The Medicine Book

CELLS AND MICROBES 151 1861–65 By the time Lister retired from surgery in 1893, his contributions 1865–69 to safe surgical practice were universally accepted. Among the 45% scientists researching ever safer ways of controlling infection was 15% German bacteriologist Robert Koch. Asepsis, Koch’s system of keeping When Joseph Lister took charge of the new Male Accident a surgical environment free of germs Ward at the Glasgow Royal Infirmary in Scotland, almost half through heat, antiseptics, and soap of all patients were dying from post-operative infection. After and water, was a natural evolutionary Lister introduced his antisepsis method, the mortality rate on advance on the antisepsis methods the ward dropped to 15 per cent. pioneered by Lister. remained unconvinced that Lister’s the attention of colleagues by wiring Koch demonstrated that dry antisepsis system – antiseptic a patient’s fractured kneecap. First, heat and steam sterilization were sprays and washes as barriers to he turned the single fracture into a just as effective as antiseptics at infection – constituted any kind of compound one, greatly increasing killing germs. Expanding this advance. The spray hurt surgeons’ the risk of infection and death. theory further, German physician eyes and could damage healthy By using his antisepsis techniques, Gustav Neuber introduced sterile tissue as well as infected tissue. however, Lister was able to treat gowns, rubber gloves, and face the wound, and the patient masks to surgery. Easy-to-disinfect In 1869, Lister succeeded his recovered. Few could now dispute floors and walls in operating rooms friend James Syme as professor of that these antiseptic methods were to follow. Edinburgh University’s clinical provided anything but life-saving surgery, where he continued his value to surgical procedures. These practices remain the key work on germ theory. His ideas tenets of safe surgical procedure brought acclaim on a lecture tour Royal approval today, with the sterilization of of German surgical centres in 1875, In 1871, Lister further enhanced instruments and the operating but were met with strong criticism his reputation by lancing a large environment in general being of in the US the following year. abscess in Queen Victoria’s armpit. paramount importance. The theory During the procedure, carbolic acid behind them stems directly from Undeterred, Lister continued to was accidentally sprayed into the Lister’s findings in the 1860s – that publish his findings in articles for queen’s eyes. Lister had introduced germs must not gain entry to any the British Medical Journal and The the use of a carbolic steam spray wound during an operation. ■ Lancet. But he was not a naturally after theorizing that the air around gifted writer, and his refusal to an operating table might also print statistics did not endear him contain germs. Luckily, the queen to his readers or peers. For many in suffered no lasting effect and Lister the medical profession, Edinburgh later abandoned this practice. was considered a second-rate centre of surgical expertise when compared Lister’s operation on Queen Victoria with London. Lister would have to might have had a very different outcome prove himself in the capital. without the use of antiseptic to prevent infection. His success won him the role Lister’s chance came in 1877 of personal surgeon to the queen in 1878. when he became professor of clinical surgery at London’s King’s College Hospital. Here, he captured

152 POTHHFEEVNIFTOIAEMLLEDNA PHYSIOLOGY IN CONTEXT P hysiology is the study of the experiments, yet the scientific functions of an organism, as approach to medicine was slow to BEFORE opposed to the study of its evolve. It was dramatically bolstered 1540s French physician structure (anatomy). An approach by cell theory, the principle that all Jean Fernel coins the term to medicine first advocated in the organisms are composed of units “physiology” for studying mid-19th century by a number of called cells, formulated by German the body’s functions. German physicians and French botanist Matthias Schleiden and physician Claude Bernard, it takes physician Theodor Schwann in 1543 Andreas Vesalius account of the biological systems of 1838–39. This paved the way for publishes De Humani Corporis organisms at cellular, tissue, and Johannes Müller, Justus von Liebig, Fabrica (On the Structure of the whole-body levels. and Carl Ludwig to put physiology Human Body), revolutionizing on a sound experimental footing. the way medicine is taught. A scientific approach Physiology arguably began in 1628 Justus von Liebig’s laboratory at 1628 William Harvey publishes when William Harvey published his the University of Giessen, Germany, was De Motu Cordis et Sanguinis findings on the circulation of the one of the first purpose-built laboratories (On the Motion of the Heart blood, deduced from meticulous designed for teaching and research. and Blood), transforming the scientific outlook on the human body. AFTER 1891 Russian physiologist Ivan Pavlov begins his research into conditional responses, training dogs to salivate at the sound of a bell. 1926 Walter B. Cannon coins the term “homeostasis” for an organism’s propensity to maintain stability.

CELLS AND MICROBES 153 See also: Anatomy 60–63 ■ Blood circulation 68–73 ■ Histology 122–23 ■ Cellular pathology 134–35 ■ Diabetes and its treatment 210–13 Anatomical knowledge – knowledge of the body’s structure – is not enough to treat disease. Physicians must also understand physiology – Claude Bernard the body’s chemical, physical, and mechanical processes The son of a winegrower, that work together to sustain life. Bernard was born in 1813 in Saint-Julien, a village in the A scientific understanding of such systems is gained Rhône department of eastern through physiological experiments. France. On leaving school, he became a pharmacist’s Müller was particularly interested has no effect on the sensory nerves. apprentice and later enrolled in the effect of stimuli on the sense He also performed groundbreaking at the Faculty of Medicine in organs and provided insights into work on the role of the pancreas in Paris, graduating in 1843. the nerve pathways of reflex actions. digestion and the function of the Two years later, he entered Liebig and Ludwig made precise liver as a store for glycogen, a a marriage of convenience measurements of functions such as starchy substance that can be with Marie Martin. Her dowry respiration and blood pressure and broken down into glucose (sugar) helped finance his scientific carried out chemical analyses of if the body requires energy. experiments, though she left body fluids. him after he vivisected the One of Bernard’s most important family dog. Experimental medicine insights was his concept of a milieu Claude Bernard was one of the intérieur (internal environment), In 1847, Bernard was founders of experimental medicine. which describes the self-regulating appointed deputy to François He viewed test-tube experiments mechanisms that keep the internal Magendie at the Collège de as being too limited, and thought environment of an organism in France, in Paris, succeeding vivisection (or animated anatomy, equilibrium when the external him as full professor in 1855. as it was then called) was the only environment is constantly changing. In 1868, Bernard became way to understand the complexities Developed in 1865, it describes the professor of general physiology of organisms. relationship between cells and their at the Museum of Natural environment as being fundamental History of the Jardin des Bernard studied the effects of to the understanding of physiology. Plantes and was admitted as poisons such as carbon monoxide It is the underlying principle of a member of the Académie and curare on the body. He showed what would be called homeostasis Française the same year. He how carbon monoxide combined by American physiologist Walter B. died in Paris in 1878. with haemoglobin in the blood Cannon in the 1920s. A small part causes oxygen starvation, and that of the lower front brain called the Key works curare attacks the motor nerves, hypothalamus plays a key role in causing paralysis and death, but maintaining homeostasis. ■ 1865 An Introduction to the Study of Experimental Medicine 1878 Lectures on the phenomena of Life Common to Animals and Plants

DAEGFAEINNSCTE INTRUDERS THE IMMUNE SYSTEM



156 THE IMMUNE SYSTEM IN CONTEXT There is at bottom only one No one knew how immunity worked, genuinely scientific treatment but it seemed real enough for many BEFORE physicians to try inoculation – c. 900 ce Al-Razi theorizes for all diseases injecting diseased material into about how the body might and that is to stimulate patients to stimulate immunity. become immune to smallpox. British doctor Edward Jenner’s the phagocytes. breakthrough with vaccination in 1546 Girolamo Fracastoro George Bernard Shaw 1796 put the issue of immunity – to suggests that the body gains smallpox at least – beyond doubt. immunity to smallpox through from Act I of his play The Doctor’s purification of the blood. Dilemma, 1906 Vaccination quickly spread, saving many lives, but it was still 1796 Edward Jenner’s class of proteins called antibodies. not clear how it worked. Nor could vaccination gives people First, there is the non-specific physicians work out whether the immunity to smallpox. “innate” system, on hand all the fever and inflammation that often time to provide an immediate followed infection damaged the 1861 Louis Pasteur publishes defence against germs and other body like a destructive fire, as his germ theory, in which foreign bodies. Then there is the some believed, or whether they he argues that bacteria specific “adaptive” (or acquired) were part of the body’s defences. cause disease. system, which ramps up specifically to tackle a new threat, and retains Germs and cells AFTER a memory of it to provide future Part of the problem was that no one 2016 US-based researchers immunity against that threat. even knew what caused disease. Matthew Halpert and Vanaja Adaptive immunity is something That changed in the 1870s when Konduri pin down the role of only vertebrate animals have. Louis Pasteur and Robert Koch dendritic cells in working with found that tiny microbes, or germs, T-helper cells. Once bitten, twice shy are the culprits. Yet Pasteur and Physicians knew of old that people Koch believed the body is ultimately 2018 American and Japanese rarely catch smallpox twice. After defenceless against them. Then, in immunologists James P. Allison one bout, they seemed immune to 1882, Élie Metchnikoff, a Russian and Tasuku Honjo receive the reinfection. Some believed it was physician living in Sicily, heard that Nobel Prize for their discovery God protecting the righteous, but Koch had discovered the bacteria of cancer therapy by inhibiting there were scientific ideas, too. In that caused tuberculosis (TB). negative immune regulation. the 9th century, Persian physician al-Razi suggested that smallpox Metchnikoff wondered why his D octors have long believed pustules expel all the excess body wife had contracted TB while he that the body has a way moisture the disease would need to seemed immune. He knew that of protecting itself against thrive a second time. In the 16th disease. This protection came to century, Italian doctor Girolamo The physician be called immunity, but its nature Fracastoro suggested that smallpox of the future remained a mystery. Since the was the final purification of toxic will be an immunizator. 1880s, medical scientists such as menstrual blood from birth, and Almroth Wright Élie Metchnikoff, Paul Ehrlich, and thought this might be why it Frank Macfarlane Burnet have seemed to attack children most. Inaugural address at St Mary’s gradually uncovered the immune Hospital, London, 1905 system, a defence system of almost miraculous complexity. The immune system defends the body in two main ways, using white blood cells (leucocytes) and a

CELLS AND MICROBES 157 See also: Roman medicine 38–43 ■ Islamic medicine 44–49 ■ Vaccination 94–101 ■ Germ theory 138–45 ■ Targeted drug delivery 198–99 ■ Transplant surgery 246–53 ■ Lymphocytes and lymphatics 256–57 ■ Monoclonal antibodies 282–83 Élie Metchnikoff made these drawings of phagocytosis, the process in which a type of white blood cell called a phagocyte changes shape to engulf and destroy a pathogen. white blood cells gather at infection of infection. He also distinguished or “humours”. The battle line was sites. Indeed, microorganisms were between larger phagocytes, called drawn between the humoral camp sometimes seen inside white blood macrophages, and smaller ones – in Germany and the cellular cells. The prevailing theory was microphages, now called neutrophils. camp in France, where Metchnikoff that white blood cells spread disease was now working at the Pasteur around the body, but Metchnikoff Battle of beliefs Institute in Paris. wondered whether the massing Although Metchnikoff received white blood cells were a sign of the the Nobel Prize in Physiology or For a while, the German camp body defending itself. Medicine in 1908, his ideas met made most progress. In 1890, Emil with scepticism at first. He became von Behring, aided by Japanese To test his idea, Metchnikoff caught in a war between scientists researcher Shibasaburo Kitasato, pricked starfish larvae with rose who took up his idea of cellular reported that serum (blood fluid) thorns. Under a microscope, he saw immunity involving phagocytes, and from animals infected with tetanus white blood cells gathering around those who insisted immunity is or diphtheria contains chemicals, or the thorn. He quickly developed the humoral (provided by molecules in “antitoxins”, that work against toxins theory that certain white blood cells body fluids). The word “humoral” released by bacteria. They also found attack, engulf, and destroy germs. came from the ancient idea that that these antitoxins could be used He called these cells “phagocytes”, illness stemmed from an imbalance to immunize, or even cure, another from the Greek for “eating cells”. in four different kinds of body fluid, animal. Behring’s work reinforced These white blood cells, he argued, the idea that just as the causes of were not spreading germs at all, Emil von Behring found that serum disease are specific, so are the body’s but fighting the infection. from infected animals such as horses defences. He went on to play a major contained antitoxins. The diphtheria role in the development of vaccines. Metchnikoff went on to suggest antitoxin was used to protect humans that inflammation was part of the until a vaccine was created in the 1920s. Meanwhile, another German, body’s innate immune system, Paul Ehrlich, was teasing out drawing phagocytes to the site the importance of antigens and antibodies. Antigens are any ❯❯

158 THE IMMUNE SYSTEM substance that provokes an immune Ehrlich suggested developing new also described the “complement” response in the body. (These were kinds of drugs that mimicked system – so-called because it works later found to include cancer cells antibodies – “magic bullets” that alongside the antibody system. and foreign tissue as well as germs.) could hunt down and destroy When this is activated – for Antibodies, or immunoglobulins, particular pathogens (disease- example, by a pathogen – a cascade are proteins that can inactivate or causing microbes). This led to the of proteins is released (mainly from weaken germs, and each one is creation of Salvarsan, the first drug the liver) into the bloodstream and matched to a particular antigen. effective against syphilis. Even fluids around cells. These proteins more importantly, Ehrlich’s theory cause invading cells to burst (lysis) Key to the puzzle showed how inoculation protects and encourage phagocytes to ingest In 1900, Ehrlich refined his “side- the body, by triggering a surge of them, as well as stimulating the chain” theory, which describes how unique antibodies against the inflammation that draws infection- antigens and antibodies interact disease. This launched the ongoing fighting white blood cells in. like lock and key. Antibodies form search for new vaccines, which receptors called side-chains on the have become the key life-saving It had been assumed that there surface of white blood cells. When weapon against infectious diseases. was a neat division in immunity, an antigen locks on to its matching with cells providing the crude side-chain, the cell releases floods Building on the work of fellow innate first defence while the clever of antibodies, which then lock on German Hans Buchner and Belgian adaptive immunity targeted at to the toxin and neutralize it. scientist Jules Bordet (based at the specific germs was chemical or Pasteur Institute in France), Ehrlich “humoral”. Yet the complement The human immune system has two levels of immunity – innate (non-specific) and adaptive (specific) immunity – which act together to protect the body. The innate immune system The adaptive immune system acts rapidly to defend against acts more slowly, using white blood invading organisms that penetrate the body’s outer barriers – for instance, cells called lymphocytes that target specific organisms. through a cut in the skin. All invaders are treated in the B-lymphocytes, or B-cells, have same way: white blood cells called antibodies on their surface that phagocytes and natural killer cells, match specific antigens on or NK cells, destroy them. the surface of pathogens. When a B-cell meets its matching antigen, it multiplies rapidly. The resulting B-cell clones release a flood of antibodies that lock on to the antigens, enabling phagocytes and NK cells from the innate immune system to identify and attack them.

CELLS AND MICROBES 159 The white blood cells (orange) in this illustration are in attack mode, secreting antibodies (white) that bind to the invading antigens (blue), weakening them or marking them for destruction. system was not only untargeted and innate but humoral too, so there was no such neat division. Over the next few decades, British scientist Almroth Wright cast further doubt on the cellular- humoral division. Some bacteria can naturally evade phagocytosis, but Wright showed that antibodies help phagocytes to identify them. Self-defence Burnet went on to lay out how the swallow invaders indiscriminately, The great breakthrough came in body learns to identify foreigners. the body is armed with an array of the 1940s and 1950s, when failures If a foreign substance is introduced white blood cells that can identify with transplant surgery led to the into the embryo early on, its antigens and target, called lymphocytes. discovery that the immune system are accepted by the body as “self”, does not just fight germs; it also and no antibodies against it are Clonal selection helps the body to recognize cells produced later in life. In this way, In 1957, Burnet introduced his that are foreign. Every body cell has the body actively identifies its own groundbreaking “clonal selection” its own personal identity marker, or but attacks invaders (“non-self”). theory. This involved an array of HLA (human leucocyte antigen). lymphocytes now known as B-cells, British scientist Peter Medawar Burnet and others began to because they were first discovered and Australian scientist Frank draw the picture of the immune in the bursa organ in birds. Each Macfarlane Burnet realized that the system together, returning cells, B-cell, Burnet suggested, is primed immune system identifies foreign not humoral chemistry, to centre to identify the antigen of a particular cells and fights them. This was why stage. They discovered that invader. Whenever a B-cell meets ❯❯ transplants were being rejected. besides the phagocytes, which Frank Macfarlane Born in Traralgon, Australia, in awarded the Nobel Prize in Burnet 1899, Frank Macfarlane Burnet 1960, and his clonal selection took an interest in biology from theory. Later in life, he lectured a young age, collecting beetles. and wrote extensively about After graduating with a medical human biology, ageing, and degree from the University of cancer. He died in 1985. Melbourne, he studied in London, UK, then returned to Melbourne Key works to work in medical research. 1940 Biological Aspects Although his experiments of Infectious Disease on viruses that attack bacteria 1949 The Production of and animals, especially influenza, Antibodies (with Frank Fenner) led to major discoveries, Burnet is 1959 The Clonal Selection best known for his achievements Theory of Acquired Immunity in immunology – in particular, his 1969 Cellular Immunology theory of acquired immunological tolerance, for which he was

160 THE IMMUNE SYSTEM its corresponding antigen, it clones It will be obvious “monoclonal antibodies”, which itself, multiplying rapidly. As the that this attempt at (like Ehrlich’s magic bullets) could B-cell clones multiply, they release a comprehensive discussion be used to target specific antigens, a flow of antibodies. These latch on of antibody production or test for the presence of them. to the invaders so that the body’s is hampered in all directions innate defences – including by lack of knowledge. Despite these advances, it was phagocytes and another type of still unclear how the body can lymphocyte called “natural killer” Frank create such a mindblowing variety (NK) cells – can recognize and Macfarlane Burnet of antibodies, vastly outnumbering attack them. In 1958, Austrian- the genes that produce them. In Australian immunologist Gustav The Production of Antibodies, 1949 1976, Japanese scientist Susumu Nossal and American biologist Tonegawa showed how this is done Joshua Lederberg proved Burnet away from bone marrow to mature by the shuffling of genes within right, showing that each B-cell only in the thymus gland just above the a cell when it is developing into produces one kind of antibody. heart. It was later discovered that an antibody-producing B-cell. these thymus-maturing cells, or Filling in the gaps T-cells, play a crucial role in fighting Helpers and killers In 1959, British immunologist viruses, which evade B-cells. By the early 1980s, researchers James Gowans discovered that knew a great deal more about how lymphocytes can migrate around Meanwhile, back in 1959, two B-cells and T-cells collaborate to the body, and that they circulate chemists, Rodney Porter in the UK provide adaptive immunity. In through both the blood and the and Gerald Edelman in the US, essence, there are two responses. lymph system. The lymph system discovered the Y-shaped molecular is the body’s drain, carrying away structure of antibodies. In 1975, Humoral immunity targets toxins and the debris from the first German immunologist Georges pathogens that circulate freely in scuffles between phagocytes and Köhler and Argentine César Milstein the body, such as bacteria, mainly germs. The system also includes described a technique for producing using floods of antibodies. The hundreds of lymph nodes, where sequence starts with T-cells called clusters of lymphocytes check for “helpers”. There is a T-helper (Th) antigens “presented” by passing for each antigen. When a Th meets phagocytes and other kinds of cells. its match, it locks on and multiplies, triggering B-cells with matching The same year, French-born antibodies to multiply and split scientist Jacques Miller found that into plasma cells and memory cells. one group of lymphocytes migrated Plasma cells pump out a stream of antibodies, which bind to the germ Stings from insects such as bees Hypersensitivity people ingest nuts, for example, and wasps can cause a severe their innate immune system anaphylactic reaction in a small Sometimes, the immune system goes into overdrive, giving them number of people. overreacts, with damaging symptoms such as shortness of consequences. As early as 1902, breath and low blood pressure. French clinician Charles Richet Anaphylaxis can be fatal within showed that “hypersensitivity” – just a few minutes, so people an overproduction of antibodies with severe allergies carry an in response to an antigen – could adrenaline auto-injector at all be harmful, leading to excessive times. Adrenaline is a hormone inflammation, or worse. Allergies produced in response to stress, are one reaction of this kind. and it reverses the effects of anaphylaxis. Antihistamines Several years later, Richet or steroids that suppress the identified “anaphylaxis” – an immune system are also used allergic reaction so extreme it can to treat allergies. be life-threatening. When some

CELLS AND MICROBES 161 B-cell Immune responses Antigen- macrophages (large phagocytes) binds to presenting cell and dendritic cells (tiny immune matching Freely circulating cells in the skin and linings of the antigen antigens Th-cell airways and guts), have special Cytokines receptors that enable them to B-cell is detect molecular patterns produced activated by pathogens. These toll-like by Th-cell receptors (TLRs) can distinguish between “pathogen-associated Macrophage molecular patterns” (PAMPs), is activated which signify disease-bringers, and “damage-associated molecular Plasma B- and T-memory Cytotoxic patterns” (DAMPs), which are found cells release cells store details (cell-killing) on damaged or dying host cells. antibodies. about past threats, T-cell locks on Macrophages and dendritic giving longer-term Infected cell cells then “present” antigens to Antibodies bind to the is destroyed Th-cells – thus linking the innate invading antigens, immunity. and adaptive immune systems. inactivating them. Prevention and cure In humoral immunity, antigen- Cell-mediated immunity targets Since Metchnikoff’s discovery of specific antibodies are produced to germs within cells, such as viruses. A phagocytes, scientists have made destroy extracellular pathogens. A Th-cell is exposed to an antigen on the vast progress in understanding B-cell binds to its matching antigen, surface of an infected cell. Cytokines the immune system. Immunologists aided by a T-helper (Th) cell. The B-cell are then released, activating cytotoxic have revealed an incredibly complex then multiplies rapidly, producing T-cells, which (along with macrophages) interlocking system of cells and plasma cells and memory cells. destroy infected cells. proteins that work together to fight disease. There still remains a great and neutralize it, make it burst, or cell with chemicals to kill it, virus deal to discover, but what has been make it a target for phagocytes. and all. Occasionally, the T-helpers learned so far has revealed the Memory cells store information were found to overreact and produce way in which the body defends about the germ, so the body can uncontrolled floods of cytokines. itself against myriads of germs. It react quickly to repeat infections. These “cytokine storms” cause has also provided a whole new such severe inflammation that it range of possibilities for both Cell-mediated immunity, on the can be fatal. They are a disturbing prevention, through more precise other hand, is directed against complication in viral epidemics vaccination and other methods, pathogens such as viruses that such as the COVID-19 pandemic. and also cure, through drugs that invade and take over cells. This work in tandem with the body’s is where T-cells come into their Linking the systems own defences. ■ own. When a virus invades a cell, In 1989, American immunologist it leaves tell-tale antigens on the Charles Janeway brought attention outside. When Th-cells find these back to the innate system with his antigens, they release signalling theory that certain cells, such as proteins called cytokines. In turn, the cytokines activate cytotoxic After detecting an invading virus, (cell-killing) T-cells, which bind a T-helper cell (centre) releases cytokines to an infected cell’s identity tag (bottom; top left). These are interleukins, (called the major histocompatibility part of a family of cytokines that also complex or MHC). Once locked on, includes interferons and chemokines. cytotoxic T-cells flood the infected

162 IMASOSASILNQLGULIITTEOTABKITEES MALARIA IN CONTEXT T he causes of malaria and the body through the mouth and other insect-borne diseases nose, causing disease. The idea BEFORE were a mystery in the had little support until 1717, when 2nd century ce Miasmas ancient world. For centuries, most Lancisi published De Noxiis (poisonous vapours) are “the people thought that “miasmas” – Paludum Effluviis (On the Noxious seeds of pestilence”, according noxious vapours in the air – were Effluvia of Marshes). Like Varro, to the Roman physician Galen. to blame. The word malaria reflects Lancisi thought that tiny organisms this belief, as it stems from the old might cause malaria. He suggested 1670s Antonie van Italian term mal’aria (bad air). In that mosquitoes transmitted them Leeuwenhoek reveals the Europe, miasmas were associated to humans via the small incisions existence of microorganisms. with the air circulating over fetid made when they bite. Although his swamps and marshes, where local theory was correct, Lancisi was AFTER people were frequently infected. unable to test and prove his ideas. 1940s Chloroquine is used to treat all types of malaria but, In the 18th century, Italian By the mid-19th century, the from the 1950s onwards, many clinician Giovanni Maria Lancisi germ theory of disease was taking strains of the disease develop proposed that insects might be hold. Louis Pasteur in France and resistance to the drug. involved in the transmission of Joseph Lister in Britain had both malaria. Finally, in the 1880s, demonstrated that infection is 1955 The WHO launches its French physician Alphonse Laveran caused by living organisms. first Global Malaria Eradication identified the specific organism Program, which runs until 1969; responsible for malaria, carried campaigners Bill and Melinda by mosquitoes. Gates renew the fight in 2007. The mosquito vector 1980s Scientists report the As early as 30 bce, Roman scholar first significant resistance Marcus Terentius Varro suggested to the highly effective that, in marshy areas, minuscule antimalarial drug quinine. creatures floating in the air entered 2015 In the US, scientists Laveran’s drawing of the life stages create genetically modified of malaria parasites (from the lowest mosquitoes incapable of row upwards, as they develop in blood) spreading the malaria parasite. appeared in 1881 in the bulletin of the Société Médicale des Hôpitaux de Paris.

CELLS AND MICROBES 163 See also: Greek medicine 28–29 ■ Roman medicine 38–43 ■ Germ theory 138–45 ■ Antibiotics 216–23 ■ Global eradication of disease 286–87 First First Infected Infected infected person liver red blood mosquito infected cells cells In the vicious cycle of malaria Second Second Alphonse Laveran transmission, an infected mosquito person mosquito bites a victim, passing on the infected infected Born in Paris in 1845, Charles malaria parasite. If an uninfected Louis Alphonse Laveran insect bites the victim, the victim’s studied medicine and became blood can infect the insect, whose a military physician, serving bites further transmit the disease. as a surgeon during the Franco-Prussian war of 1870. In 1880, Laveran was examining a Scientists now know that females of Ten years later, while working blood specimen from a malaria 30 to 40 Anopheles species can carry at the military hospital in patient in Algeria, using a powerful the Plasmodium parasite. As the Constantine, Algeria, he microscope, when he noticed female bites to get blood to nurture identified the malaria parasite. crescent-shaped bodies moving her eggs, the parasite enters the energetically beside the red blood victim’s blood, then infects the liver Between 1884 and 1894 cells. He realized he had found the and red blood cells. Uninfected he was professor of military parasite that caused malaria and mosquitoes that then bite the victim hygiene at the Val-de-Grâce identified the bodies as protozoa, become Plasmodium carriers (vectors) military hospital in Paris, and rather than bacteria (which are and continue the spread of malaria. later worked at the Institut smaller and, unlike protozoa, have Pasteur. He became a fellow no nucleus). When Laveran failed to Quest for an antidote of the Académie des Sciences, find the parasite in the air, water, Malaria and other mosquito-borne was awarded the Légion and soil of marshland, he began to diseases (such as the Zika, dengue, d’honneur, and was elected suspect it was carried in the body of yellow fever, and West Nile viruses) a fellow of the Royal Society. mosquitoes, which he proposed in remained deadly throughout the In 1907, he received the Nobel his 1884 “Treatise on Marsh Fevers”. 20th century and still cause more Prize in Physiology or Medicine than a million deaths a year. There for his discoveries of parasitic Scientists who believed that a are now effective vaccines for a protozoans as agents of bacterium caused malaria were few mosquito-borne diseases, and infectious disease. He died sceptical of Laveran’s new idea, so research is ongoing to develop more. in 1922 after a brief illness. Laveran invited Pasteur to examine The World Mosquito Program is the organism; Pasteur was instantly breeding mosquitoes to carry the Key works convinced. In 1885, Italian zoologists harmless bacteria Wolbachia, which Ettore Marchiafava and Angelo affects the ability of some mosquito- 1875 Treatise on diseases and Celli classified the parasite in a borne viruses to reproduce and epidemics of the armed forces new Plasmodium genus. Finally, in so reduces their transmission by 1881 Parasitic nature of 1897, British physician Ronald Ross mosquitoes. However, the quest malaria accidents demonstrated the presence of the for a similar means to combat 1884 “Treatise on Marsh parasite in the stomach of an malaria continues. ■ Fevers” Anopheles species mosquito.

SAVAENRCTUCIBMINISOE 1890–1945

STAINCDS

166 INTRODUCTION Emil von Behring and Austrian neurologist Dutch physiologist Alois Alzheimer, a Shibasaburo Kitasato Sigmund Freud pioneers Willem Einthoven German psychiatrist, find that antitoxins identifies a leading produced by the body psychoanalysis, a develops the therapy that helps electrocardiograph cause of early- in response to a patients to reveal and to record the pattern onset dementia: pathogen can be used process repressed Alzheimer’s disease. to prevent disease. of a heartbeat. experiences. 1890 1896 1903 1906 1895 1898 1904 1910 When he publishes Dutch scientist Martinus Charles Scott Salvarsan, the an X-ray image of his Beijerinck uses the word Sherrington, a British first synthetic “virus” to describe the chemotherapeutic wife’s hand, clearly neurophysiologist, agent, is created by showing the bones, agent – far smaller unveils his integrated Paul Ehrlich as an Wilhelm Röntgen than any bacterium – neural network model effective treatment of the nervous system. launches a new that causes tobacco for syphilis. diagnostic tool. mosaic infection. I n the last decade of the 19th They found that the blood serum of for syphilis, and launched the first century, infectious diseases animals infected with diphtheria chemotherapeutic drug (Salvarsan) such as flu and tuberculosis contains a chemical, or “antitoxin”, in 1910 to treat the disease. killed millions every year. In the US, that works against bacterial toxins. life expectancy was just 44 years By injecting the antitoxin into Prevention and cure in 1890. Despite earlier advances in another animal, they could cure the Gradually, vaccines were found microscopy and anaesthesia, and disease. “Serotherapy” became a for the deadly diseases of cholera, an understanding of germ theory life-saver for many people who had tetanus, whooping cough, bubonic and the cellular basis of disease, contracted diphtheria, although the plague, and yellow fever. In 1921, there remained much to discover search continued for a vaccine to French scientists Albert Calmette about how the body works and what prevent infection in the first place. and Camille Guérin developed the causes it to go wrong. In addition, first live attenuated (weakened) the pathogens responsible for many Behring and Kitasato’s work vaccine against tuberculosis (TB) – diseases were still unknown. By inspired German scientist Paul the BCG vaccine. Another live 1945, physicians had acquired new Ehrlich to find a “magic bullet” to attenuated vaccine soon followed – tools to prevent and treat disease. fight disease. Ehrlich noticed that this time, against diphtheria. some chemical dyes attach only War on pathogens to certain pathogenic cells and In 1928, Scottish bacteriologist German physiologist Emil von theorized that antitoxins work in Alexander Fleming accidentally Behring and Japanese physician the same way to target specific discovered that Penicillium fungus Shibasaburo Kitasato made a pathogens. After years of research, kills Staphylococcus bacteria, which breakthrough in 1890 in the hunt he discovered that the synthetic cause many infections. As a result, for new ways to fight pathogens. compound arsphenamine targeted penicillin became the first naturally and killed the bacteria responsible occurring antibiotic to be used

VACCINES, SERUMS, AND ANTIBIOTICS 167 The Great Influenza Insulin, the first Alexander Fleming Vitamin C – a pandemic (“Spanish effective treatment stumbles across deficiency of which flu”) begins, infecting causes scurvy – is one-third of the world’s for diabetes, is the first naturally isolated by Hungarian population and killing tested on a patient occurring antibiotic, physiologist Albert 50 million people for the first time in before it ends in 1920. Toronto, Canada. which he calls Szent-Györgyi. penicillin. 1918 1922 1928 1931 1921 1923 1929 1940 The BCG vaccine, Nurse and feminist German biochemist Scientists notice a live attenuated Margaret Sanger opens Adolf Butenandt antibiotic resistance vaccine, is created discovers the by Albert Calmette the first legal birth sex hormone for the first time, and Camille Guérin control unit in the US, oestrogen. in E. coli bacteria. to protect against enabling women to tuberculosis. access contraceptives. therapeutically. In 1945, 6.8 trillion Papanicolaou published the results was found to regulate blood sugar units were produced in the US. It of his research into screening for levels, and in 1922, a patient with was the first of many antibiotics, cervical cancer. By the 1950s, the diabetes was treated with insulin which have saved millions of lives. “Pap smear” test was being used for the first time. widely in the US. The battle against Vaccines and antibiotics aside, cancer was at last underway. Physicians had long known the fight against pathogens was the cause of scurvy, the deadliest often untargeted, especially in the Understanding the body deficiency disease. In 1912, Polish- case of cancer. The X-ray machine, At the start of the 20th century, born biochemist Casimir Funk invented by German physicist scientists believed that organs described the preventative role of Wilhelm Röntgen in 1895, was a communicated with each other vitamins. By the late 1940s, all the crucial tool in the diagnosis and using electrical signals carried by essential vitamins were known. treatment of trauma, and X-rays were nerves. However, in 1902, British also used by many doctors to attack physiologists Ernest Starling and New ways of “reading” the body, cancer tumours – but this radiation William Bayliss demonstrated that such as the electrocardiograph and therapy killed healthy as well as some communication was chemical, electroencephalogram, also helped cancerous cells. It was not until 1942 in the form of secretions from the clinicians to make faster diagnoses that American pharmacologists pancreas into the bloodstream. and save more lives. By 1945, life Louis Goodman and Alfred Gilman The discipline of endocrinology expectancy in the US had leapt to produced the first chemical was born, and these chemicals, or 65 years. But medicine faced new treatment for cancer – nitrogen hormones, and the endocrine glands challenges. Bacterial resistance to mustard injected into the blood to that produce them were gradually antibiotics had been detected, and kill cancerous cells. The next year, identified. One hormone, insulin, changing lifestyles created different Greek American physician George problems, including widespread obesity and new forms of cancer. ■

SOLVING OTHFECPAUNZCZELRE CANCER THERAPY



170 CANCER THERAPY I n 1890, American surgeon evidence of cancer. Coley found William Coley was deeply similar cases in the medical IN CONTEXT affected by the experience of records and surmised (wrongly) treating a young woman with a that bacterial infections can release BEFORE malignant tumour in her hand. With toxins that attack malignant tissue. c. 17th century bce Egypt’s no effective therapies available, he Edwin Smith papyrus details was forced to amputate her forearm, In 1891, when Coley injected the cauterization of cancers. but within a few weeks she died live Streptococcus bacteria into a because the cancer had already patient who had only weeks to live, c. 1000 ce Al-Zahrawi removes spread to other parts of her body. the patient made a full recovery and a breast tumour surgically. lived for eight years. Coley continued Keen to find an alternative experimenting, but was forced to 1871 Campbell de Morgan treatment, Coley searched hospital switch from live to dead bacteria discovers how cancers spread. records and found an intriguing after several patients died from the case. A patient treated for a neck infection he had given them. He AFTER tumour several years before had persisted for 30 years, treating more 1932 Scientists discover a suffered a severe post-operative than 1,000 people, and achieved a way to measure radiation skin infection that had almost high rate of lasting remissions. therapy doses accurately. killed him – a common occurrence Through his work, Coley discovered before the invention of antibiotics. a link between administering what 1947 Sidney Farber uses When Coley traced the patient, he became known as “Coley’s toxins” aminopterin to halt the spread found the man no longer had any and a reduction in tumour size. of leukaemia in children. William Coley observes that He believes that 1975 César Milstein and some cancer patients who the infection Georges Köhler find a way to suffer from post-operative stimulate the production of produces cancer- immune system antibodies. infections have better fighting toxins. long-term outcomes. 1976 Harald zur Hausen proposes that cervical cancer is caused by a virus. 2002 Cancer immunologists find a way to “arm” T-cells to seek and destroy cancer cells. Nature often gives us hints Coley’s treatments are Coley administers to her profoundest secrets, regarded with scepticism streptococcal and are largely supplanted by and … may lead us bacteria (“Coley’s on to the solution the development of toxins”) to destroy of this difficult problem. radiotherapy. William Coley tumours. Contribution to the knowledge In the late 20th Coley’s work forms the basis of sarcoma, 1891 century, scientists of immunotherapy, a now discover that mainstream discipline antibodies examining how the body’s can destroy immune system can attack cancer cells. tumours as well as bacteria.

VACCINES, SERUMS, AND ANTIBIOTICS 171 See also: Cellular pathology 134–35 ■ The immune system 154–61 ■ Cancer screening 226–27 ■ Ultrasound 244 ■ Interferon 254 ■ Tobacco and lung cancer 266–67 ■ Monoclonal antibodies 282–83 ■ Genetics and medicine 288–93 While Coley was convinced his century bce. Later, the ancient The Edwin Smith papyrus – the treatment was valid, the medical Greek physician Hippocrates cited oldest known scientific text that establishment disagreed. His several varieties of cancer in the promotes rational observation of injury methods were questioned by the 5th century bce, and Roman medical and disease – gives evidence of cancer American Cancer Society, and in writer Aulus Celsus described patients as early as c. 17th century bce. 1894 the American Medical the excision of breast tumours Association described them as an with a knife in the 1st century ce. The 17th century saw the invention “alleged remedy”. When radiation Al-Zahrawi, the great surgeon of of a practical microscope, which therapy was discovered around the Islam’s Golden Age, detailed the enabled physicians to examine the same time, Coley’s therapy was removal of breast tumours in his human body at a cellular level. largely dropped and did not become medical encyclopaedia, the Kitab The advent of general anaesthesia a standard cancer treatment. al-Tasrif, in around 1000 ce. in 1846 was a further breakthrough, allowing for far more radical and However, Coley’s work left a invasive surgery to search for and legacy. Modern cancer research remove more tumours. shows that some tumours are sensitive to an enhanced immunity, In 1894, American surgeon so when a body’s immune system William Halsted pioneered radical attacks invasive bacteria, it can tissue removal, which many others also attack tumours. This cancer emulated – but in their efforts to immunotherapy, which began remove every secondary tumour, to be used in the late 1990s, was surgeons often cut out parts of foreshadowed by Coley’s work. organs, muscle, and bone. Patients were left disfigured, and the cancer Early cancer treatments had often already spread unseen. The catastrophic effects of cancer Survival from cancer is now have been known since at least understood to be more closely ancient Egyptian times. Breast related to how much the cancer cancer was described in the Edwin has spread before surgery than Smith papyrus, one of the oldest how much tissue is removed medical texts, dating from c. 17th during the surgical procedure. ❯❯ William Coley Often described as the “Father faded from view. Coley died of cancer immunology”, William in 1936, but his clinical Coley was born in Connecticut, contribution is remembered US, in 1862. He graduated from in the annual William B. Coley the Harvard Medical School in Award, presented by the US 1888 and worked as a surgical Cancer Research Institute to intern at New York Hospital. major contributors to tumour immunology research. Coley realized the limitations of surgery as a cancer treatment, Key works and became convinced that an alternative involved stimulating 1891 Contribution to the the body’s immune system to knowledge of sarcoma fight cancer. His bacteria-based 1893 “The treatment of “Coley’s toxins” were used to malignant tumours by repeated treat various forms of cancer, in inoculations of erysipelas” the US and overseas, but were widely criticized and gradually

172 CANCER THERAPY In the late 19th century, British cancer, and this procedure was Radiation was surgeon Campbell de Morgan adopted by others. Unfortunately, a powerful invisible knife, demonstrated the first genuine radiation also kills the genetic understanding of how cancer material of healthy cells – a major but still a knife. works. He explained the process of problem before accurate targeting And a knife, no matter metastasis – the spread of cancer became possible. It can also cause how deft or penetrating, from a primary tumour through cancer, as many early radiologists could only reach so far lymph nodes to other sites in the found to their cost. Many would in the battle against cancer. body. Crucially, de Morgan noted test the strength of the radiation Siddhartha Mukherjee the practical relevance of this: when on their own arms before treating cancer is discovered, it should be a patient, without realizing the Indian American oncologist treated immediately, before the damage it was doing to them. (1970–) tumour spreads any further. Overall, early radiation treatment had inconsistent results, and the the delivery of individual radiation Radiation therapy side effects on healthy tissues were beams to the shape of each tumour. X-rays were discovered in 1895, and often worse than the benefits. Another variety is conformal proton just a year later American surgeon beam radiation therapy, which uses Emil Grubbe used them to treat a Radiation targeting techniques positively charged subatomic breast cancer patient. Although it increased during the 20th century. particles called protons instead of was not understood at the time, Modern radiotherapy may be X-rays. Whereas even targeted X-rays radiation works by disabling the delivered externally or internally: can damage healthy tissues, protons DNA that allows cells to divide. In the former by a beam directed at a deliver less of a radiation dose to the first decade of the 20th century, tumour; the latter either by a source these surrounding tissues while radiation therapy (or radiotherapy) implanted near the tumour, or by a still attacking the tumour. was used mainly to treat skin liquid source injected into the cancers. In 1900, Swedish physicist bloodstream. There are several Chemotherapy Thor Stenbeck used small daily varieties of external delivery. In late 1942, American research doses of radiation to cure a skin Conformal radiation therapy (CRT) pharmacologists Louis Goodman uses computerized tomography and Alfred Gilman experimented A patient receives cobalt-60 (CT) imaging to precisely map a with the medicinal effects of radiotherapy to treat cancer. Cobalt-60 tumour in 3D. The tumour is then nitrogen mustard. This agent of was developed during the 1950s and blasted by radiation from several chemical warfare was used to widely used to deliver radiotherapy angles, and the direction and make mustard gas, which had been externally via a beam of gamma rays. intensity of the rays can be adjusted. deployed to deadly effect in World 3D-CRT was developed to customize War I. It is a cytotoxic compound, meaning that it is harmful to cells. Goodman and Gilman knew that it killed lymphocytes (a type of white blood cell) and administered it via intravenous injections to terminally ill blood cancer patients who hadn’t responded to radiotherapy. The treatment temporarily eliminated

VACCINES, SERUMS, AND ANTIBIOTICS 173 cancerous lymphocytes and, while Metastasis is the process Secondary cancer they later returned, this therapy by which cancer cells spread represented a major breakthrough from an original site of A metastatic (secondary) in treating cancer. Developed development to form tumour forms as cancer through trial and error, the age of additional tumours around cells spread from the chemotherapy had dawned. the body. The new tumours primary tumour to other that form are still the same parts of the body. In the 1940s, aware that folic type of cancer as the original, acid could have positive effects on regardless of where in some anaemia sufferers, American the body they reform. pathologist Sidney Farber tried administering it to child leukaemia Breakaway Breakaway patients. When it worsened their cancer cells cancer cells condition, he changed tack. Farber travel in the travel through realized that to divide rapidly, cancer bloodstream. the lymph cells depend on folic acid – if deprived system. of it, they would die. In one of the first examples of drug design (rather Primary cancer, than accidental discovery), Farber from which created two synthetic compounds, aminopterin and amethopterin cells split off (later called methotrexate), both analogues of folic acid. Primary cancer An analogue chemical has a remains a staple of chemotherapy. when grown, treated it with a structure that is similar to another, In the early 1950s, chemotherapy variety of chemotherapeutic agents. but differs sufficiently to interfere was considered an experimental Her team then assessed the results with cell function. In 1947, Farber method of tackling cancer, while and decided on the most effective used aminopterin to successfully surgery and radiation remained the course of treatment for each patient. stop the synthesis of DNA in core: this was soon to change. cancer cells, which was necessary African American oncologist Metastatic cancer for their growth and proliferation. Jane Wright, based at New York’s Whereas surgical removal and This was the first step to finding a Harlem Hospital Cancer Research radiotherapy have to be targeted successful treatment for childhood Foundation, helped to establish at specific areas of the body, leukaemia. While aminopterin was chemotherapy as a mainstream chemotherapeutic agents are carried abandoned in 1956, methotrexate cancer treatment. In 1951, Wright to cells in many areas of the body. led research that demonstrated This type of therapy is useful if the My plans how chemotherapy could destroy cancer has spread from a primary for the future are solid tumours (abnormal masses of tumour. In the early 1950s, however, to continue seeking tissue). She successfully treated there was no effective treatment for a cure for cancer. breast cancer patients with metastatic (spreading) cancers. Jane Wright methotrexate, and experimented Successful as methotrexate had been with adjustments to the treatment against leukaemia, it was not known Acceptance speech for regime according to an individual to be effective against solid tumours. the Merit Award, 1952 patient’s symptoms. In a move towards personalized therapy, she In 1956, American researchers and her colleagues cultured tumour Min Li and Roy Hertz made critical tissue taken from patients and, breakthroughs. Li showed that methotrexate was able to destroy ❯❯

174 CANCER THERAPY metastatic melanomas (skin Targeted therapies By the early 21st century, a tumours), and Hertz used it to cure have been developed that combination of radiotherapy, surgery, metastatic choriocarcinoma (cancer substitute subtle intervention chemotherapy, and vaccination had of the placenta). The effect of these for brute force, aiming to produced a dramatic increase in discoveries was dramatic: before, disable or block processes survival rates for many cancers, choriocarcinoma had nearly always that enable cancer cells to especially in the developed world. been fatal; by 1962, 80 per cent of grow, divide, and spread. This was true particularly for cases in the US were cured. cancers of the breast, lung, bowel, Nigel Hawkes and prostate. In the US, death The American team of James rates for breast cancer fell by 39 Holland, Emil (Tom) Frei, and Emil British health journalist, 2015 per cent between 1989 and 2015, Freireich knew that in the treatment with survival rates five years after of tuberculosis several antibiotics papillovirus (HPV) viral infection treatment of around 90 per cent there were used concurrently to reduce had been identified as responsible and 85 per cent in Western Europe. the risk of the bacteria developing for inducing cervical cancer. In the resistance. In 1965, the team late 1980s, Australian immunologist Success did not apply to all rationalized that cancer cells could Ian Frazer and Chinese virologist cancers, however. For pancreatic, also mutate to become resistant to Jian Zhou began research for a liver, and a number of lung cancers, a single agent, but if more than one vaccine. After 25 years, they were survival rates remain very low: in agent was used, this would be less successful in developing the HPV 2015, five-year survival rates for likely. By using a cocktail of up to vaccine, which first became pancreatic cancer were still below four drugs, including methotrexate, available in 2006 and is now widely 15 per cent. Typically, treatment they successfully treated cases of used to protect against cervical may involve surgery, followed by acute lymphocytic leukaemia and and anal cancers and some kinds daily radiotherapy, then regular Hodgkin’s lymphoma – previously of mouth and throat cancer. combination chemotherapy over considered incurable. This technique a period of months. became known as combination chemotherapy and is now the norm. Immunology Cancer immunotherapy (immune- Vaccination oncology) loosely echoes the radical In 1976, German virologist Harald therapy developed by William Coley zur Hausen proposed that viruses in the late 19th century, in which played a role in cervical cancer, he injected bacteria into cancer and within a decade the human patients. Modern immunotherapy Jane Wright Born in 1919 in Connecticut, US, stroke policy. As a pioneering Jane Wright followed her father researcher and surgeon, Wright into medicine and graduated from led international delegations New York Medical College in 1945. of oncologists in Europe, Asia, She then worked at the Harlem and Africa, and treated cancer Hospital in chemotherapy research. patients in Ghana and Kenya. She died in 2013. A believer in systematic clinical trials and a pioneer of personalized Key works chemotherapy treatment, Wright became head of her father’s Cancer 1957 “Investigation of the Research Foundation at Harlem Relationship between Clinical Hospital aged 33. She co-founded and Tissue Response to the American Society of Clinical Chemotherapeutic Agents on Oncology in 1964, and joined a Human Cancer” commission set up by President 1984 “Cancer Chemotherapy: Lyndon B. Johnson to advise Past, Present, and Future” on cancer, heart disease, and

VACCINES, SERUMS, AND ANTIBIOTICS 175 focuses on “educating” and boosting Natural killer cells are lymphocytes cells. Later, Allison sought ways to a body’s immune system so that it that recognize infected body cells and “rearm” T-cells to destroy cancer can recognize and attack cancer attack, but have no specific immunity. cells. In 2002, researchers used cells. Natural killer cells (a type of This image shows a natural killer cell CAR (chimeric antigen receptor) white blood cell) are harnessed to (pink) attacking a cancerous cell. T-cells to destroy prostate cancer identify and target infected cells. cells in a laboratory experiment. infection, the body makes T-cells to After successful clinical trials, CAR In 1975, two biochemists – fight that specific disease. After T-cells are now used to fight certain César Milstein (from Argentina) and T-cells have performed their search- kinds of leukaemia and lymphoma Georges Köhler (Germany) – laid the and-destroy mission, the body keeps cancers. In this form of therapy, foundations for using antibodies as a few of them in reserve, in case the T-cells are taken from a patient’s a means to destroy cancer cells. same infection reoccurs. However, bloodstream, and their receptors are Antibodies are protein molecules even though T-cells are good at modified so they can recognize a made by B-cells, which are a fighting infections, they find it hard specific protein on cancer cells. type of lymphocyte. They bind to to identify cancer cells as “enemies”. Then, the CAR T-cells are put back molecules (antigens) on the surface into the patient’s bloodstream. of targeted cells, such as bacteria, During the 1980s, American Similar procedures are being and signal to the immune system immunologist James P. Allison and researched for solid tumours, too. to destroy them. Milstein and his Japanese counterpart Tasuku Although still at a relatively early Köhler found a way to stimulate Honjo had discovered the chemical stage of development, this huge B-cells to produce unlimited mechanism T-cells use to recognize innovation represents the potential numbers of one specific type of “hostile” infection cells and realized for a new type of cancer therapy. ■ antibody (monoclonal antibodies). their potential to identify cancer The next step was to develop them to target cancer cells, a technique CAR T-cell therapy is a complex and specialist treatment in which now used in the diagnosis and a patient’s T-cells (immune cells) are extracted from the body and treatment of some cancers. genetically altered. Once modified into CAR T-cells, they are able to actively target and fight cancer cells in the body. The quest for immunotherapy with a greater reach has continued T-cells are collected T-cells are into the early 21st century. Much from a patient’s modified into contemporary research focuses on bloodstream CAR T-cells. T-cells, another type of lymphocyte. and transferred The role of killer T-cells is to travel to a lab. around the body finding and destroying defective cells. When CAR T-cells someone comes in contact with an multiply. CAR T-cells CAR T-cells are find and attack reintroduced into the cancerous cells patient’s bloodstream in the body. via a drip.

176 STTHHHEEADDBOAOWRNKEOSEFR X-RAYS IN CONTEXT I n December 1895, German Röntgen’s X-ray of his wife’s hand physicist Wilhelm Röntgen (and wedding ring) prompted her to say BEFORE published a paper announcing she had seen her death. Some 3.6 billion 1800 German-born British his discovery of “a new kind of X-ray scans are now performed annually. astronomer William Herschel rays”. He had produced the first discovers infrared light from X-ray images, including one of his patients are only minimally exposed the heat energy it carries. wife’s hand. Physicians around the to low radiation levels, making X-ray world soon realized the potential of scanning virtually risk-free for most 1801 In Germany, physicist X-rays for clinical diagnosis, and people. In the mid-1970s, hospitals Johann Wilhelm Ritter detects in 1901 Röntgen received the first began to introduce computed ultraviolet light by exploring Nobel Prize in Physics for his work. tomography (CT), which uses X-rays the purple end of the spectrum. to provide 3D images by rotating the X-rays are a form of invisible X-ray source and detector around the AFTER electromagnetic radiation. When body as it passes through a tube. ■ 1905 American X-ray pioneer they pass through the body, different Elizabeth Fleischman dies types of tissue absorb the radiation’s of cancer – the result of energy at varying rates. A device over-exposure to radiation. placed on the opposite side of the body detects the differences and 1971 Radiographers at a turns them into a photographic London hospital conduct the image. X-rays are used to diagnose first computed tomography conditions such as bone fractures, (CT) scan. tooth problems, scoliosis (spine curvature), and bone tumours. 1984 The US Food and Drug Administration (FDA) Early risks approves the use of a whole- The dangers of radiation were not body magnetic resonance fully understood in the early days imaging (MRI) scanner. of X-rays. Several researchers and physicians suffered burns and hair 2018 Scientists in New loss, and at least one died. Today, Zealand conduct the first 3D colour X-ray on a human. See also: The stethoscope 103 ■ Histology 122–23 ■ Ultrasound 244 ■ Orthopaedic surgery 260–65 ■ MRI and medical scanning 278–81

VACCINES, SERUMS, AND ANTIBIOTICS 177 PAVRIRREEUDASALETPSOHRAS VIROLOGY IN CONTEXT O f the trillions of viruses not culture it; it spread only when that exist in the world, injected into leaves. He concluded BEFORE around 220 are known to that it was not a microbe but a new 1880–85 Robert Koch draws cause disease in humans. They are liquid pathogen, which he called up four criteria to establish up to a thousand times smaller “virus” – Latin for “poisonous fluid”. the link between a germ and than bacteria and consist of DNA a disease. or RNA enclosed in a protein coat. Viruses were soon implicated in Viruses are inert until they infect human diseases; the first was yellow AFTER other organisms and can replicate fever virus, discovered in 1901. In 1901 American army doctor only when they take over the the US, scientist Francis Holmes Walter Reed discovers yellow host’s cells. showed that viruses were discrete fever virus in the blood of a particles, rather than fluids, in 1929, colleague; it is first isolated Isolated from tobacco sap and virologist Wendell Stanley in 1927. Dutch microbiologist Martinus crystallized tobacco mosaic virus Beijerinck first used the word “virus” from infected leaves in 1935. ■ 1980 The WHO declares that in his 1898 study of tobacco mosaic smallpox, caused by the Variola infection. Six years earlier, Russian The true nature virus, has been eradicated. botanist Dmitri Ivanovsky, who also of viruses was studied the disease, had filtered sap a complete mystery. 2019 SARS-CoV-2, the virus from infected tobacco leaves through Wendell Meredith causing COVID-19, emerges porcelain in a bid to isolate the in Wuhan, China, triggering parasite but found that the filtered Stanley a worldwide pandemic. sap remained infectious. He had concluded that the sap must contain Nobel Lecture, 1946 2020 British scientist Michael bacteria smaller than any known or Houghton and American a soluble bacterial toxin. researchers Harvey Alter and Charles Rice are awarded the In 1897, Beijerinck conducted Nobel Prize in Physiology or similar experiments, adding a Medicine for their discovery second filter of gelatin. The filtered of the hepatitis C virus. sap was still infected, yet he could See also: Vaccination 94–101 ■ Germ theory 138–45 ■ Bacteriophages and phage therapy 204–05 ■ HIV and autoimmune diseases 294–97 ■ Pandemics 306–13

DREAMS RUARNOECAOTDHNTESOCRIOTOYHUASEL PSYCHOANALYSIS



180 PSYCHOANALYSIS P sychology – a term derived for Bertha Pappenheim. She from the Greek psychologia, suffered from hysteria, displaying IN CONTEXT meaning “study of the soul” – symptoms including paralysis, was in its infancy in the 1870s, convulsions, and hallucinations BEFORE when Austrian neurologist Sigmund that had baffled other doctors. c.1012 Islamic physician Ibn Freud studied medicine in Vienna. After a series of sessions with Sina mentions the unconscious A few notable European physicians, Breuer during which she freely in The Canon of Medicine and such as Wilhelm Wundt in Germany, expressed any thought that came recognizes that inner feelings had begun to work in the new area into her mind, she had begun to can trigger physical effects. of experimental psychology and improve. Breuer termed this “the were studying the senses and talking cure”. 1758 British physician William nerves in a bid to discover how the Battie publishes his Treatise brain processes information. Freud, It transpired that Anna O’s on Madness, which advocates however, grew more interested in symptoms had emerged during her sensitive treatment for people exploring the non-physical roots of father’s long, terminal illness. The suffering from mental illnesses. mental disorders, a field he later anxiety this provoked had, among called psychoanalysis. her other symptoms, prompted an 1817 In his Encyclopedia of aversion to liquids – seemingly the the Philosophical Sciences, French neurologist Jean-Martin result of a repressed childhood German philosopher Georg Charcot, who used hypnosis to memory of a dog drinking from her Wilhelm Friedrich Hegel treat a condition then known as glass. It was evident that her talks describes the unconscious hysteria, was a key early influence. with Breuer had revealed previously as a “nightlike abyss”. In 1885, Freud spent 19 weeks in hidden emotions and painful Paris working under Charcot, who memories and that voicing them AFTER introduced him to the idea that the had effected her cure. 1939 Austrian psychoanalyst source of mental disorders lay in Heinz Hartmann, who was the mind – the domain of thought Freud wrote about Anna O in analysed by Freud, publishes and consciousness – rather than in his 1895 Studies on Hysteria, in Ego Psychology and the the physical brain. which he proposed that repressed Problem of Adaptation. conflicts manifest themselves Its ideas spread in the US, The case of Anna O physically. This, in turn, led him dominating psychoanalysis Returning to Vienna, Freud began a there for three decades. partnership with Austrian physician Jean-Martin Charcot lectures on Josef Breuer, who became his mentor. hypnosis at the Salpêtrière Hospital, 1942–44 Psychoanalysts He was particularly fascinated by Paris, as an assistant doctor holds a Melanie Klein and Anna Freud the case of Anna O, a pseudonym hysterical patient, in this copy of an clash over differing theories 1887 painting by André Brouillet. about child development in “Controversial Discussions” – a series of meetings of the British Psychoanalytical Society in London. 1971 In The Analysis of the Self, Austrian American psychoanalyst Heinz Kohut rejects Freudian ideas about the role of sexual drive and recognizes empathy as a key force in human development – a view that underpins modern psychoanalysis.

VACCINES, SERUMS, AND ANTIBIOTICS 181 See also: Islamic medicine 44–49 ■ Humane mental health care 92–93 ■ The nervous system 190–95 ■ Lithium and bipolar disorder 240 ■ Chlorpromazine and antipsychotics 241 ■ Behavioural and cognitive therapy 242–43 Experiences too painful for the conscious mind to bear are repressed in the unconscious mind. Because the mind has not resolved the experiences, they cause psychic tension – conflict between the conscious and unconscious mind. The Nightmare, painted by Swiss artist The conflict manifests itself as mental illness, Henry Fuseli around 1790, portrays the such as anxiety, depression, or neuroses. suffocating anxiety of a terrifying dream. Freud is said to have had an engraving of it in his Vienna waiting room. to suggest there were three levels To successfully treat such problems, the of the human mind: the conscious, unresolved issues must be exposed. preconscious, and unconscious. To describe the three levels, the Psychoanalysis probes the unconscious, revealing and releasing analogy of an iceberg is often used. repressed experiences, and encouraging the patient’s The tip of the iceberg, visible on conscious mind to manage them. the water’s surface, represents the conscious mind – the thoughts and dream, he received a hospital bill had revealed a jealousy of his father feelings that a patient is aware of for someone who had been in the and love for his mother – something and understands. Residing just family home 40 years earlier, before he later described as an Oedipus beneath the conscious mind is the his own birth. In the dream, his complex, from the Greek myth of preconscious mind, which contains father’s ghost admitted to getting Oedipus, king of Thebes, who memories and knowledge that a drunk and being detained. Freud killed his father and unwittingly person can easily access. At the believed the dream indicated there married his mother. deepest level of the iceberg, and was something that his unconscious occupying the largest area, lies mind would not allow him to see in In his landmark 1899 text, The the unconscious mind. For Freud, his father’s past, such as a sexual Interpretation of Dreams, Freud this area was a sealed chamber abuse or other hidden vices. His outlined his theory that repressed of repressed emotions, primitive relationship with his father had emotions or urges (often of a sexual desires, violent impulses, and fears. been difficult. Freud told a friend, nature) are expressed or acted out German physician Wilhelm Fliess, in dreams and nightmares in a Delving into dreams that his self-analysis and dreams form of wish-fulfilment. Dreams, In 1896, after his father died, Freud he considered, were the outlet of ❯❯ had a series of disturbing dreams, which he wrote down and studied as he began his self-analysis. In one

182 PSYCHOANALYSIS Freud’s view of the human mind: the mental iceberg Conscious Thoughts The id is totally Preconscious Perceptions non-moral; the ego tries hard to be moral; and Memories Stored, retrievable the superego is hyper-moral knowledge and shows a degree of cruelty. Sigmund Freud “The Ego and the Id”, 1923 Ego Fears Violent impulses Superego Unconscious Deviant sexual desires The ego and Primitive urges Selfish needs During early childhood, as the ego develops, the superego, similarly superego span the Id straddling all three levels, becomes apparent, controlling impulses and three levels of the Excessively painful experiences imposing moral standards. metaphorical mental iceberg. The id resides Freud proposed that one element only in the unconscious, is always at odds with the other two which holds the repressed Disturbing wishes elements, which then causes inner conflict. Typically, when the goals thoughts that provoke of the id and superego come into mental disorders. conflict, the ego has to step in to mediate. When this happens, the emotions too powerful and painful human personality – the id, ego, ego deploys defence mechanisms, for the conscious mind to tolerate. and superego – which developed at such as denial and repression. He became increasingly convinced different points of childhood. In the that it was traumatic events in iceberg metaphor, the id – the most Instincts and fixations childhood that led to mental health primitive, instinctive component – Freud grouped all human instincts issues in adults, as such memories is submerged in the unconscious into two opposing groups – Eros, were invariably repressed. and consists of inherited traits, deep the life instinct for personal and fears, and aggressive and sexual species survival, and Thanatos, As patients could not explain or urges. It drives much of what goes the death instinct. Eros instincts understand feelings or behaviour on in the mind, but the conscious include sex, thirst, and hunger, caused by factors outside their mind is unaware of it, although while Thanatos is destructive. realm of consciousness, the only inadvertent words or behaviour – Because the Eros instinct is for route to a cure lay in probing the what we now term “Freudian slips” – survival, it thwarts the Thanatos unconscious, and dreams were a can reveal its hidden impulses. urge to self-destruct. As a result, potent route to this unknown area. Thanatos is often expressed as The ego, according to Freud, is aggression or cruelty to others. Id, ego, and superego the self, perceiving and interacting By the 1920s, Freud had extended with the outside world while also Thanatos is also in conflict with the model of the unconscious, mediating conflicts in the mind’s libido, the psychosexual energy conscious, and preconscious inner world. It develops during which fuels Eros. Freud believed minds to contain what he believed infancy and spans the conscious, that sexual impulses are a key were the essential parts of the preconscious, and unconscious.

VACCINES, SERUMS, AND ANTIBIOTICS 183 What we learn about the the nature of the sessions can create Sigmund Freud child and the adult through an unhealthy imbalance of power psychoanalysis shows that all between therapist and patient. Born in 1856 to Jewish parents the sufferings of later life are Freud himself noted problems with in Freiberg, Moravia, for the most part repetitions that relationship – a patient projects Sigismund (later Sigmund) feelings about his or her parents Freud was raised in Leipzig of these earlier ones. onto a therapist, later termed the and Vienna. After studying Melanie Klein “transference phenomenon”. medicine at the University of Vienna, he spent a formative Love, Guilt, and Reparation, 1921–45 Over time, Freud’s theories have period in Paris. On his return been modified, and psychoanalysis to Vienna, he worked with factor in child development. He today embraces more than 20 Josef Breuer on the treatment identified five crucial stages in different schools of thought, largely of hysteria and set up a private infancy when sexuality develops – taught in institutes separate from practice to treat patients with oral, anal, phallic, latent, and those of other medical disciplines. nervous disorders. In 1886, he genital – as children become This is one point of contention married Martha Bernays; the fixated initially with an area of their with its detractors, who criticize couple had six children. mother’s body and then with other psychoanalysis for basing theories areas of their own bodies. Those on clinical experience rather than In 1897, Freud began an who failed to successfully complete replicable scientific evidence. One intense self-analysis, the basis any one of these stages, Freud attempt to address this is the new of his book on dreams. He was believed, would as adults become field of neuropsychoanalysis, which appointed Vienna University’s fixated on that stage, prompting a combines brain imaging with professor of neuropathology range of destructive behaviours. psychoanalysis; however, some in 1902 and founded the psychiatrists are not yet convinced. International Psychoanalytic To probe a patient’s problem, Association in 1910. In 1938, Freud used tools such as Rorschach While its practice has declined, Freud, his wife, and other inkblots (in which he analysed a the study of psychoanalysis still family members fled Austria patient’s perception of inkblot attracts a large number of clinical (newly annexed by Nazi patterns) and free association of psychologists, and psychiatrists Germany) and settled in words, as well as dream analysis. acknowledge the legacy of Freud’s London. Suffering terminal The patient lay on a sofa, while central belief in the importance of cancer, Freud died in 1939. Freud sat taking notes behind. patients’ life histories and the value of listening to what patients say. ■ Key works Modified but still potent The Freud Museum in Hampstead, 1899–1900 The Interpretation Freud was a dominant figure in the London, is housed in Freud’s last home. of Dreams field of psychiatry throughout his life It includes his original psychoanalytic 1904 The Psychopathology and is rightly hailed as the father of couch, preserved in the study where of Everyday Life psychoanalysis. He had detractors, he treated his patients. 1923 “The Ego and the Id” however, and many of his theories are now thought antiquated. Critics have argued that his ideas have no scientific basis, that psychoanalysis is too long and expensive, and that

184 IN CONTEXT IRATECMFHLUEESMXTICBAEL BEFORE 1865 Claude Bernard shows HORMONES AND ENDOCRINOLOGY that the body can both build up and break down complex chemical substances. 1894 British physiologist Edward Sharpey-Schafer demonstrates the existence of adrenaline and coins the term “endocrine”. AFTER 1920 Human growth hormone is identified by American scientists Herbert McLean Evans and Joseph Long. 1923 Frederick Banting and John Macleod are awarded the Nobel Prize in Physiology or Medicine for their discovery of insulin. E ndocrinology is the branch of medicine that deals with hormones – the body’s chemical messengers. Hormones are made by specialized cells mostly found in the endocrine glands: the hypothalmus, testes, and ovaries, and the thyroid, parathyroid, pituitary, adrenal, and pineal glands. Travelling through the body mainly in the bloodstream, hormones from one endocrine gland can stimulate another gland to adjust the levels of hormones it is producing, or can carry instructions to cells in organs and tissues. In this way, hormones regulate almost every organ, process, and function in our bodies, including muscle and bone growth, fertility, appetite, metabolism, and heart rate. Until 1902, it was believed that organs only communicated with each other using electrical signals

VACCINES, SERUMS, AND ANTIBIOTICS 185 See also: Physiology 152–53 ■ The nervous system 190–95 ■ Diabetes and its treatment 210–13 ■ Steroids and cortisone 236–39 ■ Hormonal contraception 258 The endocrine system is a series of glands that secrete hormones that regulate a range of body functions. Secretion of hormones is triggered by factors Ernest Starling such as concentrations of certain chemicals in the blood, responses to other hormones, and signals from Born in 1866 in London, UK, Starling studied medicine at the nervous system. Guy’s Hospital Medical School, and became a demonstrator in Most hormones travel through the bloodstream physiology in 1887. In 1890, to their target cells in the body and activate these he began a lifelong association with fellow physiologist cells to respond in the desired way. William Bayliss at University College, London. They made a Feedback loops monitor the level good team: Starling was said of hormones in the blood and increase or to be visionary and impatient, while Bayliss was cautious and lower secretion of these hormones. methodical. Bayliss married Starling’s sister Gertrude in conducted by nerves. That year, substance and release it directly 1893. In addition to his work British physiologist Ernest Starling into the bloodstream. In 1849, with Bayliss on the function of and his brother-in-law William intrigued by the behavioural and the endocrine system, Starling Bayliss, working at University physical changes that castration made significant contributions College London (UCL), performed induced, German physiologist to the understanding of the an experiment that proved beyond Arnold Berthold removed the testes mechanism that regulates doubt that organs communicate from four male chicks and noted that heart function. using chemical messengers, as they failed to develop male sexual well as via the nervous system. characteristics such as combs and Starling was elected a Their discovery kick-started the wattles or interest in hens. He then fellow of the Royal Society in field of endocrinology. transplanted testes from a rooster 1899. Committed to improving into the abdomens of two castrated medical education, he assisted Early indications birds, and found that they developed the 1910 Royal Commission on Pioneering experiments in the 19th male characteristics as normal. university education. He died century suggested the existence of in 1927, while on a Caribbean hormones and hinted at their roles. The prevailing theory was that cruise, and was buried in Claude Bernard’s studies of liver sexual development was controlled Kingston, Jamaica. function in 1848 first established by the nervous system; but when the concept of “internal secretion”, Berthold dissected his chickens, the Key works or the ability of an organ to make a transplanted testes had established a new blood supply but no neural ❯❯ 1902 “The Mechanism of Pancreatic Secretion” 1905 “On the Chemical Correlation of the Functions of the Body”

186 HORMONES AND ENDOCRINOLOGY Blood vessel Target cell Hormone enters Non-target cell the target cell by Different receptors attaching to a fit other hormones. receptor. Hormone enters the bloodstream. Secreting cell Hormone molecules mostly travel through the body via the bloodstream and bind to receptor proteins on the surface of, or inside, a target cell. Each target cell has 5,000–100,000 receptors shaped specifically to fit particular hormones. connections. Whatever triggered strength, stamina, and ability to had posited that these pancreatic sexual development had to be concentrate. He attributed this to an secretions were controlled by nerve travelling via the bloodstream. action on the nervous system and signals that travelled from the small Despite Berthold’s research, belief suggested that similar extracts intestine to the brain and then back in nerves as the only conduit of could be used to rejuvenate men. to the pancreas. In 1902, aiming to messages in the body persisted. test these claims, Starling and The following year, Brown- Bayliss carefully cut away all the In 1889, French neurologist Séquard reported that Augusta nerves linked to the pancreas in Charles-Édouard Brown-Séquard, Brown, an American doctor working an anaesthetized dog. When they then aged 72, reported to the in Paris, had injected several women introduced acid into the small Academy of Sciences in Paris with the filtered juice of guinea pigs’ intestine, the pancreas still secreted that he had injected himself with ovaries, which appeared to show digestive fluids. This implied that a concoction of veins, semen, and benefits for hysteria, uterine the secretions were not controlled other fluids from the testicles of dogs disorders, and ageing. This claim by nerve signals. and guinea pigs. Brown-Séquard could not be validated, but it fuelled noted a marked improvement in his interest in the idea that internal To prove their hypothesis that secretions produced by organs a factor released from the intestine … the discovery of might have significant functions into the bloodstream triggered the the nature of these and therapeutic applications. pancreas to secrete digestive fluids, [chemical] substances Starling and Bayliss injected a will enable us … to acquire Chemical signalling solution of intestinal material and absolute control over the At UCL in the late 1890s, Starling acid into a vein. Within a few workings of the human body. and Bayliss were researching the seconds, they detected secretions Ernest Starling physiology of the small intestine. from the pancreas. This proved After becoming the first scientists that the triggering link between the Croonian Lecture, 1905 to describe peristalsis (the muscular small intestine and the pancreas contractions that propel digested was a chemical messenger and was food along the intestine), they began not carried by the nervous system. investigating whether the nervous system influenced digestion. The first hormone In a lecture at the Royal College of Starling and Bayliss knew that Physicians in 1905, Starling used a the pancreas secreted digestive new term “hormone”, from the Greek fluids after food passed from the word ormao (“to excite or arouse”), stomach to the intestines. In 1888, to describe the substance found. Russian physiologist Ivan Pavlov

VACCINES, SERUMS, AND ANTIBIOTICS 187 He named this hormone “secretin”. therapies for previously untreatable A polarized light micrograph of The 1902 experiment showed that endocrine disorders. Pharmaceutical the female sex hormone progesterone. the small intestine releases secretin companies were quick to explore Secreted by the ovaries following the into the bloodstream when gastric these new opportunities as more release of an egg, it prepares the inner acid fluid arrives in the intestine hormones were identified. lining of the womb for pregnancy. from the stomach. Secretin then stimulates the pancreas to secrete Just two years after Banting and popularity in the 1960s, as women bicarbonate, which neutralizes the Macleod’s isolation of insulin, the seized the opportunity to counter acid fluid in the intestine. American pharmaceutical company debilitating menopausal symptoms Eli Lilly began manufacturing Iletin, such as hot flushes and osteoporosis. The discovery of secretin soon the first commercially available prompted the identification of other insulin product for treating diabetes. During the late 1970s, advances hormones. Insulin, released by the By the mid-1930s, oral and injectable in biotechnology enabled genetically pancreas to regulate blood sugar oestrogens were also available for engineered human hormones. New levels, was isolated by Canadian treating menstrual irregularities gene-splicing techniques meant scientist Frederick Banting and and the symptoms of menopause. that common bacteria (usually Scottish physiologist John Macleod Escherichia coli) could be genetically in 1921. The sex hormone oestrogen Demand for hormone therapies modified to produce hormones, was identified in 1929 by German synthesized from animal products, such as insulin, in the laboratory. biochemist Adolf Butenandt, and which were expensive and only also independently by American available in limited quantities, As research continues adding biochemist Edward Doisy, followed quickly outsripped supply. Scientists to our knowledge of hormones, recent by progesterone in 1934, and both began to investigate biochemical studies have begun to question the testosterone and oestradiol in 1935. processes that could enable hormone safety of some hormone treatments, In all, scientists have identified more synthesis on a larger scale. recording evidence of side effects than 50 human hormones to date. ranging from fatigue to cancer. In In 1926, British biochemist 2002, for example, studies linking New therapies Charles Harington acheived the first HRT to an increased risk of breast After isolating secretin, Starling chemical synthesis of a hormone, cancer and stroke showed that the and Bayliss discovered that it was thyroxine (originally isolated by risks versus the benefits of altering a universal stimulant: secretin from American chemist Edward Kendall hormone levels must be carefully one species stimulated the pancreas in 1914). This significant step calculated. The adverse effects of of any other species. This suggested towards mass-producing hormones some drugs on the body’s delicate that it might be possible to use also helped to improve the efficacy of balance of hormones is also an animal-derived hormones as hormones such as insulin. The first ongoing area of research. ■ insulin preparations, derived from We don’t want to horse pancreas, varied greatly in alarm women, strength and required several daily injections. By the 1930s, the addition but we don’t want to of zinc prolonged the action of give them false reassurance. insulin to around 24 hours. Gillian Reeves Modern developments Progress in hormone synthesis British cancer epidemiologist, also allowed for wider applications. on the risks of HRT, 2019 The contraceptive pill, containing synthetic progesterone and synthetic oestrogen, was introduced in 1960, and marked a turning point in the availability and marketing of manufactured hormone products for general use. The use of synthetic oestrogen for hormone replacement therapy (HRT) also gained mass

188 CTTHHUEERRAHECENTATIROSTNOF ELECTROCARDIOGRAPHY IN CONTEXT I n the ancient world, physicians Electrocardiographs record the listened to the body for signs pattern of a patient’s heartbeat by BEFORE of disease. The heart had a detecting (via electrodes on the 1780s Italian physicist Luigi recognizable pulse, which, two body) the varying electrical signals Galvani stimulates electrical millennia later, could be clearly the heart produces – a procedure responses in animal muscles, heard through the stethoscope called an electrocardiogram (ECG). calling it “animal electricity”. invented in France by René Laënnec in 1816. In 1903, Dutch Animal experiments carried out 1887 To measure the heart’s physiologist Willem Einthoven took by Italian physicist Carlo Matteucci electrical activity, Augustus D. heart monitoring a crucial step in 1842 had shown that an electrical Waller uses a machine based forward when he introduced the current accompanies each beat of on the capillary electrometer first viable electrocardiograph. the heart. In the following decades, developed by French physicist scientists sought ways to record the Gabriel Lippmann. An electrical impulse Electrodes attached AFTER generates each heartbeat to the skin measure 1909 With the aid of an early electrocardiograph, British and pulsates the impulses physician Thomas Lewis towards the skin. in microvolts (μV). discovers atrial fibrillation – a condition that causes an The more intense The electrodes transmit irregular heart rate. the impulse, the information that appears 1932 New York cardiologist higher the point on as a graph of Albert Hyman invents a device the graph. voltage vs. time. to restart a stopped heart and calls it an artificial pacemaker. The pattern of impulses reveals any abnormalities in heart signals. 1958 In Sweden, cardiac surgeon Åke Senning implants the first cardiac pacemaker, designed by engineer and former doctor Rune Elmqvist.

VACCINES, SERUMS, AND ANTIBIOTICS 189 See also: Traditional Chinese medicine 30–35 ■ Blood circulation 68–73 ■ The stethoscope 103 ■ Transplant surgery 246–53 ■ Pacemakers 255 This 1911 electrocardiograph took five people to operate it. Instead of wearing electrode pads, patients dipped their arms and left leg into saline, an electrical conductor. human heart’s electrical activity. Einthoven became interested after seeing British physiologist Augustus D. Waller demonstrate a device that detected the heart’s electrical surges from the way they made mercury move inside a tiny glass tube. Refining the machines The early electrocardiographs were Since Einthoven developed his first By 1903, Einthoven had developed a large and cumbersome, but over the machine, the ECG has been in sensitive string galvanometer. When years, the machines were modified constant use. While many new electrical current from the heart and shrank in size. Today’s portable treatments have emerged – such as passed through a fine wire, or string, devices can be used to monitor a beta-blockers (drugs to slow down set between two electromagnets, patient’s heart digitally over days or the heart rate), pacemakers (devices the string moved, and the shadow weeks. The number of electrodes to regulate the heart’s contractions), cast by its movements was recorded used for a standard ECG has risen heart transplants, and bypass and on moving photographic paper. to 10 – six on the chest and one on valve replacement surgeries – the Einthoven’s model produced more each limb – giving 12 measurements ECG still plays a key role in the early accurate readings than Waller’s, and (“leads”) of the heart’s activity from diagnosis of heart disease, which is reduced the electrode points from different combinations of electrodes. the world’s leading cause of death. ■ five to three to give readings from the left and right arm, and left leg, creating what was later known as Einthoven’s triangle. Willem Einthoven Born in 1860, Willem Einthoven to describe how various heart spent his early years on the island disorders appear on an ECG, and of Java in the Dutch East Indies corresponded regularly with (now Indonesia). When he was British physician Thomas Lewis, six, his father died, and in 1870 who worked on the device’s the family went to live in Utrecht clinical application. In 1924, in the Netherlands. Einthoven was awarded the Nobel Prize in Physiology or Einthoven trained as a doctor Medicine, and died three years in Utrecht, and in 1886 was made later, in 1927. professor of physiology at the University of Leiden. He initially Key works studied optical illusions and the eye’s electrical response to light, 1906 “The Telecardiogram” but his interest turned to building 1912 “The different forms of a machine to monitor the heart’s the human electrocardiogram electrical activity. After introducing and their significance” his electrocardiograph, he went on

SPARKSSATNRDINGTSROAFVFELLALSHININGG THE NERVOUS SYSTEM



192 THE NERVOUS SYSTEM IN CONTEXT I n a series of lectures at Yale “Sherrington’s law” established University in 1904, British that for every activation of a BEFORE neurophysiologist Charles Scott muscle, there is a corresponding c. 1600 bce The Edwin Smith Sherrington gave the first extensive relaxation of the opposing muscle. papyrus describes the impact exposition of the human nervous When, for example, you flex your of spinal injury on the body. system. Published two years later arm at the elbow, the bicep muscle in The Integrative Action of the is activated (contracting the arm), 1791 Luigi Galvani shows Nervous System, this research but the tricep muscle is inhibited that a frog’s leg responds to resolved several issues about how (relaxing to allow the movement). electrical stimulus. the nervous system functions, and directly influenced the development In 1897, Sherrington coined the 1863 Otto Deiters describes of brain surgery and treatment for term “synapse” for the meeting point the axon and dendrites of a neurological disorders. between two nerve cells (neurons). nerve cell. Although he could not observe synapses (microscopes were not 1872 Jean-Martin Charcot Muscle messaging advanced enough), he believed these publishes his pioneering work Three of Sherrington’s ideas were junctions existed because reflexes Lectures on the Diseases of the particularly groundbreaking. He (involuntary motor responses) were Nervous System. explained that muscles do not simply not as fast as they should be if they receive instructions from the nerves involved the simple conduction of AFTER that travel to them from the spinal impulses along continuous nerve 1914 Henry Dale finds the cord (which conducts messages to fibres. He explained how a neuron neurotransmitter responsible and from the brain); they also send communicates via electric signals, for chemical communication information back to the brain about which pass along thread-like fibres between nerve cells. muscle position and tone. The body (axons) protruding from the neuron needs this information, which he and are transmitted to neighbouring 1967 Levodopa becomes the called proprioception, to control cells by chemical messengers (called first effective drug treatment movement and posture. neurotransmitters) across a synapse. for a neurodegenerative condition (Parkinson’s disease). Back in 1626, French philosopher Ancient observations and scientist René Descartes had As far back as ancient Egypt, the 1993 A disease-associated observed reciprocal innervation – Edwin Smith papyrus notes how gene (for Huntington’s disease) the way the activation of one muscle brain injuries are associated with is mapped to a human influences the activity of others – but changes in the functioning of other chromosome for the first time. Sherrington’s studies in the 1890s body parts, and describes the brain’s clarified how the process works. The nervous system The neuron (nerve cell) Charles Scott Sherrington is understood to govern is established as shows that neurons communicate via bodily functions, the basic unit of the electric pulses and reactions, thoughts, nervous system. across a synapse The integrated (meeting point) by and emotions. neural network This approach chemicals, and are part transforms brain forms a new approach of an integrated imaging, surgery, to understanding neural network. and drug treatments for neurological conditions. the nervous system.

VACCINES, SERUMS, AND ANTIBIOTICS 193 See also: Anatomy 60–63 ■ Histology 122–23 ■ Alzheimer’s disease 196–97 ■ Electroencephalography 224–25 ■ MRI and medical scanning 278–81 exterior folds and the colourless fluid The brain is a world Charles Scott surrounding it – the cerebrospinal consisting of a number of Sherrington fluid (CSF) that provides physical and immune protection. unexplored continents Born in London, UK, in 1857, and great stretches Charles Scott Sherrington Using a mixture of observation of unknown territory. studied medicine at Cambridge and philosophy, the ancient Greeks University and was inspired to were the first to attempt a detailed Santiago Ramón y Cajal begin serious neurological description of the nervous system. research after attending a Hippocrates pioneered the concept Spanish neuroscientist (1852–1934) lecture on nerve function at a of the brain as the seat of cognition, medical conference in 1881. A thought, sensations, and emotion CNS. This pointed to the existence year spent at Berlin University, in the 4th century bce. In the 3rd of the autonomic nervous system, under the tutelage of German century bce, Herophilus understood which connects the CNS with the microbiologist Robert Koch, the brain and spinal cord’s combined heart, lungs, stomach, bladder, and gave him a good grounding in role in what we now call the central sex organs, and which operates physiology and histology. nervous system (CNS). This gathers without us thinking about it to information from the rest of the regulate involuntary functions such Between 1892 and 1913, body and our external environment, as breathing and heartbeat. Sherrington conducted his and controls movement, sensations, seminal research into reflex thought, memory, and speech. He Increasing knowledge reactions, the nerve supply of identified six of the cranial nerves, There is evidence of early attempts muscles, and how neurons and also the peripheral nerves that to treat neurological disorders. In communicate, while teaching link the brain and spinal cord to the Muslim Spain around 1000 ce, for at the universities of London rest of the body’s organs, muscles, example, al-Zahrawi operated on and Liverpool. In 1932, when limbs, and skin. patients with hydrocephalus (excess he was a tutor at Oxford cerebrospinal fluid in the brain), and University, he shared the Nobel By dissecting animals’ brains in with head and spinal injuries, but Prize in Physiology or Medicine the 2nd century ce, Roman physician there was little progress in neural with Edgar Adrian for their Galen of Pergamum established that understanding until the 16th-century work on the function of neurons. the nerves directing motor functions revival in human dissection. Three of Sherrington’s Oxford and those linked to the senses are students went on to become controlled by different parts of the In 1543, Flemish anatomist Nobel laureates. He retired Andreas Vesalius published De from Oxford in 1936, and died Humani Corporis Fabrica (On the of heart failure in 1952. Structure of the Human Body), ❯❯ Key works De Humani Corporis Fabrica depicted the different brain regions 1906 The Integrative Action and the cranial nerves (seen here of the Nervous System from below), which originate from 1940 Man on His Nature the cerebrum and the brainstem.

194 THE NERVOUS SYSTEM which included thorough Nerve cell Synapse descriptions of the human brain (neuron) based on his dissection of cadavers. This book transformed anatomical The axon conducts knowledge and medical practice. Its electrical signals neurological information was later to other cells. supplemented by English physician Thomas Willis, who elucidated the Dendrites receive Receptor brain and cranial and spinal nerves, electrical signals Neurotransmitters providing explanations of their from other cells. (chemical messengers) function, in the early 17th century. The axon terminal transmit signals to contains vesicles, receptors on the In 1791, Italian physicist and which release receiving neuron. physician Luigi Galvani published neurotransmitters. his description of an important breakthrough: his observation that Nerve signals travel along neurons in electrical form, but pass a dead frog’s legs twitch when in between them – or from neurons to cells in muscles and glands – contact with a spark. His discovery across synaptic junctions in chemical form. Neurological disorders of bioelectricity was the first may occur if this communication between cells is disrupted indication that nerves function through viral infections, drug use, ageing, or genetic factors. by electrical impulses, and that the electrical stimulation of nerves produces muscle contraction. Understanding disease by lesions in the cervical spinal He went on to detail particularly The growing understanding of cord, his systematic and analytical large neurons (now called Purkinje brain structure and nervous system approach was significant. cells) with branching, thread-like function gave scientists new means extensions in the cerebellum. of studying neurological and Parkinson’s was one of several In 1863, German anatomist Otto psychological diseases. In 1817, diseases studied between 1868 and Deiters described these extensions British surgeon James Parkinson 1891 by French clinical neurologist (later known as dendrites), which described the symptoms of six Jean-Martin Charcot. He also conduct messages to neurons, and people suffering “the shaking described multiple sclerosis (MS), also identified the cell’s axons – thin palsy” (later renamed Parkinson’s which damages the insulating fibres that conduct messages away disease). Although he wrongly sheath of nerve cells in the brain and from neurons. believed the disease was caused spinal cord, and noted three signs of MS, subsequently known as The first anatomical proof that The brain seems a Charcot’s triad. Modern psychiatry different parts of the brain performed thoroughfare for nerve-action also owes much to Charcot, who is specific functions was presented in probably best known for his use of the early 1860s by French anatomist passing its way hypnosis to study the symptoms Paul Broca. He discovered that to the motor animal. of hysteria while teaching at the aphasia (the inability to understand Charles Sherrington Salpêtrière School in Paris. and formulate language) was linked to lesions in part of the frontal lobe The Brain and its Mechanism, 1933 Age of the microscope of the brain (later named Broca’s In the early 19th century, better area) after conducting autopsies on quality achromatic microscopes recently deceased patients. created the new field of histology – the microscopic study of cells and During the 1870s, Italian biologist tissues – which led to a number and pioneering neuroanatomist of neurological revelations. Czech Camillo Golgi produced detailed anatomist Johann Purkinje was the descriptions of the spinal cord and first to describe a neuron in 1837. the brain’s olfactory lobe, cerebellum, and hippocampus. In 1873, he

VACCINES, SERUMS, AND ANTIBIOTICS 195 Neurotransmitter Major neurotransmitters in the body Acetylcholine Role in the body Dopamine All body movements are controlled by this neurotransmitter, which activates muscles. In the brain, Gamma-aminobutyric acid it plays a role in memory, learning, and attention. (GABA) Linked to the brain reward system, this neurotransmitter produces feelings of pleasure, affecting mood Glutamate and motivation. It also influences movement and speech. This neurotransmitter blocks or inhibits brain signals, decreasing activity in the nervous system to allow Glycine processes such as sleep or the regulation of anxiety. Noradrenaline The predominant neurotransmitter in the brain and central nervous system, glutamate stimulates brain (or norepinephrine) activity and is critical for learning and memory. Serotonin Used mainly by neurons in the brainstem and spinal cord, glycine helps the body process motor and sensory information. Part of the body’s flight-or-fight response, this neurotransmitter is released into the bloodstream as a stress hormone. It regulates normal brain processes including emotions, learning, and attention. This neurotransmitter regulates many body processes and influences mood, appetite, and memory function. It also plays a role in managing our response to pain. invented a new staining technique German pharmacologist Otto Loewi electron microscope. This enabled using silver nitrate, which showed confirmed its role as a chemical scientists to examine much smaller the intricate structure of neural neurotransmitter in 1926. So far, elements of the nervous system, cells on a microscope slide much more than 200 neurotransmitters including the synapses described more clearly. This was the second have been identified. but never seen by Sherrington. great technological enabler. In 1924, German psychiatrist New technologies, such as Golgi went on to propose that the Hans Berger performed the first magnetic resonance imaging (MRI) brain is made up of a single network human electroencephalogram (EEG). and computed tomography (CT) (or reticulum) of nerve fibres, through Able to record brain activity by scanning, continue to widen the which signals pass unimpeded. This detecting the electrical signals fired applications of Sherrington’s initial reticular theory was challenged at by neurons, EEG tests allowed findings. They currently fuel research the time by Spanish neuroscientist British physiologist Edgar Adrian on behaviour, brain function, the Santiago Ramón y Cajal, who argued to conduct detailed studies of brain efficacy of drugs for neurological that the nervous system is a function in the 1930s. conditions, brain surgery, and the collection of many individual, but causes and effects of diseases such interconnected, cells. Cajal’s view In 1952, two British scientists, as epilepsy and Alzheimer’s. ■ came to be known as the “neuron Alan Hodgkin and Andrew Huxley, doctrine”. Supported by Sherrington, published their research on the this theory was proved to be correct nervous system of squid. This work, in the 1950s, when new electron now known as the Hodgkin-Huxley microscopes were able to show the model, showed how electrical connections between cells. signals are generated in nerve cells. Later advances By this time, the third great New discoveries continued during technological leap forward had the 20th century, many based on occurred – the invention of the Sherrington’s landmark description of neural pathways. In 1914, British Magnetic resonance imaging (MRI) physiologist Henry Dale noted the is often used to provide detailed images effect of acetylcholine on nerve cells. of the brain for diagnostic purposes, such as detecting dementia, tumours, injury, stroke, or developmental issues.

196 DCAIEPSREEECABUSRLEAIOALRFCTOHRETEX ALZHEIMER’S DISEASE IN CONTEXT D ementia is not a disease, In 1906, he gave a lecture on “a but a blanket term used peculiar disease of the cerebral BEFORE to describe a number of cortex” based on a study of Auguste 6th century bce The Greek conditions associated with a decline Deter, a patient at a Frankfurt philosopher Pythagoras of in brain function, such as memory asylum. Alzheimer had begun Samos describes mental and impairment, loss of physical and observing Deter in 1901 (when she physical decay in old age. social skills, and a decline in was 51) on account of her problems intellectual ability. It has many with memory and language as well 1797 Philippe Pinel uses the causes, including chronic alcohol as disorientation and hallucinations. term “dementia”, derived from abuse, strokes (often leading to Her symptoms had matched those the Latin for “out of the mind” vascular dementia in which the of dementia, but Alzheimer had to describe a gradual decline brain’s blood vessels are damaged), diagnosed “presenile dementia” in brain function. Creutzfeldt-Jakob disease (a fatal because of her relatively young age. brain disorder), and Alzheimer’s 1835 British physician James disease – an irreversible and After Deter’s death in 1906, Cowles Prichard uses the term ultimately fatal neurogenerative Alzheimer had sought and received “senile dementia” to describe disease that accounts for two-thirds permission to perform an autopsy on a state characterized by of dementia cases. “forgetfulness of recent impressions” in the elderly. Early-onset dementia Like other causes of dementia, AFTER Alzheimer’s disease generally 1984 American biochemists affects the elderly, but it is also the George Glenner and Caine most common form of early-onset Wong isolate beta-amyloid, the dementia, found in those aged under protein that forms plaque in the 65. The disease was identified as brains of Alzheimer patients. a distinct cause of dementia by Alois Alzheimer, a German psychiatrist. 1993 Tacrine is the first cholinesterase inhibitor Plaque formed from the beta-amyloid drug for Alzheimer’s, but is protein in the brain is characteristic of withdrawn from general use Alzheimer’s disease. Clumps of plaque in 2013 due to safety concerns. (orange in this illustration) block the synapses between nerve cells (blue).

VACCINES, SERUMS, AND ANTIBIOTICS 197 See also: Humane mental health care 92–93 ■ Inheritance and hereditary conditions 146–47 ■ The nervous system 190–95 ■ MRI and medical scanning 278–81 ■ Genetics and medicine 288–93 ■ Stem cell research 302–03 Cerebral How Alzheimer’s progresses Severe cortical cortex shrinkage Cortical shrinkage Hippocampus Shrinking Severe shrinkage The hippocampus and cortex are hippocampus of hippocampus the parts of the brain involved with As the hippocampus shrinks, As the cortex becomes thinner, memory. Alzheimer’s disease causes it becomes harder to learn new distant memories are also lost. As the these areas to atrophy (waste away). information. Mild cortical shrinkage brain tissue dies, the body loses its affects short-term memory. ability to function, leading to death. her brain. He had found extensive physicians look for these plaques levels of acetylcholine, a chemical atrophying in the cortex, the part and tangles in brain scans when that helps to send messages of the brain involved in memory, diagnosing Alzheimer’s disease. between neurons. language, and thought in general. On examining thin slices of brain A growing problem The causes of Alzheimer’s tissue under the microscope, Like other forms of dementia, the disease are still not understood. Alzheimer found insoluble protein incidence of Alzheimer’s has risen Scientists think that early-onset deposits, or plaques, and twisted with increased life expectancy. forms may be the result of a genetic protein threads (neurofibrillary Worldwide, there are approximately mutation, while late-onset may tangles) that impede the electrical 50 million people with dementia, arise from a combination of genetic, impulses between neurons (nerve including 5–8 per cent of people lifestyle, and environmental factors cells). He was not the first person to over the age of 60. There is currently that trigger changes to the brain note these signs, but this was the no cure for Alzheimer’s, although over decades. A healthy diet, first time they had been seen in cholinesterase inhibitor drugs can exercise, and mental stimulation someone as young as Deter. Today, alleviate symptoms by boosting the may reduce the risk of getting Alzheimer’s, but there is little proof. ■ Alois Alzheimer Born in Markbreit, a small village the following year, Kraepelin in Bavaria, Germany, in 1864, named the disease after Alzheimer Alois Alzheimer excelled in in the 1910 edition of his textbook science at school. He went on to Compendium of Psychiatry. study medicine in Berlin, Tübingen, and Würzburg. After graduating In 1913, on his way to take in 1887, he joined the staff at the up the post of chair of the state asylum in Frankfurt, where department of psychology at the he studied psychiatry and Friedrich-Wilhelm University, in neuropathology and began to Berlin, Alzheimer caught an research the cortex of the brain. infection from which he never fully recovered. He died in 1915, In 1903, Alzheimer became at the age of 51. assistant to Emil Kraepelin, a psychiatrist at the Munich medical Key work school. After Alzheimer described Auguste Deter’s form of dementia 1907 “About a Peculiar Disease in 1906 and published his lecture of the Cerebral Cortex”

198 BMUALGLICETS TARGETED DRUG DELIVERY IN CONTEXT A t the dawn of the 20th that the chemical structure of drugs century, German scientist needed to match the organisms BEFORE Paul Ehrlich devised an that they were targeting in order 1530 Paracelsus pioneers the entirely new way of treating disease to be effective. use of mercury as a treatment using chemical drugs. He described for syphilis. his compounds as “magic bullets”, In 1890, German physiologist because they were formulated Emil von Behring and Japanese 1856 William Henry Perkin to hit disease-causing microbes physician Shibasaburo Kitasato discovers mauveine, the first (pathogens) hard, while leaving discovered that antitoxins made by synthetic organic dye. the body unharmed. the body in response to a pathogen could be used to prevent disease. 1882 Élie Metchnikoff The idea occurred to Ehrlich Ehrlich theorized that the antitoxins discovers macrophages. while he was investigating the involved in this immune response synthetic dyes discovered in 1856 were chemical receptors or “side- 1890 Emil von Behring by teenage British chemistry student chains” attached to cells, just like and Shibasaburo Kitasato William Henry Perkin. Ehrlich was the structures he had observed on discover the first antitoxin. fascinated by the way that some dyes. He believed that these side- dyes, particularly methylene blue, chains (antibodies) exactly fitted AFTER stained animal tissues dramatically, the side-chains on pathogens like 1932 German pharmaceutical while others didn’t, allowing cells to a lock and key. If he could find a dye company Bayer introduces be differentiated in the laboratory. with exactly the right side-chain, he Prontosil (sulphonamide), the It was clear to Ehrlich that there would have his magic bullet. first drug broadly effective was some connection between the against bacteria. chemical structure of the dyes and Targeting syphilis living cells. He became convinced In 1905, German scientists Erich 1943 Penicillin, the first Hoffmann and Fritz Schaudinn, naturally occurring antibiotic working together in Berlin, found to be developed as a drug, Treponema pallidum, the bacterium is prescribed to treat syphilis, responsible for syphilis, a disease and becomes the standard therapy for this disease. Ehrlich’s illustration of side-chain theory, from his Croonian Lecture, 1900, 1970s Tamoxifen, a targeted proposed that body cells form receptors cancer therapy, is launched. specific to a particular substance or pathogen, which lock together.

VACCINES, SERUMS, AND ANTIBIOTICS 199 See also: Pharmacy 54–59 ■ Cancer therapy 168–75 ■ Bacteriophages and phage therapy 204–05 ■ Antibiotics 216–23 ■ Monoclonal antibodies 282–83 Natural antitoxins Dye molecules have have side-chains side-chains that match that bind to pathogens. chemical structures in organisms. A dye with the correct side-chain Paul Ehrlich can lock on to a particular pathogen. Born in 1854 in Strehlen, This dye can be a magic bullet that is toxic to Germany, Paul Ehrlich studied the pathogen but leaves the body unharmed. medicine before concentrating his research on how dyes stain that had ruined lives for centuries. effects if not stored correctly. In 1912, animal tissues. His work on Ehrlich decided to make this Ehrlich’s laboratory developed a less dye classification and tissue bacterium his first target. toxic version, Neosalvarsan. staining laid the foundations for the science of haematology. Working in the laboratories of While Ehrlich’s dream of finding the Hoechst chemical company, a chemical magic bullet to treat In 1890, Ehrlich joined Ehrlich and his team started with every disease has not been realized, Robert Koch at the Institute for a dye synthesized from an arsenic his immunological breakthrough Infectious Diseases, and began compound, atoxyl. They tried established the concept of to focus on immunology. Over hundreds of variations to find an chemotherapy, launched a global the next 20 years, Ehrlich exact match. In 1907, they found one: pharmaceutical industry, and proved that the body makes the arsenic-based arsphenamine, fuelled the invention of countless antibodies that can target which they called “compound 606”. other drugs. ■ specific germs using chemical The team tried this formulation on structures that hook together. patients in the terminal stages of Success in research needs … For this groundbreaking syphilis, and found that several luck, patience, skill, discovery he was awarded made a complete recovery. Clinical and money. the Nobel Prize in Physiology trials soon showed that 606, given Paul Ehrlich or Medicine in 1908, along the trade name Salvarsan, was most with Élie Metchnikoff for his effective if administered in the early discovery of macrophages. stages of the disease. Salvarsan was Ehrlich’s magic bullet drug launched in 1910 and by the end of Salvarsan was launched in the year, nearly 14,000 ampoules a 1910, but controversies day were being produced. surrounding the drug took a toll on his health and he died While Salvarsan was the first from a heart attack in 1915. effective treatment for syphilis, it was difficult to administer safely, Key works and could have devastating side 1900 Croonian Lecture: “On immunity with special reference to cell life” 1906 “The Tasks of Chemotherapy”

200 IN CONTEXT FUESOSNURSKBESNLNOTIFTAWEINANCLES BEFORE c.1500 bce The ancient VITAMINS AND DIET Egyptians recognize that night blindness can be treated with specific foods. 1747 James Lind shows that citrus fruit is an effective treatment for scurvy. 1881 Russian biochemist Nikolai Lunin proposes that some foods contain “unknown substances essential for life”. AFTER 1929 Christiaan Eijkman and Frederick Hopkins are awarded the Nobel Prize in Physiology or Medicine for their work on vitamins. 1931 Albert Szent-Györgyi suspects that hexuronic acid (since renamed ascorbic acid) is vitamin C, and its effectiveness in curing scurvy is later confirmed. V itamins are essential nutrients that every animal needs in small amounts to remain healthy. The human body needs 13 different vitamins. Nearly all must be obtained through diet as they cannot be produced by the body. Vitamins work with other nutrients to ensure that cells function well. When any are absent, ailments or diseases develop, and some can prove fatal. Despite their importance, the discovery of vitamins is relatively recent. In 1912, Casimir Funk, a Polish-born biochemist, coined the term “vitamine” when he published his hypothesis that deficiency diseases, such as rickets, pellagra, and beriberi, are caused by a lack