One of the major differences in my account of the development of penicillin from all the others, is that I don't plan to tell the 'exciting' story of penicillin, with World War Two merely as part of the backdrop.
The fact is that during the war penicillin was never more than a sidebar to the main story, even on both sides of September 1943 when it was a major news item for about eight weeks .
Events elsewhere in the war moved penicillin forwards or backwards in importance in the eyes of war planners and nothing anyone in the entire circumscribed world of penicillin development had anything like the impact upon penicillin development that changes on the war front did.
The Eisenhower-Marshall proposed dates for a major cross-channel invasion - in summer 1942 or March 1943 (Operation Sledgehammer and Operation Roundup) - meant the US Army accepted and indeed demanded mass quantities of so-so but available medical supplies now over the possibility of better medical supplies later.
Penicillin was put on the back burner - deliberately - even though its superior qualities to sulfa was sensed early on.
The decisions to take the British tack of delaying the cross-channel invasion till May 1944 (or later), allowed US Army planners, early in 1943, to admit that the sulfa drugs had always had a lot of problems and that they were increasing in intensity.
Sulfa faced growing and widespread bacterial resistance.
In addition, powdered sulfa had proven frequently deadly when used in 'real life' sun-baked combat areas where water is usually in short supply.
This, in my view, was the result of too many combat-shy senior doctors making assumptions about battlefield conditions, when they had actually avoided the battlefield as young men during World War One .
The existing Army Surgeon was sent into retirement in the Spring of 1943 and a less cautious general (Norman Kirk) replaced him --- this has not been recognized as one of the new key factor in penicillin's improved prospects in getting up to mass production in America in late 1943.
But above all, penicillin now gained the time it needed if it was to be to eased into the military medicine cabinet.
All because of the extra year of breathing room gained for war planners because of the revised dates for the cross channel invasion from 1943 to 1944.
Martin Henry Dawson's 'SBE and penicillin' work went on regardless of the war's ebb and flow and his first success with SBE patients in the Spring of 1943 had roused John L Smith of Pfizer and others and so we might have had abundant penicillin by early 1944 ,irregardless of the new military demand for it ---we will never know.
The two penicillin stories ran in parallel ,not in series, and their climax coming together during the Spring of 1943 was, in fact, a coincidence ....
Monday, August 9, 2010
Sunday, August 8, 2010
How to tell a lie - and prosper
On February 1st 1964, the journal NATURE ran a long feature article by Dr A N Richards, a foreign member of the Royal Society, a professor emeritus in pharmacology at the University of Pennsylvania and the head of the medical section of America's all powerful science agency, the OSRD......
(Blogger ate about 1000 words right about here - I'll re-type it when my temper cools down - I have learned to print my blog posts out as PDFs right away since this 'incident' - ARRRGH !!!!!!)
......Fulton had been out in Central California investigating aviation medicine for the military and had wandered into a lab where a fungi researcher was working with this fungi ,without proper modern precautions, and Fulton was soon stricken onto death.
(Or he simply got it during the days he spent on a military base deep in this valley - the more likely explanation but a lot less colorful story...)
The disease was worked up by the American Military during the Cold War to use as a possible Germ Warfare weapon but in fact it was usually not fatal even if not treated.
But if it spreads from your lungs to everywhere else in your body, it was and is usually fatal.
Fulton eventually knew he was very sick from this fungus but he also knew he was also getting the best possible care one of the best medical schools in the world would naturally give to one of its most senior doctors - he wasn't excessively worried.
Nor where his doctors, until they took a routine swab from a unrelated boil he had on his abdomen to type it for sulfa treatment. Unfortunately, to their shock, it was filled with the fungus --- it seemed he was a goner and all kinds of "heroic' ( ie risky, foolhardy) medical interventions were suggested, as he seemed likely to die anyway.
Fulton had been telling his main doctors that his very best friend Howard Florey was working with a totally new substance, penicillin ---- produced by another fungus --- and finding it could kill an ever-widening array of microbes.
These doctors decided not to tell Fulton that his boil meant he likely faced a painful death and instead enlisted him to pull strings to get some penicillin for a fellow patient, Anne Miller.
They secretly would divert a bit of it, to see if killed off rival fungus and so save Fulton.
This was good peacetime science - but in wartime, the medical establishment tended to say, if it isn't a common military disease, let the man die - we need the penicillin more elsewhere.
Luckily for Fulton, the military had lots of bases in this valley and military men were getting sick and dying from this fungus - so a military need could be evoked - in a stretch.
Merck, the OSRD,and the COC had all gotten pitiful pleas for penicillin before the phone calls from John Fulton---- and turned them all down.
The calls usually involved SBE, an almost always fatal form of endocarditis that - in those days - usually stricken young teens and young adults.
These kids were considered by the medical establishment as the $Fs of the $Fs, as people not worth wasting penicillin on during an all out total war.
Martin Henry Dawson had said since 1940 that he felt that penicillin could cure SBE - war or no war - and they should be saved.
No other doctor in the world believed strongly that they should - at the time.
Most still didn't feel SBEs could be cured or were a priority, even at the time of his death in 1945 - by which time he had about three dozen cures - some cured for as long as three years with a repeat bout.
Norman Heatley of Florey's Oxford University penicillin team was working for Merck and reporting everything back to Florey in England.
He had already recorded in his diary, in November 5 1941 and December 3 1941, receiving pleas to provide penicillin to individuals dying of SBE, while visiting labs in Canada, Dawson's home country.
Merck, the ORSD, the COC hadn't helped young Joan Murray with her SBE then, so why help Anne Miller now ?
(Heatley, not a medical doctor, seems to have felt in his 1942 diary that Miller might have SBE.)
Let us, for a moment, return to Richards.
The thesis of Richards and all the other medical bureaucrats in charge of wartime penicillin was simple - "give us lots of taxpayers' money, leave us alone away from taxpayer scruntiny, and we will produce penicillin quickly and cheaply and distribute it objectively and absolutely without favouritism."
In fact, the very first case the OSRD/COC and Merck was involved in was a blatant case of favoring the mighty and the wise over the weak and foolish.
Once it was secretly told to a very few people - perhaps only Richards - that the penicillin for Miller was also going to go to help save Fulton, it made it likely that penicillin would be forthcoming.
In his own right, Fulton was considered a valuable part of the medical brains that America felt it needed to husband if it was to win the war --- he and his own doctor, Francis Blake, were high up in the war medicine committees deciding American health priorities.
The scientists found that even the politicians, the military and the business elite (and perhaps the general public as well) agreed that healthy, fit 1A scientists shouldn't be drafted - too valuable to the war effort.
The same thinking said penicillin was wisely used if it saved Fulton --- unwisely used if it merely went to save 4F useless SBE kids..
More importantly, Fulton was the very best friend of Florey, a man with few really close friends.
The other closest friend that Florey had in America was Richards himself.
Richards and Merck needed Florey on their side if they were to convert a largely British effort into a profitable venture for Merck in America.
While Blake secretly pulled strings for Fulton and Fulton openly pulled strings for Miller, the key person, I believe, was Richards.
The OSRD and CMR, the COC ,the NRRL,the British MRC and TRC, Merck and other drug firms , the NRC-NAS, the military Surgeons General, basically every official and semi official body connected to wartime penicillin all reveal a long paper trail of documents showing they usually bowed to Richards' dictates.
Luckily for Fulton, while the penicillin didn't do anything for his strain of fungus, careful nursing care kept him alive till his own body pulled him through.
He apparently never knew how he had been 'used' to help save his own life.
Anne Miller's case was not the first one involving penicillin in North America.
Dawson and Meyer's homebrew penicillin and Pfizer penicillin had treated at least 15 cases by March 14th 1942, the day Anne Miller got her famous first needle.
One had gotten penicillin - in fact history's very first needle of penicillin - and been cured - but not by penicillin.
Some had been cured by Dawson's penicillin - but the penicillin hadn't been injected internally as an antibiotic only dropped into an eye as an antiseptic.
A few cases of Dawson's had already been treated by the first commercial penicillin used clinically in North America - Pfizer lot number 696, first injected March 5th 1942, according to his co-worker, Gladys Hobby,in her lab records and correspondence file, as recounted in her 1985 book, PENICILLIN - MEETING THE CHALLENGE.
Because Pfizer wasn't in the OSRD-COC-Merck-Squibb agreement, its commercial penicillin wasn't counted by Richards and the OSRD when it came to proclaiming Anne Miller the first patient cured by penicillin in America.
Nor was Abbott or Eli Lilly, both huge drug companies back then, soon to do their own independent-of-the-OSRD/COC clinical trials.
But interestingly, the OSRD/COC were glad to add Dawson's cases, produced from this invisible Pfizer penicillin, to their total of the first 100 cases treated by penicillin in America.
AND Hobby says that Richards knew and personally approved Pfizer sending this commercially-produced penicillin to Dawson to use clinicallly , though Pfizer was not bound to listen to Richards at all.
A few of the most careful historians today say that Anne Miller was the first person cured by penicillin provided by the OSRD and I think this is exactly right.
But there was a vast world of penicillin activity around the globe between 1938-1945 and much of it was not directed by the OSRD or any OSRD-bodies in other countries - it was the work of individuals who like Dawson merely thought they could do something right now, not perfect or big, that might help save a few lives around them.
Ironically once those agape scientists and amateurs got to Doctor Mom, she lit the fire under Richards' ass that finally got us penicillin en masse,overnight, 15 years after it was first discovered...
addendum : I just discovered that TV megastar Dr Gregory House did reference Fulton's rare fungus disease in one of his episodes....
(Blogger ate about 1000 words right about here - I'll re-type it when my temper cools down - I have learned to print my blog posts out as PDFs right away since this 'incident' - ARRRGH !!!!!!)
......Fulton had been out in Central California investigating aviation medicine for the military and had wandered into a lab where a fungi researcher was working with this fungi ,without proper modern precautions, and Fulton was soon stricken onto death.
(Or he simply got it during the days he spent on a military base deep in this valley - the more likely explanation but a lot less colorful story...)
The disease was worked up by the American Military during the Cold War to use as a possible Germ Warfare weapon but in fact it was usually not fatal even if not treated.
But if it spreads from your lungs to everywhere else in your body, it was and is usually fatal.
Fulton eventually knew he was very sick from this fungus but he also knew he was also getting the best possible care one of the best medical schools in the world would naturally give to one of its most senior doctors - he wasn't excessively worried.
Nor where his doctors, until they took a routine swab from a unrelated boil he had on his abdomen to type it for sulfa treatment. Unfortunately, to their shock, it was filled with the fungus --- it seemed he was a goner and all kinds of "heroic' ( ie risky, foolhardy) medical interventions were suggested, as he seemed likely to die anyway.
Fulton had been telling his main doctors that his very best friend Howard Florey was working with a totally new substance, penicillin ---- produced by another fungus --- and finding it could kill an ever-widening array of microbes.
These doctors decided not to tell Fulton that his boil meant he likely faced a painful death and instead enlisted him to pull strings to get some penicillin for a fellow patient, Anne Miller.
They secretly would divert a bit of it, to see if killed off rival fungus and so save Fulton.
This was good peacetime science - but in wartime, the medical establishment tended to say, if it isn't a common military disease, let the man die - we need the penicillin more elsewhere.
Luckily for Fulton, the military had lots of bases in this valley and military men were getting sick and dying from this fungus - so a military need could be evoked - in a stretch.
Merck, the OSRD,and the COC had all gotten pitiful pleas for penicillin before the phone calls from John Fulton---- and turned them all down.
The calls usually involved SBE, an almost always fatal form of endocarditis that - in those days - usually stricken young teens and young adults.
These kids were considered by the medical establishment as the $Fs of the $Fs, as people not worth wasting penicillin on during an all out total war.
Martin Henry Dawson had said since 1940 that he felt that penicillin could cure SBE - war or no war - and they should be saved.
No other doctor in the world believed strongly that they should - at the time.
Most still didn't feel SBEs could be cured or were a priority, even at the time of his death in 1945 - by which time he had about three dozen cures - some cured for as long as three years with a repeat bout.
Norman Heatley of Florey's Oxford University penicillin team was working for Merck and reporting everything back to Florey in England.
He had already recorded in his diary, in November 5 1941 and December 3 1941, receiving pleas to provide penicillin to individuals dying of SBE, while visiting labs in Canada, Dawson's home country.
Merck, the ORSD, the COC hadn't helped young Joan Murray with her SBE then, so why help Anne Miller now ?
(Heatley, not a medical doctor, seems to have felt in his 1942 diary that Miller might have SBE.)
Let us, for a moment, return to Richards.
The thesis of Richards and all the other medical bureaucrats in charge of wartime penicillin was simple - "give us lots of taxpayers' money, leave us alone away from taxpayer scruntiny, and we will produce penicillin quickly and cheaply and distribute it objectively and absolutely without favouritism."
In fact, the very first case the OSRD/COC and Merck was involved in was a blatant case of favoring the mighty and the wise over the weak and foolish.
Once it was secretly told to a very few people - perhaps only Richards - that the penicillin for Miller was also going to go to help save Fulton, it made it likely that penicillin would be forthcoming.
In his own right, Fulton was considered a valuable part of the medical brains that America felt it needed to husband if it was to win the war --- he and his own doctor, Francis Blake, were high up in the war medicine committees deciding American health priorities.
The scientists found that even the politicians, the military and the business elite (and perhaps the general public as well) agreed that healthy, fit 1A scientists shouldn't be drafted - too valuable to the war effort.
The same thinking said penicillin was wisely used if it saved Fulton --- unwisely used if it merely went to save 4F useless SBE kids..
More importantly, Fulton was the very best friend of Florey, a man with few really close friends.
The other closest friend that Florey had in America was Richards himself.
Richards and Merck needed Florey on their side if they were to convert a largely British effort into a profitable venture for Merck in America.
While Blake secretly pulled strings for Fulton and Fulton openly pulled strings for Miller, the key person, I believe, was Richards.
The OSRD and CMR, the COC ,the NRRL,the British MRC and TRC, Merck and other drug firms , the NRC-NAS, the military Surgeons General, basically every official and semi official body connected to wartime penicillin all reveal a long paper trail of documents showing they usually bowed to Richards' dictates.
Luckily for Fulton, while the penicillin didn't do anything for his strain of fungus, careful nursing care kept him alive till his own body pulled him through.
He apparently never knew how he had been 'used' to help save his own life.
Anne Miller's case was not the first one involving penicillin in North America.
Dawson and Meyer's homebrew penicillin and Pfizer penicillin had treated at least 15 cases by March 14th 1942, the day Anne Miller got her famous first needle.
One had gotten penicillin - in fact history's very first needle of penicillin - and been cured - but not by penicillin.
Some had been cured by Dawson's penicillin - but the penicillin hadn't been injected internally as an antibiotic only dropped into an eye as an antiseptic.
A few cases of Dawson's had already been treated by the first commercial penicillin used clinically in North America - Pfizer lot number 696, first injected March 5th 1942, according to his co-worker, Gladys Hobby,in her lab records and correspondence file, as recounted in her 1985 book, PENICILLIN - MEETING THE CHALLENGE.
Because Pfizer wasn't in the OSRD-COC-Merck-Squibb agreement, its commercial penicillin wasn't counted by Richards and the OSRD when it came to proclaiming Anne Miller the first patient cured by penicillin in America.
Nor was Abbott or Eli Lilly, both huge drug companies back then, soon to do their own independent-of-the-OSRD/COC clinical trials.
But interestingly, the OSRD/COC were glad to add Dawson's cases, produced from this invisible Pfizer penicillin, to their total of the first 100 cases treated by penicillin in America.
AND Hobby says that Richards knew and personally approved Pfizer sending this commercially-produced penicillin to Dawson to use clinicallly , though Pfizer was not bound to listen to Richards at all.
A few of the most careful historians today say that Anne Miller was the first person cured by penicillin provided by the OSRD and I think this is exactly right.
But there was a vast world of penicillin activity around the globe between 1938-1945 and much of it was not directed by the OSRD or any OSRD-bodies in other countries - it was the work of individuals who like Dawson merely thought they could do something right now, not perfect or big, that might help save a few lives around them.
Ironically once those agape scientists and amateurs got to Doctor Mom, she lit the fire under Richards' ass that finally got us penicillin en masse,overnight, 15 years after it was first discovered...
addendum : I just discovered that TV megastar Dr Gregory House did reference Fulton's rare fungus disease in one of his episodes....
Friday, August 6, 2010
Roth Spots, eye doctors lead way with penicillin
All the many good claims to be "the first ever penicillin case" involved eye problems ---- even Martin Henry Dawson's SBE cases!
In this order:
Paine/Fleming ---- pen as an antiseptic.
Dawson/Fletcher ----------pen as an antibiotic.
Let us not forget that the first to "concentrate" penicillin was another eye doctor, young Doctor Ridley, under Fleming's watch back in 1929.
Karl Meyer was a biochemist in an Eye department and needed some thin excuse to go along with Dawson's plan to use penicillin to cure SBE --- a heart disease.
Dawson's excuse - even thinner - was that SBE was a sequel of Rheumatic Fever which had arthritis as one of its features and might be connected, somehow, to Rheumatoid Arthritis.
Most doctors till recently, felt the surest sign of SBE was Roth Spots, white spots, on the retina.
Curing SBE would also cure the Roth Spot eye problem....
In this order:
Paine/Fleming ---- pen as an antiseptic.
Dawson/Fletcher ----------pen as an antibiotic.
Let us not forget that the first to "concentrate" penicillin was another eye doctor, young Doctor Ridley, under Fleming's watch back in 1929.
Karl Meyer was a biochemist in an Eye department and needed some thin excuse to go along with Dawson's plan to use penicillin to cure SBE --- a heart disease.
Dawson's excuse - even thinner - was that SBE was a sequel of Rheumatic Fever which had arthritis as one of its features and might be connected, somehow, to Rheumatoid Arthritis.
Most doctors till recently, felt the surest sign of SBE was Roth Spots, white spots, on the retina.
Curing SBE would also cure the Roth Spot eye problem....
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?
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?
Ignoring 'day jobs' at our peril
Historians may think they are telling a faster paced tale when they leave out the minutiae
of ordinary daily life to focus on the high points of their subject's life - reasoning that these dramatic episodes are why you are buying their book.
But real people - even larger-than-life heroic real people - are worn down each day by picking up baby nappies at the store, taking out the trash, dealing with colleagues and relatives, answering routine letters or phone calls.
Remembering Mother's Day cards -- trying to fix a bank overdraft.
Perhaps the events they are famous for only took up a small fraction of each day during the period in question - squeezed in between the rest of their life.
All the more credit then for changing diapers and changing the world - when most of us can barely get through our routine day.
Alexander Fleming was ,mostly, the manager of a very large Vaccine Factory -- he discovered penicillin in his spare time.
I will not be the first or the last to say that how he dealt with penicillin after he discovered it was highly colored by the need to keep his vaccine factory profitable - because it paid for the entire institute he worked for.
Florey's day job was even more demanding - he did his famous mouse experiment in Room 46 of the Dunn Institute of Pathology that he ran.
That room number alone should tell how truly huge the Dunn Pathology Building really was.
He could have a hundred people in and about that building - and because he didn't have a hugely profitable vaccine line to sustain it, he spent most of his time trying to secure long term grants to pay them and buy them supplies and equipment.
He always freely admitted that is why he got interested in life-saving penicillin--- as an easy way for an increasingly desperate Institute Director to secure a nice large long term grant.
An honest account of Florey and penicillin would also mention his personal research interests outside of penicillin - which ranged very widely.
His mistress/closest co-worker intimated in a famous postscript in a letter to Norman Heatley that not till early 1942, four years after the penicillin project got started at Florey's institute, did it become the top research interest of Florey himself !
So for the years 1938-1941, how much time did Florey really give each day to the only research work he is remembered for today?
And Alfred Newton Richards over at the OSRD CMR - how much time did he really give to penicillin on a day by day basis ?
Supposedly plenty to judge by the hagiographies he had commissioned.
But when I follow the actual money trail from the OSRD to penicillin researchers --- or rather the non-money trail ---- I am left feeling he did nothing for penicillin much of the time.
Most of the millions he dished out each year - when millions meant plenty - went elsewhere - and I trust the money trail far more than I trust the post-success spin doctors.
Martin Henry Dawson had a day job too.
He ran an Arthritis Clinic - and in those days, arthritis was a symptom, not a cluster of diseases - much as fever isn't a disease but a symptom of many diseases.
Arthritis occurs ,transiently, in many diseases, so trying to determine what unusual disease a person might mean dragging them over to Dawson to get his opinion.
This kept the job interesting but it meant that it couldn't be regarded as a routine affair that could be handed of to a junior member while Dawson engaged in his personal research interests.
He fitted in his penicillin work between the Clinic hours, teaching classes, marking papers, doing grand rounds, helping grad students, attending committee meetings - going to his Dad's funeral back in Nova Scotia - picking up a great Persian carpet cheap the day the World's Fair closed.
Maybe while picking up baby food for the new baby because Marjorie was running late at her school.
Or maybe he did some penicillin work in between sitting down on a couch to recover his strength as his Myasthenia Gravis kicked in.
That is Real Life stuff.
And I intend to put Real Life back into my account of the Penicillin Saga.
of ordinary daily life to focus on the high points of their subject's life - reasoning that these dramatic episodes are why you are buying their book.
But real people - even larger-than-life heroic real people - are worn down each day by picking up baby nappies at the store, taking out the trash, dealing with colleagues and relatives, answering routine letters or phone calls.
Remembering Mother's Day cards -- trying to fix a bank overdraft.
Perhaps the events they are famous for only took up a small fraction of each day during the period in question - squeezed in between the rest of their life.
All the more credit then for changing diapers and changing the world - when most of us can barely get through our routine day.
Alexander Fleming was ,mostly, the manager of a very large Vaccine Factory -- he discovered penicillin in his spare time.
I will not be the first or the last to say that how he dealt with penicillin after he discovered it was highly colored by the need to keep his vaccine factory profitable - because it paid for the entire institute he worked for.
Florey's day job was even more demanding - he did his famous mouse experiment in Room 46 of the Dunn Institute of Pathology that he ran.
That room number alone should tell how truly huge the Dunn Pathology Building really was.
He could have a hundred people in and about that building - and because he didn't have a hugely profitable vaccine line to sustain it, he spent most of his time trying to secure long term grants to pay them and buy them supplies and equipment.
He always freely admitted that is why he got interested in life-saving penicillin--- as an easy way for an increasingly desperate Institute Director to secure a nice large long term grant.
An honest account of Florey and penicillin would also mention his personal research interests outside of penicillin - which ranged very widely.
His mistress/closest co-worker intimated in a famous postscript in a letter to Norman Heatley that not till early 1942, four years after the penicillin project got started at Florey's institute, did it become the top research interest of Florey himself !
So for the years 1938-1941, how much time did Florey really give each day to the only research work he is remembered for today?
And Alfred Newton Richards over at the OSRD CMR - how much time did he really give to penicillin on a day by day basis ?
Supposedly plenty to judge by the hagiographies he had commissioned.
But when I follow the actual money trail from the OSRD to penicillin researchers --- or rather the non-money trail ---- I am left feeling he did nothing for penicillin much of the time.
Most of the millions he dished out each year - when millions meant plenty - went elsewhere - and I trust the money trail far more than I trust the post-success spin doctors.
Martin Henry Dawson had a day job too.
He ran an Arthritis Clinic - and in those days, arthritis was a symptom, not a cluster of diseases - much as fever isn't a disease but a symptom of many diseases.
Arthritis occurs ,transiently, in many diseases, so trying to determine what unusual disease a person might mean dragging them over to Dawson to get his opinion.
This kept the job interesting but it meant that it couldn't be regarded as a routine affair that could be handed of to a junior member while Dawson engaged in his personal research interests.
He fitted in his penicillin work between the Clinic hours, teaching classes, marking papers, doing grand rounds, helping grad students, attending committee meetings - going to his Dad's funeral back in Nova Scotia - picking up a great Persian carpet cheap the day the World's Fair closed.
Maybe while picking up baby food for the new baby because Marjorie was running late at her school.
Or maybe he did some penicillin work in between sitting down on a couch to recover his strength as his Myasthenia Gravis kicked in.
That is Real Life stuff.
And I intend to put Real Life back into my account of the Penicillin Saga.
Thursday, August 5, 2010
Jack Frost Dark saved more lives ....
... than Al-Qaida will ever spend.
If you live in the Greater New York area, you don't need to be told that the Jack Frost brand of dark brown sugar, made in Yonkers, is good stuff.
Damn good stuff.
Your doctor might not agree though - so here is an argument that should appeal to their
medical 'sense of being': did they know that Jack Frost Dark led to the development of the greatest life-saver the world has ever known??!
I know, I know, I also said this about Vegamite, but both stories happen to be true.
Alexander Fleming got a lot of criticism over his use of ox heart medium to grow the first penicillin.
This abuse came from the first generation of penicillin authors -all sycophants of Howard Florey and all modernist to the core.
Ox heart medium is rich and complex and undefined - ie we don't know what all is in it or in what percentages.
As a result, chemists ( the modernist archetype ) hate it with a passion.
They prefer something like the all synthetic Czapek-Dox 'defined' medium - a bland mixture of water and salts you could just see Jeremy Bentham urging the British government to use to feed prisoners ,because it meant that they would remain alive while ensuring that they got no illict enjoyment from their food.
Unfortunately, the penicillium mold hates the stuff as much as prisoners do - it prefers the rich murk of the ox heart stew.
Fleming grew his mold juice in 4 to 5 days in ox heart stew while the chemists led by Raistrick took 15-20 days to get their mold juice on the sparse Quaker-approved diet.
(Interestingly, Fleming started his penicillium on a synthetic medium (Sabouraud's). He did know about them and used them ,despite what his hostile biographer, Ronald Hare, says.
But he found pre-digested extracts of spoiled meat made the penicillium produce faster AND was much much cheaper to buy. Engineers would approve on both counts - though chemists won't.)
Florey, being a chemist-manque, dismissed the ox heart brew and went for some Czapek-Dox synthetic purity instead. But it was so slooooow, and so he "modified" it.
In fact he modified it right back to Fleming's brew, more or less: he added brewer's yeast (the cast-offs from brewing beer - rich, dirty, complex, undefined, cheap.)
Vegamite is basically brewer's yeast.
Florey retained the concept of his all important 'purity' (in his own mind ,at least) while he got the speed of faster production from this dirty stew.
Coghill, out in Peoria at the NRRL, was a chemist, but a chemist-out-of-water, in charge of a biologically-oriented Fermentation Station.
He devoted much time and effort to try to first purify and then synthesise penicillin - when that failed, he fell back to raving about the use of corn steep liquors to speed production times and increase penicillin output.
Corn steep is another industry cast-off, the stuff left over after all the pure starch has been removed from corn.
It is complex, undefined, dirty and cheap.
Coghill and Merck and many others spent the entire war, trying to figure out what was the one ingredient in corn steep liquor that gave the much better results they got with it.
They planned to synthesis that one ingredient and then dump the corn steep like a used condom.
Others, like the Dawson team, just took the dirty complex stuff as a 'black box' and a gift - they wanted penicillin for patients ,not penicillin for academic papers and academic acclaim.
In the end, it was dozens of things in the corn steep or the dirty sugar that the mold loved - we still use this stuff today - as 'undefined' as ever.
Chalk one up for the post modernist way of thought.
Adorno, the German philosopher working on the Columbia campus in 1941 could explain (and did explain) this Modernist preference for inefficient and expensive defined growth mediums over cheap and efficient but undefined growth mediums.
(Or for that matter, the equally odd Modernist obsession of favoring toxic but defined drugs over drugs that are undefined but perfectly non-toxic. As a patient, I know which one I would prefer to have coursing through my veins !)
In his 1944 "DIALECTIC OF ENLIGHTENMENT", published at Columbia, (the seminal work that ushered in the post modernist era), he said that the Enlightenment's promise to lead us out of the darkness of ignorance was really an exaggerated fear of the unknown.
Not a sensible fear of the dangerous but an a priori fear of anything unknown, even ahead of things that are dangerous but known.
For penicillin read Dangerous= toxic.
Let us turn, finally, from Adorno to Meyer and Hobby and Chaffee and Dawson.
In 1942, they told the world of their secret food for their pilot penicillin plant: Jack Frost Dark.
Many others, Merck Inc among them, took up their idea, seeking the dirtiest, darkest, cheapest substitute they could find in their own local area --- if Jack Frost wasn't around.
The best brown sugar was natural or industrial brown sugar - sugar with lots of crude molasses's minerals and bio-organism waste products still in it.
It could be gotten directly from some sympathetic sugar factory chemist. Since so many industry chemists in the New York area were German or Jewish ( or both) in those days, Meyer wouldn't have found it hard to get a few hundred pound bags right off the boats from the West Indies.
It was dirt-cheap and because it was also dirty, it gave the best yield of penicillin .
You see 'defined' medium means we know exactly what the microbes like to eat, to make them produce what ever it is we want.
But using complex, un-defined ,industrial cast-off brews means we throw our hands up in the air and admit we really don't know Nature.
Instead we gave them everything and the kitchen sink and said "pick whatever you think suits you best".
I see the entire Penicillin development story 1940-1945 as a prime example and the most suitable metaphor of the shift from Modernity to Post Modernity.
So while I am making a little sport with Vegamite and Jack Frost Dark - I am also deadly serious .
Both of these common domestic foodstuffs did not just give us greater penicillin supplies when they were so badly needed.
They also represented some of the first examples of the green post-modernist way of viewing Man's relationship to Nature's creatures as being co-equals rather than Master and Slave --- when we feed penicillium Jack Frost or Vegamite, we say " maybe you are smarter than us" .
Pass the brown sugar won't you ?
If you live in the Greater New York area, you don't need to be told that the Jack Frost brand of dark brown sugar, made in Yonkers, is good stuff.
Damn good stuff.
Your doctor might not agree though - so here is an argument that should appeal to their
medical 'sense of being': did they know that Jack Frost Dark led to the development of the greatest life-saver the world has ever known??!
I know, I know, I also said this about Vegamite, but both stories happen to be true.
Alexander Fleming got a lot of criticism over his use of ox heart medium to grow the first penicillin.
This abuse came from the first generation of penicillin authors -all sycophants of Howard Florey and all modernist to the core.
Ox heart medium is rich and complex and undefined - ie we don't know what all is in it or in what percentages.
As a result, chemists ( the modernist archetype ) hate it with a passion.
They prefer something like the all synthetic Czapek-Dox 'defined' medium - a bland mixture of water and salts you could just see Jeremy Bentham urging the British government to use to feed prisoners ,because it meant that they would remain alive while ensuring that they got no illict enjoyment from their food.
Unfortunately, the penicillium mold hates the stuff as much as prisoners do - it prefers the rich murk of the ox heart stew.
Fleming grew his mold juice in 4 to 5 days in ox heart stew while the chemists led by Raistrick took 15-20 days to get their mold juice on the sparse Quaker-approved diet.
(Interestingly, Fleming started his penicillium on a synthetic medium (Sabouraud's). He did know about them and used them ,despite what his hostile biographer, Ronald Hare, says.
But he found pre-digested extracts of spoiled meat made the penicillium produce faster AND was much much cheaper to buy. Engineers would approve on both counts - though chemists won't.)
Florey, being a chemist-manque, dismissed the ox heart brew and went for some Czapek-Dox synthetic purity instead. But it was so slooooow, and so he "modified" it.
In fact he modified it right back to Fleming's brew, more or less: he added brewer's yeast (the cast-offs from brewing beer - rich, dirty, complex, undefined, cheap.)
Vegamite is basically brewer's yeast.
Florey retained the concept of his all important 'purity' (in his own mind ,at least) while he got the speed of faster production from this dirty stew.
Coghill, out in Peoria at the NRRL, was a chemist, but a chemist-out-of-water, in charge of a biologically-oriented Fermentation Station.
He devoted much time and effort to try to first purify and then synthesise penicillin - when that failed, he fell back to raving about the use of corn steep liquors to speed production times and increase penicillin output.
Corn steep is another industry cast-off, the stuff left over after all the pure starch has been removed from corn.
It is complex, undefined, dirty and cheap.
Coghill and Merck and many others spent the entire war, trying to figure out what was the one ingredient in corn steep liquor that gave the much better results they got with it.
They planned to synthesis that one ingredient and then dump the corn steep like a used condom.
Others, like the Dawson team, just took the dirty complex stuff as a 'black box' and a gift - they wanted penicillin for patients ,not penicillin for academic papers and academic acclaim.
In the end, it was dozens of things in the corn steep or the dirty sugar that the mold loved - we still use this stuff today - as 'undefined' as ever.
Chalk one up for the post modernist way of thought.
Adorno, the German philosopher working on the Columbia campus in 1941 could explain (and did explain) this Modernist preference for inefficient and expensive defined growth mediums over cheap and efficient but undefined growth mediums.
(Or for that matter, the equally odd Modernist obsession of favoring toxic but defined drugs over drugs that are undefined but perfectly non-toxic. As a patient, I know which one I would prefer to have coursing through my veins !)
In his 1944 "DIALECTIC OF ENLIGHTENMENT", published at Columbia, (the seminal work that ushered in the post modernist era), he said that the Enlightenment's promise to lead us out of the darkness of ignorance was really an exaggerated fear of the unknown.
Not a sensible fear of the dangerous but an a priori fear of anything unknown, even ahead of things that are dangerous but known.
For penicillin read Dangerous= toxic.
Let us turn, finally, from Adorno to Meyer and Hobby and Chaffee and Dawson.
In 1942, they told the world of their secret food for their pilot penicillin plant: Jack Frost Dark.
Many others, Merck Inc among them, took up their idea, seeking the dirtiest, darkest, cheapest substitute they could find in their own local area --- if Jack Frost wasn't around.
The best brown sugar was natural or industrial brown sugar - sugar with lots of crude molasses's minerals and bio-organism waste products still in it.
It could be gotten directly from some sympathetic sugar factory chemist. Since so many industry chemists in the New York area were German or Jewish ( or both) in those days, Meyer wouldn't have found it hard to get a few hundred pound bags right off the boats from the West Indies.
It was dirt-cheap and because it was also dirty, it gave the best yield of penicillin .
You see 'defined' medium means we know exactly what the microbes like to eat, to make them produce what ever it is we want.
But using complex, un-defined ,industrial cast-off brews means we throw our hands up in the air and admit we really don't know Nature.
Instead we gave them everything and the kitchen sink and said "pick whatever you think suits you best".
I see the entire Penicillin development story 1940-1945 as a prime example and the most suitable metaphor of the shift from Modernity to Post Modernity.
So while I am making a little sport with Vegamite and Jack Frost Dark - I am also deadly serious .
Both of these common domestic foodstuffs did not just give us greater penicillin supplies when they were so badly needed.
They also represented some of the first examples of the green post-modernist way of viewing Man's relationship to Nature's creatures as being co-equals rather than Master and Slave --- when we feed penicillium Jack Frost or Vegamite, we say " maybe you are smarter than us" .
Pass the brown sugar won't you ?
Wednesday, August 4, 2010
Iron Ring to Martin Henry Dawson's kids
People sometimes ask if I think if Martin Henry Dawson deserves a Nobel Prize for all his efforts in medicine and science.
Nobel Prizes only go to living scientists -a maximum of three per prize - and more often than not the Nobel Committee gives it to the wrong living scientists !
No, I think we Canadians should honor our fellow Canadian Henry Dawson in our own Canadian way.
He was not - formally - an engineer, unlike his two brothers.
But I think he fully deserves the symbol of a true engineer - the famous iron ring.
Engineers don't usually invent something truly new and significant - that is the scientist's job.
But they are the people called in to scale it up from the lab bench to pilot plant, then to full scale production, so it can start doing some good for humanity.
The people who should have been ordering the engineers in to do this work in the case of penicillin - the owners and executives of the big and little pharma firms in the UK,USA and Canada - declined to do so.
So a dying doctor - Henry Dawson - did it all up instead.
The first patient cured back in 1931 (by Cecil Paine) with penicillin-the-antiseptic, a newborn baby facing a lifetime of blindness, needed only the equivalent of one microgram (mcg) of pure penicillin.
That is the amount found in a milliliter (ml) --- or an eyedropper's worth--- of the unprocessed penicillium juice.
(A microgram is a thousandth of a milligram or a millionth of
a gram or a billionth of a kilogram.)
A milliliter (ml) aka a cubic centimeter (cc) aka a gram (gm) of liquid penicillium juice was needed (during 1928-1941) to produce that microgram.
That is a extraction ratio of one to a million, solid from liquid.
In terms of solid out from solids in, it took about 100 grams of relatively expensive solid "food"/ medium to produce 1 mg of solid bioactivity -BEFORE the huge producing and purifying losses found in large scale operations run at routine competency.
I would say that only 10% of nominal penicillin producing capacity was actually converted to finished clinical penicillin, between 1940-1942 ,in the larger pilot plant operations, based on the numbers and type of patients treated.
That is, in plain english, a conversion ratio of 1 kg of solid food producing 1 mg of solid bioactivity - a million to one ratio.
With these sort of ratios, engineers can already see the difficulties that lie ahead - before I tell them about penicillin's extreme lability and fragility...
The smallest test tube we have available is all the factory needed to produce a mcg or two of penicillin.
Which is enough to save Paine's baby, or one of Howard Florey's famous baby mice, or provide the material needed for Fleming to do all his 1928-1929 initial research using his patented micro-slide cell approach.
Scale it up 1000 times, you would now need a half dozen 2 liter Ernlenmeyer flasks to grow 1000 mcg's ( ie one milligram) worth of penicillin - about as much as Duhig and Gray used to save lives with in Brisbane in 1943.
But Dawson wanted to scale the Mount Everest of infectious disease - green SBE - the most dreaded form of the dreadful endocarditis.
He had a few lucky patients who held a strain of green strep in their heart valves that was as sensitive to penicillin as ordinary pyogenes strep was - so he could cure them with just a million times as much penicillin as Pain's baby or Florey's mouse - ie a gram of the stuff.
But other patients of his had SBE from strains about one thousand times less sensitive than ordinary pyogenes strep.
For them, he needed a kilo of pure penicillin- one billion times as much as Paine's baby needed.
That means he and his tiny pilot plant on the eighth floor of Columbia P and S would need
to process a million liters of penicillium juice over a two or three month period - ie 10 production runs of 100,000 liters each.
(That is about 200,000 milk bottles a run. In a big city dairy setup, that means processing 1000 milk bottles an hour, every hour, 24/7 for eight days straight, for each run.)
He couldn't have done that in P and S , even if his bosses had been helpful - which they weren't--- to put it mildly.
But Columbia University is set in th verye heart of New York's dairy factory district - the university fathers could have leased a vacant dairy and produced this quantity of penicillin, (much as the University of Toronto did with insulin in 1922 when they had an opportunity to help humanity.)
Dawson wanted so badly to save any and all SBE patients, not just those who were relatively healthy and had sensitive strains of bacteria, but died in early 1945 before he could get his hands on the huge amounts of penicillin needed.
But his assistant Thomas H Hunter soon had enough penicillin to save anyone who had SBE, no matter how old and sick - Dawson's ultimate goal.
Dawson knew penicillin could do the job from the moment he first read about it back in September 1940 - he knew it didn't need more purifying and perfecting for years and years - just a swift application of the production engineer's "MORE button" .
His "Manhattan Pilot" had to be content with only producing between 50 Imperial gallons and 100 US gallons of penicillium juice per eight day run - with a 50% production loss, just enough to save one SBE patient (with a very sensitive green strep strain) every two months.
However, he never actually got that level out of his 700 two liter Erlenmeyer flasks pilot plant, because he never got the cool dark room (or two or three) he needed on a permanent basis, if his penicillium were to settle down and produce.
Columbia chose instead - because it did have a choice, as Brian Mulroney said - to perfect the process (gaseous diffusion) that produced most of the world's nuclear bombs ---- ironically in that same dairy district that was more suited to making life-saving penicillin...
Nobel Prizes only go to living scientists -a maximum of three per prize - and more often than not the Nobel Committee gives it to the wrong living scientists !
No, I think we Canadians should honor our fellow Canadian Henry Dawson in our own Canadian way.
He was not - formally - an engineer, unlike his two brothers.
But I think he fully deserves the symbol of a true engineer - the famous iron ring.
Engineers don't usually invent something truly new and significant - that is the scientist's job.
But they are the people called in to scale it up from the lab bench to pilot plant, then to full scale production, so it can start doing some good for humanity.
The people who should have been ordering the engineers in to do this work in the case of penicillin - the owners and executives of the big and little pharma firms in the UK,USA and Canada - declined to do so.
So a dying doctor - Henry Dawson - did it all up instead.
The first patient cured back in 1931 (by Cecil Paine) with penicillin-the-antiseptic, a newborn baby facing a lifetime of blindness, needed only the equivalent of one microgram (mcg) of pure penicillin.
That is the amount found in a milliliter (ml) --- or an eyedropper's worth--- of the unprocessed penicillium juice.
(A microgram is a thousandth of a milligram or a millionth of
a gram or a billionth of a kilogram.)
A milliliter (ml) aka a cubic centimeter (cc) aka a gram (gm) of liquid penicillium juice was needed (during 1928-1941) to produce that microgram.
That is a extraction ratio of one to a million, solid from liquid.
In terms of solid out from solids in, it took about 100 grams of relatively expensive solid "food"/ medium to produce 1 mg of solid bioactivity -BEFORE the huge producing and purifying losses found in large scale operations run at routine competency.
I would say that only 10% of nominal penicillin producing capacity was actually converted to finished clinical penicillin, between 1940-1942 ,in the larger pilot plant operations, based on the numbers and type of patients treated.
That is, in plain english, a conversion ratio of 1 kg of solid food producing 1 mg of solid bioactivity - a million to one ratio.
With these sort of ratios, engineers can already see the difficulties that lie ahead - before I tell them about penicillin's extreme lability and fragility...
The smallest test tube we have available is all the factory needed to produce a mcg or two of penicillin.
Which is enough to save Paine's baby, or one of Howard Florey's famous baby mice, or provide the material needed for Fleming to do all his 1928-1929 initial research using his patented micro-slide cell approach.
Scale it up 1000 times, you would now need a half dozen 2 liter Ernlenmeyer flasks to grow 1000 mcg's ( ie one milligram) worth of penicillin - about as much as Duhig and Gray used to save lives with in Brisbane in 1943.
But Dawson wanted to scale the Mount Everest of infectious disease - green SBE - the most dreaded form of the dreadful endocarditis.
He had a few lucky patients who held a strain of green strep in their heart valves that was as sensitive to penicillin as ordinary pyogenes strep was - so he could cure them with just a million times as much penicillin as Pain's baby or Florey's mouse - ie a gram of the stuff.
But other patients of his had SBE from strains about one thousand times less sensitive than ordinary pyogenes strep.
For them, he needed a kilo of pure penicillin- one billion times as much as Paine's baby needed.
That means he and his tiny pilot plant on the eighth floor of Columbia P and S would need
to process a million liters of penicillium juice over a two or three month period - ie 10 production runs of 100,000 liters each.
(That is about 200,000 milk bottles a run. In a big city dairy setup, that means processing 1000 milk bottles an hour, every hour, 24/7 for eight days straight, for each run.)
He couldn't have done that in P and S , even if his bosses had been helpful - which they weren't--- to put it mildly.
But Columbia University is set in th verye heart of New York's dairy factory district - the university fathers could have leased a vacant dairy and produced this quantity of penicillin, (much as the University of Toronto did with insulin in 1922 when they had an opportunity to help humanity.)
Dawson wanted so badly to save any and all SBE patients, not just those who were relatively healthy and had sensitive strains of bacteria, but died in early 1945 before he could get his hands on the huge amounts of penicillin needed.
But his assistant Thomas H Hunter soon had enough penicillin to save anyone who had SBE, no matter how old and sick - Dawson's ultimate goal.
Dawson knew penicillin could do the job from the moment he first read about it back in September 1940 - he knew it didn't need more purifying and perfecting for years and years - just a swift application of the production engineer's "MORE button" .
His "Manhattan Pilot" had to be content with only producing between 50 Imperial gallons and 100 US gallons of penicillium juice per eight day run - with a 50% production loss, just enough to save one SBE patient (with a very sensitive green strep strain) every two months.
However, he never actually got that level out of his 700 two liter Erlenmeyer flasks pilot plant, because he never got the cool dark room (or two or three) he needed on a permanent basis, if his penicillium were to settle down and produce.
Columbia chose instead - because it did have a choice, as Brian Mulroney said - to perfect the process (gaseous diffusion) that produced most of the world's nuclear bombs ---- ironically in that same dairy district that was more suited to making life-saving penicillin...
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