The Pissing Evile

The discovery of insulin may be rated the first great triumph of medical science. The first important contribution of the great pharmaceutical companies to human welfare was surely the preparation, purification, standardisation and marketing of insulin in a form suitable for self-administration by the afflicted patients.

The entire episode brought to an end, with an appropriately reverberant thunderclap, the long epoch of therapeutic nihilism described by Lewis Thomas in his most recent book.* The insulin story begins, of course, as other medical stories begin, at the bedside – with the taking of a history and an appraisal of the patient’s general health. The history would be loss of weight, debility and general malaise, of intractable thirst, the continual passing of urine that led to a 17th-century London surgeon’s describing diabetes as the ‘pissing evile’, and apparent susceptibility to infections. All this would raise in the physician’s mind a suspicion of diabetes mellitus – sugar diabetes – soon to be directly confirmed by testing the urine or watching house flies congregate around a drop of evaporated urine. Older physicians still recount these diagnostic exercises in order to rebuke or silence enthusiastic young medical scientists who babble incoherently about the place of nuclear magnetic resonance spectroscopy in a country practice. The discovery and marketing of insulin put it for the first time within the power of the profession to restore to something like normal life victims of juvenile diabetes who would otherwise have had before them a life of invalidism terminated by early death.

The insulin story is here recounted as a sabbatical exercise by the Professor of Canadian History in the University of Toronto. It is not now likely that there will be any further windfall of evidence relating to the matter: this, it seems, will be the definitive history. More than that, it is well-written and highly readable.

Before the story begins, physiological research had already made it clear that the pancreas had something to do with diabetes, very probably by the manufacture of an internal secretion. The extraction of such a secretion – it was later discovered to be a protein – was felt to be a chancy and difficult business because the secretion might be destroyed during extraction by the powerful digestive enzymes already known to be manufactured by the pancreas. A young surgeon, Frederick Banting, of London, Ontario, conceived the idea that extraction of a hypothetical secretion would be made easier by a ligation of the pancreatic duct to bring about atrophy of the enzyme-secreting parts of the pancreas, which could thereby be converted into a predominantly endocrine organ: that is, into an organ principally responsible for manufacturing internal secretions, which would then be liberated directly into the bloodstream instead of travelling through a duct to their place of action. The Professor of Physiology at the University of Toronto, J.J.R. Macleod, was not carried away by the notion, but he owes his place in history to having thought well enough of it to give Banting a room and the services of a medical student, Charles Best, whose principal duty would be to carry out the crucially important job of estimating the concentration of reducing sugars in blood and urine – a simple procedure now that it has been streamlined and virtually automated by the pharmaceutical companies’ diagnostic kits, but something which at the time required single-minded attention.

Although the research of Banting and Best, like all other research enterprises everywhere else, encountered some disheartening snags to begin with, they had what experimenters call a reliable ‘system’ to work with. Dogs deprived of their pancreases live no longer than a few weeks: if the pancreatic extracts were to work, they would bring the blood-sugar concentration clattering down and allow these dogs to survive for more than a couple of weeks.

In the fall of 1921 Professor Macleod returned from holiday to find that Banting and Best had kept a diabetic dog, Marjorie, alive for twenty days by means of pancreatic extracts. Macleod now put the whole laboratory to work on the problem and wisely called in his colleague Dr J.B. Collip and a big American pharmaceutical company to help with the extraction and large-scale production. The drug company, Eli Lilly, brought with them, not only great practical know-how, but whatever impetus might be imported to the research by the prospect both of huge profits and of conferring a great benefaction on mankind. Considering that the Toronto team did not know the commercial practices of pharmaceutical companies as they became apparent from their skulduggery in the development of penicillin,† it was remarkably prescient of the University of Toronto to patent the extraction process, so far as they were able to do so, in order to exercise some degree of control over the quality of the manufactured product. Meanwhile Banting and Best were ready to attempt a clinical trial of their product on a boy (Leonard Thompson) at the Toronto General Hospital. One of the first people in England to benefit from insulin treatment was a young physician at King’s College Hospital, R.D. Lawrence, who survived to become England’s principal authority on diabetes.

The experiments carried out by the Toronto team were, as sometimes happens when great discoveries are announced, the subject of sour and unfair disparagement – in this case, by a Dr Ffrangcon Roberts, who in turn was sharply rebuked by Sir Henry Dale OM, FRS.

Some very great advances in medicine have been brought about by clinical reasoning alone, without recourse to experimentation on animals – vaccination against smallpox was one such discovery – but this is the exception rather than the rule. Experimentation, however, is at all times unconditionally necessary. The tests of the safety and therapeutic efficacy of medical procedures are carried out either on the poor, as Bernard Shaw implied in the uproariously funny preface to The Doctor’s Dilemma, or upon prisoners, for as Voltaire records in his letters from England, the efficacy and safety of variolation against smallpox was carried out with the enthusiastic connivance of King and Court on six condemned felons in Newgate Gaol.

It is better that laboratory animals should be used than that tests should be made directly upon human beings. So far as insulin is concerned, it was only by experimentation on dogs that it came to be learnt that removal of something manufactured by the pancreas caused diabetes. At one time anti-vivisectionists – who perform a very useful function in safeguarding animals against wanton experimentation inspired more by curiosity than by serious medical or scientific intentions – tried to belittle the discovery of insulin by claiming that the death rate from diabetes did not decline significantly for many years after the introduction of insulin into clinical practice. This, however, was due to an accident of medical demography: whatever may have been the proximate cause of death, diabetes was always entered as a contributory cause on the patient’s death certificate if he had at one time suffered from it. In the continuing debate between experimentalists and champions of the rights of animals, the discovery of insulin remains a shining example of the benefactions experimental animals have conferred upon man.

Research upon diabetes is still in progress. Scientific research has now demonstrated what was until recently only a clinical surmise – that the insulin-dependent diabetes of juveniles is a quite different clinical entity from the diabetes that can be controlled by diet which sometimes occurs in middle age. The suspicion is growing, moreover, that there is an important auto-immune element in diabetes: an element of immunological self-destruction, perhaps of viral origin though this is not yet certain. If this auto-immunity turns out to be an important factor in the disease it may be that control of autoimmunity, such as is attempted in the treatment of rheumatoid arthritis, thyroiditis and ulcerative colitis, will play an important part in the treatment of diabetes. By far the most exciting future possibility, however, is that we will be able to transplant insulin-forming tissue, either in the form of a whole pancreas or in the form of populations of individual cells operated from islet tissue – the tissue which manufactures insulin.

‘This is a book about life, disease, death, salvation, and immortality.’ It is also about clinical appearances and earlier treatments of diabetes – amongst which Osler frowningly noted the use of blistering and the administration of opiates. Unhappiest of all the treatments for diabetes propounded in these dark days of medicine was that of a French doctor, Piorry, who sought to make good the wasting associated with diabetes by supplementing the patients’ carbohydrate intake with extra-large quantities of sugar. At a time when these, as we now see, idiotic notions were still prevalent, Paris was besieged by the German Army and in the semi-starvation consequent upon the state of siege, a French doctor made amends for Piorry’s aetiological blunder by noting the disappearance of glycosuria from diabetic patients in extreme privation. This doctor, Bouchardat, also noted that exercise increased a diabetic’s tolerance of carbohydrate.

Bliss, who has a nice sense of what is important and what is not, describes how it comes about that the metabolism of fat in the extremities of diabetic starvation imparts a sweetish odour to the breath – the ‘ketosis’ which I remember J.B.S. Haldane’s unhesitatingly proposing as the cause of that ‘odour of sanctity’ which surrounded holy men who starved themselves for the greater glory of God.

The first salvo in the struggle against diabetes was fired in 1889 by experiments in which Oscar Minkowsky and Josef von Mehring showed that pancreatectomy of dogs led to all the symptoms of diabetes. We learn thereafter how it had become almost certain by the time of Banting and Best that certain cells in the pancreas – those of the ‘islets of Langerhans’ – manufactured an internal secretion the deprivation of which would lead to diabetes. It was quite new to me that just about the time that Banting and Best started their work, a Rumanian scientist, Nicolas Paulesco, started to treat diabetes with a pancreatic extract called ‘pancreine’. These pioneering efforts were forgotten – crushed by the resources and enormous know-how of the goal-orientated research that happened in Toronto and the USA. Paulesco’s claim was indeed weighty enough to have induced the International Diabetes Federation to publish in 1971 a report which, while acknowledging Paulesco’s priority, attributes the principal credit for the introduction of insulin therapy to the research of Banting and Best. Bliss records that Charles Best read Paulesco’s publication and indexed it in his file. Best seemed however, to have misunderstood Paulesco’s paper, to which he made an inaccurate reference in his own first publication of 1922. When Paulesco came to hear of Banting’s work he wrote to ask him for reprints, but Banting, a bad correspondent anyway, did not reply. On the award of the Nobel Prize for the discovery of insulin Paulesco’s appeal to the Nobel Committee was ignored. It is a sad story of the triumph of the big battalions over lonely amateurs and must be repeated much more often than we are aware of.

After Bliss’s account of these early contributions to the understanding of diabetes, he turns naturally to the life and contribution of Dr Frederick Grant Banting, who enrolled as a medical student in 1912 in one of North America’s largest medical schools – in the University of Toronto on the shores of Lake Ontario. Bliss says he was a tall and handsome young man who spent much of his spare time with his girlfriend. He was intended for the Methodist ministry and perhaps for this reason never learned to dance. War shortened the medical course and in 1917, after his fifth year, he left for England as a member of the Canadian Army Medical Corps. ‘He saw a fair bit of action and received the Military Cross for his courage under fire at Cambrai, where he was wounded in the arm by shrapnel.’ By September 1919 he returned as a surgeon to the Hospital for Sick Children in Toronto, where he had been profoundly influenced by a brilliant chief surgeon, Clarence Starr.

Banting set up in practice in London, Ontario, but patients wouldn’t come and in one month he earned only $4: ‘every week of medical practice drove him deeper in debt.’ Banting built a garage where he dabbled in oils and tinkered with his rotten car but he went on studying for his FRCS and got a part-time job as a demonstrator in surgery and anatomy in the Western University in London, Ontario. Although he lectured the physiology students on carbohydrate metabolism, he had no special interest in diabetes and no practical experience of it – indeed, he failed to recognise it in a friend and classmate.

While preparing his lecture on carbohydrates Banting read a paper in the journal Surgery, Gynecology and Obstetrics, on the obstruction of the pancreatic duct by a stone, which had apparently led to atrophy of the cells secreting digestive juices, while the cells of the islets of Langerhans, already reputed to manufacture the anti-diabetic hormone, remained intact. ‘The sole importance of Barron’s article in the history of medicine is that Fred Banting happened to read it in the evening of a day he had been thinking about carbohydrate metabolism.’

In his personal memoir of 1940, The Story of Insulin, Banting describes the sleepless night he spent thinking constantly of Barron’s paper and wondering if ligation of the pancreatic duct might not make it possible to extract an anti-diabetic principle from the pancreas free of its enzymic secretion. He got up and wrote down his idea in a little memo at 2 a.m. on 31 October 1920 – this, Bliss notes, dispels the myth ‘that the idea came to him in a dream.’ Many scientists will recognise the fretful churning of Banting’s mind as something quite common in the generation of scientific ideas. Banting’s notebook, now in the archives of the Academy of Medicine in Toronto, contains a very explicit programme of research. (The authenticity of these notes is endorsed by their misspelling of two key words.) Banting soon sought an interview with the Professor of Physiology in the University of Toronto, Macleod, to whom he explained his notion, asking for facilities to try it out in Macleod’s laboratory. Macleod offered his department’s hospitality, but it was a very big step for Banting to give up his practice and medical school job, so there was quite a long period of indecision and prevarication. Banting wrote later on to Macleod specifying a two and a half month period in 1921 as the time when he would like to take up Macleod’s offer, if it still stood. It did, and Banting, initially with Macleod’s surgical assistance, embarked on his programme with the least possible delay.

His scheme – a perfectly rational one – was to execute pancreatectomy in two stages. The first involved ligating the pancreatic ducts that carry the digestive juice and freeing the pancreas from its other bodily attachments, leaving a small piece intact and well vascularised in order to protect the dog from diabetes. It was hoped that after an interval the cells manufacturing digestive juices would wither and make it easier to extract the anti-diabetic principle without running the risk of its being degraded by digestive enzymes. Such extracts might then be injected into dogs made diabetic by completing the two-stage pancreatic removal. Macleod gave not only surgical help but also very sensible advice on the extraction procedure. Unhappily, 14 of the first 19 dogs experimented upon died. The appalling heat of a Toronto summer did not help the dogs – or the surgeons. Eventually two diabetic dogs survived and were judged suitable for experimental rescue by pancreatic extract made by crude and conventional means from the ostensibly atrophied pancreases of dogs whose pancreatic ducts had been tied off for seven weeks. The first two dogs on which they tried their procedure died comatose.

The rest is history – is now, I should say, after Bliss’s scrupulous reconstruction from laboratory notebooks of what went on. The results from the third dog investigated were much better: pancreatic extracts brought down the blood sugar, though heated extracts and extracts made in the same way from liver and spleen did not. The dog eventually died from infection: something not to be wondered at considering that no attempt would have been made to procure sterility – there were no antibiotics and no filters such as we use today to remove bacteria. In the course of these experiments Banting had had a sharp tiff with Best about what Banting considered to be Best’s slovenly laboratory procedures in carrying out his sugar estimations, but after his success with the third dog Banting wrote warmly to Macleod about Best, who, he said, ‘assisted me in all the operations and taught me the chemistry so that we work together all the time and check each other’s findings’.

The promise of success must have had a profound moral effect on Banting and Best, for the life they were now leading would have made a good libretto for a Puccini opera. They worked night and day, cooking steaks and eggs over a bunsen burner. Banting, who had almost no money, paid two dollars a week for a tiny cubicle in a rooming-house he had lived in as a student, and he sometimes got a meal by attending the Bible class which he had also attended as a student. The work was going splendidly; they had become friends with the dog that survived and were able to test on it a number of variations in the extraction procedure.

The Nobel Prize for the discovery of insulin was shared between Banting and Macleod. Banting shared the prize with Best and Macleod with Collip. But sharing the cash is not sharing the credit, and it was widely felt that Best had suffered an injustice, though, to be sure, his function was not ostensibly more elevated than that of an assistant. There was a lot of bitching about why Macleod was mentioned at all. He certainly did not deserve the prize for the magnitude of his scientific contribution to the great discovery. On the other hand, he did his stuff as an administrator and performed very well what he himself described as the function of an impresario. He gave Banting his chance, gave what technical advice and assistance he could, and helped to make sure that the discovery was used for the benefit of mankind and not for lining the pockets of the great pharmaceutical companies. All this deserves a place in history, but not a Nobel Prize; nor did it, on the other hand, deserve the contemptuous antipathy he received from Banting.

I know from experience that it is almost always impossible in collaborative work to allocate credit exactly and justly because of the impossibility of assessing the precise contribution of synergy, which is often the most important factor of all in the work carried out by colleagues and friends. The idea was Banting’s, even if it was in some respects conceptually mistaken (ligation of the pancreatic ducts wasn’t really necessary), and it is therefore appropriate that the shy, barely articulate, self-taught country doctor should be rated the great romantic hero of 20th-century medicine.