taxpayers' money.

But the work was not going anywhere useful.

Meanwhile Pfizer was now producing more penicillin than even their wildest estimates had allowed for and Coghill threw in the towel and, being a good bureaucrat, moved smartly to Plan B.

In April 1944, with the biological production of penicillin an outstanding success, it was suddenly deemed to no longer be a deep military secret and Coghill spilled all the details in public - claiming his division was responsible for its success.

In a sense that was true - his low level employees had made natural penicillin possible - but Coghill himself,had been busy trying to screw them in the ear by creating synthetic penicillin to make all their work irrelevant.

More importantly, if biological penicillin was now a big success, shouldn't that mean that it was MORE of a military secret than ever - not less?

Was it really only kept secret so that synthetic penicillin could gain time to trump it ?

In May 1944, Coghill ( in his other role as the erstwhile head of the Fermentation Division ) had to go inspect the fermentation tanks at Pfizer and see vials of 100,000 units of penicillin come off the Pfizer line faster than he could count.

And Coghill the Chemist had to stand there while Pfizer's Biologists went about with shit-eating grins.

A GREEN Day indeed.

Chemists and Chemistry, the Queen of the Sciences from 1840s to the 1940s, received a blow that day that they never really recovered from.

I'd give anything to be there, the day that Modernity died and Post Modernity was born....

Alexander Fleming's "HAY" identified?

I wish to offer up a possible identification of Alexander Fleming's long mysterious "HAY" bacteria and a possible explanation why it was among the very first bacteria he tested penicillin on.

It is well accepted that Fleming seeded that famous Petri dish at the end of July 1928, discovered that a mold had dissolved mature staph colonies on it in early September 1928 but that he only recorded his first experiment with the mold juice on October 30th 1928.

The results of this (quick) experiment implied to Fleming, I believe, that penicillium juice clearly inhibited the growth of staph-type (gram positive) bacteria .

However it had no effect on coli-type bacteria (gram negative) or acid-fast HAY-type bacteria (ie mycobacterium, the group of bacteria that causes Tuberculosis.)

The Timothy Hay Bacillus, Mycobacterium Phei , I suggest was that "HAY" bacteria and was used as a safe stand-in for the deadly tuberculosis bacteria that had killed so many lab workers in the past.

It is almost tuberculosis-on-steroid in some ways, but is almost completely harmless to humans.

Like all mycobacterium, it is one of the hardest types of bacteria to kill, because it is covered in mycolic acids that resist anything the chemical industry or the immune system can throw at them.

Perhaps Fleming thought an agent that could dissolve even mature staph colonies would be up for dissolving the tough coat of the mycobacterium group - if so he was disappointed.

Because it is not only harmless to humans, but is also the fastest growing of the very slow growing mycobacterium - always important for increasing lab productivity - Mycobacterium Phei seemed a useful addition to the well equipped Bacteriology Lab.

It also has a very unusual nucleic acid composition - 75% GC content - making it of interest to early workers in what we now call DNA research.

Parke Davis, the drug company that bought Fleming's institute's vaccines and serums , was very interested in this bug in the summer of 1928.

They had assisted a group at Yale in investigating some of its characteristics as they related to and contrasted with the deadly TB bug that was killing so many people world wide.

This was a potentially fresh approach to solving the age old TB problem - approaching the beast from an indirect angle.

This Yale team was led by Robert D Coghill - another famous leader in the penicillin saga.

Perhaps the Detroit drug firm had also communicated their interest in the Timothy Hay Bacillus to all researchers connected to Parke Davis International that summer --- including Fleming ?

I would be interested to hear what more experienced writers on Fleming and penicillin think of this suggestion...

Sunday, August 15, 2010

The things they buried...

I know, I know, a shameless knock-off from Tim O'Brien's classic.

What I am about to compare is the contrasting ways Fleming and Florey chose to deal with the more amateurish and stochastic areas of their involvement in the Penicillin Saga.

Fleming's discovery of penicillin was not - Horrors ! The Shame of it ! - peer-reviewed funded.

It was an accident and he wasn't being paid to discover or develop it.

 But he made the most of that fact and in fact delighted in it.

He preserved the famous accidental Petri Dish so that all can still see it in the British Museum, 82 years later. He saved a bit of the accidental mold, sent its children out to any that asked.

 Hundreds of collections worldwide still keep its great-grandchildren going and growing.

He kept his sparse notebooks for the entire period 1928-1945 dealing with his steady work on penicillin - not bold or visionary work sadly - but he still kept proof of just how little he did do -and revealed it for all to see, without shame.

He and his institution (St Mary's Hospital) positively delight in exposing and preserving just how amateurish his penicillin work was -- there is a museum dedicated to that amateurishness and the sheer unlikely stochastic-ness of his discovery.

Unauthorized but sympathetic biographers of Florey's work with penicillin also delight in revealing the utterly amateurishness of Florey's extraction equipment, assembled as it was from old bathtubs, coal hoppers, pie tins etc etc - Rube Goldberg on Acid.

Not Florey though: no, no, never.

He always (mis) presented his team as having a much more sophisticated operation than what even a well-equipped teaching hospital's Lab Service could ever put together.

 He even told anyone foolish enough to ask that only his Oxford-produced penicillin or that produced by Big Pharma was safe to put into patients .

And that any teaching hospital lab's penicillin was bound to be unsafe .

All this despite the fact that Florey was not , in the conventional sense, a clinically-oriented medical doctor with patients and hence in a position to properly judge patient safety.

Instead he was a medical researcher working in a lab on basic science.

Part of this animus against teaching hospitals was because Florey hated patient-oriented doctors with a passion, but mostly it was because he wanted to keep his part in the penicillin Saga on the Dignified/peer-reviewed funded/team side rather than the heroic individual/amateur/unfunded side of the story.

But in fact his penicillin plant or that of any drug company, from 1940 till about mid 1944, was as purely amateurish as those run by individuals out of a corner of a hospital lab - perhaps differing only in being a tiny bit bigger.

But the minute he heard that Pfizer was producing more NATURAL penicillin in 5 minutes than his lab had produced in 5 years,Florey shut down his penicillin plant and had all his Rube Goldberg extraction equipment torn up and then buried in a backyard rubbish heap.

After his death,Norman Heatley built some replicas for museum use.

 But generally Florey supporters have explained this by saying that  Florey was forced to use amateur methods at first, until he assembled a vast Anglo-American joint effort involving governments, universities, corporations and the military, all working together, to bring us high tech penicillin - Big Science at its best.

Academics just love this myth, the myth that says if the taxpayer just gives science lots of money and then stays out of the way, they will pull rabbits out of hats every time.

The public loves the other myth - that kindly old Fleming discovered penicillin just messing about and gave it to the world without charge ------and that it was a piece of cake to get it into mass production.

Neither myth is totally untrue but both only give a part of the story.

Hopefully my effort will give a fair hearing to both Fleming and Florey but include the rest of the penicillin Story as yet unheard.....

Saturday, August 14, 2010

Biggest disease that penicillin conquered

....was not SBE, Subacute Bacterial Endocarditis, as important as it was and as important as it was to Martin Henry Dawson.

I am not writing my account of the Penicillin Saga because it conquered SBE.

I am going after much bigger game.

The dreadful disease I think NATURAL penicillin conquered in 1944 was Modernity.

I think today's GREEN movement can trace some of its beginnings to that blue green penicillium mold's triumph against the best efforts of man to recreate everything natural in an artificial form, merely because they could.

Defeating Modernity was the best thing natural penicillin ever did.

That's why I am writing this work - that's why I do what I do....

World's most important medical journal?

That's easy - there are only four types to consider when announcing a really important medical discovery.

Number four - but way at the bottom - is announcing a new medical discovery in the pages of something like LANCET or JAMA, the journals that medical doctors read .

Number three would be if that new medical discovery got reported in NATURE or SCIENCE, the journals that scientists read.

Number two would be if that new medical discovery ended up on the business pages of THE NEW YORK TIMES, the pages that the men with money read.

But all of these still remain near the bottom in importance in their ability to move a discovery out of the lab and into the GP's handbag - quickly.

Doctors,scientists and businessmen do many worthy things, but moving quickly is rarely one of them.

No,alone and way at the top as my choice to move people to action would be if that new medical discovery became attached to a human face and ended up on the pages of a women-oriented magazine in your neighbourhood supermarket's magazine stands.

 Doing so, directs it to the immediate attention of........ "DOCTOR MOM".

Don't believe me ?

That's what happened back in August 1943, when Dante Colitti and CITIZEN HEARST put their heads together to make the wartime government of FDR stop focusing on killing long enough to think about the living.

At the beginning of August 1943, I bet one educated person in a million worldwide could tell you what penicillin was. By the end of September 1943, I bet 90% not only could tell you but also wanted to know why their government wasn't making it available to their citizens like yesterday .

Fifteen years earlier, penicillin had first become privately known, to Alexander Fleming.

Fourteen years earlier, penicillin had first become publicly known - as scientists are wont to say in their self-absorbed way- when it was published in a peer-reviewed journal with a few hundred readers.

And there it sat, in the British Museum of medical curios, basically unused.

It was only when penicillin became popularly known, virtually overnight 15 years later in August 1943, that it began to be used en masse to save lives.

Now getting the attention of DOCTOR MOM , a very,very busy person, is never easy but once you do that, Ms or Mr Discoverer ---- stand back a safe distance and watch the wheels spin !

So, the top medical journal in the world ????

I'd rate THE LADIES HOME JOURNAL pretty high....

Pearl Harbour Saves Florey?

As long as America was at peace ,America's businesses could compete against each other relatively freely without the ability of the "dollar a year men" in Washington to make use of  " the emergency " to misuse government's wartime muscle to restrain competition, so as to favor the firms they represented in peacetime.

If Japan's attack on Pearl Harbour hadn't happened, America would have probably remained a neutral at least throughout the first half of 1942 - long enough for Pfizer and Dawson to be free to fully publicize the life-saving powers of naturally-brewed penicillin in the national media.

This would have been enough, in peacetime, to create an overwhelming public demand for its immediate mass production.

Penicillin would then become just another in a series of remarkable drug discoveries that first emerged as a small but notable success and just kept on growing in importance.

Sulfa drugs started that way - they really had no immediate or dramatic success to introduce themselves to the world.

Rather it was a series of notable successes, among a number of different years and a number of different continents that gradually made them famous.

Newer and newer sulfa variants kept on being discovered and were then put to work curing additional diseases.

Likewise,Penicillin's initial success would have focused attention on the possibility of ever more drugs from molds and bacteria - as of course happened from about 1947 onwards to today, but in a non-dramatic ,and above all, industry-directed fashion .

85 years after sulfa and penicillin first emerged in the lab (around 1928), only one drug has got any kind of universal dramatic legend attached to it and this is penicillin.

The deleterious effect of the American declaration of war on what should have been its normal emergence from lab to drug company to its acceptance by GP and patient is the reason why.

Without Pearl Harbour happening in December 1941, Florey and Merck would have been free to pursue their synthetic penicillin mirage while Dawson and Pfizer would have been equaly free to introduce natural penicillin - first grown in large trays and then from deep tanks.

The winner would have been the same (Pfizer) but they just might have emerged in May 1942 rather than be delayed until May 1944.

Ie, it would be as if the dramatic events of May 1941 to May 1944 never ever happened.

Let us go to a concrete example:
DOI: 10.1021/ed018p552.2
Publication Date: December 1941

This is a monthly publication of the American Chemical Society.

 In 1941, when the public heard the word scientist, they thought only of chemists - chemistry was the Queen of the Sciences back then to an extent we can't begin to imagine ,unless we were living back then.... before 1945 (Physics) and 1953 (Biology).

This journal was directed towards chemistry teachers and undergraduates in North America's high schools and universities--- a huge audience well beyond more prominent chemistry journals with a select but tiny audience.

This particular column was a monthly roundup of news from the popular press that had a chemical industry aspect to them.

Just reading the column in its entirety makes it clear that "WHAT"S BEEN GOING ON" for December 1941 was written and released before Pearl Harbour.

Using language from The New York Times's description of Dawson's work on penicillin back in May of 1941, the paragraph seems a little out of date to fit this speedy "up to the minute" news digest column's style.

It credits Fleming with discovering penicillin in 1929, but says nothing happened to it until Dawson at Columbia proved it up.

I admit it - I love it !!!

No mention of Oxford nor Florey no Merck no OSRD nor of the NRRL and COC.

I think it reflects a little quiet PR spin that Pfizer put behind on its corporate decision to seriously help Dawson use Pfizer-brewed NATURAL penicillin on clinical cases.

That brewing, and that corporate decision, happened in mid October 1941, a date much closer to the date the column would normally have been researched and written --- rather than about events from way back on May 5th 1941.

A Merck-oriented paragraph on penicillin in this same time period would have credited Florey and ignored Dawson totally.

Merck never had to do that media-spinning, not after Pearl Harbour.

One wartime government agency,the OSRD-CMR, run by Merck men, now controlled almost all of the news on penicillin and they spun it to focus exclusively on Florey and hence indirectly on Merck.

But they forgot to put a muzzle on Dante Colitti  (and Doctor Mom) and penicillin became a legend despite the best efforts of  OSRD,Merck and Florey....

Friday, August 13, 2010

PoMo Green versus Institutional Green

We all know institutional or hospital green, though we probably don't know much about it.

Technically it is called Chromium Oxide Green and though it is no longer made (much) it was a technical wonder in its day.

Most chromium paint wasn't green - the green color was selected for the paint used in public institutions like prisons (remember the Green Mile ?), hospitals and institutions for the chronically ill and mentally insane.

Today it gives a bad vibe for being associated with these places of discomfort and shame, but this pastel like shade of green was originally selected because color scientists judged it the most calming shade for institution inmates.

The reason why it was made from chromium oxide was because this paint was tough tough tough and chemically toxic - it resisted stomach contents and common hospital cleaners AND because it was so tough and smooth,that made it harder for germ-sustaining dirt to hang about.

It was the most typical color of the Streamlined Moderne Decade from about 1934-1944 - by no coincidence the Apogee of the Modernist Age.

But that is soooooo yesterday.

Today's green is PoMo Green and it is not a paint at all - it is the natural verdant color of Nature itself - green grass, green trees, green ocean deeps.

The very first PoMo green?

Glad you asked !

It was all those Kodachrome-vivid color photographs of green-blue penicillium molds in the color supplements so popular during the World War Two years (when neither TV or film gave you much color) that appeared post the Spring of 1944.

That was about the time when it became embarassingly apparent that man-made medicine was being eclipsed by life-saving medicine from a humble and slimy low life normally found in our basements --- a shock Modernist Science never really recovered from.

Now it would just take Adorno and Horkheimer to make it official, which they did - in The Dialectic of the Enlightenment.

Move over Mo, Po has arrived.....

Thursday, August 12, 2010

"Jabbing" BIG PHARMA awake

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

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

Example ?

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

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

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

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

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

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

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

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

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

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

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

NRRL1249.B21 was WWII's top secret

It is not hard to replicate an Atom Reactor - just ask Joe,Mao, Winnie or Chuck.

(Stalin, Mao Tse Tung, Churchill and de Gaulle.)

Even George gave it a good shot.

(George Laurence was a junior Nova Scotia-born scientist who decided to build one on his  own time,by himself and with his own money --- he did a good enough job of it to be invited , along with Canada, into the very small wartime circle  of the atomic bomb elite.)

The American Army built one - along with a few Bombs.

But they found The Bomb a piece of cake compared to building a Frank Sinatra.

Since the original guy was draft-exempt because of a torn eardrum (no wonder he sang so good !), I am sure the Army tried - it was bad for the fighting man's morale to have the gal-pal back home swooning over a 4Fer.

NRRL 1249 B.21 sounds like a top secret bomber, or a new super explosive, but it actually was just a bit of mold like you might scrape off an orange or a dank basement wall.

But it was a lot more like a Hollywood star or a Billboard chart-topping singer - an exact replicate couldn't be build and even a close substitute won't do at all.

All or nothing.

When the Russians and the Japanese heard rumours that the Germans, British and Americans were building an uranium bomb, based on the principle of fission they could at least hope to duplicate it.

Uranium isn't particularly scarce and the basic principles of fission were made known to all atomic physicists worldwide between 1938 to 1940.

The costs and difficulties of the chemistry and engineering were far more daunting, in practise - but it could be done, given a little time - ah, Joe ?

But without a spore or two of NRRL 1249.B21 or NRRL 832 or NRRL 1951 (still in use world wide 65 years later) , you were reduced to using Fleming's original "PD" spores - freely available - but only producing 2 units of penicillin per milliliter not 200 units a milliliter.

That meant if you weren't part of the NRRL-OSRD charmed circle, you'd have to do 100 times as much labour as those specially favoured by Coghill and Richards.

A sweet deal for a few lucky corporations - particularly since it was all paid for by the long suffering taxpayer.

Let's recap: the private stuff was PD but the publicly funded stuff was proprietary.

Only in America, you say ?

Let's just call it a New Deal for the Rich and Influential.....

NDM-1 SUPERBUG - the TRURO connection

A mobile gene that creates an enzyme that destroys almost all known antibiotics have been reported in NATURE this week, leading the news around the world.

Bacteria (and microbes generally), kick dust in the face of Charles Darwin and his theories of genetic inheritance.

They can send their 'seed' sideways - not just vertically down to their offspring like humans with PhDs -  but also to other species or even towards other forms of life.

It is called HGT ( for Horizontal Gene Transfer) (aka Transformation) and Martin Henry Dawson from Truro,Nova Scotia (the doctor whose biography I am writing) was the first person to try to make HGT a big issue in the science world.

That happened between 1928 to 1943 but unfortunately few scientists back then cared to face his unpleasant message ---- "simple creatures are anything but."

(And its corollary, that scientists are less brillant than they think they are.)

If we start dying en masse from these new superbugs, maybe more of us will start listening to Dawson's still-pertinent message

Wednesday, August 11, 2010

Why stop at THREE mold samples...

...when  four would feel oh so good?

In 1970,Lennard Bickel, using information from Gladys Hobby, says that Martin Henry Dawson and Karl Meyer used a sample of Alexander Fleming's penicillin-producing strain received from Roger Reid in Baltimore to deliver History's first jab of antibiotics October 16 1940, before a sample of  Ernest Chain's strain of penicillin-producing mold arrived from England via the wartime postal service.

Chain's sample - if it even was penicillium notatum - turned red and gave off no penicillin.

This story was repeated by Hobby in her 1985 definitive book on the wartime development of penicillin ---- and by most penicillin authors ever since.

Reid had originally got his penicillin strain in November 1930 from Charles Thom, the world expert on penicillium strains.

Who had gotten his sample from Harold Raistrick who got his from Fleming who got it as a contaminant in the air drifting upwards from the lab of LaTouche who scrapped it off a basement wall of somebody very rich in Belgravia.

(Finally !

The idle rich do something useful.....)

On July 9th 1941, Howard Florey visited Charles Thom who says that HM Dawson ( ie MH Dawson) contacted him directly to get a sample of Fleming's strain, after Chain's strains arrived in late October 1941.

So Dawson contacted at least three people that Fall of 1940 for a good penicillin-producung strain of the mold : Chain, Reid, Thom.

Why not then Alexander Fleming ???

Why not go to the Source, the Mother Load ?

This might account for Fleming's boss (Dr Wright) knowing all about penicillin-making at New York's Columbia University in March 1941, as referenced in Dr John Hedley-Whyte's account.

Dawson had meet Fleming at least twice, for sure --  in 1936 and 1939 when both were high poo-pahs in International Microbiology Congresses.

Anyone got any opinions on this ??

The Crude and the Dignified, ...

....are two wildly different versions of the Saga of Penicillin Development during World War Two.

You know only too well the Dignified version, as propagated by the OSRD of Vannevar Bush and by just about every academic writer on penicillin (I think it is a requirement for them to retain tenure or something) - I call it the dignified rendition of "The Revenge of the Nerds".

Martin Henry Dawson's efforts to grow, purify and apply his own homegrown penicillin to
save patients dying from invariable fatal SBE - all the while fighting off his own hospital, his own government and his own (dying) body - is the most tasteless,  the most over the top and the most crude Hollywood medical bio-pic imaginable ,since the days of the dying Marie Curie laboring long into the night over her radium ores ,in a tin shed with a leaky roof.

A Forties three hankie melodrama full bore, for sure.

Enough to make any modernist scientist recoil in distaste.

Fair enough - stone-heartedness is a disease  -and they are more to be pitied than blamed, etc etc.

But the patients, the punters, the bums on the seat love it.

They like - nay - love and worship - the idea of doctors who care about them enough to be willing to die for them.

I'm telling the tale for them ---- and in hopes that a few modernist scientists and academics might re-think how they deal with the real people affected by their lab efforts....

Australians give away British Store

Mark Oliphant flew to America in a bomber to beg them to make the Atomic Bomb after British scientists had pushed its development while the American government held back.

Howard Florey flew to America in a Clipper plane to do ditto with Penicillin, a British development that the American government had also put on the back burner.

For both Australians, they did this out of strong personal conviction that it was the right thing to do.

It is true that both also did it with approval from some mid to upper level bureaucrats within the British government.

But there hadn't been anything like a full debate at the top of the British government  about the matter, before the Australians were allowed to give away the store.

If there had been, it might have led to very different decisions on what was to become so portentous to Britain's dismal post-war fate.

Try to imagine our world post-1945 if the British , not the Americans , held the whip hand in atomic bombs and penicillin.....

Monday, August 9, 2010

The NEEDLE that wasn't there....

.... changed History.

In the early 1940s ,a parent was bemoaning to a doctor that by the time he got his sick child to the New London hospital from his summer home in Stonington Connecticut a few miles away, the doctors told him it was too late and his sixteen year old daughter Mary Louise was dead from spinal meningitis.

The doctor lectured him, as was his want, that if every GP carried a needle and some penicillin G in their black bag and gave it to every suspected case of meningitis, without waiting to get the patient to hospital to have their spinal fluid tapped and typed, no child ever need die from meningitis.

But unfortunately, the doctor went on to say, drug company executives are still too slow off the mark and GPs have no penicillin to put into their bags, 15 years after its discovery....shooting a meaningful glance at the parent.

The parent went home and thought about it a while  ---- God he hated that guy - always wanting more and always giving you a lecture instead of thanks for whatever you could give him ------- but he did think about it and probably even talked it over with his wife.

Who knows what happened that night. Did he tell his wife," I'd like to help Henry but you know me, I don't like to move quickly."

And perhaps his wife said softly, "I know" and then immediately wished she had never said it.

Perhaps they always agreed to never again talk about that awful night so long ago.

Who knows ?

What we do know, is that something totally unexpected happened, thanks to that parent.

True he was notoriously known as a very frugal and cautious man, but now that he actually decided to ' do something about it'  , he worked like a whirling dervish.

His name was John Lawrence Smith and if you know his name at all, you know him as one of the owners of the famed Brooklyn Dodgers.

During June 1944, the Brooklyn Dodgers had one terrible road trip after another.

But John L's other Brooklyn team scored one knockout after another that June in 1944, in places like Omaha ............ Utah ...... Juno ...... Silver........ and  Gold.

This is the true story of  " How Omaha Got Its 'P' " - and the doctor's advice is still good today - doctors are still advised to carry and use a needleful of Pen G on every suspected case of meningitis, ASAP, if they want to save a life.

If your child's life has been saved by a prompt needleful of Penicillin G, aka benzylpenicillin , offer up thanks to that parent.

(John L Smith ,the head of Pfizer, when it produced most of the penicillin that landed on the D-Day beaches - British and Canadian beaches as well as the American ones.)

And of course to that ever nagging doctor ,Martin Henry Dawson...