Wednesday, January 23, 2013

James Baxter's Pulitzer Prize winning nonsense about wartime penicillin

As part of OSRD's campaign to spin its considerable successes and many failures, William College president and historian  James Phinney Baxter III was hired in mid war (1943) to assemble a bewitching mixture of hitherto-secret facts and sheer blarney, called "Scientists Against Time".

It sure fooled the 1947 Pulitzer Committee, but it shouldn't continue to fool us.

In mid 1943, reports of the consistent creation of crystal pure penicillin began to came in from various laboratories - the final necessary difficult perquisite to beginning the 'easy' chemical synthesis of penicillin.

In what appeared to be a very astute move (at the time!), the OSRD moved to hand off the Congressional blame for the wasting tens of millions of 1940s taxpayers dollars on a failed expansion of biological penicillin production to an inferior Washington bureaucratical competitor (the War Production Board's OPRD).

The OSRD wanted to focus on garnering in all the certain glory coming to the Washington agency that was seen as funding and running the program that led to the synthesis of cheap and abundant artificial penicillin.

But the OSRD lost its gamble.

Instead it was the lowly OPRD that won, in a highly dramatic and timely fashion just in time for D-Day, while high-and-mighty OSRD had to eat millions of taxpayers' dollars spent generating not one nickel of therapeutic synthetic penicillin.

Baxter's job, in the chapter devoted to the OSRD's penicillin efforts, was to spin these awkward facts otherwise.

He was helped by the failure of the underfunded OPRD not to have the money needed to pay for its own tame house historian.

Baxter's job was to convert the biological success of the latecomers OPRD into being just a minor part of the final success of the long time efforts of OSRD-funded chemists to "purify" penicillin.

He sought to tie together the "chemical" ( his words - page 342 of his book) success of in natural penicillin production) as somehow coming out of the 16 years wasted on the "chemical" synthesis of the antibiotic.

The chemical "Purification" of the "crude" mixture of biological penicillin and its biological impurities was to provide that intellectual bridge.

But in fact, the body could care less about purification - it does worry about toxicity, but regards neutral fillers and water as largely irrelevant.

Quite rightly, it only regards the absolute amounts of biological activity (measured in "Units") of soluble penicillin as being important to cure an infection.

It cares not at all about their original relative degree of dryness (concentration), the amount of neutral bulk filler that comes bundled with them, or the amount of water that penicillin comes dissolved in.

After all, the human body is between 50% to 75% water and it quickly dilutes all drugs to incredibly small concentrations.

Now just to remind readers, one gram of water (mass) is one cc (cm3) of water (cubic area) is one ml (volume) --- and a gram of penicillium juice holding 3% of dissolved solids isn't going to fundamentally change this formula much.

James Duhig got 400 to 800 units of biological activity from each one litre flask (containing 200 grams of penicillin liquid) that he grew in his Brisbane lab in 1943-1944, using the exact same strain of penicillium and the exact same low level of technology that Alexander Fleming had in 1928.

That is he got 2 to 4 units per ml/cc/ gm of penicillium medium, the exact same as Fleming got way back in the Fall of 1928.

Basically Duhig and Fleming got about one microgram of active penicillin per gram of water : one part per million, one ppm.

You don't have to be a rocket scientist to know that is not much of a ratio of useful to useless !

But even when Fleming diluted that 1 ppm in a lot more sterile water - down to the level of  one part per billion -, a tiny drop of extremely diluted stuff could still kill deadly bacteria.

But Duhig didn't dilute his stuff any further. Instead he chilled his penicillin liquid, only running it through a filter to remove solid solids.

It still contained its 3% of soluble solids "impurities", along with its  97% pure water. It was still as 'crude' as the day it was born.

Then Dr Duhig injected that liquid straight into a woman's blood stream in 300 to 600 gram amounts (aka 300 to 600 ml/cc of solution). (A thousand or two units of biological activity per injection.)

And incredibly (considering that today we would use millions not thousands of units per injection) Duhig's crude penicillin pulled a dying woman almost literally out of her grave.

He finally did in remote Queensland Australia in 1943 what Alexander Fleming  in 1928 London - and every single doctor in the world  after him - criminally failed to do : use the original penicillin , entirely untouched by the hands of the chemists, to save lives.

But it is another Australian-born doctor, Howard Florey (originally from Adelaide) now operating out of Oxford University, who scientists and historians (including our Dr Baxter) give all the credit for making Fleming's crude "novelty-only" penicillin into a refined/purified life saver, in a famous experiment in May 1940.

But does he - and this famous "mouse" experiment - deserve that credit?

By Florey's own words, he doesn't think so.

And incredibly,  Baxter had Florey's actual words in front of him, when he wrote his own account just after the war's end.

Its all there in Florey's second penicillin article, "Further Observations on Penicillin" ,LANCET, August 1941.

(This incredibly detailed article should have been sufficient, in and of itself, for any competent hospital or multinational drug company anywhere in the world of WWII to make life saving penicillin  --- provided they could get their hands on Fleming's strain of penicillium, or one like it.)

In this article, Florey does indicate that his March 1941 human therapeutic penicillin has 40 units per mg of powder (page 178).

But on the next page (page 179) he clearly indicates that the powder used in the May 1940 mouse experiment probably had less than 1/10 the biological activity of the current human therapeutic penicillin.

So that powder had 2 to 4 units per mg , compared to the 2 to 4 units per gram of original crude fluid.

That is , we have gone from having penicillin consisting of about one part per million of liquid to consisting one part per thousand of dry powder.

Since all the water is gone, what is in the other 999 parts of that milligram ? Yep, its the same 3% of soluble biological impurities that were in the original crude watery mixture of Fleming.

Florey has not purified his penicillin at all, merely concentrated it  (that is merely removed its water ; we make orange or milk powder from their watery originals in the same way, by evaporation).

My essential point is that Fleming's 1928 mixture of natural penicillin and biological impurities was safe to inject, with or without its sterile water being removed.

(And remember, Florey had to put water back into his powder to get it into his patients ; if it was to go in as a slow IV drip, it could be as diluted as it was in the original brew, before all that expensive concentrating.)

That concentration process took not just an awful lot of human energy to perform ; it also destroyed two thirds of the available penicillin.

Concentrated penicillin didn't save more patients ; criminally it actually saved two thirds less.

By late 1942 - early 1943, biological improvements in growing penicillin now gave us raw penicillin brew that gave 40 units per cc of liquid.

The Russians, logically enough, felt there was no need to waste human energy and expensive scarce equipment merely to destroy two thirds of this life-saving liquid, just so they could falsely claim to "purify" it, aka 'concentrate' it.

The other Allies might well have followed their example and then we would have had no mid-war penicillin famine.

Life saving did not require purified penicillin - in fact, the wartime  purification of penicillin tended to reduce the amount of penicillin of penicillin available for the dying in figures varying from two thirds to infinity.

Yes infinity : in the Spring of 1943 Glaxo was - briefly - the world's largest penicillin producer.

Incredibly, in the middle of a bloody war, none of that penicillin went to save human lives. It all went to the Glaxo chemists to destroy, trying to get it to go into crystal so they could synthesis it, analogue it and profitably patent it.

Purification, inessential to life-saving, was crucial to the efforts to synthesis penicillin.

Enough penicillin to save millions would have come years earlier if universities and drug companies had released their chemists to the Draft Boards and hired mycologists instead.

But Baxter doesn't play it that way.

Florey had merely evaporated Fleming's penicillin and had thus obtained penicillin that was relatively 1000 times stronger than Fleming.

However, in absolute terms of therapeutic penicillin per flask of penicillin brew, it was actually three times less strong (and remember our bodies and their germs only care about absolute amounts, not relative amounts.)

But Baxter (who wasn't at the experiment) deliberately ignores Florey's own words (and Florey was at the experiment) to confidently and falsely claim that the mouse experiment penicillin was 3% pure.

Actually it was .3% pure , as Florey himself admitted in 1941,the same as Fleming's 1928 crude mixture.

Fleming deserves a lot of credit for making penicillin available - but also a lot of blame as well, when he failed to confirm his failed micro experiment on the possible systemic use of his crude penicillin - by trying it again on a variety of animals and humans.

Florey, similarly, deserved much credit for pushing penicillin to the front of scientific attention - but also a lot of blame for his obsessive  need to put make purified crystal penicillin for chemical synthesis.

Worse, he mis-used his scientific authority to actively brow-beated many other decent doctors into stopping their production of "good enough" penicillin, merely to try to save lives in the middle of a savage war.

If they saved lives with crude penicillin, he saw his sole claim to scientific fame disappearing.

Florey readily admitted that he wasn't the first to discover penicillin (Fleming) and tried not to admit that he was not the first to put it into a patient (Dawson) ,but he wanted very much to claim that he was the first to purify it, so it could be injected into humans.

Duhig would dismiss that claim.

As would Dawson, who was at great pains (in his May 1941 article on penicillin) to publicly emphasize that his first human injections were taken from crude, concentrated "not purified, yet non-toxic" penicillin.

And so should have Dr Baxter......

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