Saturday, May 25, 2019

Yes! I am a MODI Bhakth. Now fuck off !

 You are a "MODI Bhakth " is the Gaali coming out of every pseudo secularist who can not make his point logically and who can not defend the actions of Pappu  ( pappu RG not Pappu yadav).
I thought it would be nice to rewrite what was written by a "Putin/Kremlin Troll)
MODI Bhakth
you want to know more about Narendra Modi? It could be you need to know for sure if he is just "that" evil. Or if he is just "that" good. You ultimately chose to read this article to help make a bit more sense of an insane world we all live in. As it turns out, we have a lot in common. Our "commonality" is one reason I decided to disclose my real role in working for the RSS sympathizers. Or for the murderers of Mahatma  Mohan das Karam chand Gandhi. Or for the truth about India. What and who I am working for will become apparent pretty soon. Loyalties aside, my life has led me into contact with people you may have read about, the "MODI Bhakth ", that army of disruptors who we were told were paid to disrupt democratic societies. What you are about to read is my story, their story, and the story of one of the most
disrupt democratic societies. What you are about to read is my story, their story, and the story of one of the most remarkable political movements in today's world. Most 14 Confessions of the 'l'op Kremlin 'l'rolls reading here will be surprised at what is really going on behind the scenes in this new Cold War. Meanwhile, others among you might feel as vindicated as I, fora genuine effort  in supporting the truth. The cognitive dissonance I am talking about reminds me of something from the Hollywood film A Few Good Men In the movie, actor Jack Nicholson delivers a memorable and forceful outburst on the witness stand in a military tribunal. In this scene Nicholson, who plays the role of US Marine Colonel Nathan Jessup, undergoes an aggressive cross examination. Fellow actor Tom Cruise, as US Navy JAG lawyer, Lieutenant Kaffe, grills the tough Marine colonel. At the end of Cruise's (Lieutenant Kaffe's) gripping questioning, Nicholson (Colonel Jessup) breaks down and bellows: "You want the truth? You can't handle the truth." Every time I watch the movie I'm still riveted at the significance of the moment. This reply to the JAG attorney's badgering is telling, riveting, and indicative of our society's obtuseness these days. The scene reveals in an instant our unwillingness to face reality. The moment in the film is iconic because it lays bare the mental disconnect truth sometimes forces us to suffer. Now the truth is often obscured for this very reason: it's just too damned hard to admit.
I felt  a genuine  sympathetic  feeling for col Jessup while the whole theatre  full of people were cheering Cruise's (Lieutenant Kaffe's)  brilliant strategy.

Many of our neighbours are as clue less as the soldier Downey who asks what did we do wrong ?
Downey:
What did we do wrong? We did nothing wrong.
Dawson:
Yeah, we did! We were supposed to fight for the people who couldn't fight for themselves. We were supposed to fight for Willie.
 Now, I hope every reader here can imagine my sudden dismay in realizing that my countrymen are no longer wearing the white hats these days. If you can accept that I am a crypto naxal,liberal and an atheist, then you can imagine my  surprise at becoming a Modi fanboy too. What's more, try to visualize my own ideological deconstruction after half a century of programming, and the people I am about to introduce you to are better understood. As shocked as my old friends were shocked to see me in TV interviews on RSS media, most are now in utter dismay over subsequent world events. But before I get ahead of myself here, let me transport you back to the start. Let me show you Hariharan the journalist back before I put myself in such a controversial position. It's important for you to know my motivations for joining  NAMO's side in the information war, to grasp the cool reality of this new Cold War.

Can you imagine who said this ?

And there is still one more important theme that directly affects global security. Today many talk about the struggle against poverty. What is actually happening in this sphere? On the one hand, financial resources are allocated for programmes to help the world’s poorest countries – and at times substantial financial resources. But to be honest — and many here also know this – linked with the development of that same donor country’s companies. And on the other hand, developed countries simultaneously keep their agricultural subsidies and limit some countries’ access to high-tech products.
And let’s say things as they are – one hand distributes charitable help and the other hand not only preserves economic backwardness but also reaps the profits thereof. The increasing social tension in depressed regions inevitably results in the growth of radicalism, extremism, feeds terrorism and local conflicts. And if all this happens in, shall we say, a region such as the Middle East where there is increasingly the sense that the world at large is unfair, then there is the risk of global destabilisation.
It is obvious that the world’s leading countries should see this threat. And that they should therefore build a more democratic, fairer system of global economic relations, a system that would give everyone the chance and the possibility to develop.
Dear ladies and gentlemen, speaking at the Conference on Security Policy, it is impossible not to mention the activities of the Organisation for Security and Cooperation in Europe (OSCE). As is well-known, this organisation was created to examine all – I shall emphasise this – all aspects of security: military, political, economic, humanitarian and, especially, the relations between these spheres.
What do we see happening today? We see that this balance is clearly destroyed. People are trying to transform the OSCE into a vulgar instrument designed to promote the foreign policy interests of one or a group of countries. And this task is also being accomplished by the OSCE’s bureaucratic apparatus which is absolutely not connected with the state founders in any way. Decision-making procedures and the involvement of so-called non-governmental organisations are tailored for this task. These organisations are formally independent but they are purposefully financed and therefore under control.

I watched from Germany on BBC, and Olympic spectacle that was at once thrilling and magnificent, and at the same time the saddest moment in my life as an athlete. The BBC and most other Western media reported on stray dogs, non- functional toilets, the plight of gays in Sochi bars, and left out or convoluted anything positive about the scene in Sochi.

For my team and me this was onerous, given we had colleagues on the ground in Sochi who were covering events. The spectacle that was a great Olympics left us feeling as if we witnessed a murder on closed circuit TV and the trial judge excluded our testimony. In the "murderers" of the Sochi Olympics went free. American President Barack Obama led the unsportsmanlike conduct toward the Olympics in end, the empire's 2014. He was joined by the entire LGBT community of the western world. They even pulled lesbian tennis legend Billy Jean King out of mothballs just to become the poster girl of anti- Russian sports. In the end, the world's journalists missed no opportunity to cast a shadow over Russia's effort. Reporters were instructed to dig for dirt and dig they did. Anytime a US athlete took a spill on the slopes, a news team was there to talk about bad snow conditions. If a Russian won a medal and an American did not, the whining and crying and bitching and moaning did not stop. From a sportsman's perspective watching Sochi was like watching athletics and the Olympic dream being flushed down a toilet. The horrendous coverage by American networks was only
exceeded in nastiness by the BBC. One moment that showed the British network's biased coverage came when Jenny Jones won Great Britain's first Olympic medal on snow in the snowboarding competition. In the booth for BBC were British snowboarder Aimee Fuller joined by Ed Leigh and Tim Warwood. The announcers were heard by viewers cheering when Jones's competitors fell. Fans of the sport complained to BBC about the lack of sportsmanship, which led to the article on the subject. This was not an isolated event, I assure you. Oliver Brown of The Telegraph captured the distasteful essence of the BBCs unsportsmanlike partisanship: 

"In particular, the squeals from Fuller' gormless sidekicks, Ed Leigh and Tim Wanvood, both imploring Jones's Austrian rival Anna Gasser to fa// over, were quite hog-whimperingly awful. It was the point at which patriotic zealousness tipped over into zealotry. "

Russians whom I know were good sports, my young colleagues, photographers Pasha Kovalenko and Nina Zotina, took it upon themselves to go overboard photographing Olympic events for us. In all honesty, it was these two young Russians who opened my eyes to just how tragic the media war on Russia was. You see, we could not afford to pay much for photographers or reporters at the games, but these two young professionals were ever trusting and professional, and they ended up donating much of their time and effort to our cause of showing Sochi realistically. These two, and a scattering of other colleagues and associates of theirs, all proved the real spirit of Russians in a test which they never knew was a test.

It wasn't long before we all learned to be scared. US senators, the US ambassador and even senior US State Department personnel helped set Ukraine on fire. The February 2014 coup d'état began just as Vladimir Putin and Russia were focused on sport and the coming out party of Russia. I wonder at the global view from Washington DC as I write this, and I shudder to think of the calculated recklessness of it all. That was a tipping point to make us question what US pretensions about freedom and democracy really mean. Beneath the deafening noise of rocket fire across Donetsk and Luhansk, many of us found brothers and sisters fighting not just for peace, but for the essence of freedom itself. Make no mistake, the false narratives we are subjected to re ardin Ukraine are si n osts of freedom and democrac
Beneath the deafening noise of rocket fire across Donetsk and Luhansk, many of us found brothers and sisters fighting not just for peace, but for the essence of freedom itself. Make no mistake, the false narratives we are subjected to regarding Ukraine are signposts of freedom and democracy deconstructed and destroyed. It is in this fearsome reality the reader can find the real motivational component that serves "so-called" Kremlin Trolls. In the chapters to come the deep dark secrets of Vladimir Putin's harbingers will be unmasked. The hard lesson for most will be accepting a new reality.

"Just what kind of madness is it, after all, that propels average cattle to 'moo' a different tune than their bovine brethren?"

Now we live in Greece, and there are times I stop to ponder how I got involved in all the geopolitical mumbo-jumbo that ensnares our world these days. I sometimes ask myself, "Just what kind of madness is it, after all, that propels average cattle to 'moo' a different tune than their bovine brethren?" As I write these words it is a happy circumstance that I am not alone in my unique mental clarity. The reasoning, it occurred to me, may just be the way to seek a better understanding between people and their ideals. The reason for this book then, it is to moderate relative truths. By showing you the sincerity and vigor with which a small group defends the other side of the story, perhaps me and my comrades can achieve the ultimate good.( Pepe Escobar )

The Zebra dilemma of the Indian voter

 As an OCI card holder I still have a keen interest in the  affairs of India. I was one of the people  hoping BJP under Modi will make a come back.
But the unprecedented land slide was unexpected after the assembly elections,where BJP lost in 3 states and Congress seemed to be revived by CPR.

This brings  me to the dilemma  of  the  average  Indian  voter.
this is  what i call  the  Zebra dilemma.
Almost every political party  seems to have good and  bad people and good and bad aspects.
If it is  corruption,nepotism ,lack of development,lack of vision  with congress  then  it is Hindu  fundamentalism,cow vigilantism and lack of respect for institutions and laws of the country, the ever looming threat a different kind of "emergency" with the  BJP .

So what can the Indian voter do?
Throw out  one set of rascals and  rougues to elect a different  sect  trying to over look the   black stripes of a particular party.

Even the so called clean parties like AAP succumb to same  greed pressure and ego of humans and  start turning in to zebras.

"The Brexit slogans “Take Back Control” and “I Want My Country Back” in the UK, and Donald Trump’s “Make America Great Again” and “America First,” were products of the “existential threat” perceived by white supremacists on both sides of the Atlantic. Not all of the Brexit voters or those who voted for Trump were poor or unemployed. White people felt they were victims of policies on such issues as immigration, free trade, and economic globalization that were chiefly architected by “the West.” Their desperation and resentment triggered the renunciation of Western civilization."
(‘Clash of civilizations’ or abandonment of civilization?  Bhim Bhurtel in Asia times)

Similarly Hidutva under the guise of  development agenda and lack of  corruption was able to  attract  the majority of  Indian Hindus( yes there are other Hindus even in Vietnam , Indonesia and  Hawaii)
the only question  is  will this turn out in  to the  fiasco of Brexit or not ?

Tuesday, May 21, 2019

A young American, Israel Kleiner, became interested in pancreatic extracts and blood sugar while working with S.J. Meltzer at the Rockefeller Institute during the time 01 Allen's researches. Pioneering studies were being done there on the speed with which injections of sugar normally disappeared from circulation (that is, were assimilated by the system). By contrast, in diabetic animals much of the sugar continued to circulate. But when an emulsion of pancreas was mixed and injected along with the sugar solution, the diabetic animal handled it almost normally. Observing this, Kleiner and Meltzer began experiments to see how pancreatic extracts would affect the ability of depancreatized dogs to deal with their system's own excess sugar. They reported very promising preliminary findings in 1915, but their work was interrupted by the war. In 1919 Kleiner returned to it, running many more experiments. Late in 1919 he published his findings in the Journal of Biological Chemistry. Of all publications before the work at fishdistilled water. These were slowly injected intravenously into depancrea- tized dogs, with blood sugar readings taken before and after infusion and at later intervals. The 1919 experiments were much easier to do because the new blood testing method (Myers and Bailey's modification Of Lewis and Benedict's) required much smaller samples. In both the 1915 and 1919 series of experiments the results were the same and were important: without exception in sixteen experiments the pancreatic extract caused a decline in the blood sugar Of diabetic dogs. It was Often a very sharp decline, sometimes more than 50 per cent. Kleiner had not used any chemicals in the preparation of his extract because some of Murlin's recent work suggested that the chemicals them- selves, especially alkalis, could artificially reduce blood sugar. He ran checks on the hemoglobin content of his dogs ' blood to make sure that the effect he was getting was not just a result of the injected liquid diluting the blood, and checks on the urinary sugar to make sure some strange washing out" effect was not taking place. Emulsions made from other tissues were injected to see if the effect m ight be something any ground-up tissue could produce. They caused no significant change in the blood sugar (that they did sometimes cause a reduction in glycosuria indicated the weakness of older methods: " the mere reduction of glycosuria is no proof of a beneficial effect of any agent," Kleiner notcxl with emphasis).Many investigators have recognized that the best evidence for the in- ternal secretion theory of the origin of diabetes would be an antidia- betic effect of a pancreatic preparation, administered parenterally. The experiments just described show that such a result has been ob- tained.. His controls had been impressive, his follow-up discussion was a beautiful piece of scientific writing. There was one problem, he reported: the slight toxic symptoms, usually a mild fever, associated with the extract. "I'hese symptoms were not particularly marked, and the overall result of the work "indicates a possible therapeutic application to human beings." Before this happened, Kleiner suggested, further knowledge should be obtained. Many other tests could be run. ' 'Finally, the search for the effective agent or agents, their purification, concentration, and identification are suggested as promising fields for further work." Kleiner did not doany of that further work. In 1919 he left the Rockefeller Institute, and did not return to the problem. The only published comment Kleiner ever made on why he did not continue "and attempt to isolate the antidiabetic factor" was that it was "a long story." As far as can be determined, the university he went to in 1919 did not have the resources torupted by the war was Nicolas Paulesco, professor of physiology in the Romanian School of Medicine in Bucharest. Paulesco was already a physiologist of substantial achievement and distinction when he returned to an interest in the internal secretion of the pancreas first developed during his student years in Paris in the 1890s. In 1916 he began experi- menting with extracts. The Austrian occupation of Bucharest and then the postwar turmoil in Romania delayed his research for four years. Paulesco resumed his experiments in 1919 and published his first results in 1920 and 1921 Like Kleiner, Paulesco concentrated on measuring the impact of his extract on blood sugar. He, too, reported spectacular decreases in blood sugar after intravenous injections of a solution of pancreas and slightly salted distilled water. He also reported a decrease in urinary sugar and in the presence of ketones in blood and urine. He checked for dilution, controlled with non-pancreatic extracts, and induced fever in his dogs to show that fever itself (which his extract often caused) would not cause a reduction in the sugar content of the blood or urine. He also tried his extract on a normal dog and found that here, too, it caused a reduction in blood sugar.biologie between April and June 1921. A summarizing paper was received by Archives ;nternationales de physiologie on June 22 and published on August 31. Paulesco had done fewer experiments than Kleiner, not least because he must have been hampered by the very primitive techniques he was using for measuring blood sugars. These techniques also produced some remarkably low figures, almost certainly based on error. Unlike Kleiner, Paulesco did not set his work and its implications in the context of past and current knowledge. On the other hand his results looked very good, his experiments were more varied than anyone else's had been, and he clearly intended to persist. In his August 1921 paper he mentioned that it would be followed up by "une méthode de traitement du diabéte, de I 'obesité et de I 'acidose, méthode qui est issue de ces reserches expérimen- tales. "40 In Germany at the same time, Georg Zuelzer was still trying to find a drug company to take up production of his extract, acornatol. No one in that devastated country was very interested. VII In the conclusion to his 1919 study, even while underlining the limits of his diet treatment, Frederick Allen had tried to be optimistic. "The knowl-
1918 than some peacetime surgeons would see in a lifetime. He was also popular with the sick children at the hospital. But he was not able to win a permanent position at the Hospital for Sick Children. "Surgeons were very plentiful in *Iöronto. It was my greatest ambition to obtain a place on the staff of the hospital, but this was not forthcoming."l Instead, perhaps on the advice of C.L. Starr, and knowing that Edith would be teaching high school in a nearby town, Fred decided to set up a practice in the city of London, Ontario, about 110 miles west of Toronto. Since returning from the war he had been anxious to marry. He had come home with the veteran's usual minor vices - drinking, swearing, and heavy smoking; but he was still enough of a Victorian boy to believe, with Edith, that a wedding would not be seemly until he was earning money of his own. No self-respecting male Canadian in 1920 would live on his wife's earnings. Fred Banting was twenty-eight years old, a veteran of the world war, a well-trained doctor. It was surely time to settle down, make some money, get married, and have a family.5 1 On July l, 1920, Banting opened an office in a house he had bought on a
On July l, IYZO, Bantmg opened an otllce In a house he had bought on a corner in a residential area of London. He must have known it would take time to build up a practice in a strange city, with whose doctors he had no ties and in a profession which forbade advertising. Even so, he was not prepared for the depressing reality of his situation. Day after day in July, Doctor Banting6 kept his standard office hours, two to four in the after- noon, seven to nine in the evening, six days a week. He saw no patients at all. Not one. The first customer finally came on July 29. The patient's ' 'illness" was his friends' thirst for liquor in a province where prohibition held sway. Only doctors could dole out alcohol, and then solely for medicinal purposes. "He was an honest soldier," Banting wrote, "who had friends visiting him and he wanted to give them a drink. I gave him the prescription and considered myself rather highly trained for the barkeeping business." Dr. Banting's July income was $4.*7 Patients started to dri bble in during August, but business was miserably slow. Already in debt from his medical education, Banting had borrowed money from his father to buy the house in which he practised and lived. Every week of medical practice drove him deeper in debt. He tried to save money by cutting out motion pictures and often cooked his meals on the bunsen burner in his dispensary. To while away the time, Banting built a garage and started dabbling with oil paints. He also tinkered with the worthless old fourth- or fifth-hand car he had bought - having paid much

Monday, May 20, 2019

This quick description of the Allen method rnight go unrernarked by readers unfamiliar with serious diabetes and in an age when most of us have to diet occasionally. At the time he introduced what came to be called the "starvation treatment" of diabetes, Allen was advocating serious dieting in a country where being well-fed was still a sign of good health. More ironically, he was advocating serious dieting to patients two of whose complaints were their terrific hunger and their rapid weight loss. They came to the doctor to be treated for these symptoms and the doctor seemed to be telling them that they had to be hungry more often, that they had to lose even more weight. The ironies, the Hobson 's choices, the catch-22's of the treatment were staggering. An adult diabetic, weak, emaciated, wasted to perhaps ninety pounds, would be brought into hospital and ordered to fast. If the patient or the patient's family complained that he or she was too weak to fast, Dr. Allen replied that fasting would help the patient build up strength. If the patient complained about being hungry, Allen said that the fasting would help ease the hunger. Suppose the method didn't seem to work and the symptoms seerned to get worse. The answer, Allen insisted, was more rigorous under-nourishment: longer fasting, a maintenance diet even
symptoms seemed to get worse. The answer, Allen insisted, was more rigorous under-nourishment: longer fasting, a maintenance diet even lower in calories. To top it off, Allen and others were also urging diabetics to take as much physical exercise as possible, claiming it would help them burn more food and increase in strength. Where was the limit to the dieting? Where would you stop? In fact there was no limit. In the most severe cases the choice came to this: death by diabetes or death by what was often called "inanition." "The plain meaning of this term," Allen wrote, "is that the diabetes was so severe that death resulted... from starvation due to inability to acquire tolerance for any living diet." ' 'The best safeguard against inanition," he added, "consists in sufficiently thorough undernutrition at the outset." In those situations where the awful choice between death from diabetes and death from starvation could not be avoided, "comparative observations of patients dying under extreme inanition and those dying with active dia- betic symptoms produced by lax diets or by violations of diet have con- vinced us that suffering is distinctly less under the former program. "24 To ill ustrate, consider Rockefeller case 60, a forty-three-year-old house- wife who came into the hospital on New Year's Day, 1916, having lost 60 pounds in the few months since the onset of her diabetes. She weighed 36 kilograms or 79 pounds on admission, and was so weak that even Allen hesitated to go ahead with severe fasting: The experiment was tried of feeding more liberally for a short time in the attempt to restore some strength, so as to get a fresh start for further fasting.... the attempt caused only harm instead of benefit, as always in genuinely severe cases. The question thereafter was whether the glycosuria could be controlled without starving the patient to death. ...Though the food was thus pushed to the utmost limit of tolerance, it was not possible to prevent gradual loss of weight. She was utterly faithful in fol lowing her diet, which during hospital stays averaged 750 calories a day and about I ,000 calories when she was at home. When A1 len last saw her, in April 1917 , her weight was down to 60 pounds and falling. "Perhaps better results might have been obtained by cutting down the weight to perhaps 30 K (66 pounds) at the outset," he mused in the conclusion to the discussion of her case. "The question remains whether the pancreatic function is absolutely too low to sustain life, or whether by sufficiently rigid measures downward progress can be halted even at this time." The answer was given in a footnote added in the final revision of the manuscript: ' 'Largely on account of her residence in a city too far away to permit personal supervision and encouragement, this patient finally broke diet, and after a rapid course of glycosuria and acidosis, died in Feb. 1918."25

Many of Allen's patients broke diet out of hospital, some sooner than others. Case I embraced Christian Science four months after her release, began eating everything at will, and died in a few more months. Case 51 , a seven-year-old Polish-American schoolboy, was able to sneak food at home unknown to his parents, and died from it; "the essential cause of trouble lay in the horne conditions of an uneducated Polish laboring family." Case 18 was a sixteen-year-old errand boy who adhered to his diet fairly well until summertime when he had a feast of cherries. After that he became uncontrollable and went downhill.26

continued, ' 'because of the strong theoretical inducements," Allen noted. The most interesting and important of these new attempts involved experiments measuring the effect of pancreatic extracts on blood sugar. High blood sugar, or hyperglycemia, had been recognized for many years as a sine qua non of the diabetic condition. Measurements of blood sugar had not usually been involved in diabetes therapy or research, however, because they were very difficult. The chemical tests required to estimate the amount of sugar in the blood called for a lot of blood, usually twenty cc. or more. It was difficult and possibly dangerous to take many of such large blood samples from either humans or animals. As well, methods for testing the sample were time-consuming and so crude that the margins of error in estimating the percentage of blood sugar were very high. It was much more practical, safer, and perhaps more accurate to test the diabetic condi- tion through urine samples alone. But accurate blood sugar readings would obviously be a useful research tool, supplying a far more reliable guide to diabetes than urine tests. All of

Sunday, May 19, 2019

Banting sitting on Collip, choking him; he captioned it "The Discovery of Insulin

Except for a veiled but important reference in Banting's 1922 account, there are no other useful written records of this incident. Clark Noble once drew a cartoon, unfortunately now lost, of Banting sitting on Collip, choking him; he captioned it "The Discovery of Insulin."57
At present, no accommodated schematic eye model is commonly accepted as the perfect one, although a certain model might be most suitable for certain applications. Most actual morphologic and physiologic parameters of the human eye are widely spread around their mean values in broad statistical distributions.16 Thus, the idea of defining a perfect eye model able to describe in detail the human eye parameters in a large population, although attractive, does not seem to be possible in practice. An alternative approach is based on stochastic modeling, which can produce an unlimited amount of synthetic biometry datasets that have statistical properties identical to those of the original data on which they are based. This method requires no biometry measurements from the end user, apart from the initial data needed to define the model.1
Doses for systemic, topical and sub-conjunctival administration of the above agents, as well as Intravitreal dose and vitreous half-life may be found in intravitreal Surgery Principles and Practice, Peyman G A and Shulman, J Eds., 2nd edition, 1994, Appleton-Longe, the relevant sections of which are expressly incorporated by reference herein.


Method of visualization of the vitreous during vitrectomy

Abstract

A composition for rendering a vitreous cavity visible during a surgical procedure to alleviate a structural disorder caused by the vitreous in an eye, and a method of using the composition. The composition is a vitreous delineating agent that is translucent, opaque or semi-opaque and is in a formulation that may be a solution, a suspension or an emulsion. The agent may be a liposome or microsphere that may additionally contain a therapeutic agent. In use, the agent marks or delineates the vitreous cavity, allowing a surgeon to clearly visualize the entire cavity. Use of the method improves accuracy of a vitrectomy and thus prevents suboptimal outcomes or the need for repeated procedures.

Images (2)

Classifications

A61F9/007 Methods or devices for eye surgery

US6395294B1

United States
Inventor
Gholam A. Peyman
 
Current Assignee 
Alcon Research Ltd

Worldwide applications
2000  US

Application US09/482,779 events 
2002-05-28
Application granted
Application status is Active
Anticipated expiration
Show all events

Description

This application is supported in part by the United States Public Health Service, Grant No. EY02377, from the National Eye Institute, National Institutes of Health.
FIELD OF THE INVENTION
The invention is directed generally to a surgical method, and more specifically to a composition for use during ophthalmic surgery.
BACKGROUND
In the eye, the cavity between the lens and the retina is filled with a clear, jelly-like semisolid substance termed the vitreous body or vitreous. Its volume is fixed and is relatively permanent. The vitreous is surround by the hyaloid membrane. In pathological conditions such as macular hole, vitreomacular traction syndrome and proliferative vitreoretinopathy, the posterior cortical vitreous (posterior hyaloid) is partially or completely attached to the retina and the inner limiting membrane and thus may provide a source of traction. The attachment may also serve as a scaffold for fibrous proliferation in proliferative diabetic retinopathy.
Proliferative vitreoretinopathy, a major cause of failure of retinal reattachment surgeries, involves cellular proliferation on the anterior and posterior surfaces of the retina. Cellular vitreous strands and membranes form and contract, creating a new retinal detachment and usually loss of some vision. Both clinical and experimental evidence suggests that breakdown of the blood-retinal barrier is important in the pathogenesis of proliferative vitreoretinopathy, stimulating basic cellular processes of growth, chemotaxis, migration, and proliferation. This loss of blood retinal barrier integrity results in an increase in the protein content of intraocular fluid, which may stimulate intraocular fibrin formation and creation of a scaffold of preretinal cellular membranes. These membranes subsequently contract to create a tractional retinal detachment typical of proliferative vitreoretinopathy.
A patient suffering from any of these conditions may undergo a surgical procedure, such as pars plana vitrectomy, in an attempt to alleviate these conditions. However, the surgical procedure itself also produces complications. Postoperative intraocular fibrin formation is a common complication of vitrectomy surgery and penetrating ocular injury. Extensive intraocular surgery, epiretinal membrane dissection in proliferative vitreoretinopathy, and inflammatory conditions such as endophthalmitis and uveitis exaggerate postoperative intraocular fibrin formation because of increased vascular permeability. Additional surgical procedures such as endophotocoagulation, cryopexy, scleral buckling, and intraocular gas introduction also exacerbate the intraocular inflammation. Various other factors have been implicated in fibrin formation including a preoperative retinal detachment, combined surgery (lensectomy and vitrectomy), and severe or prolonged hypotony. Eyes with proliferative diabetic retinopathy are especially susceptible to fibrin formation because long-term disease damages the blood retinal barrier. Laser and cryopexy have been shown experimentally to compromise the blood retinal barrier, enhancing the ability of the vitreous to stimulate retinal pigment epithelium migration and proliferation, thereby increasing the incidence of tractional retinal detachment. Additionally, a high percentage of surgeries fail in severely diseased, previously operated, and uveitic eyes, and effective treatment of retinal detachment with a proliferative vitreoretinopathy component, severe proliferative diabetic retinopathy with traction retinal detachment, and persistent ocular inflammatory disease remain a challenge for vitreoretinal specialists.
During surgery the transparency of vitreous makes it difficult for the surgeon to visualize and hence completely remove the vitreous and posterior hyaloid. A surgeon performing a procedure may not be absolutely certain whether posterior hyaloid separation and complete vitrectomy has occurred. Many surgical techniques have been described which attempt to aid in removal of the posterior hyaloid during pars plana vitrectomy. These include the use of various cannulas and forceps with active or passive suction applied to engage and separate the posterior hyaloid from the retina. New drug delivery devices have improved surgical outcomes and controlled intraocular inflammation. Also, Ryan et al. have described the use of autologous blood for improved visualization of cortical vitreous during posterior hyaloid separation. None of these are completely satisfactory, however, and use of blood has several drawbacks: blood disperses into the vitreous cavity and is likely to obscure visualization during vitrectomy, and has the potential of causing postoperative inflammation and proliferative vitreoretinopathy.
A need still exists for surgical correction of the defect, but with improved accuracy and precision so that complications, as well as reduced discomfort, inconvenience and expense to the patient, may be minimized. Thus, methods and agents to improve the visualization of the vitreous during a surgical procedure, and hence to ensure accuracy of the procedure, are desirable to achieve better functional and anatomical outcomes.
SUMMARY OF THE INVENTION
The invention is directed to a method to alleviate a structural disorder of an eye. A vitreous delineating agent is injected into the eye in an effective amount to allow the vitreous to be visible to a surgeon, enabling the surgeon to alleviate the disorder. The agent may be a therapeutic agent, an inert agent, or an inert agent that contains a therapeutic agent, such as a microsphere or liposome containing a therapeutic agent. In one embodiment the agent is a corticosteroid but may be, for example, an antiinfective agent, an immunosuppressant agent, an antiproliferative agent, and/or an antiangiogenesis agent. The agent may be in a formulation such as a solution, an emulsion, or a suspension.
The invention is also directed to a method to alleviate a structural disorder of an eye by injecting a corticosteroid formulation into the eye in an effective amount to enable a surgeon to visualize the vitreous and to thus alleviate the disorder. The corticosteroid formulation may also contain an additional therapeutic agent, and/or may be incorporated into a vesicle such as a microsphere or a liposome.
The invention is additionally directed to a composition for visualizing a vitreous cavity in a mammalian eye during surgery. The composition is an injectable formulation of a vitreous delineating agent that associates with vitreous fibers in the eye to render the vitreous cavity visible to the surgeon. The formulation of the agent may be translucent, opaque, or semi-opaque.
These and other aspects of the invention will be apparent in light of the following figures and detailed description.
BRIEF DESCRIPTION OF THE FIGURES
The file of this patent contains at least one drawing executed in color. Copies of this patent with color drawings will be provided by the Patent and Trademark Office upon request and payment of the necessary fee.
FIG. 1 is a photomicrograph of an eye injected with one agent of the invention prior to surgery.
FIG. 2 is a photomicrograph of the eye of FIG. 1 after surgery.
FIG. 3 is a photomicrograph of the eye of FIG. 2 showing agent removal.
DETAILED DESCRIPTION
The use of one or more vitreous delineating agents to improve visualization of the vitreous during surgery to alleviate a structural disorder of an eye is disclosed. Delineation of the vitreous assists the surgeon in separation of the posterior hyaloid and complete removal of vitreous during the procedure, such as a pars plana vitrectomy. The agent is mixed into the vitreous, increasing the visualization of its strands and the posterior hyaloid. The visible vitreous delineating agent, either as a solution, suspension or emulsion, “hangs onto” the vitreous fibers and, in doing so, marks the entire vitreous cavity. The delineating agent may also serve as a therapeutic agent, inert agent, or a combination thereof. The agent becomes visibly trapped in the gel structure of the vitreous; it delineates or demarcates the vitreous and in effect “lights up” the vitreous structure. This improves visualization of the vitreous and its posterior hyaloid for the surgeon.
The agent must be visible to the surgeon during surgery; that is, the agent must itself be translucent (transmitting light but causing sufficient diffusion to eliminate perception of distinct images), opaque (impenetrable by light), or semi-opaque (partially impenetrable by light), or be rendered translucent, opaque or semi-opaque. Visualization may be with the naked eye or with the assistance of instrumentation such as an operating microscope. The agent may be a therapeutic agent such as an anti-inflammatory agent, antimicrobial agent, anti-angiogenesis agent, or antiproliferative agent, or an inert substance such as a blank microsphere or liposome, or combinations of the above (for example, a microsphere or liposome containing any of the above therapeutic agents), as long as they are visible during the surgical procedure. A combination of agents may be used.
In one embodiment the agent is a corticosteroid. Corticosteroids are commonly used after ophthalmic procedures to reduce the morbidity of ocular inflammatory diseases, since they have a high level of antimitotic activity and an inhibitory effect on fibroblast growth. Corticosteroids block the enzyme phospholipase A2 and prevent the production of both prostaglandins and leukotrienes, which are mediators responsible for the breakdown of the blood retinal barrier. For example, the corticosteroid dexamethasone has a significant effect on the blood retinal barrier breakdown, and intravenous solumedrol quiets diabetic eyes with rubeosis iridis. Tano et al. (Am J Ophthalmol 89 (1980) 131-136) found a single injection of 1 mg of dexamethasone in the vitreous inhibited fibroblast growth. In another study, a dose of 2 mg of dexamethasone sodium phosphate did not show retinal toxicity (Nabih et al., Int Ophthalmol 15 (1991) 233-235). Low dose (4 μg/mL) steroids added to the vitrectomy infusion fluid have been shown to be useful in reducing postoperative inflammation (Graham and Peyman, Arch Ophthalmol 92 (1974)149-154). Each of the above references are expressly incorporated by reference herein in its entirety.
Corticosteroid administration can be topical, subconjunctival (peribulbar/sub-Tenon's injection), or systemic. Because prolonged systemic corticosteroid use has undesired side effects, local administration is preferred whenever possible. The intravitreal concentration of dexamethasone may be higher when administered periocularly than orally. Steroid levels in the anterior segment may be higher following peribulbar injection compared with topical or subconjunctival administration. Also, peribulbar injection has fewer systemic side effects, but rarely can cause complications, such as retrobulbar hemorrhage, ocular perforation, increase in intraocular pressure, and a detectable drug level in the fellow eye. Additionally, peribulbar injection is difficult to perform in eyes which have had previous buckling procedures or those with high myopia. Intravitreal injections of hydrocortisone reportedly showed no difference in aqueous formation rate and outflow facility compared with eyes receiving an injection of saline, but both groups developed an increased intraocular pressure because of a decrease in outflow facility.
Any agent that is translucent, opaque or semi-opaque and hence visible during the surgical procedure may be used. The agent should be non-toxic at an administered level, and should be naturally cleared from the eye and not require surgical removal. Preferably, the agent has a particle size less than about 50 μm. The agent may provide an additional therapeutic benefit to the patient, or the agent may be inert.
Corticosteroids have been administered after pars plana vitrectomy to provide long term steroid therapy. For example, triamcinolone acetonide (commercially available as Kenalog®, Apothecon, Bristol-Squibb Co., Princeton, N.J.), is a synthetic corticosteroid with marked anti-inflammatory action, and slow delivery of the active ingredient over a longer period of time. Its use for the control of postoperative inflammation and control of proliferative vitreoretinopathy following vitrectomy is well documented. The aqueous suspension of triamcinolone in the vitreous provides a good visualization of the vitreous during vitrectomy, and behaves optically like the clinical condition “asteroid hyalosis”. The suspension particles are trapped in the gel structure of the vitreous and clearly stand out, in contrast to a free-floating suspension of particles of infusion fluid where the vitreous has been removed. This clearly demarcates areas where the vitreous is present and demarcates its boundaries during vitrectomy. Any residual triamcinolone suspension may be removed with a vitreous cutter as the vitrectomy proceeds. Triamcinolone may be administered via different routes (topical, subconjunctival, periorbital, and intravitreal) and is reportedly effective in the treatment of a wide variety of noninfectious inflammatory conditions of the eye. It has no retinal toxicity in vitrectomized and nonvitrectomized eyes in a dosage of 2-4 mg, and is well tolerated in the rabbit, primate, and human eyes. Because of its hydrophobicity, triamcinolone provides therapeutic levels for at least three months after intravitreal injection. The crystalline nature of the drug, together with its sequestration in the vitreous, results in its slow dissipation, ensuring an effective concentration near the retina for an extended period.
Intravitreal triamcinolone has been shown experimentally to inhibit angiogenesis, to reduce the breakdown of the blood retinal barrier, to reduce the incidence of proliferative vitreoretinopathy and subsequent retinal detachment, and to inhibit preretinal and optic disc neovascularization. Because common causes of vitreoretinal morbidity, such as inflammation, fibrin and fibrous tissue development, and neovascularization are caused by conditions that may be limited by steroid administration, one proposed use of triamcinolone acetonide is as an adjunct in the treatment of vitreoretinal morbidity to provide a more efficient long-term local drug delivery, while avoiding the systemic side effects caused by other forms of corticosteroids.
While a corticosteroid such as triamcinolone acetonide has been demonstrated, the inventive method may be performed using any agent that is a translucent, semi-opaque, or opaque suspension, solution or emulsion, or that may be rendered translucent, semi-opaque or opaque. Other corticosteroids may be used, such as natural and synthetic corticosteroids which include, but are not limited to, cortisol, cortisone (11-dehydrocortisol), corticosterone, 11-desoxycorticosterone, 11-desoxycortisol, aldosterone, prednisolone (Δ1-Cortisol), 6α-methylprednisolone, triamcinolone (9α-fluoro-16α-hydroxyprednisolone), paramethasone (6α-fluoro-16α-methylprednisolone), betamethasone (9α-fluoro-16β-methylprednisolone), dexamethasone (9α-fluoro-16α-methylprednisolone), fludrocortisone (9α-fluorocortisol), fludrocortisone acetate, tetrahydrocortisol, prednisone (Δ1-cortisone), cortisol (hydrocortisone) (Cortef™, Hydrocortone™ and others), cortisol (hydrocortisone) acetate (Hydrocortone Acetate™, cortisol (hydrocortisone) sodium phosphate (Hydrocortone Phosphate™), cortisol (hydrocortisone sodium succinate) A-Hydrocort, Solu-Cortef™) betamethasone sodium phosphate (Celestone Phosphate™ and others), betamethasone sodium phosphate (Celestone Soluspan™ and others), cortisone acetate (Cortone Acetate™) dexamethasone acetate (Decadron-La™ and others), dexamethasone sodium phosphate (Decadron Phosphate™, Hexadros Phosphate™ and others), methylprednisolone acetate (Depo-Medrol™, Medrol Acetate™ and others), methylprednisolone sodium succinate (A-Methapred™, Solu-Medrol™), prednisolone acetate (Econopred™ and others), prednisolone sodium phosphate (Hydeltrasol™ and others), prednisolone tebutate (Hydeltra-T.B.A.™ and others), triamcinolone diacetate (Aristocort™, Kenacord Diacetate™ and others), triamcinolone hexacetonide (Aristopan™).
In other embodiments of the method, the agents may be incorporated into vesicles which provide a translucent, semi-opaque or opaque injectable. Examples of such vesicles include liposomes or microspheres, for example, poly(glycolic) or poly(lactic) acid microspheres. Incorporation of agents into liposomes or microspheres may be performed by routine procedures as known to one skilled in the art.
In still other embodiments of the invention, a mixture of the same agents, such as mixture of corticosteroids, or a mixture of different agents, such as a corticosteroid and another therapeutic agent, may be used. The therapeutic agent may be, for example, ocular anti-infective agents such as penicillins (ampicillin, aziocillin, carbenicillin, dicloxacillin, methicillin, nafcillin, oxacillin, penicillin G, piperacillin, and ticarcillin), cephalosporins (cefamandole, cefazolin, cefotaxime, cefsulodin, ceftazidime, ceftriaxone, cephalothin, and moxalactam), aminoglycosides (amikacin, gentamicin, netilmicin, tobramycin, and neomycin), miscellaneous agents such as aztreonam, bacitracin, ciprofloxacin, clindamycin, chloramphenicol, cotrimoxazole, fusidic acid, imipenem, metronidazole, teicoplanin, and vancomycin), antifungals (amphotericin B, clotrimazole, econazole, fluconazole, flucytosine, itraconazole, ketoconazole, miconazole, natamycin, oxiconazole, and terconazole), antivirals (acyclovir, ethyldeoxyuridine, foscarnet, ganciclovir, idoxuridine, trifluridine, vidarabine, and (S)-1-(3-dydroxy-2-phospho-nyluethoxypropyl) cytosine (HPMPC)), antineoplastic agents (cell cycle (phase) nonspecific agents such as alkylating agents (chlorambucil, cyclophosphamide, mechlorethamine, melphalan, and busulfan), anthracycline antibiotics (doxorubicin, daunomycin, and dactinomycin), cisplatin, and nitrosoureas), antimetabolites such as (antipyrimidines (cytarabine, fluorouracil and azacytidine), antifolates (methotrexate), antipurines (mercaptopurine and thioguanine), steroids, bleomycin, vinca alkaloids (vincrisine and vinblastine), podophylotoxins (etoposide (VP-16)), and nitrosoureas (carmustine, (BCNU))), immunosuppressant agents such as cyclosporin A and SK506, and anti-angiogenesis agents such as anti-inflammatory or suppressive factors (inhibitors) that prevent endothelial cell proliferation, and inhibitors of proteolytic enzymes such as plasminogen activator inhibitors


Variable refractive power, expandable vitreal substitute

Abstract

Disclosed are intraocular lenses which have an expandable or fillable bag means comprising the central lenticular portion of the lens and lenses which are expandable by filling chambers within a flexible central lenticular portion. The central lenticular portion additionally can comprise a solid lens portion. The expandable bag means or chambers are filled correlating to a desired refractive power after placement in the eye. The intraocular lenses can be inserted in the eye through relatively small incisions (less than about 4 mm). Subsequent changes in refractive power can be accomplished without removing the implanted intraocular lens and with minimal or no trauma. The intraocular lenses can be implanted in either the posterior chamber or capsular bag.

Discovery of Insulin History and controversies

The Discovery of Insulin was researched and written hiring a unique window of opportunity. The 1978 of Charles Best, the last surviving member of the discovery team, happened to coincide with the release of the papers of Sir Frederick Banting. Suddenly it was possible to obtain access to complete documentation of the highly controversial events at the University of Toronto in 1921-23 that led to the isolation and emergence of insulin. At the same time, many individuals who had been witnesses to or participants in the discovery, and who were approaching the end of their lives, now felt free to speak frankly for the historical record. Working on this book, I not only uncovered many new collections of documents, but also found alive two of the original patients who had been treated with insulin in Toronto in 1922. Since publication, no significant new collections of documents have surfaced, but 66 of the 68 individuals I interviewed have died. No one can talk to them individuals I interviewed have died. No one can talk to them now, except through the notes of my interviews, which themselves are now part of the archival record.
project were remarkable, exciting, and life changing. They culminated in several of the most exhausting and rewarding days of my life in Cambridge, England, with the late Sir Frank Young, a grand old man of diabetes research and British science generally, as he challenged not only my conclusions, but my spelling and commas, insisting that a book that would be read around the world and for many years be as perfectly argued and polished as possible. "Bliss," he would say, "this book will be read by Fiji Islanders and Nobel laureates. You have to get it right."

so much has happened in the world of diabetes in our time. Although I moved on to other work in the history of medicine and Canadian topics, I made a point of staying in touch with this subject, and expanded upon The Discovery of Insulin with a number of publications. The most important are Banting: A Biography (Toronto, 1984; 2nd ed., University of Toronto Press, 1992), and a scholarly article, "Rewriting Medical History: Charles Best and the Banting and Best Myth," Journal of the History of Medicine and Allied Sciences, 48 (July 1993): 253—74. Read singularly or together, these publications underline the foolishness of believing that insulin was discovered by fish

foolishness of believing that insulin was discovered by Banting and Best. As I believe I make clear in The Discovery of Insulin, it was a collaborative process, drawing on the talents of at least four people as well as the comparatively great research capacity of the University of Toronto, where for many reasons a field of medical dreams had been built. I should have been more explicit in suggesting that J.B. Collip ought to have shared the Nobel Prize for insulin with Banting and Macleod, and in criticizing the sad attempts at historical falsification engineered by Charles Best, a troubled soul. I also have published "Banting's, Best's, and Collip's Accounts of the Discovery of Insulin," Bulletin of the History of Medicine, 56 (Winter 1982-83): 554—68; and "J.J.R. Macleod and the Discovery of Insulin", Quarterly Journal of Experimental Physiology, 74 (1989): 87-96, along with several condensed

foolishness of believing that insulin was discovered by Banting and Best. As I believe I make clear in The Discovery of Insulin, it was a collaborative process, drawing on the talents of at least four people as well as the comparatively great research capacity of the University of Toronto, where for many reasons a field of medical dreams had been built. I should have been more explicit in suggesting that J.B. Collip ought to have shared the Nobel Prize for insulin with Banting and Macleod, and in criticizing the sad attempts at historical falsification engineered by Charles Best, a troubled soul. I also have published "Banting's, Best's, and Collip's Accounts of the Discovery of Insulin," Bulletin of the History of Medicine, 56 (Winter 1982-83): 554—68; and "J.J.R. Macleod and the Discovery of Insulin", Quarterly Journal of Experimental Physiology, 74 (1989): 87-96, along with several condensed
members of the insulin team:J. B. Collip and the Development of Medical Research in Canada, by Alison Li (2003); J.J.R. Macleod: The Co-discoverer of Insulin, by Michael J. Williams (Royal College of Physicians of Edinburgh, Supplement to Proceedings, 1993); Margaret and Charley: The Personal Story of Dr. Charles Best, by Henry Best (2003). E.C. Noble, who lost the famous coin toss to Charles Best, finally receives attention in M. Jurdjevic and C. Tillman, "E.C. Noble in June 1921, and his account of the discovery of insulin," Bulletin of the History of Medicine, 78, 4 (2004): 864-875. With the development of the Internet the University of Toronto has been able to make more than 7,000 pages of the original documents available on its "Discovery and Early Development of Insulin" website, http://digital.library.utoronto.ca/insulin. An Oxford-based British team has done marvelous work creating an oral
What Happened at Toronto? le discovery of insulin at the University of Toronto in 921-22 was one of the most dramatic events in the history of the treatment of disease. Insulin's impact was so sensational because of the incredible effect it had on diabetic patients. Those who watched the first starved, sometimes comatose, diabetics receive insulin and return to life saw one of the genuine miracles of modern medicine. They were present at the closest approach to the resurrection of the body that our secular society can achieve, and at the discovery of what has become the elixir of life for millions of human beings around the world. This book is an attempt to re-create the discovery of insulin as accurately and fully as can be done in a single volume. It draws on a vast body of primary source material never before available to researchers. It reflects no point of view other than a professional historian's obligation to be as objective
and fair as possible. It is written to be read by anyone from a scientist to a high school student, and especially by those in between. Many readers will begin this book believing they have a reasonably clear understanding of the discovery of insulin. It is a story told in several books, in textbook accounts, in films, tapes and television programs. In broad outline, the conventional history is something like this: By the early years of the twentieth century it was understood that the disease named diabetes mellitus involves the body's inability to metabolize or utilize its food, especially carbohydrates. It was also understood that the pancreas holds  vthe key to carbohydrate metabolism. When experimental animals had their pancreases removed, they immediately lost the ability to utilize carbohydrates, the amount of sugar in their blood and urine rose sharply, and they soon died from severe diabetes. Various researchers speculated that the pancreas, which secretes digestive enzymes into the gut (its external secretion), must also produce another kind of secretion, one enabling the body to utilize its fuel. The search for the internal secretion of the pancreas had occupied a number of physiologists throughout the world, but by 1920 it had not produced any practical results. In the autumn of 1920 Frederick Banting, a young surgeon in London, Ontario, happened to be reading an article about the pancreas. Banting began thinking about the problem of the internal secretion, and late that night jotted down an idea for an experimental procedure — ligating the pancreatic ducts - that might be a way of isolating an internal secretion. He took
internal secretion, and late that night jotted down an idea for an experimental procedure — ligating the pancreatic ducts - that might be a way of isolating an internal secretion. He took his idea to his alma mater, the University of Toronto, where the Professor of Physiology, J.J.R. Macleod, was an internationally known expert in carbohydrate metabolism. Macleod was at first skeptical of Banting's suggestion, but reluctantly agreed to give him a lab and some dogs for a few weeks during the coming summer. He assigned him a young science student, Charles Best, to do the chemical tests necessary for the work, and then went off to Scotland for his summer holidays. Banting and Best experienced a number of problems with their work in that summer of 1921, the story goes, but soon found that their approach was yielding remarkable results. With the extract of pancreas they had made from duct-ligated
dogs they were able time after time to lower the blood sugar and remove other symptoms from diabetic dogs. Prof Macleod came home to a pair of excited researchers who, by the autumn of 1921, were keeping a severely diabetic dog, Marjorie, alive with their extracts. Marjorie eventually lived for seventy days before being sacrificed; until then diabetic dogs had died within a week or two of their pancreas being removed. By the winter of 1921—22 Banting and Best were giving their first papers on the internal secretion of the pancreas. They were also ready to test their extract on humans. In Toronto General Hospital a young boy, Leonard Thompson, became the first diabetic to receive insulin. His life was miraculously saved. Professor Macleod put his whole laboratory to work on insulin. An American drug firm, Eli Lilly and Company, was
Professor Macleod put his whole laboratory to work on insulin. An American drug firm, Eli Lilly and Company, was brought in to help prepare it in commercial quantities. At the same time, however, the University of Toronto patented the process in order to control the quality of insulin sold to diabetics. By 1923 insulin was being produced in virtually unlimited quantities, and was the stuff of life itself for thousands of diabetics. Late in 1923 the Nobel Prize was awarded for the discovery of insulin. It was awarded to Banting and J.J.R. Macleod. This raises what seems to be the single really controversial point about the discovery: why should Macleod have shared a Nobel Prize for work done in his lab while he was on holiday? It is fairly well known that Banting was dissatisfied with the Nobel Committee's decision. He immediately announced that he was

that he would share his half with J.B. Collip, a biochemist who had joined the team late in 1921 and worked on the development of the extract. There are several commonly held views about this problem of credit. Perhaps the Nobel Committee just made a mistake, possibly because Macleod's name was on some of the early publications. Perhaps Macleod, a German-trained professor, held Teutonic-type notions about the head of a lab meriting credit for everything done in his fiefdom. Perhaps it was a case of human weakness - perhaps Macleod deliberately tried to steal credit from the inexperienced young men who had actually made the discovery. Whatever happened, the judgment of history, at least in North America, has been to remember Banting and Best as the discoverers of insulin. And, of course, it was a magnificent discovery, a medical fairy tale come true of the lone doctor and his partner overcoming

all obstacles to realize an idea and save the lives of millions and millions of people. Surely this is truth stranger than fiction, or it is the truth that makes fiction plausible. Even at first glance, however, we are left with some curiosities. For completeness' sake, it would be interesting to know exactly why Macleod got his half of the Nobel Prize. More curious, come to think of it, who was J.B. Collip? Why did he end up with the same share of the Nobel Prize money that Banting and Best each got? More generally, why was insulin discovered by two inexperienced researchers in a city and a country which had no particular stature in the world of medical research? Was existing research so poorly developed that a total outsider could confound all the experts with a brilliant, untried suggestion? Or was there somehow a large
element of chance involved? Perhaps the Canadians were just lucky. A few readers will know that some articles have already been written on the points raised by these and similar questions. Even most experts, though, will be surprised to know how early the controversy about the discovery of insulin actually began. The first attempt at serious historical assessment of the Toronto work was made almost immediately. In December of 1922 a physiological researcher in Cambridge, England, Dr. Ffrangcon Roberts, wrote a long letter to the British Medical Journal reviewing Banting and Best's first publications. It was a scathing critique of the Toronto "The production of insulin," Roberts investigation. concluded, "originated in a wrongly conceived, wrongly conducted, and wrongly interpreted series of experiments."l Roberts was immediately rebuked for the intemperance of his
letter, indeed for writing the letter at all, by Dr. Henry H. Dale, a leading figure in British research who had recently been in Toronto studying insulin at first hand. Roberts' review, Dale wrote, was "armchair criticism," the kind of destructive comment that "seldom leads to anything but verbal controversy." Whatever might or might not finally be decided about Banting and Best's experiments, nobody could deny that a first-rate discovery had been made. "It is a poor thing," Dale scolded, "to attempt belittlement of a great achievement by scornful exposure of errors in its inception."2 Dale's view that critical discussion of Banting and Best's work amounted to belittlement of a great achievement prevailed in medical and historical circles for the next three decades. There was no point to be served, it was believed, in discussing

made in refining both Banting and Best's flawed experiments and their crude pancreatic extract. "Credit for the discovery of a preparation of insulin that could be used in treatment," Pratt wrote, "belongs to the Toronto investigators Banting, Best, Collip, and Macleod working as a team. Each of these men made an important contribution."3 Pratt's attempt to rewrite the history of the discovery of insulin prompted a sharp reply from a medical historian in Toronto, Dr. W.R. Feasby, who was also an ardent admirer of C.H. Best. The burden of Feasby's 1958 article, "The Discovery of Insulin," in the Journal of the History of Medicine, was that the conventional history of the discovery was correct in all important particulars. "The published and unpublished records of Banting and Best's work establish the fact that convincing proof of the presence of insulin was available in the summer of 1921, when they were working alone..."

Banting and Best discovered insulin, Feasby reiterated; the others helped somewhat in its development.4 Pratt had died. Feasby died before finishing the biography of Best on which he worked for several years. Frederick Banting's second wife, Henrietta, died before making any significant progress on the biography she planned to write of her husband. The Toronto doctor who took over her work, Ian Urquhart, also died. In the meantime medical historians in other countries were beginning to consider the discovery of insulin from the point of view of other people besides the Torontonians who had been working on pancreatic extracts. Before his death (the death rate among those trying to write about the discovery of insulin sometimes seems higher than it is among diabetics), a Scots medical historian, Ian Murray,

published several articles in the late 1960s and early 1970s on the search for insulin. His aim was to show how the Toronto work related to half a century of earlier investigation of the pancreas and diabetes. Insulin had not emerged out of a vacuum, but was the culmination of years of work by dozens of scientists in many countries. Murray was particularly interested in a Romanian scientist, Nicolas Paulesco, who in 1921, just as Banting and Best were starting to work, published very important papers describing successful experiments with pancreatic extracts. Unfortunately for Paulesco, the North Americans moved so quickly into the testing and production of insulin that he never got serious clinical tests of the material he called "pancréine" under way. Paulesco and his work disappeared from history. Now they were resurrected. "Banting and Best are commonly believed to have been the first to have succeeded in isolating
Now they were resurrected. "Banting and Best are commonly believed to have been the first to have succeeded in isolating insulin," Ian Murray wrote. "They have been hailed as its 'discoverers'. Their work, however, may more accurately be construed as confirmation of Paulesco's findings."5 Murray's work revived Romanian interest in a countryman who had apparently achieved so much and been so little honoured. Influenced by the impending fiftieth anniversary of the discovery, members of the Romanian School of Medicine in Bucharest launched a campaign to have Paulesco given his due. As a result of their agitation, the International Diabetes Federation decided to establish a special blue-ribbon committee to prepare a factual account of the various researches leading to the discovery of insulin. The report, published in 1971, was a careful, tightly written summary of historical knowledge about the discovery. Its conclusions,

difficult to simplify because of the subtlety of the argument, were to the effect that Paulesco might indeed have discovered insulin as a therapy for diabetes had not the North Americans been able to move so swiftly and successfully to develop the results of Banting and Best's research. Pancréine probably contained insulin — so did the pancreatic extracts prepared by several earlier researchers, especially a German named Zuelzer — but it was the Canadians who made insulin suitable for the treatment of diabetes.6 The Romanians were not satisfied. Their continued complaints about the composition and work of that committee were secondary to their deep anger at an egregious error Banting and Best had made in their first paper, published in February 1922. In their only reference to Paulesco's work, published before theirs, Banting and Best imply quite wrongly that his results were negative. It is such
complaints about the composition and work of that committee were secondary to their deep anger at an egregious error Banting and Best had made in their first paper, published in February 1922. In their only reference to Paulesco's work, published before theirs, Banting and Best imply quite wrongly that his results were negative. It is such an odd error, with apparently such devastating consequences for Paulesco's reputation. Was this why the Nobel people neglected him? the Romanians asked. The leading Romanians interested in Paulesco's rehabilitation decided that Banting and Best's misrepresentation of his work was too suspicious to explain away as a simple mistake. It was a deliberate distortion of Paulesco's work by Banting, wrote Dr. Constantin Bart in a 1976 article entitled "Paulesco Redivivus." Bart went on to deduce what he thought was the real truth behind Macleod getting half of the Nobel Prize:
Redivivus." Bart went on to deduce what he thought was the real truth behind Macleod getting half of the Nobel Prize: Macleod, well versed in the literature, must have found out about Banting's falsification and threatened him with public exposure unless Banting shared the credit and glory with him, Macleod. The history of the discovery of insulin seems to have included scientific blackmail and a vicious conspiracy to cheat Paulesco out of his rightful share of honour and prizes. Truth indeed stranger than fiction.7 Fanciful as their speculations were, the Romanians had a
Fanciful as their speculations were, the Romanians had a point in wondering why more had not been written about the events at Toronto. Their reviews of the literature on the history of the discovery alerted them to the quarrelling among the discoverers and to all the unresolved historical controversies about Banting and Best's research. With European authorities writing almost jeeringly about the "vrai panier de crabes" at Toronto in 1921—22,8 it was surely time to find out what had really happened. There was one more important publication in the late 1970s. J.J.R. Macleod had died in Scotland in 1935. Thirteen years later a copy of a document found among his papers reached North America. Dated September 1922, it was entitled "A History of the Researches Leading to the Discovery of Insulin," and was Macleod's personal account of the events at Toronto. From 1948 to 1978 the Macleod manuscript had had an underground circulation among a small circle of scholars.
Insulin," and was Macleod's personal account of the events at Toronto. From 1948 to 1978 the Macleod manuscript had had an underground circulation among a small circle of scholars. Fearful of reopening a controversy that might do no one any good, the president of the University of Toronto in the mid- 1950s had quite improperly used his influence to prevent its publication.9 Lloyd Stevenson, who had written Banting's biography many years earlier, finally published the Macleod document in the Bulletin of the History of Medicine in 1978. As the research for my book developed, Macleod's account turned out to be only one of many new documents shedding light on the discovery. It was clear from a careful reading of Macleod that Banting and Best had prepared similar accounts

at the same time in 1922. Manuscripts of these were found. In the Banting Papers was a second long account that Banting had written in 1940. So was the correspondence Banting and Best had had with Macleod in the summer of 1921. So were the original index cards on which Banting and Best had recorded the notes taken from their reading, including their note on Paulesco's prior article. Banting's original notebook, in which he recorded his first idea and the first series of experiments, was discovered. So were many other documents. Some of them were coming to light in the natural course of events, as when the University of Toronto made the Banting Papers available for scholarly research, and when the Nobel Committee of the Caroline Institute in Stockholm agreed to open its archives to qualified researchers. Others emerged because of this project. At the outset I decided to make a more determined and careful search for documents than anyone had previously undertaken, and that search was

than anyone had previously undertaken, and that search was rewarding. My aim was to carry out the historian's job of re-creating the discovery of insulin. As far as possible I wanted to work from contemporary sources. I wanted to ignore the judgments of later writers and put aside the partisan recollections of the discoverers themselves, at least until I had found out from the documents generated at the time - laboratory notebooks, correspondence, published articles, etc. - exactly what had happened. I wanted to reconstruct the insulin research dog by dog, day by day, experiment by experiment. After that it would be proper to reflect on the fallibility of the participants' memories and the validity of the scientists' claims and counter-claims.


of that drama — the tension, interludes, crises, climaxes, ironies, and occasional absurdities — exactly as it happened. In offering this history, I reject the view that the truth will lead to a belittlement of the discovery of insulin or of the discoverers. This is a book about life, disease, death, salvation, and immortality. It is a wonderful thing to be a witness to the struggles of men, weighed down with all the burdens manhood bears, to find a way of enlarging the possibilities of our human condition.

Tasting the urine was doctors' original test for diabetes. Early in the nineteenth century chemical tests were developed to indicate and measure the presence of sugar in the urine, that is, the condition of glycosuria. A patient showing glycosuria was generally deemed to be diabetic (other disorders that could cause sugar in the urine were far less common than diabetes and were usually ignored), so diabetes was sometimes defined as a condition in which glycosuria exists.

But there was no agreement on the exact definition of diabetes. Diagnostic methods were uncertain and changing. So were statistical methods. This all meant that it was impossible to know how many diabetics there were in any given country in, say, the year 1920. There tended to be more diabetics among peoples who were prosperous and well- nourished rather than among the poor and lean. In the early twentieth century the disease was particularly noticed among wealthy Jewish people, and seems to have been most visible in the richest countries, notably the United States and Germany. As nations became richer and peoples became better nourished, and as vaccines, anti-toxins, and sanitary measures began to reduce the death rate from infectious diseases, the prevalence of diabetes was increasing. By 1920 between 0.5 and 2.0 per cent of the population of industrialized countries had diabetes.

Another French doctor, Bouchardat, more than made up for Piorry's disaster by beginning to work out individual diets for his diabetic patients. Already experimenting with the use of periodic fast days, on which no food would be taken, Bouchardat observed the actual disappearance of glycosuria in some of his patients during the rationing while Paris was besieged by the Germans in 1870. He also noticed that exercise seemed to increase a diabetic's tolerance for carbohydrates. "You shall earn your bread by the sweat of your brow," Bouchardat remarked to a patient pleading for more of what was then everyone's staple.4 The unwillingness of diabetics to follow diets was and still is the single most difficult problem physicians had to face as they tried to treat the disease. The important late nineteenth century Italian specialist, Cantoni, isolated his patients under lock and key. A disciple of his system, the German physician Bernard Naunvn. would lock Datients in their rooms for LID to

century Italian specialist, Cantoni, isolated his patients under lock and key. A disciple of his system, the German physician Bernard Naunyn, would lock patients in their rooms for up to five months when necessary to obtain "sugar-freedom."5 Because diabetes was then thought to involve only a failure of carbohydrate metabolism, the diets contained a minimum of carbohydrates and a very high proportion of fat, sometimes extremely high if a doctor believed he should replace lost calories and build up a diabetic's weight and strength. Any low carbohydrate diet, even if fats more than compensated for the calories lost, was unappetizing over a long period of time. So it seemed a great breakthrough in 1902 when the German, von Noorden, announced his "oat- cure" for diabetes. Suddenly a diabetic could increase his
carbohydrate rations so long as they were in the form of foods made from oatmeal. An enormous research effort was begun by nutritionists to find out what it was that made oatmeal more assimilable than other carbohydrates (bananas, the von Noordenites found, seemed to be the next best). Actually, the oat-cure was only the most popular of a long line of carbohydrate "cures" offered from time to time - the milk diet, the rice cure, potato therapy, and others.6 There may be a direct link between these early fads in diet therapy for diabetes and popular fad diets of the late twentieth century. Low-carbohydrate diets did often reduce or eliminate glycosuria (leading almost as often to the conclusion that the diabetes was cured, followed by a resumption of normal diet, followed by more glycosuria). Milder diabetics, usually older ones, who kept to a diet reasonably well were sometimes able
ones, who kept to a diet reasonably well were sometimes able to live with their disease for years without too much discomfort. Severe diabetics, especially children, seemed seldom helped by high-calorie, low-carbohydrate diets. They deteriorated almost as quickly as before, and in fact it was later argued that the high fat content of the diets speeded the development of acidosis leading to coma. Like cancer, diabetes was not a satisfying disease to treat. (It could be financially rewarding to treat, of course, particularly if a doctor specialized in mild cases and thereby claimed a high success rate as measured by the long lives of his patients; it also helped if all patient deaths from infections, tuberculosis, or other complications were not counted as deaths from diabetes.) A British doctor made a famous flippant remark about a French diabetologist: "What sin has Pavy committed,
or his fathers before him, that he should be condemned to spend his life seeking for the cure of an incurable disease?"7 111 The quip was actually a tribute to the dedication of medical scientists. Their basic strategy in the search for a cure for diabetes involved first finding the cause of the disease. The common-sense assumption that the problem was in the stomach gradually faded as physiologists came to understand the role of other organs in metabolism. Claude Bernard, for example, showed that it is the liver, transforming material assimilated in digestion, that dumps sugar into the bloodstream. So perhaps diabetes was a liver disease. Except that from the middle of the nineteenth century there was a gradually accumulating body of evidence from autopsies on diabetics that the disease was sometimes accompanied by

gradually accumulating body of evidence from autopsies on diabetics that the disease was sometimes accompanied by damage to a patient's pancreas — and, more important, that patients with extensively damaged pancreases almost always had diabetes.8 The pancreas is a jelly-like gland, attached to the back of the abdomen behind and below the stomach. It is long and narrow and thin, irregular in size, but in humans usually measuring about 20 x 6 x 1 centimetres and weighing about 95 grams. To the layman the pancreas appears to be a not very interesting cluster of blobs of fleshy material. Animal pancreases, along with thymus glands and sometimes testes, have long been considered delicacies; their gourmet name, sweetbreads, appears to have nothing directly to do with sugar or diabetes. 

medical student, Paul Langerhans, announced in his dissertation that the pancreas contains not one, but two systems of cells. There are the acini, or clusters of cells, which secrete the normal pancreatic juice. But scattered through the organ and penetrating the acini in such a way that they often seem to be floating in a sea of acinar cells, Langerhans found other cells, apparently unconnected to the acini. He declared himself completely ignorant of their function. Several years later the French expert, Laguesse, named these mysterious cells the islands or islets of Langerhans (fles de Langerhans). He suggested that if the pancreas has some other function in the system besides secreting digestive juice, the islet cells are probably involved. Evidence connecting the pancreas and diabetes was still tenuous in 1889 when an astonishing discovery was made in the medical clinic of the University of Strasbourg. OskarThe main function of the pancreas appeared to be to produce digestive enzymes. These are secreted through the pancreatic ducts into the duodenum (or small intestine), where they become the important constituents of the juices working to break down foodstuffs passing down the alimentary canal. Surely a straightforward enough job for an organ. Close studies of the pancreas under the microscope revealed a situation not quite so straightforward. In 1869 a German medical student, Paul Langerhans, announced in his dissertation that the pancreas contains not one, but two
\ two systems of cells. There are the 
situation not quite so straightforward. In 1869 a German medical student, Paul Langerhans, announced in his dissertation that the pancreas contains not one, but two systems of cells. There are the acini, or clusters of cells, which secrete the normal pancreatic juice. But scattered through the organ and penetrating the acini in such a way that they often seem to be floating in a sea of acinar cells, Langerhans found other cells, apparently unconnected to the acini. He declared himself completely ignorant of their function. Several years later the French expert, Laguesse, named these mysterious cells the islands or islets of Langerhans (fles de Langerhans). He suggested that if the pancreas has some other function in the system besides secreting digestive juice, the islet cells are probably involved. Evidence connecting the pancreas and diabetes was still tenuous in 1889 when an astonishing discovery was made in
islet cells are probably involved. Evidence connecting the pancreas and diabetes was still tenuous in 1889 when an astonishing discovery was made in the medical clinic of the University of Strasbourg. Oskar Minkowski and Joseph von Mering had disagreed on whether or not the pancreatic enzymes were vital to the digestion of fat in the gut. To settle the issue they decided to try the very difficult experiment of removing the pancreas from a dog, and then observing the result. What would happen to digestion without pancreatic juice? In an account written many years later,9 Minkowski described, or clusters of cells, which secrete the normal pancreatic juice. But scattered through the organ and penetrating the acini in such a way that they often seem to be floating in a sea of acinar cells, Langerhans found other cells, apparently unconnected to the acini. He declared himself completely ignorant of their function. Several years later the French expert, Laguesse, named these mysterious cells the islands or islets of Langerhans (iles de Langerhans). He suggested that if the pancreas has some other function in the system besides secreting digestive juice, the islet cells are probably involved.

Evidence connecting the pancreas and diabetes was still tenuous in 1889 when an astonishing discovery was made in the medical clinic of the University of Strasbourg. Oskar Minkowski and Joseph von Mering had disagreed on whether or not the pancreatic enzymes were vital to the digestion of fat in the gut. To settle the issue they decided to try the very difficult experiment of removing the pancreas from a dog, and then observing the result. What would happen to digestion without pancreatic juice? In an account written many years later,9 Minkowski described how he had kept the 
how he had kept the depancreatized dog tied up in his lab while waiting for von Mering to return from a trip. Even though the animal was housebroken and regularly taken out, it kept urinating on the laboratory floor. Minkowski had been taught by his supervisor, Naunyn, to test for the presence of sugar in urine whenever he noticed polyuria. His tests revealed 12 per cent sugar in the dog's urine, the realization that it was suffering from something indistinguishable from diabetes mellitus, and the hypothesis, subsequently demonstrated in case after case, that without its pancreas a dog becomes severely diabetic. Somehow the absence of the pancreas caused diabetes. This was a great experimental breakthrough, due not just to good luck and close observation, but also to the skill of researchers who apparently were performing some of the first successful total pancreatectomies. (Much of the fair amount of skepticism

pancreatectomies. (Much of the fair amount of skepticism with which their finding was greeted related to doubts that they had actually excised the whole pancreas, for parts of it could be easily missed.)* The next problem was to discover how the pancreas regulated sugar metabolism. Was it the absence of pancreatic juice, for example, that brought on the diabetes in a depancreatized dog? Apparently not, for Minkowski confirmed the observations of other experimenters who had ligated and/or cut the ducts leading from the pancreas to the duodenum. Stopping the flow of pancreatic juice in this way caused minor digestive problems, but it did not cause diabetes. Only total pancreatectomy did. When critics pointed out that duct ligation often failed to work, for tied ducts were by-passed and new ducts often formed to replace cut ones, the French dog tied up in his lab  while waiting for von Mering to return from a trip. Even though the animal was housebroken and regularly taken out, it kept urinating on the laboratory floor. Minkowski had been taught by his supervisor, Naunyn, to test for the presence of sugar in urine whenever he noticed polyuria. His tests revealed 12 per cent sugar in the dog's urine, the realization that it was suffering from something indistinguishable from diabetes mellitus, and the hypothesis, subsequently demonstrated in case after case, that without its pancreas a dog becomes severely diabetic. Somehow the absence of the pancreas caused diabetes. This was a great experimental breakthrough, due not just to good luck and close observation, but also to the skill of researchers who apparently were performing some of the first successful total

pancreatectomies. (Much of the fair amount of skepticism with which their finding was greeted related to doubts that they had actually excised the whole pancreas, for parts of it could be easily missed.) * The next problem was to discover how the pancreas regulated sugar metabolism. Was it the absence of pancreatic juice, for example, that brought on the diabetes in a depancreatized dog? Apparently not, for Minkowski confirmed the observations of other experimenters who had ligated and/or cut the ducts leading from the pancreas to the duodenum. Stopping the flow of pancreatic juice in this way caused minor digestive problems, but it did not cause diabetes. Only total pancreatectomy did. When critics pointed out that duct ligation often failed to work, for tied ducts were by-passed and new ducts often formed to replace cut ones, the French

revelation helped spread the idea that these hormones, the "vital juices" of popular lore, could be very potent. In the less exotic field of diabetes research, it certainly seemed that both theory and experimental observation pointed towards a potent hormone being produced in the pancreas to regulate metabolism.10 As soon as it was realized that the pancreas controls diabetes, attempts began to treat the disease, literally, with pancreas — just as diseases of the thyroid were being treated with thyroid. Minkowski was the first of many researchers to try to restore the pancreatic function to diabetic animals (others experimented on human diabetics) by preparing and administerin extracts of ancreas. The extracts could be


administering extracts of pancreas. The extracts could be made in a variety of ways; they could also be administered in a variety of ways, although the most obvious were orally and by injection. The important observation would be of sugar in the urine. If an extract reduced glycosuria it might be potent. It might contain the internal secretion; indeed, it might supply the proof that there actually was an internal secretion, for until its effect could be practically demonstrated, the internal secretion of the pancreas was merely a good-looking hypothesis. The results of the early experiments with pancreatic extracts were mixed, tending towards the negative. Some extracts had no effect; some had decidedly harmful effects, throwing the animals into shock or worse. Others had temporary sugar- reducing effects that were more than cancelled out by harmful side-effects — so much so that it was impossible to

tell whether it was the extract or its toxic effect on the system that was the true cause of the reduction in glycosuria. If an extract caused kidney failure, for example, it might be changing the contents and quantity of the urine without affecting the diabetic condition at all. A few researchers did report encouraging results with extracts, but others who tried to repeat their work got discouraging results. It will never be known precisely how many researchers tried giving pancreatic extracts to diabetic animals and humans. Estimates run to more than four hundred. It was an easy experiment for even a country doctor to try, but if the results were not encouraging many would decide there was no point publishing. As it was, there was no shortage of publication, on every conceivable aspect of the problem of diabetes and the pancreas, it seemed. In 1910 Opie complained that the literature on diabetes was voluminous. A few ears earlier
pancreas, it seemed. In 1910 Opie complained that the literature on diabetes was voluminous. A few years earlier Lydia Dewitt estimated that more thought and investigation was going into the islets of Langerhans than any other organ or tissue of the body.ll Despite the discouragement, the search for a workable pancreatic extract continued. Perhaps the problem with extracts was that somehow the pancreas's external secretion, or the tissues producing it, destroyed the internal secretion in the extirpated organ. Laguesse suggested using extracts made from fetal pancreases, because it seemed that the islet cells develop well before the acinar cells in gestation. If the experiment was tried, it failed. So did a number of other experiments involving fish. In certain species of fish the islet tissue had been found to be anatomically distinct from the acinar tissue, making it possible, it seemed, to get an extract
which was more purely an extract of the islets of Langerhans. Between 1902 and 1904 two Scots researchers in Aberdeen, John Rennie and Thomas Fraser, fed an extract of boiled fish islets to four diabetic patients. After inconclusive results, including a toxic reaction when they tried to inject the extract into a fifth patient, they gave up.12 The most persistent and important of the early extractors was Georg Ludwig Zuelzer, a young internist in Berlin who in the early 1900s became interested in the theory that diabetes was actually caused by adrenalin. Experimental evidence that large doses of adrenalin could produce glycosuria convinced Zuelzer that the function of the internal secretion of the pancreas was simply to neutralize adrenalin in the system. He decided to try to prove this by injecting an extract of pancreas into rabbits along with adrenalin. When no glycosuria developed, Zuelzer was encouraged to go on and

glycosuria developed, Zuelzer was encouraged to go on and see if his extract could reduce diabetic symptoms in depancreatized dogs. When it appeared to reduce the sugar excreted in the urine of two diabetic dogs, Zuelzer was encouraged to go further. Dying diabetics were hopeless cases, so it must have seemed that nothing could be lost in experimenting on them. On June 21, 1906, Zuelzer injected eight cubic centimetres of his pancreatic extract under the skin of a comatose fifty-year-old diabetic in a private clinic in Berlin. The next day he injected another ten cc. Whatever effect the extract was having on the patient's glycosuria could not be measured, for the man had lost control of his bladder and was wetting his bed. What was clear was that the patient seemed to be coming back from the edge of the grave. His overall condition improved, his
appetite returned, and his severe dizziness disappeared. But there was no more extract. The patient sank into deep coma on June 30 and died on July 2. What Zuelzer had seen was tremendously encouraging, a diabetic momentarily pulled out of coma. "Whoever has seen how a patient lying in agony soon recovers from certain death and is restored to actual health will never forget it," he wrote years later just after insulin had been discovered in Toronto. He was almost certainly referring to his first experience with his own pancreatic extract, which he named "acomatol."13 Zuelzer had immense practical difficulties carrying out his experiments. It was hard to get a supply of pancreases, for example. Workers at local slaughterhouses thought the doctor who wanted them to give him fresh sweetbreads for medical research must be a little crazy. The extract was not at all easy to make, and had a frustrating tendency to lose its

medical research must be a little crazy. The extract was not at all easy to make, and had a frustrating tendency to lose its potency (Zuelzer tested his batches on rabbits, measuring the potency by the amount of extract needed to neutralize the sugar-creating effects of a unit of adrenalin). But there were those early results, and it was obvious that a workable pancreatic extract would be a wonderful thing. When Zuelzer approached the Schering drug company with his idea they offered him financial support and technical help and applied for patents on his methods. By the summer of 1907 he was ready to try again on humans. The extract produced the amazing effect of completely suppressing for a few days glycosuria and acidosis in a twenty-seven-year-old man. Other diabetics — a six-year-old, a thirty-five-year-old, and two sixty-five-year-olds - had their symptoms dramatically relieved by acomatol. (Some others, it
appears, did not; Zuelzer reported only the most interesting cases.) On the other hand, in every case after the first two there were serious reactions to the injections: vomiting, high fevers, sometimes convulsions. Knowing that his preparation was not yet a practical therapy, Zuelzer was still confident enough to publish his results in 1908. He came to the triumphant conclusion "that it is possible through the injection of a pancreatic extract to eliminate the excretion of sugar, acetone, and acetoacetic acid by a diabetic without making any changes in the patient's diet."14 These exciting findings caught the attention of a worker in the clinic directed by Minkowski in Breslau. J. Forschbach obtained samples of Zuelzer's extract and tested it on three dogs and three humans. His verdict was negative. Yes, Zuelzer's was the first pancreatic extract to suppress glycosuria in both the short and the long run. But it did so at

glycosuria in both the short and the long run. But it did so at the cost of severe toxic side-effects, especially fever, so severe that Forschbach stopped his human experiments for fear of doing permanent damage to achieve only temporary relief. "It will be difficult to convince a patient who has been made severely ill by a single injection," he wrote, "that this result was connected to a significant beneficial effect upon his diabetes." Forschbach was fairly convinced, especially after some impotent extract caused no ill effects in one case, that the cause of the potency and the cause of the side effects were the same. So there was no future in it. Forschbach's 1909 paper on his tests of Zuelzer's extract was decidedly discouraging, and must have been more so because of Forschbach's association with the great Minkowski himself. The giants in the field had passed judgment.15


Using extracts which had gone through various stages of development through mixing the pancreas with alcohol, filtering it, treating the residue, and other chemical procedures, Scott found one formula that gave encouraging results on three of the four diabetic dogs he treated with it. Not only did their sugar excretion diminish, but "if one dared to say it," Scott wrote, the dogs "seemed even brighter for a time after the injection than before it." Like Zuelzer before him and others afterwards who observed the subjective signs of improvement in diabetic animals and patients, Scott was convinced that he had been successful. The first two conclusions of his master's degree thesis were: 1st. There is an internal secretion from the pancreas controlling the sugar metabolism. 2nd. By proper methods this secretion may be extracted and still retain its activity.

still retain its activity. Scott's thesis adviser, the noted physiologist Anton Carlson, did not share his student's confidence. Having just read of recent work by Hédon questioning the effectiveness of pancreatic extracts, Carlson worried that Scott had not sufficiently controlled his experiments. He urged that the conclusions be rewritten, probably supplying the new wording himself: It does not follow that these [good] effects are due to the internal secretion of the pancreas in the extract. The injections are usually followed by a slight temporary rise in the body temperature, and this may be a factor in the lowered sugar output. Physiologists are not agreed as to whether the internal secretion acts by diminishing or retarding the passage of sugar from the tissues into the blood, or by

increasing the oxidation of the sugar in the tissues. The pancreas extract may decrease the output of sugar from the tissues by a toxic or depressor action, rather than by a specific regulatory action of the pancreas secretion....The work is being continued in the hope of clearing up these points.17 Despite his conservatism, Carlson urged Scott to continue the research and work out his "salvation or damnation along the pancreas extract line.... There is something ahead in that line — possibly both shoals and open water. Puzzle: find the channel." Scott tried half-heartedly, attempting to buttress his urinary sugar results with studies of his extract's effect on the blood sugar of cats. He reported the "very surprising" result that it caused an increase in their blood sugar.18 Having struck a shoal, Scott veered away from pancreatic extracts to study problems relating to blood sugar. Before giving up the work, Scott chatted about it with some of
study problems relating to blood sugar. Before giving up the work, Scott chatted about it with some of the other experts in the field. One of these was a professor at Western Reserve University in Cleveland, Ohio, John James Rickard Macleod. Macleod was a Scotsman, trained in Aberdeen, Germany, and London, who had emigrated in 1903 to take his American appointment at the age of twenty-seven. He had been working for several years in the area of carbohydrate metabolism. A competent researcher and a prolific writer and synthesizer of current knowledge in physiology, Macleod was particularly knowledgeable about the literature in his field. The only knowledge we have of his discussion with Scott is that it began with a consideration of how to cure Scott's child's diarrhoea. When the talk turned to pancreatic extracts, Macleod may have discouraged the oun er man, for about this time he was workin on his own

main research contribution to the search for the internal secretion of the pancreas. Macleod was able to show that the findings of two leading Britishers, Knowlton and Starling, who thought they had a pancreatic extract which assisted the heart of a diabetic dog to utilize sugar in the blood, were not repeatable.19 Knowlton and Starling's joined Scott's and Zuelzer's in the list of apparently ineffective pancreatic extracts. Two young Americans, John R. Murlin and Benjamin Kramer, continued to fiddle with pancreatic extracts similar to Knowlton and Starling's, but their work led them off into examinations of the influence of alkaline solutions on metabolism.20 Macleod summarized the state of the search for an internal secretion in his 1913 book, Diabetes: Its Pathological Physiology. After due deliberation he concluded that there was an internal secretion of the pancreas, but suggested several

After due deliberation he concluded that there was an internal secretion of the pancreas, but suggested several reasons why it might never be captured in a pancreatic extract. The powerful pancreatic juice might destroy it; there might be no reserves of it in the pancreas to be captured by extraction; or it might exist in the pancreas only in latent form and not be activated until secreted into the blood. Macleod's own interest and his work tended to be on the behaviour of blood sugar rather than pancreatic extracts. He thought the most convincing proof of the existence of an internal secretion came in Hédon's early work (now questioned by Hédon himself) using grafts of pancreatic remnants to show that a small, isolated portion of the pancreas could stave off diabetes.21 In 1913 Dr. Frederick Allen pronounced what seemed to be the epitaph of a generation's attempts to treat diabetes with
pancreatic extracts: "All authorities are agreed upon the failure of pancreatic opotherapy in diabetes....injections of pancreatic preparations have proved both useless and harmful. The failure began with Minkowski and has continued to the present without an interruption....The negative reports have been numerous and trustworthy. "22 Frederick Madison Allen wrote with particular authority. Born in Iowa in 1876, trained in medicine in California, Allen had come east to do medical research, drifted into a poorly paying fellowship at the Harvard Medical School, and found himself working on problems of sugar consumption. The study turned into three years of intensive research concentratinon diabetes. Most research is reorted u on in