Smallpox, Syphilis and Salvation

by Sheryl Persson

  Dr Frazer began his research twenty years ago working in a basement at Brisbane’s Princess Alexandra Hospital. Two decades on, his research is likely to revolutionise women’s health worldwide. The vaccine is based on Dr Frazer’s 1991 discovery of a way to create artificial HPV in the test tube, minus any infectious material. The vaccine works by provoking an immune response to HPV. The researchers made the skin or shell of the virus without the insides so that to the immune system it looks like the virus but is not infectious. The vaccine is now in use in many countries.

  On 1 September 2006 it was widely reported that, for the first time, gene manipulations had been shown to cause tumour regression in humans in research carried out by Dr Steven Rosenberg and his colleagues at the US National Cancer Institute. According to the research, two out of seventeen patients with a deadly form of skin cancer, metastatic melanoma, had their tumours wiped out by genetically altered immune cells.[57] Some scientists are hailing the findings as evidence that the troubled field of gene therapy can successfully treat cancer, while other experts say the results are disappointing. As with all great medical breakthroughs, only time will tell.

  There may never be one single cure for cancer but over the past century since Paul Ehrlich produced the first magic bullet, a cure for syphilis, there have been many significant breakthroughs. In universities and pharmaceutical laboratories all over the world the hunt goes on for miracle cures.

  POSTSCRIPT

  In 1940, during World War II, a Hollywood movie, Dr Ehrlich’s Magic Bullet was released. The film was particularly timely considering the treatment the Jewish intelligentsia endured during the Nazi regime in Germany and the horrors that would take place during the war. The film was made at the very time that the development of penicillin, the new weapon against syphilis, was occurring in war-torn Britain. It tells the story of a great scientist and benefactor of humanity who went against convention to search for a drug that would cure syphilis. At the time the film was made the full legacy of Paul Ehrlich’s humanitarianism and genius could not have been imagined.

  CHAPTER 7

  A EUREKA MOMENT

  THE DISCOVERY OF INSULIN

  Insulin is not a cure for diabetes; it is a treatment. It enables the diabetic to burn sufficient carbohydrates, so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of life.[1] Frederick Banting

  At the beginning of the twentieth century, if you were feeling particularly unwell, had the urge to drink and eat incessantly, felt extremely lethargic, were losing weight and passing urine far too frequently, you would probably have sought advice from your doctor. Given these symptoms, the doctor would have immediately tested your urine, and if a high amount of grape sugar was found, the doctor would probably have diagnosed diabetes.

  As to the treatment, the doctor would have suggested that you take a daily alkaline-sponge bath, prescribed sugar of lead to restrict the flow of urine and, if that didn’t work, suggested you take creosote in two-drop doses, or even clear opium. You would have been instructed to avoid any foods that contained sugar and eat only fresh meats. The doctor would also have told you that your thirst would continue but would have strongly encouraged you to suppress this urge and drink very little.

  The prognosis would have been even harder to swallow. In all probability, in a matter of days you would have lapsed into a coma and death would soon have followed.

  In 1950, if you presented with the same symptoms, the doctor’s examination and explanation would have been much more thorough and detailed. The doctor would have noticed a cloudiness around your retinal arteries and when checking your carotid arteries and the arteries in your feet, would have felt a weaker than normal pulse. Your urine sample would have shown a high level of glucose. The diagnosis: diabetes mellitus, caused by the pancreas not producing enough insulin and therefore preventing the body from absorbing the glucose in your blood. Treatment would have begun immediately with the first and most critical step being to stabilise your blood sugar with insulin. You would have been shown how to test your urine and how to inject insulin and you would have been placed on a special diet. The prognosis would certainly have been better than 50 years earlier. The doctor would regularly monitor the early stages of your disease and give you advice on how to manage the other health issues associated with diabetes—but you would have lived.

  What made the difference between life and death for those who develop diabetes was the discovery of insulin. In 1900, many people who were diagnosed with what is now called Type I diabetes died within days of finding out they had the disease, and those with Type II diabetes became ill and deteriorated over a matter of months to years. To say that the discovery of insulin revolutionised treatment for diabetics is an understatement. It saved lives. Although insulin may not be a ‘cure’ for diabetes—indeed, that search continues today—it has had a profound effect on morbidity and has literally brought salvation to millions of diabetics since it was first used in Canada in 1922.

  The discovery in 1921 that insulin, a pancreatic hormone, could be used to treat diabetes was one of the most amazing advances in medicine in the twentieth century. The story has its own subplots of false starts, serendipity, personal and professional rivalry and creative teamwork. The four names most closely associated with the discovery at the University of Toronto are Frederick Banting, a doctor who had been in private practice; Charles Best, a student who had just finished his medical degree; John Macleod, head of the physiology department at the University of Toronto; and James Collip, a gifted biochemist.

  UNCOVERING INSULIN

  Progress towards the discovery of insulin was cumulative during the late 1800s and early 1900s and was taking place in laboratories all over Europe. Paul Langerhans, a German medical student, was studying the pancreas while writing his MD dissertation in Berlin in 1869. He observed small collections of ‘clear cells’ within the pancreas that appeared distinct from the surrounding pancreatic tissue. It was known that the pancreas produced digestive enzymes, but Langerhans was puzzled about the function of these isolated cells. The cells now bear his name and are called the ‘islets of Langerhans’.

  The French physiologist Etienne Lancereaux suggested in 1887 that the pancreas might be related to diabetes. While studying a dog pancreas in 1889, German scientists Joseph von Mering and Oscar Minkowski noticed that flies (not the most sterile of conditions) were swarming around the dog’s urine and discovered it contained high levels of glucose. This led them to believe that the pancreas played a role in diabetes but their research took them no further. In 1893 it was the French scientist Gustave-Eduard Láguesse who first referred to the ‘islets of Langerhans’ and suggested that they made a substance that prevented excess blood glucose.[2]

  The research was disparate. In 1901 Eugene L. Opie, an American pathologist studying at Johns Hopkins University, demonstrated the association between the degeneration of segments of the pancreas and diabetes.[3] In 1906 Lydia de Witt, an American experimental pathologist who researched the anatomy of the pancreas, made an extract from the pancreas of cats that produced a significant drop in blood sugar levels. In Germany in 1908, Dr G. Zuelzer produced a pancreatic extract (from whole pancreas) using alcohol as the extractive. When it was given to patients dying from diabetes they experienced a definite fall in blood sugar but the toxic effects were so great that Zuelzer ceased his experiments.[4] In 1912 Aldo Massaglia demonstrated that the destruction of pancreatic segments resulted in glycosuria, the condition in diabetics that causes excretion of glucose in the urine.

  The discovery at the beginning of the twentieth century of hormones, which act as ‘chemical messengers’, was an important step forward. In England in 1916, Edward Sharpey-Schäfer armed with this new knowledge made a discovery, the significance of which was overlooked at the time. He found that the islets of Langerhans remained intact when the pancreatic duct was tied off. It was then that he concluded that these cells manufactur
ed what he referred to as ‘insuline’, a hormone responsible for regulating blood sugar.[5] Independently in 1916, Nicolas Paulesco, a Romanian physiologist, observed that when pancreatic extract was given intravenously to a diabetic dog it experienced rapid but short-lived symptomatic relief. Paulesco was hampered in his work because he could only produce limited quantities of the extract. His experiments came to an abrupt halt when Bucharest was occupied in 1916 during World War I but he finally published his work in June 1921 when Frederick Banting and Charles Best were conducting groundbreaking experiments in Toronto.[6] They were aware of the article but thought that Paulesco’s results showed no significant success. Today, however, Paulesco is credited with being the first person to describe the actions of what is now called insulin. He demonstrated that it was a hormone that acts on all aspects of metabolism.

  Ironically, in 1911 Ernest L. Scott, a graduate student at the University of Chicago, experimented with diabetic dogs and was successful in significantly decreasing their blood sugar. His dissertation was later printed in the American Journal of Physiology, but apparently a change to the text made his research seem inconclusive. Later, when the Toronto team was having difficulties purifying their pancreatic extracts Scott explained the method he had used to his supervisor, Professor Macleod.[7] When Banting and Best published their results in 1922, they acknowledged the use of Scott’s techniques.

  What this shows is that in more recent times medical breakthroughs are often the result of many individual, discrete discoveries that finally come together. The breakthrough comes when the picture is complete, like putting the last pieces into a jigsaw puzzle. And by the 1920s the body of scientific knowledge surrounding diabetes was formidable enough to enable a major discovery to be made.

  Louis Pasteur’s adage that ‘Chance favours the prepared mind’ is certainly apt in this instance. Late one night in October 1920, the Canadian doctor Frederick Banting chanced to read an article that had been written in 1919 by Moses Barron, a researcher at the University of Minnesota. The content of the article left Banting unable to sleep. It concerned an autopsy that Barron had carried out on a patient who had an obstructed pancreatic duct. Barron found that although the pancreas itself was shrivelled, the islets of Langerhans were not. The blockage of the duct connecting the two major parts of the pancreas caused shrivelling of a second cell type, the acinar. Barron thought his findings suggested the patient had not been diabetic.[8] The paper that he wrote and that Banting read in October 1920 suggested that the islets of Langerhans played some part in blood sugar metabolism. When Banting read this, he immediately conceptualised that by tying off the pancreatic duct to destroy the acinar cells, he could preserve the hormone and extract it from islet cells and that he may be able to extract the hormone in an experiment which involved tying off the pancreatic ducts in dogs. And there it was! In the early hours of that fateful morning Banting put his thoughts down on paper in his diary: ‘Ligate pancreatic ducts of dog. Keep dog alive till acini degenerate leaving islets. Try to isolate the internal secretion of these to reduce glycosurea [ sic].’[9]

  Without delay Frederick Banting approached the head of the University of Toronto’s Physiology Department, Professor John Macleod, a Scottish scientist who had moved to Canada in 1918 to take up the position. Macleod doubted Banting’s proposal but diabetes was a hugely important area of research so almost grudgingly he supplied Banting with laboratory space, ten dogs and an assistant. The assistant was the medical student Charles Best. What followed was to have monumental consequences. Their discovery of insulin has been described as one of the spectacular triumphs of medical science.

  ***

  Insulin is a hormone that humans cannot do without. It is produced by the islets of Langerhans cells in the pancreas, which regulates the amount of glucose (sugar) in the blood and is required for the body to function normally. The pancreas is an organ that sits behind the stomach and has many functions in addition to insulin production; it also produces digestive enzymes and other hormones. The islet cells in the pancreas continuously release a small amount of insulin into the body, but also release surges of insulin in response to a rise in the blood glucose level. [10]

  Certain cells in the body change the food that we ingest into energy, or blood glucose, that can be used by cells. Every time you eat, the blood glucose rises. Raised blood glucose triggers the cells in the islets of Langerhans to release the required amount of insulin which allows blood glucose to be transported from the blood into the cells. The cell’s membrane controls what enters and exits the cell. Insulin binds to receptors on the cell’s membrane and this activates a set of transport molecules so that glucose and proteins can enter the cell. The cells can then use the glucose as energy to carry out their functions. Once transported into the cell, the blood glucose level is returned to normal within hours.

  Without insulin, the blood glucose builds up in the blood and the cells are starved of their energy source, which means that diabetics can eat a large amount of food and actually be in a state of starvation because cells cannot access the calories contained in the glucose.[11] Symptoms suffered by diabetics include fatigue, constant infections, blurred eyesight, numbness, tingling in the hands or legs, increased thirst and slow healing of bruises or cuts. The cells will also begin to use fat that the body has stored as an emergency energy source. If this process happens for an extended time, the liver produces chemicals called ketones which can poison and kill cells. When ketones build up in the body the result is serious illness and coma.

  Because of the discovery of insulin it became possible for researchers to study diabetes more effectively and two principal types were distinguished. Type I diabetes is caused when the pancreas stops producing insulin altogether. Type II diabetes occurs when the pancreas does not produce sufficient insulin and the body does not respond to insulin properly. Ten to 15 per cent of people who develop diabetes have Type I, which is also called juvenile-onset diabetes.[12]

  Diabetes is an auto-immune condition, meaning that the body’s immune system turns on its own tissue—in the case of diabetes it is the insulin-producing cells that are destroyed. Type I diabetes occurs in a small number of people who have the genes that confer susceptibility to this form of the disease, and research is still being conducted to find what triggers diabetes in some people. The triggers could be a virus or some other toxin. Type I diabetics must have insulin shots to sustain life. On average they have three to four injections a day.

  The majority of people with diabetes have Type II. Insulin is still produced by the pancreas but it is less effective than normal. Type II diabetics respond sluggishly to the insulin they make, which can be in similar or even higher amounts than normal. The problem is that their cells do not absorb the sugar molecules efficiently which leads to blood sugar levels that are higher than in non-diabetic people. This insulin resistance is an inherited characteristic made worse by lifestyle factors such as excess weight or a lack of exercise and is more common in middle-aged or older people. Occasionally Type II diabetics will need insulin shots but most of the time other methods of treatment will work including a regulated diet. A form of diabetes that occurs during pregnancy is called gestational diabetes, and affects approximately 1 in 20 pregnant women. It is usually detected when a woman is around 26 to 28 weeks pregnant and disappears after pregnancy but there is a 2 in 3 chance that it will return in future pregnancies.

  People who suffer from diabetes often develop other serious health issues. Diabetic retinopathy causes blindness and occurs as a result of long-term accumulated damage to the small blood vessels in the retina. After fifteen years of diabetes, approximately 2 per cent of people become blind and about 10 per cent develop severe visual impairment. Diabetes is among the leading causes of kidney failure, with approximately 10 to 20 per cent of people with diabetes dying as a result. Diabetes also increases the risk of heart disease and stroke; 50 per cent of people with diabetes die of cardiovascular disease.[13]

  *
**

  There is a misconception today that diabetes is a lifestyle disease, but this is not at all the case with Type I diabetes. Like many of the other life-threatening diseases it has a long history in many countries and cultures. Medical historians believe that diabetes has been known for well over three millennia. In written texts from India dating back to 800BC there are descriptions of diabetic symptoms. Arataeus of Cappadocia, an eclectic medical philosopher who lived in Alexandria some time between 30 and 150AD described the condition as ‘a melting down of the flesh and limbs into urine’, reflecting the weight loss and excess passing of urine that occurs in acute diabetes.[14]

  The name of the disease, diabetes mellitus, is derived from the Greek word diabetes, meaning ‘to siphon’ or ‘to pass through’, and the Latin mellitus, meaning ‘honeyed’ or ‘sweet’. This latter word refers to a major symptom of diabetes, sugar in the urine, and was first used in the eighteenth century when it was recognised that this is a symptom of diabetes. In 1670 the British physician Thomas Willis discovered that people ‘labouring with this disease piss a great deal more than they drink’ and that the urine of diabetics was ‘very much sweet, loaded with sugar or honey’.[15] Willis knew this because he dipped his finger in chamber pots and tasted the urine. It was soon confirmed that the sugar was glucose and the standard way for physicians to test for its presence in urine was the somewhat unscientific and unsavoury taste method. In the seventeenth century the disease had been commonly known as the ‘pissing evil’, certainly a less acceptable name than diabetes mellitus—but far more descriptive.