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 .....

CHEMISTRY made Joseph Florey family rich and famous

Tanning leather is an ancient and highly skilled activity involving many chemical processes --- a process humans have been doing world wide for tens of thousands of years.

But tanning leather by use of formal chemistry (man-made rather than naturally found chemicals) is only about 150 years old and was brand new to the Southern Hemisphere when Joseph Florey set out to make his fame and fortune in the backward colony of South Australia.

This new method was called "chrome leather"  and consisted of tanning leather by means of various compounds of the metal chromium.

 The traditional, natural way, was via using tannin from the bark of various hardwoods, together with urine,dung and brains of animals and humans, as well as involving a lot of expensive, capricious hand labour.

 And a lot of time.

Joseph Florey was also a part owner of a new wattle plantation near Mount Cone in the interior of South Australia.

Wattles make an important variant of leather, suitable where chrome leather was too soft.

Till then,  virtually treeless South Australia had to import its tannin at great cost.

Chrome leather, by contrast, was modern, fast, machine-oriented, capital oriented.

It was made without the use of foul-smelling human urine and excrement collected by little poor children on the street corners of the poor neighbourhoods .

The chemically active ingredients of those natural products had been learned and synthetically made equivalents were used instead.

This was Victorian Progress and Joseph Florey never let anyone forget it - it was the focus of his firm's static displays at the Exhibitions of Industry and Progress so beloved by the Victorian and Edwardian middle class.

It was encompassed in his trade mark,Chromella, which he had secured throughout all of Australasia (sic). He repeatedly defended that trademark in expensive court cases.

Joseph Florey hadn't invented chrome leather but he acted as he had.

He successfully won via the courts , at least locally, the right to prevent any other competitor from using any trade name that hinted that their leather was produced by the 'chrome' method - though the patents on the original process had gone by then.

Chemistry - and a very competitive and ligatious nature - made the Florey fortune.

These were lessons learned well by Howard Florey and why he wanted to become a chemist - and why he was so highly competitive.

Ironically, chromium, a heavy metal, in those days and today gives many  customers contact dermitious or worse -- it is banned in very young children's shoes.

And its waste products are far worse for the environment than urine and dung ever were.

So today a new progressive modified organic, natural, method called 'wet white' is replacing the Old School chrome, wet blue, method......

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 ..."