The Medicine Book

VACCINES, SERUMS, AND ANTIBIOTICS 201 See also: Ayurvedic medicine 22–25 ■ Traditional Chinese medicine 30–35 ■ Preventing scurvy 84–85 ■ Germ theory 138–45 ■ Physiology 152–53 ■ Evidence-based medicine 276–77 Foods such as citrus Studies suggest not chickens fed with polished rice fruit are observed all diseases are caused developed beriberi, but they soon to have beneficial recovered when their diet reverted properties. by infections to kitchen scraps. He concluded or toxins. that white rice lacked an essential ingredient, which he called the Specific factors – vitamins and other nutrients whose “anti-beriberi factor”. absence in diet produces illness – are isolated … Later, his colleague Adolphe Vorderman conducted controlled experiments with prison inmates, some eating polished rice and some eating unpolished rice, showing that the “anti-beriberi factor” was present in rice husks and kernels. … and are used to prevent nutritional diseases. Isolating vitamins The “anti-beriberi factor” was of vital substances in the diet. as a cause. An exception was finally identified by Japanese Funk initially believed that all scurvy, which was known to be researcher Umetaro Suzuki. In 1911, these substances were amines (a treated effectively by including Suzuki described a nutrient (he compound crucial for the creation, citrus fruit in the diet, although the called it aberic acid), which he had growth, and metabolism of human vitamin C responsible for preventing extracted from rice bran and given cells), but the “e” was later dropped this disease was only isolated by to patients as a cure for beriberi. when it was discovered that most Hungarian physiologist Albert The article was not widely read, vitamins are not amines. Funk’s Szent-Györgyi in 1931. but his discovery was later found work transformed understanding to bTehtehifoalmloiwnein, goryveiatra,mBirnitiBs1h. of diet and initiated a new era of Searching for a cure biochemist Frederick Gowland nutritional science. Funk’s attempts to isolate the Hopkins proposed that some foods substances in food that affect contain “accessory factors”, which Misunderstood causes health were inspired by the work the human body needs in addition ❯❯ Until Funk’s research in the early of earlier researchers, especially years of the 20th century, the that of Christiaan Eijkman. In the Protein supply existence of vitamins had not been 1890s, Eijkman, a Dutch physician and energy supply proven. Diseases related to nutrition working in Indonesia, was tasked do not alone secure that appeared to have no effective with finding a cure for beriberi, normal nutrition. treatment, such as rickets, were which was commonplace in Frederick Gowland common. Ironically, the revolution Southeast Asia. Causing immense in medical thinking sparked by suffering, symptoms include Hopkins French chemist Louis Pasteur’s dramatic weight loss, swelling and discovery of microbes in the 1860s paralysis of the limbs, and brain Journal of Physiology, 1912 may have held back cures for these damage, often resulting in death. diseases, because it was assumed that most were caused by infections, Eijkman stumbled across the and poor diet was mostly overlooked link between diet and beriberi by accident in 1897. He noticed that

202 VITAMINS AND DIET Table of vitamins Chemical Main food sources Deficiency-related compound disease A Retinol Oily fish, fish liver oils, Night blindness All the deficiency diseases *B1 Thiamine liver, dairy products can be prevented by *B2 Riboflavin Whole grains, meat Beriberi a complete diet. Dairy products, meat, Inflammation Casimir Funk green vegetables of tongue Journal of State Medicine, 1912 *B3 Niacin Meat, fish, whole grains Pellagra Skin paresthesia *B5 Pantothenic acid Meat, whole grains Anaemia *B6 Pyridoxine Meat, vegetables *B7 Biotin Meat, eggs, nuts, seeds Dermatitis British biochemist Edward Mellenby Anaemia, experimented with dogs’ diets *B9 Folic acid Leafy vegetables, legumes birth defects between 1918 and 1921. Inspired Anaemia by the work of Funk and McCollum, *B12 Cobalamin Meat, fish, Mellenby found that when fed on *C dairy products Scurvy oatmeal alone, puppies developed D Ascorbic acid Rickets rickets, but when given a diet rich Calciferol Citrus fruit Mild anaemia in cod-liver oil or suet, they Fish oils, dairy products Excessive bleeding recovered. He had demonstrated E Tocopherol Unrefined vegetable oils, beyond doubt that the disease is the product of a dietary deficiency. K Phylloquinone nuts, seeds Leafy vegetables Mellenby explained that in the *water-soluble vitamins absence of “accessory food factors” (which we now know are vitamins), to proteins, carbohydrates, fats, he called “fat-soluble factor A” the phytic acid present in the oats while researching the nutritional suppressed the absorption of and minerals. Also in 1912, Funk needs of animals. He found that calcium and phosphorus (needed for without this factor (later named healthy bone growth). However, the presented the results of studies he vitamin A), his laboratory rats died. vitamin D in fish (and in milk, eggs, and suet) helps that absorption. His had performed after reading about Tackling dietary disorders work changed attitudes towards the By establishing nutrition as an prevention of rickets so dramatically Eijkman’s earlier work on beriberi. experimental science, Funk’s work that by the early 1930s, London was paved the way for research into cures thought to be free from the disease. Funk had fed pigeons polished for disorders such as rickets, which ravaged populations in the 19th and Pellagra, whose symptoms rice and found that they became early 20th centuries, contributing include dermatitis, diarrhoea, mouth to high child mortality, especially sores, and dementia, affected unwell, but if they were given the in newly industrialized cities. three million Americans between 1906 and 1940, causing 100,000 extract from rice hulls they soon Rickets is a skeletal disease that deaths in areas where maize was produces weak, soft bones, stunted the dominant food crop. In the recovered. He realized that some growth, and skeletal deformities in early 20th century, scientists young children. Finding a cure had assumed that maize either carried chemical in these extracts was long challenged physicians, and the disease or contained a toxic diet had not been considered until substance. However, pellagra required, albeit in tiny quantities, to maintain health. While it took until 1936 for the chemical structure of this “anti-beriberi factor” (later named thiamine, or hvaitdamidienntBif1)ietdo be described, Funk the existence of vitamins. Shortly afterwards, in 1913, Elmer Verner McCollum, an American biochemist, identified a substance

VACCINES, SERUMS, AND ANTIBIOTICS 203 wasn’t prevalent in Mesoamerica, Testing the vitamin content of foods cones to detect light. Its absence where maize had been a dietary during the 1940s allowed nutritionists leads to deteriorating eyesight and, staple for centuries. to understand the components of a ultimately, blindness, but research balanced diet – one that would protect has yet to establish whether In 1914, the US government against deficiency diseases. vitamin A can protect against tasked physician Joseph Goldberger particular eye disorders, such as with finding a cure. Observing a means they are readily excreted from the development of cataracts and higher incidence of pellagra among the body, and so a regular dietary age-related macular degeneration. people with a poor diet, he tested a supply is needed. Vitamins A, D, E, range of supplements. Goldberger and K are fat-soluble and can be Synthesizing vitamins concluded that a diet that included stored in the body. The growth of nutritional science meat, milk, eggs, and legumes – or during the 1920s spurred attempts small amounts of brewer’s yeast – Vitamins work in many different to synthesize vitamins. In 1933, prevented pellagra. The vitamin ways, and research continues to British chemist Norman Haworth link was finally confirmed in 1937 investigate all their functions and was the first to manufacture a when American biochemist Conrad actions in the body, many of which vitamin – vitamin C – and by the Elvehjem demonstrated that niacin remain unclear. Scientists know, 1940s, a new vitamin industry (vitamin B3) cured the disease. for example, that the eye needs a had developed. From an original form of vitamin A for its rods and focus on the use of vitamins for Filling the gaps treating nutritional disorders, Between 1920 and 1948, vitamins mass production allowed their use E and K and seven more B-complex as a popular dietary supplement. vitamins were identified, bringing It is now possible to reproduce the total to 13. These are all essential every vitamin from either plant for body function; vitamins given or animal materials, or to make the letters F to J and L to Z are vitamins synthetically. Vitamin C, substances that are non-essential, for example, can be taken from have been renamed or reclassified as citrus fruits, but is synthesized they are not true vitamins (vitamin more cheaply from keto acid. With F, for example, is a fatty acid), or are new research into how vitamins are not recognized scientifically. taken up by the body, additives are also often included in vitamin pills Of the 13 essential vitamins, to aid their absorption. ■ the eight B-complex vitamins and vitamin C are water-soluble, which Casimir Funk Born in Warsaw, Poland, in 1884, World War II meant it was not Casimir (originally Kasimierz) safe for him to remain in France, Funk studied chemistry at the so he returned to New York and University of Berne before working set up the Funk Foundation for at the Pasteur Institute in Paris, Medical Research. Apart from and then at the Lister Institute in his work on vitamins, Funk also London. It was at the latter that carried out research into animal he conducted his pioneering work hormones and the biochemistry on vitamins, researching beriberi, of cancer, diabetes, and ulcers. scurvy, pellagra, and rickets. He died in New York in 1967. Funk moved to New York in Key works 1915. Sponsored by the Rockefeller Foundation, he returned to 1912 “The Etiology of the Warsaw in 1923 before founding Deficiency Diseases” the Casa Biochemica research 1913 “Studies on Pellagra” institution in Paris four years later. 1914 Vitamins As he was a Jew, the outbreak of

204 MAANNICTIRANOGVBOISENIIBSLTEI,C BACTERIOPHAGES AND PHAGE THERAPY IN CONTEXT B acteriophages are viruses That same year, d’Hérelle was that infect bacteria. There working in Tunisia for the Paris- BEFORE are an estimated 10 million based Pasteur Institute and made a 1854 In Italy, anatomist Filippo trillion trillion of them in the world – similar discovery to Twort while he Pacini describes the bacillus around twice as many as there are cultured a bacillus to use against that causes cholera. bacteria. Félix d’Hérelle, a French- locusts. Back in Paris, in 1917, he Canadian microbiologist, described found patches much the same in a 1892 Dmitri Ivanovsky them in 1917 and realized they could culture of dysentery bacillus. It was discovers infective agents have potential for treating bacterial clear that something was actively tinier than bacteria; in 1898 diseases – called phage therapy. attacking bacteria, which d’Herelle Martinus Beijerinck calls believed was a virus and called it a them “viruses”. Dead patches bacteriophage (bacteria-eater). British microbiologist Frederick AFTER William Twort was the first to Miracle cure? 1952 American scientists encounter bacteriophages in 1915. No one knew for certain what a Alfred Hershey and Martha He was trying to culture the vaccinia bacteriophage was for some time. Chase use phages to identify bacteria used to create the smallpox D’Hérelle believed it was a microbe, DNA as life’s genetic material. vaccine, but kept finding transparent while others believed it was a patches of dead bacteria. Twort chemical. But he immediately saw 2002 In the US, adalimumab, speculated that a virus could be phages’ medical possibilities. If a drug based on phage-created killing the bacteria, but his research they could kill bacteria, surely they antibodies, is approved for was curtailed by World War I. could treat bacterial diseases? In treating rheumatoid arthritis. 1919, after testing it on himself, d’Hérelle successfully treated 2017 At a hospital in London, several dysentery patients in Paris. UK, phages are successfully Soon he repeated his success with used to treat a 15-year-old treatments of a cholera epidemic in patient for a bacterial infection India, and plague in Indochina. For after a double lung transplant. Enterobacteria T2 phages attack 2019 The US FDA approves E. coli bacteria cells, shown here in the first clinical trial of an an electron micrograph. Their tail fibres intravenously administered inject genetic material, which may bacteriophage-based therapy. replicate in the cells or remain dormant.

VACCINES, SERUMS, AND ANTIBIOTICS 205 See also: Epidemiology 124–27 ■ Germ theory 138–45 ■ The immune system 154–61 ■ Virology 177 ■ Antibiotics 216–23 ■ Monoclonal antibodies 282–83 Advantages and disadvantages of phage therapy Advantages Disadvantages Phages destroy harmful bacteria; bacteria Some bacteria may evolve resistance to Félix d’Hérelle can become resistant to antibiotics. phage attack. Phages are effective against treatable and While taking over a bacterial cell, a phage Born in 1873 in Paris, France, antibiotic-resistant bacteria. may acquire DNA harmful to humans. Félix d’Hérelle was schooled Unlike antibiotics, phages have few Finding the exact phage or cocktail of in Paris, travelled widely, and adverse effects on good bacteria and are phages to treat an illness effectively is moved to Canada at the age also less harmful to the environment. difficult and time-consuming. of 24, where his interest in microbiology began. Largely Phages multiply naturally during treatment, More research is required to determine self-taught, he worked first in so only one dose may be necessary. which phages to use and in what dosages Guatemala, then in Mexico, they are safe and effective. where he found a bacteria that infects locusts. He began a while there was a boom in plans famous Phage Group of scientists working on this in Tunis for the for phage therapy. Phage therapy, set up in Cold Spring Harbor in the Pasteur Institute, and observed d’Hérelle believed, depends on a US in 1940, phages became central something killing the bacteria. “cocktail” of phages to blitz the to the discovery of DNA’s structure. bacteria, just in case they develop Alfred Hershey and Martha Chase At the Institute in Paris, resistance to one. used them to prove in 1952 that d’Hérelle pursued his work DNA is the genetic material of life. on the bacteria killer and Other scientists, however, found identified bacteriophages for that they were unable to replicate Researchers have now discovered the first time. From there, he d’Hérelle’s success, and doubts two ways in which phages take moved to Leiden, Holland, and began to spread about the usefulness over bacterial cells. In both cases, then to Alexandria, Egypt. He of phage therapy. By the time the phage’s tail fibres attach to the taught at Yale University in the antibiotics came along in the 1940s, cell wall, then puncture it to inject US and worked in the USSR enthusiasm for it had faded. In the their double-stranded DNA genome before returning to Paris in Soviet Union (USSR), however, it into the cell. In the “lytic” cycle, the 1938 to develop phage therapy. had been pioneered in the 1930s phage uses the cell’s resources to by microbiologist Georgi Eliava. replicate multiple times until the Despite many nominations D’Hérelle went there to work with cell ruptures. But in the “lysogenic” for the Nobel Prize, d’Hérelle him, but was forced to flee in cycle, the DNA lies dormant within never received it, but continued 1937 when Eliava was suddenly the cell, replicating as the host his work until his death in 1949. executed as an enemy of the people. cell divides, but leaving its host Nevertheless, with no access to the relatively unharmed. Key works West’s antibiotics, the USSR was soon using phage therapy as a key As bacteria become resistant to 1917 “An invisible, antagonistic weapon against bacterial infections, antibiotics, enthusiasm for phage microbe of the dysentery and it continues to be popular in therapy has revived; many trials are bacillus” Russia today. now underway. Key benefits include 1921 The Bacteriophage: Its the phages’ swift replication rate Role in Immunity Phages rediscovered and their ability to target specific 1924 The Bacteriophage and By the late 1930s, though, the huge bacteria. Phages could also be used its Behaviour biological, if not medical, importance to test for pathogens and to create of phages was beginning to be antibodies that can work against widely understood. Steered by the illnesses such as rheumatism and gastrointestinal disorders. ■

206 IN CONTEXT FTAOHWREMEGAEOKRFEMNED BEFORE 1796 Edward Jenner tests the ATTENUATED VACCINES first vaccine, against smallpox. 1881 Louis Pasteur immunizes farm animals against anthrax. 1885 Pasteur introduces the first rabies vaccine. AFTER 1937 Based in the US, South African-born virologist Max Thieller creates the 17D vaccine against yellow fever. 1953 American virologist Jonas Salk announces he has found a vaccine against polio. 1954 Thomas C. Peebles, an American physician, identifies and isolates the measles virus. A vaccine is made in 1963 by John F. Enders, and improved in 1968 by Maurice Hilleman. 1981 A plasma-based vaccine against hepatitis B is approved for use in the US. F ollowing Louis Pasteur’s success in the 1880s with finding vaccines for anthrax in livestock and for human rabies, interest in vaccination grew rapidly. Countless scientists began to hunt for new vaccines, believing that vaccination might one day rid the world of disease. The quest proved more difficult and dangerous than anyone could have imagined, and involved both terrible losses and huge heroism from the scientists and also many ordinary people willing to be used for trials. New methods had to be found for creating vaccines and enhancing their effectiveness, yet vaccines were gradually found for

VACCINES, SERUMS, AND ANTIBIOTICS 207 See also: Vaccination 94–101 ■ Germ theory 138–45 ■ The immune system 154–61 ■ Global eradication of disease 286–87 ■ Genetics and medicine 288–93 ■ HIV and autoimmune diseases 294–97 ■ Pandemics 306–13 Where youth grows pale, damage partly by secreting a toxin. to weaken the germ. But Haffkine’s and spectre-thin, In 1890, in Germany, Emil von aim was to boost its virulence to and dies … Behring and his Japanese colleague ensure it would provoke the human John Keats Shibasaburo Kitasato showed in immune system. He then “killed” experiments on animals that the the pathogen by boiling it in a British poet, who died from TB body gains immunity to diphtheria broth to prevent it causing the at the age of 25, in his poem by developing antitoxins. Having disease. In 1892, Haffkine bravely Ode to a Nightingale, 1819 captured some of these antitoxins tested the vaccine on himself. from blood serum, they went on many deadly diseases, including to develop an antiserum that could Initially, Haffkine’s vaccine was cholera, diphtheria, tetanus, be used to cure diphtheria victims. met with scepticism, despite a whooping cough, and bubonic “Serotherapy” provided the first courageous demonstration later in plague. Most famously, French effective treatment of diphtheria, 1892 by New York Herald reporter scientists Albert Calmette and and prevented tens of thousands Aubrey Stanhope. Having been Camille Guérin created the BCG of deaths before a vaccine was injected with the newly developed vaccine in 1921, saving millions developed in the 1920s. vaccine, Stanhope went right into of lives from tuberculosis. the midst of a cholera epidemic Killed vaccines in Hamburg, Germany. He slept The hunt for a cholera vaccine was among cholera sufferers and even led by Ukrainian bacteriologist drank the same water, but survived Waldemar Haffkine. Haffkine came unharmed. The next year, Haffkine up with a method that began with went to India, where there was a a “passage”: passing the pathogen desperate need for an answer to on through a series of animals such cholera. As with serotherapy, there as pigeons to give it the right form. were setbacks, but Haffkine’s With some vaccines, the idea was cholera vaccine saved hundreds of thousands of Indian lives. ❯❯ New methods A live vaccine must be virulent enough to Today, many vaccine researchers stimulate the immune system, but not so virulent look for genetic material to find new vaccines, but in the 1880s, they as to cause illness. tried to make vaccines from the A pathogen that is too virulent, such as pathogens themselves, or from the that of bovine tuberculosis, needs to be weakened, toxic chemicals they secreted. or attenuated, before it can be used as a vaccine. Edward Jenner had used a less Passing the germ through successive cultures dangerous cousin, cowpox, to results in a weakened strain, which can be used make his smallpox vaccine; Pasteur as a vaccine to promote an immune reaction. attenuated (weakened) the pathogen to make his anthrax vaccine. The difficulty with these “live” vaccines lay in robbing the pathogen of its power to make the patient ill, while keeping it potent enough to activate the immune system. In 1888, French bacteriologist Émile Roux and his Swiss-born assistant Alexandre Yersin found that diphtheria bacteria do their

208 ATTENUATED VACCINES Other scientists, including British Together in heart and mind Calmette and Guérin had created bacteriologist Almroth Wright, [in] the prevention BCG – an attenuated form of bovine followed suit, and a typhoid vaccine of tuberculosis tuberculosis bacteria. BCG did not was produced in 1896 using a killed by the BCG vaccine. cause TB when injected in animals, pathogen. Like Haffkine, Wright but provoked an immune response. tested the vaccine on himself. Memorial plaque to In 1921, Calmette decided to test Despite nasty side effects at first, Calmette and Guérin BCG on the baby of a woman who it worked, and the entire British had died of TB after giving birth. army was immunized against Pasteur Institute, Paris Following vaccination, the baby typhoid at the start of World War I. became immune to the disease. Calmette and Guérin began to Creating BCG culture the bacteria in their lab in Ever-safer vaccines Perhaps the most significant glycerine and potatoes, with ox bile By 1930, thousands of infants breakthrough in the search for added to stop the germs clumping. in France had been successfully new vaccines was the tuberculosis Every three weeks, they removed vaccinated with BCG. Yet scientists (TB) vaccine created by Calmette the bacteria and started another still feared that the bacteria might and Guérin, known as BCG (Bacillus culture. The bacteria became less revert to their more virulent form Calmette-Guérin) in their honour. virulent with each successive and give those who had been culture. It was a slow process, and vaccinated the disease. That year, In the 1890s, scientists had only after five years were the pair the fear seemed confirmed. When looked to cattle for a TB vaccine, ready to test their vaccine on cows. 250 babies were vaccinated with as Jenner had done with smallpox. BCG at Lübeck hospital in Germany, But bovine tuberculosis proved too The trials were interrupted by 73 died of tuberculosis and 135 virulent for humans, and a trial in the outbreak of World War I, but the fell ill but recovered. Italy ended disastrously. On the culturing went on through the war. other hand, TB bacteria killed by After 11 years and 239 subcultures, The investigation that ensued boiling or chemical treatment had concluded that BCG was not to no effect on the human immune blame; the vaccine had been system. Calmette and Guérin knew contaminated with virulent TB in they had to use a live germ, but the Lübeck laboratories, and two weaken it enough to make it safe. doctors were sent to prison. It took decades for confidence in BCG to Using a strain of Mycobacterium return, but it is now recognized as bovis (bovine TB) taken from the one of the safest of all vaccines. milk of an infected cow, in 1908 Albert Calmette Born in Nice, southern France, in In 1895, Calmette was made 1863, Albert Calmette went on to head of the new Pasteur Institute train as a doctor in Paris. As a in Lille, and it was here he was student, he spent some time in joined by Camille Guérin, with Hong Kong learning about tropical whom he created BCG. The medicine, and after graduating, he Lübeck disaster took its toll worked in the French Congo and on Calmette, even though the Newfoundland, Canada. When the BCG vaccine turned out not to Pasteur Institute set up a branch be the culprit. He died shortly in Indo-China (now Vietnam), afterwards, in 1933. Calmette became its head and organized vaccination campaigns Key work against smallpox and rabies. After illness forced him to return home, 1920 The Infection by he continued his studies of snake Tuberculosis Bacilli in the venom and made one of the first bodies of humans and animals successful antivenoms.

VACCINES, SERUMS, AND ANTIBIOTICS 209 This French Ministry of Health secreted by diphtheria. In the UK, one person. The immunity provided poster from 1917 urges parents to take immunologists Alexander Glenny by the vaccine does not always last up free BCG vaccinations to protect and Barbara Hopkins discovered a lifetime, but with occasional their children against tuberculosis. that formaldehyde did the same. boosters it is very effective and this deadly disease is now rare. Meanwhile, other scientists at the Back in 1913, Behring had made Pasteur Institute where Calmette a diphtheria vaccine by combining The search goes on and Guérin worked were devising a the toxin that provokes the immune By 1930, medics had three main new way of creating a vaccine, this reaction with an antitoxin to stop ways to create vaccines: using a time for diphtheria. Serotherapy was it causing damage. But this toxin- live, attenuated form of the germ a life-saver for those who fell ill with antitoxin (TA) mixture often went (as in the smallpox vaccine and the disease, but a vaccine would wrong – as in Dallas, US, in 1919, BCG); using killed organisms (as stop many more from falling ill in when 10 vaccinated children died. in the typhoid, cholera, plague, and the first place. In 1923, French Ramon and Glenny’s neutralized whooping cough vaccines); and veterinarian Gaston Ramon found toxin, or “toxoid”, could still provoke using neutralized toxins, or toxoids that formalin neutralizes the toxin the body’s immune reaction, but (as in the diphtheria and tetanus was much safer. vaccines). Vaccination was never foolproof, but hundreds of millions of Adjuvants lives were saved and, in developed Ramon and Glenny also discovered countries, the experience of major that certain substances called diseases began to fade into memory. adjuvants enhance the potency of vaccines, although it was unclear Since the mid-1980s, genetic why this was the case. Ramon’s engineering has led to subunit and adjuvant was tapioca; Glenny’s was conjugate vaccines against diseases alum, an aluminium salt, the most such as human papillomavirus (HPV) widely used adjuvant today. The and hepatitis. Scientists are now combined diphtheria vaccine (toxoid developing DNA vaccines, in which with adjuvant) was so effective that a short DNA length containing a within five years, it was being used germ’s antigen sequence triggers across the world. In New York City an immune response. As shown in 1922, 22 people in 100,000 were by the COVID-19 pandemic, the dying of diphtheria each year. By quest for new vaccines is as 1938, the rate had dropped to just critical today as ever. ■ Types of vaccine Living viruses or Killing germs using chemicals Toxins are removed Specific parts of a bacteria are weakened or heat makes them safe to from bacteria or viruses germ, such as sugars to make live vaccines. use in a vaccine. and neutralized. or proteins, are used. Live attenuated Inactivated “whole Toxoid vaccines such Subunit and conjugate vaccines such as BCG killed” vaccines such as as tetanus use inactivated vaccines such as HPV contain living germs. polio use bacteria or viruses toxins (toxoids). They target are made from parts of an In healthy people, they that have been killed. the part of the germ that organism that stimulate create a strong and lasting Boosters may be needed causes illness (its toxins), an immune response (such immune response. to maintain immunity. not the whole germ. as its antigens).

210 IN CONTEXT POTTAHOFNETICMHARICETETAAITSOEN BEFORE 1776 Matthew Dobson DIABETES AND ITS TREATMENT confirms an excess of sugar in the blood and urine of diabetics. 1869 Paul Langerhans discovers distinctive cell clusters – the islets of Langerhans – in the pancreas. 1889 A link between the pancreas and diabetes is confirmed by Joseph von Mering and Oskar Minkowski. AFTER 1955 British biochemist Frederick Sanger determines the molecular structure of insulin. 1963 Insulin becomes the first human protein to be synthesized in the laboratory. 1985 The insulin pen is launched in Denmark, making the delivery of insulin easier for diabetics. W hen Frederick Banting discovered the cause of diabetes in 1920, he cracked a medical mystery that had perplexed physicians for centuries. The earliest recorded mention of what is thought to be diabetes – a reference to frequent urination – is contained in ancient Egypt’s Ebers papyrus, dating from around 1550 bce. More detailed accounts of the disorder appeared during the Golden Age of Islamic medicine in the 9–11th centuries ce. Ibn Sina and others describe the sweet urine, abnormal appetite, gangrene, and sexual dysfunction associated

VACCINES, SERUMS, AND ANTIBIOTICS 211 See also: Ancient Egyptian medicine 20–21 ■ Hormones and endocrinology 184–87 ■ Genetics and medicine 288–93 ■ HIV and autoimmune diseases 294–97 Possible effects of Possible effects of high blood glucose low blood glucose (hyperglycaemia) levels: (hypoglycaemia) over 200 milligrams levels: below 72 per decilitre milligrams per decilitre Diabetic ketoacidosis Blurred vision Frederick Banting (build-up of acids) Fits Organ damage Born in 1891 in the Canadian Amputations Passing out town of Alliston, Ontario, Death Coma Banting was the youngest son of farmers. On finishing Poor control of blood glucose his medical degree at the levels leads to serious disease. University of Toronto in 1916, Before the discovery of insulin, he served as a battalion people with type 1 diabetes were medical officer in Europe often dead within a year. during World War I. with diabetes, and examination of found that dogs developed the Banting returned home to the colour, odour, and taste of urine symptoms of diabetes when their Canada in 1919 and opened was a common means of diagnosis. pancreas was removed. a surgical practice in London, In 1776, British physician Matthew Ontario, while also lecturing Dobson published a paper in which The exact nature of the link and teaching. It was while he he suggested that the sweet taste of between pancreas and diabetes was preparing a lecture on the the urine was due to excess sugar was not yet known. Twenty years function of the pancreas that (glucose) in the urine and the blood. earlier, German medical student he began to investigate the He also observed that diabetes Paul Langerhans had discovered organ’s link with diabetes. was fatal in some instances but clusters of cells in the pancreas not in others, which was the first whose function was unknown to In 1923, Banting received indication of there being two types him. In 1901, American pathologist the Nobel Prize in Physiology of diabetes: type 1 and type 2. Eugene Opie linked damage to or Medicine for his work these cells (now named the islets on diabetes and was also The role of the pancreas of Langerhans) with the onset of made head of the University In the mid-19th century, Apollinaire diabetes. In 1910, British physiologist of Toronto’s Banting and Bouchardat, a French chemist and Edward Sharpey-Schafer proposed Best Department of Medical physician, developed treatments that diabetes developed when a Research. On the outbreak of for diabetes. He recommended substance produced by the beta World War II in 1939, Banting reducing starchy foods and sugar cells in the islets of Langerhans rejoined the Royal Canadian from the diet and emphasized the was deficient. He called this Army Medical Corps. He died importance of exercise. He was substance insuline (from insula, in 1941, following a plane among the first to suggest that the Latin for island); it was later crash in Newfoundland. diabetes was linked to problems identified as a protein hormone. with the pancreas. This idea was Key work supported by experiments on dogs. In 1920, Frederick Banting, a In 1889, German physicians Joseph Canadian physician and scientist, 1922 “Pancreatic extracts von Mering and Oskar Minkowski realized that pancreatic secretions in the treatment of diabetes might hold the key to treating mellitus” the symptoms of diabetes. He ❯❯

212 DIABETES AND ITS TREATMENT Non-diabetic person Person with type 1 diabetes Beta cells Immune cells Insulin does not in the pancreas monitor destroy the beta cells belong to me, glucose in the blood. in the pancreas. it belongs to the world. Frederick Banting On the sale of the patent for insulin, 1923 Beta cells produce No insulin is produced. insulin to regulate blood glucose. Insulin moves Most glucose stays in in the deaths of several dogs, they glucose from the blood the blood. Some succeeded in keeping a severely to the body’s cells, sending diabetic dog alive with injections spare glucose to the passes through the of an extract made from the tied-off kidneys into urine. pancreas. They called this extract liver for storage. isletin. Their next challenge was to find a way of producing enough Cells use glucose Insulin must be extract to make it a practicable for energy and to fuel added to the blood in treatment for diabetes. order for glucose to pass brain activity. Realizing that relying on a into the cells. supply of dogs was going to hold back research, Banting and Best took his ideas to John Macleod, altogether developed diabetes, as moved on to using the pancreas a Scottish expert in carbohydrate expected, while the dogs whose of cows, obtained from a local metabolism. Thinking Banting’s ducts had been tied did not. While slaughterhouse. They managed to theories were worth investigating the pancreatic cells that produced extract a substance that contained further, Macleod made a laboratory digestive secretions degenerated a greater amount of the active available for him at the University in the dogs whose pancreatic ingredient and injected it into one of Toronto and provided an assistant, duct had been tied, the islets of of the laboratory dogs that had had Charles Best. Langerhans remained undamaged. its pancreas removed. The dog’s Clearly, the islets of Langerhans blood sugar dropped significantly. The discovery of insulin produced the secretions that In May 1921, Banting and Best prevented diabetes occurring. Human testing began to conduct experiments on At the end of 1921, Macleod invited dogs. They removed the pancreas Banting and Best wanted to James Collip, a skilled biochemist, of some dogs and tied off the extract and isolate these secretions, to help purify Banting and Best’s pancreatic duct of others. The dogs but it was difficult to keep the dogs pancreatic extract for clinical whose pancreas had been removed alive long enough to carry out tests. testing in humans. On 11 January After numerous setbacks, resulting 1922, the extract was injected into 14-year-old Leonard Thompson, a diabetic patient who was close to death, at the Toronto General Hospital. The first test proved disappointing, but it was repeated

VACCINES, SERUMS, AND ANTIBIOTICS 213 with a purer version of the extract Types of diabetes in people over 30, although it is around two weeks later, this becoming common among time with much better results. There are two forms of diabetes. younger age groups too. Thompson’s blood sugar returned Type 1 is caused by the body’s to normal levels and his other inability to make insulin as a Research is ongoing into why symptoms abated. result of the immune system people develop type 2 diabetes, mistakenly attacking the cells but lifestyle seems to play a role. In May 1922, Macleod delivered involved in insulin production Obesity, for example, is a known a paper, “The Effects Produced on in the pancreas. It can be risk factor. If exercise and a Diabetes by Extracts of Pancreas”, treated, but not cured, by healthy diet fail to make a on behalf of the team at the annual administering artificial doses difference, doctors may prescribe conference of the Association of of insulin. People with type 2 insulin. As this can reduce blood American Physicians. He received diabetes produce insulin but glucose levels too much, type 1 a standing ovation. The paper used they may not produce enough or and type 2 diabetics who use the word “insulin” for the first time. are unable to use it effectively. insulin must measure their Type 2 diabetes is by far the glucose levels by testing their The triumph of an effective most common. It is usually blood several times a day. treatment for diabetes was marred diagnosed in later life, generally by rivalries. In Banting’s opinion, of extraction that he pioneered it was his idea and his and Best’s University of Toronto for just $1. produced a much purer and more experiments that had led to the However, producing sufficient effective form of insulin than breakthrough. Others thought they quantities of insulin commercially anything obtained previously. would not have succeeded without was no easy undertaking and the Now that the production problem the help of Macleod and Collip. The university allowed American had been solved, the company Nobel committee awarded the 1923 pharmaceutical company Eli Lilly was able to build up large reserves Prize in Physiology or Medicine to and Company to take on the task. of insulin. Banting and Macleod jointly. Banting shared his prize money with Best; The scientists at Eli Lilly began Further breakthroughs Macleod shared his with Collip. work on insulin in June 1922, but Over the next few decades, they found it difficult to increase the researchers continued to make Manufacturing insulin yield from the pig pancreases they improvements in the way insulin Insulin was not a cure for diabetes, used, or to achieve full-strength was produced and delivered. but it was an extremely effective insulin consistently. Lilly started Scientists had succeeded in treatment with the potential to shipments to the newly opened decoding the chemical structure save millions of lives. Banting, Best, diabetes clinic at Toronto General of insulin in the 1950s and then and Collip held the patent rights Hospital, but the potency varied so identified the exact location of the for insulin but sold them to the much that doctors were constantly insulin gene in human DNA. on the lookout for the symptoms of hypoglycaemia (low blood sugar) In 1977, a rat insulin gene was caused by too much insulin. These successfully spliced into the DNA included sweating, dizziness, of a bacterium, which then produced tiredness, and even passing out. rat insulin. By 1978, the first human insulin was being produced using Towards the end of that year, genetically engineered E. coli Lilly’s chief chemist, George Walden, bacteria. Marketed under the made an important breakthrough. name Humulin by Eli Lilly in The isoelectric precipitation method 1982, this was the first genetically engineered human medication. Workers at a factory in postwar Today, the vast majority of people Germany make insulin from pancreatic with diabetes rely on insulin tissue derived from animals. Before the produced in this way. ■ manufacture of insulin, diabetics had to control the condition by diet alone.

214 HNWEOHRWOBODOMODEAYSNNISOTFROEWEN BIRTH CONTROL IN CONTEXT Unwanted pregnancies Removing legal barriers can subject women to birth control allows BEFORE women to take charge 1484 Pope Innocent VIII to ill health, botched of their health and approves the killing of “witches” abortions, and their lives. who provide contraceptive even death. advice to women. With safe, accessible birth control, a woman 1855 American chemist and can call herself free and own her body. engineer Charles Goodyear manufactures condoms from A merican nurse and own reproductive systems, and vulcanized rubber. feminist Margaret Sanger sometimes asked her to share “the viewed birth control as secret” to limiting their family’s size. 1873 In the US, the Comstock a fundamental women’s right. Act prohibits the distribution Working in the slums of New York’s Legal obstacles of birth control. Lower East Side, she was familiar America’s Comstock Act of 1873 with the devastation caused by had deemed all contraceptives and AFTER unwanted pregnancies among literature about them “obscene” and 1942 The Planned Parenthood the suburb’s poverty-stricken outlawed their distribution. Sanger Federation of America is immigrants. Sanger was often called made it her mission to defy this formed. to the homes of women who had Act and provide contraceptives to undergone dangerous backstreet as many women as possible. She 1960 The US government abortions, usually performed by an believed it was every woman’s approves the first oral untrained person with unsterilized right to control when she became contraceptive, later known instruments. She discovered that pregnant, and that contraception as “the Pill”. many of these women did not have was an essential first step in ending even a basic understanding of their the cycle of female poverty. With no 1973 In the US, the Supreme Court rules that women have the right to seek an abortion. 2012 The UN declares access to birth control to be an essential human right.

VACCINES, SERUMS, AND ANTIBIOTICS 215 See also: Midwifery 76–77 ■ Women in medicine 120–21 ■ Hormonal contraception 258 ■ In vitro fertilization 284–85 part of the Planned Parenthood Federation of America, the vehicle used by Sanger over the next 30 years to bring birth control to the American masses. Women wait outside America’s first Hard-won reform Margaret Sanger birth control clinic, set up by Margaret Sanger lobbied for changes in the Sanger in Brooklyn, New York, in 1916. law and achieved many victories. Born Margaret Higgins in The clinic was closed down by the In 1936, for example, New York, Corning, New York, in 1879, government after just 10 days. Connecticut, and Vermont were the Sanger was one of 11 children first states to make it legal for family in a working-class Irish control over the size of her family, a doctors to prescribe contraceptives; family. Her father was woman would always struggle to and later, in 1971, reference to progressive-thinking and make ends meet and have no means contraception was removed from supported women’s suffrage. to educate herself. The number of the Comstock Act. In 1902, after training to be dangerous, illegal abortions would a nurse, Margaret married also continue to rise. By then, the oral contraceptive William Sanger, an architect. known as the Pill was widely The couple campaigned for In 1914, Sanger launched The available. Sanger, who had always various causes, and Sanger Woman Rebel, a feminist publication been frustrated by the small number joined the Women’s Committee in which she insisted that all women of contraceptives available to of the New York Socialist Party should have access to contraception women, had spearheaded the Pill’s and the Industrial Workers of and coined the term “birth control”. development. She had enlisted the the World. After being charged with breaking financial help of heiress Katharine the law, Sanger fled to the UK, McCormick and the expertise of Sanger fought against US but she returned a year later. The biologist Gregory Pincus. When the contraception laws all her charges were dropped in the face of US government approved the Pill’s adult life. This included being public sympathy following the death manufacture in 1960, Sanger had an enthusiastic supporter of of Sanger’s five-year-old daughter. finally won the fight for American eugenics, which sought to women to control their own fertility. ■ reduce “undesirable” In 1916, Sanger was sent to jail populations through enforced for 30 days after opening a birth Our laws force women into birth control and sterilization. control clinic in Brooklyn, New York. celibacy … or abortion … She did not support eugenics During her appeal, the court ruled Both conditions are declared on the base of race or class, that physicians could prescribe but her views tarnished her contraceptives for medical reasons. by eminent medical reputation. She died in 1966. To exploit this legal loophole, in authorities to be injurious 1923 Sanger opened the Birth Key works Control Clinical Research Bureau, to health. staffed solely by female doctors. Margaret Sanger 1914 “Family Limitations” The organization would later become 1916 What Every Girl Should Know 1931 My Fight for Birth Control

MMAROVEULLLOUDS THAT SAVES LIVES ANTIBIOTICS



218 ANTIBIOTICS B efore the 20th century, there Alexander Fleming’s original were no effective treatments culture of Penicillium notatum (shown IN CONTEXT for bacterial infections, here) resulted in the groundbreaking including pneumonia, tuberculosis, discovery of antibiotics and marked a BEFORE diarrhoea, rheumatic fever, urinary turning point in the history of medicine. 1640 English pharmacist John tract infections, and sexually Parkington advises the use of transmitted diseases such as Initially, he called the substance moulds to treat wounds. syphilis and gonorrhoea. In 1928, “mould juice”, but then used the this all changed with the work of name “penicillin” in 1929. 1907 Paul Ehrlich discovers Scottish bacteriologist Alexander arsphenamine, which is later Fleming, who was working at St Fleming demonstrated that released as Salvarsan, the first Mary’s Hospital, London. Fleming penicillin could kill some kinds of synthetic antimicrobial. was experimenting on the bacteria bacteria, but not others. Scientists Staphylococcus – which cause divide bacteria into two categories: AFTER illnesses such as septicaemia (blood Gram-positive and Gram-negative. 1941 Howard Florey, Ernst poisoning) and food poisoning – In 1884, Danish bacteriologist Hans Chain, and Norman Heatley when an error occurred that proved Christian Gram had devised a new treat a septicaemia patient to be a major medical breakthrough. with penicillin, and mass production of the drug begins. The first antibiotic Returning from a holiday, Fleming 1948 Benjamin Duggar found a mould had contaminated discovers the first tetracycline the culture growing in one of his antibiotic, which has its origin Petri dishes. On closer examination, in a soil sample. he noticed the mould had cleared a ring of bacteria from around it. This 1960 In Britain, Beecham, mould was the fungus Penicillium a pharmaceutical company, notatum, which is now called P. launches the new antibiotic chrysogenum. By chance, Fleming methicillin to tackle pathogens had discovered the first naturally that are resistant to penicillin. occurring antibiotic drug that would be produced for therapeutic use: it 2017 The WHO publishes a list would change the world of medicine. of pathogens to be prioritized in antibiotic research. Born in Ayrshire, Scotland, in 1881, role in the development of Alexander Fleming followed his penicillin, but was knighted for Alexander Fleming brother into medicine. In 1906, his work in 1944, and in 1945 Fleming graduated from St Mary’s accepted the Nobel Prize in Hospital Medical School in London, Physiology or Medicine, jointly where he assisted Almroth Wright, with Florey and Chain. He also a pioneer of immunology as well as received the US Medal for Merit vaccine therapy, in the hospital in 1947. Fleming died in 1955. research department. Key works In World War I, Fleming served in the Royal Army Medical Corps, 1922 “On a remarkable witnessing the effects of sepsis on bacteriolytic element found injured soldiers. Returning to St in tissues and secretions” Mary’s Hospital, he discovered the 1929 “On the antibacterial first lysozyme, an enzyme in tears action of cultures of a penicillin” and saliva that inhibits bacteria. Fleming was modest about his

VACCINES, SERUMS, AND ANTIBIOTICS 219 See also: Epidemiology 124–27 ■ Nursing and sanitation 128–133 ■ Cellular pathology 134–35 ■ Germ theory 138–45 ■ The immune system 154–61 ■ Malaria 162–63 ■ Targeted drug delivery 198–99 ■ Pandemics 306–13 Gram-positive Penicillin prevents Gram-negative bacterium bacterium from bacterium Thick outer replicating itself. Thin inner cell wall cell wall of of peptidoglycan peptidoglycan Protective outer membrane Penicillin molecule Cell wall Penicillin penetrates layer of ruptures and molecule bacterium dies. cannot access peptidoglycan. peptidoglycan layer and is ineffective. Penicillin attacks bacteria by invading an area called the peptidoglycan layer. In Gram-positive bacteria, this layer forms part of the cell wall, so penicillin can easily attack it. In Gram-negative bacteria, it is internal and difficult for penicillin to access. method of staining that separated penicillin’s potential. Florey’s team Early in 1941, the team carried out bacteria with an outer membrane included Ernst Chain, a Jewish the first clinical trials on Albert around the cell wall from those refugee from Germany, and Norman Alexander, a patient suffering from without. This technique is still Heatley and Edward Abraham, who acute septicaemia on his face. No widely used by microbiologists: were both British. The team faced one knew how much penicillin to bacteria with no membrane (Gram- formidable obstacles: the mould administer, nor the necessary positive) retain the purple staining, contained just one part in 2 million length of treatment, so they worked visible under a microscope; those of penicillin, which was unstable by trial and error. Alexander was with a membrane (Gram-negative) and difficult to work with. Producing given an intravenous infusion of do not retain the colour. the penicillin was very slow, but the antibiotic. Within 24 hours, Heatley devised a way to separate it his temperature had fallen and the Fleming showed that penicillin from its impurities and then return infection had subsided. However, affected Gram-positive bacteria, it to water for easier processing. Florey’s team only had access to a including those responsible for small supply of penicillin, which pneumonia, meningitis, and One sometimes finds ran out after five days, and the diphtheria. It also killed the Gram- what one is patient relapsed and died. negative gonorrhoea bacteria, but not those responsible for typhoid or not looking for. Florey realized that far larger paratyphoid. Fleming published his Alexander Fleming quantities of Penicillium mould findings in 1929, but they aroused were needed. His team began to little interest at the time. grow the cultures inside different vessels including laboratory flasks, Mass production bedpans, and ceramic pots – yet the The idea of developing penicillin production remained slow. as an antibiotic lay dormant until 1938, when Australian pathologist With World War II raging, the Howard Florey assembled a team of need for penicillin was great, but biochemists at Oxford University’s the British pharmaceutical industry Dunn School of Pathology to realize was working at full capacity on other drugs. Florey and Heatley ❯❯

220 ANTIBIOTICS flew to the US for assistance, and A poster issued during World War II by late 1941 the US Department of shows an American penicillin advert, The structure of Agriculture had organized mass targeting doctors. The US government penicillin production of the antibiotic. A year ordered 20 companies to mass-produce later, a woman with streptococcal the drug, and it was heavily promoted. In 1945, British biochemist septicaemia was successfully Dorothy Hodgkin used X-ray treated with penicillin in the US. in the 19th century. In 1871, British crystallography to discover Production increased exponentially, physiologist John Sanderson noted the molecular structure of with 21 billion units produced that bacterial growth was impeded penicillin fungi. She saw that in 1943 and 6.8 trillion units in by spores of Penicillium. The same a penicillin molecule has a 1945, saving thousands of lives. year, British surgeon Joseph Lister beta-lactam ring at its core, Also in 1945, British biochemist observed the antibacterial effects made up of one nitrogen atom Dorothy Hodgkin discovered the of a mould on human tissue. Then and three carbon atoms. This molecular structure of penicillin, in 1897, French physician Ernst was a vital discovery as the enabling the drug to be chemically Duchesne used Penicillium notatum beta-lactam ring is the reason synthesized. This meant that to cure typhoid in guinea pigs. for penicillin’s effectiveness. scientists could alter penicillin’s structure to create new, derivative In 1900, German scientist Paul The outer wall of a Gram- antibiotics able to treat a wider Ehrlich embarked on a quest to find positive bacteria cell consists range of infections. a “magic bullet”, which would be of layers of peptidoglycan able to seek and destroy all held together by cross-links From natural to synthetic pathogens, but leave healthy body of proteins. If the penicillin is For centuries, people knew that cells alone. He noted that certain present while bacterial cells certain substances cured ailments. dyes would colour some bacterial are dividing, the beta-lactam In ancient Egypt, mouldy bread was cells but not others. Methylene blue rings bind to the cross-links applied to infected wounds, and was one example, staining the while they are still under mould treatments were prescribed single-celled parasite Plasmodium, construction, preventing the in many other cultures, including in which was known to be responsible completion of cell division. ancient Greece, Rome, and China, for causing malaria. The bacteria cell wall is left and in medieval Europe. While not weakened, osmotic pressure understood at the time, these were Ehrlich aimed to find a cure for bursts it, and the cell dies. antibiotic treatments in all but name. the sexually transmitted disease Experiments with the antibacterial syphilis. His Japanese assistant In 1964, Hodgkin received properties of mould gathered pace the Nobel Prize in Chemistry for her work on the structure Without Fleming, of biochemical substances. no Chain or Florey; without Florey, no Heatley; To recognize her work on the without Heatley, no penicillin. structure of penicillin, Dorothy Hodgkin was elected as a member Henry Harris of the Royal Society in 1947. Australian pathologist (1925–2014)

VACCINES, SERUMS, AND ANTIBIOTICS 221 The first rule of intelligent is not effective against every kind of The second way that antibiotics tinkering is to save bacterium. Over time, new varieties attack bacteria is by inhibiting all the parts. of antibiotics were developed that production of essential proteins, Paul Ehrlich operate differently. which stops the cells multiplying. The first antibiotic to do this was Sahachiro Hata trialled a series of The 1950s and 1960s became streptomycin. It was discovered synthetic arsenic compounds, and known as a “golden era” of antibiotic after soil samples taken in 1943 found that one – arsphenamine – discovery. Many pharmaceutical by American microbiology student was able to select and destroy companies conducted wide-ranging Albert Schatz revealed the bacteria Treponema pallidum, the bacterium searches for microorganisms that Streptomyces griseus, from which responsible for the disease. Ehrlich could be used to produce these new streptomycin was produced; it was marketed it as the drug Salvarsan drugs. By 1968, 12 new groups of effective against bacterial infections in 1910. However, it had nasty side antibiotic had been discovered, and including tuberculosis. effects, and the Russian Orthodox to date more than 20 groups exist. Church denounced the treatment, The tetracyclines are another claiming that syphilis was a divine There are three primary ways family of antibiotics that work as punishment for immorality. In 1912, that antibiotics can attack bacteria. protein inhibitors. In 1948, plant Ehrlich introduced the improved The first (as shown by penicillin) is biologist Benjamin Duggar identified version, Neosalvarsan, which then to disrupt the pathogen’s cell wall the bacterium called Streptomyces became the standard treatment for synthesis (see diagram on p.219). aureofaciens from a soil sample in syphilis. As such, arsphenamine Vancomycin is another antibiotic Missouri, US. Chlortetracycline was was the first synthetic antimicrobial. that works this way. It was produced isolated from the bacteria, the first Yet as an arsenic-based compound from the bacterium Streptomyces of the large family of tetracycline Neosalvarsan still carried bad side orientalis, and became available in antibiotics. Marketed as the drug effects, and was also hard to store. 1958. Vancomycin was effective Aureomycin, it was subsequently In the 1940s, penicillin became the against most of the Gram-positive used to treat infections in animals new treatment for syphilis as it was pathogens, including penicillin- as well as humans. considered a safer alternative. resistant bacteria. It was eclipsed by drugs that produced fewer adverse Microbiologists developed other effects, but regained popularity after tetracyclines during the 1950s, and the appearance of more antibiotic- many have since been used to treat resistant bacteria in the 1980s. a range of conditions, including ❯❯ Finding new antibiotics Bacteriologists now understand that penicillin is a bactericide – it works by directly killing bacteria. Yet as Fleming discovered, penicillin Leafcutter ants grow a fungus on harvested leaves. This fungus produces the bacteria Pseudonocardia (seen as a white powder). Some scientists believe this bacteria could be used to develop a new class of human antibiotic.

222 ANTIBIOTICS A patient takes antibiotics to treat a bacterial infection. bone and joint infections, typhoid fever, diarrhoea, and respiratory and urinary infections. The antibiotics kill most of the bacteria, Rise of the superbugs but a small number of bacteria survive because Staphylococcus aureus (SA) was they have existing resistance to the antibiotics. discovered by German scientist Friedrich Rosenbach in 1884. It This resistant strain of bacteria multiply is the bacterium responsible for in the first patient and can be passed on infections including septicaemia, by contact to infect another person. respiratory illnesses, and food poisoning. Scientists estimate that This new patient takes antibiotics, but they fail to kill of those infected with SA before the now completely resistant bacteria. 1941, 82 per cent died. However, since the introduction of antibiotics, acne, respiratory tract infections, production by stimulating growth. an “arms race” has begun between stomach ulcers, chlamydia, and Their overuse in agriculture is the bacteriologists inventing new Lyme disease. They are also used likely to have caused the increased drugs, and pathogens developing to tackle the Plasmodium protozoan resistance among many pathogens: resistance to them. parasites that cause malaria. Unlike now, tetracyclines are no longer as some antibiotics, tetracyclines can effective for animals or humans. Bacteria reproduce very rapidly, work against both Gram-negative therefore mutation and evolution and Gram-positive bacteria. Quinolones, another class of also take place quickly. Chain and antibiotics, use the third method Abraham, two members of Florey’s Tetracyclines inhibit protein of attack: preventing the bacteria research team, had first noticed synthesis by entering the pathogen from reproducing their genetic penicillin resistance in the bacteria cell and preventing key molecules material so they cannot multiply. Escherichia coli (E. coli) in 1940, from binding to its ribosomes (tiny Quinolones include ciprofloxacins, before the drug had even gone into cellular structures, or “organelles”). which were introduced in the late production. E. coli can be harmless, The proteins that build and run the 1980s. They work by damaging the but certain strains (genetic variants) cell are made by these ribosomes, DNA of targeted pathogen cells. are linked to food poisoning as and when this process is stopped These antibiotics are used to treat well as gastrointestinal infections. the cell cannot multiply. Resistance to penicillin became The bacteria in this image were more common in the late 1940s. Almost half of all tetracyclines taken from the back of a mobile phone, Scientists developed alternative are used in animal husbandry. The which provides an optimal breeding antibiotics, vancomycin and drugs are given to pigs, cattle, and ground due to its warmth. Bacteria methicillin, to try and defeat the other intensively reared animals to identified on phone handsets include resistant strains in the 1950s and prevent gastrointestinal infections E. coli and the superbug MRSA. and to increase meat and dairy

VACCINES, SERUMS, AND ANTIBIOTICS 223 early 1960s – but methicillin- Resistance to common antibiotics resistant SA (MRSA) appeared in the same decade, and is now The increasing misuse of antibiotics has led to bacterial resistance classed as one of the “superbugs”. against drugs that were previously effective. In the US alone, prescriptions in 2018 reached 258.9 million. The global antibiotics market was valued at These superbugs are resistant US$45 billion in 2018, and is predicted to reach US$62 billion by 2026. to antibiotics and are more virulent than their ancestors. An example is Antibiotic Release First resistance Pseudomonas aeroginos, which is identified a bacterium once found in burn- Penicillin 1941 1942 wound infections. In the early 21st Vancomycin 1958 1988 century, it developed resistance to Methicillin 1960 1960 certain antibiotics and became a Azithromycin 1980 2011 more virulent and common infection Ciprofloxacin 1987 2007 in hospitals. In the first decade of Daptomycin 2003 2004 the 21st century, new categories of Ceftazidime-avibactam 2015 2015 extremely drug-resistant (XDR) and totally drug-resistant (TDR) strains of pathogen were described. Global health problem The World Health Organization their course of antibiotics, which Superbugs pose a major threat to (WHO) has identified antibiotic enables bacteria to survive and humanity. Tuberculosis treatments resistance as one of the biggest gain immunity. The second form have been compromised because risks to global health and food of misuse is the inappropriate the Mycobacterium tuberculosis security, one that threatens to roll administration of these drugs to bacterium responsible has evolved back many achievements of modern animals. In 1950, food scientists resistance to both isoniazid and medicine. Physicians find it harder in the US discovered that adding rifampin, previously the two most to treat pneumonia, tuberculosis, antibiotics to livestock feed powerful antibiotics used against food poisoning, and gonorrhoea accelerated the animals’ growth, it. Cholera (caused by the Vibrio because the appropriate antibiotics probably by affecting their gut flora. cholerae bacterium) is also harder to are less effective. Even standard Since these drugs were cheaper treat, having developed resistance procedures, such as Caesarean than traditional supplements, many in Asia and South America. sections and organ transplants, are farmers embraced the practice. more dangerous due to the reduced The world is headed for a effectiveness of antibiotics used for By 2001, the Union of Concerned post-antibiotic era, in which postoperative infections. Each year Scientists estimated that around in the US, 2.8 million people are 90 per cent of antibiotic use in common infections and infected with antibiotic-resistant the US was for non-therapeutic minor injuries which have bacteria or fungi, and more than purposes in agriculture. The WHO been treatable for decades 35,000 die as a result. now campaigns for antibiotics not to be given to healthy animals, can once again kill. Misuse of antibiotics whether the intention is to prevent Keiji Fukada While antibiotic resistance occurs disease or to promote growth. naturally, misuse of the drugs has Assistant director general of the accelerated the process. Misuse The need for antibiotics can World Health Organization, 2010–16 falls into two main categories. First, be minimized by maintaining the antibiotics are overprescribed for basic rules of hygiene, including humans, often being used to treat handwashing, as such practices viral infections for which they are will reduce the spread of bacteria. entirely ineffective. Added to this, Antibiotics have saved millions of patients frequently fail to complete lives, but microbiologists now face the challenge of finding new and effective models to beat infection. ■

224 INNETWO WTHIENDBORWAISN ELECTROENCEPHALOGRAPHY IN CONTEXT I n 1935, British neurophysiologist The brain contains billions of William Grey Walter diagnosed neurons (nerve cells) that form a BEFORE a patient with a brain tumour vast, complex network. Neurons 1875 British physician Richard using an electroencephalogram communicate with one another at Caton observes electrical (EEG). This technique, measuring junctions within the network called activity on the exposed brains electrical activity (“brain waves”) in synapses – any activity at a synapse of a monkey and a rabbit. the human brain, had already been creates an electrical impulse. The used by German neuropsychiatrist voltage at any one synapse is too 1912 Russian physiologist Hans Berger in the 1920s; Walter small for an electrode to detect, Vladimir Pravdich-Neminsky improved the technology to detect a but when thousands of neurons publishes the first animal EEG. range of brain waves, enabling EEG fire simultaneously – which is what to be used as a diagnostic tool. happens all the time in a human 1924 Hans Berger records his first EEG on a boy undergoing Special sensors Electrical impulses neurosurgery. (electrodes) are attached produced in the brain are detected by the AFTER to the scalp in order to electrodes and relayed 1936 The first EEG laboratory monitor electrical activity opens at the Massachusetts to a computer General Hospital, Boston, US, in the brain. for analysis. as a research facility. Clinicians analyse The computer 1953 Two American the patterns to translates the electrical neurophysiologists, Eugene detect abnormal Aserinsky and Nathaniel activity by graphically Kleitman, demonstrate the link activity and diagnose depicting brainwave between rapid eye movement irregularities. (REM) sleep and dreaming. patterns. 1992 American neuroscientist Kenneth Kwong pioneers the use of functional magnetic resonance imaging (fMRI) to explore the human brain.

VACCINES, SERUMS, AND ANTIBIOTICS 225 See also: X-rays 176 ■ The nervous system 190–95 ■ Alzheimer’s disease 196–97 ■ Ultrasound 244 ■ MRI and medical scanning 278–81 William Grey Walter Born in Kansas City, US, in 1910, shape and slow movement, and William Grey Walter moved to the used them to show how a small UK aged five. He graduated with number of instructions can give a degree in natural sciences from rise to complex behaviours – Cambridge University. Fascinated something he believed was by Hans Berger’s work with EEG, applicable to the human brain. Walter then worked with British neurologist Frederick Golla at the In 1970, Walter crashed his Maudsley Hospital, London, using motorcycle while trying to avoid self-built EEG equipment. a runaway horse. He spent three weeks in a coma and lost sight In 1939, Walter moved to the in one eye. Walter died in 1977. Burden Neurology Institute in Bristol where he conducted his Key works most famous work as a pioneer of cybernetics, building electronic 1950 “An imitation of life” robots. Walter referred to these 1951 “A machine that learns” as his “tortoises” because of their 1953 The Living Brain brain – they generate an electric such as in meditation or reflection. inflammation), stroke, dementia, field that is strong enough to be Beta waves are typical of an alert and sleep disorders. EEG is measured by electrodes. or strongly engaged mind. Finally, noninvasive and entirely safe. gamma waves, which have the Walter performed experiments highest frequency, are linked to Scanning alternatives during which he placed detecting periods of peak concentration. There are now other tools used for devices (electrodes) around each analysing the human brain’s health, patient’s head to map electrical EEG techniques have increased although these do not measure activity of the brain beneath. His in sophistication since Walter first electrical activity directly. Positron EEG machines differentiated developed his model, but the basic emission tomography (PET) a range of brain signals reflecting principles remain unchanged. measures the brain’s metabolic various states of consciousness, Electrodes placed around the scalp activity, while functional magnetic from high-frequency waves to low- detect electrical signals when the resonance imaging (fMRI) records frequency (delta) waves. Walter’s neurons in the brain send messages changes in blood flow. However, great breakthrough was to discover to one another. These are recorded EEG is the only technique that a correlation between disrupted and a neurologist then analyses the can measure the extremely rapid delta waves, and the presence of results. EEG is used primarily to changes in the brain’s electrical brain tumours and epilepsy. diagnose and monitor epilepsy, as activity, detecting these to the level well as disorders of the brain such of one millisecond or less. EEG’s Different wave bands as tumours, encephalitis (brain disadvantage is that the electrodes While much is still not understood located on the scalp are not always about electrical impulses in the able to precisely identify the exact brain, neurophysiologists now sources of electrical activity that recognize five main frequency occurs at depth in the brain. ■ bands. Very low-frequency delta waves dominate when someone is This EEG shows the chaotic brain in deep sleep. Theta waves occur if waves of a patient during an epileptic the brain is awake but relaxed – on episode (or seizure). Seizures are often autopilot or daydreaming. Higher- recurrent, and are caused by sudden frequency alpha waves occur during surges in the brain’s electrical activity. periods of targeted rest in the day,

226 ESCAIALRNELNBYTE DFIOSUENADSE CANCER SCREENING IN CONTEXT Early diagnosis Screening the apparently of cancer is healthy population BEFORE can identify those 1908 Austrian gynaecologist crucial to improve Walther Schauenstein notes treatment with the potential to observable differences between outcomes. develop cancer, but who a healthy cervix and one that will become, or is, cancerous. have no symptoms. 1927 Aurel Babes, suggests If abnormal cells Screening can that cervical cells can be used are detected, they can reveal early signs to detect cancer. be removed before of certain cancers, 1930 Austrian pathologist they develop into including Walter Schiller charts the cancerous cells. precancerous cells. progression of cancer from cells to lesions and promotes G lobally, cancer is estimated fourth most common cancer among the idea of routine testing. to cause almost 10 million women. Prevention depends on the deaths per year. That figure early detection of cell abnormalities AFTER would be much higher if scientists (precancerous lesions) that can 1963 A trial in New York City, had not found ways to identify develop into full-blown cancer. US, finds that mammography certain cancers before they develop. reduces mortality from breast The most effective way to do this is In the 1920s, Greek American cancer by 30 per cent. by screening – testing apparently physician George Papanicolaou healthy individuals to identify those and Romanian gynaecologist Aurel 1988 The world’s first mass who have the disease but are not Babes, devised tests that used swab breast cancer screening showing symptoms. samples of cells from a woman’s programme begins in the UK, cervix. Working independently, they for women aged 50–70 years. Using a smear test introduced discerned that differences could be in 1943, the first mass screening observed between healthy and 2020 The World Health programme was established in the cancerous cells. Crucially, Babes, Organization (WHO) proposes US during the 1950s and aimed to established that malignant cells a global strategy to eliminate identify cases of cervical cancer, the were often preceded by a detectable cervical cancer by 2030.

VACCINES, SERUMS, AND ANTIBIOTICS 227 See also: Histology 122–23 ■ Cellular pathology 134–35 ■ Cancer therapy 168–75 ■ Tobacco and lung cancer 266–67 ■ Stem cell research 302–03 it is identified early. Exploratory procedures such as colonoscopy, sigmoidoscopy (examining the lower colon), and faecal occult (hidden) blood testing (FOBT) have proven effective in detecting the disease. It is estimated that 60 per cent of deaths from colorectal cancer can be avoided through screening. George Papanicolaou’s Atlas of Mixed results George Papanicolaou Exfoliative Cytology aimed to train Screening has not always proved other clinicians in his screening successful. Prostate cancer is Born on the Greek island method, and used drawings to help the second most common cancer of Euboea in 1883, George them identify changes in cervical cells. in men. Since the 1990s, physicians Papanicolaou studied medicine have been able to test for it using a at Athens University. In 1913, precancerous stage. Papanicolaou’s prostate-specific antigen (PSA) test. he and his wife Mary emigrated “Pap smear” test became a standard Above-average blood levels of this to the US. He obtained posts screening procedure for cervical antigen may indicate the presence at New York University’s cancer after 1943, and has since of cancer, but may also be produced Pathology Department and reduced mortality significantly. by other factors. There is no clear at Cornell University Medical evidence that mortality rates have College’s Anatomy Department, Successful screening fallen since PSA testing was where his wife was also The Pap smear proved that early introduced and several countries employed as his technician. cancer detection was key to saving have now abandoned it. lives, and its success fuelled interest From 1920, Papanicolaou in developing tests for other cancers. Balancing the gains of screening began studying changes in By the late 1960s, tests had been programmes against the costs and the structure of cervical cells, devised for two of the most prevalent risks (such as falsely positive results) performing the first “Pap test” forms: breast and colorectal cancers. therefore remains key in establishing on his wife. A larger study successful cancer tests. Research followed, which revealed the Mammograms became standard continues to develop new tests, first instances of cancer cells procedure for breast screening. and to establish which existing obtained using a smear test. These X-ray tests detect tumours policies are most effective. ■ Papanicolaou’s initial findings too small to see or feel. New had gained little interest, but technology has improved the test A mammogram is nothing the publication of these results since 2000, with 3D digital imaging to be afraid of. It’s not an in 1943 was well received and allowing analysis of breast tissue the Pap test became widely layer by layer. Colorectal cancer is enemy, but a friend. adopted. Papanicolaou moved one of the most treatable cancers if Kate Jackson to Florida to head the Miami Cancer Institute in 1961, but American actor (1948–) died just three months later from a heart attack in 1962. Key works 1943 Diagnosis of Uterine Cancer by the Vaginal Smear 1954 Atlas of Exfoliative Cytology

GLOBAL 1945–1970

HEALTH

230 INTRODUCTION The International John Cade discovers In France, Jean Delay American surgeon Health Conference in that lithium is an and Pierre Deniker use Joseph Murray carries New York, US, agrees effective treatment to set up the World for bipolar disorder. chlorpromazine out the world’s first Health Organization, to treat patients successful organ on the principle that with schizophrenia health is a human right. transplant, of and mania. a kidney. 1946 1949 1952 1954 1948 1951 1953 1956 American physician Philip Canadian engineer Francis Crick and In Scotland, Ian Donald Hench uses cortisone John Hopps invents the James Watson at uses ultrasound as first effective heart the University of a safe, noninvasive (“compound E”) to relieve Cambridge, UK, publish means of checking for a patient’s rheumatoid pacemaker. their model of DNA as a double helix. foetal abnormalities arthritis pain. during pregnancy. I n the wake of World War II, the conditioned to relearn previously was an untreatable and life- bloodiest conflict in history, learned behaviours and emotional threatening disorder until 1945, the World Health Organization responses, enabling them to act when Dutch physician Willem (WHO) was officially established on more appropriately. From the 1940s, Kolff’s dialysis machine was used 7 April 1948. Its vision of universal he honed his behavioural therapy successfully to filter toxic material health included the notion that the techniques, which were influential and excess fluid from a patient’s highest possible standards of care in the development of cognitive blood. Although dialysis techniques should be available to all. Over the behavioural therapy in the 1960s. improved over the next few years, following decades, millions of lives patients still had to be connected were improved or saved thanks to Other psychiatric treatments to a machine for long periods. the development of new drugs; involved the use of drugs. In 1949, advances in genetics, immunology, Australian psychiatrist John Cade In 1952, French surgeon Jean and orthopaedics; a revolution in found that lithium – previously Hamburger transplanted a healthy organ transplant techniques; and used to treat gout – was effective kidney from a mother to her son, new ways of treating mental illness. as a treatment for bipolar disorder. who had renal failure. But donor Likewise, chlorpromazine initially and recipient were not closely related Healing the mind had another use, as an anaesthetic, enough – the boy’s body rejected War had left millions of combatants but in 1952, it was used successfully the organ and he died soon after. and civilians alike suffering from to treat schizophrenia and mania. The first successful organ transplant disease, injury, and psychiatric (of a kidney) took place in the US conditions such as depression. Changing lives between identical twins in 1954. American psychologist B.F. Skinner Life for those with long-term believed that humans could be physical conditions also improved The main issue with transplant in the post-war era. Kidney failure surgery was in finding suitable donors. South African heart surgeon

GLOBAL HEALTH 231 Marthe Gautier In the US, John Charnley The first human discovers the the FDA approves performs the heart transplant is chromosomal Enovid (“the Pill”) first successful carried out in Cape cause of Down for use as an oral Town, South Africa, by syndrome. contraceptive. total hip Christiaan Barnard. replacement. 1958 1960 1962 1967 1959 1960 1965 1967 In immunology, James The FDA’s Frances The British Doctors British doctor Cicely Gowans describes Oldham Kelsey refuses Study, set up by Richard Saunders establishes how lymphocytes to approve thalidomide Doll and Austin Bradford the first purpose-built circulate between as an anti-nausea drug Hill in 1951, shows a clear link between smoking hospice for the lymphatic system for pregnant women palliative care. and the bloodstream. in the US. and lung cancer. Christiaan Barnard performed the system in 1959, when he showed approved for use in 1960. Not only a first successful heart transplant in that lymphocytes (a type of white medical advance, this added pace to 1967, but it was not until the 1980s blood cell) do not vanish but travel the female liberation movement, and that an effective immunosuppressant in the lymph system, and that they contributed to the counterculture drug to reduce the risk of rejection – produce antibodies – a central part campaigns gaining prominence in cyclosporine – was licensed for use. of the body’s immune response. Western culture from the mid-1960s. Understanding the body Medical advances were not The need for caution As the 1950s progressed, more of confined to the cellular level. In Although new treatments and drugs the mysteries of the human body orthopaedics, British surgeon John usually improve lives, there is always were explained. In genetics, the Charnley performed a total hip an element of risk – and it is crucial structure of DNA was discovered replacement in 1962, and in 1968, that they are thoroughly trialled. In in 1953, and in 1956, scientists at Canadian surgeon Frank Gunston 1961, it emerged that thalidomide – the University of Lund, Sweden, carried out the world’s first total a drug introduced in some countries established that humans have 46 knee replacement. In obstetrics, to relieve nausea in pregnant chromosomes, arranged in 23 pairs. ultrasound – a new, noninvasive women – had caused birth defects In 1958, French researcher Marthe method for looking inside the body in at least 10,000 children worldwide. Gautier found that Down syndrome without using X-rays – became the A year earlier, pharmacologist was caused by having three copies technique of choice to examine Frances Oldham Kelsey at the Food of chromosome 21 instead of two. pregnant women. and Drug Administration (FDA) had refused to authorize its use in the British physician James Gowans For those who wished to avoid US, not satisfied it was risk-free. made a huge contribution to the pregnancy, the oral contraceptive, Her action saved many lives. ■ understanding of the immune or “Pill”, transformed the lives of millions of women after it was

232 ERWVIGEEHRDTYEOFTNEONEH’DSEALTH THE WORLD HEALTH ORGANIZATION IN CONTEXT T he concept of a specialist United Nations Conference on body responsible for International Organization on 25 BEFORE international public health April 1945, in San Francisco. The 1902 The Pan American was first raised by Chinese doctor US and UK delegates had explicitly Health Organization is Szeming Sze in 1945. Sze had been stated that health would not be on founded; it becomes the first stationed in the US as an aide to the agenda, but Sze, with support international health agency. the Chinese foreign minister T.V. from Brazilian Dr Geraldo de Paula Soong, and it was only by chance Souza and Norwegian Dr Karl 1923 The Health Organization that Soong asked Sze to attend the Evang, put forward a declaration at the League of Nations is established. Improve Promote worldwide Prepare access to health and support for health AFTER medicines and vulnerable communities. emergencies 1974 The WHO launches its promote and develop immunization programme universal Main goals tools to deal against six diseases: measles, of the with them. tetanus, pertussis, diphtheria, health poliomyelitis, and tuberculosis. coverage. World Health Organization 1980 Smallpox is the first human disease to be Prioritize health Eradicate eradicated worldwide. and wellbeing in high-impact all policies and communicable 1988 The WHO launches health settings. its Global Polio Eradication diseases. Initiative; by 2020, cases of polio worldwide have decreased by 99 per cent. 2018 The first WHO global conference on air pollution, climate change, and health is held.

GLOBAL HEALTH 233 See also: Vaccination 94–101 ■ Germ theory 138–45 ■ Malaria 162–63 ■ Global eradication of disease 286–87 ■ Pandemics 306–13 that a conference be called to outbreaks of malaria, tuberculosis, Szeming Sze discuss the establishment of an and venereal diseases, developing international health organization. strategies against leprosy and Born in Tientsin, China, in Sze’s declaration received trachoma, and exploring ways to 1908, Szeming Sze was son overwhelming support, and one improve children’s health. to the Chinese ambassador year later an International Health in the UK and later the US. Sze Conference in New York approved The WHO today was educated at Winchester the constitution of the World Health By 2020, the WHO had grown to College and then Cambridge Organization (WHO). 194 member states and a budget University, where he studied of US$4.2 billion. Among its key chemistry and medicine. Earlier organizations functions are the issuing of global For Sze, the WHO represented a public health guidelines, providing Sze worked as an intern new age in which international sanitary regulations, health at St Thomas’s Hospital in health would engender a postwar education, and mass vaccination London, but returned to China era of global cooperation. Previous campaigns, and collecting global in 1934 in order to devote his attempts at health cooperation data on health problems. Its most life to public service. During between countries had taken place celebrated achievement to date is World War II, Sze worked in in Europe during the 19th century. the eradication of smallpox. the US as part of its Lend- In 1851, an International Sanitary Lease programme, supplying Convention was held in France to In response to the COVID-19 the Chinese government with try and form a collective response pandemic that erupted in 2020, defence aid. Instrumental in to cholera outbreaks (which killed the WHO acted as a worldwide helping establish the WHO thousands), but political differences information centre on the deadly in 1945, Sze then joined the prevailed until the Convention respiratory illness, issuing practical newly formed United Nations reconvened in 1892 and agreed advice for governments, updates in 1948. He became the UN’s joint policies to tackle the disease. on scientific research, and news medical director in 1954, a on the virus’s spread – including role that he held until his From the early 20th century, global mortality figures. retirement in 1968. Sze died new international health agencies in 1998. sprang up on both sides of the The establishment of the WHO Atlantic, such as the Pan American is celebrated each year on 7 April Key works Health Organization in 1902, the as World Health Day, which aims to European L’Office International promote global health awareness. ■ 1982 The Origins of the World d’Hygiène Publique in 1907, and the Health Organization: a Health Organization at the League of Health is a state of personal memoir, 1945–48 Nations in 1923. These organizations complete physical, mental 1986 Working for the United mainly worked in disease control Nations: a personal memoir, and eradication (for smallpox and and social wellbeing 1948–68 typhus), with quarantining measures and not merely the absence where needed. of disease or infirmity. The WHO formally began work WHO Constitution on 7 April 1948. It inherited the tasks and resources of the earlier organizations, and was given a broad mandate to promote “the highest possible level of health” for all peoples. With a budget of US$5 million, funded by its 55 member states, it began by addressing

234 KSTHIADVENEAEARYTLCIIFAFINECIAL DIALYSIS IN CONTEXT A cute and chronic kidney early 20th centuries, there was little (renal) failure are serious, understanding of kidney problems BEFORE potentially life-threatening and no effective treatment until 1861 Scottish chemist Thomas disorders. The function of kidneys the 1940s, when Dutch physician Graham coins the term is to eliminate excess salts, fluids, Willem Kolff’s kidney dialysis “dialysis” and uses the process and waste materials from the body, machine successfully filtered out to extract urea from urine. which accumulate in the blood if the toxic materials and excess kidneys fail. Until the late 19th and fluid from a patient’s blood. 1913 In the US, doctors John Abel, B.B. Turner, and Leonard During dialysis, blood from the body German physician Georg Haas Rowntree test their kidney passes through thin, hollow fibres, had attempted the first kidney dialysis machine on animals. which filter out excess salt and waste dialysis on human patients in the products into a dialysis solution flowing 1920s, using varying machines of 1923 German physician Georg in the opposite direction. The filtered his own design. His original choice Ganter pioneers peritoneal blood then flows back into the body. of anticoagulant (to stop the blood dialysis which uses the lining forming clots, impeding its flow) of the abdomen (peritoneum) Blood from was hirudin from the saliva of as the dialysing membrane. patient’s body leeches, which caused allergic reactions. Haas later used heparin, AFTER Used dialysis an anticoagulant that occurs 1950 Ruth Tucker of Illinois, solution naturally in humans and is still US, is the first to receive a used today. However, the dialysis successful kidney transplant. Hollow fibres procedures were too short to have a therapeutic effect, and none of 1960 American physician Haas’s patients survived. Belding Scribner develops a shunt that allows Fresh dialysis Kolff’s machine permanent access to veins solution The breakthrough came in 1945, for repeated dialyses. Blood returned to when Kolff performed a week-long patient’s body dialysis on a 67-year-old patient 1962 In the US, a team led by with acute kidney failure, using physician Fred Boen develops a rotating drum dialyser, the the first automated home forerunner of the modern kidney peritoneal dialysis device. dialysis machine. He built it with materials he could easily access,

GLOBAL HEALTH 235 See also: Blood circulation 68–73 ■ Scientific surgery 88–89 ■ Blood transfusion and blood groups 108–11 ■ Physiology 152–53 ■ Transplant surgery 246–53 including wooden bed slats for the I don’t hesitate hollow membranes to create a larger drum, semipermeable cellophane to try something that surface area, which allows more sausage casing for the tubes, and most other people will not try efficient filtration of the blood. an electric motor. if I see a possibility. Modern dialysis During treatment, blood from Willem Kolff Haemodialysis, filtering the blood the patient’s body, with the added through a dialyser, is still the most heparin anticoagulant, passed Interview after receiving the Russ common form of kidney dialysis, through the cellophane tubes. These Prize for bioengineering, 2003 but for an estimated 300,000 kidney were wrapped around the wooden patients worldwide, peritoneal drum, which rotated through an from post-traumatic kidney failure. dialysis is a viable alternative. electrolyte solution (dialysate) in a Later machines used ultrafiltration, In this home procedure, dialysis tank. As the drum turned, the blood first proposed by Swedish doctor solution flows via a catheter into was filtered by diffusion: small Nils Alwall in 1947, which removes the abdomen, and the abdominal molecules of toxins passed through more excess fluid from the blood as lining (peritoneum) filters out waste the semipermeable tubes from the a result of differing pressures in the products from the blood, which are more concentrated fluid (blood) to blood and dialysate. then drained out of the body. The the less concentrated dialysate until patient repeats the procedure four an equilibrium was reached. The A further refinement in 1964 to six times a day, or a machine can filtered blood, retaining its larger was the development of the first operate the dialysis during sleep. molecules of proteins and blood cells, hollow-fibre dialyser, which is still then flowed back into the body. the most common type today. It The challenge today is no longer uses around 10,000 capillary-sized the technology that Kolff pioneered, Further refinements but the sheer number of patients Kolff’s machine was adapted and with kidney failure. More than two improved at the Peter Bent Brigham million people worldwide undergo Hospital in Boston, US. The new dialysis (of whom around 90,000 Kolff-Brigham dialyser was shipped receive a kidney transplant), but this to 22 hospitals around the world and is thought to represent a mere tenth used in the Korean War (1950–53) of those in need who cannot access to treat soldiers who were suffering or afford treatment. ■ Willem Kolff Born in Leiden in the Netherlands Kolff moved to the US in 1950 in 1911, Willem “Pim” Kolff studied and next turned his skills to medicine in his home city and, as cardiovascular problems and a postgraduate at the University of the development of an artificial Groningen, became interested in heart. He was inducted into the the possibilities of artificial kidney Inventors Hall of Fame in 1985 function. After Nazi Germany’s and continued to work until he invasion of the Netherlands in retired in 1997. Kolff died of 1940, Kolff founded Europe’s first heart failure in 2009. blood bank in The Hague, then moved to a small hospital in Key works Kampen. There, he developed his first kidney dialysis machine in 1943 “The artificial kidney: 1943. Two years later, he used it a dialyser with a large for the first time to save the life surface area” of a woman imprisoned for 1965 “First clinical experience collaborating with the Nazis. with the artificial kidney”

236 IN CONTEXT NDARNATTAUIMDRAOETT’ISEC BEFORE 1563–64 In Italy, anatomist STEROIDS AND CORTISONE Bartolomeo Eustachi first describes the adrenal glands, located just above the kidneys. 1855 British physician Thomas Addison describes a disorder, later called Addison’s disease, which occurs when the adrenal glands produce too little of the hormone cortisol. 1930s Researchers in the US and Switzerland begin to isolate adrenal hormones. AFTER 1955 The Schering Corporation in the US first synthesizes prednisone, a new safer corticosteroid for treating inflammatory diseases. 2020 The WHO welcomes the positive UK clinical trial results for the use of the corticosteroid dexamethasone to treat severe COVID-19 symptoms. R heumatoid arthritis is an autoimmune condition that occurs when the body’s immune system misfires and attacks healthy cells that line the joints, causing inflammation and swelling. First described in 1800 and named in 1859, it was poorly understood and there was little to relieve the pain when American physician Philip Hench began to study the disorder in the 1930s. The 1948 discovery that cortisol, a hormone naturally produced in the adrenal cortex (the outer part of the adrenal gland above each kidney), could help alleviate the condition led to the first effective treatments and paved the way for

GLOBAL HEALTH 237 See also: Cellular pathology 134–35 ■ The immune system 154–61 ■ Hormones and endocrinology 184–187 ■ Transplant surgery 246–53 ■ Monoclonal antibodies 282–83 ■ Genetics and medicine 288–93 Rheumatoid arthritis patients who are pregnant or suffer from jaundice experience temporary relief from joint inflammation and pain. In these conditions, the body releases a natural anti-inflammatory agent, dubbed substance X. Rheumatoid arthritis can produce however, was not convinced. In Further research suggests severe, crippling deformities of the 1929, while head of the Mayo substance X is located hands, as shown in this X-ray. It mainly Clinic’s department of rheumatic in the adrenal glands. affects the capsule (synovium) around diseases in Minnesota, he noticed the joints, causing painful swelling. that a patient’s rheumatoid arthritis Over several years, became less severe the day after researchers in Switzerland the development of a new class of he developed jaundice. For several anti-inflammatory drugs called months after his recovery from and the US isolate corticosteroids, or steroids. Hench, jaundice, the patient continued to 28 adrenal compounds. his colleague Edward Kendall, and experience less arthritic pain. Hench Compound E, later named Swiss researcher Tadeus Reichstein observed similar effects when other cortisol, proves the most were awarded the Nobel Prize in arthritic patients developed jaundice. effective for relieving Physiology or Medicine in 1950 rheumatoid arthritis pain. for their work. By 1938, Hench had detailed studies of more than 30 cases in Jaundice brings a clue which jaundice temporarily relieved In the mid-19th century, British his patients’ arthritic symptoms. physician Alfred Garrod laid the He observed that other conditions, groundwork for rheumatoid arthritis especially pregnancy, induced research by distinguishing the the same relief. Knowing that the disorder from gout, which involves concentration of steroid hormones an excess of uric acid in the blood; in the blood is higher than normal Garrod noted that this was not under these conditions, Hench evident in any form of arthritis. reasoned that a natural steroid hormone might be responsible for By the 1920s, most cases of the effect. Allergic conditions, such rheumatoid arthritis were thought as asthma, hay fever, and food to be the result of infection. Hench, sensitivity, also improved when a ❯❯

238 STEROIDS AND CORTISONE Biochemical action Corticosteroids treat days she was walking with a slight triggered to suppress inflammatory disorders by limp and, four days after starting the production of crossing the membrane around treatment, she was spending three inflammatory proteins. a cell and binding to a specific hours shopping. Over the following receptor. The drug and receptor months, 13 more patients, all with Receptor complex then moves to the symptoms as severe as those of Mrs nucleus and binds to DNA. Gardner, received compound E and DNA Here the drug can act on the found the same level of relief. When DNA, suppressing the genes Hench described his results to a Receptor- that encode the synthesis of meeting of fellow doctors in April corticosteroid many inflammatory proteins. 1949, he received a standing complex ovation. The Nobel Prize awarded Cell membrane a year later to Hench, Kendall, and Nucleus Reichstein had never been offered Corticosteroid at such speed. patient developed jaundice or became pregnant, suggesting Service and director of the US Potential side effects that in these conditions, too, the Army’s Rheumatism Center at the News of compound E, which Hench same hormone was responsible. Army and Navy General Hospital. renamed cortisone (the naturally Unfounded reports that German occurring compound was later The search for substance X Luftwaffe pilots could fly at high named cortisol), spread quickly. In collaboration with Kendall, a altitudes thanks to injections of The New York Times, among other professor of physiological chemistry adrenal extract persuaded the US newspapers, touted it as a “miracle at the Mayo Clinic, Hench began to government to increase funding cure”, and patients with rheumatoid investigate the possibility that the for adrenal hormone research. After arthritis began bombarding their adrenal glands were the source of the war, Kendall collaborated with doctors to prescribe it. Yet Hench the hormone he called substance X. Lewis Sackett of pharmaceutical himself never claimed it was a Kendall was one of several American company Merck to produce larger perfect solution. He soon became researchers who, throughout the amounts of compound E, and aware that cortisone was not a cure; 1930s, had been studying cortin, an Hench obtained enough of it to use when the treatment was withdrawn, extract of the adrenal cortex which in rheumatoid arthritis studies. the patient always suffered a contains a mixture of hormones that relapse. In a 1950 paper, he wrote have important biological actions. Immediate success that its use should be considered By 1940, the Mayo Clinic, other For his first subject, Hench chose only as an “investigative procedure”. American laboratories, and the 29-year-old Mrs Gardner. For five The adverse side effects he had Basel laboratory where Reichstein years she had suffered from such started to observe also troubled him. worked, had isolated 28 compounds. severe rheumatoid arthritis that she By 1941, Hench and Kendall were was confined to a wheelchair and [Cortisone] is expensive, convinced that one of these – which had been an inpatient at the Mayo and it has potentially they had named compound E – was Clinic for almost two months. Hench dangerous side effects. what they had been searching for. began giving her daily injections The Lancet of compound E in 1948. The effect World War II brought all their was spectacular. Within two days, Editorial, 1955 research to a temporary halt. Hench Mrs Gardner noticed significantly was appointed chief of the Medical reduced joint pain. Within three

GLOBAL HEALTH 239 Corticosteroids, such as cortisone, Current uses of corticosteroids mimic the effects of hormones produced naturally in the adrenal Corticosteroid Treats glands. In the body, naturally occurring cortisol is involved in Betamethasone Severe dermatitis (skin conditions) the conversion of proteins to carbohydrates and also in the Budesonide Asthma, allergic rhinitis, autoimmune hepatitis regulation of salt levels. When used as the anti-inflammatory Dexamethasone Croup, macular oedema, joint and soft tissue inflammation drug cortisone, however, the dose Hydrocortisone Nappy rash, eczema, and other mild inflammatory skin prescribed is much larger than the disorders, severe acute asthma, Addison’s disease, severe amount normally present in the body. inflammatory bowel disease This leads to imbalances that can result in dangerous side effects, Methylprednisolone Joint inflammation, inflammatory and allergic disorders, such as oedema (swelling), high organ transplants, relapse in multiple sclerosis blood pressure, osteoporosis, and psychiatric disorders. These were Prednisolone Chronic obstructive pulmonary disease, severe croup, apparent in Mrs Gardner and other mild to moderate acute asthma, ulcerative colitis, patients with prolonged use of high- Crohn’s disease, systemic lupus, acute leukaemia dose cortisone. Hench subsequently refused to prescribe cortisone to Triamcinolone acetonide Allergic rhinitis, inflammation of joints and soft tissues patients he considered especially susceptible to these side effects. cortisone and other corticosteroids Since the 1950s, the powerful for treating other disorders. In 1950, effects of synthetic corticosteroids The rise of corticosteroids four separate studies had described have transformed many branches The use of cortisone as a treatment the beneficial effects of cortisone of medicine – from rheumatology for rheumatoid arthritis declined for conditions including asthma, to dermatology, gastroenterology, from the late 1950s as medicines eye diseases such as conjunctivitis, ophthalmology, and respiratory with fewer side effects, such as new and connective tissue disorders medicine – and proved effective in non-steroidal anti-inflammatory such as lupus. When treating these treating conditions from hepatitis drugs (NSAIDs) came on the scene. conditions, the side effects of the to psoriasis. They are also helpful However, by this time researchers drugs are less of a consideration during organ transplantation as, by had identified the potential of because the doses required are far suppressing the immune response, lower than those used to treat they reduce the risk of the body rheumatoid arthritis. rejecting the transplant. ■ Philip Hench Born in 1896, Philip Showalter Clinic, where he became Hench grew up in Pittsburgh, professor of medicine in 1947. Pennsylvania. He enlisted in the Hench retired in 1957 and died US Army Medical Corps in 1917 of pneumonia while on holiday and in 1920 received a doctorate in Jamaica in 1965. in medicine from the University of Pittsburgh. In 1923, he joined the Key works Mayo Clinic, and became head of its department of rheumatic 1938 “Effect of spontaneous diseases in 1926. He married jaundice on rheumatoid arthritis” in 1927 and had four children. 1950 “Effects of cortisone acetate and pituitary ACTH Hench was a founding member on rheumatoid arthritis, of the American Rheumatism rheumatic fever and certain Association and its president other conditions” (with in 1940 and 1941. He served in Edward Kendall, Charles senior medical posts during World H. Slocumb et al) War II, then returned to the Mayo

240 ETFHFEEQCUTIETENING LITHIUM AND BIPOLAR DISORDER IN CONTEXT A ustralian psychiatrist John Talking Cade made a breakthrough therapies BEFORE with the drug lithium to 1871 In the US, neurologist treat bipolar disorder in 1949. He Medication Lifestyle William Hammond uses had noticed that autopsies on the lithium “salts” to treat mania. brains of bipolar patients often Bipolar patients may be treated with revealed physical symptoms, such medication, talking therapies such as 1894 Danish psychiatrist as blood clots, and thought there cognitive behavioural therapy, and Frederik Lange proposes could be an organic cause for bipolar lifestyle management techniques such using lithium to treat illness. Cade hypothesized that a as better diet and regular exercise. “melancholic depression”. manic bipolar patient was in a state of intoxication due to an excess of a findings, published in 1949, gained AFTER certain chemical in the body; when little acclaim, yet work with lithium 1963 During trials at Hellingly the patient was melancholic, it was continued and it was adopted as a Hospital in Sussex, UK, doctor caused by a deficit of that chemical. medication for mania in various Ronald Maggs finds lithium European countries from the 1960s. has “value during the acute Guinea pig theory manic illness”. Cade injected urine from bipolar Danish psychiatrist Mogens patients into guinea pigs and found Schou published research in 1970 1970 Mogens Schou publishes the urine from manic patients was showing lithium was effective for an article showing that lithium more lethal for the animals than bipolar disorder. Accepted by the has a preventative effect in urine from non-bipolar patients. US in 1970, lithium is the main bipolar mood disorders. He added lithium (formerly used to bipolar medicine used today. ■ treat gout) to the urine and realized 1970 The US Food and Drug that it made the urine less toxic, Administration approves the and that large doses of lithium made use of lithium to treat acute the guinea pigs passive. Reasoning mania, becoming the 50th it could also pacify bipolar patients, country to do so. Cade gave 10 patients lithium and noted dramatic improvements. His 1995 The advent of “mood stabilizers” provides an See also: Pharmacy 54–59 ■ Humane mental health care 92–93 alternative to lithium. ■ The nervous system 190–95 ■ Chlorpromazine and antipsychotics 241

GLOBAL HEALTH 241 PAEPNSICYCILHLIICN CHLORPROMAZINE AND ANTIPSYCHOTICS IN CONTEXT I n the 1940s, French surgeon by blocking dopamine receptors Henri Laborit suggested the in the brain, which lessened the BEFORE drug company Rhône-Poulenc transmission of messages between 1920 In the US, David Macht, should develop an antihistamine brain cells. This relieved psychotic a pharmacologist, coins the that would have an effect on the symptoms, such as delusions and term “psychopharmacology” central nervous system, claiming hallucinations. Chlorpromazine also to describe drugs with that the sedative effect would be reduced reliance on treatments neuromuscular effects. a useful anaesthetic for patients such as electroshock therapy. before surgery. The drug produced 1949 John Cade discovers in 1950 was chlorpromazine. Despite new antipsychotics that lithium is successful being developed from the 1960s, in treating bipolar patients. Two French psychiatrists at St none has proved as successful as Anne’s Hospital, Paris, Jean Delay chlorpromazine, now recognized AFTER and Pierre Deniker, began using as the world’s first antipsychotic. ■ 1958 Scientists including chlorpromazine in 1952 to treat pharmacologists, psychiatrists, inpatients experiencing mania and I couldn’t believe that and psychologists hold the first schizophrenia. The drug proved psychotic symptoms … conference of the Collegium effective in controlling patients’ Internationale Neuro- agitation or overexcitement. It was could be affected Psychopharmacologicum labelled as a “major tranquillizer”, by a simple pill. (CINP); it reports on research later known as an “antipsychotic”. Heinz Lehmann methodology, therapeutic efficacy and side effects, World’s first antipsychotic Recollections of the History of and clinical needs. After small but highly successful Neuropsychopharmacology, 1994 trials by Canadian psychiatrist 1960s In the US, large-scale Heinz Lehmann, chlorpromazine trials of chlorpromazine are was used in the US from 1954. By conducted and demonstrate the 1960s, it was widely prescribed that antipsychotics are in Europe and North America for effective against a range of patients with schizophrenia and symptoms of schizophrenia. bipolar disorder. The drug worked See also: Pharmacy 54–59 ■ Aspirin 86–87 ■ Lithium and bipolar disorder 240 ■ Behavioural and cognitive therapy 242–43

242 CWHAAYNYGOINUGTHTHINEK BEHAVIOURAL AND COGNITIVE THERAPY IN CONTEXT I n the 1940s, the need for influencers of behaviour and effective, short-term therapies emotion. Pioneering this theory, BEFORE to treat anxiety and depression American psychologist B.F. Skinner 1897 Ivan Pavlov describes among troops returning from World formulated a science of behaviour the principles of a classic War II combined with advances in by 1953 that now underpins much of conditioned response. behavioural research to produce a modern psychotherapeutic practice, new approach to psychological and which led to the development 1913 John Watson outlines a disorders: “behavioural” therapy. of cognitive behavioural therapy. new philosophy of psychology, Supporters of behaviourism rejected which he calls “behaviourism”. Sigmund Freud’s introspective and Conditioning behaviour more subjective psychoanalytical Skinner’s theories were based on 1924 American psychologist approach, which focused on the role the research of earlier behaviourists Mary Cover Jones is dubbed of the unconscious mind. Instead, Russian physiologist Ivan Pavlov and “the mother of behaviour they maintained that measurable American psychologist John Watson. therapy” after her study of external factors, such as events and Pavlov’s experiments with dogs in desensitization involving a environment, were more important the 1890s showed that responses boy called Peter. Behavioural theory Cognitive theory AFTER shows that repeated positive suggests that the way 1955 American psychologist we perceive, interpret, and Albert Ellis launches cognitive or negative responses attribute meaning to events therapy based on confronting to behaviours condition influences our behaviour irrational beliefs. our future actions and emotions. 1962 Australian physician and emotions. Claire Weekes publishes Self Help For Your Nerves, a By modifying our behaviours and changing bestseller on treating anxiety our thought patterns using cognitive behavioural therapy, with CBT. we can regulate our emotions and solve psychological problems. 1967 Aaron Beck publishes his cognitive model to explain depression.

GLOBAL HEALTH 243 See also: Humane mental health care 92–93 ■ Psychoanalysis 178–83 ■ The nervous system 190–95 ■ Lithium and bipolar disorder 240 ■ Chlorpromazine and antipsychotics 241 can be learned, through “classical conditioned responses demonstrated Permanent recovery lies in conditioning”: repeatedly ringing by Skinner could not explain or the patient’s ability to know a bell (an unrelated stimulus) just control all behaviours, and that before presenting food taught the unhelpful or inaccurate thinking how to accept the panic dogs to salivate at the sound of the must also play a role. Identifying until he no longer fears it. bell alone. Watson later suggested and evaluating these negative Claire Weekes, 1977 that conditioning could explain all perceptions or automatic thoughts – human psychology. and then correcting them, so that thoughts, these methods include they reflect reality rather than a mindfulness, visualization, and In 1938, Skinner first theorized distorted or dysfunctional view of acceptance-based therapies. that if all behaviours and emotional reality – formed the basis of Beck’s responses are learned (conditioned), cognitive approach. Although CBT continues to we have the capacity to relearn how evolve, it is still rooted in scientific to behave more appropriately. This Therapists began to combine experiments and clinical case relearning process, which he called behavioural and cognitive theories, studies to obtain measurable “operant conditioning”, involved developing a practice termed results and quantifiable data, as positive or negative reinforcement – “cognitive behavioural therapy” were Skinner’s efforts to develop shaping behaviour by rewarding (CBT). Studying and amending psychotherapy and psychology as a small movements towards a desired visible behaviours, as well as science. His emphasis on the value behaviour and disincentivizing assessing and reprogramming of reinforcement as a means of undesired behaviour. conscious thoughts, gained support effecting behavioural change has as studies repeatedly showed the also had a long-lasting impact. ■ Cognitive revolution efficacy of this combined approach. In the 1960s, interest in how thinking (the process of cognition) A third wave affects emotions and behaviour led Since the 1990s, a third wave of to a re-evaluation of Skinner’s work therapies has emerged, broadening and a second wave of psychological the field of CBT. With a focus on therapies. Cognitive therapists, changing people’s relationship with such as American psychiatrist their thoughts and emotions rather Aaron Beck, maintained that the than changing the content of their B.F. Skinner Born in 1904 in Pennsylvania, box”. This featured levers for US, Burrhus Frederick Skinner rats to pull or pigeons to peck initially planned to become a in order to receive food or water, writer, but became interested in proving that behaviour can be the scientific study of human modified and reinforced by the behaviour after reading about the process Skinner termed “operant research of Ivan Pavlov and John conditioning”. This pioneering Watson. Inspired by their work, he research influenced approaches set out to prove that behaviour is to psychology and education. controlled by the surrounding He died in 1990 from leukaemia. environment, not by subjective mental processes or free will. Key works Between 1948 and 1974, while 1938 The Behavior of Organisms professor of psychology at Harvard 1953 Science and Human University, Skinner conducted Behavior behavioural experiments using 1957 Verbal Behavior inventions such as his “Skinner

244 DDAIINMAGEEWNNOSSIOTNIC ULTRASOUND IN CONTEXT T he first person to apply noninvasive and safer than X-rays, ultrasound technology to which expose the foetus to radiation. BEFORE the field of obstetrics was A device called a transducer sends 1794 Italian priest and British physician Ian Donald at the the ultrasound into the body and scientist Lazzaro Spallanzani University of Glasgow, Scotland. In detects the returning echoes. A discovers that bats use 1956, Donald, helped by engineer computer then converts the echoes echolocation (the detection of Tom Brown and obstetrician John into images. sound waves) to navigate McVicar, built the first successful around objects. ultrasound diagnostic scanner. Diagnostic firsts Ian Donald was not the first medic 1917 French physicist Paul Ultrasound – high-frequency to experiment with ultrasound as a Langevin and colleagues sound waves above the range of diagnostic tool. In 1942, Austrian develop sonar, using ultrasound human hearing – enables doctors to neurologist Karl Dussik and his to detect submarines during obtain key information on the foetus. brother, Friedrich, attempted to World War I. Also called medical sonography, it is locate brain tumours by measuring the transmission of an ultrasound AFTER Any new technique beam through the skull. Other 1975 A medical sonography becomes more attractive pioneers include American George company in the US develops if its clinical usefulness Ludwig, who used ultrasound to the linear array scanner, which detect gallstones in animals in the produces the first clear real- can be demonstrated late 1940s, and British physician time imaging in obstetrics. without harm … John Wild, who developed the first Ian Donald handheld contact scanner with 1986 In Japan, Kazunori Baba the help of electrical engineer uses ultrasound to capture the John Reid in 1951. In 1953, Swedish first 3D image of a foetus. cardiologist Inge Edler and German physicist Hellmuth Hertz performed 2019 Scientists working for the first successful echocardiogram, the iFind project in London, using ultrasound to study the UK, use computer-guided workings of the heart. ■ ultrasound to produce the clearest scan of a foetus See also: Midwifery 76–77 ■ X-rays 176 ■ Electrocardiography 188–89 to date. ■ Electroencephalography 224–25 ■ MRI and medical scanning 278–81

GLOBAL HEALTH 245 CCALEHLLRLOTSMHEHOASDOM47ES CHROMOSOMES AND DOWN SYNDROME IN CONTEXT I n 1958, Marthe Gautier, a Spanish actor Pablo Pineda, star of French researcher in paediatrics the film Yo, también (Me Too), is the BEFORE in Paris, discovered the cause first person with Down syndrome in 1866 British physician John of Down syndrome. Examining Europe to obtain a university degree. Langdon Down describes the slides in a hospital laboratory, she features of the syndrome now found that Down syndrome children chromosome, but trisomy 21, which named after him. had three copies of chromosome 21 causes Down syndrome, is the instead of two. most common, affecting about one 1879 German biologist birth in every 1,000. It results in Walther Flemming discovers Two years before Gautier made distinctive physical characteristics vertebrate chromosomes. her discovery, geneticists at Lund such as a flatter facial profile and University, Sweden, had discovered poor muscle tone, and learning 1956 Sweden’s Albert Levan that most people have 23 pairs of disabilities that range from mild and Joe Hin Tjio from the US chromosomes (46 altogether) in to moderate. Edwards syndrome, discover that humans have almost all of their body cells – one causing heart defects, arises from 46 chromosomes. in each pair inherited from their trisomy 18 and affects about one mother, and the other from their in 6,000 babies. ■ AFTER father. Sperm and egg cells, however, 1999 The Human Genome each have a single set of 23 unpaired Project to map all the genes chromosomes. When an egg is in the human body reveals fertilized by a sperm, it becomes a the first full genetic code of a cell with 23 pairs of chromosomes. chromosome (chromosome 22). Trisomy 2000 Chromosome 21, the one Geneticists now know that the that is associated with Down presence of a third copy or extra syndrome, is sequenced. bit of a chromosome – a condition called trisomy – can arise during 2013 Researchers in the US meiosis, the production of sperm find that the characteristics and egg cells in the reproductive of Down syndrome may organs. Trisomy can occur in any be linked to low levels of a particular protein in brain cells. See also: Inheritance and hereditary conditions 146–47 ■ Genetics and medicine 288–93 ■ The Human Genome Project 299 ■ Gene therapy 300

LIFEDEATH BECOMES TRANSPLANT SURGERY



248 TRANSPLANT SURGERY IN CONTEXT T ransplant surgery – the moved a kidney from the dog’s replacement of damaged abdomen up to its neck and BEFORE or failing body parts with reconnected it using brass tubes. 1668 The first successful bone healthy ones – is one of modern Young French surgeon Alexis Carrel graft is performed by Job van medicine’s most astonishing feats. performed similar operations, and Meekeren in the Netherlands. A successful kidney transplant in even transplanted the heart of a 1954 led the way, and just 13 years dog to its neck. 1838 In the US, Richard later the world’s first human heart Kissam transplants the cornea transplant was hailed as the Carrel’s experiments also led of a pig into a young man, who pinnacle of transplant surgery. him to invent the micro-sewing temporarily regains his sight. Since then, hundreds of thousands techniques that were later used to of lives have been saved by heart, reattach severed blood vessels in AFTER kidney, lung, and liver transplants. human transplant operations. In 1979 Spain passes legislation While transplants are still major 1894, Carrel had witnessed the establishing presumed consent medical procedures for the patients, stabbing of French president Sadi for organ donation after death; many surgeons now consider such Carnot and was appalled that it is the first country to have an operations routine. surgeons were unable to save the “opt-out” system. president simply because they had Early experiments no way to repair a damaged vein. 1998 French surgeon Jean- Surgeons did not entertain the Determined to avoid such tragedies Michel Dubernard performs possibility of organ transplantation in future, Carrel spent months the first hand transplant. until the discovery of general learning how to sew with tiny anaesthesia in the mid-19th century. needles from Madame Leroidier, 2002 In the US, cloned pigs This allowed surgeons to operate the finest embroiderer in Lyons. are specially bred for research inside the body without causing “Carrel’s suture” is still used in into animal-to-human organ the patient unbearable pain or transplant operations today. transplants. The pigs are sending their muscles into spasm. genetically engineered to Success and failure reduce the chances of rejection. At the beginning of the 20th In 1905, Austrian eye surgeon century, surgeons began to practise Eduard Zirm performed a 2008 French surgeon Laurent transplant surgery on animals. In successful corneal transplant on Lantieri claims to have carried 1902, Hungarian surgeon Emerich Czech farmworker Alois Glogar, out the first full face transplant. Ullmann performed the world’s first who had been blinded in an kidney transplant on a dog when he accident while working with lime. Carrel’s suture is a simple but ingenious way of joining the blood vessels of a new organ to those of its host. In 1912, Carrel was awarded the Nobel Prize in Physiology or Medicine for his method of suturing blood vessels. The ends of the blood vessels are By gently pulling the stitches The straight edges are then easily stitched brought into contact. They are united outwards, the circumference of together without the need for forceps to hold by three stitches at equidistant points the blood vessel is transformed the tissue in place, thus avoiding the risk of around the circumference of the vessels. into a triangle. tearing or bruising.

GLOBAL HEALTH 249 See also: Blood transfusion and blood groups 108–11 ■ Anaesthesia 112–17 ■ Skin grafts 137 ■ The immune system 154–61 ■ Electrocardiography 188–89 ■ Dialysis 234–35 ■ Regenerative medicine 314 ■ Face transplants 315 It’s the gift of life itself. Dick Cheney 46th US vice president (2001–09), on his heart transplant Zirm used corneas from an 11-year- antibodies against infection, so In 1935, Alexis Carrel (right) joined old boy. The effects of the operation it produces antibodies against forces with American aviator Charles lasted. Glogar was back at work transplants. The body appears to Lindbergh (left) to design a perfusion within three months of the surgery accept the transplant at first, but it pump – a precursor to the heart–lung and retained his sight for the rest slowly builds antibodies against machine used in open-heart surgery. of his life. the invader, and within a few weeks the body’s immune system Organ transplants had little chance Carrel and other surgeons begins to attack it. of success while rejection was such began to believe that a human a major problem. Yet surgeons were organ transplant was just a matter Medawar then found that skin desperate to save lives, and clung of time. Yet whenever attempts grafts between identical twins on to the hope that if closely related were made to transplant organs were not rejected. Nor were grafts donors could be found, the same between dogs, the dog receiving between cows, which are closely immunological tolerance would the organ died within weeks, even interbred and have the same help the patient survive. ❯❯ if the operation had initially immunological tolerance as twins. seemed successful. By the 1940s, many surgeons had the surgical skills to perform organ transplants on humans, but any attempt always ended in the death of the patient. New insight Research into skin transplants during World War II helped throw light on the problem. During the war, many bomber pilots suffered horrific burns, but skin grafts from donors were never successful. To find out why, British biologist Peter Medawar conducted experiments on rabbits. He found that bodies actively reject a “foreign” piece of skin. Just as the body develops

250 TRANSPLANT SURGERY Kidney transplants seem so routine now. Most early transplants failed even after a successful operation. But the first one was like Lindbergh’s This is because the patient’s immune system flight across the ocean. rejected foreign tissue. Joseph Murray The New York Times, 1990 One solution was to Another solution kidney was rejected. Only the find a better-matched was to suppress the transplants between identical donor by tissue typing, immune system with twins were successful. Doctors but many patients died X-rays, but this left patients were desperate to find a solution. waiting for a donor. fatally vulnerable to infection. The immunosuppressant drug cyclosporine Overcoming rejection proved to be a safer way of reducing To reduce the chances of organ the risk of organ rejection. rejection, transplant surgeons tried bombarding the patient with Meanwhile, in 1945, Dutch inventor the operation initially seemed to be X-rays to suppress the body’s and physician Willem Kolff pioneered successful. In less than a fortnight, immune system. However, this the dialysis machine, a mechanical however, the kidney was rejected weakened the body’s defences filter that took over from damaged and the boy died. so much that even the mildest kidneys for a short period of time, infection made the patient very ill. giving the kidneys the chance to Two years later at a hospital in American blood specialist William recover. Physicians began to wonder Boston, in the US, Joseph Murray Dameshek proposed using the if dialysis could help a patient made the world’s first successful anti-cancer drug 6-mp, which stops survive during a kidney transplant. organ transplant when he took a cancer cells from multiplying by kidney from Ronald Herrick and interfering with their chemistry. In 1952, at a hospital in Paris, gave it to his identical twin brother He hoped that the drug would slow French surgeon Jean Hamburger Richard. Richard survived for eight the proliferation of the immune transplanted a mother’s kidney to years, during which he married and system’s white blood cells, which her son, whose single kidney had had children. He died from heart recognize foreign tissue, and been damaged in a fall, and used failure, with the donated kidney therefore reduce the chances of a dialysis machine to keep the boy still working. organ rejection. alive during the operation. The donor could not have been more Inspired by Murray’s success, In the early 1960s, British doctor closely related to the recipient other surgeons tried their hand Roy Calne tried the idea out on (aside from identical twins), and at kidney transplants. Yet nearly dogs. After performing kidney every patient died, as the new transplants on the animals, he gave them azathioprine, a similar drug to 6-mp. Azathioprine worked so well with a dog called Lollipop that Calne made the decision to