Wartime Penicillin's coke-addled Janus Month : March 1943

In March 1943 (midway through the war) , for the very first time in WWII, a part of wartime penicillin research that had been hitherto public was finally and effectively put under official government censorship : anything involving the chemistry of penicillin.

At the very same time, other (hitherto effectively secret) parts of the penicillin story were about to become globally publicized in official government propaganda !

"I am not making this up", as Canada's Liberal Party is wont to say.

Fleming never saved Churchill, but Gladys Hobby saved Florey's sister when his own penicillin couldn't !

Howard Florey was never more sleazy than in his dealings with Henry Dawson's team, as he desperately fought to restore the family name that his father dis-honored, by trying to remain the sole "hero" of wartime penicillin.

Just try to imagine what an university ethics committee today might say about a professor using his main rival's unpublished paper, sent to him in secret by his close friend (the same government official who censored his rival's paper and forbade its release) to improve his own work that is about to be allowed to be freely published !

That is what full Professor Howard Florey and university vice president and full Professor A N Richards actually did to associate professor chemist Professor Karl Meyer of Dawson's team , in mid 1942.

(As they say, tenure is 'red in tooth and claw'.)

Thanks to SAMJ (the SOUTH AFRICAN MEDICAL JOURNAL), we can learn of first published guess as to penicillin's chemical structure

SAMJ : the South African Medical Journal

So much has been written about the earliest days of trying to determine the chemical structure of pure penicillin, in such truly massive tomes like "THE CHEMISTRY OF PENICILLIN" and "ANTIBIOTICS,VOLUME II", and much more delightfully in John Sheehan's lucid-but-learned "THE ENCHANTED RING" , that there seems little more to add.

But that is not so, thanks to the South African medical journal SAMJ and its enterprise at putting all of its over 100 years of back issues online and free to access.

Henry Dawson "jump-started" The Age of Antibiotics because, almost alone in the medical world, he wasn't obsessed with 'purity' but rather with 'charity'

We have the records of only a few contemporary reactions to Henry Dawson's surprise decision to dramatically kick-start The Age of Antibiotics, 12 years after it should have begun but three months before it was scheduled to begin , but they are suggestive.

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....

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....

Working with the like-minded

Why didn't Martin Henry Dawson work with the biochemist (Michael Heidelberger) that his own Department already had among its staff?

Why did biochemist Karl Meyer work on penicillin with Dawson rather than with clinicians in his own department?

Dawson did work with Heidelberger - but only once  - once in their entire 15 year career together in the Department of Medicine.

Meyer did get two clinicians in his own department of Ophthalmology to try penicillin - but they won't publish until penicillin had become respectable.

His own boss (Phillips Thygeson) pretty well admitted he couldn't get along with Meyer.

Dawson's boss (WW Palmer) didn't believe anything could permanently cure SBE --- he also was on the same chemically-oriented wavelength as Heidelberger - who he had personally hired.

Dawson was much more biologically - almost ecologically - oriented.

Beyond that, Dawson got on with Karl Meyer because Meyer was a very rare biochemist, at least in those days.

He actually wanted his biochemical work to have an immediate and direct
impact on the patients' well being.

Dawson, too, always put the individual patient before the dictates of
abstract Science.

Pulvertaft, Queen, Duhig were all in bacteriology departments - I think this is why their penicillin pilot plants, while less important than Dawson's pioneering effort, probably came off better - and with a lot less heartaches - because growing penicillin was a natural fit in such departments.

Life isn't always fair - you must deal with it as it comes - but I wonder would Dawson have gotten Myasthenia Gravis if his boss had been more in tune with Dawson's vision of the potential of penicillin?

Personal animosities at Columbia Eye Institute pushed Meyer into Dawson's arms on penicillin?

Blepharitis , a chronic inflammation of the eyelids, remains one of the world's most common eye problems.

Much of the time it is caused by staph bacteria and at the start of world war two, staph was one of the few common pathogen bacteria not killed by the various sulfa drugs - the 'antibiotics' of the day.

This was a big problem for the military of all the combatant nations of that war.

They regarded aviation as the alpha and the omega of modern warfare and so gave inordinate attention to the brand new field of "aviation medicine".

One only has to recall the moral panic the Allies fell into on mere rumours that the Germans had discovered the Viagra of aviation - a cortisone that let their pilots fly higher faster longer, well you get the picture.

Meyer had a consultancy with Schering Corp America - an German-owned company - involving ,among other things, attempts to create stable esters of penicillin.

Fears that Schering's work on cortisone was at the behest of the Nazis, ( it was not) rendered Schering totally suspect in the eyes of British and American intelligence circles.

Anyone connected with Schering - like Karl Meyer and his penicillin efforts - went into a little black book of "no-nos".

Aircrews and Blepharitis

An existing, generally intractable, case of blepharitis kept a lot of potential air crews out of the various air forces right at the recruiting office - that was problem A.

Problem B was that a lot of crews seemed to get blepharitis,  either after they had been through training or while out on active service .

This was perhaps due to the strain of operating in the air of five miles up, behind an oxygen mask for hours.

It doesn't directly worsen your vision but it gives you blurry eyes which comes much to the same thing.

It also needlessly worried aircrews, who feared it meant worse things than it did.

Not just pilots or gunners are hit by its effects - engineers, navigation officers and bomb setters all had to look at lots of crucial numbers on lots of dials in very dim light - one pair of blurred eyes at the wrong moment could be terminal for the entire plane and crew.

Karl Meyer ,as a German Jewish emigre, had an easier relationship with Dr Ludwig Von Sallmann, who also was in exile --- from his native Austria because his wive was Jewish.

But even Sallmann only seemed to want to put Meyer's semi-purified penicillin into animals and then didn't publish anything on the results till a few years later (in 1943 - at least 2 years after the first experiments).

Typically of many,many doctors, he published freely on his early work with penicillin only after Baby Patty Malone made penicillin world famous, safe and respectable.

At least Dr Phillips Thygeson did put the crude penicillin into the eyes of 8 patients with chronic blepharitis caused by (sulfa-resistant) staph bacteria, between the late Fall of 1940 and the early Spring of 1941, with some very good results.

But he refused to publish on this success (adding his name to Fleming and Paine et al in England who also refused to publish their spectacular early successes with crude penicillin and eye diseases.)

The history of penicillin might have been much different if these doctors had crowed just a little.

Thygeson finally published on bleparitis and penicillin - in 1945 - noting its key military importance !

I think an oral history interview with Thygeson late in life suggests what happened:
I don't think he could stand Meyer much.

He accused him of being a constant paranoid about his work--- and having a gutteral accent that no student could understand.He said nothing about Sallmann's accent - though Sallmann had arrived in America about 8 years after Meyer.

Now a young student had heard all of these stories, feared dealing with Meyer but found him soft spoken and kind and stuck with him throughout his career long enough to write his  affectionate obit - so opinions clearly differed on Meyer's manner and personality.

Dawson hung in with him for almost 10 years, so he couldn't have been impossible to work with.

In fact, Meyer gradually transferred himself from the eye clinic to the internal medicine department where Dawson worked.

Thygeson chose not to help out Meyer, Dawson or the fate of penicillin by publishing in an area sure to advance penicillin's importance in the eyes of the military-oriented OSRD of Vannevar Bush.

Instead he stuck to publishing on his results with sulfa drugs - these were totally pure, came via the highly conventional route of a commercial drug company - and didn't work and had potential toxic side effects.

But they didn't come from the home brew lab of Karl Meyer and that might have been a big point in their favour...

@MichaelMarshallMogoesPo

Dawson had been set to be the "invisible man", the Charles Fletcher of The Manhattan Pilot

I believe that for two critical weeks at the very beginning of the The Manhattan Project, Martin Henry Dawson was not set to be the team leader/senior investigator - in fact he was not expected to be involved at all.

The team was supposed to be led by the biochemist Karl Meyer, with someone (anyone) acting as the microbiologist to test the 'in vitro' activity of the penicillin produced , again with some doctor (anyone) from Columbia Presbyterian's eye clinic in the clinician's job  (the nominal job of Dawson on the final Pilot team) .

The penicillin pilot's aim, at that point, was simply (!) to purify and then synthesize penicillin - most of the small amounts of crude penicillin produced would have to be destroyed in crystallization (purification) experiments.

Only tiny, tiny amounts could be spared to show the resulting penicillin still retained the needed biological activity against bacteria on a glass slide or against bacteria on/in a human.

These were expected to be merely subordinate activities to the main show - "making penicillin".

Now any drug, not just penicillin, needs to be first proven safe for humans when taking internally and be available in huge amounts, before it can be injected into the body as a 'systemic' --- versus simply being dropping a bit of it into the restricted/external area around the eyeball as an 'antiseptic'.

Penicillin, in particular, quickly slips out of the body and so needs even larger amounts than most drugs to work successfully as a systemic.

This is why penicillin's first successes in Britain during the 1930 (but tragically for humanity never published), were in removing deadly bacteria from the area around the eyes.

Meyer ,working in an eye clinic ,knew these truths better than most. In fact, he did involve two doctors from his clinic to use some of his penicillin with their patients but both doctors (Von Sallmann and Thygeson) seemed dubious about its usefulness around and in the eyes (as well they should have been).

 The results were not spectacular and were published a few years later.

Eyes were saved in the early 1930s from a lifetime of blindness with treatments of diluted crude penicillin that in total must have consisted of only 1.6 Oxford units of biological activity (that is equal to one millionth of a gram of pure penicillin).

By contrast, Dawson's disease of choice to test penicillin upon, SBE, subacute bacterial endocarditis, may today require 1.6 billion units of penicillin to cure.

That is one kilogram of pure penicillin - one billion times as much penicillin.

It was known in 1940 that SBE would need an extraordinary large amount of whatever drug that could kill the bacteria in its vegetations because of the unique location of the lesions and the poor blood supply of the heart valves they rested upon- that is the problem in fact that still makes SBE the 'gold standard' of intractable infections.

All drugs to date, as of 1940, had to be used in such large amounts to kill the bacteria that they killed the patient first - because even a relatively "non-toxic" drug is deadly if used by the shovelful !

It was Dawson's genius to see that penicillin's strength was not what the popular books on it still proclaim - its ability to kill bacteria - but rather its ability not to kill the patients, even when used in extraordinarily high amounts for months at a time.

And SBE proved to be just the disease to demonstrate that fact....

@MichaelMarshallMogoesPo