Wednesday, December 5, 2012

Dawson jumps the gun on Meyer's penicillin project

Henry Dawson does not deserve the credit he always gets for starting the wartime penicillin project at Columbia University.

(Honoured for taking control of it and making it into something to be universally and eternally admired, is a different story.)

Karl Meyer started it up - pure and simple. And as it happens, purity and simplicity were also the goals of his penicillin project.

Here's how it  allcame about, as I see it ,though I should say in advance that I wish to thank three other historians for discovering the important pieces needed to solve the puzzle.

(My interpretation of their findings is, of course, not something I can blame them for !)

I the order that I came across their work, let us start with David T Durack ,writing a relatively brief article detailing the history of the early work curing endocarditis with antibiotics.

"Early Experience in the Treatment of Bacterial Endocarditis"

Durack says that in August 1940, Meyer was reading the new copy of Lancet and comes across a report by Ernst Chain and others on the substance penicillin.

The Oxford team demonstrated the efficacy of semi-purified penicillin in stopping bacteria stone cold in vitro ( ho hum) and in experimentally induced massive infections in mice ( new - long overdue - and important).

( I personally think this issue wouldn't likely have arrived in New York from London ,in wartime, in less than about two weeks - so assuming it was first issued in London close to its cover date of August 24th, Chain was reading his New York copy on about September 7th.)

Durack got from Karl Meyer the frank admission ( 30 years or more after the original event) that Chain had gotten him all rilled up.

Meyer and Chain had probably met earlier in germany while both were training to be biochemists and frankly, Chain got a whole lot of people rilled up pretty easily.

In this case, Meyer who had done a lot of original work with lysozyme (along with Fleming, Florey and Chain and Leslie Epstein), felt that Chain had denied Meyer his rightful priority on some aspects of the research in Chain's own articles on lysozyme.

Clearly the August 24th article indicated Chain wanted to totally purify and then hopefully totally synthesize penicillin. But Chain was a fool - Meyer felt sure he could quickly solve the problem ahead of Chain.

Chain and Meyer were not technically enemy aliens, but as Germans and Jews and left wing (ish)  recent naturalized citizens they both felt insecure in their new homelands.

It was only natural both were hoping to do some big piece of research that would ensure they weren't discharged during some security scare.

(Remember, the only reason so many German Jewish refugee scientists ended up doing atomic bomb research was because they weren't trusted to do the real important research --- on radar and asdic !)

This background made the story plausible to me when I came across it seven years ago --- besides, it hardly flattered Meyer so why tell it unless it was true ?

Next up is Ronald Bentley recounting the story of young Leslie Epstein ( later Leslie Falk), an American Jewish - left wing - Rhodes Scholar who is in Oxford working with Ernst Chain in Florey's lab.

Florey didn't have much time for more than about three dozen people on the whole Earth --- so him not much liking left wing American Jews was par for him - but he was willing to work with them ---- if they brought badly needed money and pairs of hands into his hard-pressed institute.

Falk had done large scale biological work with Chain (highly unusual for biochemists) growing massive amounts of the bacteria that lysozyme consumed, in a successful efforts to find the exact substrate that this enzyme broke up - and how it did so.

They had tried the same method, beginning in early 1938, to grow large amounts of penicillin - with less than no luck.

This penicillin work had only been done in fits and starts, because lysozyme was more important.

But once lysozyme was solved and the war arrived, along with a large grant for penicillin work, Epstein carried on with lysozyme for his thesis while Chain and Heatley set to growing penicillin.

So Epstein was a second hand witness to all the key events of the oxford team , up to about June 1940 where he was orderd home after the Fall of France.

Home turned out to be Johns Hopkins in Baltimore, via New York.

While in New York ( and perhaps on summer return trips), Epstein spent time with another Jewish , mildly left wing, biochemist interested in lysozyme : Karl Meyer , Chain's rival !

Kudos to Bentley for noting Epstein thanking both Chain and Meyer in his final published October 1940 article and chasing down Epstein's biography for the full story.

I believe Epstein told Meyer of what his supervisor, Chain, wanted him to say about Meyer's role in lysozyme ( ie to be dismissive) and that Chain was having success with penicillin and an articles was due soon in one of the three or four important British medical cum scientific journals.

That is why, I believe, Meyer both found the article so quickly and was so quick to react to it in an organized manner.

To purify penicillin, Meyer did not need clinical work stealing the penicillin he needed for his destructive chemical studies.

But he did need Dawson to grow the stuff and test it against bacteria in vitro  and in artificially infected mice and to compare the potency level of each new purified sample.

dawson had great skill and experience in all these areas - [articularly in his pioneering work on recombinant DNA (aka bacterial transformation) .

Meyer might need to do a few limited clinical trials to justify his wages as purifying penicillin was hardly a big concern of an eye institute.

But he could use expect to only use tiny amounts ( a few units per treatment - ie about the amount grown in a single one litre flask ) of very crude penicillin to successfully treat simple eye infections topically.

(From Cecil Paine's unpublished work, we know this amount would have given clinical successes.)

But find the purity and the amount needed to cure - by needle - multiple cases of adults with invariable fatal SBE ; that was like racing up and down Everest before you could even crawl !

No , I believe Meyer made a bargain with Dawson and then Hobby : help me purify penicillin ( I expect success in about four months) and i will give you more pure penicillin than you can use for whatever clinical cases you want.

But for now, let me stall my bosses by helping me work with Phillips Thygeson on some cases of chronic eye infections.

I believe the original agreement was that from October to December, the best purified penicillin went to chemical studies, any crude left over was for Thygeson to trst against minor eye infections.

Come January, Dawson was to get clinical priority , with more and more refined penicillin, suitable for safe injection.

But Dawson jumped the gun, largely for symbolic reasons, by injecting tiny amounts over a brief two day period into two SBEs before they began their normal treatment with massive daily amounts of sulfa drugs sustained for months on end.

After this, from mid october to mid december, what little clinical penicillin was available went to Thygeson's eye infections.

I had long accepted that Meyer not Dawson started the project but that Dawson didn't know why it had been started --- because othrwise Dawson's letters to Chain made no sense.

But i had followed all  theother writers' lead that SBE was the original clinical goal and eye infections only added at the end when the supply was too small to really cure SBE.

But the timeline never made any logical sense (not to a PK {Philosopher's Kid} anyway !)

So when I read Mary Ellen Bowden explaining that the move to treat SBEs in October was months ahead of schedule, it all made sense.

For the normally very circumspect Gladys Hobby had fairly broadly hinted that Dawson was very impatient to get started.

And just five weeks from drug discovery to clinical use is certainly
among the most unusual medical processes ever recorded in modern times in a research-oriented hospital.

But I doubt even Hobby really knew what lay behind Dawson's haste: in my next post, let me offer up my explanation....

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