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.

It is little known that Karl Meyer, the chemist on the tiny pioneering Columbia university team ( the first ever to use penicillin as an antibiotic), contributed an unique intellectual portion to Henry Dawson's first presentation on penicillin.

This presentation was delivered in Atlantic City, at the 33rd annual meeting of the American Society for Clinical Investigation, ( the famous "Young Turks" ) May 5th 1941 --- attended by top medical researchers from all over the world and covered by the scientific and popular media.

To add to the journalistic fun, their more senior and sober counterparts, the American Association of Physicians, met the very next day in the same place - and the two generations of doctors didn't always agree on everything, naturally .

Most penicillin historians seemed to have limited their knowledge of this seminal event to the New York Times report on it, easily available anywhere on microfilm.

But the official abstract of Dawson's presentation , formally published in the Journal of the Society in July 1941, mentions - in passing - two important subject areas that all the popular media left out in describing Dawson's paper.

His presentation talked of the methods of preparation ( and importantly made it clear this took place in Dawson and Meyer's hospital lab and not in some drug company lab), without saying anything more.

 Fortunately later articles do amplify on the earliest methods of growing and extraction in great detail.

But the precis also indicates that information as then known of penicillin's chemical nature , ie known as of late 1940-early 1941 , was discussed --- without saying what was speculated.

This speculation is NOT repeated in any later article, because this early speculation was not even close to penicillin's final chemical structure, as found with the help of hundreds of chemists, five long gruelling years later.

But, while I am not a chemist, I think I can say it wasn't a bad guess for what was known - almost by sight and smell - about the earliest dry penicillin powder.

Thanks to SAMJ, the South African Medical Journal

But back to SAMJ - because it was all down to one of their most enterprising correspondents , H O Hofmeyr, that we know anything at all about the earliest chemistry of penicillin.

Hofmeyr came from a very politically powerful Afrikaner family and so it is not surprising he was sent abroad, during WWII, to be South Africa's scientific eyes and ears in places like Washington DC.

He wrote a very complete diary of his visit to the Clinical Investigators annual meeting and it was published, in full ,in the September 1941 monthly issue of SAMJ.

I think I remain the only one to ever cite Hofmeyr's eyewitness report on the opening of the Age of Antibiotics.

I have always treasured his report on Dawson's paper , partly for his slightly snide tone relating that this particular paper caught the imagination of ("sniff") the ("popular") press who gave it ("lurid") headlines like 'Giant Germicide Yielded by Mold'.

But in addition, Dr HO ( as everyone called him) correctly noted in 1941 what current historians always, always miss : that Dawson's use of penicillin on subacute bacterial endocarditis, the dreaded SBE, was in some ways, highly conventional.

Hofmeyr said it still remained in 1941, the absolute "acid test" for the claims of every new potential chemotherapeutic agent.

But buried in middle of the paragraph, Hofmeyr indicates that the Columbia team is willing to speculate publicly that penicillin seems related to the hydroquinones.

The hydroquinones are a big family best known for their use in photo developing and skin whitening, but one in particular, paraquinone ,strikes me as looking, smelling and acting rather like early penicillin powder.

Yellow , arid penetrating smell, very sensitive to acids and bases, yes it sure does look, smell and act like early penicillin.

But paraquinone has only has about one third the molecular weight and number of atoms that penicillin has (and was thought to have in 1941) so it would have to be quite an elaborated version to fit the known facts.

WE have to wait to 1942 and the much better known journals such as NATURE and SCIENCE to find the next set of informed guesses as to penicillin's structural nature, but thanks to SAMJ, we have recovered an important fragment of medical history .....

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

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

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

Florey was no country hick and disdained 'farming' penicillin

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

He remained a chemist-manque all his life.

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

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

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" ....