The Medicine Book

GLOBAL HEALTH 251 prescribe the drug to human The transplant patients match those of the patient. The transplant patients. Nonetheless, that I’ve treated closer the match, the less likely it is only a few of his patients survived. that an organ will be rejected. This have become members is called tissue typing. A breakthrough came in 1963, of what you might consider when American surgeon Thomas Liver transplants Starzl gave his transplant patients an extended family. As kidney transplants became more azathioprine immediately after the Thomas Starzl common in the 1960s, surgeons operation. If it looked as though began to explore the possibility of their body was going to reject the The New York Times, 2009 liver and heart transplants. Livers donor heart, he also gave them a were much bigger and more complex huge dose of steroid drugs, which called human leucocyte antigens than kidneys, and there was no suppress the immune system. The (HLAs) on the outside of cells. machine to stand in for the liver combination of azathioprine and These are like chemical passports. during an operation. In addition, steroids significantly boosted From the pattern of HLAs on a cell, whole livers can only come from dead patients’ chances of survival. the body’s immune system can donors, and are sensitive to a lack instantly recognize whether cells of blood supply. They must be taken Around this time, biochemists are its own or foreign and therefore out of the body and chilled within at the Swiss drug company Sandox to be rejected. No two people have 15 minutes of the donor’s death. were investigating soil samples for the same HLAs (apart from some fungi that might be a source of identical twins), but some are more In 1963, Thomas Starzl in the antibiotics. Examining a soil sample similar than others. Blood relatives US and Roy Calne in the UK both from Norway, they found the fungus are more likely to have similar HLAs attempted the first liver transplants, Tolypocladium inflatum, from which than people who are unrelated. on patients who would certainly die they extracted a substance called Blood tests on potential donors otherwise. The patients survived cyclosporine, an immunosuppressant can show how closely their HLAs the operations, but the livers were with few toxic side effects. Licensed then rejected and both patients for use in the early 1980s, the drug died. This remained the pattern for revolutionized transplant surgery, the next 20 years, with three out reducing the chance of organ of four liver transplant recipients rejection and stopping patients dying within a year. But when from succumbing to infections. cyclosporine became available in the early 1980s, the situation was Researchers were also finding transformed. Today, nine out of ❯❯ better ways to identify suitable donors by using marker proteins Christiaan Barnard Born the son of an impoverished donor. He retired from heart preacher in Western Cape, South surgery at the age of 61 after Africa, in 1922, Christiaan Barnard developing rheumatoid arthritis decided to become a heart surgeon in his hands. During his when one of his brothers died from remaining years, he wrote a heart disease at the age of five. novel and two autobiographies, He became world-famous in 1967, and established the Christiaan when he carried out the first Barnard Foundation to aid human heart transplant, in Cape underprivileged children. Town, South Africa. Barnard died in 2001, aged 78. Barnard went on to perform Key works “auxiliary transplants”, which involved placing a healthy heart 1970 One Life alongside the patient’s ill heart. 1993 The Second Heart He also pioneered the use of 1996 The Donor monkey hearts to keep patients alive while waiting for a suitable

252 TRANSPLANT SURGERY A reconstruction of the first heart transplant was created in 2017 to mark the 50th anniversary of the event. The tableau is displayed in the museum at Groote Schuur Hospital, Cape Town. ten liver transplant patients survive Shumway waited for a suitable The operation was successful. for at least a year and many regain patient and donor, South African Washkansky’s new heart started full health. surgeon Christiaan Barnard beat to beat and everything looked him to it. Making headlines around fine for a few days. However, Heart transplants the world, Barnard used Shumway his immune system was badly The ultimate challenge in transplant and Lower’s techniques to carry weakened by the drugs he had surgery was a heart transplant. In out the world’s first human heart taken to stop rejection of the the early 1950s, Russian scientist transplant on 3 December 1967, new heart. Washkansky died Vladimir Demikhov carried out at Groote Schuur hospital in Cape from pneumonia 18 days after the heart transplants on dogs, but his Town. Barnard’s patient was Louis operation. Nevertheless, the era success rate was patchy. It was Washkansky, a 54-year-old grocer. of heart transplants had begun. difficult to take the old heart out The donor heart came from a young With the arrival of cyclosporine and insert the new heart without woman who had been killed by a in the early 1980s, the success the dogs dying. In the late 1950s, car while crossing the road. rate soared. surgeon Norman Shumway of Stanford University in the US Heart–lung transplants Donor shortages discovered he could stop a patient’s Heart transplants are limited by a heart beating and the blood flowing Many heart transplant patients shortage of donors. Almost half the while it was taken out simply by have damaged lungs as well. As kidneys for transplants come from chilling it with ice-cold water. He heart transplants began to seem living donors. They are carefully also invented an improved artificial feasible, surgeons also started selected to be a good match, heart machine to pump the blood to think about combined heart– with many willingly donated by until the new heart was working. lung transplants. relatives. Hearts, however, have Together with pioneering cardiac to come from donors who have surgeon Richard Lower, Shumway In 1968, just a year after the died. A patient can die waiting practised taking hearts out of dead first heart transplant, American for a donor. Donor hearts may bodies and putting them in again. surgeon Denton Cooley carried become available in a location out the world’s first heart–lung After practising on dog hearts transplant, on a two-month-old University decided to try again for several years, Shumway decided baby. The baby survived just because the newly licensed drug it was time to try a human heart 14 hours. The idea was then cyclosporine gave a better transplant, even though there was abandoned until 1981, when chance of success. The patient still a major risk of rejection. While surgeon Bruce Reitz of Stanford was 45-year-old Mary Gohlke. The operation worked and Mary survived for five years. Nowadays, almost half of heart–lung transplant patients survive for at least five years. However, a shortage of donors and the rapid deterioration of lung tissue after the donor’s death limit the number of heart–lung operations.

GLOBAL HEALTH 253 The list of organs and tissues that can be transplanted is growing. Hands and faces have recently been added to the organ transplant list. So far, only a few hundred hand or face transplants have taken place around the world. It is infinitely better Face transplants Corneal donors to transplant a heart are particularly don’t have to than to bury it to be complex, match recipients devoured by worms. because multiple like organ Christiaan Barnard types of tissue donors do. are involved. Time magazine, 1969 50 per cent of 72 per cent of patients who heart transplant far away from the patient, or at have received patients survive the wrong time. Procuring and lung transplants for at least five transporting the heart, and setting are alive five years. Some live up the operation, is a race against years later. for more than the clock. Starved of oxygen, the Living donors 30 years. heart tissue starts to deteriorate can donate a Hand transplants within four to six hours of being portion of their can restore harvested from the donor. liver, pancreas, function in ways or intestine. that artificial limbs cannot. Kidneys can be donated by living as well as deceased donors. Electric hearts infection a short while after the Tissues can also Powered by an electric battery, natural heart was implanted. Some be transplanted. “total artificial hearts” (TAHs) surgeons condemned Cooley for Skin is used by could be the answer to donor heart implanting a device that they did burns victims. shortages. In the 1960s, Domingo not consider ready to be tried on Liotta, an Argentinian cardiac humans. Nonetheless, as more it revived when the shortage of specialist working in the US, and patients rejected their new heart donors became more acute in the American surgeon O.H. “Bud” and died, some surgeons wondered 21st century, partly because TAH Frazier tried using TAH technology whether electric hearts could be the technology allowed patients with at the Texas Heart Institute in answer, and not just as bridges. end-stage heart failure to wait longer Houston. These early artificial for a transplant. hearts were called bridges because An electric heart called the they were meant to keep a patient Jarvik-7 was given to a number of Electric hearts have not become alive only until a donor could be dying cardiac patients in the US long-term replacements for diseased found. They included an external air in the early 1980s, one of whom hearts as first hoped. Most cardiac pump kept by the side of the patient. survived for two years. Interest surgeons believe it will be hearts in electric hearts began to wane grown in a laboratory from stem cells In 1969, American heart surgeon when the immunosuppressant and other cloned organs that will Denton Cooley, who had already cyclosporine boosted the survival revolutionize transplant surgery, carried out 29 transplants, was rate of donor heart transplants, but though their use is still some way confronted with a patient called off. Meanwhile, kidney, liver, and Haskell Karp who would die within heart transplants continue to save days because no donor heart was tens of thousands of lives each year available. Cooley implanted a TAH. and are among the medical world’s A donor heart was found two and a most remarkable achievements. ■ half days later, but Karp died from an

254 BMAUOPTLREOUCMNURILSUEILNYG INTERFERON IN CONTEXT I nterferon – named for its ability In science, to interfere with infections – is as in showbusiness, BEFORE any of several proteins in the there really is no such thing 1796 Edward Jenner performs large class of cytokines and is part as an overnight sensation. the first effective inoculations of the body’s natural defence against Mike Edelhart and against the smallpox virus. viruses. Alick Isaacs and Jean Jean Lindenmann Lindenmann, virologists at the UK’s 1882 Élie Metchnikoff National Institute for Medical Interferon, 1981 discovers phagocytes – cells, Research, first described it in 1957. including macrophages (large alpha interferon gene at a Swiss white blood cells), that attack, Viruses spread within the body laboratory led to the mass production engulf, and destroy germs. by hijacking cells. Cells infected by of alpha and other interferons. viruses release interferons to slow 1931 German physicist Ernst down cell replication, curtailing the In animal research, interferon’s Ruska invents the electron progress of the virus, and to block ability to suppress cancer had microscope, which enables the future infections. Interferons also appeared highly promising, but first detailed studies of viruses spread to healthy cells, alerting them patients experienced serious side and their effects on the body. to the danger and limiting their effects, including flu-like symptoms, replication. There are three main nausea, and severe depression. In AFTER types of interferon – alpha, beta, and low doses, however, interferon is 1959 Jacques Miller discovers gamma – with slightly varying roles. still used to treat various cancers, T-cells, which are essential hepatitis, and multiple sclerosis. ■ for the immune response to Initially, there was considerable viruses; T-cells are later found excitement about the potential of to produce the gamma form interferon to make antiviral drugs of interferon. and, because it interferes with cell growth, to treat cancer. In the 1960s, 2016 In the US, Matthew Finnish scientist Kari Cantell found Halpert and Vanaja Konduri that infecting white blood cells pin down the role of dendritic with the Sendai virus triggered cells which, together with them to produce alpha interferon. macrophages, produce the In 1980, genetic engineering of the alpha form of interferon. See also: Vaccination 94–101 ■ The immune system 154–61 ■ Virology 177 ■ Antibiotics 216–23 ■ HIV and autoimmune diseases 294–97

GLOBAL HEALTH 255 PFAAOSTREIENTNHSTEATION PACEMAKERS IN CONTEXT T he human heart beats more Elmqvist moulded the components than two billion times in the from resin in a plastic cup, and BEFORE average lifetime – usually Senning implanted it on 8 October 1887 Augustus D. Waller with great regularity. However, the 1958. Although it had to be replaced measures the electrical activity hearts of around three million people the next morning, a second model that precedes every heartbeat. across the world rely on the stimulus worked perfectly. Larsson went on to provided by an artificial pacemaker receive 25 more pacemakers over the 1903 Willem Einthoven’s to keep their heartbeat on track. next 43 years and died aged 86. electrocardiograph measures cardiac activity and displays a From bulky to minute Patient-controlled, variable-rate reading – known as an In 1951, Canadian engineer John pacemakers arrived in 1960 and electrocardiogram (ECG). Hopps developed the first effective lithium batteries, introduced in 1972, pacemaker – an external, bulky, extended battery life from around 1928 Australian doctors Mark mains-powered machine, which the two to 10 years. Recent innovations Lidwill and Edgar Booth use a patient wheeled around on a trolley. include pill-sized pacemakers and needle attached to an electrical Seven years later, aided by the sensors that enable the devices to power source to revive the invention of small batteries and tiny change the heart pace automatically heart of a stillborn baby. transistors to control the signal, according to body activity. ■ Swedish engineer Rune Elmqvist AFTER and cardiac surgeon Åke Senning 1990s Microprocessor-driven created a pacemaker that could be pacemakers modify pacing implanted in the chest. automatically according to the patient’s needs. Else-Marie Larsson persuaded the pair to try out the device on her 2012 Heart surgeons at dying husband, Arne. Short of time, Homolka Hospital in Prague, Czech Republic, implant a An X-ray shows a pacemaker wireless pill-sized pacemaker. implanted just below the collarbone. Its wire, guided into the right ventricle, 2019 American and Chinese carries an electrical pulse to the heart. scientists invent a battery-free See also: Blood circulation 68–73 ■ The stethoscope 103 pacemaker that harvests its ■ Electrocardiography 188–89 ■ Transplant surgery 246–53 energy from the beating heart.

256 ROTHEUSERPCIOMENNMSTUERNEEOF LYMPHOCYTES AND LYMPHATICS IN CONTEXT T he lymphatic system is the The discovery that lymphocytes body’s main circulating circulate between the lymphatic BEFORE drainage system, and a key system and the blood was made by 1651 French scientist Jean defence against infection. Its many British physician James Gowans Pecquet highlights the role vessels, or lymphatics, wash toxins in 1959. This was a crucial step of the thoracic duct (the main and other waste away in lymph in understanding the central role lymphatic vessel). fluid, while lymphocytes (a type of that lymphocytes and lymphatic white blood cell) identify and fight circulation play in the body’s 1652 Thomas Bartholin shows germs that enter the system. immune system. the lymphatic vessels extend throughout the body, and The lymphatic system includes key organs – such The thymus coins the term “lymphatics”. as the thymus, bone marrow, and spleen – in which enables lymphocytes are produced and matured. Activation T-cells 1701 Dutch anatomist of lymphocytes takes place in lymph nodes (small to mature. Frederik Ruysch describes “glands”), where the lymphocytes detect antigens. lymphatic circulation. Lymphocytes travel 1770 William Hewson in the lymph, and are identifies tiny round cells that activated on contact are later called lymphocytes. with an antigen. 1784 Italian anatomist Paolo Mascagni describes how The spleen filters blood and brings lymphatics must drain the it into contact with lymphocytes. spaces between body cells Bone marrow produces and end up in lymph nodes. precursors of T-cells and B-cells; B-cells remain and mature there. AFTER: Lymph vessels transport 1959 French-born scientist lymph and its infection-fighting Jacques Miller discovers lymphocytes around the body. T-lymphocytes, or T-cells. Lymph nodes filter lymph to remove 1980 Researchers establish damaged cells and germs, and house the way T- and B-lymphocytes lymphocytes that fight antigens. They give adaptive immunity. cluster at the armpits, groin, and neck.

GLOBAL HEALTH 257 See also: Blood circulation 68–73 ■ Vaccination 94–101 ■ The immune system 154–61 ■ Cancer therapy 168–75 ■ Targeted drug delivery 198–99 ■ Monoclonal antibodies 282–83 Society and humanity tissue that filters the lymph to Lymphocytes are white blood cells, as a whole are trap germs and toxins. Lymph also including B-cells and T-cells, which carries lymphocytes, tiny pale blood respond to and remember specific richer for [Gowans’] work. cells found in places such as the invaders. B-cells (shown here) release Andrew Copson spleen and lymph nodes. They were antibodies against a particular antigen. first described in 1770 by British CEO of Humanists UK (1980–) surgeon William Hewson, but their the antibodies around the body. He function was not understood. showed that lymphocytes react with Earlier knowledge Lymphocytes had already been antigens (molecules on a pathogen’s An early description of lymph nodes detected in inflammatory reactions surface) to instigate an immune (small “glands” where lymphocytes and bacterial diseases, but until response. They are now recognized cluster) was recorded by the Greek James Gowans’ discovery it was as the central cells of the body’s physician Hippocrates in the 5th assumed that lymphocytes were targeted, adaptive immune system. ■ century bce, and Galen of Pergamum short-lived cells because they in the 2nd century ce wrote about seemed to vanish from the blood. lymphatic system. He was the lymphatic vessels. Only during the Society’s research professor for 1650s did Danish physician Thomas Gowans’ breakthrough was to 15 years, and head of the UK’s Bartholin and Swedish scientist show these cells do not vanish, Medical Research Council in Olaus Rudbeck independently but are absorbed into the lymph 1977–87. In 1989, he became discover that lymphatics extend system, then circulate through the the first secretary-general throughout the whole body. Over tissues and lymph nodes, before of the Human Science Frontier the following centuries, scientists returning into the blood. Far from Program, based in Strasbourg, gradually pieced together how the being short-lived, lymphocytes France. Gowans was knighted system and its circulation worked. can live for up to 15 years, with the in 1982, and died in 2020. same cells continually recirculating. A vital system Gowans went on to suggest that Key works Once blood has delivered nutrients lymphocytes are the cells that carry and oxygen to body cells, it carries antibodies, and that by circulating 1959 “The recirculation of away cell waste in blood plasma. through the tissues, they spread lymphocytes from blood to Most of the plasma stays in the lymph in the rat” bloodstream, but some, along with James Gowans 1995 The mysterious lymphocyte other fluids, seeps into body tissues. 2008 The origin and function of From there, it drains into the Born in Sheffield, UK, in 1924, lymphocytes lymphatic vessels as lymph. James Gowans took a degree in medicine at King’s College, Lymph is a clear fluid, like blood London. He graduated in 1947 plasma. It slowly moves around after volunteering as a medical the body, removing the cell waste, student at the newly liberated before returning to the bloodstream. Bergen-Belsen concentration Throughout the system are around camp at the end of World War II. 600 nodes filled with a meshlike Gowans attended Oxford University and in 1955–60 was a medical research fellow at Exeter College, where he conducted his pioneering work on lymphocyte recirculation. Gowans was elected to a fellowship of the Royal Society in 1963 for his work on the

258 TTHOEDPEOCWIDEER HORMONAL CONTRACEPTION IN CONTEXT I n the mid-20th century, the two were unaware of the Pill’s possible main forms of contraception side effects, such as dizziness, BEFORE were condoms and diaphragms, nausea, headaches, and blood clots. 1920s American scientist yet the scientific basis of hormonal George W. Corner pinpoints contraception had been understood In 1960, the US Food and Drug the role of progesterone and since the 1920s. In the US in 1951, Administration approved Enovid as oestrogen in the female birth control crusader Margaret an oral contraceptive, despite the reproductive cycle. Sanger challenged Gregory Pincus, side effects of such high levels of a biologist, to develop a hormonal hormones (they were halved in 1961). 1930s Scientists in both contraceptive in pill form. Around Because it was based on the work of Europe and the US isolate the same time, chemist Carl Pincus and Djerassi, both men are oestrogen and progesterone. Djerassi, working for the drug known as the “father of the Pill”. ■ company Syntex in Mexico City, AFTER synthesized norethindrone, an 100 1965 Around 6.5 million artificial version of progesterone, American women are using the female sex hormone. EFFECTIVENESS (%) 80 the Pill, rising to 151 million women worldwide in 2019. Pincus knew that high levels of 60 98 82 progesterone inhibited ovulation in 99 91 1968 Pope Paul VI issues an laboratory animals. By 1953, with encyclical banning the use of gynaecologist John Rocks, he had 40 contraceptives by Catholics. trialled a birth control pill for women, which became known as “the 20 1999 The FDA approves the Pill”. Anti-birth-control laws and morning-after pill, which opposition from the Catholic Church 00 THE PILL CONDOMS prevents pregnancy if it is persuaded Pincus and Rocks to Key: Correct use Typical use used up to 72 hours after move their trials to Puerto Rico, a US sexual intercourse. territory, in 1955. Known as Enovid, There is only 1 per cent difference their drug contained 10 times the between the effectiveness of condoms 2014 In the US, Bloomberg oestrogen and progesterone found in and the Pill when they are consistently Businessweek claims one-third the modern Pill. The 200 volunteers used correctly, but typical use results of wage gains among women in 9 per cent difference. can be attributed to the Pill. See also: Women in medicine 120–21 ■ Hormones and endocrinology 184–87 ■ Birth control 214–15 ■ The FDA and thalidomide 259

GLOBAL HEALTH 259 PSARSAOFKEOINTFGYOFFOR THE FDA AND THALIDOMIDE IN CONTEXT I n 1937, more than 100 US [Kelsey’s] citizens, many of them children, exceptional judgement … BEFORE died in pain after taking a new has prevented a major tragedy 1848 The US passes the Drug drug called elixir sulfanilamide. … in the United States. Importation Act to prevent The elixir had been tested for adulterated drugs being flavour and appearance, but there John F. Kennedy imported from overseas. was no requirement to test it for toxicity. While sulfanilamide itself 35th US president (1961–63) 1875 Britain’s Sale of Food and is safe and effective, diethylene Drugs Act aims to stop food glycol, in which it was dissolved, it down, on the grounds that the and drugs being adulterated is a poison. Public outrage led to risk assessment had not considered with harmful ingredients. the 1938 Food, Drug, and Cosmetic possible effects on the foetus. Act, which set out the mechanism 1930 In the US, the Food, Drug, for the control of drugs in the US. In 1961, reports emerged in and Insecticide Administration The law required companies to Germany and the UK that mothers becomes the Food and Drug demonstrate that new drugs were who had taken thalidomide were Administration (FDA). safe and allowed for government having babies with severe birth inspections of factories. defects. The drug was crossing the AFTER placenta and causing deformities in 1962 Congress authorizes the The team at the Food and Drug the foetus. At least 10,000 children FDA to set out comprehensive Administration (FDA) responsible worldwide were affected, half of new standards for drug testing for approving new drugs included whom died within months of being and approval. pharmacologist Frances Oldham born, but only 17 were in the US. ■ Kelsey, who was then studying for 2001 The European Clinical her doctorate. In 1960, the FDA Trials Directive is issued to appointed Kelsey to review a drug regulate all clinical research called thalidomide, which proved throughout Europe. effective in reducing nausea in pregnant women. Although the 2018 The US passes a law that drug had already been approved in allows terminally ill patients to 40 other countries, Kelsey turned seek access to experimental drugs without obtaining the See also: Pharmacy 54–59 ■ Women in medicine 120–21 ■ Steroids and approval of the FDA. cortisone 236–39 ■ Evidence-based medicine 276–77

FAURENTCUTRNIOTNO ORTHOPAEDIC SURGERY



262 ORTHOPAEDIC SURGERY IN CONTEXT T he total hip replacement The cart has been performed at Wrightington put before the horse; BEFORE Hospital, Wigan, UK, in the artificial joint has been 1650 bce Ancient Egyptians 1962 was a landmark in 20th-century made and used, and now use splints to help mend orthopaedic surgery. The brainchild we are trying to find out fractured bones. of British orthopaedic surgeon John how and why it fails. Charnley, it is now one of the most c. 1000 ce Al-Zahrawi compiles commonly performed major surgical John Charnley the medical encyclopedia procedures in the world. Kitab al-Tasrif, which describes The Journal of Bone and Joint orthopaedic practices in detail. Osteoarthritis of the hip joint Surgery, 1956 disables an estimated 10 per cent of 1896 X-rays are first used to people over the age of 60, with wear 300,000 total hip replacements were evaluate skeletal damage, after between the ball of the femur (thigh being conducted annually in the US being discovered by Wilhelm bone) and the hip socket becoming alone. Charnley’s work also initiated Röntgen the year before. excruciatingly painful. Previous the development of replacement attempts to carry out the procedure techniques for other joints. AFTER had used a variety of materials, 1968 Frank Gunston carries from steel to glass, but none had Musculoskeletal repair out the first successful full been completely successful. Orthopaedic surgery is used to knee replacement. repair broken bones and their After many years of research, associated soft tissues (ligaments, 1986 Japanese biomedical and several false starts, Charnley tendons, and cartilage); correct engineer Kazunori Baba used a cobalt-chrome alloy ball- skeletal deformities such as invents 3D ultrasound, which ended stem fitted into the femur scoliosis (curvature of the spine); allows detailed bone imaging. and a socket made of a type of high- rebuild or replace damaged joints density polyethylene. This allowed (a procedure known as arthroplasty); 1990s Robot-assisted hip and the thigh bone to move in the socket remove bone tumours; and treat knee replacement operations with minimal friction – and therefore a range of other bone conditions. are introduced. minimal wear. After five years of conducting joint replacements, The word orthopaedic comes Charnley declared the procedure from the Greek words ortho, safe, and other surgeons began to which means straight, and pais, replicate it. By 2019, more than meaning child. It was coined by French physician Nicolas Andry in 1741 and describes one early focus of the discipline – attempts to straighten the crooked spines A painting from the tomb of Ipuy at Luxor in Egypt, dating to the reign of Ramesses II in the 13th century bce, shows a physician fixing a dislocated shoulder with a method still used today.

GLOBAL HEALTH 263 See also: Ancient Egyptian medicine 20–21 ■ Greek medicine 28–29 ■ Islamic medicine 44–49 ■ Battlefield medicine 53 ■ Scientific surgery 88–89 ■ X-rays 176 ■ Ultrasound 244 ■ Minimally invasive surgery 298 ■ Robotics and telesurgery 305 The hip joint is worn or Damage to the The difficulty of finding damaged by use over time, hip joint results materials that are not by high-impact sports, in swelling, rejected by the body, that will or by conditions such as stiffness, pain, last, and that will restore osteoarthritis or fractures. and reduced natural movement hinder mobility. progress in finding a cure. John Charnley pioneers a total hip Surgeons attempt hip replacement operation in 1962 which uses operations during the 1940s and ’50s, but none are completely successful. new materials to reduce friction and improve longevity. and limbs of children. Until the operated on spinal injuries and sustained in training and combat. 1890s, the field of orthopaedics was skull fractures. In France, Guy de One of Britain’s most famous mainly concerned with correcting Chauliac, author of the surgical bonesetters was “Crazy” Sally Mapp, skeletal deformities in the young treatise Chirurgia Magna (1363), who plied her trade near London and mending broken bones. pioneered the concept of pulley in the early 18th century. traction to treat fractures. Early practice Modern pioneers The origins of orthopaedics are While orthopaedic surgery made In 1876, Hugh Owen Thomas, son much older than its name, as many little progress for several centuries, of a renowned Welsh bonesetter, early civilizations developed ways bonesetting – usually by self-taught described his revolutionary hip and to manage orthopaedic injuries. practitioners without formal medical knee splint in Diseases of the Hip, Written in ancient Egypt, c. 17th training – became established in Knee, and Ankle Joints. The splint century bce, the Edwin Smith many parts of the world. In China used a steel rod and leather straps papyrus describes physicians and Japan, the traditional art of to stabilize a fracture and help the placing padded boards of palm bark bonesetting (known as die-da and bone heal. When his nephew over broken limbs, held in place with sekkotsu, respectively) developed Robert Jones, director of military linen bandages. In ancient Greece, in association with martial arts orthopaedics, advocated its use Hippocrates (c. 460 bce–c. 375 bce) schools, where practitioners refined during World War I, the Thomas ❯❯ wrote of wrapping injured limbs in techniques for treating injuries bandages soaked in wax and resin. During the Islamic Golden Age, in Cordoba, Spain, renowned surgeon al-Zahrawi (936–1013 ce) Hugh Owen Thomas’s leg splint transformed outcomes for compound fractures when it was adopted during World War I. Prior to its use, amputation was the usual treatment offered.

264 ORTHOPAEDIC SURGERY High-density Acrylic bone cement inspired Canadian surgeon Frank polyethylene cup anchors the implants Gunston to tackle the challenge of into existing bone. making a knee joint. This was even Polished metal “smaller-than- more complex because the knee life” head reduces friction. or nail, which was fitted into the has three parts: the bottom of the central cavity of a fractured femur to femur, the top of the tibia, and Cobalt-chrome alloy give support while the bone healed. the kneecap. German surgeon femoral stem This enabled patients – not least Thermistocles Gluck had made the German soldiers – to regain mobility first attempt with an ivory implant John Charnley realized quickly. Refined many times since, in 1860, but efforts to reproduce a that reducing the friction the technique is still used for knee that worked like a healthy between the ball and socket fractures of the femur and tibia. joint had foundered until 1968, when of a hip implant was key to Gunston used the same materials its success. His innovative Another type of metal implant – as Charnley’s hip replacement. combination of plastic and a system of hooks attached to a steel metal created a highly durable rod – was developed by American Gunston attached a curved joint that could withstand high surgeon Paul Harrington during the cobalt-chromium alloy component forces and allowed natural, 1950s. Used to straighten curvature to the end of the femur, which rocked fluid movement. of the spine, the technique was on a polyethylene platform attached replaced by the Cotrel-Dubousset to the tibia, replicating the natural splint reduced mortality from double rod in the 1980s. From the bending and extension of the knee. compound fractures of the femur 1950s, Russian surgeon Gavriil Surgeons now carry out about from more than 80 per cent to less Ilizarov devised fixators (now known 600,000 total knee replacements than 20 per cent. Thomas’s other as Ilizarov apparatuses) – frames every year in the US. Although innovations included the Thomas fixed to limb bones to correct designs have evolved since Gunston collar (a brace for neck injuries), the angular deformities, rectify leg- performed the first procedure, the Thomas test (for hip deformities), length differences, and mend bones materials used are similar. and the Thomas heel (a corrective that failed to heal in a cast. children’s shoe for flat feet). Orthopaedics today John Charnley’s revolutionary The scope of modern orthopaedics Other important developments advances in hip replacement is broad, and continues to expand included the discovery, by Dutch surgery in the early 1960s soon as lengthening lifespans, changing military surgeon Anthonius occupational demands, and evolving Mathijsen in 1851, that bandages lifestyles present new challenges soaked in water and plaster of Paris (gypsum plaster) hardened Sir John was in minutes and made excellent a perfectionist … he would casts to support fractures. In 1896, newly invented X-rays were used to not be satisfied until produce a radiograph showing the an instrument did position of a bullet lodged in a boy’s wrist bone. X-rays would play an exactly what he wanted ever-increasing role in orthopaedics it to in his mind. in the 20th century. Maureen Abraham Early in World War II, in 1939, German surgeon Gerhard Küntscher British scrub nurse introduced the intramedullary rod,

GLOBAL HEALTH 265 Recent technological advances bone is restricted and a splint He had this engineering bent have initiated a new era of minimally or cast is applied. However, new and really redesigned nature. invasive orthopaedic procedures, such research and advances in medical as this keyhole surgery on a knee. technology continue to refine Lady Jill Charnley procedures and attempt to promote and drive innovation. Charnley’s the faster healing of bone. on her husband John Charnley seminal work on replacement joints has retained its significance as Continuing innovation during the 1960s. Different types of factors such as an ageing population The invention of 3D ultrasound in metal, ceramics, and plastics have and rising obesity levels worldwide 1986 enabled noninvasive mapping been trialled, and “resurfacing”, continue to increase the incidence of bones and joints. Assisting the which leaves patients with more of musculoskeletal conditions such diagnosis and treatment of disorders, of their original bone than a as osteoarthritis. According to a it has also facilitated better training total joint replacement operation, 2013 prediction by the World Health in orthopaedics. The more recent is also now an option. Organization, 130 million people development of video-assisted globally will have osteoarthritis by keyhole surgery with computer- Surgeons are investigating 2050. The disease affects mostly aided navigation means that many cartilage transplantation and the knees, hips, and the spine when procedures can now be completed use of tissue grown from stem cartilage wears away, causing the less invasively. cells to replace damaged tendons bones to rub together. While walking and ligaments in joints. While frames and other devices can help Keyhole surgery has especially many of the mechanical principles mobility, and palliative medicines advanced orthopaedic oncology, a and treatment aims of orthopaedic can ease pain, joint replacement is specialism dealing with cancerous surgery have remained the same often the only effective approach. tumours in bone and surrounding over the centuries, the field has soft tissues. Previously, amputation come a long way from the use of Bone fractures remain one of the was often the recommended early bark splints. ■ largest areas of treatment, affecting treatment for malign bone cancer, more than 6 million people a year but progress in keyhole surgery, and the hip socket material, he opted in the US. Wrist fractures are the in chemotherapy and radiation, for polyethylene from 1962. most common breaks in those mean that this can now be avoided Charnley continued to strive to aged under 75, with hip fractures in many cases. improve hip operation outcomes the most common in the over-75s. for many years, and also made Fractured bones are still treated Research focused on refining important contributions to the using methods similar to those joint replacement techniques has reduction of post-operative that were practised in ancient continued since Charnley’s work infections, for which he was times: movement of the broken awarded the prestigious Lister John Charnley Medal in 1975. He died in 1982. Born in Bury, UK, in 1911, John Key works Charnley served as a medical officer in the British Army during 1950 The Closed Treatment World War II. After the war, he of Common Fractures became interested in the effect 1979 Low Friction Arthroplasty of compression on fractures, and of the Hip the lubrication of artificial joints. Charnley knew it was vital to collaborate with mechanical engineers to achieve replacement joints that worked well. In 1958, he established a hip surgery centre at Wrightington Hospital in Wigan. After experimenting unsuccessfully with Teflon for

266 KSIMLOLKSING TOBACCO AND LUNG CANCER IN CONTEXT W orld Health Organization lung cancer and other diseases data from 2018 showed than non-smokers. Those who had BEFORE lung cancer to be the started smoking before World War II 1761 Italian physician and most common cancer worldwide, lost, on average, ten years of life. Hill anatomist Giovanni Battista accounting for 2.1 million diagnoses applied nine criteria (the Bradford Morgagni recognizes lung and 1.76 million deaths – 22 per cent Hill criteria) to the data to ensure cancer as a disease. of all cancer deaths. Tobacco that the correlation was robust smoking is responsible for around enough to stand up to opposition 1929 In Germany, physician 80 per cent of these deaths. For from tobacco companies. Fritz Lickint publishes decades, the link between tobacco statistical evidence of the link and lung cancer was strongly denied Triggering cancer between lung cancer and by cigarette companies, which Environmental and occupational smoking tobacco. funded and published research that exposure to radon gas, asbestos, supported their position and then and air pollution can all cause 1952–54 A survey among employed statisticians to challenge lung cancer, and around 8 per cent 188,000 male smokers in the any evidence to the contrary. of cases are inherited, due to US concludes that smokers have a greater chance of dying The British Doctors Study Advancing knowledge … from lung cancer or heart In 1951, British epidemiologists does not confer upon us disease than non-smokers. Richard Doll and Austin Bradford Hill embarked on the British Doctors a freedom to ignore AFTER Study to establish the strength of the knowledge 1966 Health warnings appear the link between smoking and lung we already have. on cigarette packets in the US. cancer. At that time, most British men smoked, including the majority Austin Bradford Hill 1986 The International of doctors (smoking among British Agency for Research on women peaked at 45 per cent in the “The Environment and Disease: Cancer concludes that passive mid-1960s). Doll and Hill interviewed Association or Causation?”, 1965 smoking is carcinogenic. more than 40,000 physicians about their smoking habits and conducted 2015 The US Food and Drug follow-up surveys until 2001. Administration approves the first immunotherapy to treat By 1965, the British Doctors lung cancer. Study clearly showed that smokers had a greater chance of contracting

See also: Occupational medicine 78–79 ■ Epidemiology 124–27 ■ Cellular GLOBAL HEALTH 267 pathology 134–35 ■ The immune system 154–61 ■ Cancer therapy 168–75 Anti-smoking The Bradford Hill criteria legislation Devised in 1965, the Bradford Hill criteria identify nine principles that should Campaigns to raise public be considered when looking for the causes of a disease. Although genetics and awareness of the dangers of molecular biology have provided new research tools, these criteria are still used. smoking, and government interventions, such as raising Principle Question tobacco taxes, banning 1. Strength How strong is the link between cause and effect? advertising, and outlawing 2. Consistency Have other studies shown similar results? smoking in public places, can 3. Specificity Are any other diseases present? be effective in reducing rates 4. Temporality Does the cause precede the effect? of cancer. In the UK, cigarette 5. Dose-response Does greater exposure increase the effect? adverts were banned on TV in 6. Plausibility Is the relationship between cause and effect credible? 1965 and completely in 2005, 7. Coherence Do laboratory tests fit with epidemiological knowledge? and smoking was banned in 8. Experiment Can the disease be altered by experimental interventions? enclosed public places in 2006. 9. Analogy Has a strong enough cause-and-effect relationship been Smoking in the UK has fallen established for weaker evidence of a similar cause and effect as a result, and with it the to be accepted? incidence of lung cancer. mutations on chromosomes 5, 6, the first successful pneumonectomy In many parts of the world, or 15. Most cases, however, are the (lung removal) in 1933. Radiotherapy smoking has not declined, and result of smoking. Tobacco smoke was introduced as a treatment it is rising in some countries, contains a cocktail of particulates in the 1940s, and chemotherapy including China, Brazil, Russia, and other carcinogens, which are was added in the 1970s. Modern and India. In China, a law to cancer-triggering substances. These treatment involves a combination prohibit smoking in bars, activate oncogenes (genes with the of radiotherapy and chemotherapy, restaurants, offices, shopping capacity to cause cancer), which often after surgery, but outcomes malls, and on public transport drive abnormal cell proliferation are still generally poor. was enacted in 2015. In the or deactivate the body’s natural US, legislation varies between tumour suppressor genes. One recent development in the states, but awareness of the ongoing search for an effective dangers of smoking is high, People with lung inflammation treatment for lung cancer is TRAIL and the level of smoking and are also susceptible to lung cancer. therapy. TRAIL, or CD253, is a incidence of lung cancer in the Emphysema and bronchitis, for cytokine, a protein secreted by US as a whole have fallen. example, are caused by particulates cells in very small quantities, which entering the body’s airways. These binds to certain cancer cells and Children take part in a rally diseases make it more difficult for destroys them. TRAIL causes no in Kolkata, India, on World No the lungs to remove such irritants, harm to healthy tissue and can be Tobacco Day, held every year increasing the chances of a person delivered via an intravenous drip at the end of May. contracting cancer. but oncologists have found that cancer cells quickly become Treating lung cancer resistant to TRAIL. Nevertheless, Lung cancer therapy has improved trials continue in the hope that new dramatically since American treatments may prove successful in surgeon Evarts Graham carried out curing many cancers. ■

268 IN CONTEXT LHYIOEVLUEPDUTINEOTIL BEFORE 1843 Jeanne Garnier sets up PALLIATIVE CARE a facility to care for the dying in Lyon, France. 1879 Australia’s first hospice, the Home of Incurables, is set up in a convent in Adelaide. 1899 St Rose’s Hospice opens in New York City, to look after patients with incurable cancer. 1905 The Religious Sisters of Charity found St Joseph’s Hospice in Hackney, London. AFTER 1976 Balfour Mount in Montreal, Canada, holds North America’s first conference on palliative care. 1987 The UK, New Zealand, and Australia recognize palliative care as a sub- speciality of general medicine. 1990 A report by the World Health Organization (WHO) on palliative care says the “control of pain … and of psychological, social, and spiritual problems is paramount.” T he concept of palliative care – specialized support for the terminally ill – was pioneered by British nurse, social worker, and doctor Cicely Saunders. In 1967, Saunders founded the world’s first purpose-built hospice, St Christopher’s, in London. Saunders believed that dying people should be treated with compassion, respect, and dignity, with access to painkilling medicine to alleviate their suffering. This ethos led to Saunders’ theory of

GLOBAL HEALTH 269 See also: Ayurvedic medicine 22–25 ■ Herbal medicine 36–37 ■ Hospitals 82–83 ■ Anaesthesia 112–17 Physical Total Psychological Saunders pain believed that Physical pain Anxiety dying patients Other symptoms Depression experienced Coexisting illnesses Loneliness different types Side effects of drugs Loss of control of mental and physical distress, Spiritual Social a concept she called “total pain”. Anger with God Financial worries Fear of death Concern about Cicely Saunders Loss of hope family and friends The eldest of three children, left behind Cicely Saunders was born in Hertfordshire, UK, in 1918. She “total pain” – the idea that a commonplace and often quick, but studied politics and philosophy patient’s physical pain was one by the late 19th century, advances at Oxford University before aspect of overall distress that in medicine and science meant training as a nurse during included emotional, social, and people were generally living longer. World War II, and later as a spiritual elements. After opening A longer life increased the chances hospital-based social worker. St Christopher’s Hospice, Saunders of a longer death from diseases advocated that every terminally ill such as cancer, and the possibility Saunders began to form her patient should be listened to as an of a protracted period of pain and ideas on care for the dying individual, receive tailored medical suffering. Having a doctor present, while looking after Polish treatment, and be given holistic armed with judicious doses of opium refugee David Tasma in 1948. care by a team of specialists up or laudanum (a tincture of opium), Before his death, Tasma until their death. became as important as having a suggested to Saunders that priest at the deathbed. she open a home for the dying Saunders developed her ideas and included a bequest for her during a time of great change in In the early 20th century, to do so in his will. In 1967, British healthcare. Founded in 1948, doctors were still a long way from 10 years after retraining as the National Health Service (NHS) developing a process for identifying a doctor, Saunders opened provided free healthcare for all. In requirements for end-of-life pain St Christopher’s in London. its early days, however, the NHS relief. They usually gave all dying provided little in the way of care patients morphine, and repeated the Saunders was awarded for the terminally ill. Such patients dose only when the effects of the the prestigious Order of Merit often spent their last hours in previous one had worn off. Patients in 1989. She died at St hospital, with doctors administering were in constant dread of the next Christopher’s in 2005. Her generic pain medication. wave of pain. publications on palliative care have since been translated Changing practices Another source of anxiety for into many languages. Having a doctor present at a patient’s dying patients was their isolation. deathbed is a modern phenomenon. Most patients wanted their lives to Key works Historically, doctors had focused end at home, given the choice, but purely on curing disease rather only the wealthy could afford to 1959 “Control of pain than aiding the terminally ill. In have a physician present. From 1948, in terminal cancer” medieval Europe, an early death NHS-funded hospitals became the 1970 “An individual approach caused by disease or disaster was place where most terminally ill to the relief of pain” people in Britain died. There ❯❯ 1979 “The nature and management of terminal pain and the hospice concept”

270 PALLIATIVE CARE were also a small number of homes, Reasoning that “constant pain You matter called hospices, that tended to needs constant control”, Saunders because you are you, the needs of the dying, but they discovered that by relieving a typically relied on older traditions patient’s anxiety about pain, and you matter to of religious care and were almost the pain often receded faster, the end of your life. entirely separate from the NHS. eliminating the need for long-term Cicely Saunders In some cases, hospices provided pain relief. She also established innovative ways of looking after the a system for identifying levels of family and friends into consideration. terminally ill, but their provision of pain – mild, medium, and severe – By 1970, St Christopher’s had care was not comprehensive, nor each of which was to be treated gained enough recognition to was it regulated. differently, rather than with a one- receive financial support from fits-all medicine such as morphine. the NHS and be the template for Managing pain several new hospices that were Saunders set out to change this This fed into Saunders’ theory then springing up around Britain. landscape for the dying. While of “total pain”. She believed that working as a volunteer nurse at St pain was made up of physical, The movement spreads Luke’s Hospital in London, she had psychological, social, and spiritual During the 1970s, end-of-life care become versed in the theories of its distress, and that each patient’s became a talked-about medical founder, Dr Howard Barrett. Barrett pain needed to be treated on an issue, both in Britain and abroad. instigated the policy of giving pain individual basis. She argued that In 1972, the British government relief regularly to prevent the doctors needed to listen to their held a symposium on Care of the recurrence of pain, not just when the patients describe their pain in Dying in London that highlighted last dose ran out. Saunders imitated order to understand their the haphazard and inadequate this approach after retraining as a requirements. In Saunders’ view, delivery of palliative care. doctor and working at St Joseph’s pain was a syndrome and needed Hospice in east London. Finding the same attention as the underlying It was Canadian doctor Balfour that many patients felt deserted illness that was causing it. Mount who coined the term by their doctors at the end, she “palliative care”, in the mid-1970s. decided that doctors should make Saunders’ research culminated A supporter of Saunders, Mount up only one part of a hospice team in the opening of St Christopher’s, used the term instead of “hospice”, who would deliver holistic care and where staff combined expert pain which had different connotations in pain relief until a patient’s death. relief with holistic care that met French-speaking Quebec. Palliative the individual needs of patients, care soon became the favoured Anticipation of and also took those of their visiting term, even by Saunders, who pain leads to initially disliked it, and Mount Anxiety increases opened the first palliative care ward anxiety in terminally the amount of in Quebec in 1975. It was based on ill patients. St Christopher’s, but also embraced pain experienced. some of the teachings of Elisabeth Pain needs Kübler-Ross, a Swiss American the same attention The timely receipt psychiatrist who urged the medical as the underlying of pain relief profession to treat the terminally ill illness causing it. with the utmost respect. lessens anxiety and therefore pain.

GLOBAL HEALTH 271 Staff at St Christopher’s Hospice, London, are trained not just to attend to the physical needs of terminally ill patients, but to engage with their lives and comfort them. The palliative movement began illnesses. It is now broadly accepted medication is usually a complex to spread worldwide, and in 1987, that pain manifests itself in different cocktail of medicines, including Australia, New Zealand, and Britain but interlinked forms, just as Cicely analgesics (opioid and non-opioid all established palliative care as Saunders had maintained in her painkillers) and adjuvant drugs a specialized area of medicine. In theory of total pain. (drugs that are not painkillers that same year, oncologist Declan but are useful in managing pain), Walsh developed the Cleveland The different forms of pain such as antidepressants, muscle Cancer Center in Ohio, the first experienced by the terminally ill relaxants, and anti-anxiety pills, palliative care programme in the US. are variously defined as physical; which form part of holistic The clinic was set up to address the psychosocial or interpersonal; programmes. Such programmes needs of patients with incurable emotional or psychological; and dedicated to the alleviation of diseases that were not being met spiritual or existential. Palliative suffering, alongside a wide network by existing health providers. patients are asked to describe their of hospices, form the basis of Cicely pain to health professionals who Saunders’ legacy to medicine. Modern care make assessments based on Today, palliative care is considered examinations and conversations Palliative care benefits not only a distinct branch of medicine in about a patient’s history and patients and their families but the many countries. It is usually situation. Their conclusions are rest of the medical service, which is practised by interdisciplinary teams then matched to pain severity then freed up to do other vital work. that include doctors, nurses, care assessment tools, provided by Due to an ageing global population, workers, chaplains, therapists, and authorities such as the World the need for palliative care is ever social workers. Palliative medicine Health Organization (WHO). growing, with an estimated 40 focuses on alleviating pain in million people worldwide in need patients with life-threatening Far from the all-purpose pain every year. Yet there is a long way to relief medicines prescribed during go, as the WHO stated that in 2020 the Victorian era, palliative pain only 14 per cent of people in need of such care currently receive it. ■ The concept of “total pain” [and] her observation that patient and family need to be considered together as the unit of care … are Cicely’s enduring contributions. Balfour Mount

GTEECNHENSOAL 1970 ONWARDS

NOGDY

274 INTRODUCTION In the UK, the world’s The first positron The WHO In the US, Kary Mullis first computed emission tomography announces the invents the polymerase eradication of chain reaction (PCR) tomography (CT) (PET) scanner goes scanner is installed into service in St Louis, smallpox. technique, massively at a London hospital, accelerating the speed of Missouri, in the US. for head scans. genetic analysis. 1971 1975 1980 1983 1974 1978 1981 1988 British physicist Peter In the UK, Louise The first cases of AIDS The WHO launches Mansfield carries out the Brown becomes the emerge in the US; the Global Polio first baby to be born as two years later, first magnetic a result of in vitro Eradication resonance imaging fertilization (IVF). French scientists Luc Initiative. (MRI) scan of part of Montagnier and Françoise Barré-Sinoussi identify the the human body. virus responsible, HIV. H uge advances in the fields development of diagnostic tools, WHO declared that smallpox had of cell biology, genetics, such as computed tomography (CT), been eradicated, and eight years and immunology have magnetic resonance imaging (MRI), later it instigated the Global Polio changed the landscape of medicine and positron emission tomography Eradication Initiative. By 2020, since the 1970s. Techniques that (PET) enabled physicians to view the polio, a potentially fatal disease, were once confined to the pages of body’s interior in astonishing detail. was endemic in only two countries science fiction have become medical Minimally invasive keyhole surgery (Afghanistan and Pakistan). Various reality. Scientists are able to clone made many operations safer, and campaigns to eradicate malaria, a cells, analyse and modify DNA, and laser technology made surgery mosquito-borne illness affecting grow body tissue, transforming easier. Robotic and telesurgery have 228 million people and causing diagnostic tests and treatments. allowed surgeons to perform surgery 405,000 deaths in 2018, continue. remotely, sometimes thousands of The ensuing decades have also miles from the patient. In the not too Meanwhile, new diseases have presented unforeseen challenges. In distant future, nanomedicine – the emerged. HIV, the virus causing 1970, no one could have forecast the diagnosis and treatment of disease AIDS (acquired immunodeficiency deaths of more than 30 million people at molecular level – should enable syndrome) was discovered in 1983, from a new virus called HIV, or the physicians to target individual cells. by which time it was already scale and speed at which bacteria spreading rapidly. The subsequent causing some infections – including Defeating disease development of antiretroviral drugs pneumonia and tuberculosis – The World Health Organization has suppressed the development of would develop antibiotic resistance. (WHO) has led international efforts AIDS in individuals, but no cure has to eradicate some of the deadliest so far been found: in 2018, almost Many of the breakthroughs infectious diseases. In 1980, the 38 million people lived with the became possible because of the HIV infection, two-thirds of them revolution in technology. The

GENES AND TECHNOLOGY 275 Femtosecond laser Researchers on the The UN Declaration The WHO reports that technology is Human Genome Project on Human Cloning 32 million people determine the genetic prohibits all forms of introduced in the US, code for chromosome have died worldwide transforming human cloning. from the AIDS eye surgery. 22. It is the first epidemic. chromosome to be mapped. 1995 1999 2005 2018 1996 2001 2006 2019 Scientists in the UK clone Surgeons in New York Japanese researcher COVID-19, caused by Dolly the sheep from City in the US perform Shinya Yamanaka a new coronavirus, another sheep by discovers that some emerges in Wuhan, long-distance stem cells can China, and spreads transferring genetic telesurgery on be reprogrammed rapidly. In March 2020, material from a mature the gallbladder of to grow into any the WHO declares it cell to an egg cell whose type of cell. nucleus has been removed. a patient in a pandemic. Strasbourg, France. in sub-Saharan Africa. The danger Another breakthrough, in 1978, scientists to identify genes linked of infectious diseases was again offered a solution to the problem of to particular diseases and opening highlighted with the spread of the infertility. In vitro fertilization (IVF), up the possibility of gene editing. COVID-19 virus. Within nine months in which a human egg is fertilized of the virus emerging in Wuhan, with sperm in a laboratory and then Revolutionary techniques can China, in December 2019, only 12 implanted into the womb as an sometimes raise ethical dilemmas. countries had no reported cases. embryo, led to more than 8 million Gene therapy, which involves births over the next 40 years. introducing healthy DNA to a cell Transforming medicine with defective DNA, potentially A host of new treatments in the Advances in microsurgery and ending a range of genetic diseases, last few decades have improved immunosuppressant drugs have is particularly controversial. Critics or saved millions of lives. In 1975, also extended the possibilities of point out that such techniques could immunologists César Milstein transplant surgery. The first full be abused to “improve” humanity. and Georges Köhler discovered how face transplant, an intricate feat, Objections are also raised by the to make unlimited, identical copies was performed in France in 2008. use of embryonic stem cells to grow of the same antibody (monoclonal tissue for regenerative medicine. antibodies), leading to many new Some of the biggest medical treatments. Monoclonal antibodies advances have been made possible Balancing ethical concerns with are used to help prevent the rejection by the strides made in genetics the desire to save and improve lives of transplanted organs, to carry since British biochemist Frederick has never been so pertinent. Stem drugs or radiation to particular cells, Sanger developed a method for cell research and genetic editing and to fight autoimmune diseases sequencing DNA. Sanger’s work have the potential to transform such as rheumatoid arthritis. paved the way for the Human health to an extent on a par with Genome Project, the complete the development of anaesthesia, mapping of human genes, allowing antibiotics, and vaccines. ■

276 RTIALNLDIOTMHIUZRETS EVIDENCE-BASED MEDICINE IN CONTEXT To give a patient identify a clear clinical optimum care, a question that arises from BEFORE doctor should: c.1643 Flemish physician Jan the patient’s problem; Baptista van Helmont proposes a randomized controlled assess the evidence research the latest clinical trial to determine the in relation to the clinical evidence in efficacy of bloodletting. relation to that question; individual patient; 1863 In the US, physician Austin Flint offers 13 patients apply clinical judgement apply the most up-to-date a dummy remedy (placebo) to based on personal research on treatment compare its effects with those of an active treatment. experience and expertise; and interventions. 1943 The UK’s Medical E vidence-based medicine random (to avoid bias) to similar Research Council conducts (EBM) is concerned with groups of people, so that outcomes the first double-blind controlled using the best-quality, most can be compared and measured. In trial (where neither subjects nor up-to-date research available to 1972, Scottish epidemiologist Archie researchers know who gets a find answers to medical questions Cochrane’s influential Effectiveness specific therapy or treatment). and to give clinicians and patients and Efficiency highlighted both the evidence they need to make the value of RCTs and the perils of AFTER informed choices about treatments. ineffective treatments. 1981 A series of articles by clinical epidemiologists at Central to EBM are randomized RCTs were pioneered in 1747 McMaster University, Canada, controlled trials (RCTs) that measure by James Lind, a Scottish naval advises physicians how to the effectiveness of one or more surgeon. He selected 12 sailors, all assess medical literature. interventions by allocating them at sick with scurvy to a similar degree, 1990 Physician Gordon Guyatt, at McMaster University, uses the term “evidence-based medicine” for the first time.

GENES AND TECHNOLOGY 277 See also: Nosology 74–75 ■ Case history 80–81 ■ Preventing scurvy 84–85 ■ Epidemiology 124–27 ■ Vitamins and diet 200–03 Not all evidence in evidence-based medicine is Randomized controlled trials Archibald Cochrane given the same weight. The most valued evidence, in which one or more groups at the top of the pyramid, is systematic reviews that of people, randomly chosen, The son of tweed-makers, evaluate and synthesize the results of carefully receive a treatment and other Archibald (Archie) Cochrane designed randomized controlled trials. groups do not was born in 1909 in Galashiels, Scotland. He graduated from Systematic reviews of different Case-control studies King’s College, Cambridge, in randomized controlled trials (comparing “cases” 1930. He qualified as a doctor Cohort studies of a large to a control group) at University College Hospital, group of people over a that involve a London, in 1938, having earlier long period of time, relatively small volunteered with a British often used to determine number of people ambulance unit between 1935 long-term effects and 1937 during the Spanish Civil War. In World War II, Expert opinion he served in the Royal Army Medical Corps before he was divided them into six pairs, and condition in the camp, he allocated captured and interned. ensured they had the same living daily doses of yeast (B vitamins) to conditions and followed the same six of those affected and vitamin C In 1948, Cochrane joined daily diet. Each pair also received to a further six. The efficacy of the the MRC at its Pneumoconiosis one of six daily treatments, which yeast treatment persuaded his Research Unit in Wales. He left included seawater, vinegar, cider, captors to give all the prisoners to take up a professorial post and two oranges plus a lemon. The daily yeast to improve their health. at the Welsh National School citrus fruits worked best, followed of Medicine in 1960 and, in by cider, indicating that daily doses After the war, Cochrane worked 1969, he became director of a of vitamin C treat scurvy. at an MRC research unit in Wales new MRC epidemiology unit studying pneumoconiosis (“dust in Cardiff, where he conducted More trials and studies lung”) in coal miners. In this and several groundbreaking RCTs. Clinical trials progressed during later research, Cochrane paid the 19th century, but largely as the meticulous attention to the accuracy Cochrane was also an work of individual practitioners. In and standardization of the data he award-winning gardener and the 20th century, the establishment collected and its reproducibility. a collector of modern art and of national bodies such as the UK’s sculpture. He suffered cancer Medical Research Council (MRC), World resource in his later years and died in founded in 1913, helped coordinate Cochrane was passionate about 1988 at the age of 79. investigations, provide funding, and improving scientific evidence to raise the standard of clinical trials. validate medical interventions. In Key work 1993, the Cochrane Collaboration Cochrane, who later joined the (now known simply as Cochrane) 1972 Effectiveness and MRC, conducted his first RCT in was founded in the UK to collect and Efficiency: Random Reflections Salonika, Greece, while a prisoner disseminate reviews of clinical trials. on Health Services of war during World War II. To test Today, it operates in 43 countries, which vitamin supplement might encouraging healthcare professionals help treat ankle oedema (swelling as to make clinical decisions based a result of fluid retention), a common on the best evidence available. ■

278 IN CONTEXT ISTNHESEEIIDNBEGODY BEFORE 1938 Polish American MRI AND MEDICAL SCANNING physicist Isidor Rabi discovers nuclear magnetic resonance, the basis for MRI. 1951 Robert Gabillard uses varying magnetic fields to locate the origin of radio waves emitted by the nuclei of atoms. 1956 David Kuhl builds a device for tracking radioactive isotopes in the human body. AFTER 1975 The first PET scanner goes live at Washington University, in St Louis, US. 1977 Peter Mansfield invents the echo-planar technique to speed up MRI scanning. 2018 Scientists in New Zealand develop the first 3D colour medical scanner. M edical scanning allows physicians to see inside the body, helping them to diagnose and treat disorders. A variety of techniques are used, including X-rays, ultrasound, magnetic resonance imaging (MRI), computed tomography (CT), and positron emission tomography (PET). While X-rays were used from the end of the 19th century, most of the other methods developed in the late 1960s or early 1970s. These new techniques could differentiate between types of soft tissue, making the detection of injuries, tumours, and other abnormalities easier. Experiments in physics MRI is based on the principle of nuclear magnetic resonance (NMR) – the application of a magnetic field

GENES AND TECHNOLOGY 279 See also: Cancer therapy 168–75 ■ X-rays 176 ■ The nervous system 190–95 ■ Cancer screening 226–27 ■ Ultrasound 244 ■ Nanomedicine 304 Hydrogen is one of the most An MRI scanner produces abundant elements in the human body. a magnetic field, causing the nuclei to align. It then uses The nuclei of hydrogen atoms radio waves to knock them are like tiny magnets. out of alignment. By measuring these radio When the radio waves are turned signals, the scanner’s computer can off, the nuclei realign and send out create a detailed image of the body part radio signals. being examined. to matter, so that the nuclei of its could be distinguished from healthy This made it possible to determine hydrogen atoms release energy. cells using NMR. He reasoned that where each atom was in relation to Measuring this energy reveals the cancerous cells would show up the others and identify differences chemical structure of the matter. because they hold more water and in the resonance signals more therefore have more hydrogen atoms. precisely. (This idea was first NMR techniques had been used Two years later, he demonstrated proposed by two physicists to analyse chemical samples since this in experiments on dead rats. working independently, Robert 1945. Chemist Paul Lauterbur and Gabillard in France and Hermann physician Raymond Damadian in In 1972, Lauterbur, then working Carr in the United States, but it the US and British physicist Peter at Stony Brook University in New had not been taken any further.) Mansfield were all familiar with the York, showed that clear images Lauterbur tried the technique technique when, in 1969, Damadian could be produced by introducing on the contents of two test tubes, ❯❯ hypothesized that cancerous cells gradients to NMR magnetic fields. Paul Lauterbur Born in 1929 in Sidney, Ohio, in quickly scribbled a model of the the US, Paul Lauterbur was so MRI technique on a paper enthusiastic about chemistry as napkin, then set about refining a teenager that he built his own the idea. laboratory in his parents’ house. He was awarded a doctorate from In 2003, Lauterbur and Peter the University of Pittsburgh in Mansfield were jointly awarded 1962 and lectured in chemistry at the Nobel Prize in Physiology or Stony Brook University, New York, Medicine for their work on MRI. from 1963 to 1985. Lauterbur died in 2007. Lauterbur worked with NMR Key work technology for several years, but it was not until 1971 that he 1973 “Image formation by thought of using it to make images induced local interaction; of human organs. The revelation examples involving nuclear happened while he was eating a magnetic resonance” burger in a Pittsburgh diner; he

280 MRI AND MEDICAL SCANNING one holding regular water, and the other heavy water (whose hydrogen atoms have a neutron as well as a proton, making it “heavier”). The heavy and regular water looked different from one another – the first time that imaging had shown this. Lauterbur also used the technique on a clam found by his daughter, clearly showing its tissue structure. He was convinced that his imaging method could be used to distinguish between different types of human tissue without harming the patient. The first body scans Mansfield used echo-planar imaging MRI allows doctors to view In 1974, Mansfield made the first in his prototype scanner, which the brain in “slices” of 1–4mm MRI scan of a human body part – went into experimental use in 1978. (0.04–0.16in). False colour can be cross-sectional images of a student’s In the US, Damadian unveiled the added to highlight particular features. finger. However, the scans took up to first whole-body MRI scanner in 23 minutes to create. To speed up May 1977. The US Food and Drug Scanners with powerful 3T (tesla) the process, he developed the echo- Administration (FDA) approved it magnets produce very high-quality planar imaging technique, which for use in 1984. images of the minute details of the produced multiple nuclear NMR musculoskeletal and nervous echoes from a single excitation The big advantage of MRI is systems. Engineers are building of the protons. This meant that that it provides extremely detailed increasingly powerful scanners an entire MR image could be images. It is used for noninvasive that will provide even more detailed obtained in a fraction of a second. examination of the brain and spinal images of the body faster. The advantage of echo-planar cord, bones and joints, breasts, imaging is that it can image rapid blood vessels, the heart, and other CT scans physiological processes, such as organs. One disadvantage is the British electrical engineer Godfrey respiration and cardiac rhythm. cost of an MRI scanner – as high Hounsfield and American physicist as £1.5 million (US$2 million). The Allan MacLeod Cormack developed We began to produce other disadvantage of MRI is that CT (computed tomography) – also quite nice images … it cannot be used on patients with known as CAT (computerized axial as the 1980s ticked by, metallic implants. Despite this, tomography) – scanning for medical the quality became there were more than 50,000 MRI diagnosis. Hounsfield’s first scanner, more and more acceptable scanners in service in 2018, with in 1968, took nine days to capture to our clinical colleagues. the highest concentration – 55 per a full three-dimensional (3D) image Peter Mansfield 1 million people – in Japan.

GENES AND TECHNOLOGY 281 The X-ray source of receptors in the doughnut-shaped rotates around scanner. A computer then plots the the patient. gamma rays to produce a 3D image of tracer concentrations. The bed moves X-ray detectors send the slowly through the images to a computer, PET technology emerged in the scanner while which creates a 3D image. US in 1956, when scientist David the tube rotates. Kuhl developed a photoscanner CT scanning takes a series of X-ray images based on the earlier work of from different angles while the patient lies flat. physicist Benedict Cassen. It The process takes 10–20 minutes. worked on the same principle as modern PET, creating images from of a dead pig’s brain. He later used accumulate if the body is scanned radioactivity detected in the body. X-rays and reduced the scanning repeatedly, fractionally increasing a Development continued during time to nine hours. It worked by patient’s risk of getting cancer. the 1960s and 1970s, and the first firing gamma rays as it rotated clinically practical whole-body around the brain, one degree at a PET scans scanner, known as PET (III), was time, creating thousands of cross- Positron emission tomography (PET) used to examine patients in 1975. sectional images. A computer can reveal biochemical changes in Combined PET–CT scanning takes programme then assembled these tissue at cellular level, something advantage of the great detail that is “slices” (the word tomography that CT and MRI cannot do. The possible with CT scans to create derives from tomei, the Greek word patient ingests or is injected with a 3D images of even greater clarity. for slice) to produce the 3D image. radioactive drug called a radiotracer, Combined PET–MRI scanning which collects in areas of the body is also possible. The first head-scanning CT with greater chemical activity, machine was installed at Atkinson often a sign of disease. The tracer PET scans are used to monitor Morley Hospital, London, in 1971. emits subatomic particles called cancer, to plan surgery, and to Its first scan was of the head of a positrons. When these collide with diagnose, manage, and treat patient with a frontal lobe brain electrons in the body tissue being neurological disorders, including tumour. The first whole-body CT examined, they produce gamma Parkinson’s disease, dementia, and scanner was introduced in 1976. rays, which are detected by a ring epilepsy. They are, however, not given to pregnant women – the CT scans are used to detect radiation emitted by the tracers is tumours and bone fractures, and to potentially damaging to foetuses – monitor changes in a disease such or to some diabetics, because the as cancer. Although CT scanners tracer is combined with glucose. ■ are much more sophisticated than they were in the 1970s, and quicker and quieter than MRI machines, their images of organs and soft tissues are not as clear. Importantly, CT radiation may be up to 1,000 times more than traditional X-ray. This is still small, but the doses may A doctor examines a PET scan for chemical activity that indicates cancer. The tracer fluorodeoxyglucose (FDG) is usually used in such cases, as cancer cells absorb glucose at a faster rate.

282 OANNTDIBEMODAINEDS MONOCLONAL ANTIBODIES IN CONTEXT M onoclonal antibodies Antibodies are proteins the body (mAbs) are unlimited, uses to target alien cells such as BEFORE identical copies of the germs. There are millions of kinds, 1882 Russian microbiologist same antibody that are produced each matching a different alien Élie Metchnikoff discovers artificially. They were first made protein (or antigen), and they latch bacteria-eating white blood in 1975 by two immunologists, on to their specific antigen either cells called phagocytes. César Milstein from Argentina and to neutralize it or to identify it as a Georges Köhler from Germany, target for the body’s immune cells. 1890 Emil von Behring and and although research is ongoing, Shibasaburo Kitasato describe they have already proved useful Paul Ehrlich coined the term antitoxins, a type of antibody in many areas of medicine. They “antibodies” in 1891, and went on found in blood serum that make up a high proportion of new to describe how they interact with works against bacterial toxins. drugs and diagnostic tests, from antigens like lock and key. By the innovative treatments for cancers 1960s, scientists knew they are 1906 Paul Ehrlich proposes to identifying blood types. made by white blood cells called “magic bullet” drugs that B-cells, or B-lymphocytes, each mimic antibodies. Plasma cells produce a mix of Myeloma cancer 1957 Frank Macfarlane antibodies in response to the cells can multiply Burnet proposes the theory of clonal selection. presence of a pathogen. limitlessly. AFTER Scientists fuse a myeloma cell with a plasma cell just as it is 1981 The first patient is producing one type of antibody, creating a hybridoma. treated for cancer with The hybridoma can multiply to produce limitless supplies monoclonal antibodies. of that one type of antibody. 1982 Monoclonal antibodies are created for blood typing. 1997 Polish virologist Hilary Kroprowski creates the first approved monoclonal antibody drug for cancer treatment.

GENES AND TECHNOLOGY 283 See also: Vaccination 94–101 ■ Cellular pathology 134–35 ■ The immune system 154–61 ■ Cancer therapy 168–75 ■ Targeted drug delivery 198–99 Experiments on the International Milstein’s original intention was to César Milstein Space Station aim to grow a crystalline find a way to make antibodies for form of a monoclonal antibody used in research. But he and Köhler quickly Born in Argentina in 1927, cancer treatment, so it can be injected realized that mAbs might also be a César Milstein studied at the rather than delivered intravenously. “magic bullet”, offering tailor-made University of Buenos Aires. antibodies to target any disease. After completing a doctorate, primed with its own antibody. When Milstein was invited to join triggered by its matching antigen, Increasingly useful tool the biochemistry department a B-cell clones itself, producing Although monoclonal antibodies at Cambridge University in the multiple copies of plasma cells, have not yet proved to be a magic UK. His main interest was in which release floods of antibodies. cure-all, they are finding new uses the body’s defences, and most As plasma cells produce more than all the time. They can even be of his professional career was one kind of antibody, the process used to detect biological weapons. devoted to antibody research. is described as “polyclonal”. In pregnancy tests, mAbs detect the hormone HCG, and in tissue At Cambridge, Milstein Harnessing immune cells typing, they help prevent a donor collaborated with biochemist Milstein and Köhler’s breakthrough organ from being rejected by Frederick Sanger (a double was to create limitless copies of blocking the immune response. Nobel Prize recepient), and identical “monoclonal” antibodies They can identify blood clots and later Georges Köhler, with using cells made in the lab called rogue cells, and are used in cancer whom he carried out the hybridomas. These are artificial treatment to carry drugs or radiation groundbreaking work on fusions of plasma cells and myeloma to targeted cells. monoclonal antibodies. cells (abnormal plasma cells that Milstein and Köhler did not cause cancer) primed to produce Monoclonal antibodies are also take out a patent on their the desired antibody. Plasma cells used to fight autoimmune diseases discovery, so did not benefit are short-lived, whereas myeloma including rheumatoid arthritis, and financially, but in 1984, they cells reproduce indefinitely. By new mAb drugs are in the pipeline were awarded the Nobel Prize fusing them, Milstein and Köhler for malaria, influenza, and HIV. in Physiology or Medicine. created an endlessly multiplying In 2020, scientists found several Milstein went on to help source of their chosen antibody. mAbs that appear to neutralize the develop the field of antibody COVID-19 virus in cell cultures. ■ engineering. He died in 2002. Key works 1973 “Fusion of two immunoglobulin-producing myeloma cells” 1975 “Continuous cultures of fused cells secreting antibody of predefined specificity”

284 NSCOAOTUWULRDEEDNIODT, IN VITRO FERTILIZATION IN CONTEXT O n 25 July 1978, the medical the first IVF pregnancy in a rabbit, world celebrated the birth but the fertilization probably took BEFORE of Louise Brown, the first place in vivo (“in the body”) rather 1959 Working in the US baby to be born as a result of in vitro than in vitro (“in glass”, outside at the Worcester Foundation, fertilization (IVF). The pioneers of the body). Having shown in 1951 Min Chueh Chang proves IVF this groundbreaking event were that spermatozoa needed to reach is possible in mammal eggs by British scientist Robert Edwards a certain stage of maturity before using it to conceive rabbits. and gynaecologist Patrick Steptoe. being capable of fertilizing an egg, Chinese American scientist Min 1969 Robert Edwards fertilizes The concept of IVF was not new. Chueh Chang successfully used a human egg outside the body. Austrian embryologist Samuel IVF to impregnate a rabbit in 1959. Schenk attempted IVF on rabbit 1973 A team at Australia’s eggs in 1878 and discovered that British breakthrough Monash University achieves cell division could occur outside In 1968, Edwards teamed up with the first human IVF pregnancy, the body when sperm was added Steptoe, who was an early expert but this ends in a miscarriage. to an egg cell. In 1934, American in laparoscopy (keyhole surgery), doctor Gregory Pincus laid claim to a technique that could be used to AFTER collect eggs without abdominal 1979 The first IVF baby boy This image from 1968 shows Purdy surgery. Many of Steptoe’s patients is born in Glasgow, Scotland, passing Edwards a dish containing in Oldham, Lancashire, agreed to after treatment from Robert in-vitro-fertilized human egg cells. The donate eggs to aid the research. Edwards and Patrick Steptoe. UK’s Medical Research Council refused With the help of Jean Purdy, an to fund the work, deeming it unethical. embryologist, the team achieved 1981 Monash University fertilization of eggs, followed by cell announces the birth of nine division, in a Petri dish. But their babies following IVF. goal of successfully implanting an embryo into a woman’s uterus 1992 The first ICSI baby is remained elusive. born in Belgium. British couple John and Lesley 2018 About 8 million children Brown approached Edwards and worldwide have been born Steptoe in 1976. They had been using IVF and similar methods trying to conceive for nine years, but of assisted conception. had failed due to blocked fallopian tubes. In November 1977, timing

GENES AND TECHNOLOGY 285 See also: Midwifery 76–77 ■ Inheritance and hereditary conditions 146–47 ■ Birth control 214–15 ■ Ultrasound 244 ■ Genetics and medicine 288–93 ■ Minimally invasive surgery 298 Stages in IVF treatment 1. The mother takes fertility 2. The egg and sperm cells 3. The eggs that are fertilized 4. After several days, the drugs to stimulate production of are mixed in a Petri dish and are monitored closely as they selected embryo is placed into eggs. Mature eggs are collected left in an incubator for several begin to divide. Each egg the mother’s uterus. If the from her ovaries, and a semen hours to allow fertilization becomes a hollow ball of cells embryo implants successfully, it sample is taken from the father. to take place. called an embryo. is likely to develop into a baby. the process with Lesley Brown’s which they considered unnatural. children. In most modern treatment natural ovulation cycle, Edwards But as more and more healthy cycles, the mother is given fertility and Steptoe collected one of her babies were born as a result of IVF drugs to stimulate the maturation eggs and added it to a Petri dish treatment, attitudes began to of multiple eggs and therefore containing her husband’s sperm. change. By the time Edwards was increase the chance of achieving Closely watched by Purdy, the awarded the Nobel Prize in 2010 for one or more viable embryos after fertilized egg began to divide. After his pioneering work, more than 4.5 fertilization. Unused embryos, two and a half days, Edwards and million IVF babies had been born. as well as eggs and sperm, can Steptoe transferred the resulting be frozen for use in later cycles. eight-cell embryo into Lesley IVF today Intracytoplasmic sperm injection Brown’s uterus. Nine months later, Assisted-conception techniques (ICSI), in which a single sperm is Louise Brown was born. continue to evolve, as do people’s injected into an egg, is a common reasons for undergoing treatment. treatment for male infertility. Once Although a medical milestone, More and more same-sex couples, the subject of fierce opposition, the birth of baby Louise was not single women, and surrogates are IVF is now safer, more successful, universally popular. Many baulked using fertility services to conceive and more popular than ever. ■ at the idea of a “test-tube baby”, Robert Edwards Born in Yorkshire, England, in 1925, set up the world’s first IVF clinic Robert Edwards served in the at Bourn Hall, near Cambridge, army during World War II before in 1980. Edwards received the studying agricultural science, and Nobel Prize in 2010, and was later zoology, at the University of knighted a year later. He died Wales, Bangor. In 1951, he studied in 2013. artificial insemination and mouse embryos for his doctorate in Key works genetics at Edinburgh University. 1980 A Matter of Life: The Story After moving to Cambridge of a Medical Breakthrough in 1963, Edwards set himself the 2001 “The bumpy road to goal of removing human eggs human in vitro fertilization” and fertilizing them in vitro. But 2005 “Ethics and moral it was not until he met Patrick philosophy in the initiation of Steptoe in 1968 that Edwards was IVF, preimplantation diagnosis able to attain this goal. Following and stem cells” the birth of Louise Brown, the pair

286 SVIMCATLOLRPYOOXVER GLOBAL ERADICATION OF DISEASE IN CONTEXT An infectious disease can be controlled, eliminated, or eradicated. BEFORE 1796 Edward Jenner proves If a disease If a disease If a disease is the effectiveness of cowpox is controlled, is eliminated, eradicated, as a vaccine against smallpox. new cases and there are no mortality rates there are no new cases 1909 A campaign to eradicate new cases worldwide. hookworm is launched by the are reduced in a specific Rockefeller Foundation. to a locally geographical acceptable 1927 Fred Soper initiates area. programmes aimed at the level. eradication of yellow fever and malaria. O n 8 May 1980, the World can protect the whole community. Health Organization The more who are vaccinated and 1955 The Global Malaria (WHO) declared smallpox gain immunity, the fewer hosts Eradication Program is to be eradicated – the first major the germ can find, and the less the initiated by the WHO. disease, and the only human disease disease can spread. to date, to have been beaten. For AFTER centuries smallpox had been a major However, intense opposition to 1988 The WHO launches scourge, killing millions of people a mass vaccination programmes was its Global Polio Eradication year. As recently as the 1950s, more sparked as vaccines accidentally Initiative, following a meeting than 50 million people every year became contaminated on occasion of the World Health Assembly. were infected by the disease. with other germs, such as syphilis. In the 1890s, British physician 2011 Rinderpest becomes British physician Edward Sydney Copeman introduced the the second disease to be Jenner had discovered a vaccine technique of storing vaccine in entirely eradicated. in 1796, and smallpox deaths slowly glycerine, dramatically improving reduced as vaccinations became its safety. Trust in vaccination rose, 2020 The Africa Regional widespread. As well as providing and by 1953 smallpox had been Certification Commission immunity to individuals, vaccines eliminated from the US and Europe. declares that wild polio has been eliminated from Africa.

GENES AND TECHNOLOGY 287 See also: Vaccination 94–101 ■ Epidemiology 124–27 ■ Malaria 162–63 War on vectors ■ The World Health Organization 232–33 ■ Pandemics 306–13 The first major efforts at Infected person Everyone within a disease eradication were led is identified and certain radius is by epidemiologist Fred Soper isolated – their vaccinated to block at the Rockefeller Foundation contacts are the transmission in the US. Yet rather than also traced. of the disease. focusing on vaccines, Soper’s campaigns targeted disease Anyone who has No vaccination vectors – organisms such been in contact is needed outside as flies, mosquitoes, and with the infected the ring: since the parasitic worms that pass person, directly disease cannot diseases on to humans. or indirectly, find new hosts is immediately inside the ring, The three priorities were vaccinated. it will die. the vector-borne diseases hookworm, yellow fever, The ring strategy successfully stopped the Key: and malaria, and eradication spread of smallpox by immunizing all potential Infected focused on eliminating their hosts. This meant that under 50 per cent of a Vaccinated vectors. These programmes population required vaccination in order for the Unvaccinated had considerable success, disease to be eliminated within a fixed area. but were mired in controversy during the late 1950s by the Extending vaccination programmes An infected person was isolated widespread use of insecticides to tropical regions was difficult as and all potential contacts were such as DDT, which posed the vaccine went off within a few immediately tracked, traced, and severe risks to human health days in warm conditions. Then two vaccinated. If that failed, everyone and the environment. major innovations progressed the within a given radius would be given fight against smallpox. First, British the vaccine. This avoided the need The WHO estimates vector- scientist Leslie Collier found a way for mass vaccination programmes. borne diseases make up more to freeze-dry the vaccine, enabling than 17 per cent of infectious it to be stored as powder for up to In 1975, a three-year-old from diseases today, and cause six months, even in hot weather. Bangladesh became the last person 700,000 deaths globally a year. Then the bifurcated (two-pronged) to naturally contract the severe Efforts to eradicate malaria, needle was invented by American variant of smallpox; in 1977, the one of the key threats to public microbiologist Benjamin Rubin, last case of the minor variant was health, now include genetic enabling the powdered vaccine to identified in Somalia. In both cases programmes to prevent the be simply pricked into the skin. the ring strategy was used, and the mosquitoes from breeding. battle against smallpox was won. The road to eradication This species of the parasitic In 1967, the WHO launched the So far, only the animal disease hookworm, Ancylostoma duodenale, Smallpox Eradication Programme rinderpest has also been eradicated, is one of the most common causes in South America, Asia, and Africa. in 2011. The success with smallpox of hookworm infestation in humans. Key to the campaign’s success was led the WHO’s global immunization its “ring” strategy, which involved programme to target other vaccine- containing outbreaks within a set preventable diseases, such as zone, or ring, of immunity in order measles, tetanus, diphtheria, and to prevent further transmission. whooping cough. It is hoped that polio and Guinea worm disease may soon be eradicated. ■

GLOIUEESRNINFEAOTUSER GENETICS AND MEDICINE



290 GENETICS AND MEDICINE IN CONTEXT I n 1983, American biochemist The first image of a strand of DNA, Kary Mullis invented a way of known as Photo 51, revealed the BEFORE rapidly cloning small segments structure of DNA for the first time. 1842 Swiss botanist Carl of DNA (deoxyribonucleic acid), The X-shape proves that DNA has Wilhelm von Nägeli discovers the molecules that are packed into a double-helix structure. chromosomes in plants. chromosomes in the nucleus of cells and carry genetic instructions. The New York’s Rockefeller Institute. 1865 Gregor Mendel outlines technique, called polymerase chain It had previously been assumed the laws of inheritance after reaction (PCR), was later refined by that proteins in the chromosomes experimenting with pea plants. fellow American Randall Saiki. This were responsible for passing on development revolutionized the hereditary traits. 1869 Swiss physiologist study of genetics and opened up Friedrich Miescher discovers new areas of medical research and Scientists’ understanding of the molecule DNA, but does diagnostics. PCR is used to detect genetics quickly accelerated. In not understand its role. hereditary mutations of genes that the early 1950s, Austrian-born can cause many serious medical biochemist Erwin Chargaff showed 1879 Walther Flemming disorders, including Huntington’s that the composition of DNA varies observes threadlike material, disease, cystic fibrosis, and sickle between species, and in 1952, later called chromosomes, in cell anaemia. British chemist Rosalind Franklin the cells of vertebrate animals (co-working with physicist Maurice as the cells divide. Building understanding Wilkins) photographed DNA for the The development of PCR built on first time. The following year, two AFTER the huge strides made in the field molecular biologists, James Watson 1999 The genetic code for of genetics since the early 1940s. from the US and Francis Crick in chromosome 22 is mapped. The hereditary role of DNA in Britain, modelled DNA’s structure chromosomes (“the transforming at the Cavendish Laboratory in 2003 The Human Genome principle”) had been recognized Cambridge, UK, as two connected Project – aiming to map all in 1944 by a team of American strands that form a double helix. human genes – is completed. chemists led by Oswald Avery at Watson then discovered the pairing James Watson (left) and Francis Crick with their 3D model of DNA. Based on all available research into DNA at the time, its metal rods are arranged in a spiral around a stand.

GENES AND TECHNOLOGY 291 See also: Inheritance and hereditary conditions 146–47 ■ Alzheimer’s disease 196–97 ■ Chromosomes and Down syndrome 245 ■ In vitro fertilization 284–85 ■ The Human Genome Project 299 ■ Gene therapy 300 structure of the four chemical bases symptoms begin with a decline in DNA has two that form the “rungs” in a DNA coordination and gradually progress strands made of molecule: guanine always pairs with to language problems and dementia, sugar phosphate. cytosine, and adenine always pairs had been known since at least the with thymine. In 1962, Watson, Crick, medieval era, but was described The strands are and Wilkins received the Nobel Prize in detail by American physician connected by in Physiology or Medicine for their George Huntington, after whom it rungs – pairs of work on nucleic acids and how these was named, in 1872. In 1979, the chemicals (adenine, carried information. Hereditary Disease Foundation thymine, cytosine, began to analyse the DNA of 18,000 or guanine) Mapping DNA people in two Venezuelan villages called bases. British biochemist Frederick Sanger that had a very high incidence of spent 15 years trying to discover a Huntington’s. They discovered the Key: The order of the rapid way to reveal the sequence approximate position (a genetic Adenine bases along a of the bases in a strand of DNA. In marker) of the gene responsible, Cytosine strand is a code for 1977, he and his team published and pinpointed it precisely in 1993. making proteins, a technique called the dideoxy or This enabled scientists to develop the building Sanger method that uses chemical the first pre-symptomatic genetic blocks of life. reactions to sequence up to 500 test for Huntington’s disease. base-pairs per reaction. It was the Thymine start of a revolution in the mapping A medical game-changer Guanine of DNA. The modern technique of The invention of PCR by Kary pyrosequencing can read up to Mullis in 1983 enabled easier and The DNA molecule, which makes up 20 million bases per reaction. more targeted analysis of DNA, our genes, looks like a spiral staircase, massively improving the diagnosis a shape known as a double helix. Each Sequencing has helped identify of disease. PCR has been called strand of DNA contains a unique the genes responsible for certain molecular photocopying. It involves sequence (code) of genetic information. disorders, including Huntington’s heating a DNA sample so that it disease, an inherited condition that splits into two pieces of single- results in the progressive death of stranded DNA. An enzyme ❯❯ brain cells. The disease, whose Kary Mullis Born in the foothills of the Blue Chemistry in 1993. Mullis later Ridge Mountains, North Carolina, invented an ultraviolet-sensitive US, in 1944, Mullis became ink and worked as a consultant interested in chemistry while on nucleic acid chemistry. building home-made solid-fuel rockets as a teenager. After Some of Mullis’s views were gaining a doctorate in biochemistry controversial: he questioned the from the University of California, evidence for climate change and Berkeley, in 1973, he spent a ozone depletion and disputed brief spell writing science fiction the link between HIV and AIDS. before taking up research posts Mullis died in 2019. at various universities. Key work In 1979, Mullis joined the Cetus biotech corporation in California. 1986 “Specific enzymatic It was here that he invented the amplification of DNA in vitro: PCR technique, for which he The polymerase chain reaction” was awarded the Nobel Prize in

292 GENETICS AND MEDICINE (Taq DNA polymerase) then builds It was PCR that made the Human British geneticist Alan Handyside two new strands, using the original Genome Project physically possible. pioneered preimplantation genetic pair as templates. A biochemist Between 1990 and 2003, researchers diagnosis (PGD). The following year, can then use each new strand to mapped almost all of the base-pairs Handyside and clinicians Elena make two new copies in a machine that make up human DNA – some Kontogianni and Robert Winston called a thermocycler; if the process 3 billion in total. It was an enormous successfully used the technique is repeated 12 times, there will be scientific undertaking. Clinicians at Hammersmith Hospital, London. 212 as much DNA as at the start of also use PCR for tissue typing – to the process – more than 4,000 match donors with recipients prior Parents who are at high risk of strands. Repeated 30 times, there to organ transplantation, and for the having children with an inherited will be 230 (over 1 billion) strands. early diagnosis of blood cancers disease can now opt for IVF with PCR duplication speeds up the such as leukaemia and lymphomas. genetic analysis, so that only detection of viruses and bacteria, the embryos without genetic mutations diagnosis of genetic disorders, and Prenatal screening are implanted in the womb. Nearly DNA fingerprinting – a technique The invention of PCR has facilitated 600 genetic disorders can now be used to link biological evidence to screening for many serious genetic detected using PGD, including suspects in forensic investigations. conditions, even pre-birth. In 1989, cystic fibrosis and sickle cell anaemia. In the case of a non-IVF In a polymerase chain reaction, a sample pregnancy, prenatal genetic of the target DNA is extracted from cells in blood, diagnosis can be conducted on an embryo in the uterus by taking body fluids, or other tissue. cells from the placenta or foetus. If genetic mutations are found to The sample is heated to 94–96ºC (201–205ºF), be present, parents and medical so that the two strands of DNA separate. professionals can then discuss options. In the future, it may be possible to reverse some inherited conditions before birth. PGD can also be used to screen embryos for hereditary breast and ovarian cancers. Most cases of these cancers are not inherited, but in 1994 and 1995 scientists identified the two genes (BRAC1 The DNA is cooled and the enzyme polymerase is added. The enzyme enables the making of a new Beginning with a complementary DNA strand for each existing strand. single molecule of The process is repeated until there are millions of copies the genetic material DNA, the PCR can generate of the DNA sample – enough for genetic analysis. 100 billion similar molecules in an afternoon. Kary Mullis Scientific American, 1990

GENES AND TECHNOLOGY 293 A medical worker in Japan takes liver cancer. It is one of the world’s Alzheimer’s with mutations in three a nasal swab for a PCR test for biggest killers. According to the genes, on chromosomes 1, 14, and COVID-19. PCR is used to identify WHO, 2 billion people have been 21, that cause the production of the genes of viruses. infected with hepatitis B worldwide: abnormal proteins. 260 million live with a chronic form and BRAC2) responsible for the of the disease and around 887,000 Scientists also know that most hereditary forms. Women who people die from hepatitis B each cases of late-onset Alzheimer’s relate carry mutations in these genes year. The most common route of to the APOE (apolipoprotein E) gene have a 50–85 per cent chance of transmission is from an infected on chromosome 19. This is involved developing breast cancer and a mother to her child at birth. in making a protein that helps carry 15–50 per cent chance of getting cholesterol and other fats in the ovarian cancer. Men who carry Valenzuela isolated the non- bloodstream. APOE comes in one these mutations run an increased infectious part of the virus that of three forms, or alleles. Two are risk of prostate and breast cancer. makes the surface protein HBsAg not linked with Alzheimer’s but one, Having a mutation of the BRAC2 and put it into yeast cells. When APOE4, has been shown to increase gene also increases the chance of the cells multiplied, they produced the risk of developing the disease. getting skin, oesophageal, stomach, many copies of the protein, which About 25 per cent of people carry pancreatic, and bile duct cancers. was then used in the vaccine. The one copy of this allele and 2–3 per vaccine causes the baby’s immune cent carry two copies, but some Fighting viruses system to produce its own protection people with APOE4 never get the In 1986, Chilean biochemist Pablo against the disease. disease, and many who develop it Valenzuela, working at the University do not have the allele. of California, San Francisco, used The search goes on genetic engineering to develop the Great advances have been made Determining and understanding world’s first recombinant vaccine in understanding the relationship the genetic variants of early- and (one that stimulates cells in the between genetics and health, but late-onset Alzheimer’s disease may immune system) to protect children much remains unknown. At least be the first step in developing an from hepatitis B. This virus, first 70 per cent of cases of Alzheimer’s effective treatment for cases that identified by American geneticist disease are thought to be inherited have a genetic basis. While drugs Baruch Blumberg in 1965, attacks but the mechanism of inheritance today are only able to manage the liver and causes cirrhosis and is not fully understood. Researchers (rather than cure) symptoms, gene have, however, linked early-onset research could potentially lead to earlier detection and treatments that slow or even stop the onset of Alzheimer’s and other disorders. ■ Genomics is … exciting science with the potential for fantastic improvements in prevention, health protection and patient outcomes. Sally Davies UK’s Chief Medical Officer, 2017

294 IN CONTEXT EPTRVHEOISRBYLISBEOMDY’S BEFORE 1950s US medical researcher HIV AND AUTOIMMUNE DISEASES Noel Rose’s experiments with rabbits prove the previously rejected notion of autoimmunity. 1974 In Britain, Gian Franco Bottazzo and Deborah Doniach discover that type 1 diabetes has an autoimmune basis. 1981 The first cases of AIDS emerge among previously healthy gay men in California and New York City. AFTER 1996 Antiretroviral therapy (HAART) is introduced as an anti-HIV treatment. 2018 New Zealand becomes the first country in the world to fund PrEP (pre-exposure prophylaxis) drugs for the prevention of HIV in people at high risk of catching the virus. I n May 1983, French virologists Luc Montagnier and Françoise Barré-Sinoussi announced in the journal Science their discovery of the virus that causes AIDS (acquired immunodeficiency syndrome). It was a retrovirus, a type of virus with RNA as genetic material (rather than the usual DNA). It converts the RNA into DNA, which it then integrates into the host cell’s DNA to replicate. AIDS had already killed more than 500 people in the US and by the end of 1983, the number had risen to more than 1,000. The French team isolated the virus from a patient with swollen lymph nodes and physical tiredness, the classic

GENES AND TECHNOLOGY 295 See also: Epidemiology 124–27 ■ The immune system 154–61 ■ Virology 177 ■ The nervous system 190–95 ■ Diabetes and its treatment 210–13 ■ Steroids and cortisone 236–39 Fibromyalgia Multiple Type 1 Rheumatoid Multiple sclerosis (MS) – which sclerosis diabetes arthritis affects 2.3 million people worldwide and produces symptoms such as Psoriasis Graves’ Muscular Coeliac tiredness, poor coordination, and disease dystrophy disease mobility problems – was identified as an autoimmune disease in the There are more than 80 known autoimmune diseases, 1960s. Neurologists know that it is, most of which can only be managed, not cured. Many are at least in part, the result of the characterized by alternating periods of flare-up and remission. body’s immune system attacking the cells (oligodendrocytes) that produce symptoms of AIDS. Montagnier harmless substances in the myelin, a fatty protein that forms a and Barré-Sinoussi named the virus environment (an allergic response) protective sheath around the neurons lymphadenopathy associated or attack and damage its own (nerve cells) of the nervous system. virus (LAV), but it was renamed tissues and organs (an autoimmune HIV (human immunodeficiency response). Immune deficiency Graves’ disease, another virus) three years later. Their reduces the body’s ability to fight autoimmune disorder, interferes discovery unlocked the mystery infection and disease, as in AIDS. with the thyroid gland, which of one of the deadliest immune controls how the body uses energy. disorders the world has known. Autoimmune diseases The immune system makes The concept of autoimmunity – that antibodies called TSIs that bind to Abnormal responses antibodies produced by the body thyroid cell receptors, the “docking Immune disorders – when the to fight disease could be directed stations” for thyroid-stimulating natural production of antibodies against the body itself – was first hormone (TSH). By binding there, to fight infection is disrupted – postulated by Alexandre Besredka the TSIs trick the thyroid into present some of the most intractable at the Pasteur Institute in Paris, in producing high and damaging levels problems in medicine. They include 1901. His ideas were largely rejected, of hormone, causing insomnia, many chronic and deadly diseases, and it was not until the mid-20th muscle wastage, heart palpitations, whose triggers and pathogenesis century that scientists began to heat intolerance, and double vision. (development in the body) are only accept the premise of autoimmune slowly being understood. diseases and understand some of For many years, physicians their complex mechanisms. recognized autoimmune diseases There are two main categories without knowing their cause. British of immune disorders: those that Many common diseases are physician Samuel Gee described ❯❯ cause overactivity of the immune thought to have an autoimmune system and those that produce basis, including type 1 diabetes, The challenge of AIDS immune deficiency. Overactivity rheumatoid arthritis, inflammatory can be overcome can make the body overreact to bowel disease, lupus, and psoriasis. if we work together as a global community. World Economic Forum, 1997

296 HIV AND AUTOIMMUNE DISEASES the symptoms of coeliac disease, HIV enters HIV enters CD4+ cells, a condition triggered by eating the body and seeks makes copies of itself, gluten, in 1887, but its autoimmune CD4+ white blood cells basis was not understood until 1971. (immune system cells). and destroys In sufferers of coeliac disease, the The immune system the host cell. body mounts an immune response can no longer fight With fewer CD4+ cells, the that attacks the fingerlike villi that body’s immune system line the small intestine, reducing the other infections. is weakened. body’s ability to absorb nutrients. This can cause growth problems in children and increased chances of coronary artery disease and bowel cancer in adults. HIV and AIDS Left untreated, AIDS-related diseases There are two categories of immune weaken and ultimately kill the patient. deficiency diseases – primary disorders, which are hereditary, per mm³. Someone with HIV has “gay plague”. This tended to limit and secondary disorders caused a T-helper cell count below 500 per knowledge about HIV in other by environmental factors. HIV, the mm³ – if it drops below 200 per mm³, sections of the population, who retrovirus responsible for AIDS, is the immune system is severely thought it was irrelevant to them. now believed to have originated weakened and there is a high risk of However, by 1984, scientists had in non-human primates in West infection from bacteria and viruses. confirmed that female partners of Africa, crossing over to humans in HIV-positive men could contract the early 20th century after coming Left untreated, a person with the disease through sexual contact into contact with infected blood HIV is unlikely to live more than 10 and drug-users could transmit it by (a process called zoonosis). In 1983, years, and often much less. In the sharing needles. Montagnier and Barré-Sinoussi early years of the epidemic, Kaposi’s discovered that the virus attacked sarcoma (KS) was a recognized The spread of HIV was dramatic. and destroyed the body’s infection- illness in people with advanced In 1985, just over 20,000 cases were fighting T-helper cells (also known HIV. Kaposi’s sarcoma is caused known, the vast majority in the as CD4+ cells), a type of white by a virus (HHV-8). While the virus blood cell. A healthy person has a is carried by many people who do HIV has shown the way to T-helper cell count of 500–1,500 not develop Kaposi’s sarcoma, the go in the field of science. cancer can develop in those with a You can’t be isolated in History will surely judge us … weakened immune system. The your laboratory. You need to if we do not respond with virus attacks genetic instructions controlling cell growth, resulting in work with others. all the energy and resources tumours and skin lesions. Françoise Barré-Sinoussi that we can … in the fight The spread of AIDS against HIV/AIDS. HIV passes from person to person Nelson Mandela in certain bodily fluids such as blood, semen, and breast milk. Since many of the early cases involved gay men, damaging misinformation suggested AIDS was confined to this group, even describing it as a

GENES AND TECHNOLOGY 297 US, but in 1999 the World Health entering a CD4+ cell; “nukes” Françoise Organization (WHO) estimated that (nucleoside reverse transcriptase Barré-Sinoussi 33 million people were living with inhibitors) and “non-nukes” (non- the virus. By then, AIDS-related nucleoside reverse transcriptase Born in Paris, France, in 1947, diseases had become the fourth- inhibitors) prevent HIV from Barré-Sinoussi was fascinated biggest cause of deaths worldwide, translating its RNA to the DNA by nature as a child. She and the largest in Africa, having necessary to multiply; integrase considered pursuing a career killed 14 million people since the inhibitors stop HIV from inserting in medicine, but opted to study epidemic began. In 2018, the WHO its DNA into the chromosome of a life sciences at the University announced that since the start of CD4+ cell; and protease inhibitors of Paris, while also working at the epidemic, 74.9 million people had prevent the virus from maturing. the Pasteur Institute, initially become infected and 32 million By using a combination of drugs as a volunteer. After gaining a had died of AIDS-related illnesses. from at least two of these classes, doctorate for her research on By 2019, 38 million people had HAART reduces the problem of retroviruses and leukaemia in HIV, including 1.8 million children; drug resistance, and it has been 1974, she went to work at the two-thirds of people with HIV were very successful in suppressing laboratory of virologist Luc living in sub-Saharan Africa. HIV in those carrying the virus, Montagnier. Their discovery thereby reducing their viral load and of HIV in 1983 earned them Virus suppression their chance of spreading the virus. the Nobel Prize in Physiology The majority of people who are or Medicine in 2008. HIV positive are now receiving Like other immune disorders, antiretroviral treatment (ART). This AIDS has not yet been conquered, Barré-Sinoussi spent more treatment helps people live longer, but research into immune diseases than 30 years trying to find a healthier lives and dramatically and their development in the body cure for AIDS. In 1996, she reduces the risk of transmission. is advancing rapidly. One day, became head of the Retrovirus In 1996, highly active antiretroviral physicians will not just treat the Biology Unit at the Pasteur therapy (HAART), the most effective symptoms and manage the progress Institute, and she headed the treatment to date, was introduced. of these debilitating diseases, but International AIDS Society This uses a combination of drugs, deliver effective cures. ■ from 2012 to 2014. In 2013, drawing on various antiretroviral Barré-Sinoussi was made (ARV) drugs that each work in a Men on a Gay Pride march in New Grand Officer of the Légion different way. They target HIV York City in 1983 demand medical d’honneur, one of France’s at different stages of its life cycle: research into AIDS. Congress approved highest accolades. entry inhibitors prevent it from funding for research in July 1983, having refused it the previous year. Key work 1983 “Isolation of a T-lymphotropic retrovirus from a patient at risk for AIDS”

298 KTAHERYREHOVOUOLGLEHUTTIHOEN MINIMALLY INVASIVE SURGERY IN CONTEXT T he first minimally invasive Laparoscopy is … a highly procedures known as perfected technique … [that] BEFORE keyhole surgery emerged 1805 German army surgeon in the early 20th century, but the has revolutionized the Philipp Bozzini invents the first landmark moment was 1981 when science of gynaecology. endoscope to view inside the German gynaecologist Kurt Semm body; his “light conductor” is performed the first appendectomy Hans Troidl a candle in a leather tube. (appendix removal) using the keyhole technique. At first deemed unethical President of the 1988 International 1901 Georg Kelling, a German and dangerous, keyhole procedures Congress on Surgical Endoscopy surgeon, inserts a cystoscope became increasingly accepted from through a dog’s abdominal the mid-1980s and now include not that most abdominal surgical wall, after pumping gas into its only laparoscopic (abdominal) but procedures can now be carried out stomach to prevent bleeding. also joint (arthroscopic) and chest using keyhole techniques; in areas (thoracoscopic) surgeries. such as urology, robot-assisted 1936 Swiss gynaecologist laparoscopy is also widely used. P.F. Boesch performs the first In 1910, Swedish surgeon Hans laparoscopic sterilization, Jacobaeus described the first use of Keyhole surgery has several using an electrical current to diagnostic laparoscopy, performed advantages over open surgery: it cauterize the fallopian tubes. by inserting a cystoscope through requires a single incision of just the patient’s abdominal wall. He 5–15 mm (0.2–0.6 in); it causes AFTER recognized the dangers but also the less pain and bleeding; a local 1997 Surgeons in the US use potential of the technique. In the US, anaesthetic is usually sufficient; keyhole procedures to bypass internist John Ruddock popularized and the patient recovers quickly. ■ large, diseased blood vessels its practice in the 1930s, when the in the abdomen and groin – first surgical laparoscopies were aortofemoral bypass surgery. carried out, but progress was slow. 2005 The US Food and Drug Technological advances in the Administration (FDA) approves 1980s – especially the advent of 3D the da Vinci robotic system for videoscopic imaging – made keyhole keyhole hysterectomy. surgery safer and more precise, so See also: Scientific surgery 88–89 ■ Anaesthesia 112–17 ■ Orthopaedic surgery 260–65 ■ Robotics and telesurgery 305

GENES AND TECHNOLOGY 299 IOTNHFSEOTFURIRURCSOTTWIOGNNLIBMOPOSKE THE HUMAN GENOME PROJECT IN CONTEXT A genome is an organism’s sheep, creating Dolly, a replica of the complete set of genetic donor sheep. This paved the way for BEFORE instructions, in the form research into therapeutic cloning – 1953 Francis Crick and James of the chemical DNA. In 1990, the the possibility of using a patient’s Watson discover the chemical Human Genome Project (HGP) was own cells to treat their disease. structure of DNA. launched to map human DNA. By 2003, researchers had sequenced While both the Human Genome 1988 James Wyngaarden, the whole genetically active region Project and SCNT have led to new director of the US National of the human genome – 92.1 per cent. fields of research, they have also Institutes of Health, invites Scientists could begin to identify raised social, ethical, and legal international experts to plan genes linked to disease and study concerns about who has access the Human Genome Project. how genetic engineering could to genome data and the risk of modify genes to prevent disease. discrimination against those who AFTER carry gene mutations. ■ 2005 The UN Declaration on While the HGP was progressing, Human Cloning prohibits all scientists led by Ian Wilmut at the forms of human cloning. Roslin Institute in Scotland were investigating a cloning technique 2013 The US Supreme Court called somatic cell nuclear transfer rules that naturally occurring (SCNT), in which genetic material DNA cannot be patented. from a somatic (mature) cell is transferred to an egg cell whose 2015 The 1000 Genomes nucleus has been removed. In 1996, Project, an international the team inserted the nucleus of collaboration to sequence the a cell from a sheep’s udder into an genes from different ethnic unfertilized egg cell of another groups, provides an extensive catalogue of genetic variation. Dolly the sheep, the first successful clone of an adult mammal, was grown 2018 Chinese scientists use into an embryo in a laboratory and then SCNT to clone two female transferred to a surrogate mother. long-tailed macaques, the See also: Cancer therapy 168–75 ■ In vitro fertilization 284–85 ■ Genetics and first time SCNT has been medicine 288–93 ■ Gene therapy 300 ■ Stem cell research 302–03 successful in primates.

300 FBIRXOINKGENAGENE GENE THERAPY IN CONTEXT G ene therapy involves the Anderson’s team took white blood delivery of healthy DNA cells from the girl’s blood, inserted BEFORE into a cell with defective the ADA gene using a viral vector, 1972 American scientists DNA to cure a disorder. In 1990, and then injected the modified cells Theodore Friedmann and American geneticist William French back into her bloodstream. Within Richard Roblin propose that Anderson first used it successfully six months, the child’s white blood “good” DNA can be used to treat a girl with severe combined cell count rose to normal levels. The to replace defective DNA immunodeficiency (SCID), who technique offered promise, but as it in people suffering from lacked the enzyme (adenosine does not place the new DNA in its genetic disorders. deaminase, or ADA) required to natural position within the host’s make infection-fighting white blood genome, the cell’s functioning can be 1984 It becomes possible to cells. Only three treatment options disrupted. This disruption triggered engineer a retroviral vector were available at the time: enzyme leukaemia in some later recipients. system for gene transfer, injections, which did not always which exploits the natural work; a bone marrow transplant from Geneticists have since found ability of a virus to enter a cell a compatible donor; or isolation in ways to put the introduced DNA in and insert “foreign” genes into an artificial germ-free environment. the right place, and also to conduct the cell’s chromosome. “in-body” gene editing. These offer the prospect of curing a range of AFTER genetic conditions, but they also 2003 Several countries halt raise ethical questions about what their gene therapy clinical constitutes a disability, and whether trials after two SCID patients gene editing might be abused to taking part in a trial in France “improve” the human race. For now, develop leukaemia. gene therapy is still risky, and is used only if there is no other cure. ■ 2011 The TALEN method for editing genes is developed, Before gene therapy, children with enabling great precision. SCID had limited options. Born in 1971, American “bubble baby” David Vetter 2015 In the UK, genome lived for 12 years in a sterile bubble. editing is used to treat two See also: The immune system 154–61 ■ Genetics and medicine 288–93 babies with leukaemia. ■ HIV and autoimmune diseases 294–97 ■ Stem cell research 302–03